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HANDBOOK OF PHYSIOLOGY
SECTION 1: Neurophysiology, volume i
HANDBOOK OF PHYSIOLOGY
A critical, comprehensive presentation
of physiological knowledge and concepts
SECTION 1:
Neurophysiology
VOLUME I
Editor-in-Chief: JOHN FIELD
Section Editor: H. W. MAGOUN
Executive Editor: VICTOR E. HALL
American Physiological Society, Washington, d. c, 1959
@ Copyrighl ig5<), American Physiological Society
Library of Congress Catalog Card No. ^g-isg^y
Printed m the United States of America by Waverly Press, Inc., Baltimore 2, .Maryland
Distributed by Williams & M'ilkins Co., Baltimore 2, Maryland
Foreword
The original literature in the field of physiology
has become so vast and is growing so rapidlv that
the retrieval, correlation and evaluation of knowledge
has become with each passing year a more complex
and pressing problem. Compounding the difficulties
has been the inevitable trend toward fragmentation
into smaller and smaller compartments, both of
knowledge and of research skills. This trend is not
only inevitable, but it is necessary to healthy growth.
It must, however, be accompanied by the develop-
ment of mechanisms for convenient and reliable re-
integration in order that knowledge shall not be lost
and research efTort wasted.
The American Physiological Society has enlisted
the cooperation of physiological scientists over the
world in attempting to provide a mechanism in this
Handbook of Physiology series for providing a com-
prehensive but critical presentation of the state
of knowledge in the various fields of functional
biology. It is intended to cover the physiological
sciences in their entirety once in about ten years,
and to repeat the process periodically thereafter.
Board of Publication Trustees
MAURICE B. visscHER, Chairman
W I L L I .^ M F. H .^ M I L T O N
PHILIP BARD
Preface
This Handbook of Physiology , like its predecessors from
von Haller on, is designed to constitute a repository
for the body of present pliysioiogical knowledge,
systematically organized and presented. It is addressed
primarily to professional physiologists and advanced
students in physiology and related fields. Its purpose
is to enable such readers, by perusal of any Section,
to obtain a working grasp of the concepts of that field
and of their experimental background sufficient for
initial planning of research projects or preparation
for teaching.
To accomplish this purpose the editors have
planned a book which would differ from textbooks in
being more complete, more analytical and more
authoritative. It would differ from a series of mono-
graphs in being organized on a consistent plan with-
out important gaps between topics and with as nearly
as possible the same relation of intensity of coverage
to importance of topic throughout. It would differ
from publications emphasizing new developments in
that the background of currently accepted or classical
concepts would be set forth, newer ideas receiving
not more than their due proportion of emphasis
relative to the whole body of knowledge in the field.
Finally it would differ from a collection of original
papers on a series of topics in that it would provide an
integrated condensation and evaluation of the mate-
rial contained therein. Moreover, the overall plan
provides that the key experimental findings in the
development of each field of investigation be de-
scribed and discussed in sufficient detail (with appro-
priate illustrations, quantitati\e data and adequate
documentation) to make clear their nature, validity
and significance for the fundamental concepts of the
field. The success of this endeavor must be left to the
reader's judgment.
This Handbook stands as the current representative
of an historic series of efforts to collect and system-
atize biological knowledge — a series continued when
the Board of Publication Trustees of the American
Physiological Society decided in 195;] to sponsor the
present undertaking. A brief list of notable prede-
cessors may interest .some readers. First known of
the series is a brief Sumerian 'pharmacopeia" dating
from perhaps 2100 B.C. Later examples included
several Egyptian papyri such as the Ebers and the
Edwin Smith. Far more extensive compilations char-
acterized the Greco-Roman period. Outstanding
among those were the Hippocratic collection (written
ijy several authors) and the encyclopedic writings
associated with the names of Aristotle, Theophrastus,
Celsus and Galen (Pliny's work is useful chieflv to
the student of folklore). These treatises systematized
knowledge of the day over a wide range and set forth
new information based on the authors' observations.
Thus they combined the roles of handbook and scien-
tific journal, a pattern that persisted until develop-
ment of scientific journals (in the seventeenth cen-
tury). Other important compilations were made by
the writers of the 'Moslem Renaissance' such as Rhazes
and Avicenna, to whom much of the Greco-Roman
literature was available.
European biological compendia of the Christian
era, from the fourth century Physiologus to the exten-
sive biological encyclopedias of the sixteenth and
seventeenth centuries, differed greatly in character
from Greco-Roman and 'Moslem Renaissance' work.
Marked by strong theological and anthropocentric
orientation, they lacked the descriptive accuracy and
rational approach of the ancients. Scientia was con-
sidered ancillary to sapientia. Nature was studied
chiefly to obtain illustrations for moral tales and
HANDBOOK OF PHVSIOI.OGV
NEUROPHYSIOLOGY I
religious dogmas, not to gain knowledge or insight,
or to learn how to manipulate and control the en-
vironment. Writers showed little critical capacity and
failed to distinguish between the tfue and the fabu-
lous, the important and the trivial. These elements
are .still evident in such major sixteenth century
biological encyclopedias as Gesner's Historiae Ant-
malium (5 volumes, 1551 1587), and Aldrovandi's
Opera Omnia (13 volumes, 1399-1677). In both the
mark of the medieval Bestiary is strong.
However, the tide was turning in the sixteenth
century despite these notable examples of medieval
Weltanschauung. The range and precision of anatomi-
cal knowledge were greatly extended by publication
in 1543 of Vesalius' De Hiimani Corporis Fabrica. It is
interesting to note that increasingly accurate hand-
books of descriptive botany began to appear. At about
this time the great transition from the medieval to
the modern outlook (the 'scientific revolution of 1500-
1800') was under way. This has been succinctly
described by Raven: "Little by little, nonsense was
recognized, fables were exploded, superstitions were
unmasked and the world outlook built up out of
these elements fell to pieces. The seemingly irrelevant
labors of men like Turner or Penny to identify and
name and describe bore fruit in a refusal to accept
tradition on authority and in an insistence that state-
ments must be based upon observation and capable
of verification" (C. E. Raven. English Naturalists
from Neckam to Ray. 1947, p. 227).
The rise of the mechanical philosophy in the seven-
teenth century and the rationalism of the eighteenth
furnished an intellectual climate favorable for science.
This was reflected in the papers, monographs and
compendia produced. In the spirit of the time,
Diderot, d'Alembert and their associates prepared
the Encyclopedie ou Dictionnaire Raisonne Des Sciences,
Des Arts et Des Metiers (35 volumes, Paris, i 751-1 780).
While the major contribution of this influential work
was to diffuse the rationalist interpretation of the
universe in mechanistic terms, it included many con-
tributions in the biological sciences. Together these
constitute a transitional stage of biological handbook
— quite modern in spirit but not in respect of fact or
concept.
While the Encyclopedic was in preparation in Paris,
the Swiss savant Albrecht von Haller was compiling
the Elementa Physiologiae Corporis Humani (8 volumes,
Lausanne, 1 757-1 765). This comprised both a hand-
book of anatomy and physiology and a vehicle for
publication of much original work by the author.
Compared to earlier work the writing shows impres-
sive critical capacity, detailed familiarity with tlie
achievements of others, ability to distinguish the trivial
and the important and over-all scientific insight. This
was the first of the great series of German Handhuch
of physiology.
The vast increase in scientific activity, with multi-
plication of investigators, laboratories and journals,
that characterized the nineteenth century led to more
frequent collection and systematization of knowledge
in the several active fields. This was naturally centered
in Germany where scientific activity was greatest.
Notable examples of handbooks of physiology were
R. Wagner's Handworterhuch der Physiologic mit Ruch-
sicht aiif Physiologisches Pathologic (Braunschweig,
1 842-1 853); L. Hermann's Handhuch der Physiulogie
(Leipzig, 1 879- 1 883); G. Richet's unfinished Dic-
tionnaire de Physiologic (Paris, 1 895-1 928); E. A.
vSchafer's Text-Book of Physiology (Edinburgh and
London, 1898- 1900); W. Nagel's Handhuch der
Physiologic des Menschen (Leipzig, 1905-1910); the
massive Handhuch der Normalen und Pathologischen
Physiologic, mit Berikksichtigung der Experimentellcn
Pharmakologie, edited by A. Bethe, G. von Bergmann,
G. Embden and A. Ellinger (Berlin, 1 926-1 932);
and our immediate predecessor, G.-H. Roger and
L. Billet's Traite de Physiologic Normale et Pathologique
(Paris, 1 933-1 940). Characteristically these hand-
books comprised the contributions of many authors
and, in the last two, collaboration of several editors
as well. These, with comparable coitipilations in
cognate fields such as K. von Bardeleben's Handhuch
der Anatomic des Menschen (Jena, 1896-1911) and
E. Abderhalden's Handhuch der Biologischen Arheits-
methoden (Berlin, 1 925-1 939), have provided a corpus
of collected and systematized scientific knowledge. A
notable feature of all handbooks, including the pres-
ent one, is their increasingly international character,
reflecting the broadening base of the world of science.
Survey of these codifications from the earliest on
provides a basis for Abraham Flexner's trenchant
comment on the history of medicine. "From the
earliest times medicine has been a curious blend of
superstition, empiricism, and that kind of sagacious
observation which is the stuff out of which ultimately
science is made. Of these three strands — superstition,
empiricism and observation — medicine was consti-
tuted in the days of the priest-physicians of Egypt and
Babylonia; of the same three strands it is still com-
posed. The proportions have, however, varied sig-
nificantly; an increasingly alert and determined
effort, running through the ages, has endeavored to
expell superstition, to narrow the range of empiricism
PREFACE
and to enlarge, refine and systematize the scope of
observation. . . . The general trend of medicine has
been away from magic and empiricism and in the
direction of rationality and definiteness" (A. Flexner.
Medical Education. A Comparative Study. New York,
1925). We trust that continuation of this trend is
reflected in this Handbook.
It is difficult to acknowledge properly the devoted
and effective work which has made this vast under-
taking possible. Its success is due alike to the con-
tributors, to the editorial staff and to the Board of
Publication Trustees of the American Physiological
Society. Alike to all of these is due the gratitude of the
world of physiologists for a task well done.
JOHN FIELD
Editor-in-Chief, ig§4-ig§8
Preface to the Section on Neurophysiology
As the Editor-in-Chief has pointed out, tlie decision
of the American Physiological Society to sponsor a
Handbook of Physiology continues an historic series of
efforts to collect and systematize knowledge in more
readily available forms. Although sharing many of
the features of its predecessors, the present Handbook
of Physiology is likely to be less formidable than most
of them. Its goal, like that of chariot racing, has been
to secure a balanced perch astride the rushing progress
of investigative advance. It attempts to survey the
status of physiology just past the mid-mark of the
twentieth century. In the case of each topic, the com-
pilative accumulation of analytic data is either intro-
duced or concluded by synthesizing comments of an
'elder statesman' still active in the field. Thus a bal-
ance is sought between the presentation of specific
information and conceptualization appropriate to it.
Appropriately also, the Handbook begins with con-
sideration of the nervous system by which the activities
of other portions of the body are coordinated and
controlled. The nervous system remains the last organ
of the body still formidably to resist investigative
attack; many fundamental concepts of its function lie
waiting in the future. Views proposing a spiritual
basis for neural function have obtained since classical
antiquity. Only in the past century have materialistic
outlooks been effectively introduced, first with respect
to the nerve impulse, then in refle.x function and, most
recently, in Russian views applying concepts of reflex
physiolos^y to an understanding of higher activities
of the brain. In this latter area, however, subjective
experience and the mind still receive major attention
in the West from the disciplines of psychology and
psychiatry, a testimony to continuing dualistic points
of view regarding function of the neural organ. In
contemporary studies of physiological psychology the
gap between brain and mind seems most rapidly to
be closing; prominent representation of this field is
probably the most novel feature of the table of con-
tents of the present Neurophysiology Section.
More than customarily, appreciation should be
expressed to the contributing authors of this Hand-
hook. Each has been willing to add to the many energy-
draining burdens of a busy career the difficult task
of surveying a field of investigative specialty both for
the benefit of associates and for the general welfare
of physiological science. The remarkably fine series
of articles testifies to the generosity and skill of each
contributor. It is to be hoped that reader appreciation
may compensate these authors.
Special gratitude should be expressed also for the
efforts of the Executive Editor, Victor Hall. His back-
ground of editorial experience with the Annual Review
of Physiology enabled the manifold labors of this
'sweet-blooded' man to be performed so deftly as
perhaps to escape the attention of the general reader.
Hopefully, all who use this Handbook will wish as
I do to thank, if only silently, the contributing authors
and the Executive Editor for their generous efforts
and to applaud them for such a fine accomplishment.
H. w. M A G o u N
Section Editor
Contents
VII.
VIII.
XIII.
XV.
The historical development of
neurophysiology
MARY A. B. BRAZIER I
Neuron physiology — Introduction
J. C. ECCLES 59
Conduction of the nerve impulse
ICHIJI TASAKI 75
Initiation of impulses at receptors
J. A. B. GRAY 123
Synaptic and ephaptic transmission
HARRY GRUNDFEST 147
Skeletal neuromuscular transmission
PAUL FATT 199
Autonomic neuroeffector transmission
U. S. VON EULER 2 15
Neuromuscular transmission in
invertebrates
E. J. FURSHPAN 239
Brain potentials and rhythms — Introduction
A. FESSARD 255
Identification and analysis of single unit
activity in the central nervous system
KARL FRANK 261
Intrinsic rhythms of the brain
VV. GREY WALTER 279
The evoked potentials
HSIANG-TUNG CHANG 299
Changes associated with forebrain
excitation processes: d.c. potentials
of the cerebral cortex
JAMES L. o'lEARY
SIDNEY GOLDRING 315
The physiopathology of epileptic seizures
HENRI GASTAUT
M. FISCHER-WILLIAMS 329
Sensory mechanisms — Introduction
lord E. D. ADRIAN 365
XIX.
XXI.
XVI. Nonphotic receptors in lower forms
hansjochem autrum 369
XVII. Touch and kinesthesis
jerzv e. rose
VERNON B. MOUNTCASTLE 387
XVIII. Thermal sensations
YNGVE ZOTTERM.'^N 43 1
Pain
WILLI.\M H. SWEET 459
The sense of taste
CARL PFAFFMANN 5O7
The sense of smell
W. R. ADEY 535
Vestibular mechanisms
B. E. GERNANDT 549
Excitation of auditory receptors
HALLOWELL DAVIS 565
Central auditory mechanisms
HARLOW W. ADES 585
Vision — Introduction
H. K. HARTLINE 615
Photosensitivity in invertebrates
LORUS J. MILNE
MARGERY MILNE 62 I
The image-forming mechanism of the eye
GLENN A. FRY 647
The photoreceptor process in vision
GEORGE WALD 67 1
Neural activity in the retina
RAGN.-^R GRANIT 693
Central mechanisms of vision
S. HOWARD HARTLEY 713
XXXI. Central control of receptors and sensory
transmission systems
ROBERT B. LIVINGSTON 74 1
Index 761
XXV.
XXVI.
XXX.
CHAPTER I
The historical development of neurophysiology
MARY A. B. BRAZIER \ Ma'^sachusetts General Hospital, Boston, Massachusetts
CHAPTER CONTENTS
Early Concepts of Nervous Activity
ENcitability anci Transmission in Nerves
Spinal Cord and Reflex Activity
Physiology of the Brain: Development of Ideas and Growth of
Experiment
Short List of Secondary Sources
Biographies
EARLY CONCEPTS OF NERVOUS ACTIVITY
IN CONTRAST TO MEDICINE, a sciencc demanding
synthesis of observations, experimental physiology,
with its reliance on analysis and laboratory work, has
little significant history before 1600. Leaders in
medicine developed and practiced its therapies for
many centuries before they felt the need to under-
stand the nature and functions of the body's parts in
any truly physiological sense and, when the urge for
this knowledge first arose, it was to come as mucli
from the philosophers as from the healers of the sick.
Neurophysiology (a term not to come into use
until centuries later) had as a legacy from the ancients
only their speculative inferences and their primitive
neuroanatomy. Aristotle had confounded nerves
with tendons and ligaments, had thought the brain
bloodless and the heart supreme, not only as a source
of the nerves but as the seat of the soul. Herophilos
and Erisistratos had recognized the brain as the
center of the nervous svstem and the nerves as con-
cerned both with sen.sation and movement. However,
preliminary to all disciplines was the development of
the scientific method and in this Aristotle was a fore-
runner. If Aristotle is to be evaluated as a scientist, it
must be admitted that he was almost always wrong in
every inference he made from his \ast collections of
natural history and numerous dis.sections; yet in spite
of the stultifying effect of the ininujdcrate worship
gi\en him by generations to follow, he stands out as a
pioneer in the background of every scientific dis-
cipline. He owes this position to his in\ention of a
formal logic, and although his system lacked what the
modern scientist uses most, namely hypothesis and
induction, his was a first step towards the introduc-
tion of logic as a tool for the scientist. Unfortunately
Aristotle did not use his logic for this purpose him-
.self ' As Francis Bacon put it, Aristotle "did not con-
sult experience in order to make right propositions
and axioms, but when he had settled his system to
his will, he twisted experience round, and made her
bend to his system."
In the .second century A.D., Galen's experimental
work added little to establish the functions of the
animal structures he dissected, though the hypotheses
he suggested were put forward so authoritatively
that they remained unchallenged for nearly 1500
years. To the intervening centuries, dominated as
they were by the Christian church, the teleology
implicit in Galen's approach was attractive. Early
Western acquaintance with his writings depended
entirely upon Latin translations of Arabic. It was only
after the fall of the Byzantine Empire and the expul-
sion of the Greek monks from the area of Turkish
concjuest that the Greek language began to be read at
' The fragments of Aristotle's writings that e.xist (probably
his lecture notes} were not collected until more than lioo
years after his death. His Opera were among the early scientific
works to be printed (in Latin, 1472), nearly 1800 years after his
death. English translations (The Works of Aristotle) were pub-
lished by the Clarendon Press, Oxford, in several volumes
between 1909 and 1931, edited by J. A. Smith and W. A. Ross.
HANDBOOK OF PHYSIOLOGY ^ NEUROPHYSIOLOGY I
all generally by scholars in Western Europe (i, 2).
In the sixteenth century Thomas Linacre (3), physi-
cian to Henry V'lII, who had taught Greek to Eras-
mus at Oxford, translated some of Galen's works into
Latin directly from the Greek. The copies he gave to
Henrv VIII and to Cardinal VVolsey can be seen in
the British Museum. Erasmus, commenting on Lin-
acre's translations, said, "I present you with the
works of Galen, by the help of Linacre, speaking better
Latin than ever they spoke Greek."
Galen's emphasis, in spite of his dissection of ani-
mals, was not so much on the structures he found as
on the contents of the cavities within them. Function,
according to his doctrine, was mediated by humors
which were respon.sible for all sensation, movement,
desires and thought, and hence pathology was
founded on humoral disturbance. The role of the
organs of the body was to manufacture and process
these humors. His teaching about the nervous system
was that the blood, manufactured in the liver and
carrying in it natural spirits, flowed to the heart where
a change took place converting them into vital spirits.
These travelled to the reie muahtle (the terminal
branches of the carotid arteries at the base of the
brain) where they were changed into animal spirits,-
a subtle fluid which then flowed out to the body
through hollow nerves. Some of the.se ideas Galen
developed from those of his predece.s.sors (such as
Alcmaeon, Herophilos, Erisistratos), some were
inspired by his dissection of animals, but all were
hypothetical, none had any experimental proof or
1. Galen (130-200 A.D.). Opera Omnia (in acdibus Atdi el
Andrea Asulani) (in Greek). Venice, 1525. 5 vol.
2. Galen. Opera Omnia (in Greek). Basle, 1538.
3. Galen. De Facullalibiis naturalibus, Latin translation by
Thomas Linacre. London: Pynson, 1523; English transla-
tion by A. J. Brock, Loeb Classical Library. London:
Heineman, 1916.
' The usage of the term animal spirits' throughout the
centuries carries the connotation of the Latin anima meaning
soul and has no reference to the modern meaning of the word
'animal.'
^ No other was to appear until the beginning of the eighteenth
century when Johann Gottfried von Berger (1659-1736)
published his textbook entitled P/iysiologa Medica sine natura
humana. Wittenberg: Kreusig, 1701.
' "Nor lesse Worthy of Commendation are the Cravings. . .
those eleven pieces of Anatomic made for Andrea Vessalius
design'd by Calcare the Fleming, an Excellent painter, and
which were afterwards engraven in Copper by Valverdi in
little." Evelyn, John. Sculpltira: or the History, and Art of Chalcog-
raphy. London, 1662. The reference is to the plagiarism of the
Spaniard, Juan Valverde. Vivae Imagines Partium Corporis
Humani. Antwerp: Plantin, 1566. (His artist was Becerra.)
even partial support, yet some of them were to last
well into the nineteenth century.
The sixteenth century gave to physiology its first
textbook.^ This was the contribution of Jean Fernel,
physician and scholar, who in 1542 published his
De Naturali Parte Medicinae (4). This was so well
received that it saw inany editions. In the ninth of
these Fernel changed the title to Medicina (5) and
named the first section of the revised book Physio-
logia. According to Sherrington (6) this was the first
use of the term 'physiology.' There is, however, a
manuscript in the Danish Royal Library entitled
Physiologus that deals with animals and inonsters.
This copy is an Icelandic version of an apparently
much-copied treatise; it is a kind of bestiary. For some
time after Fernel's revival of it, the term 'physiology'
was still used by most writers to mean natural philoso-
phy. An example of this usage is to be found in the full
title of Gilberd's book on the magnet published in
1600. Although still grounded in a classification de-
rived froin the four elements of the ancients, Fernel's
physiology nevertheless shows dawning recognition
of some of the automatic movements which we now
know to be reflexly initiated for, although only the
voluntary muscles were known to him, he realized that
sometimes they moved independently of the will.
Before the seventeenth century opened, a technical
achievement in another field laid a foundation on
which physiology was to spread. Lagging about 50
years after the invention of printing came the develop-
ment of copper plate engraving and accurate repro-
ductions of anatomists' drawings became more
widely distributed. Supreine, however, ainong the
woodcuts contemporary with the early engravings
were those made from the drawings of Jan Stephen of
Calcar for the anatoinical studies of Vesalius (7^9).
These, published in 1543, were to draw the praise of
John Evelyn in his treatise on chalcography.^ After
4. Fernel, Jean (1497- 1558). De Naturali Parte Medicinae.
Paris: Simon de Colines, 1542.
5. Fernel, J. Medicina. Paris: Wechsel, 1554. P/iysiologia,
translated into French by Charles de Saint Germain,
Les VII Livres de la Physiologic, composes en Latin par Messire
Jean Fernel. Paris: Guignard, 1655.
6. Sherrington, C. S. The Endeavour of Jean Fernel. Cam-
bridge: Cambridge, 1946.
7. Vesalius, Andreas (1514-1564). De Humani Corporis
Fabrica. Basle: Oporinus, 1543; translated into English
by J. B. de C. M. Saunders and C. D. OMallcy. New
York: Schuman, 1947.
8. Vesalius, A. Epitome. Basle: Oporinus, translated into
English by L. R. Rind. New York: Macmillan, 1949.
9. Vesalius, .\. Tabulae Sex. Venice, 1538.
THE HISTORICAL DEVELOPMENT OF NEUROPHYSIOLOGY
centuries in which human dissection could onl\' be
done relatively furtively, a more liberal view had
grown up in Italy and among a number of con-
temporary anatomists, Vesalius is pre-eminent. In
themselves, however, with the exception of an experi-
ment showing that the nerve sheath is not vital for
conduction, his studies made no contribution to the
dynamics of function. Although an opponent of
Galen and an exposer of his anatomical errors,
Vesalius had no more satisfactory concept of nervous
activity to offer than that of animal spirits flowing
from the brain down pipe-like nerves to the muscles.
Yet for the study of the nervous system, as for other
branches of physiology, the publication of De Humam
Corporis Fabrica is the outstanding contribution of
the sixteenth century, the earlier chalk drawings of
Leonardo Da Vinci (1452-1519) not being widely
known to his contemporaries. The major contribu-
tions of Vesalius were not in physiology but in anat-
omy and in the demonstration that Galen was capa-
ble of error (though he himself was not without error).
At the opening of the seventeenth century the im-
portant event for all science was the appearance
(in 1600) of William Giiberd's* classic book De
Magnete (10, 11). The significance of this work was
not only as a landmark for the future of the physical
sciences and of electrophy.siology through its dawning
recognition of a difference between electricity and
magnetism; it was the first book to advocate empirical
methods and in this way heralded the scientific
ferment of the eighteenth century. If one overlooks
the last two chapters oi De Magnete, the book is revolu-
tionary in its experimental approach. It stood out
alone in an age when scholasticism was concerned
with classification on qualitative lines without meas-
urement and without validation. Authoritative state-
ments of the ancients were the guides, and induction
from experiment was virtually unknown. Gilberd's
book makes a plea for "trustworthy experiments and
demonstrated arguments" to replace "the probable
guesses and opinions of the ordinary professors of
philosophy."
Gilberd was physician to Queen Elizabeth (whom
he only just survi\-cdj and a sketch identified as a
portrait of him appears in the contemporary draw-
ing (now in the British Museum) made by William
Camden, the Court Herald, of her funeral proces-
sion in 1603. A contemporary oil portrait of him
painted in 1591 has been lost and remains to us only
in engravings. Gilberd was born and lived part of
his life in his father's house in Colchester in East
Anglia; a portion of this house still stands and, at
the time of writing, is being restored. This flowering
of the .scientific method came during the golden age
of Elizabethan England; among Gilberd's contem-
poraries were Shakespeare, Walter Raleigh, Philip
Sydney, John Donne, Christopher Marlow and
Francis Bacon.
Francis Bacon has a place in the history of all
.sciences, for he took scientific method a step farther,
to observation he added induction and to inference he
added verification. Scientists before him were content
with performing an experiment in order to make
an observation; from this oijservation a series of
propositions would follow, each being derived from its
predecessor, not by experiment but by logic. (Bacon
somewhat unjustly criticizes Gilberd for proceeding
in this way.) Bacon's contribution to scientific method
was to urge, in addition, the rigorous application of
a special kind of inductive reasoning proceeding
from the accumulation of a number of particular
facts to the demonstration of their interrelation
and hence to a general conclusion. This was in-
deed a new instrument, a Novum Organum (12). By its
application he overthrew reliance on authority of
the ancients and opened the way for planned experi-
ment. Although he had no place in his method for
the working hypothesis, and his forms of induction
and deduction are scarcely those of the modern
methodology, they were of considerable influence in
its development. The intelligent lines of Bacon's
face can be seen in his portraits. John Aubrey (13)
tells us that he "had a delicate, lively hazel eie" and
that "Dr. Harvey told me it was like the eie of a
viper."
The first major work in physiology exemplifying
10. Gilberd, William (1540 (or 1544)- 1603). De Magnete,
Magnetisque corporibus; et de mag?io magnete lellure; Physio-
logica nova plurimis et argumentis et experimentis demonstrata.
London: Peter Short, 1600; translated into English by
the Gilbert Club, William Gilbert of Colchester, physician
of London. London; Chiswick Press, igoo.
11. Ibid. (2nd ed.) (posthumous). Gotzianio in Stettin, 1633.
This book, far rarer than the first edition, carries more
plates than the original, and has some additions by
Wolfgang Lochmann of Pomerania (1594- 1643).
12. Bacon, Francis (1561-1626). .Novum Organum. 1620;
translated into English by Kitchin. Oxford, 1855.
13. Aubrey, John (1626- 1697). Brief Lives set Down i66g-
i6g6, edited by Andrew Clark. Clarendon Press, 1898,
vol. 2.
' The spelling of Gilberd's name follows the form seen on his
portrait and memorial tablet; his name on his book is spelled
Gilbert.
HANDBOOK OF PHYSIOLOGY
NEUROPH^'SIOLOGY 1
FIG. I. Portrait of William Gilberd from an oil painting on wood, found by Silvanus P. Thompson
in an antiquary's shop. The artist and the authenticity of the date on this portrait are unknown.
The portrait is now in the possession of Miss Helen G. Thompson, by whose courtesy it is repro-
duced here. The photograph of Tymperleys,' Gilberd's home at Colchester, was taken in 1957
when the house was undergoing extensive restoration. A portion only of the house dates from Gil-
berd's time. (Photograph by courtesy of Dr. G. Burniston Brown.)
Bacon's methodolos;y was iioi on the nervous .system
but on the circulation of the blood. Harvey's magnif-
icent treatise De Motu Cordis (14) was a model for
workers in all branches of physiology to follow. This
small book (it has only 72 pages) was the first major
treatment of a physiological subject in dynamic
rather than static terins. By experiment Harvey dis-
proved the Galenist doctrine that the motion of the
blood in the arterial and venous systems was a tidal
ebb and flow, independent except for .some leakage
through 'pores' in the interventricular septum. By
further designed experiments Harvey proved his own
hypothesis "that the blood in the animal body is im-
pelled in a circle, and is in a state of ceaseless motion."
Harvey had advanced this hypothesis in 1616 but,
14. H.^RVEV, VViLLI.aiM (i 578- 1 657). Exercttatin analomica de
motu cordis et sanguinis in animiilihus. Frankfurt : Fitzeri,
1628; translated into English by VVillius and Keys, Car-
diac Classics, 1 94 1, p. 19.
15. H.ARVEV, \V. Praelecliones anatomiae universalis. London:
Churchill, 1886. (Reprint of Harvey's Lumleian lecture
1616.)
as a forerunner of modern scientific method, had
proceeded to verify it before publishing his book.
But even this triumph of the empirical method did
not unseat in Harvey's thinking the belief in a soul
located in the blood ('anima ipsa esse sanguis') (15).
Harvey was Galenist enough to accept the rete mirabile
as the destination of the blood within the craniitm,
although doubt as to its existence in man had already
been raised by Berengario da Carpi (16, i 7) a hun-
dred years before. Harvey (18) had his own \'iews
of nervous function. "I believe," he said, "that in the
nerves there is no progression of spirits, but irradia-
tion; and that the actions from which sensation and
16. Berengario da Carpi, Giacomo (1470- 1550). Com-
menlaria cum amplissimus addilionibus super analomia Mun-
dtni. Bologna : Benedictis, 1 52 1 .
17. Berengario da Carpi, G. Isagogae breves, perlucidae. In:
Analomiam hurnani corporis, ad suorum scholasticorum preces
in lucem edilae. Bologna, 1522; translated into English by
H. Jackson, under the title A description of the Bnd\ of Mnn,
being a practical Anatomy. London, 1664.
18. Harvey, W. Praelecliones Analo?nwe Universalis, autotype
reproduction edition. Philadelphia: Cole, 1886.
THE HISTORICAL DEVELOPMENT OF NEUROPHYSIOLOGY
FIG. 2. Borclli and one of his sketches to show the center of
gravity of man when carrying a load. (From BorelU, G.A. De
Mntu Animalium, 2nd ed., Leydon : Gaesbeeck, 1685.)
motion result are brought about as light is in air,
perhaps as the flu.x and reflu.x of the sea."
That nerves might play a role in the working of
the heart as a mechanical pump was first suggested
by Borelli the Neapolitan, professor of mathematics at
Pisa and later at Florence, who applied the reasoning
of his discipline to physiology and e\olved mechani-
cal models for various bodily functions. His concept
of the innervation of muscle was an initiation by the
nervous fluid ('succus nervcus') of a fermentation in
the mu.scle swelling it into contraction, for there were
still many years to go before a dynamic concept of
muscle was to emerge in spite of Harvey's demon-
strations on the heart. Peripheral muscles were still
regarded as passive structures rather like balloons to
be inflated by nervous fluid or gaseous spirits reach-
ing them through canals in the nerves. Borelli, by
an ingenious experiment in which he submerged a
struggling animal in water and then slit its muscles,
demonstrated that the spirits could not Ije gaseous
since no bubbles appeared in spite of the violent
contractions. It was this experiment that led him to
the suggestion of a liquid medium from the nerve,
mixing in the muscle to cause a contraction by ex-
plosi\e fermentation ('ebuUitio et displosio') (19).
Giovanni Alphonso Borelli was a member of the
group of experimental scientists banded together in
the Accademia del Cimento under tlie patronage of
the .science-loving Medici brothers in Florence. This
small .scientific society, successor to the Lincei, existed
for only a decade but was typical of the independent
ig. Borelli, Giovanni .Alfonso (1608-1679). De molu ani-
malium (pubUshed posthumously). Rome: Bernado, 1680-
I ; a small section has been translated into English by
Michael Foster. Lectures on the History of Physiology. Cam-
bridge: Cambridge, 1901.
groups centered on laboratory experiment that were
to spring up in independence of the universities where
the scholars had still not looked up from their books.
Few as they were (there were only nine members)
these laboratory scientists of the Accademia were to
have a far-reaching though delayed influence on
European thought, for in the final year of the acad-
emy's existence they published their proceedings (20).
Founded entirely on empirical methodology, this was
a truly scientific text. It was, however, written in
Italian although soon translated into English, and it
did not reach the scientific world at large until Petrus
van Musschenbroek of Leydeii made a Latin transla-
tion (21). It was this book that, for example, influ-
enced Stephen Hales so greatly in his experimental
work. The volume included only one series on animal
experimentation, but almost all the rest deals with
the physics which are basic to the work a physiologist
does in his laboratory.
To his contemporary, Descartes, Borelli owed his
application of mathematics to muscular action. This
pungent philosopher, who rarely did an experiment,
wrote a text that was to influence all experimenters,
The Discourse on Method (22). It is not experimental
method that he discusses, i)ut his own method of
thought, his theory of knowledge." Scientists had
just begun to look around them to olaserve nature
and to let the statements about her by the ancients
lie in the books when they had to meet a new and
brilliant challenge; mathematics was the tool they
were to use. Mathematics would not only elucidate
the laboratory experiment but would provide the
basis for an all-embracing theory of science.
This great man bred in the gentle landscape of
Touraine was to devote his life to a search for the
truth, .seeking for himself a quiet environment for
free thinking.' This he found for 25 years in the
20. Saggi (It naturali esperienrji fattr nell Aecadeniui del Cimento,
edited by L. Magalotti. Florence, 1667; translated into
English by Richard Waller. Essayes of Natural Experiments
made in the Accademie del Cimento. London, 1684.
21. VAN Musschenbroek, Petrus (1692-1761). Testamina
Experimentortum Naturaliuin captoruni in Accademia del Ci-
mento. Leyden, 1731.
22. Descartes, R. Discours de la Methode. 1637 ^ English trans-
lation by E. S. Haldane and G. R. T. Ross. Philosophical
Works of Descartes. Cambridge : Cambridge, 1 904.
* "Methode de bien conduire sa raison, pour trouver la
verite dans les sciences."
' "Cum nil dignum apud homines scientia sua invenisset,
eremum ut Democritus aliique vcri Philosophi elegit sibi
juxta Egmundum in HoUandia, sibique solitarius in villula per
25 annos remansit, admirandaque multa meditatione sua
detexit" (Borel, p. 9).
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
FIG. 3. Rene Descartes and his concept of the pineal gland. The photograph is from the portrait
by Franz Hals in the Louvre, and the diagram is taken from de la Forge, Louis. Traili de I' Esprit
de I'Homme, de ses Facultez, de ses Fonclions, et de son Union avec le Corps. SuiranI les principes de Mr.
Descartes. Geneva : Bousquet, 1725.
village of Egmond in liberal Holland, though even
here he could not entirely escape lieing hounded by
bigots. The mistake he made that the world regrets
was to leave a milieu so congenial to his philosophic
nature for the cold of Sweden and the exacting de-
mands of Queen Christina. There, within a year, he
died. His striking face with the intelligent eyes and
quizzical eyebrow has been preserved for us in the
fine portrait by Franz Hals that hangs in the Loux-re.
A great man has many lives' written about him
but those set down by his contemporaries usually
have a special flavor. In the case of Descartes, the
short account of his life and his philosophy written
by Borel (23) (the inicroscopist) in 1669 gi\es one the
feeling of bridging the centuries. Borel gives a list of
the manuscripts found in Stockholm at Descartes's
death in 1650, including the early treatise he wrote
on music when he was only 22. Several of his letters
were found, some of which Borel reproduces. The
letters date from 1632 and give an intimate glimp.se of
the struggle Descartes had to face in overcoming re-
sistance to his theories among some of his con-
temporaries.
23. Borel, Pierre (1620- 1689). Vitae Renati Cartesii, Summt
Philosophi Compendium. Frankfurt: Sigismund, 1676.
* "It is an error to suppose the soul supplies the body with
its heat and its movements." Passions de I'Ame, Article 5.
Descartes (24, 25), having become convinced that
in mathematics lay the tool for a unified theory of all
science, had now to explain its role in physiology. It
followed logically that the animal body and all its
workings was a machine, the operation of this machine
being directed from a control tower. In the brain with
its bilateral development, the singly represented
pineal body was chosen by Descartes to play this
master role and (in man) it was given the added
responsibility of housing the soul. In the concept of
the body as a machine, energized not by an iniina-
terial aninia* but by the external world impinging on
it, lies a germ of the idea of reflex activity.
To coming generations of neurophysiologists Des-
cartes bequeathed the notion that impressions from
the external world were conveyed by material animal
spirits to the ventricles and there directed by the
pineal gland into those outgoing tubular nerves that
could carry them to the part of the body the subse-
quent action of which would be the appropriate one.
In animals this was presumed to be a purely mechani-
cal action, but in man the soul, resident in the pineal,
could have soine say in the direction taken by this
24. Descartes, Rene (1596-1650). Passioru de fAnie.
.-\msterdam, 1649.
25. Descartes, R. De homine figuris, et latinate donatur a
Florentio Schuyl, posthumous Latin version by Schuyl.
Leyden: Moyardum & Leffen, 1662; first French edition,
Traile de I'Homme, 1664; second French edition, 1677.
THE HISTORICAL DEVELOPMENT OF NEUROPHYSIOLOGY
central relay. Descartes recognized, however, that
perhaps some of these actions lay outside the control
of the will, citing as examples involuntary blinking
and the withdrawal of the hand on burning.
To neurophysiologists Descartes bequeathed an-
other seed — what was later to be known as the re-
ciprocal innervation of antagonist muscles. In order
to ensure that while animal spirits were flowing
into one set of muscles the opposing set should relax,
he argued that the latter must have their supply of
spirits blocked and he postulated that this must be
eflTected by valves. Whether or not he was influenced
in his thinking by Harvey's explanation of the
valves of the veins is not known, although he was
certainly aware of, and had commented on, Harvey's
discoveries.^ Descartes was a member of what a sub-
sequent irreverent generation was to call 'the bal-
loonists.' Apparently unaware of Borelli's experiments,
he thought the animal spirits to be "like a wind or a
verv subtle flame" and that "when they flow into a
muscle they cause it to become stiff and swollen, just
as air in a balloon makes it hard and stretches the
substance in which it is contained."
A young contemporary of Descartes, though less
directly influenced bs' him than was Borelli, was Wil-
liam Croone who was working on muscle action. He
too thought that the nervous 'juice' must interact in
some way with the muscle (26). The "spiritous liquid"
flowed in, mixed with "the nourishing juice of the
muscle," and then the muscle "swell'd like a Bladder
blown up. " Later (27} Croone was to modify this to
a number of small bladders for each muscle fiber.
Just as Borelli had been a founding member of a
scientific society, so was Croone. He was one of the
original group who in England formed the Royal
Society, a society which unlike the Cimento has con-
tinued to flourish and in which to this day eminent
.scientists not only discuss but demonstrate their ex-
periments before the members. The Royal Society
has several distinguished lectureships, among which
is the Croonian Lecture founded by the widow of
William Croone.
The Royal Society of London received its charter in
1662, being founded for the promotion of "Natural
Knowledge,' and it numbered among the founding
members many who.se contributions are fundamental
26. Croone, William (1633-1684). De raiione motus muscu-
lorum (published anonymously). London: Hayes, 1664.
■27. Croone, W. An Hypothesis of the Structure of the Muscle, and
the Reason of its Contraction. Hooke's Philosophical Collec-
tions, No. II. London, 1675.
to physiolog)-. The mo\ing spirit was Robert Bovle,
the 'father of chemistry' (whose first published work
was, however, on Seraphick Love). Famous for his law
(28) of gaseous pressures, he made his most directly
physiological experiments on the respiration of ani-
mals. It was still many years before physiologists were
to elucidate the efTects of anoxia on the nervous
system, and another hundred years were to pass before
Priestley's and Lavoisier's work on oxygen, but Boyle,
by using an ingenious compression chamber, demon-
strated that air is essential for life. Almost unnoticed
at the time, but since then perhaps overpraised, were
the observations of John Mayow (29) on the chem-
istry of respiration. His publication preceded (al-
though his work was contemporary with) the some-
what similar experiments of the Accademia del
Cimento.
In the early seventeenth century emphasis on the
search for a chemical foundation for living phe-
nomena characterized for the most part work in
Holland and England in contrast to the physical and
mathematical approach of the Italians and the
French. The two contrasting .schools of thought were
long to be known by the clumsy names of the iatro-
chemical and iatromechanical schools. latrochemis-
try, on the rather shaky foundations given to it by
van Helmont (1577-1644) and by Sylvius (de La Boe)
(1614-1672), provided the approach to the study of
the nervous system of Thomas Willis, Sedleian Pro-
fessor of Natural Philosophy at Oxford (30). Willis,
whose clinical achievements outshone his scientific
acumen, is recognized in neurology for his description
of the circle of Willis and his dissection of the spinal
accessory nerve. (Galen had identified only seven
pairs of cranial nerves.) Willis was a close colleague at
Oxford of Richard Lower, the Cornishman, champion
of the theory that spirits flowing into the heart from
28. Boyle, Robert (162 7-1 691). .\ew experiments physico-
mechamcal, touching the spring of the air, and its effects, made,
for the most part, in a new pneumatical engine. Oxford : VV.
Hall, 1660.
29. Mayow, John (1645-1679). Tractus Duo, quorum prior
agit De Respiratione : alter De Radutiones. O.xford: Hall, 1668.
30. Willis, Thomas (1621-1675). Cerebri anatome: cui accessit
nervorum descriptio et usus. (Z)f systemate nervosa in genere"),
illustrated by Sir Christopher Wren. London: Flesher,
1664; translated into English by S. Pordage. London:
Dring, Harper and Leigh, 1683.
' Letter to Mersenne dated 1632, quoted in Oeuvres Com-
pletes de Descartes, edition of Adam and Tannery, Paris; Cerf,
1897-1910, vol. n, p. 127.
8
HANDBO(iK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
its nerves were what caused it to beat (31). Lower's
more spectacular achievement was the apparent
transfusion of blood, first in dog and then in man (32,
33). We are surprised today that the man survived as
long as he did, for the blood donor was a sheep.
Thomas Willis had added to the prevalent Galenic
ideas of nervous function the concept that the soul
had two parts which he likened to a flame in the vital
fluid of the blood and a light in the nervous juice.
When they met in the muscle, they formed a highly
explosive mixture which inflated the muscle. Yet even
before the seventeenth century had run out, a voice
was raised against such visionary explanations. Sten-
sen (34)' '^he great Danish anatomist, writing from
Florence in 1667, stated unequivocally that "Animal
spirits, the more subtle part of the blood, the vapour
of blood, and the juice of the ner\-es, these are names
used by many, but they are mere words, meaning
nothing."
The seventeenth century, or grand siecle as it was
known to Europe, had been gloriously opened by
the De Magnete and gone on to the achievements of
Galileo, Kepler, Huygens, Leibniz and Newton, and,
although these were essentially achievements in
mathematics, physics and astronomy, all branches of
science were fermenting with the implications of these
disco\'eries. The break with dogma was now more
than a crack, though the Index Librorum Prolnb-
itorutn fought a delaying action. The men of the
arts were liberal in their championship of the scientists.
John Milton's Areopagitica (35) is a clarion call for
freedom of knowledge and distribution of books.
Milton was a young contemporary of Galileo and
went to see him in his old age. There is a poignancy
about this visit to the old blind astronomer from the
poet about to become blind.
The students of the nervous system had the hardest
fight against dogma for in their province lay the
31. Lower, Richard (1631-1691). Tractatus de Corde item de
Motu & Colore Sanguinis el Chyli cum Transitu. London:
AUestry, i66g; English translation by K. J. Franklin.
Early Science in Oxford. Oxford, 1932, \ol. g.
32. Lower, R. The method observed in transfusing the blood
out of one live animal into another. Phil. Trans, i : 353,
1665-6.
33. Lower, R. and E. King. An account of the experiment
of transfusion, practised upon a man in London. P/ul.
Trans. 2: 1557, 1667.
34. Stensen, Nicholas (1638- 1686). Elernentorum myologiae
.'Specimen. Florence: Stella, 1667, p. 83.
35. Milton, John (1608-1674). Areopagitica. A speech for the
Liberty of Unlicensed Printing to the Parliament of England.
1644.
structures most suspect as being the guardians of
man's soul. But ranked behind them and influential on
them were some of the greatest philosophers of their
time. Prominent among the.se was Locke (36), the
father of empiricism. Born in the West of England and
trained as a physician, this man with his colorless
personality and his clumsy prose was to channel the
efforts of the next several generations of workers on
the nervous system into a .search for the physiology
of the mind. For his Essay on Humane Understanding
he received immediate recognition and monetary
reward, obtaining for it more than was paid to John
Milton for Paradise Lost.
Straddling like a colo.ssus the division between the
seventeenth and eighteenth centuries is Newton,
friend and correspondent of Locke, though to .scien-
tists it is perhaps a bit disappointing to find that the
subject of their correspondence was the interpretation
of the New Testament (biblical history was a life-long
interest of Newton). Newton's insight into the move-
ment and forces of nature led him to make some
tentative suggestions about the working of the nerv-
ous system, and these were noted by the physiologists
of the time. There is scarcely a single neurophysiolo-
gist of the eighteenth century who does not explicitly
attempt to align his findings with these conjectures
of Newton.
In the General Scholium (37) which he added to
the second edition of the Principia (26 years after its
first publication), Newton included a speculation.
This was the idea of an all-pervading elastic aether
"exceedingly more rare and subtle than the air,"
which he again suggested in the form of a question in
the .series of Queries added to the second English edi-
tion of his Opticks (38). Applying this suggestion to
the nervous system, he said, "I suppose that the Capil-
lamenta of the Nerves are each of them solid and
uniform, that the \ibrating Motion of the Aetherial
Medium may be propagated along them from one
End to the other uniformly, and without interrup-
tion. . . ." It is easy to understand how eagerly such a
statement would be received by those who accepted
the idea of a nervous principle running down the
nerves but were worried that they knew of no fluid
sufficiently swift and invisible. Newton's rather sketchy
suggestion was therefore eagerly embraced by many
of his contemporaries, one of whom, Bryan Robinson,
36. Locke, John (163J-1704). An Essay concerning Humane
Understanding. London: Holt, 1690.
37. Newton, Isaac (1642-1727). Principia. London: 1687;
edition with General .Scholium, 171 3.
38. Newton, L Opticks (2nd ed., 24th Query). London: 1717.
THE HISTORICAL DEVELOPMENT OF NEUROPHYSIOLOGY
Regius Professor of Physic at the L'ni\ersity of Duljlin,
even went so far as to claim that "Sir Isaac Newton
discovered the Causes of Muscular Motion and Secre-
tion" (39).
At the opening of the eigthteenth century the sci-
ence of the nervous system had reached diflferent levels
in the various countries of Europe. In Germany in
the first half of the century the Thirty Years War
had brought science almost to a standstill, and in the
fields of chemistry and physiology this stagnation de-
veloped into a retrogression owing to the emergence
of an extremely influential figure, Georg Ernst Stahl.
In opposition to both the chemical and mathematical
schools, Stahl set back the clock by the reintroduction
of an immaterial anima which he held to be the sole
activating principle of the body parts (40). The
latter were regarded as having no dynamic properties
of their own, being essentially passive structures.
Since the search for an immaterial agent lies outside
the scope of science, Stahl's doctrines, promulgated
with arrogance and dogmatism, virtually extinguished
experimental inquiry among his followers. Yet even
writers sympathetic to his viewpoint granted that in
attempting to follow his arguments one became "in-
volved in a labyrinth of metaphysical subtlety" (41).
The metaphysical approach of Stahl later came
under criticism from Vicq d'Azyr (42) who suggested
that the invention of an imaginary soul to resolve those
phenomena that could not yet be explained by the
laws of physics and chemistry was merely a cloak for
ignorance, van Helmont did not escape the same
criticism.
In opposition to humoral or vitalistic concepts of
nervous and muscular activity was a prominent
champion of a 'solidist' theory, Giorgio Baglivi. This
young man, whom Pope Innocent XII had appointed to
be profes.sor of the theory of medicine and anatomy
at Rome, put emphasis on the fibers of the muscles
and the nerves, and so foreshadowed the importance
that was to be given in the eighteenth century to the
intrinsic structural properties of these tissues. He de-
39. Robinson, Br\an (1680- 1754). A treatise of the Animal
Oeconomy (3rd ed.). London: Innys, 1738.
40. Stahl, Georg Ernst (1660-1734). Theoria Medica Vera
Physiologiam et Pat/iologium, tanquam Doctrinae Medicae
Partes veres Conternplativas e Naturae et Artis veris Junda-
mentis. Halle, 1708.
41. BosTOCK, John (1773-1846). Sketch of the History of Medi-
cine from Its origin to the commencement of the nineteenth century.
London: Sherwood, Gilbert & Piper, 1835.
42. Vicq d'.'Kzvr, F. (1748-1794). Oeuvres de Vicq d'Azyr.
Paris, 1805, vol. 4.
FIG. 4. (iiorgio Bagli\i rising like a phoenix from the flames.
veloped a theory (43) of an oscillatory movement of
nerve fibers in order to account for both efferent and
afferent activity and envisaged the dura mater as the
source of these movements and the recipient of the
returning oscillation.
The leading medical center in Europe at this
time was the University of Leiden. The empirical
approach was urged by the physicist S'Gravesande
(44) who advised that "It is Nature herself that
should be examined as closely as possible . . . progress
may be slow, but what we find will be certain."
Petrus van Mmschenbroek (45), who had come to
the Chair of Physics at Leiden from Utrecht in 1 740,
had in a discourse on scientific method emphasized
that physics should stand apart from metaphysics,
that experimental analysis should antecede synthesis,
that in the collection of evidence the exception should
not be ignored, and that argument by analogy was
fraught with danger. Yet it was essentially by analogy
that the early eighteenth century viewed the func-
43. Baglivi, Giorgio (1668-1707). De fibra motrice et
morbosa. In: Opera Omnia. Leyden: Antonii Servant, 1733.
44. S'Gravesande, Wilhelm Jacob (1688-1742). Physices
Elementa Mathematica Experimenlis conjirmata sire Intro-
ductio ad Philosopham .\ewtoniatinm. 2nd ed., 1725; 3rd
ed., 1742,2 vols. Leiden.
45. VAN MusscHENBROEK, Petrus (1692-1761). Discours a
i' Organisation de V Experience. 1730. (His swansong as
Rector at the University of Utrecht.)
10
HANDBOOK OF I'HVSIOLOGV ^ NEUROPHYSIOLOGS' I
FIG. 5. Bocrhaave giving a class in botany. (From the en-
graving by Jacob Folkema, reproduced by permission of the
Rijksuniversiteit in Leiden.)
tions of the nervous system; the brain was analogous
to the heart and the nerves analogous to the arteries.
In the one case the content was blood; in the other,
nervous fluid. Some writers even spoke of "the systole
of the brain . . . whereby the animal Juices are forci-
bly driven into Fibres of the Nerves" (46).
van Musschenbroek had been a pupil of Hermanii
Boerhaave who came to the Chair of Medicine in
Leiden in 1701. Boerhaave, essentially a chemist
and a clinician, had an almost leaiendary fame as a
teacher, which must, one feels, have been due to his
personality, for he was not an experimenter and his
doctrines were not at all progressive. He added little
if anything new to the existing body of physiological
46. Robinson, Nichol.a.s. A new system of /he Spleen, Vapours,
and Hypoehondriak Melanchoh. London, 1729, p. '^62.
knowledge. In his lectures (47, 48) on the nervous
system he taught that "The Ventricles of the Brain
have also many Uses or Ad\antages in Life, such as
the perpetual Exhalation of a thin \'apour, or moist
Dew." Himself a chemist, he made no experiments
in ph\siology and was content to teach that "Tho'
the nervous Juice or Spirits separated in the Brain
are the most subtile and moveable of any Humour
throughout the whole Body, yet are they formed
like the rest from the same thicker Fluid the Blood,
passing thro' many Degrees of Attenuation, till its
Parts become small enough to pervade the last
Series of Vessels in the Cortex, and then it becomes
the subtile Fluid of the Brain and Nerves." His au-
thority for this doctrine which he handed on to his
eighteenth century pupils was the works of Galen
who had died in 200 A.D. These teachings are difficult
to reconcile with the exhortation expressed in his
Aphorismi (49) that attention to facts and observations
is the best means of promoting medical knowledge.
Yet among his pupils Boerhaave numbered nearly
all the prominent students of the nervous system in
the eighteenth century: Haller, van Swieten, Monro,
CuUen, de Haen, Pringle. His pre-eminence lay
in the clinical field, and there can be no doubt that
he had the greatest gift of a teacher, that of lighting
the fire of enthusiasm in his students. It was two of
them, Haller (50) and \an Swieten (51), who were
responsible for the wider publication of his lectures,
for on his own initiative he published little.
van Swieten, who as a Catholic had little chance of
advancement at the L'niversity of Leiden, went to
Austria under the patronage of Maria Theresa and
there founded the 'Old Vienna School,' patterning it
on the medical clinic at Leiden. He was an advocate
of a spare diet and active exertion and quoted in sup-
port of his views "the case of a rich priest, who had
47. BoERH.^.WE, Herm.-^nn (1668-1738). Instituliones Medicae
in usus animal exercitationis domesticae. Leyden, 1708; anony-
mous English translation. Academical Lectures on the Theory
of Physic, being a genuine translation of his Institutes, and Ex-
planatory Comment. London: Innys, 1743. 5 v'ol.
48. BoERH.^.AVE, H. Praelectiones Academicae de .\lorbis Nervorum.
Quas ex Audilorwn Manuscriptis collectas edi curavil. Jacobus
van Eems. Leyden: van der Eyk & Pecker, 1761. 2 vol.
49. BoERH.^AVE, H. .Aphorismi de cognoscendis et curandis
morbis. Leyden: van der Linden, 1709.
50. VON Haller, Albrecht (i 708-1 777). Commentarii ad
Hermann Boerhaave Praelectiones Academicae in proprias
Irutitutiones Rei Medicae. 1 739-1 744. 7 vol.
51. VAN Swieten, Gerhard L.B. (1700-1772). Commentaria
in Hermanni Boerhaave, aphorismos, de cognoscendis et curandis
morbis. Leiden: Verbeek, 1742-1776. 6 vol.
THE HISTORICAL DEVELOPMENT OF NEUROPHYSIOLOGY I I
FIG. 6. Albrecht von Haller, the greatest physiologist of the eighteenth century, and de La Mettric
whose treatise L'homme machine, addressed to Haller, caused a controversy that highlighted the ques-
tion as to whether the soul lay in the province of the physiologist. The portrait of Haller is from the
frontispiece of his Elementa Physiologiae and is an engraving by Tardieu; that of de La Mettrie is
from an engraving in the Bibliotheque Nationale (reproduced here with permission), the original
painting being a pastel by Maurice Quentin La Tour.
enjoyed a fat living and long been a martyr to gout,
chancing to be carried into slavery by a Barbary
corsair, and kept for two years to hard labour and
spare diet in the gallics lost his gout and his obesity
together. ..." His master, Boerhaave, a martyr to
gout, had died 34 years before, corpulence hastening
his end.
We have a contemporary description (52) of Boer-
haave's habits and also of his looks. "He had a large
head, short neck, florid complexion, light brown hair
(for he did not wear a wig), and open countenance,
and resembled Socrates in the flatness of his nose. ..."
We are told that he ro.se at four in the inorning, but
in the cold Dutch winters he allowed himself an e.xtra
hour in bed before settling to work in his unhealed
study. His chief relaxation was music and he played
several instruments of which his favorite was the lute.
It is at about this period — the middle of the eight-
eenth century — that experimental work on the nerv-
ous system began to be channeled into three main
divisions: a) the elucidation of peripheral nerve
52. Burton, William. An account of the Life and Writings of
Hermann Boerhaave. London: Lintot, 1743.
physiology and its differentiation from that of muscle,
A) the recognition of the function of the spinal cord
together with the development of ideas about reflex
action, and c) the growth of knowledge about the
brain as a neural structure unencumbered by dogma
concerning the soul.
EXCIT.iiiBILITY .AND TR.ANSMISSION IN NERVES
In the field of physiology Boerhaave's most prom-
inent pupil was Albrecht von Haller. Haller, a Swiss,
was born in Berne and studied at Tubingen but was
drawn to Leiden by the magnet of Boerhaave's
teaching. After taking his medical degree he returned
to .Switzerland where he divided his time between
medicine, poetry and botany. In 1736 George II of
England, Elector of Hanover, appointed him to the
chair of the mixed sciences Anatomy, Surgery and
Botany at Gottingen, a newly-founded university.
It was here that Haller spent the experimental phase
of his life as a scientist.
Unlike his master Boerhaave, Haller was a great
laboratory worker as well as a phenomenal scholar
12 HANDBOOK OF PHYSIOLOGY -^ NEUROPHYSIOLOGY I
FIG. 7. Two men whose ideas of irritability anteceded tiiose of Haller. Glisson's concept (1677)
included a psychic stage between stimulus and contraction thereby differing from Haller's which
postulated a purely peripheral reaction. Johannes de Gorters proposal of irritability based on
mechanical movement was published in 1734. The portrait of Glisson is an engraving from the
original painting in the Royal College of Physicians. That of de Gorter is photographed from an
engraving, the generous gift of the Director of the National Museum of Science in I^eiden. The
original painting was by J. M. Quinkhard, the artist of the portrait of van Musschenbroek repro-
duced in figure 1 1 .
and was the author of the most famous of the eight-
eenth century textbooks of physiology, the Elementa
Physiologiae (53). Although these volumes came into
print after Haller's retirement to Berne, he had while
teaching at Gottingen brought out his Primae Lineae
Physiologiae (54) for, as he proceeded with his ana-
tomical and experimental studies, his master's texts
became less and less useful to him. In the preface to
his own work he remarks that, since the time of Boer-
haave, anatomy had developed so greatly as to be-
come almost a new science. Haller had himself
brought out an anatomy book (55) with fine engrav-
ings, and anatomy was one of the four subjects on
which he compiled bibliographies (56-59) that are a
great source of information for the medical historian.
They contain tens of thousands of references.
For neurophysiologists Haller's most interesting
work is his development of the concept of irritability.
An earlier student of Boerhaave's at Leiden was
Johannes de Gorter who later became physician to
the Empress Elizabeth of Russia. He had in 1737
published a volume (60) in which he brought out of
obscurity the idea of the intrinsic irritability of tissues
that had been postulated by Francis Glisson in the
previous century. It is not clear whether de Gorter
owed any of his ideas to Glisson. He mentions hiin
only once (in De AIolii vitale, paragraph 58, p. 40) and
this only in reference to the capsula hepatis. In any
53. VON Haller, Albrecht (i 708-1 777). Elementa Physi-
ologiae corporis humani. Lausanne: Marci-Michael Bous-
quet et Soc, 1 757-1 765. 8 \ol.
54. VON H.'iLLER, A. Primae lineae physiologiae in usiim praelec-
tionium academicarium. Gottingen: Vandenhoeck, 1747.
55. VON Haller, A. hones analomicae. Gottingen: Vanden-
hoeck, 1 743-1 756.
56. VON Haller, A. Bibliotheca Bolanica. Zurich: Orell, 1771-
1772.
57. VON Haller, A. Bibliotheca Chirurgica. Basle: Schweig-
hauser, 1774; Berne: E. Haller, 1775.
58. VON Haller, A. Bibliotheca Anatomica. Zurich: Orell,
I774-I777-
59. VON Haller, A. Bibliotheca medicinae practicae. Basle:
Schweighauscr, 1776; Berne: E. Haller, 1778.
60. DE Gorter, Johannes (1689-1762). Exercitaliones medicae
quatuor. I: De motu vitale, 1734; il: Somno et vigilia;
HI: De Jame; IV: De Siti. Amsterdam, 1737.
THE HISTORICAL DEVELOPMENT OF NEUROPHYSIOLOGY
13
FIG. 8. Swammerdam's experiments including the one by which he proved that muscles were not
swollen by an influx of nervous fluid when they contracted. Fig. V is of an experiment to show the
change in shape of a muscle when stimulated by pinching its nerve. Fig. VI illustrates the pulling
together of the pins holding the tendons when the muscle contracts. Fig. VIII is the crucial one in
which a drop of water is imprisoned in the narrow tube projecting from the vessel enclosing the
muscle. Swammerdam found that when he stimulated the nerve by pulling it down by a wire, the
muscle contracted but the drop of water did not move. He concluded that the volume of the muscle
did not expand on contraction. It is the fact that the wire was made of silver (filium argenteum)
and the loop of copper (filium aeneum) that has credited Swammerdam with the use of bimetallic
electricity as a stimulus to nerve. Some authors however interpret the action in this experiment as
the mechanical pull on the nerve. Some originals of Swammerdam's plates can be seen at the
National Museum of the History of Science in Leiden. (From Biblia .Naturae. Amsterdam, 1 738).
case his concept of intrinsic irritability differed from
that of GHsson in being part of a dynamic scheme in
which inovements of muscles and nerves acted me-
chanically on each other (61). Glisson (62) had been
among the few scientists of the seventeenth century to
test experimentally the Galenist doctrine that muscu-
lar contraction was due to an inflow of nervous fluid
inflating the muscle. He had demonstrated by immer-
sion of a inan's arm in water that the level did not
rise on contraction. Swammerdam,'" in Holland,
reached the same conclusion from experiments on
frogs (fig. 8). From such experiments, Glisson had
gone on to develop a concept of intrinsic irritability
varying in kind for the different nervous functions.
As Regius Professor of Physic at Cambridge, Glisson
61. DE GoRTER, J. Exercilaliones Medico Qiiinta V: De aclione
viventium particulari. Amsterdam, 1 748.
62. Glisson, Francis (1597^1677). Traciatus de venlricuto el
inleslinis. London: Henry Brome, 1677.
was to a certain extent bound by the statutes goxern-
ing these professorships to teach the doctrines of
Hippocrates and of Galen, and this may have limited
him in the development of this new idea of irrita-
bility.
In Haller's hands the idea blossomed into a concept
that was to dominate physiology for over a century.
His theory differed from Glisson's in that he omitted
the intermediate element of psychic perception be-
tween the irritation and the contraction. The first
expression of his theory of the relationship of con-
tractility to irritability is found in 1 739 in his com-
mentaries on Boerhaave's lectures and a fuller de-
velopment in his Elementa Physiologiae, but it is in his
"No known portrait of Swammerdam exists. In the nine-
teenth century a publisher took one of the heads from Rem-
brandt's Anatomy Lesson and put out a lithograph w'nich he
labelled with Swammerdam's name. This was a stroke of
imagination rather than fact.
H
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
Gottingen lectures (63) gi\cn in 1752 (and published
the following year) that the concept is most full\- de-
veloped and supported by experimentation. Haller's
own definitions for the dual properties of irritability
and sensibility were as follows: "I call that part of the
human body irritable, which becomes shorter on
being touched; very irritable if it contracts upon
slight touch, and the contrary if by a violent touch it
contracts but little. I call that a sensible part of the
human body, which on being touched transmits the
impression of it to the soul; and in brutes, in whom the
existence of a soul is not so clear, I call those parts
sensible, the Irritation of which occasions evident
signs of pain and disquiet in the animal."
One sees immediately the bogey of the early physi-
ologists raising its head — the necessity, on invoking
the soul, for differentiating processes in man from
those in animals. Haller describes his technique for
determining sensibility as follows: "I took living ani-
mals of different kind, and different ages, and after
laying bare that part which I wanted to examine, I
waited till the animal ceased to struggle or complain,
after which I irritated the part, by blowing, heat,
spirit of wine, the scalpel, lapis infinalis, oil of vine-
gar, and bitter antimony. I examined attentively,
whether upon touching, cutting, burning, or lacerat-
ing the part, the animal seemed disquieted, made a
noise, struggled, or pulled back the wounded limb,
if the part was convulsed, or if nothing of all this
happened."
Haller recognized that nerves arc "the source of all
sensibility," but applied his dichotomy of irritability
and sensibility to various types of nerves, noting that
all nerves are not irritable according to his definition
(with its insistence on resultant contraction). He thus
approached the differentiation of motor and sensory
nerves. Still incorporated in his hypothesis was the
1600-year-old concept of a nervous fluid within the
nerves. It might be thought that once the microscope
had been invented, the question of whether or not
the nerves were hollow pipes might have been
quickly settled. Indeed in 1674 Leeuwenhoek (64),
with the limited magnification of his simple micro-
63. VON Haller, A. De paitibus corporis humani scnsibilibus
et irritabilibus. Comment. Soc. reg. Set. Gottingen 2: 114,
1753; English translation by M. Tissot, M.D. A disserta-
tion on the sensible and irritable parts oj animals^ from a
treatise published in the Transactions of the Royal Society
of Gottingen and read in the .'\cademy of Gottingen by
Haller on April 22, 1752. Printed by J. Nourse at the
Lamb opposite Katherine-street in the Strand, 1755.
64. VAN Leeuwenhoek, .■\ntonj (1632-1723). Phil. Trans. 9:
178, 1674.
scope, had specifically searched for cavities in the
nerves of a cow but his results were equivocal. One
hundred years later this issue was still unresolved.
The only competing hypothesis, which received
but little support, was that the nerves were cords
that communicated sensation to the brain by their
\ibrations (rejected by Boerhaave as "repugnant to
the Nature of the soft, pulpy and flaccid nerves").
This view was also rejected by Haller.
In considering how a fluid could possibly flow as
swiftly as nerves can be observed to act, Haller pro-
posed that it must indeed be a very subtle fluid imper-
ceptible to the eye yet more substantial than heat,
aether, electricity or magnetism. In another comment
he granted that electricity was a most powerful stimu-
lus to nerves but that he thought it improbable that
the natural stimulus was electrical. Thinking always
in terms of electricity flowing as down a wire, Haller,
like so many physiologists after him, felt the lack of
insulation around the nerve to be a critical argument
against nervous influence being electrical.
However, the notion of electricity as a transmitter
of nervous acti\ity kept cropping up at about this
time. Alexander Monro (65), Professor of Medicine
and Anatomy in the University of Edinburgh, a
pupil of Boerhaave and first of the great dynasty of
Monros, pointed out that no cavities could be seen in
nerves, that no drops of fluid came out when a nerve
was cut, and that the nerve did not swell when ligated;
and he rather cautiously skirted the possibility of
electricity being the agent. But he too considered it
only in terms of electricity running down a wire and,
like Haller, was bothered that the nerve was inade-
quately insulated to prevent loss. "We are not suffi-
ciently acquainted," he said, "with the properties of
aether or electrical effluvia pervading everything, to
apply them justly in the aniitial oeconomy; and it is
difficult to conceive how they should be retained or
conducted in a long nervous cord."
Electricity had also been suggested by Stephen
Hales (66) in refuting a suggestion that the swelling
of muscles was due to inflow of blood. This country
clergyman, without formal scientific or medical train-
ing, by his experimental skill and keen observation
became one of the outstanding contributors to knowl-
edge of the circulation. In writing of the nerves he
said, "From this very small Force of the arterial Blood
65. Monro, .-Xlexander (1697-1762). The works of Alexander
Monro (collected by his son). Edinburgh: Charles Eliot,
1781.
66. Hales, Stephen (1677-1761). Statical Essays. London:
Innys and Manby, vol. I, 1726; vol. II, 1732.
THE HISTORICAL DEVELOPMENT OF NEUROPHVSIOLOG V I 5
^f^'l
FIG. 9. Thf Abbe Nollt-t and some of his experiments in which he electrified plants and animals.
The portrait, which shows the Abbe in his study at La Mouette, is from the oil painting by Jacques
de Lajoue that hangs in the Musee Carnavalet in Paris and is reproduced by kind permission of the
Conservateur, M. Charageat. The illustration on the right is from Nollet's book, Recherches sur les
Causes Particuliers des Phenomhies Electnques. Paris, I 749.
among the muscular Fibres we may with good reason
conclude, how short this Force is of producing so
great an Effect, as that of muscular Motion, which
wonderful and hitherto inexplicable Mystery of Na-
ture, must therefore be owing to some more vigorous
and active Energy, whose Force is regulated by the
Nerves; but whether it he confined in Canals within
the Nerves, or acts along their surfaces like electrical
Powers, is not easy to determine."
At the end of the century came Galvani. His
famous Commentary, published first in 1791, appeared
at a time of intense interest in electricity. The demon-
stration by Stephen Gray (67) in England that the
human body could be electrified had been taken up
and popularized by the Abbe Nollet (68) at the
French Court and by Hausen (69), the Professor of
Mathematics in Leipzig. Each had copied Gray's ex-
periment in which he suspended a boy by ropes from
the ceiling, bringing a flint-glass tube that had been
charged by friction close to his feet and watching the
attraction of a leaf-brass electroscope to his nose (see
fig. 10).
Electroscopes of this primitixe type were the only
instruments then available for the detection of elec-
tricity, the most sensitive one being that developed by
the curate of a rural parish in Derbyshire (70). This
delicate instrument with its gold leaves was identified
by his name as Bennet's electrometer, though it was
.scarcely a metrical device. Sources of electricity were
still the frictional machines, first globes of sulphur,
gla.ss or porcelain, and later revoking discs. It was
67. Gray, Stephen (?-i736). Experiments concerning elec-
tricity. Phil. Trans. 37: 18, 1731.
68 Noi,i.ET, Jean-Antoine (1700-1770). Essai sur I'electricile
des corps. Paris: Guerin, 1746.
69. Hausen, Christian August (1693-1743). Novi projeclus in
historia electricitatis. Leipzig, I743'
70. Bennet, Abraham (1750- 1799). .New Experiments on Elec-
tricity. Derby : John Drewry, I 789.
1 6 HANDBOOK OF PHYSIOLOGY -^ NEUROPHYSIOLOGY I
FIG. lo. The experiment of electrifying a boy, from the French translation of the book by F. H.
VVinckler (Professor of Greek and Latin at Leipzig) entitled, Essai sur la Nature. Les ejjets el les causes
avec description de deux nouvelles machines a Eleclricite. Paris: Jorry, 1748. (Photographed from the
copy in the Wheatland collection by kind permission of Mr. David Wheatland.)
vw,. I I. \ an Mnsschciiljroek and a Leyden jar. The portrait
is from the oil painting by J. M. Quinkhard which hangs in the
Museum of the History of Science in Leiden. The jar is an
early one, rather large in size, also from the same museum,
by the courtesy of which these photographs are reproduced.
not until the development of the Leyden jar by Petrus
van Musschenbroek, Professor of Physics in Leiden,
that physiologists gained a much more stable and
powerful source of electricity.
van Musschenbroek, striving to conserve elec-
tricity in a conductor and to delay the loss of its
charge in air, attempted to use water as the con-
ductor, insulating it from air in a nonconducting glass
jar. However, when he charged the water through a
wire leading from an electrical machine, he found the
electricity dissipated as quickly as e\er. His assistant,
Andreas Cuneus, while holding a jar containing
charged water, accidentally touched the inserted wire
with his other hand and got a frightening shock. W'ith
one hand he had formed one 'plate,' the charged
water being the other, and the glass jar the inter-
\ening dielectric. A condenser was born. On touching
the wire with his other hand he had shorted this
condenser through his body giving himself such a
jolt that he thought "his end had come" Q]i). van
Musschenbroek wrote to Reamur describing a similar
experience. Storage of electricity had now become
pos.sible and in fact had been achieved independently
by almost the same means (an electrified nail dipping
into a vial containing liquid) by von Kleist (72) of
71. Quoted in J. -A. Nollet. Metnoire de l' Academic Royale de
Sciences. Paris, 1746, p. 1-25.
72. VON Kleist, Ewald Juroen (d. 1748). Letter to J. G.
Kriigcr, quoted in Geschichte der Erde Halle 1746, p. 177;
and letter to Winkler (J. H. Winkler. Die Eigenschaften
der electrischen Materie und des electrischen Feuers. Leipzig,
■ 745)-
THE HISTORICAL DEVELOPMENT OF NEUROPHYSIOLOGY
Kamin in Pomerania, yet another of the indefatigable
company of eighteenth century clergymen to whom
science owes so much.
Both the electroscope and the Lcsclen jar were
used by Galvani in the experiments he had begun
not later than 1 780. He was also familiar with the
fact that some animal forms, notably the marine tor-
pedo and the electric eel, had intrinsic electricity.
Scientific studies of this type of animal electricity
had begun with the work of John Walsh (73) in 1733
and have continued to this day. In those days the
production of a spark was considered a sine qua non
for full acceptance of the electrical nature of a
phenomenon; this was lacking for the fish until after
Gahani's time when Matteucci developed a tech-
nique for demonstrating it (see fig. 12). For many
years before Galvani's day, as demonstrated for
example by Swammerdam and by the French anato-
mist Joseph Guichard Duverney,^^ it had been known
that the limbs of a frog could be convulsed by me-
chanical irritation, and electricity applied directly to
the muscle already had been used by many phy.sicians
(and quacks) to animate paralytics.
The three chief observations that stand out from
the many experiments reported by Galvani in his
original Commentarius (74) were a) that a frog's nerve
muscle preparation, although at a distance from a
sparking electrostatic machine, would twitch when
touched by an observer (in the light of later knowledge
this was called induction at a distance, with stimula-
tion occurring by the 'returning stroke' at the moment
of sparking); *) that atmospheric electricity could be
used to stimulate frogs' legs if a long wire were erected
(the principle of the lightning conductor); and c) that
frogs' legs twitched when hung by brass hooks to an
iron railing even in the absence of a thunderstorm.
This last, the most important discovery in his first set
of experiments, was due to the current that flows be-
tween dissimilar metals when connected in a circuit,
though Galvani did not understand this at the time
and attempted to explain all his results as the presence
of intrinsic animal electricity.
The Commentartus was reprinted three times, twice
in 1 791 and again in the turimlent year i 792 (the year
that France seized Savoy); then it reached scientists
73. Walsh, John (1725-1795). On the electric property of
the torpedo. Phil. Trans. 63: 461, 1773.
74. Galvani, A. (1737- 1798). De viribus electricitatis in
motu musculari. Comment ar his De Bononiensi Scientiarum el
Artium Insliluto alque Academic Commenlarii 7: 363, 1 791;
English translation of 2nd reprinting of Galvani's Com-
mentary by M. G. Foley. In: Galvani: Effects of Electricity
on Muscular Motion. Norwalk: Burndy Library, 1954.
FIG. 12. Galvani and the experiment on muscle contraction
in the absence of any metals. The portrait is from the contem-
porary oil painting in the Library of the University of Bologna
(reproduced by courtesy of Dr. G. Pupilli). The experiment
in which one leg is being stimulated by touching the nerves
from the severed spinal column is reproduced from Aldini's
book, Essai sur Ic Galvanisme. Paris: Piranesi, 1804.
outside Italy. Through the great controversy stirred
up by Volta which continued after Galvani's death in
1798 (Galvani's less prudent nephew Aldini cham-
pioning his cause), two extremely important areas of
knowledge developed from the original observations.
One was the recognition and elucidation of the
electrical properties of mu.scle and ner\'e which were
to lead directly to the discovery (by du Bois-Reymond
in the next century) of the action potential of nerve,
and the other was the developinent (by Volta) of bi-
metallic electricity into the electric battery, one of
the major technological steps in the history of science.
Volta had striven to explain all the frog experiments
by bimetallic currents, insisting that to produce elec-
tricity three substances were always necessary, two
heterogeneous metals and a third conducting material
" This, one of the early public demonstrations of the stimula-
tion of muscle through irritation of its nerve, was made before
the Academic Royalc de Sciences in Paris in 1700, and is
reported for that year as follows: "M. Du Verney shewed a frog
just dead, which in taking the nerves of the belly of this animal
which go to the thighs and legs, and irritating them a little
with a scalpel, trembled and suffered a sort of convulsion.
Afterwards he cut these nerves in the belly, and holding them
a little stretched with his hand, he made them do so again by
the same motion of the scalpel. If the frog has been longer dead
this would not have happened, in all probability there yet
remained some liquor in these nerves, the undulation of which
caused the trembling of the parts where they corresponded,
and consequently the nerves are only pipes, the effect whereof
depends upon the liquor which they contain." History and
Memoirs of the Roy. Acad. Sci. Paris. Translated and abridged by
John Martyn and Ephraim Chambers. London: Knapton,
1742, p. 187.
i8
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
FIG. 13. Volta and the experiment cf Galvani that led to the development of the Voltaic pile.
The engraving of Volta is from the drawing by Roberto Focasi. Volta was an admirer of and was
honored by Napoleon, one of whose gestures he seems to have caught. Behind him is a Voltaic pile.
The sketch at the right was composed by an artist from a drawing made by du Bois-Rcymond when
he visited Galvani's house 54 years after the latter's death. It depicts the experiment (designed to
test atmospheric electricity) in which Galvani stumbled on the phenomenon of bimetallic electricity.
(From Reden von Emit du Bois-Reymond, 1887, vol. 2.)
to complete the circuit. If thi.s third material were a
frog's muscle, it would by \irtue of its irritability react
to the flow of bimetallic electricity, but its role (ac-
cording to Volta) was solely that of an electroscope
(75). When Aldini (76) demonstrated by dipping
ends of nerve and muscle in mercury that the same
effect could be obtained with a single metal, Volta
replied that the .surface in contact with the air
suffered a change that made it heterogeneous with
the depth. This tortuous argument was disproved by
von Humboldt (77).
Before Galvani's death an anonymous (78) tract
was published, almost certainly with his collaboration,
in which an experiment was described on the twitch-
ing of muscles in the absence of any metals or external
75. Volta, Alessandro (1745-1827). On electricity e.xcited
by the mere contact of conducting substances of different
kinds. Phil. Trans, go: 403, 1800.
76. Aldini, Giovanni (1762- 1834). De animali Electricitate
dissertationes dime. Bologna, 1794.
77. VON Humboldt, Frederick Alexander (1769-1859). Ver-
suche iiber die gereizle Muskel- und .Nervenjasser. Posen und
Berlin, 1797.
78. Anonymous. Dell'uso e dell' attivita dell'Arco condultore nelle
contrazioni del muscoli. With Supplemento. Bologna: S.
Tommaso Aquino, 1 794; part of the Supplemento has
been translated into English by M. Tschou in: B. Dibner.
Galvani-Volta. Nor walk: Burndy Library, 1952.
source of electricity. A contraction was demonstrated
when the cut end of a frog's spine fell over onto its
muscle or when one limb was drawn up to touch the
exposed sciatic nerve (see fig. 12). In this case the
source of electricity was what we now recognize as
the current of injury. Even after this demonstration
(79) Volta tried to explain the current flow as the re-
sult of heterogeneity of tissues (muscle and nerve).
The design of Humboldt's experiments and the
clarity of his reasoning are a pleasure to study in
the welter of acrimonious controversy that greeted
GaKani's findings. Without bias towards either
protagonist Humboldt repeated their experiments,
examined their interpretations, designed new experi-
ments to test their hypotheses and came to the con-
clusion that Galvani uncovered two genuine phe-
nomena (bimetallic electricity and intrin.sic animal
electricity) and that the.se were not mutually exclu-
sive. Humboldt demonstrated that both great scientists
erred in their interpretations of their experiments;
however, from these were to grow the science of
electrophysiology on the one hand and, on the other,
the brilliant development of the electric battery. Not
only does Humboldt expose the erroneous parts of
Galvani's and of Volta's interpretations but also
79. Volta, .\. Phil. Mag. 4: 163, 1799.
THE HISTORICAL DEVELOPMENT OF NEUROPHYSIOLOGY
those of the writers who rushed in so precipitately to
take up arms for one or the other protagonist — Pfaff
(80), Fowler (81), Valli (82), Schmuck (83), each re-
ceived his rebuke. He tells us that he thought some
of the problems out while sitting at the foot of Mt.
Bernard reading de Saussures' Voyages dans les Alpes
(84). Humboldt was a great traveller (especially at a
period when he was an inspector of mines) but did
not let this interfere with his experiments, for he took
his apparatus along with him, even on horseback.
The pursuit of research in animal electricity was
carried on in many countries, the most valuable contri-
butions coming first from the Italian .scientists. Their
task was made easier for them by Oersted's discovery
of electromagnetism and its de\elopment by Nobili
into a useful form of galvanometer. Oddly enough
Oersted's researches (85, 86) that led to his important
experimental demonstration of the relationship be-
tween electricity and magnetism were motivated by a
metaphy.sical belief in the universality of nature, a
faith inspired by his adherence to Natiirphilosophie.
This romantic doctrine with its facade of facts was
very powerful in Germany from about 1810 to 1840
and was derived from Kant's rejection of empiricism
and his philosophy of universal laws known a priori
by intuition. Oersted's own a priori belief was so
strong that he did not hesitate to make his first experi-
mental test of it in the classroom during a lecture to
advanced students at the University of Copenhagen.
The experiment worked; when current flowed in a
single loop of bent wire, a magnet below it moved. This
great discovery led to the development of instruments
with multiple windings and to moving coil galvanom-
eters. The contribution of Nobili, Professor of Physics
80. Pfaff, Chrktophe-Henri (1773-1858). ,\bhandlung
liber die sogennante thierische Electrizitat. Gren's J.
Physik. 8(2): 196, 1798.
81. Fowler, Richard. Experiments and observations relative to
the influence lately discovered by M. Galvani, and (oninionly
called Animal Electricity. Edinburgh: Duncan, 1793.
82. Valli, Eusebe (1755-1816). Experiments in Animal Elec-
tricity. London: Johnson, 1793-
83. ScHMiJCK, Edmund Joseph. Beitrdge zur neuern Krnntniss
der thierische Elektricitdt. Mannheim, 1792.
84. DE Saussures, H. B. Voyages dans les Alpes. Neuchatel, 1796.
85. Oersted, Hans Christian Ci777^i850- Experiences sur
un effet que le courant de la pile e.xcite dans I'aiguille
aimantee. J. Phys. Chim. 91: 72, 1820: English translation
in Ann. Phil. 16: 273, 1820. The earliest announcement of
Oersted's discovery was in a four-page pamphlet (now
rare) entitled Experimenta circa efectum conflictus electrici
in acum magneticum. Copenhagen, 1820 (copy in the
Wheeler collection, New York).
86. Oersted, H. C. Galvanic magnetism. Phil. .\iag. 56: 394,
1820.
FIG. 14. Matteucci and two of his experimental procedures.
The portrait is reproduced from the old yellowing photograph
in the Schola Normale .Superiore in Pisa (by courtesy of Dr. G.
Moruzzi). .-Xbove on the right is Malteucci"s illustration of his
rheoscopic frog, and below is his experiment demonstrating
that the discharge of a marine torpedo can make a spark cross
a gap.
and Natural History at Florence, was the astatic
galvanometer (87) in which two coils of wire wound in
opposite directions cancelled the effect of the earth's
own magnetism.
It was Matteucci, the Professor of Physics at Pisa,
who laid the groundwork of muscle electrophysiology
that was to be developed so exhaustively by du Bois-
Reymond. Carlo Matteucci (88) was one of the
prominent figures in the Risorgimento. A great liberal
and a great patriot, he attempted to coordinate the
efforts of all European liberals when the 1 848 revolu-
tion broke out. When Italy was united in 1859, he
was made a Senator. He was one of the early Min-
isters for Public Instruction in Italy. His contribu-
tions have never received adequate recognition, mainly
owing to the acrimonious attacks made on his work
by du Bois-Reymond who came near to diminishing
his own stature by his sour polemics. Matteucci had
rai.sed the question as to where in the nerve-muscle
87. Nobili, C. Leopold (1784-1835). Uber einen neuen
Galvanometer. J. Chem. u. Phys. 45: 249, 1825.
88. Matteucci, Carlo (1811-1865). Leqons sur les Phe-
nomenes Physiques des Corps Vivanls, translated by Clet.
Paris: Masson, 1847; English translation by Jonathan
Periera. Lectures on the physical phenomena of living beings.
Philadelphia: Lea and Blanchard, 1848.
20
HANDBOOK OF PPn'SIOI.OGV
NEUROPHYSIOLOGY I
FIG. 15. Johannes Miiller and his famous pupil von Hehn-
holtz. The deHcate chalk drawing of Miiller was at one time
in the Surgeon General's Library (now the National Library
of Medicine). The picture of von Helmholtz shows him as a
young man in the period when he made his major contribu-
tions to the physiology of peripheral nerve.
preparation the electricity lay and had thought that
muscle alone could produce it. The preparation
used by Matteucci was a frog's leg complete be-
low the knee with only the isolated nerve abo\e
it. Galvani's frogs retained a piece of the vertebral
column with the insertion of the nerve into its
portion of the spinal cord. Matteucci's contribu-
tions in brief were a) the galvanometric detection of
a current flow between the cut surface of a muscle
and its undamaged surface, demonstrated in Ijoth
animal and man (89, 90); h) the multiplication of
current by serial arrangement of cut muscles so that
the transverse section of each touched the longitudinal
section of the next; c) the decrease in this current dur-
ing tetanus caused by strychnine (90) (the germ of the
89. Matteucci, C. Sur le courant electrique de la grenouille.
Ann. chim. et phys. 68: 93, 1838.
90. M.\TTEUcci, C. Deu.Kieme memoire sur le courant elec-
trique propre de la grenouille et des animau.x a sang
chaud. Ann. chim et phys. 80: 301, 1842.
" ". . . while each organ of sense is provided with a capacity
of receiving certain changes to be played upon it, as it were,
yet each is utterly incapable of receiving the impression
destined for another organ of sensation." Quoted from Bell,
Charles (1774-1842). Idea of a new anatomy of the brain, submitted
for the observation of his friends. Privately printed, 1811.
""It is more probable that every nerve so affected as to
communicate sensation, in whatever psirt of the nerve the
impression is made, always gives the same sensation as if
affected at the common seat of the sensation of that particular
nerve. ..." Quoted in The Works of John Hunter edited by J. F.
Palmer. London; Longmans, 1835. 4 vol.
discovery of the action current); and d) the aljility
of a frog's mu.scle contraction to generate enough
electricity to stimulate the nerve of another nerve-
muscle preparation when laid across it (the rheo-
scopic frog) (91, 92). Matteucci was inconsistent in
his interpretation of this finding and showed his
characteristic vacillation between an explanation in
terms of electricity and one based on nervous force.
He named the effect the 'secondary contraction.'
Matteucci (93) also noted such important laijoratory
phenomena as the difference in stimulating effect of
make' and 'break' shock.s, and the polarizing effects
of prolonged flow of current on electrodes. He noted
that polarization could occur inside the muscle and
thus laid the ground for all the work that was to
follow on polarization and electrotonus.
du Bois-Reymond, of French name and Swiss
descent, lived all of his working life in Berlin. He was
a pupil of the greatest physiologist of the time,
Johannes Miiller. Miiller, professor first at Bonn and
then at Berlin, was a gifted teacher who could count
among his pupils von Helmholtz, von Briicke and
Sechenov. His Handbuch der Physiologie (94) was the
great textbook of the nineteenth century, and the
journal he founded, Mtiller's Archives fiir Analomie und
Physiologie, as a successor to Reil's first physiological
journal, was the main outlet for the stream of research
that was coming from the German schools at that time.
His own interests lay mostly in sensory physiology
where his name is always associated with the "Law of
.Specific Nerve Energies,' although this concept in
fragmentary form had certainly occurred to others
before him, including notably Charles Bell''- and John
Hunter.'-' By this law Miiller formulated the findings
that wherever along its course a sensory ner\e was
stimulated, the resultant sensation was that appropri-
ate to the sense organ it served. On the issue of elec-
tricity in nerve, Miiller took the position that it was
indeed an artificial excitant but had no part in natural
excitation. He reached this conclusion largely from an
experiment in which he mashed the nerve and demon-
9 1 . Matteucci, C. Sur une phenomene physiologique produite
par les muscles en contraction. Compt. rend. Acad, sc,
Paris 4: 797, 1842.
92. Matteucci, C. and F. H. A. Humboldt. Sur le courant
electrique des muscles des animaux vivants ou recemment
tues. Compt. rend. Acad, sc, Paris 16: 197, 1843.
93. M.\TTEUCCi, C. Compt. rend. Acad, sc, Paris 52: 231, 1861 ;
53: 503, 1861; 56: 760, 1863; 65: 131, 1867.
94. MiJLLER, Johannes (1801-1858). Handbuch der Physiologic
des Menschen. Coblentz: Holscher, vol. I, 1833; vol. II,
1840; English translation by William Baly. vol. I, 1838;
vol. II, [842.
THE HISTORICAL DEVELOPMENT OF NEUROPHYSIOLOGY
strated that, although electricity passed through the
damaged zone, mechanical stimulation of the nerve
above the injury provoked no twitch.
During the era of intense concentration on electro-
physiology in the Italian and German schools, labora-
tories in other countries were developing a different
approach. Among these was that of Claude Bernard
(95), pupil of Magendie. Claude Bernard made use of
curare as a blocking agent, interpreted by him as a
nerve poison that spared the muscle. He found that
in a curarized preparation the muscle would not
twitch if he stimulated it directly and hence concluded
that normally transmission could not be electrical
either. In these experiments he used the ingenious
little stimulator built from a Voltaic pile of alternate
copper and zinc plates that is shown in figure 16.
He did not recognize that his failure to evoke a con-
traction by direct stimulation of the muscle was due
to his 'pile' giving too feeble a current.
Miiller was the last of the great physiologists to
retain a trace of vitalism in his thinking. This he
probably owed to his exposure as a student at Bonn
to Natiirphilosophie and the influence of its leader,
Schelling (96). Although more extensively indoc-
trinated in this sterile philosophy than Oersted had
been, Miiller was later able to free himself more ea,sily
from its stultifying effects, and he eagerly encouraged
the physical and chemical approaches to biological
experiment. Not a trace of vitalism is found in his
pupils.
Towards the half-century a marked swing away
from the metaphysics of Natiirphilosophie char-
acterized neurophysiology, du Bois-Rcymond con-
sidered himself (and with some right) to be the
champion of this movement which strove to explain
all physiology on chemical and physical grounds.
And in fact, as we have .seen, it was the physicists of
the period who were contributing most of the new
experiments and concepts of muscle and peripheral
nerve action. Before this, neurophvsiologists had
reached a stage in their work in which progress was
hampered by lack of sufficiently sensitive instruments.
The physicists came to their help and indeed were
themselves intrigued by the types of physical phe-
nomena that biological preparations provided.
In 1841 du Bois-Reymond received from his
95. Bernard, Claude (1813-1878). Lf(,ons sur la phynoloiie
el la pathologie du systeme nerveux. Paris: Bailli^re, 1B58. 2 vol.
96. Schelling, Frederick Wilhelm Joseph (i 775-1854).
Sammiliche Werke. .Stuttgart and Augsburg, 1856-1861,
14 vol.; English translation of vol. Ill by T. Davidson.
In J. Specula! . Philos. I: 193. 1867.
%
\ I
FIG. 16. Claude Bernard at the age of 53, and the ingenious
stimulators he used in his electrophysiological studies of nerve.
They were miniature voltaic piles built up of alternate discs of
copper and zinc. Just before use they were moistened with
vinegar. Such dc\ices were made obsolete by the du Bois-
Reymond induction coil and it is rather surprising to find
Bernard still advocating them in his day. Although adequate
for nerve stimulation, they gave too feeble a current to stimulate
a muscle directly; from this Bernard concluded that the nervous
effect on muscle could not be electrical.
master a copy of Matteucci's book Essai sur les
Phenomenes Electriques des Animaux (97), together with
the suggestion that he repeat and extend Matteucci's
experiments. By November of that year he had al-
ready completed a preliminary note C98), but his
major work, the Thierische Elektricitdt C99)j did not
appear until 1848. The first part of this long and de-
tailed book, unlike its later sections, shows little
originality in scientific ideas, the author with a chip
on his shoulder being carried along in the wake of
Matteucci of whose publications he was outspokenly
critical. However, where du Bois-Reymond shines,
and what makes his book a classic, is his skill in in-
struinentation, far surpassing that of Matteucci, so
that he was able to extend and improve on these
earlier observations. Moreover, not being hampered
(as Matteucci was) by residual traces of a belief in
97. Matteucci, C. Essai sur les Phenomenes electriques des
Animaux. Paris; Czirilian-Goeury and Dalmont, 1840.
98. DU Bois-Revmond, Emil (18 18-1896). Vorlaufiger Abriss,
einer Untersuchung iiber den elektromotorischen Fische.
Ann. Physik. Chem. 58: i, 1843.
99. DU Bois-Revmond, E. Uniersuchungen iiber thierische Elek-
tricitdt. Berlin: Reimer, vol. I, 1848; vol. II, 1849.
22
HANDBOOK OF PHYSIOLOGY ^ NEUROPHYSIOLOGY I
FIG. 17. du Bois-Reymond and one of the schemata he postu-
lated for transmission at the end plate.
'nerve force,' he brought clearer inductive rea.soning
to the interpretation of his obser\'ations.
du Bois-Reymond confirmed Matteucci's demon-
stration that not only nerve-muscle preparations but
muscles themselves could produce electricity and,
with .soine acerbity, claimed priority for naming this
the 'muscular current' (Muskelstrom). Both Mat-
teucci and du Bois-Reymond distinguished muscular
current from the frog current' (la correnta propria
della rana), so named by Nobili to describe the current
flow between the feet of the prepared frog and any
other part of the animal. Neither Noijili (100) nor
Matteucci, nor even du Bois-Reymond at this time,
recognized that the so-called frog current was an
injury current consequent to their having trans-
sected their frogs. Nobili had thought it was a thermo-
electric effect due to differential cooling times of
nerve and muscle.
du Bois-Reymond, using faradic stimulation, also
confirmed Matteucci's finding that the muscle current
was reduced during tetanic stimulation and named
this the negative variation. It is what is now called
the action current of muscle, du Bois-Reymond went
on to demonstrate the same negative variation in
nerve during activity and thus discovered the action
current of nerve which Matteucci had failed to find
with his less sensitive instruments, du Bois-Reymond
made the following claim, "If I do not greatly de-
ceive myself, I have succeeded in realizing in full ac-
tuality (albeit under a slightly different aspect) the
hundred years' dream of physicists and physiologists,
to wit, the identity of the nervous principle with
electricity." His great contemporary Carl Ludwig
(loi) was unwilling to accept this for, thinking still
in terms of the nerve as a telegraph wire, he held
100. Nobili, L. Ann. chiin. el phys. 38: 225, 1828; 44: 60, 1830.
(among other objections) that its resistance was too
great and its insulation too poor for it to be a good
conductor.
Pfliiger (102) tried to o\ercomc some of these
difficulties by his 'liberation hypothesis.' In this he
stated that nervous transmission was "not a simple
advancing undulation in which the sum of the living
forces is not increased" but a situation in which "new
tension forces are set free by the living forces of the
stimulus and become in turn living forces with each
onward step." In spite of the obscurity of the termi-
nology (this is Morgan's translation), one can detect a
foreshadowing of the ideas held by today's physi-
ologists.
du Bois-Reymond elaborated a theory that all un-
damaged muscle had a resting potential between the
middle (positive) and the tendons (negative) and
that during activity this decreased, thus giving the
'negative variation.' He was still not clear on the
role of injury currents for he thought injury merely
intensified the resting potentials. On this point he
entered into acrimonious dispute with his pupil Her-
mann who was equally stubborn in insisting that
there were no resting potentials in the absence of in-
jury and that all current flow in muscle and nerve
was due to damage (103). Hermann therefore intro-
duced the term 'demarcation currents' to describe
them. Later experimentation has shown both men to
have been partially right and partially wrong.
du Bois-Reymond's conception of regularly oriented
'electromotive particles' arranged along the surface
of muscle and of nerve was the forerunner of the
schemata of polarization that were to be developed
more fully and more accurately by his pupil Berns-
stein (104) and that lie at the core of modern theory.
The critical issue as to whether the negative variation
in nerve potential was identical with the excitatory
process (i.e. the nerve impulse) was taken up by
Bernstein who set out, at du Bois-Reymond's sugges-
tion, to compare their velocities, von Helmholtz, one
of the same brilliant group schooled in Miiller's
famous laboratory, had in a triumph over primitive
apparatus succeeded in measuring the velocity of
101. Ludwig, C.-^rl (1816-1895). Uber die Ki-afte der Ner-
venprimitivenrohr. Wien. med. Wchnschr. 46: 47, 1861.
102. Pfluger, E. (1829-1910). Vnter suchungen iiber die Physi-
ologie des Eleclrolonus. Berlin: Hirschwald, 1859.
103. Hermann, Ludim.\r (i 838-1 91 4). W'eitere Untcrsungen
iiber die Ursache der electro-motorischen Erscheinungen
an Muskeln und Nerven. Arch. ges. Physiol. 3:15, 1870.
104. Bernstein, Julius (1839-1 9 17). Untersuchungen iiber den
Erregungsvorgang im Nerien- und Muskelsysleme. Heidelberg :
Winter, 1871.
THE HISTORICAL DEVELOPMENT OF NEUROPHVSIOLOGV
23
the excitatory processes (105) in the frog. In his
success he had proved his old teacher wrong. In 1844
Miiller had said, "The time in which a sensation
passes from the exterior of the brain and spinal cord
and thence back to the muscle so as to produce a con-
traction, is infinitely small and immeasurable." von
Helmholtz's technique was as follows: the moment of
nerve stimulation, by the break shock of an induction
coil, was signalled by the closing of the primary cir-
cuit. The resultant muscle contraction lifted a contact
in the same circuit, thus breaking it. The break sig-
nalled the arrival of the nerve impulse in the muscle.
By timing this inter\al, with stimulation at measured
distances along the nerve, von Helmholtz was able
to calculate its conduction velocity. This simplified
description masks the extreme ingenuity of the original
experiment. In technique von Helmholtz had coine
a long way from Haller's attempt to discover the
velocity of nervous action. Haller had read parts of
The Aeneid a\oud, timing himself, counting the syllables
and calculating the length of the nervous paths used
in reading and speaking. In some way that is not
entirely clear, he arrived at a figure of 50 m per sec.
The conduction rate found by Bernstein (approxi-
mately 29 m per sec.) tallied sufficiently well with
von Helmholtz's final results, 27 to 30 m per sec, for
him to be satisfied with the inferred identity of the
impulse and the negative variation. Bernstein's experi-
ments, using for stimulation a rheotome devised by
himself with a galvanometer for detection of response,
enabled him to plot the time course of what we now
call the nerve's action potential and to determine its
latency, rise-time and decay. One of the pregnant ob-
servations he made was that the negative variation
caused a deflection of his galvanometer that some-
times crossed the base line, thus exceeding the value
for the resting nerve potential. In today's terminology,
he found the overshoot of the action potential beyond
the resting potential level.
Bernstein (106) became widely known for his
theory that the membrane of the inactive fiber of
nerve or muscle was normally polarized, having po.si-
tive ions on the outside and negative ions on the in-
side, and that the action potential was a self-propa-
gating depolarization of this membrane. This was
105. VON Helmholtz, H. (1821-1894). Messungen iiber den
zcitlichen Verlauf der Zuchung animalischer Muskein
und die Fortpflanzungsgeschwindigkeit der Reizung in
den Nerven. Arch. Anat. Physiol. 111, 1850.
106. Bernstein, J. Uber den zeitlichen Verlauf der negativen
Schwankung des Nervenstroms. Arch. ges. Physiol, i : 1 73,
1868.
based on his assumption that the membrane is se-
lectivelv permeable to potassium ions. His explana-
tion of injury currents was that they were the result
of a break in the membrane.
In the later nineteenth century, after a long hiatus,
phvsiology in England was again coming into its own.
At the half-century, which saw such brilliance in the
German schools, there was virtually no physiological
work in progress in England. There were no physi-
ological laboratories and there was no systematic
physiological research. A dual chair in anatomy and
physiology had i:)een created in 1836 at University
College, London, and had been given to the anatomist
William Sharpey. Such teaching as he gave in physi-
ology was from books and his pupils saw no experi-
ments, yet from among them came the leader of one
of the more famous English schools of physiology,
Michael Foster (1836-1907), founder of the Cam-
bridge School. Though not himself a neurophysi-
ologist, Foster could count among his pupils some to
become later among the most brilliant in the field,
Sherrington (1857-1952), Gaskell (1B47-1914), Lang-
ley (1852-1925) and, as descendents from the last,
Keith Lucas and in turn Adrian.
This, the late nineteenth century, was an age of
great progress in the development of instrumentation
and, with their improved tools, physiologists were able
to make more accurate observations of stimulus
strength, response characteristics and time relation-
ships than had their predecessors. In 1871 Bowditch
(107) demonstrated that heart muscle did not respond
with graded contractions to graded stimuli. He as-
sumed that the global response he observed was due
to a leakage of excitation throughout the fiber popu-
lation of cardiac muscle. It was in fact the experi-
mental evidence for what was later to be called the
'all-or-nothing law.' Bowditch, an American, did
these experiments in Ludwig's laboratory in Leipzig
where he worked on the problem with Kronecker, the
teacher of Harvey Cushing. On his return to Harvard,
Bowditch founded the first laboratory for physiological
research in the United States.
Forgotten by Bowditch, or unread, were the writ-
ings of Fontana in the eighteenth century in which,
in discussing heart muscle, he said, "... the irritability
of the fibre can be activated by a small cause, and by
a feeble impression : but once activated, it has a
power proportional to its own forces, which can be
107. Bowditch, H. P. (1840-191 1). Uber die Eigenthumlich-
keiten der Reizbarkeit welche die Muskelfasern des
Herzens zeigen. Bcr. Konigl. Sachs. Gesellsch. Wiss. 23:
652, 1 87 1.
24
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
much greater than those of the exciting cause. . . ."'^
Fontana (loS) went on to a recognition of the re-
fractory period (a term introduced by Marey) in
heart muscle which he explained as an exhaustion
of irritability resulting from the contraction.
That skeletal muscle might share this property
was also foreshadowed by Fontana but did not receive
experimental proof until the work of Fick (109), an-
other pupil of Ludwig's, although the finding was
not further developed until the ingenious experi-
ments of Keith Lucas (no) at the beginning of this
century. In the meantime, an all-or-nothing property
in nerve had been detected by Gotch (m), the
predecessor of Sherrington in the Chair of Physiology
in Liverpool, a finding that was to reach definitive
form in the hands of Keith Lucas' pupil, Adrian (i 12,
113). That the law applied to sensory as well as to
motor nerves was established by Adrian & Forbes
(114) in 1922 (in a paper whose title replaced the
term 'all-or-none' by the more grammatical one
'all-or-nothing'). This line of work led on to investi-
gations of the refractory period of peripheral nerve
and the accurate plotting of the time course of after
potentials. The invention of the vacuum tube ampli-
fier and the cathode ray oscillo.scope opened the
modern era of electrophysiology, and with them the
foundations of today's techniques were laid by
Gasser & Erlanger (i 15).
One branch of peripheral nerve physiology remains
108. Fontana, Felice Caspar Ferdinand (1730-1805). De
Legibus Irritabilitatis. Lucca : Riccomini, 1 767.
109. Fick, Adolf (1829- 1901). Mechanische Arbeit und Wurme-
fntivicklung bei der Miiskelthritigkeit. Leipzig: Brockhaus,
1882.
1 10. Lucas, K. The "all-or-nonc" contraction of ampiiibian
skeletal muscle. J. Physiol. 38: 113, igog.
111. Gotch, Francis (i853-igi3). The sub-maximal electrical
response of nerve to a single stimulus. J. Phyuol. 28:
395. 1902-
112. Adrian, Edgar D. (i88g- ). On the conduction of
subnormal disturbances in normal nerve. J. Physiol. 43:
389, 1912.
113. Adrian, E. D. The "all-or-none" principle in nerve. J.
Physiol. 47: 460, 19 1 4.
114. .Adrian, E. D. and A. Forbes. All-or-nothing responses
in sensory nerve fibres. J. Physiol. 56: 301, 1922.
115. Gasser, Herbert S. (1888- ) and Joseph Erlanger
(1874- ). A study of the action currents of nerve
with a cathode ray oscillograph. Am. J. Physiol. 62: 496,
1922.
" Quoted from Hoff, H. E. The history of the refractory
period. Yale J. Biol. & Med. 14: 635, 1942.
to be outlined. This is the subject of neuromu.>;cular
transmission. Its history is short for, before the latter
half of the nineteenth century, continuity between
nerve and muscle was assumed, the neuron theory
had not been formulated and neuroneural synapsis
had not been conceived. The i 700-year-old hypothe-
sis of a nervous fluid implied humoral transmission in
structures having continuity and only at mid-nine-
teenth century, when this was finally abandoned, did
the possibility of junctional tissues become a live one.
In 1862 Willy Kiihne (116, 117), pupil of von
Briicke and later professor of physiology in Heidelberg,
published a memoir on the end organs of motor nerves.
Noting the histological differences between muscle
and its innervating ner\e, he suggested that action
currents of the nerve by invasion of the muscle
caused it to contract. That there was a delay at the
neuromuscular junction was noted in du Bois-Rey-
mond's laboratory and the master him.self considered
the possibility of a chemical influence (the agents he
mentioned were ammonia and lactic acid which
Leibig had demonstrated in muscle in 1847); he went
to great pains, however, to sketch electrical fields in
support of what was called the 'modified discharge
hypothesis' (as shown in fig. i 7).
The controversy surrounding the mode of trans-
mission at the motor end plate was carried into the
modern era and, at a time not yet history, essential
agreement was reached that transmission at the neuro-
muscular junction is chemical in nature. The major
contribution that settled the issue came from pharma-
cological experimentation of today's scientists, stem-
ming from the pioneer work of Elliott (118), Dale
(119) and Loewi (120) in the early part of the cen-
tury. Elliott, while a student at Cambridge, noticed
that smooth muscle responded to adrenin even when
deprived of its sympathetic nerves and this led him
116. KiJHNE, Willy (1837- 1900). Uber die periphniuheii
Endorgane der molorisehrn .Herven. Leipzig: Engelmann,
1862.
117. Kuhne, VV. On the oiigin and causation of vital move-
ment. Proc. Roy. Soc, London, ser. B 44: 427, 1888.
118. Elliott, Thomas Renton (1877- ). On the action
of adrenaline. J. Physiol. 32: 401, 1905.
119. Dale, Henry Hallett (1875- ). Transmission of
nervous effects of acetylcholine. Harvey Lectures 32: 229,
'937-
120. LoEVvi, Otto (1873- ). Uber humorale Ubertrag-
barkeit der Hcrtznervenwirkung. Arch. ges. Physinl. iBg-
23g, 1 92 1.
THE HISTORICAL DEVELOPMENT OF NEUROPHYSIOLOGY
to suggest that adrcnin "might then be the chemical
stimulant liberated on each occasion when the im-
pulse arrives at the periphery." Langley (121), who
was at that time professor of ph\ siology at Cambridge,
recognizing that in some smooth muscle the action
both of sympathetic nerve stimulation and of adrenin
was to produce contraction whereas in others the
result was a relaxation, postulated the existence of
two kinds of receptor substance — excitatory and in-
hibitory. That adrenin mimicked sympathetic action
was then accepted.
The possibility of a chemical mediator for the
vagal action on the heart was explored experi-
mentally in several centers. Bottazzi (122), Martin
(123) and Howell (124) thought the agent must be
potassium, Dixon (125) that it was muscarine, an
alkaloid closely related in structure to the cholines.
These substances had been shown to be active in sev-
eral puzzling ways. In 1906 Hunt & Taveau (126)
had demonstrated the extremely potent effect of
acetylcholine on arterial pressure, and by 1914 the
work of Dale (127) was already pointing so strongly to
acetylcholine being the drug involved in parasympa-
thetic action, that he described it as 'parasympatho-
mimetic' Direct experimental proof was lacking that
a chemical substance excreted as a result of nerve
stimulation would in fact activate a tissue in a similar
way, although the hypotheses both for epinephrine in
the sympathetic and acetvlcholine in the parasympa-
thetic system seemed highly plausible.
The direct proof came from the brilliant researches
of Otto Loewi (128) in which he demonstrated that
12!. Langley, John Newport (1852-1906). On the reaction
of cells and of nerve-endings to certain poisons, chiefly as
regards the reaction of striated muscles to nicotine and to
curare. J. Physiol. 33: 374, 1905.
Bottazzi, P. Arch. Physiol. 882, 1896.
Martin, E. G. The inhibitory influence of potassium
chloride on tlie heart, and the eff^ect of variations of
temperature upon this inhibition and upon vagus in-
hibition, .-im. J. Physiol. II : 370, 1904.
Howell, VV. H. Vagus inhibition of the heart in its re-
lation to the inorganic salts of the blood. Am. J. Physiol.
15: 280, 1906.
Dixon, W. E. On the mode of action of drugs. Med. Mag.
16:454, '907-
ijfi. Hunt, R. and R. de M. Taveau. On the physiological
action of certain cholin derivatives and new methods for
detecting cholin. Bril. A/. J. ■2: 1788, 1906.
127. Dale, H. H. The action of certain esters and ethers of
choline, and their relation to muscarine. J. Pharmacol.
& Exper. Therap. 6: 147, 1914.
128. Loewi, O. Uber humorale Ubertragbarkeit Herz-
nervenwirkung. .^rch. ges. Physiol. 189: 239, 192 1.
122
123
124.
125-
^^
FIG. 18. Lift: an early representation of spinal roots and
tracts as drawn by Domenico Mistichelli in his Traltalo dtU'.i/io-
plessia, 1 709 (from the copy in the Boston Medical Library by
courtesy of Dr. Henry Viets). Mistichelli is considered to be
one of the first workers to recognize the crossing of the pyra-
mids. Right: the crossing of the pyramids was described and
experimentally demonstrated on injury to the brain in dogs by
Pourfour du Petit, a pupil of Duverney. His drawings are from
his Lettres d'un medicin, 1 727. (From the copy in the Bibliotheque
Nationale. Reproduction by courtesy of Dr. Auguste Tournay.)
the fluid bathing a frog's heart which had been stimu-
lated through its vagus had an inhibitory action on
the beat of another heart. He named the agent
'Vagusstoffe.' From this cla.ssic observation, one of
the landmarks of physiology, experimentation spread
cut to the examination of other tissues, other nerves,
and other mediators and inhibitors, and forms one of
the wide fields of today's research. With the recogni-
tion of neuroneural synapses the problem of trans-
mission was carried from the peripheral neuromuscu-
lar svstem into the central nervous svstem.
SPINAL CORD AND REFLEX ACTIVITY
The functions of the spinal cord long remained an
enigma to the early physiologists. For as long as the
belief persisted that every nerve in the body required
its own canal leading directly from the brain in order
to insure its supply of animal spirits, the spinal cord
appeared to be merely a bundle of nerve fibers
grouped together. In other words, it was a prolonga-
tion of the peripheral nervous system channeling into
the brain.
26
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
The relationship of the spinal cord to peripheral
nerves and to the rest of the central nervous system
could hardlv be understood until the structure of the
neuron had been learned. The period that saw the
great development of knowledge of cell structure came
with the high-power microscopes of the nineteenth
century. Before then descriptions of the finer elements
necessarily lacked exactness, though in 1767 Fontana
had given a good account'^ of the axis cylinder, and
there seems little reason to doubt that the bodies
Alexander Monro (129) saw in the spinal cord in
1783 were the anterior horn cells. Nerve cells were
certainly seen by Dutrochet (130) in 1824 though we
do not find a very exact description of them before
1833, when Ehrenberg (131, 132) published his find-
ings on the spinal ganglia of the frog.
The visualization of axis cylinders on the one hand,
and of cell bodies on the other, still did not help the
physiologist very much in his search for understanding
of nervous connections. It was from the botanists that
the next lead came. The cell theory had a long history
among plant physiologists and its emphasis on the
role of the nucleus and the cellular matrix appealed
to microscopists who could see similar structures in
animal tissues. In 1837 Purkinje (133), working at
home for lack of a laboratory at the Universit>- of
Breslau where he was profes.sor, realized the .signifi-
cance of the ob.servations on plant tissues and sug-
gested that the cell theory might justifiably be ex-
129. Monro, .\lex.\nder (secundus) (1733-1817). Observa-
tions on the structure and Junctions of the nervous system.
Edinburgh: Creech, 1783.
130. Dutrochet, Rene Joachim Henri (i 776-1847). ^f-
ckerches anatomiques et physiolooiques sur la structure intime
des animaux et des vegetaux. Paris : Bailliere, 1 824.
131. Ehrenberg, C. G. Notwendigkeit einer feineren mecha-
nischen Zerlegung des Gehirns und der Nerven. Ann.
Physik. u. Chem. 104: 449, 1833.
132. Ehrenberg, C. G. Beobachtung einer unhekannten Structur
des Seelesorgans. BerHn, 1836.
133. Purkinje, Johann Evangelista (1787-1869). Uber die
gangliose Natur bestimmter Hirntheile. Ber. Versamml.
deutsch. Natmjorsch. Artze, Prague 1837, p. 175.
'^ "Le nerf est forme dun grand nombre de cylindres
transparents, homogenes, uniformes, tres-simples. Ces cylindres
paroissent formes, comme d'une parol, ou tunique tr& subtile,
uniforme, remplie, autant I'oeil peut enjuger, dune humeur
transparente, gelatineuse, insoluble dans I'eau. Chacun de ces
cylindres recoil une enveloppe en forme de gaine exterieure,
la quelle est composee d'un nombre immense de fils torteux."
Fontana. Traite sur le venin de la I'ipere. Florence, 1781.2 vol.
tended from botany to zoology. Two years later
Schwann (134) marshalled the facts and crystallized
the idea in his classic monograph.
For an understanding of function, knowledge of the
cell bodies was not enough. The nerve tracts were of
primary importance, and during this same period
histologists were finding that the medullated axon was
not the only kind of fiber. In 1838, in a little book that
was one of the last scientific texts to be published in
Latin, Remak (135) revealed the existence of non
medullated nerves. His work is illustrated by many
delicate drawings of cells from various parts of the
nervous system, mostly taken from ox and man. But
by 1865 phy.siologists knew that in addition to medul-
lated and nonmedullated nerves there were other
fibrous processes which Dieter's (136) work (published
posthumously) showed to be dendrites. In the saine
monograph there is a description of the glia. The cell
theory did not explain how all these fibrous structures
related to the cell body, and a student's thesis was one
of the early publications to take this step. In 1842
von Helmholtz (137), in the earliest of the many
brilliant contributions he made to physiology, estab-
lished the connection between peripheral nerve and
ganglia in invertebrates using the crab, von Helmholtz
was 2 1 years old when he wrote this inaugural thesis.
The next major advance came in 1850 from Waller
(138) with his demonstration that axons degenerate
when cut off from their cell bodies and his conclusion
that the latter were their source of nutriment. The
development by Marchi & Algeri (139) of the osmic
acid stain for degenerating myelin sheaths gave the
physiologist a technique for tracing the nerve tracts.
134. Schwann, Theodore (1810-1882). Mikroskopische Unter-
suchungen iiber die Ubereinstimmung in der Struktur und dem
Wachsthum der Thiere und Pflanzen. Berlin: Sander, 1839;
English translation by Sydenham Society, 1847.
135. Rem.\k, Robert (181 5-1 865). Observationes anatomicae el
microscopuae de systematis nervosi structura. Berlin: Reimer,
1838.
136. Dieters, Otto Friedrich Karl (1821-1863). Unter-
suchungen iiber Gehirn und Riickenmark des Menschen und der
Sdugetiere. Brunswick: Vieweg, 1863.
137. VON Helmholtz, H. De Fabrica systematis nervosi Everte-
bratorum (Inaugural Thesis). 1842.
138. Waller, .Augustus Volney (1816-1870). Experiments
on the section of the glossopharyngeal and hypoglossal
nerves of the frog, and observations of the alterations
produced thereby in the structure of their primitive
fibres. Phil. Trans. 140: 432, 1850.
139. Marchi, V. and C. Algeri. Sulle degenerazioni discen-
denti consecutive a lesioni della corteccia cerebrale. Riv.
sper. Frernat H: 492, 1885.
THE HISTORICAL DEVELOPMENT OF NEUROPHYSIOLOGY
27
TAB 11; 1
FIG. iq. Left: Jiri Pfochaska of Prague, the proponent of
automatic reflexion in the medulla and spinal cord. Ri«ht:
Prochaska's illustration of the spinal roots and their ganglia.
The definitive study of the relationship of the medul-
lated axon to the nerve cell followed in 1889 and was
the work of von Kolliker (140), profes.sor of anatomy
in Wiirzburg. From this wealth of accumulated
knowledge, a generalized concept of neuron behavior
became possible and in i8gi a clear formulation was
achieved by Waldeyer-Hartz (141). The neuron
theory was established. In reviewing thfse basic steps
that had to be taken before any unravelling of central
nervous system pathways could proceed with cer-
tainty, one is struck by the fact that so many of the
contributors (Schwann, Remak, von Helinholtz,
Kolliker) were pupils of Johannes Miiller.
Another of the early stumbling blocks to an under-
standing of the spinal cord was the difTerentiation of
motor and sensory function. It was early suspected
that the ganglia of the spinal roots were in some way
involved in this question. Galen had thought that the
presence of a ganglion indicated that the nerve was
powerfully motor in action and here the matter rested
for some centuries. In 1783 Alexander Monro (129)
noted that the spinal ganglia were formed on the
140. VON Kolliker, Rudolf Albert (1817-1905). Mikro-
skopische Analomie. Leipzig, 1850- 1854.
14L Waldever-Hartz, Heinrich Wilhelm Gottfried
(1836- 1 921). Uber einige neuere Forschungen im Gebiete
der Anatomic des Centralnervensystems. Deutsche med.
Wchnschr. 17: 12 13, 1244, 1287, 1331, 1352, 189L
posterior roots and that their coalescence with the
anterior roots occurred peripherally to these swellings.
But like Galen he thought that they were concerned
with 'muscular' nerves and defended them as such
against the suggestion by James Johnstone (142) that
their action was to cut ofT sensation. This rather
bizarre concept had received .some consideration in
the mid-eighteenth century.
The presence of ganglia suggested to several minds
a specialization of function in the nerves on which
they were formed. Both Prochaska C'43) 3"^
Soemmering (144) had drawn attention to the re-
142. Johnstone, James (i 730-1802). Essay on the use of the
ganglions of the nerves. Phil. Trans. 54: 177, 1765.
143. Prochaska, Jiri (1749-1820). De Structura .Nervorum.
Prague: Gerle, 1780-1784. 3 vol.
144. Soemmering, Samuel Thomas (1755-1830). De bast
encephali et originibus nervorum cranio egredienlum. Got-
tingen : Vandenhoeck, 1778.
28
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
semblance between the ganglia of the fifth cranial
nerves and those of the posterior roots, and Bichat
(145), the brilliant French pathologist who died so
young, had gone so far as to associate all ganglia with
the nervous processes of involuntary, unconscious
'organic' life.
The differentiation between the ganglia found in
the sympathetic nersous system and those on the
roots of the central nervous system was to come later.
Charles Bell made the distinction but admitted he did
not know what role was pla\ed b\- the .sympathetic
nerves or by their ganglia (146). His many studies on
the fifth and seventh cranial nerves (146-148), illus-
trated by his own beautiful drawings, are classics, and
his demonstrations of the function in the nerves of
the face are perpetuated in the name Bell's palsy.
Bell had come from Edinburgh to the famous ana-
tomical school that William Hunter had founded in
Great Windmill Street near Piccadilh'. A brilliant
di.ssector but not primarily an experimentalist. Bell
relied heavily on his brother-in-law, John Shaw, in
this aspect of his work and suffered a great loss when
Shaw died.
In the cord the various columns had been dissected
by the anatomists and the grouping together of nerves
in such larue bundles had certainly seemed suggestive
of parcellation of function. But not all anatomists
were agreed. Bichat on dissecting out some nerve
filaments found them centrally located in the lower
cord but more lateral higher up. He therefore con-
cluded that although the filaments had individual
properties, the fasciculi were mixed. The idea per-
sisted, however, that the columns and also the spinal
roots might have different functions according to
whether they were anterior or posterior. An early idea
was that the anterior roots carried Ijoth motor and
sensory supplies for the muscles while the posterior
roots gave a sensory service for the skin. An Edinburgh
145. Bichat, Marie Francois Xavier (1771-1802). Aualomie
generale, appliquee a la physiologie el a la medecine. Paris:
Brosson, 1801, 2 vol., English translation by G. Hay ward
Boston: Richardson and Lord, 1822. 3 vol.
146. Bell, Charles (1774-1842). The Nervous System of the
Human Body as explained in a series of papers read be/ore
the Royal Society 0] London. Edinburgh: Black, 1836.
147. Bell, C. On the nerves; giving an account of some ex-
periments on their structure and functions, which lead
to a new arrangement of the system. Phil. Trans. 1 1 1 : 398,
1 82 1 .
148. Bell, C. Of the nerves which as.sociatc the muscles of the
chest in the actions of breathing, .speaking, and expres-
sion. Being a continuation of the paper on the structure
and functions of the nerves. Phil. Trans. 112: 284, 1822.
anatomist, Alexander Walker Ci49)> suspected that
they might serve .separate roles but unfortunately
picked the posterior root as the motor and the
anterior root as sensory.
In 181 I a small pamphlet was pri\-ately primed,
entitled Idea oj o new anatomy of the brain suhmitled jir
the observation of his friends. The author was Charles
Bell (150). This pamphlet had no general distribution,
no more than 100 copies being printed. (Only three
are known to exist today, one of which is in the Na-
tional Library of Medicine in Washington; in Eng-
land, copies can be seen at the British Museum and
at the Royal Society.) Bell stated that the purpose of
this pamphlet was to assure his friends that in his dis-
sections of the brain he was investigating its structure
and not searching for the seat of the soul. In this work
he stated his opinion that nerves owe their differences
in properties to their being connected to different
parts of the brain. He said that, holding this opinion,
he wondered whether the double roots of the spinal
nerves might indicate that "nerves of different en-
dowments were in the same cord, and held together
by the same sheath." To test this idea experimentally,
he cut "across the posterior fasciculus" and noted
that there were no convulsive movements of the
muscles of the back; but that on touching the anterior
fa.sciculus with the point of a knife, the muscles of the
back were immediately convulsed. From this experi-
ment he concluded at that time, "The spinal nerves
being double, and having their roots in the spinal
marrow, of which a portion comes from the cerebrum
and a portion from the cerebellum, they convey the
attributes of both grand divisions of the brain to every
part, and therefore the distribution of such nerves is
simple, one nerve supplying its distinct part."
It may be noted that there is in this pamphlet no
suggestion that the posterior columns or roots might
be sensory in function. Bell considered the cerebellum
to be concerned with involuntary and unconscious
functions ("the .secret operation of the bodily frame"
and "the operation of the viscera") whereas he recog-
nized the cerebrum "as the grand organ by which
the mind is united with the body. Into it all the nerves
from the external organs of the senses enter; and from
it all the nerves which are agents of the will pass out."
149. Walker, Alexander (1779-1852). New anatomy and
physiology of the brain in particular, and of the nervous
system in general, -irch. Universal Sc. 3: 172, 1809
1 fjo. Bell, C. Idea of a new anatomy of the brain submitted for the
observation of his friends. Privately printed, 1811; repro-
duced in J. F. Fulton. Selected Readings in the History of
Physiology. Springfield: Thomas, 1930, p. 251.
THE HISTORICAL DEVELOPMENT OF NEUROPHYSIOLOGY
29
In essence, thcrcroic, Bell regarded the cerebellum,
posterior columns and posterior spinal roots as con-
cerned with unconscious impressions and involuntary
movements; the cerebrum, anterior columns and
anterior roots as conveying conscious sensation and
willed moxements.
On Julv 22, 1822, Frangois Magendie, member of
the Academy of Sciences of Paris (and later to be
professor at the College de France), read a paper (151)
to the Academy as a result of which the following
entry was made: "M. Magendie reports the discovery
he has recently made, that if the posterior roots of the
spinal nerves are cut, only the sensation of those nerves
is abolished, and if the anterior roots arc cut, only the
movements they cause are lost." This report was
followed by a fuller account (152, 153) in the journal
that Magendie himself had founded. The experiments,
made on puppies which survi\ed the surgical pro-
cedures, gave Magendie the confidence to state "that
the anterior and posterior roots of the nerves which
arise from the spinal marrow, have different func-
tions, that the posterior appear more particularly
destined to sensibility, whilst the anterior seem more
especially allied to motion."
In spite of his not having suggested a function of
conscious sensation for the posterior roots in either
the privately printed pamphlet or published papers
(147) on the fifth and seventh cranial nerves, Bell
with a questionable lack of scruple claimed full pri-
ority and engaged in a wrangle that invaded the scien-
tific journals for many years. This carried the un-
pleasant flavor of evidence twisted by hindsight. Bell's
"republications' in 1824 (154) of his earlier writings
contained .subtle changes in wording that deceived
his supporters into believing his claims to be better
founded than they were.^^ Among those hoodwinked
were Flourens and, at first, Magendie's pupil, Claude
Bernard. Posterity gives each some credit by pre-
151. Magendie, Franqols (1783-1855). Proces-verb, 1822.
Acad. Sc. 7: 348, 1820-1823.
152. Magendie, F. Experiences sur les fonctions des racines
des nerfs rachidicns. J. phystol. exper. et path. 2; 276, 1822.
153. Magendie, F. Experiences sur les fonctions des racines
des nerfs qui naissent de la moelle epiniere. J. physiol.
exper. et path. 2: 366, 1822. [References 152 and 153 can
be read in English in Alexander Walker's translations
in. Documents and dales of modern discoveries in the nerv-
ous system (Pub. anonymously) London: Churchill,
1 839-]
154. Bell, C. An Exposition of the Natural System of the Nerves of
the Human Body with a Republication of the Papers Delivered
to the Royal Society, on the Subject of .Verves. London: .Spot-
tiswoode, 1824.
FIG. 20. The protagonists in the Bell-Magendie controversy.
Bell (/f//) and Magendie Qright} as young men. The portrait
of Bell was painted by .Antony Stewart of Edinburgh in 1804;
that of Magendie (attributed to Guerin) is at the College de
France.
serving the nomenclature of the Bell-Magendie Law.
In spite of his claims. Bell made no move to get ex-
perimental proof of the function of the posterior roots
and as late as 1832 (155) was stressing that their
sensory nature was only inferred. He said in his lec-
tures to the Royal College of Physicians, ". . .as we
have proved the anterior column to be the origin of
the motor nerves, we may infer the posterior roots are
those which render the entire nerve a nerve of sensa-
tion." In 1844 Johannes Miiller (156) confirmed the
law experimentally, something Bell had never done,
but the conclusion seems inescapable that the concept
in its complete form as well as its experimental proof
was first contributed by Magendie.
Magendie, whose youth coincided with the French
Re\olution, came from surgery into physiology where
his urge towards experimentation could give him
greater satisfaction. So strongly empiricist was he that
he rarely made generalizations from his observations
155. Bell, C. Lectures on the physiology of the brain and
nervous system. Reported in: Ryan's Med. .Surg. J. i:
682, 752, 1832.
156. MtJLLER, J. Bestutigung des Bell'schen Lehrsatzes. Notiz.
a. d. Geb. d. natur- u. heilk. (Weimar) 30: 113, 1831;
this is more readily available in French in Ann. Sc. Natur.
23: 95, 1831, and a section is translated into English in
\V. Stirling. Some Apostles of Physiology. London : Waterlow,
1902.
'^ For a detailed comparison of the texts see Flint, A. Con-
siderations historiques sur les proprietes des racines des nerfs
rachidiens. J. de ianat. et de physiol. 5: 520, 1868.
30
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
in the laboratory which were many and varied. His
work on the spinal roots led him to follow the differ-
entiation of function into the spinal tracts where he
found that pressure on the posterior columns, but not
on the anterior, caused signs of pain. One other aspect
of Magendie's work on the spinal cord should be
mentioned, his rediscovery of the cerebrospinal fluid
(157). Sixty years earlier this had been seen and
described by Cotugno (158), at that time a young
physician in the Hospital for Incurables in Naples,
but his monograph had stirred no general interest
though it helped to win him the chair of anatomy at
the university. Magendie described the forainen
known by his name, but oddly revived a valve-like
role for the pineal as controller of this opening. He
thought the fluid was secreted by the arachnoid mem-
brane, and it was many years later that its origin in
the choroid plexuses was discovered. A later pamphlet
by Magendie (159) on the cerebrospinal fluid has
some fine illustrations by H. Jacob.
Once the differentiation of function between the
anterior and posterior roots had been accepted, the
finer points as to which regions were inner\ated by
their fibers began to occupy the physiologists. The
question as to whether all the fibers of an anterior
root served the same or many muscles was paralleled
by its corollary as to whether one muscle received
fibers from one or many roots. That the last arrange-
ment is the correct one was first clearly shown by
Eckhardt (160) in frogs and by Peyer (161) in rabbits.
Both were working in Carl Ludwig's laboratory. The
definitive demonstrations came later from Sherring-
ton's (162) careful analyses, mostly in the monkey,
from which he concluded that '"the position of the
157. Magendie. Memoire sur la liquide qui se trouve
dans le crane et canal vertebral de Thomme et des
animaux mammifiercs. J. physiut. cxph. el path. 5: 27,
1825.
158. Cotugno, Domenico (i 736-1822). De Ischiade Nervosa
Commentarius. Naples: Simonios, 1764; a portion has been
translated into English. A Treatise on the Nervous Sciatica^
or Nervous Hip Gout. London: Wilkie, 1775, p. 14.
159. Magendie, F. Rkherches physiologiques et cliniques sur le
liquide cephalorachidien ou cerebro-spinal. Paris: Mequignon-
Marvis, 1842.
160. Eckhardt, C. Uber Reflexbcwcgungender vier letzten
Nervenpaare des Frosches. ^Ischr. rat. Med. (ist series)
I : 281, 1849.
161. Peyer, J. Uber die pcriphcrischcn Endigungen der
motorischen und sensibelen Fasern der in den Plexus
brachialis des Kaninchens eintretenden Nerven wurzeln.
Zlschr. rat. Med. (ist series) 4: 67, 1853.
162. Sherrington, Charles Scott (1857- 1952). Notes on
the arrangement of some motor fibres in the lumbosacral
plexus. J. Physiol. 13: 621, 1892.
nerve-cells sending motor fibres to any one skeletal
muscle is a scattered one, extending throughout the
whole length of the spinal segments innervating that
muscle."
Tracing of the fibers of the sensory roots was in-
trinsically more difficult. Tiirck's (163) studies in
X'ienna had indicated the complexity of sensory inner-
vation in the dog, and Herringham (164) had found
the segmental relationship with the vertebrae; but
again it was Sherrington (165) who, using the reflex
as criterion of the existence of afferent fibers, un-
ravelled the phenomena of overlapping of segmental
cutaneous innervation. Until the time of Sherrington
it had been thought that the motor fibers to a given
muscle were derived from the same spinal segment
that received the sensory inflow from the skin sur-
rounding it. This was particularly the view of Krause
(166). Sherrington's mapping of myotomes and der-
matomes showed this rule to be erroneous.
.Sherrington's development of a comprehensive
theory of reflex action could scarcely have been en-
visaged before the sensory endings in muscle had been
discovered. This advance was mainly the work of
Rufiini (167, 168) who in 1892 identified as sensory
organs muscle spindles, tendon organs and Pacinian
(169) corpuscles. These structures had been seen and
dcscriljed by others, but their function had not been
appreciated. The need for an apparatus for muscle
sense had been felt by Charles Bell (170) in order to
convey "a sense of the condition of the muscles to the
brain," and he postulated "a circle of nerves," saying
that "every muscle has two nei^es, of different proper-
ties supplied to it." That sensations are aroused by
163. TiJRCK, Ludwig (1810-1868). Uber die Haut-Sensibili-
tatsbewirke der enzelnen Riickenmarksnervenpaare.
Denkschr. Akad. Wiss. 29: 299, 1868.
164. Herringham, VV. P. The minute anatomy of the brachial
plexus. Proc. Roy. Soc, London, ser. B 41: 423, 1887.
165. Sherrington, C. S. Experiments in examination of the
peripheral distribution of the fibres of the posterior roots
of some spinal nerves. Phil. Trans. 184 B; 641, 1894.
166. Krause, Fedor (1856-1937). Beitrdge zur Neurologie der
oberen Extremildt. Leipzig, 1865.
167. RuFFiNi, Angelo. Di una particolare reticella nervosa e
di alcuni corpuscoli del Pacini che si trovano in conces-
sione cogli organi musculo tendinei del gatto. Atti R.
Accad. Lincei 1 : 12, 1889; French translation in: Sur un
reticule nervcux special et sur quelques corpuscles de
Pacini qui se trouvent en connexion avec les organes
musculo-tendineux du chat. Arch. ital. biol. 18: loi, 1893.
168. RuFFlNi, .\. Observations on sensory nerve endings in
voluntary muscles. Brain 20: 368, 1897.
169. Pacini, Filipfo (181 2-1883). -^uovi organi scoperti net
corpo humani. Pistoja: Cino, 1840.
170. Bell, C. On the nervous circle which connects the volun-
tary muscles with the brain. Phil. Tram. 2: 172, 1826.
THE HISTORICAL DEVELOPMENT OF NEUROPHYSIOLOGY
31
movements of the limbs is an oljservation that goes
back at least to Descartes' posthumous treatise (171),
but that the act of volition in itself could also be 'felt'
was an idea espoused by some, including, rather sur-
prisingly, von Helmholtz." But a peripheral rather
than a central mechanism had more adherents for,
like Bichat, they thought that muscles must be sensi-
tive.
Infiltrating the early work on spinal cord physi-
ology is the gradual development of the idea of the
reflex. The eventual emergence of a concept of reflex
activity grew out of centuries of attempts to explain
animal movements, motion receiving more attention
than sensation for it was considered to be the sign of
life. Galen had regarded movements as three in kind :
natural (such as the pulse), governed by the heart;
voluntary, governed by the soul (located in the brain);
and unconscious movements of voluntary muscles
(such as in respiration). Involuntary muscle was un-
known even in the days of Fernel (i 72) and Descartes
(i 73), both of whom emphasized a distinction between
movements dictated by reason and those due to the
appetites. The ideas of Fernel and of Descartes have
both long been regarded as forerunners of the concept
of reflex activity. The claims for Fernel rest on his
observation of automatic movements, some of which
we now know to be reflexly initiated; but the pe-
ripheral origin or the stimulus that caused them was
not recognized by him. An ardent supporter of
Descartes as the originator was du Bois-Reymond
(174) who stressed this claim in his eulogy of Miiller,
written at the time of the latter's death.
The first suggestion that perhaps the spinal cord
could be a center for communication between nerves
was made by Thomas Willis (i 75) who came very
close to picturing the reflex. He thought that all
voluntary movements came from the cerebrum, all
involuntary from the cerebellum and that they were
ruled by a soul that resided both in the blood and in
the nervous fluid. For Willis the medulla was an
appendix of the brain which he likened to a musical
organ (30) taking air into its bellows (i.e. animal
spirits from the brain) in order to blow them out into
171. Descartes, R. Traite de I' Homme, first French ed. 1664,
chapt. 77.
172. Fernel, J. De Naiurali Parte Medicinae (ist ed.). Paris:
Simon de Colines, 1542; 2nd ed. Physiologia. 1554.
173. Descartes, R. Traite de I' Homme, first French cd. 1664.
174. DU Bois-Reymond, E. Gedachnissrede auf Johannes Miiller.
Berlin, 1858; reprinted in Reden, vol. 2. Leipzig: Veit,
1887.
175. Willis, Thomas (i 621 -1675). De Anima Brutorum {De
Scientia seu Cognitione brutorum^. London: Davis, 1672.
the appropriate organ pipes (the nerves). Elsewhere
(176) Willis showed his interest in the organ as a
musical instrument and gave some description of it.
Where Willis came close to describing reflex action
was in stating that sen.se impres.sions carried by the
animal spirits to the sensorium commune (which he
put in the corpus striatum) went on to higher levels
of the cerebrum where they were perceived and
formed into memories. Some, however, were reflected
back towards the muscles ('species alia reflexa'). Al-
though the resultant movement was automatic and
although one might be unaware of the sensory stimu-
lus, Willis held that one was conscious of the resultant
muscular effect. The example he gives is irritation of
the stomach causing vomiting, and it is noticeable
that Willis's discussion of 'reflexes' comes in his chap-
ter on knowledge and recognition.
Willis used 'motus reflexus' and the verb refluere'
in making this proposition and the terms were used
again by Baglivi (i 77) who refers to him. Their usage
of 'reflexus' reads as though it were closer to the
modern term than Descartes' 'esprits reflechis'.'*
Across the centuries the changing nuances of word
meanings make it impossible to catch the exact conno-
tation intended by an author, but Descartes' interest
in the reflection of light rays suggests that this may
have been the analogy he had in mind.
A mechanism for the mediation of involuntary
movements was not the only one for which physiolo-
gists were .searching. The early workers were much
exercised by what they termed 'the sympathy of parts'
for they recognized an integration of body mecha-
nisms that eluded nervous influence flowing only from
the brain. Some suggested an interaction taking place
peripherally in a plexus, an anastomosis of the
sensory and motor nerve endings. Winslow (178),
176. Ibid., chapt. 6.
177. B.'\GLivi, Giorgio (1668-1707). De fibra moirue. 1700,
book I, chapt. 5.
178. Winslow, James Benignus (1669-1760). Exposition
anatomique de la structure du corps humain. Paris: Duprez
and Desessartz, 1732, pt. VI (illustrated by plates from
Bartolomeo Eustachius (i 520-1 574). Tabulae anatomicae.
Rome: Gonzaga, 171 4); English translation by G. Doug-
las. Edinburgh: Donaldson & Elliot, 1772. 2 vol.
" In discussing the sensation of outward movement of an
eyeball the external rectus of which is paralyzed, he says, "We
feel, then what impulse of the will, and how strong a one, we
apply to turn the eye to a given position." von Helmholtz,
H. Handbuch der physiologischen Optik. Leipzig: Voss, 1867,
parts translated into English by William James in his Principles
of Psychology.
" Descartes used this term only once, in Passions de I'Ame.
32
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
working in Paris and later in Copenhagen, thought
he had found the clue in the ganglia of the sympa-
thetic chain. These he envisaged as small brains in
wliich intercommunication between nerves could take
place, efTecting sympathy between various visceral
organs. "These ganglions . . . may be looked upon,"
he said, "as so many origins or gcrmina dispersed
through this great pair of nerves, and consequently as
so many little brains." This ingenious but erroneous
theory has left its name on the structures, the sympa-
thetic ganglia. Winslow illustrated his te.xt with the
fine plates of Eustachius that had lain for so long un-
noticed in the \'atican Library. These plates do not
however show the 'small brains.'
In following the early ideas about 'sympathy be-
tween the parts' it must be remembered that, although
so much emphasis was laid on the humors by early
physiologists, endocrines were unknown and conse-
quently their influence could not be in\oked. There
were, however, all down the centuries, some who held
that the blood was the great integrator. In the
eighteenth century, for example, John Hunter (179)
was teaching that the blood was the agent of sym-
pathy.'^ He was drawn to this view from his work on
inflammation and fevers arising from gunshot wounds
in the soldiers he cared for as an army surgeon in the
Seven Years' War with France.
Only slowly did the concept of reflex activity gain
ground. Hunter's contemporary and fellow Scot,
Robert VVhytt, was accumulating observations and
making experiments that are fundamental to modern
physiology, although his descriptions of them are also
often cloaked by his terminology. In the first place
(180), he recognized the in\oluntary nature of pupil-
lary contraction and dilation and demonstrated the
dependence of this action on the integrity of the
corpora quadrigemina, thus anticipating the work of
Herbert Mayo (181) in the next century. He went on
179. Hunter, John (1728-1793). Trealise on the Blood, Inflam-
mation and Gunshot Wounds. London : Nicol, 1 794.
180. Whytt, Robert (17 14- 1766). An essay on the vital and
other involuntary motions of the animal. Edinburgh: Hamil-
ton, Balfour and Neill, 1751.
181. Mavo, Herbert (1796- 1852). Anatomical and Phynological
Commentaries. London; Underwood, vol. I, 1822; vol. II,
■ 823.
"Samuel Taylor Coleridge's comment on some of John
Hunter's writings is perhaps a little harsh: "The light which
occasionally flashes upon us seems at other times, to struggle
through an unfriendly medium, and even sometimes to suffer
a temporary occultation." Coleridge, S. T. Hints towards the
Formation oj a more Comprehensive Theory of Life. Philadelphia:
Lea & Blanchard, 1848.
to the study of in\oluntarv movements of voluntary
muscle systems in decapitated animals. The move-
ments of animals after their heads had been severed
was common knowledge to every housewife who had
ever killed a chicken and had attracted the attention
of scientists since Leonardo's day. Even in the seven-
teenth century Boyle C'82) had recognized the impli-
cations of these phenomena, realizing that "these may
be of great concernment in reference to the common
doctrine of the necessity of unceasing influence from
the brain, being so requisite to sense and motion."
Boyle's curiosity about the i^rain and its workings was
interwoven with his great interest in theology, al-
though his views on the latter did not please the
theologians. Dean Swift was even moved to parody
them in a satire called A Pious Meditation upon a Broom-
stick in the Slv/e of t/ie Honourable Mr. Boyle.
Glis.son (62) had also distinguished between 'willed'
mo\ements and those of decapitated animals. He
thought the latter analogous to a class of movements
depending on a lower form of perception not reaching
the mind. One might become aware of them (^perceptio
sensitiva) but the\' were not ruled by the mind as were
\'oluntarv mo\'ements Qierceplio perceptioms^.
Whytt's experiments (183) carried the argument
farther for he showed that this type of in\oluntary
motion could not be explained as due to the innate
irritability (jf muscle tissue (Haller's vis insita~), for
preservation of the spinal marrow was essential for it.
He was, however, not the first to discover that the
spinal cord was essential for this type of movement.
He had been anticipated by the Reverend Stephen
Hales, whose many and brilliant physiological experi-
ments make one wonder how^ much time he gave to
his parishioners in Teddington. Whytt gives full credit
to Hales, for he says, "The late reverend and learned
Dr. Hales informed me that having many years since
tied a ligature about the neck of a frog to prevent any
effusion of blood, he cut ofT its head ... the frog also
at this time moved its body when stimulated, but that
on thrusting a needle down the spinal marrow, the
animal was strongly convulsed and immediately after
became motionless." Alexander Stuart (184) repeated
i8a. Boyle, Robert (1627-1691). Considerations touching on the
Usefulness of Experimental Natural Philosophy. London,
,663.
183. VVh^tt, R. Observations on the .Xalure, Causes and Cure of
those Disorders which are commonly called .\ervous. Hypo-
chondriac, or Hysteric, to which are prefixed some remarks on the
sympathy of the nerves. Edinburgh : Balfour, 1 765.
184. Stuart, A. Three lectures on muscular motion, read before
the Royal Society in the year MDCCXXXVHI. London:
Woodward, 1739.
THE HISTORICAL DEVELOPMENT OF NEUROPHYSIOLOGY 33
^r<u>.3 ■
FIG. ii. Lejt: Alexander Stuart's experiment contirming the observations of Stephen Hales that a
decapitated frog convulses on being pithed and then becomes immobile. (From Stuart, A. Crooman
Lectures 1738. London: Woodward, 1739.) Ri^ht: Robert Whytt whose experiments demonstrated
reflex action in decapitated animals and the eflTects of spinal shock. (From the portrait in the Royal
College of Physicians, Edinburgh, by courtesy of Mr. G. R. Pendrill.)
and confirmed this experiment and described it in a
lecture to the Royal Society in 1738.
Whytt in his experiments on the frog came very
close to defining the segmental reflex. He also noted
spinal shock, for he remarked that a decapitated frog
could not be made to move immediately after transec-
tion although if one waited about 15 min. it would
react to stimuli. But perhaps the most striking of his
observations is the one in which he anticipated
Sherrington in regard to the stretch reflex. "Whatever
stretches the fibres of any muscle so far as to extend
them beyond their u.sual length, excites them into
contraction about in the same manner as if they had
been irritated by any sharp instrument, or acrid
liquor" (183, p. 9).
With the publication of Whytt's work physiologists
were divided between regarding the movements of
spinal animals as a lingering in the cord of powers
originally derived from the brain, and the view that
the spinal marrow itself was capable of sensation and
movement. Whytt inclined to the latter view in his
explanation of the writhings of decapitated and
eviscerated snakes. "We are naturally led to con-
clude," he said, "that they are still in some sense alive,
and endued with feeling, i.e. animated by a sentient
principle."
Before the end of the century, Whytt's publications
had been followed by thase of Unzer (185), of Halle
185. Unzer, Johann August (i 727-1809). Ersle Griinde einer
Physiologie der eigenltchten thierischen Nairn thicrischer hovper
and of his pupil Proehaska (186) who was a practising
ophthalmologist in Prague. Both these men contrib-
uted more in systematization and formulation at the
conceptual level than in the addition of new experi-
mental facts. In England, the Sydenham Society gave
Ijoth their books to the same translator, Thomas
Laycock (the teacher of Hughlings Jackson), and
through him the word reflexion became the accepted
term. Unzer postulated several sites where reflexion
of impressions might take place — in the brain, in the
ganglia, in bifurcations of nerves and in plexuses. Only
if they reached the brain would these impressions be
consciously perceived. Unzer in discussing automatic
movements protected himself against the attacks en-
countered by soine of his predecessors by saying that
"the animal machines are mysteriously and inscru-
tably endowed by the Creator."
Proehaska, with one foot in the past, believed in a
sensorium commune where automatic reflexion took
place and thought this might be in the medulla or the
cord but did not agree with Unzer that reflexion
might be at the level of the ganglia. He reverted to
Leipzig: Wiedmanns, 1771; English translation by T.
Laycock. Principles of a Physiology of the Mature of Animal
Organisms. London: Sydenham Society, 1851.
186. Prochaska, JiRi (1749-1820). Part III: De functionibus
systematis nervosi, et observationes anatomico-pathologi-
cae. In: Adnotationum Academicarum . Prague: Gerle, 1784;
English translation by T. Laycock. Dissertation on the
Functions of the Nervous System. London: Sydenham Society,
1851.
34
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
Afinlifsts
of
Tlir Iliustiillir iVu.,u.s Sj/slem.
FIG. 22. Lffl. Marshall Hall. Right: one of his experiments
to demonstrate the three parts of the reflex arc. The arc was
broken by any of the following procedures: a) skinning the
extremity (at 5) (the 'esodic' nerves); A) sectioning of the
"brachial or the lumbar or femoral nerve leading to the point
irritated" (i.e. the exodic nerve' at 2); or c') removing the spinal
mcirrow (the spinal centre')- (From Hall, M. Synopsis of the
Diastalttc J^'ervous System: being outlines of the Croonian Lec-
tures delivered at the Royal College of Physicians in April
1850.)
the idea of an inherent vis nervosa in the nerves that
enabled them to function in isolation from the brain
and he supported this argument by citintr the move-
ments of anencephalic monsters. In his view the
■purpose' of reflex activity was preservation of the
individual.
Here the history of reflex activity rested for nearly
30 years and the next advance was a technical rather
than a conceptual one. This was the perfection by
Legallois (187) of a method for the artificial respira-
tion of mainmals and from then on, in many labora-
tories, heads began to fall. Legallois, by sectioning the
neuraxis serially from above and from below, nar-
rowed the center of activity drastically and was so
impressed by the amount of sensorimotor function
left in a segment that he rather sweepingly concluded
that the spinal cord was the principal seat of sensation
and the source of voluntary motion. Although this
extreme view did not gather many adherents, it was
clear that the spinal cord could no longer be thought
of as a mere prolongation and bundling together of
peripheral nerves. On the contrary, the tendency now
187. Legallois, Julien Jean Cesar (1770-1814). Experiences
sur la principe de la vie, notamment stir celui des mouvemenls
du coeur, el sur le siege de ce principe. Paris: D'Hautel, 1812.
was to regard it as a caudal extension of the brain.
Legallois should be remembered for being the first to
recognize clearly that the respiratory center lay in the
medulla oljlongata.
This was the setting of the stage for the man who
lifted the whole subject of reflex activity into the
framework of modern neurophysiology and into
clinical science. Marshall Hall, an Englishmen edu-
cated in the great school at Edinburgh where he was
a pupil of the third Monro, was a successful practising
physician who set up a laboratory in his own house
(in Malet Street where the present buildings of
London L'niversity stand). Here he worked on his
animals, mostly frogs and reptiles, collating his obser-
vations (188) with those he made on patients (189).
His acumen enabled him to perceive several details
that had escaped his predecessors. For example, the
writhings of the decapitated snake that had led Whytt
to a postulate of lingering 'life' within the cord were
recognized by Hall as motor responses to the renewed
sensory stimuli set up by each movement
Like Unzer, Hall in his work on the machine-like
movements of decapitated animals protected himself
from onslaught by stating them to be "all beautiful
and demonstrative of the wisdom of Him who fashion-
eth all things after his own Will." Hall, again like
LTnzer, realized that the sensory impression that set
ofl' a reflex need not be consciously perceived, al-
though he was consistently remiss in acknowledging
the contributions of his predecessors. He also ignored
the work of his contemporaries, for nowhere does he
refer to the great blossoming of knowledge of nerve
physiology that was taking place at this time and
which has been reviewed in an earlier section of this
essay. He seems also to have ijeen unaware of the con-
tractility of involuntary muscle although Baglivi
(190) over a hundred years before he had made the
distinction between smooth and striated muscle. Hall
had many detractors who vigorously accused him of
plagiarism, both from Miiller and from Prochaska.
The first challenge was easier to meet than the second,
for Hall's earliest communication (191) antedated
Miiller's publication (94) on decapitated animals by
one year. In the published report of this first paper,
188. Hall, Marshall (1790-1857). .\'ew Memoir on the Nerv-
ous System. London, 1843.
189. Hall, M. Diseases and Derangements of the Nervous System.
London: Bailliere, 1 841.
190. Baglivi, Giorgio (1668-1707). Opera omnia medico-
praclica et anatomica. Leyden: Anisson & Posuel, 1704.
191. Hall, M. On a particular function of the nervous system.
Proc. Z^ol- •^O'^- part 2, p. 189, Nov. 27, 1832.
THE HISTORICAL DEVELOPMENT OF NEUROPHYSIOLOGY
35
which Hall gave to the Zoological Society of London
in November 1832, there is, however, no full descrip-
tion of the reflex arc nor does he use these terms. The
emphasis is on "a function of the nervous system . . .
distinct from sensation and \oIuntary or instinctive
motion," being a "property which attaches itself to
any part of an animal, the corresponding portion of
the brain and spinal marrow of which is entire."
The attack was pursued by others-" with great
bitterness and its leaders engaged in such unworthy
acts as checking on library slips to prove that Hall had
borrowed Prochaska's book. (The slips however post-
dated Hall's original publications.) To the modern
worker the battle seems puerile and undignified and
one regrets that its protagonists did not spend the
time on experiment instead of polemics.-' Of the men
for whom priority was being claimed, Prochaska was
dead and it is noticeable that Miiller, a truly gieat
man, after making generous acknowledgement to
Hall in his Handbuch stood aloof from these bicker-
ings.
In essence Marshall Hall's inajor contributions to
neurophysiology were, first (192), that sensory impres-
sions coming into the medulla spinalis had far reach-
ing effects in the nervous system in addition to the
segmental efTector response,'" secondly the recognition
that although reflex activity took place at a spinal
level it could be influenced by the wilP^ and thirdly,
the relationship of this fact to the exaggeration of
reflex response on removal of the brain (193). These
are not the only areas in which he anticipated
Sherrington. He gave a preliminary glimpse of the
stepping reflex, "In the actions of walking in man, I
iinagine the reflex function to play a very considerable
part, although there are, doubtless facts which
demonstrate that the contact of the sole with the
ground is not unattended by a certain influence upon
the action of certain muscles."
Marshall Hall introduced the word 'arc' to describe
the refle.x pathway. Many of his other terms have,
happily, not been retained by physiologists, for he was
a great lover of neologisms, as his definition of the
arc shows: "the existence in Anatomy and Physiology, of
a continuous Diastaltic Nervous Arc including an
Esodic Nerve, the Spinal Centre and Exodic Nerve in
192. Hall, M. On the reflex function of the medulla oblongata
and medulla spinalis. Phil. Trans. 123: 635, 1833.
193. Hall, M. On the true spinal marrow, and on the excito-motory
system of the nerves. Lectures given before the Royal So-
ciety, privately printed, 1837.
essential relation and connection with each other —
and of a series of such Arcs. . . ." (194). (One recog-
nizes here that Queen Victoria had a rival among her
subjects in the use of italics.)
One further contribution of Hall's at the conceptual
level should be noted. Implicit, if not explicit, in the
theories of the earlier physiologists was the notion
that in voluntary movement volition directed a
nervous influence towards the individually appropri-
ate iTiuscles. Hall pointed out that the will was inore
teleological and less specific in its action and not
"directed to any muscle or set of muscles, but to an
aim, object and purpose of their contraction" (195).
Hall's contributions were not evaluated as highly by
his contemporaries as they have been by later physi-
ologists, though he himself had no doubts as to how
they should be ranked; he stated that they were the
greatest advance in medical science since William
Harvey.
The iinpact of the work of the physiologists on the
concepts of the psychologists was very great and so
disturbing that their literature was filled with contro-
versy for many years. Long before the concept of
reflex acti\ity was carried into the brain by Sechenov
to explain its higher functions, the psychologists were
in distress over the implication for 'sensation,' for
'consciousness' and for 'volition,' of the developing
knowledge of spinal reflexes. The most conspicuous
controversy was that waged between Eduard Pfliiger
(196), von Helmholtz's successor at the Physiological
194. H.'VLL, M. Synopsis oj the diastaltic nervous system. Crocnian
Lectures, London, 1850.
195. Hall, M. Memoirs on the Nervous System. London, 1837.
196. Pfluger, Edouard (1829-1910). Die sensorischen Func-
tionen des RUckenmarks der Wirbelthiere nebsi einer neuen
Lehre iiber die Leitungsgesetze der Reflexionen. Berlin, 1853.
''"Such as, for example, George, J. D. Contribution to the
history of the nervous system. Lond. med. Gaz- 22: 40, 93,
1837-1838.
-' A full account of the controversy (though scarcely an
unbiased one) can be found in Longet, F. A. Traite d'Anatomie
de Physiologie du Systeme Nerveiix de I'Homme et des Animaux
Vertehres. Paris, 1842. 2 vol.
''- "But the operation of the reflex function is by no means
confined to parts corresponding to distinct portions of the
medulla. The irritation of a given part may, on the contrary,
induce contraction in a part very remote." Phil. Trans. 123:
635, 1833.
'' "The true spinal system is susceptible of modification by
volition. . . ." Memoirs on the .Nervous System. London, 1837,
part 2, p. 73. (This part of the observation was anticipated
bv Whvtt.)
36
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
Institute at Bonn, tmd Rudolph Lotze (197), pro-
fessor of Philosophy at Gotlingen. Back and forth the
battle raged, swinging from physiology into meta-
physics and back again into experiment. The argu-
ments all centered around the problems of whether a
spinal animal was sentient and conscious, and whether
its movements were purposeful. Was such an animal
intelligent? Did it have memory? Pfliiger espoused the
idea of consciousness in the cord, Lotze denied it;
both were dogmatic inn to neither can we look for
advancement of knowledge of the central nervous
system in this context.
In the nineteenth century, while Marshall Hall was
still alive, the nature of inhiiiition became of major
interest to physiologists and before the end of the
century was to have its role in reflex activity demon-
strated by Sherrington. Although the po.ssibility of
inhibition had been suggested by several workers, the
actual phenomenon had first been observed (and re-
jected as an error of experiment) by Volkmann (198)
in 1838 in relation to the action of the vagus on the
heart. It was again observed, and this time accepted,
by the Weber brothers (199) in 1845. The elder
brother, Ernst, held the joint chair of anatomy and
physiology at Leipzig until Carl Ludwig came in 1866
to take over the latter section and set up his famous
institute. The technique of the classic experiment that
established the existence of vagal inhibition was the
stimulation by a voltaic pile of both vagi of the frog.
Later the Webers found that unilateral stimulation
had the same effect and they confirmed the result by
stimulating the vagus of a cat with an induction cur-
rent. They reported this discovery, one of the land-
marks of nerve physiology, at the Congress of Italian
Scientists held in Naples in 1845 (which accounts for
their publication being in Latin rather than in
German). This type of inhibition, like that which was
eventually evoked to explain Bernard's (200) obser-
vation of the influence of the chorda tympani on the
197. Lotze, Rudolph Heinrich (1817-1881). Instinct. In: R.
Wagner. Handwortrnbuch. pt. ■!. Brunswick: Vieweg, 184.!-
1853-
ig8. Volkmann, Alfred Wilhelm (1800-1871). Uber Re-
flexbewegungen. Arch. Anat. u. Physiol. 15, 1838.
igg. Weber, Eduard Friedrich Wilhelm (1806-1871) and
Ernst Heinrich Weber (i 795-1878). Experimenta,
quibus probatur nervos vagos rotations machinae gal-
vano-magneticae irritatos, motum cordi retardare et
adeo intercipare. Ann. Univ. Med.., Milano 20: 227, 1845.
200. Bernard, Claude (1813-1878). Recherches anatomiques
et physiologiques sur la corde du tympan, pour servir a
I'histoire de I'hemiplegie faciale. Ann. med.-psychol. i : 408,
'843-
submaxillary blood \'essels, seemed simple to later
physiologists faced with the complexities of inhibition
in the central nervous system. These had to await
exploration by Sherrington.
An enduring interest of Sherrington and one ex-
haustively explored by him in the laboratory was re-
ciprocal inner\ation of antagonist muscles, and many
of his publications were on this subject. The attempt
of Descartes (25) in the seventeenth century to reach
an explanation based on channeling of vital spirits
had no immediate successor. In the early part of the
nineteenth century Charles Bell (201) had postulated
the existence of peripheral inhibition by insisting on
the need for nerves which had the opposite of an
excitatory effect on muscle. "The nerves," he said,
"have been considered so generally as in.struments for
stimulating the muscles, without thought of their act-
ing in the opposite capacity, that some additional
illustration may be necessary." He went on to describe
an experiment in which contraction of a flexor muscle
coincided with imposed relaxation of its opponent
extensor.
The possibility of a peripherally exerted inhiljition
of muscle contractility attracted many people at
about this time. One of the earliest was a Dr. West
(202) of Alford in Lincolnshire (who had heard Bell's
lectures at the Royal College of Surgeons). \Vest's
suggestion was that contraction was an inherent prop-
erty of muscle and that the action of the nerve supply-
ing it was not to evoke, but to 'restrain' or 'rein' this
innate tendency to contract. He explained a volun-
tary contraction as a withdrawal of this nervous re-
straint "so as to allow the peculiar property of muscu-
lar fibre to shew itself." The publication of West's
hypothesis provoked some expostulation, one anony-
mous correspondent saying this was "certainly one of
the clumsiest contrivances that nature was ever
accused of" The mechanism of rigor mortis was not
understood at this time and West felt that his theory
off"ered a possible explanation. The idea was also
present in the arguments of many others, for example
those of Engel (203), of Stannius (204) and of Duges
201. Bell, C. On tiio ner\es of the orbit. Phil. Trans. 113: 289,
1823.
202. West, R. Uvedale. On tlic inHucnce of the nerves over
muscular contractility. Ryan's Med. Surg. J. 1 : 24, 245,
445, 1832.
203. Engel, Joseph. Uber Muskelreizbarkeit. ^Ischr. Gesellsch.
Arize, yVien i : 205, 252, 1849.
204. Stannius, Hermann (1808-1883). Untcrsuchungen iiber
die Leistungsfahigheit der Muskeln u. Todtenstarre.
Vierordt's Arch, physwl. heilk. i, 1852.
THE HISTORICAL DEVELOPMENT OF NEUROPHYSIOLOGY
37
f). OO If!
Tiglira Murculi [eamdum auto- "''■'"'■ ^-^
FIG. 23. Lc//.- Descartes' sketch of reciprocal muscles of the eye (/Jf Humine, the Latin translation by
Schuyl). Center: a redrawing showing closure of valves on relaxation, opening on contraction to allow
animal spirits to How in and swell the muscle QL' Homme, the French edition of 1677). Right: Sherring-
ton's diagram of the connections and actions of two cells of a dorsal root ganglion. The plus sign
indicates that at the central synapses the afferent impulses excite the ipsilateral flexor muscle and
the contralateral extensor, while inhibiting the ipsilateral extensor and the contralateral flexor
muscle. (From Sherrington, C. S. The Integratwe Ac/inn nf Ike Nervous Svslem, 2nd ed. Cambridge:
Cambridge, 1947.)
(205) in Montpellier. The latter favored a peripherally
exerted nervous influence acting against an inherent
elasticity of muscle.
In 1868 Hering (206) and Breuer(207) found in the
respiratory system a parallel to Bell's experiment
whereby distention of the lung acting through the
pulmonary branch of the vagus inhibited inspiration
while exciting expiration, the well-known Hering-
Breuer reflex. And in 1883 Kronecker (208) working
on the swallowing reflex in Ludwig's laboratory with
his American pupil, Meltzer, demonstrated the in-
hibitory action of the superior laryngeal nerve on in-
spiratory muscles during contraction of expiratory
ones. The reflex nature of .swallowing had been recog-
205. Duces, Antoine. Traile de Physiologie Comparee de I'homme
et des Animaux. Montpellier & Paris, 1838; Compt. rend. Sac.
de biol. March 17, 1847.
206. Hering, Karl Ewald Konstantin (i 834-1918). Die
Selbststeuerung der Athmung durch den Nervus Vagus.
Silzber. Akad. Wiss. Wien 57; 672, 1868.
207. Breuer, Joseph (1842-1925). Die Selbstseuerung der
Athmung durch den Nervus Vagus. Sitzber. Akad. Wiss,
Wien 58: 909, 1868.
208. Kronecker, Karl Hugo (1839-1914) and Samuel
James Meltzer (1851-1920). Der Schluckmechanismus,
seine Erregung und seine Hemmung. Arch. Anat. Physiol.
Suppl. : 328, 1883.
nized by Marshall Hall (195) in 1823 and the direct
afferent nerve for it had been identified by Magcndie
(209) to be the glossopharyngeal, but the reciprocal
effect had not been noted by them.
It is the fact that there are no inhibitory nerves to
vertebrate skeletal muscle that drew the whole subject
of reflex inhibition into the central nervous system.
With the realization that reflex inhibition had its site
in the central nervous system, attention was turned to
the connection between the incoming sensory element
of the arc and the motor component, to the junction
between them, in other words, to the synapse (Sher-
rington's word). That there might be an interaction of
a synaptic kind between neurons in the periphery had
occurred to several workers, one among whom was
Sigmund Freud (210). His work on fresh-water crabs
and his illustrative sketches of how he conceived of
intercommunication between the axons of their
ganglia came close to what is now termed an ephapse,
although he pictured transverse crossings that sug-
gest a uniting of fibers rather than a contiguity.
209. Magendie, F. Lei^ons sitr les fonctions du systhne nerveux.
Paris, 1839.
210. Freud, Sigmund (1856- 1939). Uber den Bau der Nerven-
fasern und Nervenzellen beim Flusskrebs. Sitzber. Akad.
Wiss. Wien 85: 9, 1882.
38
HANDBOOK OF PHYSIOLOGY ^ NEUROPHYSIOLOGY I
.<V. DIAGRAMS ILLCSTHATrNG THE ELEMENTARY
COMBINATIONS OF THE NERVOUS SYSTEM.
r A
FIG. 24. Above: Schema of the connections between the posterior and an-
terior roots of the spinal cord as taught to students in the days before the
neuron doctrine and the theory of the synapse. [From Bernard, C. Lemons
sur la Physiologie el la Palhologie du Sysleme .Nerveux. Paris: Balliere, 1858.)
Right: Connections in the nervous system as taught to students in 1885.
(From Pye-Smith, P. H. Syllabus of a course of lectures on Physiology delivered at
Guy's Hospital. London: Churchill, 1885.)
Recognition of the synapse could come only after
the neuron theory had replaced the reticular theory.
According to the latter, strongly championed by
von Gerlach (211), nerve cells were connected with
each other by a diffuse fibrillary network forming an
anastomosis. This hypothesis received support from
Golgi (212), although it was his silver staining tech-
nique in the hands of Ramon y Cajal (213) that
finally disproved it, for Ramon y Cajal established
that both axons and dendrites had free endings. To-
gether they shared the Nobel prize in igo6, Golgi
devoting his address to an attack on the neuron theory
that his fellow prize winner had done so much to up-
hold. In modern times, the synapse (an abstraction)
is having to be remodelled in the light of what the
electron microscope is revealing.
The nature of central inhibition, a still incompletely
211. VON Gerlach, Joseph (1820- 1896). The spinal cord. In:
S. Strieker, A Aianual of Histology (English translation).
London: New Sydenham Society, 1872.
212. Golgi, Camillo (1844-1926). Atti Soc. ital. progr. sc.
3rd reunion. 1910.
213. Ramon y Caj.\l, Santiago (1852- 1934). Neuron theory
or reticular theory. Arch. Jisiol. 5, igo8; translation by
Purkiss and Fox. Madrid, 1954.
resolved issue, has e\oked many hypotheses. Among
them, those depending on mutual interference of
impulses at the effector component of the reflex arc
form one class. An example is the schema suggested
by Rosenthal (214) in 1862 to explain the effect of
efferent vagus fibers on the respiratory center. He
proposed that an effector system excited into action
by one nerve could have the pulsating rhythm of its
nervous supply disturbed by inflow from another
nerve, the result being a redistribution of previously
grouped impulses into more frequent but less powerful
(and hence inadequate) discharges. Lack of evidence
for a pulse-like time-rhythm in nerve trunks led to the
rejection of this hypothesis by W'undt, Sherrington
and others.
In the 1870's and 1880's attempts to explain inhi-
bition on metabolic effects depending directly on the
cell's response to stimulation being an assimilation of
chemical nutrients were espoused by Gaskell (215)
214. Rosenthal, Joseph. Die Atembeweg und ihre Bezichung zum
nervus Vagus. Berlin, 1862.
215. Gaskell, Walter Holbrook (1847-1914). On the
rhythm of the heart of the frog and of the nature of the
action of the vagus nerve Phil. Trans. 173; 993, 1882.
THE HISTORICAL DEVELOPMENT OF NEUROPHYSIOLOGY
39
(for the vagus) and Hering (216) (for black-white
sensations of the visual sense), by Vervvorn (2 1 7) (in
his Biogenhvpothese). The hypothesis did not survive
for long. As Forbes (218) said in his critique, "To
assume that increase of anabolism necessarily implies
decrease of catabolism, is to suppose that increasing a
man's salary ensures decrease of his expenditure." A
theory of immobilization of ion transfer during inhi-
l)ition was propo.sed by Macdonald (219) in 1905, at
a time when the release of potassium from injured
nerves was receiving considerable attention.
With the discovery of the refractory period in nerve
[by Gotch and Burch (220) in 1889] there was some
tendency to regard block of conduction due to excita-
tory impulses arriving during refractoriness caused by
preceding excitation to be the mechanism of inhibi-
tion. This is now recognized as a misuse of the term,
and in fact Sherrington's demonstration that after
discharge persisting after cessation of excitation could
be cut short by inhibitory nerve action was an early
salutory corrective.
In the course of researches on the inexhaustibility
of nerve, a subject which engrossed the early electro-
physiologists, Wedensky (221) found that a rapid
series of strong stimuli would fail to produce more
than a single twitch if the transmission from nerve to
muscle were blocked either by fatigue at the end plate
or by artificially impairing a section of the nerve by
narcosis. If however the frequency or the strength of
the tetanus were then reduced, the muscle went im-
mediately into tetanic contraction. Wedensky con-
cluded that the nerve was inexhaustible and that the
phenomenon was one of inhibition. This may, how-
ever, be regarded as a special usage of the term since
the effect he observed was merely a characteristic of
the relative refractory period of nerve and its time
course as related to strength of stimulus (222).
It was Sherrington's insistence on a central site for
216. Hering, Heinrich Ewald (1866-1948). Zur Thcorio dc
Vorgange in der lebendigen Substanz. Lotos g: 35, 1889;
translated in Brain 20: 232, 1897.
217. Verworn, Max. Die Biogmhypothcse. Jena: Fischer, 1903.
218. Forbes, Alexander. Reflex inhibition of skeletal muscle.
Quart. J. Exper. Physiol. 5: 149, 1912.
219. Macdonald, J. S. The structure and function of nerve
fibres. Proc. Roy. Soc, London, ser. B 76: 322, 1905.
220. Gotch, F. and G. J. Burch. The electrical response of
nerve to two stimuli. J. PhysioL 24: 410, 1899.
221. Wedensky, Nicholai Yevgenevich (1852- 1922). Die
Erregung, Hemmung und Narkose. .Arch. s^es. Physiol.
100: I, 1903.
222. Adrian, E. D. Wedensky inhibition in relation to the
"all-or-none" principle in nerve. J. PhysioL 46: 384, 1913.
the inhibitory mechanisms of skeletal muscle that
emphasized the reflex nature of inhibition. The con-
tributions of Sherrington and his school are the basis
of modern ideas of the reflex at the spinal level. A
great number of findings (223-227) made by Sherring-
ton and brought together into a unifying explanatory
scheme included the following major observations: that
postural tonus of a muscle is dependent not only on
efferent nerves but on afferent nerves from that muscle
itself, the stimulus to the latter being from stretch re-
ceptors [the myotatic reflex (223)]; that decerebrate
rigidity (224) is an e.xaggerated muscle tonus in the
antigravity muscles — a reflex standing ["an harmo-
nious congerie of stretch-reflexes" (225)]; that the
afferent nerve from a given muscle can elicit a con-
traction in that muscle itself (228), without involve-
ment of the opposing muscles of the joint;-'' that the
main stimulus for the stepping reflex (229) does not
come from contact of the foot with ground, as might
be expected;-" that stimulation causing fle.xion in one
223. LiDDELL, E. G. T. AND C. S. SHERRINGTON. ReflcXCS in
response to stretch (myotatic reflexes). Proc. Roy. Soc,
London, ser. fi 96: 212, 1924.
224. Sherrington, C. S. Cateleptoid reflexes in the monkey.
Proc. Roy. Soc, London, ser. B 60: 41 I, 1897.
225. Sherrington, C. S. Problems of muscular receptivity.
Linacre Lecture. Mature, London 113: 732, 892, 929, 1924.
226. Sherrington, C. S. Selected Writings of C. S. Sherrington,
edited by D. Denny-Brown. London: Hamish Hamilton,
1940.
227. Sherrington, C. S. Note on the knee-jerk and the corre-
lation of action of antagonistic muscles. Proc. Roy. Soc,
London, ser. B 52: 556, 1892-3.
228. Sherrington, C. S. On reciprocal innervation of an-
tagonistic muscle (eighth note). Proc Roy. Soc, London, ser.
B 76: 269, 1905.
229. Sherrington, C. S. Flexion-reflex of the limb, crossed
extension-reflex, and reflex stepping and standing. J.
Physiol. 40: 28, 1 910.
''* From a series of 1 4 articles by Sherrington on reciprocal
innervation stretching over the years from 1893 to 1909 (and
developed in many other of his writings), the following excerpt
may be quoted as one of his crucial experiments: "All the
nerves of the limb being severed, except those of the vasti and
crureus, the animal is inverted and the knee then gently but
fully extended by raising the foot, the thigh being held vertical.
The foot is then released, the anticrus falls, and in doing so is
seen to be suddenly checked by exciting a contraction of the
extensor of the knee. This contraction is different from a knee-
jerk, for it only slowly passes off." Sherrington, C. S. Proc.
Roy. Soc, London, ser. B 76: 283, 1905.
'' ". . .in the intact animal (cat, dog), severance of all the
nerve trunks directly distributed to all four of the feet up to and
above the wrists and ankles impairs walking so little £is to make
it highly unlikely that the loss of receptivity of the feet destroys
any large factor in the reflex basis of these acts ' (235).
40
HANDBOOK OF Pin'SrOLOGY
NEUROPHYSIOLOGY I
In
K^\ )>
"/
' 'I '- y
Fio. 25. Charles Scott Sherrington, from the drawing by Reginald Eves (reproduced by permis-
sion from Selected Writings of Sir Charin Sherrington, edited by D. Denny Brown. New Vorii: Hoeber,
1940). Right: Sherrington's classic picture of the areas for the scratch reflex in the dog. (From
Sherrington, C. S. The Integrative Action of the Nervous System. Cambridge: Cambridge, 1947.)
limb frequently evokes an exten.sor movement in the
contralateral homologous limb [the crossed-extensor
reflex (229)]; that this reflex can also be centrally
inhiljited; and that after prolonged inhibitory stimu-
lation there is, on withdrawal of the stimulus, an in-
crease of contraction ['reflex reljound' (230)]. These
are only a few of the reflex phenomena that received
elucidation through .Sherrington's work.
Out of a vast numljcr of laboratory experiments
grew his unifying hypothesis of reflex excitation and
reflex inhibition, and hence of an interdependence of
reflex arcs resulting in an integrative action of the
nervous system. .Sherrington's clas.sic book bearing
this title was published (231) when he was Professor
of Physiology at Liverpool University and was based
on lectures he gave at Yale University. The concepts
of 'the final common path,' of 'synaptic connections,'
of 'central inhilaition,' of 'central excitation" and of
'reciprocal innervation' are incorporated in modern
ph\siology which recognizes its deln to Sherrington.
The nineteenth century which had opened with only
one method for tracing fiber tracts — that of dissecting
them out as Bichat had done — gave to physiologists
two great new tools, the histological method of
2'50. Sherrington, C. S. Strychnine and reflex inhibition of
skeletal muscle. J. Physiol. 36: 185, 1907.
231. Sherrington, C. S. The Integrative Action of the .\ervous
System. New York; Scribners, 1906; new edition. Cam-
bridge: Cambridge, 1947.
Wallerian degeneration and the technique of electrical
recordings. In the hands of \'ictor Horsley and his
associates, Gotch, Beever, Schafer and others, electro-
physiology of spinal-cord systems made great advances
which can be followed in the series of papers pub-
lished in the Philiisoji/itcal Transactions between
1886 and 1 89 1. An overall view of what could be
achieved by this new method is given in the Croonian
Lecture of Gotch and Horsley in 1891 (232).
Towards the end of the century these techniques
were being applied, not only by Horsley, but by many
of his contemporaries to the study of the physiology
of the brain.
PHYSIOLOG^■ OF THE BR.MN : DEVELOPMENT OF
IDE.'SiS AND GROWTH OF EXPERIMENT
At the mid-eighteenth century, scientists seeking
knowledge of the brain could look back on a history
of their field that revealed a gradual evolution of
anatomical knowledge about its structure but only
conjecture about its physiology.
Among the early Greeks the teachings of Plato had
placed man's rational faculties where we would put
232. Gotch, F. .\nd Victor Horsley. On the mam-
malian nervous system, its functions and their localization
determined by an electrical method. Phil. Trims. B 182
267, 1 89 1.
THE HISTORICAL DEVELOPMENT OF NEUROPHYSIOLOGY
4'
*j.'~
J..'^*— >^ ..«»|o1.lCr'Jv.-'l>*-'"''
FIG. j6. /,('//• th<" tliree ventricles of the brain as ens isaged by Albertus Magnus. Right: Leonardo
da Vinci's wax cast, the first CNperimental determination of their shape.
them now, in the head; the passions he put in the
spinal marrow relating them to the heart, and the
lower appetites were given a place in the cord below
the diaphragm where they could play upon the liver.
For Plato these were the divisions of man's tripartite
soul.
Under the influence of Galen the spinal nervous
system lost this position of importance, for according
to his doctrine other organs of the bod\', the liver and
the heart, were the primary sites for manufacture and
transmutation of the spirits. From the Islamic physi-
cians came the emphasis on three ventricles with
different functions, an anterior ventricle being the
receiver of all incoming spirits, a 'sensus communis,'
whereas a posterior ventricle formed the reservoir for
the outflow of animal spirits to all muscles through
their nerves. In a middle ventricle was to be found
man's rea.son. Similar ideas about triple cavities in
the brain and their allotted functions were generally
accepted throughout the imenlightencd middle ages
until finally an anatomist, no less a man than Leo-
nardo da Vinci (233), mapped the true shape of the
ventricles by pouring into them melted wax to form
a cast.
Throughout the sixteenth and seventeenth cen-
turies, the structure of the brain was being unfolded
by the anatomists but still without a parallel investi-
gation of function. It was the cranial nerves that
■2;j3. DA Vinci, Leonardo (1452-1519). On Ike Human Body:
The Anatomical, Physiological, and Embryological Drawings of
Leonardo da Vinci, with translations, emmendations and a
biographical introduction by C. D. O'Malley and
J. B. deC. M. Saunders. New York: Schuman, 1952.
yielded first and Galen's seven pairs-^ (accepted on
his authority for 1400 years) swelled to nine in the
seventeenth century. In 1660 Schneider (234) identi-
fied the olfactory pair and 2 years later Willis (235)
dis.sected the accessory nerve that bears his name.
Today's recognition of 1 2 pairs of cranial nerves dates
from the eighteenth century and the work of von
Soemmering (236), whose books are illustrated by
engravings rivalled only by those of Charles Bell,
von Soemmering wrote copiously on anatomy, illus-
trating some of his work by his own hand and some
by the drawings of his pupil Koeck.
The role played by each pair of cranial nerves was
still in soine degree obscure, for some nerves appeared
to have more than one function, and Whytt (237)
was one of the earlv workers to obserx'e how complex
their action might be. He found that the optic nerve
234. Schneider, Conrad Victor (1614-1680). Liber primus de
catarrhis. Wittenberg: Mevius & Schumacher, 1660.
235. Willis, Thomas (1621-1675). ^^ Anima Brutorum. In:
Opera Omnia. Leyden : Huguetan, 1681.
236. Soemmering, Samuel Thomas (1755-1830). /> basi en-
cephali ei originibus nervorum cranio egredientum. Gottingen:
Vandenhoeck, 1 778.
237. Whytt, Robert (1714-1766). An essay on the vital and
other involuntary motions of animals. Edinburgh : Hamilton,
Balfour and Neill, 1751.
^* According to Galen's numbering, the seven pairs of
cranial nerves were: /) optic; 2) oculomotor and abducens
taken together; 3) and 4) were both parts of what is now called
the trigeminal, j) facial together with the auditory; 5) the
glossopharyngeal, vagus and accessory nerves; 7) the hypo-
glossal.
42
HANDBOOK OF I'H\SIOLOGY
NEUROPHYSIOLOGY I
FIG. 27. Thomas Willis and the illustration of the base of
the brain taken from his book De cerebri anatome. The circle of
Willis, named for him, had been depicted by several anato-
mists before him. Willis was fortunate in having Christopher
Wren as his illustrator.
was not .solely concerned with vision but that it car-
ried the stimulus that led to the contractile response
of the iris to light. In the post-mortem examination
on a child with fixed pupils he found a lesion blocking
the inflow from the optic nerves to the thalamus and
inferred that this impairment of sen.sory inflow was
responsible for the motor deficit that had been the
clinical sign. This was indeed the recognition of a
reflex arc, and the pupillary reflex was for many years
known by his name.
As noted above, Willis had di.ssected the spinal
accessory nerve to its junction with the cord but he
believed it to convey voluntary control. Lacking a
.scientific acumen equal to his skill as a dissector, and
influenced by Galen, he thought this nerve anasto-
mosed with the vagus (the "wandering' nerve).
Schneider, on the other hand, had no doubts as to
the action of the olfactory nerves for it was his work
on the nasal mucosa and olfactory processes that led
to his identification of them. Willis also was aware of
their function for he called them the 'smelling' nerves.
He noted that within the skull they had 'mammillary
processes' and said, "As to the Fibres and Filaments
or little strings stretching out from the more soft
nerves through the holes of the Sieve-like Bone into
the caverns of the Nose, these are found in all Crea-
tures who have the mammillary Processes: so it is
not to be doubted, but that these Processes, with this
appendix and its medullary origine is the Organ of
Smell."-' Willis called in his knowledge of compara-
" The quotations arc from Pordagos translation (1683) of
Willis, T. Cerebri anatome: cui acces\it nervorum descnpho el usus.
London: Flesher, 1664.
five anatomy and noted that "the filaments or little
strings" of the organ of smell were "more remarkable
in hunting Hounds than in any other Animal whatso-
ever.
The ner\es that had ijoth sensory and motor
branches proved the most difficult. Magendie (238)
at first thought the fifth nerve was sensory and nutrient
to the face, and the seventh nerve entirely motor,
since cutting it caused facial paralysis without reliev-
ing neuralgia. In 1820 Charles Bell (147), dissecting
the nerves of the face, noticed that the fibers of the
seventh nerve went to muscle whereas those of the
fifth entered the skin. He suspected they .served diff'er-
ent functions, and being himself an anatomist rather
than an experimentalist, asked his brother-in-law,
John Shaw, to make a study of the effect of sections
of these nerves. Using an unusual experimental
animal, the donkey, Shaw was able to demonstrate
paralysis in the one case, loss of reaction to touch in
the other; neither he nor Bell whose fine drawings
illustrate his findings recognized the mixed nature of
these nerves. After this beginning several workers
added their contributions to the further clarification
of the cranial nerves, prominent among these being
Mayo (239) (who taught the course in anatomy and
physiology at King's College, London).
It was only in the eighteenth century that doubt
was first thrown on the assumption that the sympa-
thetic trunk (or 'intercostal' nerve, as it was then
called) was an appendage of the brain. This grew
from the transection experiments of Pourfour du
Petit (240) and his oijsers'ations on contraction of the
pupil. For centuries anatomists had shown this nerve
as stemming from the brain. V'esalius (7), in his
drawings of the human nervous system, put it in one
trunk with the vagus. (In the dog, though not in man,
the two nerves lie in the same sheath in the neck
region.) Eustachius (241) separated the two, but like
many after him, including Willis, he depicted an
intracranial origin. These drawings of the anatomists
must have been designed to be consistent with Galen-
■238. Magendie, F. J. physiol. exper. et path. 4: 176, 302, 1824.
239. Mayo, H. Anatomical and Physiological Commentaries.
London: Underwood, vol. I, 1822; vol. II, 1823.
240. Pourfour du Petit, Franqois (1664-1741). Memoire
dans lequel il est demonstre que les nerfs intercostaux
fournissent des rameaux que portent des esprits dans les
ncrfs. Hnt. Acad. ray. Sc. Paris i, 1727.
241. Eustachius, Bartolommeo (1520-1574). Tabulae anato-
micae (posthumous). Rome : Gonzaga, 1 7 1 4.
THE HISTORICAL DEVELOPMENT OF NEUROPHYSIOLOGY
43
ist doctrine, rather than with observation I'rom dis-
section, du Petit's experiments came very close to
uncovering the action of vasomotor nerves, the suij-
ject that was to receive so much investigation in later
years from Claude Bernard (242, 243), from Clarl
Ludwig (244) and from Pavlov's other teacher, Cyon
(245). Bernard's experiments were mostly on skin
temperature changes due to vasomotor action, al-
though at no time would he relinquish entirely an
explanation on a metabolic basis. Ludwig had found
the secretory action of the lingual nerve but he did
not separate it from the chorda tympani as Bernard
did later.
A marked advance in understanding the physiol-
ogy, not only of the cranial nerves but of the brain
itself, came when techniques were developed for
ablating and stimulating parts of the central nervous
system without the animal succumbing to the pro-
cedures. The surgery in the early attempts was fre-
quently so drastic that results were rarely specific.
For example, the experimental results of Willis that
confirmed his belief in the cerebelliun as a vital
center were probably due to his animal's having suc-
cumbed to injuries near the fourth ventricle. Other
early experimenters such as Duverney (246) with his
pigeons, Chirac (247) and Perrault (248) with their
dogs had to be satisfied with very brief durations of
survival.
At the opening of the nineteenth century interest in
localization of cerebral function had been widely
stirred by the lectures of Franz Gall (249) in Vienna.
Unfortunately Gall's reputation as a phrenologist has
242. Bernard, Claude (18 13-1878). InHucnce du Kiand
sympathique sur la sensibilite et sur la calorification.
Cnrnpt. rend. Soc. de biol. 3; 163, 1851.
243. Bernard, C. De I'influence de deux oidies dc ncifs qui
determine les variations de couleur du sang veineux dans
les organes glandulaircs. Compt. rend. Acad, sc, Paris 47:
^4.5. 393. 1858.
244. Ludwig, Carl Friedrich VVilhelm (1816-1895). Mill,
naturjorsch. Gessellsch. ^urich 50, 1851.
245. Cyon, Ilya (1842-1912) and C. F. \V. Ludwig. Die
Reflexe eincs der sensiblen Nerven des Hcizcns auf die
motorischen der Blutgefasse. Arb. Physiol. Insl., Leipzig 1 :
128, 1867.
246. Duverney, Joseph Guichard (1648-1730). Phil. Trans.
Roy. Soc. 19; 226, 1697 (reported by Preston).
247. Chirac, Pierre (1650-1732). Du niolu cordis analylica.
Montpellier, 1698.
248. Perrault, Claude (1613-1688). Mernoires pour servir a
I'histoire des animaux. Paris: Acad. d. Sci., 1671-1676.
249. Gall, Franz Joseph (1758-1828) and Johann Caspar
Spurzheim (1776-1832). Recherches sur le systeme ner-
veux en general, et sur celui du cerveau en particulier.
Mem. Inst. Paris 1808.
fc:
fig. 28. Above: Gall and Spurzheim's map of a skull with
certain areas marked for correspondence with different mental
acu Ities. Below, for comparison : Gall's skull on the left, that of
Spurzheim on the right. Although Gall's own ideas were chan-
neled into phrenology, they were influential in directing interest
to the study of cerebral localization. (The skull of Gall is in the
Musee de I'Homme in Paris and is reproduced here by the
kindness of Dr. Ardvege; that of Spurzheim is in the Warren
Museum at the Harvard Medical School, and has been photo-
graphed by permission of Dr. P. L Yakovlev.)
overshadowed his more important work on the fiber
tracts of the white matter of the brain, work which
clarified the pre\iousl\- contradictory ideas as to the
anatomy of the commissures and of the pvramidal
decussation. But, while his contemporaries were con-
cerning themsehcs with sites for sensory and motor
functions. Gall was propo.sing localization of mental
faculties and he may be regarded as a pioneer in
emphasizing the importance of the grey matter for
intellectual processes. It was when, together with his
pupil, Spurzheim (250), he proceeded to assign
separate 'organs' in the brain to the different mental
faculties and to relate these to bumps on the skull
that he isegan to be challenged. All the same, in spite
250. Gall, F. J. and J. C. Spurzheim. Anatomic et physiologic
du systhne nerveux en general et du cerveau en particulier, avec
des observations intellectuelles et morales de r hotnme et des ani-
maux, par la configuration de leur teles. Paris: Schoell 1810—
1819 (vols. I & II by Gall & Spurzheim; vols. Ill & IV
by Gall).
44
HANDBOOK OF PHYSIOLOGY '-^ NEUROPHYSIOLOGY I
FIG. 29. Two investigators of the cerebellum, Pierre Fiourens
(1794- 1 867) and Luigi Luciani (i 840-1 921).
of its bizarre concepts, phrenology had a surprisingly
wide acceptance for a considerable period even
among the medical profession. It was to the psychol-
ogists (although that term was not yet in use) that
phrenology particularly appealed, for it was the first
major consideration of mental characteristics as
attributes of brain function.
One of the more prominent men to attack Gall's
doctrines was Fiourens who made a sweeping rejec-
tion of all such ideas, denying the brain any discretely
localized action. But Fiourens' monograph (251)
appeared some years after the deaths of Gall and
Spurzheim both of whom had built up comfortable
careers out of their speciality. Fiourens recognized
three major functional regions of the brain (the
cerebral hemispheres, the medulla and the cere-
bellum), but within these entities he envisaged their
action as global and their roles as being sensory, vital
and motor, respectively. Concerning the cerebral
hemispheres he said that animals that survive their
removal "lose perception, judgment, memory and
will . . . therefore the cerebral hemispheres are the
sole site of perception and all intellectual abilities"
(252). He did not hesitate to infer subjective qualities
and faculties. In one of the more renowned of his
experiments (253) he had kept a pigeon alive after
removal of its cerebral hemispheres. The bird was
■251. Flourens, Pierre (1794-1867). Examai de Phremlogie.
Paris, 1842; English translation by D. de L. Meigs.
Phrenology Examined. Philadelphia, 1846.
252. Flourens, P. Recherches experimentales sur les proprietes et les
fonctions du systeme nerveux dans les animaux verlebres. Paris:
Crevot, 1824.
253. Flourens, P. Arcli. gen, de med. 2: 321, 1823.
'blind' and 'deaf and appeared to be asleep although
it stirred when poked. Flourens went so far as to say
that the bird lost its volition and "even the faculty of
dreaming." He noted that it retained the sense of
equilibrium and that its pupils still reacted to light.
Others repeating Flourens' experiments were uncon-
vinced, for their decerebrate pigeons could be starded
by a loud noise and could avoid obstacles.
Since sudden death followed section of the medulla,
Flourens concluded that here lay the essential mecha-
nism for respiration and the maintenance of life. In
this conclusion he had of course been anticipated by
Legallois. Much of Flourens' fame as an experimental-
ist derived from his observation that extirpation of the
cerebellum (in birds and mammals) caused loss of
coordinated movement. Flourens, who.se interest lay
so deeply in the elucidation of the control of voluntary
movement, was himself to suffer paralysis for a long
period before his death.
In the 1820's when Fluorens was pursuing these
experiments, many workers were 'mutilating' ani-
mals (to use Gall's phrase) (254), and some jockeying
for priority was inevitai)le. Most of Flourens' observa-
tions, particularly those on the cerebellum, had been
anticipated by Rolando at Sassari, whose treatise
(255) of 1809 (written in the Italian language and
printed and illustrated ijy himself) was therefore re-
published in French in an abbreviated form in 1824
C256).
Rolando did not succeed in keeping his animals
alive. Even his tortoises died after removal of their
brains, although Fontana who had been successful
with these animals showed him his own technique.
Many of Rolando's conclusions (257) were therefore
incorrect since he mistook surgical shock for paralysis.
Less ruthless extirpations, of the hemispheres only, he
found to be compatible with life. Rolando believed
the cerebellum to be a kind of 'voltaic pile' and the
source of all movement. Flourens thought it merely
the regulator. Magendie (258) disagreed, holding
cerebellar function to be maintenance of equilibrium.
254. Gall, F. J. Stir les fonctions du cerveau et sur eelles de chacune
de ses parties. Paris, 1822-1825. 6 vol.
255. Rolando, Luigi (1773-1831). Saggio sopra la vera strutlura
del cervello delV uorno de degi animali e sopra le funzioni del
ststerna nervoso. Sassari, 1 809.
256. Rolando, L. Experiences sur les fonctions du systeme
nerveu.x. J. physiol. exper. et path. 3: 95, 1823.
257. Rolando, L. Osservazioni sul cervelletto. Mem. reale
aecad. sc. Turin 29: 163, 1825.
258. Magendie, F. Precis elhnenlaire de Physiologic. Paris, 1825;
English translation by E. Mulligan. Edinburgh: C^arfrae,
1826.
THE HISTORICAL DEVELOPMENT OF NEUROPHYSIOLOGY 45
FIG. 30. Lejt: Magendie's technique for sectioning the fifth nerve in the living rabbit. The dissec-
tion is to demonstrate the insertion of his instrument. On the rabbit's right, the probe is seen entering
the base of the siiull and reaching the trunk of the fifth nerve at H. On the animal's left, the end
of the instrument is seen at E and the sectioned nerve at G. (From : Bernard, C. Leqons sur la Pkysiologie
el la Pathologif du Sysleme .^eri'eux. Paris: Bailliere, 1858. Right: pigeon deprived of its cerebral hemi-
spheres in position described by Flourens. (From: Luciani, L. Human Physiology, English ed. Lon-
don: Macmillan, 1915.)
He reached this conclusion from studying the dis-
turbance of gait in a duck-* from which he had re-
removed the cerebellum unilaterally. He followed
these experiments with bilateral destructions and
noticed forced movements. The great contribution
towards our modern knowledge of cerebellar mecha-
nisms came from Luciani of Florence whose book //
Cervellelto (259) is a classic, as is also his te.xtbook of
physiology (260).
Magendie in the obsersations he made on decere-
brate animals (261) anticipated Sherrington by an
accurate and detailed description of decerebrate
rigidity in rabbits. This was in the days before the
discovery of anesthesia and Magendie was severely
.■59. Luciani, Luigi (1840-1921). // Cervelletto. Florence, 1891.
260. Luciani, L. Human Physiology. English translation by F. A.
Welby. London: Macmillan, 1915.
■261. Magkndie, F. Sur le siege du mouvement et du sentiment
dans la moelle epiniere. J. phvsiol. cxper. ct path. 3; 153,
1823.
criticized for his practice of vivisection. But extirpa-
tion experiments on animals could give no clue to the
cortical representation of speech. This had to come
from clinical observation with studies at autopsy.
Gall had placed language in the anterior lobes and the
first clinical reports seemed to confirm this. In fact,
the great surge of work aiming to establish localized
centers in the human brain began with the speech
center. In his studies of encephalitis Bouillaud (262},
a pupil of Magendie and later Professor of Medicine,
had reasoned that the anterior lobes of the brain were
necessary for speech and went on to ob.serve that
other focal lesions of the brain caused localized im-
262. Bouillaud, Jean Baptiste (i 796-1 881). Traite clinique et
physiologique de V encephalitt' ou inflammation du cerveau. Paris :
Bailliere, 1825.
^' Sherrington in quoting this experiment mistranslated
Magendie's word 'canard' as 'water-dog.'
46 HANDBOOK OF PHYSIOLOGY ^ NEUROPHYSIOLOGY I
'i-yanuC
Strasssui
FIG. 31. Goltz and one of his decorticate dogs. (Studio portraits of man and dog are reproduced
here by the tcind permission of Dr. Paul Dell.)
pairment of mu.scular movement. The cause of cere-
bral localization was taken up by his son-in-law,
Auburtin (263), who predicted that a lesion would
be found in the anterior lobes of an aphasic patient
who was at that time in the hospital of Bicetre under
the surgeon Pierre Broca. Autopsy confirmed Aubur-
tin's prediction, pinpointing the lesion in the left
anterior lobe. The next aphasic patient on Broca's
service was found at autopsy to have an even more
discrete lesion — in what is known to this day as
Broca's area ('-64)- The name of Auburtin has been
forgotten, as has Broca's term 'aphemia' for aphasia.
Broca's speech area (the left third frontal convolu-
tion) which he thought to be concerned with articula-
tion was to be challenged by Pierre Marie (265) in
the twentieth century, but the new concept of cerebral
localization de\eloped like a wave in the later 1800's
• — a wave that is only now beginning partially to
263. AuBERTiN, Ernst (18-25- )■ Considerations sur les
localisations cerebrales, et en particulier sur le siege de la
faculte du langage articule. Ga:^. hehd. med. et chir. 10: 318,
348, 397. 455. 1863.
264. Broca, Pierre Paul (1824-1880). Perte dc parole,
ramoUissement chronique et destruction du lobe anterieur
gauche du cerveau. Bull. soc. anthropol. Paris 2: 235, 1861.
265. Marie, Pierre (1853- 1940). Revision de la question de
I'aphasie; la troisieme circonvolution frontale gauche ne
joue aucun role special dans la fonction du langage. Sem.
med. Paris 26: 241, 1906.
recede. For the physiologists the impressive experi-
ments were those of Goltz of Strasbourg who, after
starting with frogs (266}, mastered the technique of
keeping warm-blooded animals ali\e for prolonged
periods after drastic extirpations of large portions of
their brains (267). Three of his dogs became famous.
The first two survived 57 and 92 days respectively,
the third being purposely sacrificed at 18 months.
Goltz exhibited them at international congresses,
killed one of them before an audience and gave their
brains to Langley in Foster's laboratory to dissect
(268, 269). Sherrington's participation in the necropsy
of one of these dogs was the subject of his first pub-
lished paper (in 1884) (270). All who witnessed the
remarkable degree of retention of sensibility and
266. Goltz, Friedrich Leopold (1834-1902). Beilrcige z"r
Lehre den Funktionen der Nervenz.enlren des Frosches. Berlin :
Hirschwald, i86g.
267. Goltz, F. L. Der Hund ohne Grosshirn. .irch. ges. Physiol.
51: 570, 1892.
268. Langlev, J. N. Report on the parts destroyed on the
right side of the brain of the dog operated on by Professor
Goltz. J. Physiol. 4: 286, 1883.
269. L.ANGLEV, J. N. AND A. S. Grunbaum. On the degenera-
tion resulting from removal of the cerebral cortex and
corpora striata in the dog. J. Physiol. 1 1 : 606, 1890.
270. Langlev, J. N. and 0. S. Sherrington. Secondary de-
generation of nerve tracts following removal of the cortex
of the cerebrum in the dog. J. Physiol. 5: 49, 1884.
THE HISTORICAL DEVELOPMENT OF NEUROPHYSIOLDGV
47
mobility by these animals and who later studied the
necropsy findings from the Cambridge laboratory
were astounded, and there can be no doubt that these
experiments gave a great impetus to neurosurgical
procedures in animals and in man.
The physiology of the brain was now beginning to
unfold and to reveal itself in dynamic terms after
centuries of static representation in the two-dimen-
sional pages of the anatomy books. To clinical obser-
vation of impairment by disease states, three experi-
mental techniques were added : regional ablation,
stimulation (both mechanical and electrical) and
eventualh' the recording of the brain's own electricity.
Mechanical and chemical irritation of the cortical
surface had suggested itself to many in\estigators down
the years, some of the attempts reaching the extremes
of the bizarre (see, for example, fig 32). Cabanis
(271), the celebrated physician and ideologue, had
provoked convulsive movements in muscle groups
that .seemed to vary with the region irritated. Earlier,
Haller (272), searching for irritability, had pricked
the brain and applied irritating fluids and concluded
that the grey matter was insensitive to stimulation
and that the white matter was the seat of sensation
and the source of movement.
The Italian physiologists had been more successful.
The Abbe Fontana (273) and Caldani (274) (Gal-
vani's predecessor in the chair of anatomy at Bologna)
had convulsed their frogs by electrical stimulation
inside their brains. Rolando (255), following their
lead, extended his experiments to pigs, goats, sheep,
dogs and also to birds. The influential Magendie
however had failed and had proclaimed the cortex
electrically inexcitable; an opinion in which he was
backed by Flourens (252). In these days before the
neuron had been recognized as the unit of the nervous
system, before the pyramidal fibers were known to be
processes of cortical cells, there was no a priori reason
to expect electrical stimulation of the cortical surface
to have a peripheral effect, but soon an incontro-
\ertible proof was to be given.
FIG. 32. One of the bizarre experiments of .Mdini on two
freshly-decapitated criminals. In the center is a voltaic pile, the
circuit through the heads being completed by conducting
arcs. .Mdini, Galvani's impetuous nephew, lacked the sagacity
and scientific acumen of his famous uncle. (From Aldini, G.
Essai Theorique el Experimental sur le Galvanisme. Paris; Fournier,
1804. 2 vol.)
FIG. 33. Two pioneers in attempts to stimulate the brain:
the Abbe Fontana, physician to the Archduke of Tuscany and
professor of physics in the University of Pisa; and Caldani,
Galvani's predecessor in the chair of anatomy at Bologna.
(The portrait of Fontana is reproduced by courtesy of Dr. G.
Pupilli.)
271. Cabanis, Pierre J.-G. Rapports du physique et du moral de
I'homme. Paris: Bibliotheque Choisie, 1830.
272. ZiNN, JoHANN Gottfried (i 727-1 759) and A. Haller.
Memoir es sur les parties sensibles et trrilables du corps animal.
Lausanne: D'Arnay, 1760.
273. Fontana, Felice (1720-1805). Acead. Sc. 1st. Bologna,
>757-
274. Caldani, Leopoldo (1725-18 13). Institutiones phystologicae
et pathologicae. Leyden: Luchtmans, 1784.
The pioneers were Fritsch & Hitzig (275) (two
young privatdocents in Berlin) with their now famous
experiments in which they u.sed a galvanic current
and from which evolved the idea of a 'motor cortex.*
275. Fritsch, Gust.w Theodor (1838-1891) and Eduard
Hitzig (1838-1907). Uber die elektrische Erregbarkeit
des Grosshirns. .Irch. Anal. Physiol, miss. Med. Leipzig 37:
300, 1870.
48
HANDBOOK OF Pm-SIOLOGY
NEUROPHYSIOLOGY 1
fXi^*^:\m^.l
FIG. 34. Gustav Fritsch and Edouard Hitzig. (Photographs
reproduced by kind permission of Dr. A. E. Walker, for whom
Professor Stender of Berlin obtained the picture of Hitzig.)
Ferrier (276-278), a few years later, in a long series
of experiments using faradic stimulation in monkeys
was able to bring out not merely muscle twitches of an
indeterminate kind but also grosser movements. Of
course, as we now know, these are imprecise and even
athetoid in comparison with movements made by the
animal naturally. Benefitting from the parallel devel-
opment of electrical techniques, Victor Horsley, in a
series of papers with Beevor (279, 280) in the next
decade, described more closely the motor areas in the
monkey cortex. From these experiments there emerged
the designation of the precentral gyrus as predomi-
nantly motor in function and the postcentral as sen-
sory. Between the two, Beevor & Horsley (281,
^76. Ferrier, David (1843-1928). The localization of function
in the brain. Proc. Roy. Soc. 22: 229, 1873-4.
277. Ferrier, D. Experiments on the brain of monkeys. P/ut.
Trans. 165:433, 1876.
278. Ferrier, D. The Function of Ihf Brain. London Smith
Elder, 1876.
279. Beevor, C. E. and V. Horsley. A minute analysis (ex-
perimental) of the various movements produced by stim-
ulating in the monkey different regions of the cortical
centre for the upper limb as defined by Professor Ferrier.
Phil. Trans. 178: 153, 1887.
280. Beevor, C. E. and V. Horsley. A further minute analy-
sis by electrical stimulation of the so-called motor region
(facial area) of the cortex cerebri in the monkey. Phil.
Trans. 185: 39, 1894.
281. Beevor, C. E. and V. Horsley. An experimental in-
vestigation into the arrangement of the excitable fibres of
282) recognized an area which they called 'the zone
of confusion.' An important point that emerged from
their use of this technique was that in addition to areas
of maximal representation of a given movement, the
cortex also has marginal zones that are less specific.
In other words, they found no sharp demarcation
lines.
With Schaefer (283), Horsley went on to further
studies of both motor and sensory function, using
ablation as well as electrical excitation. The basic
interest was of course in the application of these find-
ings to man, especially in the light of the observations
of Hughlings Jackson on the march of symptoms
during the epileptic fit (284). Species differences
came markedly to light when Beevor & Horsley
compared their findings on the bonnet monkey with
those in the orangutan. The first pioneers to attempt
electrical stimulation of the cortex in man (through
holes in the skull) were Bartholow in America in
1874 (285) and Sciamanna 8 years later in Italy (286).
These were followed by Keen (287), in his youth an
army surgeon in the American Civil War and later
professor of surgery at Jefferson Medical College. In
1888, in a patient whose seizures began in the hand,
he removed the area the stimulation of which caused
movements of the wrist. He used a 'faradic battery,'
and with it found areas for hand, elbow, shoulder
and face movements. When respiration and circula-
tion became poor, he revived the patient with brandy
injected into the forearm. In the same year several
other workers applied a similar technique in man but
the internal capsule of the bonnet monkey. Pliil. Trans.
181 : 49, 1890.
282. Beevor, C. E. and V. Horsley. A record of the results
obtained by electrical excitation of the so-called motor
cortex and internal capsule in the orang-utang. Phil.
Trans. i8i : 129, i8go.
283. Horsley, V. and Edward Albert Schaefer (1850-
1935). A record of experiments upon the functions of the
cerebral cortex. Phil. Trans. 179: i, 1888.
284. Jackson, John Hughlings (1835-191 i). Unilateral
epileptiform seizures, attended by temporary defect of
sight. Med. Times Gaz. I : 588, 1863.
285. Bartholow, Roberts (1831-1904). Experimental in-
vestigations into the functions of the human brain. .Im.
J. M.&. 67:305, 1874.
286. Sciamanna, E. Gli avversari delle localizzazioni cercbrali.
Arch, psichiat. Turin 3: 209, 1882.
287. Keen, William Williams (1837-1932). Three successful
cases of cerebral surgery including (i) The removal of a
large intracranial fibroma; (2) Exsection of damaged
brain tissue; and (3) Exsection of the cerebral centre for
the left hand; with remarks on the general technique of
such operations. Am. J. M. Sc. 96; 329, 452, 1888.
THE HISTORICAL DEVELOPMENT OF NEUROPHYSIOLOGY
49
^P^^l
P^^^
v.^, \_rrg<^
HHHHHH^^HHIi^^^Hiiii^wiKd^^-.-je^^ ^
FIG. 35. Victor Horsley and one of his experiments on the locaUzation of the motor cortex. (The
latter illustration from Trans. Congr. Am. Physic. Surg, i : 340, 1888.)
systematic exploration had to wait for Gushing,
Foerster and Penfield in the modern age of neuro-
surgery, and for the development of clinical neuro-
physiological investigation.
In the light of clinical oljser\ation and the results of
electrical stimulation, the concept that the cortical
grey matter acted as a whole and that motor function
had no representation above the basal ganglia began
to crumble. At this same period, the birth of a new
technique brought yet another method of approach
for the investigator. This was the recording of brain
potentials evoked by sen.sorv stimulation and the
discovery of the Ijrain's own electrical activity, the
dawn of electroencephalography.
In 1875 Richard Caton (288), at the Royal Infir-
mary School of Medicine in Liverpool, while searching
for the cerebral counterpart of du Bois-Reymond's
action potential in nerve, not only found it, but
noticed that when both of his electrodes lay on the
cortical surface there was a continuous waxing and
waning of potential. This oscillation of the base line
was present in the unstimulated animal and Caton
proved it to be unrelated to respiratory or cardiac
rhythms. He also proved these fluctuations to be
biological in origin ijy showing them to be vulnerable
288. Caton, Rich.^rd (1842-1926). The electric currents of
the brain. Brit. M. J. 2: 278, 1875.
to anoxia and to anesthesia and to be abolished by
death of the animal. In his first work Caton's experi-
mental animal was the rabbit and his detecting
instrument was a Thomson's galvanometer. This
was in the days before photographic recording of
laboratory observations and Caton's first publication
of his findings took the form of a demonstration before
the British Medical Association (289). Superimposed
on these o.scillations Caton found potential swings
related to sensory stimulation and realized immedi-
ately the meaning of this for cerebral localization
studies. Caton went on to use monkeys and gave fur-
ther reports of his results in 1877 and in 1887 (290).
the latter at the International Medical Congress held
that year in Washington, D. C.
Strangely enough, in spite of the prominent groups
before whom Caton gas'e his demonstrations and the
popular medical journal in which he reported them,
his work received little attention at the time, even
among English-speaking physiologists. Meanwhile in
Poland, a young a.ssistant in the physiology depart-
ment of the University of Jagiellonski in Krakow,
289. Caton, R. Interim report on investigation of the electric
currents of the brain. Brit. M.J. i : Suppl. 62, 1877.
290. Caton, R. Researches on electrical phenomena of cere-
bral grey matter. Tr. Ninth Internat. Med. Congr. 3 : 246,
1B87.
50
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
FIG. 36. Richard Caton, shown in his thirties at the period
when he was working in electrophysiology. (From a photo-
graph in possession of the writer, being the generous gift of
Miss Anne Caton.)
Adolf Beck, not knowing of Caton's work 15 years
earlier, was searching initially for the same phenom-
enon, namely for electrical signs in the brain of im-
pulses reaching it froin the periphery. Like Caton
before him he succeeded, but he also found the brain
wave. His animals were mostly dogs and he pub-
lished the protocols of all his experiments in the
Polish language for a doctoral thesis (291). In order
to reach a wider audience he sent a short account to
the most widely read journal in Germany, the
Cenlralblatt jur Physiologie (292). A spate of claims for
priority for finding sensorily evoked potentials fol-
lowed the German publication of Beck's findings —
the first coming from Fleischl von Marxow, Profes.sor
of Physiology in Vienna (293), and the next from
291. Beck, .Adolf ( 1863-1942). O-z'tacz^nie lokalizocyi w moz^u
i rdzt'niu za ponwca zj^^^'i^^^ elektry czynch (Thesis). Krakow;
Univ. Jagiellonski, 1890.
Q92. Beck, A. Die Bestiinmung der Localisation der Gehirn
und Riichenmarksfunktionin vermittclst der elektrischen
Erscheinungen. Centrathl. Physiol. 4: 473, 1890.
293. Fleischl von Marxow, Ernst. Mittheilung betrefTend
die Physiologie der Hirnrinde (letter to the editor dated
Vienna, Nov. 24, 1890). Centralbl. Physiol. 4: 537, 1890.
Gotch and Horsley (294). It is noticeable that it was
the electrical response of the brain to sensory stimula-
tion that drew the most interest, for this was a finding
that lay directly in the main stream of current think-
ing about cortical localization of function. The
completely novel idea of a continuously fluctuating
electrical potential intrinsic to the 'resting' brain
was, at that time, of interest only to its two independ-
ent discoverers, Caton and Beck.
The somewhat acrimonious wrangle over priority
was based in Fleischl von Marxow's ca.se on work
done in 1883. This had not been published but only
noted down in a sealed letter which he had deposited
with the University and which he asked to have
opened after reading Beck's report in 1890. He was
solely concerned with response potentials and noted
"little or no movement of the base line." He was
clearly unaware of Caton's reports and demonstra-
tions. Gotch and Horsley's ignorance of their country-
man's work is less easily understood. Caton was a
prominent figure at Liverpool, the first holder of the
Chair of Physiology in which Gotch was to follow him
(and later Sherrington).
The dispute in the columns of the Centralblalt o\er
priority for discovery of the electrical currents of the
brain was finally stilled by a letter from Caton (295),
drawing the attention of the protagonists to his
publication of 1 5 years earlier. By the turn of the
century the electrical activity of the brain had reached
the textijooks (296). Caton's interests had developed
along many lines and he became prominent in
.se\eral fields of medicine and scholarship as well as in
public affairs, becoming in turn President of the Medi-
cal Institution and Lord Mayor of Liverpool. Beck
(297), who at the age of 32 became professor of
Physiology at the University of Lvov, continued to
work on the subject into this century, publishing with
his old professor Cybulski, and interest was thereby
aroused in Germany and in Russia. He met a tragic
death during the German occupation of Poland.
294. Gotch, F. .and V. Horslev. Uber den Gebrauch der
Elcktricitat fiir die Localzirung der Erregungserscheinun-
gen im Centralnervensystem (letter to the editor received
Jan. 17, 1891). Cenlralbl. Physiol. 4:649, 1891.
295. Caton, R. Die Strome des Centralnervensystems (letter
to the editor received Feb. 22, 1891). Cenlralbl. Physiol. 4:
785, 189!.
296. ScHAFER, E. .\. Ti'xlhook of Physiology. Edinburgh: Young
& Pentland, London: Morrison & Gibb; 1898, 1900. 2 vol.
297. Beck, A. and Napoleon Cvbulskl VVeitere L'ntersuchun-
gen iiber die elektrischen Erscheinungen in der Hirnrinde
der .AflTen und Hunde. Cenlralbl. Physiol. 6:1, 1892.
THE HISTORICAL DEVELOPMENT OF NEUROPHYSIOLOGY
51
ll..-w,.,,l, ,,„,, IX
IN.'-* *in/y u
.■kiirfir\/.i>M:iii\. P'ifkul.i iiiM/;;,nv.n pra^^.i .lr<lria
p|«klr»<U im "lH/.;ip/
w/r'»k'iw\m ,r. 'IniL';! 11:1 Mlf»/..ir/.' tii''t.irvf/.iivMi
dl»
[•nwdiii'-j k"ric/.viiv *" liir 17>""i ( i4tf;rlo!ii' olm i-li-kir-Ml ,in nmi
A
Wvrt.vl.iiir: i'l. ',o. l.t. ;i.\ 3M. in. ;.\ ;Mh.
I
/■.rtilnztiiono swialfcin nia;:n<'Wi'ni «>ko lewf !H;
•|Mi (intitiiiu ilra7in.-nia; i*.'t. ;U). 2."», in. -i"J. l.'t. lO;
.irariiirnir ndii'ip [irzrdnifj 70;
|K) ii«wniii <ln»7.iiii'nta: ">iS. IHI, ."m, 4H-
■| r^/i
A) Po (UuTBWJ |iaii«ic |im>^aiii;to tvlna eloktro-
Tu '^
dt,> 0 '► mm. kii lyjowt (Hk- 17 rw). Wychylenie
i'fy
wyk«7.ywftl.>. 70 ok'.liia la j. .-t .kklrv-iijcriina;
wvnDtilu 'trK- :
-^^^ y
L>ti.".. IM,".. IH.-,. isH. iT.i. IT.'i. IMt. ir.:,. l.V>, Ifil;
~
u
(K) ziiilra/nieniii iwiatJcni . I>2;
l><i uilaiiin draznun-a; IV.. Il">. l.'iti. I.')*t, I'i7;
lirzv (Int/niriiiii 'iJiii»;:i pr^'- Inirj : Ihii;
.
fij 1:
|><i U'<taiiiii dra/nii-nia : 1 I't. 1 1"
FIG. 37. Beck and protocol from one of the experiments in his original thesis on the electrical
phenomena of the brain and spinal cord, i8go. (Obtained through the courtesy of Dr. Andrei Jus of
Pruszkow.)
Interest became widespread in 1929 with the first
publication on brain potentials in man. In that year
Hans Berger (298), a psychiatrist in a hospital in
Jena, revealed to the scientific world the results of
work he had been pursuing in secretive seclusion for
over 5 years. He had repeated and confirmed the
findings of Caton (to whom he gave full credit) and
had extended them to man. He studied (and named)
the electroencephalogram in normal man, finding
the two major rhythms, alpha and beta, that Nemin-
ski had found in dogs (299). He applied Caton's
tests for the biological origin of the potentials he found,
showing them to be affected by hypoxia and by anes-
thesia. He also found them to be changed by sleep.
Berger's outstanding contribution was the founda-
tion of clinical electroencephalography. Having
proved that brain waves could be recorded in man
through the unopened skull, he went on to demon-
strate that their characteristics could be used as an
index of brain disease and thus he opened up a new
line of approach for the physiologist and the clinician
to the study of brain mechanisms. Berger's major dis-
covery in the clinical field was that the electroen-
cephalogram is abnormal in epilepsy. He did not with
298. Berger, Hans (i 873-1 941). Uber das Elektrenkephalo-
gramm des Menschen. Arch. Psychial. 87: 527, 1929.
299. Prawditz-Neminski, W. W. Zur Kenntnis der elektrischen
und der Innervationsvorgange in den functionellen
Elementen und Geweben des tierischen Organismus.
Elektrocerebrogramm der Saugcrtiere. Arch. ges. Physiol.
209: 362, 1925.
ii
FIG. 38. Hans Berger, the first to record electroencephalo-
graphic potentials from man, and the founder of clinical
electroencephalography. Below is the first published electro-
encephalogram of man. The subject was Berger's son, Klaus.
His alpha rhythm is shown in the upper trace above a 10 per
sec. sine wave from an oscillator.
centainty record the spikes that are now associated
with the seizure discharge, for with the technique he
used there was serious interference by muscle poten-
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
tials. His instruments were a double-coil galvano-
meter and a string galvanometer, and in much of his
initial work he used only two electrodes, these being
large plates fixed one to the forehead and one to the
back of the head. He thus missed the localizing poten-
tialities of the EEG, and in addition gathered in all
the muscle potentials of the frontalis and trapezius
muscles. In later experiments he changed to needle
electrodes pushed into the skin. In his early experi-
ments he tried a reference electrode consisting of a
silver spoon held in the subject's mouth. The develop-
ment of concepts about the EEG concomitants of
grand mal epilepsy had their grounding in Fischer's
(300) recordings during experimentally-induced
seizures in dogs.
The demonstration of the 3 per sec. wave-and-
spike formation so typical of the petit mal type of
epilepsy was the achievement of the team of Lennox,
Davis and the Git)bses at the Harvard Medical .School
(301). This discovery (which Berger came very close
to making), together with that of Grey Walter (302)
published the following year (1936), namely that
brain tumors can be located through the skull by the
abnormally slow waves of their surrounding tissue,
form the two main foundations of clinical electro-
encephalography. Altenburg & Foerster (303) had
during a brain operation found abnormal potentials
a.ssociated with a tumor, but Walter's demonstration
that neoplasms could be located by the reversal of
sign of the slow waves recorded from the unopened
head and his confirmation that the tumor itself was
electrically silent made this a practical clinical test.
The subsequent expansion and development of
electroencephalography is part of the continuing
story of modern times not yet history.
In the history of electroencephalography one other
figure should be mentioned. One year after Caton's
discovery, Danilewsky, the Russian neurophysiologist,
noted the same phenomenon of oscillating cortical
potentials in the absence of applied sensory stimula-
tion in five dogs on which he was experimenting. He
did not publish this at the time and reported it only
in retrospect C304) as a confirmation of Caton's
original ob.ser\ation. Danilewsky's primary interest
lay in the autonomic eff'ects of stimulation of the cor-
tex, such as arterial pressure changes (305), and in the
mechanisms of temperature control (306), and he was
active in the design of new instrumentation for electro-
physiological experimentation (307). Together with
his brother (Alexis Y. Danilewsky) he was prominent
among the Russian physiologists at the end of the
nineteenth century.
In the latter half of the nineteenth century, Russian
neurophysiology saw a development that was to in-
fluence all future concepts about the brain and be-
havior. At this period it was usual for Russian physiol-
ogists to go to centers in Western Europe for training
and experience under the outstanding teachers of the
time, and to Miiller's laborator\' in 1856 came I. M.
.Sechenov. Secheno\', later to be known as 'the father
of Russian neurophysiologv' was then 27 years old and
during the next 6 )ears he received training from six
of the more outstanding physiologists: Miiller, du
Bois-Reymond, Ludwig, \'on Helmholtz, Bunsen and
Claude Bernard. The influence of these leaders can
be traced in .Sechenov's later thought and develop-
ment. Among them, only one, Miiller, retained even
a lingering trace of allegiance to the concept of a vital
force, and with him Sechenov- had the least contact,
for Midler was at the end of his life, still lecturing but
no longer experimenting.
In neurophysiology the most influential of Seche-
nov's teachers were du Bois-Reymond and Claude
Bernard. Sechenov took du Bois-Reymond's cour.se in
animal electricity and in i860 returned to St. Peters-
burg with one of his master's induction coil stimula-
tors and a galvanometer and with them introduced
electrophysiology into Russian science. Two years later
he was back in Western Europe, this time in Claude
Bernard's laboratory in Paris, and it was here that
the experiments were made that were to mold his
thinking and to suggest to him a concept of brain
mechanisms later to flower in the hands of Pavlov
into the theor\' that has dominated Russian neuro-
300. Fischer, Max H. Elektrobiologische ."^uswirkungen von
Krampfgiften am Zentralnervensystem. Med. K/in. QMu-
mch^'^g: 15, 1933.
301. GiBBS, F. A., H. Davis and W. G. Lennox. The EEG in
epilepsy and in conditions of impaired consciousness.
A. M. A. Arch. .Neurol. & Psychial. 34: 1 133, 1935.
302. Walter, VV. Grey. The location of cerebral tumours by
electroencephalography. Lancet 2: 305, 1936.
303. Foerster, O. and H. Altenburger. Elektrobiologische
Vorgange an der menschlichen Hirnrinde. Deuliche
Zlschr. .Nervenh. 135: 277, 1935.
304. D.\nile\vskv, Vasili Y.\kovi.evich (1852- 1 939). Zur
Frage iiber die elektromotorischen Vorgange im Gehirn
als Ausdruck seines Thatig keitszustandes. Centralbl.
Physiol. 5: I, 1 89 1.
305. Danilewsky, V. Y. Experimentelle Beitrage zur Physi-
ologic des Gehirns. Arch. ges. Physiol. 11 : 128, 1875.
306. Danilewsky, V. Y. Die Verbrennungswarme der Nah-
rungsmittel. Biol, ^enlralbl. 2: 371, 1882.
307. D.^NiLEWsKv, V. Y. A new electrical machine for rhyth-
mically altering the strength of galvanic currents (in
Russian). Vralsch. 22, 1883.
THE HISTORICAL DEVELOPMENT OF NEUROPHYSIOLOGY
53
FIG. 39. Ivan Michailovich Sechenov and his diagram illustrating reflex arcs in the spinal cord
and brain of the frog, a-b-c-d represents a spinal refle.x arc with sensory (a-A), central (b-c) and
motor ((■-(/) components. The reflex arc of the brain consists of the sensory nerve (O), the central
component (.V-f) and the motor efferent (<:-(/). P is the region in the brain stem where Sechenov
concluded the inhibitory apparatus lay.
physiology ever since, the theory of conditional re-
flexes.
Sechenov's experiments that proved so crucial to
his future thinking were on the effect on reflex move-
ments of salt crystals placed at various levels of the
transected neuraxis (308). His preparation (309) was
the decapitated frog, a toe of which he dipped into
acid, a procedure that had been developed by Tiirck.
He timed the interval between stimulus and onset of
withdrawal of the frog's foot by counting the beats of
a metronome. In this way he got some index of the
degree to which application of the salt crystal to the
brain stem slowed withdrawal. Sechenov interpreted
lengthening of withdrawal time as inhibition of reflex
activity. The selection of a salt crystal as a stimulus
seems strange in the hands of a pupil of du Bois-
Reymond's and is reminiscent of Marshall Hall's use
of it half a century earlier to study depression and
308. Sechenov, Ivan Mich.mlovich (1829-1905). Physiolo-
gische Studien iiber die Hemmungsmechanismus fur die Re-
flexthdiigkeit des Riickenmarks im Gehirne des Frosches. Berlin :
Hirschwald, 1863.
309. Sechenov, I. M. Note sur les moderateurs des mouve-
ments reflexes dans le cerveau de la grenouille. Acad. Sc,
Paris 1863.
augmentation of spinal reflexes. Only later (310) did
.Sechenov use electrical stimulation in his experiments
on the 'spontaneous' variations of spinal cord poten-
tials which he regarded as signs of activity in the
spinal centers. This was the first experimental ap-
proach towards a centrally exerted inhibitory action
on skeletal ('voluntary') muscle.
Although at this stage his own experimental evi-
dence seemed slender, Sechenov must have been
pondering its meaning in much wider terms, for a
year later, on his return to Rus.sia, he published as a
series of articles the essay (31 1) that proved to be so
influential in Rus.sian physiology. This essay on the
Reflexes of the Brain was later (1866) published as a
book after a stormy period during which efforts were
made to suppress its publication and censure its
author. This opposition was stirred by Sechenov's
assertion that all higher brain function was a material
reflex consisting of three sectors — an afferent initia-
tion by sensory inflow, a central process entirely sub-
310. Sechenov, I. M. Galvanische Erscheinungen an dem
Verlangerten Marke des Frosches. Arch. ges. Physiol. 27:
524, 1882.
311. Sechenov, I. M. Reflexes of Ike Brain. Medizinsky Veslnik,
1863; English translation in Sechenov's Selected Works.
Moscow-Leningrad: State Publ. House, 1935, p. 263.
54
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
ject to physical laws and an efferent component result-
ing in a muscular movement. All reactions, however
they might be described in common parlance as
pleasure, fear, distress or other descriptive terms were,
according to him, in essence muscular in expression.
During the passage of the inflow through the central
portion of the arc there could either be excitation
which would augment the reflex motor response (as
in so-called emotional states) or inhibition which
would decrease the reflex muscular movement, the
resultant beine; 'rational' controlled behavior. It is
interesting that Sechenov conceived that inhibition
could be learned and that with maturity an increase
in the degree of inhibition exerted was achieved.
Thus, according to Sechenov, all human behavior
was a balance between inhibition and excitation
operating mechanically at the central link of the re-
flex arc. A so-called 'willed' movement according to
him only apparently lacked the first component of the
arc, its afferent inflow being material memory traces
left by external stimuli in the past. It was in elaborat-
ing this part of his theory that Sechenov approached
the concept of the conditional reflex, for he postulated
that the memory trace of a past sensory experience
could be evoked by the recurrence of any fraction of
it even if this fraction were quite insignificant and
unrelated in its apparent meaning. This is essentially
the principle underlying the formulation of the condi-
tional reflex theory, namely the potency of an indiffer-
ent external stimulus provided it is repeatedly time-
locked to the original experience. One further point
should be noted in this early attempt to relate mental
processes to brain physiology. Sechenov believed that
man had the special faculty of increasing the degree
of inhibition exerted at the central link until a level
of total inhibition of the efferent discharge was
reached, and he held that thought was an example of
this condition.
Although terms such as 'cerebral reflexes' and
'psychical reflexes' abound in the nineteenth century
literature, they were mostly used by psychologists
to describe automatisms. At this period only a few
writers had broached the problem of explaining
mental processes in physiological terms. Thomas Lay-
cock C312), whose belief in cortical localization no
doubt influenced his pupil Hughlings Jackson, wrote
in 1845 a paper On the reflex function of the brain. In this
he stated his belief that "the brain although the organ
of consciousness, was subject to the laws of reflex ac-
tion, and that in this respect it did not differ from other
312. Laycock, Thomas (1812-1876). On the reflex function
of the brain. Brit. & For. Med. Rev. 19: 298, 1845.
ganglia of the nervous system." He too envisaged a
three-component arc, the central link in the brain
being one where 'ideagenous' changes took place that
influenced the motor output. He came close to antic-
ipating one of Sechenov's postulates by stating that
the actual sensory impression of an object or the mere
idea of it could evoke the same 'ideagenous' change
in the brain and result in a similar reflex motor effect.
So firmly did Laycock believe in the neuronal basis
of ideas that he calculated how many there could be
to the square inch of grey matter (the answer was
8000) and argued that "as there must be an immense
number of square inches of surface in the grey matter
extended through the cerebrospinal axis of man, there
is space sufficient for millions." We find echoes of this
kind of calculation in some of today's conjectures
about the number of possible interconnections in the
brain.
Laycock did not test his hypotheses by experiment
though he argued from a basis of clinical observation,
for he said "an experiment is occasionally made by
nature." There is no evidence that Sechenov was
aware of Laycock's ideas, although he was influenced
by the writings of two other nonexperimentalists,
Herbert Spencer (313) and George Henry Lewes
(314). These two men, united through their relation-
ships with George Eliot, were influential not only on
Sechenov but on Pavlov. Their writings, now largely
unread, were translated into Russian almost immedi-
ately after publication and were everywhere highly
regarded. .Spencer's work was an argument for cortical
representation of mental function, and Hughlings
Jackson was one who expressed indebtedness to him.
Spencer based much of his argument on comparative
evolution though he was writing 4 years before the
publication of the Origin of the Species by Darwin
(315), another writer whose books were extremely
influential on Ru.ssian thought. Spencer stressed
localization of mental processes, saying that "whoever
calmly considers the question cannot long resist the
conviction that different parts of the brain must in
some way or other suhserve different kinds of mental
action." When we find in his Autobiography (316) that
313. Spencer, Herbert (1820-1903). Principles of Psychology.
1855. 2 vol.
314. Lewes, George Henry (18 17-1 878). The Physiology of the
Common Life. London: Blackwood, 1859. 2 \'ol.
315. Darwin, Charles Robert (1809-1882). On the Origin of
Species by means of .Kaiural Selection or the Preservation of
Favoured Races in the Struggle for Life. London: John
Murray, 1859.
316. Spencer, H. .In Autobiography. London: Williams &
Norgate, 1904. 2 vol.
THE HISTORICAL DEVELOPMENT OF NEUROPHYSIOLOGY
FIG. 40. Ivan Petrovich Pavlov (reproduced from Babkin's Pavlov, A &'ogra/)A> by permission of the
publishers. University of Chicago Press). On the right Pavlov watching an experiment (Sovfoto
* 3' 9573 Moscow USSR).
he had the bumps on his head read by a phrenologist
(with flattering interpretations)^' we perceive a deri-
vation of his ideas from Gall and Spurzheim. Spencer
became hypochondriacal about his own head, believing
it to have an inadequate blood supply. To improve
the circulation he exercised at rowing and at racquets
in 15 mill, spurts, dictating his books in the intervals
between exertions. His friend, Lewes (3 1 7) in his
Physical Basis of Mind was doubtful about the localiza-
tion of the various mental processes but convinced of
their physiological nature.
Pavlov, the towering figure of Russian neurophysiol-
ogy, repeatedly throughout his life stressed his in-
debtedness to Sechenov'" and to Lewes^' (whose book
on physiology he read when a schoolboy). The
influence of these men, one too little known outside
Russia, one almost forgotten, was so great that they
feature not only in the scientific writings of the times
but in Russian fiction. Turgeniev is said to have
taken Sechenov as his model for the science student,
Bazarov, in Fathers and Sons and Dostoievsky cited
the reading of Lewes' book as a sign of education in
the wife of a drunk in Crime and Punishment.
Pavlov dated his interest in the digestive system
(318) from reading Lewes, an interest that was to
occupy the first 25 years of his working life and to win
for him the Nobel Prize. And it was a feature of the
digestive system, the salivary apparatus, that was to
be drawn by him into the work suggested by Sech-
317. Lev^^s, G. H. The Physical Basis of Mind. Boston, 1877.
318. Pavlov, I. P. (1B49-1936). Lectures on the Work of the
Principal Digestive Glands (in Russian). St. Petersburg:
Kushnerev, 1897; translated into English by W. H.
Thompson. London: Griffin, 190J.
enov's theories of 30 years before. Fundamental in
Pavlov's thinking (319) was the concept of temporary
connections established in the cortex by the repetition
of external stimuli linked only by a constant time
interval, although one gets the impression that he
thought more in terms of influence than of specific
neuronal connections. Thus, for example, in his
classical experiment, the repeated sound of a metro-
nome, at a fixed interval before food was made avail-
able to his experimental dogs, caused salivation to
begin with shorter and shorter latency and at an
increasing rate. Later more complex situations were
developed as laboratory procedures, and this type of
reflex was used for mapping the response of the
cerebral cortex to various sensory inputs, Pavlov
(319) naming the areas as "analyzers' for the various
modalities.
The instability and temporary character of the
conditioned reflex in contrast to that of the inborn
319. Pavlov, I. P. Lectures on Conditioned Reflexes, English
translation by \V. H. Gantt. New York: Internat. Pub.,
1928.
"'The opening sentence of the phrenologist's report read:
"Such a head ought to be in the Church." When we seek the
basis for this statement in the itemized score for Spencer's
bumps, we find both Firmness and Self-esteem 'very large;'
Language 'rather full,' and Wit and Amativeness only 'moder-
ate.'
'° See Shaternikov, M. N. The life of I. M. Sechenov. In :
Sechenov, Selected Works. Moscow-Leningrad: State Publ. House,
■935-
^' See Babkin, B. P. Pavlov. Chicago: Univ. Chicago Press,
1949, p. 214.
56
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
unconditioned reflexes serving instinctual movements
for preservation of life led to Pavlov's ideas of cortical
inhibition and its relationship to sleep and hypnosis.
Pavlov distinguished between natural conditional
reflexes learned in early life and the artificially
conditional reflexes of the laboratory. Among the
first he classed the connections formed in infancy
between the smell or sight of food and the salivary
response. This observation goes back many centuries
and is well described by Whytt (i8i), who like Lay-
cock after him, recognized that the 'idea' could be as
powerful a stimulus as the sensory impression.
Pavlov had in his youth been a student of Ludwig
and of Heidenhain; from the former he had brought
the insistence on a physical basis for all biological
processes and from the latter an interest in secretory
mechanisms and the phenomena of hypnosis. The
fertility of Pavlov's ideas and his indefatigable energy
drew to him an enthusiastic school of workers and b\'
the 1920's he had a large team working under him on
the many features of establishment, reinforcement,
extinction and inhibition of conditional reflexes. He
was a well-loved teacher, though a man of fiery
temperament. Sherrington has left a vignette of him
at the age of 65 describing him as "overflowing with
energy, although an elderly man; he was spare in
figure and alert and humourous in manner." Even
at the end of a long working day on encountering a
stairway he "ran up it rather than walked." Sherring-
ton came away from this visit, made in 191 4, with a
great enthusiasm for the leader of Russian neuro-
physiology C320).
Pavlov's ideas of the reflex became more diffuse
and more nebulous as he grew older. Experiments to
test the modes of behavior of animals to conditioning
stimuli were less difficult to design than ones to test
the hypothesis advanced to explain them. Temporary
neuronal connections in the cortex proved easier to
postulate than to prove. Pavlov's own attempts were
with decorticate preparations (a technique that had
been u.sed before him by Sechenov) and it is only in
recent times that the electrophysiologist's tools have
been applied to this problem.
320. Sherrington, C. S. Marginalia. In: Science, Medicine and
History. Essays in Honour of C. Singer, edited by E. A. Un-
derwood. London: Oxford, 1953.
As the second half of the twentieth century unfolds
the neurophysiologist in his search for brain mech-
anisms continues to use the three main categories of
experimental procedure: anatomical, ablative and
electrical. It is the great advance in electrical stimula-
tion and recording that marks this era of investigation
from its predecessors, although it is only through
knowledge from all sources that progress can be
achieved in an understanding of the brain.
Neurophysiology came into being as a specialized
branch of endeavor when the nervous system no
longer had to compete with the humors and with the
blood as the principal coordinator of the body. With
the recognition that sensation and motion were medi-
ated by the nerves their position became unassailable,
for movement was regarded as the sign of life. Slowly
the concept of neural organization began to be pieced
together and levels of integration were postulated, in
the spinal cord, in the cortex and in the deeper struc-
tures of the brain. The period of analysis of the func-
tion of each structural unit, of each sector of the
nervous system, was followed b\' a shift of emphasis
towards a synthetic consideration of neural activity.
The search began for the physiological mechanisms
of mental processes, of consciousness, of memory — all
terms and concepts that had belonged to another do-
main of thought. In the neurophysiolog\' of today we
find both angles of approach, ranging from analysis
of the intimate physicochemicai basis of nervous
structure and dynamics to the synthesis of action that
we call behavior of the organism.
The writer expresses her great indebtedness to the authors
of many articles and books not listed in the abridged bibli-
ography that follows. She adds her thanks to those who have
sent her material in correspondence, and in particular would
mention appreciatively: Dr. Maria Rooseboom for the use of
material and microfilms from the National Museum for the
History of .Science at Leiden; Dr. Palle Birkelund, Director of
the Danish Royal Library; Dr. .\uguste Tournay for a photo-
stat copy of Pourfour du Petit's Letters, the Institution of Elec-
trical Engineers and Miss Helen G. Thompson for access to
material collected by Silvanus P. Thompson on Gilberd; Miss
Anne Caton for family photographs and material from the
diaries of Richard Caton; Dr. Andrei Jus of Pruszkov for photo-
stats of Adolf Beck's doctoral thesis; and F. Czubalski of War-
saw for information about Beck's works. For details of Beck's
life the writer expresses warm appreciation to his daughter,
Mme. Jadwiga Zahrzewska.
A SHORT LIST OF SECONDARY SOURCES
Space does not permit the listing of all the articles to whose
authors the writer is indebted for information. The following
books have been selected for the special interest they may
have for the physiologist. Where possible, works in the English
language have been chosen.
Bence Jones, H. On Animal Electricity. London: Churchill, 1852.
Bettmann, O. L. .4 Pictorial History of .Medicine. Springfield:
Thomas, 1956.
Boring, E. G. A History of Experimental Psychology. New \'ork:
.\ppleton, 1 929.
THE HISTORICAL DEVELOPMENT OF NEUROPHYSIOLOGY
57
BosTOCK, J. Sketch of the Hutory nf Medicine from its Origin to
the Commencement of the .\ineteenlh Century. London: Sherwood,
Gilbert and Piper, 1835.
Brown, G. B. Science, its Method and 1/1 Philosophy. London:
Allen & Unwin, 1951
Canguilhem, G. La Formation du Concept de Reflexe. Paris:
Presses univ. France, 1955.
Castiglioni, a. Italian Medicine. New York: Hoeber, 1932,
Clio Medica Series, vol. 6.
Castiglioni, A. .-i History of Medicine (2nd ed.)- New York:
Knopf, 1947.
CoMRIE, J. D. A History of Scottish Medicine. London: Wellcome
Historical Medical Museum, 1932.
Corner, G. \V. Anatomy. New York : Hoeber, 1 930, Clio Medica
Series, vol. 3.
Cooke, J. A Treatise on Nervous Diseases. Boston: Wells and
Lilly, 1824. (Previously published in England.)
Dampier, W. C. a History of Science. Cambridge: Cambridge,
1946.
Dana, C. Textbook of Nervous Diseases. New York : Wm. Wood,
1925. (Includes a chapter by F. H. Garrison on the history
of neurology.)
D.^REMBERG, C. Essai sur la determination et ies caracthes des
periodes de I'histoire de la medecine. Gaz. med. Paris, 1850.
Fearing, F. Reflex Action. Baltimore: Williams & Wilkins, 1930.
Foster, M. Textbook of Physiology (1st American ed.), edited
by E. T. Reichert. Philadelphia: H. C. Lea's son and Co.,
1880. (1st English ed., 1876.)
Foster, M. Lectures on the History of Physiology. Cambridge:
Cambridge, igoi.
Fr.^nki.in, K. a Short History of Physiology. London: Staples,
1949-
Fulton, J. F. Muscular Contraction and the Reflex Control of
Movement. Baltimore: Williams & Wilkins, 1926.
Fulton, J. F. Selected Readings in the History of Physiology. Spring-
field: Thomas, 1930.
Fulton, J. F. Physiology. New York: Hoeber, 1931, Clio Medica
Series, vol. 5.
Fulton, J. F. Physiology of the Nervous System (3rd ed.). New
York : O.xford, 1 949.
Garrison, F. H. An Introduction to the History of Medicine. Phila-
delphia: Saunders, 1929.
Hall, A. R. The Scientific Revolution ijou-iSuo. London:
Longmans, 1954.
Hamilton, W. The History of Medicine, Surgery and Anatomy from
the Creation of the World, to the Commencement of the Nineteenth
Century. London: Colburn and Bentley, 1831.
Lenard, p. Great Men of Science, translated by H. S. Hatfield.
New York: Macmillan, 1933.
M.«.jor, R. --1 History of Medicine. Springfield: Thomas, 1954.
Morgan, C. E. Electro-Physiology and Therapeutics. New York:
Wood, 1868.
Morton, L. T. and F. H. Garrison. A Medical Bibliography
(2nd ed.). London: Grafton, 1954.
Nordenskiold, E. History of Biology, translated by L. B. Eyre.
New York: Tudor, 1935.
Pettigrev\', T. J. Medical Portrait Gallery. Biographical Memoirs
of the most Celebrated Physicians, Surgeons, etc. London: Fisher,
1872. 3 vol.
PoTAMiN (Brother) and J. J. Walsh. Makers of Electricity.
New York: Fordham Univ. Press, 1909.
Renouard, p. V. History of Medicine from its Origin to the .\ine-
teenth Century, translated by C. G. Comegys. Philadelphia:
Lippincott, 1856. 2 vol.
Rothschuh, K. E. Geschichte der Physiologic. Berlin : Springer,
1953
Russell, T. R. The History of Heroes of the Art of Medicine.
London: Murray, 1861.
ScHAFER, E. A. Textbook of Physiology. Edinburgh and London:
Y. J. Pentland, 1898, vol. i ; 1900, vol. 2.
Shryock, R. H. The Development of Modern Medicine. New
York: Knopf, 1947.
Singer, C. .-1 Short History of Medicine. New Y'ork: Oxford, 1928.
Singer, C. J. Essays on the History of Medicine. London: Oxford,
■9^4-
Singer, C. J. The Evolution of Anatomy; a Short History of Ana-
tomical and Physiological Discovery to Harvey. London : Paul,
Trench, Trubner, 1925.
Soury, J. Le Systhne nerveux central. .Structure el Fonctions. Paris:
Carre et Naud, 1899.
Sprengel, K. Histoire de la Medecine, translated and abridged
from the 2nd German ed. by A. J. L. Jourdan. Paris:
Deterville, 1792-1803. 2 vol.
Stirling, W. Some Apostles of Physiology. London: Waterlow,
1902.
Sudhoff, K. Essays in the History of Medicine, English translation
edited by F. H. Garrison. New York : Medical Life Press,
1926.
Whewell, W. History of the Inductive Sciences. London: Parker
1837- 3 ™1-
Whittaker, E. T. History of the Theories of Aether and Elec-
tricity from the Age of Descartes to the Close of the Nineteenth
Century. London and New York: Longmans, Green and Co.,
igio, revi.sed 1951, second volume added 1953.
Wightman, W. p. D. The Growth of Scientific Ideas. New Haven:
Yale Univ. Press, 1951.
Wilkinson, C. H. Elements of Galvanism in Theory and Practice.
London: Murray, 1804.
Wolf, A. A History of Science, Technology and Philosophy in the
1 6th and lyth Centuries (2nd ed.). London: .-\llen and L'nwin,
I950-
Wolf, A. A History of Science, Technology and Philosophy in the
1 8th Century (2nd ed.). London: .\llen and Unwin, 1952.
BIOGRAPHIES
For each of the following scientists one biographical study
only has been listed. Again the choice has been made on the
grounds of interest to the physiologist and, where possible, text
in the English language.
Aristotle. Taylor, A. E. Aristotle. London: Nelson, 1943.
Bacon, Francis (i 561-1626). Farrington, B. Francis Bacon,
Philosopher of Industrial Science. New York: Schuman, 1949.
Baglivi, Giorgio (1668-1707). Stenn, F. Giorgio Baglivi. Ann.
Med. Hist. (3rd ser.) 3: 183, 1941.
Bell, Charles (i 774-1 842). Pichot, A. The Life and Labours of
Sir Charles Bell. London: Bentley, 1880.
Berger, Hans (1873-1942). Ginzberg, R. Three years with
Hans Berger. .\ contribution to his biography. J. Hist. Med.
4: 361, 1949-
Bernard, Cl.aude (1813-1878). Olmsted, J. M. D. and E. H.
58
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
Olmsted. Claude Bernard, Physiologist, and the Experimental
Method in Medicine. New York: Schuman, 1952.
BicHAT, Marie Francois Xavier (1771-1802). Busquet, P.
Les Biographies Medicates I: 37, 1927.
BoERHAAVE, HERMANN (1668-1738). Burton, W. An Account of
the Life and Writings of Hermann Boerhaave. London: Lintot,
1743-
CoTUGNO, DoMENico (1736-1822). LevinsoH, A. Domenico
Cotugno. Ann. Med. Hist. 8: i, 1936.
DA Vinci, Leonardo (1452-1519). O'Malley, C. D. and J.
B. deC. M. Saunders. Leonardo da Vinci on the Human Body.
New York: Schuman, 1952.
Descartes, Rene (1596- 1650). Haldane, E. The Life of Rene
Descartes. London, 1905.
Fernel, Jean (1497-1558). Sherrington, C. S. The Endeavour
of Jean Fernel. Cambridge: Cambridge, 1946.
FoNTANA, Felice (1730-1805). Marchand, J. F. and H. E.
Hoff. Felice Fontana. The Laws of Irritability. J. Hist. Med.
10: 197, 302, 399, 1955.
Galen (130-200). Sarton, G. Galen of Pergamon. Lawrence:
Lfniv. Kansas Press, 1954.
Gall, Franz Joseph (1758-1828). Temkin, O. Gall and the
phrenological movement. Bull. Hist. Med. 21 : 275, 1947.
Galvani, Alovsius (i 737-1 798). Fulton, J. F. and H. Gush-
ing. A biographical sketch of the Galvani and Aldini writings
on animal electricity. Ann. Sci. i : 239, 1936.
GiLBERD, William (1540 or 1544- 1603). Waldron, F. G.
Biographical Mirrour. London : Harding, 1 795.
Hales, Stephen (1677-1761). Burget, G. E. Stephen Hales,
1677-1761. Ann. Med. Hist. 7: 109, 1925.
Hall, Marshall (1790- 1857). Hall, Charlotte. Memoirs of
Marshall Hall. London, 1861.
Harvey, William (1578-1657). Chauvois, L. William Harvey.
His Life and Times.- his Discoveries: his Methods. London:
Hutchinson, 1957.
Horslev, Victor Alexander Haden (1857-1916). Paget, S.
Sir Victor Horsley, a Study of his Life and Work. New York:
Harcourt Brace, 1920.
Hunter, John (i 728-1 793). Paget, S. John Hunter. London:
Fisher Unwin, 1897.
LiNACRE, Thomas (1460-1524). Johnson, J. N. The Life of
Thomas Linacre. London, 1835.
LuDWiG, Carl Friedrich Wilhelm (i 816-1 895). Lombard,
W. P. The Life and Work of Carl Ludwig. Science 44: 363,
1916.
M.agendie, Francois (1783-1855). Olmsted, J. M. D. Francois
Magendie. New York: Schuman, 1944.
Monro, .^LEXANDER (1697-1762) and Monro, .Alexander
Secundus (1733-1817). Inglis, J. A. The Monros of Auchin-
bowie. Edinburgh, 1911.
MOller, Johannes (1801-1858). Haberling, W. Johannes .Mai-
ler. Leipzig, 1924.
Nollet, Jean Antoine. Torlais, J. Un Physicien au Steele des
Lumieres: Abbe JVollet. Paris: Siprico, 1954.
Oersted, Hans Christian (i 770-1851). Stauflfer, R. C.
Speculation and experiment in the background of Oersted's
discovery of electromagnetism. Isis 48: 33, 1957.
Pavlov, Ivan Petrovich (1849-1936). Babkin, B. P. Pavlov.
Chicago: Univ. Chicago Press, 1949.
Prochaska, Jiri (1749-1820). Laycock, T. Introduction.
To: The Principles of Physiology. London: Sydenham .Society,
1851, p. ix.
Ramon y Cajal, Santiago (1852-1934). Cannon, D. Explorer
of the Human Brain. New York: Schuman, 1949.
Sechenov, Ivan Mihailovich (1829-1905). Shaternikov, M.
N. The life of I. M. Sechenov (in English). In: Sechenov,
Selected Works. Moscow-Leningrad: State Publ. House, 1935.
Stahl, Georg Ernst (1660-1734). Metzger, H. Newton, Stahl,
Boerhaave et la doctrine chimique. Paris: Alcan, 1930.
Stensen, Nicholas (1638-1686). .Nicolaus Steno and His Indice,
edited by G. Scherz. Copenhagen: Munksgaard, 1958.
Unzer, Johann August (1727-1799). Laycock, T. Introduc-
tion. To: The Principles of Physiology. London: Sydenham
Society, 1851, p. i.
VAN Leeuwenhoek, .Antonj (1672-1723). Dobell, C. Antony
van Leeuwenhoek and his "Little Animals." New York: Harcourt
Brace, 1932.
Vesalius, .■\ndreas (1514-1564). Gushing, H. A Bio-bibliog-
raphy of Andreas Vesalius. New York: .Schuman, 1943.
Volta, Alessandro (1745-1827). Cohen, I. B. Introduction.
To: Galvani's Commentary, English translation by M. G.
Foley. Norwalk: Burndy Library, 1954.
von Guericke, Otto (1602-1686). Hoffmann, F. W. Otto von
Guericke. Magdeburg, 1874.
VON Haller, Albrecht (1708-1777). Klotz, O. Albrecht von
Haller 1708-1777. Ann. .Med. Hist. 8: 10, 1936. Also: Hem-
meter, J. C. Albrecht von Haller, his scientific, literary and
poetic activity. Bull. Johns Hopkins Hosp. 19: 65, 1908.
VON Helmholtz, Hermann Ludvvig Ferdinand (1821-1894).
McKendrick, ]. G. H. L. F. von Helmholtz- London: Unwin,
1899-
VON Humboldt, Frederick .'\lexander (i 769-1859). de Terra,
H. The Life and Times of Alexander von Humboldt. New York:
Knopf, 1955.
Whytt, Robert (1714-1766). Seller, W. Memoir of the Life and
Writings of Robert Whytt, .\L D. Edinburgh: Neill, 1862.
Willis, Thomas (1621-1675). Miller, W. S. Thomas Willis
(1621-1675). Bull. Soc. Med. Hist. Chicago 3: 215, 1923.
CHAPTER II
Neuron physiology — introduction
J. C. ECCLES I Department of Physiology^ Australian National University, Canberra, Australia
CHAPTER CONTENTS
Morphological Features of the Neuron
Physiological Properties of Surface Membranes of Neurons
Transmission Between Neurons
Excitatory Synaptic Action
Inhibitory Synaptic Action
Factors Controlling Impulse Generation
Central Inhibitory Pathways
Inhibitory and Excitatory Transmitter Substances
MORPHOLOGICAL FEATURES OF THE NEURON
THE CONCEPT that the nervous system is composed of
discrete units or nerve cells was first proposed in
1886-7 tiy His and Forel, later it was strongly sup-
ported by van Gehuchten and Cajal, and finally in
1 89 1 it was given an appropriate nomenclature,
' neuron' and ' neuron-theory', by Waldeyer. Al-
though all the great neurohistologists of that classical
era were ranged for or against the neuron theory, it
was pre-eminently the achievement of Cajal to estab-
lish the fact that the functional connections between
individual nerve cells, or neurons, are effected by
close contacts and not by continuity in a syncytial
network, as was proposed in the rival reticular theory
of Gerlach and Golgi. Appropriately, Cajal's last
great contribution (11) was devoted to a critical sur-
vey of the evidence for and against the neuron theory,
which has not been seriously challenged since that
time, at least for the vertebrate nervous system.
Neurons have the most diverse forms, yet there are
certain features that are common to all. The nucleus
always lies in an expanded part, the soma or cell
body, from which the axon takes origin and often runs
for long distances before breaking up into the synaptic
terminals that make contact either with other neurons
or with effector cells such as muscles, glands or elec-
tric organs. Under physiological conditions of opera-
tion, axons (with the exception of primary afferent
axons) transmit impulses only in the centrifugal
direction and thus constitute the effector apparatus of
the nerve cell. The different types of nerve cells show
much more variation in their other branches, the
dendrites, which normally share with the soma the
receptive function for the nerve cell. Pyramidal cells
of the cerebral cortex and the Purkinje cells of the
cerebellum have the most extensively branched den-
drites, but most neurons of the central nervous system
have fairly elaborate dendritic structures. By contrast,
in the dorsal root ganglion cells the receptive structure
is remotely located in the receptor organs which are
connected to the soma by a long axon-like fiber that
normally conducts in the centripetal direction, and
which we may call the primary afferent axon.
\'ery great functional significance is attached to the
surface membrane of the neuron. This membrane
must not be confused with the fibrous, glial and
myelin structures which contribute a sheath to
neurons, providing them with mechanical strength
and electrical insulation. Until the advent of electron-
microscopy the surface membrane had not been ob-
served directly; yet it was an essential postulate in
explanations of the electrical properties of the surface
of the neuron and of the manner in which its interior
was maintained at a very different compo.sition from
the exterior, particularly in respect to such ionic
species as sodium, potassium and chloride. It also
provided a structural basis for explaining such funda-
mental processes as the conduction of the impulse and
the operation of excitatory and inhibitory synaptic
junctions. Recently, numerous electronmicroscopic
59
6o
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
Studies (21, 22, 2;5, 48, 66, 67, 70) have revealed it as a
boundary membrane of uniform thickness, about
50 A, which stands out with remarkable clarity from
the interior of the neuron and its surround. There is
much more uncertainty with respect to the chemical
composition of the membrane, which generally is sup-
posed to be a thin, proi)ai)ly bimolccular, layer of
mixed phospholipids and cholesterol, supported by a
protein framework. It is further postulated that the
transport of molecules and ions across this membrane
is largely a diffusion process, the respective net move-
ments being determined by the electrochemical
potentials However, metabolic energy must also be
made available for net transport against the electro-
chemical gradients of such ions as sodium and potas-
sium. With some memljranes, it is also necessary to
postulate that specific permeability functions are
'built in'; for example, in all membranes giving the
self-regenerative responses that are characteristic of
impulses, depolarization initiates a brief permeability
to sodium ions; and at excitatory synapses the excita-
tory transmitter substance probably causes the mem-
brane to become like a sieve with pores permeable to
all small ions, while at inhibitory synapses the inhib-
itory substance causes much more selective ion
permeability, which may, however, be due to a still
finer sieve-like structure.
It will emerge in the sub.sequent .sections on neuron
physiology that as yet very little functional significance
can be attached to all the detailed structural features
occurring within neurons, which are well described in
a recent review by Young (79). At the present level of
understanding, the behavior of neurons is explained in
terms of the properties of their surface membranes,
including the specialized surface membranes of the
synaptic regions. The interior is assigned a function
merely on account of its ionic composition and its
specific conductance. Doubtless this unsatisfactory
state of affairs will be remedied as new insights are
gained into the metabolic functions of the nerve cell
and their integration with the membrane functions.
Some beginnings have already been made. For
example, energy derived from metabolic processes in
the neuron is necessary in order to move ions across
the surface membrane against their electrochemical
potentials. There is now evidence that, with the
linked transfer of sodium outwards and potassium
inwards, the rate of this ionic pump is determined by
the internal concentration of sodium ions (15, 16, 53,
54). Another correlation between the neuron interior
and the surface membrane is beginning to emerge in
relation to the synaptic vesicles in the presynaptic
terminals. There is evidence .supporting the postulate-
that these vesicles are concerned in the quantal
emission of transmitter from the presynaptic terminals-
of the neuromuscular junction (26, 63, 70); and that
the level of the membrane potential of the presynaptic
terminals determines the rate of emission of quanta
therefrom, the rate rising by more than a million-fold
during a nerve impulse. Thus it has been postulated
that in some way the properties of the .surface mem-
brane are able to influence profoundly the state of
relatively large structures (spheres of 300 to 500 A in
diameter) in the immediately adjacent cytoplasm
(26, 63); and, by analogy, a similar postulate has been
suggested for the synaptic vesicles which also form
characteristic features of all synaptic junctions that on
other grounds are regarded as functioning by chemical
transmission (21, 29, 67).
The internal structure of neurons is profoundly
altered in pathological states induced, for example, by
section of the axon or by the action of toxins (4).
There is good evidence that such a striking feature as-
the Nissl substance or ergastoplasm is concerned in
the protein manufacture that occurs during growth
and regeneration (58). But as yet there is little under-
standing of the ' trophic' action which the cell body
exercises on the axon, apparently by maintaining an
intra-axonic pressure and a continual tran.sfcr of
material along the fiber (79).
Electronmicroscopy has already contributed much
information that is of the greatest value in interpreting
the mode of operation of synapses. Despite the very
wide range in the grosser features of synapses, at the
electronmicroscopic level there is a remarkable simi-
larity between all synapses that are believed to work
by a chemical transmitter mechanism (fig. i). Es.sen-
tially, in these structures considerable areas of the
presynaptic and postsynaptic membranes are sepa-
rated bv a very narrow cleft that shows a remarkable
uniformity in width for any one type of synap.se and
that varies in width from 150 to 500 A with different
types Presumably, this accurate apposition of the
two membranes is maintained by some structural
linkage across the cleft, which appears in elcctron-
microphotographs as a granular material The pre-
synaptic and postsynaptic membranes are continuous
with the surface membranes of their respecti\e cells,
neurons or effector cells, and as yet ha\e not been
shown to have any distinctive structural features
except the deep transverse folds that distinguish the
subsynaptic mu.scle membrane at the neuromuscular
junction (figs. iZ), E) (19, 69, 70). Finally, in all
cheinical-transmitting synapses the presynaptic termi-
NEURON PHYSIOLOGY INTRODUCTION 6 1
FIG. I . Drawings showing dimensions and form of various types of synaptic junctions as revealed
by electronmicroscopy. In all transverse sections the presynaptic terminals are sho%vn above and the
postsynaptic element below. In addition the presynaptic terminals can be identified by the contained
synaptic vesicles. The synaptic cleft is seen as the narrow space between the juxtaposed presynaptic
and subsynaptic membranes and is shown communicating at the sides of the synapse with the inter-
stitial spaces. A, A large synapse on a motoneuron of the abducens nucleus. [From Palay (67).] B.
Synapse in the ventral acoustic ganglion of the guinea pig. [From de Robertis (21).] C. Synapse
between red receptor and postsynaptic cell in the rabbit retina. [From de Robertis & Franchi (23).]
D, E. Elongated nerve terminal of amphibian muscle as seen from above (Z)) and in transverse
section (£). The naturally occurring irregularities of the junctional folds are neglected in order to
give a regular geometrical diagram with approximately equivalent dimensions. A junctional fold is
shown by a broken line in E. [From data and figures of Couteaux & Taxi (19) and Robertson
(70).]
nals contain the characteristic synaptic vesicles which
o
are 300 to 500 A across and which are often ckistered
close to the synaptic region.
The word synapse, as proposed by Sherrington
(71), may be applied to the presynaptic terminal with
its contained synaptic vesicles, the synaptic cleft of
150 to 500 A, and the subsynaptic membrane with its
special receptive and reactive mechanism. Later,
when the mode of operation of synapses is discussed,
it will appear that much of the old morphological
characterization of synaptic endings is of little signifi-
cance, at least for many types of neurons. Thus the
various localizations designated axosomatic, axoden-
dritic and axoaxonic would be almost equipotent in
their action except for those neurons that have very
elongated dendrites, as for example the pyramidal
cells of the cortex. Furthermore, there can be little
significance in the detailed form of synapses as de-
scribed bv such terms as hautons lerminaux and en
passant, giant club endings, basket-type endings, etc.
[cf. Bodian (3)].
PHYSIOLOGICAL PROPERTIES OF SURF.iiCE
MEMBRANES OF NEURONS
By inserting an electrode within a nerve fiber or
the soma of a neuron and analyzing the potential
changes produced by current pulses, it has been
shown that the surface membrane has a high electrical
resistance, corresponding to its low ionic permeability,
and a high electrical capacity, as would be expected
for a membrane no more than 50 A thick. The elec-
trical resistance shows wide variations with different
62
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
types of nerve fibers and neurons, the values ranging
from looo to approximately io,ooon-cm- for squid
and sepia giant fibers, respectively (49, 77), and it
probably lies within the range of 500 to loooli-cm^
for mammalian motoneurons (15, 29, 44). Values for
specific capacitance of giant fiber membranes range
from I to 1.5 mF per cm- and for mammalian moto-
neurons are probably at least 3 nF per cm-. In addi-
tion, there is a considerable potential difference across
the surface membranes of neurons, including all
their branches, the inside being —50 to —80 milli-
volts relative to the exterior under normal resting
conditions.
It may be claimed that only one hypothesis, which
may be termed the membrane ionic hypothesis,
attempts to account quantitatively for propagation
within neurons both of impulses and of the events
which control the generation of impulses, and also for
transmission across synapses. The earliest ionic
hypothesis was proposed by Bernstein (2) in 1902.
For the modern version of this ionic hypothesis, as
applied to the responses within a neuron, reference
may be made to Hodgkin (49, 50), to Hodgkin &
Huxley (52) and to Huxley (57). Its application to
synaptic transmission has been specially developed
for neuromuscular junctions and the synapses on
mammalian motoneurons (15, 16, 17, 26, 28, 29, 38,
4i)-
Essentially it is postulated that the resting mem-
brane potential of neurons and muscle fibers ( — 50 to
— 100 mv) is due to the relatively free diffusion of the
small ions, K+ and Cl~, across the membrane, while
the Na+ permeability is of a much lower order. For
example, in the giant axons of squid the resting K+
and Na+ conductances are, respectively, about 0.5 and
of the order of 0.0 1 mmho per cm-. As a consequence,
an electrical potential difference is set up across the
membrane so that there is little or no electrochemical
potential gradient of the freely diffusing ions, K+ and
Cl~, across the membrane despite the very large
concentration differences that obtain, (Ki)/(Ko) and
(Clo)/CCli), both being of the order of 20 to 50. It
may be noted that subsidiary hypotheses, such as the
ionic pump mentioned in the preceding section, are
required in order to explain how these concentration
differences are maintained along with the very low
internal sodium concentration. It is further postulated
that, if the resting potential of the membrane is sud-
denly reduced by a considerable amount (say from — 50
mv to o), both the Na+ and K+ conductances undergo
characteristic increases. As summarized by Huxley
(57), the conductance " for Na ions rises in one or two
tenths of a millisecond to perhaps 15 mmho, cm-, and
then falls to a low value with a time constant of about
I msec. That for K ions does not change noticeably at
first, but rises along an S-shaped curve, becoming
appreciable as the Na conductance falls from its peak,
and eventually flattening out and remaining at about
20 mmho/cm- as long as the membrane potential
difference is held at zero. When the membrane poten-
tial difference is restored to its ordinary resting value,
the K conductance returns to its resting value along an
exponential decay curve, without an S-shaped start.
The Na conductance remains low, but the ' inactiva-
tion' which caused it to fall after its peak during the
period at zero membrane potential difference per-
sists, decaying exponentially with about the same
time constant as the K conductance." Meanwhile the
Na and K ions have been moving down their electro-
chemical gradients. For a giant axon there is a gain
in Na of 3 to 4 X io~'- moles per cm- per impulse and
a loss of an equivalent amount of K.
According to the ionic hypothesis, the membrane
may be represented by an electrical diagram (fig. 2)
in which the membrane capacitance (a) is shown in
parallel with two battery-resistance elements (6 and
(-) representing, respectively, the K and Na difi'usion
channels across the membrane. The respective
batteries are at the approximate equilibrium poten-
tials for K and Na ions, and the resistances which
represent reciprocals of the respective conductances
are both capable of variation over a wide range. For
the .squid axon the respective resistances of the resting
membrane are about 2 X lo'fi cm^ and lo^fi cm-,
while during activity the values are as low as 25^ cm^
and loi] cm-.
On the basis of quantitative studies of the time
courses of the conductance changes as produced by
a wide range of membrane potential changes, it has
been possible (52) to set up differential equations
which relate three parameters to the membrane po-
tential changes, viz. the 'turning on' of the Na con-
ductance, the 'turning on' of the K conductance and
the 'inactivation' of the Na conductance, and in which
all the coefficients are experimentally determined.
These equations give a very satisfactory quantitative
account of a wide range of performance of the giant
fibers from which the coefficients were derived. It will
suffice to show how the propagation of the nerve
impulse is explained.
The explanation of the propagation of the nerve
impulse is based on measurements of the cable
properties of the nerve fiber in addition to the differ-
ential equation relating the ionic conductances to the
NEURON PHYSIOLOGY INTRODUCTION 63
Vnb
• External fluid
'\/\/\/\/\/\/\/\/\/\/\/\/\/\/ Inlenor of fibre
llSmV
12 mV
FIG. 2. Theoretical action potential (F) and membrane conductance changes gNa and ^k obtained
by solving the equations derived by Hodgkin & Huxley (52) for the giant axon at i8.5°C. Inset
shows diagram of an element of the excitable membrane of a nerve fiber — a, constant capacity;
b, channel for K+; c, channel for Na+. [From Hodgkin & Huxley (52); Huxley (57)-]
membrane potential. At any instant the nerve im-
pulse will be extended as a potential change along
the nerve fiber as shown in figure 35. According to
the ionic hypothesis, there will be a net inward move-
ment of Na ions during the rising phase of the impulse
(figs. 2, 3.4) because the Na conductance has been
greatly increased by the depolarization so that Na
ions move freely down their electrochemical gradient
carrying positive charges inwards, thus adding to the
depolarization and hence to the Na conductance. In
this self-regenerative manner, when the level of
depolarization of any element of the nerve membrane
increases above a critical value, it causes the mem-
brane potential to be carried almost up to the Na
equilibrium potential which is about +50 mv, i.e.
internally positive (fig. 2). The delayed development
of the other two ionic processes checks this potential
change and eventually restores the resting membrane
potential; the Na conductance is inactivated and the
K conductance increases so that, during the falling
phase of the impulse, the membrane potential is
dominated by the flux of K ions moving outwards
along their electrochemical gradient across the
membrane (figs. 2, 3.-1}, which eventually is restored
to its original resting potential close to the potassium
equilibrium potential. Propagation occurs because
of the cable properties of the nerve fiber, current
flowing outwards across the membrane ahead of the
impulse in the circuits, as shown diagrammatically in
figure 3C. This current efTects a discharge of the mem-
brane capacitance so that in the zone ahead of the
impulse the membrane is depolarized sufficiently to
initiate the regenerative increase in Na conductance,
by which time the impulse may be said to have
arrived at this new zone, which will in turn go through
the conductance changes outlined above. It will be
appreciated that propagation will be a continuous
and uniform process along a stretch of nerve with
uniform properties. The propagation velocity calcu-
lated from the differential equation and the measured
cable properties of a nerve fiber is not only of the
correct order, but is in very close agreement with that
actually observed (52). Saltatory propagation along
the nodal structure of a medullated nerve also can be
satisfactorily explained by the occurrence of essen-
tially similar processes at each node. This propagation
64
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
A ^15?
Fig. 3. A. Diagram showing postulated movement of sodium
and potassium ions across the membrane during an impulse
advancing in the direction of arrow, and the resulting alteration
of charge on the membrane and its recovery. B. Potential
distribution of the impulse along a nerve or muscle fiber.
C. Resulting flow of electric current both in the external
medium and within the fiber. Note the reversal of membrane
potential during the spike. Figure 3/J is drawn so that the
impulse is at approximately the same position as in figure 3.4
and C.
is treated very iulK in the following chapter by
Tasaki.
After the events depicted in figures 2 and 3, the
ionic hypothesis would predict that a length of nerve
fiber would have gained a quantity of Na ions that
was at least adequate to displace the charge on its
capacitance so that there is the maximum change in
the membrane potential, and that there would also
have been an equivalent loss of K ions in the recharg-
ing process. The actually observed values have been
several times larger, which is to be expected because
the periods of Na entry and K emission overlap so that
much of the ionic influx cancels out as far as the
membrane potential is concerned. Thus the immediate
energy source for the propagation of the impulse
derives from the concentration batteries for Na and K
ions, and metabolic energy is only later required in
order to restore the ionic composition. However, the
ionic flux per impulse is so small relati\e to the ionic
composition of the fiber that, even in the alj.sence of a
restorative process, many thousands of impulses can
be propagated along large nerve fibers without
significaniK changing the effectiveness of the con-
centration batteries.
The ionic hypothesis can also explain satisfactorily
a great many other properties of nerve fibers [(cf.
Hodgkin (49); Hodgkin & Huxley C52)], for example
the subthreshold and threshold phenomena including
the all-or-nothing behavior, the refractory period fol-
lowing the impulse, the effects of anelectrotonus and
catelectrotonus, including accommodation, the effects
produced on the nerve impulse and the other re-
sponses by changing the Na or K concentrations, or
both, in the external medium and in the axoplasm
(54). This is such an immensely impressive per-
formance that the ionic hypothesis of the nerve fiber
must rank as one of the great conceptual achieve-
ments in biology.
It is admitted that as yet the ionic hypothesis, in so
far as it has been formulated, does not give a com-
plete description of the behavior of the nerve mem-
brane. For example the nature of the specific changes
in Na and K conductance is not explained; the in-
tensity-time courses of changes are merely measured
and utilized in the explanations. The effect of external
calcium ions on these conductances also is not yet
understood. Again, nothing is known about the manner
in which metabolic energy is employed to drive
sodium and potassium ions across the membrane
against their electrochemical gradient.
As would be expected, such a comprehensive and
precisely formulated hypothesis has been subjected to
much critical attack. However much of this criticism
has been based on imperfectly controlled experiments.
For example deviations from the predicted effects of
variations in the external potassium concentrations
on the resting membrane potential probably have
been largely due to secondary changes in the internal
potassium. In this context great significance attaches
to the recent experiments of Hodgkin & Horowicz
(51) on the membrane potential of isolated single
muscle fibers. Extracellular diffusion time is thus re-
duced to a minimum, so that a steady membrane
potential is observed within a second of changing the
external ionic composition and thu« before there is any
appreciable change in the internal composition.
Under such conditions, with changes in (Kq), the ob-
served membrane potentials agree very closely with
those predicted by the ionic hypothesis. It was also
remarkable that, making use of the anomalous
rectification in K ionic diffusion across the membrane
[cf. Katz (59)], it was possible by changing the internal
composition of the muscle fiber to have a membrane
NEURON PHYSIOLOGY INTRODUCTION
65
the potential of which was virtually controlled by the
(C'i„)/(Cli) ratio and then later to restore the normal
ionic composition of the fiber, as revealed by a normal
behavior of the membrane potential to variations in
(K„).
In conclusion it may he stated that, though detailed
modifications and developments of the ionic hypoth-
esis are recjuired in order to explain such phenomena
as the falling phases of the action potentials of medul-
lated nerve fibers and cardiac muscle fibers and the
effect thereon of repolarizing currents, in essentials
the ionic membrane hypothesis has survived the most
severe tests and remains as the only conceptual frame-
work for our discussion of the electrical events that
are so essentially concerned in all activities of the
neuron. It will therefore be pertinent to consider now
the mode of operation of synapses in the light of the
ionic hypothesis.
TRANSMISSION BETWEEN NEURONS
The synapse is a device for the transmission of
information from one neuron to another. Excitatory
synaptic action is effective only in so far as it leads to
the discharge of an impulse by the postsynaptic
neuron, for only under such conditions does this
neuron in turn exert effective action on other neurons.
It may be provisionally concluded from the available
experimental evidence that any neuron, other than a
primary sensory neuron, requires excitatory synaptic
action in order to generate an impulse. In the absence
of an afferent input even the most complex assem-
blages of neurons remain silent, as may be seen in the
isolated cortical slabs of Burns (10).
On the other hand, inhibitory synaptic action
attempts to suppress the discharge of impulses and is
effective in so far as it diminishes or shortens the dis-
charge produced by any given synaptic excitation.
Inhibition can be thought of as exercising a sculptur-
ing role on what would otherwise be the massive
incoordinate activity of a convulsing nervous system,
thus reducing it to the organized responses character-
istic of normal nervous activity. However, just as
with the excitatory synapses, inhibitory synap.ses
require activation by presynaptic impulses. Hence, an
investigation of the transmis.sion between neurons
can be reduced to a study of the mode of operation of
excitatory and inhibitory synapses. It will emerge
that the ionic hypothesis of the nerve membrane
provides the basis for our atteinpls to understand both
these types of synaptic activity.
Excitatory Synaptic Action
Excitatory synaptic action on neurons is exhibited
in its simplest form by the monosynaptic action which
afferent impulses from the annulospiral endings of
muscle spindles exert on motoneurons. When recorded
by an intracellular electrode, the monosynaptic
action by a single volley generates a depolarizing
potential, the excitatory postsynaptic potential
(EPSP), that runs virtually the same time course
regardless of volley size (fig. 4.4 to C). This observa-
FiG. 4. A to C. EPSP's obtained in a biceps-semitendinosus
motoneuron with afferent voIley.s of different size. Inset records
at the left of the main records show the afferent \olley recorded
near the entry of the dorsal nerve roots into the spinal cord.
They are taken with negativity downward and at a constant
amplification for which no scale is given. Records of EPSP are
taken at an amplification that decreases in steps from A lo C as
the response increases. Separate vertical scales are given for
each record of EPSP. All records are formed by superposition of
about 40 faint traces. D to G. Intracellularly-recorded po-
tentials of a gastrocnemius motoneuron (resting membrane
potential, —70 mv) evoked by monosynaptic activation that
was progiessively increased from D to G. The lower traces are
the electrically differentiated records, the double-headed arrows
indicating the onsets of the IS spikes in E to G. HtoK. Intra-
cellular records evoked by monosynaptic activation that was
applied at 12.0 msec, after the onset of a depolarizing pulse
whose strength is indicated in m^ia. A pulse of 20 m^ua was just
below threshold for generating a spike. H shows control EPSP
in the absence of a depolarizing pulse. Lower traces give
electrically differentiated records. Note that the spikes are
truncated. [From Coombs el at. (14).]
66
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
tion indicates that each excitatory presynaptic impulse
generates in the postsynaptic neuron a potential
change of this same time course, and that the recorded
EPSP's of figure 4.4 to C are produced by a simple
summation of these elemental EPSP's. It thus pro-
vides an illustration of the classical concept of spatial
summation (72, 73).
As shown in figure 4D to G, if the EPSP is increased
beyond a critical threshold level, it causes the neuron
to discharge an impulse, the latency being briefer the
larger the EPSP. In figure 4.E, F, G the increase of the
EPSP to above threshold was brought about by in-
creasing the size of the presynaptic volley, but, as
would be expected, the EPSP can also be made to
generate an impulse by conditioning procedures that
change the membrane potential towards the critical
threshold level. For example in figure 4/ to A' the
same EPSP as in figure 4// was made effective by the
operation of a background depolarizing current
which was commenced 1 2 msec, before and which
changed the membrane potential by the amount
shown in each record. The impulse is seen to arise
(at the arrows) at a total level of depolarization of
about 18 mv, which is made up in varying proportions
by the conditioning depolarization and the super-
imposed EPSP. The threshold level of depolarization
may be attained also by superimposing an EPSP on
the depolarization produced by a preceding EPSP
(temporal summation), as is illustrated by Grundfest
(Chapter \', fig. i 7).
All these investigations conform with the hypothesis
that synaptic excitatory action is effective in generat-
ing an impulse solely by the depolarization of the
neuron, i.e. by producing the EPSP (17, 28, 29, 44).
As far as the generation of an impulse by the EPSP is
concerned, the same processes obtain as with the
propagation of an impulse from one part of a neuron
to another.
In order to produce the EPSP, the activated syn-
apses must cause an electric current to be generated
which depolarizes the postsynaptic membrane. Thus,
as shown in figure ^B, a current must flow inwards
immediately under the activated synapses, i.e. across
the subsynaptic membrane, in order that a return
current may flow outward across the remainder of the
postsynaptic membrane, so depolarizing it. When a
brief current pulse is applied across the membrane, it
builds up a potential difference that on cessation of
the current decays considerably faster than the EPSP
(12). Hence it is postulated that the current producing
V/scc
o
NORMAL MEMBRANE
3x|6'f
6
E SYNAPSES
as low OS
5x 10 n
FIG. 5. A. The continuous line is the mean of several monosynaptic EPSP's, while the broken line
shows the time course of the subsynaptic current required to generate this potential change. B.
Diagram showing an activated excitatory knob and the postsynaptic membrane. .As indicated by the
scales for distance, the synaptic cleft is shown at 10 times the scale for width as against length. The
current generating the EPSP passes in through the cleft and inward across the activated subsynaptic
membrane. [From Coombs et al. (12).] C. Formal electrical diagram of the membrane of a motoneu-
ron with, on the right side, the circuit through the subsynaptic areas of the membrane that are
activated in producing the monosynaptic EPSP. Maximum activation of these areas would be
indicated symbolically by closing the switch.
NEURON PHYSIOLOGY INTRODUCTION
67
the EPSP is not suddenly switched off after the summit
of the EPSP, but that, as shown in the analysis of
figure 5/I (broken line), a small residual current
continues to flow and thus delays the repolarization
during the decline of the EPSP (continuous line). It
will be appreciated that the EPSP's of figures 4 and
^A are produced by the operation on the neuron of
the postsynaptic currents generated by many synaptic
knobs that have been activated simultaneously by
the afferent volley.
By passing an extrinsic current across the neuronal
membrane it has been possible even to reverse the
potential across it, its interior then being po.sitive to
the exterior. When this occurs, the EP.SP is also
reversed in sign (cf. Grundfest, Chapter V, fig. 35),
which indicates a reversal of the postsynaptic currents
shown in figure 5^ and of the ionic flux across the
subsynaptic membrane (17). The effects on the EPSP
of diminution and reversal of the membrane potential
and of changes in the ionic composition of the neuron
are explicable by the postulate that the activated sub-
synaptic membrane becomes permeable to all small
ions, such as Na"*", K"*" and Cl~. The time course of
this permeability change is given by the broken line
of figure ^A, and its effect on the membrane potential
can be derived from the electrical diagrain of figure
5C. A similar investigation on the endplate potential
of the neuromuscular junction (24, 26; Fatt, Chapter
VI) has shown that reversal occurs at a membrane
potential of about — 1 5 mv, which would be close to
the liquid-junction potential between the muscle fiber
and its environment. More accurate investigations on
the EPSP may likewise reveal that a battery of about
— 1 5 mv should be inserted in the synaptic component
of the diagram in figure 5C.
It can now be taken as established that transmission
across synapses occurs not by the spread of electrical
currents, but by the specific chemical substances
which impulses cause to be liberated from the pre-
synaptic membranes (29, 38, 43). These substances
alter the ionic permeability of the subsynaptic mem-
brane and consequently initiate specific ionic fluxes
across this membrane. These fluxes in turn are re-
sponsible for the postsynaptic currents that cause the
transient depolarizations or hyperpolarizations of the
postsynaptic membrane which are produced respec-
tively by excitatory or inhibitory action (16, 1 7). Since
it gives the time course of the ionic permeability
change, the broken line of figure 5.-I may be taken to
give the time cour.se of action on the subsynaptic
membrane of the brief jet of excitatory transmitter
substance that a presynaptic impulse causes to be
emitted from the presynaptic knob. .Acetylcholine is
the transmitter substance at a few types of central
synapse, but the excitatory transmitter has not yet
been identified for the great majority.
Impulses can also be generated in a nerve cell by
another method that is of particular value in relation
to the problem of locating the site at which impulses
arise in nerve cells. When the a.xon of a nerve cell is
stimulated, an impulse travels antidromically up to the
nerve cell and usually invades it, generating an anti-
dromic spike potential as in figure 6A. When thus
recorded by a microelectrode in the soma, the anti-
dromic spike potential has two main components, as
shown by the step on the rising phase which is greatly
accentuated in the electrically differentiated record
lying immediately below the potential record in
figure 6.4. Evidence from recent intensive investiga-
tions (i, 7, 13, 39, 40, 46) can all be satisfactorily
explained by the postulate that the initial small spike
is generated by the impulse in the initial segment of
the neuron (axon hillock plus nonmeduUated axon),
while the later large spike is produced when the
impulse invades the soma-dendritic membrane (13,
46). The two spikes may therefore be called the IS
and SD spikes.
When the neuronal spike potentials generated by
synaptic or direct stimulation are recorded at suffi-
cient speed, they are likewise seen to be compounded
of IS and SD spikes, particularly in the differentiated
records (fig. 6B), though the separation is always less
evident than with the corresponding antidromic
spike potential. It must therefore be postulated that
the EPSP produced by the activation of synapses
covering the soma and dendrites is effective not by
generating an impulse in these regions, but by the
electrotonic spread of the depolarization to the initial
segment, as is illustrated by the lines of current flow
in figure 6C. By recording the impulse discharged
along the motor nerve fiber in the ventral root it is
found that usually this impulse started to propagate
down the meduUated axon about 0.05 msec, after the
initiation of the IS spike, i.e. the meduUated axon is
usually excited secondarily to the initial segment (14).
The critical level of depolarization for generating an
impulse thus gives the threshold for the IS mem-
brane, as marked by the horizontal arrow labelled
IS in figure 65, and not of the SD membrane. An
approximate measure of the threshold for the SD
membrane is given by the membrane potential ob-
tained at the first sign of inflection produced by the
incipient SD spike, as is indicated by the differentiated
records in figure 6.4 and B. This potential is measured
68 HANDBOOK OF PHYSIOLOGY ^ NEUROPHYSIOLOGY I
r'
100 ^
ImV
FIG. 6. Tracings of intracellularly recorded spike potentials evoked by antidromic (.4) and mono-
synaptic (B) stimulation of a motoneuron, respectively. [From Coombs et al. (14).] The lower traces
shosv the electrically differentiated records. Perpendicular lines are drawn from the origins of the
IS and SD spikes, as indicated in the differentiated records, the respective threshold depolarizations
being thus determined from the potential records and indicated by horizontal lines labelled respec-
tively IS and SD. C. Diagram showing the lines of current flow that occur when a synaptically
induced depolarization of the soma-dendritic membrane electrotonically spreads to the initiaj
segment.
at the levels of the horizontal SD arrow.s and is
approximately the same for the antidromically and
synaptically evoked spikes, as illustrated in figure 'oA
and B. Synaptic excitatory action thus generates an
SD spike not directly by its depolarizing action, but
only indircctK through the mediation of the IS spike
which lifts the depolarization of the SD membrane to
threshold by currents that flow in the reverse direction
to those drawn in figure 6C'.
With normal motoneurons the threshold level of
depolarization has always been, as in figure 6.4 and B,
much higher for the SD membrane than for the IS
membrane. There has been a consideraljle range in
the threshold values for motoneurons that are shown
by their resting and spike potentials to be in good con-
dition. The IS threshold has ranged from 6 to 18 mv,
and the SD threshold from 20 to 37 mv (14). However,
for any one motoneuron the SD threshold has been
about two to three times the IS threshold. Several
other types of neurons in the central nervous system
also reveal a threshold difference between the IS and
SD membranes. The functional significance of these
distinctive threshold areas of neurons will be con-
sidered after synaptic inhibitory action has been
considered.
The difference in threshold between the IS and SD
membranes must not be confused with the concept
that membranes excited by chemical transmitter are
inexcitable electrically (cf. Grundfest, Chapter V).
This concept would be applicable merely to the sub-
synaptic areas of the SD ineitibrane and not to the
whole of that membrane. It should be noted that the
receptor membrane of the bare nerve ending in the
Pacinian corpuscle also appears to be inexcitable
electrically, though acting as a primary focus for
depolarizing the first node of the meduUated axon
(27; Gray, Chapter IV). There is some analogy here
with the SD membrane acting to depolarize the IS
membrane, so generating an impulse there; but the
analogy does not hold for subsequent e\ents because
the impulse in the IS membrane usually invades the
SD membrane, whereas with the Pacinian corpu.scle
there is no such antidromic invasion.
Inhibitory Synaptic Action
Strictlv, the concept of inhibition is restricted to
depressions of neuronal excitability which occur
independently of any conditioning excitatory synaptic
activity on that neuron, and also independently of any
depression of the excitatory .synaptic bombardment
that is employed in testing for the suspected inhibition.
It mav be noted that conditioning by large afferent
voUevs causes a fairlv prolonged depression in the size
NEURON PHYSIOLOGY — INTRODUCTION
69
of the primary afferent volley and hence depresses its
excitatory action (8, 45, 55). This effect has been
attributed to the dorsal root reflex and the dorsal root
potential set up by the powerful conditioning volley
(8) and probably is of little significance with more
physiological types of afferent input. Apart from this
effect it has been shown that inhibitory actions on
motoneurons are explained satisfactorily by the tran-
sient increase which is produced in their membrane
potentials and which has been designated the inhibi-
tory postsynaptic potential, IPSP (6, 16, 18). A com-
parable synaptic inhibitory action has been observed
with crustacean stretch receptor cells (60), and has
also been recorded on the neurons of Clarke's column
by Curtis, Eccles & Lundberg (19a).
As shown in figure 75 to H, a single volley in the
afferent fibers from annulospiral endings in quadriceps
muscle evokes a hyperpolarizing response, the inhibi-
tory postsynaptic potential (IPSP) in a motoneuron
of the antagonist muscle (biceps-semitendinosus). The
IPSP is observed to be increased in a series of stages
as the afferent volley is increased in size, but it is not
altered in time course, showing that a simple spatial
summation occurs when several inhibitory synapses on
the same neuron are simultaneously activated. With
the maximum spatial summation in figure jE the
membrane potential was increased from —60 to
-63.5 mv.
In order to produce the observed hyperpolariza-
tion, current must be flowing inward across the moto-
neuronal membrane in general, and there must be a
corresponding outward current in the region of the
activated inhibitory synapses (fig. 8A, inset). As with
the excitatory synaptic action in figure 5^, the time
course of the current that produces the IPSP may be
determined if the time constant of the membrane is
known. The broken line in figure 8.4 plots the time
course so determined and shows that the high intensity
phase has virtually the same time course as with
excitatory synaptic action, though there is much less
r-r-i~r-rT-n
msec
Fig. 7. A to H. Lower records give intracellular responses of
a biceps-semitendinosus motoneuron to a quadriceps volley of
progressively increasing size, as is shown by the upper records
which are recorded from the si.xth lumbar dorsal root by a
surface electrode (downward deflections indicating negativity).
All records are formed by tfie superposition of about 40 faint
traces.
B I ELEMENT ^ ORDINARY
i-l
ELEMENT
I 70 mV I 90 mV | TO mV
I T . T
INSIDE CELL
FIG. 8. A. Continuous line plots the mean time course of the IPSP set up in a biceps-semitendinosus
motoneuron by a single quadriceps la volley. The measured time constant for the membrane was
2.8 msec. The broken line gives the time course of the inhibitory subsynaptic current that would
produce the IP.SP, the calculation being similar to that used in deriving figure ^A. Inset shows lines
of postsynaptic current flow in relationship to an inhibitory synaptic knob. B. Diagrammatic
representation of the electrical properties of an ordinary element on the neuronal membrane and of
an inhibitory element with K+ and Cl~ ion components in parallel. Further description in the
text.
70
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
residual action. By investigating the effects of varying
the membrane potential by current applied through
the microelectrode (cf Grundfest, Chapter V, fig. 1 2),
it has been shown that the IPSP is produced by a
process of ionic diffusion across the subsynaptic
membrane that has an equilibrium potential at about
10 mv more hyperpolarized than the resting mem-
brane potential, i.e. at about —80 mv (16). Further-
more, it has been shown by ionophoretic injection
through the microelectrode that this ionic diflusion is
satisfactorily explained by the hypothesis that the
inhiijitory synaptic transmitter increases the perme-
ability of the subsynaptic membrane to ions below a
critical size, e.g. to K+ and Cl~, and not to somewhat
larger ions, e.g. to Na+ (16; Grundfest, Chapter V,
fig. 12). This type of ionic mechanism appears to
occur with all types of central inhibition so far investi-
gated and also with the IPSP of the crustacean
stretch receptor cells (37, 60). It is remarkaljle that
a somewhat similar ionic mechanism explains the
vagal inhibitory action on the heart (25, 56, 76) and
probably for the inhibitory action on crustacean
muscle (42).
The electrical diagram in figure 8C illustrates the
hypothesis that the inhibitory transmitter increases
the conductance of the subsynaptic membrane to
both K+ and Cl~ ions, which have the equilibrium
potentials indicated by the respective batteries, and
so cau.ses the flow of a current (fig. Bfi) which tends to
hyperpolarize the rest of the neuronal membrane to
about —80 mv, which is the mean of the equilibrium
potentials for K+ and Cl~ ions.
Factors Controlling Impulse Generation
The currents which flow from the subsynaptic
membrane to exert a hyperpolarizing action on the
motoneuronal membrane and .set up an IPSP (fig. 8 A,
inset) also effectively hyperpolarize the membrane of
the initial segment. However the currents generated
by this ionic mechanism are even more effective in
checking depolarization (18). On this account, with
any of the three methods of stimulation, synaptic,
direct or antidromic, there is an increased difficulty in
generating an impulse in the motoneuron. All the
various types of inhibitory action can be sufficiently
explained by the increased ionic conductance pro-
duced by the inhibitory transmitter substance and the
consequent flow of postsynaptic currents that oppo.se
the excitatory currents [fig. 8; cf Coombs et al. (18);
Eccles (29)].
The low threshold of the initial segment relative to
the soma-dendritic membrane accounts for the ob-
servation that with normal motoneurons impulses are
always generated in the initial segment. As a conse-
quence the motoneuron acts as a far better integrator
of the whole synaptic e.xcitatory and inhibitory bom-
bardment than would be the case if impulses were
generated anywhere over the whole soma-dendritic
membrane. If these latter conditions obtained, a
special strategic grouping of excitatory synapses [cf
Lorente de No (65)] could initiate an impulse despite
a relative paucity of the total excitatory synaptic
bombardment and a considerable inhibitory bom-
bardment of areas remote from this focus. As it is,
both e.xcitatory and inhibitory synaptic action are
effective onlv in so far as they affect the membrane
potential of the initial segment. It is here that the
conflict between excitation and inhibition is joined,
not generally over the motoneuronal surface, as was
envisaged by Sherrington in his concept of algebraic
summation.
In the account so far given the soma-dendritic
surface functions merely as a generating area for the
postsynaptic currents that are eff"ective only in so far
as they act on the initial segment either in generating
an impulse or in preventing it. If an impulse so
generated invades the soma-dendritic membrane, it
does so after the discharge has occurred along the
axon (14). It might thus appear that the invasion of
the soma-dendritic membrane is of no consequence in
the essential function of the neuron in discharging
impulses down its axon. However, in contrast to the
initial segment and the medullated axon of neurons,
the soma-dendritic membrane of many species of
neurons develops after an impulse a large and pro-
longed after-hyperpolarization (15, 68). This after-
hyperpolarization delays the generation of the next
impulse by the neuron and thus very eflTectively slows
the frequency of the rhythmic discharges of neurons
[cf Eccles (28), pp. 174-8]. This frequency control
by the soma-dendritic membrane is \ery important in
limiting the frequency with which motoneurons
activate muscles. Recently it has jjcen shown that the
motoneurons supplying the slow postural muscles ha\e
much more prolonged after-hyperpolarizations than
those supplying the fast phasic mu.scles (30).
Central Inhibitory Patliivays
It may be taken as established that at least some
afferent fibers, e.g. those from annulospiral endings
and tendon organs, act as pathways both for excita-
torv and inhibitory actions on motoneurons, and in
NEURON PHYSIOLOGY INTRODUCTION
addition exert excitatory actions directly on other
neurons in the spinal cord (31, 32, 33, 35, 61, 62).
Until recently values for the central conduction time
of the so-called direct inhibitory pathway (annulo-
spiral afferent fibers to motoneurons of antagonist
action) were derived by measurements of the shortest
interval at which an inhibitory volley can precede a
monosynaptic excitatory volley and yet be eflfective in
inhibiting the reflex discharge. Since such intervals
approximated to zero, it was erroneously concluded
that the latency of direct inhibitory action approxi-
mated to that of monosynaptic excitatory action, and
hence that the inhibitory pathway was also monosyn-
aptic, i.e. that the annulospiral afTerents of muscle
had inhibitory synaptic endings on motoneurons (5,
28, 61, 64). However the IPSP generated under such
conditions has a latent period at least 0.8 msec.
longer than the monosynaptic excitatory action of a
comparable pathway (35), which is just the interval
that would be expected if there were a synaptic relay
on the inhibitory pathway. It has further been found
that the annulospiral afTerents establish a synaptic
relay in the interinediate nucleus which conforms in
every respect with the properties of the direct inhibi-
tory pathway (35)- Of particular significance is the
recent observation that the summed action of im-
pulses in several annulospiral fibers is required before
any IPSP is produced by them, which contrasts with
their monosynaptic excitatory pathway, where the
individual impulses are independently effective in
generating EPSP (36). Evidently the spatial summa-
tion of the inhibitory impulses also requires the
synaptic relay station that has been found in the
intermediate nucleus and that is required in explain-
ing the long central latency of the 'direct' inhibitory
pathway. The same additional latency and inter-
neuronal relay are observed for the IPSP generated
through the contralateral inhibitory pathway which
Wilson & Lloyd (78) have discovered in the Sj and
S3 segmental levels (20). Finally, the monosynaptic
excitatory action of afferent impulses from the quadri-
ceps and gracilis muscles on soleus and biceps-semi-
tendinosus motoneurons, respectively, (32) provides a
sufficient explanation of Sprague's observation (74)
that some afferent fibers entering by the L5 dorsal
root establish synaptic connections directly with
motoneurons of the L7 and Si segments [cf. Eccles
(29), p. 156]. It may therefore be taken as established
that a single interneuron is interpolated on the direct
inhibitory pathway, as shown diagrammatically in
figure g.-l. Similarly there is a single interneuron on
the inhibitory pathway from motor axon collaterals
to motoneurons (34), as is shown diagrammatically
in figure gfi. By a systematic study of the IPSP's pro-
duced by afferent impulses in the fibers of Golgi
tendon organs, it has recently been found that there is
always at least one interneuron on the inhibitory
pathway, though sometimes two are interpolated (33)-
Inhibitory and Excitatory Transmitter Substances
Strychnine has been found to have a highly specific
and rapid action in depressing inhibitory synaptic
action (cf. Grundfest, Chapter V, fig. 12), at least
with the five types of inhibitory action that have so
far been investigated in the spinal cord (5, 18, 29).
Similarly, tetanus toxin very effectively depresses all
these inhibitory synaptic actions (9). In fact the
clinical effects of both strychnine and tetanus toxin
can be sufficiently explained by these actions. Since
the activation of the inhibitory interneurons is not
affected when synaptic inhibitory action has been
virtually abolished by strychnine or tetanus toxin, it
may be concluded that these agents exert their de-
pressant action on the inhibitory synapses, as indi-
cated in figure 9.4 and B. On account of the rapidity
and effectiveness of its action it seems likely that
strychnine acts competitively with the inhibitory
transmitter for the receptor patches of the inhibitory
subsynaptic membrane. Certainly the highly specific
actions of tetanus toxin and strychnine indicate that
inhibitory synaptic action is mediated by a specific
inhibitory transmitter substance.
The interneuron on the inhibitory pathways (cf.
fig. 9.4 and E) can be regarded as being introduced in
order to change over from a neuron that manufactures
and liberates an excitatory transmitter substance to
one that operates through the inhibitory transmitter
substance. It is, therefore, postulated that any one
transmitter substance always has the same synaptic
action, i.e. excitatory or inhibitory, at all synapses on
nerve cells in the mammalian central nervous system.
According to this principle, any one class of nerve
cells in the mammalian central nervous system will
function exclusively either in an excitatory or in an
inhibitory capacity at all of its synaptic endings, i.e.
it is postulated that there are functionally just two
types of nerve cells, excitatory and inhibitory. The
interneurons illustrated in figure 9.4 and B are ex-
amples of 'inhibitory neurons'. On the other hand,
the dorsal root ganglion cells with their primary
afferent fibers, proi^ably the neurons of all the long
tracts both ascending and descending, the moto-
neurons, and many interneurons belong to the class
72
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY 1
/f
■ Blocked b/ dihydfo-^-erythroi'j rt
ToT "^V
BLOCKED BY STRYCHNINE, TETANUS TOXIN
MOTO
NEURONE
FIG. g. A. Schematic drawing of tiie anatomical and physiological features of the direct inhibitory
pathway. It shows the events in the primary afferent hber, in its excitatory synaptic connections with
an intermediate neuron (I cell) and finally in the inhibitory synaptic connection of this neuron with a
motoneuron, where the inhibitory subsynaptic current is shown by a broken line and the IPSP by
a continuous line (cf. fig. 6A). B. Diagram summarizing the postulated sequence of events from an
impulse in a motor axon to the inhibition of a motoneuron. All events are plotted on the time scale
shown below and the corresponding histological structures are shown diagrammatically to the left
(note indicator arrows). The four plotted time courses are from above downwards for the following
events: the electrical response of impulse in motor-axon collateral; the electrical response evoked in a
Renshaw cell by the cumulatixe effect of acetylcholine at many synapses, showing impulses super-
imposed on a background depolarization; the IPSP generated in the motoneuron by the Renshaw
cell discharge; and the aggregate IPSP evoked in a motoneuron that is bombarded repetitively by
many Renshaw cells, which become progressively more asynchronous, so smoothing the latter part
of the ripple. The structural diagram to the left shows converging synapses on the Renshaw cell
and on the motoneuron. [From Eccles c/ at. C34)-j
'excitatory neurons'. Conceptually, by this subdivision
of nerve cells into excitatory and inhibitory types, a
great simplification is produced in the physiology of
central synaptic mechanisms, for all branches of any
one neuron can be regarded as having the same
synaptic function, i.e. as being uniformly excitatory
or uniformly inhibitory. Terzuolo & Bullock (75)
give experimental evidence that this principle of
neuronal specificity does not hold for the cardiac
ganglion of Limulus.
In attempting to understand the operation of any
neuronal system in the mainmalian central nervous
system, a useful provisional postulate would be that
all inhibitory cells are short-axon neurons lying in the
grey matter, while all transmission pathways including
the peripheral afferent and efferent pathways are
formed by the axons of excitatory cells. Such a postu-
late would be of most direct application in relation to
such simple problems as the modes of termination of
the descending tracts, but eventually it may be
applicable also to more complex situations in the
brainstem and even in the cerebellar and cerebral
cortices. In all these situations there is as yet no infor-
mation on the structural features of the inhibitory
mechanisms.
It will be sufficiently evident from the above
account of nerve cells that interactions between nerve
cells are attributed to synaptic contacts which operate
by a specific chemical transmitter mechanism. The
alternate postulate is that, at least in part, interaction
between neurons is attributable to the flow of electric
currents generated by active neurons. There is at
present no experimental evidence that the nervous
system ot \ertebrates operates in this way. The flow
of electric currents between neurons is far too small
to have any significant effect, even in experiments
using the unphysiologicai procedure of large syn-
chronous volleys. In contrast it should be mentioned
that some synapses in Crustacea do operate by elec-
trical transmission, there being special permeai:)ility
and rectification properties of the apposed synaptic
memijranes (47). Such a mechanism would have been
detected if it were operative at any of the central
synapses of vertebrates that have been systematically
investigated.
NEURON PHYSIOLOGY INTRODUCTION
73
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74 HANDBOOK OF PHYSIOLOGY -" NEUROPHYSIOLOGY I
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CHAPTER III
Conduction of the nerve impulse
ICHIJ I TASAKI
Laboratory of Neurophysiology, National Institute oj Neurological Diseases and Blindness,
National Institutes of Health, Bethesda, Maryland
CHAPTER CONTENTS
Introduction
Compound Character of Peripheral Nerve
General Character of the Nerve Impulse
Cable Properties of the Invertebrate Axon
Cable Properties of the Myelinated Nerve Fiber
Conductance of the Membrane During Activity
Threshold and Subthreshold Phenomena
Threshold Membrane Potential
Strength-Duration Relation
Subthreshold Response
Measurement of Excitability by Using Test Shocks
Abolition of the Action Potential
Nervous Conduction Along Uniform Axon
Nervous Conduction in Myelinated Nerve Fiber (Saltatory
Conduction)
Effect of Increase of External Resistance
Safety Factor
Does the Nerve Impulse Jump from Node to Node?
Field of Potential Produced by a Nerve Impulse
Conduction in a Polarized Nerve Fiber
Pfliiger's Law of Contraction
Effect of Narcosis upon Nervous Conduction
After-Potentials and Rhythmical Activity
After-Potentials
Rhythmical Activity
Current Theories of the Resting and Action Potentials
Resting Potential
Action Potential
THE MODERN DEVELOPMENT of the coiicept of thc neivc
impulse may be said to have started with the measure-
ment of the velocity of the nerve impulse by von
Helmholtz (141) in 1850. He measured the time
interval between delivery of an electric shock to the
nerve of a nerve-muscle preparation and the start
of contraction of the muscle by two different methods.
The first method used was to start a constant current
throuE;h a ballistic galvanometer at the lime of
delivery of the shock and to interrupt the current
automatically by a switch opened by the twitch of
the muscle. The second method he used was based
on graphical registration of the muscular contraction
on a moving surface. He compared the time intervals
measured by stimulating the nerve near its two ex-
treme ends.
Helmholtz's finding and the subsequent con-
firmation and expansion of his observation by a
number of investigators established the fact that a
nerve impulse travels along the nerve at a rate far
slower than that of light or sound in a similar medium
but substantially faster than the process of transporta-
tion of substances by streaming or diffusion in a slender
tube like a nerve fiber. Later, in 1908, Lucas (80)
found that the velocity of the nerve impulse doubles
with a rise in temperature of about 10 degrees. The
question of whether or not the nerve impulse is
associated with any chemical reacdons, however,
was not solved until Tashiro (138), Parker (98),
Fenn (32) and Gerard (40) established the increase
in production of carbon dioxide and consumption of
oxygen related to nervous activity. The demonstra-
tion of heat production associated with propagation
of nerve impulses by Downing et al. (24) gave a
further strong support to the view that chemical
reactions underlie the process of nervous conduction.'
An entirely different line of approach to the study
of the processes underlying nervous conduction
originates with Hermann (47). He worked on a
'core-conductor model' of nerve which is the prede-
cessor of the passive iron model (75). The basic idea
' Some investigators are of the opinion that all the chemical
reactions take place late in the recovery phase and not during
the period in which electrical signs of activity can be observed
[e.g. Hodgkin & Huxley (59)].
75
76
HANDBOOK OF PHVSIOLOGV ^ NEUROPHYSIOLOGY I
developed from the observations on the model is that
nervous conduction may l^e mediated by a flow of
electric current between successive portions of the
nerve, i.e. by local circuits. Through very extensixe
investigations of bioelectricity by Matteucci (86),
Du Bois-Reymond (25), Biedermann (12) and others,
it became known that a transient potential variation
is generated by a stimulation of a nerve between the
portion of the nerve or the muscle carrying an impulse
and the killed or resting portion. The existence of a
local circuit is therefore a logical consequence of the
direct observations on the bioelectricity of the ner\e.
A direct demonstration of the decisive role played
bv a local circuit in the propaeation of an impulse
was brought forward, a long time after Hermann's
prediction, first by Osterhout & Hill (95) who worked
not on the nerve but on a large plant cell, Xitella.
They found that propagation of an impulse along this
elongated cell can be reversibly blocked under certain
experimental conditions by removing or reconnecting
a salt bridge which constituted a part of the local
circuit. Later, similar obsersations were made both
on isolated invertebrate nerve fibers (52) [cf. also (50)]
and on single nerve fibers of the toad (i 17).
The development of the concept of the all-or-none
relationship between the intensity of stimulus and
the 'size of the response' followed a long, confusing
course. In 1871, Bowditch (16) found that the
magnitude of contraction in an excised heart muscle
of the frog is independent of the intensity of the shock
used; a weak shock, if effective at all, causes a con-
traction which is as large as that caused by a strong
shock. A similar quantal relationship between the
twitch and stimulus intensity was demonstrated in
individual muscle fibers of the frog sartorius muscle
(loi) and also in a ner\-e-mu.scle preparation of the
frog containing a small number of nerve fibers (81).
In these cases the 'size of the response' represents
the magnitude of muscular contraction observed at
some distance away from the site of stimulation.
Attempting to expand the concept of 'size of
response' to include the response in the nerve itself,
Lucas (82) and Adrian (i) introduced the idea of
measuring the nerve impulse by its ability to stimu-
late the adjacent portion of nerve, or by its capability-
to travel across a narcotized region of nerve — the
logic being analogous to measuring the power of a
man by his ability to cross a desert. Through a num-
ber of ingenious experiments, Lucas and Adrian
concluded that the size of the nerve impulse in in-
dividual nerve fibers was independent of the way
it was elicited. Kato (69) and his associates and also
Da\is ('/ al. (23) pointed out that there was an er-
roneous assumption in this argument as to the
mechanism of narcotic action. However, the con-
clusion that a propagated ner\'c impulse obeyed the
all-or-none law turned out to be perfectly correct.
Another .series of somewhat controversial argu-
ments was evoked among investigators when the
concept of 'local' or 'subthreshold' response was
introduced in physiology. In 1937 Rushton (105)
predicted the existence of a local response in nerve
by the following argument. If propagation of a nerve
impulse is due to successive stimulation of a resting
portion of ner\-e by the neighboring active (respond-
ing) area, a definite minimum area of a nerve has
to be excited by the stimulating current in order that
the response at the site of stimulation can generate a
propagated all-or-none response. In other words,
he stipulates that there should be a 'response' at
the site of stimulation that is too small to initiate a
full sized propagating response.
.Soon after Rushton's prediction, Hodgkin (51)
obtained clear-cut records indicating the existence
of 'subthreshold responses' in the invertebrate nerve
fiber. However, it was found later that Hodgkin's
demonstration did not prove the legitimac\ of
Rushton's argument. Cole & Curtis (19) proved that
the resistance of the surface membrane of the squid
nerve fiber decreases at the peak of its response
to about '200 "' the resistance at rest; a responding
area of the squid axon behaves like a battery with no
appreciable internal resistance. Lender ordinary
experimental conditions, it is practically impossible
to elicit a full-sized response in an area too small to
initiate a propagated impulse. Furthermore, these
subthreshold respon.ses were demonstrated in sc)uid
axons of which a large area was subjected uniformly
to a stimulating current. Later we shall discuss
similar phenomena obser\-ed in the nixclinaied nerve
fiber (p. 98!
We have discussed up to this poiiu the coin-se of
development of some of the basic concepts concerning
the nature of the nerve impulse. We shall describe
on the following pages the main experimental facts
known ai)Oul the nerve filler and its ai)ilit\' to carry
impulses. Emphasis will be placed on the data ob-
tained from in\ertebrate and vertebrate single nerve
fibers. There is good reason to belie\e that, at least
in this field of physiology, the iiehavior of an as-
sembh' of many nervous elements can be understood
if the beha\ior of indi\idual fibers under simple,
well-defined, experimental conditions is known.
It is generally extremely difiicult to infer the behavior
CONDUCTION OF THE NERVE IMPULSE
77
of individual fibers from observations on the nerve
trunk.
COMPOUND CHARACTER OF PERIPHERAL NERVE
Soon after the first World War, Forbes & Thacher
(34) introduced a condenser-coupled vacuum tube
amplifier into the field of electrophysiology. Aided
by the continued development of electronic engi-
neering, Gasser & Erlanger (38) in 1922 took the
first photograph of a ner\e response recorded with
an instrument ideal in being inertialess. They
started using a cathode ray oscillograph to register
the time course of responses of the nerve.
The standard technique of recording electric signs
of activity of a whole nerve trunk is to kill (ordinarily
by crushing) one end of a nerve and to place one
of the recording electrodes on this killed end (see
fig. i^). The other electrode needed to measure the
potential difference is placed on the intact part of
the nerve near the killed end. Ordinarily, either lightly
chlorided siKcr wire (abbreviated as Ag-AgCl)
or calomel half cells (Hg-HgCl) are used for recording
for they are nonpolarizable. Stimulating electrodes
(S in fig. i) can be either the Ag-AgCl Ringer type
or a pair of plain platinum wires. A precaution has
to be taken to ' isolate' the stimulus from ground,
namely, to eliminate metallic connection of the
stimulating electrodes with ground. The main reason
for the necessity of stimulus isolation is to prevent
flow of stimulating (and other) currents between the
stimulating and ground electrodes. The electrodes
and the nerve are generally mounted in a moist
chamber to prevent evaporation of water from the
surface of the nerve.
The arrangement of the recording electrodes just
described is called a 'monophasic lead' and a re-
sponse of the nerve recorded with this arrangement is
referred to as a 'monophasic action potential'. The
traditional picture illustrating the principle of this
method of recording action potentials is as follows.
The portion of nerve carrying an impulse is 'elec-
trically negative' to the portion at rest. When an
impulse started by a stimulus emerges in the region
of the recording electrode Ei, the potential differ-
ence between Ei and E2 undergoes a transient vari-
ation which makes the potential at E2 more positive
(or less negative) to that at Ei. Since the impulse does
not reach the region of E2, a potential variation
representing the ner\ous activity at Ei is recorded
monophasically.
The modern picture illustrating the principle of
monophasic recording (83, 1 24) is slightly different
from the classical one. Attention is now focused
upon the nerve fibers and the intercellular space in
the nerve trunk. When a nerve fiber carries an im-
pulse, it generates a transient flow of current in the
surrounding fluid medium. In the region of Ei and
E2, this transient current in the intercellular space is
directed from E; to Ei, raising the potential at E2
relative to Ei for a short period of time. The currents
produced simultaneously by many fibers in the
nerve are superposed in the intercellular space and
give rise to a large coiTipound action potential. In
this modern picture, the 'electrical negati\ity' in
40-
20-
O.Zmtce
100
129
150-1
FIG. I. A. Demonstration of the constant velocity of
propagation of the a- and /3-waves in the action potential of
the sciatic nerve of the bullfrog. S, the stimulating electrodes;
El and E», recording electrodes, the latter at the killed end
of the nerve. The distance from the site of stimulation to the
recording electrode Ei is indicated on the \ertical line. The
starting points of the oscillograph trace show the distances at
which the records were taken. Abscissa, time. [From Gasser &
Erlanger (38).] B. A similar observation made on a three-
fiber preparation of the toad. The diameters of the fibers were
13, 9 and 5 II. The strength of the stimulating shocks employed
was twice the threshold for the smallest fiber. [From Tasaki
(124)-]
78
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
the classical picture- is clearly defined as an IR drop
in the intercellular space.
We shall now proceed to discuss the time course of
the action potential of a buUfroE; sciatic nerve re-
corded with this arrangement. When the distance
from the stimulating; electrode (S) to the recording
electrodes (Ei) is relati\ely large and the shock is
strong enough to stimulate most of the fibers in the
nerve, an action potential with several separate
peaks is observed (fig. i.-!, bottom). As the distance is
altered, the time intervals between the peaks are
found to alter, indicating that separate elevations
in the potential record represent processes travelling
along the nerve at different velocities. Gasser, Erlanger,
Bishop and others (13, 38) interpreted these findings
as resulting from differences in the conduction velocity
of the different fibers in the ner\'c trunk.
In figure \B, a set of records is presented showing
the validity of the interpretation just mentioned.
Here, the connective tissue sheath around the sciatic
nerve is removed near its distal end and all except
three nerve fibers are cut (for the detail of this opera-
tion, cf. 113, 124). The two recording electrodes
are placed in two small pools of Ringer's solution
separated by a narrow air gap (o. i mm wide) across
which the exposed nerve fibers are mounted. Under
these circumstances, the electric currents which the
nerve fibers produce when the impulses arrive at the
site of recording inevitably flow through the resistor
QR in the figure) connected between the electrodes.
The IR drop thus produced is amplified and recorded
with an oscillograph.
It is seen in the records that the number of peaks
observed is equal to the number of the fibers left
uncut. Three fibers are now generating three sepa-
rate potential variations. It is also clear that each
fiber carries an impulse at a rate which is approxi-
mately constant for the whole length of the sciatic
nerve.
It is simple to demonstrate the statistical rule
formulated by Erlanger and Ga.sser that the con-
duction velocity increases with increasing fiber
diameter. If only one large fiber is left uncut, we
find a high conduction velocity; a weak electric
shock is sufficient to excite it. If one small fiber is
- It is important to distinguish a negative potential from a
negative electric charge. The potential along a uniform electric
conductor is inevitably related by Ohm's law to a flow of
current in the conductor; it has to be expressed as a potential
difference between the two points on the conductor, for in-
stance, 'the potential of Ei is 10 mv below (or abose) that of
E;' but not E; is negative and Ei is positive.'
40 - m/sec
30
20
10
o
o o
o o
o
o
UJ
>
z
o
I-
o
z>
o
z
o
o
o
o
000
o
o
8 °
o
o o o o
0
o
O o
FIBER DIAMETER
J I I I
8
10
12
14
16)1
FIG. 2. Conduction velocity of individual nerve fibers, V,
plotted against fiber diameter, D. Single fibers were isolated
from sciatic-gastrocnemius preparations of the bullfrog. The
outside diameter of the fiber was measured at the operated
region near the muscle. Temperature, 24°C. [From Tasaki
et al. (l3i)-]
isolated in the region of recording, we find a small
response which arrives at the site of recording after a
long delay; a strong shock is needed to stimulate
such a fiber.
In figure 2 the conduction velocities of about 50
different fibers in the bullfrog sciatic nerve are plotted
against their outside diameter. There is a rough
proportionality between the fiber diameter and the
conduction velocity, the correlation coefficient be-
tween the two being 0.92 in this measurement. The
relation between the minimum effective intensity or
threshold of shock and the fiber diameter determined
by this method can be found elsewhere (124).
It is well-known that the internodal length (the
distance between the two neighboring nodes of
Ranvier) increases with the fiber diameter. For the
fibers in the bullfrog sciatic nerve, the relation be-
tween the diameter D and the internodal length L
was found to be expressed by the formula
L = 0.146 X io'L»,
CONDUCTION OF THE NERVE IMPULSE
79
the correlation coefficient between the two being
0.62. The relation between the conduction velocity
V (expressed in m per sec.) and the diameter (in fji)
presented in figure 2 can be expressed by
V = 2.50/)
(at 24°C)- From the two formulae abose, it follows
immediately that
L
- = 0.059 (fnsec).
I
The ratio L'V represents the average conduction
time for one internodal length. The last expression
indicates that, statistically speaking, the internodal
conduction time is roughly independent of the fiber
diameter.
In the experiments involving electric stimulation of
whole nerve trunks, it is customary to designate
groups of nerve fibers of different conduction velocities
as a, /3, 7, (6), B and C. Group a represents the
fastest myelinated nerve fibers in the nerve with
velocities of 20 to 30 m per .sec. in the frog, while B
fibers are the slowest group (5 m per sec. or less)
at room temperature. The first three (or four) groups
are often included in .1. Group C represents non-
myelinated fibers. This cla.ssification is somewhat
arbitrary.
The distribution of the fiber sizes in a nerve trunk
generally shows several peaks of numerical pre-
dominance. Reflecting this situation, action potentials
recorded at some distance away from the site of
stimulation develop sev-eral peaks. However, be-
cause of the difference in size and duration of the
action potentials among diflferent fibers, it requires a
tedious calculation to predict the configuration of
the action potential of a whole nerve trunk on the
basis of its fiber size distribution. A detailed treat-
ment of this problem is found in a monograph by
Gasser & Erlanger (38).
GENERAL CH.ARACTER OF THE NERVE IMPULSE
In the preceding section we have seen an example
of simplicity and clarity of the experiments done
with isolated single nerve fibers. It was Adrian &
Bronk (5) in 1928 who made the first successful at-
tempt to reduce operatively the number of active
fibers in a nerve to record single fiber responses.
The operation of isolating single nerve fibers of the
frog and the toad was developed in Kato's laboratorv
(70).
Another successful approach to single fiber experi-
ments was achieved by the use of nerve preparations
of invertebrates, such as crabs, lobsters, crayfish
or squid. The operative procedure of obtaining single
fibers in these invertebrate nerves is simpler than the
dissection of a single frog nerve fiber, since some of
the fibers in these lower animals are larger than 100
/i in diameter. So-called squid giant axons, which
Young (146) has introduced to electrophysiologists,
are as large as 400 to 900 n in diameter and are an
excellent material for investigating the potential
inside the axoplasm.
Through the use of single fiber preparations, the
demonstration of some of the basic properties of the
propagated nerve impulse has become extremely
simple and direct. The following properties are
common to all the nerve fibers examined, vertebrate
and invertebrate.
a) All-or-none law. The historical aspect of the
development of this law has been mentioned in the
introduction of this chapter. This law may be stated
as follows: with other factors constant, the size and
shape of any electrical sign of a propagated nerve
impulse is independent of the intensity of stimulus
employed to initiate the impulse.
It has been mentioned that a definite threshold in-
tensity is needed to initiate an impulse in a nerve
fiber. As signs of an impulse, one may take the current
de\eloped by the fiber, the action current, or the
potential changes inside the axoplasm, or any other
electrical response of the fiber. When the stimulus
intensity is varied, these signs may appear slightly
earlier or later; but the whole time course remains
uninfluenced by how far above threshold the stimulus
intensity is.
The records presented in figure 3 show the time
course of the action currents produced by a single
nerve fiber of a toad in response to electric shocks of
varying intensities. The shocks were applied to the
sciatic ner\e trunk and the current associated with
an impulse traveling along a single nerve fiber in the
nerve was recorded by the technique described in the
discussion of the experiment of figure iB. At threshold
(the lowest trace), the action current of the fiber
started after a long and variable delay. The time
course of this action current, however, was identical
with that of the other responses to stronger shocks.
It is possible to modify the time course of the electric
response of a fiber by changing physical or chemical
environmental conditions, such as temperature or
composition of the fluid around the fiber. This fact
should not be regarded as a violation of the all-or-
8o
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY
Fio. 3. Demonstration of the all-or-none behavior of the
electric response (binodal action current) of a single myeli-
nated fiber. The distance between the stimulating electrodes
and the site of recording was 20 mm. The strengths of the
stimulating shocks were, from the bottom upward, 100, 105,
150, 200, 250, 300 and 350 per cent of threshold, respectively.
Time marker, 5000 cycles per sec. Temperature, 20.5°C.
[From Tasaki (124).]
none law. This law refers to the identity of the re-
sponses obtained by changing only the stimulus
intensity and nothing else.
The all-or-none law is not applicable, at least not
in as strict a form as described above, to electrical
responses recorded at the site of stimulation
(cf. p. 98).
/)) The refractory period. The time course of the
response of a nerve fiber is not influenced bv the rate
at which the stimulating shocks arc repeated as long
as the rate is less than about 10 per sec. When, how-
ever, the repetition rate is increased up to about 100
per .sec. at room temperature, it is found that the
responses are difl'crent in their size and shape from
the responses obtained at lower frequencies. During
a short period of time after an impulse has swept over
the fiber, the 'condition' of the fiber is different from
that of a normal resting filler. This period is called
the refractory period of the nerve fiber.
It is customary to investigate the properties of a
nerve fiber in the refractory period by using a series
of paired stimuli, a brief conditioning shock followed
by a brief test shock at an adjustable interval. The
response of the fiber to the first conditioning shock
has the normal configuration, while the response to
the second test shock varies with the time interval
between the paired shocks. The threshold for the
second shock is known to undergo a pronounced
change during the early stage in the refractory period.
The curve representing the time course of the
gradual change in threshold with increasing shock
intervals is generally called a "recovery curve'. In the
first recovery curve published by Adrian & Lucas (6)
in 1912, the reciprocal of threshold, the 'excitability',
was plotted against the interval between the two
shocks. The thick continuous line in figure 4 shows a
recovery cur\e determined by using the propagated
impulses of a single nerve fiber as the index. The
threshold for the test shock alone (measured i sec. or
more after the conditioning shock) is taken as unity.
The oljserved data indicate that, as the interval be-
tween the conditioning and test shocks decreases, the
threshold for the test shock rises first gradually and
then more rapidly. There is a sharp break in the curve
at the moment when the threshold is about J. 5 to
3 times the normal \alue, namely, when the excita-
bility is about 30 to 40 per cent of the normal level.
This break in the recovery cur\e indicates that, in
the period following initiation of a propagated nerve
impulse in a nerve fiber, there is a definite period
during which the fiber is incapable of carrying a
second impulse. This period was designated b\' pre-
vious workers as the 'aljsolutely refractory period', but
more recently the term the 'least (or critical) interval'
between two effective stimuli (124, 136) is preferred.
The reason for this recommendation is the fact that,
when one determines the recovery curve at the site of
stimulation, a continuous curve without a break is
obtained. The term 'functional' absolutely refractory
period has also been recommended to describe this
period (103).
The period during which the excitability recovers
continuously is called the 'relatively refractory period'.
Following this period there is often a period of
heightened excitability which is called the supernor-
mal phase. During the 'supernormal phase', the size of
the action potential and the conduction velocity are
practically normal.
The thin line in figure 4 shows the recovery curve
for the same fiber determined at low temperature.
The temperature-dependence of the recoxery curve
is pronounced, the Qio being about 3.5 (2, 1 19). The
effect of temperature change is reversible.
The conduction velocity is known to be subnormal
during the relatively refractory period. This is shown
in figure 5, in which the shock response intervals for
two impulses were plotted against the distance be-
tween the site of stimulation and the site of recording.
The two impulses were set up at an interval slightly
longer than the least interval of the fiber. It is seen
in the figure that the shock response interval for the
first impulse increases proportionately with the con-
CONDUCTION OF THE NERVE IMPULSE
10 15 20
SHOCK INTERVAL
2 3 4 5 6
SHOCK RESPONSE INTERVAL
FIG. 4. Recovery curves of a toad nerse hber determined at two different temperatures. [From
Tasaki (119).]
FIG. 5. Relation between the conduction distance and the shock response interval for two impulses
elicited at an interval of 2 msec. A motor nerve fiber of 1 1 /j in diameter inner\.ating the flexor
digitorum brevis of the toad. Temperature, 23°C.
duction distance. Evidently, the first impulse travels
along the filler at a normal constant rate.
If the second impulse had travelled at the normal
velocity, the shock response interval for the second
impulse should be represented by the dotted line in
the figure which has the same slope as the straight
line for the first impulse. Actually, it is seen that the
observed shock response interval increases with in-
creasing conduction distance more rapidly than that
for the first impulse.
It is easy to figure out the space-time pattern of the
two impulses based on the experimental data present
in figure 5. Evidently, the tangent (slope) of the curve
in the figure represents the velocity of the second im-
pulse at that moment. At the point where the two
impulses were initiated, the velocity of the second
impulse is approximately 50 per cent of the velocity
of the first impulse. Because of this large difference in
velocity between the two impulses, the second im-
pulse lags, spatially and temporally, behind the first
as they travel along the fiber. As separation between
the two impulses increases, however, the second im-
pulse gains more speed because of increasing recovery
from the refractoriness left behind the first impulse.
Thus, as they travel along a nerve fiber, the interval
between the two impulses approaches asymptotically
a constant value which is independent of the initial
interval at which they started.
c) Two-way conduction. It is simple to demon-
strate that a nerve fiber is capable of carrying im-
pulses in both directions, from its proximal end
toward the distal and also in the reverse direction.
An observation illustrated by figure 6 shows this.
Here a squid giant axon is used. An entirely analo-
gous observation has been made on the vertebrate
myelinated ner\'e fiber.
The axon is placed in a pool of fresh sea water on
a glass plate. Near each of the two ends of the axon
a pair of stimulating electrodes is placed. A recording
electrode, a glass pipette of about i ix at the tip filled
with isosmotic potassium chloride solution in this
case, is pushed into the axoplasm of the axon through
its .surface membrane. The grounded sea water is
taken as a reference point for measuring the action
potential. A stimulus applied at one end, A in the
figure, gives rise to a response of the all-or-none type,
indicating that the impulse starting at A trav"els
toward B. When another stimulating shock is applied
at the other end, B, sometime after the impulse from
A has swept o\-er the fiber, the impulse arising at B
can be recorded by the pipette in the middle of the
axon (see the top record in fig. 6 ). Since the recording
pipette can be placed anywhere between A and B
with essentially the same result, this observation proves
that the axon is capable of carrying impulses in both
directions.
When the time intersal between the shocks at A
and B is reduced below a certain limit (see the record
in the middle), the second shock becomes ineffective.
The explanation of this fact is simple. Soon after
region B of the axon is traversed by the impulse
arising at A, this region becomes refractorv and does
not respond to the second shock.
What happens if two shocks are applied simulta-
neously at the two ends A and B? There is no refrac-
toriness at the site of stimulation in this case since
these regions have not been traversed by any impulse.
Hence, an impulse should be initiated at A propa-
82
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
gating toward B. Simultaneously, another impulse
starting at B should travel toward A. Then, the im-
pulses are bound to undergo a collision at a point
about half way between the two sites of stimulation
of the axon. After such a head-on collision, it should
be impossible for the two impulses to travel further
since the region where the impulse from A is heading
is freshly traversed by the impulse from B and is conse-
quently incapable of carrying another impulse. The
same thing can be said of the region on the other side
of the site of collision.
In the bottom record of figure 6, the two stimu-
lating shocks are delivered in such a way that the two
impulses collide exactly at the site of recording. This
is accomplished by adjusting the delays of the two
shocks after the start of the sweep of the oscillograph
beam in such a manner that the respon.se to shock A
alone appears at the same spot on the oscillograph
screen as the response to shock B alone. Delivery of
two shocks under these conditions elicits, as can be
seen in the figure, only one response which has
almost the same configuration as the respon.se to one
shock. The shock response interval is known to be
slightly reduced by collision. A further discussion on
this topic may be found elsewhere (120).
d) Multiplication of impulses at the branching point of a
nerve fiber. Histological studies indicate that vertebrate
motor nerve fibers frequently undergo dichotomy or
ramification at nodes of Ranvier, one mother fiber
giving rise to two (or more) daughter fibers [cf. e.g.
Eccles & Sherrington (26)]. During the course
of isolating single nerve fibers innervating the toad
gastrocnemius muscle, such branching motor fibers
are sometimes encountered. It has been shown
in such preparations that the muscle tension developed
by stimulation of the mother fiber (with two daughter
fibers intact) is nearly twice as great as the tension
observed after severing one of the daughter fibers.
Obviously, this indicates that the iinpulse travelling
down the mother fiber invades the two daughter
fibers. By this process of successive dichotomy, an
impulse travelling along a motor nerve fiber multi-
plies itself before it reaches a large number of muscle
fibers.
Sensory nerve fibers generally dichotomize as they
approach their peripheral endings. They also branch
off many collaterals in the spinal cord. It is generally
believed that impulses multiply themselves at the.se
bifurcating points. In the squid axons, multiplication
of impulses at bifurcation points has also been ob-
served.
e) Interaction between nerve fibers. When a group
of fibers in a nerve trunk carries nerve impulses, it
never happens, under ordinary experimental condi-
tions, that these impulses are transmitted to the other
surrounding nerve fibers. This can be shown bv the
following simple observation.
The gastrocnemius muscle of the toad or frog is
innervated by a small nerve twig branching off from
the large tibial nerve which innervates also plantar
muscles and the skin of the foot. Stimulation of the
tibial nerve at a point distal to the exit of the muscle
nerve to the gastrocnemius does not evoke any po-
tential variation in the muscle nerve nor any contrac-
tion in the muscle. Such a stimulus sets up a ' volley
of impulses' in the majority of the fibers in the tibial
nerve, but these impulses do not spread to the nerve
fibers entering the muscle.
It has been found, however, that there is a very
weak, barely detectable interaction between the
nerve fibers in a common nerve trunk. Otani (96)
found that, when the peroneal branch of the sciatic
nerve carries a volley of impulses, the threshold for
the fibers from the tibial branch undergoes a transient
change. This observation was confirmed and ex-
panded by several investigators, notably by Marrazzi
& Lorente de No (85). This result is now interpreted
on a purely electrical basis: when a group of fibers
carries impulses, the fluid in the intercellular space is
traversed by action currents developed by these active
fibers. If a stimulating current pulse is delivered in
this region of nerve, the effect of the stimulus is
modified when it is superposed on or antagonized by
the action currents. The maximum change in thresh-
old is of the order of 10 per cent.
If the mechanism of interaction between nerve
fibers is electrical in nature, it would be expected that
the interaction should be greatly enhanced by re-
ducing the shunting effect of the fluid medium around
the nerve fiber. Katz & Schmitt (73) have shown
that this is actually the case.
The diagram at the top of figure 7 illustrates their
experimental arrangement. Two nerve fibers of the
crab were immersed in a pool of mineral oil. Fiber I
was stimulated with electrodes A and B and its re-
sponse was observed by means of the recording elec-
trodes D and E in the figure. At about the time of
arrival of an impulse from B at the site of recording,
testing current pulses were delivered through elec-
trodes C and D to determine changes in threshold of
fiber II at D. The triphasic curve at the bottom of
figure 7 is the time course of the threshold changes
observed. Katz & Schmitt explained these results,
with good reason, as due to the flow of the action cur-
CONDUCTION OF THE NERVE IMPULSE
83
^ I// h'^ ^
FIG. 6. Action potentials of a squid giant axon elicited by
stimulating shocks at the two ends, A and B, of the axon. The
recording micropipctte was pushed into the axoplasm through
the axon membrane. Demonstration of two-way conduction
{top'), refractoriness (jniddli) and collision of impulses {hol-
torri). Temperature, '2o°C. (Discussion in text.)
rent developed by fiber I through the surface mem-
brane of fiber II. They also demonstrated that the
velocity of an impulse in fiber II is afTected by the
impulse in fiber I when the amount of the fluid is
reduced and when the two impulses are not spatially
far apart.
Arvanitaki (9) and Tasaki (124) showed that,
under special experimental conditions, it is possible
to make an impulse jump from one fiber to another
by leading; the action current of one fiber through the
other.
CABLE PROPERTIES OF THE INVERTEBR.\TE .^XON
It is easy to introduce a small glass pipette or a set
of metal wires longitudinally into a squid giant axon.
By using such internal electrodes, electric properties
of the giant axon have been extensively investigated
by a number of physiologists. We shall discuss in this
section some of the basic observations which serve to
clarify electric properties of the resting giant axon
(fig. 8).
When a glass pipette electrode of about 100 \l in
diameter is inserted longitudinally into a giant axon,
it is found that the potential of this electrode (relative
to the large ground electrode in the surrounding sea
water) goes down gradually as the pipette electrode
is advanced along the axis of the axon. The potential
inside the axon is negative to (i.e. lower than) that
of the surrounding fluid medium. When the electrode
is advanced more than about 10 mm from the point
of insertion on the surface membrane, the potential
level of the axoplasm is practically independent of
the position of the tip of the pipette. In other words,
the space occupied by the axoplasm is practically
equipotential. The potential difference between the
surrounding fluid medium and the axoplasm deter-
mined by this or other .similar methods is called the
'resting memljrane potential'.
I2(H
Exciubility change in fibre [I
T
T
FIG. 7. Top: Electrode arrangement used for demonstration
of excitability changes in a single nerve fiber of the crab caused
by the passage of an impulse in the adjacent fiber. A, B, leads
for stimulation of fiber I; C, D, leads for stimulation of fiber II;
D, E, recording leads connecting with amplifier and cathode
ray oscillograph. Bollom: Excitability changes in fiber II during
the passage of an impulse in fiber I. Abscissae: time in msec.
Ordinates: threshold intensity of fiber II in percentage of its
resting threshold. [From Katz & .Schmitt (73).]
84
HANDBOOK OF PHYSIOLOGY ^ NEUROPHYSIOLOGY I
I y/// //////// //T
FIG. 8. .1. Resting and action potential of the squid giant axon recorded witli an intracellular glass
pipette electrode. Time marker (0.5 msec.) indicates the potential level observed when the recording
electrode was in the surrounding sea water. Temperature, 23°C. B. Exponential variation in the
meiBbrane potential caused by passage of a constant current through the membrane of a squid giant
axon with a long intracellular silver wire electrode. The thick portions of the wire in the diagram
on the top show the exposed surface of the electrodes. Time marker, 1000 cycles per sec. Temperature,
20°C. (The axons in the diagrams are disproportionately thick and short.)
The fact that the potential level is the same every-
where in the axoplasm indicates, according to Ohm's
law, that there is no measurealjle flow of electric cur-
rent in the axoplasm at rest. It also proves that the
resting potential represents, as in the frog muscle
fiber (76) and in other nervous elements, a sharp drop
of electric potential across the space occupied by the
thin surface memijrane of the cell. The resting poten-
tial of an excised squid giant axon is known to be 50
to 60 mv; it is considerably smaller than that of verte-
brate skeletal muscle and nerve cells.
When a pulse of stimulating current is applied to
a giant axon with an internal recording electrode,
there occurs a transient rise of 100 to 120 mv in the
potential of the axoplasm referred to ground (fig. 8.-1).
The magnitude of the action potential measured by
this method is practically independent of the position
of the electrode tip in the axoplasm. If the tip of the
internal electrode touches or pierces the surface mem-
brane, both the resting and action potentials are pro-
foundly diminished or completeh' eliminated. The
action potential represents, therefore, a transient
variation of the potential difference across the surface
membrane of the axon. It is important to distinguish
this 'memljrane action potential' from those recorded
with external electrodes.
When it was discovered that the membrane action
potential is suisstantially larger than the resting po-
tential of the membrane (22, 56), some investigators
who believed the membrane hypothesis of Bernstein
(10) were greatly surprised. In 1902 Bernstein postu-
lated, without clear supporting e\-idcnce, that the
action potential may be a mere diminution or disap-
pearance of the resting memijrane potential (see
p. 117). The finding that the inside potential rises
above the outside potential near the peak of the ac-
tion potential, therefore, conflicts with this postulate
of the membrane hypothesis.
Besides the role in maintaining a potential differ-
ence, the surface membrane of the resting axon plays
another important part in electrophysiology of the
nerve fiber. The resting membrane has a high re-
sistance to a direct current. This can be shown by
the use of the arrangement of figure Bfi, in which a set
of two metal wire electrodes was used instead of a
glass pipette.
CONDUCTION OF THE NERVE IMPULSE
85
The electrode set shown in the figure consists of one
wire with a long (about 1 2 mm) exposed surface and
the other with a short (i mm) exposed surface. The
long wire is used to send a constant current into the
axon and the other for recording potential changes
caused by the current. The short electrode has its
exposed (uninsulated) surface in the middle of the
long one. The remaining surface of each electrode is
insulated with a layer of enamel. A pulse of constant
current can be generated by connecting a high
voltage source to the current electrode through a
high resistance.
When the sign of the applied current is such that
the axon membrane is traversed by an inward di-
rected current, the potential inside the membrane is
found to be lowered by the current. However, as can
be seen in the record in the figure, the potential
change at the onset of the current is gradual —
mathematically speaking, exponential. The potential
change varies roughly proportionately with the in-
tensity of the applied current. When the current is
reversed, the sign of the potential change is simply
reversed, provided that the change in the resting
potential does not exceed about 5 mv.
This behavior of the axon can be readily under-
stood if one assumes that the axon membrane con-
sists of a condenser with a parallel resistance (fig. gA).
As is well known, the current flowing through a con-
denser of a capacity, C, is given by C dV/dt, where
dV/dt is the rate of change in the potential difference,
V, across the condenser. The current, /, through a
system of a conden.ser and a parallel resistance is
given by the expression
A
B
il
out
T
[) i (!) in "5 ~
r,flx V(x-4X,t) V(x,t) y(x+ftx,t)
dV V
I = C 1- - ,
dt R
(4-0
i.e. by the sum of the capacitati\'e current and the
ohmic current. When the current, the capacity and
the resistance, /?, are all constant, the time course of
the potential is given by
IR (i - e-"«'0,
(4-0
Cm-AX rm/4X
v = o
where I is the time after the onset of the current. By
comparing equation (4-2) with the observed result of
figure 8B, the values of R and C can be determined.
The capacity, C, of the giant axon membrane deter-
mined by this method is approximately i /xf/cm-
and the membrane resistance is between i and
2.5 kl2-cm-. [cf. Hodgkin et al. (61), p. 440]. The
time constant of the membrane, RC, is, therefore,
I to 2.5 msec.-'
In the argument developed abo\e, the resistances
of both the axoplasm and the sea water have been
ignored. Cole & Hodgkin (20) and Schmitt (ro6)
have shown that the axoplasm is a homogeneous con-
ductor with a specific resistance of about 40 ohm -cm
at 2o°C. The specific resistance of the sea water is
approximately 20 ohm -cm at the same temperature.
These resistances are too small to have any observable
effect upon the measurement of figure QB.
Now the cjuestion arises of how the voltage .source
representing the resting membrane potential fits in
the system of a capacity and a parallel resistance of
figure 9.-I. It is po.ssible to draw a continuous current
from the resting membrane; therefore, it is legitimate
lo represent the source of the resting potential by a
battery. There are obviously two simple wa\s, B and
C in the figure, of connecting a battery in the circuit
ot A. Both ways fit with the obser\ed data. There is
at present no direct experimental procedure that can
serve to determine which one of them represents the
axon membrane better. In the sodium theory (cf
p. 118), the electromotive force of the membrane is
assumed to be connected in parallel with the con-
denser as in B.
As the result of the above discussion, it has become
clear that a squid axon behaves like the core-conduc-
tor of Hermann (see p. 75) or like a submarine cable.
Using elementary calculus, we may proceed slightly
FIG. 9. Structure of the squid giant axon revealed by the
use of intracellular electrodes. C, capacity, and R, resistance
of the membrane. Two possible ways of connecting the source
of the resting potential in the circuit of R and C arc shown by
diagrams B and C. (Further detail in te.xt.)
^ These figures were obtained by eliminating the effect of
the current flowing near the end of the current electrode by
the technique described by Marmont (84). The reader is
reminded in this connection to pay attention also to the di-
mensions of these figures.
86
HANDBOOK OF PHYSIOLOGV
NEUROPHYSIOLOGY
further to discuss the spread of electricity alons a
uniform resting axon.
In figure qD, the electric properties of an axon im-
mersed in a large volume of sea water are represented
by a network of resistances and capacities. Since we
are interested only in the change of potentials, the
batteries are omitted in the figure. The resistance of
the axoplasm of a unit length is represented by r-,; it
is related to the specific resistance of the axoplasm
Ri by the expression
"■i =
(4-3)
where D is the diameter of the fiber.
Symbols fn, and („, denote, respectively, the resist-
ance and the capacity of the memljrane covering the
axoplasm of a unit length. They are related to the
corresponding figures for a unit area, R„. and Cm, by
the formulae
':« = -^ . (4-4)
c„, = ttDC,,,. (4-5)
Let V(^x, t) denote the potential of the axoplasm,
referred to the potential of the surrounding fluid
medium, at position x and time /. Then the ssmi^ols
f'(.v — A.v, 0 and ['(v + ^x, 0 can be used to denote
the potentials at position (,v — A.v) and at (.v -|- A.v),
respectively. The axon is now imaginati\elv divided
into a series of .segments of a length lA.v. The a.xoplasm
resistance (to a longitudinal current) of such a seg-
ment is then rjA.v. Similarly, the membrane capacity
and the resistance of one segment are given by
c„Ax and rn,/A,v, respectively. By applying Ohm's
law, it is found that the longitudinal current in the
section labelled i is equal to [("(.v, /) — '(•* — ^x, 0]/
(riAAr). Similarly, the longitudinal current through
■section 2 is equal to [F(.v + A.v, /) — r'(.v, 0]/C''iA.v).
The difference between the current through i and
that through 2 is equal to the membrane current,
which has the form given by equation (4-1). This
us to the equation
I^Cv + \x. 0 - r(.v, /) F(.v, 0 - F(.v - Sx.O
r,Ax
r\Ax
dVix, 0 Vix, 0
= f„,A.v 1 .
dl r,^/Ax
By taking the limit A.v to zcio, we obtain the well
known cable equation:
r, a.v2
dl'Cx, 0
It is obvious that the spread of currents in other non-
myelinated nerve fibers and in a uniform muscle fiber
can be described by the same equation.
In the steady state the potential is a function of
position X alone. Equation (4-6) is then reduced to
dnXx)
dx^
= VixX
(4-7)
in which \\x) represents ['(a:, k). The general solu-
tion of this equation is
r(.v) = Aft-^l^- -|-Be+''\
C4-8)
where X, the 'space constant', is related to the mem-
brane resistance and the axoplasm resistance by the
expression
Constants A and B in equation (4-8) depend on the
boundary conditions.
In a special case where a constant current of in-
tensity /o is .sent into the axon at .v = o, constant B
has to be equal to zero; otherwise, \\x') approaches
infinity as .v increases. At .v = o where the current is
sent into the axon, dr(A)'d.v is equal to — '2 ''i^» > the
factor '2 being introduced to meet the situation where
the current spreads on both sides of the point .v = o.
From these boundary conditions, it is found that
A = ^-n^lfi and B = o. The solution of equation
(4-7) for this special case is, therefore.
K*) = }i nX-Zoe-
C4-10)
at
-h Vix, 0.
(4-6)
The 'effective' resistance }-2^i^ can be expressed by
virtue of equation (4-9) as 3^2 ^/^^n^i ■ The space
constant, X, is a measure of the spread of electricity
along the axon; the greater the value of X, the more
extensive is the spread. In the squid giant axon, X is
of the order of 0.6 cm (20). Solutions of the general
cable equation for several special cases have been
achieved (30, 63, 130).
C'SiBLE PROPERTIES OF THE MYELINATED NERVE FIBER
Large nerve fibers in the vertebrate nerve have a
thick layer of fatty substance, the myelin sheath, be-
tween the cylinder of the axoplasm and the outermost
layer of connective tissue, the neurilemma or the
sheath of Schwann. The myelin sheath is broken at
so-called nodes of Ranvier where the surface of the
axis cvlindcr is covered dircctlv bv the neurilemma.
CONDUCTION OF THE NERVE IMPULSE
87
The width of the nodal membrane uncovered by the
myehn sheath is roughly 0.5 to i m- The distance be-
tween the nodes has been discussed on p. 78.
The first experimental evidence indicating that the
myelin sheath has a high resistance to a direct current
was obtained in Tokyo in 1934 [Kubo, Ono & Tasaki
cited in (70)]. When the threshold of an isolated
single nerve fiber was determined with a small
electrode placed near the fiber, it was found that the
threshold varied regularly with the distance from the
nodes of the fiber (fig. 10). In these early experiments
the threshold was determined by taking twitches of
the muscle innervated by the isolated fiber as an index
that a nerve impulse had been initiated in the fiber.
Later, measurements were made by taking electric
responses of the fiber as an index [e.g. fig. i in Tasaki
(123)]. All these experiments indicate that the
threshold is lowest when the small electrode (stimu-
lating cathode) is placed directly on one of the nodes
(the other electrode placed in the fluid medium away
from the fiber), and is highest when the electrode is at
the point half way between two neighboring nodes.
These findings have been interpreted as indicating
that, because of the high (d.c.) resistance of the
myelin sheath, the stimulating current enters and
leaves only at the nodes and consequently that the
nerve fiber is excited only at the nodes. A further
discussion on this subject may be found elsewhere
(71, 124).
It was found later that the myelin sheath is not a
perfect insulator but that short current pulses can flow
readily through this sheath (66, 1:24, 125, 136). To
illustrate this point, we shall mention an observation
published in Germany during World War II (136).
The diagram in figure 11. 4 illustrates the experi-
mental arrangement used.
A single nerve fiber of the toad is mounted across
three small pools of Ringer's solution divided by two
narrow air gaps of o.i to 0.3 mm width. The pool in
the middle is about i mm wide and contains only the
myelin covered part of the fiber. All the nodes (Ni,
N2 and others) are kept in the larger, lateral pools. In
\
\/
FIG. 10. Threshold strength of a long stimulating current
(in amperes) plotted against distance from a node of Ranvier,
Ni. Motor nerve fiber of the toad immersed in a shallow pool
of Ringer. Black circles show the results obtained with the
cathode of the battery connected to the microelectrode, and
the crosses with current flowing in the opposite direction.
Temperature, 23°C. [From Tasaki (124).]
_n_
-T
No N, N2
1
WHtt/t
t 1 msec
FIG. II. .-i. Membrane current led through i mm long myelin covered portion of toad motor nerve
fiber. B. Similar to .1 ; there is a node (Ni) in the middle pool. The fibers were stimulated through
the electrode on the nerve trunk. Note that the action potential at the node is about 0.9 msec, dura-
tion at 24°C. (The nerve fiber in the diagram is disproportionately thick and short.)
88
HANDBOOK OF PH%SIOLOGY
NEUROPHYSIOLOGY
each of the pools, a nonpolarizable electrode is im-
mersed. The electrodes in the lateral pools are directly
grounded and the one in the middle pool is grounded
through a resistor of o. i to 0.3 megohms. The cur-
rents produced by the fiber in response to an electric
shock applied to the fiber near its cut end are recorded
by amplifying the IR drop across the resistor.
If the myelin sheath were a perfect insulator of
electricity, no flow ol current should be recorded with
this arrangement. Actually, a relatively strong flow of
current is observed through the myelin sheath. As can
be seen in the records of figure 11.^, the membrane
current led through the myelin sheath has clear
double peaks of an outward flow, followed by a long
phase of a weak inward current.
When a node of Ranvier is introduced into the
middle pool (fig. iiE), an entirely different result is
obtained. The flow of current through the membrane
of the fiber in the middle pools is triphasic, first out-
ward, then inward and finally outward (weak).
Comparing the two records in figure 11, it is found
that a strong flow of inward current takes place only
at the nodes of Ranvier. Since the total amount of
current leaving a fiber at any moment has to be equal
to the sum of the current entering the fiber at the
same moment, the peaks of the outward current
through the myelin sheath (record A) should corre-
spond roughly to the peaks of inward current at the
neighboring nodes (Ni and N2). The effects of more
distant nodes are naturally far smaller than those of
the neighboring nodes.
That the first peak in record .-1 of figure 1 1 is caused
by the response at node Ni and the second peak by
the response at N2 has been shown in the following
manner. When a few drops of cocaine-Ringer's solu-
tion are introduced in the lateral pool in which N2 is
immersed, the height of the second peak is immedi-
ately reduced. When the same cocaine-Ringer's solu-
tion is applied to the portion of the nerve fiber in the
middle pool, no change in the current is observed.
Finally, v\hen the narcotizing solution is introduced
gradually into the pool of Ni, the height of the first
peak is gradually reduced, while the second peak re-
mains unchanged until it disappears suddenly at the
moment when the propagation of the impulse is
blocked.
Further evidence indicating that electric responses of
a myelinated nerve fiber are evocable only at the
nodes of Ranvier has been obtained by narcotizing
the portions of the fiber located in the lateral pools
and stimulating the fiber through two of the elec-
trodes (124, 132). When there is one node in the
middle pool (as in the diagram of fig. 11 B), a full-
sized action current can be recorded from a short (i
mm) nonnarcotized portion of the nerve fiber. But,
when no node is left in the normal Ringer's solution
in the middle pool (as in fig. i lA), no action current
can be elicited from the fiber.
The size 01 the membrane action potential at the
node was estimated by Tasaki & Takcuchi (135) by
measuring the action current and the resistance of
the single fiber preparation. Huxley & Stampfli (67)
estimated it by compensating the action current with
an external voltage source (assuming that the myelin
sheath is a perfect insulator). Later, a direct method
of recording the action potential of the nodal mem-
brane was developed (128). All the.se indirect and
direct methods give a figure between 95 and 115 mv
at the peak of activity. Later, we shall discuss the
difTerence between the shape of the nodal action
potential and that of the squid action potential.
If one assumes that the rnyelin sheath behaves like
a condenser with a parallel resistance as shown by
the diagram of figure g.^, the flow of current through
the myelin sheath should be described by equation
(4-1) in the preceding section. The voltage I' in the
equation can be either an applied voltage or an
action potential developed at the nodes. The two
peaks in the current flowing through the myelin
sheath (fig. 11. -1^, therefore, are indicative of the
situation in which the voltage inside the myelin
sheath rises in two steps, one step at the beginning of
the action potential at Ni and the other step when
X> is also activated. Actually, the time interval be-
tween the two peaks is close to the internodal con-
duction time discussed previously on p. 79.
It requires a slight mathematical treatment of the
data to separate the current led through the myelin
sheath into its capacitative and ohmic components
and to determine the absolute values for the capacity,
(■„,, and the resistance ;„,, of the myelin sheath (125).
Although this method of measuring the membrane
capacity and the resistance is not as direct as that
for the squid axon, the accuracy of the measurement
is fairly high (the probable error being about 10 per
cent). The results of recent measurements of these
membrane constants are listed in the uppermost
column of table i. The observed values of f,„ and r,,.
were converted into the values for myelin sheath of a
unit area (represented by capitalized figures) by using
equations (4-4) and (4-5) in the preceding section.
The capacity and the resistance of the nodal mem-
brane given in table i were determined by measuring
the current through node (Ni) in the middle pool of
CONDUCTION OF THE NERVE IMPULSE
89
TABLE I . Resistances and Capacities nf the Myelin Sheath, the Squid Axon and the Nodal Membrane
farad/cm
farad/cm*
ohn
ohm-cm^
Myelin sheath (fiber diameter 12 fi)
Squid giant axon (diameter 500 ii)
Nodal membrane
.6 X lo-i
.6 X 10-"
I -5 y-t^^
5 X 10-9
ID"*
(3-7) X lo-s
2.9 X 10'
(6-15) X 10'
41 Mn*
10*
(1-2.5) X io»
8-20
Data from references (20, 61, 125).
* Values for one whole node of Ranvier of the toad motor ner\e fiber.
figure iii5, alter treatint; this node with a sodium-
free Ringer's solution or with a dilute cocaine-
Ringer's solution. The details of the principle of the
method can be found elsewhere (125). Since it is
difficult to estimate the area of the nodal membrane,
the figures for a unit area of the nodal memijrane are
somewhat inaccurate. For comparison, the membrane
constants of the squid giant axon are also listed in the
same table.
It is interesting to note that the capacity of ijoth
the myeHn sheath and of the nodal membrane is ex-
tremely insensitive to changes in the temperature and
the chemical composition of the surrounding fluid
medium, while their resistance can be strongly modi-
fied by slight changes in the environinent C'-4> 125).
There is, however, one siinple way of increasing the
capacity of the inyelin sheath, that is, by dissolving
the fatty substance of the myelin sheath by an appli-
cation of a saponin-Ringer's solution or some other
detergent solution. During the early stage of a
saponin treatment of the myelin sheath, the capacity
increases as the resistance decreases, the product
c,„r,„ remaining almost unchanged. This fact strongly
suggests that the capacity of the inyelin sheath is
dielectric in nature, determined by the thickness of
the sheath and the dielectric constant of the myelin
substance. The dielectric constant of the myelin sheath
is known to be similar to that of many other fatty
compounds (66, 125).
CONDUCT.\NCE OF THE MEMBR.ANE DURING .ACTIVITY
VVe have seen in the preceding section that the
development of the action potential represents a tran-
sient variation in the potential difference across the
surface membrane of the nerve fiber. In 1939, Cole &
Curtis C19) demonstrated in the .squid giant axon
that this variation in the meinbrane potential is asso-
ciated with a pronounced change in the resistance of
the membrane. Tasaki & Mizuguchi C'SS) showed a
similar change in the membrane at the node of Ran-
\ier. We shall discuss the principle of measuring the
membrane impedance during activity under relatively
simple experimental conditions. The method to he
described is slightly different from that employed by
Cole & Courtis but the principle is the same.
In the arrangement shown in the upper part of
figure 12, a long silver wire electrode about 100 ^i in
diameter is thrust into a squid a.xon immersed in sea
water This internal electrode and a large electrode
immersed in sea water surrounding the a.xon are
connected to one arm of an alternatino current
FIG. \i. Measurement of the membrane impedance of a
squid giant axon during activity with an a.c. impedance
bridge. The bridge was balanced for the impedance of the
resting membrane. The two records on the left were taken at
nearly the same stimulus intensity, but the bridge output was
amplified 10 times the normal (ix) in the lower record. The
upper trace in the records displays the unfiltered bridge out-
put; the potentials recorded are slightly reduced and distorted
by the bridge. The bridge a.c, 20 kc per sec; temperature,
22 °C. (Further discussion in text.}
90
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
Wheatstone bridge. The ratio arms, ri and r-2 in the
figure, consist of ohmic resistors, r2-ri being io:i or
larger. The remaining arm consists of condensers
(C and C) and a resistor (/f). When a high fre-
quency alternating current is applied to the bridge, a
sinusoidal potential variation is produced across the
membrane. By proper adjustment of the variable
resistance and the capacity, however, it is po.ssible to
reduce the a.c. output of the bridge to zero.
As has been mentioned above (p. 85) the axon
membrane can be represented by a condenser and
parallel resistance. The relationship between the po-
tential difference (F) across the membrane and the
current (/) through the membrane is expressed by
equation (4-1) which can be rewritten as
Therefore,
I = C \- GV,
di
(6-1)
where G is the conductance of the membrane, i.e. the
reciprocal of resistance R in equation (4-1)- We are
now interested in the relation between a steady
sinu.soidal current and a sinusoidal voltage that satis-
fies equation (6-1). We denote the current by
/ii sin ut
and the voltage bv
V = I'll sin (ail + 9),
(6-2a)
C6-2b)
where /o and i'l, are the current amplitude and the
voltage amplitude, respectively, co is 27r times the
frequency and 9 the phase difference between the
current and the voltage. Introducing (6-2a and b)
into (6-1), we find that
/o sin u>t = I'd o>C cos (u/ + d} + GVo sin (_uit + S)
= Vq (G cos 6 — o>C sin $') sin u/
+ Vo (C sin e + uC cos 9) cos oil
The last equation is satisfied when (and only when)
the coefficient of cos a;/ is zero and simultaneously
when the coeflicients of sin oj/ on both sides of the
equation are equal. This leads to the relations
(6-3a)
and
/u = Vd (C cos e — uC sin 9).
From equation (6-3a) it follows that
— (jC G
h = t'o y/o^C -f- G2
Fo = /„
Vw^C' -I- (? '
(6-3b)
y/ufC'^ -h G2 '
V"'C2 -I- G^
When the impedance bridge in the upper part of
figure 12 is roughly balanced for a given intensity of
the bridge a.c, the current / through the axon mem-
brane is determined by the variable condensers and
the variable resistance of the bridge, because r-i »
ri. Under these conditions, the amplitude \\ is pro-
portional to the impedance, i /-\/G- -|- co^C', of the
membrane. When G increases during activity, Fn de-
creases. In the method involving use of the impedance
bridge, small changes in the membrane impedance are
detected by balancing the bridge with the membrane
impedance at rest and recording small unbalances
after a high amplification. Under such circum-
stances, not only a change in the amplitude \'n but
also any change in the phase d brings about a bridge
unbalance. When the bridge is at balance, the voltage
between the two electrodes across the axon membrane
is completely cancelled by the voltage across ri. A
change in the phase 6 or in the amplitude Fo , makes
this cancellation imperfect.
[In order to detect changes in the membrane im-
pedance during activity, it is necessary to make the
frequency of the bridge a.c. high enough so that in
the period to be examined there are a number of full
cycles of the a.c. The time resolution in the im-
pedance measurement is affected also by the char-
acteristic of the filter circuit in the recording system.]
.After the Wheatstone bridge has been accurately
balanced for the membrane impedance at rest, a short
pulse of outward current is passed through the axon
membrane. If this pulse is well below the threshold,
the potential trace (the upper trace in the records of
fig. 12) shows an exponential decay of the membrane
potential after the end of the pulse; in this case there
is very little or no bridge unbalance detectable. When
the pulse intensity approaches the threshold, the fall
of the membrane potential after termination of the
pulse becomes slow and erratic (see p. 98); con-
comitantly there is a sign of a decrease in the mem-
brane impedance (record .-1) which can be recorded
distinctly by increasing the amplification of the a.c.
bridge output (record B). With supra threshold pulse
intensities, large unbalances of the bridge are ob-
served (record C), indicating that there is a marked
reduction in the membrane impedance associated
with production of an action potential.
The temporal relation between the action potential
and the bridge unbalance shown in record C is similar
to that observed by Cole & Curtis with their external
impedance electrodes. They explained their data as
indicating that at the peak of activity there occurs a
200-fold increase in the membrane conductance. In
the squid giant axon, the membrane conductance
stays above the resting level for some time after the
end of the falling phase of the action potential.
In the myelinated nerve fiber of the frog, the im-
pedance measurement is complicated by the fact
that the change in the membrane impedance takes
place only at the node (133). An example of simul-
taneous recording of the action current and of the
membrane impedance in a single node is shown in
figure 1 3. A quantitati\'e analysis of this data is com-
plicated by the fact that the bridge a.c. flows readily
through the myelin sheath because of its capacity.
.Some quantitative information in regard to the con-
ductance at the peak of activity can be obtained by
passing testing current pulses through the node and
comparing the change in the membrane potential due
to the current pulse before and during activity. It has
been shown by this method that at the peak of ac-
tivity the membrane conductance increases approxi-
mately 10 times. In the nodal membrane, there is a
close parallelism between the time course of the action
potential and the time course of the loss in the mem-
brane impedance (129, 133); in this respect the nodal
membrane is in sharp contrast with the squid axon
membrane.
More recently, Hodgkin, Huxley & Katz (57, 58,
FIG. 13. Simultaneous recording of action potentials and
changes in the membrane impedance during activity of a
single node of Ranvier. In the left-hand record, the bridge was
balanced for the impedance at rest; in the right-hand record,
the best balance was obtained near the peak of activity. [From
Tasaki & Freygang (129).]
CONDUCTION OF THE NERVE IMPULSE 9 1
OUT, , IN
o I o— -oJT.
0 -!-^==^^^"»-r
A2
XT
^xouyz^v^^v^ V
i L
I 1
o o—
Ai
4:
4
|- I
2
mA/cm*
/
50
100 ^
° 150
_ ,. n 1 1
' f-< 1
1
-2
-4
\
\
0
/
V
FIG. 14. L'/i/)fr.- Arrangement used for clamping the membrane
potential of a squid giant axon along rectangular time courses.
This circuit is slightly different from that used by Hodgkin
et al. (61), but the principle is the same. Ai is a low-gain differ-
ential amplifier; An, a high-gain differential amplifier (1000
times). The thick portions of the lines in the axon represent
the exposed surface of the metal wire electrodes. The distance
between the two partitions (P) was 8 mm. (The diameter of
the axon and the wire drawn in the diagram is dispropor-
tionately large.) Resistance r was 2.5 (sometimes 50 or 250)
ohms. Lower: Relation between the membrane depolarization
(F) and the membrane current at the peak of the inward
surge (/). Near V = o, the V-I relationship is roughly linear,
but its slope is about '250 °f ''^'" °f 'he straight line on the
right-hand side. Temperature, 2 2°C. The labile portion of
the V-I relation shown by the broken line represents either all-
or-none (probably nonsynchronous) responses in some parts
of the membrane (the patch theory), or a partial increase in
the conductance uniformly all o\'er the membrane (the sodium
theory).
61) measured in a series of beautiful experiments the
conductance of the squid axon membrane by a very
direct, theoretically simple method, often referred to
as the ' method of voltage clamp'. The diagram in the
upper part of figure 14 illustrates the principle of the
method.
A giant axon is placed across three pools of sea
water separated by two narrow partitions. A pair of
metal wire electrodes is thrust through the axon; one
is used for measuring the membrane potential (F)
and the other for passing currents through the axon
9^
HANDBOOK OF PHYSIOLOGY'
NEUROPHYSIOLOGY I
membrane. The uvo lateral pools are directly
grounded with large silver wire electrodes. The middle
pool is also grounded but through a resistor (r) of a
few ohms. When a current is sent through the l^ng
internal electrode, this resistor (/■} is traversed by a
current (/) passing through the axon membrane in
the middle pool; the small potential drop (/r) is
amplified and is taken as the measure of the membrane
current. The membrane potential is measured across
the axon membrane in the middle pool. The circuits
connected to the axon are constructed in such a
manner that the membrane potential (f) can be
maintained at any desired level by an automatic
adjustment of the membrane current (/).
The principle of the automatic control of the mem-
brane current by the feed-back mechanism is as
follows. In the diagram of figure 14, Ai is a preampli-
fier which transmits the membrane potential (I) at
its input to one of the inputs of a differential amplifier
A-). The other input of A., marked i in the figure, is
connected to a source of rectangular (or other) voltage
pulses. The output of amplifier A2 has the .same
phase as that of input i and opposite to that of
input 2.
First let us consider the case in which input i is
grounded. When membrane potential (T) tends to
rise by some intrinsic process in the axon, the poten-
tial of input 2 starts to rise immediately. This po-
tential is then amplified and, after reversing its
polarity, transmitted to the long wire electrode in the
axon. This immediately causes a flow of an inward
membrane current which lowers the membrane po-
tential (r). As a consequence, if the gain of Ao is
sufficiently high, any change in the membrane po-
tential (r) can be almost completely suppressed by an
automatic control of the membrane current (/). In
practice, the over-all gain of this feed-back amplifier
was 1000 to 3000.
Next, we consider the case in which the potential
of input I of amplifier A2 varies along a rectangular
time course. .Xt the moment when the potential of
input I starts to rise, thert is a sudden flow of an out-
ward current through the axon membrane. This flow
immediately raises the membrane potential (!'). The
rise in Fis transmitted to input 2, tending to lower the
output voltage of A-i. In the steady state there is a flow
of a constant membrane current which is sufficient to
maintain the membrane potential at the constant
level. If the gain of Aj is unity, the time course of the
membrane potential (T) reproduces the potential
applied to input i fairly accurately.
The records furnished in figure 15 show the rela-
FiG. 15. Relationship between the membrane potential (dotted trace) and the membrane current
(continuous trace) obser\ed with the arrangement of fig. 14. In records A to D, the membrane po-
tential was 'clamped' along rectangular time courses by automatic adjustment of the membrane
current. In E and F, rectangular current pulses were applied through the current electrode and the
variation in the membrane potential was recorded with the other internal electrode; the defection
sensitivity of the current trace is 20 times as high as in other records. Blanking of the potential trace
indicates 0.25 msec. Temperature, 22 °C.
CONDUCTION OF THE NERVE IMPULSE
93
tionslup between the membrane putential and the
membrane current as revealed Ijy the method of
voltage clamp. When the membrane potential is
raised suddenly from its resting le\el to a new level
slightly above the ordinary threshold (i.e. abo\e 12
to 15 mv) and is maintained at this constant le\el
(record ^4), it is found that the membrane is trax'crsed
by a current which flows first outward, then inward
and finally outward again. The first phase of the out-
ward current is .so short that it is .seen as a mere break
in (he upper (current) trace in the record. The second
phase of an inward current is seen as a downward
deflection in the record. The third phase of a steady
flow of an outward current is shown by the current
trace staying above the zero level in the right-hand
side of the record.
The obvious explanation of the time course of the
membrane current in records A and B is as follows.
The a.xon membrane has a capacity of the order of
I ^f per cm- (p. 85). In order to shift the membrane
potential suddenly by an amount (', a total charge of
C- r (where C is the capacity of the memijrane in the
middle pool) has to be supplied by the current
electrode. This capacitative flow of current takes
place within the extremely short period of time during
which the membrane potential is actually rising. The
second phase is related to the ability of the membrane
to produce an action potential in response to a sudden
rise in the axoplasm potential. If the membrane
potential had not been clamped (as in fig. 15/^), the
potential inside the axon should start a rapid rise; an
inward membrane current is needed to counteract this
potential ri.se during activity and to maintain the
membrane potential at the constant level. The third
phase of the membrane current reflects the situation
in which a relatively strong continuous current is
needed to maintain the membrane at a steady
'depolarized' level.
When the voltage step in the clamping rectangular
pulse is increased, the intensity of the inward mein-
brane current is found to decrease. The relation
between the depolarizing voltage step and the peak of
the inward surge of current is plotted in the lower
part of figure 14. When the voltage step is approxi-
mately equal to the peak value of the meinbrane
action potential, the peak of the inward surge is
found to reach zero (fig. 15C). As the voltage step is
increased further, the peak stays above the zero
level; i.e. even at the peak of the inward surge of
current, the membrane current is in the direction
imposed by the applied voltage. As can be seen in
the figure, the relation between the voltage step V
and the current / at the peak of the inward surge is
represented by a straight line in a wide range of
voltage.
The fact thai the \oltage-current relation is linear
can he taken as indicating that, in thi^ range of
membrane depolarization, the axon membrane be-
haves like a ' battery' with a definite electromotive
force (emf) and a definite internal resistance. The
voltage at which there is no current flow represents
the emf of this i)attery and the slope of the voltage-
current straight line corresponds to the internal
resistance. The membrane emf at the peak of the
inward surge of current coincides with the peak of
the membrane action potential. In the experiments
of Hodgkin & Huxley (57, p. 465), the membrane
resistance determined from the slope of the ] -I rela-
tion is about 30 ohm -cm'-. The figure obtained
recently by several investigators from the National
Institutes of Health is 7 to 12 ohm -cm- (at i5to22°C).
The resistance of the resting membrane, measured
with small voltage steps (less than 5 mv or negative
voltages) is 2 to 3 kl2-cm- (61, p. 440). At the peak of
activity, therefore, the membrane conductance is
increased by a factor of one to three hundred.^
In agreement with the notion that the inward surge
of current is associated with the ability of the inem-
brane to develop an action potential, narcosis of the
axon with ethanol or urethane is known to eliminate
the inward surge reversibly. A recently popularized
method of reversible elimination of the action po-
tential is to reduce the sodium concentration of the
.surrounding sea water.
The finding that sodium ions are necessary in the
process of excitation is not new. More than half a
century ago, Overton (97) pointed out that the frog
nerve-mu.scle preparation loses its ability to respond
to stimuli unless there are .sodium or lithium ions in
the medium. He also pointed out that chloride ions in
Ringer can be replaced with bromide, nitrate, ace-
tate, salicylate, etc. without eliminating the excita-
bilit\-. Recently Hodgkin & Katz (62) have shown the
importance of sodium ions in a inore quantitative
manner [cf also Huxle>- & Stampfli (68) ]. They have
found that the spike amplitude of the squid giant axon
* Quite recently similar voltage-clamp experiments were
carried out on single node preparations of the toad. It was
observed that the voltage-current relationship obtained was
similar to that shown in figure 1 4 except that the labile portion
of the cur%'e indicated by the broken line was limited in a
narrower voltage range. The membrane conductance deter-
mined by this method was approximately 10 times as high as
that of the resting nodal membrane.
94
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
decreases with the logarithm of the external sodium
concentration, the proportionality constant being very
close to 58 mv which is the coefficient of Nernst's
equation (cf. p. 1 1 7).
Based on this and other experimental facts, Hodgkin
& Huxley (59) formulated a hypothesis in which the
inward surge is interpreted as the consequence of an
increase in the membrane permeability specific to
sodium ions. We shall discuss this point later (p. 1 18).
THRESHOLD AND SUBTHRESHOLD PHENOMENA
In the early part of this century when physiolo-
gists had no way of directly observing the potential
difference across the excitable membrane, a great
number of articles were published dealing with the
problem of threshold excitation of the nerve or the
muscle. At first, physiologists were charmed by the
elegant physicomathematical scheme of the ionic
theory of nerve excitation formulated by Nernst (91).
He derived the relation between the threshold in-
tensity of current and its duration on the assuinption
that excitation took place when the concentration of
some ion reached a certain critical level near the
semipermeable membrane of the nerve. Nernst
argued that the passage of an electric current through
a uniform electrolytic conductor in the nerve cannot
bring about any electrochemical changes (except for
raising temperature) that might be responsible for
initiation of an impulse. His argument is ba.sed upon
the principles of electrolytic conductors and un-
doubtedly it is still valid at present. Nevertheless,
physiologists .soon abandoned Nernst's approach to
the problem and accepted more formal, physico-
chemically vague arguments which reached a climax
with Monnier-Rashevsky-Hill theory ol nerve excita-
tion (48, 88, 102).
At present it is possible to pass rectangular pulses of
current uniformly through the excitable membrane of
the nerve fiber, and to determine how the membrane
potential behaves when the stimulus reaches thresh-
old. The assumptions adopted by previous investi-
gators can thus be subjected to direct tests.
Threshold Membrane Potential
The excitable membrane at the node of Ranvier of
the vertebrate myelinated nerve fiber is a narrow
ring-shaped band. Its width (0.5 to i m) is far smaller
than the diameter of the fiber at the node or than the
distance between neighboring nodes. It is possible to
record potential changes across this membrane by the
use of a positive feed-back amplifier [e.g. McNichoI
& Wagner (87)].
At the top of figure 16 is shown the experimental
arrangement used to siud\ the behavior of the nodal
meiTibrane in threshold excitation. The fiber is
mounted across three pools of saline solution separated
by two air gaps. The large pool, where node Nn in the
figure is immersed, is filled with a dilute cocaine-
Ringer's solution. The pool in the middle, where the
node under study, N,, is located, is filled with normal
Ringer's solution. In the small pool, filled with
cocaine-Ringer's or an isosmotic pota.ssium chloride
solution, the small portion of the nerve fiber including
N; is immersed. The electrode in the large pool is
connected to a source of a .square voltage pulse. The
middle pool is grounded, and the smallest pool is
connected to the high impedance input of a positive
feed-back amplifier. .Since there is practicalK no
current in the portion of the fiber in the air gap
between Ni and No, the potential measured by the
amplifier approximates the potential drop across the
nodal membrane of Ni. A rectangular voltage pulse
FIG. 16. Demonstration of the constancy of the threshold
membrane potential in stimulation of a single node of Ranvier
(Ni) with rectangular \oltage pulses (S). Nodes N,, and N2
are inexcitablc. V indicates the input of a positive feed-back
amplifier for recording the membrane potential. In each record
the stimulus intensity and duration used are given. [From
Tasaki (1^6).]
CONDUCTION OF THE NERVE IMPULSE
95
applied between No and Ni sets up through the mem-
brane of Ni a current, the time course of which is
distorted by current flow through the myelin sheath.
The records in figure i6 show the behavior of the
membrane potential at threshold as observed with
this arrangement. The duration of the stimulating
pulse was varied in the range between 0.05 and 6.4
msec. At every stimulus duration the stimulus inten-
sity was adjusted to threshold, and without changing
the intensity, five to seven sweeps of the oscillograph
beam were superposed on each record. Because of
spontaneous variation in the property of the nerve
fiber (14, 99), the node sometimes responded with a
full-sized action potential and sometimes failed to
produce an action potential.
We may define the 'threshold membrane potential'
as the highest potential level of the membrane which,
after the end of the applied stimulating pulse, decays
without producing an action potential (63, 126). The
level of the threshold membrane potential measured
from the resting potential level is often called the
'threshold (or critical) depolarization.' It is seen in
the records that the threshold depolarization is
practically independent of the stimulus duration.
When the duration is short (e.g. 0.05 msec), a very
large voltage (200 mv) is needed to excite the node;
the observed fact is that this high a voltage is required
to raise the membrane potential within a short period
of time to the threshold level, which is about 15 mv
above the resting potential. This is exactly what has
been assumed in most of the classical theories of nerve
excitation.
As we have discus.sed in a previous section, the
surface membranes of the nerve fiber, both the myelin
sheath and the nodal membrane, have relatively large
capacities. Consequently, in order to raise the mem-
brane potential by a constant amount, higher stimu-
lus intensities are required at shorter stimulus dura-
tions.
However, there is in this type of experiment one
complication that has not been fully understood by
previous investigators who worked only on nerve
trunks. It is the gradual rise in the membrane po-
tential that precedes the rapid rising phase of the
action potential in stimulation by a long pulse (see
fig. 16, record for 6.4 msec). In response to a long
stimulating pulse, an action potential either appears
within a few msec, (within 10 msec, at the most)
after the start of the pulse or fails to appear at all.
When the action potential fails to appear, the be-
havior of the membrane potential does not diverge
from what is expected from the physical constants of
the resting nerve fiber. When the membrane potential
starts to diverge distinctly from the simple time
course, provided that the applied pulse has not been
withdrawn within 5 msec, or so, there is alw-ays (at
least in a normal node) an action potential.
Action potentials evoked by long stimulating
pulses have a more-or-less gradual rising phase
followed by a phase of rapid potential rise. If the
applied stimulating pulse is withdrawn before the
start of the rapid potential rise, the production of
a full-sized action potential is prevented. Such a
gradual potential rise followed liy a sudden potential
fall caused by a withdrawal of the applied pulse is
seen in the record labelled 46 mv (1.6 msec.) in
figure 16.
The nonlinear phenomenon just described is con-
sidered at present to indicate the following. The pro-
duction of an action potential is a kind of 'regenerative'
or 'autocatalytic' process similar to the explosion
induced by heating of a mass of gunpowder (105).
The heat applied from outside causes combustion in
only some of the gunpowder particles; the heal arising
from these particles in turn induces combustion in
other neighboring particles. Similarly, when the
stimulus duration is sufficiently long, the start of a
■ response' (the start of comljustion in the analogy
above) tends to raise the membrane potential (tem-
perature) together with the applied stimulus (applied
heat). If the external source of current (heat) is
maintained, this process eventually raises the mem-
brane potential (temperature) to a critical explosive
point. If, however, the applied pulse is withdrawn
before the critical level of the membrane potential is
reached, the potential returns to its resting level
along a variable time course. With very short current
pulses, the membrane potential has to be raised by
the external source up to the critical level. ^
In the excitation of the invertebrate axon with
rectangular current pulses, results similar to those in
figui-e 16 have been obtained by several investigators
[e.g. Hodgkin & Rushton (63)]. To stress the similar-
ity between the vertebrate myelinated ner\e fiber
and the squid a.xon, unpublished records obtained
by Hagiwara and others are presented in figure 1 7.
The arrangement of the stimulating and recording
electrodes used is similar to that in figure 14; two
metal wires about 30 mm in length were inserted
along the axis of an axon. Pulses of constant current
' It should be pointed out that some physiologists have
slightly different viewpoints in regard to the statement made
in this sentence (104, 107).
96
HANDBOOK OF PHVSIOLOGV -^ NEUROPHYSKJLOGV I
RECTANGULAR CURRENT PULSES
SLOWLY INCREASING CURRENT PULSES
5 msec
FIG. 17. Upper portion: Stimulation of a squid giant axon by rectangular current pulses applied
through a long intracellular metal electrode. The membrane potential was recorded with another
intracellular electrode. Stimulus durations used are indicated by the bars in the records. Lower por-
tion: Stimulation of a squid giant axon by slowly rising current pulses. The time courses of the current
pulses used are indicated by the broken lines. [From S. Hagiwara et al., unpublished.]
were applied through one of the internal wire elec-
trodes and the change in the membrane potential
was recorded with the other electrode. Under these
experimental conditions, the axon memiarane is
traversed by the applied current uniformly over the
whole area under investigation. The intensity of the
stimulating pulses was adjusted to the threshold at
every stimulus duration.
It is seen in the figure that the threshold membrane
potential defined as the highest subthreshold level of
the membrane potential is approximately constant
(within about 5 per cent), irrespective of the stimulus
duration. As in the nodal membrane of the toad
myelinated nerve fiber, the decay of the membrane
potential in barely subthreshold stimulation is ex-
tremely variable. In response to long current pulses
(see record £)), however, a phenomenon we have not
discussed before is seen. A barely subthreshold, long
current pul.se sets up an approximately exponential
change at the beginning; later, in spite of maintained
flow of the constant current, the memijrane potential
is found to fall gradually. This is the behavior of the
membrane associated with the phenomenon classi-
cally known as ' accomodation' [see Erlanger & Blair
(27)]. In the nodal membrane, the process of accom-
modation progresses more slowly than in the squid
axon and is not apparent in figure 16.
It has been known for many decades (79) that a
slowly increasing current fails to excite a nerve fiber
even when its intensity rises well abo\e the rheobase.^
Evidently, this phenomenon is related to the ' accom-
modative fall in the membrane potential' just men-
tioned. This point is illustrated by the records in
the lower part of figure i 7. When the rate of current
increase is greater than a certain critical \alue, a
full-sized action potential starts when the membrane
potential reaches the threshold level. When the
membrane current rises .slower than the critical
rate, the potential begins to fall while the current
intensity is increasing. Once such an accommodative
fall in the membrane potential has taken place, the
potential can rise well above the ordinary threshold
le\el without initiating an action potential.
Now, let us turn to the corresponding obsersation
on the toad myelinated nerve fiber. Figure 18 shows
the beha\ior of the nodal membrane in threshold
stimulation bv linearlv rising \oltage pulses. The
experimental arrangement used is the same as that
used in the experiment of figure 16. Since there is a
high ohmic resistance in the axis-cylinder between
" This is the threshold for a long rectangular pulse. For
pulses longer than 5 msec, the threshold is practically in-
dependent of duration.
CONDUCTION OF THE NERVE IMPULSE
97
Fio. 1 8. Variations of the membrane potential of a single
node (V) caused by linearly rising voltage pulses (S). The
arrangement of fig. i6 was used. In records A' and B' the miss-
ing portions of the potential trace (V) indicate production of
action potentials of about lOO mv in amplitude. The trace for
the stimulating voltage (S) was blanked at too cps. Large
motor nerve fiber of the toad. Temperatine, 1 1 °C. [From
Tjisaki (127).]
nodes No and Ni and since the time constant of the
membrane is far shorter than the time scale employed
in these observations, the time course of the current
through the nodal membrane is similar to that of the
applied \0lta5e. In records .-1, B, Cand D, an accoino-
dative fall in the membrane potential is evident.
Each of the paired records. A- A' or B-B', was taken
at almost the same stimulus intensity; in one QA or 5)
the node failed to respond, and in the other (J' or
B') a large action potential was evoked. The peak
value of the subthreshold membrane potential in
these cases is more erratic than in the experiment of
figure 16; it is roughly independent of the rise time of
these stimuli.
In most classical theories of nerve excitation [e.g.
Hill C48)], the process of accommodation has been
regarded as a gradual rise in the threshold level of
the nerve during the period of prolonged d.c. stimula-
tion. The direct observations mentioned above
indicate that this is not exactly the case. It is due to a
secondary change in the property of the membrane
which decreases the effectiveness of the current to
raise the membrane potential. Undoubtedly, this is
related to the phenomenon of delayed rectification
described first by Cole (18); he found that the axon
membrane of the squid shows a resistance to an
outward directed maintained current far smaller than
that measured with an inward current [see also
Hodgkin (53)]. Hodgkin & Huxley (59) attributed
this process mainly to an increased permeability of
the membrane to potassium ions. In the nodal mem-
brane, there is some e\idence indicating that there is
a change in the resting potential when the membrane
undergoes an accommodative change (127).
Strength-Duialion Rilalum
The relation between the threshold intensity of a
stimulus and its duration is called a strength-duration
or intensity-time relation. In the squid giant axon
excited by means of a long internal metal wire elec-
trode, the significance of this relation is now very
clear. When a rectangular pulse of current is applied
to the membrane through the internal electrode, the
inembrane potential rises exponentially as described
by equation (4-2). If a stimulus which lasts no longer
than about 2 msec' (at i4°C) is to initiate an action
potential, the membrane potential has to reach the
critical level, l\, at the end of the pulse. This leads to
the relation
F, = IRii - e-J-'Rf),
in which T is the duration of the current pulse, / is
the current intensity and RC the time constant of the
membrane. Rearranging the terms, we have
/
T = RC log .
This is known as Blair's equation for strength-
duration relation (15). Because of the interaction
between the stimulating current and the response of
the membrane mentioned abo\e, this equation is
only a poor approximation near the rheobase.
Stimulation of a squid giant a.xon through a glass
pipette can be treated in a similar fashion by using the
solution of the cable equation for the corresponding
conditions. Again the rheobase will be slightly (20
to 30 per cent) smaller than that expected from the
space and time constants of the resting axon mem-
brane. When the duration becomes far shorter than
the membrane time constant, another complication
(related to the phenomenon of abolition of an action
potential to be discussed in the next section) prob-
ably sets in. When the current pulse is extremely
short, the uncharged membrane on both sides of the
site of stimulation is expected to prevent a further rise
in potential at the site of stimulation and to suppress
the start of an action potential. These factors have
not yet been carefully investigated.
' This figure was kindly supplied by Dr. S. Hagiwara.
98
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
In the myelinated nerve fiber, the strength-
duration relation is determined primarily by the
complicated network formed by the nodal membrane,
the axis cylinder and the myelin sheath. Because of
the interaction between the applied current and the
start of a response, the rheobase is 20 to 30 per cent
smaller than that expected from the membrane
properties at rest (see fig. 16). So far, no one has
derived the equation describing the distribution of
the membrane potential caused ' by a rectangular
voltage applied at one point between two neighboring
nodes. In practice, however, the strength-duration
relation is expressed by a purely empirical formula:
.= .(.+^).
in which .S' is the threshold voltage, /; the rheobase
voltage and a a constant which has a dimension of
time and is known as'chronaxie'. It is known that the
chronaxie for a node varies markedly with the distance
between the node under study and the stimulating
partition (65).
Subthreshold Response
It has been shown in the explanations of figures 16
and 1 7 that the membrane potential raised by a
brief shock of barely subthreshold intensity decays
along a variable time course which is far slower than
that expected from the physical properties of the
resting nerve fiber. This delay in the fall of the mem-
brane potential is said to be due to a "subthreshold
response' or a 'local response'. Such delay occurs only
when the stimulus intensity is greater than 80 to 90
per cent of the threshold (in single node preparations).
This phenomenon is more marked in a preparation
with high threshold and a poor action potential than
in a fresh normal preparation. The phase of the
potential rise in these cases is determined bv the
physical properties of the resting membrane. The
subthreshold response is considered as a sign of the
beginning of the regenerative process which has
subsided without growing into a full-sized response.
The historical aspect of the concept of the sub-
threshold response has been discussed in the intro-
duction of this chapter.
A subthreshold 'response' is different from an
ordinary full-sized response in that it does not leave
behind it a clear refractoriness. In the period during
which the membrane potential stays above the level
of the resting potential, the threshold for the second
shock (necessary to evoke a full-sized response) is
lower than the threshold at rest. (In the squid axon, a
subthreshold response is followed by a small ' under-
shoot', during which the membrane potential is below
the resting level; the threshold is higher in this period
than at rest.) Like an ordinary response, a sub-
threshold response is associated with a reduction in
the membrane impedance; the reduction is, however,
far smaller than that associated with a full-sized
response (see fig. 12).
The arriplitude of the full-sized action potential
depends slightly on whether or not it is preceded by a
marked subthreshold response. It is seen in the rec-
ords of figure 16 that the action potentials preceded
by a slow gradual potential rise are consistently
smaller than those preceded by an abrupt potential
rise. Because of this variation in the amplitude of the
response and of the subthreshold responses, the
response recorded at the site of stimulation is said to
be only approximately all-or-none.
In the experiments of figures 16 and 17, the stimu-
lating current is applied uniformly through the ex-
citable inembrane. It is not possible, therefore, to
interpret the subthreshold response as an action po-
tential localized in a small area subjected to a strong
stimulating current (see p. 76). This area hypothesis
of the subthreshold response can be saved if one
assumes that the surface of the excitable membrane is
not uniform but that there are spots or patches where
the sensitivity to electric stimuli is higher than at the
remaining surface. In the sodium theory (59), a sub-
threshold response is attributed to a small increase in
the sodium conductance of the membrane.
When a nerve fiber is excited by a stimulating cur-
rent distributed nonuniformly over the membrane, the
time course of the subthreshold response is compli-
cated by the spatial factor. Especially when the state
of the nerve filler has been altered locally by the
stimulating or recording electrode or when there are
large stimulation artifacts, pictures very different
from those in figures 16 and 17 can be obtained. Be-
cause of these complications, there have been a num-
ber of confusing reports on this topic.
Measurement oj Excitability by L "sing Test Shocks
In classical physiology writers used to .speak of
measuring the 'excitability' of the nerve by test
shocks. Insofar as we define the excitability as the re-
ciprocal of the threshold (p. 80), this procedure of
measuring the excitability is simple and straight-
forward. It seems, however, that to old phy.siologists
the term 'e.\cital3ilit\' or ' irritabilitv' had some
CONDUCTION OF THE NERVE IMPULSE
99
anthropomorphized meaning [e.g. Verworn (140)]
and the procedure of measuring it was more-or-less
comparable to determining a man's ability by
mental tests. Such a concept of excitability has no
clear physiological meaning.
Here, we shall discuss the significance of the method
of using test shocks to explore the state of the nerve
fiber. This method has been used mainly on verte-
brate nerve fibers.
In the arrangement illustrated in the inset in figure
19, an isolated nerve fiber is mounted across two pools
of Ringer's solution. The narrow air gap is located
between nodes Ni and No. Through the electrodes im-
mersed on the pools, short pulses superposed on long
rectangular \-oltage pulses are applied to the fiber.
The intensity of the short pulse, .S', the voltage of the
long pulse, V, and the time interval, /, from the begin-
ning of the long pulse to the start of the short pulse
are three variables in this experiment. The data pre-
sented in A were obtained by fixing voltage, v, at one
of four different values ( — 20, —10, 10 and 20 mv)
and adjusting S to make the composite stimulating
pulses barely eflfective in eliciting a nerve impulse at
varying values of /. The data in B were obtained by
fixing t at 2 msec, and adjusting v and .S* to make the
pulses barely effective. Thresholds were determined
by taking the response of the muscle innervated by
the nerve fiber as an index of initiation of an im-
pulse; the same result, however, can \)e obtained by
taking the action potential of the nerve fiber as an
index.
In B, the observed point for .S' = o is at j) = 30 to
31 mv, indicating that the rheobasic voltage of the
fiber under these experimental conditions was about
30 mv. The threshold for the brief shock depends on
the duration of the shock; for durations shorter than
about 30 /isec, the threshold rises inversely as the du-
ration. The shock used in the present experiment was
within this range and its threshold was taken as unity.
The curves in A show how the threshold for the test
shock, S, is modified by the subthreshold pulse, v. At
any fixed value of /, the change in S is roughly pro-
portional to I', except when v is greater than about
50 per cent of the rheobase (5). One thing that looks
strange in this figure at first sight is the change in
threshold observed at / = o and for negative values of
/. This is a constant finding in single fiber experiments
and has also been observed by Erlanger & Blair in
their experiments with nerve trunks (27). If the test
shocks measure the state of the nerve fiber at the
moment when the shocks are delivered, it is obviously
absurd that the threshold starts to change before the
beginning of the subthreshold pulse used to modify
the state of the fiber.
There are two factors that serve to explain this
strange fact. One factor is the time required for the
spread of membrane potential along the myelin
sheath, and the other factor is the production of a
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:n
o 1»
A '-I
ir
-20
20
40 mV
FIG. 19. Changes in threshold for a brief shock (S) caused by application of a subthreshold rec-
tangular voltage pulse (v). The sign of the stimulating \oltage pulse is positi\ e when the pulse induces
an outward current through node N-j in the diagram. S(, represents the threshold for the brief shock
alone.
lOO HANDBOOK OF PHYSIOLOGY ^^ NEUROPHYSIOLOGY I
subthreshold response. We shall first discuss the lime
factor.
When a rectangular pulse of voltage is applied
across the air gap in the arrangement of figure ig, the
membrane potential at the nearest node (Ni and Nj)
rises (or falls) along a sigmoid curve. This sigmoid
time course arises from the situation that both the
myelin sheath and the nodal membrane have a
capacity which delays spread of the membrane po-
tential. The problem of spread of potential along a
uniform cable is discu.ssed in some detail on p. 86.
The situation in the myelinated nerve fiber is compli-
cated by the discontinuities at the nodes, and un-
fortunately no rigorous mathematical solution of the
problem is at present available. It is certain, however,
that both V (the membrane potential at the node)
and dV/dl are zero at / = o, and 1' rises first gradually,
then faster and finally approaches the plateau.
The variation in the membrane potential caused by
a brief voltage pulse is given by the derivative, dl'/dt,
times a constant, because a brief pulse can be re-
garded as a diff"erence between two long rectangular
pulses of the same intensity but starting in succession
at a small time interval. From this it follows that the
maximum of the membrane potential change caused
at the node by the test shock is reached a certain
period of time, t,,, after the delivery of the shock [see
curve 1-/4 on p. 492 of Lorente de No (77)]. This time
(to) depends on the distance from the stimulating par-
tition to the node under study (122). Now, in the
range of voltage, v, where the relationship between S
and !> is expressed by straight line I in figure igfi,
action potentials are elicited when the algebraic sum
of the potentials caused by v and S reaches the
critical level. Therefore, the origin of time has to be
shifted to the left by to if the curves are to represent
the change in the state of the fiber caused by the sub-
threshold pulse, V. The argument along this line was
developed first by Erlanger & Blair (14, 38) and
later by Tasaki (118, 122).
Next, we discuss the second factor that has to be
taken into consideration in the analysis of the curves
in A of figure 19. W'hcn the test shock, S, precedes the
start of the subthreshold pulse, v, the change in the
threshold of S is small. It has been mentioned that,
when a brief shock is close to its threshold, the fall in
the membrane potential at the node is far slower
than that expected from the physical constants of the
resting nerve fiber. If a weak (positive) rectangular
pulse (j/) follows such a barely subthreshold test pulse,
it is possible that the membrane potential is raised
to the critical level, thus initiating a full-sized response.
This can account for a decrease in threshold in the
region where / is negative and v is positive. Katz (72)
developed this argument to explain the results of his
experiments in which the effect of a brief shock was
tested by another brief shock. His argument is not
entirely correct since he ignored the first (time) factor
mentioned above. Erlanger & Blair as well as
Tasaki neglected the second factor arising from the
subthreshold phenomenon; their argument, there-
fore, has to be partly modified.
Finally, we shall discuss the significance of the
break in the v-S relation in the experiment of figure
195. Some physiologists believe that this break is a
sign of the development of subthreshold response to a
subrheobasic rectangular pulse alone [e.g. Nieder-
gerke (92)]. As we see, however, in the lower right
part of figure 16, this is not exactly the case. The
continuous transition from straight line I to II is evi-
dently due to the interplay of the two stimuli related
to the development of ' the slowly rising phase of the
membrane potential' which precedes a full-sized ac-
tion potential.
."iBOLlTION OF THE .ACTION POTENTI.AL
Initiation of an action potential can be regarded
as a transition of the membrane from its resting state
into the active state which is characterized by a low
membrane resistance and a high potential level. The
reverse process, i.e. a transition from the active state
of the membrane to the resting state, was first demon-
strated in the cardiac muscle of the kid (142), then
in the toad nodal membrane (126) and finally very
recently in the squid axon membrane. The action po-
tential of the cardiac muscle is associated with a
systolic contraction. The fact that this contraction can
be abolished by a strong (anodal) current pulse in an
all-or-none manner has been known since the time of
Biedermann (12, pp. 257-264).
The regenerative process of initiating an action po-
tential is set off by a change (rise) in the membrane
potential up to a certain level. In an analogous man-
ner, the process of abolition of an action potential is
set off by a change (fall) in membrane potential
down to a critical level. This is shown in figure 20.
These records were obtained from a single node
preparation of the toad. The arrangement of the
stimulating and recording electrodes used is similar
to that for the experiment of figure 16. The first pulse
of outward membrane current raises the membrane
potential to the level slightly above the critical po-
CONDUCTION OF THE NERVE IMPULSE
FIG. 20. Abolition of the action potential of a single node by pulses of inward membrane current.
The lower trace in each record indicates the time course of the voltage applied between No and Ni
in the diagram of fig. 16, top. The amplitude of the recorded action potential was approximately 100
mv. Time marks in msec. A toad nerve fiber at io°C. [From Tasaki (126).]
tential necessary to initiate an action potential. The
second pulse of inward current is applied during; the
falling phase of the action potential and lowers the
membrane potential down to various levels.
When the change in the membrane potential
caused by the second pulse is slight (records B, B', C),
the potential rises after the end of the pulse back to
the level which might have been reached if the sec-
ond current pulse had not been applied. When the
membrane potential is lowered by the second pulse
below a certain critical level (records C, D), the po-
tential does not rise after the end of the pulse but falls
further to the potential level of the resting membrane.
At the critical intensity of the second pulse (record
D'), the membrane potential in .some instances rises
to the level of the active membrane and in others ''alls
to the level of the resting potential. A further increase
in the intensity of the second pulse lowers the mem-
brane potential below the resting potential (record E,
E'); however, after the end of the pulse, the mem-
brane potential rises and settles usually at the level of
the resting potential.
Similar records of abolition of action potentials
have been taken from a squid giant axon which has
been treated with intracellularly injected tetraethyl-
ammonium chloride. This chemical when applied ex-
ternally is known to prolong the duration of the ac-
tion potential of the frog nerve and muscle fiber (46,
78). Prolonged action potentials of the squid or of
the toad motor nerve fiber show a remarkable resem-
blance to the action potential of the heart muscle.
When the action potential is prolonged as it is in these
cases, the time constant of the membrane is far
shorter than the duration of the action potential and
the demonstration of the phenomenon of abolition is
thereby made easy.
It is seen that the critical potential le\el for aboli-
tion gradually rises during activity. Toward the end
of the prolonged action potential, the critical level for
abolition is close to the level of the ' shoulder' of the
action potential at which the membrane potential
starts to fall rapidly.
It is an interesting fact that the action potential
which has been abolished in its very early phase
leaves behind it no refractory period. This is shown
by the superposed record in figure 21. Record A in
the figure is an ordinary unabolished action potential
of a single node of the toad motor fiber. When this
action potential is abolished in its later stages by a
pulse of inward current through the node (record B),
there is a relati\ely refractory period following this
prematurely terminated response; a strong current
I02
HANDBOOK OF PHYSIOLOGY -^^ NEUROPHYSIOLOGY
FIG. 21. Recovery of the amplitude of the action potential
following abolition of a response of a single node. The ar-
rangement shown by the diagram in the upper part of fig. i6
was used. .4. Action potential of a single node (,top~) and a
truncated 60 cycle wave indicating 100 mv level in applied
stimulating and abolishing pulses (^bollom). B, C and D. Super-
posed recordings showing recovery after an abolished response.
Temperature, io°C. [From Tasaki (126).]
pulse is needed to initiate a second action potential
and the amplitude of the second response decreases
continuously with decreasing interval between the
two responses. Record D shows that, following; the
action potential abolished at its peak, the node
exhibits no refractoriness to the following stimulating
pulse. In record C, the action potential has been
abolished after the potential has fallen slightly from
the peak; it is seen that the amplitude of the second
response is slightly subnormal at the beginning and
recovers gradually.
These observations reveal how the process respon-
sible for the refractoriness progresses during the falling
phase of the action potential. As was pointed out by
Adrian (2) in 1921, the end of the action potential
coincides roughly with the beginning ot the relatively
refractory period [cf. Tasaki {119, 124)]. When the
action potential is abolished in the middle of its falling
phase, the recovery in the amplitude of the second
response starts in the middle of the normal recovery
curve (126). It has been suggested therefore that the
refractoriness is due to some chemical product which
accumulates during the falling phase of the action
potential. In the sodium theory (see p. 1 18) a different
explanation is given to the origin of the refractoriness.
The rapid falling phase following the shoulder of a
normal action potential appears to be a transition of
the membrane from the active state to the resting
state resulting from the gradually rising critical level
for abolition reaching the level of the continuously
falling potential level of the membrane.
NERVOUS CONDUCTION .iiLONG UNIFORM .AXONS
We are now ready to discuss nervous conduction as
a process that involves production of action poten-
tials in successive portions of the surface membrane of
the nerve fiber in an orderly fashion. In the squid
giant axon, the rise in the membrane potential** at the
peak of the action potential is 100 to 120 mv and the
critical depolarization necessary to initiate an action
potential is 12 to 15 mv. Furthermore, the resistance
of the membrane in the active area is far smaller
than that of the membrane at rest (see p. 89).
Therefore, when a portion of an axon membrane is
thrown into action by a pulse of stimulating current,
the adjacent portion of the membrane is automatically
brought to action Isy the restimulating effect of the
local circuit between the active and resting area of the
axon. By a repetition of this process of stimulation
by the local circuit, the activity spreads indefinitely on
both sides of the site of initial stimulation.
The local circuit cannot be closed if there is no
conducting fluid medium outside the nerve filler.
Therefore, nervous conduction is expected to stop if
the saline solution outside the fiber is completely re-
moved. In practice, it is not possible to remove the
fluid outside the fiber completely, but it is easy to re-
duce it by immersing a cleaned single nerve fiber in
mineral oil. Hodgkin (52) has found that, when an
isolated nerve fiber of the cralo is immersed in mineral
oil, the velocity of the nerve impulse is markedly re-
duced. This is a clear-cut demonstration of the im-
portance of the local circuit in the process of propaga-
tion of a nerve impulse.
In figure 22 a set of records from Hodgkin's paper
is reproduced. The velocity of the crab nerve fiber in
normal sea water was 4 to 5 m per sec. This was re-
duced by 20 to 40 per cent when the fiber was trans-
ferred into a bath of mineral oil. This reduction in the
* The membrane potential is defined as the energy required
to transfer a unit charge across the membrane from the ex-
ternal medium to the axoplasm. If the potential difference
between the fluid in the intracellular micropipette and the
axoplasm (which is probably small but indeterminable) is
ignored, this coincides with the potential of an intracellular
electrode referred to the medium. Since the membrane potential
at rest is a negative quantity, a small rise in the membrane
potential represents a decrease in its absolute magnitude.
CONDUCTION OF THE NERVE IMPULSE
103
FIG. 22. Demonstration ol the dependence of the conduction
velocity of a crab nerve fiber upon the resistance of the external
medium. A and C. Action potential recorded with sea water
covering 95 per cent of the intermediate conduction distance.
B and D. Fiber completely immersed in oil. Conduction
distance, 1 3 mm. Time in msec. [From Hodgkin (52).]
velocity was prompt and completely reversiijle; there
seems to be little doubt, therefore, that the effect is due
to the increased electric resistance of the surrounding
medium.
The velocity of a nerve impulse is determined by a
mechanism involving the interplay of many factors. In
a uniform axon immersed in a large volume of highly
conducting fluid medium, the mechanism determin-
ing the conduction velocity is as follows. In the inactive
area of the axon ahead of the active area, the mem-
brane is traversed by an outward current (see fig. 23)
the intensity of which depends on the velocity of the
impulse. This current is supplied by the active area
immediately behind the active-inactive boundary.
The membrane current in the active area is inward
(see fig. 23), and this inward current tends to delay
the rate of potential rise in the active region. If the
membrane is capable of developing an action poten-
tial rapidly in spite of the existence of a strong inward
current, the velocity tends to be high. If the capacity
and the conductance of the resting membrane are
large, the active area of the membrane has to supply
a strong current to bring the membrane potential of
the inactive area up to the critical level, and conse-
quently the velocity tends to be small. A large longi-
tudinal resistance (small fiber diameter) is expected to
have the same effect upon the velocity as an increased
external resistance.
Hodgkin & Huxley (59) determined the relation
between the membrane potential and the membrane
conductance on the squid axon. By using the cable
equation and a set of empirical formulae relating the
membrane potential and the membrane conductance,
they calculated the velocity and obtained a solution
of the right order of magnitude.
We have discussed in a previous section (see p. 83)
the cable properties of a uniform invertebrate axon.
In a uniform axon carrying an impulse of a constant
velocity, there are certain features that deserve further
discussion. First of all, it should be pointed out that
there is an inseparable relationship between the
spatial distribution of the membrane potential and
the time course of the action potential. A diagram
representing the time course of an action potential
can be converted into a diagram showing the spatial
distribution simply by converting the time scale into
the distance scale by using the conduction velocity as
a conversion factor. This and the following statements
are not applicable to axons with any macroscopic
nonuniformity along their length in regard to the
size and shape of the action potential.
Next to be discussed is the relationship between the
spatial distribution of the action potential and the dis-
tribution of the longitudinal and the membrane cur-
rent of the axon. According to Ohm's law, the longi-
tudinal current in the axoplasm is proportional to the
gradient of the potential in the axoplasm, i.e.
_ -I dV
/"i dx
-_i dV
r,v at '
(9-1 a)
(9-ib)
where h is the longitudinal current, r, the axoplasm
resistance per unit length of axon, V the potential of
the axoplasm (as a function of time, t, and distance
along the axon, .v) and u the conduction velocity. A
variation in the longitudinal current with respect to
space is associated with the membrane current, /„,
(Kirchoff's law), i.e.
(9-2 a)
(9-2b)
(9-2c)
a/i
ax
I a^v
ri dx^
I a^v
^
)-i02 dt^
104
HANDBOOK OF PHYSIOLOGY ^ NEUROPHYSIOLOGY I
100
-V
r-N Fig 23
lm..c
mV
15 mm
50
-
MEMBRANE
POTENTIAL
0
•////////////\,
J_
-100
IMPULSE
Fig. 24
r\f 1
-J V
V ^
■^
'' X 0 N-//////iy/////////.
'''/////,V.\//////^/-
LONGITUDINAL
CURRENT
FIG. 23. Diagrams showing tiie spatial and temporal distribution of the membrane potential, V,
the longitudinal current, li, and the membrane current, Im- The curves for I^ and Im were obtained
from the upper curve for V by the graphical method of determining derivatives.
FIG. i\. Simultaneous recording of the membrane action potential (V) and the membrane cur-
rent (Im). The width of the middle pool was about 2 mm. The potential drop across the resistor r
was taken as the measure of the meinbrane current. Temperature, 20°C.
These equations show that the membrane current of
a uniform axon is proportional to the second deriva-
tive (with respect to either time or space) of the mem-
brane action potential [cf. Katz & Schmitt (73)]. It
should be pointed out in this connection that equa-
tions C9-2) were derived without any assumption as to
the behavior of the resting or active membrane. These
equations fail to hold only when the axoplasm dis-
obeys Ohm's law or when the propae;ation of the im-
pulse is macroscopicalh' nonuniform.
Figure 23 shows the space and time patterns of the
membrane potential, the longitudinal current and the
membrane current as calculated by equations (9-1)
and (9-2). To emphasize the similarity between the
space pattern and the time course of the action po-
tential, the impulse is assumed in this figure to travel
from the right-hand end of the axon to the left. The
resistance r; is assumed to be 1.5X10^ ohm per cm
[cf. Schmitt (106)] and the velocity to be 15 m per sec.
It is seen that the longitudinal current is diphasic and
the membrane current is triphasic. It is simple to
prove that the total area under the curve for the longi-
tudinal current or under the curve for the memijrane
current has to be equal to zero.
The upper part of figure 24 shows an approximate
method of recording the membrane current of the
giant axon of the squid. A giant axon is mounted
across three pools of sea water separated by two nar-
row partitions. The large lateral pools are directly
grounded, and the small middle pool is grounded
through a small resistor. The membrane current flow-
ing through the portion of the fiber in the middle
pool is measured by amplifying a small potential drop
across the resistor between the middle pool and
ground. In order to obtain a simultaneous recording of
the membrane action potential, a microelectrode is
inserted into the portion of the axon in the middle
pool. The axon is excited by a shock applied near its
end. The record presented in the figure shows that
the temporal relation between the action potential
and the membrane current is very similar to what has
been expected from the results of the calculations in
figure 23.
W^e shall now discuss the field of potential in the
CONDUCTION OF THE NERVE IMPULSE
surrounding fluid medium produced by the triphasic
membrane current just mentioned. If the space-time
pattern of the membrane current is given, the problem
of finding the potential field in a volume conductor is
a purely physical problem, namely, an application of
Ohm's law to the electrolytic conductor around the
axon.
The simplest example of problems of this type is the
case in which a uniform axon is surrounded through-
out its length by a conducting fluid of a uniform thick-
ness (fig. 25/I). We assume that the volume of fluid
is not so small as to modify the spatial distribution of
the membrane current di.scussed above. Let s denote
the resistance per unit length of the surrounding fluid
medium; in the present case, s « ^i, where r-, is the
resistance per unit length of the axoplasm. We express
the potential diflerence across the axon membrane at
point .V and time / explicitly as l^x + vO, indicating
that the variation in the membrane potential travels
leftward at a constant velocity, v. Similarh, the
longitudinal current and the membrane current are
functions of (.v -{- vt).
It is simple to show that the total current flowing
through the whole cross section of the surrounding
fluid medium at any point, .v, at any moment, t, is
equal and opposite to the longitudinal current in the
axon at the same x and /. To the present one dimen-
sional approximation, the current in the medium at
.V and time ; is given by — /i(.v + vt'). Denoting the
^1
Xz
_fL
'<'^(«?<^{M(((^</fulff:::::ffffrkh
^ ^ / / /y /^//.
y.
X| X
V77\
//////////A
X2
!>i>;'Hi>!>^!>;';
//^^////
JL
222
FIG. 25. A. A uniform axon immersed in a conducting Huid
medium of uniform diameter; the action potential recorded
with electrodes at xi and x-; is given by the equation (9-3).
B. The case in which the diameter of the fluid medium changes
at x'; the action potential recorded is given by equation (9-4).
C. A uniform axon immersed in a large volume of fluid; the
potential near the axon is given by the triphasic curve in the
diagram.
potential at .vo in the medium referred to that at .vi by
U2-1, it is found that
- = L
si, fix + I'Odx
VQx, + vt) V(,Xi + vt}.
(9-3)
[Note that the integral above represents a summation
of the IR drops along the fluid medium at a given
moment /.] The action potential recorded externally
with electrodes placed at Xi and X2, U2-1, consists of
two terms, one representing the activity at Xi,
F(Ar2 -f vt), and the other, the activity at xi, F(xi +
vt). The amplitude of the observed potential variation
is reduced by a factor of j/n- Equation (9-3) is a
mathematical expression of what is known as 'diphasic
recording' of the action potential. Because of the
negative sign in front of VQx^ -\- vt), it was believed
that the surface of the active portion of an axon was
'electrically negative' to the surface at rest. It should
be borne in mind, however, that, if the surrounding
inedium is not uniform, the potential on the active
surface is not always negative to that on the resting
surface.
The next simple example of the volume conductor
problems is the case in which the resistance per unit
length of the conducting fluid medium changes at x'
suddenly from si to so (fig. 25Z?). Expressing j- as a
function of ,v, it is found that
U,^i
-f
<.v)/,(.v -I- vt) d.v
- 1 n , - SV(^x -I- ;./) ^
dx
(9-4)
_5 K(.v, + ,-0 - — ' F(.v> + vt)
+
V\x' -I- vt).
[The last step of the calculation above was accom-
plished by integration by parts.] The right-hand mem-
ber of equation (9-4) contains three terms, the first
term representing the activity at x-t, the second term
that at .V] and the third term arising from the activity
at .v'. The third term changes its sign, depending on
whether s-i < s\ or .f-.> > S\;\X vanishes when si = 5\.
If Si is nearly zero, i.e. if the amount of fluid around
the axon is very large on one side of x' , the second
term in equation (9-4) vanishes and the equation in-
dicates that the electrode at .vi effectively records the
potential variation at x' .
io6
HANDBOOK OF PHVSIOLOGV
NEUROPHYSIOLOGY 1
The final case to be discussed is the potential field
produced by a uniform axon suspended in a large
volume of conducting fluid. In this case, the potential
in the fluid at a great distance away from the axon is
not influenced by the nerve impulse; therefore, the
electrode on such a point is truly "indifferent'. Under
such circumstances, the potential in the space is in-
vensely proportional to the distance from the source
of current. Since there is a line source in the present
case, the potential at point P in the fluid medium is
given by
f/.
4^ J
d.v,
where .S' is the specific resistance of the fluid medium
and /?,,(.v) is the distance between point P and point x.
If point P is on the surface of the axon (at x = p),
U,. cc /,„(/) + ,.t\
since the source in the immediate neighborhood ol the
recording electrode is expected to have an over-
whelmingly large effect in determining U,,. The time
course of Up is now triphasic as is the time course of
the membrane current in figures 23 and 24. Under
these circumstances it is incorrect to say that the sur-
face of the active region of the axon is 'electrically
negative'.
More complicated cases of the volume conductor
problems can be solved by finding the solution of
Laplace's equation AT' = o under the boundary con-
dition described roughly by ( — i /.S) (3 r/c)«) =
/,„(.v + r/), where n is the normal to the surface of the
axon. To apply this concept of volume conductors to
the potential field in the body, one has to consider
both the nonuniformity of the excitable tissues and
the nonhomogeneity of the conducting medium. The
arguments described above on the potential field
cau.sed by nerve impulses are based on the work of
Craib (21), Marmont (83), Lorente de No (77),
Tasaki & Takeuchi (136) and others.
NERVOUS CONDUCTION IN MYELINATED NERVE
FIBER (SALT.ATORY CONDUCTION)
The mode of propagation of a nerve impulse in
the vertebrate myelinated nerve fil)er is expected to
be somewhat diflferent from that in the invertebrate
nerve fiber because of the structural discontinuities
along the myelinated nerve fiber. We have seen that
the myelin sheath of the vertebrate nerve fiber shows
an cxtremelv hia;h electric resistance to a direct cur-
rent (p. 87). We have also become acquainted with
the experimental evidence indicating that the elec-
tric response of the nerve fiber derives from physio-
logical activity localized at nodes of Ranvier of the
fiber (p. 88). The myelinated nerve fiber has a
cable structure; when one of the nodes of the fiber is
thrown into action, there is a local current which
tends to raise the membrane potential of the adjacent
node to a level higher than the threshold potential.
When all the nodes of the fiber are excitable, there-
fore, it is expected that the activity will spread from
node to node indefinitely along the fiber. We shall
examine the line of evidence indicating that this is
actually the mode of nervous conduction in the
mvlinated nerve fiber.
Effect of Increase of External Resistance
It is a fairly difficult problem to demonstrate that
an increase in the resistance of the external fluid
medium does affect propagation of a nerve impulse
in the myelinated nerve fiber. The reason is that the
resistance per unit length of the axis cylinder is very
high (150 to 250 Mfl per cm) even in the largest
nerve fiber in the frog .sciatic nerve. Unless the ex-
ternal resistance is raised above this level of the in-
ternal resistance, it would not be possible to demon-
strate a clear effect upon the process of nervous
conduction.
The first piece of evidence along this line was ob-
tained in the nerve fiber of which a portion was
rendered inexcitable by narcosis (117, 135). The
upper part of figure 26 shows the experimental
arrangement employed. An isolated nerve fiber of
the toad is mounted across three pools of Ringer's
fluid separated by two narrow air-gap partitions. A
portion of the fiijer, including two nodes of Ranvier,
is introduced into the small middle pool, and the
remaining portions of the fiber are immersed in the
large lateral pools. In each of the three pools, an
electrode of Ag-AgCl Ringer (agar) type is im-
mersed. The electrode in one of the lateral pools is
connected to a low input amplifier, and the remaining
two electrodes are grounded.
With all three pools filled with normal Ringer's
solution, the nerve impulse arising at E in the figure
alwavs travels across the two narrow partitions (record
A). When the portion of the fiber in the middle pool
is treated with a cocaine-Ringer's solution (0.2 per
cent), the impulse fails in some preparations to
propagate beyond the narcotized region (record B).
When the electrode in the small middle pool is
CONDUCTION OF THE NERVE IMPULSE 1 07
Fig. 28
y AMP.
'MX^^
Fig.26
v-r>.
FIG. 26. Demonstration of the dependence of ncivous conduction upon the flow of electric current
outside the fiber. A. Action current recorded with an amphfier connected between the middle and
the distal pools; stimulus given at E. B. Block of conduction caused by replacing the Huid in the
middle pool with an 0.2 per cent cocaine-Ringer's solution. C. Restoration of conduction by lifting
the middle electrode from the surface of the fluid. Time marks, i msec, apart. [From Tasaki (123).]
FIG. 27. Demonstration of the effect of a shunting resistance of 20 megohms across the insulated
internode upon nervous conduction. AMP represents a high input-impedance preamplifier. Record
A was taken with the resistance disconnected; Record B with the resistor connected. [From Tasaki &
Frank (128).]
FIG. 28. Measurement of the safety factor in nervous conduction by narcosis. Top record: Normal
binodal action current. Second through Joiirth records: 3, 7, 38 and 38.1 minutes after introduction of a 3
per cent urethane-Ringer's solution into the proximal pool. [From Tasaki (124).]
lifted above the surface of the saline at this moment,
there occurs a marked increase in the recorded cur-
rent and, at the same time, the tiine course of the
current becomes diphasic (record C). In a motor
nerve fiber with its innervating; muscle left intact, it
is seen that the diphasicity in the recorded current is
always associated with propagation of an impulse
across the narcotized region in the middle pool.
The mechanism of restoration of conduction in
this experiment is as follows. The portion of the fiber
in the middle pool treated with cocaine is inexcitable.
The activity of the portion of the fiber in the lateral
pool induces a current that spreads along the fiber in
the middle pool, but this spreading current is too
weak to e.xcite the portion of the fiber beyond the
middle pool. When the electrode in the middle pool
is removed, the leakage of the spreading current
through the portion of the fiber in the middle pool
is reduced and, consequently, the current that reaches
the other side of the middle pool is increased. Thus,
the spreading current becomes suprathreshold for
the portion of the fiber beyond the middle pool.
The question has been raised (37, 66, 128, 145) as
to whether it is possible to block propagation of a
nerve impulse by insulating a nerve fiber between
the two neighboring nodes. First, we must discuss a
troublesome factor related to the experiment de-
signed to answer this question.
io8
HANDBOOK OF PHYSIOLOGY ^ NEUROPHYSIOLOGY I
In order to detect propagation of ner\e impulses
across an insulating air gap, it is necessary to have
an amplifier or the innervated muscle attached to
the single fiber preparation. Stimulating electrodes
and a muscle or recording electrodes connected to
the two sides of the insulating gap introduced an
electric capacity which, under ordinary experimental
conditions, is large enough to establish a local circuit
(by this capacitativc pathway). The resistance of a
single fiber preparation mounted across a wide air
gap is of the order of 50 MfJ. If there is a capacity of
about 2 MMf between the two portions across the gap,
the local circuit between the two portions of the
preparation will be very effectively closed by the
capacitative pathway for a period of about o. i msec.
In fresh single fiber preparations, it is actually im-
possible to demonstrate a conduction block at an
insulating air gap if muscular contractions are taken
as an index of such conduction'' (128, 145).
The capacitative coupling between the two insu-
lated portions of a single fiber preparation can be
markedly reduced by the use of a positive feed-back
amplifier. In the diagram of figure 27 the small por-
tion of the preparation on one side of the insulating
air gap is connected to the input of a unity-gain
preamplifier and is completely enclosed in a metallic
shield driven by the output of the preamplifier. (Note
that, when the potential of the insulated portion
rises above the ground potential, the potential of the
shield around the fiber rises to the same extent and,
consequently, no electric charge is induced between
the insulated portion of the preparation and ground.
The input impedance of the preamplifier can l)e
made as high as 1000 MQ.)
It is surprising to see that most single-fiber prepa-
rations mounted as shown in this figure are still
capable of carrying impuLses across the air gap (128).
Washing the surface of the internode in the gap with
a nonelectrolyte solution does not generally help to
bring about a block at the insulating air gap. Prob-
ably, the cell of Schwann on the surface of the nerve
fiber does not permit us to raise the external resist-
' There are somewhat controversial viewpoints on this
subject in the literature. Huxley & Stampfli (66) reported
that conduction was blocked when the external resistance was
raised. Wolfgram & van Harreveld (145) failed to demonstrate
a block under similar experimental conditions and expressed
the view that their experimental results were inconsistent
with the concept of saltatory conduction. Frankenhauser &
Schneider (37) reported that they could demonstrate a block
with a 20 MSJ shunting resistance across the insulating air
gap. For a further discussion on this point, see Tasaki & Frank
(128).
ance high enough to cause a conduction block in
fresh preparations.
Record .-1 in figure 27 was obtained after circulat-
ing dry air around the portion of the fiber on the air
gap for a short period of time. This causes a rapid
e\aporation of water from the surface of the fiber
followed by a slow desiccation of the axis cylinder.
The monophasicity of the response indicates that the
block has actually taken place. Record B in the
figure was taken while the small insulated portion
of the preparation was grounded through the 20 M12
resistor in the figure. The response is now diphasic
(or rather binodal), indicating that conduction was
restored by the shunting resistance. A similar revers-
ible restoration of conduction can be obtained by re-
ducing the feed-i)ack voltage to the driven shield,
thereijy increasing the capacity of the insulated por-
tion of the preparation to ground.
The obsersation just described indicates that the
abilit\- of the ner\e impulse to excite the adjacent
resting region is \cry large. As a consequence, a re-
versible conduction l:)lock by increasing the external
resistance has been demonstrated so far in prepara-
tions with a somewhat reduced safety margin. How-
ever, it seems safe to conclude from the observations
described above that ner\-ous conduction in the
myelinated nerve fiber does depend on the electric
pathway outside the myelin sheath.
Safety Factor
The safety factor in ner\ous conduction inay be
defined as the ratio of the action current of the nerve
fiber to the minimum current intensit\ necessary for
ner\ous condtiction. If an action current generated
at one point of the nerve fiber acts as an electric
stimulus to the adjacent point, it should be po.ssible
to measure the action current in terms of the normal
threshold.
The first attempt to determine the safety factor was
made bv using a dilute narcotic solution to reduce
the action current from one portion of a nerve fiber
and by measuring the minimum intensity of the cur-
rent necessary to excite the adjacent portion of the
fiber (135). In the uppermost part of figure 28 is
shown the experimental setup used. A motor nerve
fiber of the toad is mounted across two pools of
Ringer's fluid separated by a narrow air gap. The
muscle innervated by the fiber is left uncut, and
twitches in the muscle resulting from stimulation of
the fiber near its proximal end are taken as an index
of nervous conduction. An ohmic resistor (of about
CONDUCTION OF THE NERVE IMPULSE
109
0.2 M12) is connected between the two electrodes im-
mersed in the pools, this resistor serves to close the
external pathway of the local circuit and also to
measure the lons^itudinal current flowint^ through the
axis cylinder bridging the air gap.
When the two pools are filled with normal Ringer's
solution, a familiar action current which we often
refer to as a ' binodal' action current is recorded.
Based upon the arguments described on earlier pages
(p. 88), this action current is explained as deriving
mainly from activity at the nodes (Ni and No in the
figure) in the immediate neighborhood of the record-
ing partition. The rapid rising phase of the action
potential at Ni develops a large gradient of potential
along the axis cylinder between node Ni and N2; the
phase of a strong (2 to 3 times lo"" amp.) current
flow in the binodal action current is the period during
which Ni is active but N2 is still inactive. When the
action potential starts also at node N>, the potential
gradient along the axis cylinder is greatly diminished,
resulting in a sudden fall in the longitudinal current
between Ni and N-j. At the end of the action potential
of a single node (fig. 16), the membrane potential
falls very rapidly. The abrupt end in the binodal
action current is related to the difference in the time
of termination of the action potential at Ni and N2.
Because of the capacities of the nodal membrane and
of the myelin sheath, the spread of current from No
to the internode between Ni and N2 prior to the
start of activity at Ni is very small.
When a urethane-Ringer's solution barely strong
enough to block nervous conduction is introduced
into the proximal pool (in which Nj is immersed), the
upward deflection in the record (representing posi-
tivity of the right-hand electrode in the diagrain)
gradually decreases, indicating that the current arising
at Ni (partly from No) is reduced b)' narcosis. When
the upward deflection is reduced to one-fifth to one-
seventh of the original size, the downward deflection
which has gradually increased during narcosis sud-
denly drops out and, simultaneously, conduction
across the recording internode fails (the lowermost
record in fig. 28). From these observations, it is
found that the safety factor is between fi\e and seven
in large myelinated nerve fibers of the toad.
The safety factor can be estimated from the meas-
urement of the threshold membrane potential and
the nodal action potential. It has been shown that
the action potential of a normal node is approximately
1 10 mv at the peak. When a membrane potential of
this size is developed at node Ni, the adjacent node
N2 is subjected to a strong outward current which
would raise the membrane potential by 50 to 60 mv
if N2 had been made ine.xcitable (124). Since the
threshold depolarization of a fresh node is 10 to 15
mv, it is found that the safety factor estimated by this
method is about five. There are other methods of
estimating the safety factor (124). They all give a
figure between four and seven.
As the result of this large safety factor in nervous
conduction, a nerve impulse can travel across one or
sometimes two completely narcotized nodes (124).
In the experiment of figure 26 it is often seen that
conduction across the middle pool remains unsus-
pended after introduction of a strong narcotic solu-
tion. A nerve impulse cannot travel across three
inexcitable nodes.
Dots the .\ervc Imjnihc Jiiinji Jrom A'odr to Node?
In 1925 Lillie (75) found that, when his iron wire
model of a nerve was covered with glass tubing broken
at regular intervals, the activation process jumped
from one break to the next. On the basis of this ob-
servation, he pointed out the possibility that the
nerve impul.se in the myelinated nerve fiber may
jump from node to node as in the model. This model
of 'saltatory conduction' has the following two fea-
tures: (a) the electrochemical changes underlying the
process of 'conduction' are localized at the 'nodes'
and (i) the time required for the conduction of the
impulse is determined solely by the rapidity of the
process at the node. In the model, therefore, the role
of the internodal segment is simply to provide an
ohmic conductance to the local circuit.
We have described the main line of evidence indi-
cating that, in the vertebrate myelinated nerve fiber,
the physiological process responsible for producing
action potentials is localized at the nodes. We have
also seen that, although the d.c. resistance of the
myelin sheath is very high, the capacity of the myelin
sheath is large enough to have a marked effect upon
the threshold of the nerve fiber measured with short
current pulses (p. 99). This capacity of the myelin
sheath, therefore, sets a certain limitation to the
analogy between propagation of the activation wave
in the iron-wire model and the actual process of
ner\'ous conduction in the mvelinated nerse filjcr.
The upper part of figure 29.I illustrates the arrange-
ment to demonstrate saltatory conduction in the
model nerve fiber. An iron wire covered \vith glass
tubings except at the ' nodes' is immersed in a bath
of nitric acid. When the wire in the passive state is
stimulated at one end, the process of activation as
HANDBOOK OF PHYSIOLOGY ^ NEUROPHYSIOLOGY I
B
^/ //////////////J^''//S^/////, j-LL.
'////''
v^y-ri^
Iz
I I a/.
r -►
4 Ql2 mite
FIG. 29. A. Time courses of the longitudinal current at two points in one internode of Lillie's salta-
tory nerve model. [From Franck (35).] B. Time courses of the longitudinal current recorded at two
extreme ends in one internode of a frog nerve fiber. Stimulus at E. [From Hodler ei al. (64).]
recognized by color changes and bubbling on the
surface spreads from node to node. The trace repro-
duced in the figure is the time course of the longitudi-
nal current taken from a recent article by Franck (35).
Since the glass tubing is a perfect insulator of elec-
tricity, the time courses of the longitudinal currents
recorded at two different points in one internode are
undoubtedly the same.
Figure 29^ shows a corresponding observation on
the real myelinated nerve fiber. By the arrangement
illustrated at the top, the longitudinal current is re-
corded at two points in one internodal segment. As
can be seen in the tracing below, there is a large dif-
ference between the longitudinal currents recorded
at two points which are about 1.5 mm apart in this
case. The difference between the two longitudinal
currents represents the double peaked membrane cur-
rent recorded through the myelin sheath (fig. 11 A).
We see in figure 2(jB that the two longitudinal
currents recorded at two different points in one
internode rise at different rates, reach the peaks at
different moments and fall at different rates. This is
a direct consequence of the existence of a large capaci-
tative flow of current through the myelin sheath.
Like a signal travelling along a submarine cable, the
longitudinal current spreads along the axis cylinder
at a finite rate.'" Because of this slow spread of the
membrane potential (cf. p. 100) and of the longi-
'" A different viewpoint is stated in a previous paper by
Huxley & Stampfii (66). The slight difference between
their experimental results and the results described in the text
is probably due to their use of a high input resistance in their
amplifier which tends to lower the time resolution in recording
[cf. footnote on p. 11, Tasaki (124)].
tudinal current along the internode, it is not legiti-
mate to state that a nerve impulse jumps from node
to node without spending any time in the internode.
This point has been stressed in an article by Hodler
et al. (64) [cf. also Stampfli (i 14)]. It has been pointed
out (125) that the major portion of the temperature
dependence of the conduction velocity (Qio of about
1.8) can ije attributed mainly to a change in the
cable properties of the nerve fiber [cf. also Schmitt
C106)].
Field of Piitential Produced by a .\enr Impulse
We have discussed in the preceding section the
field of potential produced in the surrounding fluid
medium by a nerve impulse travelling along a uni-
form invertebrate nerve fiber. Because of the struc-
tural discontinuities along the myelinated nerve
fiber, the statements made in the preceding section
are not in a strict sense applicable to the myelinated
nerve fiber. However, there is a special case in which
the effect of the discontinuities is very small.
Let us consider the case in which a single nerve
fiber of a uniform diameter is enclosed in a glass
tubing of a uniform diameter filled with Ringer's
.solution (as in fig. 25.-1). In this ca.se, the longitudinal
current at one point along the fiber is equal in in-
tensity and opposite in sign to the current flowing
through the medium at the same point. From the
argument described in the preceding section, it is
found that the spatial distribution of the potential
along the fluid medium in the glass tubing is a mir-
ror image of the potential inside the axis cylinder,
its absolute value being determined by the ratio of
CONDUCTION OF THE NERVE IMPULSE I I I
the resistance per unit length of tlie outside fluid to
that of the axis cylinder (equation 9-3). This field of
potential travels along the fiber at the average ve-
locity of the impulse. Insofar as one disregards the
variations in the potential that occur within one
internodal distance (about 2 mm) or within one
internodal conduction time (about o. i msec), the
potential field produced by a myelinated nerve fiber
in the fluid medium is similar to that produced by a
uniform invertebrate axon.
The distribution of the potential on the surface of
a uniform nerve trunk produced by a nerve impulse
travelling along a single nerve fiber in the trunk can
be regarded as analogous to the case described above.
To the approximation that the potential variations
within 0.1 msec, are disregarded, therefore, the
principle of 'diphasic recording of the action poten-
tial' described in the preceding section is applicable
to this case. A further discussion on this problem can
be found elsewhere (124). Frankenhauser (36),
Hodler el al. (64), Stampfli & Zotterman (i 15) and
others have investigated the details of the potential
variations occurring within one internodal conduction
time and also within one internodal length.
When a myelinated nerve fiber is immersed in a
two-dimensional or three-dimensional volume con-
ductor, the potential field produced ijy a nerve im-
pulse is very different from the field produced by an
impulse of a uniform invertebrate axon. As has been
shown in figure 1 1, strong sinks of electric current are
localized at the nodes while the sources are distributed
along the internodes as well as at the nodes. There-
fore, the time course of the potential picked up by a
recording electrode placed near one of the nodes is
expected to be very different from the record ob-
tained with the electrode on the myelin co\ered por-
tion of the fiber.
Figure 30 shows the time courses of the action
potentials recorded with a metal microelectrode
placed at various points near a node of Ranvier of
an isolated single nerve fiber immersed in a thin
layer of Ringer's solution. The vertical straight line
in the middle of the figure represents the course of
the fiber, and the center of the two concentric circles
represents the position of the node under study. It is
seen in the figure that the largest negative potential
is observed when the recording electrode is placed in
the immediate neighborhood of the node. The ampli-
tude of the negative component of the action poten-
tial decreases as the distance from the node increases,
and this decrease is roughly independent of the direc-
tion in which the electrode is moved awav from the
FIG. 30. Records of action potentials taken with a small
metal electrode placed around a node of Ranvier. The nerve
fiber was immersed in a shallow layer of Ringer's solution.
The vertical line represents the nerve fiber, and the center
of the two concentric circles the node under study. The im-
pulse travels downward. Five records on the vertical line were
taken with the electrode along the fiber and slightly to one side.
Other nodes of the fiber were not exposed in the operated
region of the preparation. The conduction distance was about
45 mm. Temperature, 2o°C. [From Tasaki (137).!
fiber. For further details of this experiment see Tasaki
(124).
Conduct uin in a Polarized Nerve Fiber
When a direct current is applied to a nerve trunk
through a pair of nonpolarizable electrodes in con-
tact with its surface, the portion of the nerve fiber
near the anode is traversed by a continuous inward
membrane current, and the region near the cathode
is subjected to an outward membrane current. The
behavior of the nerve impulse in such ' polarized'
regions of the nerve fiber was discussed by Pfliiger
(too) more than a half century ago. A nerve fiber
modified by a constant current is said to be in an
'electrotonic' state. In order to understand the be-
havior of a nerxe impulse in the nerve fiber under
'electrotonus', it is desirable to investigate the be-
havior of a single node preparation under influence of
a constant current.
Figure 31 shows the effect of a passage of a short
rectangular current pulse upon the threshold and the
action potential of the single node. The arrangement
employed is the same as that for figure 16 (p. 94).
HANDBOOK OF PH^■SK5I,0^,Y
NEUROPHYSIOLOGY I
FIG. 3 1 . Effect of short polarizing current pulses upon the
action potential of a single node of Ranvier. The arrangement
shown in the upper part of fig. 16 was used. The action poten-
tial was initiated by a short stimulating pulse approximately i
Qejl) and 4 msec. (jighQ after the start of the polarizing pulse.
Voltage calibration, 50 mv; time marks, i msec. .\ toad nerve
liber at 1 1 °C. [From Tasaki (126).]
When a pulse of outward subthreshold current is
applied through the nodal membrane, the potential
inside the node rises above the resting level, resulting
in an upward deflection in the record. The threshold
membrane potential measured during the period of
current flow (of about 10 msec.) is nearly identical
with the level before the start of the subthreshold
pulse. In other words, a weak additional current,
which is sufficient to raise the membrane potential
from the new level reached by application of the sub-
threshold pulse to the normal threshold level, re-
leases a full-sized action potential. The membrane
potential at the peak of the action potential is also
unaff"ected by the constant current.
When the polarity of the constant current is re-
versed, a stronger additional stimulating pulse is re-
quired to raise the membrane potential to the
threshold level. The membrane potential at the peak
of the action potential is not affected by application
of a constant inward current of about 10 msec,
duration.
In the experiment just described, if one regards the
threshold for the short (additional) current pulse as a
function of the rectangular polarizing current, one
finds that the threshold is lowered by an outward
polarizing current and raised by a current of opposite
polarity. Similarly, if one measures action potentials
from the level immediately before the delivery of the
short stimulating pulse, it is found that the amplitude
is reduced by an outward (or cathodally polarizing)
current and increased iiy an inward (or anodally
polarizing) current. This is the direct, or primary
eff'ect of the polarizing current upon the threshold
and the action potential.
A long polarizing current brings about a secondary
change in the membrane. A strong maintained
cathodal polarization caused an additional decrease
in the amplitude of the action potential (cathodal
depression) accompanied by changes in the mem-
brane conductance and probably in its emf The
effect of a strong anodal polarization is somewhat ob-
scured ijy the strong stimulating current required to
raise the membrane potential up to the threshold
level. Using intact sciatic nerves, Lorente de No (77)
made an extensive investigation on the changes in
the membrane potential caused by long polarizing
currents.
Now let us disctiss in this connection the well-known
experiment iiy Erlanger & Blair (28) who in 1934
discovered the electric sign of the discontinuous na-
ture of nervous conduction in the myelinated nerve
fiber. They applied anodal polarization to the por-
tion of the nerve under the recording electrode (mono-
phasic lead) and found that, when the intensity of
the polarizing current was gradually increased, the
configuration of the action potential of a single nerve
fiber in the nerve underwent a sudden discontinuous
change. Figure 32 furnishes an example of their
record. In record B the intensity of the polarizing
current was maintained at the critical level for the
discontinuous change. The action potential showed
in one sweep a distinct notch in its rising phase, and
in the next .sweep (superposed on the same film)
FIG. 32. Changes in the configuration of a monophasic
action potential of a single nerve fiber in an intact nerve trunk
produced by anodal polarization at the proximal recording
lead. .-1. The normal spike potential. B. The spike under anodal
polarization just strong enough to block at the most accessible
node; two action potentials superposed. C. Further increase
in the polarizing current to the next critical strength. [From
Erlanger & Blair (28).]
CONDUCTION OF THE NERVE IMPULSE
I'3
the component of the action potential above the
notch dropped out completely.
They did not consider this observation as indicating
the saltatory nature of nervous conduction in the
myelinated nerve fiber. However, they correctly ex-
plained this discontinuity as being related to the
existence of nodes along the myelinated nerve fiber.
Takeuchi & Tasaki (nS) repeated this observation
on isolated single nerve fibers and obtained substan-
tially the same result.
The explanation of the discontinuous change in
the single fiber respon.se (fig. 32) is as follows. When
the threshold membrane current of the anodaliy
polarized node under the recording electrode rises
above the membrane current caused by the activity
of the adjacent node, the response of the node under
study drops out and a small potential variation arising
from the activity of the adjacent node is observed.
A further discussion on this subject may be found
elsewhere (124).
Pfliign' s Law of Contraction
The law of contraction formulated by Pfli'iger (loo)
in 1859 is at present of almost historical interest only.
To demonstrate this law one has to use a pair of non-
polarizable electrodes, e.g. long chlorided silver wires
imbedded in 2 per cent agar-Ringer's gel filled in
glass tubings or classical electrodes of the Zn-ZnS04
type. A sciatic-gastrocnemius preparation of the frog
or toad is the standard material used for this demon-
stration. When pulses of constant current (of about
10 sec. duration) are applied to the nerve trunk
through the nonpolarizable electrodes, one generally
finds that contractions of the muscle, if there are
any, occur only immediately following the onset or
following the end of the pulse but not during the
period of constant current flow. The presence or ab-
sence of contraction depends upon the intensity of
the current and also upon the arrangement of the
anode and the cathode of the stimulating electrodes
with respect to the muscle. In table 2 an example is
presented of the results of this type of observation.
The symbol -|- indicates the presence and — the
absence of a muscular contraction. The appearance
of a contraction is a sign of arrival of nerve impulses
in the muscle.
If one takes nerve impulses carried to the muscle
by a single nerve fiber as an index, one obtains a
result somewhat different from that stipulated by
the classical law. The result obtained after cutting
all but one fiber near the mu.scle is also shown in
T.\BLE 2. Demonstration of Pfliiger' s Law of Contraction
Current
Cathode-
Anode-Muscle
Anode. Cath
ode-Muscle
Intensity
(Ascending)
(Descending)
wA
Make
Break
Make
Break
4.5
+ (-)
-
+ (-)
—
6
-1-
—
+
—
18
-f-
—
-f
—
30
+
—
+
—
.52
+
-f-(±)
-f-
+ C-)
75
+ C-)
+ (±)
-1-
+(-)
98
+(-)
+
-1-
+ C±)
120
+(.-')
+ (±)
+
+(±)
144
+(-)
+ C±)
+
+(-)
166
_
+(±)
+
±(-)
188
—
+(-)
+
—
This table indicates the presence, 4-, or the absence, — ,
of a muscular contraction on make or break of long current
pulses applied to the nerve trunk of a sciatic-gastrocnemius
preparation of the toad. The orifice of the electrodes (Ag-
AgCl type) was about 6 mm in diameter and the space be-
tween the two electrodes was also about 6 mm. The resistance
of the nerve between electrodes was approximately 10
kilohms. The results obtained after cutting all the nerve fibers
near the muscle except one large motor fiber are presented
in parenthesis, and is mentioned only when it is different
from that for the whole nerve preparation.
table 2. There are more negative signs in this case
than in the case for the whole nerve trunk. This
difference arises from the situation that there are in
the nerve trunk many fibers which are situated in
different parts of the potential field (produced by the
applied current). The existence of the small motor
nerve fibers which produce slow muscular contrac-
tions (134) in the nerve trunk makes also some dif-
ference between a single fiber and a nerve trunk ex-
periment.
If one applies current pulses directly to the iso-
lated portion of a single motor nerve fiber in this
type of observation, one finds more negative signs
than in the two previous cases. In this type of direct
stimulation of a single nerve fiber, it is very difficult
to demonstrate excitation of the fiber on break of an
applied current. Break excitation which is readily
observable in the nerve trunk is evidently due mainly
to the capacities of the myelin sheath and of the con-
nective tissues. These elements in the nerve trunk
tend to generate outward membrane currents at the
nodes of the fibers on withdrawal of the applied cur-
rent.
The mechanism of anodal block of nerve conduc-
tion has been discussed on previous pages. The ab-
114
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
senceof a contraction on" make' of a strong' ascending'
current pulse in the table indicates that the nerve
impulse initiated under the cathode could not pass
through the anodally polarized region of the nerve
between the cathode and the muscle.
Effect of Narcosis upon Nervous Conduction
It has Ijeen pointed out that narcotics, such as
cocaine, urethane, ethanol and others, depress or
eliminate electric responses of the nerve fiber when
they are applied to the nodes of Ranvier of the fiber
(p. 109). The action of these chemicals, as well as
the effect of low sodium in the medium, progresses
with surprising rapidity; an equilibrium between the
single fiber and the surrounding fluid medium con-
taining these chemicals is established within one
second (68, 71, 124).
It is well known that the action of these narcotics
upon the whole nerve trunk is extremely slow and
gradual, as emphasized by Winterstein (144). Evi-
dently the time required for dififusion of the chemical
into the nerve trunk accounts for the slow action of
these chemicals upon it. The diagram in figure 33
illustrates this great difference in the rapidity of ac-
tion of urethane between the intact sciatic nerve and
O min
O
_J
CD
-:»40
I-
O
q30
Z
o
o
tr
020
b.
Q
UJ
cc.
510
o
LJ
CC
UJ 0
', SCIATIC
' NERVE
o
9
e>
©
o
\
o
^8. §
SINGLE
NERVE FIBER
o ~«
o o
I
20 2 4 6 8% 10
^ URETHANE RINGER
FIG. 33. Relation between the concentration of urethane
(abscissae) and the time required for conduction block (ordi-
nates') in a single fiber preparation (continuous line) and in the
whole sciatic nerve (circles'). [From Tsukagoshi, cited by Tasaki
in (124).]
the exposed nerve fibers. The circles in the figure
represent the times required for conduction block at
various concentrations of urethane-Ringer's solution
in intact sciatic nerves. The narcotic was applied to
a 1 5 mm long uniform portion of the sciatic nerve
of the toad, and the disappearance of muscular con-
traction was taken as an index of block. The relation-
ship between the time required for conduction block
and the concentration of urethane is given by a
smooth curve.
When a single nerve fiber preparation or a few
fiber preparations with a 15 mm long exposed region
are used in this type of e.xperiment, an entirely dif-
ferent result is obtained. For concentrations lower
than about i .8 per cent, conduction through the
narcotized region remains unblocked for an hour or
more; and for concentrations higher than about 2.2
per cent, conduction block sets in within one second.
At the critical concentration, which was appro.xi-
mately 2 per cent in this experiment, conduction
block occurs within about i minute. The relationship
between the concentration and the time required for
blocking is, therefore, given by the thick line (bending
at almost a right angle) in the figure.
We have pointed out that a nerve impulse can
jump across one or two complete inexcitable nodes.
If one reduces the length of the narcotized region
down to about 5 mm or less, a longer time is required
to block conduction since time must be allowed for
diffusion of the narcotic along the nerve. This fact
was once taken as evidence for ' decremental conduc-
tion' in the narcotized region of the nerve (23, 69,
82).
Narcotizing solutions of below the critical concen-
tration applied to a node raise the threshold and lower
the amplitude of the response. The magnitude of this
narcotizing effect depends on the concentration used.
Based on the experimental data on the effects of
narcosis on single nodes, it is possible to explain
nianv phenomena related to narcosis of the nerve.
The detail of the accounts along this line may be
found elsewhere (124).
.\FTER-POTENTL^LS .^iND RHYTHMICAL .\CTIVITY
We shall devote this section to two subjects which
are less clearly understood at present than tho.se
previously discussed, namely after-potentials and
rhythmical activity of the nerve fiber. The relation-
ship between after-potentials and rhythmical activity
CONDCCTION OF THE NERVE IMPULSE
is not a direct one, but in some cases they are clearly
related to each other.
After-Piilentials
The term ' after-potential' was introduced by Gasser
and his associates [cf. Gasser & Erlanger (38); Gas-
ser & Graham (39)] to describe the small, slowly
declinina; potential change that follows the large,
short 'spike-potential' in the monophasic action po-
tential of a nerve trunk. The records furnished in the
left column of figure 34 show monophasic action
potentials of the nerve trunk taken at slow sweep
speeds. The action potential of A-fibers (top) shows
very little after-potentials, but the responses of B-
and C-fibers manifest large after-potentials following
the sharp spike-potentials. These potentials were re-
corded with extracellular electrodes (fig. i) from three
different nerve trunks of the cat.
Let us ne.xi discuss the after-potentials recorded
from single fiber preparations. In the right-hand
column of figure 34 are shown the time courses of
the action potentials of three different kinds of e.\-
citable elements. An upward deflection in these
records represents a rise in the intracellular potential
(referred to the potential of the surrounding fluid
medium). The 'retention' of a higher potential level
Mf
I... I..
.I...I...I.
Tiiiec
50
msec
200 msec
FIG. 34. After-potentials in nerve trunks Qejl) and in single
fibers (right). A. Response of mammalian .-X-fibers. B. Re-
sponse of mammalian B-fibers. C. Response of mammalian
C-fibers. [The three records on the left are from Grundfest
(43)-] ^J' Action potential of a toad muscle fiber, recorded
intracellularly. Nf. Response of a toad nerve fiber poisoned
with veratrine. Sf. .Action potential of a squid giant axon.
Time marks on the right in msec.
in the upper two records is often called a ' negative'
after-potential, because an action potential was con-
sidered in the classical physiology as a " negative'
variation of the potential of the nerve surface (cf. p.
105). Evidently, the term 'negative' after-potential is
at present confusing and inadequate.
The after-potential of the frog (or toad) muscle
fiber (fig. 34, right top) seems to decay roughly at
the time constant of the membrane (30). This after-
potential is not associated with any measurable change
in the membrane resistance. These facts suggest that,
following one whole cycle of activity of the muscle
fiber membrane, there is an excessive charge of elec-
tricity remaining in the large capacity of the mem-
brane and this charge is dissipated through the mem-
brane resistance. In the nodal membrane of the toad
(or frog) nerve fiber, the time constant of the mem-
brane is far shorter than the duration of the spike
potential (table i, p. 89); therefore, an after-poten-
tial of this type does not exist in the amphibian nerve
fiber.
The after-potential of the frog nerve fiber shown in
figure 34, right center, was induced by poisoning the
fiber with veratrine, an alkaloid which is known to
cause rhythmical activity in the mu.scle and nerve.
Gasser & Graham (39) have shown that this chemical
greatly enhances the (negative) after-potential of the
nerve trunk. The after-potential of this type is asso-
ciated with a concomitant decrease in the membrane
resistance (108, 133).
The after-potential in the squid giant axon i.fig. 34,
right bottom) is often referred to as an 'undershoot':
the membrane potential stays, after the end of the
main spike potential, below the initial level of the
resting potential. As we have seen in the record of
figure 12, this after-potential is associated with a
pronounced decrease in the membrane resistance.
Grundfest el al. (45) found that there is a phase of
slightly increased membrane impedance following the
period of decreased membrane impedance. In the
sodium theory (p. 118), the undershoot in the squid
giant axon is attributed to an increase in the potas-
sium permeability of the membrane.
The nature of the after-potentials in B- and C-
fibers in the vertebrate nerve is not clear. Further
discussions on the after-potentials of the nerve trunk
are found in the monograph bv Gasser & Erlanger
(38).
Rhythmical Activitj!
In excitable tissues in living organisms, action po-
tentials appear, as a rule, in more-or-less rapid sue-
lib
HANDBOOK OF PHVSIOLOGV
NEUROPHVSIOLOCi' I
cession. Thus motor nerve cells in the vertebrate
spinal cord discharge impulses repetitively over a
wide rang;e of frequency depending; on the state of
the cell. Similarly, sensory nerve fibers carry a series
of impulses toward the spinal cord in response to
sensory stimuli delivered to their endings. There is
at present a large amount of data concerning the
pattern of impulse discharge obtained by the method
of recording single fiber responses originated by
Adrian (3, 4).
In many excitable tissues, application of a long
constant current generates a train of action potentials,
as shown by Arvanitaki (8), Fessard (33), Erlanger &
Blair (29), Katz (72) and others. The records fur-
nished in figure 35 show repetitive firing of action
potentials in the .squid giant a.xon induced by con-
stant outward membrane currents of four different
intensities. The stimulating pulses are sent into the
a.xon through a long intracellular metal wire elec-
trode, and the responses are recorded with another
intracellular electrode. It is difficult to maintain
repetitive firing indefinitely under these experimental
conditions. It is to be observed that each action po-
tential is preceded by a slowly rising phase of the
membrane potential. This slowly rising phase has
been demonstrated at the sites of naturally induced
repetitive responses in the automatically beating
cardiac muscle [cf. VVeidmann (143)].
The site at which impulses are initiated repetitively
is called a 'pacemaker'. At present, it is not clear how-
sensory nerve endings or the motor nerve cells become
pacemakers. However, there is one thing that can be
inferred from the mechanism of the nervous conduc-
tion in the peripheral nerve fiber. As has been dis-
cussed on previous pages, nervous conduction is ef-
fected through excitation of each segjment (or node
of RanvierJ l)y the electric current generated b\ the
adjacent active segment. From this one can infer that
a sensory stimulus or a natural stimulus for the motor
nerve cell has to be transformed eventually into an
electric stimulus in order that it initiates a propagated
impulse. (If the size and shape of the electric current
generated by a sensory stimulus are similar to those
of the ordinary action current, the statement just
made has no meaning; however, it is generally ac-
cepted that the first electrical sign of the response to
a sensory stimulus is variable in size and very differ-
ent from the ordinary all-or-none response.) Since a
constant current applied to a peripheral nerve fiber
can gi\'e rise to a repetitive firing of impulses, it is
generally believed that natural pacemakers resemble
in some respect an artificial one induced i)y applica-
tion of a constant current (fig. 35).
The mechanism of repetitive firing proposed by
Adrian (3, 4) to interpret the injury and sensory dis-
charges of impulses is as follows. An electric stimulus
of a constant intensity sets up the first action potential
in accordance with the law of electric excitation.
Then, the nerve fiber falls into the refractory period
which makes the stimulus totally ineffective. As the
fiber recovers from this refractoriness, the stimulus
becomes effective again and the second action po-
tential is set up. The second response leaves behind
it another refractory period. The nerve fiber thus
exhibits a kind of oscillatory phenomenon similar to
that in a neon lamp connected to a battery, a con-
denser and a resistor.
It is simple to express Adrian's concept in terms of
the membrane potential and the threshold depolariza-
tion. At the beginning of the refractory period, the
critical membrane potential is close to the level of
the shoulder of the action potential (see fig. 20).
FIG. 35. Repetitive firing of action potentials in a squid giant axon. The relative intensities of the
stimulating currents used are indicated by the broken lines. Both stimulating and recording elec-
trodes were long intracellular metal wires. [From S. Hagiwara e! al., unpublished.]
CONDUCTIOiN OF THE NERVE IMPULSE
11/
During the relatively refractory period there is a con-
tinuous recovery in the threshold membrane potential.
This concept of Adrian seems to explain many facts
known al:)out repetitive firing. In tissues with a time
constant which is much longer than the duration of
the action potential, however, not only the recovery
process, but also the time required to charge the
membrane capacity is considered to influence the
rhythm of repetitive firing (54). It is also known that
the oscillation in the membrane potential at sub-
threshold levels (8, 9) plays an important role in
production of rhythmical activity in some tissues.
In connection with the pacemaker mechanism,
there is an interesting phenomenon which seems to
deserve a short discussion. That is 'resetting' of the
rhythm of the repetitive response by an ' extra im-
pulse' reaching the pacemaker. In 1936 Gilson (41)
examined the effect of an artificial (electric) stimula-
tion of the sinus of the turtle heart upon the rhythm
of the heart beat. He found that the time interval
between the artificiallv induced response and the
following (natural) response is approximately equal
to the normal inter\'al of the automatically induced
responses, regardless of the interval between the
artificially induced respon.se and the preceding one.
Similar phenomena have been demonstrated in
natural and artificial pacemakers in the sensory
nerve fiber and in the motor nerxe fiber [cf. Tasaki
(121)].
CURRENT THEORIES OF THE RESTING .-^ND
.ACTION POTENTI.ALS
In the last section of this chapter, we shall briefly
discuss the current theories dealing with the mecha-
nism whereby the resting and action potential of the
nerve or muscle fiber is generated. This problem has
been extensively and authoritatively reviewed by
many recent inv estigators in a svmposium Electrochemis-
try in Biology and Medicine, edited by Shedlovsk\- (l 1 1).
The great variety of the views maintained by recent
investigators toward the present problem indicates
that the current theories to be described below are
not yet accepted as unequivocal. We shall make an
attempt to explore the sources of equivocalities and
controversies in the present problem.
Resting Potential
Twenty years before the turn of the century,
Biedermann (12, p. 354) discovered that application
of an isosmotic potassium chloride solution to a por-
tion of a muscle generates a large potential difference
between the site of application and the remaining
surface of the muscle. Later, Hober (49) extended
this observation and found that the ability of various
cations to affect the resting potential of the muscle
increases in the following series: Li, Na, Mg, Cs,
NH4, Rb, K. Hober found also that the correspond-
ing series for anions is CNS, NO3, I, Br, CI, acetate,
HPO4, SO 4, tartarate.
In 1902 Bernstein (10) published the .so-called
' membrane theory' in which he postulated a) that
the resting potential is pre-existent at the plasma
membrane of the cell (prior to injury or application
oi potassium salts), and h) that the resting potential
is maintained by virtue of the semipermealsility of
the plasma meinbrane. At that time, the pre-existence
of ions in the electrolyte solution (Arrhenius, 1883)
was known, and osmotic phenomena in the mem-
brane of some plant cells and in artificial membranes
(Pfeffer, 1877) were also well understood. Nernst's
book on theoretical chemistry dealing with concentra-
tion cells had just appeared at that time (1900).
A present, there is no doubt about the validity of
the membrane theory in the form described above.
There are in Bernstein's theory two additional postu-
lates. He speculated that the resting potential is a diffu-
sion potential resulting from the difference in the mo-
bility of potassium and phosphate ions through the
membrane and also that the action potential is caused
by a reduction of the resting potential resulting from
a nonspecific increa.se of permeability of the mem-
brane during activity.
Later on, a large volume of work was published
showing that, within a certain limit, the relationship
between the resting potential, Er, and the external
potassium concentration, [K]o, can be expressed by
the Nernst equation
E, = 58 los r— r ^'"^'^
(.2-0
where [K]i represents the concentration of potas-
sium in the protoplasm (7, 55, 68, 76, 94). However,
the validity of equation (12-1) does not by itself
prove that the process of diffusion of potassium ions
is responsible for the resting potential.
Equation (12-1) represents the theoretical maxi-
mum (absolute) value of the resting potential that
can be attained if the concentration gradient of
potassium were the cause of the resting membrane
potential. If, therefore, it happens under any circum-
HANDBOOK OF PHYSIOLOGV
NEUROPHYSIOLOGY I
Stances that the observed membrane potential ex-
ceeds the value given by equation (12-1), one is
forced to believe that the resting potential is gener-
ated primarily by some electrochemical mechanism
other than the diffusion of the potassium ion. This
type of evidence against the potassium theory has
been expressed by several in\estis;ators though not
in a written form until the recent work of Shaw et al.
(109)-
The electrochemical nature of the plasma mem-
brane is not yet clearly understood. Osterhout (94),
Beutner (ii) and others assume that the resting
potential is maintained across an oil (nonaqueous)
layer. Teorell (139), SoUner (112) and others have
developed the concept of a charged porous mem-
brane as the site of bioelectric potential. .Shedlo\'skv
(iio) stressed the asymmetry of the membrane with
respect to two surfaces and the possible role of protons
in generation of the bioelectric potentials.
To explain the divergence of the obser\ed resting
potential from the Nernst equation, Hodgkin (55)
used the modified Goldman equation (42). There is
.some doubt as to the applicability of this equation
to li\ing cells, because of the assumption of a uniform
field (i.e. no charge in the membrane) adopted in
deriving this equation (139, p. 338). Boyle & Conway
(17) found that the ratio of chloride across the muscle
fiber membrane is close to the ratio [K]o/[K], and
argued that the resting potential of the skeletal
muscle fiber is a Donnan potential. There are, how-
ever, some arguments against this notion (44).
Actum Poleiilial
There is at present only one widelv accepted
theory of action potential production. That is the
so-called sodium theory postulated by Hodgkin &
Huxley (57, 58, 59). Previously Nachmansohn
(89) advanced a theory in which acetylcholine is
assumed to play a decisive role in action potential
production. Recently, however, he shifted his effort
toward an attempt to supply a biochemical basis
for the sodium theory (90).
This theory started with the de\elopmcnt of the
modern technique of recording and controlling the
intracellular potential. When it was found that the
amplitude of the membrane action potential is sub-
stantially larger than the resting potential across the
memjjrane (p. 84), physiologists realized that Bern-
stein's postulate as to the origin of the action potential
(p. 117) is incorrect. The finding of Hodgkin &
Katz (62^ that the amplitude of the action potential
of the squid giant axon varies with approximately
58 mv times the logarithm of the concentration of
sodium in the external medium (p. 93) has led
the.se British physiologists to postulate that the mem-
brane potential at the peak of acti\its- is determined
by the concentration gradient of the .sodium ion
across the axon membrane. (According to this pos-
tulate, the amplitude of the action potential should
vary with 58 m\- times the logarithm of the intracel-
lular concentration of sodium; however, it is difficult
in practice to alter the sodium concentration in a
wide range.)
Hodgkin & Huxley (59) elaborated this concept
further and explained the mechanism of action po-
tential production by assuming that the increase in
the membrane conductance during activity (p. 89)
is a specific increase of permeaijility to sodium ions.
They tried to substantiate this idea by voltage clamp
experiments (p. 91). Their success in reconstruct-
ing the action potential from the data obtained by
the voltage clamp technique is often regarded as
sufficient proof of the sodium theory.
The diatjram in figure 36, right, shows the equiva-
lent circuit of the excitable membrane postulated in
the theory. When the membrane is at rest, the con-
ductance of the membrane is maintained by the per-
meabilit\' of the membrane to potassium ions; i.e.
gK » gsii! where gk is the 'potassium conductance'
and g^a the 'sodium conductance' of the membrane.
This situation should iiring the potential of the
resting membrane close to E^i which is defined by
equation (12-1). E^ia in the diagram represents the
'sodium equilibrium potential' defined ijy the equa-
tion of the type of equation (12-1) for the sodium
ion; the polarity of E^., is opposite to that of Ek- If
g^:, increases at the peak of activity to a \alue well
aboN'e gK, the niemljrane potential should approach
RESTING
+- + -»- 4-
RESTING
+ -1- + + + +
+ + +-
_
ACTIVE
REGION
-1-
+ + + *-^
FIG. 36. Right. ■ The equivalent circuit proposed by Hodgkin
& Hu.xley to represent tiie membrane of the squid giant
axon. Left: The state of an axon carrying an impulse proposed
by the same authors. The signs 4- and — indicate the electric
charges on the capacity which are assumed to determine the
membrane potential. Note that this concept of charges on the
condenser determining the membrane potential is inapplicable
to the circuit diagram of fig. 9C.
CONDUCTION OF THE NERVE IMPULSE
"9
E^,,; this explains the reversal of the membrane poten-
tial during activity. If ^^a is increased to some extent
b\ a stimulating current pulse, a further increase in
gif., can be brought about by a regenerati\e process;
an increase in ^^a causes a rise in the memijrane
potential which in turn gives rise to a further increase
in gf^i,. The theory is self-consistent. The readers who
are interested in this beautiful scheme are referred to
the original article (59).
It may be worth pointing out that there are in the
sodium theory a number of assumptions that are not
directly proved by experiments. They assume in the
first place that the axon membrane under voltage
clamp is spatially uniform; this may not be a safe
assumption. They assume also that the capacit\- of
the membrane is connected in parallel to the cmf of
the membrane (p. 85). They did not exclude the
possibility that the sodium ions bound in the sub-
stance of the membrane (instead of the free sodium
ions in the medium) exert direct influence upon the
amplitude of the action potential. There are several
more assumptions in the theory. Although most of
these assumptions appear to be reasonable, it is also
true that one can make a set of entirely difTerent
assumptions and explain almost the same amount of
experimental data.
There is at present a large volume of work dealing
with the movement of sodium or potassium ions
across the excitable membrane. The principal findings
pertinent to the discussion in this chapter are a) a
steady outward current through the axon membrane
is carried almost exclusively by potassium ions (60),
and b) there is an exchange of intracellular potassium
with extracellular sodium associated with repetitive
excitation of the axon (74). It is generally agreed that
the amount of the Na-K exchange associated with
repetitive excitation observed in invertebrate axons
is close to the \alue expected from the sodium theory.
It should Ije kept in mind in this connection that
there are excitable tissues which do not require any
sodium ion in the medium to produce action potentials.
Crustacean muscles studied by Fatt & Katz (31)
are a well-known example, and the plant cell, Nilella,
investigated by Osterhout and his associate (93, 94)
is another. This fact suggests that the role of the
sodium ion in the medium inight be only indirectly
connected with the process of action potential pro-
duction. The alternatis'e explanation of this fact is
that the mechanism of action potential production is
verv different in difTerent tissues.
The author wishes to express his gratitude to the following
colleagues who have kindly read the manuscript of this chapter
and have given many important suggestions; Dr. M. Fuortes,
Dr. S. Hagiwara, Prof. A. L. Hodgkin and Dr. C. S. Spyro-
poulos. The manuscript was prepared with the valuable help
of Mrs. Mary Allen, Mrs. Claire Mayer and Mrs. Lydia N.
Tasaki, to whom the author also wants to express his apprecia-
tion.
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CHAPTER IV
Initiation of impulses at receptors
J. A. B. GRAY I Department oj Physiology, University College, London, England
CHAPTER CONTENTS
General Properties
Type of Energy Required to Excite Receptors
Adaptation
Receptive Fields
Information
Repetitive Responses and Tonic Receptors
Stimulus-Frequency Relations
The Effect of a Reduction of Excitation
The Nature of Repetitive Firing
Modification of Afferent Discharges by Current
Excitation of Impulses by Controlled Pulses and Phasic Re-
ceptors
Quantitative Aspects of Excitation
On and Off Responses
Summation
Receptor Potentials and Other Generator Potentials
Generator Potentials in Complex Organs
Receptor Potentials Generated in Nerve Terminals
Relation of Receptor Potentials to Impulse Initiation
Quantitative Relations between Stimulus and Receptor
Potential
Absolute Magnitude of the Receptor Potential
Summation of Receptor Potentials
Depression
Site of Impulse Initiation
Effect of Procaine and Sodium Lack on Receptor Potentials
Transmission of Energy to the Receptor Elements
Effects of 'Transmitter' Substances
Action of Acetylcholine
Action of Blocking Agents and Anticholinesterases
Effects of Sympathetic Stimulation and Epinephrine
Other Substances
Minute Structure of Receptors
Hypotheses Concerning the Mechanisms of Receptors
IN THE INTACT ORGANISM impulses are set up in pri-
mary afferent fibers as a result of activity in those
receptors with which the fibers are associated. These
receptors may consist solely of specialized termina-
tions of the afferent nerve fibers, or the nerve endings
may be associated with other cells which play a
significant role in the initiation of impulses. In either
instance, the role of the receptor is to record the
state of, or changes in, the physical or chemical en-
vironment by the initiation of impulses which are
then conducted in the primary afferent fibers to the
central nervous system. A primary afferent fiber may
be connected with a single receptor or with many;
but even when it is supplied by numerous receptors,
a single afferent fiber remains a single channel into
the central nervous system and must be considered as
such. When dealing with the activity in such a fiber
it is necessary to consider the fiber and all its periph-
eral connections as a whole, that is as a sen.sory unit.
It is the purpose of this section to consider something
of the general behas'ior of sensory units and of the
mechanisms by which indi\idual receptors initiate
impulses in the primary afferent neurons.
GENERAL PROPERTIES
A few words should first be said concerning classi-
fication. Sensory units can be described by reference
to the properties of the specific stimulus, the nature
of the activity and the site and distribution of the re-
ceptive field. All these factors, together with the con-
duction velocity of the fiber, are measurable quanti-
ties and a precise description of a sensory unit is thus
possible. It seems better in this context to avoid terms
such as warmth, pain or red; these terms describe
sensations which depend on the activity of the whole
nervous system, not just on the properties of one
sensory unit.
Type of Energy Required to Excite Receptors
In most animal organisms there are receptors that
respond to the following forms of energy: mechanical,
123
[24
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
thermal, electromagnetic (as light) and chemical.
With the exception of one important group, it ap-
pears that nearly all receptors are especially sensitive
to one form of energy and either completely or rela-
tively insensitive to all others. The excepted group
consists of those receptors that have a low sensitivity
to all types of energy, but will respond to any form
of energy that reaches a damaging or near damaging
level; these receptors are of course those that give
rise to defensive reflexes and are associated with the
sensation of pain. The specificity of receptors to a
particular form of energy was first propounded in
modern times by Miiller (76). As a whole this con-
cept is not seriously challenged, but recently an
attack has been made on its application to receptors
situated in the skin (99). The objections are based
both on the finding that there are areas of human
skin in which morphologically specialized endings
are not found but from which all modalities of sen-
sation can be elicited (39), and on the results of
certain sensation experiments (65, 66). There need
be no rigid correlation between morphological and
functional specializations; it is indeed interesting to
note that the bulk of the direct evidence for the func-
tional specificity of sensory units has come from
preparations of frog and toad skin which contain
few morphologically differentiated nerve endings
(24). As regards to sen.sation experiments it must be
realized that sensations are the end result of compli-
cated processes and that such experiments, while
giving information about sensations and their specific-
ity, cannot weigh heavily against direct evidence on
the properties of sensory units.
Direct evidence of the specificity of units has been
obtained by recording the responses of single ones to
different stimuli. In the earlier experiments of this
type single fibers were not isolated in an anatomical
sense, but small bundles of nerve fibers were used so
that the activity of indi\idual units could he identi-
fied and analyzed; using this technique it was possible
to show that therrnal and near-damaging stimuli
only excited activity in small fibers and did not
produce activity in the larger fibers which responded
only to mechanical stimuli (2, 50, 103, 104). This
type of work has now been carried a stage further by
isolating and recording from single afferent fibers
that have their receptive fields in the skin of toads and
of cats (73). Results of such experiments show that
mechanically sensitive units are not easily excited by
thermal stimuli [though this has been shown to hap-
pen in the cat's tongue (45)] or by acid; that ther-
mally sensitive units do not normally respond to
mechanical stimulation [the rattlesnake pit organ is
an exception (15)]; and that units responding to
acid, prick or burning do not respond to small
mechanical or thermal stimuli.
The specificity of sensory units is not confined,
however, to a simple distinction between different
types of energy but involves distinctions between
other properties of the stimulus. Of these properties,
those connected with its time course are perhaps the
most obvious; the different rates of adaptation ex-
hibited by different units is an example which will
be considered again. .Specificity to a particular band
of frequencies of a periodic function is another ex-
ample; thus there is evidence that different units in
the retina respond to different frequencies of light
waves (31, 91) and that primary units from the
mammalian cochlea have particular characteristics
in relation to the frequency of the sound waves (93).
In both these instances the sensory units are display-
ing a specificity, ijut there is clearly a difference in
the way this specificity is brought about. In the
retina it seems probable that individual receptors are
different, but in the cochlea it is the mechanical
properties of the system that are mainly responsible
for the results. Such a distinction between the proper-
ties of the receptor and the properties of the support-
ing tissues is one that ari.ses in other situations but is
one that is irrelevant in the context of describing the
properties of sensory units. The examples of specificity
so far given in this paragraph are concerned with
time factors, but there are others. Thus there are
two types of thermal unit found in the cat's tongue;
in both types the frequency of the impulse discharge
depends on the temperature of the receptors, but in
one group the maximum frequency is found at a
temperature of 30 to 32 °C (46), while in the other it
occurs at 37.5 to 4o°C (22). Again, units in the cat's
tongue responding to chemical stimuli, and pre-
sumably responsible for the sensation of taste, can
be grouped in respect to the substances that are able
to set up activity in them (82).
Adaptation
When a piece of tissue containing a receptor sensi-
tive to mechanical stimuli is subjected to an abrupt
increase in the forces applied to it and the new situa-
tion is then maintained, the sensory unit will dis-
charge impulses at a frequency, which starts at a
relatively high value and then decreases with time
(4, 74, 75) (fig. i). This decline in frequency is known
as adaptation and may be slow or rapid. In those
INITIATION OF IMPULSES AT RECEPTORS
12-
units that are described as tonic, the frequency of
the impulse discharge declines relatively slowly to a
steady value which is characteristic of the applied
force (fig. i); the frequency of the discharge from
other units, those called phasic, adapts more rapidly
and finally falls to zero (5). In an extreme case a
sensory unit may only discharge a single impulse
during the change in the applied forces and will
then remain silent until another change takes place.
Adaptation is also observed in sensory units specifi-
cally sensitive to forms of energy other than mechani-
cal.
Adaptation is a word that describes the response of
a sensory unit to a particular function of the type of
energy concerned. When adaptation is rapid, it can
be said that the unit is not signalling a pressure, a
temperature or a concentration; but it does not tell
us what particular function in respect to time is
signalled.
To say that a function is signalled means that a
constant value of the function gives rise to a constant
and repeatable frequency of impulse discharge in the
fiber of the sensory unit. In most situations it is very
difficult to maintain a constant velocity or accelera-
tion for a sufficiently long time to see whether or not
a constant frequency of discharge is in fact set up
[a notable exception has appeared in the experiments
on the semicircular canals using constant angular
velocities and accelerations (72)]. Even if such ex-
periments were performed it is by no means certain
that simple relations would be found. This is there-
fore a situation in which it is necessary to continue to
use an empirical description.
It should be noted that in the first sentence of this
section, reference is made to the tissue surrounding
the receptors. Even in the instances in which a recep-
tor has been isolated, e.g. the muscle spindle and
Pacinian corpuscle, there is far more supporting tis-
sue than active element. These supporting tissues
may be of fundamental importance in the adapta-
tion of 'simple' receptors in the same way as the
structures of the middle ear and cochlea cause
'adaptation' of the ear to steady pressures applied
to the tympanic membrane. This problem will be
considered at a later stage when all the relevant
evidence has been discussed.
Receptive Fields
A sensory unit has a particular situation and par-
ticular size of receptive field, i.e. the area from which
the single afferent fiber receives branches. The size
of these receptive fields can vary quite considerably,
for example up to 9 by 5 cm, not mm, in cat's skin
(73) and up to 100 sq. mm in frog's skin (3); while
other sensory units have receptive fields which com-
prise only a single end organ. Variation of size of re-
ceptive fields occurs with different types of unit in
skin and also in specialized organs such as the eye.
There is wide overlap of receptive fields and it is
clear that spatial discrimination must depend on the
coordination of information supplied through a con-
sideraljle number of primary channels.
FIG. I. Response of cat muscle spindle to stretch. Abscissa:
time in sec. Ordinate: impulses frequency per sec. Each curve
for a diflferent force. [From Matthews (75).]
Information
Sensory units constitute independent channels
which signal to the central nervous system informa-
tion about the physical and chemical environment of
the organism. This information is conveyed by the
pattern of activity in any one unit and by the charac-
teristics and organization of each channel. These
factors can be classified as follows:
a) Factors related to time
i) Interval between impulses
ii) Duration of activity
h) Factors related to the properties of units
i) Characteristics of the 'normal' stimulus,
e.g. the nature of the energy and other
relevant factors
ii) Size and position of the receptive field
iii) SensitivitN' of the unit
i->6
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
REPETITIVE RESPONSES AND TONIG RECEPTORS
Stimulus-Frequency Relations
There are many sensory units, the function of
which is to signal to the central nervous system the
properties of a steady state, e.g. temperature, con-
centration or intensity of illumination. At any time,
except shortly after an aljrupt change from one state
to another, the frequency of the impulse discharge
of the unit will depend on the value of the physical
or chemical function in question; and a particular
frequency will, in the working range of any one unit,
be consistently related to a particular value. One
example is seen in figure 2 where the frequency of
impulse discharge in five single fibers from pressure
receptors of the carotid sinus is plotted against pres-
sure in the sinus. Another example appears in figm-e
22 of Chapter XVIII on Thermal Sensations in this
volume (p. 452), in which the impulse frequencies in
two units from the cat's tongue responding to thermal
stimuli are plotted against temperature. The curves
in the two figures are clearly quite different; the
pressure units, while showing individual variations,
all start to fire at a certain pressure above which the
frequency of discharge increa.ses as the pressure in-
creases until an upper limit of frequency is reached
(12, 60). The temperature units on the other hand
both show maxima in their temperature-frequency
relationship, but these maxima occur at two widely
different temperatures. The two types of response
represent the activity of two distinct groups of units
found in cats (22, 46) and it is presumed that the
FIG. 2. Responses of five single pressure sensitive units QA
to £) from the cat's carotid sinus. Abscissa: intrasinusal pres-
sure in mm Hg. Ordinate: impulse frequency per sec. [From
Landgren (60).]
activity of these two types of unit bears a close causal
relationship with the subjective sensations of cold
and warmth.
Looking at the two examples shown, it would seem
improbable that any relationship between 'stimulus'
and frequency having general relevance to sensory
units of all types could be found. This is strictly true,
but there is a relationship that has been found to de-
scribe reasonably well the response characteristics of
certain types of unit in their working range. This is
what is known as the Weber-Fechner law. This law
derives from an observation made by Weber that the
smallest difference in the weight of two objects bears
a constant relation to the weight of the objects. It is
usually given as AI/I = C, where / is intensity of
stimulus. A/ the smallest detectable difference in
intensity and C a constant. Fechner developed this
observation in a theoretical way by making the as-
sumption that each discriminable step of stimulus
intensity corresponds to a imit increase in sensation,
that is to say he stated that AI/I = kAS where AS
is the increase in sensation. From this it follows that
d5/d/ = I /k/ and S = a log / + A. This equation
was originally put forward in an attempt to quanti-
tate .sensation, a thing we are not concerned with
here; howe\er, we are concerned with its relevance
to 'stimulus' -frequency relations. The relation be-
tween the applied force and impulse frequency re-
corded from a frog's muscle spindle has been found
to be consistent with this relationship (95). The cor-
responding relationship between intensity of illumina-
tion and response from an ommatidium of the eye of
Limiilus is also consistent with the equation under
certain specific conditions (41). These findings have
inevitably raised the question of whether this rela-
tionship indicates anything about the mechanisms
invoked in the initiation of impulses or whether it
must be regarded simply as an empirical description
(31). The fit between equation and experiment is not
sufficiently good to suggest that the fundamental
processes depend on a simple logarithmic relation-
ship, but if, as seems possible, the.se processes are
related to ionic equilibria across cell membranes, a
logarithmic term might he expected to appear in the
relationship.
Effect fij a Reduction oj Excitation
It has already been pointed out that while a tonic
sensory unit will respond to a certain steady state
with a certain frequency, a sudden increase in, for
INITIATION OF IMPULSES AT RECEPTORS
127
instance, the applied force will cause a relatively large
increase in the frequency of the discharge, an increase
which will then decline until the correct frequency
for the new steady state has been reached. A similar
process occurs if there is a sudden decrease in, again
for instance, the applied force. In this instance the
frequency falls abruptly to a value below that ex-
pected for the new steady state and then increases
with time. Thus, if a muscle spindle is discharging
rhythmically and the muscle in which it lies is
stretched for a time and then suddenly returned to
its resting length, the frequency of the discharge from
the spindle falls well below its resting value, possibly
to zero; after a time the resting rhythm re-establishes
itself (75). Similar changes can be observed in other
types of unit, for example in temperature sensitive
units (46), and the pressure sensiti\e units of the cat's
carotid sinus (60). It should be noted that the beha-
vior of such units contrasts with that of phasic units
which are considered in another section below.
Nature of Repetitive Firing
Ideas on the mechanisms by which firing takes
place started with the proposals of Adrian (i). Essen-
tially these were that special nonaccommodating
regions of nerve exist at sensory nerve endings and
that repetitive activity is initiated in these regions; the
frequency of the discharge depends on the refractory
period which may be longer here than in other parts
of the nerve. Broadly speaking, work on the nature of
repetitive firing by sensory receptors has followed two
lines. The first has attacked the problem of nerve
accommodation and the other, the mechanism that
determines the interval between impulses.
Many investigations have been carried out on the
rate of accommodation of nerve and these have shown
that accommodation need not be rapid and that in
crustacean (49), amphibian (26) and mammalian
(32, 89) nerve it is in fact possible to obtain main-
tained repetitive firing during the passage of a con-
stant current. Further it has been found that most
experimental procedures tend to increase the rate of
accommodation (81); it is possible that the common
eflfect of all these procedures is to lower the membrane
potential, a reduction of which is known to increase
the rate of accommodation (94). These findings led
to the view that the mechanism of repetitive firing
from sensory receptors could be explained on the
known properties of nerve fibers. This view was
elaborated in particular by certain Scandinavian
workers (9, 30) who suggested that the receptor
develops a 'generator potential' which causes current
to flow in the nerve fiber so acting like a constant
current stimulus in setting up a train of impulses.
This idea has remained the basis of most subsequent
work on the subject.
The concept that the inter\als between the im-
pulses of a train are dependent on the rate of recovery
after an impulse is faced with the difficulty that
rhythmic discharges of very low frequency, a few
impulses per second, can be obser\ed. These intervals
are much longer than the total duration of the re-
covery process as known in nerve. Investigations on
the repetitive firing of crustacean nerve during the
passage of a constant current have introduced another
idea C49)> that the intervals between impulses are
determined by the response time. That is to say the
intervals are determined in the same manner as the
latency from the l:)eginning of a current stimulus to
the initiation of the first impulse.
The passage of a constant current through a crusta-
cean axon sets up a repetitive discharge as shown in
figure 3. Several points can be seen in this figure; the
frequency of discharge is related to the current
strength; the interval between the beginning of the
current and the first impulse is always closely related
to the intervals between the other impulses; these
intervals are all dependent on the development of
the local response, an impulse being initiated when-
ever this local response reaches the critical potential;
the critical potential at which the impulses are set up
is the same with all but the greatest strengths of cur-
rent and all but the highest frequencies of impulses.
Apart from this direct evidence that it is the time
course of the development of the local response that
sets the interval between impulses, the recovery time
of these axons is such that it cannot explain the fre-
quencies observed. These crustacean axons have long
response times and can therefore give regular low
frequency discharges.
The events taking place in certain stretch receptors
in Crustacea are very similar (27). A microelectrode
in the cell body of one of these primary sensory neu-
rons is able to detect a receptor potential generated in
the terminals and, superimposed on it, a discharge of
nerve impulses. The receptor potential will be con-
sidered in a later section. Here it is sufficient to point
out that after an impulse the membrane potential
builds up again in a manner very similar to that
shown in figure 3, and the next impulse is set up
when this potential reaches the critical value. The
121:
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
50 50
AAA/WWWW\ AA/\/WWWW\=^^/""
eye./
FIG. 3. Responses at the cathode of single carcinus a,\ons to
constant currents. A-H: increasing currents as indicated. /-A .■
near threshold currents at higher amplification and faster sweep
speed. L. potential change at anode, conditions as /-A. [From
Hodgkin (49).]
critical potential remains the same at all but the
highest values of impulse frequenc\ .
The initiation of impulses b\ the receptor potential
generated in the muscle spindle of the frog has also
been observed (58). In this preparation the critical
potential remains constant for all except the first im-
pulse in a discharge at a constant frequency, but the
value is different for different frequencies; in fact
there is a direct and linear relationship between the
value of the critical potential and the frequency of
the discharge. An explanation of this phenomenon
has been given as follows (58) : recovery after a nerve
impulse depends on two processes o) a restoration of
membrane resistance and 6) a return of excitability
(see 48). If the first of these processes is the more
rapid in the frog muscle spindle fibers, but not in
the crustacean fiber, then results such as have been
observed would be expected.
Modifuation 0/ Afferent Discharges by Current
Afferent discharges can be modified by the applica-
tion of currents to the regions in which such dis-
charges are set up. This can be seen in the frog's
muscle spindle (25); if the spindle is made to dis-
charge at a suitable frequency by stretch and a current
is applied between an electrode on the afferent nerve
and another on the muscle, the frequency is increased
if the electrode on the muscle is the cathode and de-
creased if this electrode is the anode. The increase or
decrease of frequency is related to the intensity of
current, though the relation is not a simple one. Other
preparations exhibit similar effects. Current passed
through the nerve terminals of the isolated labyrinth
of the rav causes an increase in the frequency ot
discharge in these fibers when the cathode is on the
tissue surrounding the .sensory endings and the anode
on the afferent nerve fibers; a current in the opposite
direction causes a reduction in the discharge fre-
quency (71). These changes caused by the flow of
current summate with those due to angular accelera-
tion in the appropriate direction. Similar results can
be observed by polarization of the lateralis organs of
Xenopus laevis. It has been shown that when the applied
current flows along the nerve fiber, as in the instances
already described, an increase in frequency occurs
when the cathode is on the terminal and the anode on
the nerve; however, if the current flows between elec-
trodes placed on either side of the skin, the frequency
is increased when the cathode is on the inside and the
anode on the outside (77). The frequency of discharge
in the nerve fibers from the lateral line organ of the
Japanese eel is also increased by a current passed
between an anode on the outside of the skin and a
cathode on the inside (55); the passage of a current in
the same direction has been shown to excite afferent
fibers from touch receptors in frog skin (73). Currents
can al.so modifv the discharge from a compound eye
(40).
These results are important in two respects. First,
depolarization of the terminal parts of the axon
membrane can summate with end organ activity
which suggests that the latter involves a depolariza-
tion of the terminals. This is in fact known to occur
in manv instances which will be considered below.
Second, it can be argued from the results obtained
with currents pas.sed across the skin instead of along
the ner\e that, during sensory activity, impulses are
initiated away from the terminal (77)- Direct evi-
dence that this is so in certain instances will be given
later.
INITIATION OF IMPULSES AT RECEPTORS
129
EXCITATION OF IMPULSES BY CONTROLLED PULSES
AND PHASIC RECEPTORS
In the last section stimulus-frequency relations
were considered. Such relations give important in-
formation about units that signal the values of steady
states by indicating them as particular and repeatable
frequencies of impulses. That is to say these relations
are important for nonadapting or tonic units. On the
other hand, the response of phasic units, and the
adapting part of responses of tonic units, are de-
pendent on the time course of the stimulus; in partic-
ular the rates of change at the beginning and end of
the pulse are important. To investigate these phasic
units in detail, it is therefore important to use stimuli
of known time course. It is also important that the
stimulus should be adequately damped. The im-
portance of this can be shown by an example: Pacin-
ian corpuscles have thresholds of a few tenths of a
micron and, for the amplitude threshold to be mini-
mal, the displacement must be complete in less than
a millisecond (34); if large displacements of tens of
microns are used, it only requires a one per cent oscil-
lation to give rise to what appears to be a repetitive
response. Various techniques have been used for this
purpose. Thus for mechanical receptors, electro-
magnetic (6, 57) and crystal transducers (34, 35)
have been used. The former have bigger displace-
ments, but generally have a slower time course than
the latter which can have a damped rise time of 0.2
msec, and a displacement of 10 to 20 /j. It should be
noted that even 0.2 msec, is not very short compared
with the latency from the beginning of the stimulus
to the impulse.
Quantitative Aspects of Excitation
Using such methods, the latencies for impulse ini-
tiation in Pacinian corpuscles and frog skin receptors
have been measured (34, 35). In the Paciniaii cor-
puscle latencies after the onset of mechanical deforma-
tions of any duration are longer (i.e. 0.5 to 3.0 msec.)
than those following the beginning of a constant
current stimulus to the receptor's own nerve fiber
within a millimeter of the ending. After mechanical
stimulation of frog skin even longer latencies have
been observed. The latency observed in the Pacinian
corpuscle can be shown to be due to the time taken
for the receptor potential to develop (37); it seems
likely, therefore, that the longer latencies found with
frog skin receptors indicate even more prolonged
receptor proces.ses. Curves of recovery after the ini-
tiation of an impulse by a short mechanical pulse to
a Pacinian corpuscle have been shown to be similar
to the curves of recovery obtained after electrical
excitation of the ending's own nerve fiber close to the
corpuscle and of nerves in general (34). Thus, in this
instance at least, there is direct evidence that the
time course of recovery at the site of impulse initiation
is not much different from that in other parts of
nerves.
The change of amplitude threshold with change of
stimulus velocity has also been measured, and the
minimum velocity of stimulus necessary for excitation
found. Thus, just as there is a critical slope in the
excitation of nerve by a linearly increasing current,
so there is a critical slope in the excitation of phasic
receptors by linearly increasing displacements. Such
measurements give a quantitative measure of the
adaptation of such receptors. Thus the critical slope
for a Pacinian corpuscle is given as 1 200 rheobases
per sec. (36) and that for receptors in frog's skin 61
rheobases per sec (35).
As a means of investigating the fundamental mech-
anisms of receptors, such measurements have been
superseded by direct recording of receptor potentials;
but they are still of use in certain types of quantitative
investigation (53).
On and Off Responses
At least some phasic receptors respond with one or
a few impulses to a change from one state to another;
this response is not qualitatively dependent on the
sign of this change. Thus many photoreceptors re-
spond when the intensity of illumination on them is
suddenly raised from one level to another and again
when the intensity is suddenly reduced (30). The same
type of response to change of state is seen in receptors
in toad and cat skin (73). Measurements of the
threshold amplitude for on and oft" responses to rec-
tangular displacements have been made for Pacinian
corpuscles and frog skin receptors; in the former the
threshold for a compression (the 'on response') is
usually slightly lower than that for a decompression
(the 'off response'), but not infrequently the reverse is
true (34); on the other hand the excitability of the
frog's cutaneous receptors to a compression is much
greater than the excitability to the decompression
(35). These difTerences may well be due to the
mechanics of the systems, for in these experiments
compression is a result of an externally applied force,
while decompression depends solely on the restoring
forces inherent in the tissue; it is likely that restoration
I30
HANDBOOK OF PHYSIOLOGY
NELROPHYSIOLOGY I
is a much more rapid process in a Pacinian corpuscle
than in frog's skin.
Summatiim
Two subthreshold short pulses applied to a phasic
receptor within a suitable interval of each other can
summate and set up an impulse; the essential point
in this experiment is that the first pulse is over before
the beginning of the second and the summation takes
place in the receptor. Further discussion of this point
will be left to the ne.xt section where receptor poten-
tials are discussed. One particular case can, however,
be discussed here. It is possible to observe summation
between the subthreshold activity evoked by a small
short mechanical pulse and a brief electrical test
shock. .Such a test shock can be used to measure the
excitability of the receptor at different times after the
application of the mechanical pulse; in this way in-
direct evidence of the time course of a receptor poten-
tial has been obtained (34)-
RECEPTOR POTENTIALS AND OTHER
GENERATOR POTENTIALS
It is now widely held that the immediate cause of
impulse initiation in receptors and sense organs is the
development of an electrical potential change which is
graded according to certain characteristics of the
stimulus and which is confined to the region of the
receptor or organ. .Such potentials have now been
found in a number of situations of different types and
these findings, together with supporting evidence such
as summation results from other sites, form the justi-
fication for such a generalization.
In this .section I shall use the term 'generator po-
tential' to describe any graded potential change oc-
curring in a sensory receptor or in a complex sense
organ that can reasonably be supposed to be a cause
of the initiation of an impulse. The term 'receptor
potentials' I will confine to those generator potentials
occurring in a single receptor. Thus the cochlea
microphonic is a generator potential but not a re-
ceptor potential.
Generator Potentials in Complex Organs
These lie outside the scope of this particular chapter
but are included briefly for completeness. The cochlea
is the best example of this group. In this organ there is
a potential difference maintained between the endo-
lymph and the perilymph (96). During the application
of a sound wave, an alternating potential can be re-
corded and shown to have its greatest intensity at the
point on the basilar membrane at which the hair cells
are situated (16). This potential is directly related to
the sound pressure wave (100). There is reason to
suppose that this microphonic potential, as it is called,
is the cause of impulse initiation (16). 'Microphonic'
potentials have also been found in other sites, e.g.
the lateral line organs (54) and sacculus (105). These
potentials serve a similar function to the receptor
potentials of neurons but, in the cochlea at least,
they represent changes of potential between multi-
cellular compartments instead of across cell mem-
branes. It is not improbable that there are common
factors in the development of these two types of po-
tential, but we cannot expect to find close parallels.
Receptor Potentials Generated in Nerve Terminals
.Such potentials have been recorded from certain
mechanically excitable receptors (6, 27, 37, 58}, from
photoreceptors (42, 79) and from olfactory receptors
(78). In all these instances the receptor potential has
been recorded at a distance from its source, and in no
case has the membrane potential of the receptor
region been recorded directly. In each of the three
mechanical examples on which we have information
at present, the records were obtained by recording
the currents flowing along the nerve fiber, the nerve
fiber behaving as a pair of passive concentric conduc-
tors. The changes in these currents must have been
related to changes in potential across the membrane
of the terminal portions of the afferent nerve fiber,
since all currents recorded must have crossed the
membrane peripheral to the recording region; this
does not prove of course that the changes are actively
generated across the terminal membrane. Reasons for
believing that the receptor potentials are in fact
actively generated at this site are given in the last
section of this chapter.
Examples of receptor potentials are shown in
figure 4. Figure 4.-1 and B are records from muscle
spindles from the frog (58); in both experiments the
preparations had been procainized to prevent impulse
activity. Figure ^A shows the changes that occur at
the beginning of a maintained stretch; it can be seen
that there is a relatively large initial change of poten-
tial and that this is foOowed by a small but main-
tained potential change. The earlier phase, called the
dynamic phase, is related to the velocity of the
stretch. The smaller maintained change of potential
INITIATION OF IMPULSES AT RECEPTORS
'S'
FIG. 4. Receptor potentials from different receptors. .1 and B. from frogs muscle spindle, pro-
cainized. Top: stretch. Bottom: receptor potential. Time, A, 500 cps; B, o.i sec. [From Katz (58).]
C: from cat's Pacinian corpuscle, procainized. Upper trace {at starty amplitude and duration of
displacement and time in msec. Note that this trace crosses the other trace during displacement.
Lower trace (at starty receptor potential record. [From Gray & Sato (37).] D: from crayfish
stretch receptor. Arrows mark duration of stretch. Time, i sec. [From Eyzaguirre & Kuffler (27).]
depends only on the amplitude of the stretch. Figure
4B shows also the events occurring when the stretch is
released. It can be seen that there is a change of
potential in the opposite direction to the other deflec-
tions, that is the electrode near the receptor goes posi-
ti\e to the distant electrode. The tiine course of this
deflection tends to be slower than that of the initial
dynamic phase, but it must be remembered that
relaxation of the muscle depends on the restoring
forces in the tissue while the stretch is actively im-
posed. The three phases of the receptor potential
correspond to the initial burst, to the maintained
discharge and to the reduced discharge that follows
the end of a stretch.
Figure 4C (37) shows a receptor potential from a
Pacinian corpuscle and with it the voltage pulse ap-
plied to the crystal transducer that was used to stimu-
late; impulse activity has been prevented with pro-
caine. This potential differs in several respects from
that found in the muscle spindle. There is no main-
tained plateau, the potential declining to zero once
the peak is past. The shape of the receptor potential
is nearly or completely the same whether excited by
a short pulse of say 0.3 msec, duration, Ijy the be-
ginning of a long pulse (fig. 4C) or by the end of a
long pulse. As in the case of the muscle spindle these
results are consistent with the results of experiments
on the excitation of impulses by these receptors. These
two examples illustrate contrasting types of receptor
potential, the one associated with tonic behavior and
the other with phasic behavior. In particular it is
worth noting that a receptor potential, and with it an
impulse, is set up by decompression of a Pacinian cor-
puscle, while relaxation of a muscle spindle is asso-
ciated with a positive going receptor potential and
an inhibition of the impulse discharge.
The receptor potential in figure 4Z) is that of a
slowly adapting stretch receptor from the crayfish
(27). This was recorded by means of a microelectrode
in the cell body of the neuron which, in this instance,
lies in the periphery close to the muscle; the receptor
part of the cell lies still further to the periphery in the
terminations that ramify in the receptor muscle. The
record shows a steady depolarization well maintained
throughout the stretch; there is no marked dynamic
phase, even when the early part of the potential is not
obscured by spikes, as in figure 4Z), though there is
soine initial decline in the level of the depolarization;
'32
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
at the end of the stretch the potential simply returns
to its resting level. This difference from the muscle
spindle potentials may be due to the effective velocity
of the stretch. In this record, unlike those that are
illustrated in figure ^A, B and C, the impulse dis-
charge has not been interfered with and five spikes
are shown arising from the receptor potential. It can
be seen that each impulse is preceded by a relatively
slow decrease in membrane potential (the prepoten-
tial) and that when this decrease reaches a critical
value the impulse is discharged.
Receptor potentials are not confined to mechani-
cally excited receptors. It has long been known that
slow potentials could be obtained from the retina and
from compound eyes (31). There has been reason to
suppose that part at least of these potentials repre-
sented activity of the receptors themselves. Direct
evidence that single ommatidia produce receptor
potentials has now been obtained. In the single
isolated ommatidium of Limulus (42) a receptor
potential builds up rapidly when the ommatidium
is illuminated. The potential then dies away, but
with suitable recording conditions some depolari-
zation appears to remain as long as the receptor is
illuminated. The cessation of illumination is not
accompanied by hyperpolarization. The olfactory
mucosa of the frog produces slow potential changes
when excited by air containing a suitable agent (78).
The distribution in area and in depth of these
potentials and their relative insensitivity to cocaine
suggest that they are due to synchronous activity of
the olfactory receptors.
Relation of Receptor Potentials to Impulse Initiation
There can be little doubt that receptor potentials
are the immediate cause of the initiation of impulses.
They always precede the impulse and the impulses
appear when a critical potential has been reached.
In the crustacean stretch receptor this critical level
remains constant under a variety of conditions. With
the frog's muscle spindle the critical potential depends
on the frequency of the discharge, an observation
which has been discussed above. In this preparation
the frequency of discharge is linearly related to the
amplitude of the receptor potential, a fact which sug-
gests that the receptor potential is causally related to
the impulse discharge. That such a relationship is not
immediately visible in the results obtained from the
crustacean stretch receptor does not mean, of course,
that the frequency of the impulse discharge is not
related to the amplitude of the receptor potential.
This is perhaps best explained by considering the
steps involved in the initiation of the impulse. There
are reasons, which will be considered below, for sup-
posing that the impulses are initiated at a point which
is near but not identical with that at which the re-
ceptor potential is generated. Currents due to the
receptor potential will then flow through and dis-
charge the membrane of the neighboring parts of the
nerve fiber; this part of the membrane will develop
local responses (48, 56), and if the membrane poten-
tial falls to the critical level an impulse will he
discharged. This sequence of events is essentially the
same as that found during the repetitive firing of a
carcinus axon in response to an externally applied
constant current (49). The slowly rising prepotentials
of the crayfish stretch receptor (fig. 4Z)) are similar
to those of the current excited carcinus axon (fig. 3).
In both these examples the recording conditions are
such that what is recorded is related to the membrane
potential at the point of impulse initiation and not
to the intensity of the charging current or the po-
tential of the source supplying this current. In conse-
quence what is seen is the passive discharging and
local response of the membrane at the site of initiation
followed by the impulse if and when the memlDrane
potential falls to a critical level; this part of the
membrane is then repolarized and the cycle starts
again. The rate of discharging of the membrane and
hence the frequency of the impulses depends on the
intensity of the discharging current which in turn
depends on the size of the receptor potential; this,
however, is masked during a train of impulses. If the
amplitude of the receptor potential could be measured
during the impulse discharge a relationship between
receptor potential amplitude and frequency would
no doubt be found, and this might be similar to the
relation Ijetween applied current and frequency in
the carcinus axon. A relation was found in the case of
the frog's muscle spindle because, between impulses,
conditions were such that the full amplitude of the
receptor potential was recorded; this was proved by
subsequent procainization. Possible reasons for this
behavior have already been considered.
Qjiantitatwe Relations Between Stimulus and
Receptor Potential
The amplitudes of the receptor potentials of the
muscle spindle and Pacinian corpuscle increase with
the amplitude of the displacement up to a certain
point and then level off to a maximum. An example is
shown in figure 5. This particular example was ob-
INITIATION OF IMPULSES AT RECEPTORS
'33
100 r
%
90
70
60
SO
■10
)0
20 -
10
F19.5
Stiinulus scrength
10
1
Fig 6
o O
oo
10
2
0
0 0
0 0
0 0
0
0°
Stimului strength
IS 20
25
30
3 4
S
«
FIG. 5. Receptor potential amplitude in relation to the displacement of the mechanical stimulus
with velocity constant in a Pacinian corpuscle. Abscissa: stimulus strength in arbitrary units. Ordi-
nate: receptor potential amplitude as percentage of maximum. O same points as •, but stimulus
strength scale expanded five times. [From Gray & Sato (37).^
FIG. 6. Receptor potential rate of rise in relation to the displacement of the mechanical stimulus
with velocity constant in a Pacinian corpuscle. Abscissa: stimulus strength in arbitrary units. Ordi-
nate: receptor potential rate of rise as percentages of maximum amplitude per msec. O same points
as •, but stimulus strength scale expanded five times. [From Gray & Sato (37).]
tained from a Pacinian corpuscle (37), but a siinilar
relationship has been observed in the muscle spindle
of the frog (58}. The value of the receptor potential
reaches a constant level with large displacements; this
is not conclusively proved by the published data,
partly because of the limits to the size of stimulus used
and partly, in the Pacinian corpuscle experiments,
because the biggest stimuli introduced artifacts that
tended to sum with the response. The question of the
absolute amplitude of this ma.ximum is considered in
a later section.
The rate of rise of the potential is also related
to the size of the exciting displacement (37). This is
shown in figure 6. There is a change in the slope of
this graph at that level of stimulus strength above
which the amplitude increase is limited, but even
above this point the rate of rise of the potential con-
tinues to increase with stimulus strength. That this is
a genuine effect is supported h\ the fact that the time
of rise of the potential continues to shorten over this
range of stimuli. Since the recorded potential is a
result of a potential change across the terminal mem-
brane (whether or not the potential is actively gen-
erated at this site), the rate of rise of the receptor
potential will reflect the rate at which current flows
in to the capacity of this membrane. In other words
these results suggest that the current across the mem-
brane of the nerve fiber terminal continues to increase
as the stimulus increases even though the peak po-
tential has reached a maximum \alue.
The amplitude of certain receptor potentials, for
example those of the Pacinian corpuscle and the
early phase of that of the frog's muscle spindle (fig.
\A), is also dependent on the velocity of the displace-
ment. Indirect evidence shows that this is also true of
other receptors responding to other forms of energy,
for example thermal receptors (46). Figure 7 illus-
trates the change in relati\e ainplitude of the receptor
potential that accompanies change in the velocity of
the mechanical stimulus, the amplitude of the stimu-
lus ijeing kept constant. It is immediately clear that
the amplitude of the receptor potential, while inde-
pendent of velocity at high values, is over a certain
range closely related to the velocity of the stimulus.
The 'angle' of this curve occurs, for the Pacinian
corpuscle, at a compression velocity of about i mm
per sec. (i.e. about 5 thresholds per msec). This
means that many physiological stimuli may be ex-
pected to lie within the velocity-sensitive range.
The time course of the receptor potential is in most
instances dependent on the properties of the stimulus.
It has already been pointed out that the rate of rise
of the potential \aries with stimulus amplitude and
this change in the rate of rise of the potential change
is accompanied by a change in the time of rise (37,
58). The rate of rise of the potential change may also
be affected by the \elocity (or comparable time
'34
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
100
%
K
00
70
M
SO
40
M
20
10
0
•• •
Stimulus velocity (V/miec)
_I I
FIG. J. Receptor potential amplituide in relation to the
velocity of the mechanical stimulus with displacement constant
in a Pacinian corpuscle. Abscissa/ stimulus velocity in arbitrary
units. Ordinate: receptor potential amplitutie as percentage of
maximum. [From Gray & Sato (37).]
function of the relevant form of energy) of the pulse
used to excite; thus the rate of rise of the receptor
potential of the frog's muscle spindle gets less as the
velocity of the stimulus is reduced. In the Pacinian
corpuscle there may Ije some change in rate of rise,
but often there is no effect attributable specifically to
the stimulus velocity; that is to say that, though the
rate of rise of the potential change increases as its
amplitude increases, the time course of a receptor
potential of a given amplitude is often the same
whether it is produced by a small displacement
having a high velocity or by a larger displacement of
lower velocity. In other words there are many me-
chanical pulses having different values of amplitude
and velocity that are equivalent as 'stimuli'.
The duration of static receptor potentials, e.g. that
of the frog's muscle spindle and the slowly adapting
stretch receptor of the crayfish, is directly dependent
on the duration of the applied force. The rate of decay
of those potentials, which are velocity sensitive, may
possibly depend on the duration of the applied force
under certain circumstances; however, the rate of
decay of the receptor potentials of the Pacinian cor-
puscle, the only end organ in which this particular
point has been investigated, is normally independent
of the duration of the stimulus (37). Off responses
have the same time course as on responses.
Absolute Magnitude oj the Receptor Potential
Receptor potentials reach a ma.ximum at a certain
value of stimulus strength. It is of considerable theo-
retical importance to know the absolute value of this
potential change. Up to the present, it has been pos-
sible to make only a rough estimate of its value in the
Pacinian corpuscle (20). This has been done by re-
cording the external current flowing along the axon
between the second and third nodes of Ranvier during
activity of each of these nodes and of the receptor
potential. By the use of blocking techniques and by
taking diff"erences, the.se components were obtained
separately and measured. Under suitable conditions
these currents will he proportional to the driving
potentials. The results given are that the receptor
potential amplitude is 59 per cent (n = 6, S.D. =
14 per cent) of the amplitude of the impulse at node 2
and 38 per cent (n = 5, S.D. = 17 per cent) of the
amplitude of the impulse at node 3. The difference
between the figures is due to a decline in the impulse
amplitude as the terminal is approached. The atten-
uation per internode of the receptor potential is likely
to be less than the 0.5 for large myelinated fibers of
toads C92), so the absolute value of the receptor
potential can be considered as of the same order of
magnitude as the resting and action potentials. This
conclusion is supported by results from the crayfish
stretch receptor (27). The amplitude of the recorded
receptor potential at threshold ranges from 8 to 25 mv
depending on the type of receptor. It has been esti-
mated that the loss due to passive conduction along
the nerve filler will have reduced the true value of the
receptor potential by 20 to 80 per cent; also a maxi-
mum receptor potential must be appreciably greater
than a threshold one. The ratio for the Pacinian
corpuscle is 10 to i (37).
Summation oj Receptor Potentials
If, during a maintained receptor potential, the re-
ceptor is subjected to increase in the stimulus strength
the final value of the receptor potential will correspond
to the final value of the stimulus. In this instance both
the stimulus and the receptor potential have summed.
With short pulse excitation it has been shown that
summation of receptor potentials occurs after the
stimulus is over (6, 37) as shown in figure 8. This
summation appears similar to that found with end-
plate potentials and synaptic potentials. A special case
of summation occurs when an 'on' response summates
with an 'ofli" response (37). Summation of sub-
threshold receptor potentials can in this way set up
impulses (6) and it seems likely that this process is of
INITIATION OF IMPULSES AT RECEPTORS
135
FIG. 8. Summation of receptor potentials with different
intervals between stimuli. Upper trace: stimulus signal and time
in msec. Lower trace: receptor potentials. [From Gray & Sato
(37)-]
considerable functional importance in determining
maximum sensitivities. It is probably also important
in determining the thresholds for sensation at different
frequencies of vibration (83).
Depression
After the production of one receptor potential by a
Pacinian corpuscle a subsequent one, occurring within
a few milliseconds, is depressed. This is most easily
seen with a preparation in which impulse activity has
been prevented; it can then be seen that the depres-
sion of the test responses increases as the conditioning
stimulus is increased and decreases as the interval be-
tween the conditioning and test pulses is increased
(18, 37). Depression of the receptor potential is also
caused by an impulse set up as a result of mechanical
stimulation; this depression is much greater than that
produced by a threshold receptor potential alone,
though it does not appear to be as great as the de-
pression caused by really large mechanical stimuli,
whether an impulse is present or not. Antidromically
conducted impulses also cause depression of a subse-
quent receptor potential, though for any given time
interval after the impulse the depression is slightly less
than when the conditioning impulse is excited me-
chanically. At the time of writing there are a number
of problems which require elucidation and on which
the e\idence is conflicting.
Depression has not been described for other recep-
tor potentials, but this is not surprising as the stim-
ulating conditions have been very different. It would
be interesting to know, however, if any part of the
initial decline of other receptor potentials were due
to the same cause as this depression; the decline of
the Pacinian corpuscle potential appears to be due
to other and more rapid processes.
SITE OF IMPULSE INITIATION
There is evidence from the rapidly adapting type
of stretch receptor of the crayfish that impulses are
set up in the cell body (27). The records in these ex-
periments were made through an electrode that was
inside the cell body and it was found that the change
of memijrane potential required to excite an impulse
was the same whether this change was brought about
by a receptor potential spreading from the periphery
or by current spread from an antidromically con-
ducted impulse that had been blocked before it
invaded the cell body. If the receptor potential set up
impulses peripheral to the cell body, the apparent
threshold value of the receptor potential, as recorded
by this method, would be less than the true value by
the amount of decrement occurring between the site
of initiation and the cell ijody; this is in fact what
occurs in the slowly adapting stretch receptors of the
same species. Direct distortion of the cell body and
the larger dendrites does not produce any potential
changes; receptor potentials are produced only by
stretching the muscle fibers in which the finer termi-
nals of the neuron ramify. It therefore seems certain
that while the impulses are initiated in the cell body
of the rapidly adapting receptor, the receptor poten-
tials are developed peripheral to this in the finer
dendritic terminals.
A similar state of affairs appears to occur in the
Pacinian corpuscle (20). In this receptor a straight
nonmyelinated fiber of 2 pi diameter runs down the
central core of the corupscle; at the end of this central
core the axon becomes myelinated. One node of
Ranvier is regularly found inside the corpuscle about
half way between the end of the central core and the
point at which the axon leaves the capsule, and the
second occurs near the latter point (86). The imme-
diate surroundings of the nonmyelinated terminal
.36
HANDBOOK OF PHYSIOL(K;V
NEUROPHYSIOLOGY I
have been shown to be specialized (85), and it must
be supposed that it is in this region that the receptor
potential is generated. By recording across a barrier
surrounding the internode between the second and
third nodes of Ranvier, it was found possible to record
distinct phases of activity due to each of the first two
nodes if the thresholds of these nodes were raised by
anodal polarization. No phase of impulse activity
could be found attributalile to the nonmyelinated
terminal even though thresholds were raised by an
amount that, on theoretical grounds, should have
been quite adequate to reveal such impulse activity
if it existed. It therefore appears that after a mechani-
cal stimulus the impulse is set up at the first node of
Ranvier.
Indirect evidence that impulses are not initiated in
the terminations of the afferent nerve fibers of certain
other preparations has already been considered in the
section on the effects of applied currents.
Not only is there evidence that impulses are, in
some receptors at least, set up away from the termi-
nals in which the receptor potentials are generated,
but there is also evidence that such terminals are not
invaded by antidromically conducted impulses. In
the crayfish stretch receptor the receptor potential
is not abolished by an antidromic action potential; if
the impulse invaded the membrane that is involved
in the production of the receptor potential one would
expect a complete short circuiting of this membrane
and the temporary abolition of the receptor potential
(28). A similar observation has been made with the
olfactory mucous membrane of the frog (78); stimula-
tion of the olfactory nerve at different strengths and
frequencies had no effect on the response of the olfac-
torv membrane to an exciting .substance. As has
already been stated in the last section, an antidromic
impulse causes slightly less depression of the receptor
potential in the Pacinian corpuscle than does an
impulse set up by a mechanical pulse. It has already
been argued that an impulse initiated in this receptor
by a mechanical stimulus starts at the first node of
Ranvier; if an antidromically conducted impulse in-
vaded the nonmyelinated terminal then it would be
expected to produce a greater depression of the
receptor potential. This is not the case and it seems,
therefore, that antidromic impulses do not invade the
nonmyelinated terminal (18).
Evidence that impulses set up by physiological
stimuli to receptors do not start in the receptor region
might simply mean that all-or-nothing impulses can-
not occur there during receptor activity. That anti-
dromic impulses do not invade the terminals might be
a result of Ijlock at regions of low safety factor, though
from parallel situations elsewhere this does not seem
ver) likely. The most probable explanation of all
these results is that those regions of membrane that
are not in\aded are different from the rest of the
neuron surface and are not capable of producing a
regenerative all-or-nothing response.
When a frog's muscle spindle is discharging at low
frequency small all-or-nothing potentials can be seen.
These are much smaller than the propagated impulse
and may occur in a number of discrete sizes (57).
They disappear if the frequency of discharge of full-
size impulses is increased and also if the receptor is
bombarded antidromically. After a full-size impulse
there is always a delay before the next all-or-nothing
event, whether full-size or small, but after one of the
small all-or-nothing potentials the interval may be
quite short. An explanation of these events may be
that impulses are set up in the terminal branches of
this type of receptor, but an impulse in a single branch
is unable to pass the regions of low safety factor that
occur where the branches join (57). A full-size im-
pulse would then only be set up if there were sufficient
synchrony in the activity of the terminal branches.
On the same argument all-or-nothing activity in a
single branch would fail to invade other branches and
therefore would not depress their activity, while a
full-size antidromic impulse would invade them all.
EFFECT OF PROC.MNE .J^ND SODIUM LACK ON
RECEPTOR POTENTIALS
In the frog's muscle spindle concentrations of pro-
caine from 0.1 to 0.3 per cent abolish impulse acti\ity
but leave the receptor potential apparently unaffected.
Higher concentrations of procaine reduce the ampli-
tude of the receptor potential, affecting the static
phase more than the dynamic (58). Similar results
can be obtained with the Pacinian corpuscle of the
cat. The impulse is abolished by concentrations of
o.i to 0.5 per cent procaine in the bathing fluid, but
if the procaine is washed out after aijout 10 min.
there is no reduction in the amplitude of the receptor
potential. Prolonged soaking in these concentrations
causes a reduction of the receptor potential amplitude
(37)-
Similar eff"ects can be obtained in both these prep-
arations if they are soaked in sodium-free solutions.
Ten minutes .soaking in such a solution abolishes
repetitive firing from the muscle spindle while thirty
minutes is enough to abolish the initial spike (58).
INITIATION OF IMPULSES AT RECEPTORS
137
Thirty minutes soaking is about the time needed
to abolish the impulse from a Pacinian corpuscle
preparation (37). In neither instance is the receptor
potential effected.
The times of action of these solutions are remark-
ably similar for the two preparations and in both
instances are very long compared with the time such
solutions take to act on isolated single nerve fibers. It
seems likely that diffusion times play an important
part. It is known from direct experiments with
labelled sodium, potassium and bromine that diffu-
sion through the capsules of the Pacinian corpuscle is
slow C38).
In the Pacinian corpuscle, however, it is possible to
perfuse the receptor through the capillary loop that
enters the corpuscle with the axon and ramifies in its
proximal pole (19). Using a perfused preparation of
this kind it is found that procaine in a concentration
of 0.02 to 0.05 per cent in the perfusion fluid abolishes
the impulse; 0.05 per cent and higher concentrations
of procaine cause a reduction of the receptor potential
amplitude. The abolition of the impulse occurs within
1.5 min.
If these preparations of the Pacinian corpuscle are
perfused with a sodium-free solution the amplitude of
the receptor potential falls and after about 20 min.
the amplitude is constant and very small. This is
illustrated in figure 9. This reduction in amplitude
occurs whether the sodium chloride of the physi-
ological solution is replaced by choline chloride or
by sucrose. The effect, under faNoraisle conditions,
is reversible and recovery occurs on changing the
perfusion fluid back to a physiological solution.
When different concentrations of sodium are per-
fused it is found that the amplitude of the receptor
potential, measured after a constant le\el has been
reached, is related in a graded manner to the con-
centration of sodium. When sodium is absent there
is a small remnant of the receptor potential; it is
probable that this represents a genuine property
of the receptor (19).
The receptor potentials of other types of receptor
have also been found to be resistant to local anes-
thetics. Cocaine (0.5 per cent) applied externally has
little or no effect on the potentials of the olfactory
mucous memljrane, though the same application
abolishes the responses of the olfactory bulb (78).
Procaine in concentrations of 0.05 to o. i per cent in
the bathing fluid abolishes the impulses but not the
receptor potential of the crayfish stretch receptor.
The position at the present time seems to be that
while receptor potentials are more resistant than
FIG. 9. Effect of perfusion with a sodium-free solution on
receptor potential amplitude. Abscissa: time in min. Ordninle:
receptor potential amplitude, arbitrary units. Sodium chloride
was replaced with sucrose and changes in recording resistance
have been corrected for. Impulses were abolished with pro-
caine but were allowed to reappear during the period marked
by the dotted line. [From Diamond, J., J. A. B. Gray & D.
Inman. Unpublished figure.]
impulses to procaine, in the Pacinian corpuscle at least
quite low concentrations (0.05 per cent) do affect
the receptor potential if the diffusion barriers are
avoided by perfusion. Perfusion also reveals that the
receptor potential is almost completely abolished in
the absence of sodium.
TRANSMISSION OF ENERGY TO THE RECEPTOR ELEMENTS
It has long been recognized that there are factors
in the transmission of the exciting energy to the re-
ceptors that are important in the functioning of the
138
HANDBOOK OF I'HVSIOLOGV
NEUROPHYSIOLOGY I
more specialized sense organs. For example the
ability of the cochlea of the higher vertebrates to act
as a frequency analyzer is due to its mechanical prop-
erties (97). In compound eyes the distribution of
absorbing pigments affects the distribution of light on
the receptors so as to increase cither the sensitivity
or the discrimination of the eye (84). The same situa-
tion can be seen if the skin is taken as a whole. It has
been shown that thermal receptors respond to the
temperature at a given point at a given time (106);
the distribution, both in time and space, of tempera-
ture in the skin, and consccjuently the nature of
sensation aroused, will depend on the physical proper-
ties of the whole system. Another, and rather different,
example of the effect of external physical factors is
the decrease in the rate of adaptation of mechanical
receptors in frog's skin that occurs as a result of
stretching the skin (68).
All the examples mentioned in the last paragraph
refer to the physical properties of a whole tissue or
organ and their effect on the behavior of a population
of receptors. The factors involved in the transmission
of energy inside what is normally described as a
single ending can also be of fundamental importance.
The Pacinian corpuscle consists of a central core sur-
rounded by thin laminae which form the boundaries
of coaxial spheroids; the spaces between the laminae
are filled with fluid. When the ending is .squeezed
displacements of the laminae occur and these can be
recorded from photographs taken with short flashes
(51, 52). During and immediately after the onset of a
compression, relatively large displacements of the
laminae occur (fig. 10 lejt); but these decline rapidly
to a steady value which is maintained as long as the
corpuscle is compressed. This maintained displace-
ment \aries with the position of the lamina measured,
those near the periphery of the corpuscle showing large
displacements while those near the center show none;
figure 1 1 is a plot of maintained displacement against
distance from the center of the corpuscle. The time
course of the compression can be recorded and there-
fore the displacement that would be expected at any
instant, if the response of the system were inde-
pendent of time, can be calculated. Subtraction o
0 2 4
70
so
Fig. II
.III
flOO
II 200
2>L
300
500
600 M 700
FIG. 10. Mechanical properties of the Pacinian corpuscle. Left: time course of displacements
of 3 laminae (see inset) during a compression that started at / = o, rose linearly to / = 2.6 msec,
and then remained constant. Right: dynamic component' of displacement. See text. [By courtesy
of S.J. Hubbard.]
FIG. II. Mechanical properties of the Pacinian corpuscle. Abscissa: diameter in the transverse
plane (2r). Ordinate: maintained displacement of laminae as functions of transverse diameters
(■2Ar). t marks edge of the central core. Bars indicate ±2 X standard error. [By courtesy of S
J. Hubbard.]
INITIATION OF IMPULSES AT RECEPTORS
'39
this theoretical displacement from that observed
(fig. lo left) leaves a 'dynamic component' (fig.
10 right); it can be seen that this component is
transmitted with less attenuation to the center of the
end organ, and also that its time course is similar to
that of a receptor potential (fig. 4C). It seems there-
fore that the rapid adaptation of this receptor is
primarily a mechanical phenomenon. Since neither a
change in axon length nor a bending of the axon has
been detected, it seems that radial displacements of
the axon itself, or of the tissues immediately sur-
rounding it, are responsible for activating the re-
ceptor.
EFFECTS OF TR.'SiNSMITTER SUBSTANCES
A number of investigations into the actions of
acetylcholine, epinephrine, histamine and related
compounds have been carried out. These investiga-
tions have in general had one of two objecti\es: one,
to see if these substances are normally involved in the
initiation of impulses by receptors; the other, to see
if there is specialization of the membrane of the ter-
minal part of the sensory axon.
Action of Acetylcholine
Acetylcholine has been shown to increase or initiate
a discharge of impulses from a variety of sensory
receptors. These include mechanical receptors from
the skin of the cat and the dog (13, 23), from the cat's
carotid sinus (17, 64), from the crayfish stretch re-
ceptor (102), the cat's tongue (62) and from the
frog's skin (53); also thermal receptors in the cat's
tongue (21) and chemical receptors of the cat's
tongue (62) and carotid body (98). Succinylcholine
has been found to increase the activity of mammalian
muscle spindles (33). Finally acetylcholine has been
found to effect and even initiate sensations in the
human subject; these include pain (7, 44, 90) and
thermal (10) sensations. Many of these investigations
include control experiments designed to show that
these are direct effects on the sensory pathway and
are not secondary to contractions of smooth or striated
muscle and do not result from excitation of the auto-
nomic nervous system. It seems clear therefore that
acetylcholine does have an action on some part of the
sensory pathway, and since similar applications of
acetylcholine to nerve fibers (53, 70) or to pregangli-
onic nerve terminals (11, 14) are ineffective, it seems
likely that these results represent a direct action of
the substance on the receptor mechanism itself. The
dosage and pharmacological pattern of these re-
sponses vary from one preparation to another. The
most common picture is that represented by the ex-
periments on the mechanical receptors of cats and
frogs in which responses were recorded directly from
the primary sensory nerve fibers. These responses are
produced by doses of the same order of magnitude as
those required to excite the skeletal neuromuscular
junction. They are unaffected by atropine, but are
blocked by curare or excess nicotine; smaller doses
of nicotine beha\e like acetylcholine. The picture is
thus very similar to that of the acetylcholine action at
synapses and the skeletal neuromuscular junction.
The main divergence from this pattern is that atropine
blocks the acetylcholine effect in the crayfish stretch
receptor (102). Atropine has also been found to raise
the thresholds for the sensations of pain (90) and of
cold (lo) in the human; its mode of action in these
instances is not at present clear.
There has Ijeen some difference of opinion as to
whether acetylcholine can act independently or
whether it merely sensitizes the receptor to the
natural stimulus; it is possible that the action may be
different in different preparations. In some prepara-
tions, as shown in figure 12, there is no doubt that
acetylcholine can initiate a discharge (17) and that
the action of acetylcholine summates with the physio-
logical stimulus (17, 53). In the frog's skin acetyl-
choline does not effect the time course of excitation
or recovery but does lower the threshold and increase
the rate of adaptation (53). The most likely explana-
tion of the action of this substance is that it depolarizes
the membrane of the terminal portions of the sensory
nerve fiber and that this action is confined to those
parts that take part in the generation of the receptor
potential. This conclusion might lead one to suppose
that acetylcholine plays some part in the normal re-
sponse to a physiological stimulus. This, however,
seems very doul)tful in the light of results obtained
with blocking agents and anticholinesterases.
Action oj Blocking Agents and Anticholinesterases
It has been stated above that the action of acetyl-
choline on sensory receptors is blocked by curare. It
is also blocked by hexamethonium (17, 23), and large
doses of nicotine (13). While these substances block
the action of a subsequent dose of acetylcholine or
nicotine, they have no effect, in most preparations, on
the normal response to a physiological stimulus. Thus
the mechanical receptors of the carotid sinus of the
140
HANDBOOK OF PHYSIOLOGY ^-^ NEUROPHYSIOLOGY I
iliiiiM*
mmi
\mmmmmmmmi\m\mmmi\m\M
FIG. 12. Acetylcholine excitation of pressure receptors in the cat's carotid sinus, a: pressure in
sinus, 25 mm Hg; injection of 0.5 ml saline, b: same pressure; injection of 0.5 ml of io~' g per ml
acetylcholine, c: pressure, iii mm Hg; i.o ml saline, d: same pressure; 1.0 ml acetylcholine 10 »
g per ml. Time, o. i sec. All records made 95 sec. after injection. [From Diamond (17).]
cat are still able to produce a normal frequency-
pressure curve when perfused with i per cent hexa-
methonium (fig. 13), although the acetylcholine effect
is lilocked lay a concentration of io~^ he.xamethonium
(17). In the case of the carotid body, the chemical
receptors of which appear particularly sensitive to
acetylcholine, large doses of blocking agents diminisn
the response to low oxygen tensions (61).
Physostigmine does not affect the response of
mechanical receptors in cat's and dog's skin to me-
chanical stimulation (13), nor does it alter the
pressure-frequency relationship of the pressure re-
ceptors of the cat's carotid sinus (17). In two types of
chemical receptor, anticholinesterases do enhance the
response to the physiological stimulus; thus physo-
stigmine and prostigmine increase the activity of
chemical receptors of the cat's carotid sinus and
prostigmine increases that of chemical receptors in
the cat's tongue.
These results suggest that acetylcholine cannot be
an intermediary in the normal process of excitation
at many types of receptor. Against this evidence, it
has been argued that the blocking agents do not have
access to the critical region; however, all these agents
block the acetylcholine effect and nicotine is both an
exciting and blocking agent. Such arguments can only
be valid if it is argued that there is a third region on
the sensory pathway that differs from the main part
of the neuron in its sensitivity to these substances and
from the receptor region in that it is not involved in
the production of receptor potentials. There is no
evidence that acetylcholine is present in receptors
(13), but there is evidence of the presence of cholin-
esterase in the Pacinian corpuscle (8, 43) and Meiss-
ner's corpuscle (8); in the former this appears to be all
pseudocholinesterase and its destruction does not
appear to effect function in any way during an acute
experiment (Diamond, J. & J. A. B. Gray, unpub-
lished obser\ationsJi.
The arguments against the participation of acetyl-
choline as an intermediary in the normal process of
excitation of some types of receptor do not exclude
the possibility that local concentrations of acetyl-
choline may modify the excitability of receptors under
physiological conditions. There is no evidence for
such an action of acetylcholine, but there is evidence
that a parallel action can occur with epinephrine.
Effects 0/ Sympathetic Stimulation and Epmep/inne
Stimulation of the sympathetic supply to the skin of
the frog has been shown to increase the excitability of
the cutaneous receptors (67). Stimulation of the sym-
pathetic in these preparations increases the response
to a standard mechanical stimulus applied to the skin
surface; also if the skin is stretched biu not otherwise
stimulated mechanically so that there is no discharge
in the aflferent fibers, stimulation of the sympathetic
may initiate a discharge. These results are paralleled
by the application of epinephrine to the skin. The
effects of epinephrine and sympathetic stimulation
add to those of mechanical stimulation of the skin
and the application of currents to it. These results have
been obtained in preparations which have been sub-
.sequently sectioned and shown to contain no smooth
muscle except that associated with the blood vessels
INITIATION OF IMPULSES AT RECEPTORS
141
40
30 -
X
o •
20
10
_ £
•o
X
60
-•-i-
100
-o-»J
J_
_L
_L
220
260
140 180
Pressure, mm Hg
FIG. 13. Effects of hexamethonium on the pressure-response
relationship of cat's carotid sinus receptors. Abscissa/ Pressure
in sinus in mm Hg. Ordinate: impulse frequency per sec. O,
X normal curves, • perfusion with i per cent hexamethonium.
[From Diamond (17).]
and they appear to be due to a direct effect of epi-
nephrine on the receptor. Epinephrine can also in-
crease the .size of the receptor potential of the Pacinian
corpuscle in response to a given stimulus; this results
in a lowering of the threshold (6g). In the carotid
sinus of the cat there is also an effect of epinephrine,
but in this instance the effect appears to be secondary
to its action on the muscle of the sinus (17, 63).
These results show that the activity of receptors
may be modified by centrifugal activity. The idea
is not, of course, new because the effects of stimulating
the efferent fibers to the muscle spindles are well
known (59). Centrifugal influences on the activity of
the ear (29) and eye (31) are also under investigation,
but whether or not these operate at receptor level is
not yet clear. This topic is discussed also by Livingston
(Chapter XXXI) on central effects on afferent activ-
ity in this work.
Othn Substances
Histamine is a substance that has been much inves-
tigated in relation to receptors, especially those con-
cerned with the sensation of pain in man. Discussion
of this problem belongs to another chapter. Many
other agents have also been investigated (80) and
special mention should be made of the sensitization of
receptors by anesthetics (88, loi).
MINUTE STRUCTURE OF RECEPTORS
Electronmicroscopical studies have begun to throw
some light on those structural relationships that mav
be of importance in explaining the genesis of the re-
ceptor potential in mechanical receptors. Sections of
muscle spindles from the frog and of Pacinian cor-
puscles from the cat's mesentery have been investi-
gated.
In the muscle spindle the finer branches of the af-
ferent filler which are nonmedullated lie in close rela-
tion to the intrafusal muscle fiber. These fibers, as they
approach their termination, lose their Schwann cell
sheath and come into direct contact with the muscle
fibers; the continuation of the Schwann cell also runs
in contact with the muscle but is separated from the
axon. Smaller axons, which may represent the final
terminations, are also seen in close relation to, but
not in contact with, the muscle surface. The terminal
parts of the afferent fibers contain many mito-
chondria, though with no apparent orientation
(fig. 14.4) (87).
In the Pacinian corpuscle the axon is nonmyeli-
nated from the point at which it enters the central
core (86). At this point it has a diameter of 2 /x which
it maintains until it ends. Over the whole of this
nonmyelinated section there are certain characteristic
features (85) (fig. 145). There appears to be no
Schwann cell sheath; there are numerous mitochon-
dria inside the nerve fiber arranged as a palisade
around the fiber just beneath its surface membrane.
The axon itself is not round but an ellipse in cross
section and is surrounded by a complex cellular
structure. This cellular structure is divided into two
D-shaped parts separated from each other, in the
middle by the axon, and on either side by gaps that
continue the plane of the long axis of the elliptical
nerve fiber.
At this stage of such investigations, the most striking
feature of the.se results is that both types of mechanical
receptors show the terminal axon without a Schwann
cell sheath.
142
HANDBOOK OF l'H%SIOLOGY
NEUROPHYSIOLOGY I
inner sh
FIG. 14A. Diagram of a cross section of a portion of a frog's
muscle spindle, at resting length, in the region of the sensory
innervation. Inner sh., intrafusal muscle fiber inner sheath;
m.nuc, muscle nuclei; mf., myofilaments; sarc, sarcoplasm;
m., mitochondria; peri, subst., perimuscular substance; ax.,
axons; Sch., Schwann cells. [By courtesy of J. D. Robertson.]
FIG. 14B. Diagram of a transverse section of the central core
of a Pacinian corpuscle based on electronmicrographs. [By
courtesy of A. Quilliam.]
HYPOTHESES CONCERNING THE MECHANISMS
OF RECEPTORS
Many of our present ideas on the mechanisms in-
volved in the initiation of impulses by receptors stem
from the idea of nerve as a model sense organ (9).
This concept invokes two parts; first that a constant
current would excite repetitive discharges in a nerve
fiiaer, and secondly that such currents are produced
in nerves under physiological conditions by the devel-
opment of generator potentials in the receptors.
It is now known that many receptors produce recep-
tor potentials and it is probably safe to assume that
this is a generalization that applies widely. There is
good evidence, which has already been considered,
that these receptor potentials are the immediate cause
of the impulse discharges. At present there is no evi-
dence or need to suppose that the part of the afferent
fiber in which the impulses are .set up differs from
other parts of nerve fibers in its response to a flow of
current, whether this be a flow of current due to a
receptor potential, to an external source or to the
summated effects of both. There is evidence that has
already been considered which indicates that in the
Pacinian corpuscle impulses are set up at the first
node of Ransier and that the terminal nonmyelinated
portion of the nerve fiber does not appear capable of
conducting impulses. Similar conclusions can be
drawn for the stretch receptor of the crayfish, though
in this instance it is not possible to put such clear ana-
tomical limits to impulse conduction. It may well be
a general property of receptors that impulses are set up
at a point central to the sensitive terminals by currents
which are generated elsewhere. The summation noted
between natural stimuli and externally applied cur-
rents would result from a passive summation of the
discharging process in this region of the membrane.
The results just considered further suggest that the
part of the nerve fiber that is unable to conduct a nerve
impulse is the site at which the receptor potential is
generated. This view is supported by the fact that the
conditions under w hich receptor potentials have been
recorded from the three mechanical receptors indi-
cate that the current must have crossed the nerse fiber
membrane peripheral to the point of recording. Esti-
mates of the absolute value of the maximum receptor
potentials suggest that it is unlikely that those currents
that traverse the membrane of the nerve terminal are
secondary to acti\ity in an external source. Further-
more the fine structure of these terminals shows certain
distinctive features. Thus, to take the specific example
of the Pacinian corpuscle, the nonmyelinated terminal
INITIATION OF IMPULSES AT RECEPTORS
143
appears unable to conduct impulses and this same
region is structurally specialized, in particular in not
having a Schwann cell sheath. The estimated poten-
tial change that occurs across the membrane of this
part of the fiber during a maximum receptor potential
is of the same order of magnitude as the resting and
action potentials. Many receptors are sensitive to
acetylcholine, though it is not known whether or not
the Pacinian corpuscle is sensitive. It is tempting to
suggest that the inability to conduct impulses, the
sensitivity to acetylcholine, the ability to produce re-
ceptor potentials and the absence of the Schwann cell
sheath are all connected. There is not howe\er enough
evidence at present to support such an assertion.
Olfactory receptors appear to fall in line with much
of what has been said in the last few paragraphs. To
some extent photoreceptors may as well, but these
considerations belong to other chapters. For the rest
of this discussion consideration will be given almost
entirely to simple mechanical receptors as it is from
receptors of this type that the relevant evidence is at
present available.
The next point to be considered is the immediate
source of energy utilized in the production of a recep-
tor potential. Maintained receptor potentials that last
for minutes have been recorded, and if it is assumed
that receptor potentials are responsible for the initia-
tion of impulses in certain other receptors, for example
the mechanical receptors in the carotid sinus of the
cat, receptor potentials must remain constant for
hours (17). Such potentials cannot be maintained
across a biological membrane without the continual
utilization of energy; such energy clearly cannot be
provided by the work done during the deformation of
the receptor. Since this is so, an internal store of
energy must be available. It has already been argued
that receptor potentials are generated across the mem-
brane of the terminal portions of the afferent nerve
fiber. Across this membrane is a store of energy in the
form of the electrochemical gradients of the principal
ions. It seems likely that it is this energy which is
utilized during the activity of the receptor. In all
slowly adapting receptors some such internal store of
energy must be available; this does not necessarily
follow for rapidly adapting processes such as the re-
ceptor potential of the Pacinian corpuscle and the
dynamic phase of the muscle spindle potential. While
it seems reasonable that all mechanical receptors of
the relatively simple group under consideration should
have fundamentally the same mechanism, there is no
conclusive evidence that this is so. In fact it has been
suggested (58) that the static and dynamic phases of
the muscle spindle receptor potential may have dif-
ferent mechanisms.
During receptor activity the potential across this
membrane must alter. One suggestion discussed as an
explanation of the dynamic phase of the muscle
spindle receptor potential was that the potential
change was a result of a change of membrane capacity,
the total charge remaining constant; it was, however,
pointed out that there were quantitative difficulties in
this explanation (58). Similar calculations for the
Pacinian corpuscle demand large increases in surface
area which are known not to occur. A inore likely
explanation of receptor activity is that ions transfer
charge across the membrane by moving down their
electrochemical gradients as a result of changes in the
permeability of the membrane to one or more ion
species (37, 58). If charge is to be transferred in such a
direction as to explain the observed potential changes,
cations must enter the fiber or anions leave it. The
internal anions of nerve fibers are mostly large and
less likely to move than the external cations which are
almost entirely .sodium. If the mechanism in question
were something of the kind suggested, it would then be
expected that the receptor potential would be nearly
abolished in the absence of sodium. This is in fact
what has been observed in the Pacinian corpuscle.
Another observation that can be explained on this
hypothesis is that the rate of rise of the receptor poten-
tial continues to increase with increasing stimulus
strength at a level of stimulus strength at which the
amplitude of the potential change remains practically
constant. This can be explained by assuming that the
permeability of the membrane continues to increase,
so increasing the rate at which charge is transferred,
while the final potential reached is limited by the
equiliijrium potentials of the ionic gradients con-
cerned.
If the hypothesis put forward be accepted for the
time being, the next problem is to consider how the
changes of membrane permeability are brought about.
This might be due to a distortion of the membrane or
displacements in relation to surrounding structures,
it might be due to a change of pressure in and around
the axon or there may be chemical intermediaries
outside or inside the axon. The last alternative still
leaves the problem of how the mechanical energy
produces the chemical intermediaries. At present there
are no grounds for choosing between these mecha-
nisms. However, if there are chemical intermediaries in
the Pacinian corpuscle, the time course of their action
(the latency often being less than 0.2 msec.) and their
ability to function at room temperature (37) show
'44
HANDBOOK OF PHYSIOLOGY ^ NEUROPHYSIOLOGY I
that they have quite different properties from main-
iiialian synaptic transmitters. Other e\idence has been
presented in an earlier section which suggests that at
many mechanical receptors acetylcholine does not act
as a chemical transmitter.
The adaptation of receptors is a subject that has
stimulated many hypotheses (47, 74). Until recently
these have been based mostly on the concept that
the adaptation of receptors is closely related to the
accommodation of nerve fibers. It would certainly
be expected that this factor would play a part if
impulses are set up in the nerve fiber as a result of
currents generated by receptor activity in the ter-
minals. This factor cannot be entirely discounted, but
there are now very good reasons for supposing that
other factors may be more important. The time
courses of all the receptor potentials so far observed
are in general agreement with the corresponding
time courses of the impulse discharge. Thus the
short receptor potential of the Pacinian corpuscle
corresponds to the single impulse produced by rela-
tively large stimuli, the dynamic and static phases of
the receptor potential of the muscle spindle corre-
spond to the initial high frequency burst and the
maintained discharge of impulses and the receptor
potentials found in the two types of stretch receptor
investigated in the crayfish correspond to the fast
and slow adaptation of the two endings. The adapta-
tion of the receptor potential inay simply reflect
changes in the mechanical events going on in the
terminals. This seems to ije the case in the Pacinian
corpuscle where only a brief wave of distortion can
be found in the central core during a maintained
deformation of the outside of the endorgan. In the
crustacean stretch receptors, the difference between
the slow and fast cells has been attributed to differ-
ences in the mechanical attachments between the
dendrites of the two types of cell and the muscle
fibers in which they ramify (27). The change in the
rate of adaptation of receptors in frog skin, when the
skin is stretched, is another example of the importance
of mechanical factors. It is impossible to say whether
or not such factors can account for the whole phe-
nomenon of adaptation of the receptor potential. It
is possible that there may be some mechanism that
reduces the effectiveness of a stimulus as time passes;
such a mechanism might conceivably be related to
the depression of the receptor potential observed in
the Pacinian corpuscle.
Many of our ideas on the mechanisms of receptors
are at the present time speculative. Definite ideas on
these problems may develop as work goes deeper
into the mechanisms of those few receptors which are
particularly well adapted for such investigations. Also
when results, that ha\e already been obtained on
some receptors, are repeated or contradicted by
work on other types, it may be possible to say how-
far we may generalize from such results as have been
obtained.
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CHAPTER V
Synaptic and ephaptic transmission
HARRY GRUNDFEST
Department of Neurology, College of Physicians and Surgeons,
Columbia University, New York City
CHAPTER CONTENTS
Nature of Postsynaptic Potentials
Generation Sites of Postsynaptic Potentials
Molecular Structures of Differently Excitable Membranes
Types of Postsynaptic Potentials
Interrelations of Postsynaptic Potentials and Spikes
Specific Properties of Synaptic Electrogenesis
Evidence Against Electrical Stimulation of Postsynaptic Po-
tentials
Mechanisms of Bioelectrogenesis
Other Consequences of Electrical Inexcitability
a) Sustained electrogenesis
b) Postsynaptic potentials during hyperpolarization and
depolarization
c) Electrochemical gradation and reversal of postsynaptic
potentials
d) Latency of postsynaptic potentials
e) Electrotonic effects of presynaptic impulse upon post-
synaptic region
f) Chemical sensitivity of synaptic membrane
Postsynaptic Potentials as Nonpropagated Standing' Po-
tentials
Interaction of Graded Responses
Events in Synaptic Transmission
Functional Interrelations Within Single Cell
Evolution of Electrogenic Membrane
Transmitter Actions
Genesis of Postsynaptic Potentials
Gradation of Postsynaptic Potentials
Mechanisms of Graded Responsiveness
Transfer of Activity from Postsynaptic Potentials to Elec-
trically Excitable Membrane
Synaptic Delay
Superposition of Postsynaptic Potentials and Spikes
General and Comparative Physiology of Synapses
Forms and Magnitudes of Postsynaptic Potentials
' The researches at the author's laboratory were supported
in part by funds from the following sources : Muscular Dys-
trophy Associations of America, National Institutes of Health
(B-389 C), National Science Foundation and United Cerebral
Palsy Associations.
Cells with Depolarizing Postsynaptic Po-
Hyperpolarizing Postsynaptic
vith
Postjunctional
tentials
Postjunctional
Potentials
Postjunctional Cells with Both Types of Postsynaptic Po-
tentials
Fast and Slow Responses of Invertebrate Muscles
Pharmacological Properties of Synapses and their Physiological
Consequences
Classification of Drug Actions
Identification and Characterization of Transmitter Agents
Modes of Action of Transmitter Agents and Synaptic Drugs
Physiological Implications
a) Topographic distinctions
b) Synaptic specificity and transmitters
c) Reciprocal interactions of neural pathways
Role of Elementary Synaptic Properties in Integrative Activity
Spatial Interrelations of Synaptic and Conductile Membrane
Physiological Factors Determining Transmissional Effective-
ness
a) Synaptic potency and drive
b) Excited and discharged zones
c) Facilitation
d) Homosynaptic facilitation
e) Heterosynaptic facilitation
f) Spatial summation of converging pathways
Integrative Utility of Electrical Inexcitability
Synaptic Determinants of Different Types of Reflexes
Role of Inhibition in Central Nervous System
Physiological Effects of Different Porportions of Depolarizing
and Hyperpolarizing Postsynaptic Potentials
Synaptic Activity and Electrical Concomitants
a) Interpretations of changes in amplitudes of postsynap-
tic potentials
b) Interpretation of electrotonic effects of standing post-
synaptic potentials
c) Synaptic transducer action and electrogenesis
Ephaptic Excitation
Electrical Modes of Transmission
Role of Field Currents in Central Nervous System
Dorsal Root Reflex
Ephaptic Transmission in Annelid and Crustacean Nerve
Cords
a) Unpolarized ephaptic junctions
■47
148
HANDBOC1K OF PHYSIOLOGY
NEUROPHYSIOLOGY
b) Polarized ephaptic transmission
Evolutionary Aspects of Ephaptic Transmission
Quasiartificial Synapses
CONTRACTION OF A MUSCLE when an apparently un-
reactive nerve is stimulated, the problem of trans-
mission in its most obvious form, challenged the in-
genuitv of early physiologists. Electricity quickly
became a relatively familiar force after the invention
of the Leyden jar and was inxoked in Galvani's
theory (84). Electric fluid supplied from the central
nervous system, he said, charged the interior of a
muscle as the Leyden jar is charged by an electro-
static machine. Contraction was cau,sed by discharge
of this electrical fluid when the mu.scle and its nerve
were connected by a metallic arc. The 'discharge
hvpothesis' formulated by Krause and Kiihne in
the i86o's encompassed as well the data obtained
in the two decades after the foundation of electro-
physiology by du Bois-Reymond and others. "A
nerve onlv throws a muscle into contraction by
means of its currents of action," said Kiihne in his
Croonian Lecture of 1888 (133). This electric theory
of transmis.sion (fig. i) was dominant until very recent
times (98) despite the questions and doubts raised by
du Bois-Reymond himself in 1874 (55), and by Bern-
stein in 1882 (20). The former suggested that another
inechanism, secretion by the nerve of some chemical
agent, might be the cause of neuromuscular excita-
tion.
Transmission in the central nervous system hardly
off"ered a problem to the physiologists of the nine-
teenth century, chiefly for one reason. Nerve and
muscle are distinctly diff"erent tissues performing
different functions and obviously joined together at a
specialized region, the endplate. Connections between
nerve cells, however, were thought to be continuous,
the neurofibrils of one penetrating into the body of
another. This reticular theory of Gerlach was chal-
lenged only at the end of the nineteenth century when
His, Kolliker and pre-eminently Ramon y Cajal
proposed the neuron theory (169), so named by VVald-
eyer. Sherrington, in 1897 (181), applied the term
synapse to the region of contact or contiguity at which
transmission takes place from the presynaptic nerve
cell to another, the postsynaptic cell. The present
chapter will use these terms in their general context,
including in this sense the neuromuscular and neuro-
glandular junctions.
The occurrence of demonstrai)le barriers at the
contacts between neurons, different staining qualities
B
-_-:- A£ .-,-._,
■ ■ ^IV^'") i^™^'^ il^^^i) * '
FIG. I. Models for electrical transmission. .-1, B. du Bois-
Reymond's 'modified discharge hypothesis' of 1874 for the
neuromuscular- junction. A: The current loops produced at a
large endplate surface, which is itself not part of the muscle
fiber, he thought would cause both anodal and cathodal de-
polarizations. The current fields, indicated by the arrows,
would thus alternate between excitant and depressant actions.
B: du Bois-Reymond suggested that a geometrical arrangement
which excited the muscle at a point contact would be more
effective. [From du Bois-Reymond (55).] C.- Eccles' model of
1946 proposed an essentially similar arrangement. Before the
impulse of the presynaptic fiber had arri\ed at the synapse
(left), there would be a hyperpol arizing (inward) current flow
in the synaptic membrane. When the impulse reached its
terminus (right) it would cause depolarization and excitation.
[From Eccles (57).] D: Electrical model for inhibitory synaptic
effects showing interaction of excitatory (E) and inhibitory (I)
synapses. The latter were assumed to be the terminals of a short
axon, Golgi II cell which developed a nonpropagating spike at
its soma. The anodal focus caused by the I knob was supposed
to depress the cathodal excitatory effects of the E knobs. Cur-
rent flows are simplified in the diagram, loops which are sup-
posed to diminish their excitatory effect are shown only at the
edges of each E knob. [From Brooks et at. (28).]
that indicate histochemical differences between pre-
and postsynaptic units and the independent existence
of the latter after destruction of the former (i.e.
SYNAPTIC AND EPHAPTIC TRANSMISSION
■49
absence of transneuronal degeneration) constituted
the evidence brought forward by Ramon y Cajal and
others in support of the neuron theory.
When the neuron theory became accepted, the
electrical theory of transmission, essentially as formu-
lated by Kiihne for the neuromuscular synapse, was
also generally adopted (cf. 45, 57, 140). Nevertheless,
Sherrington's life-long study of the central nervous
system emphasized that the physiological actions of
the latter were dominated by the properties of syn-
aptic transmission. These, he thought (183), were in
many respects fundamentally different from the
properties of conductile activity of nerve or muscle
fibers, in which all-or-none impulses, spikes, are
propagated by electrical local circuit excitation
within the confines of a single cell, even though the
latter may be very long in extent. A Russian school of
physiology headed by Ukhtom.sky (cf i 76) ahso main-
tained that central nervous phenomena could not be
explained solely in terms of all-or-none activity.
The neuron theory incorporates and gives physio-
logical meaning to the doctrine of polarized conduc-
tion which is embodied in the Bell-Magendie Law.
The presynaptic terminals impinge upon the synaptic,
or subsynaptic (cf. 60) membrane of the postjunctional
cell with various types of contacts. These are located
chiefly, but not exclusively, at the dendrites and soma
of neurons, and Ramon y Cajal distinguished the
different sites of contact as axodendritic and axo-
somatic synapses (cf. 1^9). Contacts between the
nerve fibers and the effector cells, muscle or gland,
are also made at specialized regions, tho.se of mus-
cle fibers being termed endplates, as noted above.
Impulses afferent in a prefiber evoke activity in the
postjunctional cell. If the cell is a neuron, its junc-
tional activity may result in a spike which propa-
gates along the latter's axon. At the terminals of this
axon, a new transfer may then take place to another
neuron or to an effector cell. In some instances
unidirectional progression is apparently invalidated,
but the general mechanism of these cases is probably
b\ ephaptic transmission (10). This appears to be
fundamentally different from synaptic transmission
and will be discussed in the last section of this chap-
ter. One recently discovered case of unidirectional
conduction (83) produced by an electrical local cir-
cuit mechanism will also be discussed at that time.
The concept of unidirectional synaptic transmission
permitted Ramon y Cajal to deduce many functional
properties of the central nervous system from anatom-
ical data (168). Changes that occur in gross and fine
structure, in histochemical properties and in physio-
logical behavior after extirpation or damage of
specific elements also give clues to function. The
information obtained by these methods relates chiefly,
however, to the study of integrative activity which is
the subject of later chapters.
While it, too, bears largely on integrative functions,
the analysis of reflexes as exemplified in Sherrington's
work (cf 44, 182) nevertheless also provides data on
the synaptic processes them.selves and discloses
phenomena such as cumulative, long-lasting excita-
tory and inhibitory slates. These two synaptic prop-
erties endow the central nervous system with its
remarkable flexibility and variety of responsiveness.
Both characteristics may also be present in simpler
peripheral synaptic organizations and are commonly
found in the peripheral synaptic structures of inverte-
brates. Sherrington's basic method, stimulation of
selected pathways and study of their effects and inter-
actions, has been refined by application of modern
electrophysiological techniques. The combination
has given information on the effects of different syn-
aptic inflows, their relative potencies, the temporal
and spatial distribution of excitatory and inhibitory
actions, particularly in the spinal cord (cf. 140; and
later chapters in this volume).
The electrophysiological study of single unit path-
ways such as nerve-muscle or neuron-neuron provides
still more detailed and intimate information on synap-
tic mechanisms (cf. 62). Microelectrode recording,
either from the vicinity of single cells or from their
interior, is a recent extension of the technique which
can provide the most definitive information (52, 59,
60, 95, 97). In all cases, transmissional activity is
found to be associated with a special type of electrical
response, the postsynaptic potential or p.s.p. The
transmissional electrogenesis at the endplates of
skeletal muscle fibers is known as the endplate po-
tential (e.p.p.). Basically, however, the properties of
e.p.p.'s arc identical with those of p.s.p.'s. A presyn-
aptic potential, occurring at the terminals of dorsal
root fibers, has also been described ijut from indirect
evidence only (140).
Pharmacological data provide much of the oldest
evidence that synaptic transmis.sion is different from
the conductile process. Claude Bernard (18) found
that curare, the Indian arrow poison, blocked excita-
tion of a muscle by its nerve. The muscle and nerve
individually retain their conductile properties, and
the primary effect of the drug is on the transmission
process. Attempts to account for the synaptic blockade
in terms of electrical transmission were not successful
(cf. 98). A host of other chemicals exert actions chiefly
I50
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
wherever synapses occur. These junctional regions
also appear to have special biochemical requirements.
Transmission, for example, is more easily disrupted
by anoxia than is conduction. Pharmacological and
biochemical tools, particularly in combination with
the techniques of electrophysiology, provide additional
data on the processes of synaptic transmission (cf.
96, 99-101, 161-166).
A challenge to the electrical theory was offered by
that of chemical transmission which evolved chiefly
from the work of Dale, Loewi, Cannon and their
associates (cf. 150, 177). According to this view,
activity of a presynaptic fiber releases at its synaptic
terminals a chemical transmitter agent. That sub-
stance excites the electrical activity of the postjunc-
tional cell. By repetition of the secretory process at
the terminals of the latter, a new action is started in
the next unit of a transmissional chain. The present
chapter adopts this view.
The conclusion that synaptic transmission obliga-
torily involves a chemical mediator derives from a
hypothesis based upon a recent examination of data
on available synaptic systems (97). All possess a com-
mon constellation of properties that are shown in
table I and discussed in the portion of this chapter
devoted to synaptic electrogenesis. The entire group
of these distinguishing characteristics appears to be
referable to a single fundamental property of synaptic
electrogenic membrane, namely that its activity is
not initiated by an electrical stimulus. Thus, there
arises a profound distinction between the conductile
activity of axons or muscle fibers and the transmis-
sional activity at synapses. The former is electrically
excitable by an applied stimulus or by the internally
generated local circuit of activity. The latter is elec-
trically ine.xcitable and must be evoked by a specific
stimulus which in the context of synaptic structure
must be a chemical excitant, or transmitter agent,
released by the active presynaptic nerve fibers.
The currently used definition of synapses is still
essentially as it developed with Sherrington and
Ramon y Cajal, a junction in contiguity between
anatomically distinct cells across which activity is
nevertheless transmitted, but only in one direction,
from the presynaptic cell to the postsynaptic. Many
other specifications are now available to distinguish
transmissional activity from conductile or ephaptic,
and these appear to derive from the one feature, that
synaptic activity is electrically inexcitable.
N.-VTURE OF PDSTSYN.\PTIC PGTENTI.^LS
The earlier studies of p.s.p.'s were made with
external recordings from muscle endplates (59, 6q,
63, 86), sympathetic ganglia (56) and the spinal cord
(57' 58)- The muscle synapses being more easily
accessible, it was most intensively studied both
electrophysiologically and pharmacologically (cf.
62). More recently, this and many other varieties of
synapses have been investigated with intracellular
recording (cf. 52, 59, 60, 68, 95, 97), and a reasonably
coherent and satisfactory description of the principles
of synaptic electrogenesis is now available.
Generation Sites of Postsynaptic Potentials
As noted above, p.s.p.'s are associated with the
occurrence of transmissional activity at junctions
between a pre- and a postunit. Only in a few systems
(e.g. neuromuscular and squid giant axon synapses)
is the junction confined to a clearly delineated area of
the postunit. In these cases it is found that the p.s.p.
is largest within the region of the junction and de-
creases rapidly as the distance of the recording
electrode from the junction increases (fig. 2). The
form of the potential is also distorted in the manner
characteristic of electrotonic spread (114, 141), both
facts indicating that the site at which electrogenesis
occurs is confined to the synaptic region. As will be
described below, the nonpropagating, 'standing'
response of p.s.p.'s is a consequence of electrical
inexcitability.
When the p.s.p. is recorded with a microelectrode,
at first externally and then internally, the sign of the
p.s.p. reverses when the electrode penetrates the cell.
Like the spike, which also undergoes reversal of sign
under the same conditions, the neurally evoked po-
tential is produced at the excitable electrogenic
membrane of the postjunctional cell, hence the term
p.s.p.
Molecular Structures of Differently Excitable Membranes
The structures of the membranes that are involved
in ssnaptic activity are not as yet known. The pre-
synaptic terminals occur in an immense variety of
shapes and sizes. In some of these electron microscopy
has indicated the presence of vesicles (54, 174). The
latter have been interpreted (cf. 52) as sites of concen-
tration of chemical mediators which presumably are
formed in the nerve fibers and ejected during activity
into an extracellular synaptic space of about 100 A.
The postsynaptic sites which respond specifically to
the chemical transmitter agents cannot, at present, be
differentiated structurally from those of electrically
excitable membranes. This is perhaps l^est exemplified
SYNAPTIC AND EPHAPTIC TRANSMISSION
FIG. 2. Some properties of depolarizing postsynaptic poten-
tials. .-1, B: The intracellularly recorded e.p.p. of a mammalian
muscle fiber is evoked by neural stimuli during hyperpolariza-
tion of the muscle fiber membrane through another intracellu-
lar electrode. The impaled hyperpolarized fiber did not re-
spond with a spike or contraction, but others unaffected by the
polarizing current and excited by the neural \olley contracted.
The resulting movement pulled the microelectrode out of the
tested muscle fiber producing the artifact seen at the end of
each record. The response in B is smaller than that in A,
partly because it is generated at a less hyperpolaiized membrane
as is described in the text. However, it is also broader than the
response in A, indicating that the recording microelectrode was
probably some distance from the focus of the e.p.p. The effects
of recording at various distances from this focus are shown in
C, D and E. The amplitude of the e.p.p. falls sharply (C); the
rising phase is prolonged somewhat (i)) and the falling phase
even more (£) as the electrode is moved farther from the focus.
[From Boyd & Martin (23).]
by electron microscopic studies of eel electroplaques
(95).
These cells possess three functionally distinct types
of membrane. One major surface is composed of
membrane that does not respond electrogenically to
any type of stimulation and has a very low electrical
resistance. The other major surface of each cell is
diffusely innervated and, presumably only under the
presynaptic terminals, there is excitable membrane
of the synaptic type which responds only to neural or
to chemical stimuli. Intermingled with this electri-
cally inexcitable membrane component is one that is
electrically excitable and produces a spike. Electron
microscopy has as yet not been able to discern differ-
ences between the two different components of the
excitable membrane, nor between their structures and
those of the nonresponsive membrane (95, 143).
Two functionally quite different junctions, in squid
and crayfish respectively, appear to be similar when
observed by electron microscopy C'75)- However,
that activating the giant axon of squid is electrically
ine.xcitable and thus conforms to the extended defini-
tion of synapses given above. On the other hand, the
junction between a medial giant fiber and the motor
giant axon of the crayfish (83), as will be discussed
below, appears to resemble the ephaptic junctions of
septate giant axons (125).
The inai)ility of present day microscopic techniques
to differentiate the structures of membranes which
differ profoundly in their functional properties indi-
cates that the differences which determine these
properties must be at the molecular level. Probably,
as microscopic methods develop, the difficulty of
visualizing molecular differences will be overcome.
At present, however, the chief tools available for
analyzing these structures are electrophysiological
obser\ations of function and of the disturbance in
function produced by various experimental means,
including the use of chemical agents (cf. gg-ioi; 163).
Types of Postsynaptic Potentials
•Synaptic electrogenesis differs from that of the
spike by being relatively small and, when more than
one nerve fiber is available to excite it, is graded in
amplitude depending on the strength of the stimulus
to the nerve. Furthermore, two varieties of p.s.p.'s can
occur. One, like the spike, tends to decrease the resting
potential, hence is a depolarizing p.s.p. The other
tends to increase the resting potential and is therefore
a hyperpolarizing p.s.p. The two varieties of p.s.p.'s
are present in different proportions in different cells.
Some cells generate only depolarizing, others only
hyperpolarizing p.s.p.'s, while in a third group both
types of responses are produced usually, and perhaps
always, by stimulation of different neural inflows. All
vertebrate muscle fibers thus far known, their em-
bryological relatives the electroplaques of most elec-
tric organs and some neurons develop only a depolar-
izing p.s.p. Certain gland cells are at present known
in which a hyperpolarizing p.s.p. is the sole electro-
genesis (144, 146). The crayfish stretch receptor,
likewise, produces a hyperpolarizing p.s.p. C'So), but
152
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
depolarizing electrogenesis is also evoked, although in
this case by stretch of the mechanosensory receptor
membrane (66, 67, 94). In other cells, notably neurons
of the vertebrate central nervous system (59, 60, 158,
159, 1 61-16 7) and some invertebrate muscle fibers
(73. 13O and neurons (33, 186), l:)oth types of p.s.p.'s
are found.
The depolarizing p.s.p., being of the same sign as
the effective stimulus for electrical or local circuit
production of a spike, can also evoke the latter and is
therefore termed an " excitatory' p.s.p. (59, 60). The
spike arises when the p.s.p. is sufficient to depolarize
the adjacent electrically excitable, spike-generating
membrane to a critical firing level (fig. 3). The latter
varies among different cells and is of the order of 10
to 40 mv change from the resting level. The hyper-
polarizing p.s.p., by the same criterion, is an ' in-
hibitorv' p.s.p. However, these names are not always
appropriate. There are cells, like some electroplaques
or muscle fibers (cf. 95, 97), that generate depolarizing
p.s.p.'s but no spikes. The depolarizing p.s.p. there-
fore may have nothing electrogenic to excite. Like-
wise, those gland cells which generate only hyper-
polarizing p.s.p.'s al.so have no spike to inhibit (cf.
fig. 20). On the contrary, the hyperpolarizing electro-
genesis of the gland cells is associated with actixity in
the form of secretion (146).
When the two varieties of p.s.p.'s occur in a cell
\shich also generates spikes, they interplay with
excitatory and inhiljitory influences upon the elec-
trically excitable membrane. The inhibitory synaptic
action may occur independently of the magnitude
and even tiie sign of the inhibitory p.s.p. As will be
descriljed below (p. 160) this p.s.p. may be de-
polarizing under certain electrochemical conditions,
or the acti\'ity of the synaptic membrane may not
manifest itself as a potential. Nevertheless, when this
synaptic activity is pitted against a depolarizing
p.s.p. it always tends to decrease the magnitude of
the latter and thereby to diminish or block its ex-
citatory effect on the electrically excitaljle membrane.
In some cases, therefore, the term "inhibitory" p.s.p
msec
msec
FIG. 3. Synaptic transfer from the p.s.p. to the spike. Intracellulai" recording, eel electroplaque.
Above: Increasing stimuU to a nerve produced a stepwise increase of the p.s.p. (.4 to C). A still larger
stimulus evoked a spike (Z) and £). Below: The p.s.p. first generates a local, graded response of the
electrically excitable spike-generating membrane. When the neural stimulus evokes a p.s.p. during
the absolute refractory period {A', B'), the response lacks this component of giaded activity of the
electrically excitable membrane. Later (C to G") the local response develops, grows, arises earlier
and fuses with the p.s.p. The combined response is seen in isolation in H'. This series of records was
taken at approximately ' 1 0 the amplification of the upper set. Baseline denotes the zero for the
resting potential and for the overshoot of the spikes. [From Altamirano el al. (4).]
SYNAPTIC AND EPHAPTIC TRANSMISSION
153
is more apt than 'hyperpolarizing' p.s.p., btit the
lattei term may be extended to denote a tendency
to maintain as well as to increase the resting potential.
Interrelations of Postsynaptic Potentials and Spikes
It has been noted above that the p.s.p. is not ac-
tively propagated as is the spike. Thus, the transmis-
sional electrogenesis of a p.s.p. is confined to the syn-
aptic site. While their local electrical activity can be
recorded in or about the cells that produce it (cf.
51, 70), p.s.p.'s do not, in general, evoke activit\' in
other cells, their effects being confined to the cell in
which they originate.
To elicit 'distant' actions in the next postjtinctional
cell, the prejunctional cell must generate a spike.
Thus, transmissional activity in a synaptically linked
chain of units is consummated only if the p.s.p. of each
unit evokes a spike. When the depolarizing p.s.p. in
one of the linked elements is insufficient to elicit a
spike, the transmissional chain is broken. Likewise, if
at one synaptic site, inhibitory p.s.p. is sufficiently
large to block the spike of that cell, the chain is also
broken.
Thus, spikes and p.s.p.'s are functionally interre-
lated. The former command the secretory activity at
presynaptic terminals of their cell, and the released
transmitter agent then evokes the p.s.p. of the next
cell, which may or may not itself elicit a new spike, to
repeat the process. It should be noted that while
hyperpolarizing p.s.p.'s can inhibit spike production,
they are themselves evoked by an excitatory activity
in the presynaptic cell that propagates within the
latter and effects the hyperpolarization of the post-
junctional synaptic membrane through the secretory
activity that it calls forth in the presynaptic terminals.
In other words, a p.s.p., whether excitatory or
inhibitory, always represents an active process, a
response of subsynaptic membrane to an appropriate
excitant.
As was noted abo\e, and will be descriiied in more
detail below, the electrically inexcitable synaptic
electrogenic membrane has different properties from
those which generate the spike. The properties even of
simple synaptic s\stems are therefore compounded
from and subject to the various properties of the differ-
ent electrogenic components. The multiplicity of syn-
aptic transfers in the central nervous system makes the
synaptic properties a dominant factor, although those
of conductile electrogenesis are also important. Since
the amount and type of synaptic electrogenesis deter-
mines the occurrence or absence of spikes, factors
which modify p.s.p.'s are therefore of sjreat significance
in the central nervous system. Among these are the
effects of pharmacological agents or synaptic drugs,
and their use as experimental tools has already been
mentioned. However, other agents and physiological
conditions may affect production of p.s.p.'s. For ex-
ample, the synaptic membrane may be altered in its
properties by previous activity (cf 95, 97; and below)
and this could affect synaptic electrogenesis. The
physiological properties of the presynaptic terminals
may also be changed by various conditions, including
previous activity. This change might affect the amount
or nature of the transmitter agent released under the
new circumstances and thereby aflfect transmission.
Thus, the magnesium ion interferes with release of
transmitter agents from the presynaptic terminals
(cf. 52). Neuromuscular transmission is then depressed
or blocked. The calcium ion acts reciprocally and in
excess antagonizes the effects of excess magnesium
ion.
SPECIFIC PROPERTIES OF SYN.APTIC ELECTROGENESIS
Evidence Against Electrical Stimulation of
Postsynaptic Potentials
The existence of varieties of postjunctional cells in
which p.s.p.'s are generated without spikes, e.g. in
Torpedo and Raia electroplaques, invertebrate and
vertebrate muscle fibers and gland cells (cf. 95, 97),
provides one kind of direct evidence for electrical
inexcitability of synaptic membrane (figs. 4/I, 5; cf.
fig. 20). An electrical stimulus which does not fire the
presynaptic nerve fibers evokes no electrical activity
in these cells. Responses are only produced by afferent
neural activity or by chemicals which thus mimic the
action of the transmitter agent (fig. 5).
Even in those cells which also generate spikes, the
p.s.p. is produced only by neural or chemical stimuli.
Direct electrical stimuli applied to the cell, or its local
circuit excitation by antidromic invasion, evoke only
spikes without p.s.p.'s (fig. 6). Finally, the occurrence
of spikes and of absolute refractoriness which is their
concomitant does not preclude the independent
development of p.s.p.'s. The electrogenesis of the
latter then can be superimposed upon that of the
spike, i.e. it can be evoked during the absolute refrac-
tory period (figs. 6, 7). Together therefore, these three
types of data provide direct evidence that the p.s.p.'s
are generated by membrane that is not itself electri-
'54
HANDBOOK OF PHYSIOLOGY ^ NEUROPHYSIOLOGY I
^
TABLE I. Characteristics and Properties of Differently
Excitable Electrogenic Membrane
FIG. 4. Differences between electrically inexcitable and ex-
citable membrane. A : The slow muscle fiber of the frog is not
electrically excitable and produces no spikes, even when the
membrane is strongly depolarized at beginning of (a). It
develops p.s.p. on stimulation of the nerve during the applica-
tion of the electrical pulse. The response at the resting potential
(«), a depolarizing p.s.p., is increased when the membrane is
hyperpolarized by the applied pulse (/, g). The p.s.p. is de-
creased by depolarizing the membrane (</) and is reversed in
direction by strongly depolarizing the membrane (a to f)- The
magnitude of the reversed depolarizing p.s.p. increases as the
interior of the membrane is driven beyond an equilibrium po-
tential given approximately by the pulse in c. [From Burke &
Ginsborg (35).] B: Responses of a cat motoneuron to ortho-
dromic stimuli show essentially the same behavior of the p.s.p.'s,
but are complicated by the appearance of a spike and the inac-
tivation of electrically excitable membrane. The response at the
resting potential ( — 66 mv) is a depolarizing p.s.p. which does
not elicit a spike. Hyperpolarization of the membrane caused
little change in the p.s.p. Depolarizations to —60 mv and —42
mv summed with the excitatory effect of the p.s.p., evoking
spikes. These are no longer produced by the p.s.p.'s at the rest-
ing potential — 32 mv, etc. These depolarizations, after evoking
spikes by the electrical stimuli, then inactivated the spike-
generating membrane. The p.s.p.'s decreased and at a mem-
brane potential of +3 mv disappeared but reappeared in
reversed sign as the internal face of the membrane was made
more positive. [From Eccles (60).]
cally excitable. Other properties of p.s.p 's that dis-
tinguish them from spikes are also referable to this
Spike
(Electrical^ Excitable)
P.s.p.'s
(Electrically Inexcitable)
A. Characterisii
Transducer action;
(i) Sequential increase of
Na^ and K+ conduct-
ances and Na* inactiva-
tion
(ii) Rates determined by
membrane potential
Electrical response:
(i) Begins with graded de-
polarization, develops
overshoot
(ii) All-or-none response
Two types:
a) increased conductances
for all ions
A) specific increase in K+
and/or Cl~ conduct-
ances
Rates not determined by
membrane potential
Two types:
a) depolarizing
6) hyperpolarizing
Graded response
B. Direct Evidence Jor Characteristic Differences
Developed only by neural or
(i) Spike absent |
(ii) Spike presentj
chemical stimuli
C. Consequences of Characteristic Differences
(i) Always in depolarizing
direction
(ii) Hindered or blocked by
hyperpolarization
(iii) Excited, then blocked
by depolarization
(iv) Pulsatile, relatively
fixed duration inde-
pendent of stimulus
(v) "Vanishingly brief la-
tency
(vi) Relatively inert to
chemicals
(vii) Decrementless propaga-
tion
Of either sign, electrochemi-
cally reversible
Electrochemical gradation
Electrochemical gradation
May be prolonged, sustained
while stimulus lasts
Appreciable, irreducible la-
tency
Sensitive in two ways: re-
sponse may be
a) evoked by synapse acti-
vators;
i) depressed or blocked
by inactivators
Nonpropagated, 'standing'
potential
single, fundamental difference in their modes of
excitation. These correlations are summarized in table
I, and form the content of this section (cf. also 97).
Mechanisms of Bioelectrogenesis
The means by which a cell can generate electrical
activity are restricted in variety by the nature of the
physiological and electrochemical systems of living
tissues (91, 112, 113). Conductile and transmissional
SYNAPTIC AND EPHAPTIC TRANSMISSION 1 55
A - r\ B
FIG. 5. Electrogenic action of acetylcholine on the elec-
trically inexcitable membrane of Torpedo elcctroplaques. Intra-
arterial injections of 10 /ng (/), 5 /ig (//) and 2.5 /ig (/!') in the
presence of physostigmine produced electrical activity, the
larger amounts evoking the larger responses. The neurally
evoked discharge of Torpedo organ lasts only a few msec. (cf.
95). The long duration of the response produced by injections
of acetylcholine presumably is due to sustained depolarization
of the electrically inexcitable elcctroplaques by an excess of the
administered transmitter agent. /// indicates a control in which
only perfusion fluid was injected. The elcctroplaques were
probably depolarized in the 'resting' state, and the 'hyper-
polarization' seen in this record may have been caused by
temporary dilution of the depolarizing e.vcitant. Calibrations:
0.5 mv, and seconds. [From Feldberg & Fessard (74).]
excitable membranes utilize the electrical polarization
or resting potential of the cell. This appears as a
potential difference across the cell membrane with its
interior negative relative to the exterior. At rest, the
membrane has a rather high resistance, indicating
that it presents a considerable barrier to the penetra-
tion of ions. The physiological electrogcnic response
of the membrane to an appropriate stimulus, its
transducer action (94), is the temporary alteration of
its permittivity to ions. The electrical change is its
consequence, derived from the prior, metabolically
energized unequal distribution of ions and the resting
potential.
Whereas the spike is generated by temporally
sequential processes comprising first enhanced sodium
conductance, then enhanced potassium conductance
and sodium inactivation(ii3),^ the transducer actions
of svnaptic membrane involve different ionic events.
- Recent data on eel elcctroplaques (3) indicate that a process
of potassium inactivation may be involved in spike production
(95). The participation of other, potential-insensitive processes
is discussed below in connection with graded responses of
electrically excitable membrane.
FIG. 6. Some differences between electrically and neurally
excitable responses. A, B: Weak and strong depolarizing elec-
trical stimuli to the eel electroplaque excited the cell directly,
the latter with almost no latency. C, D: The stimuli were ap-
plied in the reverse direction. These are ineffective for the
electrically excitable membrane but stimulate the cell indirectly
by way of the nerve terminals supplying the synaptic mem-
brane. The weak indirect stimulus evoked only a p.s.p. after a
latency of almost 2 msec. (C). The very strong stimulus (i))
shortened the latency to about 1.7 msec, and the larger p.s.p.
evoked a spike with very brief delay. No p.s.p.'s were produced
by the direct stimuli. However, the strong direct stimulus (B)
also excited the nerve fibers which csokcd a p.s.p. that occurred
with the same latency as in C and D but appearing this time on
the falling phase of the directly elicited spike. The p.s.p. there-
fore occurred while the electrically excitable membrane was
absolutely refractory. [From Altamirano et al. (4).]
Depolarizing p.s.p.'s are caused by a general increa.se
of permittivity to all ions (71 ; cf. 52, 60) which tends
to abolish the resting potential. Electrogenesis of
hyperpolarizing p.s.p.'s probably involves increased
permittivity for K+ and Cl^ (60, 61; Grundfest
el al., in preparation). Each ion species then moves in
the direction of its electrochemical gradient, K+
outward and Cl^ inward. Loss of positive charges and
gain of negative thus account for the increased
internal negativity.
The immediate consequences of electrical inexcita-
bility of synaptic transducer actions are made appar-
ent by the diagram of figure 8. Depolarization is the
stimulus that initiates transducer action of an elec-
trically excitable membrane. The entry of Na""",
forced inward because of the high concentration of
this ion in the external medium, causes further de-
polarization. This electrogenic response to the trans-
156 HANDBOOK OF PHYSIOLOGY -^ NEUROPHYSIOLOGY I
FIG. 7. Absence of refractoriness in postsyn-
aptic responses in the giant neuron of Aplysia.
A : A single shock to the presynaptic nerve first
evokes a long-lasting p.s.p. out of which rises
the spike of the giant neuron. B: A second stim-
ulus, exciting the cell during its refractory pe-
riod, adds a potential (solid line beginning at
arrow) to the initial response (broken line).
The difference (dotted line, below) is due to
the second p.s.p. C: The second stimulus was
delivered somewhat later. The added potential
also shows a local response (prep.") which was
initiated by the p.s.p. in the electrically ex-
citable membrane during the relatively refrac-
tory period. D: At a longer interval, a second
stimulus evokes the full response as in A. [Froin
Arvanitaki & Chalazonites (11).]
B
/>■»/»
looms
ducer action of the membrane can then act as a further
stimulus to the latter. The positive feedback of the
effect leads to a regenerative sequence and to the
explosive, all-or-none spike. Since the transducer
actions of electrically inexcitable membrane are not
affected by the electrogenesis of the p.s.p.'s, feedback
either positive (in the case of the depolarizing), or
negative (for the hyperpolarizing p.s.p.'s) is lacking.
Because of the absence of electrical feedback p.s.p.'s
of either sign are thus produced that are graded in
proportion to the availability of the specific excitants
of the respective transducer actions.
Ot/wr Consequences of Electrical Incxcitability
a) susT.oiiNED ELECTROGENESIS. Thc transducer actions
of the spike generator are a sequence of potential-
determined events, the first (.sodium conductance)
tending to cause the depolarizing electrogenesis,
others (potassium conductance, sodium inactivation)
tending to terminate it and to restore the resting
potential. The sensitivity of these processes to the
changes in membrane potential produced by the
electrogenesis itself thus leads to a self-limiting event,
the spike, of rather constant duration with which is
also associated refractoriness (113). Not being elec-
tricallv excitable, the transducer actions of the syn-
aptic membrane are relatively in,sensitive to the
changes of membrane potential. Hence, p.s.p.'s
may be sustained as long as the excitant of the trans-
ducer action is available (fig. g) since they are not
subject to refractoriness (figs. 6, 7) nor inactivation.
The transducers of most types of sensory membrane
are probably also electrically inexcitable (94, 95, 97).
The sustained graded electrogenesis which can de-
velop to a sustained stimulus is the means for trans-
mitting information by a train of pulsatile spikes,
coded as to frequency and number in some relation
to the intensity and duration of the stimulus (97, 103;
fig. 10; cf. fig. 13). The transducers of some mechano-
sensitive organs, at least, also have chemical sensitivity
(94, 96, 97), indicating further their relations with
chemically sensitive synaptic membrane.
Although the postsynaptic membrane, in contrast
to the electrically excitable, is capable of sustained
electrogenesis, its responsiveness to a steady stimulus
mav be affected in various ways. These reflect the
labilitN of thc membrane in the face of the very chemi-
cal agents by which it is excited (95, 96). An example
is the gradual diminution or even disappearance of
synaptic electrogenesis when a muscle or autonomic
ganglion is continuously acted upon h\ acet\ Icholine
or other agents (123, 127, 129, 187).
SYNAPTIC AND EPHAPTIC TRANSMISSION
157
Stimulus
Transducer Action
(Increosed Memtifor^e
Conduclonce)
Electrogenesis Response
Electrical
(Depolarizing)
— No* -^
Depolarizotion — • Spike ond
decrementless
Chemicol
► General — ►
Depolonzotion — • Graded excitotory
posl-synoptic
potential
Chemical
► K+and/orCr — ►
Hyper- — ► Groded inhibitory
polorizotion post -synoptic
potential
FIG. 8. The different ionic mechanisms evoked by transducer
actions in electrically excitable and synaptic membranes, and
some consequences of the different excitabilities. The depolari-
zation caused by an electrical stimulus is regenerative in the
electrically excitable membrane and produces the all-or-none
spike. The electrically inexcitable synaptic membrane can
produce either depolarizing or hyperpolarizing p.s.p.'s which
do not react back on the transducer actions. This insensitivity
to electrical effects results in responses graded in proportion to
the available chemical stimulus. The depolarizing p.s.p. can
act as a stimulus for the electrically excitable membrane, while
the hyperpolarizing is inhibitory to the latter. [From Grund-
fest (96).]
The kinetics of this reversible desensitization have
been studied thus far only in frog muscle endplates
(fig. 11). The nature of the processes involved C127)
is not yet clear; but neither the loss of responsivene.ss
nor its recovery are controlled by the membrane po-
tential.
Desensitization may be slow and unimportant
relative to the excitatory events that occur at synapses
in response to their normal neural activation. How
ever, it might become a disturbing factor if trans-
mitters are continuously released locally or svstem-
ically. This situation could result from the action of
drugs or might arise from a pathological state. Rapidly
developing desensitization has not yet been described,
but it might account for the successively decreased
p.s.p.'s sometimes produced by a train of stimuli.
This process has been termed 'defacilitation' (33,
186). Decrease in the generator potential of sense
organs acted upon by a constant stimulus, such as is
seen in the rapidly adapting stretch receptors of cray-
fish (66), might be accounted for by a desensitization
phenomenon.
100 msec
i—r
15 msec
T M M
FIG. g. Soine consequences of the differently excitable electrogenic mechanisms in neurons, a.'
The cat motoneuron excited antidromically at high frequencies (140, 205, 280 and 630 per sec.)
produces pulsatile spikes, only their after -potentials fusing. [From Brock et al. (25).] b: The p.s.p.'s
produced by orthodromic stimuli (205 and 280 per sec.) summate, a higher average level of the de-
polarization being produced by the higher frequency of stimulation. The summated response is
maintained as long as the afferent stimuli are delivered (lower record of each set). The amplitude
calibration applies to the p.s.p.'s of this .set which were taken at about lox the amplification of a.
[From Brock et al. (24).] c: Repetitive activity evoked in the rabbit cervical syinpathetic neuron by
stimulating the preganglionic supply at approximately 80, 100, 120 and 150 per sec. At the time
scale of the records the first p.s.p. is not shown (cf. fig. 17C). The p.s.p. evokes a large spike; but
even at the lowest frequency, the spikes caused by the subsequent p.s.p.'s are small, while the p.s.p.'s
themselves are summed and sustained. This synaptic depolarization, increasing at higher frequencies
of afferent drive, inactivates the spike-generating membrane. \i\.er the second depressed spike the
responses progressively decrease, and at the highest frequency disappear. The p.s.p.'s are generated
as long as there is an influx of presynaptic stimuli. [From Eccles (64).]
158
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
lOmV T
wUWWwWUUUWwwUUWUUUvi
1 1 I
!
FIG. lo. Depolarizing electrogenesis of crayfish mechanoreceptor sense organ and the effects it
evokes in the electrically excitable portion of the cell. Top: A weak stretch stimulus (I) caused a
depolarization of about 7 mv across the membrane of the cell body. This was maintained until the
stretch was released ( 1 ). Aliddle: Records at lower amplification. A weak stimulus produced a low
frequency discharge of spikes. Increased stretch (second arrow) caused a higher frequency discharge
which continued with some slowing as long as the stimulus was applied. The spikes generated during
the depolarization develop a hyperpolarizing undershoot which is absent when the response is
evoked by a single electrical stimulus. Bottom: Three increasingly larger stimulations are shown in A
to C. The spikes produced at high frequency by the strongest stimulus (C) were diminished in ampli-
tude and at the end were no longer evoked, while the receptor continued to respond with its sus-
tained, summated depolarization. D to F: The return of responsiveness of the electrically excitable
membrane after its inactivation. Note that the average level of the depolarization produced by the
mechanoreceptor dendrites is graded with the degree of the stimulus. [From Eyzaguirre & KufHer
(66).]
b) P0STSVN.\PTIC POTENTI.ALS DURING HYPERPOL.^RIZ.^-
TiON AND DEPOLARIZATION. P.s.p.'s Can bc produccd
during hyperpolarization of the cell, while spike
electrogenesis may be blocked (fig. 1 2). These differ-
ent effects may be ascribed directly to the different
modes of excitation of the electrogenic membrane
components. The effects produced by depolarization
are somewhat more complicated but can also be
accounted for on the same basis. Superposition of
depolarization by a brief extrinsic electrical stimulus
and that of a depolarizing p.s.p. enhances the excita-
tion of the electrically excitable membrane (4, 60,
79). The spike thus arises earlier on the p.s.p. since
the critical level of depolarization is thereby attained
earlier.
Sustained depolarization, in some cells even when
rather small, blocks spike electrogenesis (fig. 13}
probably (cf. 95, 96) by the augmentation of sodium
inactivation and potassium conductance that it causes
in electrically excitable membrane (113). Electrical
inexcitaijility of synaptic transducer action permits
the continued development of p.s.p.'s after the spike
can no longer be produced by direct or neural stimuli
(figs. II and 13). Other manifestations of synaptic
activity can also be evoked when the spike generating
membrane is inactivated by ionically induced depolar-
ization (50). The generator potential of a sense organ
(fig. 10) may also continue to be produced even
though that sustained depolarization inactivates the
electrically excitable membrane and no spikes can
SYNAPTIC AND EPHAPTIC TRANSMISSION
159
FIG. II. Desensitization of the synaptic membrane of frog sartorius muscle fibers by sustained
applications of acetylcholine. The drug was applied through each of two pipettes close to the surface
of the endplate. From one pipette it was released at regular intervals in brief jets of approximately
constant quantity. These testing stimuli are signaled by dots on the lower line in each set. The upper
line shows the response of the endplate recorded with an internal microelectrode. The e.p.p.'s in
these records are compressed on the slow time scale. In the course of the recordings a larger longer-
lasting jet of diflTerent amounts of acetylcholine was also applied to the endplate as a conditioning
stimulus. Lejt: An otherwise normal preparation, a: The conditioning stimulus was a weak dose of
acetylcholine applied for a long time, b to d: The concentration was higher, and the drug was applied
for different times. The testing responses diminished progressively during the depolarization pro-
duced by the conditioning stimulus. Their amplitudes recovered gradually after the conditioning
depolarization had ended. Note that the recovery from desensitization is not associated with further
change in potential. The recovery process therefore is not controlled by the membrane potential.
Right: The muscle was immersed in isotonic potassium sulfate which depolarized the fibers and
rendered them unresponsive to electrical stimuli. The tested muscle fiber was made inside-positive
by about 15 mv by means of an intracellularly applied current. The synaptic membrane remains
excitable to acetylcholine following these procedures, but the sign of the response is now reversed
for reasons that will be discussed in the third subsection of this portion of this chapter. The membrane
still exhibits desensitization to different intensities of the excitant drug (jop to bollom). The desensiti-
zation process itself therefore is also not controlled by the membrane potential. At the end of the
lower record the internal recording electrode was withdrawn from the muscle fiber (at the arrow}, the
trace going from a level of internal positivity to that of the reference zero potential. [From Katz &
Theslefr(i27).]
develop. Thus, the sustained depolarization at
sensory receptor terminals or at synaptic junctions,
which is a property of electrically inexcitable mem-
brane while initially excitatory for the associated
electrically excitable spike generator can, secondarily,
inactivate the latter and thereby block further conduc-
tile or transmissional activity.
This effect accounts for Wedensky inhibition, the
failure of transmission produced by stimulating the
presynaptic nerve at high frequency. Summated and
sustained by this synaptic drive, the depolarizing
p.s.p.'s at first evoke a few spikes which then cease to
develop while the large p.s.p.'s continue to be pro-
duced by the afferent stiinulation (fig. 9). Although
Weden.sky inhibition is probably of little importance
in physiological activity of organisms, the phenom-
enon has long interested physiologists because the
attempt to explain it in terms of electrical excitability
has proved uncon\incing (cf 81, 141). The presence
of electrically excitable and inexcitable electrogenesis
i6o
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
FIG. 12. Different effects on spikes and p.s.p.'s of cat motoneurons produced with different amounts
of membrane polarization. Tlie membrane potential was changed by passing an appropriate cur-
rent through the recording microclectrode. A Wheatstone bridge arrangement balanced out the
artifacts caused by this current, but as a consequence absolute levels of the membrane potential
could not be measured. Upper set (^A to G): Two traces are simultaneously recorded, the upper indi-
cating the amount of current flow through the electrode, the lower showing the recorded potentials.
.-1 to C, decreasing amounts of depolarizing current; D, no applied current; E to G, increasing
amounts of hyperpolarizing current. The records are aligned so that the peaks of the spikes coincide
(upper broken line). The parallel lower broken line passes through the point at which the spike
begins. When the strong depolarizing current was applied in .4, it quickly evoked a direct spike.
A subsequent orthodromic volley evoked a p.s.p. which reached the critical firing level but found
the electrically excitable membrane still refractory. Hence, an orthodromically evoked spike was
absent. At the end of this and subsequent records is a 50 mv calibrating pulse. B, C, the depolariza-
tions from the applied current were smaller. They did not elicit a spike; but summing with the de-
polarization of the p.s.p. evoked a spike earlier than the orthodromic volley alone did (D). Hyper-
polarization of the membrane operated in the opposite direction, hindering the orthodromically
evoked spike which appeared markedly late on the p.s.p. in F, and was absent in 6', although the
p.s.p. in the hyperpolarized neuron was larger (compare the p.s.p.'s in A and G). A small deflection
which follows the artifact of the stimulus to the nerve and precedes the p.s.p. by neaily i msec, is
probably elcctrotonic pick-up of activity from the presynaptic impulses. Note that it is too small to
evoke the spike. Lower set QA' to F'). In this experiment the spikes were elicited by antidromic in-
vasion from the motor axons. A' to C, decreasing amounts of membrane depolarization; D\ no
applied current; E' and F', currents applied so as to produce increasing membrane hyperpolariza-
tion. The antidromic spike (Z)') shows an inflection which probably represents a response first in
the axon hillock portion, succeeded by involvement of the rest of the cell. Depolarization of the
cell body facilitates its invasion by the antidromic spike and minimizes the inflection on the rising
phase. It is almost absent when the cell is strongly depolarized (.-l')- Hyperpolarization hinders the
invasion of the cell body (F') and when it is strong (F') prevents the response of the soma. The
smaller, early component is then seen in isolation as pick-up at the cell body of the response in the
axon hillock and nerve fiber. Timing pulses at i msec, intervals are injected into the records. [From
Frank & Fuortes (79).]
in the same cell also permits blockade of spikes by
synaptic depolarization induced by drugs that excite
the synaptic membrane (fig. 13). This blockade is
frequently useful clinically but it in often misnamed
as'curarization" (cf. 96). Blockade by o'-tubocurarine
and other similarly acting agents operates through an
entirely different mechanism as will be described
below.
c) ELECTROCHEMICAL GRADATION AND REVERSAL OF
POSTSYNAPTIC POTENTIALS. Although Synaptic trans-
ducer action is not responsive to electrical stimuli,
SYNAPTIC AND EPHAPTIC TRANSMISSION
l6l
o
D"
0",;
■^
— - —
E"
E"'
•tz
FIG. 13. Differential effects of depolarization on the spike
and p.s.p. of the eel electroplaque. Column A to F, direct
stimulation i columns A' to F', etc., weak, moderately strong,
and very strong stimuli to a nerve. A to A'", the response of the
normal cell. The resting potential is about 80 mv seen as the
deflection of the active trace downward from the zero line
(upper trace). The strong direct stimulus evoked a spike with
very brief latency (.4). The weak neural volley caused a p.s.p.
CA'"), the stronger also a spike (.-!" and .-!'") arising out of the
p.s.p. The cell was treated with weak physostigmine (25 ^g per
ml solution) for 78 min., and weak acetylcholine (i ixg per mg)
for the last 58 min. of that period. These drugs had no effect
on the potentials; 5 ftg per ml acetylcholine were then added.
Depolarization developed, the spikes 36 min. later becoming
smaller, but the p.s.p. was unaffected (S to /?'"). The diminish-
ing electrically evoked response g min. later (C to C") became
graded, as seen by its larger size in response to the strong neural
volley. These effects progressed during the next ig min. (/) to
Z)'") and 1 1 min. thereafter (£ to £""). The p.s.p. to the
threshold neural volley decreased (£"). but was still evident
later (F') when the electiically excitable membrane no longer
responded to a much stronger direct stimulus (F). The p.s.p.
to a maximal neural stimulation (f ") was still about as large
as initially (^"')- This p.s.p. was capable of evoking a small
graded response of the electrically excitable membi^ane, as seen
by the delayed additional potential on the falling phase. [From
Altamirano el al. (6).]
the magnitudes of the p.s.p.'s and also their signs may
be affected by changes in the membrane potential
(52, 60, 97). These effects, however, are secondary
and, indeed, are explicable only by the electrical
inexcitability of postsynaptic electrogenic membrane.
Suppose that a transducer action increases solely
the permittivity for CI~. More of this ion being present
in the external fluid, it tends to flow inward until the
increased internal negativity tends to prevent further
entry. Thus, the direction and amount of ionic flow
is determined both by the chemical concentration
gradient and by the electrical potential gradient, the
coinbination being termed the electrochemical gradi-
ent. For a given concentration gradient there is a
corresponding potential gradient at which the flow
of ions is balanced by the opposite force of the elec-
trical charge. If the membrane resting potential is
increased by some means, the electrogenesis caused by
influx of Cl^ would reach the electrochemical poten-
tial (Ecr) for that ion sooner. The hyperpolarizing
p.s.p. would therefore appear to be smaller. If the
membrane potential is made more negative than Eci~,
Cl~ in the cell would be forced outward. The p.s.p.
would then appear to reverse in sign, depolarizing the
hyperpolarized membrane approximately to the level
of Eci~. This effect is seen in figure 14I.
The p.s.p. can likewise be affected by changing the
Cl^ concentration either of the interior or of the
exterior. For example, suppose that the external Cl~
is replaced by another anion which does not penetrate
the membrane. During transducer action, Cl~ would
move out from the cell since it is now more concen-
trated in the interior. The electrogenesis of hyper-
polarizing p.s.p.'s can thus be reversed to depolariza-
tion. The effect of increasing internal Cl~ is seen in
figure 14. Secondary electrochemical effects therefore
can change the amplitude or sign of the p.s.p.
In the case of the depolarizing p.s.p.'s, increase of
resting membrane potential inay lead to increased
electrical responses; decrease of the resting potential
decreases and eventually reverses the sign of the de-
polarizing p.s.p.'s. These various conditions for
electrochemical grading and reversal of the p.s.p.'s
are found experimentally (figs. 4, 11, 14). The grading
and re\ersal of p.s.p.'s are strong evidence that the
tran.sducer actions of synaptic membrane are not
electrically excitable (97) since the physiological
responses are not affected even by violent changes of
the membrane potential, though the electrogenesis
itself is modified.
Cat motoneuron p.s.p.'s are electrochemically
reversible (cf 60), but anomalies have been observed
that are instructive. In theory, as outlined above, the
apparent 'depolarization' of a reversed hyperpolariz-
ing p.s.p. should only return the membrane potential
to the saine level as does the hyperpolarization of the
normal p.s.p. The 'depolarization' therefore should
not reach the critical firing level for the spike, the
membrane in theory still remaining at a hyperpolar-
ized level, and the 'depolarizing' p.s.p. should not
become excitatory. Frequently, however, this is not
the case when the reversal is produced by changing
the ionic concentration gradients of the motoneuron.
j62
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY
IT
CX " B I C
FIG. 14. Reversals of hyperpolarizing p.s.p.'s. Intracellular
recording from biceps-semitendinosus motoneuron of cat; hy-
perpolarizing p.s.p.'s evoked by stimulating quadriceps nerve.
I. A to G: The resting potential was —74 mv (Z)). Depolari-
zation augmented the p.s.p. (.4 to C). Hyperpolarization at
first diminished the p.s.p., the equilibrium potential for ionic
movements without electrogenesis being at —82 mv (£). Fur-
ther hyperpolarization reversed the sign of the p.s.p. (F, G).
The Cl~ content of the motoneuron was then increased and
K+ decreased (H to Z,). Immediately thereafter (J to Z.) the
p.s.p. was 'depolarizing' at all but the least negative values
'(//, /) of the membrane potential. M to Q: Recovery toward
initial condition not yet complete 3 to 4 min. later. II. Reversal
of the sign of the p.s.p. was produced by changing the ionic
gradient of Cl~. Initial response 0-1) was altered in B and C by
increeising intracellular Cl~ as a result of diffusion out of the
tip of the microelectrode. Depolarization of the membrane to
— 27 mv by an applied current restored the sign of the p.s.p.
(D). The Cl~ gradient was then changed drastically. The re-
versals of the p.s.p.'s produced soon thereafter (is to G) oc-
curred without significant change of the resting potential and
were sufficient to excite spikes, at first with brief latency (£),
then progressively later (F and G). Each record is formed by
superposition of many traces. In G it is seen that the depolari-
The initial resting potential may then be altered little
or not at all, as is also the case with microinjections of
ions into squid giant axons (cf. 91, 105). The changed
chemical gradient of the motoneuron then causes a
reversal of hyperpolarizing p.s.p.'s into depolarization
which develops at, or near, the initial resting poten-
tial. The reversed 'inhibitory' p.s.p. now may elicit a
spike (fig. 14II).
In crustacean muscle fibers (68, 73) and stretch
receptors (130) the equilibrium potential for the
inhibitory p.s.p. is nearly identical with the resting
potential. Stimulating the inhibitory axon therefore
may elicit no p.s.p., or the latter may be small, and
of either sign. Nevertheless, the membrane potential
tends to be clamped at or near the resting potential,
particularly if the activity of the inhibitory synaptic
membrane increases markedly the permittivity of
the membrane for the relevant ions (K+, Cl~ or
both). Excitatory depolarization, elicited at the
same time, by p.s.p.'s in muscle fibers or by mechano-
sensory dendrites in stretch receptors, therefore tends
to be depressed. When the inhibitory synapses of
lobster muscle fibers are maximally activated by
7-aminobutyric acid the membrane potential is
increased by about 4 mv, but the membrane con-
ductance is increased about 8-fold (Grundfest,
Reuben & Rickles, in preparation; cf. 99).
d) LATENCY OF posTSYN.-^PTic POTENTIALS. As men-
tioned above, the onset of the explosive response of
electrically excitable membrane depends upon the
attainment of a critical level of depolarization. A
strong electrical stimulus, causing rapid depolariza-
tion to that level, therefore evokes a spike with vanish-
ingly brief latency (fig. 6), this fact having been
established by Bernstein in 1871 (19). In all cases
zation occasionally fell below the critical firing level and con-
tinued to decrease in the later records (// to L). III. The
membrane generating hyperpolarizing p.s.p.'s maintains its
pharmacological individuality, although the electrical response
may be reversed and is then indistinguishable from that of a
depolarizing p.s.p. Prior to taking this scries of records the
hyperpolarizing p.s.p. evoked in the biceps-semitendinosus
motoneuron by stimulating quadriceps afTercnts was reversed
(by diflfusing Cl~ from the electrode into the cell). This response
is shown at the beginning of each record (/). Following it is a
depolarizing p.s.p. (£) evoked by stimulating afferents in the
biceps-semitendinosus nerve. Strychnine salicylate (o. i mg per
kg) was injected after record A and caused progressive diminu-
tion of 7, but no change in £ during the next 4 lo-sec. intervals
(fi to £). The reversed hyperpolarizing p.s.p. almost disap-
peared after a second injection (f ). [From Eccles (60).]
SYNAPTIC AND EPHAPTIC TRANSMISSION
163
where appropriate data are available (of. 97) the
neurally evoked response arises after an appreciable
irreducible latency (fig. 6), or synaptic delay (44;
cf. 140).
Between the arrival of the presynaptic impulse and
the onset of the p.s.p. of cat motoneurons there is a
latency of about 0.3 to 0.4 msec. (59, p. 130). In the
eel electroplaque the latency attains i to 2.5 msec.
(4). This delay is not conducive to, nor consistent with,
electrical excitation of synaptic membrane by the
action current of the presynaptic impulse (97) as was
pointed out by du Bois-Revmond (55) and Bernstein
(20).
Presumably, synaptic latency is compounded from
the durations required: (T) for release of transmitter
from the presynaptic terminals; («) for its transit
across a synaptic space of about 100 A (52, 54, 152,
153' '74' 553)' ^"^^ ("') fo'" development of the
electrogenic reactions when the transmitter acts
upon the postsynaptic membrane. The details of
none of these components are as yet known.
e) electrotonic effects of presynaptic impulse
UPON postsynaptic region. Intracellular recording
revealed (cf. 59, 60) that the presynaptic spike not
only arrived too early, but also that its electrotonic
efTect was too little to cause electrical excitation of the
postsynaptic membrane. Indirect stimulation of the
eel electroplaque (fig. 6C, D) excites the terminal fibers
innervating the cell membrane. Their spikes must
have occurred with vanishingly small latency upon
strong stimulation (Z)). However, no trace of elec-
trotonic effects in the electroplaque was found. The
presynaptic impulses could not be observed even at
high sensitivity of recording (fig. 3). In other prepara-
tions small, brief as well as early electrotonic pick up
of the presynaptic spikes is observed (cf. figs. 19,
2 J A). The magnitudes, i or 2 mv, are insignificant for
electrical excitation which requires critical depolari-
zations of some 10 to 40 mv.
Among the possibilities for accounting for the small-
ne.ss of electrotonic effects across synapses are the
following.
/) Theresistanceof one or both cell membranes may
be very high. In most types of synapses the presynap-
tic terminals making contact with postsynaptic
membrane are very small and this alone would de-
crease the electrotonic effects. However, the contact
between the pre- and postfibers in the .squid giant
axon synapse are broad, yet the electrotonic post-
junctional potential is small (fig. 19). Likewise, in the
eel electroplaque where the innervation is diffused
widely over the cell membrane electrotonic effects are
small.
2) The bulk of the synaptic current may be shunted
by the subsynaptic space.
3) If the nerve terminals were themselves elec-
trically inexcitable neurosecretory regions the spike
would not invade the nerve proximate to the synapse.
The extrinsic current in the synaptic region would
thus be already attenuated by electrotonic losses.
f) CHEMICAL SENSITIVITY OF SYNAPTIC MEMBRANE.
Many varieties of drugs exert effects upon synapses,
but they either do not affect electrically excitable
membrane or do so only when applied in high con-
centrations and for long times (6, 96). The high
sensitivity of synaptic membrane to chemicals is prob-
ably also a con.sequence of its chemical excitability.
Thus, many drugs cause synaptic electrogenesis,
thereby mimicking the effects of the natural trans-
mitter agents. The.se substances are known as ' de-
polarizing drugs' but are more properly designated
as 'synapse activators' (95, 96) for their action is
merely that of excitants. The type of synaptic electro-
genesis is determined by the nature of the synapse
itself For example, acetylcholine and its mimetics
cause depolarization when applied to muscle end-
plates or sympathetic ganglia, but when applied to
the cardiac pacemaker synapses which are hyper-
polarized by vagal stimuli the drugs also cause hyper-
polarization (49, 1 20). A second group of substances,
the' synapse inactivators', hinder or prevent excitation
of the membrane bv the activator drugs. These are
also called ' nondepolarizing competitive inhibitors'
(155)-
Both types of substances may cause block of trans-
mission. Depolarizing excitatory p.s.p.'s are dimin-
ished in amplitude or prevented by the inactivating
drugs. The decrease of the p.s.p. below the critical
level for discharging spikes is the mechanism of the
synaptic blockading action of these drugs. Curare or
</-tubocurarine act in this way (fig. 15). A general
feature of blockade by inactivating drugs is that the
electrically excitaijle membrane is affected little or
not at all. Thus, the postjunctional cell can remain
directly excitable.
Synapse-activating drugs induce transmissional
blockade by an entirely different mechanism which is
referrable to the fundamentally different excitabilities
of electrogenic membrane. Acting on the synaptic
membrane, the drugs evoke depolarization of the
excitatory synapses. This electrogenesis, sustained in
164
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
FIG. 15. Effect of nondepolarizing synaptic blocliing agents
on the responses of the eel electroplaque. Direct stimulation of
the cell is represented in A to F, neural excitation in A' to C.
The initial responses to both stimuli are shown in .4 and A'. At
3 min. after substituting a bathing solution containing 5 mg
per ml o'-tubocurarinc, the directly elicited spike was unchanged
(B), but synaptic excitation was less effective, the spike arising
later on the smaller p.s.p. (£')■ A* 5 ""in. (C, C) the directly
elicited response was still unaffected, but the p.s.p. had de-
creased so much (,C") that it was seen only with repetitive
stimulation at 50 per sec, and produced a single small 'spike,'
after which it could no longer affect the electrically excitable
membrane. The latter, however, remained fully responsise to a
direct stimulus 41 min. later (/)), but eventually this responsive-
ness decreased (96 min. later, E; and 1 1 o min. after this, F).
The resting potential of the cell was unchanged. Calibration
100 mv and msec. [From Altamirano et al. (6).]
the presence of the chemical stunulant, leads to
inactivation of the spike-generating membrane as
described above. The entire cell may then become
inexcitable by direct stimuli (fig. 13). In the case of
skeletal muscle fibers, the inactivating depolarization
is confined to the regions of the endplates and neuro-
muscular transmi.ssion is blocked Ijecause these
regions do not generate spikes. Neuromuscular jjlock-
ade evoked by 'depolarizing' synap.se activating drugs,
and blockade also at neuronal synapses, are usually
preceded by a brief period of hyperactivity. The dis-
organized contraction of muscles, frequently but
incorrectly termed 'fasciculation', is due to the initial
excitatory effect of the synaptic depolarization, the
individual muscle fibers responding to this stimulus
before their spikes are inactivated. Blockade by the
truly curarizing drugs, the inacti\ators of synaptic
activity, is not preceded l)y the excitatory eflfects.
Postsynaptic Potential': as \onpropagated
' Standing' Potentials
The local circuit current of activity, in combination
with electrical excitability, makes possible the con-
ductile property of electrically excitable, regenera-
tively responsive membrane (fig. 8). The all-or-none
character of the spike then leads to decreinentless
propagation. A consequence of electrical inexcitaljil-
itv is that the p.s.p.'s do not set off activity in other
portions of synaptic membrane. The electrogenesis is
therefore localized and does not propagate except
electrotonically as mentioned earlier (fig. 2). This
'standing' nature of p.s.p.'s has important physiologi-
cal consequences that will be discus.sed later. It also
introduces a technical complication in the interpre-
tation of potentials recorded from volume conductors.
The rules that apply to potentials generated by a
travelling impulse (cf. 140, 141) need not hold,
particularly since hyperpolarizing as well as depolar-
izing p.s.p.'s of the ' standing' variety can be produced
at various sites (cf. 161-167).' It is of more than his-
torical interest to note that Sherrington and his
colleagues sue:gested that the central excitatory state
(c.e.s.) "is a specialized manifestation of local exci-
tatory state." (44, p. 43). In the present da\- contexts,
the central excitatory state may be identified in large
measure with occurrence of depolarizing p.s.p.'s,
and the central inhibitory state with of hyperpolariz-
ing p.s.p.'s. However, phenomena such as desensitiza-
tion (p. 157) may obscure or eliminate this parallelism
between potentials and excitability. Thus, as appears
in figure 11, the depolarized but also desensitized
endplate may not respond to a stimulus. Such a condi-
tion might lead to blockade of transmission although
the background is one of depolarization. Desensitiza-
tion of hyperpolarizing synapses has not yet been
described, l)ut its occurrence is not unlikely. If it
exists, it could provide cases of lifting of inhibitory
blockade in the face of a background of hyperpolariza-
tion. It will be shown later that the responsiveness of
electrically excitable membrane (its local excitatory
state) can change without a parallel change of the
membrane potential, although the excitability of this
meinbrane is also a reflection of the action of tjraded
local responses.
' An extreme example of localized activity which is therefore
highly instructive has been reported in the cat cortex (150, fig.
19). Within a range of 20 /i in the depth of the cerebral cortex
the pattern and degree of electrical acti%ity undergoes great
modifications.
SYNAPTIC AND EPHAPTIC TRANSMISSION
165
Interaction of Graded Responses
Generated and propagated in electrically inexcit-
able membrane, p.s.p.'s can spread only by electro-
tonus (fig. 2), passively, without evokina; new activity
and with considerable decrement. As weak depolariza-
tions, p.s.p.'s acting upon adjacent, electrically excit-
able membrane may evoke graded local responses
(figs. 3, 7, 13). The latter are also decrementally
propagated, but the decrement may be smaller than
in the case of p.s.p.'s. The depolarizing activity of a
graded local response at one site may, in turn, give
rise to some degree of active response at other sites.
Thus, depending upon the local excitability of the
membrane and the amount of initial local response,
this graded depolarization may spread only passively,
or it may propagate with various degrees of active
contribution. The ultimate extent of the latter is that
which evokes a spike. This explosive process domi-
nates subsequent events since the magnitude of its
electrical activity usually far exceeds the require-
ments for continued local circuit electrical excitation.
In other words, when the spike generator has a high
safety factor, decrementlcss propagation is the rule.
The nature of graded local responses of electrically
excitable membrane will be discussed below (p. 167)
in conjunction with the mechanisms of gradation of
p.s.p.'s. Here, it is desired to stress that the two
graded responses provide a pathway for summative
gradation as a transition to the all-or-none spike
(fig- 3)-
EVENTS IN SYNAPTIC TRANSMISSIO.V
Functional Interrelations Within Single Cell
A generalized schema of the activities within a
single unit in a transmission chain is shown in figure
16. The input of the cell, the synaptic surface in the
present context, but which may also be the receptor
surface of a sensory cell (cf. 94, 96, 97), is activated
by a specific chemical stimulus and develops an
electrical response. Only the depolarizing variety,
excitatory for the conductile mechanism, need be
considered now. The p.s.p. may ije brief or long and
may give rise to a single spike or to a train of impulses.
This conductile activity, arriving at the terminus of
the cell, causes secretory activity which releases a
transmitter agent that can excite another unit of the
transinission chain or an effector.
INPUT , CONDUCTILE | OUTPUT
GENERATOR
ACTIVITY
CONDUCTILE
ACTIVITY
TERMINAL
ELECTROGENESIS
FIG. 16. Diagrammatic representation of functional com-
ponents and electrical responses of a receptor cell or neuron.
The electrically inexcitable input produces electrogenesis
graded in proportion to its specific stimulus and sustained as
long as the latter is applied. The possibility of hypcrpolarizing
electrogenesis is shown but is not further considered. The de-
polarization at the input, operating upon the conductile elec-
trically excitable component, can evoke spikes in the latter
coded in number and frequency in proportion to the depolari-
zation. These signals, propagated to the output, there command
secretory activity, roughly proportional to the information en-
coded in their message and sustained as long as the message
demands. The transmitter released at the output can initiate a
synaptic transfer by operating upon the depolarizing input of
another cell. The possibility of a special output electrogenesis
is indicated but is not further considered. The lower electrical
portion of this diagram may be compared with records from a
sense organ (fig. 10). [From Grundfest (97).]
Evolution of Electrogenic Membrane
The occurrence of receptor-effector cells in primi-
tive metazoa suggested to Parker (154) that the nerv-
ous systein ev'olved by parcellation of the two func-
tions among separate receptor and effector cells with
the interposition of a conductile element extending
from the receptor cell. Later in evolution, correlational
neuronal cells were presumed to have arisen. This
evolutionary schema may also be applied to the
individual cells, neurons and muscle fibers as well as
receptors (103). The receptor portion of the priinitive
unit was probably sensitive to specific stimuli and this
characteristic is retained at the electrically inexcitable
input of the present nerve cell, mu.scle fiber, gland or
receptor (fig. 16). The ouptut likewise inay be con-
sidered as representing the primitive effector, frankly
so in the contractile muscle fibers or in glands. The
terminals of the neurons likewise probably embody
the secretory capacity of primitive units adapted to a
new function, transmission at close contact. Other
neurosecretory cells of more general function are also
1 66
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY 1
common (179) and the electrically inexcitable secre-
tory cells of the adrenal medulla are regarded as
second order autonomic neurons (cf. i 77).
The conductile portion of the neuron, generating
all-or-none spikes and therefore capable of decre-
mentless propagation, requires electrical excitability
for this function. It is probably a later evolutionary
development (21) brought about in the course of
extension of the cells in the metazoa and of their
participation in complexly organized activity. That
the conductile activity represents a new evolutionary
step, mediated by a structure interposed between the
primitive input and output sections, is also suggested
by the absence of conductile electrogenesis in gland
cells and by their electrical inexcitability (96, 97).
The occurrence of muscle fibers which are also not
electrically excitable and which generate no spikes
(4, 34, 35, 97) reinforces this view. Classifying distinc-
tions with respect to excitability and the types of
responses of electrogenic membranes are by no means
exhaustive of the different varieties. Pharmacological
differences of various kinds specify an even greater
diversity amongst excitable, electrogenic membranes.
These differences are not to be seen by anatomical
methods, nor indeed, by electrophysiological means
alone, since pharmacologically distinct varieties of
membrane can all generate similar types of electrical
responses (fig. 14III).
Transmitter Actions
The varieties of transmitters will be treated below;
the present discussion will be confined to the general
electrophysiological aspects. From this point of view,
the precise chemical natures of the substances are of
little moment, the important feature being that they
all activate synaptic electrogenesis. It is unlikely that
the sign of the p.s.p. is affected by the excitant agent.
Thus, as noted above, acetylcholine is a 'depolarizing'
substance for excitatory p.s.p.'s but activating inhibi-
tory synapses, as in the pacemaker of the heart it is a
" hyperpolarizing' agent. The characteristics of the
transmitters will, however, determine to .some extent
the character of the p.s.p. a) For example, if the
transmitter is a large complex molecule, it is unlikely
that it would be available in large concentrations at
the terminals of the presynaptic element. The amount
of total excitant might therefore be limited in propor-
tion to the quantity secreted during a single activity.
Thus, a single afferent volley might cause a number
of p.s.p.'s, but repetitive activity might rapidly ex-
haust the available transmitter, b) Molecular dimen-
sions and configurations might also determine the
rapidity of diffusion of the transmitter from its site of
release to its site of action. The distances involved,
o
although probably only about 100 A are significant
in terms of molecules, c) The kinetics of interaction
between the transmitter and the postsynaptic electro-
genic surface may also be in part determined by the
transmitter itself. For example, it is conceivable that
two different agents might act on similar synaptic
sites with different kinetics, giving rise to differences
in the p.s.p.'s evoked by each. Studies in kinetics of
these interactions are only now beginning (cf 53, 127)
and the nature of interaction is as yet unknown.
Analogy with other processes is usually invoked and
two models which are at present fashionable, actisa-
tion processes of enzyme reactions and antigen-
antibody combinations, are not necessarily mutually
exclusive. The transmitter agent is presumed to com-
bine with some ' receptor' sites of the synaptic mem-
brane (cf 2, 9, 14). (f) The chemical properties of the
transmitter may also determine the characteristics of
the p.s.p. Thus, a labile agent such as acetylcholine
may be rapidly destroyed, and it might give rise to
shorter p.s.p.'s than would a more stable excitant of
the same synaptic site (cf. 53). 0 Likewi.se, the degree
of chemical binding between the transmitter and the
' receptor' or the stability of the complex may play
similar roles in determining the duration of the p.s.p.,
or in its 'competitive' behavior toward an inactivating
synaptic drug. /) Although a transmitter agent may
activate a given type of receptor it may also be an
inactivator of other types. Thus, the transmitter at
inhibitory synapses of some invertebrate muscle fibers
is thought to be an inactivator of the excitatory syn-
apses (68, 73). g~) A given synaptic complex might be
composed of several \arieties of receptors, although
all generating the same kind of p.s.p. Yet, one trans-
mitter might inactivate some of the receptors while
another transmitter did not, and the p.s.p.'s would
vary accordingly.
Two of the factors, the transit time of the trans-
mitter across the synaptic gap (6 in the preceding)
and an induction period (c above), probably deter-
mine the synaptic latency as noted earlier. Together
these two processes may last several milliseconds.
Genesis nf Postsynaptic Potentials
Important information on this matter derives from
the occurrence of spontaneous 'miniature' p.s.p.'s at
muscle endplates. Probably this activity is generated
bv random releases of transmitter from presynaptic
SYNAPTIC AND EPHAPTIC TRANSMISSION
167
sites (52). The miniature p.s.p.'s are probably quanta!
in the sense that each is composed of a minimum
electrical change generated by a 'packet' of trans-
mitter agent. The random release of packets from
presynaptic terminals at different synaptic sites and
the electrical inexcitability of the postsynaptic mem-
brane combine to cause local miniature p.s.p.'s gener-
ated now at one site, now at another (51).
Depolarization of the presynaptic nerve terminals
augments the frequency of miniature e.p.p.'s in frog
muscle fibers (52). Similar data (137) on rat dia-
phragm muscle are even more decisive (fig. 1 7).
Depolarizing electrotonus applied to the phrenic
nerve increases the rate of the miniature activity very
markedly, while hyperpolarizing the nerve terminals
decreases the activity. E.xcess magnesium, which de-
presses the release of transmitter agents (cf. 52),
depresses or eliminates the effects of the electrotonic
currents.
The action of magnesium indicates that the effects
produced by the electrotonic potentials are exerted
through the medium of the nerve terminals and are
100
50
c
c
o
'- 5
.»- Anodic Cathod'C -».
FIG. 17. Effects upon the frequency of miniature e.p.p.'s in
rat diaphragm muscle fibers of electrotonus appHed to the
phrenic nerve. Abscissae show the intensity of applied electro-
tonic current in relative units; ordinates, the frequency of
miniature e.p.p.'s scaled logarithmically. Arrows point to
frequencies of the latter observed when no electrotonic currents
were applied. 'Cathodic' current is depolarizing for the nerve
terminals, anodic' is hyperpolarizing. A: The eflfects of the
change in potential were essentially symmetrical on the loga-
rithmic scale, increa.sed frequency of miniature e.p.p.'s with
cathodic and decreased frequency with anodic current. This
was the most frequently encountered result. B: open circles,
terminal depolarization was much more efTective than hyper-
polarization in changing the frequency in this experiment;
Jilled circles, the same inuscle was exposed to 12 mmole mag-
nesium (normal concentration is i mmole). The frequency of
miniature e.p.p.'s became essentially independent of the mem-
brane potential of the nerve fibers. [From Liley (137).]
genuinely synaptic in nature. Other tests also lead to
this conclusion, a) The electrotonic effects on the
miniature e.p.p.'s are absent in muscle fibers where
the nerve supply is cut close to the muscle and thereby
made inaccessible to the electrotonic currents. This
rules out the possibility that the current flow in the
muscle fibers themselves caused the changed rate of
miniature e.p.p.'s. b') The effect of the electrotonus
was absent in endplates that were more than a few
millimeters from the site of applying the stimulus to
the nerve. Since the decay of electrotonically spread
potentials must be rapid in the terminal nerve fibers,
this result indicates that the change in rate is initiated
by effects in the presynaptic terminals. These experi-
ments show that when the depolarization produced
by a nerve impulse arrives at or near the presynaptic
terminals, their secretory activity can be initiated or
augmented. A mechanism coupling the presynaptic
impulse and transmission is thus provided.
Some additional conclusions may be deduced from
data on miniature e.p.p.'s. These activities increase in
frequency approximately lo-fold for 15 mv depolari-
zation (137). Therefore a spike, though lasting only a
brief time, could mobilize the rapid release of a
considerable number of transmitter packets since 100
mv depolarization might increase the rate of ' spon-
taneous' releases some 10' to 10* times. The number
of packets involved in an e.p.p. during neuromuscular
transmission is probably about 10- to 10^ times the
'quantal' units that cause the miniature e.p.p.'s (52).
Increase in the rate of release or .secretion of the
transmitter at the presynaptic terminals is obviously
an electrically activated event. However, the response
at the effector terminals probably differs Ijasically
from the processes that generate the spike of the con-
ductile membrane. The data of figure 1 7 were ob-
tained with prolonged applications of electrotonic
currents. The sustained increase of miniature e.p.p.'s
during sustained depolarization therefore indicates
that the processes leading to release of transmitter
packets are not subject to inactivation as is the sodium
conductance of the spike generator.
Gradation of Postsynaptic Potentials
Probably the miniature p.s.p.'s are small only be-
cause the area involved in their electrogenic activity
is small in comparison with the total area over which
the emf is electrotonically distributed. .Suppose that
we could measure the change in potential occurring
at a single isolated site which valves sodium ions. In
the resting state the emf across that site will be the
1.68
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
resting potential, approximately the value of the po-
tassium potential, EsCgi, 112, 113). When the valve
■ opens' the emf must suddenly change from the resting
value towards that of the sodium potential, £>,-,,, a
change to internal positivity (113). The hypothetical
'valve', however, is located in a physical structure,
the membrane, with finite resistance and capacity
and with both its surfaces bathed in saline media.
The step-like emf of the generator ' valve' must there-
fore distrilauie itself electrotonically o\er an area hav-
ing definite electrical properties, becoming a potential
change reduced in magnitude and distorted in form
(fig. 2). The simultaneous activity of a number of
"valves' would lead to an increased potential, thus
permitting gradation of the response from the mini-
mal observable to the full value of the electrochemical
potential. Since several species of ions are invoked,
the maximum p.s.p. strikes a i)alance ijetween the
different electrochemical potentials (cf. 52, 60).
Aferlianisms of Graded Responsiveness
The most detailed data are available on graded
responses of electrically excitable membrane and, al-
though the theory of their production is still rudi-
mentary, the same general process will probably be
found to apply also to the graded responses of synaptic
and sensory membrane (94-96). Graded local re-
sponse is usually considered to be merely a stage in
the events leading to the regenerative explosive activ-
ity which results in the spike (113). This view has
been invalidated by the finding (4, 6, 92) that under
various conditions all-or-none responsiveness can be
converted to a fully graded one. Only graded re-
sponses occur in dually-responsive insect muscle
fibers (37, 38) and probably in other electrically
excitable membranes as well (97)- The activity may
vary from the minimal observable to a maximal
response closely approximating the spike in amplitude
and form (fig. 18; cf. fig. 21). The degree of graded
responsiveness is not controlled by the membrane
potential as it is considered to be in current theory
Figure 18 also illustrates how an altered local
excitatory state need not be caused by, nor reflected
in, a changed membrane potential. Whether un-
treated or poisoned with a drug, the single cell showed
subliminally enhanced excitability which w-as evi-
denced during an interval at least 0.2 sec. after each
subthreshold stimulus. The cumulative growth of this
"excited' state in the untreated cell led to an explosive
manifestation, the spike. After the cell was poisoned
the overt manifestation look the form of a progres-
sively larger graded response, and this response
approached the spike in amplitude.
A first approximation for revising theoretical con-
cepts (94, 95) con'iiders that the excitalile memiirane
is composed of unit areas. Each has a population of
electrogenic units (transducers, valves, etc.) which
differ amongst themselves in the threshold for their
excitation. In the explosively responsive population
the thresholds for exciting the electrogenic elements
of a given unit area are probably closely similar.
Dispersion of that population distribution could re-
sult in conver-^ion of all-or-none responsi\eness to the
graded type.
Transfer of Activity From Postsynaptic Potentials to
Electrically Excitable .Membrane
In the case of the skeletal muscle endplate or the
squid giant fiber synapse a relatively well-defined
' patch' of electrically inexcitable synaptic membrane
is surrounded by electrically excitable structure. In
both cells, the p.s.p. is simple, only of the depolarizing
variety, and initiated by impulses in a single pre-
synaptic fiber (fig. 19). The p.s.p. then tends to be of
a fixed amplitude and in these two systems usually
causes sufficient depolarization of the contiguous
electrically excitable membrane to generate a spike
in the latter. Essentially, transmission then is one-to-
one, each impulse of the prefiber generating a post-
junctional spike.
Under various conditions, for example upon poison-
ing an endplate with rf-tubocurarine, the p.s.p. de-
creases in amplitude and, when the depolarization
falls below the critical firing level, no spike is gener-
ated (fig. 15). The transmission block may be over-
come by a rapidly repetitive volley of neural stimuli
which successively generate new p.s.p.'s or a local
excitatory state before the previous ha\e disappeared.
The consequent augmentation of depolarizing elec-
trogenesis may attain the critical level and transmis-
sion again occurs. This general phenomenon of
increased effectiveness of repetitive stimuli is known
as facilitation. The normally occurring p.s.p. produced
by a given afferent neural stimulus may not be suf-
ficiently large to evoke a spike. Repetitive stimuli in
this case can summate the depolarizing p.s.p.'s and
facilitation is then also manifested, the summed de-
polarization initiating a spike.
In the context of the electrophysiological mecha-
nism, a facilitated overt respon.se (e.g. of a muscle)
may be produced by two fundamentally different
SYNAPTIC AND EPHAPTIC TRANSMISSION
169
A.
JV.
A.
B
-V
/v.
-V
.^
JV
.^.
.^.
.^^
-^
.^
.^
-^
8'
.^.
FIG. 18. All-oi-none and graded responsiveness in an eel
clectroplaque. Two traces are recorded simultaneously, re-
peated at the rate of 5 per sec. The upper longer trace of each
set is the zero base line for an internal microelectrode. It also
carries the monitoring signal of a stimulus applied to the cell
and shows that the stimulus strength remained constant in
each of the two series. The lower trace of each set is that of the
potential recorded with the microelectrode. The distances be-
tween the two represent the resting potential, about 70 mv.
The weak stimulus in A, before the cell was treated with drug,
at first produced only a subthreshold electrotonic depolariza-
tion. The seventh repetition of the stimulus is followed by a
spike. The shorter latency at which successive spikes then de-
velop indicates continued growth of excitability and its per-
sistence through the 200 msec, intervals between stimuli. The
resting potential remained unchanged. B and B' . The sequence
of growth in response in the cell after 84 min. exposure to 500
Mg per ml of physostigmine. The resting potential was not
affected by the drug, which eliminated synaptic excitability
and converted the all-or-none response of the electrically
excitable membrane component to graded responsiveness. The
testing stimulus was slightly stronger than before applying the
drug, and the first trace seen (upper set of S) evoked a distinct.
synaptic processes. The one descrif)ed just above is
summation where each successive p.s.p. is no larger
(cf. fig. 27.4), and may indeed be smaller, than its
predecessor. The excitatory action leading to the
overt effect would be the increased total depolariza-
tion produced b\- the summed effects of the repeated
p.s.p.'s. The overt effect would appear as a facilita-
tion because of the profound functional difference
between the local processes at the motoneuronal or
neuromuscular synaptic junction and their production
of an explosive propagated spike which triggers the
contractile mechanism.
Essentially the same overt result, but an activity
involving more complex synaptic processes, would
(jccur if the successive p.s.p.'s augmented as a result
of the repetitive stimulation. This synaptic facilitation
will be discussed further in relation to heterosynaptic
and homosynaptic excitatory phenomena (p. 184). It
would seem to involve augmented responsiveness of
the synaptic membrane to the transmitter agent, the
converse to the decreased responsiveness in desensiti-
zation. As noted in that connection, defacilitation
probably is ascribable to desensitization. Both facili-
tation and defacilitation, however, may be only
apparent effects on the synaptic membrane, their real
cause residing elsewhere. For example, facilitation
could result from successively larger quantities of
transmitter released from the presynaptic terminals.
The converse, progressive exhaustion of the trans-
iTiitter and decrease of the amount emitted at each
impulse, would lead to defacilitation.
As is also the case with other electrical stimuli, the
depolarizing p.s.p. first evokes a graded local response
of the electrically excitable membrane (4) and the
two depolarizations then sum to cause the explosive
response of the spike (figs. 3, 7). The addition of
hyperpolarizing p.s.p. to the depolarizing diminishes
the magnitude of the latter and its excitatory effect.
If the depolarizing p.s.p. then falls below the critical
level, a spike is no longer elicited and the effect of
hyperpolarizing p.s.p.'s is therefore inhibitory. It
should be noted that inhibition may occur even
though considerable depolarization is still generated.
In other words, the countervailing inhibitory p.s.p.
though small, graded response. During the course of repetitive
stimulation at 5 per sec. the response grew, at first gradually
and then more rapidly, indicating that the rise of excitability
is non-linear. The series illustrated ends before the response
could grow to an amplitude as large as that of the spike, but
in other experiments this was observed. [From .Mtamirano el
al. (6).l
1 70
HANDBOOK OF PHVSIOLCKJY
NEUROPHYSIOLOGV
I I I I I I I
msec
FIG. 19. Synaptic transfer in squid giant axons. The incom-
ing presynaptic spike elicits only a small membrane potential
change in the postsynaptic cell. The p.s.p. arises after a brief
latency and, if it attains the critical firing level, elicits a spike.
[From Bullock & Hagiwara (32).]
need not be as large as is the excitatory one. It must
only be large enough to decrease the depolarizing
p.s.p. below the critical firing level for the spike, but
it can then produce dramatic effects since the absence
of conductile activity eliminates further transfer to
other cells and results in the disappearance of distant
actions within the organism.
Synaptic Delay
Synaptic latency, which was discussed above, in-
volves only the activity of the presynaptic terminals
and the response of electrically inexcitable synaptic
membrane. Synaptic delay includes not only the
latency but also the utilization time of electrical
excitability. This last involves the duration of the rise
of the depolarizing p.s.p. and of whatever further
depolarization this may develop in its excitatory ac-
tion on electrically excitable sites, and the consequent
time that is required for the p.s.p. (and the local
response) to reach the critical level for evoking a
spike. The rise time of the p.s.p. for this level may be
brief, about o. i to 0.3 msec. (figs. 6, 12), but can be
much longer (figs. 7, 9), particularly if the depolariz-
ing p.s.p. is liminal for discharge of the spike. Tem-
poral summation or facilitation, in which repetitively
evoked depolarization becomes larger, may then de-
crease the utilization time and thereby shorten the
synaptic delay (cf. 140). The shortening might also
occur because of decreased synaptic latency or
heightened synaptic excitability, effects which are
discussed in the next section of this chapter.
The existence of synaptic delay has been a.scribed
chiefly to slowed conduction of the afferent impulse
in the fine terminals of the presynaptic fibers (cf.
57, 140). That explanation is no longer tenable.
Strong electrical stimuli directly applied to the inner-
vated surface of the eel electroplaque, and therefore
to the nerve terminals, nevertheless cause a neurally
evoked response always after a considerable synaptic
latency (fig. 6). Further evidence may be derived
from figure ig and other data of similar nature which
show that the presynaptic spike arrives at the synap-
tic surface somewhat before the p.s.p. is elicited. Thus,
.synaptic latency and the utilization time involved
in the rise of the p.s.p. to the critical firing level are
probably the major factors in synaptic delay.
Sujifrjuisition of Pustsyriafitic Potentials and Spikes
The electrically inexcitable generators of p.s.p. 's act
independently of and in parallel with the electrically
excitable membrane that produces the spike (4,
48, 71). Thus, a p.s.p. can be evoked during the
spike, when a second response of the electrically
excitable membrane is impossible due to its absolute
refractoriness (figs. 6, 7). However, the combined
response depends upon the prevailing electrochem-
ical conditions of the cell. The p.s.p. may subtract
from as well as add to the spike, the former occiu'ring
when the spike itself carries the membrane potential
into the region at which the p.s.p. reverses as de-
scribed above (48, 136; cf 97). The conclusion that
the spike under certain conditions wipes out the
p.s.p. (cf 60, p. 30 ff) may therefore require revision.
A complicating factor that ma)' explain these find-
ings of Eccles and his colleagues is the distortion
produced in the spike when the latter is elicited in a
depolarized electrically excitable membrane (cf
95). An "undershoot' of apparently hyperpolarizing
phase then terminates the spike, even though it is
absent in the response evoked at the normal resting
potential of the membrane (fig. 10; cf 60, fig. 16).
The distortion is probably due (95) to excess of po-
tassium conductance over the sodium conductance
as in .squid giant axons (113). This excess would be
caused h\ increased sodium inactivation produced
by the depolarization.
The foregoing remarks indicate that electrical and
physiological conditions of the soma membrane affect
the recording of celhdar potentials. The soma, how-
ever, is only one part of the cell, although it is the
one most easily accessible to microelectrodcs. Even
in neurons without dendrites, as is the case in tissue-
cultured dorsal root ganglion cells, the intracellularly
recorded response to stimuli may take on complex
forms (42). This indicates that activits in and the
SYNAPTIC AND EPHAPTIC TRANSMISSION
171
properties of the axon contribute to the potential re-
corded from the soma.
The nature and degree of excitability may be dif-
ferent in various parts of the soma and dendrites.
Thus the soma may be electrically inexcitable (ry,
33, 80, 186, 189, 190). The depolarizing p.s.p.'s
or generator potentials cv'oked at the soma excite
spikes at electrically excitable regions some distance
from the cell body. The superficial portions of apical
dendrites in the cat cortex are not electrically excit-
able (loy, 165), As mentioned earlier, the receptor
portions of various sensory cells are electrically in-
excitable and for this reason are capable of develop-
ing a sustained generator potential.^
Recent evidence (7, 17, 43, 82) also indicates that
different portions of electrically excitable mem-
branes of the cell body may have different thresh-
olds. The ■ initial segment' of the motoneuron (cf.
60) in the cat (82) and toad (7) responds first to an
electrical stimulus and gives rise to the early part of
the antidromic spike (fig. I2^'-F')- The spike of the
rest of the cell body (if the latter is electrically ex-
citable) occurs slightly later, the delay giving rise
to a slight break in the recorded response.
In addition to these apparent inhomogeneities in
the excitability of different parts of the soma and
dendrites, slowed conductile spread, separate loci of
origin for spike and p.s.p.'s and different loci for
depolarizing and hyperpolarizing p.s.p.'s are all
factors that may contribute to variations in the
recorded response of the cell. Many variations can
be theoretically deduced, but their analysis is beyond
the present scope.
'Retinal receptors in lisli (184) provide an interesting new
example (102). Their electrical response is probably generated
in cells other than the primary visual cells (cones). The re-
sponse is a sustained clectrogenesis. In some cells it is only
hyperpolarizing, in others depolarization is also developed,
depending upon the wavelength of the stimulating light. The
amplitudes of the responses are graded, not only with the in-
tensity of the light stimulus but also with its spectral composi-
tion. These characteristics of electrically inexcitable activity are
produced apparently in the absence of spikes, but the electro-
genesis, both hyperpolarizing and depolarizing, affects spike
production in other conductile elements. It has been suggested
(102) that these electrogenic cells (probably horizontal or bi-
polar cells or both) are excited by transmitter agents released
by photochemically activated cones. The clectrogenesis, in
which an electrically excitable component is lacking, is in turn
associated with secretory activity as in electrically inexcitable
gland cells. The secretory products acting upon the retinal
ganglion cells evoke neuronal activity of the latter, probably
including excitatory and inhibitory p.s.p.'s which lead to
patterns of spike activity seen in the optic nerve fibers.
GENERAL AND COMPARATIVE PHYSIOLOGY OF SYNAPSES
Forms and Magnitudes of Postsynaptic Potentials
Viewed as the nonregenerative responses of elec-
trically inexcitable membrane, the forms and mag-
nitudes of the p.s.p.'s may be expected to have
rather simple relations to their excitants. The availa-
ble experimental data are as yet rather scanty, but
they do permit some general conclusions (cf. 60, 97).
As a first approximation, the degree of synaptic
transducer action reflected in the rate and amount
of clectrogenesis may be considered to be roughly
proportional to the quantity of excitant. A brief jet
of labile transmitter or activating drug causes a
Ijrief response while the continued availability of
the excitant causes a sustained clectrogenesis. The
duration of the p.s.p. in the first case will be deter-
mined by the time course of the transducer action
initiated by the excitant (cf. also 53, 127, and papers
cited there). However, the responses will be dis-
torted by the electrical circuit properties of the
membranes. Thus, the rising and falling phases of
the p.s.p. may reflect this distortion which produces
a slowing such as occurs in electrotonic propagation
(fig. 2). The rise of the p.s.p. should be slowed less
than its fall since the former occurs when the mem-
brane resistance and time constant are relatively
low. This is the case experimentally as numerous
figures in this chapter indicate. The falling phase
probably bears some relation to the time constant
of the membrane (cf. 60), lasting longer when the
time constant is larger, like the ballistic response of a
slow galvanometer to a brief current. The relation,
however, does not appear to be a simple one (95,
97), and the duration of the p.s.p. probably reflects
importanth intrinsic time courses of transducer ac-
tions.
The duration of the p.s.p. caused by a single
neural volley differs considerably in the various types
of cells. The p.s.p.'s of squid giant axons and of eel
electroplaques last only about 2 msec. (figs. 3, 19),
those of Aplysia giant neurons (fig. 7) or cat salivary
glands (fig. 20) may persist for nearly i sec. The
e.p.p.'s and p.s.p.'s of other neurons have inter-
mediate durations. In .some cases, physostigmine
and prostigmine both prolong the p.s.p., this effect
probably involving the prolongation of the life of the
transmitter, acetylcholine, by inactivation of cho-
linesterase (cf. 52, 53, 60, 68). Some of the quater-
nary ammonium compounds also prolong p.s.p.'s
(cf 52) and these actions may be caused by direct
172
HANDBOOK OF PHVSIOLOGV
NEUROPHYSIOLOGY I
Fio. 20. Different types of electrical
activity in cat salivary gland cells.
Depolarization shown as downward
deflection in these records. A: Type I
cells produce hyperpolarizing p.s.p.'s
which are graded with strength of the
stimulus. Single shocks to chorda
tympani evoke p.s.p.'s which last about
I sec. B: Type I cells produce only
hyperpolarizing p.s.p.'s to excitation ot
the sympathetic {upper iigna!) or para-
sympathetic {lower signal) nerves. How-
ever, the latencies and magnitudes of
the p.s.p.'s differ somewhat. C: Type
II cells develop hyperpolarizing p.s.p.'s
on stimulating the chorda tympani and
depolarizing p.s.p.'s through their
sympathetic innervation. D: Type III
cells (which may be myoepithelial
elements of the ducts) respond only with
depolarizing p.s.p.'s to parasympa-
thetic {above) or sympathetic {below)
stimulation. The resting potential,
about —80 mv, is large in comparison
with that of Type I or II cells and
resembles that of muscle fibers. E:
Type I cells respond with hyperpolari-
zation to epinephrine, acetylcholine
and pilocarpine. [From Lundberg
(144).] F: The hyperpolarizing p.s.p.
of the gland cell is remarkably insensi-
ti\e to changes of the membrane po-
tential. The resting potential was 30
mv. [From Lundberg (145).]
B
mV
10+-
Oh_
2sec
-60
-
-50
-
-40
-
-30
-
-20
-
2 sec
-40
-120
-80
-40
- 0
2 sec
-50 -
-40 -
-30 -
-20 -
2sec.
l/^g adr.
O.l/ig och.
-120
-100-
- 80
-60
-40-
- 20
- 0
0.5 /ig pilocar.
effects upon the kinetics of the ionic 'valving' of tiie
transducer action.
The maximum attainable amplitudes of p.s.p.'s
are probably determined by electrochemical condi-
tions as described in a previous section of this
chapter, but these need not be identical for different
varieties of cells. Thus, most hyperpolarizing p.s.p.'s
reach a limit set by the most negative electrochemi-
cal ionic species, but hyperpolarizing electrogenesis
of glands can occur in the face of very high internal
negativity (fig. 20). These differences reinforce the
conclusion (91, 105) that electrical activity of bio-
logical membranes may involve a variety of mcch
anisms, some of which are not yet understood.
Postjunctianal Cells with Dfpolaii'ing
Postsynaptic Potentials
As noted above, some cells though not electrically
excitaijle respond with depolarization to neural or
chemical stimuli. Of general interest are electrically
inexcitable invertebrate and vertebrate muscle
hbers, such as the ' slow' muscle fibers of the frog
(fig. 4i4). They are diffusely innervated and neural
SYNAPTIC AND EPHAPTIC TRANSMISSION
173
Stimuli give rise to graded summative depolariza-
tions. These diffusely generated depolarizations can
act as stimuli for the contractile mechanism, causing
localized graded contractions (34, 35, 132).
Some salivary gland cells also generate only de-
polarizing p.s.p.'s (fig. 20) and these are produced
by stimulation of either the sympathetic or para-
sympathetic nerves (144). Chemical stimulation by
epinephrine, pilocarpine or acetylcholine then all
cause the same type of electrogenesis, but it is not
known whether all the excitants activate a single
variety of electrogenic membrane or whether there
are distinct, although similarly electrogenic, cholino-
ceptive and adrenoceptive components. As is the
case with the electrically inexcitable muscle fibers,
the synaptic electrogenesis of gland cells is also asso-
ciated with and itself probably effects other cellular
activity, in this case secretion.'^
Torpedo and Raia elcctroplaqucs also generate
only depolarizing p.s.p.'s but not to electrical stimuli
(95). The cells which are derived from skeletal
muscles therefore are in reality constituted from end-
plates. A specialization of the.se and other electro-
plaques permits series additions of the voltages pro-
duced by each cell; hence the electric organs generate
considerable voltage. The discharges are under con-
trol of the nervous system and in .some forms this
may be useful for protection or aggression. The
p.s.p.'s are Ijrief in Torj>edo but long-lasting in Raia.
Vertebrate skeletal muscle fibers of the ' twitch'
system and autonomic ganglia combine depolarizing
p.s.p.'s and spike-generating membrane (cf figs. 9,
27), but the autonomic neuron may also produce
hyperpolarizing p.s.p.'s since there are indications
thai inhil)ilion may occur (64, 134). In both cases
' It was noted earlier (p. 154) that bioelectric responses of
transmissional and conductile processes are essentially passive
events resulting from the mo%ement of ions in obedience to
charged electrochemical equilibrium states. The change from
one state to another is the active phenomenon, due to specific
processes, transducer actions which are the responses of excit-
able membrane to appropriate stimuli. In gland cells, the se-
cretory activity of the output component (fig. 16) probably
occurs at membrane .structures that are intimately mingled
with those of the input component. .Secretory electrogenesis
thus is probably superimposed on the p.s.p.'s of the transducer
input, and this is suggested also by the independence of the
gland electrogenesis from electrochemical conditions (fig. 20
E and F). In some respects, therefore, electrogenesis of gland
cells may differ from that of 'pure' p.s.p.'s of neurons or end-
plates. The details of these diflferences cannot now be specified
since little is known about the nature of active transport
mechanisms, such as arc probably involved in secretion.
the p.s.p.'s have much longer durations than do the
spikes. In muscle fibers the spike energizes the proc-
esses of contraction by a mechanism that is not yet
known (cf 121). Eel electroplaques also generate
both depolarizing p.s.p.'s and spikes (cf figs. 3, 6,
13), but the contractile machinery is missing in these
modified muscle fibers. Eel electroplaques, like
neurons, are diffusely innervated Isy many nerve
fibers. Since the area of their innervated surface is
more than 10 mm-, their study has provided some
data that are not readily obtained with the much
smaller nerve cells. The results, however, very prob-
ably apply to the general case of synaptic transmis-
sion as will be described below (cf. 95).
Postjunctional Cells with Hyperpolarizing
Postsynaptic Potentials
If cells capable of generating spikes were endowed
only with hyperpolarizing p.s.p.'s, transmfssional
excitation of the electrically excitable responses would
not occur, for in all cases known the spike is triggered
by depolarization. Thus, it may be expected that
cells in which solely hyperpolarizing synaptic elec-
trogenesis occurs would be of restricted functional
significance. From intracellular recordings two cases
are known and in neither are spikes generated. These
are salivary gland cells (144, 146; cf fig. 20) and L-
cells of the fish retina (102, 184, 191 ; cf al.so footnote
4, above). As noted earlier, the memijrane trans-
ducer actions and electrochemical effects of hyper-
polarization are consistent with secretory activity;
hence neurally evoked hyperpolarizing p.s.p.'s of
glands have functional validity.
Postjunctional Cells ivith Both Types of
Postsynaptic Potentials
Two varieties may be expected and both types
occur: /) electrically ine.xcitable cells which do not
generate spikes and 2) cells which produce spikes as
well as the p.s.p.'s. A clear case of the former is
found in some salivary gland cells (fig. 20) in which
each type of synpatic electrogenesis is probably asso-
ciated with a different form of secretory activity. The
different p.s.p.'s are specifically produced by stimu-
lation of the two autonomic nerve supplies. Stim-
ulation by cholinomimetic and adrenomimetic
substances evokes oppositely signed electrogenesis.
The R-G and Y-B cells of fish retina also produce
174
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
depolarizing and hyperpolarizing potentials without
spikes (184).
Some invertebrate muscle filjers possess dual
synaptic activity (72, 73) and it has been suggested
(96) that vertebrate smooth muscle may also belong
to this category. If the fibers are not electrically
excitable, the contractions caused by their depolariz-
ing p.s.p.'s would be local, as in frog "slow' muscle
fibers (34, 35, 132). The hyperpolarizing p.s.p.'s
would serve the function of diminishing or regulating
the degree of the mechanical response by decreasing
the depolarizations of the 'excitatory' p.s.p.'s.
By far the most prominent class are the cells in
which spikes as well as the two kinds of p.s.p.'s are
generated. Most, and perhaps all, neurons of the
vertebrate central nervous system probably belong
to this group (cf. 59, 60, 158, 159, 161 -167). The
hyperpolarizing and depolarizing p.s.p.'s appear to
have nearly identical durations and the superposi-
tion of the two p.s.p.'s may decrease membrane
depolarization sufficiently to eliminate spike produc-
tion by an orthodromic excitatory pathway. This
interaction of depolarizing and hyperpolarizing
p.s.p.'s adds to the variety and flexibility of integra-
tive activity within the central nervous system. The
effects are achieved not only by relatively simple
algebraic summation of the potentials but also by
the interplay of more subtle factors which will be
described in the next section of this chapter.
Fast and Slaw Respunses of Iinrrtebratt' Muscles
The muscle fillers of some insects and Crustacea
(cf. 116, 117) are known to be electrically excitable,
but they also respond diff^erently to stimulation of
different excitatory nerves (fig. 21). Their 'fast' in-
nervation, which may be constituted of one or several
nerve fibers, produces large depolarizing p.s.p.'s
upon which is superimposed a spike-like response,
often showing a small overshoot. Stimulation of the
'slow' nerve fiber leads to a small depolarizing p.s.p.
Upon this there may develop various gradations of
the electrically excitable response. The mechanical
acti\ities are also different. The fast nerve fiber
mV
FIG. 21. Different responses produced in insect muscle fibers on stimulating their fast and slow
innervation. Intracellular recording from e.xtensor tibiae of the mesothoracic leg of Schistocerca gri'-
garia. A: The responses of six different muscle fibers, first to stimulation of the fast nerve fiber and
then the slow. In all but one muscle fiber, the fast response developed an overshoot. .^K notch on the
response of fiber ii indicates the level on the p.s.p. out of which the spike-like activity developed.
In fiber ;, as in about 50 per cent of the muscle fibers, no response resulted on stimulating the slow
nerve fiber. Various grades of activity are shown in the other examples. In three of these (iii, iv, r)
the p.s.p. was large enough to evoke some local response of the electrically excitable membrane. B:
Three examples of facilitation of the p.s.p.'s by repetitive stimulation of the slow nerve at about
30 per sec. The augmented p.s.p.'s evoked larger pulsatile local responses, and in one case (i.v) an
overshoot was obtained. Time and amplitude calibration in (0 apply to all records. [From Hoyle
(1 16).]
SYNAPTIC AND EPHAPTIC TRANSMISSION
'75
evokes a brisk twitch or a maximal tetanus. The
slow fiber calls forth small contractions which may
grow slowly during repetitive stimulation.
The apparent paradox that depolarization, an
electrical and unspecific stimulus, can evoke differ-
ent forms of response in electrically excitable mem-
brane has been resolved by the finding (37, 38) that
the membrane of the muscle fibers of the grass-
hopper, Romalea microptera, though electrically ex-
citable, responds only with graded activity. Other
physiological and anatomical circumstances co-
operate with this normally occurring graded respon-
siveness. The different nerve fibers evoke two degrees
of depolarizing p.s.p.'s in the electrically inexcitable
synaptic membrane. The p.s.p.'s evoked by the fast
nerve fiber may be larger because of greater synaptic
potency of the 'fast' transmitter system than in that
of the slow fiber (e.g. a different agent, a higher
concentration of transmitter, closer approximation
of the pre- and postsynaptic membrane or larger
area of synaptic contact). However, another alterna-
tive is that the membrane sites engaged by the
terminals of the different fibers are different. The
combination of graded p.s.p.'s and electrically
excitable local responses is abetted by the closeness
of synaptic terminations. The terminals of the fast
nerve fiber, spaced as close as 40/j apart, can each
evoke large local responses of the electrically ex-
citable membrane. This graded activity, summing
its depolarizing actions, can then evoke maximal re-
sponses which have the appearance of spikes. The
associated contraction is a twitch. The smaller
p.s.p.'s of the slow response can be graded in various
proportions and can evoke local response of various
degrees. The resulting contractions are also graded.
The mechanisms involved in the dual responses
of muscle fibers are instructive for several reasons.
Dual responsiveness is probably present in muscles
of animals quite low in the evolutionarv scale (i 17),
and this suggests that electrically excitable mem-
brane, like the sen.sory or synaptic, was originally
gradedly responsivp. The ability to develop spikes
then would have been a later evolutionary stage (2 1 ,
103). Dual responsiveness also represents an ex-
ceedingly useful mode of activity for arthropods for
their muscles are limited in number. The size of the
muscles and therefore also the numijer of their fibers
are limited by the exigencies of the exoskeleton. The
number of nerve fibers is also rather small. Despite
these limitations arthropods can manipulate their
joints intricately and with precision and carry out
locomotion with great dispatch and vigor. These
different aspects of movement are all achieved with
an economy of means because of special responsive
mechanisms and anatomical conditions.
PHARMACOLOGICAL PROPERTIES OF SYNAPSES
.^ND THEIR PHYSIOLOGIC.-VL CONSEQUENCES
The discussion in this part of the present chapter
will be limited to vertebrate synapses, concerning
which information is more extensive than on in-
vertebrate structures. However, the pharmacology
of the electrically inexcitable sensory membrane of
the crayfish stretch receptor probably parallels that
of synapses in the cat brain (96). This suggests
that in their general aspects the pharmacological
properties of vertebrate and invertebrate synapses
will be similar in principle, although, perhaps,
invoKing different chemical suijstances. In crustacean
neuromuscular synapses and in the inhibitory
synapses of the stretch receptors the actions of amino
acid drugs parallel to a degree the effects of these
substances in cat brain (cf. 99, 163, and below).
However, other invertebrate synapses appear to
have no pharmacological relation to vertebrate
synapses (cf. 99 j.
Classification of Drug Actions
Depending upon the theoretical approach and the
experimental emphasis, several varieties of classifica-
tion have arisen. Thus, drugs have been grouped as
'mimetics' or 'lytics', graded according to the degree
to which they mimic or block the action of nerve
impulses, or sometimes of a standard comparison
substance (cf. 8). Particularly in describing effects of
drugs on the more complex synaptic systems (chiefly
of the central nervous system but also those of smooth
muscle) substances have been classified as 'excitants'
(or 'stimulants') and 'inhibitors' (or 'depressants').
For example, since both pentylenetetrazol (Metra-
zol) and strychnine are convulsant agents, both
are classified as stimulants of the central nervous
system (cf. 85). Recently (cf. 156) the drugs acting
upon the peripheral cholinoceptive synapses of
skeletal muscle and autonomic ganglia have been
classified as 'depolarizing' or as 'nondepolarizing,
competitive, antagonistic inhibitors' of the latter.
This classification also applies to the simple depo-
larizing synapses of the eel electroplaques (table 2).
An extension of this classification (table 3) has
proved experimentally and analytically more useful
176
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
TABLE 2. Range of Effectiveness on Single Eel
EleUroplaques of Some Synapse Inactivating and
Synapse Activating Drugs
Minimum effective
concentration
Substance '" fg per ml
a) Compounds which inactivate the postsynaptic membrane
of eel electroplaques, do not depolarize, but convert the
all-or-nothing response of the electrically excitable
membrane to the gradedly responsive
Physostigmine 25
</-Tubocurarine 50
DFP* 100
Procaine 200
Tertiary analog of prostigmine 1000
Flaxedilt
A) Compounds which activate synapses of eel electroplaques.
The resultant depolarization secondarily inactivates the
electrically excitable membrane. Synaptic electrogenesis
still occurs
.\cetylcholinet 5
Carbamylcholine 10
Decamethonium 10
Dimethylaminoethyl acetate (DMEA)t 50
Prostigmine 5°
SuccinylcholineK
* This substance causes a secondary depolarization with
consequent inactivation of the electrically excitable mem-
brane.
t Included on the basis of the data of Chagas & Albe-
Fessard (39) that the action of Flaxedil is similar to that of
curare. These workers did not study membrane potentials or
graded responsiveness. Chemically Flaxedil is tri-(diethyl-
aminoethoxy) benzene triethyliodide.
I In the presence of 25 ^g per ml physostigmine.
Tl On the basis of the data of Chagas & Albe-Fessard
C39). who found a similarity of action with acetylcholine
(see note f).
since it applies as well 10 hyperpolarizing synapses
and to systems containing both electrogenic types
(96, 97). The two major varieties of drugs are in this
case classified as activators or inacti\ators of synaptic
electrogenesis. The nature of the latter, depolarizing
or hyperpolarizing, is determined only by the type
of synapse not by the activator substance. Each major
group is subdivided into drugs which act nonselec-
tively or selectively upon either the depolarizing or
hyperpolarizing synapses. The interactions of drugs
and synapses disclose many sui)sidiary classifications,
both in the drugs and in synaptic membranes (99,
100, 108), but these need not be considered here.
The overt manifestations of 'excitation' and 'in-
hibition' of the six classes of drugs in table 3 need
not correspond to the basic mode of achieving this
effect at the synaptic level. Thus, the 'excitant' ac-
TABLE 3. Possible Combinations of Actions of
Synaptic Drugs
Effect
Synapses Affected
Overt .Action
Agent
Depola-
rizing
(Excita-
tory)
Hyper-
polar-
izing
(Inhibi-
tory)
Type Compound
.Activators
2
3
+
+
0
+
0
+
Excitation
Excitation
Inhibition
Acetylcholine
Metrazol
Inacti\ators
4
5
6
+
+
0
+
0
+
Inhibition
Inhibition
Excitation
Curare
GABA
Strychnine
-f indicates an effect; o, none. Diphasic actions omitted.
TABLE 4. Cortical Synaptic Actions of Aliphatic
Amino Acids
Car-
bon
No. a-amino acids
w-ammo acn
ids
Glycine
3 o
(a-alanine)
)-diamino acids
X
X
(/3-alanine)
(7-aminobutyric)
(a-aminobu- (7-aminobutyric) (2,4diamino-
tyric) butyric)
50 -- o
(Norvaline) (a-amino ly-valeric) (Ornithine)
6 o +++ +
(Norleucine) (e-amino caproic) (Lysine)
8 X -f-|- + + X
(co-amino caprylic)
Symbols: — to indicate increasing blockade of
excitatory synapses which leads to overt inhibitory' action;
+ to -|- + -|--|- represent increasing blockade of inhibitory
synapses leading to 'excitatory' effects; o, compound not
active; X, not available or not tried.
tions of the two conxulsant agents, strychnine and
pentylentetrazol, are produced by entirely difTerent
fundamental processes (166). The similarities in
overt cfl'ects arise from the conditions that prevail in
systems which contain many synapses and of both
tvpes. It is then likely that an activity is a mixture
involving both excitatory and inhibitory synaptic
actions, and the study of the central nervous system
has revealed many examples of this. Blockade of
synaptic activity thus becomes a positive act, en-
hancing or diminishing overt manifestations such as
motor activity, depending upon which type of
SYNAPTIC AND EPHAPTIC TRANSMISSION
■77
FIG. 22. Synaptic actions of shorter-chain u-amino acids.
Column A shows the response evoked in the cat cerebral cortex
by a local electrical stimulus (five superimposed traces indicate
the degree of variability). The surface negative potential (up-
ward deflection) is the p.s.p. of superficial dendrites. B shows
the effects of applying 0.2 cc of a i per cent buffered w-amino
acid. The substances are identified by the letters on the left
which correspond to those in table 4. .'Ml the compounds in-
verted the surface negativity to a surface positi\'ity by blocking
production of depolarizing p.s.p.'s and thereby disclosing hy-
perpolarizing p.s.p.'s which are recorded as surface positivity
(downward deflection). The action of all four substances was
similar but differed in magnitude and rate of onset, both factors
being largest with C, (GAB.A). Column C shows that recovery
from the action of the compounds is seen 3 min. after rinsing
the cortical surface several times with Ringer's solution. Time
at bottom, 20 msec. [From Purpura el al. (163).]
synapse is inactivated. Il is for this reason that
selecti\e Ijlockade of inhibitory synapses by strych-
nine leads to excitatory' actions, augmented elec-
trical activity or convulsions.
The selective action of many drugs on either hy-
perpolarizing or depolarizing synapses introduces an
important factor. A substance may act powerfully
on one synaptic .system and yet be inert with respect
to another which lacks the appropriate synaptic
substrate for the drug. This has been experimentally
verified with strychnine which is a highly selective
inactivator of hyperpolarizing inhibitory synapses
(fig. 14). Strychnine is inert, except in very high
concentrations, on structures like the muscle end-
plate or the vermian cerebellar cortex of cat. How-
ever, when given in high concentration it does act
to blockade the depolarizing excitatory synapses
C166).
In view of the foregoing, tests on relatively simple
synapses (table 2; figs. 11, 13, 15) may not be ade-
quate for analyzing drug actions. This fact is illus-
trated by the recent demonstration and analysis of
the synaptic actions of various amino acids (162,
163). The a)-amino acids tested (table 4), substances
in which the amino group is on the terminal carbon
farthest from the carboxyl radical, are selective in-
activators of cortical synapses. The shorter chain
compounds (C2 to C5, fig. 22) block depolarizing
activity of the dendrites while compounds Ce and
Cs (fig. 23) inactivate hyperpolarizing synapses.
One of these substances, 7-aminobutyric acid
(GABA), occurs naturally in the brain (12, 173) and
has been identified (16) as a component of the 'in-
hibitory factor' which can be extracted from mam-
malian brain and which diminishes the discharge
of impulses in the mechanically excited crayfish
stretch receptor. As a selective blockader of de-
polarizing receptor and synaptic membrane, GABA
can only act as an ostensible 'inhibitor' when con-
fronted with the simple depolarizing electrogenic
membrane. Thus it acts on the cerebellar cortex as
CAPROIC (Cg)
FIG. 23. The qualitatively difl"erent effects produced by
w-amino acids with longer carbon chains. In each experiment,
responses were simultaneously evoked from the surface of the
cerebral cortex (upper trace) and cerebellar cortex (lower
trace). / and 4 show the responses in different experiments be-
fore applying the amino acids; 2 and 5, the cerebral p.s.p.'s
increased on applying C^ or Cg. The cerebellar activity was not
affected indicating that these u-amino acids are inert toward
the cerebellum. 3 and 6, responses after rinsing the cortical
surfaces with Ringer's solution. Time, 20 msec, is different in
the two experiments. Four traces superimposed in each record.
[From Purpura et al. (162).]
■78
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
it does on crayfish stretch receptor membrane by
eHminating the depolarizing electrogenesis (fig. 24).
However, when GABA is applied to the cerebral
cortex, its selective elimination of depolarizing
surface-negative p.s.p.'s discloses the previously
masked hyperpolarizing surface-positive p.s.p.'s.
Acting in the cerebral cortex (figs. 22, 24) GABA
and its congeners invert the electrocortical activity
evoked by a stimulus.
The effects of the .selective inactivators of hyper-
polarizing synapses, Ce and Cg (fig. 23), also differ
depending upon the type of electrogenic structure
20 MSEC
FIG. ^4. Different effects of the selective inactivator of de-
polarizing p.s.p.'s at different sites. A, t to 5.- Simultaneous re-
cordings from the cerebral cortex with a large surface electrode
(upper trace) and a fine wire electrode (lower trace). /, both
electrodes were on the surface and recorded nearly identically
the evoked surface negative p.s.p.'s of the superficial cerebral
dendrites. 2, the fine electrode was inserted about 0.4 mm be-
low the surface into an essentially isoelectric region. 3 and 4,
application of GABA to the cortical surface reversed the surface
response into positivity, but this change did not appear in the
subsurface recording. This indicates that the effect produced by
the amino acid was on superficial p.s.p.'s only, j, rinsing the
cortical surface restored the original activity at the surface. The
subsurface recording was still unchanged. 6, superimposed
responses before and during the action of G.^B.'K. B: The simul-
taneous recordings in this experiment were from the cerebral
cortex (upper trace) and the cerebellar (lower trace). /, before
applying GABA; 2, five drops of 0.1 per cent G,'\B.'\ were ap-
plied to each site. In the cerebral cortex the result was a reversal
of surface potential. In the cerebellar cortex the surface nega-
tivity was eliminated by blockade of the depolarizing p.s.p.'s,
but no positivity developed because of the paucity of hyper-
polarizing synapses in this structure. 3, recovery was rapid in
the cerebral and slower in the cerebellar cortex. Time, 20 msec.
[From Purpura et al. (163).]
that is used as a test object. Neither the crayfish
stretch receptor nor the cerebellar cortex is affected
by application of co-aminocaprylic acid (Cj). How-
ever, the surface negativity evoked in the cerebral
cortex is augmented by the blockade which Ce and
Cs cause amongst the surface-positive p.s.p.'s of the
hyperpolarizing synapses.
Recent work (Grundfest et al., in preparation; cf.
99, 163) indicates that the axodendritic synaptic
membrane in the cat brain stands in a doubly in-
verted pharmacological relation with some crusta-
cean synapses. GABA and other inactivators of the
cat depolarizing synapses activate crustacean in-
hibitory synapses. Picrotoxin, an activator of cat
excitatory synapses, inactivates the crustacean
inhibitory synapses. One of the selective inactivators
of cat inhibitory synapses, carnitine (cf. 163), activates
the excitatory synapses of lobster muscle fibers.
However, these inverted parallels are not complete.
The Ce and Cs co-amino acids do not affect the
crustacean synapses. Likewise, acetylcholine, d-luho-
curarine and strychnine are without effect.
In sum, it may be concluded from the foregoing
discussion that determination of the mode of action
of a drug depends not only on the degree of intimate
knowledge which may be obtained of its synaptic
effects but also upon the type of information that
may be provided by the test object. The synaptic
structure u.sed for the tests may be too complex to
yield the details required, but also it may be too
simple and provide only misleadingly partial in-
formation.
Identification and Characterization oj Transmitter Agents
The preceding section sets the theoretical and
methodological background for the problems treated
in this. The quantity of transmitters released during
activity of presynaptic terininals is probably ex-
ceedingly small (cf. 52, 59, 60, 68). The problem of
their identification therefore is strongly conditioned
by methodology. For example, norepinephrine has
been known, since its laboratory synthesis in 1904
(cf. 193), to have properties similar to those of its
homologue, epinephrine. Also, the work of Cannon
and his associates (cf. 1 77) had indicated very
clearly that there must be at least several sym-
pathetic transmitters which were designated as
sympathins E (excitatory) and I (inhibitory). Never-
theless, norepinephrine was not accepted as a pos-
sible sympathetic transmitter until it was shown in
1946 (cf 193) that it is a natural constitutent of the
SYNAPTIC AND EPHAPTIC TRANSMISSION
'79
body. Likewise, interest in GABA stems from the
demonstration of its occurrence in the brain in an
important pathway of synthesis (12, 172). Thus, the
candidate for a transmitter agent must meet a num-
ber of requirements (cf. also 65): a) it must mimic
closely the actions produced by the natural, neural
stimulus; b') its actions must be affected by the same
drugs and in the same ways as neural excitation is
modified; c) it must be a naturally occurring con-
stitutent, found in close proximity to the relevant
synaptic structures; and (/) it is desirable to demon-
strate that it is formed by an appropriate metabolic
pathway, that it is released at the time, place and in
the degree suitable to transmitter action and that its
accumulation to excess is prevented by another
metabolic pathway.
Characterized by the foregoing criteria, acetyl-
choline and the catechol amines of the epinephrine
group are still the only substances commonly agreed
upon and accepted as peripheral transmitter agents.
Most conspicuously, these substances derive their
claim to transmitter agents by their actions as
synapse activators. Thus, acetylcholine is probably
the excitatory transmitter at electroplaques, muscle
fibers, autonomic ganglia and some gland cells. At
the effector junctions of the cardiac pacemaker and
probably also in many smooth muscle systems (96),
acetylcholine activates hyperpolarizing synapses and
is inhibitory. The epinephrine group of transmitters
acts similarly at other synapses. However, these
transmitters also appear to have an accessory func-
tion (cf. 36). Thus epinephrine may antagonize the
action of decamethonium (47) or relieve ' fatigue' of
neuromuscular transmission upon repetitive stimula-
tion (119).^
In complex synaptic systems, one may as.sign
transmitter action to substances which do inac-
tivate synapses. For example, GABA is a synapse in-
activator, but if it is released by specific nerve fibers
its effects would be essentially inhibitory — with the
important exception that there would be no accom-
paniment of hyperpolarizing p.s.p. Likewise there
might be transmitters, analogous to Cg, whose overt
^ Neuromuscular blockade by decamethonium is a manifes-
tation of Wedensky inhibition discussed earlier. Antagonism by
epinephrine suggests that this transmitter agent acts as a com-
petitive antagonist, or synapse inactivator, of cholinoceptive
synaptic membrane. This type of action is apparently contra-
dicted by the ciTect of epinephrine in lifting the blockade pro-
duced by repetitive activity. However, there need be no real
contradiction for synaptic membrane may change its properties
under different experimental circumstances, an indication of
the complexity as well as lability of the active structure (cf. 96).
action, excitation, might be produced by inactivat-
ing hyperpolarizing inhibitory synapses.
These considerations indicate the difficulty of
identifying transmitters in a complexly organized
synaptic structure. The difficulty is enormously com-
pounded in the central nervous system, where even
a small volume of tissue contains a huge number of
synapses. In such a case all the criteria for categoriz-
ing transmitters cannot be fulfilled at present and
therefore identification is always tentative, based as
it must be on incomplete evidence.
Nevertheless, there is evidence from various sources
that acetylcholine and the adrenergic agents do af-
fect central nervous activity. Thus, circulatory injec-
tions of epinephrine (22) or acetylcholine (cf. iii)
bring about EEG activation as does stimulation of
the peripheral stump of the cat splanchnic nerve
(22). The electrical activity of a cortical slab, iso-
lated from its neural connections but surviving with
intact blood supply, is altered upon electrical stimu-
lation of the brain stem reticular formation (122).
Thus, brain stem activity releases some transmitter
agents which can then affect the isolated cortex.
This finding has been extended to cross-perfused
preparations (160). From that work it may be con-
cluded that what is released during brain stem ac-
tivity enters the systemic circulation and that it
must be a substance (or several) more stable than is
acetylcholine. The latter probably would have been
destroyed completely or almost so during the time
required for an exchange of circulating blood be-
tween donor and host. Many workers have shown
that acetylcholine is found in the central nervous
system as well as its synthesizing acetylating enzyme
(for references to the recent literature cf. 65). The
distributions of these substances in the brain and of
sympathetic transmitters (192) have also been
mapped. Lesions in some regions of the reticular
formation augment or depress the sensitivity of the
cortical electrical activity to epinephrine (178)
Intraventricular application of cholinomimetic and
adrenomimetic substances or of blockaders of the
two types of synapses produce a variety of central
nervous symptoms (cf. 75, and literature cited there).
Intravenous injections of (/-tubocurarine block cen-
tral nervous synapses (cf. 165).
Evidence with respect to other agents is still in-
conclusive. Although 5-hydroxytryptamine (sero-
tonin) and metabolically related substances are be-
lieved by some to be implicated in transmission,
whether they act directly or not is still in question
(cf. 26, 128, 148). As stressed earlier in this part.
i8o
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
the difficulties are largely methodological because
central synapses are so intricately interrelated and
may present many varieties. Stemming from this is
the difficulty of determining whether or not various
synaptic sites are afifected, and if they are what
results are to be looked for. Thus it has been shown
(162, 163) that the synaptically active amino acids
affect primarily only axodendritic synapses of the
cortex and only secondarily the axosomatic. Some
consecjuences are seen in figure 25. Blockade of ex-
citatory synapses of the dendrites by C4 (GABA) or
of inhibitory synapses by Ce (e-aminocaproic acid)
does not afTect the corticospinal discharge of the
pyramidal cells. However, the convulsive electro-
cortical activity induced by Cs (oj-aminocaprylic
acid) leads to prolonged discharge in the tract.
A further difficulty is the problem of accessibility
of the central synapses to testing drugs. The blood-
brain barrier apparently is highly effective for some
FIG. 25. Pyramidal tract activity when dendritic responses
in cerebral cortex are affected by u-amino acids. Column A, the
discharge recorded from the pyramidal tracts to stimulation of
the cerebral cortex in cats. Then, 0.2 cc of i per cent u-amino
acid had been applied for 10 min. The substances were C4 and
Cs as noted in each row of records. The responses of column B
were obtained when the cortical potentials had been altered as
shown in figs. 22 and 24. Despite these changes, the pyramidal
tract responses, generated by direct electrical stimuli and by
axosomatic synaptic excitations, were not affected (C4, Ce)
except when as in the case of C^, the drug caused convulsions.
Then a long after-dischsirge, associated with the convulsions,
developed. Ten superimposed traces in the upper records, five
in the middle and lower set. Time 10 msec. [From Purpura et
a/. (163).]
substances, e.g. GABA [Roberts & Baxter (172)].
Recent experiments (164) demonstrate that local
abolition of the blood-brain barrier permits the local
action of systemically injected oj-amino acids. These
results indicate that if the substances are elaborated
within the brain they might act as transmitters (using
the term for both synapse activators and inactivators;
cf. above), although the usual experimental criteria
would not disclose such action.
Modes of Action of Transmitter Agents and Synaptic Drugs
Since transmitters must be formed and, after their
release, metabolized in the body, enzymes for these
activities are components more or less related to the
appropriate synaptic systems. In the search for
mechanisms of drug action, interference with en-
zymatic or other metabolic processes has been fre-
quently stressed (cf. 2, 13, 14, 26, 65, and literature
cited in these papers). Undoubtedly-, interference
with these metabolic systems must cause synaptic
disturbance; but it is likely that such actions are
relatively slow, manifesting themselves, as in the
case of vitamin deficiences, only after depletion of
reserves. This is not the case with drugs that have
primary action on synapses (108). This may be .seen
in figures 22 to 24 in which the synaptic effects of
some of the oj-amino acids were obtained within a
second after they were applied and were rapidly
reversed by dilution.
Furthermore, substances of the same type of action
on enzymatic systems may have entirely different
synaptic actions. Thus physostigmine, DFP and
prostigmine are powerful inhibitors of cholinesterase.
By that effect all three, in very high dilution, enhance
neural action in eel electroplaques (5). This is merely
the indication that they prolong the life of the labile
transmitter agent. However, the synaptic actions of
the three drugs on the eel electroplaque are diverse
(table 2). In that capacity prostigmine is a synapse
activator like acetylcholine itself Physostigmine js an
inactivator like (/-tubocurarine and about as potent
in that effect. DFP appears to have dual actions
such as are to be found in the many other situations
(cf. 95, 96, 127).
The conclusion reached from these considerations
leads back to the view first proposed by Ehrlich (cf
2, 14, 40) that drugs exert their action by affecting,
perhaps by some form of chemical or electrostatic
combination, the performance of specific molecular
structures of the cell membrane. This receptor theory
has had many vicissitudes, apparently largely be-
cause of static conceptions of such functional units.
SYNAPTIC AND EPHAPTIC TRANSMISSION
lai
Recently the models examined have been endowed
with dynamic properties (cf. 2, 9, and literature
cited in the papers). These current theoretical
formulations have had some success in accounting
for relations between structures of drugs and their
functions. They do not, as yet, consider the implica-
tions of the recent findings concerning specificity of
drug action on one or the other type of synaptic
membrane. Thus the addition of one carbon link to
an co-amino acid converts a substance which is pre-
dominantly an inactivator of depolarizing synapses
(Cs) to another (Ce) which inactivates chiefly, or
perhaps exclusively, the hyperpolarizing type (table
4; figs. 22, 23). In other relations of drugs, similar
abrupt transitions depending upon number of
carbons (the transformation occurring at about five
carbon.s) have also been noted (cf 14, p. 147).
The occurrence of distinct varieties of synaptically
acting chcmotherapeutic agents, e.g. analgesics,
antipyretics, etc., bespeaks relatively sharp, though
not absolute, difl^erences between synaptic mem-
branes in differently acting regions of the central
nervous system. Similar distinctions, both peripheral
and central, derive from the relatively specific actions
of other drugs. Thus, whether synaptic transmission
is blockaded by atropine or by fZ-tubocurarine forms
part of the differentiation between muscarinic and
nicotinic cholinoceptive synapses.
Ph ysio/og ical Im plica lio n s
Only a few selected aspects can be discussed here
of the relations between the modes of action of trans-
mitter agents and their physiological consequences.
a) topographic distinctions. In many cases the
action of a transmitter must be rather strictly lo-
calized. This is due to a number of factors which
differ in importance for diflferent transmitters and
synaptic sites. The small quantity of transmitter re-
leased by a presynaptic nerve fiber would rapidly
lose effectiveness upon diffu.sion and dilution in the
volume away from the synaptic site. It may be
destroyed by enzymes or fLxed in various chemical
combinations. Its effectiveness at other synaptic
sites may be small or absent. The rate at which it
moves from the region in which it was liberated may
be very slow.
These, and other factors that may be postulated,
tend to restrict transmitter action to limited sites,
although under special experimental conditions dif-
fusion is easily demonstrated (cf 177). Electrical
ine.xcitability of .synaptic membrane and its chemical
specificities promote restriction of transmitter action
which is desirable in intricate synaptic relations. The
specificities of different, perhaps of alternating
synapses in a .synaptic sequence, as suggested by
Feldberg (cf 157), would be one means of achieving
this result. In the spinal cord, interneurons and
motoneurons appear to have somewhat different
pharmacological properties (cf. 60).
Diff'erent parts of the same neuron might also have
differently sensitive synaptic membranes. Thus, the
co-amino acids appear to be chiefly effective as
synapse inactivators at the superificial axodendritic
synapses of cortical neurons (fig. 25). In the context
of electrically inexcitable activity of these dendrites
(165) the function of dendritic electrogenesis is prob-
ably that of modulating somatic responsiveness, a
consequence which cannot be discussed here (cf.
lOl).
b) synaptic specificity and transmitters. Eccles
(cf. 60) has emphasized the implication of Dale's
suggestion (46) that one neuron at all its profuse
terminals probably generates only one type of trans-
mitter. This ' principle' is reasonable but is not at
all an obligatory condition. Furthermore, a neuron
secreting the same transmitter at different synaptic
sites may produce depolarization and be an 'ex-
citant' at one, or cause hyperpolarization and be an
'inhibitor' at another variety of synaptic membrane.
Likewise, the same neuron might produce at its
different terminals several varieties of transmitters
which might all have the same effect, excitatory or
inhibitory, or opposite actions, depending entirely
upon the variety of postsynaptic membrane which is
in synaptic relation with the transmitters. This
emphasizes that the nature of the transmitter can
determine synaptic potency and the kinetics of the
synaptic activity (cf 97). The type of electrogenic
action is determined by the postsynaptic membrane.'
c) reciprocal interactions of neural pathways.
The mechanisms of dual action discussed above have
bearing upon the interpretation of reciprocal innerva-
tion.r Sherington discovered in spinal reflexes (44)
that the development of reflex activity in one muscle
is associated with concurrent inhibition of antagonis-
tic muscular activity. These interactions extend to
' Interactions of some drugs evoke apparently dual actions
at the muscle endplatc (cf. 53). These may be cases of the situa-
tion commented upon earlier, in which a drug activates some
components and inactivates others in the same synaptic mem-
brane. This implies that the membrane of a single synapse is
not homogeneous.
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY 1
Other muscle groups that participate in an organized
movement (cf. 140). These effects frequently are
fully reciprocal, excitation in either path being asso-
ciated with inhibition in the other, and thus they
involve processes of reciprocal inhibition as well as
primary excitation.
A mechanism, discovered by Lloyd (cf. 138) and
termed direct inhibition, was believed to be mediated
monosynaptically, the collaterals of the same afferent
nerve fiber at one motoneuron evoking excitation,
tho.se to another producing inhibition. This mecha-
nism would imply that the same transmitter evokes
depolarizing p.s.p.'s in one neuron and hyperpolariz-
ing p.s.p.'s in another cell. From the point of view of
theoretical considerations this means of achieving
reciprocal actions is perfectly feasible, as is the possi-
bilitv that different transmitters are released at the
different terminals of the same primary afferent nerve
fiber. In the lobster cardiac ganglion (33, 186) one
presynaptic nerve causes excitation in one neuron
and inhibition in another.
The reality of monosynaptic direct inhibition of
this type in the cat spinal cord is at present in dis-
pute. Lloyd and his colleagues (cf. 194) maintain
that a monosynaptic pathway exists while Eccles
and his associates (cf. 60) consider that 'direct' in-
hibition is a disynaptic event. Whether the particu-
lar reflex pathways under discussion are mono-
synaptic or disynaptic is probably a matter of the
specific structures involved and perhaps of the
methodological details.* In principle, direct inhibi-
tion by monosynaptic reciprocal innervation can
occur. Since it is theoretically feasible it seems un-
likely that among the many types of connections
elaborated in the nervous system one possible and
rather simple variety has been omitted.
ROLE OF ELEMENT.-^RY SYN.\PTIC PROPERTIES
IN INTEGRATIVE ACTIVITY
Spatial Interrelations of Synaptic and
Conductile Aiembrane
Since p.s.p.'s are 'standing' nonpropagated po-
tentials, their effect upon the electrically excitable
" Drugs such as pentobarbital, for example, can alter pro-
foundly the pathways that produce pyramidal tract activity
through thalamocortical relays. This is disclosed by changes in
latency of several msec, when 4 to 10 mg per kg of pentobarbital
are administered (99, loi, 161 and unpublished work).
membrane of the same cell depends upon the spatial
arrangement of these differently excitable structures.
Assuming as a first approximation that the elec-
trically excitable membrane everywhere in a cell is
triggered to discharge a spike by the same level of
critical depolarization, and that the depolarizing
p.s.p.'s are everywhere equal in amplitude, the in-
tensity of excitation of the former by the latter will
depend upon the distance between the synaptic
focus and the nearest conductile membrane. The
more closely the two electrogenic membrane sites
approximate each other the more intense will be the
excitation for triggering a spike. The apical dendrites
of the cerebral cortex are not electrically excitable
(107) and the p.s.p.'s of the axodendritic synapses
generated at some distance from electrically ex-
citable membrane therefore would not be expected
to be as effective as the axosomatic p.s.p.'s generated
in close contiguity with electrically excitable mem-
brane. Thus, the apical dendrites of cortical neurons,
although they generate intense synaptic activity
(165) are not as effective in triggering spikes as are
the depolarizing synaptic loci at the soma (27, loi).
Spatial considerations may also be applied to the
effects of hyperpolarizing p.s.p.'s. The latter would
be most intensely inhibitory if they are interposed
between sites of excitatory p.s.p.'s and electrically
excitable membrane. The depolarizing p.s.p., in
that case, would be diminished not only by elec-
trotonic averaging between the opposed electro-
genic actions. The interposed hyperpolarizing site
would receive more outward current flow than rest-
ing membrane since its resistance would be lower,
and the potential gradient steeper. Consequently
this bypass would result in less current flow from
the depolarizing synaptic site to the electrically
excitable but as yet inactive membrane. Thus, the
loci at which depolarizing and hyperpolarizing
p.s.p.'s are generated, both relati\e to each other
and to electrically excitable membrane, must play
an important role in determining the effectiveness
of transmission from a given afferent volley. The
simplifying assumption that all s\naptic sites are
electrogenically equivalent is probably not justified
(see below). It is also likely that the conductile
membrane in different parts of a cell varies with
respect to its electrical threshold (79) or that it is
differently electrogenic (69), and these factors may
reinforce the transmissional inhomogeneity of dif-
ferent synaptic sites.
SYNAPTIC AND EPHAPTIC TRANSMISSION
183
Physiological Factors Determining
Transmissional Effectiveness
a) SYNAPTIC POTENCY AND DRIVE. Just as different
parts of the same cell exhibit variations with respect
to electrical threshold so also do different cells in a
population, that is, the critical firing level may be
lower for one cell than for another. In that case, an
afferent volley equally effective in generating p.s.p.'s
in all the cells may discharge some of these but not
others. It is unlikely, however, that the synaptic
potency of a given influx is identical for all cells.
Even in single multiply-innervated cells, such as the
eel electroplaque (4), the p.s.p.'s generated over the
large surface are of different amplitudes and always
largest at a definite region of the cell surface. Thus,
the p.s.p.'s generated in a population of motoneurons
would vary in magnitude depending upon the
synaptic potency of the afferents to each cell. This
variation, added to that of the distribution of elec-
trical thresholds, results in a population spread with
respect to excitatory effects or synaptic drives. It is
ob\'ious that the degree to which the given synaptic
inflow also excites hyperpolarizing p.s.p.'s as well as
depolarizing, and the relative spatial distributions of
the two electrogenic activities will affect the mag-
nitude of the synaptic drive.
The differences in synaptic drive deduced above
adequately account for a mass of experimental data.
The cells in a population of neurons impinged upon
by a sample from a population of innervating nerve
fibers will respond with different degrees of depolariz-
ing p.s.p.'s. Some of the cells will discharge spikes
which can be recorded directly (e.g. fig. 12) or by
means of other effects, as for example by their reflex
activation of muscle in the case of motoneurons. In
other cells excited by the afferent volley the p.s.p.'s
alone are generated.
b) EXCITED AND DISCHARGED ZONES. Thus, an ex-
citatory volley causing quantitatively different
amounts of synaptic activity also divides the popula-
tion of postjunctional cells qualitatively. One group,
frequently by far the smaller, falls in the discharged
zone, the other in the excited zone (fig. 26). In this
distribution the occurrence and influence of hyper-
polarizing inhibitory p.s.p.'s may also be considerable
but need not be discussed in detail, except in the
extreme case when the neural volley generates pre-
dominantly or entirely hyperpolarizing p.s.p.'s. In
that case spike electrogenesis would not occur and
the volley in isolation may produce no overt effects,
although direct recording from the cells would dis-
INNERVATED FACE
EXCITED CELLS
DISCHARGED CELLS
LEAD A
LEAD B
FIG. 26. Discharged and excited zones in a row of eel electroplaques on maximal stimulation of
their three different nerve supplies. Cells 6 to 10 were excited by Nerve I as evidenced by their p.s.p.'s
and long-lasting homosynaptic facilitation, but did not develop spikes to a single testing stimulus.
Nerve II caused discharge of spikes in cells 9 to 11, but in addition excited cells 6 to 8 and 12 and
13. Nerve III discharged cells 12 and 13, exciting also cells 10, 11, 14 and 15. The diagrammatic
representation of the recording leads shows the method that was used to test this population of cells.
[From .Altamirano et at. (5).]
1 84
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY 1
close the p.s.p.'s. These, hke the excitatory p.s.p.'s,
should vary in amplitude in the population of post-
junctional cells. An overt manifestation of the in-
hibitory p.s.p.'s would occur if the cells are at the
same time producing excitatory p.s.p.'s and spikes or
causing reflex activity in muscles. More or less selec-
tive afferent activation of inhibition, and its role in
spinal reflex activity, was demonstrated by Sherring-
ton (44, 182; cf. 140). Relatively specific descending
pathways were found by Sechenov (180) in the frog
and by Magoun and his colleagues (cf. 147) in the
mammal.
c) FACILITATION. Study of spinal cord reflexes also
demonstrated the existence of the excited zone by
the effects of temporal and spatial facilitation, the
excited cells being then termed the subliminal fringe.
Both types of facilitation depend essentially upon
the properties of summation and sustained response
of p.s.p.'s described above. However, subsidiary
effects also participate which will be discussed later.
The unitary p.s.p.'s are relatively long lasting, in
the cat central nervous system having a duration of
about 15 msec. (figs. 12, 27). For that time at least,
therefore, an excited cell is somewhat depolarized, at
first to a large degree, but not to that of the critical
level for discharge, and then to a smaller amount,
decreasing with time.
The presence of the e.xcited cells can be tested by
applying a second volley either through the pathway
which delivered the first condidoning stimulus
(homosynaptic testing) or through another inner\-at-
ing path (hcterosynaptic testing).
d) HOMOSYNAPTIC FACILITATION. In this casc, there
will be no second response, neither an electrical
activity nor a reflex contraction of muscles, if the
stimulus interval is verv short. Because of absolute
B
msec
50 mV
10 msec
^ — ^^^
FIG. 27. Temporal facilitation and shortening of synaptic delays in neurons. .-1, B: From a cat
motoneuron at high and low amplification. Two orthodromic stimuli, neither capable of discharging
the cell, can evoke a spike by summation of the p.s.p.'s produced by each stimulus. Since the spike
occurs only when the critical level of depolarization is attained, the summation interval may be
sharply delineated as shown in this example. [From Brock el al. (24).] C: From a rabbit cervical
sympathetic neuron. Progressively stronger stimuli to the preganglionic nerve increased the p.s.p.
of the neuron and evoked its spike earlier as the critical firing level (shown by arrows) was attained
earlier. [From Eccles (64).]
SYNAPTIC AND EPHAPTIC TRANSMISSION
l8n
%
zoo
""■ 300
Z50
\
\
B
150
\»
\
^v.
■~.
200
150
-
\
V
.^
2
4
6
a
10
12 Msec (
3
2
4
6
8
10
12 Msec.
FIG. 28. The time courses of facilita-
tion and direct inhibition (magnitude of
response as percent of control value)
tested on monosynaptic reflexes are
nearly symmetrical. Facilitation (upper
curves^, A in an extensor and B in a flexor
muscle. Inhibition (lower curves'), i4 in a
flexor and B in an extensor muscle.
[From Lloyd (140).]
e 10 12Msec 0 2 4
12 Msec.
refractoriness of the presynaptic fibers, no impulses
arrive at the synapses. At slightly longer intervals,
relative refractoriness or persistent absolute refrac-
toriness of the previously discharged postjunctional
cells causes a depressed testing response, but then an
interval is reached when the testing response can
become many times higher than it would have been
without the preceding conditioning activity. As noted
above, the facilitation in the simplest cases lasts
about 15 msec. (fig. 28), decreasing continuously
from its peak value during this interval. It is likely,
although this has not as yet been generally estab-
lished, that the synaptic drive of the testing volley is
also increased by antecedent activity of the nerve
fibers. This enhancement may take place in the pre-
synaptic fibers themselves. For example, invasion of
the terminal branches by the conductile activity may
be partial for a single volley and larger for a subse-
quent. Also, the amount of transmitter released by
the second activity may be larger. In many junc-
tional systems, the prolonged stimulation of the pre-
synaptic nerve at relatively high frequencies for
some time thereafter increases the effects produced
by a subsequent single testing stimulus (76, 87, 124,
135, 139). This phenomenon, post-tetanic (cf 118)
or postactivating (59) potentiation, may likewise
depend upon the mechanisms just described. In-
creased synaptic drive may also involve the post-
synaptic membrane as, for instance, by a temporary
change in the excitability of the membrane to the
transmitter agent. These residual presynaptic and
postsynaptic effects may alter synaptic drive in either
direction and act without relation to the residual
p.s.p. from the first volley. Thus, the homosynaptic
facilitation which occurs in the eel electroplaque
(fig. 29) lasts for about i sec, whereas the p.s.p.
lasts only 2 to 3 msec. (4, 5, 6).
e) HETEROSYN.'SiPTic FACILITATION. Hetcrosynaptic
testing eliminates the complications introduced in
homosynaptic facilitation except the refractoriness
of the discharged postjunctional cells. The facilita-
tion now may start at very brief intervals between
the stimuli. Strictly speaking, however, hetcro-
synaptic testing involves spatial factors for the
terminations of one pathway may activate different
synaptic sites than do those of the other. The facilita-
tion is therefore likely to take place by electrotonic
additions of the depolarization produced by the test-
ing stimulus onto the residual level of general de-
1 86
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY
ZOO
MSEC
FIG. 29. The time course of homosynaptic facilitation in a group of eel electroplaques. The testing
stimulus alone evoked responses shown by the horizontal lines at the end of the graph in B. At
various intervals after a conditioning stiinulus, the response to the test stimulus became larger than
this control value and gradually returned toward it. • : Facilitation without treatment with drug.
A : 1 2 min. after adding 50 >jg per ml physostigmine the cells became somewhat more excitable,
the whole curve of facilitation being lifted on the baseline of the larger response to the testing stim-
ulus in isolation. This effect presumably developed because of the anticholinesterase action of phy-
sostigmine; it is also produced by prostigmine. The two substances, however, have opposite synaptic
action, physostigmine being an inactivator of synaptic electrogenesis and prostigmine an excitant,
n ■ 64 min. later, the physostigmine had depressed synaptic excitability and the whole curve had
fallen. Expressed in percentile values of the response to the testing stimulus alone in each condition,
the three curves had essentially the same magnitudes and time courses (.4). [From .\ltamirano
et al. (6).]
polarization remaining from the prior stimulus. This
is, indeed, the condition found experimentally (fig.
30^) in the electroplaques from the Sachs organ of
the eel. Both depolarizing p.s.p.'s being short,
facilitation occurs only during the first 2 msec. In
cells of the main organ, however, heterosynaptic
facilitation lasts some 50 to 75 msec. (fig. 3oi?) and
in this case the effect must be due to alteration of the
excitability of the synaptic membrane since pre-
synaptic interactions are ruled out. The different
behavior of the electroplaques in the two organs is
probably ascribable to difTerent spatial relations of
their synapses. If those in the electroplaques of the
main organ are closely spaced, diffusion of transmit-
ter from the sites activated b\- the conditioning
volley might affect the excitability of the synaptic
loci innervated by the second neural pathway (95).
The data presented above derive from a particu-
larly favorable structural configuration, a large
postsynaptic cell with an extensive responsive mem-
brane (about 15 mm- in area) diffusely innervated
by several easily isolated nerve trunks. The experi-
mental conditions that obtain in nerve cells do not
usually perinit as clear a delineation between dif-
ferent spatial interactions. However, in the case of
cells with long dendrites, as in the cortex, it may be
expected that interaction between different axo-
somatic synapses will be greater than that between
these and the axodendritic.
f) sp.'Kti.'^l sum.m.ation of converging p.^th\v.\ys.
Another variety of spatial summation is more fre-
quently noted in the central nervous system. This is
the case in which two widely separated neuronal
complexes eventually converge upon one or more
common paths. In that final common path the situa-
tion then reduces to a variant of the case discussed
above. These convergent types of interaction are
further complicated in the central nervous system
by the involvement of inhibitory p.s.p.'s. Spatial
SYNAPTIC AND EPHAPTIC TRANSMISSION 1 87
FIG. 30. Heterosynaptic facilitatory actions in eel electroplaques from different electric organs.
Left: Absence of heterosynaptic facilitation in cells from the Sachs organ. .Activity of one nerve
evoked the response seen in A. This response -was preceded by that evoked through another nerve in
B to G. Only when the two stimuli (shock artifacts on the left of the records) were less than i msec,
apart (_F, G) was there a significant amount of facilitation caused by electrotonic summation of the
brief p.s.p. [From .-Mtamirano et al. (5).] Right: Heterosynaptic facilitation in cells of the main organ.
A: The response to stimulating one nerve trunk. B: This nerve trunk is used to deliver the con-
ditioning stimulus (artifact at the left, upward); the testing stimulus is applied at various intervals
later to another nerve trunk (artifact down, superimposed traces). Marked facilitation reached a
peak at 10 to 15 msec, and persisted through the end of the record at 25 msec. C: Nerve 2 was cut,
and a third nerve trunk was used for the testing stimuli. No facilitation occurred. [From Albe-Fes-
sard & Chagas (i).]
inhibition or facilitation may develop particularly
in the more complex varieties of synaptic organiza-
tion. The precise effects would depend on the specific
pathways and electrical responses involved and can-
not be discussed in this chapter (cf. 99-101, 161).
186). Thus, they can provide sites at which synaptic
potentials of both signs may be generated and this
electrical summation propagated electrotonically to
act upon an electrically excitable membrane distal
to the cell body.
Integrative Utility of Electrical Inexcitability
The foregoing group of integrative activities de-
pends essentially upon graded, algebraically sum-
mative potentials of opposite signs which are made
available in synaptic transmission by electrical in-
excitability. In some neurons, relatively large scale
areas of membrane are not electrically excitable and
this would appear to aid integrative functions. The
superficial cortical dendritic surfaces, richly supplied
with synaptic inflows, are an example of this. The
synaptic activity that goes on at these dendrites re-
sult in algebraically summated potentials. Since
these dendrites are not electrically excitable, the po-
tentials must be transmitted electrotonically to the
electrically excitable membrane of the pyramidal
neurons. In each of these the potential can serve to
modulate responsiveness to other, more potent
synaptic inflows. The soma of lobster cardiac gan-
glion cells also are not electrically excitable (33, 109,
Synaptic Determinants of Different Types of Reflexes
In the general context of principles, the precise
structural and functional complexity of a reflex
pathway is of little moment. Therefore, the specific
properties of monosynaptic or multisynaptic reflexes
need not be dwelt upon since they are finally refer-
able to the intensity of synaptic drives upon the final
common path. The analysis of synaptic mechanisms
in many varieties of reflex response can likewise be
simplified by merging all interneuronal activities with
that of the final common path, essentially involving
a reduction to the monosynaptic case.
Synaptic organizations involving very strong
synaptic drive for depolarizing p.s.p.'s will manifest
themselves by large synchronized efferent electrical
activity or a twitch-like contraction in response to a
single afferent volley. The amplitude of the response
will depend upon the proportion of neurons that lie
in the discharged zone. The lower the proportion of
1 88
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
cells with depolarizing p.s.p.'s above the critical
level, the greater will be the degree of facilitation on
repetitive stimulation. If the majority of the cells in
the excited zone develop p.s.p.'s only slightly below
the level of critical depolarization, a few repetitive
stimuli will rapidly evoke a maximal response. This
gives rise to the general class of cPemblee reflexes
(cf. 44). Augmentation of p.s.p.'s (synaptic facilita-
tion) discussed earlier (p. 168) also will favor pro-
duction o{ d' em blee refiexes.
When the p.s.p.'s of the excited zone are small,
the responses may recruit very gradually with repeti-
tive stimuli. Particularly when the synaptic organi-
zation is complex and the synaptic drives are weak
will the latency of the response be long. Under these
conditions it may also be expected that moer fre-
quent stimuli will shorten the latency markedly and
increase the rate of growth of the response and per-
haps its maximum value. In other words, the more
weakly effective synaptic drives, including multi-
synaptic pathways, will show a greater frequency-
dependence. Since the production of hyperpolarizing
p.s.p.'s also involves excitation of synapses, the de-
velopment of inhibitory activity will depend similarly
upon the stimulus parameters.
Another effect in which the complexits of the
synaptic organization plays a role is that of after-
discharge. The involvement of multisynaptic path-
ways carries the likelihood that additional side
paths will also be brought into activity and thus
give rise to a circulating activity (78) or a series of
delayed reverberations which may cause discharges
of the final common path long after the initial
stimulus is ended. This reverberation may take place
by one-to-one excitation, but it is likely that another
phenomenon plays an even greater role. This is the
summation and persistence of p.s.p.'s associated with
accumulation of a persistent transmitter agent. As
individual Renshaw cells are capable of persistent
repetitive discharge by a single stimulus (61), so
some of the interneurons mediating excitatory
p.s.p.'s can also remain active for a long time. The
interplay of excitatory and inhibitory synaptic
activity may produce complex patterns of waxing and
waning after discharge. In individual cells this pat-
terning would be reflected by a greater or lower
frequency of discharge. Complex interactions of
excitatory and inhibitory types occur even in the
relatively simple nuclear structures like that of
Clarke's column in the spinal cord (104, 115). The
involvement of a widespread network of neuron
complexes in after-discharge is indicated also by the
fact that increasing the strength of the initiating
stimulus may lead to no increase in the maximal
amplitude of the reflex respon.se but only in the dura-
tion of its after-discharge (182).
Role of Inlnhitioii in Central Nervous System
The interrelations of depolarizing and hyper-
polarizing p.s.p.'s in the.se various manifestations,
in.sofar as they are dependent upon the specific
organization of synapses, are beyond the scope of
this chapter, but some general discussion is ap-
propriate (cf. 1 01, 161). As was described earlier,
hyperpolarizing p.s.p.'s need attain only relatively
small amplitudes to produce inhibition. The effect,
a sudden cutting off of conductile activity, may
block the synaptic transfer to many systems which
would normally participate in an activity. The re-
sults of a given excitatory and inhibitory interaction
will differ depending upon the site at which an index
of the effect is obtained. In a specific example let us
assume that a single cell is acted upon by the synaptic
interplay. Whether or not it is excited to produce a
spike will have important consequences for the ac-
tivity of other downstream neurons for which the
cell chosen as an example serves as a valve. How-
ever, when recording from the interior of the cell,
depolarizing and hyperpolarizing activities may be
oi)served even in the absence of a spike. Thus, dif-
ferent criteria apply to activity in different parts of
a complex pathway. The relations between activity
in one part and another may even be dimmed or
may disappear.
The activity set into motion by a synaptically
complex pathway thus may be undetected in the
overt response. For example, a single stimulus to the
head of the caudate nucleus in the cat giv-es rise to a
relatively simple, brief electrical response in a re-
stricted cortical region. Analyses with paired or
repetitive stimuli disclose (167) that many excitatory
and inhibitory influences are activated, some for
long periods of time. It is worth noting that ana-
tomical data can rarely give information as to the
presence of such intricate synaptic linkages and, of
course, cannot distinguish those that are excitatory
from the inhibitory.
It is most likely that in its normal functioning the
central nervous system utilizes inhibitory activity as
a means for braking excitatory activity which might
otherwise be unduly prolonged or inclined to rever-
beration. In that sense, therefore, inhiijitory synaptic
electrogenesis would aid the precision of ner\ous
SYNAPTIC AND EPHAPTIC TRANSMISSION
189
activity. The remo\al of inhibitory electrogenesis
either by drugs which specifically blockade hyper-
polarizing synapses, or by pathological conditions,
would then remove these brakes upon excitatory
activity and abnormal function would result. This
would be apparently caused by 'excitation' although
its fundamental mechanism would in reality be the
block of another, opposed type of synaptic activity,
the inhibitory electrogenesis. The pharmacological
classification of strychnine as a 'stimulant of the
central nervous system', already discussed, illustrates
the basic difference between a descriptive, phe-
nomenological classification and that ba.sed on
analysis of its mode of action.
Phynulogical Effects of Different Proportions oj De-
polarizing and Hyperpolarizing Postsynaptic Potentials
Apparently different physiological and pharma-
cological properties may result from different pro-
portions of the two kinds of synaptic activity. Thus,
the electrical activity of the cat cerebral cortex
differs profoundly from that of the cerebellar, but
these differences may be accounted for by the rela-
tively small degree of inhibitory electrogenesis ol the
cerebellar cortex (161-166). Pharmacological dif-
ferences, such as the insensitivity of the cerebellar
cortex to local applications of strychnine, are equally
ascribable to this quantitative factor.
However, the response of the cerebellar electro-
cortical activity to different drugs depends upon
the mode of exciting that activity (Purpura, Girado &
Grundfest, in preparation; cf. also 99-101, 163).
Different cerebellopetal afferents may evoke po-
tentials of different forms at a single cortical site.
These potentials are composed of different propor-
tions of excitatory and inhibitory synaptic activities
as demonstrated by their different reactions to the
various specifically acting drugs.
Synaptic Activity and Electrical Concomitants
The matters discussed under this heading relate
physiological activity in the central nervous system
to the methodology of its study by electrophysiologi-
cal means. They are also considered by Frank in
Chapter X of this work.
a) interpret.ations of changes in .'\mplitudes of
POSTSYNAPTIC POTENTIALS. Since p.s.p.'s are not
subject to refractoriness but are capable of summa-
tion and of being sustained, decrease in amplitudes of
p.s p.'s cannot be ascribed to their refractoriness or
'occlusion'. A depolarizing p.s.p. therefore can
diminish only by virtue of the following factors.
/) The conductile process of the preceding unit
is blocked by refractoriness. This is probably a minor
element since profound alterations in synaptic re-
sponses occur at frequencies of repetitive activity so
low that refractoriness of electrically excitable re-
sponses does not occur.
2} The transmitter of the presynaptic terminals
may become exhausted or the receptor of the post-
synaptic membrane may become altered. The latter
factor has been discussed in connection with de-
.sensitization (p. 157).
^) Stimulation at high frequencies may, however,
produce fused sustained p.s.p.'s that show little or
no fluctuation from the steady level (fig. gfi, C).
This effect probably develops when the synaptic
membrane is maximally excited by the frequently
released packets of transmitter agent. The steady
depolarization (or hyperpolarization) can be re-
corded in the cerebral cortex (cf. 176, fig. 10).
4) Simultaneous and countervailing development
of hyperpolarizing p.s.p.'s may mask the depolariz-
ing. There is now considerable experimental evidence
that this factor is most important in the complex
synaptic organization of the central nervous system
(165-167). Indeed, the overt electrogenesis ob-
servable in the cerebral cortex after a single stimulus
may be only a small part of the total electrogenic
activity. The major part is not recorded because
depolarizing and hyperpolarizing p.s.p.'s are simul-
taneously produced and tend to cancel each other.
b) interpretation OF electrotonic effects of
STANDING postsynaptic POTENTIALS. It has been
frequently assumed that the surface negativity of the
cerebral cortex caused by dendritic p.s.p.'s produces
anodal polarization of their cell bodies (cf. i 76, pp.
56 and 57). This conclusion is drawn from analogy with
the effects of externally applied currents, a cathode
on the surface depressing and a surface anode aug-
menting excitability of the cell bodies. This analogy
is not valid in the physiological case. Externally
recorded negativity means that the interior of the
generating site is depolarized (i.e. more positive than
the resting potential). Surface negative p.s.p.'s of
apical dendrites therefore must always act as an ex-
citatory (cathodal) stimulus for the electrically ex-
citable membrane of their cells (cf. 97, loi).
c) synaptic transducer action AND electro-
genesis. The recorded electrical activity might even
I go
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY 1
STIMULUS
Subthreshold Thretshold
FIG. 31. Ephaptic excitation of squid giant axon. Two nerves
are arranged as siiown in diagram. I. Contact between nerves
in sea water. A weak stimulus (/(/O evokes a local response of
the pre-ephaptic fiber (seen in trace .4). This is not propagated
to the ephapse and has no effect on the latter (trace B). When
a pre-ephaptic spike was evoked by a stronger stimulus (.4'),
the post-ephaptic nerve generated a locaJ response (B'). .^head
of it is seen the electrotonic pick-up of the pre-ephaptic spike.
II. Excitability of the axons was increased by removing calcium
ions from the medium. The weak stimulus still could not evoke
activity in the post-ephaptic fiber (B), since conductile activity
was lacking in the pre-ephaptic unit QA). When a stronger
stimulus evoked a spike (.4') the postephaptic fiber also pro-
duced a spike (B')- This arose on a step which is the local
response of the postephaptic fiber (seen in isolation on the
lowest trace). [From Arvanitaki (10).]
be absent if ionic processes leading to hyperpolariz-
ing and depolarizing p.s.p.'s were equally balanced.
Despite this, however, the transducer actions ini-
tiated by the excitants of depolarizing and hyper-
polarizing synaptic membrane would still take place,
and the ionic transports of the transducer action
would still occur. Thus, ionic, metabolic and other
biochemical effects might be produced in the ap-
parent absence of electrical activity (96, 97).
EPH.APTIC EXCITATION
Electrical Modes of Transmission
In the course of efforts to validate the theory
of electrical transmission many attempts were made
to confirm Kiihne's dictum that "a nerve only throws
a mu.scle into contraction by means of its currents
of action." In 1882, Hering (i 10) found that a nerve
\-olley initiated in one distal branch of the frog
sciatic nerve and coursing centrally in the whole
nerve trunk could set up activity in another branch
when the impulses arrived at the centrally transected
stump of the nerve. The current flow generated by
the active fibers must have stimulated the previously
inactive fibers. The effect has been confirmed many
times (cf. 149) but nowhere more clearly than in a
preparation involving two squid giant axons (lo).
It must be emphasized that specially favorable ex-
perimental conditions are required to produce this
■ model' of transmission which is termed an ' ephap.se'
(false synapse). In the squid giant fiber (fig. 31) the
electrical excitability of the ephaptic region is
heightened by depriving the medium of calcium.
The extrinsic current of the spike in the pre-ephaptic
terminal is then capable of acting as a sufficiently
strong electrical stimulus to evoke a postephaptic
spike. As a weaker stimulus, it can elicit a graded
local response. In more complex geometrical con-
ditions between active and inactive cells, the direc-
tions of the extrinsic or field currents may produce
hyperpolarizations as well as depolarizations (figs.
I, 32). The activity travelling in one fiber generates
extrinsic current fields in contiguous parallel fibers
which have a triphasic sequence (126) that suc-
cessively produces hyperpolarization and depressed
excitability, then depolarization and heightened
excitability, followed again by hyperpolarization
and depression (fig. 32).
A weakness of ephaptic transmission as a model
of synaptic activity lies in the fact that basically it
does not offer a mechanism for polarized transmis-
sion. Thus, in figure 31 the ephaptic excitation might
very well have taken the opposite direction, from
nerve B to nerve A. Special geometric properties
were invoked by du Bois-Reymond and by Eccles
(figs. I, 32), and tlie latter also introduced the special
electrophysiological rectifying effects of anodal and
cathodal currents (fig. 32). These conditions might
account for polarized transmission with an electrical
mechanism; and, as will be described below, a high
degree of rectification recently discovered in one kind
of junction (83) does polarize conduction. However,
the crucial distinction is whether or not current
flow in a presynaptic terminal, or current flow im-
posed through the synaptic junction, can excite the
activity of the latter. The an.swer, illustrated in this
chapter with a number of examples (e.g. figs. 6, 19),
SYNAPTIC AND EPHAPTIC TRANSMISSION
191
120-
110- S
100
90-
80-
Action potential in
fibre I
Excitability chonge in
fibre IE
>A,X»-TC
Ct1"<AAt
i':i.|:>iaJ-t
msec. * — * —
FIG. 32. Excitability changes caused by field currents. I'pper lejt: A spike was produced by a stim-
ulus to one of a pair of crab nerve fibers as in diagram upper right. The electrical excitability of the
second fiber is shown (lower left) in relation to the time at which the spike passed the testing region.
In the interval before the spike had reached that site, the excitability of the fiber was depressed.
During the time that activity resided at the tested level, the excitability was augmented. This was
followed by a second depressed phase as the activity propagated out of the tested site. [From Katz &
Schmitt (126).] Right: Diagrams of the anodal, cathodal and anodal polarizing sequence generated
in the inactive fiber by the spike in an adjoining fiber ilop') and of different field current conditions
produced by different geometrical arrangements (bottom). [From Eccles (57).]
seems to be clear. The current flowing across an
active presynaptic terminal and across the post-
synaptic membrane appears to be far too small to
excite the postsynaptic cell. Furthermore, the proc-
esses associated with synaptic activity cannot be
initiated by very strong applied currents.
Role of Field Currents in Central Nervous System
The activity of masses of cells or fibers in the
central nervous system is particularly conducive to
development of field currents within the volume of
this structure (15). This fact suggested (88, 90) that
field effects might play a role in determining the
peculiarities of central nervous properties. The
hypothesis appeared to have been confirmed by anti-
dromic stimulations of motoneurons which altered
the responses of contiguous motoneurons to a testing
afferent volley (170). That conclusion, however, is
invalidated by the subsequent finding (171; cf. 60)
that the antidromic stimuli evoked synaptic activity
within the spinal cord by means of the recurrent
collaterals of the motoneurons.
Although field currents undoubtedly play some
role (cf. 106), their wide significance must now be
questioned in the light of the evidence that synaptic
transmission is not effected by electrical stimuli.
Changes in membrane potential produced in one
cell by activity of contiguous elements appear to be
small (33, 59, 125), although effects may be revealed
by tests on electrically excitable membrane (106,
126, 185). However, the effects exerted electro-
chemically on p.s.p.'s (as described in the section in
this chapter on the nature of postsynaptic potentials)
are probably insignificant. Thus, electrical ine.x-
citability renders the transmissional process insensi-
tive to fields of current in the central nervous system
(93). Teleologically considered, this is probably an
advantage. The fields must shift from moment to
moment as the loci of activity shift in the cellular
mass of the volume conductor. The effects of these
fields must therefore be highly unspecific, now pro-
ducing increase, now depression of electrical ex-
citability, actions that probably would disturb the
precision of organized orderly synaptic transfer.
Thus, electrical inexcitability of synaptic membrane
removes a major hazard, that irregular effects of
electric fields might disrupt the patterned activity
of the central nervous system.
192
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
Dorsal Root Reflex
Acting upon electrically excitable components,
however, field currents might still affect central
nervous functioning. For example, small depolariza-
tion of a cell by field current might facilitate its
discharge by an otherwise subliminal depolarizing
p.s.p. Likewise, presynaptic terminals close to an
active synaptic focus might be subjected to con-
siderable potential change (51), an action which
may account for the dorsal root reflex (188). This
prolonged centrifugal discharge of dorsal root fibers
is evoked with a latency of some milliseconds after
the same or other dorsal root fibers cany a volley
centripetally. The dorsal root reflex is enchanced
by low temperatures as is the motor root reflex (29,
89). The latency, temperature effect and prolonged
discharge of the dorsal root reflex indicate that it is
produced by a synaptic activity in the spinal cord,
and yet there is no histological evidence of synaptic
inflows to the dorsal root collaterals. In the absence
of the latter, ephaptic excitation may be invoked,
but will involve synaptic pathways also. This could
result from the field effects generated in the dorsal
root terminals by the activity of some interneuronal
pools. The activity of these cells, being evoked by
synaptic transfer, would account for the apparent
synaptic properties of the dorsal root reflex, but its
final development would be by ephaptic excitation.
Ephaptic Transmission in Annelid and
Crustacean Nerve Cords
In many species of these invertebrates there occur
junctions (septa) between anatomically distinci
elements, the segments of the septate giant axons.
Across the septa considerable electrotonic current
flow can take place and ephaptic electrical transmis-
sion is then possible (125; Kao, C. Y. & H. Grund-
fest, manuscript in preparation). The junctional
membranes of these functional ephapses must there-
fore be fundamentally different from those of
synapses, across which only insignificant electrotonic
current flow occurs. However, the anatomical data
to account for this difference are still unsatisfactory.
The transverse sheaths which separate abutting seg-
ments of the septate giant axons appear to be identi-
cal with the sheaths that invest the axis cylinders
(cf. 1 25). On the other hand, the junction between
the medial giant axon and the motor giant fiber
of crayfish seems to be formed by processes from the
postjunctional motor nerve which penetrate the
Schwann sheaths to make intimate contact with the
cell membrane of the prejunctional fibers Ci74)- The
junctions between two motor giant axons are also
similar.
a) unpol.\rized EPH.'SiPTic JUNCTIONS Thcsc havc
been studied with intracellular recordings in the
.septate giant axons of earthworm (125) and cray-
fish (Kao, C. Y. & H. Grundfest, manuscript in
preparation). The septa, sometimes called 'un-
polarized macros\napses' (cf. 30, 125), appear to be
merely the boundaries demarcating the multiple
origins of the .septate giant axons from a number of
segments of the animal. Activity in one segment of
the axon causes electrotonic potentials in the neigh-
boring segments large enough to excite the latter.
Thus, transmission is by local circuit excitation, es-
sentially as in other axons. As in the latter, the
ephaptic transmission of the septate axons is un-
polarized, capable of propagating an impulse in
either direction.
b) pol.-^rized eph.-vptig transmission. One system
recently described (83), the junction between cord
giant fibers and efferent motor giant axons of cray-
fish, may be classified in this category. Current flow-
ing outward from the depolarized prefiber can enter
the junctional membrane of the postfiber, causing
large depolarization in the latter (fig. 33.-1) and its
ephaptic excitation. However, when the postfiber is
depolarized (fig. 335) the electrotonic effects in the
prefiber are small. Likewise when the prefiber is
hyperpolarized current flow in the postfiber is hind-
ered (fig. 33.4), while hyperpolarizing the postfiber
causes large electrotonic changes in the prefiber
(fig. 33^). The junctions thus exhibit rectification,
with conductance in one direction (that tending to
depolarize the postfiber) about 20 times greater than
in the opposite direction. Thus, in the case of the
motor giant fiber ephapse, the low electrical resist-
ance in one direction and high resistance in the other
makes for polarized ephaptic transmis.sion.
Since the junction meets the criteria of anatomical
discontinuity and transmissional polarization, it
fits the definition of synapse extant since Ramon y
Cajal and Sherrington. However, though it may be
called an 'electrically excitable synapse' (83), it
probably differs profoundly from the electrically
inexcitable synapses discussed in this chapter. The
distinction between ephaptic junctions which have
low electrical resistance and synapses which have
high resistance helps to make the classification more
precise. Thus, experiments similar to those shown in
SYNAPTIC AND EPHAPTIC TRANSMISSION
'93
Vtt
MV
hypcrpolorizotion
8
5H
'9^
^'post
i^
hypcrpolarlzotion
depolarizotion
-5
'pre
•-lO
mV
FIG. 33. Rectification at the junction be-
tween a cord giant fiber and a motor giant
axon in crayfish results in polarized ephaptic
transmission. A: Current was allowed to flow
through a microelectrode in the prejunctional
cord giant axon. The changes in the membrane
of the same fiber were recorded with another
microelectrode and are shown on the abscissa.
The ordinate indicates the membrane voltage
recorded at the same time with a micro-
electrode in the postjunctional fiber. When
the prefiber was depolarized, a steeply rising
depolarizing change also took place in the
postfiber. As an extrinsic local circuit change
was produced by a spike in the prefiber, it
would lead to an electrically excited response
of the postfiber. When the prefiber is hyper-
polarized (left side of .-1), only small changes
in potential develop in the postfiber. The ratio
of current flowing in the two directions is about
20:1. B: In this experiment current was
applied to the postfiber, the abscissa shows the
change in membrane potential of this fiber
and the ordinate the change in membrane
potential of the prefiber. When the postfiber is
hyperpolarized, there is a considerable current
How into it from the prefiber, causing some
clectrotonic hypcrpolarization of the latter.
When the postfiber is depolarized, little
current flows into the prefiber and it there-
fore cannot be stimulated by a spike in the
postfiber. Electrical excitation across the
junction is thus transmitted only from the
pre- to the postfiber. [From Furshpan &
Potter (83).]
figure 33 were done on the squid giant axon synapse
by Tasaki. He "could not detect any recognizable
spread of clectrotonic effects across the synapse in
either direction" (personal communication). It is
likely that pharmacological data and various other
criteria of the constellations listed in table i will
distinguish the two types of transmission systems
further.
Several properties of the polarized ephaptic junc-
tion may be deduced from the available data and
from general considerations. Rectification is ex-
hibited by the membranes of many, though not all,
cells, although not to the same large degree (cf.
Tasaki, Chapter III). Where found, it is manifested
by a higher membrane resistance to inward current
than to outward flow. In the present case two mem-
branes are involved and, if both are rectifiers, then
they must each act in opposite polarity to the other.
On the other hand, only one of the two membranes
need show rectification and this situation is the more
probable. It also seems most likely that this property
resides in the surface of the prefiber for in that case
the membrane would permit outward current flow
and restrict inward as in other cells. The membrane
of the postfiber would then need have no rectifier
properties but would resemble that of the septa in
its low nondirectional resistivity.
As may be seen from figure 34, current probably
flows outward across the prejunctional membrane
during the ephaptic transmissional process whereas
in the rest of the active region the membrane current
is inward. Furthermore, excitation of the postfiber
must occur at membrane sites where the local circuit
current flows outward, not at the ephaptic region
where it flows inward. Therefore, neither junctional
membrane of this polarized ephapse takes part in
the active responses of the junction. Like the mem-
branes at the septa they therefore need not be ex-
citable.
194
HANDBOOK OF PH'lSKJLOGV
NEUROPHYSIOLOGV I
Intrinsic
\
Local Circuits
-> 1 I ^
Transjunctional
Ephaptic Junction
FIG. 34. Diagiam showing the current flows that probably
take place at a polarized ephaptic junction. In the prejunc-
tional fiber membrane current flow is inward in the region of
activity. Longitudinal current flow takes place behind this
region as part of the intrinsic local circuit within this fiber.
Current flows outward through the membrane recovering from
previous activity. Outward current also flows in the prejunc-
tional membrane of the ephapse. This enters the postcphaptic
cell at its junctional membrane and flows out through adjacent
regions of membrane, exciting the latter. Note the profound
difference between the current flows postulated for ephaptic
transmission in this diagram and the hypothetical situation al
synaptic junctions shown in fig. i .
Evolutiormry Aspects of Ephaplii Transmissum
In their transverse divisions the septate axons bear
the sign of their segmental origin. The processes of a
number of neurons at a nerve cord segment fuse to
produce a short length of giant axon. End-to-end
apposition of the segmental fibers then forms a long
axonal pathway. To the extent that the septa dis-
appear or that their resistance is low the segmented
axons approach the nonsegmented giant axons in
efliciency as through conduction pathways, excited
by local circuit action.
The septate axons, however, combine with through
conduction, another feature which is absent in the
nonsegmented giant fibers (Kao, C. Y. & H. Grund-
fest, manuscript in preparation). They make elaborate
local synaptic connections, both efferent and afferent,
with other fibers of the nerve cord. Although the
anatomy of these connections is not as yet clear, the
synaptic properties of the septate axons probably
derive from their segmental origin of the fibers. The
septate giant axons therefore play a much greater
role in the integrative activity of the nervous system
than can the nonseptate axon which lack these synap-
tic connections (103, 125).
On the basis of the interpretation given in the pre-
vious paragraphs, the polarized, electrically excitable
ephaptic junction may be derived from the septal
junctions by the addition of rectifier property to
one of the junctional membranes. Two other features
further strengthen the resemblance between septate
and motor giant fibers. The two motor axons of a
segment make unpolarized connections with each
other. In this case, too, electron microscopy has not
as yet revealed essential details (cf. i 74). Also, like
the septate axons, the motor giant fiber combines
'chemically mediated synapses' with an ephaptic
junction (83). The former presumably are electrically
inexcitable.
Thus, it appears likely that motor giant fibers of
the crayfish bear a close functional similarity to the
septate axons but with a significant modification away
from the latter. It remains to be seen whether ephap-
tic polarized transmission made possible by rectifica-
tion is a fairly common evolutionary variant. Another
interesting correlation, whether or not this transmis-
sion scheme developed only in those animals that
have septate unpolarized ephapses, might give fur-
ther clues to their evolutionary origin.
Qjiasiartificial Synapses
The excitation of giant nerve fillers in annelid
nerve cords by activity in other giant axons is well
documented (31) and may be an ephaptic phe-
nomenon In Protida the sites of transfer vary from one
occasion to another and have been termed quasi-
artificial synapses. These systems have not yet been
studied with intracellular recording. The latter could
help to determine whether the transmission is ephap-
tic or whether it is associated with complex synaptic
phenomena such as have been found in earthworms
(125)-
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Neurol., 1957.
Roberts, E. and S. Frankel. J. Biol. Chem. 187: 55, 1950.
Robertson, J. D. J. Biophys. & Biochem. Cytol. 2: 381,
1956-
Robertson, J. D. In: Ultrastruclure and Cellular Chemistry oj
Neural Tissue, edited by H. Waelsch. New York : Hoeber-
Harper, 1957.
Roitbak, .\. I. Bioelectric Phenomena oj the Cerebral Cortex
(in Russian). Tiflis: Publ. House, Acad, of Sciences,
Georgian S..S.R., 1955.
Rosenblueth, a. The Transmission oj Nerve Impulses at
Neuroejjector Junctions and Periphrial Synapses. Cambridge :
Technology Press and New York: Wiley, 1950.
Rothballer, a. B. Eleclroencephalog. & Clin. Neurophysiol.
8:603, 1956.
Scharrer, E. .\nd B. Sch.arrer. In: Handbuch der mikro-
skopischen Analomie des Menschen. Berlin: Springer, 1954.
Sechenov, I. In: Selected Works .\'V International Physiologi-
cal Congress, Moscow. State Publ. House, 1935.
Sherrington, C. S. In : A Textbook oj Physiology (7th ed.),
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Sherrington, C. S. The Integrative Action oj the Nervous
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■925-
Svaetichin, G. Acta physiol. scandiimv. suppl. 134, 39: 17,
1956.
Terzuolo, C. a. .and T. H. Bullock. Proc. Nat. Acad. Sc.
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Thesleff, S. Acta physiol. scandmav. 34: 218, 1955.
Toennies, J. F. J. .Neurophysiol. i : 378, 1938.
Tomita, T. Jap. J. Physiol. 6: 327, 1956.
ToMiTA, T. J. Neurophysiol. 20: 245, 1957.
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641, 1956.
CHAPTER VI
Skeletal neuromuscular transmission
PAULFATT I Biophysics Department, University College, London, England
CHAPTER CONTENTS
Morphology
Local Electrical Response
Activity of the Nerve Terminals
Properties of the Junctional Receptor
Conclusion : Mechanism of Transmission
THE EXISTENCE OF A REGION between motor nerve and
voluntary muscle which has special properties
emerged from experiments on the action of the South
American Indian arrow poison, curare, performed lay
Claude Bernard about 1850 (2). Bernard's aim in the
first place was to show that muscle was excitable inde-
pendently of its nerve supply. Having; pre\iously
paralyzed a frog with curare, he isolated a nerve-
muscle preparation and showed that, while an elec-
trical stimulus applied to the nerve was ineffective,
a contraction resulted if it were applied directly to
the muscle. Inferring that curare interfered with the
functioning of the nerve but not of the muscle, he
carried the investigation a step further by preparing a
frog with a ligature which interrupted the blood
supply to the hind legs but not the nervous connec-
tions. When curare was introduced above the liga-
ture, a paralysis developed which affected only the
anterior part of the body. Most significant was the
observation that pinching the skin above the ligature
did not elicit movement in that region but caused the
normal reflex thrust of the hind legs. It was concluded
from this that curare did not cause a loss of sensation,
and its effect was therefore ascribed to a poisoning of
the motor nerve, for, as was already seen, in the
presence of curare the muscle could still be excited
directly. But since curare apparently did not affect
the motor nerve in its more central course from the
spinal cord to the level of the ligature either, it wa
maintained that the poison acted on the motor nerve
only in its most peripheral part, where contact was
made with the muscle.
Following this penetrating study, investigations
were carried out over a number of years by other
workers into the method of action of substances that
affect nerve-muscle transmission more or less specif-
ically. Besides curare, one of the chief of these was
nicotine. When a small amount of this drug was
injected into an animal or added to the solution
bathing an isolated muscle, a contraction occurred
which was abolished by curare at the same time as
was the contraction produced by nerve stimulation.
It was further found that chronic denervation did not
eliminate the capacity of the muscle for responding
to nicotine, which was still antagonized by curare,
although the nerve terminals underwent severe
deterioration (34, 46, 57, 59). From this it was con-
cluded that the site of action of curare, as well as
nicotine, was not in the nerve endings, as had pre-
viously been supposed, but in the muscle fiber.
A quantitative investigation of the effects of these
substances was made by Langley about 1910 (58,
60, 61). By the application of small droplets of nicotine
solution along a mu.scle fiber, he found that nicotine
in low concentration initiated a contraction only when
applied in the region of the nerve endings. A concen-
tration one thousand times greater than the minimum
effective dose was required to produce a contraction
elsewhere along the muscle fiber. Furthermore,
curare interfered with the action of nicotine in low
concentration but had no effect on the contraction
produced by the high concentration that did not act
exclusively in the innervated region. The manner in
which curare and nicotine acted was inferred from the
observation that increasing concentrations of curare
'99
200
HANDBOOK OF PHYSIOLOGY ^ NEUROPHYSIOLOGY 1
were able to antagonize increasing concentrations of
nicotine over a wide range of such concentrations,
and that the effects of the two substances were to some
extent reversible, the same result being achieved
irrespective of the order of their application. This led
to the suggestion that nicotine and curare competed
with each other in forming a loose combination with
a 'receptor substance,' which was thought to occur in
the muscle fiber immediately around the nerve
endings where it could be acted upon h\ the nerve
impulse. Nicotine or the nerve impulse when acting
on this receptor would lead to a contraction, while
its combination with curare would prevent either of
them being effective.
In 1936 the concept of a distinctive chemical process
in neuromuscular transmission was given a secure
foundation by the work of Dale and his followers.
They succeeded in showing that a nerve impulse on
reaching the terminals in a muscle caused the release
of a pharmacologically active substance (iS). On the
repetitive stimulation of the motor nerve fibers, to the
exclusion of other types of nerve fibers, a substance
appeared in the fluid perfusing the muscle that was
capable of causing a contraction of muscle from the
leech and a fall in arterial pressure of the cat. From
the relative effectiveness of the substance on these two
test preparations and the modification in their
response produced by drugs, as well as from the chemi-
cal stability of the substance under various condi-
tions, it was concluded to be acetylcholine, the
pharmacological action of which was already known.
Its release was found to be undiminished when trans-
mission was abolished by curare. Further experi-
ments showed that the rapid injection of acetylcholine
into a muscle by its blood vessels caused the excitation
of muscle fibers and a contraction (7, 8, 9). This
occurred in the chronically denervated muscle as
well as in the normal one, and, as in the case of
nicotine, this excitatory action could be abolished by
curare. The effect of physostigmine was also ex-
amined. It was found to prolong and intensify the
response to injected acetylcholine and to cause repeti-
tive muscle discharges to a single nerve impulse.
From earlier studies it was known that physostigmine
has the specific action of inhibiting the enzyme that
destroys acetylcholine.
All these findings are compatible with the chemical
theory of transmission, according to which transmis-
sion is accomplished by the nerve impulse causing the
release of a small quantity of acetylcholine from the
nerve endings. This substance combines with a special
receptor substance in the junctional region of the
muscle fiber and, by so doing, alters the properties
of the fiber in such a way as to lead to excitation and
contraction. This mediation of transmission by a
specific chemical is fundamentally different from the
process occurring when an impulse is conducted along
a continuous structure, in which case an essential
factor for the spread of excitation is a flow of electric
current between adjacent parts. An alternative
explanation of neuromuscular transmission is ex-
pressed in the electrical theory, according to which
transmission is affected by the action currents gen-
erated by the impulse in the prejunctional nerve
terminals passing through the adjacent muscle fiber
in the appropriate direction and in sufficient magni-
tude to cause excitation. This theory was formulated
when the electrical events associated with the con-
ducted impulse were first studied, and the attempt
was made to account for both processes by a common
mechanism. The selective sensitivity of transmission to
various treatments was ascriljed to secondary effects,
in particular to the alteration of the electrical ex-
citability of the postjunctional structure.
The results of experiments in which chemicals are
involved, either the collection of acetylcholine after
nerve stimulation or the application of various
chemicals to evoke or modify the response of the
postjunctional structure, are consistent with the
chemical theory. A decisive result which excludes the
possibility of electrical transmission comes from the
study of the alteration of properties of the post-
junctional region during transmission. It is found that
the characteristic alteration responsible for excitation
of the muscle fiber cannot be brought about by a
current generated externally to the fiber. On the other
hand an alteration of precisely this type is produced
by the application of acetylcholine to the junctional
region of the muscle fiber. Accepting the correctness
of the chemical theory of transmission, one is able to
give an integrated account of a wide range of experi-
mental observation, distinguishing between those
events which occur prejunctionally and involve the
release of acetylcholine, and those which occur post-
junctionally and involve the reaction of acetylcholine
with the receptor and the resultant change in the
properties of the muscle fiber membrane.
MORPHOLOGY
The detailed morphological description which fol-
lows applies to junctions on skeletal muscle in verte-
brates where the normal response to a single nerve
SKELETAL NEUROMUSCULAR TRANSMISSION
201
impulse is a propagated action potential and a twitch.
These are the junctions of which both the morphology
and physiology have been most intensively studied.
There are other junctions, in the amphibian at least,
where the normal mechanical response of the muscle
fibers is a slow tonic contraction which can only be
elicited in appreciable tension by a train of nerve
impulses (53, 55). These fibers are innervated by a
special class of small diameter nerve fibers which form
numerous, widely distributed terminations of the
en grappe type on them.
The twitch muscle fibers are innervated by coarse
motor nerve fibers. On issuing from the central
nervous system, each nerve fiber branches repeatedly
both before and after reaching the muscle it supplies.
By this branching the nerve fiber forms junctions on
many muscle fibers, the number varying greatly for
mu.scles in different parts of the body in a given
animal. Conversely, muscle fibers have been found
to be supplied each with a few nerve endings at
widely separated positions along their length (47, 50).
These multiple junctions are in some cases made by
separate nerve fibers and in others bv branches of a
single fiber. The variations in the distribution of nerve
fibers to muscle fibers in different preparations and
their probable relation to differences in function have
been discussed by Tiegs (73).
In the morphology of the single junction, the pat-
tern made by the nerve fiber in terminating also
shows marked differences from species to species and
from muscle to muscle. This field was early thoroughly
explored Ijy Kiihne (56). Confining consideration to
the more familiar objects of investigation, he drew a
distinction between the plate type of ending in the
mammal and reptile and the bush type in the frog. In
both types the nerve comes into contact with the
muscle fiber immediately after losing its myelin
sheath and branches repeatedly on its surface to form
the terminal apparatus. In the former type, the
extent of this apparatus is limited to a roughly circular
space (the endplate) which has a diameter of 25 to
70 /x. Viewed in a section at right angles to the muscle
fiber surface this region is marked by a rounded
eminence. Within the confines of the endplate the
terminal branches cover a large fraction of the in-
cluded muscle fiber surface. In the case of the other
type of ending (the endbush) the nerve terminal
branches range over a much wider area. The terminal
apparatus here consists mainly of several large,
straight branches 100 to 300 /j. in length, running
parallel to the axis of the muscle fiber and connected
into a continuous system by shorter lengths at right
angles.
As a result of careful cytological examination, it is
recognized that there are three sharply defined com-
ponents of different cellular origin at the junction
(14). The first of these is the terminal apparatus of the
nerve. The second is the specialized region of muscle
fiber surface contacted by the nerve endings. A char-
acteristic of this region is an increased density of
muscle nuclei (fundamental nuclei of the junction),
the presence of which is suggestive of a higher degree
of synthetic activity here than elsewhere in the muscle
fiber. The third component is a layer of neuroglia
which in this position is referred to as the teloglia
and which appear to be continuous with the -Schwann
cell envelope of the myelinated fiber. It contributes
about half the nuclei seen in the junctional region
(the sole nuclei), the remainder being the fundamental
nuclei in the muscle. It is dispersed over the entire
endplate where it forms the rounded eminence and
accompanies the terminal nerve filaments along their
extended course in the endbush. In spite of the gross
differences that exist between the two types of ending,
the detailed relationships between these three cellular
components are fundamentally the same. From the use
of cytological and histochemical staining methods it
appears that the nerve terminal branches lie sunk in
grooves in the muscle fiber surface (14, 16). Only a
small part of the circumference of the nerve is not in
close proximity to the surface of the muscle lining the
groove. The sides of the groove appear to be marked
with a set of parallel lines 0.3 to i m apart which are
oriented more or less normal to the axis of the groove
and extend a short distance into the muscle beyond
the clearly defined edges of the nerve cylinder. In the
case of the endbush, where there are long stretches of
unbranched nerve fiber, the ruling is highly regular,
the lines running from one edge of the groove to the
other without deviating from this geometrical rela-
tion. In the endplate where the nerve filaments
usually extend for no more than a few diameters
before terminating or branching, the arrangement
of the lines is less regular, adjacent lines frequently
fuse with one another, while their spacing is main-
tained relatively constant. Examination of the junc-
tion with the electron microscope reveals regularly
spaced narrow infoldings of the membrane of the
muscle fiber lining the groove (71). These fine junc-
tional folds very probably correspond to the lines
seen under the light microscope. Figures i and 2 show
the relation between nerve and muscle over a wide
range of magnification. The width of the folds is
202 HANDBOOK OF PHYSIOLOGY ^ NELfROPHYSIOLOG\' I
Wfff^
5m
FIG. 1. Surface view of neuromuscular junction of lizarcl stained with Janus green. The only
parts to have taken up the stain are the regions of muscle bordering the ner\e terminals (the sub-
neural apparatus) and a short piece of nerve at the termination of the myelin. The final part of
the myelinated nerve fiber appears in the extreme left of the upper picture. In the lower picture a
portion of the junction is shown at higher magnification revealing the lines in the subneural appara-
tus, which are oriented at right angles to the edge of the nerve and which are uniformly spaced
about 0.4 M apart. [From Couteau.x (15).]
FIG. 2. Electronmicrograph of lizard neuromuscular junction. Two nerve terminal branches are
seen in the left side of the main picture with the muscle to the right. The dark oval bodies in the
nerve and muscle are mitochondria. The surface of the muscle at the junction is thrown into a
series of folds, which correspond in their repetition interval and depth to the lines in hg. i . From
the appearance where the surface membrane of the nerve can be clearly seen, it is established that
it does not enter the folds. The inset gives an enlarged view of the situation at the junction. The
surface membranes of nerve and muscle probably correspond to the two dense lines separated by
about 0.07 fi. [From Robertson (71)]
about 0.05 /i and their depth about 0.5 ^l. This in-
folding considerably increases the area of postjunc-
tional membrane which may have an important
bearing on the magnitude of the alteration produced
in the junctional region during transmission. The
teloglia does not occur within the grooves but appears
to remain in contact with the exposed part of the nerve
cylinder. This suggests that it plays no direct role in
the transmission process.
LOCAL ELECTRICAL RESPONSE
The study of neuromuscular transmission received
a great impetus with the application of electrical
recording techniques to the junctional region. It
was observed by a number of workers that after a
muscle had been treated with just sufficient curare to
prevent contraction from nerve stimulation, there
still occurred an electrical change in the muscle,
though this was different from the action potential
type of response (13, 30, 33, 43, 45, 72). The response
was not propagated, being recorded in monophasic
form between different positions along the muscle. In
the sartorius muscle of the frog, with one electrode
kept on the nerve-free pelvic end and the other moved
from place to place, the magnitude of the recorded
potential change was found to be correlated with the
density of nerve endings under the moving electrode.
The potential change arising at a focus of nerve
endings (recorded with respect to a distant nerve-free
point on the muscle) consists of a transient negative
deflection having a relatively brief rising phase and a
slower return, the later part of which follows an
approximately exponential time course. This response
has been generally referred to as the endplate po-
SKELETAL NEUROMUSCULAR TRANSMISSION
203
tential, noivvithstanding that in the amphibian
muscle, where it has been studied most, the nerve
ending is not of the morphological form described as
an endplate.
On increasing the concentration of curare in the
fluid bathing the muscle, the amplitude of the response
is reduced. When, on the other hand, the concentra-
tion is decreased from that required to block transmis-
sion, action potentials in individual muscle fibers
appear as more rapid and complex deflections super-
imposed on the endplate potential. With further
reduction of curare, the action potential component
increases and obscures the endplate potential. The
endplate potential was early inferred to be developed
across the surface membrane of the muscle fiber,
although confined to its junctional region, because of
the similarity of this potential with that which could
be evoked by a brief pulse of current applied any-
where along the muscle. More compelling evidence
came from the study of the interaction of the junc-
tional response and the muscle action potential, the
latter elicited by direct stimulation and propagated
into the junctional region. It was found by this
method that the action potential and the endplate
potential did not sum with each other, and that the
action potential was capable of aboli.shing the later
part of the endplate potential when timed to coincide
with its summit.
The most accurate basis for an analysis of the
potential changes in the muscle fiber to determine the
manner of their generation is the results from intra-
cellular recording (40). This involves inserting a very
fine electrode through the surface membrane of
individual muscle fibers and recording potentials
between it and another electrode in the surrounding
fluid. Intracellular recording not only makes more
accurate measurements of the electrical response
possible but also greatly simplifies its interpretation.
After minor corrections for extracellular gradients of
potential when current is flowing, the potentials
observed by this method are those obtaining across the
surface membrane of the muscle fiber at the position
of insertion of the electrode. The frog muscle fiber is
found to have a resting membrane potential of
about 90 mv (inside negative with respect to outside),
which is the same in the junctional region as elsewhere
along the fiber. The addition of curare to the solution
bathing the muscle in a concentration sufiicient to
block transmission has no effect on this resting po-
tential. With the intracellular electrode situated in
the junctional region of the fiber, an endplate po-
tential is recorded in response to nerve stimulation.
It appears as a transient positive deflection, i.e. as a
transient reduction of membrane potential from its
resting level. Its amplitude varies from fiber to fiber
and depends upon the concentration of curare. In a
frog sartorius muscle, critically curarized to abolish
contraction, different fibers have been found to dis-
play endplate potentials ranging from i mv to more
than 20 mv. The response would be expected under
these conditions to range in size up to the threshold
depolarization for initiating an action potential
which would be about 40 mv. Immediatelv at the
junction the endplate potential has a rising phase
lasting 1.5 msec. Following the attainment of the
summit, the potential declines to one half in another
2 msec. The rate of fractional decay decreases beyond
this, the time required to fall from one half to one
quarter being about 5 m.sec. A potential change can be
detected at points on the fiber up to a few millimeters
distant from the nerve ending, becoming progressively
more attenuated and slowed with increasing distance
(fig- 3)-
This potential wave has been analyzed to determine
the movement of charge underlying it. The amplitude
of the potential at various instants is plotted against
distance along the fiber. Assuming that the membrane
capacity remains constant during the response, the
curves thus formed indicate the spatial distribution of
charge displaced from the membrane capacity (rela-
tive to its initial condition of charge). The area
beneath each curve is a measure of the total charge
displaced at the given instant. The plot of these areas
against time shows that the charge is built up to a
maximum in about 2 msec, and after this it decays
exponentially with a time constant of about 25 msec.
A determination of the passive electrical characteris-
tics of the muscle fiber shows that this latter value
corresponds to the electric time constant of the mem-
brane. This result is consistent with the idea that
there is a brief phase of transmitter action, confined to
about the initial 2 msec, of the response, during which
charge is transferred inward across the membrane,
and that this is followed by a gradual dissipation of the
displaced charge at a rate determined by the electrical
characteristics of the inactive fiber membrane. It
agrees with the results of the interaction between the
endplate potential and action potential from which it
appears that the charge displacement built up by
junctional activity can be removed by the high con-
ductance of the spike at a time shortly following the
summit of the endplate potential.
From a knowledge of the membrane capacity for a
imit length of fil)er, the displacement of charge may
204
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
be calculated. For an endplate potential of 20 mv
peak amplitude the maximum displacement of charge
is found to be about io~' coulombs. Given informa-
tion on the complete electrical characteristics of the
fiber, i.e. of the separate values of membrane capacity
and membrane and core conductances, it is possible
to analyze more completely the potential wave in
the fiber. An approximate treatment, in which the
observed response of the fiber is compared with a
theoretically derived potential wave for charge placed
instantaneously at a point along the fiber, confirms
the above interpretation of the generation of the end-
plate response by a brief transfer of charge in a small
area of membrane.
In a normal uncurarized muscle, the rate of rise of
the endplate potential is about three times as fast as
in the above case, due evidently to a proportionately
more intense transfer of charge. On the endplate
potential reaching a level of depolarization of about
40 mv, an action potential is initiated, indicated by a
sudden increase in the rate of change of potential.
The threshold for the initiation of an action potential
has Ijeen examined by the direct application of a
current pulse, both at the junction and away from it,
and has been found to occur at all points at this same
level. The spike which follows the initial depolariza-
tion produced by the endplate potential is however
characteristically different at the junction where it
is evoked from elsewhere in the course of its propaga-
tion (40, 69; cf. fig. 4}. After rising from the level of
threshold to zero membrane potential at a rate which
is not noticeably different in the two cases, the
junctional spike produces a smaller reversal of mem-
brane potential than the normal muscle spike away
from the junction. Thus, at the summit of the junc-
tional spike the membrane potential is reversed to the
extent of about 20 mv (total spike height of 1 1 o mv),
compared to a reversal of about 35 mv for the normal
spike (total height, 125 mv). The summit of the
junctional spike occurs earlier and is sharper than
that of the normal spike. After reaching the summit
the potential falls to the level of zero membrane
potential where it remains nearly steady for about
1.5 msec, before declining further. In contrast, the
normal spike declines rather slowly for about 2
msec, after its summit, but then falls more rapidly
past zero membrane potential.
It can be shown that these features, which distin-
guish the junctional spike, do not depend on some
special characteristic of the action potential process in
the region where it occurs. When an action potential
is propagated into the junctional region without the
nerve having been active, the response is the normal
muscle action potential similar to that which is elicited
elsewhere along the fiber. Moreover, these features
cannot be attributed to the response having originated
in the region of observation rather than having
propagated into it, since the propagated action
potential and the one which is initiated in the region
of recording by a brief pulse of current show little
difference beyond the attainment of threshold. It is
concluded therefore that these features arise from a
10 msec
FIG. 3. Endplate potentials recorded intracellularly from a single curarized muscle fiber of a
frog. The series of five records were taken at intervals of i mm along the fiber. The top record shows
the response at the junction as inferred from the fact that the response was maximum at this posi-
tion. [From Fatt & Katz (38).]
FIG. 4. Action potentials recorded in a muscle fiber in response to a nerve impulse. The upper
record was taken at the junction, the location of which had earlier been determined by the response
in the presence of curare. The lower record was taken 2.5 mm away in the same fiber. A trace of
the endplate potential can still be seen in the lower record, appearing as a gradual rise of potential
which precedes the foot of the spike. [From Fatt & Katz (38).]
SKELETAL NEUROMUSCULAR TRANSMISSION
20 n
modification of the action potential response by
junctional activity. The effect of this activity is con-
sistently to cause a deviation toward a level near
zero membrane potential. This accounts for the reduc-
tion in peak amplitude of the spike and the delay on
the falling phase. As a first approximation it may be
assumed that the fundamental changes effected in
the membrane by the two types of activity which are
superimposed at the junction (i.e. spike and junctional
activity) do not interact. The effect of transmitter
action on the spike, as well as the initial development
of the endplate potential, can then be satisfactorily
accounted for by an increase in membrane conduct-
ance in series with an emf set near the level of zero
membrane potential. However during the action
potential the situation is complicated by the presence
in the membrane of two important components of
conductance, one due to the passage of sodium ions
and the other to potassium ions, which follow different
time courses and are dependent on the level of mem-
brane potential. In order to determine the effect of
transmitter action more accurately, the spike has been
set up independentlv of the nerve response by direct
stimulation of the muscle fiber (24). In this way, using
a suitably timed nerve impulse, transinitter action was
made to begin at any chosen stage of the action po-
tential process, and the resultant deviation of the
potential observed. It was thus shown that the
equilibrium potential for junctional activity lies
between 10 and 20 mv, with the interior of the fiber
negative.
The generation of the endplate potential has also
been studied in the absence of an action potential by
applying a steady current to the muscle fiber and
thereby altering the membrane potential at which
the transmitter operates. .Significant results have been
obtained only with currents directed inwardly across
the membrane and causing a hyperpolarization,
since with currents in the opposite directions complica-
tions arise owing to the initiation of muscle action
potentials. The endplate potential was found to vary
in such a manner as to maintain its rate of rise nearly
directly proportional to the level of membrane po-
tential at which it occurred. An equally good fit of
the data could be obtained with a straight line for
which zero respon.se would occur at a membrane
potential of 15 mv, internally negative. There is thus
complete agreement, as far as the equilibrium value
is concerned, between the results obtained from the
effect of junctional activity on the membrane at rest
and on the membrane undergoing an action po-
tential.
In the case of the endplate potential arising in the
otherwise resting membrane, an analysis has been
made to determine what size the added conductance
would have to be to produce the observed rising phase
of the response. The muscle filler has been treated as
a cable with known distributive characteristics, and
the conductance has been considered as applied
suddenly at a point along this cable. From the change
of potential occurring in the uncurarized muscle up
to the level at which the spike is initiated, the con-
ductance is calculated to correspond to a resistance
of about 20,000 ohms. This may be considered in
relation to the resting resistance of about 500,000
ohms, which is shunted as a result of junctional
activity, and which is in effect the resistance of the
membrane over a length of about 4 mm of fiber (twice
the space constant of the fiijer). An analysis has also
been made of the effect of junctional activity to reduce
the reversal of membrane potential at the .summit of
the spike, together with any additional displacement
produced by an applied current. The added conduct-
ance calculated from this information is roughly in
agreement with the value obtained from the rising
phase of the endplate potential.
There appears thus to be a convergence of evidence
to show that the effect of junctional activity on the
muscle fiber membrane can be represented as the
addition of a conductance in scries with a fixed emf
This may further be interpreted as the creation of a
new path for the diffusion of ions across the mem-
brane. The equilibrium value (15 mv, internally
negative) toward which the membrane potential is
displaced is the same as the emf that would be
expected to occur for the unrestricted diffusion of ions
between two solutions, having the ionic composition
of the intra- and extracellular media. It is therefore
concluded that in the new diffusion path created by
transmitter action, no selectivity is exerted in the
passage of different ion species other than that already
existing in the aqueous media on the two sides of the
membrane.
The investigations on neuromuscidar transmission
considered so far in this section have concerned the
amphibian muscle fibers that under normal conditions
respond to a nerve impulse with a twitch. The con-
clusions reached, as to the fundamental alteration in
the postjunctional membrane produced by the action
of the transmitter, seem likely to be valid generally for
junctions on vertebrate skeletal muscle fibers. How-
ever, marked variations in the overall electrical
response have been found to occur in different prepa-
rations, and these are adduced to stem mainly from
206
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
differences in the electrical characteristics of the
muscle fiber membrane in parallel with the junc-
tionally responding region.
In the mammalian muscle fiber under normal
conditions, the endplate potential does not form a
conspicuous step on the rising phase of the spike as it
does in the amphibian (4). The explanation for this
lies in the fact that the threshold depolarization for
initiating an action potential is here much lower
(about 10 mv compared with 40 mv in the frog), and
at this level the transition between endplate potential
and spike does not involve an appreciable change in
rate of rise of potential. In the curarized preparation
the response differs from that seen in the frog in hav-
ing a shorter decaying phase and in becoming at-
tenuated more rapidly with increasing distance from
the junction. These differences are attributable
entirely to a higher conductance of the muscle fiber
membrane with a consequent reduction in the electric
time and space constants.
The tonic muscle fibers of the frog, supplied by the
small diameter motor nerve fibers, display differences
in their electrical response from the twitch fibers of
the same animal which are again mainly attributable
to the electrical properties of the fiber membrane,
though the disposition of the nerve endings also plays
an important part (10, 11, 54). The tonic muscle
fiber is unable to develop an action potential, due
apparently to the absence of the mechanism by which
the sodium permeability of the membrane is increased
by depolarization. The entire time course of the
junctional response can therefore be observed under
all conditions without the complication of a super-
imposed spike. In addition the amplitude of the junc-
tional response can be varied by stimulation of differ-
ent nerve fibers. Owing to a wide and relatively
uniform distribution of their endings along the muscle
fiber, the potential wave does not show a marked
attenuation with distance, and at no position does it
have the initially rapid and later relatively slow
decline of the endplate potential recorded at the
junction of a twitch fiber. Another distinctive feature
of the response in these fibers is that the membrane
potential goes through a phase of hyperpolarization
after recovering from the depolarization. A similar
phase of hyperpolarization is found to follow a wave
of depolarization elicited by a current pulse applied
directly to the muscle fiber, from which it is inferred
that this feature is not due to .some peculiar charac-
teristic of the transmission process but depends rather
on the electrical behavior of the membrane.
.\CT1VITY OF THE NERVE TERMIN.^LS
In the preceding .section, the local electrical changes
brought about in the normal and in the curarized
muscle fiber by the arrival of an impulse in the pre-
junctional nerve terminals have been described. In
this section the behavior of the terminals will be con-
sidered under various conditions, in .so far as this
throws light on their specialized properties. Almost
all the information to be presented is derived from
recording potential changes in the muscle fiber.
According to the chemical theory of transmission,
activity in the nerve terminals causes a release of
acetylcholine which then reacts with the muscle to
produce an alteration in it. Hence, when recording
from the muscle, an indication of activity at the
terminals is obtained, provided that allowance is
made for possible effects in the later stages of the
transmission process. An example of such an effect is
the reduction of the responsiveness of the muscle
fiber by curare through its competition with acetyl-
choline.
When the membrane potential is recorded in the
junctional region of a muscle fiber, a sequence of
small transient changes of potential (as shown in fig.
5) is observed even in the absence of a nerve impulse
(3, 41, 62). Although their peak amplitude is only of
the order of 0.5 mv, these potential changes have
2raV
50 msec
FIG. 5. Spontaneously occurring miniature endplate poten-
tials recorded at the junctional region of a muscle liber of a
frog. The location of the recording position was confirmed by
the form of the response elicited by a nerve impulse. [From
Fatt & Katz (39).]
SKELETAL NEUROMUSCULAR TRANSMISSION
207
many of the characteristics of a response to a nerve
impulse. Their time course is similar to the endplate
potential in a curarized muscle. They appear largest
at the same place along the muscle fiber and become
attenuated by changes in the position of the recording
electrode in the same way. Furthermore, they are
diminished in amplitude by curare and increased
and prolonged by anticholinesterases. All the.se fea-
tures may be accounted for by the properties of the
postjunctional element and its reaction with acetyl-
choline. That the nerve terminals are responsible for
the release of acetylcholine producing these dis-
charges— called miniature endplate potentials — is
shown by the fact that they are abolished on nerve
degeneration and their frequency of occurrence is
modified by various treatments applied to the nerve.
In addition there is strong evidence that the end-
plate potential evoked by a nerve impulse is itself
resolvable into units of the size of miniature poten-
tials.
The miniature discharges occur in a random time
sequence, the probability of occurrence in any given
inter\'al of time remaining constant irrespective of
previous discharges. The distribution of intervals be-
tween successive discharges is accordingly found to
follow a simple exponential function, decaying with
increasing interval, and can be descril)ed by a single
parameter, the mean frequency of discharge. E.xcep-
tions to this are occasional bursts which consist of a
number of miniature endplate potentials occurring
within a short period of time. They are the only indi-
cation of a possible coupling between discharges, and
can be readily recognized and excluded from a sta-
tistical analysis. In the frog under normal conditions
the mean frequency of spontaneous discharges varies
greatly at different junctions, extending at least over
the range o. i per sec. to 100 per .sec. In mammalian
muscle the frequency is more nearly constant around
I per sec.
The distribution of amplitudes of the miniature
endplate potentials at a junction can be fitted ap-
proximately by a Gaussian curve with a standard
deviation equal to about 30 per cent of the mean.
With this relatively small variation, the amplitudes
effectively do not grade down to zero, and hence
under suitable recording conditions there is no un-
certainty in counting the discharges. By a variation in
recording technique, placing the microelectrode in
contact with the muscle fiber membrane without
penetrating it, it is possible to restrict the recording
of miniature discharges to those arising in a small
fraction of the junctional region contacted by the
nerve terminals. In this way, one tenth or so of the
miniature discharges occurring within the fiber are
recorded selectively while the remainder appear
greatly attenuated and are in eflPect rejected (27).
Even under these conditions the amplitude of the
miniature potentials appears to be continuously
distributed, there being no clear indication of a
number of discrete .sizes which are repeated.
A notable feature of the miniature discharge is
that the release of acetylcholine which produces it
does not appear to change under various treatments
which have an important influence on the genera-
tion of an electrical response (28). Even in the situa-
tion where the nerve and muscle membranes have
been completely depolarized i)y a high concentra-
tion of potassiimi ions, it can be shown by repolarizing
the muscle fiber with an applied current that the
intermittent release of sinall quantities of acetyl-
choline, capable of producing miniature potentials,
still occurs (26). It is therefore concluded that the
release of acetylcholine forming these discharges does
not depend upon the occurrence of electrical activity
of the action potential type in any structural unit
within the nerve terminal.
Unlike the amplitude (considered as a quantity of
acetylcholine released from the terminal), the fre-
quency of the spontaneous discharges is highly sensi-
tive to changes in the condition of the preparation.
Changes in the osmotic pressure of the surrounding
fluid, for example, have a strong effect, the frequency
increasing reversibly as this is raised (41, 44, 62). A
finding which is important in indicating a possible re-
lation ijetween electrical events in the nerve and these
spontaneous discharges is that their frequency can
be altered by the application of a current to the
nerve which, by spreading into the terminal portion,
will alter the membrane polarization there (23, 64).
The frequency is found to vary approximately ex-
ponentially with changes in the polarizing current in
the nerve, being increased by depolarization of the
terminals. The frequency of discharge is also increased
when the concentration of potassium ions in the
bathing fluid is raised above the normal level, this
probably operating in the same way as current by-
causing a reduction of membrane potential.
The rate of rise of the endplate potential, up to the
level at which an action potential is initiated, is
about one hundred times greater than the mean rate
of ri.se of the miniature endplate potential. A decrease
in the calcium ion concentration of the solution bath-
ing the preparation causes a reduction in the endplate
potential, while the amplitude of the spontaneous
208
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
discharge is left unchanged; the same effect is pro-
duced by the addition of magnesium ions (4, 19,
20, 21, 41, 63). Calcium appears to exert a specific
facilitatory action on the release of acetylcholine by a
nerv'e impulse, and the action of magnesium may
then be accounted for by a competition with calcium
for the reactive site. This antagonistic relation be-
tween calcium and magnesium at the terminals is in
contrast to their common action in raising the
threshold depolarization for the initiation of an action
potential in a nerve or muscle fiber. By the with-
drawal of calcium or addition of magnesium or both,
the endplate potential can be reduced to a small
fraction of its normal size and can be made to ap-
proach in amplitude the spontaneous miniature po-
tential. When this is done, the amplitude of the
response to successive nerve impulses is seen to fluc-
tuate widely, in contrast to its constancy under
normal conditions or when the response is reduced to
any degree by treatment with curare. With the
junction sufficiently deprived of calciimi, the response
occurs intermittently. When the proportion of fail-
ures is large, the responses to a series of ner\e im-
pulses have a distribution of amplitudes similar to
that of the spontaneous discharge. At a somewhat
lower level of depression, the distribution shows
several peaks, corresponding to small integral multi-
ples of the mean of the spontaneous potentials. It is
evident that the endplate potential under these condi-
tions is composed of a variable whole number of
miniature endplate potentials, the fluctuation being
due to variation in number and in size of units. The
result of an analysis of this fluctuation for the proba-
bility of occurrence of different numbers of units can
be accurately fitted by a Poisson distribution. This
implies that there is no interaction between units,
the probability of occurrence of each being unaffected
by the number of units composing the response.
With the distribution in this form, relatively large
fluctuations in response would occur only when the
number of contributing units is small. As the number
increases, the amplitude of fluctuation relative to the
mean amplitude of response will vary in inverse
proportion to the square root of the number of units,
while the additional dispersion due to variation in
amplitude of individual units will become pro-
gressively less significant. Fluctuations occur in the
curarized endplate potential, evoked under condi-
tions in which the release of acetylcholine from the
nerve terminals is normal, and these can be attributed
to a variation in the number of units around such a
magnitude as would be predicted roughly from the
size of the normal response (68). The probability
that the normal endplate potential is composed of
these units is greatly strengthened by the observa-
tion that an increase in the calcium ion concentra-
tion beyond that normally present in the bathing
fluid produces a further increase in the size of the
response, which is entirely attributable to an increase
in the release of acetylcholine from the nerve ter-
minals, and which is presumably due to an increase
in the probability of release of individual units of
acetylcholine (13, 29, 43, 52). The curarized end-
plate potential can in this way be increased two or
three times in size.
In contrast with the effect on the response to a
nerve impulse, changes in the calcium concentration
in cither direction from normal are usually found
to have no effect on the frequency of spontaneous
miniature potentials. Calcium withdrawal (or mag-
nesium addition) does, however, reduce the fre-
quency when this has first been raised by the presence
of a high concentration of potassium ions or by a
current applied to depolarize the nerve terminals. It
thus appears that the depletion of calcium ions has a
similar action in presenting an increase in the proba-
bility of a unit of acetylcholine being released during
a given time interval by a maintained depolariza-
tion, as in reducing the probability of its release by a
nerve impulse.
Another procedure which modifies the number of
units responding to a nerve impulse is the previous
activation of the nerve. In the curarized amphibian
muscle, the second of two closely spaced nerve im-
pulses elicits a larger endplate potential than does the
first (30, 43, 72). With continued repetitive stimula-
tion of the nerve, the individual responses increase
progressively until a steady condition is attained. By
this means the size of the response may be increased
to two or three times that elicited by an isolated im-
pulse. (This increase is in addition to the summation of
electrical changes in the postjunctional structure, the
later responses adding to the potential change remain-
ing from previous responses.) In the case where two im-
pulses are set up in the nerve the potentiation of the
response to the second is found to be greatest at the
shortest interval of time at which the ners-e will con-
duct. The effect falls gradually as the interval be-
tween the nerve impulses is increased, the response
having returned to its unpotentiated size at an inter-
val of about 100 msec. That this potentiation is a
prejunctional phenomenon and moreover that it in-
volves a change in the number of units of acetylcho-
line released is revealed by studying the effect under
SKELETAL NEUROMUSCULAR TRANSMISSION
209
conditions in which the number of units responding
to a nerve impulse is small. For this purpose the cal-
cium concentration is reduced (or magnesium added)
until the response to a single nerve impulse has a
mean amplitude of one or a few units. With two
nerve impulses at a short interval apart the response
to the second is found to be statistically larger, as in
the curarized preparation. Examination of the distri-
bution of amplitudes for the first and second re-
sponses in a number of trials reveals that the increase
in the second is accompanied by a reduction in its
fluctuation, indicating that the change is entirely
the result of an increase in the number of units re-
sponding (22). It is further found that the number of
units responding to the first nerve impulse in a par-
ticular trial has no effect on the number responding
to the second in that trial. This leads to the conclusion
that the potentiation of the second response depends
solely on the previous presence of an impulse in the
nerve and not on the number of units of acetylcholine
released by the impulse.
Whereas in the amphibian the second of two
ner\e impulses elicits an endplate potential which is
larger than the first, in the curarized mammalian
preparation the response to the second is smaller up
to an interval of a few seconds (30, 65, 66). Evidence
of potentiation by previous activity of the nerve is
procured where the conditioning treatment is a large
number of ner\e impulses. When between a few
hundred and a few thousand impulses are set up in
the nerve within 5 to 20 sec, the later impulses in the
train elicit a considerably reduced response owing to
the depressant efifect of preceding volleys. The time
course of subsequent changes in the effectiveness of
transmission is revealed by testing with a single im-
pulse at a variable time after the termination of the
conditioning train of impulses. It is thus found that
the effectiveness of transmission gradually increases
from the depressed state to beyond that occurring in
the absence of previous activity (5, 48, 65). The mag-
nitude and time course of this potentiation depends
on the number of conditioning nerve impulses; it is
larger, arises later and is more prolonged, the greater
the number of impulses. Following a few thousand
impulses, the maximum is not reached until about 0.5
min. after conditioning, when the response as meas-
ured by the size of the endplate potential may be 50
per cent greater than the normal and the total dura-
tion of the potentiated state may be i o min.
When the curare-free mammalian preparation is
subjected to calciuin depletion, a behavior is observed
which is similar to that in the frog. The second of two
closely spaced nerve impulses now elicits a greater
response than the first (67). The effect of condition-
ing with a train of impulses is to cause a summation
of the potentiation left behind by individual nerve
impulses. It is apparent that the potentiation in the
wake of a nerve impulse has a very prolonged phase
of low level effectiveness, which, while hardly notice-
able after a single impulse, is able to sum over a large
number of impulses to produce an appreciable po-
tentiation of very great duration. When the calcium
concentration is normal, the earlier part of this po-
tentiation is outweighed by the depression which
follows each nerve impulse but does not sum over as
long a period of time. The fact that the depression
does not occur in the calcium depleted preparation
when the number of units of acetylcholine released by
each impulse is small makes it appear highly probable
that this effect, unlike the potentiation, depends on
the amount of acetylcholine released by previous
impulses.
In the mammalian muscle under normal condi-
tions, the frequency of spontaneous discharges is
found to be increased immediately following the
response to a conditioning nerve impulse at which
time the response to a second impulse is diminished.
After conditioning with a large number of impulses,
the frequency is increased many times and returns
only very slowly to normal (6, 62). The final part of
its return parallels the time course of the subsidence
of the potentiation of transmission, as observed in the
curarized muscle. The effect of previous activity of the
nerve is apparently to increase the potentiality of the
terminals for releasing units of acetylcholine, both
spontaneously and in response to a nerve impulse.
PROPERTIES OF THE JUNCTIONAL RECEPTOR
The most direct method for investigating the
receptive properties of the muscle fiber is to add acetyl-
choline to the surrounding fluid without involving
the nerve terminals. Two techniques have been used:
the acetylcholine has been applied either uniformly
to the whole muscle fiber, or in a highly localized
manner to the region contacted by the nerve endings.
The effect is a depolarization of the muscle fiber in
the junctional region (12, 17, 36, 51). After pre-
liminary treatment with an anticholinesterase, which
prevents the enzymatic destruction of acetylcholine,
the technique of uniform application allows quantita-
tive information to be obtained on the reactivity of
the receptor with varying concentrations of acetyl-
210
HANDBOOK OF PHYSIOLOGY
.NEUROPHYSIOLOGY I
choline. When the acetylcholine concentration is as
high as I jumole per liter, muscle fibers are depolarized
sufficiently for spikes to be initiated. For low concen-
trations, not exceeding that required to elicit spikes,
the depolarization is nearly proportional to the acetyl-
choline concentration. With high concentrations the
depolarization elicited by acetylcholine can be meas-
ured in the wake of an initial burst of spikes, when
the muscle fiber in the region of the junction is re-
fractory to the initiation of further spikes. At the
lower concentrations the depolarization is maintained
for many minutes while the acetylcholine remains in
the surrounding fluid; at the higher concentrations a
perceptible decline is observed within a few minutes,
the rate of decline being greater the higher the con-
centration of acetylcholine. This effect is apparently
the result of a gradual desensitization of the receptor
by its forming a different and less readily reversible
combination with acetylcholine than that which
results in depolarization.
More accurate information on the spatial distribu-
tion of the receptor and the time course of its reaction
may be obtained by applying brief pulses of acetyl-
choline with a micropipette (25, 70). It is found that
the high sensitivity to acetylcholine does not extend
beyond very limited regions in the neighborhood of
the nerve terminal branches, for in the frog, where the
terminals are spread over about a 200 /n length of fiber,
it is necessary to position the micropipette to within
10 or 20 M in order to obtain a high sensitivity. It is
further observed that acetylcholine exerts its power-
ful action only when applied externally; it has no
specific effect when released within the muscle fiber,
even though the pipette is situated immediately be-
neath a region of the fiber surface that is found to be
sensitive to external application. With the micro-
pipette critically placed over the junction so as to
obtain maximum sensitivity, the depolarization
evoked by a brief pulse of acetylcholine rises to a peak
in about 15 msec. This order of lime would no doubt
be required for the diffusion of acetylcholine from its
point of release to the receptor some microns away.
Among agents that affect neuromuscular trans-
mission, the one that has received most attention is
curare. This term applies to a group of related sub-
stances which act by competing with acetylcholine
for the receptor. Combination of curare with the re-
ceptor does not itself aflfect the electrical properties of
the membrane, but it prevents acetylcholine combin-
ing and thereby exerting a depolarizing action, .\mong
the common inorganic ions, sodium appears to have
the most marked effect on the combination of acetvl-
choline with the receptor (36, 42). After the complete
withdrawal of sodium ions from the bathing solu-
tion, the application of acetylcholine elicits a small
depolarization, which is augmented considerably by
the presence of only a small concentration of sodium.
This effect is not produced by the addition of calcium
or potassium ions. It is inferred to be due to a change
in the reaction between the receptor and acetylcholine,
rather than in a later stage of the process leading to
depolarization, from the fact that sodium ions also in-
crease the ability of acetylcholine to compete with
curare for the receptor. A facilitation of the reaction
between the receptor and acetylcholine in muscles of
the frog is also produced by the addition to the
bathing medium of very small concentrations of epi-
nephrine and norepinephrine, the substances released
by impulses at the terminals of sympathetic post-
ganglionic nerve fibers (49}.
The anticholinesterases are a group of substances
that affect transmission by competitively inhibiting
the enzyme cholinesterase, which is concentrated in
the junctional region of the muscle fiber and normally
hydrolyzes acetylcholine soon after its liberation from
the nerve terminals. Unlike the reaction between the
receptor and acetylcholine or curare, which must be
very rapid in reaching an equilibrium, that between
the enzyme and a reversible anticholinesterase takes
many minutes. With the anticholinesterase exerting
its maximum effect and presumably completely in-
hibiting the enzyme, the time course of transmitter
action is in two stages (31, 40). The 2 msec, phase of
high intensity transmitter action is virtually un-
changed and accounts for the early rapid rise of the
endplate potential. This is succeeded by a prolonged
phase of low level transmitter action which heightens
and prolongs the endplate potential.
Other organic compounds besides acetylcholine
exert a depolarizing action at the junction. Some of
the substances that have been examined combine in
various degrees the properties of acetylcholine, curare
and anticholinesterases (32, 74). In the case where
the first two actions are combined, the agent in a
concentration which produces a small depolariza-
tion prevents acetylcholine from adding to this to the
extent obtaining when the former is absent. Different
substances are found to follow various time courses
in their action, and where the same one exerts multi-
ple types of action, each may develop along a different
time course. Furthermore the relative effectiveness for
each type of action may vary between different
preparations.
Transmission would be expected to be influenced at
SKELETAL NEUROMUSCULAR TRANSMISSION
various stages by changes of temperature. The most
conspicuous result of lowering it is a prolongation of
the phase of transmitter action. This appears to be
due largely to a reduction in the activit) of cholin-
esterase since at low temperatures treatment with an
anticholinesterase produces little additional change
(4, 31). It is found, however, that, while the time
course of the curarized endplate potential is length-
ened, the peak amplitude is not significantly in-
creased as it should be if the early phase of transmitter
action were unaltered. In the mammalian muscle this
appears to be the result of curare competing more
effectively with acetylcholine at the reduced tempera-
ture and thus ofTsetting the effect of the reduction in
cholinesterase activity on the peak potential change.
An experiment, highly relevant to the conclusion
that the alteration of the properties of the muscle
fiber produced by a nerve impulse is consistent with
the operation of a chemical mediator, is the demon-
stration that the depolarization elicited by acetyl-
choline has its origin in the same conductance change
that has been shown to occur during transmission
(26). For this purpose the muscle has first been
nearly completely depolarized by immersing it in a
solution with a high concentration of potassium ions.
In this condition the application of acetylcholine pro-
duces no discernible change in inembrane potential.
When the membrane is now polarized in either direc-
tion by the passage of current across it, acetylcholine
produces a potential change that partly compensates
for the displacement from the unpolarized state, and
this is attributable to an increase in membrane con-
ductance similar to that observed for the preparation
initially in its normal environment.
CONCLUSION : MECHANISM OF TR.ANSMISSION
From the rate at which acetylcholine appears in the
effluent from a perfused muscle during repetitive
stimulation of the motor nerve fibers, it has been es-
timated that the quantity released from the nerve
endings at a single junction in response to a single
nerve impulse is about io~'- moles (i, 35). Although
the value obtained in this way is liable to be too small
because of losses in the collection procedure and be-
cause of a depression in the release mechanism by
previous activity, it is not likely to be in error in its
order of magnitude. It may be compared with the
minimum quantity of about 5 X lo""' moles of acetyl-
choline which is required to evoke a muscle action
potential when applied to the junctional region by a
micropipette (25, 70). The factor of 200 between these
two quantities can be satisfactorily accounted for by
the geometry of the junction. The nerve endings from
which the acetylcholine is released are probably every-
where in very close proximity to the receptive region
of the postjunctional surface with a consequent high
efficiency for its reaching the receptor. On the other
hand, when acetylcholine is applied by a micro-
pipette, it would have to diffuse over a greater distance
and be considerably dispersed before reacting with
the receptor, and a larger quantity' would therefore
be required to produce a comparable effect. Even if
the micropipette were placed directly on a sensitive
region, the application of a moderate amount of
acetylcholine would no doubt lead to a rapid satura-
tion and inactivation of the receptor there because of
its high local concentration, and the initiation of an
action potential would require the action of acetyl-
choline over a greater part of the receptive area.
From the concentration of acetylcholine required to
produce an action potential when applied uniformly
to the preparation and from the quantity that is re-
leased by a nerve impulse, it is possible to calculate
the volume in which the acetylcholine released from
the nerve terminals would be present when reacting
with the receptor (37). The result shows that the
acetylcholine must exert its maximum effect before
diffusing more than i //, a distance which is consistent
with morphological findings on the minute separation
of the pre- and postjunctional surfaces. Furthermore,
assuming that diffusion occurs away from the im-
mediate neighborhood of the junction, the time dur-
ing which the acetylcholine will remain in an effective
concentration is shown to be less than i msec. The
brief duration of transmitter action may reflect the
operation of this diffusion, though the possibility re-
mains that the reaction between the receptor and
acetylcholine does not reach an equilibrium in such a
short period of time and the kinetics of this reaction
may then influence the time course of transmitter
action. At least it is clear that the enzymatic destruc-
tion of acetylcholine is not involved in the early, high
intensity phase of transmitter action, as it is not
affected by the presence of an anticholinesterase. The
failure of the destruction of acetylcholine adds a
later low level phase of transmitter action which
probably occurs after the acetylcholine has diffused
away from the immediate neighborhood of the
terminals where it is released and is dispersed over
the entire junctional region.
The high degree of chemical specificity of the
receptor and the competition for it of different sub-
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
Stances with different final effects is suggestive of the
behavior of an enzyme. It is highly relevant to this
that substances which are able to displace acetyl-
choline from the enzyme cholinesterase are also able
to displace it from the receptor. The receptor appears
almost certainly to be a protein constituent of the
muscle fiber membrane with its reactive sites exposed
on the outer surface. As a result of the combination
of these sites with acetylcholine, the physical proper-
ties of the membrane alter and a new path appears
for the diffusion of ions of various species through it.
In electrical terms transmitter action may be ap-
proximately described as the placing of an addi-
tional conductance across the membrane which short-
circuits any previously existing potential difference.
In that the experimental findings are in agreement
with this interpretation, they exclude the possibility
of electrical transmission by which the junctional
response is considered to be produced by an externally
generated current impressed upon the muscle fiber.
At the same time they eliminate the possibility that
the response may be of the nature of a local response,
a specific increase in membrane permeability to
sodium ions boosting an initially small potential
change, such as may occur when the membrane is
depolarized to near the threshold for setting up an
action potential. It appears that the junctional
respon.se cannot be brought about by any means of
electrical stimulation of the postjunctional structure
but only by a specific chemical reaction of the re-
ceptor. The presence at the junction of a region capa-
ble of responding in this way does not appear to
affect the action potential developed there, except
by an addition of the independent actions of the two
types of activity. The probable significance of this is
that the area occupied by the receptor is small and
does not detract appreciably from the area engaged
in producing the action potential.
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CHAPTER VII
Autonomic neuroefFector transmission
U. S. V O N E U L E R I Department of Physiology, Faculty of Medicine, Stockholm, Sweden
CHAPTER CONTENTS
Development of the Concept
Anatomical Considerations
Humoral Versus Electrical Transmission
T'^e Adrenergic Nerve Transmitter
dentification
Occurrence, Biosynthesis and Storage of Adrenergic Nerve
Transmitter
Release
Influence of stimulation frequency
Effects on remote organs
Stimulation of isolated nerves
Exhaustibility
Removal of Transmitter
Possible Adrenergic Nerve Transmitters Other Than Norepi-
nephrine
The Cholinergic Nerve Transmitter
Identification
Occurrence, Biosynthesis and Storage
Release in Organs
Release from isolated nerves
Removal of Transmitter
Mechanism of Action of Neurotransmitters
Neurotransmitters in Blood and Urine
DEVELOPMENT OF THE CONCEPT
THE IDEA OF CHEMICAL TRANSMISSION of nerve im-
pulses was apparently first expressed by Elliott (41)
who in 1904 suggested the possibility that when the
sympathetic nerve impulse reached the target cell it
caused an action by liberating epinephrine "on each
occasion when the impulse arrives at the periphery."
This hypothesis was based on the similarities in action
of epinephrine and sympathetic nerve activity,
irrespective of whether the action was activation or
inhibition.
Elliott's idea, although representing an entirely
new concept, must have struck many as plausible, and
it was not surprising that thinking should proceed
along similar lines. Thus Dixon & Hamill (36) ap-
plied the idea to parasyinpathetic nerves, comparing
their action with that of muscarine, and after this
time it became primarily a matter of skillful experi-
mentation to prove the correctness of the theory and
to carry the new concept to general acceptance. This
task proved more difficult than was perhaps antici-
pated. It was chiefly due to the precision of observa-
tion and judgment of Dale (25) and the ingenious
experimentation of Loewi (83) that the postulate of
chemical transmission became tran.sformed into an
accepted concept. Acetylcholine gradually moved into
the center of interest as a possible candidate for
parasympathetic nerve transmission. In Dale's paper
concerning the action of injected acetylcholine, he
stated that it caused "pronounced vagus-like inhibi-
tion of the heart, and various other effects of stimu-
lating nerves of the cranial and sacral divisions of the
autonomic system — secretion of saliva, contraction of
the oesophagus, stomach and intestine and of the
urinary bladder."
The direct experimental proof was provided by
Loewi (83) who showed that the fluid collected from
an isolated frog's heart during vagus stiinulation
inhibited a second heart (fig. i). The effect of the
"Vagusstoff" was annulled by atropine and in a large
series of experiments it could be shown that the
liberated substance behaved in every respect, phar-
macologically and chemically, like a choline ester. It
is generally assumed that it is acetylcholine.
Stimulation of the sympathetic nerves in Loewi's
experiments caused the release of a factor which
accelerated the heart and had properties similar to
those of epinephrine. Chemical transmission of
sympathetic nerve impulses was independently dem-
onstrated by Cannon & Uridil (21) who found that
the stimulation of hepatic nerves increased the rate
of the denervated heart and rai^d the arterial pres-
215
2l6 HANDBOOK OF PHYSIOLOGY -^ NEUROPHYSIOLOGY I
liliililLMi
.UiMJviiiUi
FIG. I. Bain's modification of the original experiment performed by Loevvi in 1921. The diagram
represents a reservoir of salt solution from which there is a passage to the donor heart (D); pressure
trom the reservoir assures a continuous flow of the solution through that heart to the recipient heart
(R). The donor heart still has its proper nerves. Each heart is attached to a writing lever. The record
is that of the two hearts, donor and recipient. When the vagal fibers of the donor were stimulated (S),
there was a prompt arrest of that heart (D), and later a slowing and arrest of the recipient heart
(R), with gradual recovery. Time (T) is recorded in 5-sec. intervals. [From Bain (7).]
FIG. 2. Rise of arterial pressure and increase of heart rate from
196 to 220 beats per min. following stimulation of the hepatic
nerves in the cat. Time, 5 sec. [From Cannon & Uridil (21).]
sure (fig. 2). It did not dilate the pupil, howexer,
which would have been expected if the substance
carried by the blood were epinephrine.
The principle of chemical transmission was later
greatly developed chiefly by the work of Cannon &
Rosenblueth and their associates, and by Dale,
Feldberg, Minz and their co-workers. A very useful
distinction was introduced by Dale (27) when the
tcrins adrenergic and cholinergic nerves were coined
(fig. 3). While acetylcholine still holds the position
allotted to it since 191 4 as the cholinergic chemotrans-
mitter, the concept of epinephrine as adrenergic
transmitter has had to yield to its nonmethylated
homolosiue norepinephrine (124). The "curiously
anomalous" effect on the iris observed by Cannon &
Uridil in 1921 (21) i:)ecame readilv explained by the
recognition that norepinephrine and not epinephrine
was the mediator of adrenergic nerve action.
For a detailed account of the problem of autonomic
neuroeffector transmission the reader is referred to the
monographs of Gaddum (50), Cannon & Ro.scn-
blueth (20), Muralt (133), Rosenblueth (113)
Minz (96, 97), Euler (129) and the recent survey of
neurochemistry (loi).
.^N.ATOMIC.^L CONSIDER.ATIONS
As in other tields of ph\siolog"y, valuable hints may
be gained by studying the microarchitecture of the
AUTONOMIC NEUROEFFECTOR TRANSMISSION
217
region in question, in this case the structural relation-
ships between the autonomic postganglionic nerve
endings and the target cells. These cells in principle
include the heart muscle cells and the secretory cells
of the glands in addition to those of smooth muscle.
Much conflicting evidence has been presented with
regard to the innervation of smooth muscle cells by
autonomic ner\e fibers. It inay sufhce to mention that
an histologist as experienced as Slohr (121) found
that less than one cell in a hundred was inner\ated.
The numerous reports on intracellular nerve endings
in smooth muscle cells seem to require reconsideration
since an ingrowth of axonal endings into a cell ap-
pears for many reasons unlikely, and even unneces-
sary, especially in view of the probable distribution of
the transmitter in the terminal parts of the axons,
to be discussed later. It must therefore be seriously
considered whether the alleged findings are not due to
misinterpretation of the histological pictures. It is
well known that smooth muscle cells may .serve their
proper function without innervation, and unless it
can be shown that each smooth muscle cell receives
intracellular nerve twigs there is every reason to
regard the few exceptions known at present as interest-
ing special cases of unknown functional significance.
The finding of numerous endings in the ciliary muscle
of the eye does not alter the general picture. There is
nothing known so far to indicate any kind of motor
end plate' on the sinooth muscle cell. Knoblike
thickenings ending at or near the cell surface have
been described, however, both by older histologists
and more recently. Similar structures, sometimes
assuming the picture of bead-strings, have been re-
peatedly found at autonomic nerve endings (54, 62,
72). Garven & Gairns suggest "that the small beads
on the course of the finest fibrils represent the actual
release points of the humoral agents within the cyto-
plasmic continuum provided by cells other than the
neurones. "
As will be discussed in the following section the
results of studies of electrical phenoinena in the
siTiooth muscles do not suggest direct innervation of
such cells.
Cannon & Rosenblueth (20) have regarded the
few innervated cells as having special functions and
have named them 'key cells.' Their contention was
that by chemical transmission concentrated to these,
the neighboring cells will be affected by the diflfusing
neurotransmitter. There is little evidence to support
this hypothesis, however. Moreover, since it is known
that the autonomic nerve transmitters are presept
FIG. 3. Dale's schpmatic representation of the autonomic
nervous system. A, adrenergic; C, cholinergic elements.
[From Dale (28).]
all along the axons, it is unlikely that they should
be released only at one point of the axon in a small
nuinber of special cells.
The question of the innervation of the smooth mus-
cle cell cannot be answered with coinplete certainty
but the best evidence points at a peripheral branching
system of the postganglionic autonomic nerve fibers
extending to the inynediate neighborhood of each
snipoth muscle cell (62). By release of the chemical
transmitter during nerve stimulation, the cells will
be reached by the active chemical substance through
diffusion. The proportion of cells activated in an organ
and the degree of activation will clearly depend upon
the amount of transmitter set free, which in its turn
is a function of the frequency and strength of the
stimulus applied to the nerve.
HUMORAL VERSUS ELECTRICAL TRANSMISSION
The bulk of evidence points to the conclusion that
denervated smooth muscle is electrically inexcitable
(100, 114). Even if direct stimulation of denervated
smooth iTiuscle may lead to contraction, this is weak
and differs in several respects from that produced by
the chemical stimuli. It appears likely that the direct
stimulation effect is unspecific and due to a direct
gross action on the contractile material. An important
2l8
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
argument is further that single stimuli are not capable
of eliciting contractions. Whether the negative results
of stimulating the denervated adrenal medulla (114)
can be used as support for the thesis of inexcitability of
denervated target cells is open to doubt.
The inexcitability of autonomic effectors has also
been studied by 'chemical denervation,' by use of
drugs which block the action of the autonomic nerves
on the target cells. Such experiments have been made
on the piloerectors after ergotoxin (20) and on the
salivary gland cells after chlorpromazine (42).
It may therefore be concluded that the smooth mus-
cle cell lacks the ability to respond to direct electrical
stimulation. Since there is ample evidence to show
that these cells respond readily to the chemical
stimuli which are known to Ije released from the
terminal parts of the autonomic postganglionic nerves,
there .seems to be no need to postulate electrical
transmission for functional reasons.
For a detailed discussion of the dual theory of
chemical and electrical transmission advocated by
Monnier & Bacq (100) see Cannon & Rosenblueth
(20}. While there is no evidence for electrical trans-
mission from the postganglionic autonomic nerve
fiber to the effector cell, the situation may be different
in the case of autonomic synapses (loi).
Smooth muscle thus differs fundamentally from
skeletal mu.scle in that the latter is rapidly activated
by a trigger mechanism requiring direct contact i:)e-
tween the nerve fiber and the effector and working on
the all-or-none principle. The sustained activity of
the smooth muscle appears to operate on the entirely
different principle of graded responses (115). More
data are required, however, before the activity of the
single smooth muscle cell in response to physiological
stimuli can be ascertained.
by biological tests and by colorimetric methods (1^9)-
For the identification of the transmitter the differ-
entiation from epinephrine became of primary im-
portance. On most target cells the actions of epineph-
rine and norepinephrine are qualitatively similar,
but the relative activity varies from one organ to
another. Thus the action of epinephrine may be
over one hundred times that of norepinephrine on the
rat's uterus and on the fowl's rectal cecum while the
two amines ha\e about the same activity on the iso-
lated heart. By comparing the actions of the purified
extracts containing the neurotransmitter on a series
of test preparations it is possible to ascertain whether
the relative actions of the unknown compound go
parallel with one or the other of the standard sub-
stances. Though norepinephrine passed unnoticed
by chemical tests in the so-called pure crystalline
epinephrine prepared from suprarenals for nearly
50 years, the amines are now readily separated by
chromatography (73).
Generally a single pair of test objects showing
sufficiently large differences in the activity' ratio be-
tween epinephrine and norepinephrine suffice for
differentiation between the two amines. Suitable
pairs are for instance the cat's arterial pressure and
the fowl's rectal cecum. On the former preparation
norepinephrine is from i to 5 times more active as a
pressor agent than epinephrine, while it has only ' 4
to J200 of the activity of epinephrine on the fowl's
rectal cecum (fig. 4).
The virgin uterus of the cat, and the iris are 5 to 10
times more sensitive to epinephrine than to norepi-
nephrine and may be u.sed for differentiating pur-
poses. The rat's uterus under certain conditions is
stimulated by norepinephrine and relaxed by epi-
nephrine (fig. 5).
THE ADRENERGIC NERVE TRANSMITTER
Identification
As outlined in the introductory section, Loewi's
experiments in 1921 supported the idea that the
sympathetic (adrenergic) transmitter was epineph-
rine-like. The suggestions by Barger & Dale (9), Bacq
(4) and Greer, Pinkston, Baxter & Brannon (58) that
norepinephrine conformed better with the actions of
the sympathetic transmitter than did epinephrine re-
ceived little attention until it was shown by von Euler
(124) that the adrenergic nerves contained not epi-
nephrine but norepinephrine. The identification of
the transmitter with le\'o-norepinephrine was proved
FIG. 4. Effect of epinepfirine (/-adr), norepinephrine (/-
nor-adr) and extract of beef splenic nerves (Spl. n.) on the
arterial pressure of the cat and on the isolated rectal cecum of
the fowl. [From von Euler (128).]
AUTONOMIC NEUROEFFECTOR TRANSMISSION
219
0.2 ng 0.2 (IF, 0.1 ug 0.2 |ig
Koradr. Adr. Ijore.dr. Adr.
FIG. 5. Rat uterus, 3 hours post partum. o.i and 0.2 Mg
norepinephrine stimulates, 0.2 Mg epinephrine inhibits the
uterus. [From GreetT & Hokz (56).]
It has been observed for some time that although
the actions of epinephrine on the arterial pressure of
the cat may be reversed by antisympathomimetic
substances (ergotoxine, yohimbine, benzodioxane,
dibenamine, phentolamine), the effects of sympa-
thetic nerve stimulation are at the most weakened or
annulled but never reversed. The explanation was
obtained when it was observed that the action of
norepinephrine on the arterial pressure is not re-
versed but only diminished by doses which reverse
the action of epinephrine. This difference has been
utilized for the classification of the adrenergic neuro-
transmittor both in vitro (124, 129) and in vivo (20, 48).
The identification has subsequently been con-
firmed by other methods, notably by paper and
column chromatography, allowing separation from
other catechol amines and characterization by
specific color or fluorescence reactions. Extracts of
heart yield fractions on column chromatography
which show the same R-value as pure norepinephrine
and the same biological actions (55)- A particularly
good source of the adrenergic transmitter is the
splenic nerves, from which norepinephrine can be
separated by column chromatography and identified
by location and by analysis of the active fractions
(fig. 6). Venous blood from the spleen collected dur-
ing stimulation of the adrenergic nerves contains
practically pure norepinephrine (98, 108).
The effects of reflex activation of sympathetic
nerves as well as the effects of direct nerve stimulation
show all the characteristics of norepinephrine actions
(9. 48, 52, 58)-
The release of an active substance on stimulation
of the nerves to an organ does not necessarily mean
that this substance is the corresponding chemotrans-
mitter. In the experiments of Loewi in 1921 it is likely
that the effects observed were due to released epineph-
rine, for which good evidence was obtained later (84,
124). There is no evidence, however, that epineph-
rine serves as adrenergic nerve transmitter in any
animal. In the frog the spleen contains chiefly nor-
epinephrine (105), and it can not be excluded that
the epinephrine released on sympathetic nerve stimu-
lation originates from chromaffin cells and not from
adrenergic nerve endings. In such a case the substance
released from the heart (which lacks coronary vessels
in the frog) is not a neurotransmitter proper and the
mechanism involved would be analogous to the re-
lease of epinephrine from the suprarenals on stimula-
tion of its preganglionic nerves.
Although the theory of Cannon and Rosenblueth
concerning the two sympathins is chiefly of historical
interest is may be briefly outlined here. [For a de-
tailed discussion see Cannon & Rosenblueth (20),
and Rosenblueth (113).] According to this theory
epinephrine is the adrenergic nerve transmitter, which
on reaching the target cells combines with some
20 25 30
NUMBER OF TUBE
FIG. 6. Column chromatogram of extract of beef splenic
nerves after adsorption on aluminium oxide and elution, show-
ing a maximum for norepinephrine. [From von Euler &
Lishajko (132).]
220
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
TABLE I . Norepinephrine Content of Beef Nervous Tissue
in tig per gm (129)
Splenic nerve
8.5-,8.5
Splanchnic ner\e
4
Sympathetic chain, thoracic
■! •5-4-9
Sympathetic chain, cervical
0.6
Mesenteric nerve
1-5-3
Superior cervical ganglion
I
Saphenous nerve
0.2-1
Phrenic nerve
0.15-0.25
Vagus nerve
0. 1
Spinal cord
0. T
Brain
0 . 04-0 . 20
cell constituent to form what was termed inhibitory
(I) or excitatory (E) sympathin or both. These find-
ings are readily explained on the assumption that
the actions observed were either due to the true
adrenergic neurotransmitter, norepinephrine, or to
epinephrine released from other sources, presumably
chromaffin cells, or a mixture of both, as suggested
i)y Bacq in 1934 and subsequently proved by the
demonstration of both amines in autonomically in-
nervated organs (126). The term sympathin should
preferably be abandoned in the physiological litera-
ture since it does not discriminate between the neuro-
transmitter and the hormones released as a result of
preganglionic stimulation of chromaffin cells.
Occurrence, Biosynthesis and Storage oj Adrenergic
Nerve Transmitter
Unless it is assumed that the chemical transmitters
are being formed and released at the moment of
nervous excitation it must be concluded that they
are present in the axon and relea.sed from .some kind
of store. Systematic studies of the content of trans-
mitter substances in postganglionic nerves have been
made both for the cholinergic and for the adrenergic
system. Such experiments have shown that the content
of norepinephrine in a nerve correlates well with the
number of unmyelinated fibers of autonomic origin
(i 1 1). As seen in table i the amount of norepineph-
rine varies greatly and is highest in the splenic nerves
which are known to contain practically only post-
ganglionic sympathetic fibers. In other nerves, such
as the vagus, the amount is quite small and this is
true also for most motor nerves and the majority of
sensory nerves. For technical reasons it is impossible
to prepare nerves in their most peripheral parts,
hence it has not been possible to study directly the
content of the transmitters in the immediate vicinitv
of the target cell, which for many reasons would
have been desirable. On the other hand it has been
possible partly to overcome this difficulty by making
extracts of whole organs and estimating their trans-
mitter content, thus measuring the total amount
present in the tissue including the finest nerve rami-
fications (iio, 129). Proof that the transmitter sub-
stances so found are actually due to the presence of
postganglionic nerve fibers has been obtained by
studying the effect of denervation. If the postgangli-
onic nerves are severed and allowed to degenerate,
the amount of norepinephrine in the peripheral ti.ssue
falls to very low figures or disappears completely.
This indicates that the tissue is not able to store the
transmitter by itself but does so by means of its
autonomic nerve fibers. Further support for this
opinion is provided by experiments showing that
some 4 to 8 weeks after degeneration of the cardiac
nerves the content of adrenergic transmitter in the
sheep heart increases again and after the lapse of a
few months reaches the original value (fig. 7) (55).
.Similar results have been oljtained for other organs
2P
1,8
D left cerv. symp removed
^1.5
ao
ffl right " "
5l>
e lei! stellate removed
21,2
9 right "
■
%\o
%Ofi
fB(nofmal) m
iO!&
■
|0,4
■
0.2
0
•%
■
■
1 2
3 4 5 6
lime-weeks after last operation
FIG. 7. Norepinephrine content of sheep hearts before and
various times after svmpathetic denervation. [From Goodall
(55)-]
T.\BLE 2. Norepinephrine Content in Beef Organs
in fig per gm (129)
Spleen
Lymph glands
Heart
Ciliary body and iris
Liver
Arteries and veins
Lung
Intestine
Uterus
Testicle
Skeletal muscle
Bone marrow
1-5-3-5
0.5-0.8
o . 3-0 . 6
0.4
o . 25
o. I-I
0.15
0.15
0.15
0.04
0.04
0.0
AUTONOMIC NEUROEFFECTOR TRANSMISSION
221
such as the spleen and the kidney of the sheep (129).
The stores of the transmitter substance can thus be
estimated by extracting the tissue and subjecting it to
chemical or biological analysis. The content of
adrenergic transmitter in an organ (table 2) provides
a measure of the relative supply of adrenergic nerves.
Norepinephrine was first suggested as a link in the
biosynthesis chain leading to epinephrine by Blaschko
(11). The basis for this was given by Holtz, Heise &
Liidtke (68) who discovered an enzyme capable of
decarboxylating levo-dihydroxyphenylalanine (dopa)
to its corresponding amine, hydroxytyramine (dopa-
mine). This enzyme was present in liver and kidney
and has also been demonstrated in the adrenals and
in adrenergic nerves (69). While it has been shown
experimentally that homogenates of the adrenal gland
synthesize norepinephrine from tyrosine (74), via
dopa (33) and dopamine (59), this sequence has not
been shown for adrenergic nerves although there
can be little doubt that this is the case. At any rate
it has been found that extracts of the spleen or
splenic nerves contain relatively large amounts of
dopamine (117, 132). The biosynthesis may there-
fore be depicted by the following .scheme:
OH
OH
iOH
CH2CHCOOH
CH.,CHCOOH
NH.,
NH.,
Tyrosine
Dopa
0
0
H
OH
0
A
H
OH
CH.,CH2-
NH2
CHrCHOHNH
D(
jpamine
No
repinephrine
It appears likely that the biosynthesis is located in
the place of storage (see below). Analysis of extracts
of autonomic nerves have shown that the norepineph-
rine content is a function of the proportion of adrener-
gic fibers. These contain the transmitter along their
whole length and also in the jxU soma. A very
marked accumulation in the terminal parts must be
assumed for the following reasons. Splenic nerves of
the beef contain about 15 ng norepinephrine per gm
fresh tissue after removal of the sheath, while the
content of the whole organ is about 3 //g per gm. Since
all of the splenic norepinephrine disappears on section
and degeneration of the adrenergic nerves to the
organ it is assumed that the norepinephrine found in
the organ is bound to its nerves. On the other hand
it is inconceivable that 20 per cent of the splenic
tissue consists of nerves, and it follows from this that
some parts of the nerves, presumably the endings,
contain much more of the transmitter than the main
nerve trunks.
Even after rernoval from the body, organs retaiin
their adrenergic transmitter substance for a con-
siderable time. A beef spleen may thus be stored at
room temperature for 24 hours without any detectable
loss of norepinephrine. This indicates that it is not
present in a freely diffusible form and strongly sug-
gests that it is bound in such a way as to prevent con-
tact with inactivating enzymes.
Evidence has been obtained for the storage of the
hormones of chromaffin cells in specific granules (12,
63). By increasing the acidity of the surrounding solu-
tion to pH5 or lower, the chromaffin cell hormones
are released from the granules (63). When the same
principle was applied to the isolated spleen by per-
fusi^ng it with a .solution containing acids such as as-
corbic, citric or lactic acid, the transmitter substance
was released and could be demonstrated in the per-
fusion fluid (40). Also other substances which have
been found effective in releasing the hormones from
isolated granules had a similar action on the perfused
spleen, such as detergents, digitonin and lecithinase
from snake venom.
These e.xperiments add support to the hypothesis
(127) that the neurotransmitter is stored, and proba-
bly manufactured, in specific structures in the
adrenergic axon. Experiments by Euler & Hillarp
(131) have demonstrated that a microgranular frac-
tion rich in norepinephrine can be separated by high
speed centrifugation from a homogenate of beef
splenic nerves. The chemotransmitter is apparently
stored in elements surrounded by a membrane since
a suspension of the sediment in Ringer's solution
does not give off norepinephrine to the surrounding
fluid. If acid is added to PH4 in the suspension, the
norepinephrine is instantaneously released, however,
and can be demonstrated by ijiological and chemical
methods in the suspension fluid. The micrograniilar
stores are apparently specific for the chemotrans-
mitter since the histamine which is abundant in the
beef splenic nerves (about 100 ixg per gm nerve) is not
present in the same structural elements. Certain
cellular fractions have been found to contain more
than 1.5 fig norepinephrine per mg dry weight or
222
HANDBOOK OF PHYSIOLOGY ^ NEUROPHYSIOLOGY I
around 20 times the amount per mg dry weight found
in the whole nerve before homogenization.
The theory may then be advanced that the adrener-
gic nerve transmitter is bound to elements which in
principle are of a kind similar to those found in the
chromaffin cells. Since these can be regarded as
homologues of the postganglionic neurons it might
be expected that their constituents with specific activ-
ity are stored in a similar way. The structural ele-
ments serving as stores may also well be the units for
bio.synthesis. Apparently this takes place very rapidly
so as to maintain a practically constant store. Con-
tinuous and prolonged stimulation of nerves in vitro
(88) or in vivo (129) does not deplete the stores. There
is no evidence that the granules of the chromaffin
cells leave the cell body in connection with the re-
lease of the hormones; this may be assumed also for
the storing elements of the postganglionic adrenergic
neurons. It may be postulated that the microstruc-
tures elaborating and containing the neurotrans-
mitter are formed in the cell soma and transported
along the axon towards the periphery by the axo-
plasm flow (135). These assumptions would provide
a satisfactory explanation for the findings that a) the
chemotransmitter is accumulated in the terminal parts
of the neuron, and that h~) continuous stimulation does
not deplete the nerves of its chemotransmitter. The
theory involving the assumption of intra-axonal
microstructural elements thus seems to explain
several phenomena encountered in the field of neuro-
transmission.
Release
Stimulation of the adrenergic nerves, either directly
or reflexly, immediately releases norepinephrine
which is then allowed to diffuse to the adjacent tar-
get cells. From the above section it may be inferred
that the transmitter is released from microstructures
and accumulated at the terminal parts of the nerves,
presumably in a way similar to that operating in the
chromaffin cells. The large number of discrete
terminal ramifications ofl"er only short diffusion dis-
tances, enabling each cell to be reached by the chemi-
cal transmitter in a very short time. While under
normal conditions the adrenergic chemotransmitter
is released chiefly, if not entirely, as a result of reflex
stimulation, various experimental approaches have
been made in order to study the release in more
detail, such as a) observation of the effects of direct
nerve stimulation on the innervated organ. A) record-
ing of the effects of stimulation of adrenergic nerves
on remote organs, c) quantitatixe estimation of the
content of the neurotransmitter in the venous effluent
from the stimulated organ, and (T) measuring the
release of transmitter from isolated nerves stimulated
in vitro, or from organs perfused in vitro.
INFLUENCE OF STIMUL.XTION FREQUENCY. The effect of
Stimulation of the adrenergic nerves — or usually
mixed nerves containing adrenergic fibers — provides
the basis for most of our knowledge of the action of
the adrenergic system on various target organs. A
study of these effects not only permits qualitative in-
formation on the type of effect on the organ but also
offers opportunities for gaining quantitative infor-
mation, for instance about the influence of stimulus
strength and frequency on the effect. In this way the
relea.se mechanism can be studied at least on a semi-
quantitative basis which can hardly be accom-
plished by reflex stimulation.
While the technique of studying the response of an
organ to variation in the intensity of the stimulus
gives an idea of the excitability of the nerve fibers,
information about the release mechanism is better
obtained by varying the stimulus frequency. Such
experiments are preferably performed u.sing stimu-
lation intensities which will allow participation of
all fibers. As shown in figure 8, the curves obtained
by Rosenblueth (112) showing the relationship of
stimulus frequency and effect on various autonomic
effectors have the general shape of rectangular
hyperbolas. The results show the noteworthy feature
that considerable effects are achieved even at very
low frequencies. As can be seen from figure 8, e\en
frequencies of less than i per sec. are capable of
causing marked effects. Nearly maximal actions have
been recorded with frequencies of the order of 5 per
sec, for instance on the piloerectors and the nictitat-
ing membrane. The results imply that even very low
frequencies are sufficient to release considerable
amounts of the transmitter. In table 3 the optimum
frequencies for a numjjer of effectors are given. Maxi-
mal effects are obtained with frequencies varying
from 20 to 30 per sec. in most effector systems. Even
a frequency of 10 per sec. generally elicits more than
80 per cent of the maximal response.
.\n interesting difference is noted between the
ratio of the effects of single stimuli and those of
maximal tetanic stimuli on smooth and skeletal mus-
cles, no doubt depending on the trigger mechanism in
the latter. Thus the ratio between the effects is much
higher for the smooth muscle than for the skeletal
muscle.
AUTONOMIC NEUROEFFECTOR TRANSMISSION
223
FIG. 8. Frequency-response curves of sympathetic effectors. .-1: abscissae, frequencies of stimulation
of tlie lumbar sympathetics; ordinates, angles of erection of a hair in the tail of a cat. B: abscissae,
frequencies of stimulation of the cervical sympathetic; ordinates, heights of the records of isotonic
contractions of the nictitating membrane 15 sec. after the beginning of stimulation. C: as in B, but
isometric contractions of the nictitating membrane. D : abscissae, frequencies of stimulation of the
right cardioaccelerator nerves; ordinates, maximal increases of heart rate per 15 sec. [From Rosen-
blueth (112).]
Even after cutting a considerable portion of the
nerve the maximal effect may be approached, pro-
vided the frequency of stimulation is increased suffi-
ciently. The effect of low frequencies on a partially
severed nerve is smaller than in the intact nerve,
however, which might be expected.
The conclusion drawn from these experiments is
that the neurotransmitter diffuses to the neighboring
cells as its concentration is raised by increasing the
stimulation frequency. The principle of activation of
smooth muscle cells may therefore be a general re-
lease of transmitter within the mass of these cells,
rnaking individual innervation as for the skeletal
muscle fibers unnecessary.
T.'VBLE 3. Frequencies of Preganglionic Stimulation,
Giving Maximal Response of Effectors (20)
Effectors
Sympathetic
Pilomotors
Nictitating membrane
Pregnant uterus
Intestine
Adrenal medulla
Heart (postgangl.)
Parasympathetic
Heart
Submaxillary gland
Stomach
Frequency
Stim. per sec.
■5
20
20
20
25
25
30
35
25
224
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
MAX CONSTRICTION
100
BASAL
BLOOO FLOW
PHYSIOL DISCHARGE RANGE
JSTIM
30 FREQ
FIG. 9- Vasoconstrictor effect of electric stimulation of lumbar sympathetics at \arying frequencies
in the cat. Striped area indicates the variations obser\'ed in 40 experiments. A represents a\'erage of
10 experiments with the biggest response; B, average response after vasodilator drugs. [From Folkow
(46).]
The effect of stimulation at various frequencies of
sympathetic nerves to the muscular Ijlood vessels in
the lower part of the hind limlj of the cat has been
measured by recording the outflow (46).
Figure 9 shows the correlation between stimula-
tion rate and the constrictor response. It is clearly
seen that low stimulation frequencies are very effec-
tive. This applies also to cutaneous blood vessels (22).
A detailed analysis of the mechanism of the release
has been made by Brown & Gillespie (14) using the
cat's spleen. Samples of venous blood were collected
and the norepinephrine content assayed on the ar-
terial pressure of the pithed rat. Supramaximal
stimuli were applied to the splenic nerve, the total
number of stimuli being 200, irrespective of the fre-
quencv. Both adrenal glands were removed and the
splanchnic nerves cut. The output of norepinephrine
was expressed as amount released per stimulus.
As illustrated in figure io.4 the norepinephrine out-
put per stimulus was low at low frequencies, but as
the frequency increased the amount found in venous
blood rose sharply to a maximum at about 30 stimu-
lations per sec. Since the output per stimulus was
the same before and after addition of isopropyl
isonicotinyl hydrazine (Marsilid), an effect of amine
oxidase on the transmitter liberated at lower frequen-
cies could be excluded. The possibility was also dis-
cussed that, although the amount of transmitter re-
leased by each nerve volley might be constant, more
was 'utilized' by tissue receptors at a low rate of stim-
ulation. After blocking tissue receptors with N-N-
dibenzyl-/3-chloroethylamine (dibenamine), it was
found that the output per impulse reaching the blood
was greatly increased at the lower frequencies and
maintained a constant value at different frequencies.
From these observations it was concluded that the
norepinephrine release per nerve volley is constant
and that the fraction removed by the tissues is
greater at the lower frequencies of stimulation (cf.
section on removal of transmitter, p. 227).
The experiments quoted above may have an in-
teresting implication in that the small or absent over-
flow at low stimulation frequency (or adrenergic
nerve activity) and the larger overflow at higher ac-
tivity may cause an excretion pattern in the urine
which 'amplifies' the actual release and makes differ-
ences more pronounced than would be expected from
the activity of the effector.
EFFECTS ON REMOTE ORGANS. This method of study-
ing the release of the adrenergic transmitter is the
one which led to the discovery and demonstration of
such a mechanism. The first experiments of this kind
were made by Cannon & Uridil in 1921 (21) who ob-
served the effect of stimulating the li\cr nerves on the
heart and iris .sensitized by denervation. They as-
cribed the effect to a "special and unknown sub-
stance" apparently being set free by the stimulation.
This kind of experiment was developed further by
Cannon and Rosenblueth and their co-workers in the
AUTONOMIC NEUROEFFECTOR TRANSMISSION
12
0-8
0 4
Frequency (stimuli/eec.)
J I I L
I I I I I
0
12 -
0-8
20
40
60
80 100
200 800
0 4
Frequency (per sec.)
10
2U
30
40
50
FIG. lo. --1; Mean output per stimulus of 'sympathin' plotted
against the frequency of stimulation. At all frequencies of
stimulation the total number of pulses was 2oq. The vertical
lines represent the standard errors of the means. Figures for
loo, 200 and 300 pulses per sec. are single observations. B:
First part of the graph in A with an extended scale for frequency.
The individual results from three animals previously given
dibenamine are shown. The output per stimulus at 10 pulses
per sec. has increased and equals the maximum in the un-
treated animal. There is no obvious variation with frequency.
[From Brown & Gillespie (14).]
work on 'sympathin'. While the study of the trans-
mitter release in this manner, by recording the effect
on sensitized remote target organs, was valuable in
the elucidation of the transmission mechanism as
such, its physiological significance is doubtful. Even
though Cannon and Rosenblueth and their co-
workers obtained increases in heart rate, dilatation of
the pupil and contraction of the nictitating membrane
in denervated organs after stimulation of sympathetic
nerves in other parts of the body, the appearance of
remote effects caused by transportation of the re-
leased transmitter by the blood is by no means a
constant phenomenon.
The failure of some authors (22) to observe remote
effects even on the highly sensitized denervated
nictitating membrane in spite of intense stimulation
of sympathetic nerves has been taken to indicate the
presence of peripheral inactivation mechanisms which
largely eliminate an overflow of transmitter. How-
ever, a physiologically occurring overflow in the
meaning of Cannon and Rosenblueth cannot be
denied for the following reason. If the catechol amines
are estimated in urine from adrenalectomized pa-
tients the amounts of epinephrine are very low while
the norepinephrine content tends to be even higher
than in normal subjects (129). The only possibility
for norepinephrine to occur in the urine then is a
release from some source in the body other than the
adrenals. Since the adrenergic nerves are known to
contain large amounts of this transmitter, it appears
legitimate to assume that during the incessant ac-
tivity of the adrenergic system a certain overflow of
transmitter takes place continuously.
As to the value of the remote effects studied by
Cannon and Rosenblueth as a proof of chemotrans-
mission from nerves, it should be borne in mind that
nervous stimulation might also cause a release from
chrornaffin cells present in the tissues. This criticism
does not invalidate their conclusions in principle
since there is good evidence in some of Cannon and
Rosenblueth's experiments that at least some of the
effects are due to the release of norepinephrine.
It is interesting to note that the so-called inhibitory
sympathin is obtained when the splanchnics are
stimulated but not when the hepatic nerves are stimu-
lated (fig. 1 1). It is known that the s£lanchnic_nerves
may innervate groups of chromaitiin-cells^at various
sites. Their secretory products may then be carried
by the blood stream to excite the denervated organ.
In case of the hepatic nerves there was only a stim-
ulating effect but no inhibitory effect on the dener-
vated uterus of the cat, indicating that practically only
nore£ine£hrine was released in this case. As far as
can be ascertained at the present time this norepi-
nephrine is released from adrenergic nerve endings.
The question whether reflex liberation of the
adrenergic transmitter could be large enough to
cause actions on remote organs has al.so been studied
(80). As a result of afferent sciatic or brachial nerve
stimulation it was possible to demonstrate a contrac-
tion of the denervated nictitating membrane in the
adrenalectomized cat. It has also been possible to
show a reflex liberation of the adrenergic transmitter
by action on remote organs, for instance after excite-
ment and struggle (103). The slower development of
■226
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
FIG. 1 1 . Upper curves, decentralized nictitating membrane;
■lower curves, denervated nonpregnant uterus of the cat. Con-
traction upwards. Time, 30 sec. A: hepatic nerves stimulated.
B: right splanchnic nerves stimulated after exclusion of ad-
renals. C: same as in B and injection of 1.5 Mg epinephrine.
D: duodenohepatic nerves stimulated. E: same as in D after
severance of duodenal nerves. [From Cannon & Rosenblueth
(19)-]
the blood-borne action on the denervated heart after
reflex excitation, resuhing from struggle, as compared
with the rapid and large effect in cases where the
adrenals were active may be explained by the gradual
and prolonged release of moderate amounts of trans-
mitter in the former case. The activation of the
adrenals has a tendency to cause an 'explosive' re-
lease. A continuous liberation into the blood stream
during 'sham rage' has also been noted (136) in
decorticate cats showing a quasiemotional state as
exidenced by the reduction in the rate of the dener-
vated heart after section of the hepatic nerves. Even
as a consequence of normal emotions a release of
transmitter into the blood has been observed.
On exposure to cold no sign of continuous effect on
the denervated nictitating membrane of the cat was
found, however (107). The persistent erection of hairs
when the animal is in cold surroundings is apparently
not accompanied by a liberation of enough trans-
mitter to affect remote organs even if these are sensi-
tized.
During^ypoglycemia there is no evidence for ac-
tivation of the sympathetic system as a whole. Only
a selective release of epinephrine from the suprarenal
has been demonstrated by direct analysis of the
venous blood (38). The contention expressed by Can-
non and Rosenblueth that "it is characteristic of the
sympathetic system, when specially excited, to act as
a whole; thus adrenine is secreted by splanchnic im-
pulses at the same time that sympathetic impulses
elsewhere in the body are liberating sympathin" has
not been corroborated by later experiments and
experience. It is now reasonably certain that the
secretion of epinephrine is a process which occurs in-
dependently and often during quite other conditions
than the activation of other parts of the sympathetic
system. It would also appear peculiar if the action of
epinephrine in maintaining blood sugar homeostasis
should be obligatorily linked with, for instance, a rise
of arterial pressure as a result of generalized adrener-
gic activity. The statement of Cannon and Rosen-
blueth that "adrenine and sympathin collaborate in
affecting structures innerv-ated by sympathetic
nerves" is only true in a restricted sense and its biolog-
ical significance is too limited to be set forth as a gen-
eral rule. The statement also illustrates the hazards
of using the term 'sympathin' since this may repre-
sent either epinephrine or norepinephrine. It may be
recalled that the two amines have opposite effects for
instance on the vessels of the skeletal muscles (i , 8, 37).
Even if the leakage of transmitter into the blood stream
is negligible from the point of view of physiological
action, this phenomenon has been of great heuristic
value as in Cannon and Rosenblueth's work and also
in the extensive work dealing with the excretion of
the neurotransmitter in urine (67, 129).
Information about the nerv-e transmitter may also
be gained by collecting blood or perfusing fluid from
an organ during stimulation of the sympathetic
nerves, and by recording the effects of this fluid on
suitable test organs. Studies of this kind are in prin-
ciple similar to the pioneer experiments by Loewi.
Active substances in the effluent have been demon-
strated in many instances, such as from the frog's
stomach (13), the aqueous humour (3), the rabbit's
intestine (45) and the dog's tongue (6).
By the use of an appropriate testing technique it
could be shown later that the active substance re-
leased by adrenergic nerve stimulation conformed
in its properties with norepinephrine (14, 93, 98, 106,
108). In these studies the venous plasma of the stimu-
lated organ was tested. Most investigators have also
stated that smaller amoujits of epinephrine were
sometimes also liberated. The significance of the
simultaneous appearance of small amounts of epi-
nephrine will be considered below.
The release of epinephrine-like materials on stimu-
lation of the vagus nerve to the atropinized heart has
also been reported (65, 94). The former authors con-
AUTONOMIC NEUROEFFECTOR TRANSMISSION
227
eluded that the epinephrine-Hke substance was re-
leased from intracardiac adrenergic neurons con-
trolled bv preganglionic fibers in the vagus. Whether
the substance was released from neurons proper or
from chromaffin cells is not clear, however.
STIMULATION OF ISOLATED NERVES. Attempts havc been
made to study the release of the adrenergic trans-
mitter by stimulating isolated nerves, thus avoiding
the possibility of interaction of the inner\'ated tissues.
In unpublished experiments Gaddum & Khayyal
(50) stimulated an isolated sympathetic nerve sus-
pended in salt solution and found that a sympathomi-
metic substance was released into the solution. This
efTect was later attributed to damage to the nerve by
the stimulating electrodes (53). However, the original
finding was later confirined (79). This is in agreement
with the fact that the whole nerve trunk contains
norepinephrine.
EXHAUSTIBILITY. Studies on the exhaustibility of the
transmitter sources have shown that even prolonged
stimulation, reflex or direct, does not seem to lessen
the release. Orias (104) stimulated the preganglionic
fibers of the cervical sympathetic 10 times a sec. for
I hour and found no .signs of fatigue in the responses
of the nictitating membrane. These experiments were
repeated by Dye (39) who applied not less than
108,000 Stimuli during 3 hours to the preganglionic
nerves without evidence of exhaustion. Luco & Goni
(88) found that stimulation of sympathetic nerves
for I hour did not diminish the content of transmitter
in the nerve. It may therefore be assumed that release
of the transmitter can continue for an unlimited time.
This is an indication in the first place that the trans-
mitter is readily resynthesized but also that the
release mechanism is built to render continuous
service.
Removal of Transmitter
Although it is apparent from the observations of
remote effects of adrenergic nerve stimulation and
from the excretion of norepinephrine in urine that a
certain proportion of the released neurotransmitter
is transferred into the circulating blood, it is generally
assumed that most of the transmitter is being inacti-
vated at or near the site of release (16, 47}.
The experiments of Brown & Gillespie (14) indicate
that the removal of the transmitter is more efficient
when it is released at a slow rate. As to the mechanism
of removal, their experiments suggest that the trans-
mitter is being attached to a certain extent to the
effector cells and presumably inactivated at this site.
Our knowledge about the mechanism of inactiva-
tion is still very incoinplete. The inability of iso-
propyl isonicotinyl hydrazine (Marsilid) to affect to
any noticeable extent the amount of transmitter re-
covered in the effluent blood after stimulation of the
splenic nerves does not support the common opinion
that amine oxiclase plays an important part in this
respect.
In experiments in which the transmitter was re-
leased from a perfused spleen by various chemical
means, the amount of norepinephrine found in the
effluent was not greatly influenced by adding amine
oxidase inhibitors to the perfusion fluid (129). More-
over, administration of Marsilid to an animal does
not augment the degree or duration of adrenergic
reflex actions in the cat, such as the pressor eflfect of
carotid occlusion, indicating that amine oxidase, at
any rate, does not attack the transmitter between the
moment of release and the action on the efTector cell.
The problem of the removal of the transmitter
after its release may be regarded from two aspects.
One part of the transmitter apparently is d]rectly
at_tached to the effector cells [or 'utilized' (14)] while
another portion is leaking into the blood vessels, or
by-passing the target cells as it were. It is conceivable
that after saturation of the target cells the remainder
of the released transmitter diffuses through the capil-
lary wall and enters the blood stream. The situation
might be regarded as analogous to that prevailing
during reabsorption of a threshold substance by the
renal tubules where an excess causes an ' overflow'
into the urine. If the amount of the transmitter which
is caught by the effector cells is considered first, it
appears probable that it is being inactivated by some
process so far unknown. It may well be that on many
occasions this part represents the greatest part of the
released transmitter. The second part which is not
taken up by the cells may theoretically be attacked
by enzymes on its diffusion way to the blood or
lymph capillaries. Apparently this is not the case since
amine oxidase inhibitors did not appreciably alter
the yield in the effluent Ijlood (14). Not even after
having reached the blood stream is the inactivation
complete as seen by the excretion in urine of neuro-
transmitter which undoubtedly originates in adre-
nergic nerves, as indicated by the excretion in
adrenalectomized patients. Knowing the proportion
of norepinephrine e.xcreted in urine after intravenous
infusion at a constant rate, it seems po.ssible to obtain
an idea of the ' overflow' of adrenergic transmitter
228
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
per unit of time. From infusion experiments in m^n
it has been found that the proportion of norepi-
nephrine excreted in urine is 1.5 to 4 per cent of that
infused durinc; the same time (129). If the total ex-
cretion of norepinephrine (free and conjugated) in
man during 24 hours, when the subject is performing
daily routine work but no severe muscular work, can
be estimated at 60 fxg (109, 129), the amount of
neurotransmitter overflow may be estimated at ap-
proximately 2 to 3 mg per 24 hours.
The careful study of the distribution of monoamine
oxidase (MAO) in various nerve cells by Koelle &
Valk (76) does not support the opinion that MAO is
specifically occurring in adrenergic nerves, since no
significant differences were found in the MAO ac-
tivity in nerve cell bodies and fibers of the stellate,
superior cervical, nodose, dorsal root and ciliary
ganglia of the cat. The enzyme is localized in smooth
muscle cells of blood vessels. It is absent in cardiac
muscle, but high activity is found in renal tubule
cells and hepatic cells. Since the removal of the trans-
mitter by inactivating enzymes is more likely to occur
in the target cells than in the neurons producing the
transmitter this result is not unexpected.
Small amounts of the transmitter are successfully
removed during the passage of blood through the
tissue, up to 90 per cent during a single passage
through muscle and skin. This is in harmony with
the findings that after infusion of norepinephrine and
epinephrine in man only a small percentage appears
in the urine, the rest being inactivated.
Mechanisms of inactivation other than by MAO
are conceivable, such as by catechol oxidases and
peroxidases and by conjugation. The relative unim-
portance of the inactivation of circulating catechol
amines by MAO is further borne out by the observa-
tion that cobefrine (a-methyl-rfZ-norepinephrine) is
excreted in a similar small proportion as epinephrine
and norepinephrine after injection in man (129),
although it is not attacked by this enzyme. It must
therefore have been inactivated (to more than 90 per
cent) by some other mechanism which presumably
would have been similarly active on the catechol
hormones.
POSSIBLE ADRENERGIC NERVE TRANSMITTERS
OTHER THAN NOREPINEPHRINE
It may well be asked whether there is any way of
distinguishing between the release of the chemotrans-
mitter from the nerve terminals and the secretory
products from chromaffin cells in the tissues. Since
very little is known about the mass and distribution
of such scattered chromaffin cells or whether they
secrete epinephrine or norepinephrine or both (and
in the latter case the relative proportions), it is hard
to evaluate the amount of neurotransmitter sensu
strictwn which is released upon stimulation of svinpa-
thetic nerves. Assuming that chromaffin cells are
present in an organ, they would be made to release
their secretory products by stimulation of the pre-
ganglionic fil:)ers in the sympathetic nerve.
A partial answer to this problem has been afTorded
by studies on the content of the active catechol
amines in tissues and organs. There is good evidence
that the catechol amines found in extracts of organs
and tissues are derived from their adrenergic nerves
and chromaffin cells. This is shown by a) the large
reduction or disappearance of the catechol amines
after postganglionic denervation (18, 55, 129), h) the
absence of these suijstances in the nerve-free placenta
(i 16, 124) and c) the reappearance of such substances
upon regeneration of the postganglionic nerves
(55, 129). It is known that section and degeneration
of the preganglionic fibers that innervate the chro-
maffin cells do not cause depletion of the secretory
products of these cells, while section of the postgangli-
onic fibers causes disappearance of their transmitter
substance. It is thus possible by analysis of the cate-
chol amine content of an organ after preganglionic
and postganglionic denervation to obtain information
on the occurrence of chromaffin cells. The results of
such experiments liave been that ' postganglionic'
nerve section usually leaves a small remnant of
activity. It is typical of this that the proportion of
epinephrine is higher than it is in the organ with its
nerves intact (55, 129). Sometimes the epinephrine
content is unchanged. The conclusion has been
drawn from these experiments that_gractic_ally all of
the norepinephrine_is present in the postganglionic
nerves while the epinephrine must have been located
outside the adrenergic neurons, in all likelihood in
chrouKiffin^cells. Such cells have been described in the
heart b\ Trinci (123).
Further evidence along the same line has been ob-
tained from experiments on the isolated perfused
rabbit heart either beating spontaneously or dri\'en
electrically at a faster rate (32). By recirculation of
the perfusing fluid it is possible to concentrate the
active substances released from the heart. After sepa-
AUTONOMIC NEUROEFFECTOR TRANSMISSION
229
ration by chromatography and biological estimation
on the rat's arterial pressure the following results
(expressed as micrograms per heart in 40 min.) were
obtained.
Electrically drisen
Xorepinephrine Epinephrine
Mean: 0.01 ± o.oi 0.08 ± 0.02
Spontaneously beating
Mean: 0.02 ± 0.0 1 0.08 ± 0.02
These results are of interest since they clearly show
that the proportion of epinephrine is far higher than
that occurring in extracts of hearts or in the coronary
blood plasma after stimulation of cardiac sympa-
thetic nerves (129). The reason for the large release
of epinephrine in the spontaneously beating heart is
obscure, howe\'er. It therefore appears justified to
conclude that the epinephrine released probably
originates from chromaffin cells. On the other hand
the norepinephrine left in an organ after postgangli-
onic denervation constitutes such a small part of the
total amount found in the organ with its nerves intact
that the amount normally released on sympathetic
nerve stimulation must come from the adrenergic
nerves. Analysis of the urine from adrenalectomized
patients has also shown that the amount of epineph-
rine is exceedingly small compared with that of
norepinephrine (129). Moreover, no increase in the
epinephrine output was observ-ed in the adrenalecto-
mized patients subjected to tilting head-up which
doubled the norepinephrine output. This speaks
strongly against the assumption that epinephrine is
released from adrenergic nerves in man. Moreover,
the epinephrine content of splenic nerves is as a rule
extremely low, a fact .suggesting that the small epi-
nephrine amounts found in spleen extracts (129) or
sometimes in the effluent blood from the spleen after
stimulation of its nerves (108) is not part of the
neurotransmitter. For a discussion of the adrenoxine
theory of Bacq & Heirman (5) the reader is referred
to the survey on this subject by the same authors.
It is clearly a matter of choice whether the epi-
nephrine released from chromaffin cells in the tissue
upon sympathetic nerve stimulation should be re-
garded as a chemical transmitter. If one agrees to
that terminology, the release of suprarenal medullary
hormones should likewise be called chemical trans-
mission. This, however, is apt to cause confusion of
the concepts. It must still be left an open question
whether the epinephrine-like actions observed upon
stimulation of sympathetic fibers to the skin (57) are
due to a release from chromaffin cells.
The possibility of dopamine serving as a neurotrans-
mitter requires further study. Holtz, Credner &
Koepp (66) showed that it occurred normallv in
urine. Its formation was explained as an action of
/-dopadecarboxylase on dopa. Later dopamine was
demonstrated by Goodall (55) in extracts of the
suprarenal gland and in extracts of mammalian heart.
.Since the presence of catechol amines in organs is
correlated with their adrenergic nerves or chromaffin
cells, it might be expected that the former aLso con-
tain dopamine. This has been shown to be the case;
dopamine was found in comparatively large amounts
in extracts of splenic nerves (i 17). It seems reasonable
to assume that the dopamine found in organs is pres-
ent in their adrenergic nerves. If this assumption is
correct the question arises as to how dopamine is
stored and whether it is released upon nerve stimula-
tion. Generally the amount of dopamine in an organ
is hardly large enough to cause biological efifects
comparable to those caused by the norepinephrine.
However, the bovine lung contains large amounts of
dopamine in comparison with norepinephrine (132),
and it cannot be ruled out that dopamine exerts bio-
logical actions in this case. After chromatographic
separation the amount of dopamine was found by bio-
logical and chemical methods to be 0.5 to i fig per
gm tis.sue while the norepinephrine was o.oi to 0.03
Mg per gm. Since the biological activity of the two
substances is approximately in the proportion 50 to
100: 1, it is obvious that dopamine may be biologicallv
significant in the lung.
It has been claimed that isopropylnorepinephrine
occurs in small amounts in extracts of the adrenal
gland (81). Apparently the amounts are too small to
permit detection with the usual colorimetric and bio-
logical methods, since these give very good agree-
ment with the figures for epinephrine and norepi-
nephrine. However, it has been reported that it can
be separated by chromatographic technic, a certain
fraction showing the characteristic biological action
of the isopropyl compound.
It has been reported that, after stimulation of the
sympathetic nerves to the lungs, the isopropyl com-
pound appears in the effluent blood (82). Chromato-
graphic separation of catechol compounds in extracts
of up to 1000 gm bovine lungs have failed to detect
this fraction, although catechol acetic acid, dopamine
and norepinephrine are readily identified (132).
23°
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY
THE CHOLINERGIC NERVE TRANSMITTER
Identification
Dixon & Hamill (36) pointed out as early as 1909
that there was very little inherent difference between
the action of muscarine on the heart and electrical
excitation of the vagus. They continue: "If it is per-
missible to argue from analogy there is reason in the
suggestion that excitation of a nerve induces the local
liberation of a hormone which causes specific activity
by combination with some constituent by the end
organ muscle or gland." Only a few years later
Dale (25) and Dale & Ewins (30) related the phe-
nomena observed on stimulation of parasympathetic
nerves to some earlier research by Hunt & Taveau
(71). Among a large series of choline esters prepared
by them, acetylcholine was shown to be the most bio-
logically active, on an average about 1000 times more
active than choline. During studies on ergot extracts.
Dale (26) found a substance which produced actions
similar to muscarine and identified this substance
with acetylcholine. In his further workJDale was able
to state that the actions of vagus stimulation and also
other actions of the cranial and sacral divisions of the
autonomic system were mimicked very faithfully by
ac_etylcholine. The effects were remarkably evanescent
and were always abolished by a small dose of atro-
pine. On the basis of these observations by Dale it
became extremely likely that acetylcholine actually
was the substance which causes the effect of para-
sympathetic nerve impulses on the target cells.
Further support for the idea that the substance re-
leased at the parasympathetic nerve endings was
acetylcholine was supplied by Dale & Dudley (29)
who showed in 1929 that it was present in the spleen
of the horse and the ox. They prepared the substance
and isolated it as chloroplatinate.
The identification of the parasympathetic cholin-
ergic nerve transmitter is based upon biological tests.
The amounts of acetylcholine which are liberated
and occur in the organism are generally too small to
be determined by chemical methods. Some of the bio-
logical methods are very sensitive, but on the other
hand the specificity is not always above doubt. The
methods most widely used are the negative inotropic
action of acetylcholine on the heart of the frog, the
hypotensive effect in the cat and the contracting; effect
on the intestine of the guinea pig or other animals.
Other preparations which may yield more specific
results are the leech muscle, the rectus abdominis
muscle and the isolated lung of the frog. The isolated
heart of the clam Venus mercenaria has also been used.
For the identification of acetylcholine, the finding of
Fiihner (49) that the dorsal muscle of the leech was
greatly .sensitized to acetylcholine by addition of
physostigmine was one of the more important. The
preparation was introduced as a specific and quanti-
tative biologic test for acetylcholine in 1932 by Minz
(95). After preparation the muscle is suspended in
Ringer's solution from one-half to several hours to
relax it, and physostigmine is added to the solution in
a concentration of 1-200,000 to 1-2,000,000. After
about 20 min., the muscle is highly sensitized to
acetylcholine so as to detect and measure acetylcho-
line in concentrations as low as io~'. The frog rectus
is less .sensitive but fairly specific for acetylcholine.
The isolated frog lung has also been used and may
have an even higher sensitivity than the leech muscle;
it is claimed to contract in an acetylcholine solution
of io~'* (34)- The heart of Venus mercenaria has also
been reported to have high sensitivity to acetylcholine,
up to io~^-, although it varies at different times of the
year.
In order to allow the conclusion that the actions
observed on these test preparations actually have
been due to acetylcholine, certain other conditions
must be fulfilled. The action has to be increased by
drugs inhibiting the acetylcholine esterase such as_
physostigmine, the activity should disappear after
incubation with blood and the active principle should
be inactivated when exposed to in alkali for 10 min.
at room temperature, which is typical of choline
esters. As a general rule different kinds of tests have
to be consistent, i.e. when compared with a standard
of acetylcholine the unknown extracts should elicit
the same quantitative action in relation to acetyl-
choline (fig. 12).
One of the chief difficulties in demonstrating the
neurochemical transmission from cholinergic nerves
arises from the fact that in most cases the para-
sympathetic nerves have their autonomic synapses
very close to the target organ. Therefore, stimulation
of the nerves also releases acetylcholine from the
preganglionic nerve. The acetylcholine released by
stimulation of vagus nerve in the frog's heart may
actually be due partly to the release of the substance
from the synapses.
The introduction of physostigmine in experimental
work made it possible to demonstrate the mediated
effect with greater certainty since the substance was
not immediately destroyed. Loewi's original experi-
ments were later confirmed by many others. Among
the sources of transmitter which have been tried mav
AUTONOMIC NEUROEFFECTOR TRANSMISSION 23 1
FIG. 12. Tests of a perfusate of physostigminized Locke's solution passing through the vessels of
the stomach of a dog during vagal stimulation. The samples collected before stimulation were slightly,
if at all, active. A: effects on the arterial pressure of a physostigminized cat under chloralose. B:
isolated frog heart (Straub). C: physostigminized rectus abdominis of the frog. D : physostigminized
leech muscle. In each series, B shows the effect of the perfusate collected during vagal stimulation ;
A and C correspond to two strengths of acetylcholine (C is double A'). [From Dale & Feldberg
(300
be mentioned the heart and the sahvary glands
(61, 134) in physostigminized animals. Particularly
illuminating were the experiments by Feldberg &
Krayer (44) who showed that blood from the coronary
veins of physostigminized animals produced a con-
traction of the leech muscle shortly after vagal stimu-
lation. This effect was abolished by atropine and the
active substance was destroyed by blood. Even re-
flexly released transmitter was demonstrated in this
way.
Although the cholinergic transmitter has not been
identified with the same certainty as the adrenergic
one, the sum of evidence obtained by indirect methods
leaves no serious doubt that it is either acetylcholine
or some other choline ester with very similar action
(15)-
In the autonomic neurotransmission to the salivary
glands both adrenergic and cholinergic fibers seem to
take part. By studying the distribution of cholin-
esterase Koelle (75) found in the cat, rabbit and
rhesus monkey that the concentration of the true
cholinesterase was higher in cholinergic neurons
than in adrenergic and sensory neurons. Cholin-
esterase was also found to form a fine network around
the outside of the acini while it was not found in the
acinar cells (118). The network is united with the
nerve trunk and is considered to be cholinergic in the
submaxillary gland and adrenergic in the sublingual
gland.
Occurrence, Biosynthesis and Storage
It may be assumed that, if the postganglionic nerve
endings release acetylcholine during nerve stimula-
tion, this has been synthesized and stored in the axon.
For this reason acetylcholine would be expected to
occur as a natural constituent of cholinergic nerves.
In this connection only the postganglionic fibers are
being considered. Analysis of the acetylcholine con-
tent of such fibers has shown large amounts in the
short ciliary nerves, 3 to 8 /ng per gm, which is only
a little less than the amounts found in motor nerve
fibers or in preganglionic fibers (92, 125). The figures
are much higher than the acetylcholine content in
postganglionic sympathetic fibers, such as the splenic
nerve where the acetvlcholine-like action onlv corre-
232
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
sponds to 0.2 to 0.5 Mg per gni- The difFercnce in
content suggests a specific function of the excess
acetylcholine in the postganglionic parasympathetic
fibers. The high content in these may be regarded as
strong support of the idea that these fibers act by
releasing acetylcholine. [For further details concern-
ing the occurrence and biosynthesis of acetylcholine
in cholinergic nerves see Burgen & Macintosh (15),
Gaddum (50) and Rosenblueth (113).]
The method of estimating the amount of acetylcho-
line directly in the tissue cannot be used, however, to
estimate the amount of the cholinergic postganglionic
transmitter, since this will also occur in preganglionic
autonomic fibers and in motor nerves and possibly
also in small amounts in all kinds of nerves.
The biosynthesis of the cholinergic transmitter
has been l.ir^c K elucidated by the studies of
Nachmansohn & Machado (102). These authors
were ai^le to show that an extract from rat brain con-
tained an enzyme system which could synthesize
acetylcholine in the presence of ATP as the source of
energy. This enzyme was called choline aceL)dase. It
was shown later that the acetylcholine synthesis occurs
in two steps. In a first reaction acetate is transformed
into active acetate, and in a second the active acetate
combines with choline to form acetylcholine (78).
The research work of Stern & Ochoa ( 1 20) and others
indicates that choline acetylase catalyzes the last step
in the acetylcholine formation and that the aciise
acetate is an acetyl coenzyme (coenzyme A). The
acetate used for the synthesis has to be activated by
inc. Ills of ATP, coenzyme and a transacetylase. The
active acetate thus formed is used for the final synthe-
sis of the acetylcholine. Choline acetylase has been
extracted from brain and from electric organs but is
also present in all nerve tissues. It has even been
demonstrated in tissues from various invertebrates,
such as annelids and flatworms. The presence of cho-
line acetylase in mitochondrial fractions in homoge-
nates of brain (60) suggests that this may be the case
al.so in the postganglionic neurons.
As to the storage of the cholinergic transmitter it
appears likely that it is confined to structural elements
as demonstrated for adrenergic nerves. Some indirect
support for the opinion that acetylcholine is also in-
closed in separate particles may be found in the early
experiment by Loewi & Hellauer (86). Loewi (85)
points to the finding that when nerve tissue is ex-
tracted with Ringer's solution, the bulk of acetylcho-
line is found in the insoluble residue but that the use
of hypotonic .solution causes the greater part of the
acetylcholine to be released. This suggests that the
acetylcholine is located in particles surrounded ijy a
membrane similar to mitochondria. When Ringer's
solution is used for extracting the acetylcholine in a
cholinergic nerve, such as the vagus, most of the
acetylcholine goes into solution, however. It is also
noteworthy that when acidified solutions are used,
the total amount of acetylcholine is extracted as is
also the case when extraction is made with acidified
alcohol. Some of the acetylcholine may be i^ound to
some lipid complex soluble in ether, which acetylcho-
line in itself is not (86).
An analogous i^ehavior is shown by epinephrine
and norepinephrine and histamine. It therefore seems
possible that these amines form ether-soluble but
water-insoluble compounds in the particles. It is of
interest in this connection that Hillarp & Nilson (64)
found a high content of phosphatides in the supra-
renal medullary granules.
Release in Organs
Very little is known concerning the mechanism of
release of the cholinergic transmitter in the autonomic
neuromuscular junctions. By studying the release of
acetylcholine from the spontaneously beating or elec-
trically driven rabbit's heart, it has been possible to
show that the release is significantly higher at a
faster heart rate. Thus a spontaneously beating heart
with a mean rate of 56 per min. released 0.26 ±
0.08 ^g per heart in 40 min. while electrically driven
hearts with a mean rate of 210 per min. released
0.97 ± 0.36 Kg per heart in 40 min. (32).
The relea.se of acetylcholine from an organ does
not necessarily mean that this substance originates
from nervous tissue since it is known that even nerve-
free tissue is able to synthesize and release acetylcho-
line (17). '^"
Most of the knowledge on the action of acet\ Icho-
line and its release refers to the motor endplate which
has been studied in detail from a chemical point of
view as well as by electrophysiological techniques.
There is hardly any douijt, however, that the mecha-
nism of relea.se of the cholinergic transmitter from the
postganglionic cholinergic nerves is similar in kind to
that already outlined for the adrenergic transmitter.
We may thus assume that the active transmitter is
released at a terminal portion of the ner\e and acts
directly in a chemical manner on the smooth muscle
fibers. There is no reason to believe that the sijiooth
muscle cells are directly innervated by cholinergic
postganglionic fibers any more than they are by
adrenergic fibers.
AUTONOMIC NEUROEFFECTOR TRANSMISSION
•^33
RELEASE FROM ISOLATED NERVES. Although no experi-
ments seem to have been made with stimulation of
postgansrlionic cholinergic nerves, several authors
have reported that stimulation of cholinergic pre-
ganglionic nerves causes a release of acetylcholine
(2, 10, 23, 79). It may be assumed that similar events
take place during stimulation of postganglionic
cholinergic nerves.
The inhibitory action of atropine on the effect of
cholinergic nerve stimulation has been shown to
depend on blocking of the target cell to the released
transmitter. It was demonstrated by Feldberg &
Krayer (44) that atropine does riotjnterfere with the
release as such.
The failure of atropine to block the effect of stimu-
lating the vagus nerve on the intestine may be due to
an action of a transmitter different from acetylcholine,
released from the enteric nerve system. The nature of
this postulated transmitter is not known, but it should
be recalled that substance P (51} occurs in the in-
testine and is insensitive to atropine.
Rosenblueth (113) has advanced the idea that the
cholinergic nerve transmission proceeds in two stages
of which the first is a release of acetylcholine followed
ijy a .second in which the nerve transmitter subse-
ciucntly forms ' paras)mpathin' which then acts
directly on the target cell.
Stimulation experiments on postganglionic cho-
linergic nerves (short ciliary nerves) have shown that
the optimum frequency is about 25 per sec. (89). As
in the case of adrenergic nerves, prolonged stimula-
tion caused Qnlj' slight signs of exhaustibility. Thus
stimulation for i to 2 hours caused a sustained con-
traction of the iris; thereafter the effect gradually
declined.
Removal of Trorumitter
As early as 191 4 Dale (25) had assumed that
acetylcholine was destroyed rapidly in the organism
by some hydrolyzing enzyme. Such an enzyme was
actually discovered by Loewi & Navratil (87) in ex-
tracts of frog's heart. They also found that this .en^
zyme could i)c inhibited by physostiginine. This was
in agreement with the results of earlier experiinents
of Dixon & Brodie (35) and others who found that
this drug increased some of the effects of parasympa-
thetic nerve stimulation. Moreover, Loewi & Navratil
were able to show that it increased the effect of the
substance liberated from the frog's heart upon stimu-
lation. The ' Vagusstoff ' thus behaved like a choline
ester since it was a) inhibited by atropine which is a
specific inhibitor, at least in small doses, and A) pro-
tected by physostigmine which is known to inhibit
choline esterase. It is generally assumed that the
cholinergic transmitter is being inactivated locally to
a great extent. Information about the distribution of
cholinesterase in the peripheral tissue is accumulating
rapidly as a result of the development of suitable
methods. This includes important findings about the
distribution of cholinesterase at the motor endplates
and in the central nervous system (43, 77). It may be
assumed that part of the transmitter released in
peripheral organs, such as the smooth inuscle organs
and glands, is diffusing out in the blood stream where
it is rapidly inactivated by the cholinesterase present.
It is also possible that cholinesterase is present in the
target cells in amounts large enough to destroy any
ainount of the transmitter diffusing into the cell.
MECHANISM OF ACTION OF NEUROTRANSMITTERS
The neurotransmitters exert direct action on target
cells independently of whether or not the cells are
autonomically innervated. This is shown by the pro-
nounced action of the transmitter substances on nerve-
free organs, like the placenta, or on denervated struc-
tures.
The mode of action of the neurotransmitters on the
target cells has been much discussed. Clark (24)
related the minimal effective doses of acetylcholine
and epinephrine on the frog's heart and the frog's
stomach to the total surface of the cells affected and
arrived at the conclusion that while the effective dose
of 0.02 /tig per gm covered a surface of al)out i cm- the
total area of the cells was 6000 to 20000 cm-. For this
reason it was obvious that the aQjive suijstance only
needed to attack a minute part of the cell in order to
elicit itijction.
It is generally a.ssumed that the active substance,
be it a neurotransmitter or a pharmacologically
active drug of a different kind, has to unite in some
way with the target cell before e.xerting its action.
Often the sites of binding between the cell and the
active molecule are referred to as receptors. According
to Clark these postulated receptors, in or on the cell,
occupy only a very small portion of the cell volume
or surface. Morphological evidence for specific re-
ceptor patches on the cell surface is still lacking,
however.
A discussion of the number of inolecules of a trans-
mitter required to activate a single cell depends obvi-
ously on the type of administration and on the sensi-
234
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
tivitv of the cell. If 0.02 fig acetylcholine is necessary
to inhibit one gram of frog's heart, as in Clark's ex-
ample, the minimal effective amount per gm of tissue
is about 10" molecules per cell. In isolated organs
entirely different results may be obtained. Thus
0.05 mjug epinephrine per ml suspension fluid is some-
times enough to elicit an inhibitory effect on the
fowl's isolated rectal cecum. In this case obviously a
much smaller numijcr of molecules are capable of
producing the action, since most of them are in the
suspension fluid without contact with the organ. If it
is assumed that i o per cent of the molecules are acting
on I gm of organ containing 10'" cells, then the num-
ber of molecules per cell will be only 10, provided
that the active substance is distributed on all cells.
This is probably not the case. All calculations of this
kind therefore appear very dubious.
It is conceivable that the neurotransmitter takes
part in a chemical reaction sequence which is influ-
enced thereby in a quantitative or even qualitative
manner. Whether this action is initiated at specific
receptor patches at the surface or at specific metabolic
structure elements in the interior of the cell is not
known. It may be recalled that there is good evidence
for the permeation of neurotransmitters through cell
membranes, since this is the basis for most of our
information regarding their release.
Elaborate schemes of receptor mechanisms have
been presented by several authors and terms sug-
gested for the postulated receptors. Since these efforts
primarilv represent an attempt to put the known facts
in a formal system but hardly contribute to our actual
knowledge, these systems will not be dealt with here.
Recent contributions to the discussion have been
given by Zupancic (137) and Stephenson (iig).
How the neurotransmitter elicits a relaxation or a
contraction of the target cell is still ob.scure. It can be
assumed that the active substance initiates or rein-
forces soine process which eventually causes physico-
chemical changes in the contractile material con-
ducive to such effects.
Attempts have been made to correlate the inhibi-
tory actions of epinephrine with the formation of
lactic acid (99), which is believed to be the metabolic
product directly responsible for the inhiljitory action.
The hypothesis obviously requires that the widely
varying activity ratios of epinephrine and norepi-
nephrine for an organ like the fowl's rectal cecum
(from 4 to 200) are associated with corresponding
variations in the formation of lactic acid in the react-
ing target cells, a demonstration which has not been
made
On account of the large differences in action be-
tween the levo- and dextroisomers of epinephrine,
for instance, it has been inferred that the active sub-
stance combines with an optically active constituent
of the cell (122). Recent careful studies on the bio-
logical activity of optical isomers of sympathomimetic
amines have shown that the difference in action be-
tween the isomers is even greater than has been
hitherto recognized (90).
These results suggest that the neurotransmitter is
involved in enzymatic reactions, a conclusion which
also appears most likely for other reasons.
Another approach to the study of the mode of
action of neurotransmitters on the target cell is based
on the quantitative relationships between do.se and
action. Such quantitation of the effects has ijeen used
for the elaboration of formulae of \arious kinds. It is
outside the scope of this article to discuss these studies.
It may be said generally, however, that by applying
this principle to single cells more information may be
gained. In most cases the relationship between dose
and action is approximately expressed by a rectangu-
lar hyperbola. Its precise biological significance is
not as yet clear.
Summarizing, it may be concluded that not much
more knowledge aijout the mode of action of the
neurotransmitters on target cells has been gained
since Langley's time when he ascribed the differenti-
ating effect of the transmitter, relaxation or contrac-
tion, to a receptor substance in the cell.
A relevant question is whether two neurotrans-
mitters released in the same organ act on the same or
different cells and to what extent they interfere with
one another's actions. Morison & Acheson (20) found
similar hyperijolic concentration-action curves for
epinephrine and acetylcholine on the nictitating mem-
brane of the cat. When the two substances were in-
jected together, their actions added up along the same
curve. These results would seem to allow the impor-
tant conclusion that the two neurotransmitters act
independently by exerting separate actions. Whether
or not these are on the same or different cells cannot
be decided from these experiments.
NEUROTRANSMITTERS IN BLOOD AND URINE
It has been discussed above that some of the neuro-
transmitter released at the autonomic postganglionic
nerve endings passes bevond the target cells and
reaches the l)lood stream. If this occurs to any con-
siderable extent it should be possible to demonstrate
AUTONOMIC NEUROEFFECTOR TRANSMISSION
235
the neurotransmitters in the blood. Such attempts
have been made and there is some evidence for the
opinion that the neurotransmitter of the adrenergic
system normally occurs in small quantities in the
blood. However, since the methods of demonstrating
norepinephrine in blood require fairly large quanti-
ties of blood and are rather laijorious (70, 91), they
have not been widely used. Some indirect informa-
tion has been obtained by studying the excretion in
urine (67, 130). Even if norepinephrine occurs in
peripheral blood it remains to be shown that it is
derived from postganglionic nerves and not from the
suprarenal medulla or from chromafhn cells. Proof of
its overflow and passage into the blood has been given,
however, by studies on the excretion in urine in
adrenalectomized patients. In these patients the only
important sources of norepinephrine can be the post-
ganglionic nerves. For the same rea.sons as outlined
above the excretion of acetylcholine, after treatment
of the organism with physostigmine, will not allow
any conclusions as to the release at the postganglionic
nerve endings since acetylcholine is also released at
manv other sites.
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CHAPTER VIII
Neuromuscular transmission in invertebrates
E. J. FURS H PAN | Biophysics Department, University College, London, England
CHAPTER CONTENTS
Arthropods
Crustaceans
Size of the efferent nerve supply
Polyneuronal innervation
Multiterminal innervation
Electromechanical coupling
The transmission process
The muscle spike
Peripheral inhibition
Insects
Molluscs
Coelenterates
Actinozoans
Scyphozoans
The Mechanism of Transmission in Coelenterates
TO PRODUCE THE MOST EFFICIENT CONTRACTION, a
muscle fiber must be activated along its entire length
almost simultaneously; otherwise, the contracting
portions of the fiber must lengthen inactive regions
before communicating their tension to the tendon.
That is, the active parts of the fiber will operate in a
less effective range of the length-tension curve. At
least two mechanisms are known which can achieve
this relatively synchronous excitation of the fiber:
a) a comparatively rapidly conducting muscle action
potential, and b) numerous motor ner\e endings along
the length of the muscle fiber. The term 'multi-
terminal innervation' (6i) will be used to describe this
second situation. The first device (conducted muscle
action potential) is most commonly found in the
skeletal muscle of vertebrates. The most notable
exception is the case of the slow muscle fibers of the
frog [see Kuffler & Vaughan Williams (45)] in
which there is multiterminal innervation and a lack
of a conducted muscle spike. It should be pointed
out that vertebrate twitch muscle fibers which exhibit
such a spike may have more than one motor end-
plate (38). These cases should probably not be in-
cluded within the definition of multiterminal inner-
vation, however, for in the absence of the propagated
muscle spike, the density of the nerve endings is not
sufficient to allow an appreciable contraction.
The second mechanism (many nerve endings) seems
to predominate in the somatic musculature of the
invertebrates. An examination of the evidence for
this type of innervation will serve as one of the
themes of this chapter. It will also be interesting to
consider what differences in function between the
two systems seem to follow from the dissimilarity in
the means of spreading the muscular excitation. A re-
lated question will also be examined — the other ana-
tomical specializations associated with multiterminal
innervation. One such feature commonly found is
polyneuronal innervation or the receipt by one muscle
fiber of more than one motor axon, and of particular
interest, of motor axons which elicit from the same
fiber responses of different strength and time course.
In most vertebrate muscles, by contrast, the conducted
action potential is all-or-nothing and produces a
stereotyped twitch. Thus different types of contrac-
tion evoked by different nerve fibers do not occur.
Peripheral inhibition, as found in certain inverte-
brate muscles, offers another example of polyneuronal
innervation and this topic will be considered as well.
Another question that will be discussed concerns the
number of motor neurons which innervate whole
mu.scles. Here, too, a contrast with vertebrate muscle
will be seen in many cases and again the dissimilarity
between the ways in which the excitation is spread
throughout the muscle fiber can be thought to under-
lie these differences. That is, in spite of the all-or-
nothing contractions, fine gradations of tension are
possible in most vertebrate twitch muscles because of
239
240
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
the large number of motor units. Where conducted
muscle potentials are absent, however, gradation of
contraction can be effected by variations in the
degree of excitation within each muscle fiber. In some
of these cases, therefore, one need not be surprised if
only a few motor axons are found to innervate whole
muscles. The general scheme of presentation will be
to consider together studies on the same group of
animals.
ARTHROPODS
Crustaceans
Some of the elementary features of crustacean
nerve-mu.scle systems were known in the nineteenth
century, chiefly from the work of Biedermann. In a
histological study (7) he observed that the nerve
fibers ramifying on the surface of the opener-muscle
(abductor of the dactylopodite) of the crayfish claw
were apparently all branches of only two axons.
These two fibers ran \ery close to one another and
both divided at each branch point in approximately
the same place. The a.xons remained in juxtaposition
even into the very fine ramifications on the surface
of single muscle fibers. Thus both axons seemed to in-
nervate the same muscle fibers. Mangold (51) corrob-
orated these findings and introduced the term 'diplo-
tomic' branching for this type of concomitant division
of two nerve fibers. He also corroborated the double
innervation of single muscle fibers. Mangold saw that
as a fine nerve twig, consisting of two efferent axons
within a single sheath, approached the surface of the
mu.scle fiber the nerve sheath joined and became
continuous with the sarcolemma. Then the axons
would continue to ramify beneath the sarcolemma and
thus come into close contact with the striated ele-
ments. He also saw that more than two axons might
divide together in a manner analogous with diplo-
tomic splitting, and he figures three axons doing so
on the surface of the closer-muscle (adductor of the
dactylopodite) of the crayfish claw. Hoffman (29)
examined the gross anatomy of the innervation of the
four most distal muscles of the claw. One of his un-
usual observations was that a single nerve fiber in-
nervated two muscles: an axon going to the extensor
of the carpopodite (stretcher-muscle) continued into
the next segment to end in the opener-inuscle. He
showed diplotomic branching for the opener-,
stretcher-, and bender- (flexor of the carpopodite)
muscles, and found three or more axons going to the
closer-muscle. Hoffman also studied the distribution
of these various axons within the two nerves which
run through the length of the claw .
Knowledge of the differences in function of the
two or several axons innervating a single muscle also
goes back to Biedermann. Richet (60) had observed
that with weak stimulation of the crayfish limb nerve
the claw opened, and with stronger shocks it closed.
Biedermann (8) extended these obser\ations. In ex-
periments in which he eliminated one or the other of
the two muscles (opener- or closer-muscle) operating
the dactyl, he was still able to obtain opening or clos-
ing depending on the strength of nerse stimulation;
and if electrodes placed at the muscle evoked con-
traction, excitation of the nerve could inhibit this
contraction. Biedermann correctly concluded that
there must have been separate nerve fibers to mediate
the inhibitory process; and since the opener-muscle,
for example, receixed only two axons, one of these
was designated the excitor and the other the in-
hibitor.
Lucas provided information on the function of the
additional axon in a muscle with a triple innersation.
He observed (49) both slow and twitch contractions
in the closer-muscle of the loijster claw; and further
found that the strength-duration curve for indirect
stimulation (by way of the nerve) showed a sharp
discontinuity at the point at which one type of con-
traction was replaced by the other. From these, and
additional experiments on the crayfish claw (50),
Lucas concluded that the two contraction tvpes were
e\oked by stimulation of different 'substances' (types
of nerve element.s).
This conclusion has been amph confirmed and it is
now known that more than one t\ pe of motor axon
can inner\ate a single crustacean muscle and that
the electrical and mechanical responses e\'oked by each
can differ with respect to amplitude, time course,
facilitation and fatigue. The most convincing demon-
stration of this was pro\ided by van Harre\eld &
VViersma (74) who succeeded in isolating and stimulat-
ing single functioning motor axons from crayfish limb
nerves. In particular they studied ner\e fibers exoking
contraction of the closer-muscle. In normal prepara-
tions (but not in regenerated claws) two such axons
were always found and stimulation of the remainder
of the nerve did not result in contraction of this
muscle. A single impulse in the thicker of the two
axons evoked a rapid twitch, while a train of impulses
was needed in the thinner fiber to produce even a
small contraction. About 30 sec. were required to at-
tain maximal tension during stimulation of the thin
axon at 40 shocks per sec. This time for the thick
NEUROMUSCULAR TRANSMISSION IN INVERTEBRATES
241
nerve fiber was only about i sec. and the terms
'slow' and 'fast' were therefore used to describe the
two contractions. These same terms were then ex-
tended to the concomitant muscle potentials and to
the axons themselves (e.g. 'slow a.xon'). The muscle
potentials showed even greater dififerences, the slow
potentials being very small but augmenting with
repetitive stimulation. Despite this increase (facilita-
tion) they remained smaller than a single fast muscle-
potential. In the crayfish closer muscle, which is per-
haps not typical in this respect, the fast potential
normally exhibited no facilitation.
SIZE OF THE EFFERENT NERVE SUPPLY. One of the
questions considered subsequently by these same au-
thors and their collaborators concerned the numbers
of excitatory and inhibitory axons supplying the
seven most distal limb mu.scles in different species of
decapod crustaceans. The latter included crayfish,
lobsters, rock lobsters, crabs, hermit crabs and various
other anomurans. The techniques involved isolation
and stimulation, separately, of as many of the axons
having an excitatory or inhibitory effect upon a par-
ticular inuscle as could be found, and an additional
estimate of the minimum number of efferent axons
using methylene-blue staining. All liinb muscles that
were examined received at least two axons and at most
five, and of the.se at least one was always an inhibitor.
The different groups of decapods showed diversity in
the numbers of inhibitory nerve fibers supplying a
particular muscle, but the numbers of excitatory
axons were constant from species to species. The fol-
lowing table summarizes the findings for motor deca-
pod axons only (74, 75, 76).
Note that Hoffman's histological observation that
one axon supplied two muscles was confirmed by
physiological methods. In addition to the nerve fibers
listed in table i, each muscle receives at least one
inhibitory axon and in some species there are muscles
receiving two (78). Further, it is typical for an in-
hibitory axon to supply more than one muscle (up to
seven), and variations in the particular muscles sup-
plied by a common inhibitor were also found. Wiersma
& Ripley (85) have summarized the inhibitory in-
nervation of these muscles.
POLYNEURON.'>iL INNERVATION. From the early histo-
logical work and the fact that inhibition can counter-
act excitation, it was apparent that motor and in-
hibitory axons both innervate the same muscle fibers.
Can a muscle fiber also receive more than one excita-
tory axon? There is now convincing evidence, both
TABLE I. Anmlwr oj Excitatory Axons Supplying the Seven
Most Distal Limh Muscles of Decapod Crustaceans
Muscle
(common name)
Segment Moved
Type of
Movement
No. of
Motor
Axons
Opener
Dactylopodite
Abduction
(or exten-
sion)
I*
Closer
Dactylopodite
Adduction
(or flexion)
2
Stretcher
Propodite
Extension
I*
Bender
Propodite
Flexion
2
Main flexor
Carpopodite
Flexion
4
Accesory
Carpopodite
Flexion
1
flexor
Extensor
Carpopodite
Extension
2
* This same
axon innervates both
muscles.
histological (73) and physiological, that this is indeed
possible. Although the observation is attended by
some difficulties, the fibers of the closer-muscle have
been seen to contract following stimulation of either
the fast or slow axon (72). Wiersma & van Harreveld
(84) showed that stimulation of one of the motor
axons to the closer-muscle augmented a contraction
evoked shortly afterwards by stimulation of the other
(heterofacilitation). No mutual influence with respect
to fatigue or facilitation of the muscle action poten-
tials, however, could be demonstrated. These results
suggested the presence of a pathway susceptible to
mutual influence .somewhere between muscle action
potential and contraction; and the conclusion was
drawn that at least .some of the contractile substance
was activated by both axons. More recently Fatt &
Katz (22) used intracellular electrodes to demon-
strate that muscle potentials were evoked in the
same fibers by both fast and slow axons, and it was
shown that the potentials could simimate. There is no
good quantitative determination of what percentage
of the fibers in a muscle receiving two excitatory
axons are innervated by both axons.
van Harreveld & Wiersma (76) have al.so consid-
ered the question of polyneuronal innervation in a
muscle with four motor axons (and one inhibitor).
Here, too, they found that a test contraction set up by
stimulation of one of the four axons was slightly aug-
mented by previous stimulation of any of the other
three motor axons (heterofacilitation). Their experi-
ments did not provide direct evidence, however, con-
cerning the numbers of axons supplying each muscle
fiber. More recently, Furshpan (26) has studied the
same muscle (main flexor of the carpopodite in the
242
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY
California rock lobster), recording from the muscle
fibers with intracellular electrodes while stimulating
the four motor axons separately. In this way 20 or 30
fibers in each preparation were sampled and if, upon
stimulation of a particular axon, a monophasic
muscle potential in the direction of depolarization
was recorded at the microelectrode, it was concluded
that the impaled fiber was innervated by the axon in
question. While reasons were presented for believing
that the sampling was not entirely random, the fol-
lowing results were recognized. Some of the muscle
fibers did receive all four of the motor axons (and pre-
sumably the inhibitor as well); these were, however, a
small minority comprising about 5 to 10 per cent of
those tested. The remaining fibers were approximately
equally distributed among tho.se innervated by one,
two, or three of the motor axons, and different com-
binations of two and three axons were found. Further,
the size of the muscle potential which stimulation of
a nerve fiber evoked could vary considerably from
muscle fiber to muscle fiber. Thus this muscle shows
remarkable heterogeneity with respect to the number,
combination and effectiveness of the motor axons
which supply its individual fibers. This is a factor
which it is important to consider in attempting to
correlate muscle potentials and contraction and em-
phasizes the desirability of performing such experi-
ments on single muscle fibers.
It is not known to what extent this analysis applies
to the simpler case of a muscle receiving only two
motor axons, but from experiments cited above, and
from some incomplete work with intracellular elec-
trodes (unpublished observations), it seems as if most
fibers receive both axons. Here, too, there is hetero-
geneity with respect to the size of the muscle poten-
tials evoked and some fibers have been found in which
the 'slow' axon elicited much larger responses than
did the 'fast' ; more work is needed, however.
MULTiTERMiN.^L INNERVATION. In a histological Study
d'Ancona (14) encountered considerable variation
among different crustaceans, but in extreme cases he
observed numerous nerve terminals on single muscle
fibers, at times to the extent of an ending for each
sarcomere (cf. 41). van Harreveld (73) has also de-
scribed numerous axon terminations on single fibers.
In one particularly good preparation (from the
opener-muscle of crayfish) he observed 28 nerve end-
ings on one muscle fiber, the latter being 3.5 mm
long; it is not known whether this density of endings
is tvpical. Because of the numerous terminations on
each muscle fiber and the fact that even small nerve
branches may run for considerable distances on the
fiber surfaces, a dense tree of intramuscular nerve
elements was observed, van Harreveld (72) described
this as a 'feltwork'. Holmes (30), however, contested
these observations and showed that connective tissue
around the mu.scle fibers could be made to stain to
give the appearance of a 'feltwork'. While this is un-
doubtedly so, it is very unlikely that the structures
which van Harreveld observed were not terminals
since he was able to follow them back to larger axon
branches, and since in the opener-muscle with its
double innervation, he saw two fibers terminating to-
gether at each ending.
Another controversial point which became asso-
ciated with the question of multiterminal innervation
concerned the presence of conducted muscle action
potentials of the type found in the vertebrates. Because
the potentials which were usually recorded with ex-
ternal electrodes summated and were monophasic,
Wiersma & van Harreveld generally propounded the
view that such propagated potentials would not be
found in crustacean muscle and that the spread of
excitation would be effected solely by the numerous
nerve endings (79, 82). In 1946, Katz & Kuffler (42)
were able, however, to record in crayfish and crabs
diphasic muscle action potentials which were propa-
gated at a velocity of about 20 cm per sec. The con-
ducted spikes were seen to arise from summating po-
tentials resembling the vertebrate endplate potential.
The summating potentials were recorded from only
circum.scribed regions of the muscle fibers, thus pro-
viding physiological evidence against multiterminal
innervation. Twitches were seen to accompany spikes,
while with the local-type potentials slower smoother
contractions were observed. Thus they viewed crus-
tacean mu.scle as essentially similar to that of the
vertebrates, but with some quantitative differences:
namelv, that in the crustaceans the safety factor for
transmission would be lower so that facilitation and
recruitment would be more important and the eflicacy
of local endplate potentials in evoking contraction
would be enhanced.
These two views were subsequently reconciled by
Fatt & Katz who clearly showed, using intracellular
recording electrodes, the presence of conducted
muscle spikes (20) but, on the other hand, also gave
a physiological demonstration of multiterminal in-
nervation (22). In the latter paper they reported that,
wherever a microelectrode entered a muscle fiber, an
NEUROMUSCULAR TRANSMISSION IN INVERTEBRATES
243
"endplate potential' (e.p.p.') could be recorded fol-
lowing nerve stimulation. Further, they were able to
enter a given muscle fiber at a number of points along
several millimeters of its length and to measure the
amount of variation in the amplitudes of the e.p.p.'s.
This variation was comparatively small and the dura-
tion of the rising phase of the e.p.p.'s was practically
constant along the length of the fiber. These findings
should be compared with the situation in, for ex-
ample, frog twitch muscle fibers (19). The earlier
results (42) which indicated the presence of only lo-
calized e.p.p.'s were probably due to partial denerva-
tion of the fibers in dissecting the 'strip' preparations
that were used.
Despite this clarification, major problems of crus-
tacean neuromuscular transmission remain. Little is
known about the relative effectiveness of the different
e.p.p.'s which can be set up in one muscle fiber, or of
the spike, in evoking contraction. The mechanism
whereby the nerve impulse leads to an e.p.p. is very
incompletely understood. The spike, too, has some
curious attributes which warrant further study. Each
of these problems will be considered in turn.
ELECTROMECHANICAL COUPLING. This topic is perhaps
outside of the subject of neuromuscular transmission
in the usual sense of that phrase. In inany of the
experiments which have been performed, however,
both the electrical and mechanical responses to nerve
stimulation were recorded and some of the observa-
tions concerning the latter will be considered briefly.
It has been found by Wiersma & van Harreveld (83)
that in certain muscles (e.g. the claw-closer of
Blepharipoda occidentalism low-frequency stimulation (10
to 1 5 shocks per sec.) applied to the fast axon could
elicit large muscle potentials unaccompanied by any
visible contraction; while a stimulus of the same fre-
quency delivered to the slow axon evoked much
smaller muscle potentials which, nevertheless, set
up a contraction. Reasons were presented for believ-
ing that this seemingly paradoxical behavior could
occur within a single muscle fiber. Inasmuch, how-
ever, as the electrical recording was made with ex-
ternal electrodes and the contraction ol3ser\ed was
that of the whole muscle, it is not possiljle to conclude
definitely that this was the case. The unequivocal
' There is some disadvantage in using the term e.p.p.' since
it suggests the presence of a particular anatomical structure,
which is probably absent in the crustaceans, and suggests a
functional similarity with the \ertebrate neuromuscular junc-
tion, the actual extent of which is unknown.
demonstration of this phenomenon will probably
have to be made on single muscle fibers. The possible
presence of such a phenomenon is interesting because
it would seem to suggest that the transmitter has
some other effect aside from that which is manifested
in the change in muscle membrane potential. A re-
lated observation has been made by Kuffler (43) on
the muscles of the fast and slow stretch receptors of
the crayfish abdomen. This preparation has the ad-
vantage that the muscle bundle is very small and can
be isolated, with its nerve supply, and observed under
a microscope with transmitted light, and that at the
same time a fiber can be impaled with a micro-
electrode for intracellular recording of inembrane
potential. Ii the fast muscle bundle he observed that
if a nerve impulse evoked only an e.p.p. (which was
usually 10 to 25 mv in amplitude) no contraction was
visible. Only if the e.p.p. gave rise to a spike was there
visible contraction, and then a rapid twitch was the
result. In the slow muscle bundle, however, only
e.p.p.'s (5 to 15 mv) were observed and these were
accompanied by contraction. The failure of the fast
e.p.p.'s to bring about any visible muscle shortening
is puzzling in view of the fact that they are distributed
along the length of this muscle by numerous nerve
endings and attain a size which may be a considerable
fraction of the spike amplitude. Wiersma (80) has
also recently published observations made on lobster
closer-muscles which indicate that fast e.p.p.'s may
fail to bring about contraction, while spikes succeed
in doing so.
THE TRANSMISSION PROCESS. It scems vcry likely that
the transfer of excitation across the crustacean neuro-
muscular junction is effected by a chemical trans-
mitter, rather than by the passive flow of the nerve
action current. While the total number of nerve
endings may be large (73), in any given section of
muscle fiber the ratio of areas of axon membrane to
muscle fiber meml^rane is probably always quite small.
Thus there is little current from the nerve terminals
available for charging the capacitance of the muscle
fiber, which is particularly large (approximately 40 /if
per cm-) in Crustacea (20). There are some analogies
with the vertebrate neuromuscular mechanism which
are only suggestive; during repetitive stimulation of
the nerve, random, often large, variations in the size
of the e.p.p. can be seen (22). These fluctuations
might be caused by intermittent failure of conduction
in some of the terminal nerve branches; but it is also
possible that they represent a quantal release mecha-
244
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
nism for the transmitter. Spontaneous miniature
e.p.p.'s have not, however, been oljserved (see Chap-
ter VII). Facihtation, which at the vertebrate endplate
is also a property of the transmitter-release mecha-
nism (i6), is usually present and often striking at crus-
tacean nerve-muscle junctions (42, 83).
The chemical identity of the crustacean neuro-
muscular transmitter(s) is unknown. That it is not
acetylcholine or a closely related compound seems
\ ery likely from a number of experiments (3, 1 7, 40).
Wright (88) was able to obtain blocking in the cray-
fish closer-muscle with curare and dihydroerythroidin,
but perfusion with solutions containing approximately
io~^ and 5 X lo""* gm per ml, respectively, was neces-
sary. Other physiologically active compounds that
have been found to have little or no effect on crus-
tacean neuromuscular junctions are trimethylamine,
trimethylaminoxide, tyraminc (40), choline (see,
however, 20 and below), mecholsl, carbachol, musca-
rine, strychnine, pilocarpine, dioitalin, epinephrine,
nicotine, caffeine and rotenone (17). Although a num-
ber of drugs, such as local anesthetics and veratrine,
were found to affect the response of the nerve-muscle
system, their action was probably on the nerves for
the most part.
THE MUSCLE SPIKE. As mentioned above, an e.p.p. of
sufficient size will, at least in some fibers, evoke an
additional membrane response, the spike potential.
This spike differs in several aspects from, for example,
the conducted action potential of frog twitch muscle
fibers. Although it may overshoot the resting poten-
tial, the inside of the muscle fiber becoming rela-
tively positive during its peak, often this overshoot is
absent. The spike is commonly not all-or-nothing, its
height varying continuously with the size of the de-
polarization (20) or e.p.p. (26) evoking it. It may be
nonpropagated and, when conduction occurs, the
velocity is low (25 to 40 cm per sec). A striking
property of the spike was discovered (20) during an
attempt to replace the sodium ions of the external
fluid by an 'inert' cation. Substitution of choline for
the sodium unexpectedh- resulted in an increase in
the size and duration of the spike. Fibers which had
previously shown only local spikes exhibited large
conducted ones in the choline medium. Even more
striking increases were oijtained with other quar-
ternary ammonium compounds (e.g. tetraethyl- and
tetrabutylammonium). With the latter (TBA) in-
creases in spike duration of several hundred times were
common and action potentials lasting up to 18 sec.
were observed. The TBA effect was irreversible and.
surprisingly, even after a preparation which had
been exposed to this drug was washed with a solution
containing no .sodium and no TBA (but with sucrose
and excess magnesium) large long-lasting spikes were
still observed. Experiments to determine if it were
the ammonium compounds themselves which were
carrying the current during the spike were incon-
clusive. It was noticed that during prolonged ex-
posures to TBA the resting potential decreased, ac-
companied, however, by an increase in membrane
resistance. The possibility was therefore considered
that TBA reduces potassium conductance. Although
such an assumption could help to explain the enor-
mous prolongation of the spike, the identity of the ion
carrying the inward current during the action po-
tential is still unknown. -
PERiPHER.-^L INHIBITION. It is now known that the
inhibition described above is mediated by separate
peripheral axons which run and branch with the
motor axons. A direct demonstration of this was pro-
\ided b>- van Harreveld & Wiersma (75) who were
able to isolate, as single functioning axons, the mcJtor
and inhibitory nerve fibers to several muscles in the
crayfish cheliped. It was found that contraction
evoked by the first type of axon could be reduced or
abolished by concomitant stimulation of the second.
The inhibitor was more effective in suppressing slow
than fast contractions, and in some muscles the
latter were unaffected by inhibitory stimulation (53).
A study of the comparative effectiveness of the in-
hibitors to various muscles in a number of species
was made (81). The results were expressed in terms
of the ratio of the frequency of inhibitory-axon to
that of excitatory-axon stimulation when the former
was just sufficient to suppress all contraction. The
most effectively inhibited motor system found was
the slow contraction of the bender-muscle of Pachy-
grapsis crassipes in which this ratio was about one-
third. Fast systems most usually had values of this
ratio ai:>ove, slow systems below, unity.
A surprising result was obtained when the
electrical, as well as the mechanical, events were re-
corded during inhibition. It was found (44, 53) that
contraction could be completely suppressed, while the
muscle potentials might be reduced by a variable
amount or apparently not at all. The extent to which
the e.p.p.'s were affected depended upon the relative
- Evidence that calcium ions carry this current has recently
been obtained by P. Fatt & B. Ginsborg (J. Physiol. 142: 516,
>958)-
NEUROMUSCULAR TRANSMISSION IN INVERTEBRATES
245
times of arrival of the inhibitory and motor nerve
impulses. Maximum reduction (to aljout 20 per cent)
occurred when the former slightly preceded the
latter; and no effect on the e.p.p.'s was seen if the
inhibitory impulse arrived much after the excitatory.
Thus, it was suggested that inhibition could act in
two places: on some process a) between nerve im-
pulse and muscle potential, and 6) between muscle
potential and contraction.
More recently, changes in the muscle membrane
during inhibition have been studied by Fatt & Katz
(21) using intracellular electrodes. They confirmed
previous results that the e.p.p. can be greatly reduced
during inhibition and that the extent of the reduc-
tion depends upon the relative timing of the inhibitory
and motor nerve impulses. In order to test for other
postjunctional effects of inhibitory impulses, two
microelectrodes were inserted into the same muscle
fiber, one in a recording circuit for measuring mem-
brane potential and the other connected to a current
generator for the purpose of altering the level of the
membrane potential. Then it was found that inhibi-
tory nerve impulses did not result in any detectable
postjunctional potential changes if the membrane
potential was at a certain level, usually at or near the
resting potential; but if the membrane potential were
displaced, by passing current through the other intra-
cellular electrode, inhibitory nerve impulses were fol-
lowed by transient muscle potentials, similar to, but
slower than, e.p.p.'s. They were referred to as I-po-
tentials and could appear either as transient hyper-
polarizations or depolarizations depending upon
whether the resting membrane potential had been
decreased or increased, respectively, by the current
passed through the second microelectrode. That is,
the I-potentials were seen as reductions of any dis-
placement of the membrane potential from some
equilibrium level, usually close to the resting po-
tential. These are the effects which would be expected
if the event underlying the I-potentials was a tran-
sient increase in some fraction of membrane conduct-
ance and, in particular, the conductance of some
species of ions having an equilibrium potential equal
to the membrane potential at which no I-potential
appears. K+ or Cl~ might, therefore, be the ions in-
volved. Although the conductance change underlying
the I-potential does tend to reduce any deviation of
the membrane potential (including an e.p.p.) from
an equilibrium potential near to the resting potential
and would thus serve as an inhibitory mechanism, the
effect was found to be insufficient to account quanti-
tatively for all of the inhibition actually observed.
Another mechanism was therefore suggested in which
the inhibitory and excitatory transmitter substances
would specifically antagonize one another at the
receptor sites on the muscle membrane. The original
observation that contraction can be abolished without
any reduction in the size of the e.p.p.'s still awaits con-
firmation using intracellular recording of potential
while observing contraction of the same fiber (cf. 18).
Insects
There have been fewer physiological studies of in-
sect than of crustacean motor systems, but there seem
to be many resemblances between the neuromuscular
mechanisms of these two groups, as well as some inter-
esting differences. Among the latter, one should note
the apparent lack of peripheral inhibitory axons in the
insects. Also, the histological appearance of the motor
ner\e endings can be, at least superficially, different
from that in the crustaceans; for in many insect
species, rather than continuously tapering to sub-
microscopic diiTiensions, the nerve terminals present
an enlarged bulbous or conical appearance. Accord-
ing to Marcu (52), however, these structures, re-
ferred to as Doyere's cones (cf. 25), may only repre-
sent a sudden and profuse branching of the nerve
ending in which the individual twiglets are not always
seen. Marcu also studied a species of orthopteran in
which the manner of branching of the nerve was more
similar to the situation in crustaceans. Hoyle (35),
working with the locust, has observed what may have
been the terminal apparatus still attached to the final
nerve branch after pulling the latter free from the
muscle fiber. The axons, probably beyond the place
at which they had entered the sarcolemma, were con-
tinuous with a branched claw-shaped structure which
spread over an area 20 to 30 y. in diameter.
The insects also show a difference from the crus-
taceans in the gross organization of the muscle. For
example, Hoyle (35) observed that the muscle fibers
of the locust were organized into muscle bundles
each of which received separate nerve and tracheal
branches. He referred to these bundles as 'muscle
units'. In some muscles this type of arrangement did
not seem to signify any fundamental difference from
the crustacean situation. For example, the extensor
tibia is innervated by three efferent axons and the
branches from two or all three of the axons supply
each muscle unit. But in the flexor tibia, each of the
five or six muscle units was supplied by separate
neurons. The fibers of a unit may receive, however,
more than one axon. Working with the same muscle
246
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
in another orthopteran QRomalea), Ripley (61) found
at least six steps of contraction strength as he increased
the intensity of the stimulus applied to the motor
nerve. Of these, four represented twitches and two,
slow contractions. It seems likely that at least the four
twitch contractions involved different sets of muscle
fibers.
The points of similarity between the.se two groups
of arthropods include the small number of motor
nerve fibers (35, 51, 58, 61, 62), multiterminal (15,
25, 36) and polyneuronal (36, 51, 58) innervation of
single muscle fibers, and different contraction t)pes
(fast and slow) evoked from the same muscle by stimu-
lation of different axons (36, 58, 61). The abo\e
references are to both histological and physiological
studies, and the evidence derived from the latter will
be considered in greater detail. For example, Pringle
(58) was able to distinguish twitch and slow contrac-
tions in the flexor tibia of the cockroach and observed
visually that the same muscle fibers could be involved
in either type of contraction. There have been differ-
ent explanations offered for these two contraction
types. Pringle, on the one hand, has suggested that
the distinction between twitch and slow contraction
would lie in the number of muscle fibers activated ijy
the two types of motor axons. Thus, he attributed the
facilitation observable in the slow system to a pro-
gressive recruitment of additional muscle fibers,
each fiber giving an all-or-nothing response. Wilson
(86), on the other hand, has recently studied the same
muscle, using intracellular electrodes, and suggested
that the two contraction types occur in two different
groups of muscle fibers, much as in the slow and
twitch systems of the frog. His evidence, however, was
indirect inasmuch as the contraction of the impaled
fibers was not recorded, and the motor axons were
not separately stimulated. There is yet a third pos-
sible explanation for the two contraction types in in-
sect muscle. According to this explanation, the fast
axon would give rise to a fast muscle action potential
(spike) which would evoke a twitch; while the slow
axon, innervating many of the same muscle fibers,
would give rise to a slower, smaller, facilitating
muscle potential, the mechanical response to which
would ije a slow smooth contraction. This is the
mechanism which seems largely to explain the fast
and slow systems in the crustaceans (see above). It is
known that this mechanism must be present to some
extent, and is probably the most important of the
three, although the other two may operate as well.
Both in crustaceans and in insects, however, there is
the possibility of slow potentials exokint; spikes and
thereby twitches so that recruitment may occur in the
slow as well as in the fast systems, and further there
may be muscle fibers innervated solely by either fast
or slow a.xons.
Evidence for fast and slow potentials occurring in
the same fibers of insect muscle has recently been pro-
\ided by Hoyle (36). He worked mostly with the
extensor of the tibia of the migratory locust and
showed that it received three motor axons. One of
them, which ran in a separate nerve, seemed to in-
nervate all the fibers of the muscle and evoked in
them an action potential consisting of a spike arising
from an e.p.p. The accompanying contraction was a
rapid twitch. This nerve fiber was designated by the
letter F, as an abbreviation for fast. A second axon was
referred to as Si (signifying a slow response), even
though its stimulation resulted in fast action poten-
tials and contractions in some of the muscle fibers.
That is. Si seemed to have two different types of end-
ings and could produce markedly different effects in
two classes of muscle fibers. In about two-thirds of the
Si-innervated fibers, stimulation of that axon evoked
small, remarkably slow potentials, longer than i sec.
in duration. They were capable of summating to
plateaus of depolarization of 50 mv (during repetitive
nerve stimulation) without giving ri.se to spikes. The
other one-third of the fibers supplied by Si showed
very much more rapid e.p.p.'s which could give rise
to spikes. The size and speed of these latter e.p.p.'s
were similar to, but somewhat less than those follow-
ing stimulation of F. The slow responses were desig-
nated as Shi and were accompanied by slow contrac-
tions, while the faster potentials, which gave rise to
twitches, were referred to as Sib. Of the total number
of fibers in the muscle, only about 30 per cent were
supplied with .Si endings of either type (20 per cent
Sia; 10 per cent Sib). The third axon. So, which was
smaller than either F or Si, produced an electrical
response in only a few of the fibers but a contraction
in apparently none of them. The muscle potential
consisted of a brief depolarization followed by a more
prolonged hyperpolarization (up to several hundred
msec). Although ijoth phases were small (less than i
mv) the hyperpolarizations could summate during
repetitive activity and thus raise the resting potential
of the muscle fiber. The S2 response was most clearly
seen in fibers with low resting potentials and could
not raise the membrane potential above the level of
about 70 mv. Hoyle has not been able to demonstrate
that S> causes any inhibition of either contraction or
action potentials evoked by the other two axons. In
fact, stimulation of S^ sometimes seemed to augment
NEUROMUSCULAR TRANSMISSION IN INVERTEBRATES
247
the contraction elicited by F, and Hoyle ascrilies to Si
the function of raising the membrane potential briefly
before a maximum efTort is required by the animal.
The unusual features of the Sl, and S^ responses
would certainly warrant further study of the mecha-
nism of their generation. Concerning the various
combinations of the responses which were found in a
single muscle fiber, F could apparently occur with
any of the others since that axon inner\ated all of the
fibers. Respon.ses S2 and Sia were seen together in one
fiber, but none was found which showed both Sn, and
So effects.
Aside from this demonstration of poKneuronal in-
nervation, the use of intracellular electrodes has also
provided evidence for multiterminal innervation.
Working with the flexor of the tibia, del Castillo et al.
(15) found that cooling the muscle reduced the size of
the e.p.p. so that it did not give rise to a spike. They
then found that the height of the e.p.p. did not \ary
b>- more than 10 to 15 per cent when the recording
was made from different points along the muscle
fiber. The spikes recorded in the.se experiments over-
shot zero potential (i.e. the inside of the fiber became
relatively positive) in good preparations, but the
magnitude of the overshoot was always less than 20
mv (cf. 27). Information was also obtained concerning
the mechanism of neuromuscular transmission. It was
found that the amplitude of the e.p.p. was propor-
tional to the size of the resting potential as experi-
mentally altered by passing current with a second
microelectrode. This is the result which had previ-
ously been obtained from work with frog muscle (19)
where it was found that the transmitter released by
the nerve impulse seemed to act by causing an in-
crease in the conductance of the endplate membrane.'
There is no evidence that the presumed transmitter
in insects is acetylcholine. Roeder & Weiant (62) were
unable to affect neuromuscular transmission with
curarine in a dilution of lo^''.
MOLLUSCS
Much of the preceding information on the neuro-
muscular mechanism of arthropods was obtainable
because of several fortunate characteristics of those
'Such evidence is not conclusive by itself, howe\er. It has
recently been shown by E. Furshpan & D. D Potter (J. Phy-
siol., in press) that even at an 'electrical' synapse the amplitude
of the postsynaptic response can vary with the level of mem-
brane potential.
systems. The few large motor axons, which run in
comparatively long nerves, can often be dissected free
and stimulated separately, and the muscle fibers are
most often large and can be impaled with micro-
electrodes. The absence of these features from most
other invertebrates makes experiments with them
considerably more diflicult to perform. Thus, one
finds interesting phenomena which are difficult to
interpret because it is not known whether they reflect
properties of the nerves, muscles, neuromuscular
junctions or neural synap.ses.
A good example of these difficulties is provided by
a number of studies on the anterior byssus retractor
muscle (ABRM) of Mytilus edulis. One of the more in-
teresting properties of this and mans- other lamelli-
branch muscles is the ability to maintain considerable
tension for very long periods of time. Some muscles
may remain contracted for more than ten days (46)
while durations of a few hours are common (4, 37).
Several explanations of this ability have been put for-
ward. On the one hand there is the idea of a molecular
'catch-mechanism' (71, 77). According to this hy-
pothesis, one set of nerves would bring about a change
in the contractile mechanism so that, following con-
traction, the mu.scle could reinain shortened without
expending additional energy. Another set of nerves
would bring about an active reversal of this state and
relax the muscle. On the other hand, an explanation
has been sought in terms of already known properties
of nerve-muscle systeins. According to the tetanus
hypothesis, the muscle would remain contracted
only as long as there were periodic depolarizations of
the muscle fiber membranes, relaxation ensuing at
the cessation of .such activity (12, 37, 46, 48). It has
also been pointed out by proponents of this hypothesis
that the passive tension decay in these muscles, follow-
ing activation, is very slow and that this factor would
contribute considerably to the economy of contrac-
tion (2). Molluscan muscle would then differ from
other muscles only in the slowness of its relaxation.
Intermediate between the 'catch-mechanism' and
tetanus hypothesis is one in which the 'viscosity' (and
thus the rate of passive tension decay) of the muscle
would be variable, depending upon the way in which
the muscle had been activated. When prolonged con-
traction was required the muscle could be put into
the "high viscosity' state and then infrequent activa-
tion would suffice to maintain a tetanus (39, 87). This
idea was suggested by Winton (87) following a study
of the Mytilus ABRM. He found that the muscle
responded differently to alternating and to direct
current stimulation. Following the cessation of an
248
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY
a.c. Stimulus the muscle relaxed comparatively
rapidly, but after d.c. stimulation would do so very
much more slowly. In this slowly relaxing state the
muscle would support considerable tensions for
long periods and seemed to be less susceptible to
fatigue. In one example, when a d.c. stimulus was
applied to the muscle for 14 sec. of every minute, a
continuous gradually increasing contraction was ob-
served during the experimental period (15 min.).
When, however, a.c. was used, also for 14 sec. per
min., each burst of stimulation gave rise to a discrete
contraction, the strength of which decreased during
successive minutes. It was also found that the main-
tained tension following a d.c. shock could be abol-
ished by a.c. stimulation. That is, following this a.c-
induced contraction, the rate of relaxation was rapid
even though the muscle had been in the slowly-
relaxing state immediately previously. These effects
have since been confirmed by a number of authors
(see below). In a recent paper, however, Hoyle &
Lowy (37) report that while they commonly found
similar results, they often did not. In some case both
types of stimuli gave rise to contractions of equal dura-
tion and sometimes a.c. evoked more prolonged
shortening than did d.c. Nevertheless, since the two
types of stimulation are not likely to occur naturally,
interest lies mainly in their use as experimental tools,
and the dififerent responses, although not invariable,
might still reflect two types of mechanisms within the
muscle.
Fletcher (24) confirmed VVinton's observations as
part of a general study of the ABRM in which he also
recorded the muscle action potentials. In most experi-
ments he found no muscle potentials (after the initial
one) during a d.c. -induced tonus. This observation
laid the ground for the 'catch-mechanism' hypothesis,
van Nieuwenhoven (77) also confirmed Winton's
main findings but was able, as well, to duplicate some
of these effects with indirect stimulation. Relatively
strong faradic stimulation of the pedal ganglion, from
which the muscle appeared to receive its innervation,
gave rise to the familiar prolonged contraction. Subse-
quent ganglionic stimulation of lower intensity abol-
ished the remaining tension. Thus he suggested that
one set of nerves from the ganglion would set the
"catch-mechanism" while another would reverse this
action. Twarog (71) has recently made some pharma-
cological observations which she interprets in terms of
this same scheme. She found, for example, that rela-
tively small concentrations of acetylcholine (ACh)
sufficed to give rise to prolonged contractions of
the ABRM which were accompanied by steady
depolarization. Washing out the ACh restored the
resting potential of the muscle without, however,
reducing its tension. This maintained contraction was
then found to be abolished by the addition of very
small concentrations of 5-hydroxytryptamine (5-HT).
Then subsequent additions of ACh gave rise only to
transient shortening (which could, nevertheless, be
of larger amplitude than that following the initial
application of ACh). Twarog has also demonstrated
the presence of ACh, a choline esterase and 5-HT in
this muscle. She suggests that ACh is the chemical
mediator evoking contraction (and setting the
'catch-mechanism') and that 5-HT would be the
transmitter responsible for active relaxation. That
these substances are released during activity has not
been shown. Hoyle & Lowy (37) have confirmed this
inhibiting or relaxing effect of 5-HT on this muscle
but conclude that it is not the natural transmitter.
In their experiments the contractions were evoked iiy
electrical stimulation rather than by the application
of ACh. Before considering further their observations
on 5-HT, it will be convenient to describe another
effect which they obtained. If the muscle was in a
tonic state, subthreshold stimulation would often bring
about relaxation. It is likely that in their experiments
excitation was effected by way of the nerve and this
observation is therefore very similar to that made by
van Nieuwenhoven (see above) with 'weak' shocks
applied to the ganglion. These authors, however,
refer to the phenomenon as inhibition. Returning
now to the effects of 5-HT, they found that once this
drug had been added to the bath the prolonged,
tonic contractions could no longer be evoked by
d.c. stimulation, although the phasic contractions
were still readily obtainable. The effect still per-
sisted, however, after several hours, despite periodic
washing with sea water. Inasmuch as the inhibition
(or relaxation) following subthreshold nerve stimu-
lation was rapidly reversible, they suggested that 5-HT
could not be the normal mediator of this effect.
Lowy (46, 47, 48) and Hoyle & Lowy (37) have
made a number of other observations, all of which
they interpret in terms of the tetanus hypothesis. For
example, they have almost always been able, by using
large amplifications, to record small irregular elec-
trical activity, presumably muscle potentials, through-
out the duration of a prolonged contraction in dis-
agreement with Fletcher's findings. The potentials
were localized and different patterns of activity were
recorded simultaneously from different regions of the
muscle. These potentials were considerably smaller
than those found by other authors in this muscle (23,
NEUROMUSCULAR TRANSMISSION IN INVERTEBRATES
249
59, 70). The difference would seem to lie in the fact
that on the one hand (Fletcher and others) the
synchronized response of a large part of the muscle
fibers was recorded immediately following the stimu-
lus; while on the other hand (Hoyle & Lowy) record-
ing, at much higher gain, was made from two asyn-
chronously active regions of the muscle some time
after cessation of the stimulus. (The potentials re-
corded by Fletcher were more prolonged than those
seen by other workers; but this might have been due to
his recording apparatus.) Nevertheless, the significant
point would seem to be that there is electrical activity
in the muscle during the prolonged tonic contractions;
and this was found to be true whether shortening
was brought about by d.c. stimulation or addition
of ACh. (The origin of these potentials, which persist
for so long after a stimulus, will be considered below.)
.Since these muscles do .seem, therefore, to require
periodic activation during tonic contractions, the
main support for the catch-mechanism' hypothesis is
removed. It will be recalled that Twarog (71) had
found that the muscle could repolarize during the
tonic contractions induced by ACh. Her recording
apparatus would not, however, have detected the
potentials observed by Lowy and others. It was al.so
found by these latter authors that when the muscle
relaxed, following subthreshold stimulation or the
application of 5-HT, the electrical activity ceased.
Further, it has been found by Abbott & Lowy (i)
that the heat production of the ABRM measured
during either an ACh-induced tonus or during a
tetanus (stimulating at 2 per sec.) is the same, al-
though the value obtained in both cases is very
small compared, for example, to that of frog muscle.
Thus, the most attractive interpretation of the ability
of molluscan muscles to maintain tensions for pro-
longed times would seem to be the one given by
Abbott & Lowy (2). It is based on the observation
that once the contractile elements of these muscles
shorten, they return to the rest length only very slowly,
and thus infrequent activation suffices for the main-
tenance of tension. During a d.c. -induced tonus this
repeated activation is being supplied by some means,
as evidenced by the recorded electrical activity.
What then is the source of these potentials, inasmuch
as they are present in muscles which are isolated from
the central nervous system for long times after the
cessation of a stimulus and often in the apparent
ab.sence of stimulation? To study this Bowden & Lowy
(9) have examined histologically the intramuscular
nerve supply of a number of lamellibranch muscles,
including the ABRM. Histochemical methods for the
detection of the presence of cholinesterase revealed a
dense ple.xus of nerve fibers and structures which they
interpreted to be nerve cell bodies. These findings
provide a possible explanation of the 'spontaneous'
potentials and disclose an additional factor which
must be considered in interpreting experiments on
these muscles, namely the possible presence of
peripheral interneuronal synapses. For example,
Schmandt & Sleator (70) found that the large syn-
chronous muscle potentials which they observed in
the ABRM were conducted decrementally (at a rate
of about 20 cm per sec). One possible interpretation
of their results is that the muscle fibers show no
conducted response and that the apparent conduction
is carried out by synapsing intramuscular nerve
elements. The decrement could then arise from the
failure of transmission at some of these synapses.
The finding of electrical activity during the d.c-
induced tonus also complicates the interpretation
of most of VVinton's results and diminishes the neces-
sity for an hypothesis of the type that he propo.sed.
Nevertheless it is still possible that the mu.scle can
relax at different rates depending upon the means
by which it was activated (possibly by different motor
nerves).
COELENTERATES
As experimental objects for the study of neuro
muscular transmission, the coelenterates present some
of the same difficulties as those found in the molluscs.
The motor axons are supplied by a net of synapsing
neurons. The muscle fibers are very fine, usually being
several to less than one micron in diameter when
extended. They are arranged in sheets or 'fields,'
although there are places where the arrangement is
more compact and discrete muscles can be distin-
guished.
Aciinozoans
Pantin was the first to have stimulated these
animals electrically rather than mechanically and
thus had some idea of the number of impulses set up
in the nerve net. Much of the work has been devoted
to the properties of this net, but there are a number of
phenomena which are pertinent here. Most of the
earlier work was done with the sea anemone Calliactis
parasitica, and one of the responses studied was the
contraction of the sphincter muscle (at the top of
the column) following stimuli applied to the side of
2^0
HANDBOOK OF PHYSIOLOGY ^ NEUROPHYSIOLOGY I
the column (54). A single electric shock evoked no
visible contraction. Two shocks, however, above a
certain low threshold did elicit a response. The size
of the latter was dependent upon the interval ijetween
the two stimuli, provided that this was greater than
about 50 msec, (refractory period) but not larger than
about 3 sees, (facilitation interval).
These phenomena were interpreted ijy Pantin as
follows. The first of the two stimuli applied to the side
of the column would result in a nerve impulse ar-
riving at each 'endplate' (57) of the sphincter but
would be unable to activate the muscle. It would,
however, facilitate the neuromuscular transmission
process so that a second impulse arriving soon after
might affect activation. The increase of contraction
size with shorter intervals would then be clue to the
success of the nerve impulse at a greater number of
junctions. This idea implies an all-or-nothing con-
traction of the muscle fibers. The advantage of such
an hypothesis is that the introduction of a threshold
for successful neuromuscular transmission helps to
explain the sharp difTerences between the effects of
one and two stimuli.
The evidence that the facilitation is a property of
the neuromuscular junction is that it did not seem to
reside in either the nerve net or the muscle \i\ itself.
For example, a single impulse traversed the whole
column nerve net, for a contraction could be evoked
by applying a second shock with another pair of
electrodes at some other point on the column, and a
single shock could similarly be shown to make the
entire column nerve net refractory. That the muscle
did not recjuire facilitation was shown by applying
the stimuli directly to the sphincter. Then a single
shock of intensity several times the two-shock threshold
gave rise to a contraction localized in the region of the
electrodes (56). It seems likely that stimulation of the
muscle was direct, since the shortening which fol-
lowed two weaker shocks, and which was mediated
by the nerve net, involved the whole muscle.
The above hypothesis suggests an analogy with the
partially curarized nerve-muscle preparation of the
frog in which the endplate potentials (e.p.p.'s)
following the first nerve impulse would all be sub-
threshold. Tacilitation' would then represent the
summation of successive e.p.p.'s to a supraliminal
level. This model must be modified, however, to
account for some later observations made by Ross &
Pantin (68). They found that if the interval between
two stimuli was adjusted so that the second shock
just did not give rise to a contraction, then a third
shock separated from the second by this same interval
also just failed to cause a contraction. On the basis of
the abo\e scheme, however, one would have expected
that the second shock would have brought the local
excitatory state to a le\el immediately below thresh-
old. The excitation following the third stimulus
would then have added to that level and threshold
would have been exceeded in some fibers. To explain
these oi)ser\ations the authors invoked an extra
process of sensitization of the neuromuscular junction
which would be necessary, in addition to the excita-
tion process. Alternatively, it seems possible to
account for these observations in terms of a known
phenomenon. This is the facilitation, as distinct from
the summation of e.p.p.'s, which occurs at frog
neuromuscular junctions and which is a property of
the ner\c endings (16). That is, an e.p.p. is not only
added to what remains from a preceding one but can
lie, by itself, larger. Thus in the experiment described
above, with the long intervals used, summation of
local responses might have no longer been present,
and only the facilitation process would have been
operating. It must be remembered, however, thai
any electrical concomitants of transmission which
may Idc present have not yet been recorded, and such
attempted explanations are only speculative.
The responses of the sphincter of CaUiaclis described
above are very similar to those recorded from the
longitudinal retractors of the mesenteries of Mi-tridmrn
senile (28). In both species these muscles bring about
withdrawal responses and provide the quickest con-
tractions of which the animal is capable. They may
be likened to the escape reactions of some of the
higher invertebrates (earthworm, squid and crayfish)
which are mediated by giant nerve fibers. It is
apparent, however, that all the other activities of the
anemone, such as locomotion and feeding, are built
up from \ery slow contractions (5, 28, 55). The latter
include the slowest contraction known, and are so
leisurely that usually no movement can be seen on
casual oijservation, despite the fact that very consider-
able changes in the shape of the animal are almost
continuously taking place (as shown by time-lapse
photography, etc.).
Although the fundamental difference between the
fast and slow contractions is not known, an operational
definition of the two is supplied by the following
criteria assembled from Batham & Pantin (6) and
Ross (67). It seems particularh useful to distinguish
two separate contraction types since both occur in the
same muscles, a) The slow contractions are evoked by
lower frequencies of stimulation. Whereas one shock
everv three seconds is usually about the lowest fre-
NEUROMUSCULAR TRANSMISSION IN INVERTEBRATES
-a'
quenc\' for evoking fast contractions, slow ones persist
with shock intervals up to about 15 sec. Apparently,
frequencies above one or two stimuli per second do not
succeed, and there is an optimal frequency which may
be considerably lower than this. For example, in one
experiment (67) a small slow contraction superim-
posed on the quick one followed five shocks separated
by intervals of 1.2 sec. The maximal slow contraction,
however, in response to this number of stimuli was
not obtained until the intervals between them were
increased to 13.6 sec. b) Whereas the fast contraction
ensues within less than o. i sec. after the first effective
stimulus (usually the second shock), the slow contrac-
tion may not begin until 30 to 1 50 sec. after the
beginning of a train of stimuli, c) Five or six stimuli,
rather than two, are often the fewest that will evoke
a visible .slow response. The size of the contraction
increases with additional shocks up to a maximum.
(f) The rising phase of a summated fast contraction
has the appearance of an incomplete tetanus. The
rise time for each step usually occupies less than i sec.
The slow contraction, however, is entirely smooth,
and the rising phase may extend over 0.5 to i min.
The initial rate of rise is extremely slow.
The fast and slow contractions ha\e been shown to
occur in some of the same muscles, such as the
sphincters of Calliactis and Alelridium, the longitudinal
retractors of Metridium, etc. Can, then, a single muscle
fiber contract in both ways? There is some indirect
evidence that this can happen. When the slow
contraction of muscles, capable of also giving strong
fast responses, is observed under the microscope, all
regions of the muscle can be seen to be shortening and
no local buckling occurs (6). If the recosery of tension
following a quick release is compared during the two
types of response in the same muscle, it is found that
the time course is rapid in both cases and similar to the
original rate of tension development for the fast
contraction (67). Thus, there is some reason to be-
lieve that the same contractile material gives rise to
both contractions, and that the rate and extent of
activation of the contractile substance is the distin-
guishing feature. One is then faced with the problem
of how the two different types of activation are
brought about. The fact that the slow shortening
exhibits a longer refractory period (i.e. has a higher
minimum effective stimulation frequency) than the
fast contraction suggests that different excitable ele-
ments are involved. But if the same muscle fibers give
both types of shortening, these elements must be the
nerve fibers, and thus one might expect to find more
than one nerve net innervating such muscles. W'hile
there is good histological evidence in the scyphozoans
(see below) for distinct nerve nets mediating different
contractions, no such observations have been made in
the actinians, and there is, as yet, too little information
to resolve this question.
Scyphozoans
Associated with their more free-living existence, the
behavior patterns of the medusae may differ con-
siderably from those of the anemones. Their most
conspicuous activity is a comparatively rapid, more
or less rhythmical, contraction of the circular muscu-
lature of the bell. These contractions provide the
basic swimming movement. Bullock (13) has studied
them using strip preparations (63) from three species
of scyphozoans and has compared them with the
contractions of anemone muscles. They differ from the
quick contractions of the mesenteric retractors of
Metridium (see above) in several respects, a) A single
threshold shock usually evokes some contraction of
the bell, b) The duration of the facilitation interval in
the bell is longer than in the retractor. In the
former muscle, a contraction following a previous
one by about seven .seconds is usually still augmented.
c) The duration of a single contraction is a fraction
of that in the medusa preparation. (/) The absolute
refractory period of the bell musculature is several
times longer (about 700 msec, in the medusae as
compared with probably less than 200 msec, in the
anemones).
Because of the long refractory period and the
relatively short duration of the mechanical event,
there can be very little summation of tension during a
series of contractions of the bell; and facilitation
appears as an increase in the strength of separate
successive 'twitches.' In the anemone mesenteric
retractor, on the other hand, the facilitation interval
is shorter than the duration of the contraction and
facilitation and summation are always seen together.
These differences can be related to the differences in
function of the two types of muscles. The anemone
retractors are involved in withdrawal respon.ses and,
with summation of successive contractions, can bring
about a striking decrease in the height of the animal.
These muscles can shorten to less than 20 per cent of
their extended length. The musculature of the
medusan bell, by contrast, pro\ides a pumping action
and resembles the vertebrate heart in having a
relatively long refractory period.
The site of the facilitation is probably, by analogy
with the actinians, the neuromuscular jimction. It
252
HANDBOOK OF PHYSIOLOGY -^ NEUROPHYSIOLOGY I
is not a property of the nerve net, for, following a
single shock, the excitation spreads over the entire
bell (13); Horridge (31) has shown that this excitation
consists of a single all-or-nothing nerve impulse. It
has not been proved, however, that the facilitation is
not a property of the excitation-contraction coupling
within the muscle fibers.
There have been several histological studies of the
nerve net which presumably distributes the excitation
of the swimming nio\ement. Schafer (69) described
large bipolar neurons in the subumbrellar epithelium.
The nerve fibers were more or less straight, were
usually unbranched and were comparatively thick
(15 /i). This description has recently been confirmed
by Horridge (32) who found that the nerve fibers were
in the range 6 to 12 n. Both authors described tapering
of the nerve fibers towards their ends, but there was
no consistently observed structure which would
constitute a motor nerve ending [see, however, the
illustrations in Schafer (69)]. Bozler (11) also
described the large bipolar neurons, and observed
smaller ones, as well as numerous multipolar neurons
with branching axons. One might then wonder if the
different types of neurons form physiologically
distinct nerve nets which would underlie different
behavioral responses (i.e. types of contraction). This
question will be con.sidered next.
Aside from the swimming movements described
above, localized and more prolonged contractions of
regions of the bell can also be observed (10, 13, 33).
Since it has been shown that the excitation underlying
the swimming movement is spread over the entire
bell by a single impulse traversing a nerve net (31),
the presence of local contractions does suggest the
existence of another nerve net in which the spread of
excitation is limited. Further, Romanes (63) showed
that a wave of excitation, distinct from the wave of
contraction, could cross the bell. In one demonstra-
tion of this, he removed seven of the eight marginal
ganglia (in which the e.xcitation for the rhythmical
swimming movements arise) and applied to some
point on the bell a stimulus too weak to evoke a
contraction wave (swimming movement) directly.
Then after some delay, a contraction wave would
spread out from the intact ganglion. Additional
examples suggesting the presence of more than one
nerve net can be found in Horridge (33).
One more case, however, will be considered for
here there is good correlation between histological
and physiological observations. Horridge (34) has
studied the ephyra larva of Auirllia which shows two
types of contractions. There are a) the generalized.
rapid, rhythmic swimming movements and A) pro-
longed contractions involving a variable fraction of the
animal and normally associated with feeding. Follow-
ing strong mechanical stimulation, the prolonged
contraction may involve the whole animal. In histo-
logical preparations, two types of nerve net can be
distinguished. The first is composed of bipolar neurons
which are confined almost entirely to the epithelium
overlying the radial and circular musculature. The
fibers of these neurons are highly oriented, running
in the same direction as the muscle fibers. The second
net consists mainly of multipolar cells, with some
bipolars, and is present throughout the entire epithe-
lium. The fibers of this net are not particularly
oriented except in the region around the mouth. Some
of the neurons of this diffuse net send fibers to the
surface of the epithelium and would appear to be
sensory cells. This observation alone suggests that the
diffuse net is associated with the local, prolonged
contractions since these latter are evoked by tactile
stimuli. Experiments designed to test this hypothesis
yielded affirmative results and also provided evidence
that the swimming movements are mediated by the
other net of bipolar oriented neurons. For example,
eight radial cuts were made through the disc so that
the band of circular muscle, with its overlying net of
bipolar cells, was sectioned into eight separate arcs.
The cuts were not continued all the way to the center
of the disc and the animal thus remained in one piece.
It was then found that each arm, with its arc of circu-
lar muscle, still produced the rhythmical swimming
movements but that the beat of each was independent
of all the others. A strong tactile stimulus, however,
could still produce a co-ordinated contraction of the
whole animal.
The Mechanism oj Transmission ni Coelenterates
Practically nothing is known of the actual mech-
anism by which nerve-net excitation crosses the
junction to the muscle fibers. Tissue extracts have
been made and tested on neuromuscular transmission
but without success (65, 66). Numerous drugs have
been tested on the responses ot the sphincter muscle
of intact Calliaclis. Acetylcholine, curare, nicotine,
epinephrine, histamine and a number of other drugs
are without apparent effect (64). Several drugs,
however, were effective in high concentrations and
after prolonged exposure. Tyramine, tryptamine and
933F, after immersion of the animal in solutions of
io~* gm per ml for one- and one-half to several hours,
brought about se\eral-fold increases in the muscular
NEUROMUSCULAR TRANSMISSION IN INVERTEBRATES
253
response, and contractions following single shocks
were then commonly seen. These drugs did not evoke
any contraction in the absence of other stimuli.
Depressant drugs were also found. Ergotoxin (io^°)
and trimethylamine oxide (io~'), respectively, re-
duced and abolished sphincter contraction. The fact
that such high concentrations and long application
times were required need not argue against the signifi-
cance of the.se results, since there are probably con-
siderable barriers to diffusion in the intact animal,
and all effects observed were full)- reversible. Magne-
sium chloride also depresses neuromuscular transmis-
sion both in anemones (68) and in medusae (13) and
in these cases high concentrations and prolonged
exposures are also necessary.
While the above experiments may provide interest-
ing clues, they do not allow any specific conclusions
about the mechanism of transmission, and there would
not seem to be any a prion basis on which to decide
whether this process occurs in these animals by local
circuit action ('electrically') or by means of some
mediator ('chemically').
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39. Johnson, W. H. Biol. Bull. 107: 326, 1955.
40. Katz, B. J. Physiol. 87: 199, 1936.
41. Katz, B. Biol. Rev. 24: i, 1949.
42. Katz, B. and S. W. Kuffler. Proc. Roy. Soc, London, ser. B
133: 374. 1946-
43. Kuffler, S. W. J. Neurophysiol. 17: 558, 1954.
44. Kuffler, S. W. and B. Katz. J. Neurophysiol . 9: 337, 1946.
45. Kuffler, S. W. and E. M. Vaughan Williams. J.
Physiol. 121: 289, 1953.
46. Lowv, J. J'. Physiol. 120: 129, 1953.
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54. Pantin, C. F. A. J. Exper. Biol. 12: 119, 1935.
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CHAPTER IX
Brain potentials and rhythms — introduction
A. FES SARD College de France, Paris, France
CHAPTER CONTENTS
General Nature of Brain Potentials
Special Characteristics of Brain Potentials
Functional Significance of Brain Potentials
Microphysiological Studies
Macrophysiological Studies
but an introduction to this chapter may better take
into account more fundamental features of this field
of research by considering broadly the three questions
of the general nature, the special characteristics and
the functional significance of brain potentials and
rhythms, each special aspect being dealt with in de-
tail in subsequent chapters.
FOR OBVIOUS REASONS, the stuclv of brain potentials
and of their rhythms is by far the most complicated
task that has ever been proposed to electrophysi-
ologists. It is therefore not surprising that its develop-
ment has been relatively slow. In the period from 1875
to 1913, the names of Caton C'S), Fleischl
von Marxow (25), Danilewski (19), Beck & Cybulski
(7) and Prawdicz-Neminsky (44, 45) stand out among
the few pioneers who experimented on animals,
preceding the epoch-making discovery of brain waves
in man by Hans Berger in 1924 [first published in
1929 (8)]. As a matter of fact, not before the end of
the first third of this century did cerebral electro-
physiology truly enter the regular scope of neuro-
physiological research with the first works of Fischer
(24), Kornmuller (35, 36), Bartley (6), Bishop (9),
Adrian & Matthews (2), Gerard et at. (26, 27), Wang
C50), Bremer (10), Gozzano (29), Adrian (i) and
Jasper (31). During this same period, clinical elec-
troencephalography was developing vigorously and
furnishing itself results important for the compre-
hension of cerebral mechanisms. Perhaps in no other
field of neurophysiology is there such a reciprocity
of relations between the findings of investigation on
experimental animals and those of clinical observa-
tions. This circumstance has contributed to the par-
ticular character of cerebral electrophysiology today;
GENER.'VL N.4TURE OF BR.AIN POTENTI.^LS
The question of the nature of brain potentials
leads us back to the preceding chapters on neuron
physiology, for there is nothing essentially new appear-
ing in the ijrain of a bioelectrical nature, nothing
not having a physicochcmical basis common to all
neurons. The fundamental phenomena of neuronal
activity, i.e. brief all-or-nothing spikes, graded slow
waves, potential gradients of ill-defined duration,
have been well recognized as the sole components of
brain potentials. On the other hand, conduction of
impulses along fibers, transmission of excitation or
inhibition across synapses, electrotonic spread and
"ephaptic' interactions, and finally rhythmic genera-
tion of potentials are the general kinetic operations
from which all attempts to explain the integrated ac-
tivities of the brain must start.
Detection of these elementary processes within the
brain and description of their quantitative parameters
as compared to those of neurons belonging to other
structm-es (such as the spinal cord, ganglia in verte-
brates or invertebrates, peripheral sensory neurons)
are the tasks that have been and are still being carried
out by electrophysiologists since the pioneer work of
Renshaw et al. (46) who introduced the highly re-
warding microelectrode technique in brain physiology.
255
■2.=s6
HANDBOOK OF PHYSIOLOGY -^ NEUROPHYSIOLOGY 1
Among those who early worked along; this line, let us
mention Moruzzi and several collaborators of his
school (42 and many subsequent papers), Jung et al.
(34), Amassian (5), Li & Jasper (38), Albe-Fessard
& Buser (3, 4), Tasaki and colleagues (49), Rose &
Mountcastle (48) and Phillips (43). These workers
have started a probably long-lasting and fruitful era
of intensive microexploration of cerebral structures.
For the identification and analysis of single unit ac-
tivities within the brain, knowledge already acquired
from more accessible structures, particularly from
spinal motoneurons, can be of great help (see Chapters
III and X of this work).
In another direction, leading down to the molecular
le\el, are the investigations of those interested in bio-
physical and biochemical mechanisms, as well as
drug actions, that are related to, or interfere with,
electrical activities of brain tissue. The way in which
these activities depend upon metabolic factors, circu-
latory and respiratory conditions, ionic and hormonal
content of the milieu interieur, is far from being exactly
known. An alteration of the resting potentials is
assumed to be the basis of some ionic and drug actions.
SPECI.\L CH.'^RACTERISTICS OF BRAIN POTENTIALS
Brain potentials, apart from the common aspects
they share with other biopotentials, have special
characteristics which are related to the structure and
specific properties of the tissue within which they are
engendered. How these relations can explain the
different modalities of potentials encountered is the
central theme of the chapters constituting the present
subsection of this volume. A bread survey of the
factors involved may help to grasp the wonderful
complexity and dixersity of electrical manifestations
offered by a mammalian brain, either in its .so-called
spontaneous activity or under experimental condi-
tions including controlled stimulation. Thus we come
to the classical distinction between evoked potentials
(^considered by Chang in Chapter XII) and autogenic
rhythms (discussed by Walter in Chapter XI) to
which a transitional modality must be added, that of
induced rhythmical activities of temporary character
or after-discharges (also appearing in the chapter
by Chang).
Other general distinctions within the field of brain
potentials will be considered below, together with
some of the problems confronted by the modern
neurophysiologist.
FUNCTIONAL SIGNIFICANCE OF BRAIN POTENTIALS
The third aspect is the functional significance of
brain potentials and their rhythms. We are not di-
rectly concerned here with this functional aspect
which will be examined in later chapters of this
volume. However, it is ditticult and to a certain
extent artificial, once a potential has been described,
not to speak of the link it appears to have with an
actual operation of the nervous system of which it
thus becomes a sign: projection of an afferent message,
interactions between central activities or emission of
efferent impulses. This most often invokes simple
questions of functional topography or chronology
but may also go so far as to relate to highly integrated
psychological processes (as will appear in Walter's
chapter) or to the well-defined symptoms of patho-
logical behavior such as those of epileptic seizures
(described by Gastaut in Chapter XIV) once it has
been recognized that reliable correlations exist be-
tween these phenomena and some parameter or
parameters of brain potentials or rhythms that have
initially been studied for themselves. New specific
aspects of brain potentials are often discovered as a
consequence of functional explorations of this kind.
Let us return to the special characteristics of po-
tentials arising within the brain. These appear either
in the form of more or less durable states — potential
gradients and regular periodic changes — or in the
form of responses to direct or indirect stimuli. In
l)oth cases, one must clearly distinguish the micro-
physiological approach applying to single units from
the record of potentials arising within more or less
numerous neuronal populations.
.\IlCROPHYSIOLOGIC.\L STUDIES
The microphysiological approach reveals not only
the most common processes of neural electrogenesis
but al.>;o important differences between the elec-
trical behavior of single units. Among the various
types of neurons, some are more accessible than others
to microelectrode study. The pyramidal cells of the
cerebral cortex, the Purkinje cells of the cerebellum,
the neurons of the main sensory relay nuclei and those
in the midbrain reticular formation and the centrum
medianum of the thalamus ha\c l:)een the most care-
fully studied. The general shape of the neuron, the
distribution of synapses along its surface and the
BRAIN POTENTIALS AND RHYTHMS INTRODUCTION
257
differential properties of its successive segments — the
dendrites, cell body, axon hillock, myelinated axon,
naked branches and endings — are determining factors
of its electrical behavior. One of the more important
contributions of contemporary research is the un-
veiling of the distinctive electrogenic properties of
dendrites at least in certain specialized neurons ijy
studies such as those of Buser (15), Chang (i 7), Clare
& Bishop (18), Grundfest & Purpura (30), Lorente
de No (41) and Roitbak (47). Dependency of recorded
potentials upon morphological characteristics of the
neurons was initially recognized by Lorente de No
(40) when he made a distinction between neurons
generating open fields and those generating closed or
semiclosed fields.
The problems attacked by the microphysiological
technique involve the most fundamental operations
taking place in the brain, the neuron being considered
as a relay, as a focus of integration or as a source of
rhythmic activity. All three cases pose the common
question of the way in which slow waves — i.e. post-
synaptic potentials, after-potentials, autogenic local
variations of the resting potential — and spikes or
trains of spikes interact with each other.
Bombardinent by afferent impulses leads to the
build-up of slow variations, negative in the case of
excitation and po.sitive with inhibition. These slow
waves in turn produce, accelerate, slow or suppress
efferent impulses. Through these two closely allied
reciprocal processes, the neuron performs its ele-
mentary functions. From this rather monotonous
theme of action, almost infinite varieties of neural
behavior arise, determined partly by the intrinsic
properties of the neuron and partly by those of its
environment, including its connections with other
neurons.
This last consideration draws attention to the notion
that in the central nervous system, and especially in
the brain, unit activity described in isolation would
be nonsense. Simultaneous recordings from single
units in different parts of the brain with a inultitude
of microelectrodes is a technical achievement that
cannot go very far relatively to the number of neurons
involved in the simplest operations carried out by the
cerebral structures. This brings us to examine the
resources of the macrophysiological approach.
MACROPHYSIOLOGICAL STUDIES
A priori, the macrophysiological approach can give
significant results only when a large mass of neurons
working in approximate synchrony is activated.
Fortunately this can be experimentally induced by
application of brief stimuli to nerves and central
tracts leading to the brain, or by local stimulation of
the cerebral structure themselves. On the other hand,
spontaneous synchronizations often occur, which are
imperfect and of limited extent in normal conditions
but exaggerated and widespread in convulsive states.
In any case, synchrony is essentially a feature of the
slow components of neuronal activity. Spikes usually
appear in complete asynchrony and remain prac-
tically undetectable with macroelectrodes, whereas
the microelectrode technique is well fitted for spike
recording. Thus these two approaches are more or
less compleinentary.
In addition to the basic factors which determine
the course of elementary electrogenic processes at the
neuronal level, many others come into play and com-
bine in various ways to generate the different forms
of complex brain potentials, transitory evoked po-
tentials, periodic waves, or steady gradients. All the
characteristics of a multiplicity of elements — number,
density, internal organization and extrinsic relations
— take part in the final result but cannot always safely
be inferred froin it.
Chance distribution of elementary properties, such
as latencies, excitability levels, is the familiar statistical
aspect first to be considered here. Then corne the
problems related to the physical conditions of recep-
tion: recording may be superficial or deep; electrodes
are of various types, numbers and placements; dis-
tribution of potentials in a volume conductor of
limited extent has its intangible laws which can be
applied here only with very crude approximation.
A further step considers the role of architectonic
organization, a factor of primary importance here,
for physical as well as for physiological reasons.
Laminar, nuclear or reticular structures cannot
produce similar electric fields, and the field configura-
tion in each particular case depends upon the way in
which neurons of different kinds are distributed and
oriented within the structure. For instance, surface
potentials derived from the cerebral cortex can be
thought of as engendered by polarized leaflets, the
unit components of which are parallel dipoles formed
by the long pyramidal neurons. Synchrony itself is
favored by such regularity of internal organization, as
a result of a certain congruence between the spatial
order existing in the neural structures and that dis-
played by the total electric field produced by the
active elements of these structures. However, this
assumption of a field effect, although very likely in
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
closely packed and orderly arranged populations of
neurons, has not been universally accepted. Inter-
actions can of course also occur through synaptic
connections at short distance and these must be taken
into account. Most frequently, synchrony in a popu-
lation of neurons can be explained by the triggering
action of a common pacemaker to which these neurons
are linked; it thus depends on the gross connections
within the brain or ' tractology'. But the problem
remains of how the units in a pacemaker are them-
selves synchronized.
This leads us to a major aspect of brain potentials,
their frequent appearance in regularly rhythmic se-
quences. The origin of these periodic activities has
been the object of discussions and controversies. A
pluralistic attitude seems to be the wisest, the rhythmic
state being only a formal appearance that may be
produced by diverse causes.
It may first be nothing else than the amplified ex-
pression of an elementary autorhythmic property of
some neurons whereby they emit pulses or become
the site of local oscillatory states. This is so commonly
encountered in microphysiological experiments with
isolated elements that one can hardly douljt that this
mechanism operates at times in the central nervous
system. But neurons in the brain never work in isola-
tion and the factors, synaptic, electrotonic or ephaptic,
intervening in synchronization must aflPect the proper-
ties of the autorhythmic generators. It may even be
that rhythmicity owes its existence, in many cases, to
some particular arrangement of the neuronal connec-
tions in the grey matter. Several mechanisms have
been proposed which are possible but not definitively
demonstrated. For instance, alternating states of
excitation and inhibition, with their corresponding
opposite electric signs, may appear by virtue of
reciprocal connections between the generating
neurons, as proposed by Jung (33); or closed chains
of neurons, which have been traced through central
structures by Lorente de No (41), may open the way
to recurring pulses activating a homogeneous pool of
neurons.
It seems more sound to many neurophysiologists to
replace these postulated effects of a rigid circuitry by
others attributable to the properties of diffuse net-
works. Neural nets finelv wo\en with short, inter-
connected neurons are present almost everywhere in
the grey matter. A certain average level of intrinsic
activity may be maintained within these structures
by an incessant and random circular reactivation of
their elements. This results in an asynchronous
bombardment of the neurons responsible for re-
cordable potentials. The determining factor of
periodicity is then the recovery cycle of these neurons.
This mechanism, first postulated by Eccles (22, 23),
has received strong support from the experiments
of Burns on isolated slabs of cortex (11, 12).
Finally, steady potential gradients within large
assemblies of neurons and their slow modifications
under certain conditions appear to be correlated with
spontaneous or e\oked activities in the grey matter,
according to the views of O'Leary and his collabora-
tors (28; see Chaper XIII). The correlations may
express cause-effect relationships in either direction.
For instance, long-lasting after-bursts in isolated
slabs of cerebral cortex have been related by Burns
(13, 14) to gradients that appear as the consequence
of different recovery rates of the resting membrane
potentials at the two ends of particular neurons. One
more factor capable of inducing rhythmic states has
thus been revealed. But, since the pioneer studies of
Dusser de Barenne et al. (20, 21), Libet & Gerard
(39)' Jasper & Erickson (32), Leao (37) and the
recent investigators just mentioned, very few workers
have been tempted by the delicate techniques in-
volved in direct current recordings. These may how-
ever represent the next fruitful ad\ance of brain
electrophysiology.
Brain potentials and their rhythms are the net
result of a conjunction of many heterogeneous factors
— physical conditions, anatomical organization, statis-
tical effects and the differential properties of the
neuron segments — implicated in different ways.
Consequently, brain potentials are able only to reveal
a limited aspect of cerebral activity and must always
be suspected of giving a distorted picture of the real
events. This is why it is so important to arrive at a
better understanding of their elaboration, for, cor-
rectly interpreted, they remain the unrivalled signs
of what occurs in the intimacy of cerebral tissue and
the main basis for explaining brain functions.
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CHAPTER X
Identification and analysis of single unit activity
in the central nervous system
KARL FRANK I N'llional Institute of Neurological Diseases and Blindness,
j National Institutes oj Health, Bethesda, Maryland
CHAPTER CONTENTS
Single Unit Techniques
Single Fiber Isolation
Microelectrodes
Metal electrodes
Micropipettes
Construction
Filling
Electrical properties of micropipettes
Resistance
Capacitance
Tip potential
Frequency response
Amplifiers
Identification of Single Units
Position
Axons
Damage to Penetrated Units
Primary Sensory Fibers
Motoneurons
Interneurons
Slow Potentials
Steps in the Development of Cell Spikes
Stimulation Through Microelectrodes
SOMEWHERE IN THE MIDDLE of the widc range of ap-
proaches to neurophysiology is the study of the
physiological properties of the individual neurons in
the central nervous system. In order to put this ap-
proach in its proper perspective, it should be empha-
sized that the functioning of the central nervous
system as a whole is as difficult to predict from the
known properties of each of its cellular components as
are the properties of the units from the behavior of
the whole. While it is not sufficient for understanding
the nervous system, it is necessary to study the indi-
vidual nerve cells, their various structures, their differ-
ent patterns of activity and the mechanisms operat-
ing to yield and to limit such activity.
A great body of knowledge has been built up about
the nature of neurons in the peripheral nervous
system. One of the most fruitful approaches to the
study of single units in the central nervous system is
through the extension and elaboration of these
peripheral findings. Properties of peripheral ner\-e
fibers, of sensory and motor end organs and of
ganglion cells are continually being dfscovered within
the spinal cord and brain, and these properties must
be carefully checked lest differences or totally new
mechanisms be thereby overlooked.
Neurons show a variety of changes which can be
observed in a study of their activity. Optical, thermal
and mechanical changes have all been ob.served to
accompany activity in nerve, but chemical and
especially electrical changes have been used most
extensively to acquire our present knowledge of
single cell neurophysiology.
SINGLE UNIT TECHNIQUES
Techniques for single unit studies all require some
means of isolating the unit to be studied. Cells which
cannot be isolated anatomically due to their many
connections with other cells may sometimes be iso-
lated electrically. This may be done either by limit-
ing nervous activity at a particular time to the unit
261
262
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
under study or by restricting the sensitivity of the
recording device to the electrical activity of that unit
alone.
Single Fiber Isolatian
Bv carefully dissecting trunks of peripheral nerve
fibers or spinal roots into smaller and smaller bun-
dles, it is often possible to reach a size of filament
within which only a few or even only one nerve fiber
remains functional (see Chapter III). Such a fiber
can then be stimulated or its action potential recorded
in isolation. This technique has been used to study
the patterns of activity of indi\"idual motoneurons in
response to various types of excitation and inhibition
(i, 6, 21, 31, 37, 38, 44). EssentialK' the same tech-
nique has been used by Fessard & Matthews (24), by
Kato et al. (40) and by others to limit afferent im-
pulses to those carried by a single fiber. Such single
unit aff^erent impulses have been shown to produce
long-lasting potential changes on nearby afferent
fibers (the dorsal root potential) and reflex excitation,
provided other excitatory pathways had pre\iously
brought the reflex nearly to threshold. The same tech-
nique has enabled Adrian & Zotterman (2) and
Cohen et al. (13) to study activity patterns of single
sensory receptors. Finally, Fatt (22) has similarly iso-
lated a single motor fiber from its peripheral nerve. A
nerve impulse was conducted antidromically by this
fiber, and its invasion of the motoneuron cell body
and dendrites was followed by mapping the electrical
potential field produced in the surrounding volume
conductor of the spinal cord.
MiCROELECTRODES. In the experiment just described,
isolation of the unit was achie\-ed b\' the i^eripheral
nerve dissection which permitted only one fiber to be
stimulated. An alternative method of isolating
responses from single units is to use a microelectrode
which is small enough to be selectively sensitive to the
activity of a single cell. With such a method it is not
necessary to interfere with the patterns of activity of
other cells in the nervous system since the potentials
they generate in the microelectrode are small com-
pared with the signals being studied. This method of
isolation requires that the microelectrode be of small
enough dimensions to permit it to be placed closer to
the unit to be studied than to other acti\e units. A
wire or needle sharpened to a diameter of about o.oi
mm (10 m) and insulated except at its tip satisfies this
requirement for many nerve cells in the spinal cord
and brain (7). Much larger electrodes (50 to too ^)
appear to damage individual units (50) while still far
enough away from them so that their potential fields
are masked by the background activity of other cells.
Smaller metal recording electrodes require special
techniques. A number of these ha\e Ijeen de\Tloped
and are described below.
MET.AL ELECTRODES. .Svactichin (52) dcscribes a tech-
nique for filling fine glass pipettes with silver solder
(fig. i.-l), thus providing a very small metallic record-
ing surface down to less than i /i, well insulated by a
smooth tapering glass shaft. The tips of these electrodes
are plated with rhodium and then coated with
platinum black to prevent oxidation and to increase
the surface area.
Howlancl et al. (35) has also used a glass insulated
metal wire prepared by drawing a glass pipette down
onto a I 2 ;u nichrome wire which had previously been
passed through the tube. While single unit acti\ity
has been recorded with these electrodes in the cat's
spinal cord, they are not very satisfactory for this
piu"pose and ha\e been u.sed mostly to record the
composite responses of fiber tracts and cell groups.
Dowben & Rose (16^ have devised a inore satis-
factory metal microelectrode which they have used
with consideraljle success in studving unitary activity
of the thalamus. These workers have made use of the
low melting point of the metal indium which permits
them to fill predrawn glass pipettes of 3 to 5 ^i tip
diameter with the metal (fig. iB). The metal surface
at the tip is coated with gold and then platinum
black which probably reduces the electrical resistance
of the metal-to-electroK te surface due to the porous
nature of the platinum black and reduces the rate
at which the surface becomes polarized during the
passage of electrical currents.
Perhaps the ultimate in fine tipped metal micro-
electrodes is produced by the electroetching and
polishing technique (32). Hubel (36), applying this
technique to a tungsten wire which he then insulates
with a clear lacquer down to the tip, has produced an
electrode of 0.4 /j tip diameter with which he has re-
corded the intracellular potentials of motor horn
cells in the spinal cord of the cat (fig. iC).
A metal-electrolyte interface or junction behaves
somewhat like a condenser due to polarization
eflPects. In general the greater the current density at
the junction the more rapidly it becomes polarized.
Thus, as the tip of a metal electrode becomes smaller
the difficulty with polarization increases. Successful at-
tempts have been made to reduce polarization by
coating the microelectrode tip with platinum black
(16, 52) and by using amplifiers which draw very
small currents (Bak, A. F., manuscript in prepara-
IDENTIFICATION AND ANALYSIS OF SINGLE UNIT ACTIVITY IN CENTRAL NERVOUS SYSTEM
263
tion; and 36). Electrode polarization causes a varia-
tion in sensitivity of the electrode-recording device
combination with the frequency of the recorded po-
tential. Lower frequencies are more attenuated than
higher frequencies, and slow changes in potential tend
to be lost. In addition there is sometimes a fluctuation
in contact potential between metals and electrolytes.
Because of these shortcomings, metal microelectrodes
have been used more for recording extracellular
transient potential changes and patterns of unitary
activity than for studying the exact form of the po-
tential waves or lasting potential changes.
.viiCROPiPETTES. The problems inherent in recording
from a metal surface of very small area are in part
avoided by using a glass pipette filled with an electro-
lyte. With such an electrode the electrolyte-metal
boundary is moved back from the tip to the shank
where a long wire provides a large surface area (fig.
2.4). This electrode, while not suffering from a limited
■••III
I
FIG. I. A. Silver-filled glass micropipettcs a and c show glass-insulated microelectrodes with tips
containing no metal, h and d are the same electrodes after electrolytic filling with rhodium. Scale:
10 M [From Svaetichin (52).] B. Stages in preparation of an indium-filled micropipctte: a, capillary
tubing half filled with low melting point metal; b, the capillary after tip is drawn but before metal is
pushed to fill it completely; c, electrode tip showing platinum black deposit. Calibrations: i mm for
a and A ; 10 /u for c. [From Dowben & Rose ( 1 6).] C Lacquered timgsten microelectrodes sharpened by
electropolishing: a, electronmicrograph of uncoated wire; b, optical photograph of three coated
electrodes immersed in water to show normal variation in coating. [From Hubel C36).]
Glass with Pf Plating
Glass 1 Stainless Steel
40 35 30 25 20
MILLIMETERS
^M
FIG. 2.-4. (/(■//) KCl filled microelectrode used for intracellular recording showing one method of
mounting. Platinum lead from amplifier contacts inner mercury droplet as outer shield is
clamped. If shield is driven electrically by negative capacity amplifier, platinum coating is usually
omitted. [From Frank & Fuortes (26).] B. (right) Electronmicrograph of the tip of a similar pipette.
[From Nastuk & Hodgkin (47).]
264
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
metal-electrolyte surface area, has plent)' of problems
of its own. But in addition to the important role it
has played in peripheral nerve (see Chapter III),
muscle and ganglion studies, the micropipette has
provided most of our present detailed knowledge of
the physiology of single nerve cells in the central
nervous system. This is partly because these electrodes
have been made small enough to penetrate single
nerve cells without destroying them, thus permitting
measurement of the potential across the cell mem-
brane (figs. iB and 65). For this reason and because
the use of this type of electrode appears to hold much
promise for future investigations, more space will
be devoted to its description.
Ling & Gerard (42) are commonly given credit for
introducing micropipettes, probably because they
were the first to record action potentials from inside
single muscle fibers with these electrodes. However,
Graham & Gerard (30) had previously recorded the
resting membrane potential of frog muscle fibers with
similar fine electrodes filled with saline, and many
workers before them have used coarse pipettes for re-
cording electrical potentials as in the use of small
calomel half-cells and agar bridges [references to this
work are listed by Svaetichin (52)].
CONSTRUCTION. Ling & Gerard (42) made micro-
pipettes by hand, drawing i to 2 mm glass tubing
down to a fine tip in an oxygen-gas microflame.
Alexander & Nastuk (4), Livingston & Duggar (43)
and others have devised machines for pulling pipettes
similar to that shown in figure 3. This machine heats
the glass tube over a short length until it is soft enough
to be drawn out by the pull of the electromagnet.
Increasing the heater temperature or the length of the
heater coil produces a longer, gentler tapered section
on the pipette. Figures sA and B show the size and
one way of mounting glass micropipettes. Another
method of mounting supports the tip of a glass micro-
pipette on a I mil tungsten wire (59). This method
has been used to permit recording of intracellular po-
tentials from muscle where movement would dis-
lodge a rigidly mounted pipette.
FILLING. The size of the tips of such micropipettes
ranges upward from a few tenths of a micron (fig.
2B). The problem of filling them with an electrolyte
becomes more difficult as the size of the tip is reduced.
Above about 5 m the pipettes can be filled with a
syringe by expelling the air from the tip. Boiling for
several hours submerged in the electrolyte is satis-
factory for all but the smallest tips although it appears
FIG. 3. Vertical micropipette puller. Upper clamp fixed;
lower clamp pulled down by solenoid, gently at first when
glass begins to .soften, hard just before pipettes separate. Tips
are drawn down out of heater coil which is turned off any time
after pull is completed. (Developed at National Institutes of
Health, Instrument Section.)
to enlarge them somewhat. N. Tasaki (55) has de-
vised the most satisfactory method of filling. The
pipettes are immersed in methyl alcohol in a chamber
which is gradually evacuated until the alcohol boils
vigorously for a few minutes. The low \iscosity and
low boiling point of the alcohol permit the finest tips
to be filled quickly and without damage. The alcohol
can then he replaced by the desired electrolyte by
dififusion in about two days. Preboiling and filtering
the electrolyte reduces the formation of air bubbles
and clogging by foreign particles. The micropipettes
are best stored in alcohol or water and are transferred
to the desired electrolyte a few days before they are
needed.
A micropipette can be filled with a variety of differ-
ent electrolytes. Considerations to be taken into ac-
count are electrical conductivity, similarity' of cation
and anion mobilities, the possibility of damage to cells
through the diffusion of the electrolyte out of the
pipette and the purpose for which the pipette is used.
IDENTIFICATION AND ANALYSIS OF SINGLE UNIT ACTIVITY IN CENTRAL NERVOUS SYSTEM
26s
The conductivities of several electrolytes which have
been used are given in table i. The rate of diffusion
from the tips varies widely, of course, but the magni-
tude of this effect can be seen from an example given
by Nastuk & Hodgkin (47). They report a diffusion of
KCl from a 0.5 m micropipette filled with 3 m KCl of
6 X to"'* M per sec. If a micropipette maintaining
this flow is introduced into an infinite liquid space,
the concentration of KCl at equilibrium can be de-
termined from the relation
C\ =
F
4ir.vZ)
+ c.
where C'^ is the uniform concentration ol KCll in the
space before introducing the pipette, a is the dis-
tance from the pipette tip, F is the rate of flow of KCl
from the tip and D is the difTusion coefficient. Apply-
ing reasonable values for the electrode described
above indicates that the order of magnitude of the
increase in concentration of KCl at a distance of 10
H from the tip is 3 X io~* m per 1. This may be com-
pared to the figure 1.5 X 10"^ m per 1. taken by
Coombs et al. (15) as the concentration of K+ in the
intercellular spaces of the cat's spinal cord.
When a micropipette carries an electric current,
there is a selective migration of ions through the tip
superimposed on the movement by diffusion just dis-
cussed. If the ionic concentration in the pipette is
much greater than that outside the tip then, regardless
of its direction, the current will be carried largely by
movement of ions from inside to outside the tip, by
anions if the electrode is negative and by cations if it
TABLE I . Coiuhutivity of Solutions Used in Microelectrodes*
Solution
23.S°C
38°C
KCl (3 m)
0.26
0.27
NaCl (1%)
0.018
0.02
NaCl (2 m)
0.14
0.17
K,S04 (0.6 m)
0.08
O.IO
AgNOs (sat.)
0.20
0.23
CuClj (sat.)
0.08
O.IO
FeCb (20%)
0.075
0.12
Trypan Red (sat.)
0.03
0.03
* In reciprocal ohms (mhos) per cm.
Composition of solutions: KCl 3 m solution: 224 gm KCl
dissolved and diluted to i liter. NaCl 1*^0: 0.5 gm NaCl dis-
solved and diluted to 50 cc. NaCl 2 m : 5.85 gm NaCl dissolved
and diluted to 50 cc. K.2SO4 0.6 m: 5.2 gm KoSOj dissolved
and diluted to 50 cc. AgNoj saturated: 122 gra AgNos dis-
solved in 100 cc water. CuClj saturated: no gm CuClj dis-
solved in 100 cc water. FeClj 20%: 20 gm FeCh dissolved and
diluted to 100 cc. Trypan Red saturated: about i gm/ioo
cc; excess filtered off.
is positive. When the mobilities of the ion species are
different, the electrical conductivity of the pipette
will change with the direction of current carried,
and the electrode will show rectification. These
properties of micropipettes have been used to ad-
vantage both for excitation of membranes and for de-
termining the effects of specific ions on the behavior
of single cells (15).
ELECTRic-^L PROPERTIES OF MICROPIPETTES. Resistance.
The electrical resistance of a micropipette may be
thought of as the sum of the resistance of a truncated
cone of the inside electrolyte and the resistance of the
voluine conductor around the tip. If the tip diameter
is less than i n, more than 90 per cent of the resistance
lies in the last 10 /i of the tip. In actual practice these
electrodes generally range from a few to several
hundred Mti.
The resistance of a pipette is also dependent on the
direction, amplitude and sometimes on the dura-
tion of the current it is carrying. For very small cur-
rents of brief duration, the electrode usually behaves
either like a pure resistance or a simple rectifier. The
rectifier action of pipettes has not been studied sys-
tematically for a large number of electrolytes. When
even small currents are maintained for a long time,
the resistance may increase. This has been inter-
preted by Taylor in the Appendix to Jenerick &
Gerard C39) as a movement of low-conductivity ex-
ternal electrolyte into the tip due to bound surface
charges on the glass, and is a reversible phenomenon.
Larger currents delivered in pulses at constant voltage
may cause sudden erratic changes in resistance, and
the amplitude of current pulses at which these changes
begin generally differs with polarity. Sustained ap-
plication of several volts across a micropipette will
often increase its resistance irreversibly to more than
10^0. Some form of clogging in the extreme tip is sug-
gested, and it is usually possible to break the fine tip
by gently bumping the pipette under a microscope,
thus reducing its resistance to a usable value. A pipette
of the dimensions described above might have a re-
sistance of 20 Mi2 for a current of up to about io~'
amp. in either direction and pass this current without
markedly departing from a pure resistance. Tasaki
(personal communication) has been able to select
equally fine, hand-drawn inicropipettes carrying up to
io~^ amp. provided the external volume conductor
was sufficiently acid.
When used with a good preamplifier (see page 267),
the ability of a micropipette to carry current is rela-
tively unimportant if it is to be used only for measur-
266
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY
ins; potentials. But when stimulating or polarizing
currents are to be delivered to the penetrated cell (see
page 274) or when ions are to be deli\ered through
the tip bv iontophoresis then pipettes must be selected
for their current-carrying ability.
Cajiacilnnce. The ability of a micropipettc to follow
rapid changes in the electrical potential at its tip
varies inversely with the electrical capacitance across
its walls (see below). The capacitance across the
glass wall of a micropipettc between inside and out-
side electrolytes depends upon the thickness of the
wall and on the length of that portion of the pipette
which is immersed in the external \olume conductor.
Since in a drawn glass pipette the ratio of wall thick-
ness to diameter remains approximately constant the
capacity is proportional to the immersed length. Frey-
gang (28) calculates the capacity across a pipette
drawn from Pyrex tubing No. 7740 having a ratio
OD/ID of 2 as 0.4 /i/if per mm. This is close to the
measured value for an actual pipette of 0.37 fifif per
mm of immersion. The total capacity is linear with
immersion depth except for a minor change occurring
as the shoulder of the pipette enters the external con-
ductor. Nastuk's figure of i /x^f per mm would indi-
cate a smaller ratio of OD, ID (47).
Tip potential. Nastuk & Hodgkin (47), who used
micropipettes filled with 3 m KCl, assumed pro-
visionally that measurements of potential made with
.such pipettes are not altered by a junction potential
at the electrode tip. However, Nastuk (46), del Cas-
tillo & Katz (17) and Adrian (3) showed that with
many such fine tipped pipettes there is a potential
diflference across the tip which may be as large as 70
mv, inside negative, and that this tip potential may
change suddenly with movement of the pipette in
muscle or nervous tissue. Thus measurements of
steady potential differences, e.g. the membrane po-
tential of a cell, will be in error if the tip potential of
the micropipettc differs at two points. Such a differ-
ence can arise in two ways. The tip potential of the
pipette may be changed by clogging or unclogging the
tip as it moves through the nervous tissue. In this case
alternate measurements at two points would not
generally be expected to repeat the error. A more con-
sistent error will be encountered if the two points
whose potential difference is to be measured are in
regions of different ionic composition, and if the tip
potential of the micropipettc is different in the two
regions. Adrian (3), attempting to clarify this point,
measured the tip potential of a series of pipettes in
both 100 mmole KCl and 100 mmole NaCl. He found
that the difference in tip potential in the two solutions
was proportional to the tip potential in 100 mmole
KCl. Adrian considers the mechanism of the tip po-
tential to be a selective reduction in mobility of some
of the ions, particularly that of the anion and probably
due to some form of blocking. He argues that if a
pipette has a small tip potential it is less likely to
show a change or introduce an error due to tip po-
tential. On this basis he measures the resting potential
of muscle membrane by selecting only those pipettes
whose tip potentials are less than 5 mv, inside nega-
ti\e. \Vhile it is true that such a pipette would be ex-
pected to introduce only a small error of i or 2 mv in
the measurement of potential difference between two
test solutions (100 mmole KC'.l and 100 mmole NaCl),
there seems to be less certainty that a pipette having
an initially small tip potential will not increase its tip
potential during its movement through tissue. In the
particular case of the resting potential across a cell
memijrane, errors introduced by variation of tip
potential cannot be eliminated by repeated compari-
sons since the cell memijrane is generally damaged by
repeated penetration. For this reason, micropipettc
measurements of steady potential difference between
different points in the nervous system are subject to
considerable uncertainty at the present time.
Frequency response. Metal microelectrodes are gen-
erallv poor for measurement of d.c. or of very slowly
varying potentials as described above, but at higher
frequencies their impedance drops to relatively low
values. The resistance of a glass micropipettc on the
other hand is quite independent of frequency at low
frequencies. This does not mean that an ordinary
amplifier connected to a micropipettc necessarily re-
cords biological potentials with a good frequency
response. Indeed, this is one of the failings of these
electrodes.
A micropipettc must generally pass through a
region of grounded volume conductor before reaching
the highlv localized region whose potential is to be
recorded. The capacity across the glass wall between
the inside electrolyte and this external volume con-
ductor (.see above) tends to reduce the high-fre-
quency response of the electrode. Since most of the
resistance of the pipette is located very near its tip, it
can be well represented in such an application by
the equivalent circuit of figure 4. If the input im-
pedance of the amplifier is high enough to be neglected
in comparison to Re and Ce, a sudden change in
\ oltage E will be recorded as an exponential rise hav-
ing a time constant r = Re Ce; that is, the recorded
N'oltage \' will rise to about 63 per cent of E in the
time T. For anv form of voltage signal E fed in, the
IDENTIFICATION AND ANALYSIS OF SINGLE UNIT ACTIVITY IN CENTRAL NERVOUS SYSTEM
267
:: „
k
|Re J
1
AMP
E
7
FIG. 4. Approximate equivalent circuit for an intracellular
micropipette. E, cell potential to be recorded; Re, resistance
of microelectrodc tip plus preparation, Ce, capacity between
electrolyte inside micropipette and grounded volume conductor
in which it is immersed; V, potential recorded by amplifier.
J. W., & K. S. Cole, manuscript in preparation;
Lettvin, J. Y., & B. Howland, manuscript in prepara-
tion; Bak, A. F., manuscript in preparation. This type
of preamplifier, by utilizing positive feedback to the
input grid, in effect adds a controlled negative
capacitance in parallel with the positive input capaci-
tance. By minimizing the sum of these capacities, a
considerable improvement can be made in the record-
ing time constant. Used with micropipettes like those
described above, these circuits can reach an effective
input capacitance of 0.5 /i^uf or less.
recorded voltage will be
V = E -
dV
dt""
The error in recorded voltage is thus proportional to
the electrode resistance, to its capacity to ground and
to the first derivative of the recorded voltage. When
the input voltage is a sine wave, the frequency at
which the recorded voltage is reduced to 0.7 E is
given by
f =
27rRp. Cp
Amplifiers. Amplifiers used for recording from micro-
pipettes must have special features to minimize the
effects of the inherent shortcomings of the electrodes
described above. Ideally, the amplifier must have an
input resistance which is high in comparison with the
electrode resistance, a low enough input grid current
so that its effects at the tip of the electrode can be
neglected and a negligible effectixe capacity between
input and ground. These requirements of the ampli-
fier do not include voltage gain which can be accom-
plished in a following amplifier. Thus the preamplifier,
as it is usually called, is actually an impedance trans-
former intended to isolate the source of potential being
measured from the loading effects of the conventional
voltage amplifier.
A number of practical preamplifiers have Ijeen de-
signed to meet these special requirements with varying
degrees of success. The simplest is the cathode fol-
lower circuit of which a good example is that de-
scribed by Nastuk & Hodgkin (47). This circuit gave
an overall recording time constant of 70 /z sec. when
tested with a 22 Mli pipette, showing an effective
input capacitance of 3.2 /i^if. An improved circuit
called a negative capacity amplifier has been used in
various forms by several authors: Solms el al. (51);
Woodbury (58); Wagner & MacNichol (57); Moore,
IDENTIFICATION OF SINGLE UNITS
Position
One of the more diHicult problems in the use of
micropipettes is the determination of their positions.
Identification of the structure or structures generating
the various potentials recorded by the micropipette
requires some knowledge of the relative positions of
the pipette and the structures which might be respon-
sible for the potentials. Knowledge of which neuron
the pipette is in or near is of less interest than the kind
of neuron and the position of the pipette relative to
the various parts of such a neuron. Information of
this kind has been obtained by direct microscopic ob-
servation, by marking techniques and by inferences
drawn mostly from the nature of the potentials
recorded.
Direct observation of the microelectrodc position is
limited to those structures which can be dissected
free of opaque or translucent surrounding tissues. This
technique has been used in recording from muscle
fibers [see bibliograph\- in Jenerick & Gerard (39)];
peripheral nerve fibers (Chapter III, 54); inverte-
brate heart ganglion cells (12); eel electroplaques (5);
dorsal root ganglion cells (53); photoreceptor cells
C.33); and stretch receptor cells (41). Even in struc-
tures where this technique is possible, there are
severe limitations. The tips of micropipettes are often
submicroscopic or close to the limit of resolution
with visible light, thus requiring ideal conditions of
lighting, numerical aperture, color contrast and
contrast of indices of refraction. Pressure from the
pipette often distorts the ti.ssue, and even under the
best conditions it may be difficult for example to de-
termine optically whether the pipette is inside or
outside of a particular cell wall. However, a large
part of the present body of knowledge of the electro-
physiology of single cells has been acquired by
studies u.sing this technique.
268
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
A new technique has been proposed for extending
direct \ision to structures within the central nervous
system. This is accomplished by the use of a long thin
solid cone of glass mounted in front of the microscope
objective which extends to the focal plane. Incident
illumination is supplied through the objective, and
the cone is moved through the tissue until the desired
object appears in the small field of view bounded by
the flat end of the cone. Using this technique, moto-
neurons have been seen in unfixed tissue, and their
nuclei and dendrites are clearly visible. It is hoped
that this technique can be used for determining micro-
electrode position.
Marking techniques have been used extensively for
locating gro.ss microelectrodes. One method produces
a lesion by passing radio-frecjucncy current through
an insulated metal electrode bared at its tip. The
lesion is subsequently made visiijle by staining the
fixed and sectioned material. Another method using
steel electrodes plates off iron by passing a current
through the electrode. The region where the iron
has been deposited is then stained blue by ferrocy-
anide and prepared by frozen section technique, Mar-
shall's modification of Hess' method (45). The resolu-
tion of about half a millimeter made possible by these
two techniques is not yet great enough to permit
identification of single cells or parts of cells. Success
in marking a single cortical pyramidal cell has been
claimed recently by Rayport (48) who passed a cur-
rent through a micropipette filled with a 3 n
FeNH4S04 solution. Iron ions moved by electrophore-
sis into the penetrated cell were later stained blue !)>•
the ferrocyanide reaction of Hess (34). This is the
only case known to the author of a single nerve cell
penetrated blindly and sub.sequently identified
visually.
The identification of nervous structures by infer-
ences made from the potentials recorded from micro-
electrodes is uncertain and .subject to revision when-
ever further information modifies the assumptions on
which such inferences are based. However, pending
the development of a more direct method, the study
of single unit activity in the central nervous system
is limited to such inferences as can be made based on
comparisons of potentials recorded from microelec-
trodes in the central nervous system with those re-
corded from cells under direct vision or otherwise
identified.
Axons
The potentials to be expected from axons in the
central ner\ous system can be predicted from meas-
FIG. 5. Effect of \olume conductor on potentials recorded
by intracellular electrodes. The microclectrode is inserted in a
fiber of a ventral root. In A and B the root is surrounded by
paraffin oil, in C and D the oil is replaced by Ringer's fluid.
A and C, stimulus just subthreshold for penetrated fiber; B
and D, maximal stimulus. Calibration : 50 mv. Time : i msec.
[From Frank & Fuortes (26).]
urements made on peripheral nerve (see Chapter
III). If a nerve surrounded by an insulating medium is
made to conduct a synchronous volley of impulses, a
fairly large action potential can be recorded mono-
polarly from a gross electrode in contact with the
ner\e. As seen in figure 5^4, a microclectrode simi-
larly situated records the same large external action
potential with respect to a distant electrode on inac-
tive tissue. If the microclectrode then passes through
the membrane of a fiber participating in the volley,
the action potential it records will be the algebraic
sum of the outside potential previously recorded and
the action potential produced across the fiber mem-
brane (fig. 5/}). The effect of a volume conductor,
such as the spinal cord or brain surrounding the active
fibers, can be simulated b>' replacing the insulating
medium with a conductor such as saline. Figure 5C
shows that the external recording is then markedly re-
duced and the action potential developed across the
penetrated fiber membrane is recorded by an internal
microelectrode with little distortion (fig. jD). When
the intpulses in the fibers are not synchronous, the al-
ready small external potential field becomes negligi-
ble; but, whatever the external field may be, it will
be approximately recorded by an electrode inside or
outside a resting fiber. Thus it can be anticipated that
IDENTIFICATION AND ANALYSIS OF SINGLE UNIT ACTIVITY IN CENTRAL NERVOUS SYSTEM
269
extrinsic potentials inside a volume conductor such as
the spinal cord or brain are small and do not ap-
preciably distort the potentials recorded by micro-
electrodes inserted in active neural elements except in
the presence of large synchronous volleys in a limited
volume conductor.
Fi?;ure 6.4 is a section of the lumbar region of a cat's
spinal cord showing cell bodies of neurons as black
dots. A line drawn across such a section indicates the
structures which may be encountered by a micro-
electrode as it is advanced through the tissue. A very
few motoneuron somata but many small cells and in-
numerable fibers will be in the path of the electrode.
Apparently penetration of fibers occurs only when
very fine micropipettes are used. With coarser elec-
trodes the majority of the elements which can be im-
paled behave as if they were cell somata. Figure 6B
shows the relative sizes of a cat's motoneuron and a
typical glass micropipette.
The potentials recorded from a microelectrode as
it is moved through a cat's spinal cord are indicated
A
v.. ^%^-
. \
B >'^^ ■ Y
4f^\
^•^
T
A
FIG. 6.^4. Section of cat's spinal cord at L6. Thionin stain to
show cell bodies. B. Methylene-blue stain of unfixed slice of
spinal cord showing KCl filled micropipette penetrating a
motoneuron near the surface of the slice. [From Frank & Fuortes
(26).]
in figure 7. The upper extreme of this potential is re-
peatedly recorded and is taken to indicate the poten-
tial in the extracellular spaces since it is close to the
potential recorded from the fluid conductor on the
cord surface. The negative deflections are presumed to
indicate penetration or destruction of cellular mem-
branes, on analogy with peripheral findings. While
some of the negative potentials recorded must be
from neural elements since they are correlated with
spikes like action potentials, others may be from
nonneural elements such as glia cells.
If the electrode is allowed to remain in a position
where it records a steady negative potential, spikes or
action potentials can generally be seen occurring
either spontaneously or in response to stimulation
(figs. ']A and 5). The amplitude of these action po-
r^
4,t
v_4
FIG. 7. Simultaneous records taken during penetration of a
cat's spinal cord with a KCl filled micropipette. / : Carotid
blood pressure. 2: Movement of the electrode. The limit of
deflection of the instrument was reached by a movement of 200
M- After this the pen jumped back and began recording further
movement in the same way. Upward deflection indicates in-
creased penetration. 3: Signals from shutters of the cameras
used for making records of inserts A and B. ./ : Record of elec-
trode potential relative to reference electrode on vertebral
column. Note potential fluctuations when electrode is moved
and steady negativity when it is, presumably, inside the mem-
brane of a unit. Insert A shows responses of the penetrated unit
to stimulation of a ventral root, as photographed by a single
frame camera. Insert B shows a strip of record taken by a
moving film camera at the time indicated by the two arrows in
^. Calibrations: /, 50 to 150 mm Hg; 2, 200 m; inserts A and B
and 4, 50 mv. Time; 60 sec. for /, 2, 3 and 4; i msec, for A.
[From Frank & Fuortes (26).]
270
HANDBOOK OF PHVSIOLOGV
NEUROPHYSIOLOGY I
tentials is related to the more or less steady resting
potential as shown in figure 8. The majority of units
penetrated show spikes larger than the corresponding
resting potentials. Occasionally, small or large spikes
are recorded with negligible resting potential, and
many of these have a diphasic positive-negative
shape as shown in 9^. Spikes accompanying large
steady resting potentials may be either brief like
those recorded from dorsal or ventral root fibers, as in
figure gfi, or of longer duration, as in figure gC.
0 •
/
mV
-
. 0 °. .•
/
100
-
0
0 •
• •.°
^
5
■
0
0
• 0 *'* iP ^ "^
a
0
0
••A * ^^oo '
>
0 " 0
•'* j/ ' °
50
-
0
.00 .0 °-
00 /^*
.
0 ° . •
/ •
0
/
'e
Q/
.
0 '/^
•
-
/ °
0
,/
0
/
1 1
1 1 1 1 1
1 1 1 i
50
100 mV
FIG. 8. Plot of spike amplitude against steady voltage as
measured from presumed e.xtracellular potential level. One
hundred and sixty-seven units from penetrations of cats' spinal
cords. Open circles from units identified as primary afferent
fibers; tilled circles from other units. [From Frank & Fuortes
(26).]
Damage to Penetrated Units
A unit may be considered to have been seriously
damaged when the potentials recorded from it de-
crease rapidly and are small and drawn out; and
when the pattern of activity recorded differs from that
obtained before penetration. Minor damage cannot
be recognized, and the degree of abnormality due to
insertion of the microelectrode can only be postulated
in a number of cases.
The assumption that small spikes are recorded from
damaged structures seems to be contradicted by the
observation that elements producing small spikes
may respond with normal patterns to orthodromic
stimulation. However, this is probably due to the
fact that damage can occur at the place of recording
(axon) without involving the structures responsible
for the generation of the response (.soma and den-
drites).
Primary Sensory Fibers
When the microelectrode penetrates a primary
afferent fiber after it has entered the central nervous
system, the unit can still be provisionally identified as
sensory by several features, a) The action potential
should have about the same shape, size and duration
as those recorded with microelectrodes in peripheral
nerves or dorsal roots. Of course, fine afferent branches
may not meet this requirement and other axons may
not be excluded. h~) If conduction latency is less than
about 0.5 insec, it may i)e presumed that no synapse
is tra\'ersed. This criterion cannot be used if long con-
duction paths are involved. Also this presumption ex-
cltides the possibility of very fast synapses, such as
FIG. 9..-!. Diphasic potential recorded from a cat's motoneuron just prior to penetration as indicated
by subsequent sudden development of negative resting potential. Artifact indicates shock to dorsal
root. Calibration : 20 mv. Time : i msec. B. Brief spike presumably from inside an axon in the cat's
spinal cord. Calibration: 20 rav. Time i msec. C. .Action potential from a cat's motoneuron following
first dorsal and then ventral root stimuli. Calibration: ^o mv. Time: i msec.
IDENTIFICATION AND ANALYSIS OF SINGLE UNIT ACTIVITY IN CENTRAL NERVOUS SYSTEM
might Ije required for the inhibitory interneurons
proposed by Eccles et al. (20). c) The unit in question
should follow trains of stimuli up to a rate of at least
500 impulses per sec. This figure may eliminate some
small afferent fibers and may let in some synapses of
very high safety factor but probably separates the
vast majority of postsynaptic from presynaptic ele-
ments. (T) If the unit responds to stimulation of a
dorsal root or peripheral nerve which is cut distal to
the point of stimulation, then there should be only one
response for each stimulus. This last criterion elim-
inates afferent fibers carrying dorsal root reflex re-
spon.ses (to, 25, 56), but these have never been ob-
served at shorter latencies than 2.5 msec, and cannot
follow at high frequencies (26). i) Primary afferent
fibers not separated from their sensory receptor cells
can often be made to fire repetitively by natural
stimuli such as touch, pinch or stretch. These trains
of impulses are characterized by their extremely regu-
lar rhythms under sustained excitation and can
readilv be distinguished from most postsynaptic ele-
ments in this regarded. Again this type of criterion
tends to prevent the discovery of regularly firing post-
synaptic elements should these exist. While none of
the above criteria is definitive alone, together they
form a rather satisfactory method for identifying pri-
mary afferents penetrated by microelectrodes in the
central nervous system. Using these criteria, primary
afferents have been identified as deep as 4.5 mm below
the dorsal surface of the cat's spinal cord (26).
Motoneurovs
Responses from motoneurons may be identified by
their correlation with antidromic stimulation with
the adoption of only very reasonable assumptions.
Microelectrodes in ventral root fibers of the spinal
cord give responses to ventral root shocks which are
similar to those recorded from dorsal root fibers.
When the electrode is in the spinal cord, similar short-
latency spikes are recorded following ventral root
stimulation (fig. loi?). These are presumabK- the axons
of motoneurons.
However, another type of short-latency response
may be recorded following ventral root stimuli as
shown in figure lo.-l. Brock et al. (ii), Frank &
Fuortes (26) and Woodbury & Patton (60) showed
that these responses are of longer duration than axon
spikes (figs. lo.-l and E), are followed by a long-lasting
hyperpolarization (fig. 15) and when elicited within
a critical interval following a previous spike, break at
the inflection point on the rising pha.se as shown in
U
N>m
FIG. 10. Antidromic conduction block in cat's motoneurons.
Electrodes inserted in the cord may pick up two types of short
latency responses to pairs of ventral root shocks. In unit of
column A the response to the second of a pair of shocks suddenly
drops to 30 to 40 per cent when the shock interval is reduced
below a critical stimulus interval (about i o msec, here, but
often much shorter or longer). Conduction block must occur
near microelectrode since blocked impulse is visible there. Unit
of column B shows instead a smooth decrease in height of
second response as stimulus interval is decreased. Calibration:
50 mv. Time in both columns : i msec. (Note diflferent sweep
speeds in A and B.) Only units like that in B are found in ventral
roots. [From Frank & Fuortes (26).]
figure lo.-l. The short latency of these responses identi-
fies them as from motoneurons, and the inflection in
the rising phase has been interpreted as due to a loss
in safety factor for conduction for axon hillock to
soma (i I, 26). If one accepts that the block in conduc-
tion at the critical stimulus interval occurs at the axon
hillock then, since only elements with long-duration
spikes show evidence of conduction block, it may be
concluded that long spikes originate upstreain froin
the axon hillock, i.e. in the cell bodies or dendrites,
and short spikes originate in axons.
The role of motoneuron dendrites in the generation
of potentials following antidroinic stimulation has
not yet been settled. Fatt (22) has recorded poten-
272
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
B
^^
/*-^
FIG. 1 1. Responses obtained in cat's spinal cord and identiKed
as from interneurons by criteria discussed in text. A. Spike
duration about i msec, after prespilce potential, presumably a
soma response. B. Spike duration about 0.3 msec, with no
prespike potential, presumably from an axon. Brief postspike
hyperpolarization is a frequent but not a constant finding and
may indicate damage done to a fiber by the microelectrode.
Calibration: 50 mv. Time: 1 msec. [From Frank & Fuortes
(26).]
tials which he interprets as indicating antidromic
conduction along the dendrites for a distance in excess
of I mm. But the diphasic responses of figure 9^4 can
be interpreted as due to the sum of conductive and
reactive currents outside .some inactive membrane,
according to Freygang (28). If this interpretation is
correct, then at least some of the dendrites of moto-
neurons probably do not participate in the actively
conducted action potential.
Interneurons
It is convenient, for the gross identifications possible
in the spinal cord with these techniques, to define an
interneuron as a postsynaptic unit which does not
.send its axon to ventral roots. The criteria for deciding
if a unit is postsynaptic are the latency of its response
and whether it responds with more than one impulse
to a single afferent volley. There is no doubt that if we
accept spontaneously firing units which cannot be
driven by the electrical stimuli available we may in-
clude some primary afferents from distant receptors
as interneurons, but most of these can be eliminated
bv the regularity of their firing.' Figure 1 1 shows two
' For a discussion of possible confusion between interneurons
and primary afferents conducting dorsal root reHexes see Frank
& Fuortes C26").
typical units satisfying the above criteria. Many work-
ers have studied patterns of activity of single cells
with extracellular electrodes and some have reported
patterns of intracellular potentials. For references to
these, see especially Chapters II and I\' of this
volume and their bibliographies.
One class of interneurons deserves mention in a dis-
cussion of neuron identification. Occasionally units
are penetrated which respond to a single ventral root
volley with a very high frequency train of spikes in-
stead of the single action potential shown by moto-
neurons. Eccles et at. (19) have named these Renshaw
cells in honor of Birdsey Renshaw (49) who predicted
the existance of such cells making synapses with the
axon collaterals of motoneurons. The function of these
cells has not been established, but Eccles et al. (19) be-
20
^/v ?.?v:-i:^....^,/.
■
^f^T^
-
-
/ ^
-//
1 -;
\:'- ^f.
1-2
msec
1-5
1-8
2-1
FIG. 12. Charts illustrating distribution of duration of spikes
recorded from different structures in the cat's spinal cord.
Abscissa: spike duration in msec; ordinates: number of spikes
within 0.3 msec, groups. A. Spikes recorded from dorsal and
ventral root fibers. B. Spikes recorded from motoneuron somata
or dendrites identified by criteria given in text. C. Spikes re-
corded from postsynaptic elements of the cord other than
those of .1 and B. [From Frank & Fuortes (26).]
IDENTIFICATION AND ANALYSIS OF SINGLE UNIT ACTIVITY IN CENTRAL NERVOUS SYSTEM
'^73
lieve that they supply inhibition to the motoneurons,
the activity of which excites them.
That both fibers and somata of interneurons are
penetrated is indicated by figure 12 which shows that,
after known primary afferents (^A) and motoneuron
somata (5) are eliminated, the remaining spikes from
interneurons are distributed in duration of action
potentials as though they were made up of many
fibers and fewer somata.
Slow PdtnUiali
As has been shown above it has not been possible
yet to distinguish clearly between cell somata and
dendrites with intracellular electrodes. But grouping
these two structures together a fairly clear-cut distinc-
tion is possible between soma-dendrites and fibers on
the basis of the slow potentials recorded from within
them. As seen in figure 13, a unit classified as a moto-
neuron soma shows a long lasting graded response to
subthreshold excitatory afiTerent stimulation which is
commonly called a synaptic potential. If this potential
reaches a critical level of depolarization, as shown in
figure 14, a spike is initiated and this spike is followed
-> B
f^
5 nnec
lOmV
-V-
FIG. 13. Spikes and slow potentials recorded from a cat's
motoneuron following antidromic (o) and orthodromic (0)
stimulation. .All records made from same motoneuron at difler-
ent sweep speeds and amplifications. Note respective time and
potential scales, msec, marks shown in A, B and D. Note dorsal
root spike records in C and D which are recorded with nega-
tivity downward. [From Brock et al. (i i).]
A
0
Outside Potential
11 : ""
L
J
■
- Vs
— Vth
— -Vm
j,^
J —
'
FIG. 14. Diagram illustrating terminology used to describe
antidromic (a) and orthodromic (0) spikes from cat's moto-
neurons and the level of polarization, Vth, which must be
achieved if a propagated spike is initiated. All potentials are
measured from the outside potential taken as o. Vm, resting
membrane potential, inside negative; Vs, total spike height;
Vov, spike overshoot, amount inside goes positive at peak of
spike. [From Frank & Fuortes (27).]
FIG. 15. Spike and slow potential recorded from cat's
motoneuron following antidromic stimulation. Calibration :
20 mv. Time: i msec.
by an even longer lasting period of hyperpolariza-
tion, such as those in figures 1 5 and 1 3C. These slow
potentials are apparently attentuated in the axon so
that, at the gains employed with intracellular record-
ing, no slow potentials are recorded from fibers unless
they are penetrated close to the soma (18, 26). This
finding, which is based upon identifications made
using the criteria just discussed, itself becomes a
method of identifying long duration spikes as from
somata or dendrites and short spikes as from fibers.
Steps in Development of Cell Spikes
Once the identification of the various units pene-
trated in the central nervous system has been accepted.
274
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY' 1
a further study can be made of the details of their
behavior. The most definitive of these studies has
been made on the large motoneurons of the cat by
Eccles (i8), Fuortes et al. (29) and Fatt (23), and in
the toad by Araki et al. (9), and Araki & Otani (8).
While these studies are too detailed to report in full,
it would seem pertinent to this discussion of the
identification of single unit activity to descrilje briefly
the model which has been developed to account for
the activity of certain nerve cells (fig. 16). All nerve
cells certainly do not behave according to this
model, but some features of the electrical activity of
cells are so general that they justify some generaliza-
tions from a model Ijuilt for a particular cell.
A neuron in the central nervous system might be
NORMAL THRESHOID
FIG. 16. Diagram to illustrate initiation of impulses in a
motoneuron. A spherical soma is indicated and its axis passing
through the center of the axon is used as abscissa for the plot.
Ordinate: membrane depolarization mejisured from resting
membrane potential. The dashed line indicates relative po-
tential changes evoked in various positions of neuron by
synaptic activity in soma and dendrites (not differentiated) or
by currents applied through a microelectrode in the sphere.
The solid line represents the depolarization level required to
evoke firing of different parts of the membrane. B' designates
that part of the neuron having a high threshold, and 'A' the
transitional region between this area and the lovi' threshold
axon. In normal conditions threshold stimuli, either synaptic
or applied through microelectrode, will initiate an impulse in a
region where the dashed line first crosses above the solid line
(If depolcirization is sudden, attenuation along the axon will be
steeper than that for steady depolarization due to capacity of
the membrane.) The dotted line is intended to indicate the
depolarization required to elicit firing shortly after activity
which has involved only the cross-hatched areas of the neuron,
e.g. after a blocked antidromic impulse. [From Fuortes et al.
(29)J
considered to consist of its soma and dendrites which
are connected to its axon by a thin unmyelinated seg-
ment arising from the axon hillock. Presynaptic fibers
make synaptic connections with this cell through
terminal knobs which end on its soma and dendrites.
Some of these specialized endings are excitatory and
others inhil)it activity of the cell. Probably through a
mechanism of secretion of excitor or inhibitor trans-
mitter substances by the presynaptic terminals, the
membrane of the postsynaptic cell is made selectively
permealjle to certain inorganic ions (16). Normally
these transient changes in ion permeability alter the
equilibriiuii potential of the membrane and either
depolarize it (excitation) or hyperpolarize it (inhibi-
tion). The sum of these synaptic potentials in the soma
and dendrites spreads electrotonically with decrement
to a sensitive target area, probably the thin initial seg-
ment of the axon and part of the axon hillock. The
threshold of this region, that is the magnitude of the
depolarization necessary to start an action potential in
it, is lower here than in the soma and dendrites
(normally perhaps one third l Thus, in spite of the
fact that the synaptic potential is larger in the soma
and dendrites than in the thin segment, the lower
threshold of this region permits it to be the site of
origin of the propagated action potential. The action
potential is then propagated out the axon and may or
may not spread Ijackwards over the soma and den-
drites. Following activity the soma-dendritic region
remains refractory longer than the target area so that
a second spike elicited during this period may be con-
ducted in the axon without spreading to the soma or
dendrites as seen in figure lo.-l and in the paper by
Fuortes et al. (29). It is proljable that the safety factor
for propagation from target area to soma-dendritic
region varies, not only with the condition of the cell,
but also from one type of cell to another so that
normal ijehavior in cells may differ in this respect.
But cells in so many different parts of the nervous
system show similar electrical properties that the
main features of the model just described may well be
of general application.
Stimulation Through Microelectrodes
Electric currents delivered through intracellular
microelectrodes produce excitation similar to that
caused by conducted impulses. Such direct stimula-
tion plays a role in the identification of penetrated
units, and is so generally useful in studying the proper-
ties of cells that some reference should be made to the
IDENTIFICATION AND ANALYSIS OF SINGLE UNIT ACTIVITY IN CENTRAL NERVOUS SYSTEM
275
to
Ampliher
Fig.l 9
FIG. I7..-1. A double-barrelled microelectrode and its immediate connections. Typical values are
given of the several electrical characteristics which are significant in the use of the electrode. B.
Enlarged view showing approximate equivalent circuit with motoneuron ignoring reactance.
[From Coombs el al. (14).]
FIG. 18. Diagram of arrangement for recording the response of a motoneuron to rectangular current
pulse delivered through an intracellular electrode. MN, motoneuron; Rp, microelectrode resistance;
R/, resistance of spinal cord and bath; b, unit dry cell; r, 50012 (6 and r compensate for membrane
and electrode potentials); R2, 2 kO; r', 2000; R,, 98.3 Mil; R/, 0.92 MU. Rectangular pulses applied
between E and D. Spike potentials recorded from A and C. Current through electrode was moni-
tored by recording potential across R,'. [From Araki & Otani (8).]
FIG. ig. Two arrangements used for stimulating and recording through a single micropipette
electrode. R, : i kit; R2: 10 kQ; Rj: 44MS2. Electrode resistance R,. usually between 10 and 100 Mil.
The resistor of the calibrator (Cal) and the variable resistor of the compensator (Comp), lOoO each.
The fi.xed resistor of the compensator 300S2 and the battery supplies 1.5 v. Stimulating and cali-
brating pulses are applied through radio-frequency stimulus isolation units. The indiflTerent electrode,
I.E., is a silver -silverchloride wire and is usually placed in the cat's mouth. Sw is a switch used for
d.c. compensation and for measurement of Re. In A stimulating current is measured by the voltage
drop across R2, which is equal to the drop across R3 when the bridge is balanced. B shows an alterna-
tive method for measuring current. R. and R3 are same as in A. R, has a value of 5 Ml2, and two
preamplifiers of balanced gain are used for differential recording of the voltage drop across Rj.
CRO is a double-beam oscilloscope indicating electrode current and voltage. [From Frank & Fuortes
(27).]
276
HANDBOOK OF PHVSIOLOOV
NEUROPHYSIOLOGY I
two main techniques which have been used. Coombs
et al. (14) used a double-barrelled micropipette (fis;.
17) passing stimulating or polarizing currents through
one barrel while recording the intracellular potential
with the other (barrel. Araki & Otani (8) (fig. 18) and
Frank & Fuortes (27) (fig. 19) used a bridge circuit
to penuit simultaneous stimulation and recording
through the same microelectrode tip. The.se articles
should be consulted for details and limitations of the
two techniques.
By means of these techniques it has been possible to
study the excitabilities of penetrated units. Differen-
tiation of axons from .somata is often possible on the
basis of their excitabilities. For example large axons in
the cat's spinal cord have a rheobasic current of
about 1.7 X I o~' ainp., while units identified as moto-
neuron somata or dendrites require an average of
about 7 X io~' amp. through the micropipette to
reach threshold.
Cells firing with regular trains of impulses appear
to generate their own impulses at some particular site
of origin. When depolarizing currents are applied
through the micropipette placed near such a locus the
rate of firing is increased in proportion to the applied
current. Since the applied current decrements rapidly
along an axon and presumably also along a dendrite,
current through the pipette will not affect the firing
rate when the micropipette is at a distance from this
site of origin. It is therefore possible to tell whether
the locus of recurrent firing in a cell is near to or far
from the tip of the micropipette. If it is accepted that
such a locus is normally situated near the axon hil-
lock, then the response of a repetitively firing unit to
applied polarizing currents can be used to infer
whether it is an axon or a soma.
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Granit, R. and G. Strom. J. Neurophysiol. 14: 113, 1951.
Grundfest, H., R. VV. Sengtaken, W. H. Oettinger and
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Hess, W. R. Beitrage zur Physiologie des Hirnslammes. Liep-
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Howland, B., J. Y. Lettvin, VV. S. McCulloch, VV.
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IDENTIFICATION AND ANALYSIS OF SINGLE UNIT ACTIVITY IN CENTRAL NERVOUS SYSTEM
277
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51
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CHAPTER XI
Intrinsic rhythms of the brain
W . GREY W ALTER ' Burden Neurological Institute, Bristol, England
CHAPTER CONTENTS
Generation of Spontaneous Oscillation
Piesalence of Spontaneous Rhythms
Origin of Spontaneous Activity
Conditions for Oscillation
Simple harmonic motion
Relaxation oscillators
Distinction between simple harmonic and relaxation
oscillators
Electrical equivalent of hydraulic model
Spontaneous Electrical Activity in Excitable Tissues
Rhythmic Activity in Single Units
Rhythmic Activity in Networks
Rhythmic Activity in Primitive Organs
Intrinsic Rhythms in the Human Brain
Properties of Alpha Activity as Typical of Intrinsic Rhythms
Early Reports
Individuality of Alpha Rhythms and I'heir Variation
Complexity of Alpha Rhythms
Identification of Alpha Components
Degree of Constancy and Range of Variation in Alpha
Frequency
Effects of Activation and Stimulation
Synchronization of Alpha Rhythms
Evidence from Intracerebral Electrodes
Relation Between Alpha Rhythms and Effector Function
Effect of Temperature Changes
Delta, Theta and Beta Rhythms
Relation of Delta and Theta Rhythms to Age
Delta Rhythms
Theta Rhythms
Beta Rhythms
Origin of Intrinsic Rhythms
GENERATION OF SPONTANEOUS OSCILLATION
Prevalence oj Spontaneous Rhythms
DURING THE 30 YEARS that have elapsed since Berger
first bcffan to record electrical acti\it\- from human
brains, many suggestions ha\e been made to account
for the unexpected spontaneity and regularity of these
rhythmic potential changes which resemble so little
the familiar action potentials of the peripheral nerve.
Rhythmic electrochemical activity is not in itself a
rare phenomenon; it is common in primitive or-
ganisms and can appear even in simple inorganic
chemical reactions such as that between iron and
nitric acid or between mercury and hydrogen perox-
ide (39). Such reactions, of course, involve more than a
simple combination of forces or reagents; for the
generation of rhythmic actixity there must always be
present in the system some sort of circular or feed-back
pathway through which the effect of products of
the reaction can influence the state of the original
reagents.
Origin of Spontaneous Activity
In such a system where action and reaction are
intercoupled, activity once initiated will tend to
persist, but the first cause may be obscure. ' Spontane-
ous' acti\ity is in fact a difficult conception to define
or illustrate in practice and the situation is not
simplified by substituting the terms 'endogenous',
'autogenous' or 'autochthonous', for in all these words
there is iinplicit the assumption that the behavior of
the system depends not on its previous state but in
some way on itself, as if there were an element of
choice or free will. This implication is verbal rather
than philosophical and need not be taken very seri-
ously; the difficulty is mainly that man-inade ma-
chines are designed for obedience rather than for origi-
nality and it is difficult to define the use of function of a
mechanism that seems to act independently of outside
influences. Clearly, if the electrical rhythins of the
brain were entirely spontaneous and independent
they would be very hard to fit into any hypothesis of
279
28o
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
neurophysiology, but, as is well known, these rhythmic
discharges are generally greatly affected by external
signals and need be considered as spontaneous only
in the sense that the energy required for their main-
tenance is freely available in the brain and that their
existence implies some sort of regenerative, retroactive
or feed-back loop. Even if, as several observers have
suggested (13, 21), the source of the rhythmicity may
be in the nerve cells themselves rather than in the
manner of their interconnection, there must still exist,
even within this intimate microcosm, a re-entrant
loop of energy transfer around which two sets of
variables can mutually control one another. The
physiological nature of the retroactive pathway is
hard to identify and around this point controversy
has raged for many years, involving many experiments
and strong feelings. Viewed without rancor, the
dispute seems academic; most of the claims and asser-
tions on both sides can be justified, few of the denials
can be confirmed. There seems little doubt that in
certain circumstances single nerve cells can discharge
spontaneously at a steady rate (3, 51). On the other
hand, large populations of healthy isolated brain
cells may remain quite inactive for long periods (17)
yet respond rhythmically when stimulated.
Conditions Jor Oscillation
SIMPLE H.\RMONic MOTION. It Can be shown that, when-
ever and wherever an oscillation appears, there must
be a retroactive mechanism of some kind. The most
familiar — though not perhaps most strictly relevant —
form of oscillation is the simple harmonic motion of a
pendulum. Even in the case of the simple pendulum,
sustained vibration depends on the regular transmu-
tations of position and velocity as shown in the basic
equations-
dS
dt
dV
~dt
= V,
sin 5'
where ^S' is angular position; I", velocity; g, constant of
gravitation; and L, length of pendulum
From these it is seen that changes in 6' depend on
the value of V while changes in V depend on the value
of S. This is the basic condition for feedback, and
wherever two variables are thus interdependent
oscillatory behavior is likely to occur. From the
dynamic standpoint a swinging pendulum is not a
single object but a system of two variables. Whether
the system will be ' spontaneously' active or stable is
another question and depends upon the sign of the
constants that determine the feed-back ratio. In the
case of the pendulum, the sign is negative, so the
system is stable near its resting state. An "ideal'
frictionless penduliun however would be unstable
because the random Brownian movement of its
molecules would inevitably set up an oscillation at its
natural frequency which, in the absence of damping,
would continue indefinitely. This effect can be ob-
served in the case of the very small light suspensions
of sensitive galvanometers.
A large pendulum, however, is stable in the sense
that the frictional losses limit the extent and duration
of any o.scillation. In the 'ideal' case the feed-back
factor is unity; in any practical case it is less than
unity, so to sustain an oscillation energy must be
supplied from outside the system. Furthermore, the
more massive the system, the more precisely must the
energv be distributed in tiine so as to reinforce the
movement of the pendulum; it must be phase-locked
to the oscillatory element.
This example of simple harmonic motion illustrates
two ways in which rhythmic activity may be gen-
erated: first by interaction between a 'noisy' or random
energy source and a small-scale or loss-free retroactive
system, second by interaction between a phase-con-
trolled energy source and a normally damped retro-
active system. Obviously intermediate conditions
between these extremes exist and many of them can
give the impression of ' spontaneity' because the
relation between the time-distribution of energy and
the degree of damping of the oscillatory system may
not be obvious without careful experiment. In such
a system, activity once initiated will tend to persist,
but the first cause may be obscure.
RELAXATION osciLL.\TORS. Lcst it sliould be thought
that some sort of simple harmonic motion is the only
possible source of rhythmic activity, another mechani-
cal illustration should be considered. This is in the
class of 'relaxation oscillation"; a simple example is the
autosiphon in which one end of an inverted U tube is
connected to the outlet of a water tank with the top of
the n below the top of the tank and the open end of
the n near the bottom of the tank. If the tank be now
filled from a steady source, the level will rise in a
linear fashion until the water level reaches the top of
the n . At this point a siphon will be formed and the
water tank will empty through the siphon, if the rate of
flow through the fl is greater than that from the
source. When the water level falls below the open
INTRINSIC RHYTHMS OF THE BRAIN
281
end of the pipe, the siphon will be broken and the
whole process will be repeated. The rate of change of
water level with respect to time o\er the cycle will
approximate to two intersectine; straight lines, the
slope of which will depend upon the rate of filling and
the rate of emptying respectively. An interesting case
is when the rate at which the siphon empties is exactly
equal to the rate of filling; in these circumstances the
water level will rise linearly to a maximum and remain
there indefinitely. The system is stable, but the flow
of water is continuous. Obviously, in such conditions,
a slight change in flow rate at input or output will
engender relaxation oscillations of level. Instability
in this system will result from a rise or fall in input or
output, and only very careful examination of the
rate chart would disclose which, in any particular
occasion, was the most likely cause.
Another interesting feature of this system is that a
transient change in, say, the rate of water input can
act as a " stimulus' to initiate a complete cycle of
operation provided the rate of change exceeds a
certain threshold. The value, form and scale of the
response to such a 'stimulus' will be independent of
the nature of the stimulus and will be all-or-none. It
will also have an absolute and a relative refractory
period. In fact, a system of this type is closely anal-
ogous to the schema generally proposed for nervous
action. The steady filling and emptying of the tank
corresponds with the metabolism of an excitable
structure, and the excitability-stability relation is
similarly dependent on the maintenance of a dynamic
equilibrium. Furthermore, there is illustrated a rela-
tion between excitability and homeostasis. If the
constancy of water level in the tank — or potential
diflference in a nerve cell — is regarded as an important
condition, then the system is evidently an admirable
device for autoregulation within certain limits of
external variation. The standard unit ' response' of
discharge — and replenishment — is a signal that the
limits of self control have been exceeded. Continued
rhythmic activity is a signal of sustained excess or
deficiency.
DISTINCTION BErVVEEN SIMPLE H.^RMONIC .AND RELAXA-
TION OSCILLATORS. The behavior of this elementary
hydraulic model may be contrasted with the simple
harmonic motion of a pendulum; the waveform in the
first case is a series of asymmetric transients while in
the second it is of course strictly sinusoidal. The auto-
siphon shows no tendency to oscillate after a dis-
turbance is over whereas the pendulum exhibits a
damped train of vibrations. Similarly, the autosiphon.
when stable, can be triggered to give a full cycle of
activity by a minimal but supraliminal stimulus,
whereas the pendulum requires either full scale tran-
sient deflection or repeated stimulation at its natural
frequency to evoke a maximal discharge. The res-
onance of the pendulum is typical of such systems;
the strict relation between sharpness of resonance and
length of build-up and die-away time is important.
The autosiphon exhibits no true resonance; its
response is all-or-none. However, it can display the
phenomenon of pararesonance; the maximum rate of
discharge is produced most economically when
stimuli are given at the same rate as the natural period
of the operation cycle.
ELECTRIC EQUIVALENT OF HYDRAULIC MODEL. This
detailed analogy is presented because appreciation of
the differences between the two main classes of
rhythmic activity is essential for understanding the
difliculties which still surround interpretation of the
rhythmic electrical phenomena in the nervous system.
The character of the relaxation oscillator which is
most instructive physiologically is that it is a nonlinear
system; its operation depends upon the sharp thresh-
old which separates one regime from another.
If the hydraulic model seems too trivial, the com-
ponents may be replaced with electrical ones, po-
tential difference for water-level, current for flow,
capacitors for the tank, resistors for the pipes, dis-
charge tubes with their nonlinear voltage-current
characteristics for the siphon. This produces a circuit
arrangement familiar to electronic designers as a time-
base or sawtooth oscillator. In fact, .such an electric
model has been built and is in regular use for teaching
and demonstration to illustrate the behavior of a
system containing several such circuits in a chain or
cascade C56). In this embodiment of the analogue,
a series of such systems, coupled together, can be seen
to provide for propagation, inhibition, unidirectional
synaptic transmission and other basic properties of
axonic and neuronic action. When more elaborate
forms of interconnection and switching are provided,
properties such as homeostasis and ultrastability
appear, as demonstrated by the machines constructed
by Ashby (4) and Uttley (52).
The working hypothesis embodied in the simple
model of nervous action is that every element of a
nerve cell from soma to terminal dendrite is, in
effect, a miniature relaxation oscillator. Each element
thus considered is connected to tho.se on both sides of
it so as to facilitate by its own activity their tendency
to discharge. A crude hydraulic counterpart would
282
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
be a series of autosiphons, each emptying into the one
beside it so that should any one element operate, the
whole chain would be initiated. This model would not
work, however, for it requires that each element be
above all the others which is absurd. In the electric
model this difficulty is overcome by providing capaci-
tors which direct a proportion of the discharge cur-
rent of each element to the trigger tubes of the ad-
jacent ones so as momentarily to raise the potential
differences across them to their discharge threshold.
This is an important feature, since it suggests that in
a living nerve the current generated at any active
region, the action current, may produce fields of po-
tential difference great enough to initiate at a distance
the electrochemical process responsible for the char-
acteristic depolarization and discharge. This effect is
of course demonstrated ijy the circumvention of a
blocked region in a nerve by leading the action cur-
rent through an inert conducting bridge (30).
SPONTANEOUS RHYTH.MIC ACTIVITY IN
EXCITABLE TISSUES
Rhvthmic Activity in Singh' Units
With these properties in mind we may revert to
the question of spontaneous rhythmicity. In a single
nerve cell, as in a single clement of the nerve model,
spontaneous rhythmic activity will tend to occur
whenever the discharge threshold is at or below the
polarization potential. As is well known, depression of
the threshold of excitation, or lengthening of the ac-
commodation constant by the action of drugs, does
induce spontaneous rhythmic activity, even in
normally passive peripheral nerve fibers (19). In gen-
eral, the amplitude and rate of .such a discharge de-
pends on two factors: the rate of charge or polariza-
tion, and the rate of discharge or depolarization.
These two time constants are independent variables
to a first order of approximation and may be analo-
gous to the two resistors in a sawtooth relaxation
oscillator which control the sweep speed and fly-back
speed, respectively. In this comparison the flyback is
equivalent to the action potential or spike discharge,
which need not be numerically equal to the total
available polarization potential.
Rliytlimic Activity in .Netwurks
Now, when several such elements can interact wiih
one another by their electric fields, the aggregate
system will tend to exhibit generalized rhythmic ac-
tivity at a frequency very much lower than that sug-
gested by the time constants of the single elements.
The repolarization time of neurons in the central
nervous system is probably equivalent to their re-
fractory period and lasts about i msec. The maximum
frequency of spontaneous discharge for such a neuron
is therefore of the order of 1000 pulses per sec, but
the lowest rate depends on the relation of the degree
of depolarization to the threshold. In effect this im-
plies that there should be an inverse relation between
the amplitude and the frequency of a spontaneous
rhythm.
The i^asic waveform of a discharge determined in
this way should be of an asymmetrical sawtooth
variety, the asymmetry being more apparent at
higher amplitude, though the proportions are actually
constant. It can be shown, however, that in the case
of a large population of mutually interacting unstable
elements the waveform of the aggregate discharge
may be so smoothed as to lose all traces of its angu-
larity and come to lie indistinguishable from a
sinusoidal rhythm. This principle is actually applied
in electronic circuit design to obtain a sine wave sig-
nal from a square or triangular source which can be
activated or synchronized without the inertia of a
conventional sine wave oscillator.
The conclusion to be drawn is that the wav-e form
of a spontaneous rhythm originating in a population
of active elements is of limited assistance in determin-
ing the mechanism of its .source; a pure sine wave may
originate in an assembly of relaxation oscillators, but
a relaxation wave form is less likely to be the output
of a single harmonic source.
Rhytlimic Activity in Piiinitive Organs
Having now considered the basic properties of
rhythmic generators in general, we may turn to the
specific features of this class of activity in the brain.
At the very outset it must be admitted that no con-
venient generalization is possible. Rhythmic dis-
charges are common in the nervous and muscular
systems of nearly all animals, but there is as yet no
proof that they can all be attributed to the same
mechanism.
For example, details of the intrinsic rhythms of the
cardiac ganglion cells in Crustacea have been de-
scribed by Hagiwara & Bullock {26) and Bullock &
Terzuolo (14). The wave form of the.se rhythms
seems to be typical of the relaxation oscillator type,
as shown in figure i. Harris & Whiting {27) hax'e
INTRINSIC RHYTHMS OF THE BRAIN
283
FIG. I. Spontaneous electrical discharges in single cells of lobster cardiac ganglion. The wave
form is suggestive of a relaxation oscillation vifith two separate time constants. .4 and B are from the
same cell in the lobster. It shows a large pacemaker potential, presumably arising nearby, and an-
other prepotential before the spike. This can fail to elicit a spike, can continue (end of .-1) or redevelop
(third spike of Bj after the spike, and can initiate repolarization almost as complete as a spike can.
Note the failure of the prepotential to arise following the third spike in B, with instead an undulation
leading to a new cycle. C, D and E are three different crab cells of type D, showing different forms
and permutations of pacemaker potential and repolarization. Scales: A, B, 500 msec; C, D and E,
50 mv, 200 msec. [From Bullock & Terzuolo (14).]
confirmed the early olsservations of Pa ton (45) and
Wintrebert (68) that in embryonic clasmobranchs
spontaneous rhythmic activity of the mu.sculature is
entirely myogenic in origin. A tendency to repetitive
activity seems to be intrinsic in many excitable struc-
tures and, indeed, absence of spontaneous discharges
may be a special case of control or inhibition. In
primitive or embryonic organisms the intrinsic
rhythms are generally little affected by external
stimuli, whereas in more highly developed structures,
such as the human brain, responsiveness to stimula-
tion is the general rule.
This difference suggests that, as in other living
structures and functions, a basic mechanism which
survived the first stages of evolution because of its
simple utility may, as it were, be exploited in the
later stages of specialization to fulfill a much more
elaborate function. As a crude working hypothesis, we
may consider that the rhythinic properties of primi-
tive creatures and rudimentary organs, which at
first provided a simple means of propulsion, have in
our own brains assumed an essential role in the
systematic timing and distribution of information
within the neuronic network.
Intrinsic Rhythms in the Human Brain
For the purpose of this chapter, attention will be
directed mainly to the rhythmic activity of the human
brain. This has received the greatest attention since
the discovery of Hans Berger of the human electro-
encephalogram (9); the observation and measurement
of the rhythmic features of the human EEG have been
practised on an increasing scale for 20 years in several
284
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
hundred laboratories. There is the further advantage
that such correlation with function as may be estab-
lished can be followed more closely in human sub-
jects whose mentality and behavior are more familiar
and comprehensible than are those of other animals.
The rhythmic wave-like potential changes desig-
nated as ' alpha rhythms' bv Berger are the most
prominent and peculiar feature of human brain ac-
tivity, and these rhythms will be taken as representa-
tive of rhythmic activity in normal conditions. An
example appears in figure 2. Since Berger's original
discoveries, brain rhythms have been subclassified,
not only on the basis of their frequency and ampli-
tude but also on their provenance and functional
correlation. Employing these criteria, three other main
classes of rhythm have been identified in human sub-
jects:'theta rhythms' with a frequency of 4 to 7 cycles
per .sec, occupying typically the parietal and tem-
poral regions of the brain and associated with child-
hood, and emotional stress in some adults (fig. 3);
'delta rhythms' with frequencies from less than i up
to sM cycles per sec, associated with deep sleep in
normal adults, with infancy and with organic brain
disease (fig. 4); and 'beta rhythms' with frequencies
higher than 14 cycles per sec, generally associated
with activation and tension. In considering the nature
and correlations of the alpha rhythms, it should always
be recalled that these other rhythmic phenomena
exist and that their mechanisms may be as different
from those of alpha rhythms as are their functional
associations. Moreover, in the realm of brain pathol-
ogy, relatively enormous rhythmic discharges are as-
sociated with certain types of epileptic seizures, and
these again may originate in a manner quite different
from that of the normal alpha rhythms.
1001 1" 'i'jiV^ll,'^'
FIG. 2. An example of the classical effect of eye closure on alpha rhythms in a normal subject.
Upper five traces were recorded from electrode sites shown in the diagram in the upper left corner.
These five primary records show the typical burst of alpha activity as the eyes are closed, followed by
marked amplitude modulation, the alpha rhythms being most prominent in the posterior occipital
derivations. The sixth trace representing the frequency analysis, indicates the presence of two com-
ponents at 9 and 10 cycles per sec. The seventh trace, that showing the period analysis, indicates
the presence of wave intervals varying from 90 to 1 1 o msec. The three methods of display are es-
sentially complementary since each system emphasizes certain characters at the expense of others;
all the information is present in the primary records but is not easily extracted from them visually.
INTRINSIC RHYTHMS OF THE BRAIN 285
EYES SHUT
ANSWER
PEAK-TROUGH PERI06 IfflJICATOR
FIG. 3. Alpha and theta activity in a normal young subject. Records as described for figure 2.
The primary records are particularly complex. In the frequency analysis records, the solid lines
connect the peaks related to channel 3, while the dotted lines connect the peaks related to channel
5. This analysis reveals components in the theta and alpha bands which fluctuate independently in
the two hemispheres. During the first half of the record the subject was at rest and the second
half was replying to an annoying question. During this phase the theta content increased in the
transverse derivation (channel 5) after a period of activation and fluctuation in skin resistance
(G.S.R.). The period analysis shows fluctuations in wave intervals between about 100 and 140 msec,
corresponding to periods of relative alpha and theta activity. The prolonged theta activity is a char-
acteristic of this response to annoyance.
EYES OPEN
/vv
;v\^^'J^^A/^M\KJ^\r^\^^f'''^'^ 'jhu^f^^^^njvJf'S
^/V^.^^'^VVM^/;'V^•v»v "^V'^'" ^^?, «\^a^> ,;• '^/r
.^^j\^.r'^/^^^-^^'^-hJ\Jfw-^^ ^"^MlivJ^
'\\/4'.^/H^'^\^{f\^
\m^
FIG. 4. Delta and theta activity recorded from a normal child aged 3. Six primary records (above)
and frequency analysis record (below). In early youth these rhythms are characteristically difTusc
and complex; the frequency analysis shows almost equal abundance in the range from i .5 to 9 cycles
per sec. with a peak in the theta band at 5 cycles per sec. These rhythms are almost unaffected by
stimulation.
286
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
PROPERTIES OF ALPHA ACTIVITY AS TYPICAL
OF INTRINSIC RHYTHMS
Early Rijmrls
The early studies of alpha rhythms in human beings
were made with straiehtforward recording devices —
mirror oscillographs, cathode ray oscillographs and,
later, ink writing recorders. These provide simple
graphs of voltage changes with respect to time; it is
unfortunate that the human eye is severely limited in
its capacity to analyze a curve of this sort, being at-
tracted to the most prominent features and tending to
ignore or misrepresent the minor ones. Berger's early
studies, original and detailed though they were, pro-
vided only limited information about the distribu-
tion and complexity of the alpha rhythms because he
employed only one or two separate recording chan-
nels; his impression that the alpha rhythms were de-
veloped by the whole brain was due to this limitation.
During the last 20 years however, the technical trend
has been toward multiplication of channels and
elaijoration of analyzing de\ices. There is no doubt
that in consequence the picture of alpha activity has
become progressively more and more involved and
controversial. Adrian & Matthews (i), and Adrian
& Yamagiwa (2) were the first to prove that the
alpha rhythms usually arose in the posterior regions of
the l)rain, and they were able to demonstrate in some
subjects an abrupt change in the sign of the potential
gradient of the alpha waves over the scalp, an effect
which has since become known as a ' phase-re\ersal
focus'. In the simplest case, a potential distribution
of this sort could be produced Ijy an equivalent gen-
erator within the head oriented radially with its
axis projecting toward the surface at the 'focus', and
T-
■■^iAfc*iiii»<p*Mi ijiMy*^!** I *^m^i»^
, -'^ .^^ n»^ii^w^^>i
EYES SHUT ®
^-- Nn^MAr' •NiVk*^*^'
>^»»■*'»^|«*^\/^^<»»V^ll^^i>^MlM*»^il■■■^«*W■'VN^^^WP^V^yl^j^^^»|»H*W*'^^W*^ /^v *"v-.,'Vv*'V***'**'\.
I Ui mill ,1.11
EYES OPEN* EYES SHUT®
■MiMM
' 1, V
> W V i- . — . V V
' ii|inw»iiii-»'[.r|| i'i»<M<iM*»«'>**l''V'V»if»>/«N»»<^V*»«»»«l>,f~»l>»'^>««««/*V<'>«^,ni-l<tNlii')»
.l»«»**>ii|^» » ■ l■■.^~.v^^l><|>■^Wli^|lwl\t<l«W>'|,^lll<Mr^■«^»^MlV^»««^W«*»»»v»<^ir'»«»^'|||■■<»»lj^^f»|«^<^''l|»
FIG. 5. Primary records, frequency analysis and period display from a subject of the alpha M
type. Upper portion contains foiu' primary records and a frequency analysis which is continued in
the middle portion; the lowermost record is the period display. Immediately on eye closure there
is a brief burst of alpha activity at i o to 1 1 cycles per sec, but even this is sometimes lacking. The
spectrum of brain rhythms is almost 'white,' although the absence of regular rhythms makes the
faster activity seem more obvious.
INTRINSIC RHYTHMS OF THE BRAIN
287
this was the schema tentatively suggested for the
origin of the alpha rhythms in the human brain.
Individuality of Alpha Rliytlirns and their I 'ariation
During the last 10 years several experiments have
expanded and modified the methods introduced by
Adrian & Matthews and have also widened their
survey to the study of a large number of subjects.
These obser\ations have shown clearly that, unlike
most physiological phenomena, the alpha rhythms
must be considered in relation to each individual of a
given species and not merely as a specific or generic
character. In other words the alpha rhythm patterns,
in terms both of spatial distribution, frequency and
relation to function, are highly characteristic of every
indi\idual. The variation is so wide that classification
of alpha type must include a class of normal person
in whom no alpha activity whatever is visible (fig. 5),
even in those conditions which are most favorable to
the appearance of these rhythms in other people. At
the other extreme there are people in whom alpha
rhythms persist even in circumstances which are most
inclined in other subjects to interrupt or suppress this
activity. A distribution of this sort is extremely difficult
to reconcile with any simple theory of spontaneous
activity, and any general scheme to account for
these phenomena must include considerations of
mental and even social character — aspects of human
existence which are in general far removed from the
domain of neurophysiology.
Accepting the need for considerable reserve, it is
generally true that the amplitude of spontaneous
rhythms in the alpha category is inversely correlated
with visual attention. Empirically the frequency
range acceptable for alpha rhythms is from 8 to 13
cycles per sec, and the distribution of frequency in a
large population follows a more or less normal Gaus-
sian curve, the mode falling at about 10 cycles per
.sec. The tails of the curve should extend to about 6
and 15 cycles per .sec; about one in 5,000 individuals
does in fact show rhythms at these limits which com-
ply with the arbitrary definition of alpha rhythms.
Complexity oj Alpha Rhythms
The appearance of alpha rhythms in normal people
is usually suggestive of intrinsic complexity and var-
ious methods of analysis have jjeen applied to the
study of this possibility. Whatever method is used the
great majority of alpha rhythms are compound in the
sense that there are usually several components within
the alpha band (65). The superposition of these vari-
ous components in a record produces an appearance
of continuous but irregular modulation; sometimes
the amplitudes and frequencies are so constant over a
period of time that a regular pattern of 'beats' is pro-
duced. The identification of the various alpha com-
ponents can also be accomplished geometrically by
recording from electrode patterns in which derivations
may be made from orthogonal electrode chains. With
this arrangement one component may be found to ije
more prominent in records from anteroposterior
electrodes and another from traverse ones. Further-
more, the components may be distinguished by their
functional activity or responsiveness. For example, in
those people with persistent alpha rhythms, one com-
ponent may continue when the eyes are open while
another is more prominent when the eyes are shut
during mental activity. The geometrical and func-
tional separation of alpha components is perhaps
more convincing than their display by instrumental
analysis, but the three methods can be employed to-
gether to construct a dynamic picture of spontaneous
activity in relation to function and behavior. Other
methods of analysis of alpha rhythms have been pro-
posed by Sato (47), Krakau (35), Burch (15), Koz-
hevnikov (34) and Bekkering (8). These have not so
far been applied to a very wide range of subjects and
situations but their trials have been promising (15, 16,
24, 25, 36, 66).
In experiments designed to exploit the three prin-
cipal methods of analysis, simultaneous observations
of changes in the autonomic nervous system and the
behavior of the subject are of considerable value.
These techniques have not yet been fully developed
so the information is still inadequate to give a clear
indication of alpha significance in terms of somatic
change. A further difficulty is that such experiments
involve some selection of ' suitable' subjects and this
has caused considerable difficulty in comparing re-
sults from diiTerent laboratories. For example, there is
a natural inclination to choose for study people with
large regular alpha rhythms since they seem likely to
provide records which are easier to measure and inter-
pret. Selection of people in this group inevitably
limits the scope of investigation, and there is even
some evidence that subjects with extremely prominent
and persistent rhythms may display mental characters
bordering on the pathological.
Identification of Alpha Components
When allowance is made for these limitations, there
remain certain general features which seem incon-
testable. First, the attenuation and constriction of
288
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
alpha activity during visual attention and mental vigi-
lance is almost invariable. When means are available
for instrumental analysis, a convenient form for the
measure of alpha activity is 'aisundance'. This in-
cludes dimensions both of amplitude and of persist-
ence. It is comparable with a measure of energy, but
this term is undesirable because of its precise connota-
FiG. 6. An a.ssembly of cut-outs showing Huctuations in
abundance of alpha components over long periods during the
performance of various tasks: (/I) in a subject of the alpha-
responsive type showing an immediate and sustained rise in all
alpha components on eye closing and a lack of response to
mental activity with the eyes shut; (/?) with greatly increased
analyser gain the alpha components are barely perceptible in
an alpha-M type subject; (C) in a responsive versatile subject
the various components fluctuate over a wide range during the
performance of a psychological task.
tion in physical systems. When analyzed in terms of
the abundance of its various components, the changes
of alpha activity during spontaneous or induced varia-
tions of behavior can be plotted as abundance with
respect to time (fig. 6). Necessarily, each component
is arbitrarily identified by its frequency, usually as a
whole number of cycles per second, but a composite
plot of these arbitrary components reveals the nature
and extent of the complexity previously referred to.
Often the various components exhibit some degree
of independence, particularly during the performance
of an exacting task, and the individuality of the spon-
taneous rhythms is considerably emphasized by this
procedure. The classical responsive types of alpha
rhythm rise and fall inversely according to the in-
tensity of concentration of the subject, but during a
period of tranquillity the pattern of frequency and
distribution may remain almost constant so that even
short samples of record are similar to one another.
.At the other extreme, subjects showing little alpha
activitN display an extremely varied pattern, even
during rest. Those alpha components which are
present in such records fluctuate in abundance from
moment to moment, so that extremely long samples
of record must be taken if the samples are to resemble
one another.
This observation has .suggested that a useful measure
of alpha character would be the length of sample
necessary for all of a set of such samples to fall within
a specified range of variation. This computation is
performed automatically with a wave analyzer fitted
with an electronic averaging device. This measure
pro\ides an estimate of the repertory of a person's
alpha activity and has been found to be related to
the .scope and variety of interests in a population of
normal young adults. The aspect of cerebral men-
tality defined in this way has been termed versa-
tility (jo). Detailed analysis of alpha responses has
suggested that, in some people at least, relative
abundance of the slower alpha components may be
associated with rest or inactivity of the mechanisms
of internal imagination, while abundance of the
faster components is more closely linked with the lack
of significant afferent signals from the receptors.
Thus with the eyes closed and the subject relaxed, the
most abundant rhythm may be at 9 cycles per sec;
but when the subject is given a mental task to per-
form with the eyes shut, the frequency of the dominant
rhythm may seem to rise to, say, i i c\cles per sec. In
some cases, however, the apparent acceleration is due
to attenuation of the lower frequency components
during concentration, leaving the higher frequency
INTRINSIC RHYTHMS OF THE BRAIN
289
ones unmasked. In this condition the siilyect is attend-
ing to imaginary or endogenous signals and is ignor-
ing external ones.
The intricate and elusive relations between the
various brain rhythms and mental functions have
been explored also by Mundy-Castle (43) who has
identified three types of theta thythm and two of beta
rhythm, as well as various categories of activity in the
alpha range of frequencies. The statistical relations
between types of brain rhythm and psychological
character have been analyzed in detail by Werre (66)
who concludes that, although no unique associations
can be established between any single EEG variable
and any specific psychological parameter, none the
less certain electrical patterns are contingent on psy-
chological grouping. For example, alpha frequency is
related to the performance of psychotechnical tests,
since subjects with low frequencies perform slowly but
steadily, those with high frequencies fast and regu-
larly and those with complex alpha rhythms er-
ratically.
Although the alpha-blocking effect is seen most
clearly in response to visual stimuli, it can also be pro-
duced in some subjects by nonvisual stimuli which are
novel and startling. The effect of nonvisual stimuli
usually wears off quite rapidly, but if an ineffective
stimulus is then accompanied or followed by an
effective visual one the neutral stimulus may become
'conditioned'. Conditioning of alpha blocking was
first studied intensively by Jasper & Shagass (31)
and has recently been extensively employed in the
experimental analysis of learning by Gastaut ti al.
(24). They attribute generalized desynchronization
of intrinsic rhythms by a novel stimulus to activation
of the brain stem reticular system, and local desyn-
chronization by a specific stimulus to activation of the
thalamic reticular system.
Degree of Constancy and Range of I'aiuilnm
in Alpha Frequemy
Although the frequency and distribution of alpha
rhythms in any particular subject are characteristic
and individual, the rate of an alpha rhythm can some-
times be shifted slightly. The range of normal varia-
tion is limited to a fraction of a cycle per second,
however, and such changes cannot be identified and
measured ea.sily in conventional records. The effect is
easily demonstrated with a toposcope display system
(56, 57, 61, 64) designed to emphasize and correlate
rhythmic activity in many regions. An example taken
from a normal subject is shown in figure 7. The fre-
quency of the major alpha rhythms is here 8.80 cycles
per sec. over a wide area at rest. During mental ac-
tivity the rhythm disappears in all but two derivations
in the right centroparietal region where the frequency
rises to 9.45 cycles per sec. and then gradually subsides
to its original frequency in about 90 sec. (fig. 8). This
example illustrates two very important features of
alpha activity; first, the extreme constancy in fre-
quency in tranquil conditions; second, the degree of
independence of the two hemispheres and even of
adjacent regions during activity. As can be seen in
figure g, one minute after the start of the experiment
when the right centroparietal region is showing alpha
rhythm at 9.1 cycles per sec, the left temporoparietal
derivation has resumed alpha activity but at 9.35
cycles per sec. Nevertheless, when the period of at-
tention is over, all regions return precisely to their
original rate of 8.80 cycles per .sec.
This degree of constancy is by no means unusual
and has been reported afso by Brazier & Casby
(12) and Barlow & Brazier (5) using an entirely
different method of analysis and correlation. The pat-
tern of frequency fluctuation, however, is an individual
character and is related to the complexity of the rest-
ing alpha activity; if there are .several rhythms, the
apparent changes in frequency are usually abrupt
and extensive and may be in the direction of accelera-
tion or deceleration. Changes of this type are at-
tributable to the substitution of one process for
another rather than to changes of rate in the same
process. In general, a particular alpha rhythm seems
to be capable of aijout ±0.5 cycles per sec. variation
within the physiological range; a greater change can
be induced by the administration of drugs but such
alterations are associated with signs of intoxication.
For example, ingestion of 1 00 ml of alcohol in i }'2
hr. in one subject reduced the alpha frequency from
10 to 9 cycles per .sec, but the subject was seriously
inebriated and relapsed into a prolonged stupor 40
min. later. Conversely, activating drugs such as
amphetamine or pipradrol compounds in sufficient
doses may raise the frecjuency of an alpha rhythm
by as much as i cycle per sec, but this is associated
with marked mental stimulation and agitation (fig.
10). The effects of hallucinogenic drugs such as LSD
25 are also related to mental change; doses sufficient
to raise the apparent alpha frequency, from e. g. 10 to
12 cycles per sec, induce characteristic transforma-
tions in mood and character.
290
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
FIG. 7. Toposcope display sys-
tem record of the effect of mental
activity on alpha frequency and
distribution in a normal subject.
Each of the 22 circular areas is
the face of a cathode ray tube
connected to an electrode pair
over the brain. There are thus 22
channels. In each circuit there
has been introduced a spiral
scanning time-base upon which
are projected the variations in
brilliance proportional to the
rhythmic changes of voltage re-
sulting from brain activity. In
this case the rotation speed of the
signals was one-third of the fre-
quency of the resting alpha
rhythm, which was 8.8 cycles per
sec. The duration of each expo-
sure was 8 sec. The intrinsic
rhythms are seen as white
smudges in each indicator tube.
The first exposure (.4) shows the
alpha distribution and frequency
at rest; during the next exposure
(B) the subject was asked to
begin a series of mental tasks;
the immediate effect of the in-
structions was to suppress the
alpha activity in all but two
channels in the right hemisphere
where the frequency rose to 9.4
cycles per sec. The subsequent
exposures were taken during
performance of the task and show
a gi-adual return to the resting
state. During this period the
alpha activity decelerated slowly
and returned to the left hemis-
phere where it remained accel-
erated for a longer period than
on the right side. The return to
the original condition took nearly
too sec, but the final frequency
was exactly the same as before
the activation. [From Walter
(61).]
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INTRINSIC RHYTHMS OF THE BRAIN
291
^. FREQUENCY
70 8 0 90
TIME IN SECONDS
FIG. 8. A plot of the alpha frequencies in the right centroparietal and left temporoparietal regions
derived from the experiment represented in figure 7. Independent fluctuations of the two hemispheres
are far outside the error of observation and are characteristic of the subject. [From Walter (61}.]
c/s
12 2
"o<.
FREQUENCY
121
12 0
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116
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20
30
40
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TIME
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CON
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90
100
FIG. 9. Fluctuations in alpha frequency of another normal subject studied in the same way as
in figure 7, exhibiting complex alpha analysis. The resting frequency of 1 1 .6 cycles per sec. is
replaced by others at 12 and 10.95 cycles per sec. which alternate in dominance, but the original
rate is returned to at the end of the activation period. [From Walter (61).]
292
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
97
96
95
94
9 3
92
9(
90
89
e 8
87
8«
INST.
1
1 1
MERATRAN
SUM ANS.
1
1 1
SUM A. A.
8«C/S
1 1 . 1 1.1
. 1 . 1 . 1 . 1 . 1 . 1 . 1 ^.
10
20
30
40
50
60
70
80 90 100 110
TIME IN SECONDS
120
130
140
FIG. lo. Alpha frequency changes in the same subject as in figures 7 and 8 under the influence of
pipradrol (Meratran). The steady frequency has risen by 0.4 cycles per sec. and the rate of change
during attention is abrupt and discontinuous, but again the frequency returns to precisely its orig-
inal value. [From Walter (61).]
Effects of Activation and Stimulation
The effects of generalized or nonspecific activation
on the spontaneous alpha rhythms are sHght but
characteristic; of equal interest are the relations be-
tween responses to specific physiological stimuli and
the distribution and time relations of the intrinsic
rhythms. The most dramatic and effective changes
are of course those produced by visual stimulation. In
one of the early reports on the effect of flicker, Adrian
& Matthews (i) described these as 'driving the alpha
rhythm', l:)ut more detailed study (42, 53) has shown
that, except in certain circumstances, responses to
photic stimulation are distinct from alpha waves.
Those circumstances in which alpha rhythms are in-
volved in evoked responses are of particular interest
in the study of spontaneous activity since the interac-
tion between rhythmic external stimuli and intrinsic
brain rhythms indicates a possible function of the
latter. Bishop (10, 11) reported cyclic changes in the
excitability of the visual system of the rabbit and the
relation of such changes to intrinsic alpha rhythms
has Ijeen studied by several other experimenters,
Bartley & Bishop (6), Gastaut et al. (23), Lindsley
(40) and Lansing (37) In some animals there seems
to be good evidence for periodic fluctuations in the
excitability of the visual system, but in human sub-
jects the observations are inconclusive because of the
wide variation between individuals. The properties
of the retina interfere .seriously with attempts to meas-
ure the time relations between visual stimulus times
and evoked responses; in effect, the retina acts as an
integrator for brief flashes of light so that the volley
of impulses in the visual pathways is a very ragged
one, spread over a period of o\er 50 m.sec. even when
the stimulus is a flash of light lasting only a few micro-
seconds. This means that even if the central visual
structures were totally ' blind' for half of every alpha
wave, they could still receive signals that fell in the
blind phase because the afferent volley would outlast
the critical period.
Synchronization of Alpha Rhythms
There is a further complication to be considered;
the alpha rhythms can only be 'driven' over a narrow
range of frequencies, Ijut this range is enough to
allow them to be synchronized or locked in phase by
afferent visual signals. This is demonstrated clearly in
toposcope records; this device can be arranged to
deliver brief flashes of light in a time-sequence of
doublets or triplets at any chosen repetition rate. In this
way the pattern of true evoked responses can be distin-
guished from the superficially similar but functionally
distinct pattern of synchronized alpha rhythms. When
INTRINSIC RHYTHMS OF THE BRAIN
293
the repetition rate of the flash groups is set at about
the alpha frequency or a submuhiple of this, many
subjects show no signs of the stimulus pattern but only
a sharp synchronization of the alpha rhythm. This
effect can also exist together with an evoked pattern
and the two modes of response may appear in adjacent
regions which may exchange modes from time to time.
The effects of alpha driving and alpha synchroniza-
tion can combine to corrupt an evoked response by
interpolation of the ' missing' component in a triplet
pattern, or by omission of one of the responses.
The distinction between rhythm synchronization
and true evocation is important in the interpretation
of the results of such experiments; it is not always
easy to achieve because the identity of a cerebral
process can be inferred only indirectly from its elec-
trical characters. However, with the toposcopic dis-
play .system the peculiar phase or time relations of
the alpha rhythms in different parts of the brain can
be used to supplement identification by frequency,
distribution and responsiveness. Records taken with
electrodes on the scalp almost always reveal clear
differences in the time of appearance of alpha
waves in various regions. In general, the maximum
potential change is earlier in the anterior regions
than in the occiput, and besides this anteroposterior
sweep there is evidence of an even greater discrepancy
in phase between the longitudinal and transverse
derivations covering the same region. The commonest
appearance is for the alpha waves in the transverse
derivations to lead those in the longitudinal ones by
90°; for example, the peak of the waves seen in the
parietotemporal channel occurs at the instant of zero
potential in the parieto-occipital one. These phase re-
lations are so clear and consistent that they can be
used as a diagnostic sign of alpha activity; when the
effect of a stimulus is merely to synchronize this ac-
tivity, the characteristic phase relations are usually
maintained. On the other hand, where there is a
true evoked response, this shows the expected latency,
which varies slightly from region to region, but the
phase relations are not those of the alpha activity.
Even before these details of alpha activity were
known the pos.sibility had Ijeen considered that such
rhythms represented a more elaborate process than a
simple time cycle of excitability. It may be supposed
that the regular rise and fall of threshold in the brain
resembles the ebb and flow of a tide round the globe.
The time of high tide, so to say, varying from port to
port will not merely control the accessibility of the
various relav stations but will also act as a clock.
transforming time into space patterns and contrari-
wise. From this conjecture have been derived a num-
ber of variations on the theme of scanning, elaborated
by McCulloch (41), Wiener (67), Walter (56) and
others. The nearest to conclusive evidence of such a
process is the phenomenon described by Walter (58)
as ' abscission' ; the elements of a visual time pattern
are cut off and projected in a spatial pattern in the
visual association regions of the brain. The time rela-
tions and distribution of this effect suggest that the
sweep of alpha waves through the cortex may provide
the time-space transformation. Auxiliary subjective
evidence is provided by the illusions of mottled mov-
ing patterns of colored light seen when gazing at a
featureless flickering field. The illusions are powerful
enough to produce aberrations of color vision as indi-
cated by the Ishihara test when viewed by a flickering
light (59) and they are attributed to the same cause
as the complex electric patterns evoked by flicker —
interaction between rhythmic volleys of impulses in
the visual pathways with the intrinsic scanning
rhythms.
Evidence from Intracerebral Electrodes
The spontaneous brain rhythms as .seen in scalp
records seem to have a characteristic geometry as well
as a proper frequency and relation to function. Such
records are open to the obvious criticism that being
derived from electrodes on the surface of the head,
they can represent only the average field of vast ag-
gregations of neural units, all remote from the elec-
trodes in terms of neuronic dimensions. Additional
information is now a\ailable from investigations with
microelectrodes placed in or near to individual
neurons and their processes (38) and also from elec-
trodes implanted in the brains of human subjects for
clinical study (20, 48, 49).
These methods are still in the early stages of de-
velopment, but they have nevertheless already indi-
cated that even in the intimate details of brain
mechanisms spontaneous rhythmic activity is a dis-
tinct phenomenon; it cannot be considered as an
aggregate or envelope of unitary neuronic spike
discharges. Nor is there any invariable relation be-
tween the spontaneous wave-like potential changes
near a neinon and its all-or-none action potentials.
When the probability of a cortical unit discharging is
low, then its rate of firing may be governed to some
extent by the field of the spontaneous rhythms; unit
spikes are seen more commonly in the phase when
FIG. I I . Records taken with the toposcope in the laboratory
of Dr. Sem-Jacobsen in Oslo from a psychopathic patient in
whom electrodes had been implanted intracerebrally three
days earlier. A. The approximate position of the electrodes for
the 22 indicator tubes, derived from X-ray projection drawings.
The anterior channels were connected to electrodes deep in
the medial structures, the posterior ones were in the middle of
the parietal and occipital lobes. B. The distribution of the
intrinsic alpha rhythms with the eyes shut. There are three
distinct components, one at 8.8 cycles per sec. in channel 14,
another at 8.5 cycles per sec. in channels 16 and 18 through
22, and a third at 915 cycles per sec. in channel 17. There is
also a theta rhythm at 7 cycles per sec. in channel 5. The alpha
rhythms in the posterior regions show the characteristic phase
differences suggesting a moving source. The signals in channel
8 are artefacts arising at a high-resistance electrode. C. Record
made a few seconds later during flicker stimulation at 8.8
Hickers per sec. The only regions showing clear fundamental
synchronization arc those corresponding to channels i i and 1 7
and 19. Channel 14 shows deceleration to 8.6 cycles per sec,
channel 20 is unaffected and channels 21 and 22 show a re-
sponse at twice the stimulus rate. D. Flicker .stimulation with
triplet groups of flashes at 4.2 groups per sec. evokes a replica of
the stimulus pattern only in channels 18 and 20. Channels 14,
294
INTRINSIC RHYTHMS OF THE BRAIN
-'95
the region of the neuron concerned is electronegative
with respect to the surrounding tissue. Li et al. (38)
have suggested that the microlocation of spontaneous
rhythms in the layers II to V of cat cortex may be
similar to that of the recruiting responses evoked by
thalamic stimulation. Stimulation of this type is
effective only when its frequency is close to that of the
spontaneous cortical rhythms, that is at 5 to 8 cycles
per sec, and this relation is reflected in a correspond-
ence between the phase of the recruiting response,
the spontaneous rhythms and the unit discharges. It
is not clear, however, whether the spontaneous ac-
tivity in these preparations is functionally homologous
with the alpha rhythms in human subjects.
In some cases, therefore, the spontaneous rhythms
can act as electrotonic escapements, but there are
many occasions when the spontaneous rhythms and
unit discharges are quite unrelated. This \ariability is
manifest even in conditions of normal adaptation;
Ricci et al. (46) have described the complexities of
the relations between unit firing and surface rhythms
in the occipital cortex of monkey during the estab-
lishment of conditioned responses to sounds associated
with light flashes at 7 per sec. They conclude that
such a response "is a complex pattern of interwoven
inhibitory and excitatory processes", in which the
electric fields of relatively slow wave-like spontaneous
rhythms are interlaced with the rapid all-or-none
discharges of individual cells. A similar image was
employed by \Valter C58) to describe the topologic
details of evoked and spontaneous activity in human
subjects engaged in learning: "an interweaving of re-
ciprocal electric filaments to generate an intricate and
duraijle texture of significant association."
Such observations suggest that an important factor
in cerebral mechanisms must be the geometry of the
electric fields in the region of neurons and their
processes. It is often forgotten that these fields have
vectorial as well as scalar aspects — they have direc-
tion as well as magnitude. As already mentioned, the
geometric and time relations of alpha rhythms as
seen on the scalp might be due to the adventitious
effect of remoteness from the source in a volume con-
ductor. Walter & Dovey (63) reported observations
of alpha rhythms in the depths of the occipital lobe in
patients investigated for the delimitation of cerebral
tumors, but they could not study the details of this
activity. Recently Cooper et al. (18) have been able
to obtain toposcopic records of alpha rhythms derived
from electrodes implanted in the brains of patients
with no organic brain disease. In these experiments
the subjects were provided with up to 70 fine wire
electrodes in various regions of the brain as described
by Dodge et al. (20) and Sem-Jacobsen et al. (48). In
one subject it was possible to record from intracerebral
electrodes connected to the amplifiers in the network
pattern customary for toposcope studies of scalp po-
tentials. These records (fig. 1 1) of alpha activity from
the depths of the brain show phase — and space — re-
lations quite similar to those found in the superficial
fields. The efTects of synchronization by photic stimu-
lation and of blocking by attention were also similar.
As reported by Sem-Jacobsen et al. C49), the greatest
amplitude of the alpha rhythms was found about 2
cm below the surface of the brain, but the rhythm
existed also between pairs of electrodes 4 to 5 cm
deeper. This extension of the alpha activity could not
be due to purely electric conduction, since the phase
of the waves was not alwaxs identical in the various
regions and bursts of activity sometimes occurred in
one region and not in others.
The conclusion from these studies is that some
alpha rhythms involve deep structures as well as cor-
te.x and the time relations of the alpha waves indicate
.some sort of spread from front to back and depth to
surface. The tendency of the transverse components
of the rhythm to be phase-shifted by 90° with respect
to the longitudinal ones suggests that there may be two
interlocked processes, one generated by a corticobasal
mechanism, the other, essentially corticocortical with
peaks corresponding in phase to the moment of most
rapid potential change — that is, zero potential — of
the corticobasal process.
Relation Between .Alfiha Rhythms and Effector Fiuution
The possibility that the alpha cycle may act as a
gating mechanism for afferent signals has suggested
that a similar relationship might be found for efferent
ones. Kibbler et al. (32), Kibbler & Richter (33) and
16 and 19 are synchronized at twice the group rate (8.4 cycles
per sec.) and channels 21 and 22 respond at 4 X 42 = 16.8
cycles per sec. E. Flicker stimulation with triplets at 5.6 groups
per sec. evokes true replica in channel 1 7, rhythms at 1 1 .2 cycles
per sec. in channels 16, 18, 19 and 20, and at 3 X 5.6 = 16.8
in channels 21 and 22. All these patterns were associated con-
sistently with specific frequencies and modes of stimulation
and were similar to those deri\'ed from scalp records. The
arithmetic and geometric relations of the various features in
such records suggest the presence of a number of mechanisms,
each with its own domain, intrinsic rhythmicity and responsive-
ness to stimulation.
296
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
Bates (7) reported a tendency for the \oluntary move-
ments of human sulsjects to be synchronized in phase
with their alpha rhythms, and this effect has been
observed in several ways. The experiments of Lansing
(37) indicate that the shortest and longest visuomotor
reaction times in some human subjects tend to fall at
points about 50 msec, apart in opposite phases of the
alpha cycle. There was also some relation between
motor response and spontaneous tremor, a fact sug-
gesting that cyclic changes in excitability were operat-
ing also at the level of the spinal motoneuron pool.
This is perhaps to be expected since the control of
voluntary movement is not belie\ed to depend upon
complex activation of reflex circuits through high
central structures. Obser\ations of these relations
have so far yielded only statistical information; there
is no clear indication of how the timing and gating
mechanism operates, and there are many exceptions
to any rule that can be formulated. Experiments with
auditory rather than visual stimuli have given even
less conclusive results (44). In planning and inter-
preting such experiments it is important to allow for
the tendency of some intrinsic rhythms to be pulled in
to synchrony by the signals which they or other
rhythms may in turn control. This interaction, to-
gether with integration b\- receptors, may be responsi-
ble for the discrepancies in the reports by different
observers.
EJfect of Temperature Changes
The ease with which alpha frequency can be meas-
ured and its constancy in normal conditions has en-
couraged the study of the effects of metabolic change.
Hoagland (28) induced fever artificially and reported
a rise in alpha frequency with temperature of nearly
0.5 cycles per sec. per degree C in normal subjects
and an even higher temperature coefficient in
syphilitic patients. Krakau (36), using an optical
method of frequency analysis, was unable to confirm
this effect in all his subjects and suggested that what-
ever changes may occur during artificial fever might
be due to the general arousal by the situation as much
as to the rise in temperature. This seems likely, since
measurement of alpha frequency in a few subjects
with the toposcope has shown no regular variation of
alpha frequency with the normal diurnal changes of
body temperature which would be expected to result
in fluctuations of about 0.25 cycles per sec. It would
seem that the alpha mechanisms are to some extent
protected from the primary efTects of temperature
change.
DELT.'K, THETA AND BETA RHYTHMS
Relation of Delta and Tlieta Rhythms to Age
As a representative of the class of intrinsic rhythms,
alpha activity is unique in its close and clear relation
to sensory function. The other forms of rhythmic ac-
tivity in the human brain, designated by Greek
letters for convenience rather than clarity, are more
familiar in clinical than in physiological studies, but,
apart from the paroxysmal discharges associated
uniquely with epilepsy, all are found in normal condi-
tions. Delta and thcta rhythms are characteristic of
infancy and childhood, accompanying the maturation
of normal children in a highly variable but significant
manner (60). They precede, but in later years are
often mingled with, adult alpha rhythms and their
rate of subsidence is a common measure of develop-
ment.
Delta Rhythms
When delta rhythms persist appreciably beyond
the age of 10 or 12, the character of the child
is usually suggestive of immaturity in a particular
fashion to which Hodge et al. (29) have given
the name ductility, the tendency to be led easily. In
the extreme this is associated with minor recidivist
delinquency combined with an appealing personality.
In such cases the delta rhythms are often most prom-
inent in the right teinporo-occipital region and show
little responsiveness to stimulation. Another type of
delta rhythm is seen in some children with immature
but not necessarily defective personalities. This is bi-
lateral, monorhythmic and strikingly responsi\e to
stimulation, acting almost as an alpha rhythm, par-
ticularly when it is localized to the occipital lobes. In
otherwise normal people there is no obvious explana-
tion of this effect, but a similarly responsive rhythmic
slow activity is seen also in patients with organic dis-
turbance of deep midline structures, and it is pos-
sible, therefore, that this type of slow responsive
rhvthm is an expression of inadequacy of the diffuse
arousal systems. Corroboration of this can sometimes
be obtained from suppression of the delta rhythms by
administration of activating drugs, such as ampheta-
mine, which are believed to act on the diffuse ascend-
ing reticular formation.
The association of delta activity with disease,
dystrophy, damage and deep sleep — from which
alliteration the phenomenon was accorded its designa-
tion— has suggested that it may have some sort of
limiting or protective function (54, -,6\ This notion
INTRINSIC RHYTHMS OF THE BRAIN
297
has been called by \^'alter the phylactic hypothesis.
Since the brain is poorly endowed with certain of
the protective devices conducive to the preservation
of other organs — such as pain and repair — it is reason-
able to conjecture that some mechanism may exist to
constrain or restrict the influence of conditions likely
to initiate excessive and persistent actixity. The rela-
tively great size and wide extent of delta rhythms —
which may reach potential differences of i mv on
the scalp — suggest that as electrotonic inhibitors they
may in times of distress give the brain a chance to
survive through inactivation of its cells.
Theta Rhythms
The class of theta rhythms — which were at first con-
fused with slow alpha rhythms and later identified as
related to thalamic lesions (62) — is most character-
istically associated in normal young people with feel-
ings of disappointment and frustration. They are
evoked most easily by the termination or withdrawal
of an authentic agreeable stimulus and often show a
markedly stereotyped pattern of growth and decline
over a period of about 20 sec. or so following such an
experience. Clinically their persistence is linked with
psychopathic character traits. It has been suggested
(55) that, if the alpha rhythms be considered as scan-
ning for visual pattern, then theta rhythms may rep-
resent a scanning for visceral pleasure. Such an
analogy of analogies is notoriously meretricious, but
if comprehension is to grow, some working hypothesis
must be formulated, and at least experiments can be
planned to discover why, just as the alpha rhythms
wax great at the moment when patterns are excluded
by closing the eyes, so theta rhythms tend to arise at
the conclusion of pleasure.
Beta Rhythms
The beta rhythms, which were the second class of
brain activity to be identified by Berger, are still un-
certain in their significance and even in their defini-
tion. Mundy-Castle (43) has proposed that beta
rhythms be considered in two classes, beta I and beta
II. Beta I is suppressed during cortical activity and is
often, though not invariably, harmonically related to a
component of the alpha rhythms; this relationship is
responsible for the wave form of the rythme en arceau of
Gastaut (22). In order to avoid further confusion in
this already disordered domain, it might be conven-
ient to designate his particular combination of rhythms
the ■ ^' rhythm because of its resemblance to the outline
of the Greek letter. The beta II of Mundy-Castle is aug-
mented during cortical activity and may represent
an acceleration or concentration of efferent activity
arising from the .scansion of cortical regions engaged
in the analysis of endogenous or exogenous patterns.
Precise classification of these rhythms — which are
particularly elusive because of their rate and the
restriction of their domains — must await further study
of their location and functional correlates.
ORIGIN OF INTRINSIC RHYTHMS
The various intrinsic, apparently spontaneous, yet
often responsive, electrical rhythms of the brain are
clearly in a different class of phenomenon from the
unitary propagated spike potentials which act as the
main operational code elements in the nervous system.
The slower rhythmic oscillations seem more likely to
be involved, as it were, in the administrative depart-
ments of central neurophysiology. If their rate of dis-
charge were less constant or their wave form less pure,
they might be considered as trivial projections of
spatially asymmetric postsynaptic potentials in large
populations of pyramidal cells with particularly long
dendritic proces.ses. It is indeed conceivable that the
degree of asymmetry and the electric moment of the
dendritic potentials might be large enough in some
circumstances to generate the fields observed on the
scalp. Even if this is the mechanism of generation,
however, the gross variations from person to person
and the delicate relations between the frequencies,
time relations and geometric properties of the rhythms
with the character and actions of the organism suggest
that the intrinsic rhythms are more than the resultant
of adventitious topography. The processes of evolu-
tion are too parsimonious to allow such entities to be
multiplied beyond necessity. The refineinents of
modern techniques should enable schools of investi-
gators trained in complementary disciplines to solve
this enigma which so impedes our understanding of
brain function.
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CHAPTER XII
The evoked potentials
HSIANG-TUNG CHANGE
Rockefeller Institute, New York City, and the Institute of Neurophysiology,
University 0/ Copenhagen, Denmark
CHAPTER CONTENTS
Introduction
Definition
Limitations of Evoked Potentials as Tools for Anatomical
Study-
Components of Evoked Potentials and Their Identification
The Latent Period
Effect of Repetitive Stimulation
Effect of Changes in Internal and External Milieu
Anatomical Considerations
Neural Mechanisms for the Elaboration of Evoked Cortical
Potentials
Types of Neural Elements Involved and Their Mode of
Action
The Initiation of Postsynaptic Impulses in Pyramidal
Neurons
Apical Dendrites and Electrical Signs of the Evoked Poten-
tial
Microelectrode Findings Concerning the Mechanism of Im-
pulse Initiation in Single Neurons
After-Discharges
Repetitive Firing of Individual Neurons
Local After-Discharges Involving Intrinsic Neuronal Circuits
Rhythmic After-Discharges Involving Long Neuronal
Circuits: Corticothalamic Reverberatory Activity
Excitability Changes Accompanying and Following the Evoked
Potential
Refractory Periods
Postexcitatory Depression
Periodic Variation in Cortical Excitability
Interaction of Afferent Impulses in the Cerebral Cortex
Modification of Cortical Excitability by Constant Inflow of
Afferent Impulses
Summary
INTRODUCTION
Definition
BY AN EVOKED POTENTIAL IS meant the detectable
electrical change of any part of the brain in response to
' Present address: Academia Sinica, Shanghai, China.
deliberate stimulation of a peripheral sense organ, a
sensory nerve, a point on the sensory pathway or any
related structure of the sensory system. Although
observations of evoked potentials have most fre-
quently been made in the sensory system, potentials
produced by other means such as by direct electrical
stimulation or antidromic stimulation of the neuron
fall into the same category.
In physiology the term 'potential' is often very
loosely used as signifying merely the electrical change.
Strictly speaking, the potential at a point of the tissue
implies the same meaning as in physics and thus
denotes the work necessary to bring a unit charge from
infinity up to the point in question which is located in
an electrostatic field. Its absolute value can be
measured only with one electrode placed on the active
tissue and the other grounded. It would be necessary
to record the current rather than the potential if the
two recording electrodes were placed on the same
active tissue. However, it is possible to obtain a close
approximation of the potential value by means of
Laplacian placement of electrodes in which one active
electrode is surrounded by a number of .similar
electrodes combined together as a single pole. This
method of recording seems to have certain advantages,
especially when precise localization and determination
of the distribution of the action potential are desired
(58). The evoked potential diflfers from the so-called
spontaneous electrical changes in iTiany respects,
notably the following, a) It bears definite temporal
relationship to the onset of the stimulus. In other
words, it has a definite latent period determined by
the conduction velocity of the nerve impulses, the
conduction distance between the point of stimulation
and the point of recording, the synaptic delay and the
number of synapses involved. In a given system the
latency is generally fixed and consistent under
similar experimental conditions. 6) It has a definite
pattern of response characteristic of a specific system
299
300
HANDBOOK OF PHYSIOLOGY'
NEUROPHYSIOLOGY I
which is more or less predictable and reproducible
under similar conditions, c) It usually appears in a
circumscribed area of the central nervous system
where the active tissue is located.
Identification of the evoked potential requires
knowledge of anatomical connections between the
site of stimulation and the point of recording. As
distinct from spontaneous electrical activity, po-
tentials evoked by deliberate stimulation of peripheral
sensory nerves are sharply localized in the central
nervous system. The procedure of evoked potential
registration thus becomes a useful tool for the in-
vestigation of sensory pathways. It has been particu-
larly fruitful when applied to the study of cortical
representation of the auditory, visual and various
cutaneous sense organs.
l.iimlations oj Evoked Potentials as Tools Jor
Anatomical Study
It is not intended at present to discuss in detail
sensory localization demonstrated by the evoked
potential technique. This is discussed in the chapters of
this handbook dealing with the various sensory
mechanisms. However, in order to caution against the
misuse of the technique it may be pertinent to men-
tion briefly here some fundamental aspects of the
evoked potential, especially those which limit its
usefulness in anatomicophysiological study. First, the
method is valuable in determining the area of sensory
projection on the cerebral cortex only when the
observation is made under such conditions that the
cerebral cortex is not in an e.xalted state of excitation,
if the true sensory projection area is to be determined.
It is an obvious fact that in so complex an organiza-
tion as the cerebral cortex each neuron is potentially
related to any other neuron through a vast nuinber
of chains of synaptic connections. When a given neu-
ron is activated by an afferent impulse, almost any
other neuron may become excited unless some re-
strictive influence is exerted to curb the spread of the
evoked potential to remote regions where ito afferent
fibers terminate directly. Second, the appearance of
an electrical change in a given area of the cerebral
cortex does not necessarily indicate the presence of
neuronal activity underlying that area. As pointed
out long ago by Helmholtz, measurement of the
external field of electrical current on the surface of a
living tissue is not adequate to ascertain the location of
the internal electromotive force. The electrical
changes detected from the surface of the brain may
be derived from a purelv phssical process such as the
potential field created by the pa.ssage of electrical
current along a nerve bathed in a conducting medium.
According to the \oiume conductor principle (47, 49),
when a synchronous volley of impulses passes along a
nerve embedded in a \olume of conducting medium,
there will appear in the medium a travelling electric
field around the ner\e. .Such a field is caused by the
flow of electric current from the inactive region to the
depolarized region of the ner\e. The region occupied
by the nerve impulse serves as a fictitious sink of
current flow^ and the regions lying ahead and behind
the impulse as fictitious sources. Thus, the sign of the
action current recorded from the active elements in
the brain is negati\c-positi\e diphasic at the point
where the nerve impulse is initiated, positive-negative
diphasic at the point where the conducting path ends
and positive-negative-positive triphasic at the middle
of the conducting path. At points away from the
acti\e element the sign of the detectable action po-
tential will depend on the position of the electrode
relative to the direction and the pattern of the iso-
potential lines of the traveling electric field.
COMPONENTS OF EVOKED POTENTI.^LS
AND THEIR IDENTIFICATION
The action potential in the brain evoked either by
electrical stimulation of the ascending pathways or by
adequate stimulation of the sense organs consists of
two components, the presynaptic and the post-
synaptic. The former indicates the arrival of impulses
passing along the axon and their terminals, and the
latter the acti\ities of the cell body and dendrites.
For the purpose of illustration, the evoked potential
of the sensory cortex may be taken as an example.
Following the arrival of a volley of afferent impulses
from the thalamus, the projection area of the cerebral
cortex gives rise to a surface-positive primary response
followed sometimes by a series of rhythmic after-
discharges. The primary response is made up of the
presynaptic potential produced by the activity of
thalamocortical fibers and the postsynaptic potential
produced by the discharge of intracortical neurons.
The incoming impulses from the thalamus are often
blended with, and obscured by, the powerful post-
synaptic discharge of the cortical neurons. This is
especially true when the afiferent impulses are ini-
tiated by stimulation of the peripheral sense organs
or of the pathway far away from the cerebral cortex.
In that event, the afferent impulses usually arrive at
the cortex asynchronously clue to temporal dispersion.
THE EVOKED POTENTIALS
301
In the visual system, however, the radiation potential
is discernible in the cortical response to stimulation of
the optic nerve for two reasons: first, distinct groups
of fibers according to size are present throughout the
pathway from the optic nerve to the optic radiation;
and, second, there are no intercalated neurons in the
lateral geniculate body which, if present, would
destroy the synchrony of conduction of optic impulses
and thus obliterate the characteristic triple-spike
radiation potential. In the auditory system as well as
in the somesthetic system the presynaptic component
of the evoked potential can also be demonstrated,
though less prominently than in the visual system, if
the corresponding thalamic nucleus is directly
stimulated with a brief electric shock.
In spite of the composite nature of the primary
response, the two components can be readily dif-
ferentiated from each other by various experimental
procedures as described below.
The Latent Period
The presynaptic component of the evoked po-
tential, being the initial sign of activity, has the
shortest latency with a value contingent upon the
fiber diameter and the conduction distance of a
given system. It is readily identifiable in a system
composed of fibers of uniform size. The temporal
dispersion of the presynaptic impulses passing along
a bundle of fibers of different sizes may make the time
of arrival at the point of recording vary over a wide
range so that the last impulses may overlap with the
postsynaptic discharge set up by the fast fibers.
Under such circumstances it is impossible to dis-
tinguish presynaptic from postsynaptic activity merely
by the latency; only the activity of the fastest fibers of
the group can be ascertained. In fact, such is always
the case in the cortical and subcortical potentials
evoked by adequate stimulation of peripheral sense
organs.
Another factor which may seriously limit the ap-
plicability and the value of latency measurement is
the possible reduction in conduction velocity of
impulses at nerve terminals resulting from the diminu-
tion of fiber diameter. It is not known whether the
impulses vanish instantly at the specialized pre-
synaptic endings. According to Barron & Matthews
(4), and Lloyd & Mclntyre (46) a prolonged nega-
tivity persists at the afferent terminals of spinal dorsal
root fibers and is detectable at a considerable distance
from the active fibers as the dorsal root potential
DR-IV in Lloyd's terminology. The prolonged
depolarization of a dorsal root fiber following a
single shock stimulation can be recorded with an
intracellular microelectrode (41).
Efect oj Repetitive Stimulation
It has long Iseen known that synaptic transmission
can be blocked by stimuli delivered in quick suc-
cession. At certain rates of stimulation the amplitude
of the electrical response involving synapses decreases
with each response, becoming succes.sively smaller
than the preceding one until finally the response
disappears entirely. The repolarization process of
the membrane of the neuron .soma which receives the
presynaptic excitation apparently requires a longer
time than the axon. The postsynaptic neuron is not
al)le to respond to successively arriving impulses
until the recovery of its excitability becomes complete.
The effect of synaptic block by repetitive stiinulation
is especially pronounced in subjects under deep
anesthesia by barbiturates. The method has been
successfully used in differentiation of the presynaptic
froin the postsynaptic components of the evoked
potential in the lateral geniculate body by Bishop &
McLeod (8). As another example to illustrate the
differential effect of repetitive stimulation on the
pre- and the postsynaptic potentials, the electrical
response of the pyramidal tract to electrical stimula-
tion of the motor cortex may be taken. According to
the study by Patton & Amassian (57) the pyramidal
response to cortical stimulation consists of an early-
wave resulting from direct stimulation of the motor
neurons and a later wave resulting from the activity
of cortical internuncial neurons, which is elicited
indirectly or synaptically. The former can follow
repetitive stimulation at frequencies as high as 340 per
sec. with only slight reduction in amplitude, whereas
the latter disappears from the response when stimulus
frequency is increased from 44.7 per sec. to 127 per
sec.
The presynaptic response or the response of an axon
to direct electrical stimulation is usually able to
follow faithfully the stimuli at a high rate limited only
l)y the refractory period. The degree of the blocking
effect of repetitive stimulation seems to increase with
the increase in number of synapses involved. For
instance, in the first relay station of the dorsal root
fiijers, i.e. the cuneate nucleus, the postsynaptic
discharge of a single neuron to repetitive stimulation
of peripheral sense organs or of its nerve can follow
the rate of stimulation as high as 100 per sec. without
substantial modification of either the response ampli-
302
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
tude or the latency- Increase in rate of stimulation
reduces the number of spikes of the responding; neuron.
It has been observed, though very infrequently,
that the cuneate neuron may respond to peripheral
stimulation at a rate as high as 500 per sec. (2).
Evoked potentials of the thalamic neurons, which
receive afferent impulses after a number of synaptic
relays at lower levels of the neural axis, cannot follow
rates of stimulation even as low as 20 per sec. The
somatic .sensory cortex is known to be unable to
respond fully to peripheral stimulation at a rate
higher than 7 per sec. in animals under barbiturate
anesthesia (33); in other conditions the rate may be as
high as 14 per sec. (40).
Ejjcct (if Changes in Internal and External Milicn
The axon is generally known to withstand adverse
changes of the internal or external milieu better than
the cell body and dendrites. In accordance with this
tenet, the postsynaptic potential which insoKes the
activity of the latter structures has fjeen found to be
more susceptible to the lack of oxygen than the
presynaptic potential. In complete anoxia produced
by asphyxiation or by inhaling pure nitrogen, for
instance, the postsynaptic potential can be abolished
in about 90 sec. while the activity of the presynaptic
fibers may last for a considerably longer period of time.
The greatest difference between the pre- and the
postsynaptic potentials, however, lies in the rate of
recovery from anoxia. Experimental evidence shows
that the axonal component of the cortical response to
stimulation of the medullary pyramid begins to re-
cover from the effect of anoxia in about i min. after
the readmission of oxygen and resumes its original
size in about 5 min. The postsynaptic component of
the response, on the other hand, will not reappear
until 5 or 6 min. later. A complete recovery mav re-
quire even 10 or 20 min., depending on how soon
oxygen was readmitted (21, 22). Similarly, the
synaptically elicited wave (I-wave^ of the pyramidal
response to cortical stimulation is reduced in size
after 70 sec. of asphyxia and virtually aljolished after
130 sec, while the directly elicited di.scharges (D-
wave) persist Co/)-
Like anoxia, mechanical pressure, traumatic injury
and low temperature all depress the postsynaptic
function sooner and more severely than the pre-
synaptic activity. There are some chemicals such as
strychnine and tubocurarine which may enhance
specifically the postsynaptic actisity without markedly
aflfecting the presynaptic potentials (20, 25).
It has been observed that when the cortical surface
was cooled h\ controlled refrigeration, the functional
activity of dendrites of cortical neurons was partially
blocked at temperatures below 28°C and was coin-
pletely abolished at 22 °C;, while the functional activity
of axon remained without adverse changes. From this
fact it inay be inferred that the postsynaptic potential
which invokes the process of depolarization of
dendrites must be affected Ijy low temperature more
severely than the potentials deri\ed from the directly
excited axons (21).
Anatomical CUnsiiIeratinns
In determining whether or not a potential compo-
nent is pre- or postsynaptic, the anatomical situation
must be considered as a decisive factor. Obviously one
cannot assign a potential as postsynaptic if there are
only directly excited fibers present in the system in-
volved. In the case of antidromic action potential in
the optic ner\e elicited by stimulation of the optic
tract, for instance, it is obviously not possible to have a
postsynaptic component in the potentials obtained
(24). However, it would not be so easy to be certain
in a central structure which is embedded among a
complicated mass of \arious neural elements. In that
circumstance, the characteristics of the recorded
potential must be taken into consideration together
with the related anatomical organization of the system
concerned. An approach of this kind has been adopted
frequently in analysis of evoked cortical potentials.
We may take as an example the microelectrode study
of the cortical potential evoked by stimulation of the
ventrolateral nucleus of the thalamus (43). Recordings
taken from different depths of the cerebral cortex in-
variably show the presence of positive-negative
diphasic spikes in the early phase of the potential.
These spikes which have comparatively low voltage
are frequently seen at all le\els below 0.7 mm. The
negative phase of the spike increases as the electrode
is pushed deeper into the cortex. They can easily be
distinguished from the high voltage spikes derived
from the cell bodies. The short latency and the brief
duration of the spikes makes it certain that they are
from the presynaptic thalamocortical fibers which are
known to terminate mainly in the fourth layer of the
cortex located about 0.7 mm beneath the cortical
surface in the cat. Alignment of simultaneous re-
cordings from the cortical surface with a gross
electrode and those from the depth when a micro-
electrode shows a temporal coincidence of the small
diphasic spikes and the usual elevations of the po-
THE EVOKED POTENTIALS
303
tential of surface recordings which have often been
designated as radiation potentials.
The cell body discharges are usually spikes of high
voltage and are of quite long duration. The diflference
in duration between the potentials of a single axon
and of a single cell body has been established through
the microelectrode studies on spinal ganglia (65), on
the spinal cord (68), on the lateral geniculate body
and on the cerebral cortex (66). According to Wood-
bury & Patton (68) the duration of the spike is about
0.6 msec, for the axon and i msec, for the cell body-
Tasaki et al. (66) put the values as i msec, or less for
axonal response and 1.5 to 3 m.sec. for the cell body
respon.se. Frank & Fuortes found the respective values
for dorsal root fibers and cell body of the spinal
motoneurons to be 0.6 msec, and 1.6 msec, respec-
tively (35).
NEUR.'^L MECH.^NISMS FOR THE EL.^BOR.JiTION OF
EVOKED CORTICAL POTENTI.ALS
The generation of the radiation spikes of the evoked
potential is a relatively simple problem. It is a
generally accepted opinion that the initial sharp
spikes with short latency represent the arrival of
afferent impulses which are purely presynaptic in
nature. Sufficient evidence is available that the main
part of the surface positive wave of the prima r\
response on which the presynaptic spikes may be
superimposed is made up of the discharges of the
cortical neurons.
Types oj Neural Elements Im'nlvrd and
Their Mode of Action
As to exactly what cortical elements are responsible
for the production of this potential and what is the
mechanism by which an afferent \olley initiates the
discharge of those elements, remain points to be
elucidated. Since there are few available data con-
cerning the roles played by different types of cortical
elements, the postulation of a mechanism for the
genesis of the evoked cortical potential must be made
on the basis of the histological organization of the
cerebral cortex and the estaljlished principles of
electrophysiology. In view of the fact that the basic
pattern of the cortical response to afferent impulses
appears remarkaijly constant throughout the sensory
cortex and that the sensory cortex in\'ariably receives
specific thalamic afferent fillers and possesses a verv
well developed granular layer, these latter two struc-
tural characteristics must be taken into consideration
in offering any explanation of the e\oked cortical
potential.
The specific afferent fibers arising from the thala-
mus are known to terminate mainly in the fourth
layer by a rich plexus of repeatedly arborized endings.
Afferent impulses coming along these fibers make their
first synaptic contact with Golgi type II cells in the
fourth layer. Golgi type II cells are characterized
by the presence of short axons terminating in profuse
arborizations in a localized region surrounding the
parent cell body. Their dendrites are rather few and
poorly de\eloped. By virtue of their anatomical char-
acteristics they are not able to transmit impulses to
distant regions but serve as amplifiers by which the
afferent impulses are reinforced. They are un-
doubtedly indispensable for the elaboration of the
evoked cortical potentials. However, since there is no
definite orientation of the conducting structure of
these cells and the electric field created by the dis-
charge of these cells is a closed type (48), their activitv
cannot be recorded as any sizable potential from the
cortical surface. The consequence of the discharge of
Golgi type II cells in la>er IV is probably to activate
the star p\ ramids and the star cells in the same layer
which in turn activate the numerous medium and
small p\raniids which eventually depolarize the large
pxramids in the fifth and sixth layers. The large
p\ ramids send out efferent axons to some other parts of
the central nervous s\stem.
The Initiation of Postsynaptic Impulses
in Pyramidal Neurons
The detectable surface-positive potential can be
reasonably assigned to the propagation of nerve
impulses along the vertically oriented apical dendrites
of different sized cortical pyramids. Under normal
conditions the depolarization process of cortical
pyramids resulting from a supraliminal synaptic
excitation is apt to start at the somatic membrane
around the cell body rather than at the terminal
portion of the dendrites. According to a recent
postulation (17, 23) the pericorpuscular synaptic
knobs constitute the inost effective apparatus for the
initiation of a postsynaptic discharge, whereas the
subliminal excitation of paradendritic synapses can
produce only electrotonic changes and so modifv the
state of excitability of the neuron. The paradendritic
synapses, because of their lower density of distribution
and their special manner of contact with the next
neuron, are believed to be inadequate to effect a
304
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
postsynaptic neuronal discharge under ordinary
conditions. It is well known that the dendritic shafts of
the large pyramidal neurons in the fifth and sixth
layers of the sensory cortex do not give off branches in
the fourth layer where the terminals of the thalamo-
cortical fibers and the aggregations of Golgi type II
cells arc located. The only contact between the large
pyramidal cells and the afferent elements is made
through the comparatively few paradendritic synapses
which are not sufficient to bring about a postsvnaptic
discharge. It is most unlikely that the afferent fibers
from the thalamus and Golgi type II cells in layer IV
can ever directly acti\ate the large pyramidal cells.
The discharge of the large pyramidal cells on arrival
of an afferent volley of impulses must be achieved
through the action of pericorpuscular synapses sup-
plied by small and medium pyramidal cells.
Apical Dendrites and Electrical Signs
of the Evoked Potential
From the point of view set forth above, the surface-
positivity of the primary response of the evoked corti-
cal potential can be reasonably explained. When the
pyramidal cells are indirectly activated by afferent
impulses through chains of internuncial neurons
including Golgi type II cells, star pyramids and small
and medium pyramidal cells which make pericor-
pu.scular synapsis with the large pyramids, the post-
synaptic impulses initiated at the cell body will serve
as a sink and the apical dendrites as a source of the
current flow. The record of such electrical change
taken from the cortical surface will be a positive wave.
As soon as the impulses arrive at the apical dendritic
ple.xus at the cortical surface, the electrical sign of the
potential will be reversed. The surface-negative wave
following the positive deflection of the primary
response may be accounted for, at least in part, on
this basis. As pointed out previously (14) this interpre-
tation does not exclude the possibility that other
cortical elements participate in the elaboration of the
surface negative deflection. In fact, the neurons
situated in the upper layers of the cortex must also
be involved.
The conduction velocity of impulses passing along
dendrites is less than 2 m per sec, which is many
times slower than that of impulses passing along axons.
There is also a decremental reduction in velocity as
the impulses are propagated from the proximal part
to the terminal regions of the dendrites (21). The
long duration of the surface-positive wave of the
evoked potential gives every indication of being a
manifestation of dendritic activity. It is more than
probable that the process underlying the surface-
positive wave and the following negativity lie mainly
in the apical dendrites of different groups of cortical
pyramids. The deeply situated basal dendrites of the
pyramidal cells are mostly oriented toward the sub-
cortical white matter or more or less horizontallv. In
other words, they are arranged in a direction roughly
opposite to that taken by the apical dendrites. Thus,
during the discharge of the pyramidal cells the po-
tential changes originating from the basal dendrites
must be greatly neutralized by the divergently
propagating potentials along the overwhelmingly
dominant apical dendrites, if the potentials are
recorded from a lead on the cortical surface.
Micrnelectrode Findings Concerning the Mechanism
of Impulse Initialiiin in Single .Neurons
Without going into a detailed discussion of the
fundamental mechanism by which the propagated
impulse is initiated hw electrical or synaptic excitation,
it may be relevant to mention here a few experimental
facts which seem to characterize the synaptically
evoked potentials as contrasted with the antidromi-
cally produced potentials. As revealed by intracellular
microelectrode recordings, the discharge of a neuron
elicited by synaptic excitation of the cell body or
dendrites is characteristically different from that
elicited by stimulation of its axon. The synaptically
produced discharge as well as the spontaneous firing
of a neuron is usually preceded by a slowly rising
positive deflection upon which the sharp spike rides
when the discharge threshold is reached. On sub-
liminal stimulation only the small deflection will be
present. Such preliminary potentials have been
observed in spinal motoneurons (11), in the thalamus
(60) and in Betz cells of the motor cortex (59). It has
sometimes been called the * synaptic potential". Since
it may be present without necessarily involving
synaptic transfer of impulses and since the term also
describes the potentials recorded by other means, it
has been suggested to adopt the noncommittal term
' prepotential' in its place (68).
The fact that the prepotential is present mostly in
the evoked or spontaneously occurring responses
which involve the activity of cell body and dendrites
but not in the antidromic responses seems to suggest
that activity of the dendrites plays an important role
in initiation of the spike discharge. In this respect
Eyzaguirre & Kuffler's study on single neurons of the
lobster and cravfish has thrown much light on the
THE EVOKED POTENTIALS
305
mechanism of impulse initiation in a neuron (30-32).
Eyzaguirre & Kuffler found that suljliminal excita-
tion of the dendrite by mechanical stretch of the
muscle in which the dendrites are imbedded produces
a reduction of the membrane potential of the cell body
through the electrotonic effect. A propagated discharge
takes place only when the membrane potential is
reduced to a certain level. From this it appears that
the prepotential of the evoked response may represent
nothing but a partial depolarization of the resting
membrane potential resulting from subliminal excita-
tion of dendrites by bombardments of presynaptic
nerve endings. Antidromic discharge of a neuron
apparently calls for no such build-up of the ex-
citability level as a prerequisite and is therefore devoid
of the characteristic small prepotential often seen in
responses produced by synaptic action.
.\FTER-DISCH.^RGES
The term ' after-discharge' has been conventionally
employed to describe the epileptiform discharges of
neurons following strong tetanic stimulation which
persist long after the cessation of stimulation. Since
accumulated experimental data show that repetitive
bursts occur not only after tetanic stimulation but also
after a single shock applied to the system, we will
designate all the discharges which outlast the duration
of stimulation, tetanic or single shock, as after-
discharges, in the very loose sense of the terminology.
For the sake of convenience in discussion, after-
discharges can be classified into three types: /) repeti-
tive firings of single elements which are self-main-
tained without the participation of other elements in
their production; 2) persistent local after-discharges
involving the activity of closely situated intrinsic
neurons which form short neuronal circuits; and
j) periodic discharges involving re\erberating activi-
ties of a closed neuronal circuit formed by long chains
of neurons connecting remotely separated structures.
Repetitive Firing of Individual Neurons
Microelectrode recordings from the thalamic and
the cortical neurons show that a .single neuron fires
several times in response to an afferent volley. To a
stimulus at threshold strength a neuron generally
responds by giving rise to a single spike. As the stim-
ulus increases in strength, the number of the spikes
increases correspondingly. It has been reported that a
thalamic unit may fire seven times in quick succession
in response to optimal stimulation of the skin re-
ceptors (60). A single neuron in the reticular forma-
tion, for instance, may give rise to a train of as many as
20 spikes in response to a single stimulus (3). In so far
as the length of the train is concerned, natural ade-
quate stimulation of the sense organs seems to be more
effective than electrical stimulation of the nerve. In
electrical stimulation, once the threshold is reached
further increase in intensity seems to be rather in-
effective in inducing any greater responses. On the
contrary, strong stimulation may inhibit the suc-
cessive spikes. This is true for somesthetic, auditorv,
visual and olfactory systems.
In a long train of repetiti\e discharges at high
frequency, the first spike is usually the largest in
amplitude and the second the smallest. The rest of the
spikes following the second gradually increase in size
until they approach, but rarely become as large as,
the first one. The deficit of the .successive spikes is
probably caused either by the incomplete repolariza-
tion of the neuron membrane following a forceful dis-
charge, or by the postexcitatory depression associated
with the process of hyperpolarization of the mem-
brane.
The repetitive discharge of a single neuron is
believed to be a self-sustained process which is
initiated only by the afferent volley but is not the
result of repeated bombardments by presynaptic
impulses. This belief is based on the observation that a
small deflection immediately preceding the first spike
of a train, which can be interpreted as a presynaptic
potential, is present only once at the beginning of the
train. No similar potential has ever been observed
preceding the successive spikes. The individual spikes
in a train do not correspond to the successive arrivals
of presynaptic volleys of impulses. Therefore, the
repetiti\e firing cannot be regarded as resulting from
the repetitise arrival of presynaptic impulses. Single
nerve elements are endowed with the capacity to
discharge repetitively in response to a stimulus. It has
been repeatedly demonstrated that following a single
shock applied to the dorsal root a burst of four or five
unit spikes can be recorded in the dorsal column
where, due to the absence of intercalated neurons,
synapses are not in\'olved.
The intimate nature of the .self-generating mechan-
ism of after-discharge inside the neuron is not known.
Burns (13) suggests that the repetitive firing of a
cortical neiu-on following stimulation is due to the
difference in recovery rates of resting membrane
potentials at the two ends of a neuron such that one
end is repolarized more slowly than the other. By
3o6
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
virtue of the differential rates of depolarization a
neuron is able to fire repetitively, resembling the
oscillatory discharge and recharge of two thyratron
tubes with two different-valued condensers in the
circuit. This concept of Burns is apparently derived
from his observation that after-discharge of skeletal
muscle fibers may be caused by treatment with
decamethonium iodide, which is believed to pre\ent
the end plate membrane from repolarizing as rapidly
as the neighboring membrane of the muscle fiber.
Local AJter-Discharges Involving Intrinsic
Neuronal Circuits
Although individual neurons are capable of dis-
charging repetitively in response to a single stimulus,
long lasting activities in the central nervous system are
mostly manifestations of neuronal discharges resulting
from a self-re-exciting mechanism involving numerous
neurons arranged in closed circuits in the same struc-
ture.
As demonstrated by Burns (12), an isolated slab of
cerebral cortex is able to discharge following a single
shock applied to the cortical surface. Such discharges
may last for many minutes or even hours in some
instances and are detectable not only in the circum-
scribed area directly under stimulation but also in
regions at some distance from it. They are evidently
not the repetitive firings of the directly stimulated
neurons but the responses of neurons synaptically
excited through neuronal circuits. After-discharges of
this kind usually develop increasing intensity and
then suddenly stop altogether at the climax. They
may resume the activity after a brief pause. In such a
case, the activity of individual neurons apparently
depends on the arrival of impulses from some other
neurons in the circuit for re-excitation. To perpetuate
the activity, the circulating impulses must be main-
tained above the liminal strength and arrive at the
next neuron at an opportune moment when the
excitability of the neuron is favorable. The abrupt
cessation or suspension of the after-discharge at its
climax is probably due to the postexcitatory depres-
sion of some neurons in the circuit which fail to
respond to the arriving impulses so that the circuit is
broken. The self-re-exciting circuits are present in
every part of the central nervous system where inter-
nuncial neurons exist. Many neurons, especially
those whose axons are short but have numerous
collaterals, constitute the main source for the elabora-
tion of local after-discharges.
The acti\-ation of the internuncial neurons through
collaterals has been demonstrated in the cerebral
cortex. The action potential of the motor cortex
produced by a single shock stimulation of the medul-
lary pyramid consists of the initial deflections with
short latency and in addition a rather prolonged
discharge which has a latency of 14 to 16 msec. It
cannot be interpreted as antidromic activity of the
directh' stimulated large p\ramidal neurons. Such
later components of the antidromic cortical potential
are variable, labile and more susceptible to the action
of anoxia, specific drugs (strychnine for instance) and
tetanic stimulation — showing characteristics of the
responses invoking synapses. When two successive
stimuli are applied to the medullary pyramid at short
intervals, the cortical response to the second is usually
blocked. The temporal course of the recovery process
is similar to that of orthodromically evoked potentials.
Unit activity of the internuncial neurons participating
in the development of such activity can be recorded
from different strata of the cortex with a micro-
electrode. Perhaps the most interesting is the fact that
the large pyramidal neurons whose axons ha\e been
stimulated originally can be re-excited synaptically by
their own collaterals. The discharge of the same
pvramidal neuron resulting from the internuncial
activity is detectable from the point on the medullary
pvramid where the single shock stimulus has been
first applied. Thus, the action of the self-re-exciting
circuit is completed. The particular significance of the
collateral acti\ity of the pyramidal fibers lies in the
fact that they constitute a part of the feed-l^ack
mechanism in the cerebral cortex by which a message
is sent back to the original dispatcher for modification
of the subsequent responses. If the feed-back im-
pulses are sufficiently strong and arrive when the
brain excitability is in the most favorable condition,
it is even possible to initiate a rhythmic after-dis-
charge of the efferent neurons. It is believed that the
prolonged epileptiform after-discharges following
strong stimulation of the motor cortex and the seizures
in pathological cases are produced, at least in part, by
a feed-back mechanism through the collaterals in the
closed chains ot neurons.
Rhythmic After-Discharges Involving Long Neuronal
Circuits: Corticothalamic Reverheratory Activity
The primary response of the sensory cortex to an
afferent volley is often followed by a train of regularly
spaced surface-positive waves with intervals ranging
from 50 to 150 msec. (14). The frequency of the
repetitive waves seems to l)e independent of the stimu-
THE EVOKED POTENTIALS
307
lus Strength but varies with the state of anesthesia and
the area from which the observations are made. The
repetitive discharges evoked by afferent impulses
differ from the spontaneous waves in many respects,
though they may happen to have the same frequency.
The evoked repetitive discharges are always surface-
positive waves whereas the spontaneous activity of
cortical neurons is not necessarily so. The latter
appears to be regulated to some extent by the intra-
laminar nuclear groups of the thalamus (39); but the
evoked periodic after-discharges are not affected by
surgical removal or electrical stimulation of the massa
intermedia (14).
The presence of the evoked periodic discharges is
dependent upon the integrity of the pathways between
the cerebral cortex and the thalamic nucleus con-
cerned. The periodic wa\es recorded from the cor-
responding thalamic nucleus are similar in pattern to
those observed from the sensory cortex and can be
abolished by removal of the cortex. Likewise, repeti-
tive discharge of the same kind can be evoked by
direct stimulation of the cortical surface and abolished
jjy the destruction of the corresponding thklamic
structure or by interruption of the thalamocortical
connections. From these experimental facts it is sug-
gested therefore that the specific periodic after-
discharges following afferent stimulation represent the
activity of the reverberating circuit between the
sensory cortex and the thalamus. It is as.sumed that a
volley of afferent impulses from the thalamus, after
arriving at the cortex, will return to the thalamic
nucleus and ascend again to the cortex to start
another cycle of activity along a closed chain of
neurons.
It is believed that the general periodic wa\es ob-
served in the central nervous system can be due to
many causes. The activity of reverberating circuits is
only one of many possible mechanisms underlying the
periodic waves. It would be a mistake to regard all
kinds of rhythmic discharges as being due to the
activity of reverberating circuits. The evoked repeti-
tive discharge in the sensory cortex must be dis-
tinguished from the spontaneous rhythmic waves
which sometimes present themselves in such a manner
as to confu.se or mislead the obser\er. It is true that in
unanesthetized animals or in animals anesthetized
with chloralose the rhythmic discharges following a
single sound stimulus do occur in the medial genicu-
late body after decortication (36). However, as
pointed out by Galambos, rhythmic waves al.so occur
spontaneously without deliberate stimulation. It is
obviously a mechanism entirely different from that
underlying the specific corticothalamic reverberating
waves which, under experimental conditions, can be
evoked only by an afferent volley from the thalamus
or by direct cortical stimulation. So specific is this
response that corticothalamic waves hav-e never been
obtained by stimulation of a symmetrical point on the
opposite cortex although the callosal response itself
may be a very intense one (18, 19). The failure of a
callosal volley to initiate the repetitive discharges of
the sensory cortex at the same cortical locus where the
thalamic volley can do so very well seems to provide
strong evidence that the appearance of the repetitive
waves is dependent on the presence of a specific
neuronal circuit rather than being representative of
mere local after-discharge of an unorganized ag-
gregate of neurons having autorhythmic properties
One of the main difficulties in interpretation of the
specific periodic after-discharges according to the
hypothesis of corticothalamic re\erberation is perhaps
the long interval (45 to 1 50 msec.) between the con-
secutive waves which appears to be of too great a
duration to be accounted for solely by the time neces-
sary for the impulses to travel along the neuronal
circuit between the thalamus and the cortex. A pos-
sible explanation is that the surface-positive re-
verberating waves, like the positive component of the
primary response, presumably consist of synchronous
discharges of cortical neurons triggered by the recur-
rent thalamic volleys but not the afferent impulses
themselves. The latter may not be detectable from
the cortical surface. Because of the \ariation in size of
fibers interconnecting the thalamus and the cortex and
the variation in number of synapses interposed in the
circuit, the degree of temporal dispersion of the
circulation of the reverberating impulses along the
circuit must result in a continuous train instead of
intermittent waves. It is probable that among the
returning impulses only those which arri\e at certain
phases of the excitability cycle of the cortical neurons
are capable of initiating synchronous discharges of
these neurons, and the others which arrive at the
cortex during the period of postexcitatory depression
rendered by the previous wave will not cause excita-
tion. Therefore, the interval between the reverberat-
ing waves is probably determined by the state of
excitability of the cortical neurons at the time of
action, rather than by the conduction time and the
number of synapses in the circuit. Thus, it becomes
evident that the activity of the corticothalamic
reverberating circuit cannot l^e taken as a simple
circulating of impulses along a closed chain of neurons.
According to Bremer (9) the initiation and main-
3o8
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
tenance of the periodic \\a\es in the cerei)ral cortex,
although considered by him to be fundamentally a
manifestation of autorhythmicity of neurons, neces-
sitate a minimal influx of corticipetal impulses. The
requirement of this minimal number of afferent
impulses for the production of periodic cortical waves
is in some respects close to the essential concept under-
lying the proposed mechanism of corticothalamic
reverberation. The dependence of the so-called
spontaneous activity of cortical neurons on activation
by afferent impuLses has been con\incingly pro\'ed by
Burns (12). He demonstrated that the spontaneous
activity of isolated slabs of the cerebral cortex did not
ensue unless a bridge was left connected with the
rest of the brain. However, such slabs may exhibit
periodic activity if kept normalK- oxygenated (42).
excit.IlBIlity ch.i,nges .accompanying and
following the evoked potential
Like peripheral nerves or other excitable tissues the
aggregate of neurons in the central nerxous system,
after being activated either by direct or synaptic
stimulation, undergoes a cycle of excitability change
consisting of a refractory phase and a recovery phase.
After recovery, it may go into another period of
secondary depression during which the neurons fail to
respond or respond with less vigor. Uniquely in the
sensory cortex, a periodic variation in excitability may
deselop as a result of the corticothalamic re\erberat-
insf activity.
RefraclDiy Periods
The alisolute refractory period following the re-
sponse of the somesthetic corte.x to an aflferent stimulus
was about 8 msec, and the total recovery time was i 7
msec, as determined in monkeys under ether anes-
thesia. Barbiturates have the effect of lengthening the
recovery time. For example., under pentobarbital
anesthesia the absolute and the relative refractory
periods were found to be of the order of 25 to 50 msec,
and 87 to 144 msec, respectively (52, 55). Forbes &
Morison (33) found that the amplitude of the primary
response of the somesthetic cortex was reduced to 50 to
70 per cent of its initial value when the sciatic nerve
of a cat was stimulated at a frequency of 5 to 7 per
sec, implying that the relative refractory period was
much longer than the value obtained by Marshall
et al. (55). Forbes et al. (34) later reported that stimula-
tion of the sciatic nerve at a frequency of 60 per sec.
produced no detectable cortical response after the re-
sponse to the first stimulus of the series. They also
reported the decrease in size of the primary response to
repetitive stimuli at a frequency of 5.5 per sec. and the
phenomenon of alternative response to repetitive
stimuli delivered at the rate of 14 per sec.
The values of the absolute and relative refractory
periods in the \isual cortex of man and animals as
determined by Gastaut et al. (37) were 20 and 40
msec, respectiveh'. According to Tunturi (67), the
absolute refractory period in the auditory cortex to a
click lasts 20 to 100 msec, and the duration of the
relative refractory period is 100 to 250 msec. A glance
at the figures obtained by various investigators makes
one immediately realize the impossibility of finding
standard values for these events since the experimental
conditions which determine the results are extremely
variable. Among the more important factors affecting
the excitability of the brain are the anesthetics used in
the experiment (40), the depth of anesthesia during
which the observations are made (29, 33. 62), the
arterial pressure (6), the moisture (54), the tempera-
ture, etc. The level of tonic reticular activity is also a
factor of major importance (40).
The effect of barbiturates on the excitability of the
nervous system is particularly interesting. It has been
suggested that barbiturates act selecti\ely on inter-
nuncial neurons in the corte.x rather than on the
afTercnt pathway. The suggestion remains to be
reconciled with the fact that under barbiturate
anesthesia the primary response of the exoked poten-
tial is little affected as compared with the marked
suppression of the spontaneous cortical waves. As is
known, the primary response of the ex-oked cortical
potential consists largely of the actixity of cortical
internuncial ncin-ons.
The total period of refractoriness of the auditory
cortex following a direct electric shock was about 44
msec. The absolute refractory period was estimated as
about 7 or 8 msec. This value as compared with that
of the peripheral nerve or with that of the individual
neurons in the central nervous system is indeed very
large. The absolute refractory period of a nerve fiber
is known to occupy about the same time as the rising
phase of the action potential, xvhich usuallx' does not
exceed i msec. It has been frequently ob.serxed that
the minimal interval between successix-e spikes in a
train of unit discharges may be as brief as i m.sec. or
less, implying that the refractory period of single
neurons following a discharge is substantially shorter
than that of the potential recorded from the ag-
gregates of neurons. The reason for this difference
THE EVOKED POTENTIALS
309
between single neurons and neuronal aggregates is not
entirely understood. Perhaps in the case of neuronal
aggregates the processes of postexcitatory depression
have superseded the phase of true refractoriness and
therefore make it appear that the refractory period is
prolonged. The true refractory period is believed to
be the same as the period during which the repolariza-
tion process of the membrane potential of the active
neurons is taking place. Its value is determined by
the rate of the repolarization process.
Poitexcitatury Di'pressiun
The phase of postexcitatory depression may be
defined as the period immediately following the initial
recovery from refractoriness during which the nervous
tissue undergoes various degrees of lowered excitabil-
ity. The basic pattern of the event exists in the ex-
citability cycle of any kind of nervous tissue including
the cerebral cortex, the spinal cord, peripheral
nerves and sympathetic ganglia.
The degree and duration of the postexcitatory de-
pression vary more or less proportionately with the
stimulus strength and the number of neurons pre-
viously activated by the conditioning stimulus. There
may be no obvious secondary depression following the
refractory period if the previous response is weak.
After an intense response of the cortex the postexcita-
tory depression may last for several hundred milli-
seconds. Extremely severe depression lasting for a
second or more has been observed following the
respon.se of the cortex treated with strychnine. This is
true for cortical responses to topical stimulation as
well as for those to afferent impulses (15). By u.sing
paired electric shocks applied to the optic nerve, both
Marshall (53) and Clare & Bishop (26) demonstrated
the existence, in the visual cortex and in the lateral
geniculate body, of a typical excital:)ility cycle with the
supernormal phase followed by a long period of post-
excitatory depression. When the retina is continuously
illuminated, not only the onset but also the cessation
of the photic stimulus produce the phenomenon of
postexcitatory depression of the cerebral cortex. The
visual cortex undergoes a period of severe depression
immediately after the recovery of the cortex from the
refractoriness caused by retina excitation. In extreme
cases this period of temporary depression may last for
as long as several seconds. A similar phenomenon is
present in the auditory system. Rosenblith el al. (61)
observed that the neural respon.se to a click as re-
corded from the round window and from the auditory
cortex of the cat were depressed within the first 40 sec.
after sudden exposure to continuous tones. The post-
excitatory inactivation of the cortex discus.sed here
may constitute a physiological basis for the temporary
blindness and deafness following a sudden exposure to
strong light and loud sound. The diininished excitabil-
ity of neurons during the period of postexcitatory
depression is l)elieved to be associated with the mem-
brane potential changes of the neuron following the
discharge. From recent microelectrode studies of the
electrical properties of single neurons it has been
observed that the repolarization of the membrane
potential may develop into a phase of hyperpolariza-
tion which reaches a maximum at 5 to 10 msec, and
may last for as long as 100 msec. During the period of
hyperpolarization the action potential of the neuron
is inhibited (27, 28). The time courses of the repolari-
zation and the hyperpolarization processes bear a
close relationship to the refractoriness and the post-
excitatory depression of the neuron. '
Pinodic \ nnatuin in Cortical Excitability
Unique to the sensory area, the e.xcitability state of
the cortex does not always return to the normal level
following the completion of a usual excitability cycle
but undergoes a further cyclic waxing and waning
with regular intervals. The periodic excitability
change of the visual cortex was described bv Bishop in
'933 Co)- However, he believed it was an indication of
the excitability change of the optic pathways rather
than of the cortical neurons them.selves. The periodic
\ ariation in excitability of the auditory cortex beyond
the unresponsive period caused by a sound stimulus
was obser\-ed by Jarcho (38). He noticed the periodic
depression of the cortex at a frequency coincidental
with the repetitive corticothalamic after-discharges.
No increased excitability was seen at any time, how-
ever. Jarcho's finding was soon confirmed with the
further disclosure that in company with the rising and
falling of the corticothalamic reverberating waves,
there are concomitant increase and decrease of cortical
excitability (14, 15). The temporal relation between
the repetitive waves and the excitability change of the
cerebral cortex resulting from the corticothalamic
reverberating activity was found to be such that the
cortical excitability is increased during the developing
phase of the re\-erberating wave and decreased during
the returning phase of the reverberating wave. An
alignment of the excitability curve and the contour of
the reverberating waves on the same time scale show
that the maximum of the increased excitability is
reached in the middle of the developing phase, that
310
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
the maximum of decreased excitability is reached in
the middle of the returning phase and that the ex-
citability remains unchanged both at the peak and at
the valley of the reverberating waves. Mathematically
speaking, the sinusoidal curves representing the
reverberating waves and the excitability changes are
90° out of phase, the maximum of cortical excitability
being one quarter of a period ahead of the peak of the
reverberating waves (15).
Though intimately related with the corticothalamic
re\-erberating wa\es, the periodic \ariation of cortical
excitability following an afTerent stimulation may be
manifested in the absence of detectai^le repetitive
waves. At the onset of continuous illumination of the
retina, for instance, the waxing and waning of the
cortical excitability can be demonstrated even within
the prolonged period of postexcitatory depression dur-
ing which the reverberating waves are not distinctly
visible (16). The significance of the periodic excita-
bility change of this kind is not known. Its relation
with the spontaneous brain waves has been discussed
by Gastaut (37) and Lindsley (44). The periodic
variation in excitability of spinal neurons has been
described by Bernhard (7), but the mechanism in-
volved in this case is believed to be diflferent. The rela-
tion of the reticular formation to cortical excitability
has been studied by King et al. (40).
Inlnaction of Afferent Imjnilies in the Cerebral Cortex
Information concerning the excitabilit\ change of
the cortex on which the present discussion is based is
obtained mainly from experiments in which the corti-
cal excitability is determined by a testing volley
having the same source as the conditioning one. When
two afferent volleys of different origin, an auditory
and a callosal, for instance, are sent to the same locus
of the cortex, the e\oked responses to the combined
stimuli are characteristically different. The cause of
the difference seems to lie in the fact that the callosal
and thalamic afferent volleys arri\e at diflerent strata
of the cortex and activate different sets of neurons,
among which a certain nmnber of common elements
are involved in the responses to both \-olleys (19).
Probaljly for the same reason the cortical response to
acoustic stimuli can ije inhibited or facilitated by
simultaneous or successi\e stimulation of a sxmmetri-
cal point on the opposite cortex (10).
In an extensive study of the interaction at different
levels of the variously evoked afferent impulses,
Amassian (i) observed that both the cortical and the
thalamic responses to the second of two successive
stimuli, delivered at certain intervals to the same ner\e
or to two separate branches of a peripheral nerve,
were always defective. The blocking of the cortical or
subcortical response by an antecedent volley was
interpreted as inhibition as distinguished from oc-
clusion. Occlusion, by definition, denotes the phe-
nomenon in which the total effect of two processes
when activated simultaneously is smaller than when
activated separately due to partial overlapping or
sharing of common elements. In real occlusion one
process should not be completely abolished, though
it may be greatly lessened, by another simultaneously
occurring process. If it is, it would merely indicate
that the common elements can be totally activated by
either of the two processes. Thus, the complete block-
ing of the cortical or subcortical response to stimula-
tion of the \olar branch of the ulnar nerve by previous
stimulation of the dorsal branch of the same nerve
described by Amassian may be regarded as a phe-
nomenon of inhibition, and the defect of cortical
response to splanchnic stimulation preceded by a
shock to the tibial ner\e a phenomenon of occlusion,
since the splanchnic nerve and the tibial nerve do have
separate focal areas of projection with overlapping
fringes in the thalamus and the cortex.
This argument about occlusion is perhaps also
applicable to Marshall's investigation of the inter-
action between the ipsilateral and contralateral visual
pathways which converge with overlapping terminal
branches on some common neurons in the visual
cortex (53). It is significant that bilateral interaction
does not occur at the geniculate level, since the optic
fibers from the two retinae do not mingle but termi-
nate in separate laminae of the lateral geniculate
bodv. There are no common neurons available at that
level for the impulses from both sides to act on each
other, although the impulses reach the same nucleus.
However, if two stimuli of equal strength are applied
to the same optic nerve at proper intervals the genicu-
late response to the second stimulus is greater than
that to one stimulus alone. Apparently, the neurons
in the subliminal fringe are recruited into action due
to temporal sunnnation.
Modifiealion of Cortical Excitability by Cointant
Inflow of Afferent Impulses
It has long been known that the proper excitability
level in an animal when awake is maintained by an
incessant action of afferent impulses. It has frequently
been reported clinically that patients completely
depri\ed of sensory al)ilities fall asleep immediately
THE EVOKED POTENTIALS
311
and can be aroused only by stimulation of some sense
organs. Experimental evidence shows that afferent
impulses necessary for keeping the cerebral cortex in a
state of vigilance reach it from the reticular formation.
Impulses in the main ascending sensory pathways ap-
parently travel in collaterals entering the reticular
formation, since they cannot maintain wakefulness
after destruction of the reticular formation (45, 63,
64).
Perhaps one of the more illustrative examples show-
ing the effect of constant afferent inflow on cortical
excitability is the phenomenon of photic potentiation
(16). The electrical response to stimulation of the
lateral geniculate body was found to be manv times
greater when the retina was illuminated than when
it was in the dark. Not only was the size of the cortical
response to geniculate stimulation greater but also the
threshold of the response was lower during retinal
illumination than in the dark. The effect of photic
potentiation on cortical responses dc\elopcd pro-
gressively after the onset of retinal illumination and
reached its maximum in about 5 sec. Once the maxi-
mal effect was attained, it was sustained at that level
as long as the retinal illumination persisted. The
enhanced cortical response was promptly reduced to
the preillumination magnitude as soon as the light
stimulus was withdrawn. The mechanism underhing
this potentiation phenomenon is believed to lie mainly
in the lateral geniculate body. As is well known, some
retinal elements discharge steadilv at low frecjuencv' in
the absence of light which is apparently not strong
enough to set up a discharge of the postsynaptic neu-
rons in the lateral geniculate body. Nevertheless, the
summated effect of the incessant bombardment of
these subliminal impulses will raise the excitability
of the geniculate neurons. If meanwhile an electric
shock is applied directly to the geniculate Ijody, the
neurons which are normally in the subliminal fringe
will discharge because of the summation of the existing
presynaptic impulses induced by retinal illumination
and the electric stimulus directly applied to the
geniculate body. The gradual development of the
photic potentiation effect in the case of repetitive
stimulation of the geniculate body seems to constitute
a good example of recruitment in the truly physio-
logical sense of the term.
A similar process is present, though much less pro-
nounced, in the auditory system. Rosenblith et al.
(61) described the enhancement, by exposure to
continuous tones, of potentials evoked in the cortex by
a click. Their results suggest that tones of certain
frequencies, especially tones at frequencies between
100 and 500 cycles per sec, show a very effective
potentiation effect following the initial period of
depression, while those of high frequencies are not as
effective.
Preliminary observations ha\e been reported on the
potentiation effect of continuous retinal illumination
on the cortical response to stimulation of the auditory
pathway C'6). The interaction between the visual and
auditory impulses appears to take place not only in
the cerebral cortex through the association neurons
but also in subcortical structures, since the removal of
the visual cortex cannot completely abolish the
photic potentiation effect on the auditory response.
The explanation tor the interaction between the
visual and auditory impulses at the subcortical level
is rendered diflicult by the lack of direct fiber connec-
tions between the medial and the lateral geniculate
ijodies. The pulvinar is considered a possible site of
subcortical correlation for the two great special sen-
.sory systems. Since the importance of the core struc-
tures of the brain stem in the actixation of the cerebral
cortex has been recognized (50, 51, 56), it is pos.sible
that the interaction at the cortical level between the
afferent impulses from different .sources mav be exe-
cuted indirectly through the system of the diencephalic
and mesencephalic reticular formation where collat-
erals of ascending fibers from different kinds of sense
organs converge. The centrally located area in the
brain stem comprising the midbrain's tegmentum, the
subthalamus, the hypothalamus and the intralaminar
portion of the thalamus, has been found to be able to
desynchronize the electrocortical activity when it is
stimulated repetitively at a rapid rate. It can also
exert various effects on the cortical potentials evoked
by single shock stimulation of a particular sensorv
system when it is stimulated singly in close approxi-
mation to the eliciting shock. Stimulation of this area
in the brainstem has also ijeen described as having a
catholic activating effect on the entire cerebral cortex
and especially the frontal lobe of the brain. This
activating system receives afferent impulses from
various sensory sources through the collaterals of
ascending tract fibers and transmits them to the
cerebral cortex, probably both by the thalamic and
the capsular corticipetal routes.
SUMM.'^RY
An evoked potential may be defined as the detect-
able electrical change in the brain in response to de-
liberate stimulation of any part of the nervous system.
312
HANDBOOK OF PHVSIOLOGV -^ NEUROPHYSIOLOGY I
Such potentials differ from the spontaneous electrical
activity in that they have a definite temporal relation-
ship to the onset of the stimulus, a constant pattern of
response and a focus of maximal response in the brain.
The technique of evoked potential registration has
been widely used as a tool for anatomical studies of
the central nervous system. However, the conclusions
drawn from the results of such studies are justified
only when the limitations of this technique are duly
considered.
The primary response of the evoked cortical poten-
tial consists of a presynaptic component produced by
the impulses from the afferent fibers and a post-
synaptic component produced by the discharge of
intracortical neurons. These two components can be
differentiated from each other by various experimental
procedures, such as by study of a) latency, A) the
effect of repetitive stimulation, <) the relative tolerance
to changes in internal and external milieu and above
all d) the anatomical considerations.
The neural mechanism for elaboration of the
evoked cortical potential is formulated on the basis of
the histological organization of the cerebral cortex
and the general principles of neurophysiology. In a
proposed scheme it is suggested that the afferent im-
pulses from the thalamocortical fibers first excite the
Golgi type II cells in the fourth cortical stratum which
in turn transmit the postsynaptic impulses to star
pyramids and the star cells in the same layer, then to
small and medium pyramidal neurons in the supra-
granular layers and finally to the large pyramidal
neurons in the deep layers. The surface-positive deflec-
tion of the evoked potential is attributed to the
synchronized propagation of impulses along the
apical dendrites from the cell body of pyramidal
neurons inward to the cortical surface. The depolar-
ization process of the cortical pyramidal neurons is
believed to start always at the cell body due to the
effective excitatory action of the pericorpu.scular
synapses. The subliminal excitation of the paraden-
dritic synapses has the effect onl\ of modifying the
excitability state of the neur(jn. This hypothesis is
supported by the results of microelectrode findings of
single neurons.
After-discharges can be classified into three kinds:
/) the self-sustained repetitive firing of single elements,
2) persistent local after-discharges involving the
activity of closely situated intrinsic neurons and 3)
the periodic after-discharges involving the activity
of reverberating circuits interconnecting distant
structures. Of these three, the most frequently ob-
served in the central nervous system is the local after-
discharge, maintained by a mechanism of self-re-
excitation through collaterals and numerous closed
neuronal circuits within the cortex. The activities of
the long reverberating circuit are not to be confused
with other kinds of periodic waves which may happen
to have similar frequency and similar wave form.
The ijrain undergoes a cycle of excitability changes
accompanying and following the evoked potential.
The true refractory period which lasts for less than a
millisecond is thought to be related to the repolariza-
tion process of the neuron. The postexcitatory de-
pression which may last for as long as 100 msec, is
proi:)ably a functional manifestation of the hyper-
polarization process. Because of the supersession of
the rcfraciorv phase by the process of postexcitatory
depression, the value of the true refractory period of
the neuronal aggregate cannot be accurately deter-
mined. In addition to the regular cxcitabilit\- c\cle
there is a periodic variation of excitability accom-
panying the reverberating activity of the sensory
cortex.
Although the ev'oked potentials in different systems
are independent processes, they do show interaction
proi^ably due to the overlapping of their fiber distribu-
tion or the con\crgence of the afferent impulses on the
common neurons, or through the integration in a
general activating system such as the reticular forma-
tion. Such interaction of afferent impulses in the
cerebral cortex makes it possible for the constant
afferent inflow in any particular sensory system to
modif\ the lc\ei of cortical excitability as a whole.
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55. Marshall, VV., C. N. VVoolse\ and P. Bard. J. .Neuro-
physiol. 4 : 1 , 1 94 1 .
56. MoRUZZi, G. AND H. W. Magoun. Eleclroencephalog. &
Clin. Neurophysiol. 1 : 455, 1949.
57. P.\TTON, H. D. AND V. E. Amassian. J. .Ncurophysiol. 17:
345. ■954-
58. Perl, E. R. and J. U. Casby. J. Neurophysiol. 17: 429, 1954.
59. Phillips, C. G. Quart. J. Exper. Physiol. 41 : 58, 1956.
60. Rose, J. E. and V. B. Mountcastle. Bull. Johns Hopkins
Hosp. 94: 238, 1954.
61. Rosenblith, VV. A., R. Galambos and I. J. Hirsh.
Science 1 1 1 : 569, 1950.
62. Rosenzweig, M. R. Am. J. Physiol. 163: 746, 1950.
63. Starzl, T. E., C. W. Taylor and H. VV. M.agoun. J.
.Neurophysiol. 14: 461, 1951.
64. Starzl, T. E., C. W. Taylor and H. VV. Magoun. J.
.Neurophysiol. 14: 479, 1951.
65. Svaetichin, G. .Acta physiol. scandinav. Suppl. 86, 24: 23,
1951-
66. Tasaki, I., E. H. Poi.ley and F. Orrego. J. .Neurophysiol.
17:454. ■954-
67. Tunturi, a. R. .4m. J. Physiol. 147: 311, 1946.
68. Woodbury, J. VV. and H. D. Patton. Cold Spring Harbor
Symp. Qjiant. Biol. 17: 185, 1952.
CHAPTER XIII
Changes associated with forebrain
excitation processes: d.c. potentials
of the cerebral cortex'
JAMES L. O'LEARY
SIDNEY GOLDRING
Divisions of Neurology and Neurosurgery, and the Beaumont May Institute of
Neurology, Washington University School of Medicine, St. Louis, Missouri
CHAPTER CONTENTS
Suggested Technique for Cortical D.C. Recording
Experimental .Studies
Spontaneous SP Changes Correlated with Interruption in
Usual Resting Cortical Rhythm
After-effects of Evoked Responses
SP Changes Associated with Recruiting Responses
SP After-effects of Strychnine and Veratrine .Spikes
SP Concomitants of Convulsoid Discharges
D.C. Changes Which Accompany Spreading Depression (SD)
Relation of Polarity of Evoked Transient to Polarity of SP
Change Also Consequent to Stimulation
Effects of Stimulation at a Distance Along a Multisynaptic
Path Upon Transcortical SP
Injury Potential Components
Human Studies Using Scalp Recording
Discussion of Origin of Steady Potentials
Summary
BESIDES THE SPONTANEOUS and evoked potentials con-
ventionally recorded from the cerebral cortex, the
exposed brain in a resting state ordinarily shows a
voltage difference between cortical surface and ven-
tricle (d.c. potential). If the brain is not disturbed
following its preparation for recording, this pia-
ventricular potential may remain relativeh' steady,
and for that reason we have referred to it as steady
potential (SP).
' .'Mded by grants from the .Allen P. and Josephine B. Green
Foundation and the Public Health Service (B-882).
The role SP plays in neuronal functioning can be
assayed only after taking account of the nonneuronai
sources which complicate its interpretation. It is also
necessary to differentiate such d.c. potentials from
those of pH and oxygen electrode recording. The
latter, although employing a d.c. method, depend
upon the change which occurs in a critical electrode
as a result of a tissue change in its milieu. By contrast,
the d.c. recording described hereafter employs very
stable electrodes to register changes in the distribution
of electrical charge in the intervening tissue.
Reduced oxygen tension incident to systemic de-
terioration, or intracellular poisoning of respiratory
enzyme systems (e.g. by cyanide ions) can produce
predictable changes in it. Injury effects and anesthesia
are unavoidable complications of any experimental
neurophysiological procedure and can also result in
SP alterations. Cbntrol of these and possibly other
factors which limit the applicability of the method is
necessary if we are to reach an understanding of the
relation between spontaneous and evoked potentials
of the usual electrocorticogram and SP changes
which may develop coincidentally or subsequently.
Several early studies of d.c. potential are relevant
to the approach outlined here. Libet & Gerard (30)
first showed that a pia-\entricular potential exists in
the frog brain, postulating that a change in such
potential can alter spontaneous cortical activity.
Jasper & Erickson (22) at about the same time ob-
served a d.c. voltage component associated with high
315
3i6
HANDBOOK OF PHYSIOLOGY -^ NEUROPHYSIOLOGY I
voltage convulsoid discharge. Later Leao (26, 27)
proved that a marked d.c. change also accompanies
a wave of spreading depression as it propagates across
the cortex. This phenomenon will ije discussed in
detail under experimental findings.
One may assume with Libet & Gerard (30) that a
significant component of the pia-\entricular potential
arises from an end-to-end polarization of the cortical
pyramids, and that the transcortical potential over an
area of corte.x represents chiefly the average of the
polar charges of the contained neurons. However,
the potential difference along an individual pyramidal
neuron has relative rather than absolute pertinence,
for it can be recorded not only when one end of the
cell is depolarized, but when, for any reason, the two
ends become unequally depolarized. The polarization
of both ends might, for example, be lowered un-
equally, raised unequally, or one raised and one
lowered. With externally applied polarization as
studied by Bishop & O'Leary (2) it is almost certainly
the latter which occurs. Surface-positixe polarization
applied to an area of cortex accentuates the surface-
negative component of evoked potential transients
recorded therefrom; accentuation of the surface-
positive component occurs during applied surface-
negative polarization.
Reviewed herein are: a) the requisites for reliable
d.c. recording together with an assay of difficulties
which, if unrecognized, may render experimental data
unreliable; h} the transient d.c. alterations which
have been shown to accompany or follow spontaneous
or induced changes in the pattern of the usual ECG,
such as changes in spontaneous activity, evoked re-
sponses, recruiting waves, barbiturate spindles, strych-
nine and veratrine spikes; c) changes associated with
the occurrence of high voltage convulsoid activity;
rf) d.c. change accompanying spreading depression;
i) evidence linking the polarity of usually recorded
evoked potential phenomena with those of accom-
panying d.c. change; /) d.c. cortical changes pro-
duced by repetitive stimulation at sites distant from
the recording electrodes and requiring transmission
along paths containing intervening synapses; and g)
injury potential effects.
SUGGESTED TECHNiqUE FOR CORTICAL D.C. RECORDING
For many experimental studies it is important to
monitor the potential continuously. Minor displace-
ments of the recording electrodes or injury (either of
which mav ije due to movement of the animal), an
obstruction in the airway, or periodic excesses of
stimulation, can unstabilize a preparation temporarily
or permanently. Then, swings of several millivolts
from one polarity to the other may occur. Movement
of the electrodes alone may occasion swings in po-
tential in either direction, whereas with the other
conditions mentioned the changes are characteristic;
these will be discussed later. In the rabbit (less often
in our experience in the cat) SP swings occur which
accompany either spreading depression (Leao) or
the appearance of high voltage convulsoid activity.
Li the rabbit the latter is a common enough accom-
paniment of excesses of electrical stimulation.
L nidirectional drifts may also occur during systemic
deterioration, or with oxygen lack or deepening
anesthesia. These necessitate quick recognition if the
preparation is to continue to provide reliable data.
To measure SP one needs nonpolarizable elec-
trodes. Continuous monitoring during experiments
lasting for se\eral hours indicates the need for stable
electrodes. We have used calomel half-cells having a
difference of potential in Tyrode's of 0.5 to i.o mv. A
flexible pipette may be led from one member of a
pair to the cortical surface of the selected region;
that from the other can be introduced either into the
\entricle or the subcortical white matter. In the
rabbit the former (ventricular) position to the surface
gives an individual diff'erence of potential of surface-
positive polarity amounting to i to 4 mv. If the deep
electrode tip is introduced into the subcortical white
matter the potential difference may be larger due to
the addition of injury potential. Monopolar recording
from surface cortex to a point upon the periosteum
gi\es a change of the same polarity as that evident
with transcortical recording. The diff"erence of po-
tential is greater than the pia-\entricular potential
ijut less than that led between surface and white
matter. Transcortical (or pia-ventricular) d.c. re-
cording is ijclieved to off'er greater promise for estab-
lishing correlates with spontaneous and evoked ac-
tivity of the usual ECG because of the more localized
leading.
A conventional condensor-coupled electroencepha-
lograph as well as a d.c. amplifier ma\- be used both
for monitoring and for the study of d.c. changes. It
is only necessary to short-circuit the input 4 to 8
times per sec. Each short circuit discharges such
potentials as have accumulated upon the input con-
densors because their time course has been too long
to permit passage into the amplifier. The discharge
causes the pens to return momentarily to the baseline
of the amplifier. When a chopper is u.sed, if the record-
CHANGES ASSOCIATED WITH FOREBRAIN EXCITATION PROCESSES
3'7
ing apparatus is set so that a negative ECG transient
registers as an upward deflection, a correlated nega-
tive SP change appears as a series of down-going pips,
the amplitude of which determines the \oltage of the
change. Vice versa, positive SP changes are recorded
as up-going pips. The deflection of the pips then is
opposite to the direction in which ECG transients
are recorded, although each has the same polarity.
The reason is that each interruption of the input
returns the pens from a positive or a negatise potential
value to the zero baseline of the amplifier (fig. i).
The conventional ECG can be recorded upon other
channels of the same electroencephalograph, using
neighboring pairs of polarizable electrodes tor the
pickup.
The recording system must be flexible enough to
detect microvolt changes at the same time that it is
prepared to register a change of several milli\olts. To
accomplish this two devices are used: o) several
channels of amplification record from the same lead
combination at different sensitivities; A) a balancing
potentiometer is placed in series with one of the
calomel half-cells to oppose the electrical effect of any
sizeable shift through the application of a counter-
voltage. The amplitude of an ,SP change can then be
read directly from the potentiometer. During swings
of seseral millivolts the more sensitive channels are
first turned ofl' while the least sensitive one is balanced.
Thereafter, the others are balanced in order toward
the most sensitive one. That one is used continuously
to record SP concomitants of evoked and spontaneous
activity, and the d.c. changes it records are the ones
which can he correlated most directly with ECG
manifestations of neuronal activity. From the calomel
half-cells, records of the quicker d.c. changes which
are registered upon the most sensitive channel of the
electroencephalograph can also be led through a d.c.
amplifier to a cathode-ray oscillograph. During
— Mi
,",VJ'.''.AAAM'\'^'"
I sec
FIG. I. Steady potential change accompanying cortical recruiting in the rabbit. Light ether anes-
thesia. Stimulation in medial thalamus. Recording from frontal cortex. A. Recorded by conven-
tional condensor -coupled electroencephalograph the input of which is short-circuited 8 times per
sec. Negative polarity recruiting responses are recorded as upward deflections, and black dots indi-
cate the first and last responses of a series. The SP change is recorded as a series of downward
deflections, each indicating a short circuit of the input. Although opposite in direction from the
deflections representing the recruiting transients each represents a d.c. change of negative polarity.
Records B and C serve to clarify the situation. For each the base line from which the d.c. change is a
departure is indicated by a straight white line. B. The same recruiting response recorded upon an
oscilloscope with use of a direct-coupled amplifier. Note negative steady potential change accom-
panying recruiting series. Surface of the cortex remained negative with respect to the underlying
white matter for approximately 750 msec, following the last recruiting response. C. Another re-
cruting response series recorded under similar conditions to that of B. Input is again short-circuited
8 times per sec. as in A. Note that each short circuit returns the beam to the base line of the amplifier.
Had this series been recorded by means of the same amplifier using condensor coupling, the d.c.
shift should have been eliminated and the oscilloscope record would have been the counterpart of .4.
The chopper signals on C have been retouched due to printing difficulties.
3i8
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY' I
19 20 21 Zl 23 2+
Time in Minutes
FIG. 2. Graph of change in SP during asphyxia which resuhed from clamping airway. /, tracheal
airway clamped; i', ECG completely suppressed; 3, heart stops. [From Goldring & O'Leary (11).]
oscillographic recording upon strips of film, the
chopper is temporarily disconnected. By convention,
shifts in potential from the base line will be referred
to as positive or negative with respect to the surface
electrode.
Under optimal conditions the initial determination
of pia-ventricular SP has varied usually between 0.5
and 5.0 mv positive (i i). These data include meas-
urements upon 20 rabbits which were anesthetized
with ether for only the brief tiine required to pro-
cainize the skin and paravertebral muscles over the
C5 cord segment and divide the cord there. Anesthesia
could then be discontinued, and the scalp similarly
infiltrated with procaine as a prelude to exposing the
brain for recording. With insertion of the deep lead
into the subcortical white matter (in the cat), negative
injury potential about the deep electrode tip con-
tributes to the positivity at the surface, and larger
voltage discrepancies may be recorded. In human
subjects under nitrous oxide and thiopental anesthesia
in whom the pia-ventricular potential has been re-
corded, the measurement in the majority of cases has
been 0.3 to 0.5 mv positive (17). Here injury potential
was not believed to be a significant complicating
factor. Returning to the animal experiments, we note
that SP may not fluctuate more than 0.5 mv during
several hours of continuous recording if no procedure
is undertaken after the preparation of the animal.
With the high cord section (at Ci), necessitating arti-
ficial respiration, systemic failure has often developed
in rabbits; under this circumstance SP may show a
continuous negative drift terminating with the death
of the animal. Clamping the trachea in an animal in
good condition, in which SP has not undergone sig-
nificant alterations during several hours of continuous
recording, will result m a significant SP change (11).
While \ariaijle and somewhat complex, this consists
principally of an initial positive shift (2 mv) followed
by an even more prominent negative one (4 mv).
The major change which follows clamping of the
airway usually ends in 8 min. The heart ceases to
beat between the maximum and the end of the nega-
tive deflection (fig. 2).
Leao (26) demonstrated a similar negative shift
incident to cortical anemia and van Harreveld el al.
have also shown a negative SP shift with asphyxia
(41, 43). Other investigators, leading from the cortex
and using the sciatic nerve as reference point, have
also recorded SP shifts with anoxia and asphyxia
(4, 10).
The injection of malononitrile, which liberates
cyanide ions, evokes an analagous picture (18). This
has been followed during the intravenous injection
of between 10 and 20 ml of a freshly prepared i per
cent solution delivered by Murphy drip. As the in-
jection proceeds the animal becomes hyperpneic,
and at aijout that time the ECG commences to slow,
with the appearance of random components showing
higher voltage than previously. As the ECG changes,
SP commences to shift positively. With further de-
terioration in the preparation the ECG becomes
isoelectric, and SP continues to shift positively to a
total of 2.5 mv. Clonic convulsive movements may
appear during the positive phase. These electrical
events can be reversed if 5 per cent sodium thiosulfate
is injected at the beginning of the positive SP change.
CHANGES ASSOCIATED WITH FOREBRAIN EXCITATION PROCESSES
319
Then the ECG and SP will revert to the preinjection
status. Unless the thiosulfate is injected the change
continues for 3 to 8 min.; respiration stops and shortly
thereafter the heart also. Meanwhile SP undergoes an
opposite shift which carries it 3 to 4 mv more negative
than it was at the start of the experiment (fig. 3).
We ha\e followed .SP under ether anesthesia more
carefully than under any other. Commencing at a
light level of anesthesia and deepening it gradually,
SP may remain relatively steady although occasionally
a positive shift may occur. If inhalation anesthesia
is carried too deep, SP may shift negatively by com-
parison with the preceding light anesthesia baseline.
However, as long as anesthesia is maintained at a
relatively light level, the changes it occasions in SP
are relatively insignificant, and induced physiological
variations are much like those encountered in a rela-
tively unanesthetized state. Finally, solutions added
to the cortical surface which are not isotonic may
disturb SP for sexeral minutes. These are diffusion
potential artifacts.
Summarizing, one must emphasize that to provide
a stable base for measuring induced SP changes there
should be careful control of injury, anesthesia and
oxygen tension.
EXPERIMENT.'\L STUDIES
Spontaneous SP Changes Correlated with Interruption
in Usual Resting Cortical Rhythm
It often is not possible to demonstrate SP altera-
tions which coincide with a change in the ECG
rhythm of the lightly anesthetized animal. However,
in the rabbit (12) we have noted repeated brief nega-
tive shifts amounting to 0.6 mv which coincide with
low voltage ECG intervals between runs of regular
frequency activity. Furthermore, a relatively rapid
increase in ECG amplitude with substitution of
slower for usual frequencies may show an accom-
panying positive SP shift. In the pentobarbitalized
cat a significant negative shift can be recorded during
and succeeding barbiturate spindles, sometimes out-
lasting the spindle by several seconds.
After-effects of Evoked Responses
Since singly evoked responses are quick transients,
the only SP change which could be expected to occur
would appear as an aftermath. We have studied such
after-effects in the visual cortex of the rabbit (11, 12)
together with the conditions leading to their summa-
o
7
6
5
4
3
2
/
0
/
2
3
4
5
6
+
T
ime in minuxeb
ici
I Z 3 4 5 6 7 S 9 10 1/ IZ 13 14 15 lb 17 18 19 10 2J 22 2i 24
FIG. 3. Graph of change in SP during intravenous injection of 20 ml of i per cent solution of
malononitrile. a, start of injection; b, ECG commences to become isoelectric; c, respiration stops.
320
HANDBOOK OF PHYSIOLOGY ^ NEUROPHYSIOLOGY I
tion during repetitive stimulation. The after-effects
of singl\- evoked responses may not be evident at the
beginning of an experiment but appear as the experi-
ment proceeds. They may be positise, negative or
diphasic when evoked by stimuli applied to the op-
posite optic nerve or the corresponding lateral genicu-
late nucleus. The positive SP component follows the
evoked response transient immediately and may
reach a voltage of 0.4 mv and persist for 1.5 sec. (fig.
4). In diphasic after-effects the positive component
is usually of briefer duration (0.5 sec.) and is followed
by a negative one of similar voltage lasting for 1.5
sec. When a negative after-effect alone is encountered
its start is delayed for 0.3 to 0.5 sec. after the evoked
respon.se is over.
When repetitive stimulation of the optic nerve
(submaximal for cortical evoked responses^ with fre-
quencies of 20 to 30 per sec. continued for 2 to 10
sec. is used, negative after-effects are oljserved to sum,
and positive after-effect is minimal (12, fig. 5). How-
ever, a positive change may replace the negative one
if cortical excitabilitx' had been significantly changed
by a preceding major paroxysm (fig. 5F, G). Near-
threshold stimulation of the lateral geniculate nucleus
also gives chiefly summation of negative after-effect
(12). At one half maximum to maximum stimulus
strength, positivity usually develops early in the
course of stimulation, to he replaced later by a nega-
tive SP change which persists past the end of stimula-
tion. From this and other evidence we have concluded
that in the response to repetitive stimulation, positive
and negative after-effects sum algeijraically, different
effects predominating at different strengths of stimu-
lation. This indication of the existence of processes of
opposite electrical sign, the electrical manifestations
of which can cancel completeh', may relate to the
-5^^~UAI--lA|^||J[A_w^^rv^f^
, ECS I
I" I !
Asp
V-v'-Jl^^-f..'^>
A ecg' "^'
-A/ — ._
B
■.^.t^l^/^-^-fffff^l^iffftm^
FIG. 4. .^fter-effects which follow primary visual response in
rabbit. After each evoked response there is a diphasic (positive-
negative) after-effect. Black dots indicate position of first short-
circuiting signal to occur after each response. [From Goldring
& O'Leary (11).]
B
.-v^~^^.^^M/-^V•^
-'V/-v.T^v.^^iV<virnwTlffflfnt1t^^
/v'Tr-'^^r\|nYi^nT(TiTrmTfifMfrrmf^
'%..~'*"|i''-— -'TTtTfrnrn'irfrnTiYrror^v^YiYf-^^
/vl'^-v.^TiTnifnTfr'iTinnrmr'^^
— ^^^I'h^MT*.'*'^-*^ ■ ■»- 'M* *~^»' ^Jkt^<* — w "iNo^N %^^^^iA» ■ .1^ >
FIG. 5. SP change resulting from repetitive stimulation of
the optic nerve at different strengths. A. Diphasic after-effect
of a single evoked visual response for comparison. Stimulus
frequency for subsequent records of figure was 25 per sec.
For each strip the initial evoked response in ECG marks the
beginning of stimulation and the arrow its cessation. B. Nega-
tive SP change during repetitive stimulation at threshold.
C. Stimulus strength one-third maximal; here negativity is
most prominent. I). Stimulus strength half ma.ximal; the
negativity develops somewhat later. E. .Stimulus strength
maximal; the negativity appears later and is not as maiked as
in C and D. Initial positivity in SP is seen to occur at the start
of stimulation. F. Similar repetitive stimulation 5 min. following
a major lasting shift in SP; stimulus strength as in C. The SP
change is now surface-positive. G. Same as F except that stimu-
lus strength is that o{ E. [From Goldring S" O'Leary (12).]
ditiiculty of demonstrating SP after-effects early in the
course of some experiments.
SP Changes Associated zvith Recruiting Responses
With repetitive stimulation (6 to 20 per sec, 30 v,
o. I msec, duration) in the midline thalamus of the
rabbit under light ether anesthesia, a negative cortical
SP change amounting to 0.2 to 0.6 inv ordinarily
develops during the rise in amplitude of the conven-
tional ECG transients of negative polarity as shown
CHANGES ASSOCIATED. WITH FOREBRAI.N EXCITATION PROCESSES
321
in figure i (15, 16). It also persists significantly after
tiie period of stimulation. Oscillographic recording
shows that there is a significant SP negative change
after even the first spike of a series, and that this
change is summated with the after-effects of succeed-
ing higher amplitude spikes as the recruiting series
continues. The persistence of the SP negati\ity after
the stimulus is turned off indicates that it is truly an
after-effect disturbance comparable to that which
follows single evoked responses. Increasing the
stimulus frequency to between 6 and 20 per sec. (the
voltage and shock duration remaining constant)
increases the amplitude and duration of the negative
SP change. At 20 per sec. a further increase in ampli-
tude and duration of SP negati\ely occurs if the
stimulus duration is increased from o.i to i .0 msec.
SP After-effects of Strychnine and Veratrine Spikes
The effect of strychnine has been studied in the
rabbit and the cat (12, 13, 14). In the rabbit a 0.05
per cent strychnine solution applied to the cortex
may be of sufficient strength to suppress the spon-
taneous component of the ECG; a minor 0.3 to
0.4 mv negative SP shift appears within 10 min.
following the application of the drug to the cortical
surface. The strychnine spikes which occur sporad-
ically at this time show no detectable after-effect.
However, a solution sufficiently strong to occasion
intermittent repetitive spike paroxysms (0.5 per cent)
causes a positive after-effect to appear following each
random spike which appears between the paroxysms.
With application of a crystal of strychnine, negative
after-effects follow each instead. A o. i per cent
strychnine sulfate solution applied to the cortex of
the cat also occasions a minor negative SP shift, and
here after-effects of strychnine spikes have a negative
polarity. When the single spikes occur in rapid suc-
cession the negativities associated with individual
spikes summate (fig. 6). The SP change which occurs
during a strychnine activated paroxysm will be re-
ferred to later.
X'eratrine hydrochloride (10^^) applied to the
cortex of the pentobarbitalized cat unstabilizes SP
almost immediately, resulting in one or more 5 to
1 5 mv negative shifts from each of which SP may
recov-er significantly (13, 14). A plot of several such
shifts following \eratrine application shows a down-
ward negati\e drift, and the SP does not again reach
its value at the start of the experiment. Finally, how-
ever, it stabilizes upon a plateau. At that time the
initial positive phase of the evoked response becomes
significantly prolonged and spikes of dominantly
positive polarity appear spontaneously, or may be
initiated (as in the visual cortex) by turning the room
lights on or off. Each evoked response and each such
spike is accompanied by a positive after-effect which
may endure for 5 to 10 sec. (fig. 7). Barbiturate
spindles also come to show a principally positive
polarity in the ECG, and they, too, show a positive
polaritv SP change which persists significantly after
the end of the spindle (13, fig. 8). If strychnine is
.v«,^^W^Il'>
Rg. 6
Fig. 7
,UH)to|W^MjVui/V^ A
,wv%1
. ' ' I:200/iV
I- I I sec 1 ^
200/1 V- 1\__
I sec
ZOO juW-
FIG. 6. Effect of 0.1 per cent strychnine sulfate solution
applied to cortical surface of cat under pentobarbital anes-
thesia. / and 2 indicate ECG and SP records, respectively.
A. Individual spontaneous strychnine spikes with negative after-
effects. B. Occurrence of a cluster of spontaneous strychnine
spikes with summation of the negative after-effects. [From
Goldring & O'Leary (14).]
Fic. 7. Effect of application of veratrine hydrochloride
(io~') to surface of the cortex of the cat under pentobarbital
anesthesia. / and -' indicate ECG and .SP records, respectively.
A. Single spontaneous positive veratrine spike with a long
positive after-effect. B. A series of such spikes with positive after-
effects. [From Goldring cl? O'Leary (13).]
322 HANDBOOK OF PHYSIOLOGY ^ NEUROPHYSIOLOGY I
isec
.,v<^^v^^W|fJ^A'W^^
FIG. 8. SP change accompanying barbiturate spindles in a
pentobarbitalized cat. / and 2 indicate ECG and SP records,
respectively. .-1. Spontaneous barbiturate spindles with tran-
sients which are chiefly negative accompanied by a negative
shift in SP which outlasts the spindle. B. Same cat shortly after
the application of veratrine (io~0 'o cortical surface. The
transients in the spindles are now chiefly positive and the SP
change accompanying the spindle has also become positive.
[From Goldring & O'Leary (13).]
applied before veratrine the barbiturate spindles
may at first show an accentuation of their negative
components accompanied by nes;ati\e after-effect;
when veratrine takes effect the principal polarity of
the spindle changes from negative to positise and the
after-effect also comes to have a positive polarity.
SP Concomitants of Convtilsoid Discharge
These have been studied in detail in the rabbit
(11, 12). Such a cortical discharge can be initiated
locally by surface-positive polarization across the
cortex, by repetitive stimulation (10 to 16 per sec.)
in the related thalamic relay nucleus, or by strychnine
applied locally in sufficient concentration. In animals
stimulated repeatedly and vigorously such paroxysms
may commence to appear intermittently without
preceding activation. The latter situation is analogous
to the abrupt appearance of con\ulsi\e discharge in
man.
With few exceptions the course of SP change during
convulsoid activity has been a positive shift of i.o to
1.5 mv correlated with the build-up of the discharge
in the ECG tracing. As the tonic discharge becomes
clonic the SP commences to return toward the pre-
paroxysmal balance; as the discharge ceases SP con-
tinues to shift negatively, sometimes reaching a value
of 5 mv negative to the preparoxysmal balance (fig.
9). When paroxysms follow each other in quick suc-
cession, a positive SP shift occurs with each, and a
negative one coincides with the intenseizure silent
period.
The initiation of a paroxysm by polarization
applied acro.ss the cortex from surface to white matter
has particular interest in view of the polarization
[^Oj^KRSQQS^Q
- 5oq//V
z 100 msec
pos=//p
FIG. 9. Steady potential change during paroxysm in rabbit.
Light ether anesthesia. Paro.xysm induced by repetitive 10 per
sec. stimulation of the lateral geniculate nucleus with bipolar
electrodes. Straight white line of each trace indicates the base
line of the ampliher from which the d.c. change is a departure.
Record from optic cortex with transcortical leading, positive
up. .'1. Start of stimulation of lateral geniculate nucleus indi-
cated by an evoked response following each stimulus. No con-
sistent change in SP was observed during this period. B. 1 2 sec.
after start of stimulation. In this strip the positive phase of
evoked response has dropped out and the later negative com-
ponent of evoked response has commenced to double, indicating
the start of the paro.xysm which persists into the poststimulatory
period. Vertical white lines indicate end of period of stimula-
tion. As paroxysm commences SP commences to shift positively.
C. 15 sec. after start of stimulation. SP has continued to shift
positively. D. 20 sec. after the start of stimulation. Further
positive shift as the poststimulatory paroxysm reaches its maxi-
mum. E. 25 sec. after start of stimulation. Paroxysm diminishing
in intensity and SP is now commencing to shift negatively. F
and G. 35 and 40 sec. after start of stimulation. The paroxysm
disappears as SP shifts further negatively.
theory advanced by Libet & Gerard (30) and
supported by Bishop & O'Leary (2). Such applied
polarization ma\' be expected to shift the charges
along the pyramidal neurons, perhaps increasing or
CHANGES ASSOCIATED WITH FOREBRAIN EXCITATION PRf)f:ESSES
3^3
decreasing the excitability of the substrate. By use of
surface-positive applied polarization, a paroxysm
can be initiated in the rabbit at a significantly lower
intensity than is required to produce a paroxysm
with surface-negative polarization. Such a paroxysm
is also accompanied by a positive .SP change. This,
likewise, is supplanted by a negative one after the
paroxysm disappears. If a paroxysm is initiated by
sufficiently strong surface-negative polarization, that
paroxysm is also related to a surface-positi\'e SP shift
which develops in reaction to the immediately pre-
ceding surface-negative applied polarization.
More recent studies (16) have re\ealed an SP
change accompanying a cortical paroxysm induced
by ventroanterior thalamic stimulation opposite to
the one initiated by the methods cited abo\e (stim-
ulation of relay nucleus and polarization). In this
instance the .SP shifts negatively durina; the high
\oltage discharge and then positively in the post-
paroxysmal depression period (fig. 10). A cortical
PIG. 10. D.C. change accompanying a cortical paroxysm
induced by repetitive stimulation of ventroanterior thalamic
nucleus in the cat. A. Negative d.c. shift with 20 per sec. stimu-
lation. .\ 3 sec. strip of record has been omitted between A and
B; with continuation of stimulation there is an increase in
negative d.c. change. C. Upon cessation of stimulation (white
dot) high voltage paro.xysmal activity is in evidence and the
steady potential remains shifted negatively. D. Return of
steady potential to the prestimulatory base line with termination
of paro.xysm. E. Positive shift of steady potential in the post-
stimulatory isoelectric period. Vertical line of right angle in
right lower corner represents 500 mv; horizontal line, i sec.
Positive is up.
FIG. II. .SP shift accompanying cortical paro.xysm induced
by thiocarbohydrazide in rabbit. .Straight white lines are base
lines from which shifts in SP are read. Positive is up. A. 15 min.
after intravenous injection of 30 mg of thiocarbohydrazide.
SP commences to shift negatively. B. 10 sec. later SP shifts
more negatively and paroxysmal activity begins. C. 6 sec.
later paro.xysmal activity continues and SP remains shifted
negatively. D and E. As high voltage discharge breaks up and
stops, SP shifts back to the base line. The tracing nearest the
base line in D is the same paroxysm recorded at lower ampli-
fication on the b beam of the oscilloscope. This beam is set at
lower gain in order to record the full excursions of larger SP
shifts. In the 10 sec. interval between C and D, the a beam
threatened to move off the tube face and therefore the b beam
was turned on. In all other strips only the a beam is shown
There is a 10 sec. interval between D and E.
paroxvsm initiated by the intravenous injection of
convulsive drugs such as thiocarbohydrazide and
pentylenetetrazol (Metrazol) is accompanied by a
similar d.c. change as shown in figure 1 1 (Goldring,
S., P. \'anasupa & J. L. O'Leary, manuscript in
preparation). Other workers have also demonstrated
SP shifts accompanying paroxysmal activity, van
Harreveld & Stamm (43) found a negative SP shift
with cortical paroxysm produced by faradic stimula-
tion of the cortical surface or intravenous injection of
pentylenetetrazol, and Liberson, using the guinea
pig, found SP shifts accompanying induced par-
oxysmal discharge in the hippocampus (29, 44).
D.C. Changes Which Accompany Spreading Depression (5D)
In 1944 Leao (24) discovered a depression of the
usual cortical rhvthms of the rabbit which spreads
324
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
slowly outwards from the site of a weak mechanical,
electrical or chemical stimulus to the cortex. This
reaction was elicited more readily from the rostral
pole of the hemisphere, and from there a wave of
depression could envelop almost the whole of the con-
vexity, propagating at a velocity of only 2 to 5 mm
per min. Neither .evoked potentials nor motor re-
sponses to cortical stimulation could be observed when
the front of the depression reached the sensorimotor
cortex. Leao also observed that the propagation of the
SD was accompanied by dilation of pial vessels (25),
an observation confirmed by van Harreveld & Ochs
(42) who also held that in the rabbit the vasodila-
tation is preceded by a smaller wave of vasocon-
striction. Species differences in cortical su.sceptibility
to SD have been noted. It is produced more easily
in the rabbit than in the cat and is seen only occasion-
ally in the monkey (33, 36, 45). Cortical maturity
may also play a role: Bures (3) was unable to obtain
SD during the first days of life in the rat, although
he could elicit it readily in the newborn guinea pig.
There is substantial evidence indicating that SD
is an abnormal reaction which results from exposure
of the brain to unphysiological conditions. Marshall
and co-workers (32, 34, 35, 36) have shown that SD
appears consistently only if the brain has been de-
hydrated, exposed to the atmosphere for long periods,
cooled, or bathed in Ringer's .solution having ten
times the usual concentration of potassium. In the
absence of one or another of the above conditions
they were unable to elicit SD in the cat or monkey at
all, although occasionally it could still be developed
in the rabbit. Because they were able to record SD
through the intact dura of the rabbit, van Harreveld
rt al. (45) disagreed with the view that SD is an ab-
normal reaction. However, later, utilizing the various
conditions described by Marshall and co-workers,
van Harreveld & Bogen (40) obtained SD in the area
retrosplenialis granularis dorsalis, a region into which
SD does not propagate under usual recording con-
ditions in the rabljit.
The d.c. variation which accompanies SD has a
duration of 4 to 6 min. (26). With the critical record-
ing electrode placed upon the pial surface an involved
cortical region becomes negative for i to 2 min. with
respect to a subcortical or an extracortical reference
electrode. Within that time the surface-negativity
reaches a maximum of 8 to 15 mv, thereafter decreas-
ing with somewhat greater rapidity. The involved
region then becomes 3 to 8 mv surface-positive but
returns to the predepression base line in 3 to 5 min.
(fig. 12). As the d.c. potential changes from surface-
negative to positive, large amplitude (2 to 3 mv)
negative slow waves or the repetitive spikes of con-
vulsive discharge may occur. The occurrence of these
transients or repetitive spikes led Leao to the con-
8 MIN. 9
FIG. 12. A representative experiment on the slow voltage variation accompanying the spreading
depression of activity. The curve was drawn from voltage readings taken with hve sec. intervals. In
this and the other two figures, an upward deflection denotes negativity of the corte.x with respect to
the extracortical reference electrode. Electrodes arranged as shown in the inset (s: stimulating
electrodes). Stimulation, 5 sec. of 'tetanizing' current from an induction coil, delivered at the time
marked S. In this representative curve there is indicated the time of occurrence (from .\ to B) of the
specific electrical activity which often develops during the depression of the spontaneous pat-
terns.' [From Leao (26).]
CHANGES ASSOCIATED WITH FOREBRAIN EXCITATION PROCESSES
325
elusion that SD and the spread of convulsive discharge
may be closely related.
By recording the d.c. change at successive cortical
depths Leao (27) was able to show that the negative
shift appeared later at an intracortical electrode than
at one directly above it on the surface. Also, when an
electrode upon the pial surface or in the superficial
cortex recorded a significant negative variation, a
deeper cortical electrode showed a positive variation.
From these observations Leao concluded that SD
starts in the superficial cortex and is propagated down-
ward to involve the entire cortical thickness. Freygang
& Landau (9) reached the same conclusion.
A negative voltage variation similar to the one
which accompanies SD has been observed with
cortical anemia, anexia and asphyxia (11, 17, 26, 43),
a fact suggesting neuronal depolarization as an im-
portant contributory factor in all. Extrapolating from
results obtained during depolarization in peripheral
nerve (6, 7), one would expect decreased cortical
impedance to result from both SD and cortical anoxia.
However, several workers (9, 28, 41) have reported
the opposite occurrence. Freygang & Landau (9)
have suggested that swelling of the neuronal and glial
elements of cortex may account for the increased
cortical impedance which accompanies SD and cor-
tical anoxia, arguing that cellular swelling would
increase the resistance of the extracellular current
shunt and thus the tissue resistance, van Harreveld
& Ochs (41) have agreed with this view. However,
recent studies of nervous tissue with the electron
microscope (31) have failed to reveal the existence
of an extracellular space in the cortex, thus .suggesting
that other explanations need also be entertained. On
the other hand van Harreveld (39) has reported
direct confirmation of swelling in the superficial
dendritic plexus during SD, using histological sections
prepared after freezing.
Grafstein's (21) recent observations with micro-
electrodes are also important. She noted increa.sed
firing of single units at the start of SD, sugs;esting some
other explanation for the depression of EGG con-
ventionally recorded with macroelectrodes. Asyn-
chronous firing of single units leading to cancellation
of opposing effects could, however, reconcile macro-
and microelectrode results. Grafstein's observations
have also led her to implicate depolarization resulting
from the liberation of pota.ssium as the cau.se of SD.
Thus, the increased neuronal discharge shown by
microelectrode studies could result in decreased cell
permeability (depolarization) and the liberation of
potassium. The latter could chemicalh- stimulate
adjoining cells, the process spreading to involve the
entire cortex.
Relalion oj Polarity oj Evoked Traiisiiml to Polarity
of SP Change Also Consequent to Stimulation
Much indirect evidence has been presented here
indicating; that the same neuronal activity occasions
both the transient of the conventional EGG and the
SP changes described. Direct proof is also needed and
is possible to obtain in an experimental situation
which provides a layer of neurons synapticallv ac-
tivated from one surface with impulses conducted
away from the other. The lateral geniculate nucleus
of the cat was studied by Bishop & O'Leary (2) who
showed that the postsynaptic spike recorded from a
critical electrode in the optic radiation over the genic-
ulate cell layers has a positive polarity, and that, as
the critical electrode enters the cell layers, the polarity
reverses to negative. They concluded that, with regard
to evoked potentials of the lateral geniculate, the cell
body during activity becomes negative to its own con-
ducting axon. Vastola (46) undertook to repeat this
experiment, determining the reversal point of the
evoked transient from the same electrode used to
record the summated SP shift which accompanies
rapid repetitive stimulation. For this purpose he used
glass capillary tube electrodes having a tip diameter of
250 ;u and led from calomel cells. The critical electrode
was passed from the optic radiation through the cell
layers, the reference electrode being situated in the
central white matter anterior to the lateral geniculate
body. He deterinined the maximal evoked response
transient obtainable from a single shock applied to
the contralateral optic nerve, and then proceeded to
study, at different strengths of stimulation between
threshold and maximum, the SP shift which occurs
concurrently with stimulation to 150 per sec. Dorsal
to the cell layers SP became positively shifted during
repetitive stimulation; at 0.5 mm dorsal to the cell
layers the SP shift accompanying repetitive stimula-
tion reversed polarity; with increasing depth of the
critical electrode the negative shift increased further
until the electrode tip was in the middle of the first
layer of the nucleus. Then it gradually decreased as
the electrode passed through the remaining cell
layers and into the thalamus ventral to the nucleus.
The polarity of the SP shift coincided with the polarity
of the postsynaptic wave which he recorded by the
conventional single shock method. As an added pre-
326
HANDBOOK OF PH^SIOLOGV
NEUROPHYSIOLOGY I
caution \'astola used the chopper technique at a fast
rate of interruption to prove that the SP between the
indisidual transients also shifted negatively.
Effects uf Stimulation at a Distance Along a
Mullisynaplic Path Upon Transcortical SP
Dondey & Snider (8) recorded SP from the cerebral
cortex in much the same fashion as outlined herein,
using animals prepared under ether anesthesia and
maintained under a'-tubocurarine (15 mg per kg).
Besides confirming the findings reported previously
concerning the relation between the appearance of
cortical paroxysm and of positive SP shift, and be-
tween the postictal silent period and negative shift,
they studied the effect of fast frequency cerebellar
stimulation (200 and 300 per sec, 10 to 30 v.). Such
stimulation induced a positive shift in cortical SP last-
ing for as long as 50 sec. and becoming as large as 5
mv. Suppression of cortical spindles occurred during
the shift and was the principal criterion for the effi-
cacy of the cerebellar stimulation. Under the same
circumstances slow frequency stimulation, ranging
between 10 and 20 per sec, induced a negative SP
shift in the cortex which might last as long as 70 sec.
and reach 4 mv in amplitude. With the lower frequency
stimulation the ECG did not change as significantly
and spindles might occur throughout the recording.
In both the instances of fast and of slow stimulation,
SP recording from the nucleus ventralis lateralis of
the thalamus showed oppositely polarized effects. Don-
dey & Snider found in addition that fast frequency
stimulation of the cerebellum might prevent the ex-
pected negative shift which occurs at the end of cor-
tically induced paroxysmal discharge; instead posi-
tivity continued much beyond the cessation of the
paroxysm.
Injury Potential Components
D.C. changes with injury were reported h\ Walker
et al. (47) and Meyer & Denny-Brown (37, 38). K.em-
pinsky's (23) study of the distribution of SP
change associated with experimental vascular occlu-
sion of the middle cerebral artery in the cat con-
clusively demonstrates that a significant component
of such injury effect is a demarcation potential across
the zone of injury in the white matter. He used pia-
ventricular, subcortical-ventricular and transcortical
leads simultaneously. The prompt, sustained negative
shift which he obtained in the center of the cortical
area of distribution of the vessel could be recorded
in the subcortical-ventricular and the pia-ventricular
combinations but not in the cortex-subcortex one.
When recorded simultaneously at different cortical
loci, the magnitude of the shift decremented toward
the periphery of the ischemic region.
Human Studies I'smg Scalp Recording
In a study by Goldring et al. (19) it was shown that
d.c changes can also be recorded from the human
scalp during electroconvulsive therapy. The difiiculty
which arises in the interpretation of these and other
d.c. changes recorded from the scalp with non-
polarizable electrodes is the complication introduced
by d.c. changes which occur in the skin. Of the results
reported in the literature the negative shift with 3
per sec. spike and dome discharges (5) seems most
free of this criticism.
DISCUSSION OF ORIGIN OF STE.ADY POTENTI.iiLS
Starting from a base of transcortical voltage meas-
urement called steady potential (SP), evidence thus
far accumulated supports the existence of d.c. con-
comitants of conventionally recorded cortical excita-
tion processes. The d.c. changes which correspond
have also been obtained from some subcortical centers.
In one such nucleus (the lateral geniculate) it seems
clear that there is a close association between d.c.
change and the neural excitation process (46). In
the cortex d.c. changes occur subsequent to brief
transients such as evoked responses, strychnine and
veratrine spikes, and during and after repetitive ones
like barbiturate spindles or recruiting responses.
Thus, bv means of a d.c. amplifier the electrical sign
of excitation at a cortical point can be recorded trans-
corticalK' significantK' after the acti\ity obtained with
a condensor-coupled amplifier has disappeared.
The evidence is yet insufficient to decide whether
such d.c. changes are simply a prolongation of the
same neural process which occasions a neuron's dis-
charge or are analogous to the after-potentials of
peripheral nerve. If the latter, evidence for metabolic
causation needs to ije considered. There are also in-
dications, liut no proof, for excitability change occur-
ring simultaneou.slv with certain after-effects, and
this also needs close investigation. If excitability
change does occur, the analogy with peripheral
nerve after-potentials becomes much closer.
CHANGES ASSOCIATED WITH FOREBRAI.N' EXCITATION PROCESSES
327
After-effects appear to sum algeliraically, giving
different polarity under different conditions of excita-
tion. As used here the term algebraic summation
implies something more than the simple cancellation
of opposing equal forces. Such an explanation might
suffice for the absence of detectable after-effect early
in the course of some experiments, but a somewhat
more complicated interpretation is needed to explain
all of the observed phenomena of after-effect summa-
tion during repetiti\e processes. An increasingly
negative after-effect during summation might thus
be due either to exaggeration of a negatively directed
tendency, or to suppression of a positively directed
one and vice versa. The plasticity of interaction be-
tween the two forces is exemplified in the summation
of cortical evoked response after-effects induced by
repetitive stimulation of the opposite optic nerve, as
compared to that of the lateral geniculate nucleus.
Optic nerve stimulation in our experience can cause
only a summation of positive after-effect when applied
at maximum, if at all; most usually the summation is
that of negative after-effect. Geniculate stimulation
produces summated after-effect consistently at stimu-
lus values below maximum. Another indication that
the same neuronal firing can produce negative after-
effect in one situation and positive in another lies in
the comparison between the summed negative after-
effect of clusters of strychnine spikes, and the positive
summation which accompanies the high voltage
paroxysm that develops intermittently in the same
strychninized corte.x.
The unifying concept which promises the most aid
in harmonizing knowledge of the electrical signs of
the quicker transients with those of the slower d.c.
concomitants of neural excitation is that of Libet &
Gerard (30). These writers postulated a polarization
gradient along the vertically oriented cortical neurons.
For each neuron this gradient would extend from the
surface dendritic expansions in the plexiform layer to
a deeper level, even to layer \T, where the soma-axon
junction is situated. Further evidence relating
polarization gradients to neural excitation is obtained
by the simple expedient of changing the charge dis-
tribution along the pyramidal cells artificially. This
affects significantly the positive and negative com-
ponents of evoked potential, surface-negative polari-
zation accentuating the positive phase, surface-positive
polarization the negative phase.
Other support for Libet & Gerard's view is to be
found in the change in visual esoked response during
the cycles of intense negative d.c. shift which char-
acterizes the veratrinized cortex. The effect of vera-
trine applied to the cortical surface is to depolarize
the terminal dendritic brushes of the cortical neurons
(13, 14), and from this depolarized superficial region
intense waves of depolarization appear to spread
downwards over the cortical dendrites, progressively
engulfing the cortical neurons from above. The
initial positive phase of evoked response is due to the
successive activation of groups of neurons, each ex-
cited after synaptic conduction. The summation pro-
duced is signified by the four fast spikes which appear
successively higher upon the rising phase of the evoked
potential. During the intense negative veratrine shift
these spikes are removed successively from above
downwards, and the order of their removal corre-
sponds with the expectancy from their positions in the
cortical depth as obtained by the null point of meas-
urements of Bishop & Clare (i).
The changes in charge distribution may actually
be more complicated than is suggested by the results
of these experimental studies. Besides the situation in
which the charge at the two ends might change in
opposite direction to produce an SP effect, a d.c.
change might also ensue if both ends changed in the
same direction unequally. Such a concept is now sus-
ceptible to experimental proof only from the limited
aspect of charge distribution along the neuron's ex-
terior. If interior differences of potential exist be-
tween the superficial dendrites and the cell soma, it
will require microelectrode recording to reveal them.
SUMM.\RY
Present methods of recording the d.c. potential
across the cerebral cortex are presented. These re-
quire detailed attention to oxygen tension, anesthesia
and injury, and necessitate stable electrodes for re-
cording purposes. The SP across the cortex remains
relatively steady under good experimental conditions
and serves as a base line for examining slower con-
comitants of neural excitation. In several situations it
has been shown that such SP concomitants do relate
to the quick transient phenomena conventionally
recorded from the cortex. Significant summation of
d.c. change associated with single transients can
appear during repetitive phenomena. The best prom-
ise of relating d.c. and transient phenomena is in
terms of the polarization theory of Libet & Gerard
C30).
328 HANDBOOK OF PHYSIOLOGY ^ NEUROPHYSIOLOGY 1
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CHAPTER XIV
The physiopathology of epileptic seizures
HENRI GAS TAUT I Favulte de Medecine, Marseille, France
M. F I S C H E R - W I L L I A M S j London Hospital, London, England
CHAPTER CONTENTS
Symptomatology
Types of Generalized Epilepsy
Grand mal
Petit mal of absence' type
Petit mal of myoclonic type
Types of Partial Epilepsy
Clinical aspects
Electroencephalographic aspects
Etiology
Functional Epilepsy
Organic Epilepsy
Physiopathology of Seizures Generalized from Start
Experimental Results
Grand mal
Theories of generalized convulsions
Mechanism of bioelectric discharges in generalized epilepsy
Petit mal of myoclonic type
Petit mal of 'absence' type
Interpretation of Experimental Results
Origin, nature and propagation of nervous acti\ity respon-
sible for generalized grand mal seizure
Causes of reticular discharges, thalamic and niesenceph-
alorhombencephalic, responsible for grand mal epilepsy
Duration and termination of discharge in generalized
epilepsy
Myoclonus of petit mal
Petit mal 'absence'
Physiopathology of Partial Epilepsies
Experimental Results
Experimental partial epilepsy of cortical origin
Experimental partial epilepsy of rhinencephalic origin
Experimental partial epilepsy of subcortical origin
Experimental partial epilepsy, secondarily generalized
Experimental partial epilepsy with erratic discharges
Anatomicals Studies
Physiopathogenesis of Partial Epilepsies
Origin and cause of neuronal discharge in partial epilepsy
Propagation and termination of neuronal discharge in
partial epilepsy
Distinction between two great varieties of partial epilepsy
with respect to character of their discharges
BECAUSE OF THE IMPORTANT mcdical application
of this chapter, it seems useful to preface it with a
short summary of the clinical and electroenceph-
alographic events accompanying epileptic seizures
in man.
SYMPTOMATOLOGY
There are two types of epilepsy, from both the
clinical and the electroencephalographic point of
view: a) generalized epilepsy, in which the clinical
manifestations involve the entire individual and the
EEG discharges can be recorded all over the scalp;
and 6) partial epilepsy, in which only a part of the
individual is involved clinically and the electrical
disturbance can be recorded from a part of the scalp
only.
Types oj Generalized Epilepsy
It is clear that the different types of generalized
epilepsy arc similar in their electrical and clinical
manifestations; they constitute a remarkably homoge-
neous group in symptomatology. From the clinical
point of view, the two important features which they
have in common are loss of consciousness and con-
vulsions involving the whole skeletal musculature to
a greater or lesser extent. These phenomena are so
spectacular that the other manifestations, notably
those in the autonomic sphere, are relegated to .second
place. From the EEG point of view, their common
manifestation is a seizure discharge of conxulsive
waves which are bilateral, synchronous, symmetrical
and generalized over the scalp. The following three
varieties of generalized epilepsy are distinguished
329
33°
HANDBOOK OF PHYSIOLOGY
NEt'ROPH'YSIOLOCY
accordiiiE; to the duration of the attack, to the relative
importance of motor or mental symptoms and to the
characteristics of the EEG discharge.
GRAND MAL. This is characterized by: a) duration of
more than i min.; h") initial total loss of consciousness
with postictal coma; c) generalized tonic contraction
at first continuous and later interrupted by periods
of relaxation which causes the so-called 'clonic'
phase; d) a discharge of rhythmical, bilateral, syn-
chronous and symmetrical spikes at lo ± 2 cps, the
amplitude of which increases while the frecjuency
diminishes and in which the terminal elements, sepa-
rated by intervals of electrical silence, constitute
groups, each corresponding to a jerk in the clonic
phase.
PETIT M.'^L OF '.'^bsencje' VARIETY'. This is characterized
by: a) a shorter duration (5 to 20 sec); A) more or
less complete loss of consciousness which is ne\cr
followed by postictal coma; f) aborti\e muscular
contractions, which are hardly discernible and occur
three times a second, involving the eyelids and some-
times the muscles of the head and upper limbs; and
rf) a rhythmical, bilateral, synchronous and symmetri-
cal discharge of a complex pattern, comprising a
spike followed by a slow waxe and repeated three
times a second.
PETIT MAL OF .MYOCLONIC TYPE. This is characterized
by: a) an exceedingly brief duration (a fraction of a
second); 6) a single violent jerk which, though gen-
eralized, predominantly inxoKes the muscles of the
arms or head and sometimes appears on one side
only; and f) a short burst of spikes, with or without
one or several slow waves, and constituting, as the
case may be, multiple spikes, multiple spikes and
waves, or even a spike and wave.
The 'spikes' of grand and petit mal are in reality
waves whose form and period differ only slighth from
those which characterize the waves of the alpha
rhythm and have nothing to do with the spikes, cor-
rectly so-termed, of interictal discharges in partial
epilepsy.
Types of Partial Epilepsy
The.se forms of epilepsy, b\' contrast, constitute an
essentially heterogeneous group.
CLINICAL ASPECTS. From the clinical point of view, the
seizures are manifested by mental, .sensory or motor
symptoms in\olving the autonomic or cerebrospinal
systems, o) The sensory symptoms may be classified
as somesthetic, visual, auditory, \ertiginous, olfactory
or gustatory. /)) Mental symptoms include all degrees
of clouded consciousness and also positi\e phenomena
affecting perception, ideation or mood — illusions or
hallucinations, 'forced thinking' or conversely a blot-
ting out of thought, and feelings of anxiety, fear or
anger, c) Visceral symptoms are characterized by
abnormal sensations or acti\ities in\oKing the ali-
mentary system (abdominal or epigastric sensations,
chewing with salivation, borborygmi, defecation,
etc.), the cardio\ascular or respiratory systems (pre-
cordial pain, tachycardia, vasomotor phenomena,
cough, apnea, etc.), and in addition but less fre-
cjuently, symptoms in\olving the glands, erectores
pilorum, sphincters, pupils, etc. (T) Somatomotor
symptoms include abnormal tonic or clonic move-
ments, the commonest being desiation and contra-
version. Apart from these, there are numerous ab-
normal gestures which are responses to hallucinations
(gesture of fear during a terrifying vision) or to sensa-
tions (for example, the gesture of placing the hand on
the abdomen associated with a painful epigastric
sensation), or which merely represent the release of
automatisms during an ictal or postictal confusional
episode. Gibljs et al. (88) proposed the term 'psy-
chomotor' for seizures in which there are gestures
such as these but especially for attacks with con-
fusional automatisms.
.An enumeration of symptoms cannot ser\'e as the
basis for a cla.ssification of the partial epilepsies; it is
even less satisfactory relati\e to physiopathological
interpretation. It is indeed exceptional for an attack
of partial epilepsy to be manifested by a single symp-
tom; quite the contrary, most of the seizures simulta-
neously involve various sensory, mental and motor
phenomena. In addition, it is impossible to locate a
precise region of the brain to which the origin of each
of the above-mentioned symptoms might be assigned.
The conception of "representation' is inisleading (91)
when motor and sensory 'representations' are said to be
contralateral, homolateral or bilateral, or primary,
secondary or supplementary, and to occupy different
cortical and subcortical regions. It thus becomes
impossible to relate salivation, for example, exclu-
sively to the opercular region, or deviation of the
head and eyes simply to the 'prcmotor' region.
THE PHYSIOPATHOLOGY OF EPILEPTIC SEIZURES
331
ELECTROENCEPHALOGRAPHic ASPECTS. Partial epileptic
seizures differ from generalized seizures in that their
discharges can be recorded from a part of the scalp
only, and they show a great diversity of expression.
Without attempting to give a full description, we may
divide them into two main topographical groups:
a) localized partial discharges, consisting of rhsthmic
spikes, occasionally from the frontal or central regions,
but much more frequently from the temporal or
parieto-occipital regions and b) diffuse partial dis-
charges, showing as desynchronization or slow hyper-
synchronization and arising from all or a part of one
or both hemispheres (usually the temporofrontal
regions).
In addition there are numerous cases in which
localized and diffu.se discharges both appear during
the same seizure with a variety of temporospatial
relations. The discharges appear either independently
or concomitantly, and either in or out of phase;
they usually involve the anterior temporal and frontal
or the posterior temporal and parieto-occipital re-
gions.
It is of course well recognized that any partial
seizure may become generalized and then present
the electrical and clinical characteristics of a grand
mal fit, whether or not it is preceded by myoclonic
jerks. One must therefore carefully distinguish be-
tween fits which are generalized from the start and
those which become generalized after a partial
onset.
ETIOLOGY
It is generally recognized that epileptic seizures
may be divided into two main categories, according
to whether or not there is a demonstrable brain lesion.
One category comprises the so-called secondary or
symptomatic epilepsies arising from a lesion which is
infective, degenerative, traumatic, neoplastic or
vascular; these constitute a well-recognized and un-
disputed entity. The etiology in the other category has
always been controversial; some authors regard the.se
epileptic fits as the result of brain lesions which are
undemonstrable and consider that they should be
called collectively cryptogenic epilepsy; others believe
that they represent disordered metabolism or a fault
in cerebral function, unassociated with any organic
abnormality. They should therefore be qualified as
"functional', 'metabolic' or 'primitive' as opposed to
those that are 'organic' or 'secondary'. This termi-
nology unfortunateh- has not been adhered to, and it
has become customary to call functional epilepsies
either 'idiopathic' or 'essential'. This has given rise
to a discussion the etymological origin of which has
gone unrecognized but which has caused divergence
of opinion which was more apparent than real. How-
ever this may ije, the existence of two types of epilepsy
is now accepted.
Functiomd Epilepsy
This disorder is encountered in only 5 per cent of
all cases, according to Bicard et al. (17). It is also
known as primitive, essential, genuine, idiopathic,
metabolic, genetic, etc. It results from a fault in the
functioning of the brain manifested b\- an epileptic
'predisposition', fairly often hereditary. It is not asso-
ciated with any anatomically detectable lesion of the
brain and it is not accompanied by any interictal
neurological or psychiatric manifestations; and it is
always manifested by seizures (grand mal or petit
mal) which are generalized from the start of the
attack.
Organic Epilepsy
This type is very common (95 per cent of all
cases). It is also known as symptomatic or secondary.
It is caused by an anatomically recognizable cerebral
lesion and for this reason it may be associated with
neurological or psychiatric abnonnalities between
fits; it may develop on a 'soil' already predisposed to
convulsions and thus a mildly irritative lesion inay be
markedly epileptogenic; and only rarely is it mani-
fested as a primarily generalized seizure, rather usu-
ally appearing as partial epilepsy which may or may
not become secondarily generalized.
PHYSIOPATHOLOGY OF SEIZURES
GENER.-VLIZED FROM START
This presentation will be divided into two parts.
The first will be an impartial review with some de-
.scription of the experimental results accumulated over
nearly two centuries of effort to explain the mecha-
nism of generalized seizures, particularly those of grand
mal. The second will furnish a personal interpretation
of these experimental results, based on modern neuro-
physiological data.
332
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
Experimental Results
The various types of primarily generalized epilepsy
have been reproduced experimentally in animals and
man.
GRAND MAL. It is easy to produce a grand mal seizure
in animals by any measure acting as a difTuse assault
on the brain and causing a sufficiently widespread
disorder of cerebral metabolism: l)y applying a strong
electric current to the whole of the brain (trans-
cranial electroshock), by injecting analeptic drugs
such as pentylenetetrazol (Metrazol), megimide,
picrotoxin, absinthol, by oxygen intoxication, or by
sudden withdrawal of sedati\es in chronic experi-
mental barbiturate poisoning.
On the contrary, it is very difficult in these same
animals, to cause by means of minimal and localized
measures seizures which are generalized from the
onset. Thus limited electrical stimulation and mini-
mal glial scars developed around the site of injection
of aluminum hydroxide never cause generalized
epileptic fits, although they regularly produce seizures
of partial epilepsy which may become generalized
(84). In order to produce a grand mal seizure from the
onset, one needs to increase the severity and particu-
larly the extent of the local disturbance in these
experiments, to involve mid-line structures or to ad-
minister an agent with a generalized subliminal action.
In man one obviously cannot produce focal experi-
mental cerebral lesions, but it is well established that,
as in other animals, various measures with a wide-
spread cerebral action will cause grand mal seizures:
electroshock treatment, pentylenetetrazol, oxygen
poisoning, rapid withdrawal of barbiturates (particu-
larlv in addicts of short-acting barbiturates), etc. All
these forms of experimental or accidental epilepsy
in man and animals are indeed comparable to spon-
taneous seizures of grand mal generalized from the
start, for they always include an immediate loss of
consciousness, tonic and clonic convulsions, and a
bilateral, synchronous and symmetrical seizure dis-
charge in the EEG.
We have not regarded as grand mal seizures those
which are precipitated in man and animals by \arious
types of cerebral anoxia. These seizures are tonic,
lacking the clonic phase, and are accompanied by
depression of cerebral electrical activity and not by
a bisynchronous discharge. They are none the less of
fundamental interest for the understanding of grand
mal epilepsy and we shall return to the subject later.
THEORIES OF GENERALIZED CONVULSIONS, o) Subcortical
theory. The idea that generalized convulsions have a
subcortical origin has been held by physicians ever
since ancient times for logical reasons which are easily
understood (187). In the second century A.D., Galen
attributed grand mal epilepsy to a 'thick humor' in
the middle and posterior part of the ventricles. Willis
in 1682 had a similar conception when he related the
fit to "a strong spasmodic copula distilled from the
blood into the brain, affecting the animal spirits which
lie in the middle of the brain, and causing an explo-
sion." This idea persists to our day since Hogner
[quoted by Marinesco et al. (135)] recently defended
the view that the epileptic discharge depends on dis-
tension of the third ventricle by excess formation of
cerebrospinal fluid, producing an excitation of the
centers around the ventricle.
Experimental study of this subcortical theory was
begun in the middle of the eighteenth century when
Haller showed that generalized convulsions could be
proNoked h\ irritation of the white matter in the
depths of the brain. At the beginning of the next
century Flourens (1823) performed his famous experi-
ments on the medulla oblongata. This allowed Hall
(96) to formulate his theory of the medullary origin of
reflex epilepsy, which was taken up by Schroeder van
der Kolk in 1859 ('74) who concluded that "an
exalted sensibility and excitability of the medulla
oblongata is the just cause of epilepsy." As early as
1B38 Nothnagel provoked generalized convulsions by
mechanical stimulation of the medulla oijlongata,
and much later Binswanger (18) and Bechterew (16)
repeated these experiments using an electric current
or a needle prick.
Stimulation experiments were not, however, the
only ones supporting the subcortical mechanism of
generalized seizures. Toward the beginning of the
twentieth century, a large number of ablation experi-
ments showed that the cerebral cortex, and the greater
part of the telencephalon, diencephalon and mesen-
cephalon, were not necessary for the experimental
production of generalized epilepsy. \'arious measures
were used in these experiments: transcranial applica-
tion of an electric current (89, 130, 166, 171, 191);
cooling of the brain (44); and injections of pentylene-
tetrazol (Metrazol) (14, 95, 130, 173), of insulin
(126, 153), of picrotoxin (36) or of a mixture of
chloralose and strychnine (144). Thus generalized
convulsions are seen in the diencephalic, the mesen-
cephalic and e\en in the rhombencephalic animal
THE PHVSIOPATHOLOGV OF EPILEPTIC SEIZURES
333
which possesses nothing but the medulla and pons,
but they no longer occur in the spinal animal. One
has therefore to postulate the existence of an anatom-
ical structure in the brain stem, which extends to its
most caudal part, and which is connected with the
spinal inotor neurons and ai)le to transmit to them
convulsant impulses. Such a structure, suspected
by Lucciani under the name of 'common motor
center' may, perhaps, be identified as the brain stem
reticular formation, the most caudal part of which
furnishes crossed and direct descending pathways to
the motor neurons in the spinal cord.
fe) Cortical theory. The famous experiments of Fritsch
& Hitzig in 1870 (51) led to the theory of the cortical
origin of generalized epilepsy. These authors demon-
strated that weak electrical stimulation applied to the
sigmoid gyrus in the dog provoked focal movements,
whereas more intense or more prolonged stimulation
of this region provoked generalized convulsions more
or less rapidly. Today we would consider this phe-
nomenon as a secondary (subsequent) generalization
and consider it entirely separate from seizures gen-
eralized from the start (see below). At that date,
however, these experiments led to doubts concerning
the subcortical mechanism of epileptogenesis. Thus
Ferrier in 1873 (47) concluded, "It is not necessary
to assume that the medulla oblongata is the primary
seat of the motor disturbance in fits."
Only 13 years after the famous experiments of
Fritsch & Hitzig, Franck & Pitres (49) showed that
it was impossible to localize an epileptogenic center"
in the motor cortex only, since ablation of this region
did not stop convulsions provoked by its stimulation.
Thus it became necessary to postulate the propagation
of epileptogenic activity from the point stimulated to
the whole of the cerebral cortex or to subcortical
structures able to maintain convulsions. To this end,
Unverricht (1889) announced his 'law of irradiation',
conceiving an 'intracortical' conduction of the epi-
leptic seizure which, starting from a point on one
hemisphere, is propagated superficially to the whole
cortex. Lewandoski in 1907 (131) defended the theory
of transcallosal propagation, as did Erickson (43)
much later, although he regularly obtained general-
ized seizures after section of the corpus callosum.
Since these fits were clonic on the side opposite to
the stimulated hemisphere and tonic on the .same side,
Erickson concluded that subcortical structures play
an accessory part in the propagation of the epileptic
discharge, at least as far as the clonic component is
concerned. Karplus (123) on the contrary supposed
that the spread of a discharge localized in the cortex
takes place mainly by subcortical pathways. He thus
prepared the way for later research which confirmed
this view, as we shall show in the section on .seizures
of partial epilepsy secondarih- generalized.
In these theories of the cortical origin of generalized
epilepsy the authors assumed that convulsive seizures
depended on a discharge transmitted from the motor
cortex of both hemispheres to the spinal neurons by
way of the pyramidal tracts. This concept was vig-
orously attacked by Prus in 1898 (162) who showed
that these tracts were not essential for seizure pro-
duction, von Economo & Karplus confirmed this
work in 1910, demonstrating the persistence of tonic-
clonic seizures in animals after bilateral destruction
of the pyramidal tracts and the pes pedunculi. The
same kind of experiments were undertaken by Mettler
& Mettler in 1940 (141) who wrote, "epileptiform
.seizures cannot be evoked from the cortex if only the
pyramids are intact, but can be evoked if they alone
are severed," a conclusion which leaves one to .suppose
that extrapyramidal structures and pathways play
a predominant part in the mechanism of generalized
convulsions.
Electrophysiological experiments soon came to
confirm the results of these ablation experiments.
Hoefer & Pool (99) showed that, during a seizure,
spike-discharges of cortical origin are intermittent in
pyramidal pathways but continuous in extrapyram-
idal pathways situated in the reticular formation.
Recently, Zanchetti & Brookhart (199) have demon-
strated that there is no modification in pyramidal
responsiveness after pentylenetetrazol has been ad-
ministered in doses large enough to induce
"spontaneous convulsive discharges". Schlag (172)
obtained similar results after injections of physo-
stigmine or acetylcholine. The two authors suggest
that these convulsants do not directly affect pyram-
idal neurons and cortical interneurons but act
through other neuronal structures, notably those in
the reticular formation.
All these experiments indicate that, although corti-
cal seizures may be secondarily generalized, it is
unlikely that in fits that are generalized from the
start the primary origin is cortical with corticospinal
propagation.
c) Eclectic theory nf cortual-subcortical mechanism of gen-
eralized conviilsion.s. Although there is agreement that
generalized convulsions do not necessarily depend on
the cerebral corte.x, some authors consider that this
applies only to the tonic phase. Among these one
334
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
must mention Binswanger (i8) and Wortis & Klenke
(198} who obtained only tonic seizures by mechanical
or electric stimulation of the pons and the hypothal-
amus, and Ziehen (201) who was unable to obtain
clonic con\ulsions after cortical ablation. These re-
sults have been confirmed by Samaja (171), Prevost
(161) and Bouche (19). This difference between the
sites of origin of clonic and tonic convulsions was
elevated into a law by Bechterew (16). Horsley offered
an even more eclectic opinion when he wrote in 1886
(100), "tonic and clonic spasms may be produced by
any motor center, but the combination and sequence
of tonic-clonic could originate only from the cerebral
motor cortex." Such an interpretation however is not
uni\ersally accepted. Bubnoff & Heidenhain (23),
Pollock & Davis (159), Pike et al. (157), Spiegel (180),
and Marinesco et al. (135) insist upon the fact that
clonic as well as tonic convulsions may originate e.x-
clusiveh' in subcortical structures.
MEGH.^NISM OF THE BIOELECTRIC DISCH.^RGES IN GEN-
ER.-^LiZED EPILEPSY. Certainly the most striking aspect
of generalized seizures recorded from the cortex is
the excessive synchrony of the elements responsible
for each wave of activity. For this reason the epileptic
seizure has .sometimes been called a 'paroxysmal
hypersynchrony'. Actually, the synchrony of the
components is always imperfect and what mainly
characterizes them is isorhythmicity (48). This iso-
rhythmicity, as well as the approximate synchrony, is
partly explained by the fact that different cortical
regions, primarily passive, are connected with one or
several subcortical foci of acti\it\' which act as their
common pace maker or pace makers. We know that
when several pace makers compete, only one is dom-
inant, although changeover from one to another may
take place.
This community and this unity of control rep-
resent what one might call the external factors of
isorhythmicity; there is a synchrony or at least a
grouping of elements when the controls are mediated
by fast conducting pathways.
On the other hand, the mechanism of internal
synchronization, which engenders and organizes the
convulsive subcortical pace makers of the passive
cortical areas, is much more complicated, depending
on many intricate factors. Here interactions between
neighboring neurons of the same type may arise
either from synaptic connections or from reciprocal
field effects at a short distance. The seizure occurs
when these interactions become unusually important
and especially when they thus create the conditions
for explosive autorecruitment. This may come from
different causes, according to Fessard (48) : lowering
of the excitability threshold of neurons, failure of
inhibitory mechanisms, structural arrangements favor-
able to synaptic or ephaptic interactions, alterations
of the recovery cycles so that those of a whole popula-
tion of neurons come to have more similar perio-
dicities, etc. Even chance can be invoked, for if the
other conditions are favorable, a fortuitous and ini-
tially restricted synchrony may hiring on synchroniza-
tion of excitable elements of a larger population of
neurons as a result of intense interactions which will
be powerful in proportion to the number of units al-
ready recruited. The fact that the synchrony, whatever
its cause, results in wider synchronization is the basic
principle of the paroxysmal character of seizures.
The generalized nature of the seizure discharge
which accompanies tonic-clonic conxulsions was
demonstrated by workers who studied its distribution
in the brain of animals. Thus Jung (116) by using
electroshock, and Gastaut & Hunter (66) and Starzl
('/ al. (184) by injecting pent\lenetetrazol recorded
such a discharge from the whole of the cerebellar and
cerebral cortex (i.so- and allocortex) and all the sub-
cortical structures from the caudate nucleus to the
mesencephalon. Jung observed that electrical stimu-
lation, which was insufficient to provoke a generalized
fit, caused the discharge to appear in subcortical
(thalamic and subthalamic) structures and the allo-
cortex (Amnion's horn) and spared only the isocortex.
These results agree well with those of Gastaut &
Hunter (66) who observed that following an injection
of pentylenetetrazol, bisynchronous discharges appear
first in the diencephalon.'
Thus one may suppose that generalized discharges
originate in diencephalic structures, whence they
irradiate to the whole of the brain, a hypothesis which
is confirmed by direct stimulation of the median
diencephalon.
Electrical stimulation of the nonspecific thalamic
structures at low frequency provokes a 'recruiting'
response (38-40, 106, 109, 183). Such responses, when
' These results do not however agree with those of Starzl
et al. (184) who found that a convulsant dose of pentylenetet-
razol pro\oked first a cortical discharge which was secondarily
'driven' to the subcortical structures by projection fibers.
Starzl et at. even concluded that, in the animal with an en-
tirely' isolated corte.x, the convulsant dose of pentylenetetrazol
caused a generalized cortical discharge without any response
in the diencephalon. These are obviously disturbing differences
which are difficult to reconcile, but may be due to differences
in technique.
THE P.HVSIOPATHOLOGY OF EPILEPTIC SEIZURES
335
evoked by mid-line stimulation, are widely distributed
over the two hemispheres and are synchronous and
symmetrical on the two sides; their generalized dis-
tribution thus resembles that of a grand mal seizure.
Chemical stimulation of the diencephalic brain
stem produces generalized electrical discharges.
Murphy & Geilhorn (148) obtained generalized dis-
charges by injecting strychnine into the hypothal-
amus, and recently Ralston & Ajmone-Marsan (163)
provoked bursts of bisynchronous con\ulsant waves,
predominantly frontal, by injecting penicillin into
the thalamic reticular formation in the mid-line.
These bursts could \)e precipitated by electrical stim-
ulation of the thalamus and appear in the same terri-
tory as the 'recruiting' response. The authors indeed
believe that propagation takes place along the non-
specific thalamocortical pathways responsible for the
recruiting response.
It is remarkable that generalized cortical discharges
provoked by stimulation of the thalamic reticular
formation do not persist after cessation of stimulation
and are never accompanied by convulsions, and it is
even more remarkable that generalized convulsions
may be observed in the absence of all cortical electrical
discharge. This is the case notably in the tonic seizures
which are seen in certain forms of syncope and which
appear in the EEG as total electrical silence instead
of a generalized seizure discharge, as shown by
Gastaut & Fischer- Williams (63).
It is interesting to note that techniques as unlike
each other as those which have been applied to the
study of the mechanism of generalized convulsions
and of the accompanying bioelectric discharges should
lead to similar conclusions: the incrimination of the
brain stem reticular formation in the origin of these
phenomena, the caudal part for the convulsions and
the rostral part for the bioelectric discharges.
These conclusions obviously invalidate postulation
of direct relationships between the discharge of corti-
cal neurons and the muscular contractions, since both
of these depend upon a third event, namely the reticu-
lar discharge. For the same reason, no significant
relationships between the convulsive brain waves re-
corded from the scalp and the convulsive movements
observed at the periphery are to be expected; they are
separate both causally and temporally. These con-
siderations are further emphasized by the following
three observations.
a) The onset of the EEG discharge and that of the
tonic phase of the grand mal fit may ije separated by
a relatively long time interval.
b~) The electrical seizure discharge may occur in-
dependently of any tonic-clonic manifestations of
grand mal, and vice versa. Thus EEG discharges of
the grand mal type may appear alone in sleep (8y\
whereas tonic seizures secondary to acute cerebral
ischemia are not accompanied by any electrical dis-
charge whatsoever.
f) The EEG discharge and the convulsions, even
when they begin together, do not necessarily e\olve
in a way which is, so to speak, superimposable. Thus,
simultaneous EEG and electromyographic recording
show some correlation during the clonic phase but
none during the tonic phase (5, 168).
PETIT M.\L OF MYOCLONIC TYPE. This has bccu induced
in man and animals by all the measures capable of
provoking grand mal. M\-oclonic jerks'- occur before
the convulsive seizure when widespread interference
with cerebral function acts in a sufficiently slow and
progressive manner (anoxia, oxygen intoxication,
hypoglycemia, injection of pentylenetetrazol, picro-
toxin, chloralose, bromide of camphor, etc.). One
has but to increase the interference and metabolic
disturbance slightly in order to witness the appear-
ance of a grand mal seizure, following the m\ oclonic
jerks.
However, as in grand mal, focal cerebral lesions do
not produce the bilateral myoclonic jerks of petit mal
unless they are near the mid-line or unless their action
is facilitated by the addition of a mild widespread
activator, for example a subcon\-ulsant dose of
pentylenetetrazol.
When the disturbance is severe enough to pro\ oke
spontaneous myoclonus with its accompanying mul-
tiple spikes, any moderately intense sensory stimula-
tion, such as a sound, touch or flash of light, pre-
cipitates myoclonus after a very brief latent period.
Examples include the myoclonus provoked by sound
after sodium .santonin poisoning (189), myoclonus
evoked by touch and sound after ingestion of bromide
of camphor (149), and the multiple spikes and waves
and myoclonus produced by flicker, sound and touch
after pentylenetetrazol (52). There is here a further
analogy between experimental myoclonic jerks and
-Jerks in myoclonic petit mal must not be confused with the
clonic phase of generalized convulsive epilepsy. The confusion
arises mainly out of etymology, but we consider it a source of
grave error and the subject is later treated in greater detail.
.Suffice it to say here that these jerks are positive phenomena,
related to an actual neuronal discharge in the central nervous
system, whereas the clonic phase in a generalized fit is a nega-
tive phenomenon and represents the momentary interruption
of the prolonged tonic discharge of grand mal.
336
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
those of clinical petit mal which are well known to be
precipitated by sensory stimulation, especially those
that are unexpected or repeated, for example the
intermittent photic stimulation at 1 5 flickers per sec.
used by Walter et al. (193).
The possibility of producing myoclonus at will, in
either animals or man, by the combination of camphor
and touch, or of pentylenetetrazol and photic stiinu-
lation enabled Muskens and later Gastaut to stud\
its mechanism and describe the followina; character-
istics.
a) Myoclonic jerks occur, as do the convulsions of
grand mal, even in the rhombencephalic animal.
(Similarly, bilateral myoclonic jerks, either sponta-
neous or provoked by noise or touch, are character-
istically seen in pontine anencephalics.)
i) The multiple spike and wave of myoclonus, far
from being limited to the rolandic cortex or even to
the whole of the cortex, is recorded in all the grey
matter of the brain, right into the mesencephalon.
f) In myoclonus provoked by sensory stimulation,
the electrical discharge appears in the mesencephalic
formation and the thalamus before Ijeing projected
to the cortex.
cf) A discharge with the same cerebral distribution
and in every other way comparable to myoclonic
multiple spikes is provoked by electrical stimulation
of the anterior part of the thalamic nuclei in the mid-
line.
i) The clinical and electrical phenomena of
myoclonus, as in the case of grand mal, may be en-
tirely independent in their time relationships; thus
multiple spikes and waves may occur without jerks
and vice versa.
With reference to propagation of the discharge, it
has been shown that photic stimulation in an animal
given pentylenetetrazol provokes, quite apart from
the specific geniculostriate response, a discharge in the
reticular formation of the brain stem together with
an ascending thalamocortical discharge and a de-
scending reticulocerebellar and reticulospinal dis-
charge (55, 65, 68). The existence of reticulospinal
irradiation is also implicated in the work of De Hass
et al. (37) who showed that clonic responses evoked
by afferent stimulation persist in the decorticate cat
given pentylenetetrazol. Muskens (149) in 1926
already had a presentiment of this kind of irradiation
when he related the sensoclonic phenomenon to "an
influx produced in a reflex way in the region of the
reticular substance in the pons and medulla."
Thalamocortical and reticulocortical irradiation,
observed bv Gastaut & Hunter (66) and confirmed
by Hunter & Ingvar (loi), was further demonstrated
in an indirect way by the results of De Hass et al.
(37). They showed that the presence of the specific
.sensory cortex was not necessary for obtaining an
irradiated frontal response to photic or auditory
stimulation in the cat after pentylenetetrazol ad-
ministration; this obviou.sly excludes the hvpothesis
of purely corticocortical conduction. Reticulocortical
propagation was also demonstrated \i\ Jasper et al.
(108) who showed electrographically a) that the
postdi-scharges from the visual cortex do not irradiate
to other cortical regions by corticocortical pathways
and certainly not to the frontocentral region where the
multiple spikes, irradiated under the effect of photic
stimulation, are recorded; and b') that a parastriate
postdischarge projects directly to the intralaminar
nuclei which project in turn to the frontal cortex.
It seems therefore that the concept of the subcortical
origin of petit mal iif nnoclonic type is well founded.
PETIT M.AL OF '.ABSENCE' TYPE. This is the onh' varietv
of generalized epilepsy which has not been satisfacto-
rily reproduced experimentally. The various measures
causing generalized cerel^ral disturbance, which so
effectively reproduce grand mal and myoclonus, have
never provoked in the nonanesthetized animal tran-
sient loss of 'consciousness' comparable to the
'absence' of petit mal.
It is very easy to induce brief loss of consciousness
\)\ means of focal cerebral disturbances and particu-
larly by limited electrical stimulation of many differ-
ent structures with indwelling electrodes (thalamus,
hypothalamus, sul^thalamus, the basal and limbic
rhinencephalon, etc.). Loss of consciousness in these
cases, however, is accompanied by an 'arrest' and
'orientation' reaction with postural readjustment and
various types of gesture, which are much more sug-
gestive of psychomotor attacks than the 'ab.sence' of
petit mal. One must therefore conclude that, despite
the attempts of various authors and notably of Hunter
& Jasper (102), of Kaada (i 19) and of Ingvar (103),
petit mal 'absence' has not yet been definitely re-
produced in animals. The same holds true of man
according to Gastaut & Roger (77).
On the other hand the bilateral synchronous 3 cps
spike-and-wave discharge has been reproduced in
animals under special conditions. All the authors,
having injected pentylenetetrazol or other con-
vulsants systemically in the anesthetized and cranioto-
mized animal, have provoked at will long-lasting,
self-perpetuating discharges of spike and wave which
are generalized, bilateral, synchronous and symmeiri-
THE PHVSIOPATHOLOGY OF EPILEPTIC SEIZURES
337
cal. This spike-and-vvave pattern, howexer, repeats
itself at intervals which are very variable and only
exceptionally around 3 cps. At best, it can not be re-
lated to any modification in alertness of the anes-
thetized animal. If the effect of rhythmical sensory
stimuli is added to that of pentylenetetrazol, it is
also easy to induce a spike-and-wa\'c discharge main-
tained at the frequency of stimulation, for example at
3 cps continuing for as long as desired (66). However,
the fact that the rhythm has to be maintained actively
and ceases as soon as stimulation is stopped com-
pletely disqualifies the phenomenon from being con-
sidered as a form of experimental epilepsy. The same
criticism may be levelled at the spike-and-wave in the
isocortex or allocortex which can be evoked with
great difficulty by rhythmical electrical stimulation of
the mid-line nuclei of the thalamus (12, 103, 109, 118).
Recently Ralston & Ajmone-Marsan (163) have
produced in the cat EEG patterns which are very
close to the bilateral synchronous spike-and-wave
discharge of petit mal. They produced a discrete
irritative lesion in the nonspecific thalamic system by
stereotaxic injection of penicillin. As a result, fusiform
bursts of slow waves developed at a frequency of 3.5 to
5 cps, were of great amplitude and tended to appear
synchronously over the ipsilateral hemisphere when
the lesion involved the intralaminar nuclei but over
the two hemispheres when the lesion was in the mid-
line. On the basis of the topography of these thalamic
lesions and cortical discharges, and of the identity
between these discharges and those produced by
thalamic stimulation (either single-shock stimulation
provoking 'triggered' spindles, or repetitive stimula-
tion provoking a recruiting response), the authors
conclude that these discharges are 'transmitted' by
the nonspecific thalamocortical projection system.
With a sufficiently severe lesion spikes also appear, at
first in the thalamus and later projected to the cortex
where they may be grouped with the bursts of hyper-
synchronous waves; they may thus sometimes consti-
tute rhythmical spike-and-wave complexes. From
these observations the authors have come to believe
that the discharges of petit mal depend on stimulation
of the nonspecific thalamic system near the mid-line,
but that different systems are insolved in the pro-
duction of the spikes and of the slow waves.
The fact that it has not Ijeen possible to reproduce
petit mal 'absences' in animals has not prevented
experimental studies on man. Thus Spiegel et al.
(182), Williams (197) and Kirikae et al. (125) have
recorded numerous episodes of 'absences' simulta-
neouslv in the cortex and in the thalamus. All these
authors admit that spike-and-wa\e discharge takes
place in the two structures at the same time, unless it
occurs first in the thalamus; the British and Japanese
authors e\en feel that the slow wa\e in the complex is
essentially thalamic whereas the spike represents the
cortical element. Thus Williams suggests that the
paroxysm begins in the thalamus with a rhythm of
slow sinusoidal waves of which each element propa-
gates itself to the cortex, there to fire off a spike which,
in its turn transmitted to the thalamus, pro\okes there
another slow wave and so on. Ha\ ne li al. (98) report
contradictory results, for the> do not believe that
there is any discharge in the thalamus during petit
mal 'absences' with bilateral and s\nchronous spike-
and-wave in the cortex.
Petit mal 'absence' also differs from the other types
of generalized epilepsy in its electroclinical correla-
tions. Loss of consciousness is undoubtedly associated
with the spike-and-wave discharge, since no clinical
petit mal seizure occurs without this particular dis-
charge. The reverse is quite possible, however, and
discharges are frequently recorded without clinical
manifestations.
Although electroclinically allied to the other vari-
eties of generalized epilepsy, it must be admitted
that, from the experimental point of view, the find-
ings relating to petit mal "absences' are not analogous
to those in grand mal and myoclonus. Perhaps for
this reason, there is no agreement on the mechanism
of 'absence' and its accompanying EEG pattern,
Shimizu et al. (177) believe, indeed, that the petit
mal spike-and-wave discharge has a localized cortical
origin and that it is rapidly transmitted to the whole
of the cortex of both hemispheres by means of cor-
ticocortical association pathways, chiefly via the
corpus callosum. They base this view on their electro-
thalamographic findings in man, and especially on
the following results of animal experiments: o) intra-
carotid injection of pentylenetetrazol, which carries
it to the ipsilateral cortex, provokes a bisynchronous
spike-and-wa\-e pattern more easily and more often
than does injection via a vertebral artery, which
would take it to the central grey matter; H) intra-
carotid injection provoked only unilateral spike-and-
wave complexes when pentothal had been injected
into the other carotid. However this may be, it must
be admitted that this view is peculiar to the Chicago
school and that the majority of electroencephalog-
raphers accept the theory of a diencephalic pacemaker
mechanism in petit mal 'absences' as in the other
types of generalized epilepsy (105). Ingvar (103) does
338
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
not fully support cither theory, believins; the matter
unsettled.
Cohn (30) pointed out that the spike component
of the spike-wave (spike-dome) complex in man is
not exactly synchronous over the whole of the scalp,
since its beginning, measured at two homologous
points on the two hemispheres, could show an
asynchrony of the magnitude of about 5 to 20 msec.
Such a finding appears to lead to conflict with the
theory of Jasper & Droogleever-Fortuyn (109) who
argued that the cortical discharge in petit mal de-
pends on the activity of a single mid-line pacemaker
which projects synchronously to the two hemispheres
at once. Despite their discordance, one may reconcile
the observations of Cohn and of Jasper by taking into
account the anatomical relations demonstrated by
Nauta & VVhitlock (151). These authors showed that
in the anteromedial part of the thalamus, which was
the region stimulated by the Montreal workers, there
is a band of compact fibers from the brain stem
reticular formation going, on the one hand, to the
subcortical grey matter and, on the other hand, to
the nucleus reticularis of the thalamus which in turn
projects diffusely over the isocortex. These anatomical
facts may explain how Jasper & Droogleever-Fortuyn,
stimulating in the mid-line a tract of fibers with bi-
lateral distribution, were able to obtain a bilateral
and synchronous cortical discharge, whereas the spon-
taneous spike-and-wave discharge recorded by Cohn,
arising in a central but bilateral and diffuse pace
maker in the thalamus, may give the asynchrony which
he observed. It is relevant at this point to recall that it
was in the lateral part of the thalamus that Williams
(197) recorded the start of the petit mal discharge.
IiUerpretdtioti of Experunental Results
In the previous section we ha\e limited ourselves
to a presentation of experimental results with a mini-
mum of interpretation. In this section we shall be
expressing personal views in an attempt to present a
more general unifying conception of the physiopa-
thology of generalized seizures. In the first part we con-
sider the nature and origin of the neuronal discharge
responsible for a generalized seizure, taking grand
mal as an example. In the second we shall envisage
the causes of this discharge. Finally, a third part will
be devoted to a study of the mechanisms by which this
discharge is prematurely interrupted or rhythmically
inhibited, and which are responsible for the two vari-
eties of petit mal (myoclonic and 'absence' types).
The final aim of this section will be achieved when we
have demonstrated the existence of a similar mecha-
nism in all three main varieties of generalized epilepsy.
ORIGI.N', N.\TURE .AND PROP.AG.ATION OF NERVOUS .\C-
TIVHY' RESPONSIBLE FOR GENERALIZED GRAND MAL
SEIZURE. If we envisage generalized grand mal epilepsy
as a group of clinical and electrical phenomena,
necessarily in\ol\ing convulsions, as.sociated with an
EEC discharge of generalized hypersynchronous
waves, the results which we have reviewed in the pre-
ceding section lead us to relate it to a reticular dis-
charge propagated toward the cortex, resulting in the
EEG manifestations, and toward the periphery, in-
ducing the convulsions.
This conception of generalized epilepsy is however
disputable in so far as it regards the two phenomena
as necessarily associated, and affords them equal
importance, whereas the two can be dissociated and
only one of them corresponds to the clinical definition
of epilepsy. One mas try to explain grand mal epi-
lepsy in terms of a hypersynchronous discharge, but
one can not postulate the existence of hypersvn-
chronous discharge in an affection which (until we
know more about it) is characterized only by con-
vulsions and loss of consciousness.
If we admit that the clinical and EEG manifesta-
tions of generalized epilepsy are not neces.sarily linked
and that the former are of greater 'medical' interest,
we should first of all try to explain these clinical
phenomena and afterward search for the factors that
link them to the hypersynchronous discharges by
which they are usually accompanied. We shall there-
fore examine the experimental conditions which pro-
voke transient generalized convulsions, whether or
not they are reputed to be 'epileptic', and seek to
delineate their precise physiopathological mechanism.
In the present state of knowledge, there are four con-
vulsive conditions which throw light on the problem.
a) C'onvulsions with loss of con.sciousne.ss, char-
acterized by inten.se contractions resulting in
opisthotonus, preceded or followed by one or two
muscular jerks, are precipitated in man and in ani-
mals by all forms of cerebral anoxia (anoxemic anoxia
from insufficient partial pressure of oxygen, toxic
anoxia, and ischemic anoxia due to cardiac arrest
and fall in arterial pressure). These phenomena have
been studied electrophysiologically in animals by
Noell & Dombrowsky (152), Ward (194), Ward &
Wheatley (195), Ajmone-Marson & Fuortes (4) and
Gastaut et al. (70). The concordant results of these
authors may be summarized as follows.
/) During acute anoxia, depression of electrical
THE PHYSIOPATHOLOGY OF EPILEPTIC SEIZURES
339
activity extends proSiressi\elv from the telencephalon
to the diencephalon, and then to the mesencephalon
and the metencephalon, durintj which time the most
caudal structures, notably the reticular formation
(in the pons, medulla and the spinal cord) de\elop
or continue to show considerable electrical activit\'.
1') Anoxic convulsions are no longer seen after the
bulbar part of the reticular formation has been de-
stroyed by diathermy (194). One must therefore con-
clude that anoxic seizures depend on the activity of
the caudal reticular formation when no longer under
the control of the higher nervous structures (fig. i).
ft) Convulsions without loss of consciousness, char-
acterized by intense contractions in opisthotonus,
preceded and followed by clonic jerks, are provoked in
man and animals by the administration of strychnine
or other poisons (e.g. nitrogen mustards, di-
chlorodiphenyltrichloroethane). These convulsions
have been studied from the electrophysiological point
of view in animals by Bremer (21), Markham et a/.
(136), Ruf (169), Marossero & Garrone (137),
Bremer & Bonnet (22), Johnson (112) and Gastaut
el al. (71). These studies give the following remarkably
similar results.
/) .Strychnine convulsions are accompanied by a
hypersynchronous discharge in the whole of the retic-
ular formation of the spinal cord and the brain stem
but excluding the intralaminar and mid-line nuclei
of the thalamus, stimulation of which provokes the
recruiting response.
-^) This reticular di.scharge secondarih extends to
the cerebellum. Bremer has shown that the discharges
recorded in the cerefiellar cortex are evoked by those
coming from the reticular formation which he con-
siders the site of the autorhythmic tetanic activity.
This reticular discharge also extends to the motor
neurons of the spinal cord, the hypersynchronous
activity of which is directly responsible for the con-
vul.sions. On the contrary, it does not extend to the
cerebral cortex which reacts by desynchronization.
««w«W»-W»«W»«
»wi OXi >(»"»'W
FIG. I. Schematic representation of tlie mechanism of anoxic
convulsions. The density of the horizontal lines is proportional
to the damage to the neurons due to the anoxia. This damage
is maximum at the corticothalamic level where the bioelectric
rhythms are abolished also. It is diminished at the level of the
hypothalamus and especially of the mesencephalon, where
there are still slow rhythms. It is not present in the reticular
formation of the bulb where the electrical activity is normal.
It must thus be concluded that the anoxic convulsions (repre-
sented by the arrows) depend upon the normal activity of
the caudal reticular formation when it is no longer subject to
the control of the higher nervous centers.
FIG. 2. Schematic representation of the mechanism of
strychnine convulsions. The cross-ruled areas of the brainstem
are those where the hypersynchronous discharge of the strych-
nine type occurs. The thalamocortical structures are completely
spared by this discharge and show only a desychronization
which is normal when there is an intense excitation of the
reticular formation. It must thus be concluded that strychnine
convulsions result from a caudal reticular discharge without
any participation of telencephalic structures or even of the
thalamus.
340
HANDBOOK OF PHYSIOLOCJV
NEUROPHYSIOLOGY I
jj) The neuronal reactivity of this desynchronized
cortex is normal or diminished, but never augmented
(199). Chang (26) also found that strychnine de-
creased the excitability of the cortical neurons. One
must therefore conclude that strychnine convulsions
result in a caudal reticular discharge without any
participation in the structures of the telencephalon or
even of the thalamus (fig. 2).
c) Intense tonic contraction with loss of conscious-
ness preceded by a few isolated clonic jerks and fol-
lowed by a phase of rhythmical clonic convulsions
are provoked by different convulsants (analeptics),
notably by thujone, beta-ethylbetamethylglutarimide
(Megimide) and pentamethylenetetrazol (Metrazol).
An electrophysiological study of these convulsions in
animals has been made by Gastaut & Hunter (65),
Gastaut et al. (71), AJmone-Marsan & Marossero (5)
and Starzl et al. (184) with the following results.
/} During these convulsions' a hvpers\nchronous
discharge replaces all normal activity in the di- and
telencephalic formations, clearly predominating over
the cortex and in the thalamus. This discharge de-
creases in importance in the midbrain tegmentum
where it is not able to replace local spontaneous ac-
tivity. It is practically absent from the rhombencepha-
lon and the spinal cord where normal or increased
spontaneous rhythms continue.
2) The responsiveness of the cortex to electrical
stimulation (as shown by the threshold and sensitivity
of the corticospinal neurons) remains unchanged even
when pentylenetetrazol is used in sufficientlv large
quantities to induce 'spontaneous' consulsive dis-
charges (199). Assessing neuronal excitability by the
chronaxic method, Chauchard et al. (27) demon-
strated that subconviilsant doses of pentylenetetrazol
depressed excitabilitx' of the cortex while increasing
that of the brain stem and spinal cord, an action com-
parable to that of anoxia.
One must therefore conclude that pent\lenetetra-
zol-induced convulsions are evoked b\- a mechanism
which is analogous to that of anoxic seizures, i.e. a
'liberation' of the activity of the caudal reticular for-
mation because the overlying nervous structures are
functionally e.xcluded, having been in\aded by a
discharge (fig. 3).
d) Convulsions have been pro\-oked in animals bv
the administration of pentylenetetrazol in stronglv
' We will comider in this paragraph and the next only the
tonic phase of convulsions provoked by analeptics. The rhyth-
mic clonic phase which follows the tonic phase depends on
the effect of a special inhibitory mechanism, which will be the
object of a specicil study later.
strychninized animals (3, 5). These convulsions are
expressed by:
/) hypersynchronous di- and telencephalic dis-
charge of the pentslenetetrazol type and by a reticular
discharge in the mesorhombencephalon of strychnine
type, these discharges developing completely inde-
pendently;
2) tonic spasm of purely strychnine type not bear-
ing any resemblance to pent\lenetetrazoI convulsions
or any relation to the cortical pentslenetetrazol dis-
charge.
One must therefore conclude that these seizures
result from a caudal reticular discharge of strychnine
nature, without the participation of the di- and
telencephalic structures acti\ated by pentylenetetra-
zol (fig. 4).
Comparing these different mechanisms, it appears
that generalized tonic spasm and isolated clonic con-
vulsions depend exclusively on the caudal reticular
formation which acts on the effector neurons, and
particularly on the motor neurons of the spinal cord,
by means of the various reticulospinal and vestibulo-
spinal pathways and projections. These pathways,
like the structures from which they come, are capable
of inhibiting as well as reinforcing muscle tone, but
not in the same proportion since only the medial part
of the caudal reticular formation is inhibitory, whereas
all the rest of the reticular formation and the \'estibu-
lar formation is facilitatory (133). It may therefore be
supposed that the inhibiting action is less efficacious
than the facilitating one and that it is entirely masked
when the reticular formation is activated as a whole.
These views are consistent with the findings of the
classical neurophysiologists of the Sherrington school
for when the portion of the reticular system, inhibi-
tory as well as facilitatory, lying caudal to a midbrain
transection, is liberated from the influence of higher
centers, a state of decerebrate rigidity results and not
one of hypotonia. The mode of activation of this
caudal reticular formation \aries, howe\er, for during
the tonic spasms it may represent either a positive
phenomenon, a hypersynchronous neuronal discharge
or a negati\e phenomenon, a liberation by depression
or functional exclusion of the oxerlying structures.
The lo.ss of consciousness accompanying the con\ul-
sions would .seem to depend exclusively on the rostral
thalamic reticular formation and the cortex. In man
anoxic seizures (in certain syncopes) and pentylene-
tetrazol seizures, as indeed all other generalized
epileptic seizures, are accompanied by unconscious-
ness related to functional exclusion of the thalamo-
cortical system which is either depri\"ed of oxygen or
occupied by a hypersynchronous discharge. Con-
THE PHYSIOPATHOI.OGY OF EPILEPTIC SEIZURES 34 1
FIG. 3. Schematic representation of the mechanism of pentyl-
enetetrazol (Metrazol) con\'ulsions. The density of the vertical
lines is proportional to the importance of the hypersynchronous
discharge of the pentylenetetrazol type. This discharge is
maximum at the thalamocortical level and it diminishes in
the mesencephalon and the metencephalon to disappear in
the caudal reticular formation where normal electrical activity
persists. It must thus be concluded that the pentylenetetrazol
convulsions are produced by the same mechanism as the
anoxic, i.e. a liberation' of the activity of the neurons of the
caudal reticular formation when the higher nervous centers
are invaded by a discharge which results in their functional
exclusion.
FIG. 4. Schematic representation of the effect provoked by
pentylenetetrazol in an animal already heavily strychninizcd.
The vertical lines represent the hypersynchronous pentyl-
enetetrazol discharge at the thalamocortical level, while the
squares represent the hypersynchronous strychnine discharge
in the brain stem. It can be seen that the strychnine tetanus
which is present at this time depends exclusively on the dis-
charge of the caudal reticular formation without any involve-
ment of the diencephalic structures activated by the pentyl-
enetetrazol.
versely strychnine convulsions (tetanus or raJDies
spasms and tonic cerebellar fits probably depend on
the same mechanism) do not involve the thalamo-
cortical system and are characterized by preservation
of consciousness.
We may now attempt to apply these hypotheses to
the convulsions of grand mal epilepsy, believing that
pentylenetetrazol-induced seizures are the only ones
which faithfully reproduce spontaneous epilepsy in
man with its hypersynchronous cortical discharge and
its well differentiated tonic and clonic phases. A
grand mal seizure seems to depend on a thalamic
discharge which involves the nonspecific reticular
structures and is projected to the cortex in what may
be considered a generalized recruiting response trans-
mitted along the diffu.se cortical projection pathways.
Since the system responsible for recruitment is also
responsible for generalized epileptic discharges (66,
log, 163) and, since it also seems implicated in the
production of i)ursts of barbiturate 'sleep' (107, 143),
one is tempted to compare the hypersynchronous dis-
charge of generalized epilepsy with a sort of paroxys-
mal 'sleep' localized to the thalamocortical system
and provoking a functional exclusion of this system.
This functional elimination may be directly responsi-
ble for the loss of consciousness and indirectly re-
sponsible for the convulsions b\ liberating the
underlying reticular structures. Given the antago-
nism which exists between the thalamic and the
mesencephaiorhombencephalic part of the reticular
formation,^ one may suppose that a momentary
depression of the caudal reticular system can, under
' The recruiting as well as the augmenting responses evoked
by thalamic stimulation are blocked by stimulation of the
reticular formation (85, 147); the pyramidal discharge synchro-
nous with the augmenting response is suppressed during
reticular formation stimulation (155). Conversely, the re-
cruiting response is enhanced by the destruction or the barbitu-
rate depression of the reticular formation (iii, 124), as well
as many other responses induced by thalamic stimulation.
342
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
certain circumstances, favor a thalamocortical dis-
charge indirectly responsible for the seizure, so
explaining the part that sleep plays in inducing
generalized seizures.
Finally, assuming the independence of these two
systems, one may postulate that a factor which can
precipitate thalamocortical hypersynchrony can
equally (and independently) precipitate h>-persyn-
chrony of the reticular formation. In this way there
may be a double reticular discharge of which one, the
thalamic, may be responsible for the cortical manifes-
tations of the seizure and the other, the mesencepha-
lorhombencephalic, for its peripheral manifestations.
One therefore arrives at the following conclusions.
Generalized grand mal epilepsy is related to a sub-
cortical mechanism corresponding first to a paroxys-
mal discharge of the thalamic reticular system trans-
mitted to the cortex by the diffuse thalamocortical
projection pathways, which explains the loss of
consciousness. This discharge results in functional
exclusion of the thalamocortical formations, thus
liberating 'normal' or reinforced activity of the caudal
reticular system; this release, by putting into play
the tonicogenic reticulospinal system, explains the
peripheral convulsions.
It will be noticed that this conception is closely akin
to that of Hughlings Jackson who related epileptic
seizures not only to ai^nornia! neuronal discharges
but to consequent liberation of other parts of the
brain. °
CAUSES OF RETICULAR DISCHARGES, THALAMIC AND
MESENCEPH.ALORHO.MBENCEPHALIC, RESPONSIBLE FOR
c;r.\nd m.al EPILEPSY. In onlv a \ery small number of
* In 1874 Hughlings Jackson wrote (104): "The principle
that we get over-action of lower centres from the mere re-
moval of the higher centres has very important applications.
. . . Strong epileptic discharges paralyse the nervous centre (or
much of it) in which they begin or through which they spread. "
He then applied this generalization "to the cases where the
discharge begins in the highest series. There is loss of use of
that series after a discharge beginning in it, where that dis-
charge has been excessive. But ob\'iously violent action (mani-
acal raving) could not result from this loss of use (a paralytic
condition) of the highest centres. That accounts only for loss
of consciousness. . . . That is only the patient's negative condi-
tion, and his condition is duplex. There is the positive element —
the mania — to be accounted for. My opinion is that the mania
is the result of over -action (morbidly increased discharge, but
not epileptic discharge) of the processes just below those which
have been put hors de combat." VVe realize that the above
remarks do not refer primarily to generalized giand mal
epilepsy, but they nevertheless exemplify some aspects of the
unrivalled enlightenment of Hughlings Jackson.
epileptics has a focal or diffuse irritative lesion in the
reticular formation been found to be the cause of
generalized seizures. However, characteristic lesions
in these regions have been found in certain familial
degenerative epilepsies (of the Unverricht-Lunsborg
type).
Since there are no demonstrable reticular lesions in
the majority of subjects with grand mal seizures
generalized from the start and since they are never
present in ca.ses of experimental generalized epilepsy,
the discharge responsible for these seizures no
doubt depends on a functional abnormality of these
reticular neurons. It is pcssible that this functional
abnormality depends on the unique anatomical
arrangement that is found here; numerous afferent
collaterals (183) arriving from many different parts
of the peripheral and central nervous system (fibers
from sensory lemnisci, the special senses, the cortex,
subcortical regions and cerebellum) all converge
toward common reticular elements and set up phe-
nomena of summation (146). With this spatiotem-
poral summation on neighboring neurons and, pro-
vided that these are in a hyperexcitable state (either
because of constitutional factors or acquired dis-
orders), the normal inflow of nerve impulses in the
reticular formation may cause sufficient synchronous
cellular potentials to build up an effective electrical
stimulus. This stimulus would entail a discharge of
the surrounding hyperexcitable cell bodies by direct
electrical spread independent of any process of
synaptic transmission (ephaptic phenomenon). Once
this process has been started, the discharge would
spread like an avalanche throughout the reticular
formation with a speed of the same order as that of
the transmission of the net ve impulse from neuron to
neuron. This theory, formulated by Gastaut (54), is
only a particular application of the general hypothesis
suggested by Moruzzi in 1950 (145): "A normal
neuron, by the simple fact of being subjected to a
bombardment of nervous activity at high frequency,
can enter into convulsive state. ... It is the ordinary
inflow of ner\e impulses which determine the fact
that a neuron passes from normal activity to an
'epileptic' state. . . . Any neuron may become 'epilep-
tic,' simply through the effect of bombardment of
nervous activity."
In an unstable system (such as an organization of
hyperexcitable neurons) it is usually an external force
that upsets equilibrium. It is not surprising therefore
that a volley of impulses, converging on a center whose
state of tension is abnormally raised, supplies the
energy necessary to build up a hypersynchronous
THE PHYSIOPATHOLOGY OF EPILEPTIC SEIZURES
343
discharge. This conception was held in the nineteenth
century by pioneers of the modern study of epilepsy
who from Hall (96) onwards elaborated the bulbar
reflex theory of generalized epilepsy and believed that
it depends on a "discharge produced in a reflex way in
the region of reticular substance of the pons and
medulla ..." (149) under the effect of "an exalted
sensibility and excitability of the medulla oblongata"
(174). One should not conclude, however, that
generalized epilepsy is merely a reflex phenomenon
and speak of reflex epilepsy; this unphysiological term
is not applicable today to any variety of epilepsy.
The hyperexcitable state of the neurons, which is a
factor necessary to the production of the reticular dis-
charge, may depend on the existence of an 'irritative'
cerebral lesion lying in the neighborhood or even at a
distance from the brain stem. Johnson & Walker
(i 13-115) and KopolofT et al. (127) have shown that
epileptogenic lesions localized in one hemisphere are
always accompanied by a diffuse hyperexcitable state
of the neurons manifested by a general lowering of the
convulsant threshold. It may depend equally well on
a functional factor as yet undetermined, a 'humoral'
or 'cerebral' factor acting at the level of the synapses,
the axons or the cell bodies, and responsible for an
'epileptic predisposition' found both in man and in
animals. This epileptic predisposition and hyperexcit-
able neuronic state may be quantitatively appreciated
b>- determining the convulsant threshold with the
photopentylenetetrazol method (52). The threshold
is low in patients suffering from seizures generalized
from the start and in those whose attacks of partial
epilepsy pass very easily into secondary generaliza-
tion.
DURATION AND TERMINATION OF DISCHARGE IN GENER-
.'^LizED EPILEPSY. The duration and ending of a grand
mal seizure depend on a dual mechanism: a negative
process of neuronal exhaustion, and a positi\e process
of inhibition.
The first of these mechanisms which may firing
about the cessation of the seizure, the progressive
fatigue and final exhaustion of the neurons, is at-
tributed either to the accumulation of acid metabo-
lites or to the fact that the reserves necessary for
cellular functioning have been used up, or to both
processes at once. The first hypothesis, "Ermiidung"
in the sense of Verworn (1900), has not been satis-
factorily demonstrated, for although the pH of the
motor cortex shows a tendency toward acidity during
the fatigue stage of a faradic seizure (42), it changes
toward alkaline values at the end of a pentylenetetra-
zol-induced seizure of generalized epilepsy (i lo).
On the other hand the .second hypothesis,
"Erschopfung" in the sense of \>r\vorn, has been
largely demonstrated. Ruf prolonged a pentylene-
tetrazol seizure for 30 min. by administering oxygen to
an experimental animal and for i hr. by giving
epinephrine as well as oxygen. Davis & Remond (35),
using a polarographic cathode method sensitive to
oxygen concentration, demonstrated the existence of
relative hypoxia in the cerebral cortex developing
during convulsive activity. \V'hatever may be its
intimate nature, the part played by neuronal exhaus-
tion in the electroclinical manifestations of grand mal
seizures is supported b\- the following considerations.
At the beginning of a grand mal fit the EEG dis-
charge does not diminish in frequency, for there
exists an initial indefatigability. This however may be
apparent only if, as Rosenblueth & Cannon (168)
believe, hypersynchrony is still incomplete at this
moment and if different cortical elements are respon-
sible for successive convulsive waves. It may, however,
be real if the neurons enjoy oxygen pres.sures at the
onset of the seizure distinctly higher than those which
determine its extinction and if in addition their
hyperexcitability is so intense at that time that they
could discharge with very low ox\gen pressures.
Whatever the case may be, the EEG discharge of
sustained frequency, characteristic of the beginning
of the grand mal seizure, corresponds to a discharge
of the peripheral motor units which is equally sus-
tained but of much higher frequency and which
provokes the tetanus at the beginning of the tonic
phase.
Once the seizure has lasted some seconds, progres-
sive slowing of the EEG discharge develops, indicating
increasing length of the functional refractory period
of the thalamocortical neurons as they fatigue. This
increasing state of fatigue also affects the reticulo-
spinal neurons and thereby converts the complete
tetanus into an incomplete tetanus which imprints a
vibratory character on the last part of the tonic
phase.
At a certain point of fatigue, the functional refrac-
tory period has become so lengthened that the dis-
charge is interrupted for a short time. This, the first
period of extinction, appears in the EEG as an inter-
val of electrical silence and at the periphery as relaxa-
tion of the tonic phase introducing the first clonus.
This momentary rest permits partial recovery of
energy, which entails a recrudescence of the dis-
charge (first group of spikes) and of the muscular
344
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY
contraction (first clonic jerk). A further period of ex-
tinction then follows, longer than the first, and is itself
foUovved by another discharge. The cycle continues in
this way throughout the whole of the clonic phase
until total exhaustion, which is characterized by
lasting extinction of both electrical activity and con-
vulsions.'^
Postictal recovery is slow; it is manifested elec-
trically by the appearance of abnormal rhythms, first
delta then theta, and from the clinical point of view
by coma and an episode of gradually clearing con-
fusion.
This simplified picture of a grand mal seizure might
lead one to believe that the fit is limited to a cortical
discharge recorded on the EEG and the convulsions
observed clinically. This is far from being the case,
since all the cerebral neurons discharge at the same
time as the cortical cells recorded on the EEG and
all the peripheral effector structures are activated
at the same time as the skeletal muscles. Thus the
whole of the autonomic system is involved in a grand
mal seizure, but its efTects are masked by the spectacu-
lar nature of the generalized convulsions. We may
recall, for example, the fact that the smooth muscu-
lature is brought into play, in the pupils, nipples and
viscera; that salivary, sweat and vaginal glands are
stimulated; and that there are alterations in cardiac
rhythm, arterial pressure and vasomotor activity.
This widespread action is easily understood since the
diffuse projections, which radiate out from the brain
stem reticular formation, go not only to the cortex
but to all the grey matter of the brain, and because
the reticulospinal pathways connect with the auto-
nomic preganglionic centers in the brain stem and
spinal cord just as they do with the somatomotor
centers in these same regions.
The second mechanism involves active inhibition.
It may be supposed that the rhythmical interruption
of a grand mal seizure depends not only on neuronal
exhaustion, but also on the development of inter-
mittent inhibition in ' suppressor' structures.
Expounding this theory in 1949, Jung (116) sug-
gested that the inhibitory structure was the caudate
nucleus, for it was from there that he recorded large
regular slow waves, coinciding with the episodes of
relaxation in the clonic movements and interposed
between the fast rhythms recorded from the cortex
and the thalamus. This hypothesis agrees well with the
" However, fatigue is probably responsible only for the
progressive slowing of the discharge and not for the rhythmical
interruption which depends exclusively on the inhibitory
mechanism described later.
views of Dusser de Barenne et al. (41) who believed
that inhibitory neurons situated in the caudate
nucleus were acted upon by the various cortical
' suppressor' zones, and that they were efTective
through the thalamus and a corticocaudothalamo-
cortical circuit. The close relationship between the
theories of Jung and of Dusser de Barenne is further
demonstrated by the fact that Gastaut & Hunter
(66) and Starzl et al. (184) recorded these same slow
waves in the intralaminar and mid-line nuclei of the
thalamus.
From these experimental results one may postulate
the existence of a thalamocaudate inhilsitory system'
' branched-off in a side-chain' from the nonspecific
thalamocortical projection system, a system which
may actively inhibit the reticular formation of the
thalamus as well as that of the caudal brain stem and
thus prevent the discharge of cortical spikes at the
same time as the peripheral contraction.
In other words, the thalamocortical discharge of
grand mal responsible for cortical spikes and for
reticular ' release' (with its consequent tonic phase)
may be equally responsible for putting into action the
inhibitory system, the slow wav-es from which rhyth-
mically interrupt the discharge of spikes. The slow
wave represents not a convulsion wave but a veritable
state of neuronal depression linked to a phenomenon
of active inhibition (the ' braking' wave of Jung, the
phylactic wave of Walter, or the inhibitory wave of
Gastaut).
This theory explains the absence of the true clonic
phase in anoxic and strychnine seizures, for in these
the telencephalon which incorporates the inhibitory
system is functionally depressed or not actively
brought into play. It explains why the tonic strychnine
convulsions can be interrupted by a clonic phase
when large doses of pentylenetetrazol are injected into
a slightly strychninized animal (fig. 5). It also ex-
plains why the seizures induced by pentylenetetrazol
or other analeptics in the diencephalic, mesencephalic
' The existence of definite connections between the head of
the caudate nucleus and the nonspecific formations of the
thalamus has been demonstrated by physiological neuronog-
raphy (176). Histological proof of these connections were
given: a) by Ranson et al. (164, 165) and Papez (154) who
showed direct connections (in both directions) between the
pallidum and the anterior ventral nucleus of the thalamus
(the former receiving fibers from the caudate and the latter now
incorporated in the nonspecific system of the thalamus); and
A) by Stefens & Droogleever-Fortuyn (185) and Nauta &
Whitlock (151) who demonstrated projections between the
head of the caudate and the intralaminar and mid-line thalamic
nuclei.
O.L.d
THE PHVSIOPATHOLOGY OF EPILEPTIC SEIZURES 345
■ ■ ■:^^y■ .■
strychnine -iO 9«c.
E cardiazof 2 mm
OPCg
G£.5.g
GLg
ThaLg- ■
F.PM.g.'
F.RMd
-• — ■■ — ■■^^"-4^^l;«l ,^ ,
'|.;/r.. '■
. ,
,
•■■■!i}'.^'-..,.;..
B
■J.^lll Mjl'—Uf
FIG. 5. Experimental evidence for a thalamic inhibitory system responsible for the interruption of
the tonic convulsion of reticular origin and for the tonic-clonic course of generalized epileptic
seizures. The first fi\e tracings are cortical (right lateral gyrus, left precruciate gyrus, left ectosylvian
gyrus, left lateral gyrus and left suprasylvian gyrus). The sixth tracing is from the lett thalamus. The
last three tracings are reticular (right and left mesencephalic reticular formation, below the plane
of the red nucleus, and the bulbar reticular formation). A. The cat which has received a weak dose
of strychnine 40 sec. previously begins a typical hypersynchronous discharge after an auditory stimu-
lus which provokes an evoked potential in the ectosylvian gyrus, in the thalamus and especially in the
bulbar reticular formation. Note the exclusively reticular level of the hypersynchronous strychnine
discharge and its bulbar predominance, while all the rest of the brain shows merely desynchroniza-
tion. B. When the action of the strychnine starts to show a decline, so that the reticular formation
discharge is of decreased amplitude and regularity and the peripheral tetanus is less intense, a
strong dose of pentylenetetrazol is given. This provokes first several spike discharges appearing inde-
pendently in the bulbar reticular formation and in all the rest of the brain, and then an intense
rhythmical discharge at the thalamocortical as well as the mesencephalic levels but sparing the
bulbar reticular formation where the strychnine discharge persists. This episode evidently corresponds
to a tonic seizure caused by excitation of the bulbar reticular formation by the strychnine and by
'liberation" of this structure under the influence of the pentylenetetrazol discharge which results in
what may be a type of functional exclusion of the thalamocortical level. C. Eventually there devel-
ops in the thalamus a rhythm of slow waves of large amplitude and progressively slower frequency.
During each of these slow waves there is electrical silence in all the leads, particularly in the bulbar
reticular formation where each slow wave interferes with the hypersynchronous discharge of the
strychnine type. This corresponds to active inhibition, since the tonic seizure stops for the same
time during each interruption of the bulbar discharge, thus making possible the rhythmic relaxa-
tions which characterize the clonic phase of the seizure. D. Finally all parts of the thalamocortical
system are exhausted (extinction), while the strychnine discharge continues unchanged in the bulbar
and even the mesencephalic reticular formation.
346
HANDBOOK OF I'HVSIOLOCY
NEUROPHYSIOLOGY I
or rhombencephalic animal should only be tonic;
they may be accompanied by a few clonic jerks with
brief seizure discharges, but there is never a clonic
phase for this only represents the rhythmic inhibition
of the tonic spasm. Finally, it explains the erroneous
interpretation given by Ziehen (200) and Bechterew
(16) who, on the basis of the results of decortication,
related the tonic component in grand mal to brain
stem structures and the clonic component to the
cerebral cortex.
One may conclude therefore that neuronal fatigue
and exhaustion are responsible for the progressive
slowing of the cortical and muscular discharge in
grand mal during its tonic phase, whereas the thal-
amocaudate inhil)itory system is responsible for the
periods of relaxation in the clonic pha.se and for the
episodes of cortical electrical silence or slow ' ijraking'
waves which are the EEG accompaniment of the re-
laxation periods.
MYOCLONUS OF PETIT M.\L. This disorder may be con-
sidered as a miniature or extremely short grand mal
seizure (54, 59, 149). Numerous arguments may be
adduced in favor of this concept.
a) The etiology is often the same. Myoclonus is
frequently associated with a;rand mal fits, and precedes
the majority of spontaneous grand mal attacks (52,
149, 170) or of attacks precipitated by pentylene-
tetrazol (Feuillet). In most cases the myoclonic jerks
which precede grand mal are repeated at shorter and
shorter intervals until their fusion constitutes the be-
ginning of the tonic phase (Ribot, Muskens).
6) Electrographically, the form, frequency and
topography of the discharges are the same in grand
mal as in myoclonic petit mal; the multiple spikes of
myoclonus appear like a i^urst of spikes in the clonic
phase of grand mal or, even more, like the discharge
just at the onset of the tonic phase.
c) Clinically, the peripheral manifestations are
similar in the two types, generalized increase in
muscle tone masking the fact that other effectors are
brought into play.*
d) Finally, experimental studies furnish the most
important arguments. Myoclonus is provoked experi-
mentally by the same procedures as grand mal fits
and is accompanied by a similar thalamocortical dis-
charge. This lilDcrates the facilitating reticulospinal
"* The myoclonic discharge is obviously too brief to cause
glandular secretion, but it is however able to bring about a
slight alteration in arterial pressure (Morin >& Roger, unpub-
lished observations).
system responsible for the momentary tonic reinforce-
ment which we call "myoclonus".
The one feature that difTerentiates myoclonus from
a grand mal seizure is its duration, and therefore only
the abrupt and premature ending of the myoclonic
discharge remains to be explained. The sustained
frequency testifies to the fact that it is not terminated
by exhaustion and that a process of active inhibition,
like that already envisaged in regard to grand mal
fics, is probably involved.
Ii may i^e concluded that patients suffering from
myoclonic petit mal possess a more active inhibitory
system than those with grand mal, and that this
system is thrown into action from the start of the
thalamocortical discharge, thus bringing about an
almost immediate interruption of the seizure. This ex-
plains why the generalized muscular contraction is
only momentary and why the EEG expression is
limited to a few spikes which are isolated or followed
by one or several ' braking' slow waves.
PETIT M.AL '.\bsence'. Petit mal 'absence' may be in-
terpreted on the basis of the same hypothesis as
myoclonic petit mal. It may be considered as a
thalamic discharge occurring in a subject with a very
effective inhibitory mechanism. Because of this, the
discharge is inhibited almost immediately after it
has been fired and a slow ' braking' wave appears in
the thalamus immediately after the development of
a single spike. The rhythmic repetition of the phe-
nomenon may be explained on the basis that the
termination of each wave of inhibition allows the
thalamic discharge to reappear, provoking a spike and
a new inhibitory wave.
The spikes and slow waves are transmitted to the
cortex by the system of diffuse projection and furnish
the classical spike-and-wave recorded on the EEG
during the 'absence'. Relative independence may
exist between the two mechanisms generating the
spike and the wave so that they function separately
for a certain length of time; this may explain the
numerous cases of atypical spike-and-wave, and par-
ticularly those cases in which the spike disappears and
leaves only the slow waves at the end of a clinical
'absence'. This independence also helps to explain
the observations made in man by Williams (197) and
in animals ijy Ralston & Ajmone-Marsan (163) who
dissociated the spike and the slow wave in the thala-
mus and on the cortex.
Most of the features of petit mal and notably those
which distinguish it from, or even oppose it to, grand
mal may be interpreted on the basis of the pre-
THE I'HVSIOPATHOLOGY OF EPILEPTIC SEIZURES
347
dominance in petit mal ol the thalamocaudate system
from which are generated the slow waves and a process
of active inhibition.
a) The loss of consciousness can be related to the
hypersynchronous discharge which is propagated
from the thalamus to the whole of the brain and pre-
vents normal cerebral functioning. The lack of con-
vulsions may depend on the fact that the reticular
activation is rhythmically inhibited and can e.xpress
itself only by a slight muscular contraction with each
spike of the spike-and-wave.
/)) This hypothesis of the predominance of the in-
hibitory system from which are generated the slow
waves may explain why petit mal is seen especially in
patients with a well-marked tendency to ictal and
interictal slow hypersynchronization. Certain ' alj-
sences' are characterized solely by a discharge of slow
waves. There is also a prevalence of slow rhythms in
iaetween petit mal .seizures (theta rhythms, delta
rhvthms in the frontal and occipital regions, and
hypersynchronous bursts during overbreathing).
f) This same hypothesis may explain \vhy the ' ab-
sences' are frequently precipitated by conditions
which favor this slow hypersynchronization (hy-
perpnea, sleep, closure of the eyes, and administra-
tion of pentylenetetrazol, pentothal, chlorpromazine,
etc.). These synchronizing; measures depress the
mesorhombencephalic reticular formation and thus
■ release' the thalamocortical system of spindles, the
hypersynchronous discharges which depend on this
same thalainocortical system and the accompanying
' braking' slow waves.
(T) The relative antagonism between the rostral
and caudal parts of the reticular formation may throw
light on the fact that certain physiological conditions
(such as puberty) or therapeutic agents (such as the
diones) can transforin petit mal ' absences' into grand
mal seizures. Petit mal is distinguished from grand
mal by this functional predominance of thalamo-
caudate inhibition, so that the hypersynchronous
thalamic discharge is prematurely inhibited and
liberation of the caudal reticular formation is pre-
vented. One has but to suppose that endocrine modi-
fications or certain medications selectively depress
the inhibitory system; this lessened inhibition mav
explain the prolongation of the hypersynchronous
thalamic discharge, the bulbar 'release' and the
transformation of petit mal into grand mal.
One common theoretical basis thus may explain
the three varieties of generalized epilepsy which have
been shown by empirical observation to he closely
linked. Grand mal and petit mal in their pure forms
are indeed exceptional, whereas the association,
either temporary or permanent, of two or three forms
is the general rule. This theory of common causalitv
may help in understanding the characteristics of the
EEG discharge and the .somatic manifestations of the
three types of generalized epilepsy; it may explain
the loss of consciousness which is a feature of grand
mal and the 'absence' of petit mal. Myoclonic petit
mal is too brief to interrupt the chain of psychological
events whose temporal dimensions are greater than
the duration of the seizure. Indeed one cannot en-
visage the receipt and transmission of messages, their
analysis and transformation into sensations, ideas or
actions, and their storage in the form of memory, at
a time when most of the cerebral neurons are col-
lecti\-ely occupied in discharging simultaneouslv and
when the source of this discharge is exactly the struc-
ture whose function is to regulate the whole of cerebral
activitv.
PHYSIOP.'kTHOLOGV OF P.ARTI.AL EPILEPSIES
ExperimeiUal Results
Seizures of partial epilepsy have been reproduced
in animals only by provoking a localized cerebral dis-
turbance. Since this necessitates opening the skull,
the method cannot be applied to man. All experi-
mental results have therefore been obtained in ani-
mals, but relevant information may be gathered from
patients with a \'erified epileptogenic lesion.
A localized experimental cereljral disturbance can
be epileptogenic either directly by acting on the
neurons or indirectly by causing a lesion which is
later epileptogenic. In the first case, no actual lesion
is produced in the brain; the epileptogenic stimula-
tion is either an electric current applied locally, a
source of heat or cold, or a chemical irritant (strych-
nine, penicillin, carbachol, creatine, physostigmine,
acetylcholine, nicotine, picrotoxin, etc.). On the con-
trary, in the second case, the cerebral as.sault does not
directly precipitate a seizure but leads to localized
cicatrization which is responsible for the irritation
that later provokes seizures. Aluminum hydroxide,
acting as a foreign body without immediate chem-
ical action, is the substance commonly used to pro-
voke this type of irritation. In both cases, the cere-
bral disorder may be produced in the cortex or in
the depths of the brain in various subcortical struc-
tures; in both cases, it gives rise to seizures which may
348
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
remain partial throughout their whole duration or
which may become generalized only after a certain
time.
EXPERIMENTAL PARTIAL EPILEPSY' OF CORTICAL (iSO-
cortical) ORIGIN, o) Local application of strychnine.
When strychnine or another convulsant is applied to
the isocortex, it provokes clinical and electrical mani-
festations reminiscent of certain seizures of partial
epilepsy in man. Only those clinical manifestations
which involve discharges provoked in the motor, and
notably the somatomotor, areas have been studied
[(15) and numerous more recent authors], probably
because they are the only ones which can be demon-
strated in the anesthetized animal under the special
experimental conditions required.
In the classical 'cortical strychnine clonus' of Bag-
lioni & Magnini (15), convulsions appear in the
contralateral musculature a few seconds after the ap-
plication of strychnine. They are at first confined to
the parts corresponding to the cortical region treated
but they later spread to other muscular groups on that
side of the body. Contrary to the generalized epilep-
sies already discussed, the impulses for these clonic
movements are undouljtedly transmitted from the
somatomotor cortex to the spinal motor neurons by
way of the pyramidal tracts. This conclusion arises
out of the following experimental results: /) convul-
sive discharges can be recorded from pyramidal fibers
synchronously with the clonic twitches (2); 2) both
the movements and the pyramidal discharges con-
tinue when the brain stem is interrupted at midbrain
levels, leaving only the pes pedunculi intact (196).
If the cutaneous zones corresponding to the strych-
ninized region are stimulated, these convulsions ap-
pear sooner and are intensified and rapidly general-
ized. This "reflex' reinforcement of the cortical epi-
leptic process was discovered by Amantea (8) in 1921 ;
it is lost when the strychninized cortical focus is
destroyed.
The EEG manifestations of the local application of
strychnine consist of a bioelectric oscillation of great
magnitude (more than a millivolt), known as the
"strychnine spike', which is repeated at more or less
regular intervals. This spike does not remain localized
to the spot on which the strychnine is applied but
spreads like a drop of oil to the whole of the cor-
responding area (for example to the whole of the
somatomotor area). It is also propagated at a distance
to the homologous structures of the opposite hemi-
sphere and to the allied subcortical structures (for
example to the \entrolateral nucleus of the thala-
mus when the strychnine is applied to the somato-
motor region). The strychnine spike however can
develop to its fullest and continue to be repeated even
though it is not accompanied by these phenomena of
propagation. Indeed, neuronal isolation of a cortical
area (that is to say, its separation from neighboring
cortical areas and from subcortical centers) does not
prevent the appearance of strychnine spikes on local
application.
The strychnine discharge has been very fully in-
vestigated by workers in basic neurophysiology [see
bibliographies (143, 146)] because it is so easily pro-
voked and so easily repeated. From these studies, and
particularly those of Jung (117) and Moruzzi (146)
one ma\' draw the following conclusions. /) The
strychnine spike results from a process of hyper-
synchrony, that is from the simultaneous discharge of
the great majority of the neurons in the strychninized
area, a hypersynchrony which probably is due to
ephaptic (extrasynaptic) interactions between the
different elements which are put into play by elec-
tric currents conducted through the intercellular
spaces. 2) Recorded with macroelectrodes, the
strychnine spike only shows its slow triphasic (posi-
tive, negative, positive) envelope, which corresponds
no doubt to slow potentials and to an electrotonic
spread and decremental conduction in the dendritic
plexuses. With microelectrode recording, however,
one observes in addition a burst of very rapid spikes
(400 to 1 ,000 cps) which begins with the first positive
phase and ends with the second negatise pha.se. It is
this burst of rapid spikes, which is transmitted along
the axons of the pyramidal cells (i) to the spinal
motor neurons, which provokes the muscular twitch.
i) Localized electrical stimulation. The electroenceph-
alographic effect of a single Isrief electric shock is
seen as a \ariation of the local potential which differs
little from the strychnine spike except that it is di-
phasic, at first negative and then positive. Using
intracellular microelectrodes, Buser & Albe-Fessard
(24) were aisle to record this slow variation of po-
tential at actual neuronal level. In addition the micro-
electrodes record the burst of brief spikes (less than a
millisecond) at high frequency (up to 1,000 cps) which
accompanies the strychnine discharge and which is
propagated along the length of the axons. (The.se
spikes are oljviouslv positive in the interior of the
neurons and negative in their neighborhood.)
A series of electrical shocks results in repetition of
the above phenomena so long as the frecjuency of
stimuli is not too rapid. Above a certain frequency,
the discharge appears only at the end of stimulation
THE PHVSIOPATHOLOGY OF EPILEPTIC SEIZURES
349
under the form of a self-sustained electrographic ac-
tivity known as a postdischarge.
This postdischarge has most of the features char-
acteristic of the evoked electrical or strychnine po-
tential : /) diffusion to the whole of the area contain-
ing the stimulated spot; 2) propagation to the contra-
lateral homologous area, j) subcortical propagation
to allied structures; and ^) development on a strip of
vascularized but neuronally isolated cortex. On the
other hand, it differs in that it has the peculiar at-
tribute of being self-sustained and of continuing
rhythmically for a shorter or longer time after the end
of the stimulation. It is no longer a single bioelectrical
oscillation of great amplitude repeated at variable
intervals, but a series of oscillations slowing pro-
gressively and soon interrupted by intervals of elec-
trical silence of which the last represents a long phase
of postictal extinction.
French et al. (50) have observed that all cortical
regions can be made to show a postdischarge follow-
ing supramaximal electrical stimulation, but that
only some regions show a postdischarge from stimu-
lation which is only just above threshold. On this
basis they describe zones as ' epileptogenic' in the fol-
lowing descending scale: the motor and premotor cor-
tex (motor area for the face and the hand), and the
teletemporal and uncinate cortex being most sus-
ceptible; next the posterior insular and superior
temporal cortex; and after that the parietal cortex.
On the other hand the frontal and especially the
occipital cortex are resistant to experimental epilepsy.
The clinical effects of electrical stimulation have
been studied only in respect of the somatomotor region
for the same reason as in the case of strychnine con-
vulsions. The potential evoked by a single electric
shock is accompanied by an isolated contralateral
' clonus' identical with the ' cortical strychnine clonus'
of Baglioni & Magnini (15). The electrical after dis-
charge is accompanied by a convulsive attack (which
might be termed a motor after discharge) involving
the appropriate contralateral part, each cortical
oscillation corresponding to a clonic jerk and to a
burst of high frequency activity in the corticospinal
pathways.
As in the case of strychnine, one can facilitate or
prolong the clinical and EEG effects of electrical
stimulation of the cortex by stimulating the appro-
priate cutaneous reflexogenic areas or the parts of
the brain that project to that particular cortical zone.
In this way subthreshold stimulation of the sensori-
motor region facilitates the provocation of a seizure
from the homologous contralateral area. With supra-
maximal stimulation applied to the subcortical white
matter after removal of the corresponding somato-
motor area, it is even possible to provoke a seizure in
the homologous opposite region (27).
f) Epileptogenic cortical lesions. These are caused by
local application of aluminum hydroxide, according
to the technique of Kopeloff et al. (127), and appear
as fibroglial scars developing slowly around a foreign
body. Attacks of partial epilepsy are seen 4 to 1 2 wk.
after application and persist for several years.
The clinical effects of such lesions ha\e been
studied most frequently when they were located in
the somatomotor area of the monkey. These take
the form of Jacksonian seizures beginning in one limb
or the face on the contralateral side and spreading
progressively (with Jacksonian march) to include the
rest of that half of the body. Between seizures, there
may be isolated twitches of the muscles involved in
the beginning of the paroxysm (epilepsia partialis
continua). Peripheral stimulation of all kinds, chiefly
of the special sense organs (e.g. a loud and continuous
noise), may precipitate or reinforce isolated clonic
jerks and may even fire off a Jack.sonian fit.
\'ery few authors have had the curiosity to apply
aluminum cream to cortical areas other than the
somatomotor. Cure & Rasmussen (34), however, ap-
plied it to the insula of monkeys and they mention
spontaneous seizures but unfortunately describe
only one, characterized by a bilateral tonic -clonic
spasm without any localized feature. Kopeloff et al.
(127) applied aluminum cream to the occipital,
frontal, middle and anteriortemporal cortex of the
monkey without producing seizures in which there
was any detectable motor phenomenon. Nor did
Gastaut et al. (83) observe any paroxysmal motor
effects after subpial injection of aluminum hydroxide
in the cat in regions corresponding to the occipital
lobe and to the tip of the temporal loije and the
temporal lobe proper. These negative findings are
very important, chiefly in so far as they show that
temporal and teletemporal scars, at least in the
monkey and the cat, do not provoke 'psychomotor'
seizures, sometimes attributed in man to similarly
placed lesions.
The EEG manifestations resulting from experi-
mental .scars appear in the form of slow variations of
local potential in a sporadic or in a rhythmical man-
ner. The sporadic variations are analogous to those
provoked i^y a single electric shock or the application
of strychnine, since they appear as predominantly
negati\e polyphasic variations in the form of a spike
followed b\' a single slow wave or a spike-and-wave
350
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
complex. The rhythmical variations are in every way
comparable to postdischarges provoked by an electric
current : that is to say, they appear as rhythmical dis-
charges of localized spikes whose frequency diminishes
progressively and which are often interrupted by slow
waves or intervals of silence before they come to an
end.
Recording with microelectrodes, Thomas et al.
(i88) observed in addition cellular discharges which
were rather different from those provoked by strych-
nine or a single electric shock. The units often showed
spontaneous prolonged bursts of activity, usually be-
ginning with a high frequency train of impulses (ap-
proximately I, coo cps) followed by longer bursts at
somewhat lower frequencies (approximately 300 cps).
Such a discharge may repeat its whole cycle inter-
mittently or settle down to a steady train of impulses
at about 150 to 200 cps which may be kept up in-
definitely.
(T) Propagation 0/ experimental isocortieal epileptie dis-
charges. The use of recording electrodes at a distance
from the stimulated region has shown that all epilep-
tic discharges are propagated locally and to a greater
or lesser distance. Local propagation proceeds very
slowly (from i mm per sec. to i mm per min.) through
a multitude of fine fibers and synapses, often arranged
in reverberating circuits which constitute the fibrillary
network of the cortex. Studying local propagation by
means of vector recordings. Green & Naquet (93)
came to the conclusion that it may represent extra-
synaptic spread from cell to cell following dendritic
depolarization. Sporadic and rhythmical discharges
are propagated at a distance in different manners
(160). The rhythmical discharges (the 'postdis-
charges') are propagated much more widely than
are the sporadic discharges; it is the former type only
that we shall be considering here, for it alone cor-
responds to the propagation of an epileptic seizure.
(The sporadic discharges only represent the ' inter-
seizure' irritative manifestations, and a knowledge of
them is not indispensible for understanding the actual
seizures.) Numerous authors have studied the propa-
gation of postdischarges from different parts of the
cerebral cortex. A complete bibliography of the
numerous works devoted to these cortical postdis-
charges can be found in Green & Naquet (93). We
shall give only a brief account' of subcortical propa-
gation of postdischarges engendered in different parts
of the cerebral cortex, neglecting corticocortical
propagation which takes place mainly in the homolo-
gous contralateral region by means of commissural
fibers.'"
Frontal postdischarges are propagated chiefly to
the brain stem reticular formation (tegmentum
mesencephali, hypothalamus and intralaminar nuclei
of the thalamus) and secondarily to the caudate
nucleus, the amygdala and the hippocampus. Cingu-
lar postdischarges have a similar but less marked
propagation, and orbital postdischarges propagate
particularly to the amygdala and hippocampus.
Postdischarges in the motor region travel chiefly to
the brain stem reticular formation, the septal region
and the corpus striatum. Temporal postdi.scharges
are mainly propagated to the amygdala, hippo-
campus, septal region, subthalamus, hypothalamus
and the mesencephalic reticularis, and secondarily
to the corpus striatum and the pulvinar. Occipital
postdischarges go chiefly to the thalamus (pulvinar
and lateral geniculate body, and neighboring intra-
laminar nuclei) and secondarily to the subthalamus
and the reticular formation.
Thus the postdischarges localized in the cortex are
characterized by remarkably important subcortical
propagation which nearly always involves the brain
stem reticular formation and the amygdalohippo-
campal system. This tendency for cortical epileptic
discharges to invade subcortical nonspecific structures
or the brain stem had already been evidenced by the
interseizure sporadic discharges. Thus von Baum-
garten et al. (190) demonstrated the reticular influ-
ence of strychnine spikes and potentials evoked by a
single shock in the rolandic region; this was mani-
fested by reinforcement, or conversely by inhibition
of the spontaneous discharges of single reticular units
recorded with microelectrodes.
EXPERIMENT.^L P.'^RTI.AL EPILEPSY OF RHINENCEPH.^LIC
(allocortical) ORIGIN. We shall study seizures
caused by epileptogenic measures involving not only
the allocortex but all the rhinencephalon, both its
cortical and nuclear parts.
a) Implantation of in-dwelling electrodes. This method
has permitted the study of seizures of partial epilepsy
provoked by electrical stimulation of the rhinen-
' This summary takes account of the works of Walker &
Johnson (192), Kaada (119), Ajmone-Marsan & StoU (6),
StoU et al. (186), Gastaut et al. (72), Jasper el al. (108), Segundo
et al. (175), French el al. (50), Poggio el al. (158), and Creutz-
feld(3i).
'•" Contralateral homologous conduction takes place via the
corpus callosuni or the anterior commissure according to the
site of the lesion. This was demonstrated by physiological
neuronography (140) and by study of experimental epilepto-
genic scars (127-129).
THE PHYSIOPATHOLOGY OF EPILEPTIC SEIZURES
351
cephalic formations (56, 72, 80, 81, 83, 122, 132, 150).
The clinical manifestations are of interest. Stimulation
of the hippocampus or gyrus fornicatus provokes a
simple reaction of ' attention' and contralateral 'ori-
entation' of the head when the stimulus is of weak
intensity. When a stronger stimulus is applied, it pro-
vokes more complex reactions suggestive of anxietv,
fear or anger. In every case, the animal shows some
lack of awareness and responds little or not at all to
outside influences. This impaired responsiveness con-
trasts with the accompanying portrayal of 'arrest' and
'attention' and is paradoxical if one interprets it as
the expression of clouded consciousness. The paradox,
however, disappears if one thinks that it reflects ex-
tremely concentrated attention on an abnormal psy-
chological event created by the stimulation, perhaps
an illusion or a hallucination.
Stimulation of the piriform cortex, or the under-
lying amygdala, provokes complex phenomena in
which are associated: /) contraversive deviation which
may or may not be accompanied by abnormal tonic
or clonic movements; 2) complex gestures apparently
reactive to abnormal sensations involving the bucco-
facial region or the extremities (licking the lips, clear-
ing the throat as though to get rid of a foreign body,
or lifting and shaking a paw); j) actions with a feed-
ing significance (lapping, mastication, salivation or
deglutition); and ./) changes in the autonomic, re-
spiratory and circulatory spheres, including pupillary
changes, micturition and defecation.
The electroencephalographic efifect of electrical
stimulation of the rhinencephalon has been studied
by Gastaut et al. (72, 80, 81, 84), Gloor (90), and
Feindel & Gloor (46), who investigated chiefly the
amygdala, and by Kaada (119, 121), Creutzfeldt &
Meyer-Mickeleit (32), and Andy & Akert (10, 11)
who studied the hippocampus particularly. In these
studies postdischarges were produced which involved
the structure stimulated (amygdala or Amnion's
horn) and were transmitted to: /) the homologous
contralateral region; 2) allied structures such as the
hypothalamus, the septum and the anterodorsal
thalamus; 3) the corpus striatum and midbrain
tegmentum; 4) the pyriform cortex, the orbito-
insulotemporal cortex and secondarily the anterior
part of the gyrus cinguli; and 5) sometimes even to
the rest of the isocortex. There is considerable diff'er-
ence of opinion among authors as to propagation to
the isocortex, which according to some is predom-
inantly to the frontal regions and according to others
to the occipital regions.
Propagation to these structures may be either si-
multaneous or successive, and Gastaut et al. (72, 80,
83) particularly stress the fact that the postdischarges
are erratic, and that they may be transmitted, for
example, from the amygdala to the temporal and
septal regions, then to the posterior hypothalamus and
from there to the frontal cortex, returning again to
the temporal region.
6) Local application or injection of aluminum cream.
Stereotaxic techniques have made it possible to pro-
duce epileptogenic scars in the same limbic or basal
rhinencephalic structures. The experimental results
closely resemi^le those of electrical stimulation (81,
83, 84).
The clinical manifestations are typically seizures
which occur 2 or 3 mo. after injection of aluminum
hydroxide into the amygdaloid nucleus. The following
description of seizures in cats is given by Naquet(i5o):
"The animal suddenly changes its attitude, some-
times tries to escape, becomes anxious, immobile, then
sniflfs violently, especially to the side of the amvgdaloid
scar; at the same time one notes pupillary dilatation,
clonic movements of the homolateral eyelids, rapidly
followed by facial hemispasm with deviation of the
head to the opposite side, clonic masticatory move-
ments and salivation. The seizure may stop at this
stage, or else the cat lifts its anterior contralateral paw
and there appear clonic movements of the whole of
the contralateral side of the body followed by a gen-
eralized fit with urinary incontinence. A ' confusional'
state with loud miaowing follows the seizure. In some
cases, there are in addition various types of seizures
which are predominantly 'psychological'. Suddenly
the animal becomes immobile, its pupils dilate, its be-
havior changes, it lifts its contralateral paw as though
to defend or attack, there is marked piloerection and
it bites if one tries to touch it. This seizure lasts 20 to
40 sec. and suddenly the animal becomes aflfectionate
again. Alternatively, the animal suddenly tries to
escape, miaows fiercely, its pupils dilate and its be-
havior gives the impression that it sees or hears some-
thing alarming. This seizure terminates rapidlv."
The electroencephalographic manifestations will
now be described. Between seizures, one observes
sporadic discharges of slow waves, of spikes or spike-
and-wave complexes at the periphery of the amygda-
loid, hippocampal or septal lesions, which are trans-
mitted to one or several of the following regions:
uncus, insula, tip of the temporal lobe, temporal lobe
proper, posterior orbital region (78, 84, 167). These
discharges may be on the same or the opposite side
of the lesion and sometimes may even predominate
352
HANDBOOK OF PHYSIOLOGY'
NEUROPHYSIOLOGY I
on the contralateral side, but they are never bilateral
and synchronous. Independent contralateral dis-
charges may indicate a secondary vascular extension
of the lesion to the other side (69) but may also indi-
cate a functional ' unleashing' of these homologous
contralateral structures which have acquired an
epileptogenic potential through being bombarded.
For these reasons, ablation of the epileptogenic focus
on the side of the lesion does not necessarily lead to
the disappearance of the contralateral discharges
which mav persist for several months after operation
(84).
During seizures, the discharges show a great variety
of forms: /) rhythmical discharges of spikes or slow
waves observed around the lesion, propagated to the
same cortical areas as the interictal discharges, chiefly
to the orbitoinsuloteletemporal cortex; 2) propaga-
tion of the discharge to subcortical structures, chiefly
the septum, the hypothalamus and the tegmentum
mesencephali, generally accompanied by diffuse cor-
tical manifestations like desynchronization or slow
hypersynchronization occupying all or part of one or
both hemispheres (78, 84, 167). Sloan, Ransohoff &
Pool emphasize the bisynchronous 4 to 6 cps ictal
discharges which they recorded in monkeys with
amygdaloid scars.
EXPERIMENTAL PARTIAL EPILEPSY OF SUBCORTICAL
ORIGIN. If one excludes the amygdala and septum
which have been linked to the rhinencephalon, few
subcortical structures have been studied from the
point of view of experimental epilepsy. Different parts
of the thalamus, subthalamus and tegmentum mesen-
cephali have, however, received indwelling electrodes
or been injected with aluminum cream (72, 73).
The clinical manifestations produced by limited
electrical stimulation include autonomic and devia-
tional phenomena which bear only a distant and frag-
mentary resemblance to the seizures provoked by
stimulation of the basal rhinencephalon. The scars
from aluminum implantation have never given rise
to spontaneous seizures, probably because the di-
encephalic structures have a high convulsant thresh-
old. However, injection of subliminal doses of pentyl-
enetetrazol in cats with diencephalic scars have always
precipitated seizures very similar to those provoked
from the basal rhinencephalon. This led Gastaut &
Roger (78) to believe that at least some of the aspects
of rhinencephalic seizures depend on the fact that
allied diencephalic formations are brought into play.
The electroencephalographic manifestations are of
several types. With hypothalamic, subthalamic and
tegmental epileptogenic lesions there are sporadic
and local interictal discharges, transmitted to the
orbitoinsulouncotemporal region which, as we have
already seen, is involved when the rhinencephalon
discharges. This curious observation is explained by
the findings of physiological neuronography and of
histology which demonstrate a large number of con-
nections between the orbitoinsuloteletemporal region
on the one hand and the hypothalamus, subthalamus
and tegmentum mesencephali on the other (67).
Irritative lesions of other subcortical structures
cause discharges in other parts of the cerebral cortex.
Thus lesions of the lateral (dorsal and posterior) and
of the posterior nuclei of the thalamus produce their
effects in the posterior temporal and the parietal cor-
tex, whereas lesions of the pulvinar, the lateral genicu-
late and the corresponding region of the nucleus
reticularis affect the occipital cortex. Lesions of the
medial geniculate, the suprageniculate nucleus and
the corresponding region of the nucleus reticularis act
on the superior temporal cortex.
EXPERIMENTAL PARTIAL EPILEPSY, SECONDARILY GEN-
ERALIZED. All partial epilepsies may become gener-
alized whether they are of cortical or subcortical
origin, and whether caused by direct chemical or elec-
trical stimulation or resulting indirectly from an epi-
leptogenic scar. The partial epilepsy which has been
best studied from the point of view of generalization
is that caused by localized cortical electrical stimu-
lation. Generalized convulsions develop when the
strength of local stimulation passes a threshold value
wherever this cortical stimulation may be, even after
sagittal section of the telencephalon, diencephalon
and mesencephalon (181); it is thus certain that the
subcortical structures extending as far as the rhomben-
cephalon are responsible for the generalization of the
convulsions.
A study of epilepsy of the Openshowski-Speranski
variety leads to the same conclusions. Here generalized
seizures, so frequent that they constitute status epilep-
ticus, are provoked by refrigeration of a small part of
cerebral cortex on one side. This is a generalized
epilepsy which is at first partial, for immediate abla-
tion of the refrigerated zone abolishes it, but the
generalization is of subcortical origin since convul-
sions (which are bilateral) still appear after ablation
of the somatomotor region of both hemispheres (45)
and after section of the corpus callosum (179).
Subcortical structures influence the generalization
THE PHYSIOPATHOLOGV OF EPILEPTIC SEIZURES
353
of somatomotor or occipital strychnine epilepsy under
the facilitating effect of a bombardment of afferent
' influx' coming from the corresponding sensory areas
[the epilepsy of Amantea (8) and of Clementi (28, 29),
described on p. 355]. This led Moruzzi to write:
"When, in the photic epilepsy of Clementi, we il-
luminate the retina, we not only send nervous im-
pulses into the striate area which has been strych-
ninized, but at the same time we activate the whole
of the cerebral cortex through the ascending reticular
formation of the brain stem." The generalized seizure
that follows is presumably subcortical since subse-
quent ablation of both somatomotor areas does not
prevent the convulsions from developing (9). It is
therefore most likely that any discharge of partial
epilepsy, once it is of sufficient magnitude, can be
transmitted to the centrencephalic structures from
the thalamus to the medulla, and from there be gen-
eralized to the rest of the brain.
There is supporting EEG evidence for these conclu-
sions. Jasper el al. (108) showed that the majority
of cortical postdischarges are transmitted to the
reticular formation of the thalamus and brain stem.
French et al. (50) demonstrated a .subcortical reticular
mechanism in generalized postdischarges provoked by
localized cortical stimulation. "Surface regions dis-
playing the characteristic local response (persistent
after discharge) seem to have the capacity secondarily
to excite certain diffu.sely projecting subcortical struc-
tures (reticular formation, septal region and amyg-
dala) which are capable of disseminating the induced
discharge widely." Finally, in microphysiological
studies in strychnine epilepsy, von Baumgarten et al.
(190) have shown that each strychnine spike developed
in the motor cortex alters the spontaneous activity of
the neurons of the reticular formation so that their
activity is momentarily reinforced; this effect must
play a large part in the phenomenon of generalization.
EXPERIMENTAL PARTIAL EPILEPSY WITH ERRATIC DIS-
CHARGES. In some cases, a seizure of partial epilepsy
stops as suddenly as it starts, the postictal electrical
silence appearing simultaneously in all the discharg-
ing structures. In other cases, however, the discharge
comes to an end in one formation and is transmitted
at the same time to another more or less distant part,
thus prolonging the seizure. This phenomenon was
first described by McCulloch & Dusser de Barenne in
'935 C'39) with reference to electrical postdis-
charges in animals anesthetized with diallyl bar-
bituric acid. Walker & Johnson (192), studying the
same phenomenon, showed that in the normal
monkey localized postdischarges stop abruptly,
whereas in the monkey with an experimental epilepto-
genic lesion they are transmitted froin one cortical
region to another and continue for several minutes.
McCulloch (138) reinvestigated the question, with
seizures provoked by chlorophenothane (DDT) and
other poisons and particularly in a case of status
epilepticus in a monkey with an experimental frontal
epileptogenic lesion. He describes how the epileptic
discharge would appear at one point on the cortex,
disappear and suddenly reappear at an unforeseen
spot, like a 'jack-in-the-box'. Gastaut & Roger (78)
studied multiple and successive cortical seizures fol-
lowing stimulation of the amygdaloid nucleus. They
showed that these 'surprise' discharges do not really
arise independently in different parts of the cortex,
but that they represent one and the same discharge
transmitted from a certain point on the cortex to
allied subcortical structures and from there to other
cortical regions. It was only in 1953 that Gastaut et al.
(75, 76) demonstrated in man the existence of multi-
ple cortical discharges probably corresponding to this
same mechanism of 'erratic' propagation. Since
then, the Marseilles workers have constantly empha-
sized that these erratic discharges are frequent and
especially significant in so-called 'psychomotor'
epilepsy.
Anatomical Studies
Patients with partial epilepsy usually harbor con-
spicuous organic cerebral lesions, in contrast to those
cases in which the seizure is generalized from the
start. In cases of partial epilepsy with a single somato-
motor or sensory symptom related to the pre- or post-
rolandic, occipital or superior temporal regions, a
lesion in that particular area is usually demonstrable
anatomically as well as electrographically. The most
frequent lesion is a cicatrix or atrophy, and much more
rarely a neoplasm. The lesion is usually superficial
and involves only the cortex locally (a corticomenin-
geal scar or localized cortical atrophy), but some-
times it goes deeper and is not seen on inspection of
the exterior of the brain.
In polysymptomatic partial epilepsy, however, with
the sensory, mental and motor manifestations of
psychomotor epilepsy, true focal lesions are usually
not seen. The lesions on the contrary are remarkably
diffuse in these patients. The most frequent lesion is
corticosubcortical atrophy with more or less well-
354
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
marked neuronal degeneration or necrosis, associated
with reactional gliosis. The cerebral atrophy may in-
volve the whole of one hemisphere and sometimes also
the contralateral cerebellar hemisphere, but it gen-
erally predominates in the temporal lobe and may in-
volve it alone. The lesion is maximal in most cases in
the internal aspect of the temporal lol)e and the in-
ferior surface of the frontal lobe in the region which
comprises the anterior part of the hippocampal gy-
rus— including the uncus and amygdala — Ammon's
horn, the temporal tip, the insula and its opercula, the
anterior perforated space and the posterior part of the
orbital convolutions. This is a region which is fur-
rowed from front to back by the rhinal fissure lined
by the endorhinal fissure, and which Gastaut pro-
posed to name the ' pararhinal region' for this has the
advantage of connoting the allopcriallocortical (rhin-
encephalic) nature of the parts inxoKed.
Phruiipatliogenesis of Partial Epilepsies
ORIGIN ."KND CAUSE OF NEURON.AL DISCHARGE IN PARTI.\L
EPILEPSY. The discharge in the partial epilepsies gen-
erally starts in the immediate neighborhood of the
epileptogenic lesion where the neurons show hyper-
excitability, as demonstrated by Walker & Johnson
(192). These workers found that around an alumi-
num-produced scar weaker electric stimulation pro-
duced a postdischarge, or smaller doses of pen-
is lenetetrazol were recjuired to evoke local spikes.
In certain cases, however, the discharge begins at a
distance from the epileptogenic lesions, either in al-
lied structures or even in structures which are entirely
independent. We have already seen that an experi-
mental epileptogenic lesion in the right amygdala in
a cat can cause ictal discharges in the left amygdala,
and in man a right-sided temporal epileptogenic
lesion. This is seen in the experiments of Walker &
or left temporal or in the occipital regions. These facts,
emphasized by the Marseilles school, may be ex-
plained by the conception that neuronal excitability
is heightened at a distance from the epileptogenic
lesion. This is seen in the experiments of Walker &
Johnson (192) and of KopelofTc^ al. (127) who demon-
strated a lowered convulsant threshold in cortical or
allied subcortical structures, and even in the whole
jjrain in animals with an epileptogenic scar.
It is a very important conception that neuronal
excitability may be intensified remotely from the
epileptogenic lesion in structures anatomically allied
to the lesion but not themselves showing anv organic
alteration. The degree of excitability may indeed be
so high that, under the influence of an afferent volley,
the allied structure may discharge as well as, if not
more intensely than, the epileptogenic focus itself
(61). One concludes therefore (53-55, 57) that, al-
though the existence of a sporadic spike or a rh\ thmic
discharge in an EEG or a corticogram constitutes
the most reliable proof of a local epileptic process, it
in no way guarantees that the epileptogenic lesion is
seated in the same place. Working on this general
principle, Gastaut & Roger (78) demonstrated the
following facts.
o) The epileptogenic lesion may or may not coin-
cide with a given EEG focus; it may even be a long
way off. Gastaut (82) showed that a large number of
occipital seizure discharges appear in patients with
an anterior temporalpararhinal lesion, while Segundo
et al. (175) observed true electric occipital seizures in
the monkey following postdischarges induced in the
amygdala.
h) The existence of an EEG spike focus is always
a valuable criterion for localization in partial epilepsy,
but only as a physiological argument in relation to the
clinical facts; it never permits one to incriminate a
lesion of the underlying cortex directly and with
certainty.
c) A spike focus in the electrocorticogram is always
a useful finding for the neurosurgeon, allowing him to
judge where the primary epileptogenic focus probably
lies on the basis of anatomophysiological reasoning. It
ne\'er unfailingly indicates the territory to be resected
nor its lioundaries; the surgeon has to remove the
lesion or the structure insolved and not just the spike-
ijearing area.
(/) The existence of several, concomitant or inde-
pendent spike foci does not necessarily signify a cor-
responding number of lesions. Also, the existence of a
focus of bilateral and symmetrical spikes, concomitant
or independent, does not necessarily signify a bi-
lateral lesion.
<") The persistence of a spike focus after ablation of
an epileptogenic focus does not necessarily mean that
the whole or a part of the lesion persists nor that a new
lesion has been created by the operation; it may be
that the local perilesional hyperexcitability persists or
is enhanced for a shorter or longer time. In the same
wav, the persistence or appearance of a contralateral
spike focus after ablation of an apparently unilateral
lesion does not necessarily imply that a previously
unobserved contralateral lesion exists; it may be a
matter again of local hyperexcitability which is trans-
THE PHYSIOPATHOLOGV OF EPILEPTIC SEIZURES
355
milted to the other side. This was reproduced experi-
mentally by Gastaut et al. (84). The\ provoked bi-
lateral and symmetrical spike foci with a one-sided
lesion resulting from aluminum scarring and then ob-
served that the contralateral focus persisted after
ablation of the single lesion.
This instability and variability of the epileptic dis-
charge is seen even in patients who only show peri-
lesional discharges. These discharges originate at
some point on the periphery of the lesion; when the
lesion is extensive and surrounded Ijy a large ' halo'
of neuronal hyperexcitaljility, the discharges may
arise in different seizures at places far removed from
each other. This was recorded experimentally by
Roger (167) in whose experience the seizure dis-
charges around a single ijut extensive lesion involv-
ing most of the amygdaloid nucleus sometimes began
in the hippocampus and sometimes in the ento-
peduncular nucleus or the anterior amygdaloid zone
or the lateral amygdaloid nucleus. Pathological hyper-
excitability maintained around and at a distance from
epileptogenic lesions thus plays an essential part in the
development of the seizures of partial epilepsy.
Of equivalent or greater importance is the part
played by the innate hyperexcitability of certain
regions which show a low convulsant threshold and
a striking epileptogenic predisposition. The various
authors who have studied these local difTerences in
the convulsant thresholds have come to the following
conclusions. The hippocampus has the lowest thresh-
old of excitability of all the cerebral structures so far
explored (11, 25, 31, 86, 94, 119-121, 142). The
motor cortex has the next lowest threshold (168), es-
pecially in the region corresponding to motor repre-
sentation of the face and hand (50). In order of de-
creasing e.xcitability there follows the cingular region,
the tip of the temporal lobe and the uncinate region
with the underlying amygdala, the first temporal con-
volution and, finally, the parietal region. The frontal
region and particularly the occipital region have the
highest epileptogenic threshold. It is hardly neces-
sary to stress the importance of these findings which
explain why the majority of partial epilepsies have a
somatomotor or tempororhinencephalic symptoma-
tology and why focal frontal or occipital epilepsies are
so rare.
Spontaneous regional hyperexcitability and hyper-
excitability developing around and remote from a
cerebral lesion thus play a fundamental part in the
development of seizures of partial epilepsy. It is
similar to the part played by general neuronal hyper-
excitaljility in the development of generalized seizures,
and which we have already termed a 'predisposing
role'."
The precipitating factor is also the same in the
partial as in generalized epilepsies. This factor is a
volley of afferent stimuli which, although without
pathological effect under normal conditions, can pro-
voke paroxysmal hypersynchrony when local hyper-
excitability is present. The precipitating role of
afferent stimuli was physiologically demonstrated
once (and perhaps for all) by the remarkable experi-
ments of Clementi (28), in which strychninization of
the visual cortex is in no way detectable until \isual
stimulation is applied, whereupon it provokes myo-
clonic movements of the eyelids and sometimes even
a generalized convulsive seizure. The experiments of
Amantea (8) exemplify the same principle, showing
that strychninization of the somatomotor area, is in-
sufficient to produce strychnine clonus yet precipi-
tates Jacksonian or even generalized seizures when
the appropriate reflexogenic cutaneous territory is
stimulated. It is indeed hardly necessary to remind
clinicians of the numerous cases of parietal, temporal,
amygdaloid or hippocampal partial epilepsy precipi-
tated by an unexpected movement (7), a noise (13,
74), music (33, 97), rapid ingestion of a large quantity
of water (20) or an emotion (62, i 78).'-
In most cases, however, the fact that afferent
stimuli precipitate a seizure is not clinically apparent
because local hyperexcitability increases at the ap-
proach of an attack and is finally so marked that any
volley of nervous impulses resulting from an insignifi-
cant stimulus is sufficient to fire off a paro.xysm.
PROPAGATION AND TERMINATION OF NEURONAL DIS-
CHARGE IN PARTIAL EPILEPSY. We have already seen
that a localized discharge may extend locally or be
propagated concomitantly or successively to various
" An epileptogenic lesion may obviously develop in a patient
with a predisposition for epilepsy expressed as generalized
neuronal hypere.\citability, either constitutional or acquired.
The two factors are then added together. For this reason a ce-
rebral lesion will frequently provoke seizures of partial epilepsy
in one subject and not in another. For the same reason, Lennox
found a degree of familial predisposition in the parents of
symptomatic epileptics, because partial epilepsy dc\"elops
particularly in those who are already so predisposed.
'- Conversely the continuous physiological bombardment of
the discharging region may entail its desynchronization and
abort a seizure; that is the reason why certain epileptics abort
their somatomotor or psychomotor fits by forcible extension of
the limb in which the jerks first appear or by concentrating
their attention fixedly on an idea or a perception.
356
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
allied structures or even to the whole brain. Numerous
authors have studied propagation of epileptic activity
and we may summarize their work as follows, a) Local
propagation of the discharge proceeds very slowly
like a ' drop of oil' through the filjrillary network of
grev matter. This explains the Jacksonian ' march'
so characteristic of seizures provoked by the discharge
of structures somatotopically arranged (for example
the jerks which extend from the face to the hand
while the cortical discharge travels from one repre-
sentative part of the cortex to the next adjacent
part). 6) Remote propagation takes place very
rapidly along fibers of large diameter. This explains
the almost immediate bringing into play of the whole
group of structures of a corticosubcortical ' sector' and
the stereotyped symptomatology during one or subse-
quent seizures when the discharge remains localized
to such a sector. On the contrary, when propagation
takes place to various '.sectors' successively, a variety
of disturbances appear during the course of one or
subsequent seizures.
The discharge in partial epilepsy is propagated by
means of normally functioning nerve fibers and
synapses from an epileptogenic center which is
anatomically altered to allied centers which are
anatomically healthy. This implies that the discharge
originates as a lesional (or more likely perilesional)
phenomenon but that its propagation is an exclusively
functional phenomenon. Moruzzi says: " It is ordinary
nervous activity which determines that allied neurones
pass from a state of normal activity to one of epileptic
functioning."
Although involving only normal functions, this
mode of propagation is nonetheless pathological since
it does not exist in the normal subject. Indeed, the
following two conditions are necessary for its produc-
tion, a) Hyperexcitaijility of the neuronal population
allied to the epileptic center, explaining the sensi-
tivitv \\ hich it acquires under epileptogenic iiombard-
ment. VVe have already shown that this is always the
case in generalized epilepsy; and according to John-
son & Walker (114): "Not only the primary focus is
hypersensitive, but this hypersensitivity is found in
the other cortical and subcortical structures with
which it is intimately connected. This hypersensitivity
manifests itself by a lowered threshold for electrical
and chemical stimulation and seems to result from
functional disturbance at the level of the normal
neurons, as a result of the influence of the epilepto-
genic focus."
fe) The epileptic discharge cannot be propagated
unless the bombardment from the epileptogenic cen-
ter is efficacious. For this, it requires the following
properties: the bonii)ardment discharges must be of
high frequency (1,000 cps); these discharges must
activate a sufficient number of terminals on the same
cells in order to pro\oke spatial summation; these dis-
charges must be rhythmically spaced so as to use the
facilitation of supranormality provoked in each neuron
by the previous discharge and thus to produce tem-
poral summation; and the bombardment must con-
tinue long enough to produce a progressive effect.
Although hypcrexcitability of allied centers is al-
ways required, all the conditions necessary to make
bombardment effective are not necessarily present at
one time. Certain ones, indeed, depend on the func-
tional or anatomical characteristics of the bombarded
or bombarding centers and of the pathways which
unite them. The phenomena of spatial summation,
for example, depend exclusively on the number of
fibers transmitting the bombardment and on their
mode of terminating on allied neurons. All of these
conditions vary from one system to another and make
certain epileptic propagations easier than others.
A center allied to an epileptogenic focus reacts
differently, according to its degree of excitability and
according to the efficacy of bombardment, a) It
may remain indifferent, b) Its spontaneous activity
may simply i)e increased, r) It may respond stroke for
stroke to the fjombarding discharges as they arrive;
thus true evoked potentials are produced in answer to
the convulsive waves of the primary focus, with a
latency corresponding to the propagation along axons
and across synapses. Under these conditions the allied
center can be said to have become epileptic because
of the primary focus, d) The allied center may become
epileptic on its own account, that is, it may dissociate
itself from the epileptogenic focus and show secondary
autonomous convulsive activity. This may persist
after the end of the primary discharge and be propa-
gated to allied structures as a tertiary discharge (so-
called ' erratic' discharge).
A ' center' secondarily made epileptic by bombard-
ment from a primary epileptogenic focus thus modifies
the seizure according to its own anatomical and func-
tional characteristics. One of two things usually fol-
lows; either the seizure remains partial but is en-
riched by electroclinical symptoms consequent upon
the new discharge and this discharge may lead to
another, or the fit becomes generalized.
In the first case a seizure may begin with focal
clinical and electroencephalographic signs and pass
through a series of equally focal episodes. Many psy-
chomotor attacks have this pattern, notably those in
THE PHYSIOPATHOLOGY OF EPILEPTIC SEIZURES
357
which an occipital EEG discharge accompanying a
visual episode follows or precedes a temporal dis-
charge with aphasia (60, 76).
The second eventuality explains the fact that any
partial seizure may become generalized. Generaliza-
tion takes place more readily when the partial seizure
is more intense, when it occupies a ree;ion closely con-
nected to the centrencephalic reticular formation,
and when the patient has an epileptic predisposition
or, in other words, generalized neuronal hyperexcita-
bilitx'. When all these conditions are present, the
partial seizure becomes generalized almost immedi-
ately, and the localizing signs at the onset may pass
unobserved. One must therefore always question the
patient and eye witnesses closely on the mode of onset
of ' generalized' seizures, and carry out an EEG exam-
ination, even when the diagnosis .seems indisputable,
for a large number of seizures apparentK generalized
from the start are found to be partial epilepsy second-
arily generalized.
The evolution of partial discharges originating on
the spot (primary discharges) depends upon the same
factors of fatigue as in generalized discharges and
perhaps also on the same phenomena of rhythmical
inhibition. For this reason their EEG arrangement is
usually the same as in generalized discharges. Rhyth-
mic activity is first sustained in the saine way at the
initial frequency (indefatigability), then slowed pro-
gressively (growing fatigability), and finalK' inter-
rupted by episodes of silence or slow waves which
grow progressively longer (phase of exhaustion or in-
hibition), until at the end there is silence (phase of
postictal extinction).
On the other hand, partial discharges remote from
the epileptogenic lesion develop completely differ-
ently, in a way which defies all classification because
of seizure variability. These discharges are char-
acterized by slow sinusoidal or notched waves, or by
polyphasic spikes with an initial positive phase, and
they are notable for their long duration and their in-
stability. At one moment a discharge may be rhyth-
mical and of large amplitude and at the next it has
lost these features. The discharge may be slowed or
accelerated indifferently and sometimes even pass
through two or three successive phases of speeding up
and slowing down. Finally, there may or may not be
postictal extinction, and in some cases the record be-
comes normal again immediately after the discharge
has ended.
DISTINCTION BETWEEN TWO GREAT V.^RIETIES OF PAR-
TIAL EPILEPSY WITH RESPECT TO CHARACTER OF THEIR
DiscH.\RGES. The \arious partial epilepsies have often
been classified according to the structures in which the
seizure develops, or at least in which it originates.
Such a conception obviously presupposes that the dis-
charge always originates in the same place, that it is
always propagated along the same pathways and that
it always provokes the same electroclinical signs. It
also presuppo.ses that the first symptom, the 'signal-
symptom' or 'aura' is the same every time, points in-
fallibly to the site of the lesion and guides the hand of
the neurosurgeon.
Such rules, however, apply only to a small minority
of the partial epilepsies, namely those provoked by a
very limited irritative lesion whose discharge involves
a closed neuronal system. In the majority of cases,
however, these rules are only partially applicable, par-
ticularly when the epileptogenic lesion is extensive
and when the discharge dev'elops in complex neuronal
systems where it is propagated irregularly and differ-
ently in various seizures and accordingly provokes
complex and variable symptoms. In such ca.ses, the
'signal-symptom' is clearly less valuable (54, 76, 79),
for it may reveal a discharge propagated from a
clinically silent structure and it may \ary from one
seizure to another according to the origin and propa-
gation of the discharge.
Two varieties of partial epilepsy are distinguished
in the Marseille school (59), according to propagation
of the discharge to different anatomical systems.
a) In the first variety, the causal discharge orig-
inates in a structure essentially, if not exclusively,
connected to one single other structure. Together
they constitute a limited functional system, the two
' poles' (these two structures) being united by dense
fibers. In this system, the discharge extends from one
pole to the other but always stays limited within the
system, for although other fibers unite each pole to
other nervous formations, they are never grouped
sufficiently densely to cause effective bombardment
and to render these other formations epileptic. The
most notable examples of these ' bipolar' systems in the
brain are the corticothalamic sectors connecting the
various specific areas of the cortex to the correspond-
ing specific thalamic nuclei (54).
The EEG manifestations consist exclusively of dis-
charges limited to the sector concerned and, in con-
sequence, are recorded from a very localized region
of the scalp. The interseizure discharges consist of
sporadic spikes or spikes-and-waves which, in current
EEG usage, reveal an 'epileptogenic focus'; the
seizure discharges are spikes repeated rhythmically
358
HANDBOOK OF PHYSIOLOGY ^^ NEUROPHYSIOLOGY I
and slowing; progressively, which constitute a ' partial
seizure discharge expressed focally'.
It is evident that such a focus or discharge does not
guarantee that the epileptogenic lesion is cortical, for
it may just as well be at the subcortical pole of the
system and nevertheless be expressed in the cerebral
cortex. The clinical manifestations of the seizures de-
pend upon the corticothalamic sector involved, ap-
pearing as clonic jerks when the sector of precentral
cortex :^ ventrolateral nucleus is involved; dysesthesia
for the sector of postcentral cortex ^ nucleus ven-
tralis posterolateralis; visual phenomena for the
striate region ^ lateral geniculate; and auditory
phenomena for the superior temporal ;=i medial
geniculate. '^
The discharges are not necessarily generalized
throughout the whole of the corticothalamic sector.
Some part only may be involved, for example, the
Jacksonian twitching may affect only the face. Simi-
larly, several adjacent sectors may be involved con-
comitantly or successively; for example, the Jack-
sonian jerking may accompany or be followed by
dysesthesia in the corresponding part of the body.
i) In the second variety of partial epilepsy, the
causal discharge originates in a nervous structure
which is more or less diffusely connected with several
other cerebral regions, constituting a multiple relay
system. These systems are too numerous and at
present too ill-defined to be described fully. In addi-
tion they are interconnected and a given cerebral
structure may belong to several of them. We can how-
ever distinguish two great rhinencephalic systems:
the hippocampus connected on the one hand to the
limbic lobe and on the other hand to the hypothala-
mus and tegmentum; and the basal rhinencephalic
formations (piriformoamygdaloid and olfactoseptal)
connected on the one hand to the orbitoinsulotele-
temporal cortex, and on the other to the epithalamus,
hypothalamus and tegmentum mesencephali. There
is also the most rostral part of the reticular formation
of the brain stem which projects diffusely from the
thalamus on to the whole of the cerebral cortex and
which was previously discussed. This last system may
be activated globally by way of the reticular afferents,
as in generalized epilepsy, but it may often be
brought into play in a fragmentary way in the partial
epilepsies.'*
" These seizures most commonly de\ elop in the precentral
cortex ;=i n. ventrolateral nucleus sector, not because it more
often contains the epileptogenic lesion but because it has the low-
est convulsant threshold.
" These diffuse systems are often activated in the partial
The clinical manifestations are complex because
they involve simultaneously or successively a large
number of structures with different functions. Sen-
sory, mental or motor symptoms may be associated
or succeed each other and Gowers (92) has described
cases in which a dozen visual, auditory, olfactory, il-
lusional, hallucinatory and motor symptoms follow
each other without interruption.
Vegetative and affective manifestations are particu-
larly important since the discharges usually involve
the rhinencephalon and diencephalon. These fre-
quently include abnormal epigastric, abdominal and
precordial sensations with reactional gestures: chew-
ing, salivation, deglutition, and imperious needs to
eat, urinate or defecate, as well as disorders of atten-
tion, anxiety, fear, anger, etc.
There usually is clouded consciousness and the ap-
pearance of more or less complex automatisms, since
these discharges disturb the functioning of a large
part of the brain and usually involve some of the
diffuse cortical projection system which helps to regu-
late cerebral excitability and consciousness.
The electroencephalographic manifestations take
the form of seizure discharges which may be classified
as follows a) Localized discharges appearing as spike
rhythms in the temporal region (with anterior tem-
poral and middle temporal electrodes) or in the occip-
ital region (with occipital, posterior temporal and
posterior parietal electrodes), according to whether
the discharge develops in the amygdalotemporal
system or the pulvinaro-occipitoparietotemporal
sector.
These localized seizure discharges are usually situ-
ated on the same side as the interseizure focus and its
causal lesions, but fairly frequently they are situated
on the opposite side (82). Such independent contra-
lateral discharges may indicate a secondary vascular
extension of the lesion to the other side (6g) but may
also indicate a functional ' vmleashing' of these homolo-
gous contralateral structures which have acquired
epileptogenic potentialitv through being bombarded
(78).
fe) Diffuse discharges, constituted by a rhythm of
waves gradually slowing or accelerating, more or less
generalized over one or both hemispheres but often
epilepsies through the rhinencephalic formations for two reasons:
a) the latter, chiefly the hippocampus and amygdala, aie
frequently the seat of epileptogenic lesions (pararhinal sclerosis
in the so-called temporal' epilepsies); and 6) these rhinenceph-
alic formations have the lowest convulsant threshold of all
cerebral structures Csee above).
THE PHYSIOPATHOLOGY OF EPILEPTIC SEIZURES
359
predominant in the frontotemporal region. This oc-
curs when the discharges develop in the diffuse
thalamocortical system.
f) Complex discharges, in which localized and
diffuse discharges are associated, either independently
or concomitantly, and if the latter, either in or out of
phase. This occurs when various cortical-subcortical
systems are brought into play simultaneously or suc-
cessively causing " erratic' discharges.
cf) Localized or generalized flattening of the basic
rhythm occurs when the structure involved in the
seizure is endowed with the property of desyn-
chronizing the cortical electrical activity.
e) There may be no EEG manifestation of a seizure
at all when the discharge invokes subcortical struc-
tures with very poor cortical projection or when it is
unable to cross the synapses leading to the cortex.
The interseizure discharges may be more or less
diffuse for the same reason as the seizure discharges,
but they are most often localized to the temporal
region (and particularly the anterior temporal) or one
or both hemispheres. This particular site is the most
common, as Gibbs has well shown, because these in-
terictal discharges usually originate in the diseased
cerebral structures with the lowest convulsant thresh-
old, that is to say, the tip of the temporal lobe and the
basal rhinencephalic formations (piriform cortex,
amygdala and hippocampus) which also project on
to the teletemporal region (72, 121; and later authors).
Having described these two great varieties of partial
epilepsy on the basis of pathological physiology, we
shall further describe them in terms of anatomy,
etiology, symptomatology and therapy.
a) The localized partial epilepsies not only show a
local discharge but are usually caused by a localized
superficial lesion, either atrophic or neoplastic. The
causes are not numerous and include open head in-
juries with well-defined craniocerebral wounds, lo-
calized infections, chiefly periarterial or perivenous,
local vascular accidents (malformations or throm-
bcses) and small cortical or paracortical tumors. These
lesions are discrete and, because they interfere with
the normal functioning of only a small amount of
cerebral parenchyma, the patient's mental make-up
is usually normal between seizures, especially from
the intellectual point of view. The lesion is usually
cortical for the superficial pole of the corticothalamic
sector is a much larger area and is more vulnerable
than is its deep pole. Since the lesion involves the
convexity of the cortex and spares the rhinencephalon
and diencephalon, there is usually no disturbance of
character or behavior between seizures. On the other
hand, interictal neurological symptoms are relatively
frequent (mild hemiplegia, dysphasia or hemianop-
sia) for the lesion involves a corticothalamic sector
with specific functions. Surgery may often be indicated
when medical treatment fails in this type of partial
epilepsy because of the precise and superficial locali-
zation of the lesion and because of its small size. The
operation usually is easily performed and yields excel-
lent results.
6) The diffuse partial epilepsies not only have a
diffuse discharge but arise from diffuse sclerosis, pre-
dominating in the inferomedial aspect of the hemi-
sphere, the 'pararhinal' region. The causes are
numerous and varied ijut may be divided into three
main groups, depending on the age at which the
lesion is acquired: severe and prolonged compression
of the head during delivery (156); cerebral edema in
infancy or early childhood which accompanies various
disorders clinically misnamed 'encephalitis', consist-
ing of status epilepticus with coma and subsequent
transient hemiplegia (57, 58); and closed head in-
juries in the adult (64). The principal pathogenic
mechanisms in these three conditions are wedging of
the hippocampal gyrus and the blood vessels supply-
ing it into the tentorial incisure during compression of
the brain at birth, or during intracranial hypertension
secondary to cerebral edema in childhood, and in-
jury of the orbitoinsulotemporal region by the sharp
edge of the lesser wing of the sphenoid from the contre-
coup accompanying closed head injuries. These two
mechanisms are responsible for the two aspects of
pararhinal sclerosis, incisural sclerosis (156), and
vallecular (perifalciform) sclerosis (53, 57) which
develops in relation to the tentorial incisure and
around the vallecula sylvii in the region correspond-
ing to the pararhinal region.
Because the lesions responsible for psychomotor
epilepsy are so widespread and so severe and are lo-
cated in the pararhinal region, these patients fre-
quently show interseizin-e disturbances of intellect
and particularly of character and of sexual, alimen-
tary and social behavior (62).'-^
On the other hand, these diffuse and deep lesions
do not involve the majority of the corticothalamic
sectors and the important projection pathways which
explains the fact that interseizure neurological mani-
'° The basal part of the rhinencephalon acts as a controlling
and regulating system of complex automatic activities, princi-
pally those adapted to the seeking of the opposite sex and
to the pursuit, intake and ingestion of food (56). See the chap-
ters in this work dealing with this region.
360
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
festations are rare. Finally, since the pararhinal region
is so deeply situated, surgery is difficult and only ex-
ceptionally indicated, for it requires systematic an-
terior temporal lobectomy (Penfield) extended to
the uncus, amygdala and hippocampus, or selective
amygdalohippocampectomy (Niemeyer).
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CHAPTER XV
Sensory mechanisms — introduction
LORD E. D. ADRIAN | Trinity College, Cambridge, England
THE ESSENTIAL ELEMENTS of the sense oigaiis are the
receptor cells which respond to physical and chem-
ical disturbance and transmit information about it
to the central nervous system. Naturally in these days
they are fascinating material for the cell physiologist.
The electron microscope gives him new data about
their structure, and there are new biophysical and
biochemical techniques for investigating their re-
actions. If all goes well, our understanding of the
changes which take place in the receptors will soon
have reached the molecular level.
The sense organs also provide ample material for
the electrophysiologist who deals with them as con-
stituent elements of the nervous system. The technique
of recording nervous activity has reached great pre-
cision and the flow of information can be studied in
the cell units and pathways of the central nervous
system as well as in the peripheral nerves. In the ani-
mal kingdom there is still a vast range of receptor
apparatus awaiting investigation and even in the
vertebrate there is still a good deal of exploration to
be done, particularly about the receptors which signal
internal rather than external events.
Another line of research leads beyond the receptors
and their afferent connections, for the physiology of
the sense organs must include the study of their func-
tion as well as of the properties which make them
react to the stimulus. Some of them, pain receptors
for instance, may be no more than warning devices
which signal whenever their environment sets them
in action, but many are used actively to explore the
environment and such use involves movement directed
by the central nervous system. We look with our eyes,
feel with our fingers and sniff to identify a smell.
Aclivit}- directed by the central nervous s\stem may
also be needed to protect the sense organ when the
stimulus is too strong. We may have to constrict our
pupils and shade our eyes, or cover our ears or hold
our ijreath. Since the receptors will give most informa-
tion when the stimulus falls within a particular range
of intensity, we have to study the different adjust-
ments \vhich keep it within that range.
The analysis of this kind of central control has been
carried out most fully for the receptors which signal
muscular contraction. The muscle spindle is a sense
organ excellently adapted for investigations of this
kind, for in it the signaling and adjusting mechanisms
are coupled together in a single structure and its
function is to guide the relatively simple operations
involved in posture and limb movement. Recent in-
formation on the efferent innervation of the spindle
has given us a much clearer picture in which it ap-
pears as an active participant in the feed-back mech-
anism which ensures smooth movement against a
continuous postural background.
The action involved in adjusting the stimulus to
the sense organ can vary greatly in .scale and com-
plexity, from a simple reflex contraction to an elab-
orate sequence of skilled movement, as when the
microscopist places the slide in position, focuses first
with the coarse adjustment and then with the fine
and makes appropriate use of his ocular muscles, ex-
ternal or internal. In such operations the adjustment
is carried out by muscles in the organ or elsewhere.
But in addition we may have to consider a more
direct central adjustment which does not operate
throuQjh the muscular link but by efferent nerve fibers
leading directly to the receptors or to some part of
the pathway from them to the central nervous system.
At present we know that there are efferent fibers to
the retina and the olfactory bulb. There are indica-
tions of a control of this kind in the cochlea also and.
365
366
HANDBOOK OF PHYSIOLOOV
NEUROPHYSIOLOGY I
although we do not know ilK-ir hinction, \vc know that
there are other nerve fibers which reach the peripheral
receptors but are not directly connected with the
receptor elements.
All the actions which focus the sense organs on the
stimulus will evoke afferent signals of their own to be
related to the signals from the organ itself. Thus the
full report which comes to the central nervous svstem
will be far more complex and informative than any-
thing which could be furnished by any sense organ
isolated from the body and controlled only by the
electrophysiologist.
Our primary concern, to be sure, is with the recep-
tors and their reaction to the stimulus. How and to
what purpose their reaction can be influenced by the
central nervous system opens up a different chapter
more concerned with the central than the peripheral
mechanism. But the receptors are there to decide the
line of behavior which the organism should follow;
they have to supply all the relevant information as to
what is happening from moment to moment, and from
this the central nervous svstem selects the items of
particular importance. It is essential, therefore, to
consider the sense organs not onlv as groups of recep-
tors e.xcited by particular physical or chemical events,
but as organs capable of presenting a detailed report
which will enable the event to be compared with
others of the saine class which have occurred before.
The description must ije as full as possible, yet it has
all to be conveyed l:)y trains of impulses in nerve fibers.
Though we can record the impulses there are still a
good many problems to l)e settled before we can reach
a clear understanding of how the full description of
the stimulus is handed on to the brain.
The eye, for instance, can inform us that there are
patches of light on the retina of particular shape, in-
tensity and color. We suppose that the shape is sig-
naled by the distribution of the nerve fibers which
consey the signals and the intensitv by the number of
impulses arri\ing at a particular region of the nervous
system within a given time. Thomas Young suggested
in 1807 that the color may be signaled by particular
nervous elements sensitive to particular regions of
the spectrum, but in spite of the many fresh data
which recent work has given us, we have still to reach
agreement as to the way in which the information of
color is combined with that of intensity and area.
Again we are aware that the olfactory organ enables
us to distinguish an immense variety of odors. We
know that the temporal and spatial pattern of ex-
citation in the organ mav varv with the smell and
that some of the receptors vary considerably in their
sensitivitN to different kinds of odor. It seems probable
that these different sources of information can be com-
bined to give the full range of discrimination, but
it is not yet clear how the combination is achieved.
The receptors in the skin and in the tissues beneath
can give a great deal of information about the nature
of the object in contact with it and active exploratory
movements help us to judge shape, size, hardness, etc.
But even a light contact on a passive surface will
produce a discharge of impulses in a variety of afferent
fibers of different diameter and rate of conduction
coming from receptor organs of different structure.
Zottcrman's studies of the temperature receptors
have shown that these at least form a group with a
characteristic structure and behavior. With the
receptors for touch, pressure and pain, however, .we
are still ignorant of the role of different types of axon
and ending in producing sensation which can vary so
much in c|uality and in the attention and action which
it will arouse.
With all this to occupy us at the periphery we need
not be in too great a hurry to follow the sensory dis-
charge into the central nervous system where it will
be far less easy to analyze. But there is one problem
which deserves mention at the present time because
we may be already on the way to its solution, or at all
events to its investigation. It is the problem of access
to the higher levels of the brain. The sense organs
provide a running commentary on a great varietv
of environmental circumstances, but the organism
has to select the particular reports which have an
important bearing on its present and future behavior.
The classical method of investigating the sense organs
by comparing stimulus and sensation can throw no
light on this selectixe treatment, for the subject has
to fix all his attention on the one stimulus. He must
look for a feeble illinnination or a slight change of
color or listen for a faint click or a just detectable
change of pitch. When he lectures to a class, however,
such stimuli may ha\e no effect at all on his sensory
experiences or on his course of action. Indeed this
method of research, though it can tell us the effect of
a particular sense organ on the attentive mind, cannot
be expected to tell us how the other sense organs can
be prevented from reaching it.
This problem of attention is not likely to be settled
finally until we know far more about the processes
involved in habit formation, in the factors which
attach importance to particular stimuli and in those
which balance conflicting claims from moment to
SENSORY MECHANISMS INTRODUCTION
367
moment. Clearly we attend to stimuli which are un-
expected or are intense in themselves or likely to
give rise to a chain of activity by reason of past
association, but the afiferent nerxous discharges must
be studied at all levels before we can say where and
why some fail and some reach through to conscious-
ness. Fortunately the investigation of the reticular
formation has given a new impetus to the studv of
attention. With modern techniques the afferent signals
can be traced in their passage through the intact
brain and we can e.xpect that soon there will be fresh
data bearing on this penultimate problem of the
sense organs. The ultimate problem of their effect on
the mind is scarcely one for the physiologist to settle.
CHAPTER XVI
Nonphotic receptors in lower forms
H A N S J O C H E M A U T R U M | Department oj ^oology, University of Miinchen, Germany
C: H A P T E R CONTENTS
Protozoa : Differentiation of Protoplasmic Irritability
Coelenterates : Cnidoblasts as Independent Effectors
Higher Invertebrates: Emergence of True Receptors
Anatomical Peculiarities
Comparison of ttie Senses of the Invertebrates with Those of
Vertebrates
Reactions of Simple Receptors
Specific Types of Receptors
Chemoceptors
Proprioceptors
Thermoreceptors
Mechanoreceptors : tactile sense
Mechanoreceptors : vibration sense
Mechanoreceptors : hearing
Statocysts
protozoa: differentiation of
protoplasmic irritability
PROTOZOA REACT TO STIMULI: heat, cold, chemical and
mechanical irritation, gravity, and light influence
their behavior. These stimuli therefore affect the pro-
tozoan cells. However, it is a significant morphologi-
cal and physiological problem whether sensitivity to
these stimuli is limited to certain parts of the proto-
zoan cell, or whether the whole organism can be
stimulated. Only if the former is true can we speak of
receptors.
The bodv protoplasm and its surface is not much
differentiated in the simpler protozoa, such as the
amebae. There is therefore no reason to look for
localized receptors. It appears, however, that the
protoplasm of the ameba is not irritable under certain
physiological conditions. The ameba does not react if
a narrow light beam strikes the hyalin tip of the outer
end of a pseudopodium (80, 82, 83). If the light beam
strikes the endoplasm of a p.seudopodium which is
streaming toward the tip (and is in the sol state), the
streaming of this pseudopodium is stopped and new
pseudopodia are formed in other parts. If the light
beam strikes the plasmasol some distance from the
tip, streaming will be accelerated. Experiments with
ciliates, such as Paramecium, al.so showed the suscepti-
bility of the whole body to stimulation (61, 71, 72).
Thus, separated pieces of cut Paramecium respond to
chemical stimuli, e.g. by 0.5 to i.o per cent NaCl or
0.05 to 0.0 1 per cent H-iSOj, and to temperature
stimuli in the same way as do whole animals. There
is also no difference between cut parts and whole
animals in the response to gravity. This fact is of
special interest since the sensitivity to gravity depends
on the principle of the statocyst (68, 69): hea\ier sub-
stances included in the body exert a pressure on the
underlying protoplasm.' However, there are no fa-
vored locations in the body of Paramecium sensitive to
this pressure; it can be effective in every part and
may produce orientation in relation to the gravita-
tional field.
In contrast to Paramecium, only the anterior part of
the ciliate Sptrostomum ambiguum (which can grow to
4.5 mm in length) is sensitive to thermal and chemical
stimuli according to the view of Alverdes (6) and
Blattner (18). Excised posterior parts swim into dilute
picric acid without reaction (18). However, very di-
lute picric acid attracts Spirosiomum and is less toxic to
it than to other ciliates such as Paramecium and
Stentor. Therefore the findings of Blattner cannot be
' It is not known which inclusion bodies serve as statoliths
causing excitation by the pressure they exert under normal
conditions. Koehler assumes that all inclusion bodies may func-
tion as statoliths. They have to be only heavier than the cyto-
plasm (as for example the nucleus, the content of vacuoles and
iron particles in experiments).
?)^9
370
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
taken necessarily as proof that the posterior part of
Spirostomum is not irritable to chemicals. This form
responds to other chemical and mechanical stimuli in
the anterior and posterior part.
A localized, receptorlike structure has so far been
found in only a few flagellates. Many phytoflagellates
QEuglena and others) possess an eyespot which con-
tains the pigment astaxanthin (135). In Euglena there
is a light sensitive plasma spot located in the con-
cavity of this eyespot. The eyespot itself probably has
a screening function to light (81, 84). There are other
phytoflagellates (e.g. Chlamydomonai) which are sensi-
tive to light throughout the body, even though they
possess an eyespot, as shown by mutants without an
eyespot (52). Therefore the question as to whether
the eyespots are real receptors is still open.
The effector system of the protozoa is very compli-
cated. It is certain that in no case do protozoan cells
react according to the all-or-none principle. The de-
gree of contraction of the pseudopodia of rhizopods
depends on the intensity of stimulation; the stronger
the stimulation the farther the contraction spreads
along the excited p.seudopodium; it will spread to
other parts of the body if the stimulus is sufficiently
strong (127). The contractile stalk of vorticellae can
be completely or partially contracted depending on
the intensity of the stimulation (29, 64). The rhythm
of ciliary movements in some parts of the body of
ciliates can be modified independenth of the activity
of the remaining cilia (65, 89).
COELENTER.JiTES: GNIDQBL.ASTS .■XS
INDEPENDENT EFFECTORS
The cnidoblasts are cells which are characteristic of
the coelenterates (Cnidaria, polyps and medusae). The
intracellular structures of the cnidoblasts are nemato-
cysts which consist of a bubble-like capsule. The free
pole is a long hollow thread which is introverted and
coiled, as shown in figures i and 2. The opening of
the capsule is usually covered by a cap. On discharge
the cap bursts open and the thread is ejected by
eversion. Different types of nematocysts are found in
the same species. Furthermore, they are different in
different species (56, 63, 118, 138).
So far as analysis with ordinary light microscopes
is concerned, nematocysts are the most complicated
structures formed by cells. Some cnidoblasts carry a
fine spine or a cone of fused cilia on the free end, the
cnidocil shown in figure i ; others lack this cnidocil.
Cnidoblasts which are not yet differentiated (inter--
stitial cells) form new nematocysts during their whole
life; the cnidoblasts migrate — sometimes in groups —
into or between ectodermal cells and thus form bat-
teries of nematocysts.
There exists a large number of morphologically
different nematocysts (138), but only a few types
have been analyzed physiologically. They show char-
acteristic differences with respect to irritability and
function.
/) The desmonemes (also called volvents) and
stenoteles (also called penetrants) are used for catch-
ing food. They explode upon simultaneous stimulation
by chemical and mechanical means (such as aquatic
food organisms and meat); the cap bursts open and
the thread is everted within 3 to 5 msec. The thread
of the stenoteles, supported by spines at the base,
penetrates the body of the food organism even through
FIG. I. Scheme of a stenotele nematocyst and its discharge,
a, cnidoblast (ez) with nucleus (n), nematocyst (st), and
cnidocil (en); b, stenotele nematocyst during discharge; c, after
discharge showing cap (i), spine (sp), and ejected thread (th).
The cnidoblast is not drawn in b and c. Magnification, 555 X.
[From Kiihn & Schulze (76).]
FIG. 2. Nematocysts of Hydra (cnidoblasts omitted), a, des-
moneme prior to discharge; b, same after discharge; c and d,
atrichous isorhizas. Magnification. 2200 X. [From Kiihn &
Schulze (76).]
NONPHOTIC RECEPTORS IN LOWER FORMS
371
a well developed cuticle. The distal end of the thread
of the stenoteles is open and by this means the poison
stored in the capsule can be injected through the
thread. The desmonemes on the other hand have a
thread which is closed at its distal end and it winds
only around the spines and other parts of the food
organisms.
2) The atrichous isorhizas (also called small glu-
tinants)^erve Hydra by attaching the tentacles to the
ground during the migration of the polyps.
5) Finally the holotrichous isorhizas are exclusively
a defense mechanism. They e.xplode only upon types
of stimulation which cause no feeding reaction.
The discharge of the nematocysts occurs only upon
direct stimulation; no nervous control exists. No nerve
fibers can be found which lead to the cells containing
nematocysts. With electrical stimulation only the
nematocysts directly stimulated react (88, 90). Even
repeated rhythmic stimulation by means of condensor
discharges never causes a diflfusion of excitation be-
yond the area direc-tly stimulated. Thus the cnido-
blasts contain irritable structures which act both as
receptors and effectors and are independent of a
nervous system.
Direct mechanical stimulation of the nematocysts
on the tentacles of Anemonia or of the penetrants and
volvents of Hydra does not normally lead to a dis-
charge even though the cnidocils present are diverted
(for example by epibiotic protozoa or artificially by
chemically very clean, rounded glass needles). Neither
is discharge obtained by chemical stimulation alone
(such as extracts of meat or food organisms, proteins,
amino acids or sugar). However the threshold for
direct mechanical stimulation is considerably reduced
by chemical stimuli produced by the food. The im-
mediate releasing stimulus is therefore a mechanical
one which however only becomes efTective if the
threshold is lowered in advance by certain substances
present in the food.
The nature of these very specific chemical sub-
stances present in the food organisms is unknown.
They are not proteins but they are firmly adsorbed on
the proteins; they can, however, be extracted with
ethanol or acetone (88).
The atrichous isorhizas serve to attach the tentacles
to the ground during the inigration of the polyps.
They never respond to stimuli arising from food or-
ganisms. Chemical stimuli such as extracts of food
organisms raise the threshold for this type of nemato-
cysts. The duration of mechanical stimulation neces-
sary to bring about discharge is greater for atrichous
isorhizas than for stenoteles. Food inhibits chemically
the discharge of the atrichous isorhizas (36).
In summary, it may be concluded that nematocysts
respond to a mechanical stimulus. A simultaneous
chemical stimulus, by raising or lowering the thresh-
old, determines which kind of mechanical stimulus
will explode the nematocysts. The change of the
threshold insures that the reaction will be appropriate.
The cnidoblast is therefore a unique tissue element.
As an independent effector it contains sensory, excitor
and effector elements. The sensory element is in itself
not simple and functions by means of two distinct
sense organs, mechanical and chemical in nature. The
cnidae may in fact be said to be double sense organs
as well as effectors. There are no obvious analogies
to this in the tissues of higher animals (88).
HIGHER INVERTEBR.-kTES: EMERGENCE
OF TRUE RECEPTORS
Anatomical Peculiarities
The receptor cells of the invertebrates are always
primary sense cells; every sense cell has therefore a
centripetal afferent nerve fiber. This is also the case
in organs which in vertebrates have secondary re-
ceptor cells, for example the static and auditory
organs.
In the simplest case, the sense cells are separate and
are not yet united into an organ. Such scattered sense
cells are found in all classes of invertebrates. They
have the simplest shape in hydroid-polyps and actin-
iae; here they are located in the epithelium and have
the shape of epithelial cells. They appear in the ecto-
derm as well as in the entoderm (fig. 3). They may
be absent in the column ectoderm of the actinians,
even if they are numerous in the ectoderm of the oral
disc (88). Nevertheless, the column is sensitive to
mechanical stimuli from the en\ironment, although
4000 times less so than is the oral disc (91). Such
single sense cells are found in the epithelium of lower
and higher wonns and molluscs, e.g. Lumbricus as
shown in figure 4. The sense cells of the higher in-
vertebrates are normally located subepithelially and
send one peripheral fiber into the epithelium. These
bipolar sensory neurons are illustrated in figure 5.
These single sense cells may ha\'e an auxiliary ap-
paratus; for example, the hair-sensillae of the arthro-
pods. These often, but not always, contain only one
sense cell which sends a peripheral fiber into the in-
terior of a hair which was formed bv the cuticle
(fig- 13)-
37^ HANDBOOK OF PHYSIOLOGY ^ NEUROPHYSIOLOGY I
Fig3
FIG. 3. Primary sense cells from the tentacles of the sea anemone Ceriantlms. [From Hanstrom (50).]
PIG. 4. Primary sense cells from the epithelium of the earthworm Lumbrkus. [From Hanstrom (50).]
FIG. 5. Bipolar sensory neurons from the skin of the slug Anon ater. [From Plate (9^).]
FIG. 6. Various types of scolopophorous sense cells (scolo-
pidia) from the chordotonal organs of insects, a and h, am-
phinematic scolopidia; f, d, e, and/, mononematic scolopidia.
a, simple chordotonal organ; b, scolopidium from the haltere
of a muscid (fly); c and d, scolopidia from the tympanal organ
of the cicada Cicadetta coriaria; e, scolopidium from the tympanal
organ and /, from the subgenual organ of the grasshopper
Decticus. af, axial fiber; ch, chitin cuticle; dc, cap cell; ec, en-
veloping cell; hy, hypodermis; li, ligament; sc, sense cell;
si, scolops (apical body of the sense cell); tf, terminal strand of
the sense cell; and va, vacuole. [From Weber (137).]
Some single sense cells show a further anatomical
differentiation. They have several short ramified fibers
(dendrites) which lead to auxiliary cells. E.xamples of
these are the stretch receptors at the joints in crusta-
ceans (i, 5). As a rule, the stretch receptors send a
fixed number of dendrites to a small bundle of muscle
fibers (fig. 15).
The epithelial sense cells may be located in groups
and thus form anything from primitive to highly
specialized sense organs. If they are located in the
epithelium, they may often carry fine hairs on their
surface. Specific structures are often found in the
sense cells; the most complicated of such intracellular
structures are the apical bodies (scolopidia) in the
chordotonal and tympanal organs (35) diagrammed in
figure 6 and the rhabdomeres in the eyes of the in-
sects (39, 47).
Some sense organs of invertebrates contain, side by
side, sense cells which are morphologically differen-
tiated in different degrees. An example is the sense
cone on the last joint of the antennae of the Diplopoda;
in this three different types of sense cells are located
closely together (fig. 7).
The sense cells of an organ may be morphologically
similar but differ in physiological respects; of three
sense cells which are found in the chemosensory
sensillae on the labellum of dipterans (flies), only
two send peripheral fibers into the chemoreceptive
part of the hair (fig. 11). These two cells react to
NONPHOTIC RECEPTORS IN LOWER FORMS
373
FIG. 7. Section of the last two segments of the antennae
(7 and 8) of the diplopod Polydesmus complnnatus. ep, epidermis;
fg, finger-like organ (function unknown); h, sensory hair;
j, skin joint; mu, muscle; n, nerve; p, peg-Hke sensilla; sci, sc;,
and SC3, the three types of sense cells; tr, trichogen cell. [From
Plate C92).]
are found in great numbers in all soft skinned inverte-
brates. Up to the present they have not been found in
the turbellarians and echinoderms — probably for
technical reasons. As a rule, these peripheral fibers
form a plexus which can be located subepithelially in
the connecti\e tissue or subcuticularly above the epi-
thelium. Such plexuses were first described in the
classical works by Retzius (106) and von Apathy
(129). In arthropods such neurons with free terminals
are limited to the soft skin of the joints and that be-
tween the segments (fig. 8). However, they are found
also in the epithelium (hypodermis) ol the mouth
parts (fig. 9). The cells 01 these neurons are mostly
located at some distance from the terminal ends of
the dendrites. Sometimes, as in the above mentioned
stretch receptors of the crustaceans, these dendrites
are short.
The simple type of receptors is common in inverte-
brates. On the other hand, some very complicated
sense organs are found, for example the phonore-
ceptors and eyes of the insects, the eyes of the octopus,
etc. Even in its highest form, however, the complexity
never reaches that of the vertebrates.
ch.o
different chemical substances; one neuron reacts only
to sugar (with spikes of smaller voltage), the other one
(with greater spikes) to salts, acids and alcohols (60).
Neurons with free nerve endings in the epithelium
FIG. 8. The trochanter joint of the third pair of extremities
oi an Aeschna larva, bp, bipolar sensory neuron; ch.o., chordo-
tonal organ with bipolar sensory neurons; co, coxa; fe, femur;
sc, sensory neuron with dendritic terminals at the joint; sh,
sensory hairs; tl, trochantinus. [Redrawn after Zawarzin (144).]
374
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
FIG. 9. Sensory neurons from the hypopharynx of the termite
Cattolermes flavicollis. The dendrites run between the cells of the
hypodermis. [From Richard (107).]
The morphological differentiations in single organs
are surprisingly versatile. [The special morphology
and anatomy of the sense organs of the invertebrates
may be found in the extensive monographs of Plate
(92) and Hanstrom C50). They cannot be given here.]
Physiological analysis has fallen far behind morpho-
logical description. The function of most structures
and organs is not known and only in very few cases
has been established by experimentation. The situa-
tion here is similar to that concerning the skin recep-
tors of the vertebrates. The number of these is far
larger than the number which has been analyzed or at
present can be identified physiologically.
Comparison oj the Senses oj the Invertebrates with
Those of Vertebrates
The functions of the receptors of the invertebrates
are known in detail only in a few cases. There are, in
addition to apparently very primitive organs, some
which match or in some ways even surpass the effec-
tiveness of those of the vertebrates. The absolute
thresholds (from a physical point of view) are suffi-
ciently well known only in a few instances to make
possible comparison with the vertebrates. For the
insects, accurate and comparable figures are available
only for vibratory and auditory reception (lo). The
subgenual organs of the insects, shown in figure 16,
which are most sensitive to vibration, e.g. in Peripla-
neta and Tettigonia (9), respond to amplitudes of vibra-
tion of the ground of 4 X io~'" cm (with an optimal
frequency of about 1400 cycles per sec). The thresh-
old for the perception of vibration in the human on
the other hand is about 10^^ cm (67). The ampli-
tude of movement of the membrane of the human
tympanum at the threshold of hearing is of the same
order as the \ibration threshold in the insects (143).
The thresholds of the most sensitive sense organs of
the invertebrates are as follows: the auditory receptors
of the grasshopper, Tettigonia, 4 X io~'^ watt (11);
the subgenualorgan of the cockroach, Periplaneta,
6 X io~" watt (ii). For comparison, the auditory
receptors of man require 8 X 10"'* to 4 X io~'^ watt
(120). For the sense of smell one inay also assume
that the best threshold \-alues of the insects match or
surpass those of the vertebrates. The receptors of the
invertebrates in some cases show potentialities which
are not known in the vertebrates, such as perception
of the direction of vibration of polarized light, sensi-
tivity to ultraviolet and to the moisture content of
the air (cf. p. 376) and perception of ultrasound.
The means by which comparable results are ob-
tained are different in many cases. Vertebrates gener-
ally hear well in the range of 16 to 20,000 or 50,000
cycles per sec. Insects hear soimd oscillations in the
range to about 300 cycles per sec. by means of their
hair sensillae (103, 104). The ears of the insects which
are furnished with a membrane (tympanal organs) are
actually too small to be stimulated by air vibration
below a frequency of 1000 cycles per sec; they are
most sensitive in the ultrasonic range (beyond 10 to
20 kilocycles per sec), according to VVever & Bray
(139), Antrum (9) and Pumphrey (102). Tympanal
organs cannot distinguish between pitches. Howe\-er
they are very sensitive to modulations of the ampli-
tude of ultrasonic waves (53, 105) up to modulation
frequencies of more than 300 per sec. (Antrum, H.,
unpublished observations); different frequencies of
modulation can be distinguished. Amplitude modula-
tion plays practically no part in the auditory recep-
tion of the vertebrates, but is however of decisive
importance in the hearing and recognition of species-
specific .sounds of the insects with a tympanal organ.
Analogous differences of functional nature appear
if the photoreception of the insects and vertebrates is
compared (12, 14); the small spatial resolving power
of the complex eye of the flying insects is compensated
by a high temporal resolving power. The frequency
of fusion of these eyes is as high as 250 to 300 flashes
per sec.
Many proprioreceptors of the arthropods are bas-
ically different from the corresponding systems in
vertebrates in both anatomical and physiological
respects.
Reactions of Simple Receptors
The simple receptors of invertebrates serve as im-
portant models for the analysis of the function of single
NONPHOTIC RECEPTORS IN LOWER FORMS 375
Fig. 10
FIG. 10. Sensilla basiconica from the antenna of a pupa of the wasp Vespa vulgaris, ch, chitin
cuticle; hy, hypodermis ; nl, neurilemma; sc, sense cells; tf, terminal strands; to, tormogen cell;
tr, trichogen cell. [From Weber (137).]
FIG. 1 1 . Diagram showing the histology of a labellar hair and associated cells in Phorima. The
large trichogen and tormogen cells are at the left, and three neurons with silver stained processes at
the right. The chemosensory area is confined to the silver -stained tip of the hair. The neuron in the
middle of the group of three does not have any visible connection with the chemosensory area.
[From Hodgson & Roeder (60).]
receptor cells. The lateral eyes of Lunulus (sOj the
stretch receptor cells of crustaceans and the chemo-
receptor sensillae of the flies are examples. It has been
possible to analyze the functions of single receptor
neurons in these simple organs.
Specific Types of Receptors
CHEMOCEPTORS. The chemoceptors of the inverte-
brates have been identified by physiological experi-
ments in only a few cases: in Turbellaria, in which
the auricular organs on the side of the head have
been studied by Koehler (70) and by Mljller (87); in
Limulus by Waterman & Travis (136) and Barber (16);
in Crustacea by Hodgson (58); in insects by von Frisch
(132), Wigglesworth (141), Frings & O'Neal (45),
Frings & Frings (44), Hodgson (57), Grabowski &
Dethier (48) and Hodgson & Roeder (60). [This field
has been reviewed by Dethier (31), by Hodgson C58)
and, particularly for molluscs, by Copland (28).] In
the turbellarians and molluscs these sense cells, which
are located in the epithelium, carry fine hairs covered
with mucus. Three types are found in the insects:
sensillae placodeae, pore plates described by von
Frisch (132); sensillae basiconicae, peg-like hair deriv-
atives shown in figure 10; and sensillae trichodeae, hair
sensillae drawn in figure 1 1 . They are always supplied
by more than one neuron. The covering cuticle is
very thin (less than i /x) and only partially sclerotized.
The epicuticle has a low lipid content (108). The sur-
face of the cuticle is always dry. These receptors are
suited for quantitative experimental comparisons of
different substances. [This topic has been reviewed by
Dethier (31).] Therefore they are important for the
general physiology of chemoreception.
In the vertebrates we distinguish between the sense
of olfaction and the sense of gustation. An analogous
distinction can be made in the insects but not in other
groups. Hodg.son (57) showed that the distinction be-
tween olfaction and gustation is unimportant at least
on a cellular level, if it is based on the physical condi-
376
HANDBOOK OF I'lnSIOI.OGV
NEUROPHYSIOLOGY I
tion of the stimulus. A small group of morphologically
identical receptors on the antennae and palpi of the
beetle Laccophilus respond in the same way to chemical
stimuli by suijstances whether they are dissolved in
water or applied as gases.
Man\- authors assume that, besides the senses of
olfaction and gustation, there is in insects a common
chemical sense with separate receptors [cf. Dethier
(30)]. The adequate stimuli for this common chemical
sense are high concentrations of many substances
which evoke defense reactions (e.g. ammonia, chlo-
rine, essential oils).
There is no proof, and it is even improbable, that
most animals can distinguish as many smells as can
the human. Many, if not most, animals are probably
specialized and able to respond only to one or a few-
smells in a very specific way. The females of Bomhyx
mori show no response in electrophysiological experi-
ments to female sexual i)ait substances to which the
males react with marked sensitivity. It may therefore
be assumed that the receptors are highly specific with
respect to this particular substance (113). On the
other hand, the olfactory sense of the honey bee is
strikingly similar to that of the human (131), even
with respect to the aiiility to distinguish between
stereoisomers (e.g. amyl acetate and methyl hepte-
none;/)-cresol methylether and m-cresol methylether).
For the human sense of taste, four modalities are
generally assumed : sweet, sour, salty and bitter. At
present it is difficult to say whether the invertebrates
have more or fewer of these modalities. The chemo-
ceptors of Limulus are relatively insensitive to salty,
sweet, sour and bitter solutions in electrophysiological
experiments. However, they react violently to water
extracts of marine clams (16). From about 30 sub-
stances which taste sweet to man, only a few are
attractive for insects (for example saccharine is not
effective). In this respect not only different insects,
but also different organs of the same insect, react
differently. Raffinose attracts almost all insects but
not, however, the bees; the ant Lasiiis niger shows a
positive reaction to sorbitol but the ant Myrmica
rubida does not (130, 133). The water beetle Hydrous
is able to distinguish between sugar, hydrochloric
acid, sodium chloride and quinine in behavior experi-
ments (17). Frings assumes that the distinction be-
tween the different modalities (salty, sour, sweet,
bitter) generally is not dependent on the presence of
different specific receptors for these substances in
insects. Stimulation ot the receptor cells with the
lowest threshold is supposed to cause the sensation
'sweet' and the e.xcitation of all receptors of one group
to cause the sensation 'sour'. The other modalities
would be based on the evokation ol receptor acti\ity
patterns which lie between these extremes.
Many terrestrial invertebrates respond to another
modality, moisture; this topic has been reviewed by
Dethier & Chad wick (33), by Roth & Willis (no)
and by Dethier (30). The moisture receptors of the
arthropods, as far as they can be identified, are in-
distinguishable from the other chemoceptors in mor-
phological respects. According to experiments by
Dethier (32) it is however very dubious whether clean
water has a specific 'taste' for the contact receptors of
the insects, since only two neurons are present in the
hair sensillae of the fly Phormia. The hair can be
adapted alternatively to water and to different con-
centrations of sugar; an alternative adaptation to
sugar, sodium chloride or alcohol (which react upon
the other neuron) is not possible. According to these
findings there is only one receptor for sugar and
water. A similar phenomenon was found in the verte-
brates (145). It is not possible however to generalize
and to apply these results to all hygroreceptors. It is
quite possii:)le that specific hygroreceptors exist, for
instance in the human louse Pediculus humarus corporis
(.4.).
The chemoceptors of insects are remarkably sensi-
tive to temperature changes (43). The neuron which
mediates sodium chloride detection in the fly Plwrmia
reacts to a temperature increase of o.i°C with a
measurable increase of spike frequency according to
Hodgson et al. (39).
Important progress has been made in recent years
in the electrophysiological analysis of the chemocep-
tion of Limulus and insects (16, 19, 60, 112, 113, 122).
Hodgson & Roeder (60) observed spikes of single
neurons of chemical receptors in insects. Schneider
(112, 113) found grouped spikes and slow potentials
in the antennae of Bombyx.
The theories concerning the primary events in
chemoceptor stimulation will not be discussed here
but mav Ijc found in the relevant chapters of this
work.
PROPRIOCEPTORS. Proprioceptors are defined by Liss-
mann (78) as sense organs capable of continuous
registration of deformations (changes in length) and
stresses (tensions and compressions) in the body. In
the invertebrates they are known and have been ex-
perimentally tested only in the arthropods. The
following types can be distinguished morphologically.
On the surface of the body are located: a) the
peripheral endings of multipolar neurons without
NONPHOTIC RECEPTORS IN LOWER FORMS
377
FIG. 12. Schematic drawings of the structure of an insect
campaniform sensilla (left) and an arachnid iyriform organ, a
slit sensilla (right). The arrows show the probable direction of
the stimulus exciting the sensilla. These diagrams are based on
drawings of the base plate sensilla on the haltere of Calliphora
(Pfiugstaedt, 191 2) and of the Iyriform organ on the patella of
a spider, ch, chitin cuticle; hy, hypodermis; sc, sense cells;
sf, surface (Vogel, 1923). [From Pringle (97).]
particular differentiation of the cuticle, the peripheral
branches of which terminate between the cells of the
hypodermis, e.g. in the skin over the joints in the ap-
pendages of Limulus (16, 98), or in the crustaceans
(126); 6) campaniform sense organs of the insects
(fig. 12) and slit sense organs of the Arachnoideae
(fig. 12) in which bipolar sense cells send their
peripheral fibers to special diff"erentiated structures of
the cuticle at the membrane of the joints (66, 95, 97,
128); f) hair sensillae (sensillae trichodeae), which
consist of single or larger groups of hairs, at the basis
of which enter the peripheral ends of bipolar sense
cells (fig. 1 3) — because of their location they are more
or less affected by the relatixe positions of adjacent
segments of the appendages (95) or of the body, e.g.
of the head according to Mittelstaedt (86), as shown
in figure 14.
In the interior of the body are located: a) muscle
receptors in insects, as shown by Finlayson & Lowen-
stein (40) and Slifer & Finlayson (121); ti) organs
suspended between two movable segments found in
Limulus (16, 98) and Crustacea (especially the stretch
receptor organs shown in fig. 15) (i, 2, 3, 4, 22, 23,
37, 38, 42, 74, 75, 140). To this latter group also
belong with high probability many chordotonal or-
gans which are found in the body of insects (fig. 18).
This topic has been reviewed b\' Eggers (35) and by
Snodgrass (123).
Proprioceptors in the wings of insects (124) and in
the abdominal part of Dytiscus (62) have been found
by physiological experiments; they are however not
yet identified anatoinically. In earthworms Gray et al.
(49) found sensory discharges upon passive stretching
and Prosser (100), during active movement.
The adequate stimulus for the multipolar sense cells
on the skin of the joints of Limulus, for the campani-
form organs of the insects and for the slit sense organ
of the arachnoids is tension or coinpression of the
cuticle covering the organ. The receptors in the
muscles of the insects and the stretch receptors of
Limulus and of the crustaceans respond to increase or
decrease of the tension. All these organs are — with
the exception of one of the two neurons in the stretch
receptors of the crayfish — tonic receptors with slow
and incomplete adaptation. The same holds true for
the hair sensillae on the joints of the insects. Phasic
receptors in close proximity to the tonic neurons are
often found. They respond to an adequate stiinulus
FIG. 13. Schematic diagrams of hair sensillae, that on the left from the cercus of the cricket
Liogryllus campeslris with an intraepithelial sense cell, and that on the right from the caterpillar
Pieris with a subepidermal sense cell, ch, chitin cuticle; ha, chitinous hair; hy, hypodermis; nl,
neurilemma; sc, sense cell; to, tormogen cell (secreting the chitinous joint membrane). [From
Weber (137).]
378
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
FIG. 14. Diagram showing the method of excitation of the
inner coxal hair plate by a fold of the intersegmental membrane
of the second leg of the cockroach Periplaneta. ex, coxa, hp,
hairplate; pi, pleuron. [From Pringle (95).]
with a short series of impulses and rapidly adapt;
these are in Limiilus the big cells located in the depth,
and in arachnoids organs which are not exactly iden-
tified anatomically but are located close to the slit
organs. The stretch receptors of some crustaceans are
composed of two sense organs lying close to each
other; one reacts tonically and the other one phasi-
cally. Each of these sense organs consists of a single
neuron which is located on a bundle of muscle fibers
in Homarus and Cambarus. In other crabs, such as
Carcinus, many cells are combined in this organ. Some
of these cells react tonically, others phasically. The
tonic neurons show a resting discharge. The maximum
of this resting discharge of single neurons in Limulus
is present either at maximal extension or at maximal
flection of the joint. The minimum of the resting dis-
charge of the whole organ corresponds therefore ap-
proximately to a mean position of the membrane of
the joint
The stretch receptor organs between the abdominal
segments of certain crustaceans, including Homarus
and Astacus, have been studied carefully. They are of
interest also from the standpoint of general physiology
since the activity of single sensory neurons could be
analyzed in them. The organs consist of two fine
bundles of muscles, RMi and RM2; a sensory neuron,
.SNi and SN^, is attached to each of these. This neuron
sends many dendrites to the muscle fibers. An afferent
axon is emitted from each neuron (fig. 15). The effer-
ent innervation consists of: a) motor fibers, innervat-
FIG. 15. Schematic drawing of the stretch receptors between the segments of the tail of the crab
Astaau flmnatilis. RMi, muscle bundle of the tonic receptors; RM.>, muscle bundle of the phasic
receptors. SNj and SN^, sensory neurons of the tonic and phasic receptors respectively, Si and So
their afferent axons; MO], three thin motor fibers of the tonic receptors; MO;, thick motor nerve
fiber of the phasic receptors; and I, an inhibitory axon. (By courtesy of D. Burkhardt.)
NONPHOTIC RECEPTORS I.\ LOWER FORMS
379
ing each bundle of muscles separately; b') a thick
accessory fiber which is ramified into two branches in
the vicinity of SN2 (fig. 15), one branch innervating
the area of the dendritic terminals of SNi, the other
branch innervating the dendritic terminals of SNj;
c) an additional thin accessory fiber innervating the
terminals of SNi and SN2 in Homarus (this is absent in
Astacus); and (f) a number of thinner fibers, the origin
and terminals of which are not known exactly but
mainly innervating RMj.
The details may differ in the different species of
the crustaceans and may be found in the discussions
by Alexandrowicz (i, 2, 5) and Florey & Florey (42).
The adequate stimulus for these receptors is stretch-
ing of the muscle bundles. One of the two receptor
cells of this organ (SNo, the slow cell) has tonic quali-
ties. The other one (SNj, the fast cell) has phasic
qualities. The same is valid for the corresponding
muscle bundles on efferent stimulation, RMi yielding
a fast twitch, RM2, a slow response (74). The tonic
receptor cell has a very low threshold to the adequate
stimulus (stretch) and yields uninterrupted discharges
with a low adaptation rate. The phasic cell has a high
threshold and adapts very rapidly and completely.
Excitation of the efferent nerve fibers leads to a con-
traction of the muscle bundles and in this way causes
afferent responses of the sensory neurons (74, 140).
The normal excitation originates in the dendrites.
These become depolarized by stretch deformation
producing a generator potential (37, 38). The gener-
ator potentials in the dendrites spread electrotonicalh'
and reduce the resting potential of the cell soma. Re-
duction of the resting potential (70 to 80 mv with
relaxed receptor) by 8 to 12 mv in the slow cell and
by 17 to 22 mv in the fast cell causes propagated
impulses. The neuron therefore works according to
the following scheme: stretch deformation of dendrite
terminals— ^generator potential^electronic spread to-
wards the cell .soma (prepotential) — >dendrite-soma
impulse— >axon impulse (37, 38).
Excitation of the inhibitory fiber (fig. 15) acts upon
the generator mechanism in the dendrites and stops
the discharge of the sensory neuron within a few
milliseconds, even upon application of a strong stimu-
lus (large stretch). This effect is caused by the follow-
ing sequence of events. The impulses in the inhibitory
fiber cause a postsynaptic effect in the dendrites of the
sensory neuron. This drives the potential of the re-
ceptor cell towards an equilibrium level. The inhibi-
tory effect can therefore be a postsynaptic depolariza-
tion or a hyperpolarization depending upon the
existing state of the receptor cell. Through the stretch
stimulus or its absence this may Ije pushed to either
side of the equilibrium potential (37, 38).
The stretch receptors in the abdominal segments of
the crayfish are physiologically similar to the muscle
spindles of the vertebrates. Nevertheless all described
proprioceptors are considerably different from the
analogous organs of the vertebrates; they indicate not
the functional condition of a single muscle, but of a
whole body segment. These proprioceptors signalize
the relative position of the parts of an appendage,
e.g. the hair sensillae or the multipolar cells oi Limulus,
or they indicate the relative position of different seg-
ments of the body, e.g. the stretch receptors of the
crayfish or the muscle receptors of insects. The cam-
paniform and lyriform organs and the slit sense organs
are located in such a way that they can register the
forces which arise in the chitinous shell of the legs
upon contact of the extremity with the ground. These
organs therefore control the behavior and position of
the animals (78, 93, 94, 95, 98).
Many of these organs are not designed to react to a
single specific mode of stimuli. The proprioceptors of
Carcinus respond both to the movement of the ex-
tremity and to vibration (22). The proprioceptors of
Dytiscus (which are not localized anatomically) yield
spikes during inspiration, expiration and to airborne
sounds of about 100 cycles per sec. (62). The stretch
receptors of Cambarus respond strongly to temperature
changes with a frequencv change of the discharges
(40-^
THERMORECEPTORS. Lower animals may lack tempera-
ture sensiti\'ity completely. The sea anemone CalUactis
is very sensitive to mechanical and chemical stimuli;
however, a glass tube which touches the body wall
can be heated so much that it causes burning of the
ectoderm without producing any reaction (91). On
the other hand most animals react to temperature. As
a rule the parasites of warm Islooded animals are
especially sensitive, beintr attracted by warm objects.
This has been shown for the leech and some insects,
e.g. Rhodnius by Wigglesworth & Gillet (142) and
Cimex by Sioli (119).
The temperature receptors of invertebrates have
never been anatomically localized with precision. It
is assumed to be highly probable that the pointed
hairs on the antennae of insects are thermoreceptors.
This is the case in at least some species, including
Rhodnius (142) and Pyrrhocoris (46). At the base of
these hair sensillae lie six sensory neurons.
The mechano- and chemoreceptors of the inverte-
brates very often respond to temperature by changes
38o
HANDBOOK OF PH'SSIOLGGY
NEUROPHYSIOLOGY I
in the impulse frequencies in the afferent nerves (27,
41, 43, 59). The Qio in the statocysts of the lobster is
4.5 for the nonadapting resting activity of the large
spikes, according to Cohen et al. (27). This tempera-
ture sensitivity is therefore lower than that of the
temperature receptors in the tongue of mammals,
studied by Hensel & Zotterman (55), and of the
ampullae of Lorenzi in rays, investigated by Hensel
(54). On the other hand Bullock found marked me-
chanical irritability of the thermoreceptors on the
head of the rattlesnake (21). The frequency of the
afferent signals from many receptors of cold blooded
animals depends not only on the adequate stimulus
but also on the temperature. This temperature sensi-
tivity of the sense organs of invertebrates raises a
physiological problem which has hardly been investi-
gated [cf. Bullock (20)].
A summary of the literature on the reactions of
lower animals toward temperature is given by von
Buddenbrock (130).
MECHANORECEPTORS: TACTILE SENSE. The receptois for
this modality are well known only in a few cases.
Sense cells of soft skinned invertebrates which are lo-
cated in the epidermis and carry one or more long,
hair-like spines are termed hypothetical tactile re-
ceptors. However, no full proof has been given in any
case [cf. MiilkT (87)]. Passano & Pantin (91) adopt
the view that a basal network of the sensory cells or
the nerve net or the circular and parietal muscle
sheets can be considered as receptors despite the fact
that many primary sensory neurons occur in the
ectoderm of the actinians. The tactile receptors of the
insects are definitely known to involve long, movable
hairs with joints in the chitinous skeleton at the base
of which one or many peripheral fibers of bipolar
sensory neurons end (fig. 13). They adapt rapidly if
their resting position is changed. The adaptation is
slow in certain spine-like hairs located on the legs of
insects. The initial frequency of the impulses in the
sensory a.xon depends on the velocity of displacement,
according to Pumphrey (loi). The transducer func-
tion of this sensory element was analyzed by Pringle
& Wilson (99). They were able to show that the maxi-
mum of response (recorded by the frequency of im-
pulses) precedes in phase the maximum tension of the
stimulus upon application of harmonic, sinusoidally
varying mechanical stimuli. This is a corollary of the
adaptation shown by the sensory response to a tran-
sient stimulus.
MECH.JiNORECEPTORS: VIBRATION SENSE. Specific, highly
sensitive viisration receptors were found in the ex-
tremities of insects by Autrum (8, 1 1), by Autrum &
Schneider (15) and by Schneider (115). These are
groups of sensory cells which are spread in a sail-like
fashion in the Ijody fluid of the legs (fig. 16). They
are furnished with peculiarly differentiated bodies,
such as apical bodies, or scolopidia, as shown in fig. 6.
Adequate stimuli are provided by vibrations of the
ground. The subgenual organs respond preferentially
to vibrations between 200 and 6000 cycles per sec,
with maximum sensitivity between 1000 and 2000
cycles per sec. (fig. 1 7). The amplitude at threshold
is about 4 X
" cm at 1500 cycles per sec. for
Fio. 16. Scheme of the subgenual organ in the leg of the
ant Formica, ac, accessory cells; ch, chitin cuticle; dc, cap cells;
ec, enveloping cell; hy, hypodermis; nc, nerve; nl, nucleus of a
neurilemma cell; sc, sense cells. [From Weber (137).]
Periplaneta; consequently they are smaller than atoinic
dimensions.- The adequate physical stimulus is ac-
celeration. These organs cannot distinguish between
different frequencies. The high optimal frequency of
the vibration receptors of many insects given in figure
I 7 can be understood if their small size is considered.
Such high frequencies do not occur under natural
conditions. It is therefore not necessary to distinguish
the frequencies. Pulses and pulse-like vibrations of
the ground are important for reactions of insects in
the natural environment. These pulses possess high
frequency components and during the initial tran-
- The amplitudes of movement of the human tympanum are
of the same order of magnitude at the threshold of hearing.
NONPHOTIC RECEPTORS IN LOWER FORMS
381
100.000 E3^
10.000
1000-
100 -
10-
c
2 1
0.1
0.01
0.001
\^v
\
v^\,Vespa
^ \ .Carabus
\ Bombus \
\
\ X^Pyrameis ^
Liogryi
'^^^_
Penplanela— A /
1 1
V -
00 o
00 o
000 o
•— CM
Cycles per Second
FIG. 17. Vibration thresholds at different frequencies for a
few characteristic species of different sensitivity. [From Autriim
& Schneider (15)-]
sients stimulate the subgenual organs at their reso-
nance frequency. The suddenness of the movement of
the ground is therefore important for successful stimu-
lation. This holds true also for the perception of
vibrations in spiders, according to Liesenfeld (77); the
vibratory stimuli which are emitted from the threads
of the net require a sudden onset at full intensity,
since spiders do not react to slowly increasing ampli-
tudes. The type of the tran.sients is the decisive stimu-
lus. The same is true for the t\nipanal organ of the
insects.
MECH.\NORECEPTORS: HEARING. Specific sen.se organs
for which air sound waves are the adequate stimuli
are known in arthropods. These are the hair sensillae,
the antennae or the tympanal organs which contain
a membrane, the tympanum.
The hair sensillae serve as receptors for air vibra-
tion of low frequency in spiders and many insects.
The reactions of caterpillars (85), and the hairs on the
anal cerci of the crickets and cockroaches, including
Periplaneta, (104) have been carefully analyzed. The
afferent nerve fibers of the hair sensillae respond to
low frequencies up to about 400 cycles per sec. in
synchrony with the frequency of the stimulus and in
some cases also at double the frequency. At higher
frequencies, halving or quartering of the frequencies
may appear.
The antennae of Aedes aegypti (109), Anopheles (125)
and flies (24) carry many hairs which are not inner-
vated. They are mo\ed by air vibration and transfer
this motion to the antennae and to the Johnston's
sense organ. This is located between the second and
third segment of the antennae and consists of many
sense cells.
The adequate stimulus for the hair sensillae is the
amplitude of displacement of the air particles not the
sound pressure, according to Antrum (7, 10) and
Pumphrey (102). They are thus displacement re-
ceptors.
The tympanal organs are sense organs with a
tympanic membrane. Their primary neurons have
scolopidia (cf. figs. 6 and 18). The structure of these
organs has been reviewed by Eggers (35), and their
physiology by Pumphrey (102), Autrum (8, 9, 13)
and Schaller & Timm (iii), as well as in the book
edited by Busnel (25). The maximal sensitivity is in
FIG. 18. a, chordotonal organ between abdominal segments
of the larva of Monohammus conjusor (after Hess). [From Weber
(■37)] *. auditory organ in the foreleg of the grasshopper
Decticus (after Schwabe). ch, chitin cuticle'; co, sense cells of
chordotonal organ; hy, hypodermis; li, ligament; nv, nerve;
sgn, nerve of subgenual organ; ta, anterior tympanum; tc,
tympanic cavity; tp, posterior tympanum; tr, trachea. [From
.\utrum (10).]
382
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY
the supersonic region, above 20,000 cycles per sec, as
shown by VVever & Bray (139), Pumphrey (102),
Autrum (8, 9, 10), and Schaller & Timm (i 1 1). The
upper limit of hearing in some species is at 1 75
kilocycles per sec. Electrophysiological analysis has
shown that the tympanal organs cannot distinguish
the frequency of the sound. They consequently are
not able to analyze sounds but react very sensitively
to modulations of amplitude (53, 105). In the natural
environment the stimulus is a sound of high frequency
which is amplitude-modulated. Such a sound is im-
portant for their behavior. For example, the songs of
crickets consist of sound with certain rhythms of
modulation. The impulses in the tympanal nerve do
not follow the frequency of the sound since these
frequencies are too high but follow the modulation
frequency to about 300 per sec, as shown in Tetti-
gonia by Autrum (unpublished observations). The
ultrasound therefore serves as a carrier frequency.
Acoustically these tympanal organs are displace-
ment receptors as are the hair sensillae (8, 10, 102).
The sensitivity of all acoustic displacement receptors
depends on the direction from which the sound comes.
The tympanal organs have for this reason, therefore,
an 8-shaped polar diagram, which is important for
the localization of the source of the sound (10, 13).
In the same way sound reception by means of hairs is
dependent on the direction (125).
ST.^TOCYSTS. The statocyst of the invertebrates consists
of a little ectodermal bag invaginated into the interior
of the body. It is filled with fluid, has hairs in certain
parts and contains one or more statoliths which are
little stones or concretions of greater specific gravity
than the fluid. According to the general scheme of
function the statocysts are analogous to the otolith-
containing organs of the vertebrates. Considerable
differences are found in the anatomical details. Thus,
the sensory neurons in the invertebrates are primary
sense cells with an afferent axon and there are addi-
tionally nonliving cuticular hairs but no equivalent of
the hair cells; in the vertebrates, by contrast, the hair
cells are secondary sense cells and lack an axon.
The variety of the details is also very great in the
invertebrates [cf. Hanstrom (50) and Plate (92)].
Statocysts are the first sense organs to appear in the
phylogeny of the animal kingdom, being present in
the coelenterates.
The adequate stimuli are gravity (static stimuli),
acceleration (dynamic stimuli), or both. Compensa-
tory reactions of the whole body, tonic reactions to
certain muscles, or both, are directed from the stato-
cysts. The statoliths are important for static reactions
(73).
The statocysts of crustaceans have been most care-
fully analyzed both by physiological behavior experi-
ments by Schone (117) and Dijkgraaf (34), and by
electrophysiological studies by Cohen et al. (27) and
Cohen (26). The adequate stimulus for the nerve end-
ing is a bending of the cuticular hair, not pressure or
pull of the statolith upon the hairs. Bending of the
hairs medially causes a refle.x rotational movement
about the long axis in the same direction; bending
towards the outside causes a rotation of the animal in
the opposite direction. The sensory epithelium gives
rise to a tonic impulse train which is independent
of stimulation of the statolith. The stimulus bending
the sense hairs produces either its own impulse or may
modify the tonic impulses. Between the intensity of
the stimulus (the bending) and the reaction (measured
in the tonic reactions of the eye stalk) there exists a
linear relationship. If the statoliths are removed on
one side, the zero position will move to this side since
the area of the statocyst which is adjacent to the sense
hairs is inclined outward and therefore the statoliths
in their normal position bend the hairs outward.
Compensatory processes counteract these changes of
the zero position. The position receptors are hook-
shaped hairs in Carcinus and Maja, while the receptors
for angular displacements are very thin thread-like
hairs, 300 y. long (34). The statocysts of Astacus do not
work antagonistically to each other, but in the same
lateral position each produces the same tendency
towards rotation. The impulses from both sides are
simply added up in the central nervous system.
The results of Schone (i i 7) and Dijkgraaf (34) are
in accordance with the electrophysiological findings
of Cohen et al. Q2'f) and Cohen (26) in that the stato-
cysts react to rotatory acceleration around the axes
[cf. Dijkgraaf (34)], to linear acceleration and to
static position. A tonic discharge exists which remains
even after removal of the statoliths. There exist rapidly
adapting phasic elements and also tonic elements.
The excitation of the latter depends upon the position
and they adapt only slightly. Cohen found four types
of afferent fibers, each reacting differently. The type
I position receptor shows a nonadaptive impulse fre-
quency which depends (within a certain angle to the
normal position) upon the angle between the trans-
verse axis and the normal position. The position re-
ceptor of type II may well be not a single receptor
but may result from the coordination of several re-
ceptors. It a) maintains a characteristic nonadapting
impulse frequency for each constant deviation from
NONPHOTIC RECEPTORS IN LOWXR FORMS
383
the horizontal axis and, in addition, i) yields adapting
impulses during movements, which increase in fre-
quency if the movement is carried out towards the
position of the maximal static stimulation and decrease
abruptly during movement away from this position.
A third system of receptors responds to angular ac-
celeration around every axis of the body. It shows a
tonic discharge which is independent of the position
when position is constant. This tonic discharge re-
mains even after removal of the statolith. The response
consists of a burst at the onset of rostrum-down, side-
down, or contralateral horizontal rotation, followed
by a depression at the termination of these move-
ments. The opposite movements result in a reversed
response sequence. The adaptation of the permanent
discharge to the resting value is completed in less than
I sec. This shows a striking similarity between the
basic principles of the mode of function of the crusta-
cean statocyst and the static apparatus of the verte-
brates studied by Lowenstein (79) and von Hoist
(134); in both cases the sine law is obeyed; the ade-
quate stimulus is bending of the hairs; stimulus and
reaction have a linear relationship; and the sensory
epithelium emits a tonic impulse stream which is
modified by the bending of the hairs. A loss of the
tonic impulses on one side is compensated. This
ability is important as the statocysts have to be sup-
plied with statoliths from the outside after each molt,
at least in some species. In this procedure it is not
always possible to obtain statoliths of the same weight.
Orientation to gravity occurs in many cases without
the help of statocysts, as is the case in insects accord-
ing to Mittelstaedt (86), Pringle (96) and Schneider
(114), but the eyes often play an important role in
this adjustment (116).
Professor Autrum's chapter was translated from the Ger-
man by Dr. and Mrs. Otto Scherbaum, Department of Zo-
ology, University of California at Los Angeles. — Ed.
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CHAPTER XVII
Touch and kinesthesis
VERNON B.
JERZY E. ROSE
MOUNTCASTLE
Departments 0/ Physiology and Psychiatry, Johns Hopkins
University School oj Medicine, Baltimore, Maryland
CHAPTER CONTENTS
Introduction
Definitions
Tactile stimuli
Kinesthetic stimuli
Electrophysiological Methods for Study of Somatic Afferent
Systems
Methods of stimulation
Excitability states of central neurons
Methods of recording
Current Theories of Cutaneous Sensations
Classic Concept
Pattern Theory
Concept of Head
Some Properties of Peripheral Somatic Afferent System
Receptors
Specificity of receptors
Types of discharges
Receptor potential
Peripheral Cutaneous Nerve Fibers
Impulses in peripheral nerve fibers
Impulses evoked in fibers of different size by tactile stimuli
Relation of cutaneous stimuli to activity in fibers of
different size
Relation of elevations of electroneurogram to modalities of
sensation
Summary
Central Tactile and Kinesthetic Systems
General Remarks
Classification of Central Tactile and Kinesthetic Systems
Medial Lemniscal System
Anatomical Definition
Physiological Properties
Projection Patterns in Medial Lemniscal System
Patterns in Dorsal Columns
Patterns in Dorsal Column Nuclei
Patterns in Thalamic Relay Nucleus
Definition of thalamic relay nucleus
Direct spinocortical and bulbocortical pathways
Ipsilateral pathway from dorsal column nuclei to ventro-
basal complex
Patterns in tactile thalamic area
Patterns in Postcentral Homologue of Cerebral Cortex
Modality Components of Medial Lemniscal System
Touch-Pressure
Adaptive properties of receptors and of central neurons
Peripheral recepti\'e fields
Projection of peripheral receptive fields upon central neu-
rons
Response Patterns of Neurons of Medial Lemniscal System
Repetitiveness of response to single stimulus
Response of system to single stimulus
Response to two stimuli at different intervals
Response to repetitive stimuli at diflerent frequencies
Afferent inhibition
Summary
Kinesthesis or Sense of Position and Movement of Joints
Muscle Stretch Receptors and Kinesthesis
Innervation of Joints
Joint Receptors and Their Discharge Patterns
Central Projection of Joint Aflferents
Projections of Deep Receptors Other Than in Joints
Functional Organization of First Somatic Cortical Field
Spinothalamic System
Location of Tactile Fibers in Spinothalamic System
Origin of Spinothalamic System
Termination of Spinothalamic System
Topical Organization of Spinothalamic System
Ipsilateral Pathways of Spinothalamic System
Some Further Observations on Somatic Sensory System
Relaying of Somatic Afferent Impulses
Centrifugal Pathways Impinging LTpon Sensory Somatic
Synaptic Regions
Activation of Brain Stem Reticular Formation by Sensory
Somatic Discharges
Cortical Fields Other Than Primary Receiving Area Which
Are Activated by Tactile Stimuli
Anatomical evidence
Electrophysiological evidence
Experimental psychological esidence
Concluding Remarks
387
388
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
INTRODUCTION
WE SHALL DEAL IN THIS CHAPTER With neural events
which occur in the nervous system in response to me-
chanical stimulation of the skin and of some tissues
beneath it. We shall focus our attention on those
events which presumably provide the substrate for
tactile and kinesthetic sensations.
In the past it was possible to study such sensations
only by relating the introspective report of a human
observer to the experimental manipulations at the
periphery. In this way a large body of psychophysical
data was gathered. The events which take place in
the nervous system between the time an appropriate
stimulus is applied to the receptive zone and the time
sensation is reported were not accessible to systematic
experimentation, and virtually all the knowledge
about them was derived from clinical neurological
and neurosurgical observ-ations.
Even though an introspective report is still the only
way Ijy which sensations can be studied directly, a
considerable body of electrophysiological data, relat-
ing the tactile and kinesthetic stimuli to the response
in the central nervous system, has been collected in
the past three decades. Perhaps because such data do
not permit, at present, an interpretation of sensations
in terms of neural events, their impact on theory has
been quite modest. Even in recent accounts no need
is felt to deal in any detail with the neural impulses
farther centrally than the peripheral nerve. Since it is
reasonable to believe that a detailed knowledge of
central neural events is a prerequisite for any sound
approach to the problem of sensations, we shall deal
with the material pertaining to our subject in a some-
what unorthodox manner. Thus, we shall not review
the formidable body of psychophysical data since such
data are readily available in all texts of experimental
psychology. Likewise, we shall deal with the mor-
phology of the skin receptors only to the extent which
is necessary for our purposes. We refer the interested
reader to a recent review (268) which contains an ex-
tensive list of literature on this subject. On the other
hand, we shall consider the electrophysiological data
pertaining to the receptors and the peripheral afferent
fibers and shall deal with the morphology and elec-
trical activity of the central pathways and synaptic
regions which appear relevant for tactile and kines-
thetic sensations.
We propose to consider these sensations together
since the available evidence indicates that the afferent
impulses evoked by stimulation of skin and joints are
handled in the central ncr\ous svstcin in a similar
fashion and in the same synaptic regions. By kines-
thetic sensations we understand the appreciation of
movement and position of the joints. We shall use the
term ' kinesthetic' which is current in the literature of
experimental psychology instead of the term * proprio-
ceptive' which was introduced by Sherrington and
which is almost universally used in physiological texts.
For once it appears that a Sherringtonian concept
tended to obscure rather than clarify the issues. It was
already established by Goldscheider (99) that ap-
preciation of movement of the limbs derives essen-
tially from stimulation of the joints rather than
muscles. In harmony with these findings there is, in
our opinion, no evidence for and strong evidence
against the notion that impulses provoked by stretch
receptors in muscles provide information for percep-
tion of mo\ement or position of the joints. Thus, it ap-
pears that classical proprioceptors may not contribute
at all to the arousal of 'proprioceptive' sensations.
Hence, the more neutral term of kinesthesis has been
adopted.
Definitions
Since it is desirable to utilize electrophysiological
data from animal experimentations in describing
events leading to tactile and kinesthetic sensations, it
is useful to consider such sensations in terms of the
stimuli which provoke them and to assume that in
mammals, other than man, comparable sensations
arise when similar stimuli are applied. Three diffi-
culties arise in this connection. First, the stimuli
cannot usually \x related to the receptors themselves,
as would be desirable, but must be related to the tissues
containing them; second, for the time being neural
events cannot be related in any simple way to sensa-
tions; and third, not every activity in the central
nerv'ous system evoked by tactile and kinesthetic
stimuli necessarily has a bearing on the arousal of
sensations.
From the electrophysiological point of view then,
one can speak in a strict sense only of the electrical
signs of neural activity aroused by tactile or kines-
thetic stimuli. We shall speak, however, specifically of
tactile or kinesthetic activity if the stimuli evoke
responses in the direct corticopetal pathways and ap-
propriate synaptic regions since it seems fair to infer
that at least this activity must be instrumental for the
arousal of the appropriate sensations.
TACTILE STIMULI. We shall consider as tactile stimuli
all those which cause displacement of hairs or de-
TOUCH AND KINESTHESIS
389
formation of skin without injury. Since most of the
experimental data pertain to animals, it is usually not
practical to distinguish between stimuli which cause
sensations of touch from those of light pressure.
KINESTHETIC STIMULI. Stimuli pressing upon or dis-
placing without injury the connective tissue under-
neath the skin, periosteum, bones, sheaths of tendons
or muscle fascia, and capsules of the joints lead to sen-
sations often referred to as deep sensibility. We shall
be concerned in particular with those stimuli which
cause displacement or compression of joint capsules
and shall refer to them as kinesthetic. Under physio-
logical conditions, of course, it is the contraction of
the muscle which acts as a major kinesthetic stimulus.
This fact, however, has no bearing on the assertion
which is justified on page 410 that stretch receptors in
the muscle itself play no direct role in the arousal of
kinesthetic sensations.
Electrophysiological Methods Jor Study of Somatic
Afferent Systems
When a light tactile stimulus is delivered to a small
area on the body .surface, it evokes a burst of impulses
in afferent nerve fibers. This volley is relayed through
afferent pathways and synaptic regions of the spinal
cord, brain stem and thalamus, and invades the
sensory areas of the cerebral cortex. An electrode
placed at .some point in the system samples the elec-
trical signs of this ev^oked activity and provides a tool
for study of its whereabouts and nature and of the
patterning of the central reflection of the body form.
The variables of the experiment are the form of stimu-
lation used, the state of excitability of the neurons
and the method of recording. Each deserves a com-
ment.
METHODS OF STIMULATION. The somatic afferent system
presents difficulties for experimental study for only
exceptionally has it so far been possible to deliver
quantitatively precise stimuli such as those available
for activation of the auditory and visual systems.
Various mechanical devices for quick displacement of
hairs or skin or for rotation of joints are commonly
used, but few of them provide a wide range of action.
This had led many investigators to resort to electrical
stimulation of nerve trunks to achieve an exact
temporal positioning and pattern of the stimuli. It
was often believed that a dependable correlation exists
between certain groups of fibers, separable by stimu-
lus strength, and certain modalities of sensations.
However, this correlation is far from exact, and it can
hardly be doubted that the use of massive nerve \ol-
leys has led occasionally to conclusions of question-
able physiological significance. The large electrical
fields created around massive volleys traversing the
central nervous system are likely also to lead to
ephaptic excitation of neurons of perhaps completely
unrelated function. Electrical stimuli deliv^ered within
or across the skin allow a topographical positioning
of the stimulus, but since the volley e\'oked is a svn-
chronous one it cannot, of course, be easily compared
with that produced Ijy a natural stimulus. A new ad-
vance in stimulation technique is badly needed.
EXCITABILITY STATES OF CENTRAL NEURONS. The re-
markable safety factor of synaptic transmission at
relays of at least some corticopetal tactile and kines-
thetic pathways renders them in certain aspects rela-
tively immune to the depressing effects of anesthetic
agents. By contrast the activity evoked by tactile and
kinesthetic stimuli in systems which do not conduct
towards the cortex and therefore are not likely to con-
tribute directly to conscious perception are extra-
ordinarily susceptible to these depressing effects. This
differential is of great advantage for it allows a de-
tailed mapping of the place and patterns of the
central projection of the sensory surface. However,
the temporal capacity of the corticopetal systems for
transmission as well as certain other functional char-
acteristics are severely depressed by barbiturates.
The desire to retain a high level of excitability in
an anesthetized animal has led many investigators to
use chloralose as an anesthetic agent, frequently com-
bined with a neuromuscular blocking drug. While
connections revealed under these conditions un-
doubtedly exist, the abnormal excitability of the
brain calls for particular caution in evaluating the
findings obtained. Under these conditions the trans-
mission capacity revealed is as seriously abnormal in
one direction as it is in the other under deep bar-
biturate narcosis. Recently a combination of light
barbiturate narcosis with neuromuscular blocking
agents has allowed a somewhat closer approach to the
normal state. An important advance has been made
by Bremer (30, 31) by introducing the encephale isole
preparation, although the high cervical transection
makes such a preparation suitable for study of only
certain sensory somatic problems. On the other hand,
many investigators resort to the use of unanesthetized
animals held motionless by neuromuscular blocking
drugs. The latter method, apart from the hesitations
one may ha\e in using such preparations, hardly
390
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
offers a solution of the problem for the neuromuscu-
lar blocking agents themselves have powerful effects
upon central synaptic transmission. For this reason
the method of recording from electrodes chronically
implanted in the brain or upon its surface is now fre-
quently employed. Recovery of the animals from
the anesthetic allows the study of evoked electrical
activity for periods of weeks or months under condi-
tions closely approaching the normal. The developing
technique of recording from single units by means of
implanted microelectrodes promises to be fruitful.
METHODS OF RECORDING. An analysis of the electrical
signs of neural activity evoked in the central nervous
system by sensory stimuli is treated extensively in
Chapters X and XII of this volume. Here we merely
wish to point out that it is the initially positive slow
wave which has proved of great value, particularly in
the experiments designed to determine the locations
of the responsive regions and the pattern of the
sensory projection. The usefulness of this response is
hardly minimized by the fact that its nature still re-
mains obscure.
The method of single unit analysis introduced by
Adrian precipitated a rapid advance in neurophysi-
ology. So useful has it become that an appreciable
share of present day research is based upon it. Both
intra- and extracellular microelectrodes are commonly
used. Successful application of the extracellular
method requires that the unit observed be held under
study for considerable periods of time in a relatively
undamaged state. The method permits determination
of response properties and topographic and modality
attributes of a sample of cells at a given location which
allows a reconstruction of the behavior of the popula-
tion. A full reconstruction, however, would be possible
only if the sample were sufhciently large and unbiased.
This last requirement is proljably not met, for it seems
most likely that the smaller elements of the neural
population are in fact rejected by the recording instru-
ments presently available.
CURRENT THEORIES OF CUT.^NEOUS SENS.^TIONS
Classic Concept
According to the concepts developed by von Frey
(244-247) pain, cold, warmth and touch represent the
four basic modalities of cutaneous sensation and spe-
cific receptors can be assigned to each modality. The
older anatomical and psychophysical findings were
generally interpreted in the light of these notions and
unqualified support of the orthodox view was given
by the work of VVoollard et al. (275), and earlier work
by Weddell (264, 265) and VVeddell & Harpman
(266). The views of von Frey, however, did not remain
altogether unchallenged and two formulations differ-
ing greatly from the classical concepts will be briefly
considered.
Pattern Thcnry
Recently the Oxford group of workers (113, 154,
155, 220, 223, 267-269) seems to deny altogether the
existence of modality specific receptors. The conclu-
sion of the group is that different cutaneous sensations
arise not as a result of selective activation of specific
receptors but because different stimuli affect the same
sets of fibers in a different manner. Thus, in the first
order neurons different discharge patterns in the
same fiber bundle, and not a selective activation of
some fibers in the bundle, are thought to determine
the different cutaneous sensations. The reasons for
this deduction are that these workers were unable to
relate specified endings to specific modalities in sev-
eral skin areas (113, 155, 223) and that all modalities
of sensations were obtained by stimulating the cornea
(154) which is known to have free endings only.
Moreover, histological evidence led them to believe
that all endings in the skin are essentially alike since
all arborize into fine, naked, axoplasmic filaments.
They further conclude that a classification of en-
capsulated endings into various types is untenable
since a large number of morphologically intermediate
variants exists between the usually recognized types.
We believe that the Oxford workers did produce
suggestive evidence that stimulation of free endings
may cause sensations which can be classified in the
broad spectrum of touch. Such findings however do
not at all establish that specific endings do not exist,
and the conclusions drawn from histological observa-
tions do not appear convincing. If a crisis exists in
respect to evaluating the morphology of the endings,
it is a crisis of abundance and not of scarcity. One
hesitates to accept as a solution to the vexing problem
of the morphology of the encapsulated endings a
declaration that virtually all morphological differ-
ences between them are either insignificant or are due
to artifacts of the technique.
In any case, a further elaboration of the idea of the
discharge patterns led at least some workers of the
Oxford group to opinions about touch which are
closer to classical notions than one would expect.
TOUCH AND KINESTHESIS
391
Thus, Weddell el al. (267) conclude that the ana-
tomical arrangement of the axoplasmic filaments of
the encapsulated endings is such that one could expect
them — in contrast to the free endings — to be highly
sensitive to minimal deformations. A differential
sensitivity to mechanical deformation, however, is all
that could reasonably be required to declare such an
ending as specific for touch or pressure. The differ-
ence, then, between the Oxford authors and the
orthodox view in this instance reduces itself to the
proposition that the Oxford workers presumably as-
sume that discharge in some other fibers as well must
necessarily occur before a touch sensation is recog-
nized while we are inclined to think, with von Frey,
that in principle such a sensation could arise if a single
appropriate peripheral fiber were activated.
Concept of Head
An important difficulty in drawing conclusions
from psychophysical experiments is the uncertainty
about the classifying of some sensations which may-
still be called touch. This uncertainty is clearly at the
root of the controversy as to whether or not stimula-
tion of the free endings actually arouses tactile sensa-
tions. The interpretation of von Frey denies that this
is the case and considers such sensations as akin to
pain; the O.xford interpretation affirms the tactile
quality of such sensations and denies the existence of
specific receptors. Head and his collaborators (118)
proposed that there are basically two different kinds
of sensations subserved by a dual sensory mechanism
at the periphery, the more generalized and, as they
felt, more primitive or protopathic type and the more
specific and advanced or epicritic system. The idea of
the duality of cutaneous sensations was greatly elab-
orated by Head and this elaboration might have con-
tributed to the present eclipse of his concepts. Al-
though at first accepted by many, they were soon
sharply criticized, and finally Walshe (262) in his
review of the subject delivered a cou[) de grace to these
concepts by pointing out that the crucial introspective
experimental observations of Head were not inter-
preted in the same way by any of the suljsequent
observers and that his theoretical elaboration was
sometimes hazy and contradictory in details, often
incompatible with the present knowledge and always
speculative. However much one may disagree with
some of Walshe' s criticisms the fact remains that none
of the experimental observations offered by Head in
support of his ideas has been accepted by others.
The conclusion that Head did not prove his point
is, however, irrelevant for an inquiry as to whether or
not his central idea has merit. It is apparent that a
protopathic system, if it exists, is likely to be repre-
sented anatomically by free endings. The question
may then be asked whether stimulation of such end-
ings results in sensations other than pain. There are
some indications that this indeed may be the case.
Evidence to this effect seems to be at present the chief
support for the pattern theory of the Oxford workers,
even though such findings could argue, in better
harmony with other well established facts, for the
existence of protopathic .sensibility.
Another hint that a protopathic system may exist
is offered by studies of action potentials in peripheral
nerve. We shall discuss these in some detail later. Here
it is sufficient to state that there is evidence that im-
pulses evoked by tactile stimuli are conducted in both
myelinated and unmyelinated fibers. Finally, the fact
that activity aroused by tactile stimuli is conducted
within the spinal cord in at least two independent
ascending pathways could be utilized to argue that
the idea of duality of the tactile system does not appear
unreasonable.
It should be apparent from these remarks that it is
not proposed at present to revive the concepts of epi-
critic and protopathic sensibility. We wish only to
point out that an unqualified rejection of these con-
cepts may be premature and that Head's ideas in some
form may yet prove useful in the future.
SOME PROPERTIES OF PERIPHERAL SOMATIC
AFFERENT SYSTEM
Receptors
It is convenient to consider the receptors both in
this section and in the one which deals with the cen-
tral events. In order to avoid repetition we shall con-
sider here primarilv those properties which have a
bearing on their specificity.
SPECIFICITY OF RECEPTORS. Whatever opinions one
may hold about the way tactile stimuli arouse sensa-
tions it is fundamental to recognize that there are
some receptors which are specifically sensitive to such
stimuli. Conclusive evidence in this respect is provided
by studies of discharges, usually of single units, when
mechanoreceptors are activated by natural stimuli.
In many of these studies (4-6, 16-18, 29, 42, 68, 94,
124, 127, 161, 187) the existence of a specific receptor
is inferred from the behavior of the neural discharge;
392
HANDBOOK OF PHYSIOLOGY'
NEUROPHYSIOLOGY I
in some (12, 105-108), the receptors themsehes were
identified.
It was observed early and since confirmed by all
workers in the field that the largest fibers in the cu-
taneous nerves are activated by certain types of
tactile stimuli. It may be stressed immediately that
the converse statement does not hold and that ac-
ti\ity aroused by tactile stimuli i> nut limited to large
fibers only. Since for technical reasons discharges
occurring in large fibers are particularily convenient
to study, the information given below regarding
tactile receptors pertains to those which are con-
nected to such fibers.
The specificity of tactile receptors manifests itself
both in their exquisite sensitivity to mechanical
stimuli and in their lack of sensitivity or high threshold
for other than such stimuli. The threshold to mechan-
ical stimuli is low, apparentlv commensurate with the
capacitv of the animal to recognize them, and the
details of mechanical application of the stimulus are
as a rule critical for evoking discharges. Direct meas-
urements made on the mesenteric Pacinian cor-
puscles (105) indicate that the minimal movement of
the stimulus probe necessary to excite the receptor is
of the order of 0.5 m in too /xsec; the Pacinian cor-
puscle in the toe (107) showed a similar sensitivity.
There are no figures available for any other ending.
From qualitative observations, though, there is no
reason to doubt that at least a number of them is
equally sensitive.
The problem of sensitivity of mechanoreceptors to
other than tactile stimuli has attracted but casual
interest of most observers, chiefly because it is known
that thermal and painful stimuli characteristically
cause discharges in the smaller spectrum of fibers.
Ne\ertheless, it was observed by .\drian & Umrath (5)
that thermal stimuli did not excite the mechanorecep-
tors they studied, and Hogg (127) stated that thermal
and chemical stimuli are less effectise in the frog in ac-
tivating large fibers than small ones and that the re-
verse is true for tactile stimuli. Hensel & Zotterman
(124) recently presented interesting data on the re-
sponse of some mechanoreceptors to cold. In the
tongue of the cat they found mechanoreceptors not
sensitive to strong thermal stimuli as well as thermo-
receptors unresponsive to tactile excitation. In addi-
tion to these receptors they also found a group of fibers
which responded both to pressure and to cooling. The
response to cold differed in important aspects from the
response of a typical thermoreceptor for the response
occurred only to ver\ low temperatures and rapid
cooling (while thermoreceptors respond with a sensi-
ti\ity to about a tenth of a degree below 40°C:) and it
adapted to extinction within a few seconds (while a
typical response to cooling persists for as long as the
stimulus is applied). How to interpret such a response
to cooling is an open question. It is conceivable that it
represents a secondary effect due, for example, to a
displacement of a mechanoreceptor through vasocon-
striction, although this interpretation is considered as
rather unlikely by the authors.
TYPES OF DiscH.\RGES. The mechanorcceptors in the
skin can be divided into fast and slowly adapting
types. Most receptors activated by displacement of
hairs are fast adapting. Those responding to pressure
adapt either fast or slowly. It is of interest that recep-
tors activated by kinesthetic stimuli appear to have
the same properties as the mechanoreceptors in the
skin although the slowly adapting ones seem to pre-
dominate greatly in numbers (29, 225).
It is unfortunately not known how the morpho-
logical structure of the ending relates to the dis-
charge pattern since, except for the Pacinian cor-
puscle, none of the other receptors has ever been
studied in isolation. For that reason the significance
of the capsule and of the accessory fibers is entirely
obscure. Recently Boyd (28) and Skoglund (225)
identified Ruffini's endings in the joint capsule as
slowly adapting receptors and the modified Pacinian
corpuscles as the fast adapting ones. These identifica-
tions, howe\er, must be considered tentative since
they are indirect. The Pacinian corpuscle, the best
known receptor at present, is fast adapting (107). It
is known for this receptor (106) that its adaptation to
mechanical stimuli is a property of the receptor itself
rather than of its fiber. Loewenstein C161), working on
frog's skin, presented some data to suggest that a
fast adapting receptor may be made to discharge for
a long time if the tension in the receptor region is
greatly increased, thus implying that whether an
ending adapts quickly or slowly may be determined
by the mechanical arrangement of the ending. If this
be so, the degree of coiling of the terminals could be a
determining factor in whether a receptor is fast or
slowlv adapting. The merit of this suggestion 'is at
present difficult to evaluate.
RECEPTOR POTENTi.\L. As already mentioned, the
only receptor the functional properties of which
have thus far been studied is the Pacinian corpuscle.
It has been recently established by Alvarez-Buylla &
de Arellano (12) that mechanical stimuli produce a
local response which Gray & Sato (108) propose to
TOUCH AND KINESTHESIS
393
call a receptor potential since this potential — in con-
trast to the local response of the nerve — is not affected
by near absence of sodium. The receptor potential
can summate and its amplitude depends on stimulus
strength. It is set up in less than 0.2 msec, and is the
earliest electrical event which is known to occur.
While the mechanism of its generation is at the mo-
ment quite obscure, its occurrence provides a final
indication — if such be needed — that the Pacinian
corpuscle must be regarded as a full-fledged receptor.
An electronmicroscopical description of its fairly
complex structure has been given recently by Pease &
Quilliam (195). The mechanism of excitation of
Pacinian corpuscles is discussed by Gray in Chapter
I\' of this work.
Peripheral Cutaneous Nerve Fibers
IMPULSES IN PERIPHER.AL NERVE FIBERS. ThuS far WC
have discussed only to what extent discharges in single
units reflect some properties of the receptors which
initiate the impulses. We shall now turn to electro-
physiological evidence derived from studies of cutane-
ous nerves. Since all experimental data are derived
either from studies of single units or from studies of
the electroneurogram, it will be useful to recall some
properties of the peripheral fibers.
As is well known, a cutaneous nerve consists of
fibers of different sizes. Fibers of different diameters
do not, however, occur with equal frequency and
the size-frequency distribution curve for any cutane-
ous nerve shows characteristically several peaks. It is
customary to classify all fibers into A, B and C groups
according to certain characteristics of their action
potentials which are different for each of them. How-
ever, it is unnecessary to relate here these character-
istics since in the cutaneous nerves only A and C
fibers are known and the myelinated and unmye-
linated fibers form the A and C groups, respectively.
It is known that the velocity of conduction in A
fibers varies with their diameters. If an as.sumption is
made that the amplitude of the action potential as
recorded across the membrane is about the same for
any A fiber but that the height of the externally re-
corded potential varies as the square of the diameter
of the fiber, it is possible to estimate the size of the
fiber from the externally recorded amplitude of the
discharge in a single unit preparation. Making these
assumptions for the entire nerve the shape of the com-
pound action potential can be reconstructed with
great accuracy if the fiber composition of the nerve is
known. Conversely, it is justifiable to infer from the
different elevations of the electroneurogram the
presence of fiber groups of specified diameters in a
given nerve. Usually, Greek letters are used to denote
the different elevations, each successiv-e letter referring
to a group of fibers of smaller diameter (fig. i). Some
confusion resulted occasionally in the past with the
use of this notation, for different nerves do in fact
differ in their fiber compositon and thus an elevation
denoted by the same letter in different nerves may
indicate at least somewhat different fiber groups. For
the corresponding nerves in the same species the dis-
tribution of fibers is, according to Gasser (88), quite
constant.
IMPULSES EVOKED IN FIBERS OF DIFFERENT SIZE BY
T.-iiCTiLE STIMULI. All workers agree that tactile stimuli
activate the largest fibers in the cutaneous nerves and
those who distinguish gentle contact (touch) from
sustained displacement (pressure) invariably state
that it is a gentle contact which activates the largest
fibers. Maruhashi et al. (168) report that the diam-
eters of the fibers activated hy touch vary between 8
to 14 /J in the cat and 8 to 15 |i in the frog. They
further found that movements of hairs activate fibers
in the range of 6 to 1 2 /i, while diameters of fibers
FIG. 1. Compound action potential of the saphenous nerve
of the cat recorded at a distance of 54 mm from the locus of
stimulation. Several elevations (denoted by Greek letters) are
recorded because, in the nerve, fibers of different sizes are
giouped around several peaks. Since the saphenous nerve lacks
the largest afferents arising from the muscle stretch receptors
no a elevation is indicated even though the sizes in the a and
(3 groups overlap. The /3 and 7 elevations as denoted here are
sometimes referred to as a and 0 peaks. All elevations pertain to
\ fibers. The elevation due to C fibers is not shown. Time
line: 5,000 cps.
394
HANDBOOK OF I'HYSIOLOrn-
NEUROPHYSIOLOGY I
excited by pressure are 3 to 5 /i in the cat and 4 to 5 m
in the frog. In addition, unmyelinated fibers of the C
group were seen by them to be activated by mechan-
ical stimuli both in the cat and frog.
The findings of the Japanese observers confirm the
older observations of Zotterman (282) who, recording
from strands of the saphenous nerve of the cat, noted
that, apart from the usual discharges evoked by
tactile stimuli in the large fibers, discharges were
evoked in smaller fibers also by very light stroking of
the skin. These potentials contribute to the delta ele-
vation of the electroneurogram of the saphenous
nerve and Zotterman judged the appropriate fibers to
be in the range of 5 to g n. He also noticed that with
stroking of the skin the delta potentials are followed
by a ca.scade of very small spikes which he felt must
be conducted by the C group of fillers.
REL.'^TION OF CUT.'>iNEOUS STIMULI TO ACTIVITY IN
FIBERS OF DIFFERENT SIZE. Observations on single units
indicate then that tactile stimuli can activate at least
several groups of afi'erent fibers and, if the data of the
Japanese workers are taken as a basis, the conclusion
seems inescapable that no fiber whatever within
either the A or C group can be eliminated by virtue
of its size alone as potentially responding to tactile
stimuli. Nevertheless, the data imply that a relation
may exist between the size of a fiber and the exact
quality of the mechanical stimulus which activates it.
The conclusion that fibers of all sizes may be activated
by mechanical stimuli must not imply that all fibers
in the cutaneous nerve can Ije activated by them. If
this were so, each fiber activated by other than me-
chanical stimuli would also be responsive to tactile
stimulation. This is apparently not the case since at
least some fibers which are selectively activated by
thermal stimuli have been shown to exist (120-123,
281).
The problem of C fibers is of special interest. There
is evidence available (22, 46, 149, 168, 282) that
nociceptive stimuli can activate such fibers. From the
experiments in which C fiber activity could be identi-
fied with certainty it has been inferred (46) that at
least some thermal stimuli (warmth) can also cause C
fiber activity. All workers who used single unit
preparations and were concerned with this question
(127, 168, 282) have concluded that not only nocicep-
tive but cold, warmth and mechanical stimuli acti-
vate C fibers as well. It should lie noted that with the
single fiber technique it may not always be possible
to decide that a C fiber and not a small A fiber has
been activated. Nevertheless, the evidence suggests
indeed that C fibers can be acti\ated by all modes of
cutaneous stimulation.
In contrast to the findings about A fibers there is
no conclusive evidence, either for or against, concern-
ing selective sensitivity of single C fibers to various
stimuli. It thus remains an open question to what
extent the C fibers resemble the A system.
RELATION OF ELEV.\TIONS OF ELECTRONEUROGRAM TO
MODALITIES OF SENSATION. The findings derived from
observations of single units seem to agree with the
studies which relate the different elevations of the
compound action potential to the results of psycho-
physical and animal experiments in which the periph-
eral nerve is blocked by infiltration with local anes-
thetic, made ischemic or excited by electrical
stimuli.
It has long been known for man that perineural
injection of cocaine (or a similarly acting agent)
blocks sensations in a preferential order in such a
way that cold, warmth, pain and touch disappear in
the order stated. There is some discrepancy among
various observers whether it is cold or pain which
disappears first, but there is an almost unanimous
agreement that it is touch which disappears last. [For
some discordant oljservations and a review of the
literature .see Sinclair & Hinshaw (221, 222).]
Since Gasser & Erlanger (89) demonstrated that
cocainization Ijlocks conduction in an orderly se-
quence, the smallest fibers being blocked first, it can
be inferred that the largest fibers in the nerve are
activated by tactile stimuli. This conclusion, of
course, is but a confirmation of the firmly established
findings discussed earlier. It should be stressed that
cocaine block does not permit any conclusions as to
whether smaller fibers which can be activated by
touch exist, but it does imply that activity in a group
of the largest fibers alone may be quite sufficient for
the arousal of tactile sensations. Direct stimulation of
an exposed nerve in man (119) leads to an identical
conclusion since it is possible to excite only the largest
fibers with an appropriate stimulus and since such
stimuli lead only to an arousal of tactile sensations.
In contrast to a block produced by a local anes-
thetic, application of pressure over a limb of man
leads to disappearance of sensations usually in the
following order: touch, cold, warmth, pain. In experi-
ments of Clark, Hughes and Gasser as reported by
Gasser (87), compression of a limb of a cat led first to
a conduction failure of the delta fibers and of the
largest fibers in the ner\e. The exact prosjre.ss of the
conduction failure was difficult to establish, but it was
TOUCH AND KINESTHESIS
395
clear that the failure did not follow an orderly se-
quence according to fiber size. The important finding
was that even after the entire spectrum of A fibers
failed to conduct, the C elevation was only little im-
paired. It can thus be concluded that C fibers are
more resistant to ischemia than is the A group and
since manifestations of painful sensations are still
evokable when only C fibers conduct, one can infer
that painful stimuli must activate at least some C
fibers. While this finding again agrees with what has
been more recently shown by other methods, one can
conclude in addition that activity in C fibers alone is
apparently sufficient to arouse painful sensations. It
could have been expected perhaps that some tactile
sensations should be present as long as C fibers are
conducting if it be true that mechanical stimuli excite
such fibers. The negative findings may mean, of
course, that there are no C fibers activated by touch.
It may mean as well that activity in C fibers aroused
by tactile stimuli under the experimental conditions
tested are not interpreted as touch, or finally even that
some perhaps obscure qualities of tactile sensations
which actually were present were ignored by the ex-
perimenters and the experimental subjects alike.
SUMMARY. It appears that the availaljle neurophysio-
logical evidence in respect to the peripheral aspects
of the tactile system does not support fully any of the
current ideas regarding tactile sensations.
Despite the arguments advanced by the Oxford
workers the evidence seems conclusive that there
e.xist in fact specific tactile (as well as thermal) recep-
tors, The evidence is also good that the fiber size may
be indicative of connections with some specific recep-
tors. Thus, the known thermoreceptors seem con-
nected with small or medium sized fibers only, while
the largest fibers in the cutaneous nerve are con-
nected to mechanoreceptors. Bishop (21} points out
further that the largest afferent fillers known in the
peripheral nerves do not occur at all in the cutaneous
branches, and it seems clear that these fibers are con-
nected to the muscle stretch receptors. To this extent
then von Frey's concepts appear valid. The fact that
tactile stimuli can activate A fibers of different sizes
may or may not he compatible with the classic ideas.
What seems difticult to reconcile with von Frey's con-
cepts is the suggestive evidence that C fibers (which
presumably ramify in free endings only) are also acti-
vated by tactile stimuli. If this should be so a major
question to be answered would be whether individual
somatic C fibers are modality specific or whether an
individual fiber is e.xcited by tactile as well as by
thermal and nociceptixe stimuli. If the latter should
be the case, the classical concepts would clearly
need a major revision obviouslv in the direction of the
ideas expressed by Head.
CENTR.\L TACTILE AND KINESTHETIC SYSTEMS
General Remarks
It is well known that the dorsal root fibers ramify
upon entry into the central nervous system and, by
means of their main ijranches and collaterals, estab-
lish synaptic contacts with .several nuclear regions. It
is convenient to divide into two classes those regions
to which discharges aroused by tactile stimuli can be
relayed. The first is formed by regions which are, or
which can be reasonably assumed to be, instrumental
for generation of tactile sensations. To the second class
belong those regions which are either not at all .sen-
sory, as in the case of the anterior horn cells, or those
which receive afferent information but for which
there is no reason to believe that their function has an
essential bearing upon tactile or kinesthetic experi-
ence. It is thus clear enough that the appearance of
evoked neural activity in a given synaptic region fol-
lowing tactile stimulation may indeed mean that the
region in question is relevant for tactile sensations.
.Such responses, however, may equally well merely
indicate that some other activ'ity, not necessarily even
sensory in nature, is modulated by the activity of
tactile receptors. Considerable confusion exists in the
literature in respect to this problem, since many
workers seem to believe that a response evoked any-
where in the central nervous system by tactile stimuli
is prima facie evidence that the locus in question is
linked somehow to tactile sensations. If one considers
that most morphological groupings in the central
nervous system establish synaptic contacts with
more than one other morphological entity, the
numijer of potentially activated synaptic regions may
be expected to increase in geometrical progression
with each synaptic relay. It is likely, therefore, that
within a short time a signal in an afferent filler could
be relayed, at least in principle, to almost any group-
ing within the central nervous system.
Hence it is not unduly surprising if under certain
experimental conditions a response to a tactile stimu-
lus occurs in a region which anatomically appears to
be an altogether unlikely locus. It is fortunate indeed
for an analysis by electrophysiological methods that
all potentialities for synaptic transfer are for a num-
396
HANDBOOK OF PH'iSIOLOOV
NEUROPHYSIOLOGY I
ber of reasons actually not realized, and that tactile
and kinesthetic stimuli activate usually only a limited
number of synaptic regions, even though this number
varies considerably under difTerent experimental con-
ditions.
In the sections which follow we shall concern our-
selves almost exclusively with pathways and synaptic
regions \vhich are demonstrably significant for tactile
and kinesthetic sensations. We shall not consider the
problem of how stimulation of tactile and kinesthetic
receptors may affect other activity in the central
nervous system.
Classification oj Central Tactile and fiiiieslhetic Systems
It is well known that tactile or kinesthetic dis-
charges or both are conducted centripetally in the
posterior columns of the spinal cord, in its antero-
lateral columns and in the trigeminal pathways. It
also seems evident that such impulses can enter the
central nervous system through the roots of the ninth
and tenth cranial nerves, and there is good evidence
(197) that some chorda tympani fibers may be acti-
vated by mechanoreceptors.
It is both convenient and almost certainly correct
to consider together the systems arising in the posterior
column nuclei and the one arising in the maiia sensory
trigeminal nucleus. We shall refer to them as com-
ponents of the inedial lemniscal system. Likewise, we
shall consider the spinothalamic system as consisting
of two components. The first is the spinothalamic
tract arising in the posterior horns of the spinal cord
and the second is the spinothalamic tract arising in
the spinal nucleus of the fifth nerve. W'e shall refer to
the latter, following White & .Sweet (273), as the
bulbothalamic tract.
MEDI.'^L LEMNISCAL SYSTEM
Anatamical Definition
This system is the better known of the two, both
anatomically and functionally. Anatomically we shall
mention here only the centripetal terminations of the
successive axons in the system. Some collateral con-
nections relevant for our considerations will be dis-
cussed later. The spinal component of the system is
formed by axons emanating from the cells of the
spinal ganglia and ascending on the homolateral side
of the cord in the posterior column and synapsing on
cells in GoU and Burdach's nuclei; by axons originat-
ing from the cells of these nuclei, crossing (as far as is
known, entirely) to the opposite side and ascending in
the medial lemniscus to end upon the cells of the
external component of the thalamic ventrobasal
complex; and by axons originating in the cells of the
latter element and projecting upon the postcentral
cortex or its homologue.'
The trigeminal component of the lemniscal system
arises in the main sensory nucleus of the fifth nerve.
There is complete agreement among most observers
that the main outflow of this nucleus consists of axons
crossing to the opposite side. The pathway adjoins
mediodorsally the medial lemniscus, forms an integral
part of it and terminates in the arcuate component of
the ventrobasal complex. The cells of the latter
project, as do the cells of the external element, upon
the postcentral cortex.
In addition to the crossed \entral pathways men-
tioned aijo\e, a dorsal pathway originating in the
main sensory nucleus and reaching the thalamus via
a tegmental route is frequently described. Consider-
able uncertainty prevails, however, about the origin
of this tract, its components and its terminations in
the thalamus. Wallenberg (261) described an un-
crossed and a crossed component and believed that
' It is customary to consider n. vcntialis posteromedialis and
n. ventralis posterolateralis as the two tactile thalamic nuclei.
We refer, however, to the principal tactile thalamic region as
the ventrobasal complex and distinguish within this complex the
arcuate or medial component, which receives the trigeminal
projection, and the external or lateral component, which
recei\es projections from the rest of the body (207). The reasons
for this nomenclature are as follows. First, the two components
of the ventrobasal complex are almost identical in their archi-
tecture and for that reason should not be divided into two
separate nuclei. Actually in the rabbit such a separation is very
difficult while in the cat and monkey it is best done on the basis
of a dividing fibrous lamella. Second, most workers include
into their n. ventralis posteromedialis a ventromedial element
which is not activated by tactile stimuli and which displays
structural characteristics of its own, which are different from
those of the arcuate portion of the ventrobasal complex. Only
Jimenez-Castellanos (136) and Jasper & Ajmone-Marsan (135)
do not include this element in the n. ventralis posteromedialis.
The latter workers, however, consider as a part of this nucleus a
portion of the posterior thalamic group. Likewise, n. ventralis
posterolateralis is with many workers not coextensive with the
lateral component of the \'entrobasal complex. Thus Olszewski
(i8g), for example, distinguishes within his n. ventralis posterior
lateralis an oral part which is not activated by tactile stimuli
and a caudal part which corresponds probably exactly to the
lateral component of the ventrobasal complex.
In respect to the sensory somatic cortical field we shall use
interchangeably the following terms: first somatic field, post-
central cortex (areas i to 3 in primates), postcentral homologue
and primary receiving area.
most but not all of the fibers of these tracts terminated
before reaching; the thalamus. Walker (254) confirmed
in essence Wallenberg's observations and concluded
that the uncrossed fibers predominate and that many
terminate in the most medial portion of the arcuate
nucleus. Other workers (40, 117, igi, 192) reported
that the tract is uncrossed and that it terminates in
the arcuate nucleus or in the centrum medianum, or
in both. Recently Torvik (239) presented evidence on
the basis of retrograde cell degeneration that the
dorsomedial sector of the main sensory nucleus pro-
jects to the homolateral thalamus while the rest of this
nucleus projects to the contralateral side, thus con-
confirming some older observations (140) in this
respect.
Since physiological evidence is conclusive that
both the contralateral and ipsilateral face areas are
represented in the arcuate sector of each ventrobasal
complex, it is tempting to assume that the uncrossed
tegmental trigeminal pathway exists and that it relays
tactile and kinesthetic impulses from the homolateral
face. Moreo\er, Hatschek's observation (117) that
the uncrossed tract is particularly prominent in un-
gulates would fit with the findings of Woolsey &
Fairman (277) that the ipsilateral cortical face areas
are unusually large in the pig and sheep. However,
there are also some reasons to doubt the correctness
of this assumption. First, it is obvious from the contro-
versy over whether this tract is both crossed and un-
crossed, only uncro.ssed, or whether it exists at all
(214), that different workers placed significantly
different lesions in their animals and there is no con-
vincing evidence that this tract necessarilv arises in
the main sensory nucleus. Second, it would be diffi-
cult to understand why homolateral tactile and
kinesthetic impulses should utilize a tract which is
quite different in its fiber composition from the ven-
tral pathway and why the homolateral tract should
lie so far apart from the contralateral one. Finally, the
usual observation of recent workers that the tract
ends in the most medial sector of the arcuate nucleus
does not immediately establish that it relays tactile
impulses, for in contrast to our own definition of the
arcuate component most workers include in it not
only the tactile thalamic trigeminal region but also
a ventromedial element (diff"ering considcraijly in
structure from the arcuate nucleus) which in our
opinion is not activated by tactile stimuli. It has been
suggested (207) that this element may be connected
with taste. It is of interest to point out that von
Economo (243) suggested a long time ago that the
TOUCH AND KINESTHESIS 397
dorsal trigeminal tract is in fact concerned with
gustatory impulses.
Physiological Properties
It has been known for a long time that destruction
of the posterior columns in man leads to a loss of the
capacity to appreciate the position and the movement
of the limbs, and to an inability to recognize the vi-
brations of a tuning fork applied over the bone. The
disturbances in tactile sensations were the subject of
some dispute. It seems reasonable to believe, how-
ever, that there is a severe impairment in the appre-
ciation of the spatial and temporal sequence of a
series of stimuli. In addition, increases in threshold
for tactile stimuli, a diminution in the number of
'sensory spots' and an impairment in proper localiza-
tion of the stimulus is often described.
A general property of the lemniscal system is that
the information concerning the form, natiu'e, location
and temporal sequences of the impinging stimuli is
transmitted at each synaptic station with great secur-
ity. From the point of view of its organization, the
medial lemniscal system displays two striking features.
The first of these is that the peripheral sensory sheet
is projected centrally in a precise pattern, which is
preserved to a considerable degree through the suc-
cessive relays of the system, and is finally impressed
upon the postcentral cortex. The second is that the
system encompasses within a single tcjpographical
pattern several submodalities of the general sense
of mechanoreception. We wish to discuss the system
from these two \iewpoints.
PROJECTION P.iiTTERNS IN MEDL-^L LEMNISCAL SYSTEM
Patterns in Dorsal Columns
The weight of the evidence indicates that the large
majority of ner\e fibers reaching the dorsal column
nuclei by way of the dorsal columns are axons of
first order neurons. It is not known that they are
exclusively so, however, and it is possible that some
unknown number arises from cells within the spinal
cord, cells which are activated by dorsal root afferents
and are therefore fibers of the second order. In the
cat some 25 per cent of the dorsal root myelinated
fibers which enter the dorsal columns at the seg-
mental level are believed to reach the cells of the
dorsal column nuclei directly (98).
Examination of Marchi degenerations in the dorsal
398
HANDBOOK OF I'HYSIOLOG"!'
XEl'RnpHVSIOLOGY I
FIG. 2. Topical organization of libers in the posterior column
and in the posterior column nuclei. The upper two cross sec-
tions (M) refer to the medulla, the lower five to the coccygeal
(I. Co.), sacral (I. S.), lumbar (I. L.), thoracic (II. Th.) and
cervical (I. C.) levels of the spinal cord. The relative positions
of fibers are indicated by dots for the coccygeal fibers and by
crosses, dashes, dots and dashes and triangles for fibers of
successively higher segments, i : nucleus gracilis; 2 to 4: com-
plex of nucleus cuneatus; 7 : descending root of the fifth nerve.
[From Glees et al. (97).]
columns following section of dorsal roots, or transec-
tion of the dorsal columns al various levels, indicates
that the centrally projecting fibers are arranged in an
orderly lamination (43, 65, 66, 70, 97, 258). Those
from each successively higher segment are arranged
in a series of successively more lateral laminae of fibers
(fig- 2).
Patterns in Dorsal Column Nuclei
As figure 2 shows, this precise lamellar arrangement
of the fibers of the dorsal cohunns is unchanged in the
dorsal column nuclei. Fibers from the caudal seg-
ments terminate in the most medial portion of nucleus
gracilis, those from sacral, lumbar and at least the
lower six thoracic roots terminate in successively
more lateralis' placed dorsoventrally directed lamel-
lae. Glees et al. Qqj') belie\^e that all thoracic roots
with the exception of the first terminate in this
nucleus. Fibers from the upper thoracic and from the
cervical roots terminate in nucleus cuneatus in a
similar lamellar arrangement. Other fibers of the
upper thoracic and of the cervical roots ascend in the
dorsal columns and terminate in a topographically
arranged pattern in the lateral cuneate nucleus,
whose cells in turn project upon the cerebellar cortex.
The Marchi material suggests the existence of a
considerable overlap between the terminals of neigh-
boring fibers. However, it has been shown (97, 98) by
using silver staining methods that intersegmental
overlap is minimal, though intrasegmental overlap
of the fields of termination occurs. This latter is
accentuated by the numerous branching dendrites
which reach into the synaptic fields of neighboring
cells. The linage of the body form thus composed by
this projection is distorted to allow greater volume
representation for those body parts which are heavily
innervated by afferent fibers.
One looks to electrophysiological methods for finer
details of the representation pattern. The lamination
pattern in the dorsal columns has been confirmed
(280). It appears, however, that only one study has
been made of the projection pattern in the dorsal
column nuclei, and that has been reported in only a
short note. Using physiological stimuli Kuhn (145)
has mapped the projection of the body surface upon
the dorsal column nuclei. He found the ipsilateral
body surface of the cat to be represented within the
caudal portions of the dorsal column nuclei as an in-
verted figure of the animal, with the tail pointed
dor.socaudally, extremities dorsally. No responses were
recorded following stimulation of the contralateral
side.
Unfortunately there are no experimental data to
indicate the pattern of projection of the first order
neurons of the trigeminal nerve upon the cells of the
main sensory nucleus of the fifth. That a detailed and
well differentiated pattern must exist therein is indi-
cated by the pattern formed by the terminals of the
second order elements within the thalamic relay
nucleus (see fig. 3). This latter pattern contains also
an ipsilateral projection of the peri- and intraoral
structures which are partially superimposed upon the
contralateral pattern of representation of the same
TOUCH AND KINESTHESIS 399
r<=i ci
m ^ m i^ -- %
-S- #■ '#■ •% <
-Q -y^ # c
h.!-
^-^
c=i*
(*
6
■7=
8
FIG. 3. Figurine map depicting the representation of the body surface in the ventrobasal thalamic
complex of the monkey, Macacus rhesus, constructed from data obtained in an evoked potential experi-
ment under deep barbiturate anesthesia. Inset drawing shows diagrammatically the thalamic struc-
tures in a Horsely-Clarke plane ^frontal plane 6). Dots indicate points at which electrical activity
was evoked by tactile stimulation of the body surface. For each dot in the inset an appropriately
located figurine is shown. No responses were obtained elsewhere along the explored electrode tracks.
Body areas, stimulation of which evoked large, smaller or small responses are shown in the figurines
by solid black, cross-hatching or diagonal lines, respectively. The body is represented contralaterally
except for the face and intraoral structures which are bilaterally represented. Numerals indicate the
mediolateral and vertical Horsley-Clarke coordinates. MD: raediodorsal nucleus; CM: centrum
medianum; GLD: dorsal lateral geniculate body; VBarc: arcuate component of the ventrobasal
complex; VBex: external component of the ventrobasal complex; VM: ventromedial nucleus; /.- the
inferior portion of the ventral nuclear group. [From Mountcastle & Henneman (185).]
facial regions. Whether this projection depends upon
ipsilaterai axons from the main sensory nucleus
traveling in the dorsal trigeminal tract is conjectural
(see p. 398).
Patterns in Thalamic Relay Nucleus
DEFINITION OF TH.^L.^Mic RELAY NUCLEUS. Evidence
from several experimental approaches indicates that
the ventrobasal complex, consisting of an external
and an arcuate portion, is the thalamic relay for the
medial lemniscal system. Tactile and kinesthetic ac- ,
tivity is relayed through it to the first somatic area of
the cortex. In carnivores and priinates this region of
the thalamus is distinguished from its neighbors in
the ventral thalamic group by a special cytoarchi-
tecture. It contains neurons which vary widely in size.
These sizes are grouped around two means, though in
400
HANDBOOK OF PHVSIOLOGV
NEUROPHYSIOLOGY I
the posterior third of the complex this difference is
less obvious (50). It is the thalamic area as defined
here which receives the terminals of axons of the as-
cending lemniscal system (40, 47, 48, 56, 67, 1 70,
200, 203, 242, 252, 260), and it is this thalamic com-
plex alone which undergoes retrograde degeneration
following lesions of the cortex confined to the post-
central homologue (49, 50, 143, 253). The method
of local strychninization and observation of the in-
duced behavioral changes yielded results in accord
with these facts, though the method is too crude
for any detailed analysis (59, 60). Finally, electro-
physiological experiments are consistent with the
notion that the principal area of the thalamus acti-
vated by tactile and kinesthetic stimulation of the
body is coextensive with the ventrobasal complex
(164, 182, 184, 185, 207). Two questions in this regard
require further comment.
DIRECT SPINOCORTICAL AND BULBOCORTICAL PATH-
WAYS. It is an old suggestion that certain ascending
sensory somatic fibers of spinal or dorsal column nuclei
origin might reach the cerebral cortex directly without
an intervening synaptic relay in the diencephalon. In
1890, Flechsig & Hosel (69) put forward this conten-
tion, having found some degenerations in the medial
lemniscus of a patient who died following a lesion be-
lieved to be limited to the cerebral cortex. This idea
was supported by Tschermak (240) but vigorously
opposed by other workers who failed to confirm
Flechsig & Hosel's observation and who concluded
that the fibers of the medial lemniscus all terminate
in the diencephalon. This latter view is widely sup-
ported by virtually all more extensive neuroanatom-
ical studies and prevails even though some dissent-
ing observations are occasionally described (186).
Recently Brodal & Walberg (35) and Brodal &
Kaada (33) revived again the question of the exist-
ence of both the direct bulbocortical and the spino-
cortical tracts. The first is stated to arise from cells of
the dorsal column nuclei and to project bilaterally
upon the cerebral cortex by a pathway which joins
the pyramidal tracts of either side. The second is be-
lieved to derive from neurons of the spinal cord and
to ascend directly therefrom to the cortex in the pyram-
idal tracts. Both pathways are said to be activated
by electrical stimulation of either cutaneous or muscle
nerves. However, the anatomical evidence adduced
by Brodal & Walberg does not appear to be suffi-
ciently crucial to settle this old dispute, and the
electrophysiological observations of Brodal & Kaada
need not imply the existence of such direct pathways
according to the findings of Patton & Amassian
(193) and of Landau (148).
IPSILATERAL PATHWAY FROM DORSAL COLUMN NUCLEI
TO VENTROBASAL COMPLEX. It is clear from a large
number of studies that, in so far as anatomical
methods can determine, the entire upward outflow of
the dorsal column nuclei ascends to the thalamus of
the contralateral side and terminates largely within
the ventrobasal thalamic coinplex. These observations
accord well with the results of electrophysiological
mapping experiments, which indicate that only the
contralateral body surface is projected via the lem-
niscal system upon the ventrobasal complex, while
the trigeminal component of this system does contain
an ipsilateral component, partially overlaid with the
contralateral one. This pattern of projection is fur-
ther confirmed by our single unit observations in the
thalamus (Mountcastle, V. B. & J. E. Rose, unpub-
lished observations). Moreover, single unit studies of
the postcentral homologue in cats and monkeys
indicate that its cells are activated only by stimulation
of the contralateral body surface, except for the tri-
geminal inflow (181; and Mountcastle, V. B. &
T. P. .S. Powell, manuscript in preparation). Many
observers do not agree with these findings, however,
and they report ipsilateral responses in the region of
the thalamus, evoked by natural stimuli or by periph-
eral nerve, brachial plexus or dorsal column electrical
stimulation (20, 51, 52, 90, 91, 116) although Berry
et al. (20) found that direct electrical stimulation of
one dorsal column evokes electrical activity only in
the contralateral thalamus. The latter observation is
of interest for it may provide a clue for the interpre-
tation of the divergent findings. E\idence is accumu-
lating (see p. 419) that in contrast to the medial
lemniscal system the spinothalamic system does pos-
sess an ipsilateral component from the body surface,
which may terminate partlv or wholly in the .segment
of the posterior thalamic group which adjoins the
ventrobasal coinplex posteriorly. It seems possible
that the workers who obtained ipsilateral responses
from stimulation of the body surface or nerves ob-
tained them actually in the region which lies pos-
teriorly to the ventrobasal complex. While this inter-
pretation would harmonize the existing discordant
findings, it would not immediately explain why ip-
silateral stimuli fail to actix'ate (at least under condi-
tions of moderate anesthesia) the ventrobasal complex
itself — as could be expected — unless one assumes that
TOUCH AND KINESTHESIS
401
the functional significance of the ipsilateral inflow
diflPers materially from that of the contralateral one.
PATTERNS IN TACTILE THALAMIC AREA. Detailed in-
formation regarding the pattern of projection of the
lemniscal system upon its thalamic rela\' nucleus is
provided by studies using the e\oked potential tech-
nique. This method, as applied to study of the thala-
mus, involves passing a recording electrode down
through the thalamus in successive rows of penetra-
tions so placed as to explore the thalamic areas acti-
vated. At successive intervals during its downward
passage the electrode is held stationary and the area
of the body surface in which stimulation evokes elec-
trical activitv at a given point is determined. The
figurine drawings which can be constructed from the
data for each point are placed in proper relation to
one another and to the thalamic nuclear outlines, as
determined by study of the serial sections of the ex-
perimental brains (182, 184, 185, 207). The pattern
of representation in the monkey is shown in figure 3.
Analysis of this figure reveals that the body surface
of the monkey is represented as a distorted image of
the animal. The face and head are represented within
the arcuate portion of the ventrobasal complex, the
liody in its external element. The middorsal line of the
body from nose to tail is represented across the top
of the complex, the trunk and girdle regions, proxi-
mal and then distal parts of the extremities in suc-
cessively more ventral positions. The only ipsilateral
projection is that of the peri- and intraoral regions.
Perusal of such a figurine map makes it clear that
a given small area of the body surface is not repre-
sented at a thalamic ' point' and only there. Stimula-
tion of a small spot on the skin evokes intense activity
at a limited thalamic locus and less intense activity
over a considerable surround. It follows that a given
thalamic locus can be activated to some degree from
a considerable area of skin, which is smaller for some
and larger for other parts of the topographical pat-
tern. As the peripheral spot stimulated is shifted across
the skin the peak activity shifts across the thalamic
pattern, its submaximal and liminal fringes shifting
with it. The problem is to understand the precision
of spatial discrimination of which the organism is
capable, which depends upon an anatomical sub-
strate of ' point to area' and reciprocallv, 'area to
point' projection of the receptor sheet upon the central
configurations. Some physiological mechanisms which
appear of importance in this regard will be considered
later.
When the representation pattern shown in cross-
section in figure 3 is analyzed in three dimensions, it
results that any given dermatomal (segmental) region
of the body is represented in the ventrobasal complex
in a narrow curving lamella of tissue, concave medi-
all\". Within such a narrow sheet the proximal skin
areas of the dermatome are represented dorsallv, the
distal ventrally.
Extension of such studies to a series of mammals
allows some estimate of the phyletic trends in thalamic
tactile representation. The sequence of that repre-
sentation is in principle the same in the rabi)it, cat
and monkey (fig. 4). The entire body surface is repre-
.sented in each case, but striking differences in em-
phasis exist. In the rabbit, the bulk of the available
tissue is given to the projection of head and face,
while the cat possesses a ijalanced spinal and tri-
geminal projection. In the monkey the increased de-
velopment of the hand and foot as tactile organs is
indicated by an increased share of the pattern de-
voted to their representation.
This general pattern depicted by electrophysio-
logical studies is a confirmation and extension of that
FIG. 4. Schematic outlines of body representation in the ventrobasal thalamic complex in rabbit,
cat and monkey. The figures do not intend to depict with accuracy the actual relationships but aim
to emphasize the dominance of the trigeminal representation in the rabbit, and the relative increase
of the representation of the limbs in cat and monkey. The representation of the ti'unk and extremities
is located quite anteriorly in the ventrobasal complex of the rabbit. In the cat and monkey this
representation reaches progi'essively very much farther caudally.
402
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
demonstrated anatomically. The termination of
gracilis neurons in the lateral and of those of the
cuneate in the medial parts of the external component
of the ventrobasal complex, and of the trigeminal
tracts in its arcuate component, has been established
by degeneration experiments (47, 67, 203, 253, 260).
The same pattern is shown by the locations of retro-
grade degenerations produced by lesions of the face,
arm or leg areas of the postcentral gyrus (49, 50, 143,
249. 253)-
An important confirmation of the location of the
somatic relay nucleus of the thalamus and the pattern
in it has come from the study of patients in whom the
ventral thalamic nuclei were stimulated by means of
stereotactically placed electrodes in the course of
thalamotomy for intractable pain (174, 175)- Stimu-
lation of the ventrobasal complex produced somatic
sensations referred to bodily parts in topographic
patterns similar to those in the monkey. The sensa-
tions produced by thalamic stimulation were referred
onl\' to the contralateral side of the bodv.
Patterns in Postcentral Humologue oj Cerebral Cortex
Since sensory somatic cortical projection patterns
are described by Terzuolo & Adey, Chapter XXXIII
of this work, it may he read for a surves' of this in-
formation and the description of relations between the
sensory somatic fields and the motor areas.
Here we wish to stress a few generalizations impor-
tant for our considerations. The first essential point
which emerges from the extensive mapping studies
made mainly by Woolsey and his collaborators is that
the cortical pattern in every mammal studied is a
representation of the body form itself, with distor-
tions which are almost certainly due to differences in
the peripheral innervation density. These in turn ap-
pear clearly related to the development of one or an-
other part of the body of a given mainmal as a tactile
organ. Hence, the share of a body part in cortical
representation apparently reflects the relative value
of this part for tactile discriminatory acuity.
The second point to be made is that the thalamic
pattern is projected in toto upon the cortical receiving
area with only such further distortions as could be
expected by the transfer of a three-dimensional pat-
tern upon essentially a two-dimensional surface.
While this statement is made on the basis of studies
done only in rabbit, cat and monkey, there is no rea-
son to doubt that it is true for other mammals as well.
There appears to be no part of the thalamic relay
nucleus which is functionally independent of the
cortex, a finding which is concordant with the obser-
vation that an adequate cortical removal results in
virtually complete retrograde degeneration of the
ventrobasal complex. There is, therefore, no reason to
assume that this complex is a terminal station for any
sensory somatic processes in any mammal, even
though a contrary thought in this respect was fre-
quently entertained in the past, and is implicit in the
concept of 'thalamic sensations'. For any given mam-
mal, the pattern of cortical representation is probably
essentially similar not only to the respective repre-
sentation in the ventrobasal complex but to that in
the dorsal column nuclei as well. The a\ailai3le data
in this regard are very limited. It is clear enough,
however, that this holds true for the cat and the same
can be deduced for the macaque. Moreover, the long,
sentient and prehensile tail of the spider monkey
Ateles is known to have a large representation in the
dorsal column nuclei ('43) and this rather unusual dis-
tortion of the pattern is fully reflected in the cortical
representation (45). It appears then that all relay
nuclei of the system participate fully in elaboration
of the projectional pattern, as must be the ca.se if the
organization of this projection is correlated with the
peripheral innervation density. While this conclusion
appears to be almost self-evident, it may be useful to
stress it since even modern neurological thinking is
often unduly dominated by the concept of different
fimctional levels. This tends to neglect the viewing of
the synaptic regions of a system as integral parts of
the whole, if such regions happen to lie at different
topographical levels.
An important question as to the functional mean-
ing of a morphological pattern is posed by the c\to-
architectonic differentiation of the postcentral hom-
ologue. While the number of fields distinguished here
may vary according to different criteria of various
workers, there is hardly any doubt that this region
possesses a definite gradient of morphological change.
In primates, areas 3, i, and 2 are classically distin-
guished in an orocaudal sequence and all these fields
together form the substrate for the representation pat-
tern of the body as determined by the evoked poten-
tial technique. It is possible that differences in or-
ganization of thalamocortical projections underlie
the cytoarchitectural differentiation of these fields.
In this relation it was reported recently (50) that at
least areas 3 and 2 differ substantially in this regard
from each other. Area 3 has been shown to receive
exclusive projections from the ventrobasal complex.
TOUCH AND KINESTHESIS
403
while area 2 seems to receive only a collateral outflow
from it. What this important finding may imply lunc-
tionally is at present oiascure.
MODALITY COMPONENTS OF MEDIAL LEMNISCAL SYSTEM
is induced by general anesthesia, however light. In
any case, it is at present both convenient and necessary
to consider separately the activity in the lemniscal
system evoked by stimulation of the skin, touch-
pressure, and that provoked by stimulation of perios-
teum, bones and joints, deep sensibility.
A second general property of the lemni-scal system
is that it handles, within a single topographical pat-
tern, activity evoked Ijy tactile as well as kinesthetic
and other mechanical stimuli acting upon deep tis-
sues. At each successive level of the system neurons
subserving various forms of mechanoreception are in-
termingled in a common topographical pattern.
Nevertheless, single unit studies indicate that the in-
dividual neurons at each level retain their modality
specificity. This rather surprising observation requires
an immediate comment. In work with an intact ani-
mal a given unit at a central station of the system
can be driven by stimuli delivered to the skin or to the
deep tissues. It is usually a simple matter to be certain
which of the two contains the effective receptors, and
this can be proved by direct surgical dissection of the
peripheral tissues. Some difficulty does arise when
the receptive fields lie in highly specialized regions at
the apices of the limbs, such as the claws of the cat.
Nevertheless, the lack of any evidence that stimuli to
the skin and to the deep tissues can excite the same
neuron is quite striking. Since all the findings are
derived from anesthetized preparations it is con-
ceivable, although we believe rather unlikely, that
his apparent lack of any clear excitatory interaction
Touch-Pressure
.\D.^PTIVE PROPERTIES OF RECEPTORS AND OF CENTRAL
NEURONS. It has been known for a long time (2, 3, 6}
that the mechanoreceptors of the skin and the afferent
fibers to which they are connected are not uniform in
all their properties. One can classify these afferents
according to the following criteria : the adequate
stimulus required for each, the size and conduction
velocity of the fibers concerned, the rate of adaptation
to steady stimuli and the sizes of the peripheral recep-
tive fields (168, 280, 282). When working with the
intact anesthetized animal, however, it is useful to
classify the cutaneous mechanoreceptors as (i) those
which respond steadily to steady stimuli and (it) those
which adapt quickly to such stimuli (fig. 5). Neural
elements at each of the central relay stations of the
lemniscal system, which are driven by mechanical
stimulation of the skin, fall readiK' into one or the
other of these classes (2, 3, 6, 7, 181 ; Berman, A. L.,
unpublished observations, and Mountcastle, V. B. &
J. E. Rose, unpublished observations). The type of
adaptation of a given unit is, so far as has been ob-
served, an unchanging functional property. In general,
afferents related to hairs are quickly adapting, while
On
Pressure
Off
II
Moving one thread of hair
J
( «-\
^A.
\" n
FIG. 5. .-Xction potentials in single cutaneous nerve fibers of the cat, elicited by mechanical stimula-
tion of the skin. A : \ single fiber adapts rapidly to steady pressure applied to its receptive field,
shown in the inset drawing. A short train of impulses occurs at the onset and release of the pressure.
In the second record a fiber responds to movement of a single hair. B: The receptive field for this
particular fiber is punctiform. The fiber adapts slowly to a steady mechanical stimulus. Upper row of
dots apply to the first two, the lower row to the third record. Distances between the dots indicate 10
msec, intervals. [From Maruhashi et al. (168).]
404
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
slowK' adapting 'skin pressure' units arc driven by-
light mechanical stimulation of the skin surface. This
correlation is probaljly not perfect, for some units
excited by movement of specialized hairs have been
observed which adapted slowly (68), and some rapidly
adapting units have been noted whose peripheral re-
ceptive fields were located in hairless parts of the skin.
Neurons responding steadily or with only an onset
transient to mechanical stimulation of the skin have
been observed at the level of the ventrobasal thalamic
complex and in the postcentral homologue (181; and
Mountcastle, V. B. & J. E. Rose, unpublished
obser\ations). Records of the action potentials
of a postcentral cortical neuron responding stead-
ily to a steady cutaneous stimulus are shown in
figure 6. Results such as these indicate that neurons
located at the various levels of the system reflect rather
faithfully the discharge properties of either the periph-
eral receptors themselves or those of the first order
neurons. At each level of the svstem the fast and slowlv
adapting neurons are intermingled within a single
topographical pattern.
PERiPHER.AL RECEPTIVE FIELDS. Quantitative measure-
ments of the cutaneous fields of distribution of single
fibers have been very few. By recording unitary action
potentials from fibers within the dorsal columns,
Yamamoto et al. (280) found the peripheral fields to
vary in size from a maximum of 2 to 3 cm'- on the
trunk, to a few square millimeters at the distal ends
of the limbs. Working with single fibers in cutaneous
ner\es, Maruhashi et al. (168) have in general found
similar results, though they emphasize that a) many
large afferents may have truly 'spot-like' receptive
fields, and 6) that smaller (3 to 5 n) slowly adapting
afferents may have wide receptive fields in the range
of 1 4 to 40 cm'-.
Only scattered data are available concerning the
size of the fields which project upon neurons of the
dorsal column nuclei and of the ventrobasal complex.
rMPULSES PER SECOND
CORTICAL NEURON RESPONDING TO STEADY
PRESSURE OF SKIN OF FOREARM
FIG. 6. .\ction potentials of a single cell in the postcentral gyrus of the monkey, Macacus rhesus. The
neuron is driven by steady pressure applied to the cutaneous receptive field located on the volar
surface of the contralateral forearm. Onset and release of pressure indicated by solid bar under the
graph, which shows the number of impulses per second plotted at 200 msec, intervals. Experimental
conditions described by Mountcastle el at. (183). [From Mountcastle, 'V. B. & T. P. .S Powell,
manuscript in preparation.]
TOUCH AND KINESTHESIS
405
FIG. 7. Eight excitatory peripheral receptive skin fields of
the cat's foreleg, stiinulation of which activated eight single
neurons in the contralateral postcentral cortex. The neurons in
question were isolated at the levels indicated (in ii) below the
cortical surface in the course of a single microelectrodc penetra-
tion made perpendicularly to that surface. The fields are
restricted in size and are almost identical in location. [Modified
from Mountcastle (181).]
Some measurements, however, have been made of the
fields which project upon neurons of the cerebral cor-
tex (181). Several such fields are shown in figure 7,
and the graph of figure 8 relates the sizes of the
peripheral fields to their location upon the body
surface.
PROJECTION OF PERIPHER.JiL RECEPTIVE FIELDS UPON
CENTRAL NEURONS. Figure 9 indicates that not all
parts of the peripheral receptive field of a thalamic
neuron have an equal potency for excitation of that
cell. The security of the relation varies from a ma.x-
imum usually, though not always, near the center
of the field to a minimum at its edge. The synaptic
linkages converging upon the central neuron from
afferent fibers innervating the edge of the field are
apparently .so few as to provoke only minimal activa-
tion of the cell, as measured by the early repetitive
response (which will be defined below).
From data of this kind it is possible to reconstruct
the pattern of events set in motion in the lemniscal
system by a brief mechanical stimulus delivered to the
skin. Before doing so it is convenient to describe the
response properties of single neurons of the system.
Response Patterns of Neurons of Medial Lemniscal System
REPETITIVENESS OF RESPONSE TO SINGLE STIMULUS. All
the evidence at hand from study of first order axons
(168, 280) indicates that even very brief mechanical
stimuli to hairs or skin surface elicit a short train of
impulses in afferent nerve fibers (see fig. 5), even for
quickly adapting elements. Such an aff'erent input
elicits from the second (15), third (208) and fourth
order neurons (183) short high frequency trains of dis-
charges, a response pattern which is highly character-
istic of the system (fig. 10). Amassian & DeVito (15)
have shown that the early repetitive discharge in the
cuneate nucleus occurs under different conditions of
anesthesia, in the unanesthetized or decerebrate ani-
mal, and apart from variation of body temperature
from 33 to 41 °C. It is important to emphasize that it
occurs also when the afferent volley is made up of a
single impulse in each synchronously active fiber. The
repetitive discharge therefore is a general property of
the postsynaptic cell at the first relay of the system,
and indeed of those at each successive relay thereafter.
The repetitive response is not absolutely stable even
in the deeply anesthetized animal. Here, when exactly
the same peripheral stimulus activating a given neuron
is repeated at slow intervals some variation in the
number of impulses in the early repetitive response
does indeed occur. In a population of such responses,
many contain a characteristic number of impulses
per response (the modal value) while some responses
contain more and others fewer impulses (fig. 1 1). The
shift in the modal value indicates sensitively the
changing parameters of the stimulus, e.g. its intensity,
frequency or position (see figs. 9, 10, 12 and 13).
RESPONSE OF SYSTEM TO SINGLE STIMULUS. Considering
the variations in the response of a single neuron when
the stimulus shifts across the receptive field it seems
possible to reconstruct the events in a population of
cells set in motion by a single stimulus, even though
it has not yet been possible to record the activity of
many single neurons simultaneously. .\ brief, strong
peripheral stimulus sets up a burst of impulses in a
number of afferent fibers. If the stimulus is brief
enough only one impulse occurs in each fiber; if it is
strong enough nearly all fibers are activated syn-
chronously. The impulses are conducted into the cord
and can be assumed to impinge upon a restricted
4o6
HANDBOOK OF PHYSIOLOGV
NEUROPHYSIOLOGY
CM'
PERIPHERAL RECEPTIVE AREAS
PROJECTING UPON CORTICAL NEURONS
OF SOMATIC AREA I
n = 126
THORACIC UNITS
27.7 ± 5.0 CM»
n =21
XI0I±I3
X95±I9
X707ttO
. •X''9l05r
X306t05
- J X'I610I4
•^1/"
liLC
::^
CM FROM TIP OF FORELIMB
FIG. 8. Plot relating the size (in square centimeters) of excitatory cutaneous receptive fields for
cortical neurons to the distances of the centers of those fields from the tip of the forelimb of the cat.
Crossed dots locate means (and standard errors) for these fields when .grouped into classes by 4 cm
distances from limb tip. The receptive fields close to the tip of the limb are small in size and usually
comparable in area. With the increased distance from the tip both the size of the fields and the
variability between them increase greatly. [From Mountcastle (181).]
group of cells within the dorsal column nuclei. The
cells in the center of the group will receive a maximum
number of synaptic impingements and will discharge
repetitive trains at high frequency, probably with
shortest latency. Cells surrounding the center are pre-
sumably excited to discharge trains of fewer impulses
at longer latency and at lower frequency, while cells
at the edges of the discharge zone will discharge
single impulses at even longer latencies. That a similar
distribution of activity occurs among third order cells
of the thalamic relay nucleus and among fourth order
cells in the cortical receiving area can be deduced
from single unit studies of those regions (13, 157-
■59. 183, 208).
Marshall et al. (167) have shown for the thalamic and
cortical slow waves that the recovery time is greatly
prolonged by anesthetic agents. Single unit studies
have confirmed and extended these original observa-
tions (13, 183; and Mountcastle, V. B. & J. E. Rose,
unpublished observations). The recosery time of
single neurons in the imanesthetized animal is not yet
known, though it probably is much briefer than the
recovery time observed in an anesthetized animal. In
the anesthetized animal, however, the anesthesia
itself is not the only factor affecting the recovery tiine.
At the same anesthetic level the unresponsive time of
the system shortens as the strength of the initial
stimulus decreases.
RESPONSES TO TWO STIMULI AT DIFFERENT INTERVALS.
Some information concerning the capacity of the
somatic afferent system to relay activity has been oij-
tained by measuring the ability of the system to
respond to a second peripheral stimulus at various
time intervals after the first. Marshall ('66) and
RESPONSES TO REPETITIVE STIMULI AT DIFFERENT FRE-
QUENCIES. It is clear from study of indi\-iclual neurons
that the two-stimulus experiment does not at all
specifv the capacity of the system to respond when
trains of stimuli are applied. Individual neurons at
any level show one of two types of behavior. Figure 1 2
TOUCH AND KINESTHESIS
407
^^A^
16 M 12 10 8 6 4 2 I 3 5 7 9 II
LOCATION OF THE STIMULATED POINT
13 15
FIG. 9. Graph relating the average number ot impulses
discharged per response to the position of the stimulus at
several points located in and around the receptive field. Inset
drawing on the left indicates the location of the receptive field;
inset drawing on right the positions of the stimulated points.
Electrical stimulus of the same strength is delivered through a
pair of needle electrodes thrust into the skin. The same unit
located in the ventrobasal complex of the thalamus is respond-
ing throughout. Graph is based on 1208 responses. Cat under
deep pentobarbital anesthesia. [From Mountcastle, V. B. &
J. E. Rose, unpublished observations.]
illustrates the first type, shown here for a thalamic cell.
Several characteristic phenomena for this type of
response are as follows:
a) Equilibration. The neuron follows the stiinulus
rate beat-for-beat to a certain level, usually in the
range of 30 to 70 per sec. When trains of stintuli at
higher rates are delivered, the neuron continues to
respond at about the same overall rate. There is no
desynchronization, however, for each response occurs
in a fixed and definite relation to a particularstimulus.
The equilibration occurs JDecause some stimuli ran-
domly distributed throughout the train fail to evoke
responses.
6) Early silent period. The records of figure 1 2 show
that while the first stimulus elicits a response, the next
few (i.e. numbers 2, 3, 4, 5, etc., in fig. 12) may be
ineffectual. The succeeding stimuli, however, once
again become effective. This early silent period is of
about the same duration as the unresponsive time of
the system, as measured in the two stimulus experi-
ment under the saine experimental conditions. The
important point is that the presentation of trains of
stimuli ' recruits excitabilitv' so that the svstem
FIG. 10. Shifts in the number of impulses per response and
changes in the latent periods with increased strength of the
peripheral stimulus for three units located at successively higher
synaptic regions of the medial lemniscal system of the cat.
Stimulus strength increases in each column from above down-
ward. Time lines for all columns, 1000 cycles per sec. B: Dis-
charges of a single neuron of the cuneate nucleus evoked by
stimulation of the ipsilateral radial cutaneous nerve. Note the
shift in latencies and the increase in the number of spikes with
increase in stimulus strength. The strength of the stimulus is
indicated by the traces at the extreme left {A} which show
increases in the size of the compound action potential in the
radial nerve. [From Amassian & DeVito (15).] C: Increase in
number of impulses of the early repetitive response of a single
neuron of the ventrobasal thalamic complex evoked by in-
creasingly stronger electrical stimuli (ai) delivered to the skin of
the contralateral first digit of the forepaw. Traces show the
modal number of the discharge train at each stimulus strength
and a latency which is close to the mean latency at this strength.
[From Rose & Mountcastle (208).] D: A similar series for a
neuron located in the first som.atic cortical field. Electrical
stimulation of the skin of the contralateral foreleg. Each trace
shows again the modal number for the discharge train at given
strength of the stimulus and the latency, near to the mean
latency at this strength. [From Mountcastle el a!. (183).]
4o8
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
12 3 4 5
Number of spikes per response
FIG. 1 1 . Curves illustrating the distributions of response
populations around their modal values for several neurons of
the thalamic ventrobasal nuclear complex of the cat. Number of
impulses per response to a brief peripheral stimulus graphed
against the percentage of responses with the stated number of
impulses. Although values on the abscissa are always integers,
the points belonging to the same distribution are connected by
lines to aid the eye. The number which follows the letters
TM identifies the experiment, the number in parentheses
identifies the neuron studied. .V indicates the number of
responses upon which each graph is based. Locus of peripheral
stimulus constant for each unit. In each case the neuron is
activated by electrical stimulation of the contralateral skin.
Locus of stimulation: TM 34(1), second toe on hindfoot;
TM 32(2), lower abdomen; TM 32(5), upper thigh; TM 32(6),
ankle; TM 27(2), wrist; TM 28(2), wrist. Note that most
responses in each series do not differ from the modal value by
more than one impulse. [From Rose & Mountcastle (208).]
transmits at a higher frequency than that predicted
by the recovery cycle studies.
c) Mode reduction. The records of figure 12 show
finally that, when responding at higher frequencies,
the cell discharges but a single impulse to each stimu-
lus which is effective in contrast to the repetitive re-
sponse to the first stimulus of the train. The repet-
itive response ' singles up' as a rule when the fre-
quency of the stimuli increases beyond 10 to 15 per
sec.
The equilibration type of response occurs in about
60 per cent of the neurons studied at thalamic and
cortical levels. The remaining neurons display a
different sort of lieha\ior. While following the stimulus
rate up to values which differ greatly for different
units, they respond to the presentation of still faster
trains with but an initial response and are thereafter
silent during the train, or discharge randomly at the
spontaneous rate (see fig. 13). It is not clear at present
whether the ' equilibration' and the ' cut-off' types of
response can be obtained for the same unit by suitable
manipulation of the stimulus. Most of the units ob-
served which show the ' cut-off' response pattern follow
only a low rate of stimulation. On the other hand, it
seems to be true, at least occasionally, that a typical
equilibration type of response becomes a cut-off type
when the stimulus rate is made very high (200 to 300
per sec).
AFFERENT INHIBITION. It has been shown recently
(181, 198) that the afferent volleys evoked by periph-
eral stimuli while excitatory for some cells of the sys-
tem will tend to inhibit others (fig. 14). All inhibitory
phenomena are very sensitive to anesthetic agents and
are probably at least partially abolished even under
very light general anesthesia. Nevertheless, the inhibi-
tion of both the spontaneous and the evoked activity
of central neurons has been observed for a consider-
able number of cells (198). The peripheral inhibitory
receptive field for a given neuron (in the postcentral
cortex) may surround or lie adjacent to its excitatory
field. It is an interesting observation that a cell
excited, for example by movement of a joint, may be
inhibited by skin stimulation, although a purely
excitatory intermodality interaction has not thus far
been demonstrated for units driven from the skin and
from deep receptors. In the cortex, pairs of cells which
are in one case excited and in the other inhibited from
the same receptive field have been observed at a single
electrode position. They must therefore lie very close
to one another. This suggests, of course, that afferent
inhibition may play an important role in reducing
the discharge zone of cells activated by a local periph-
eral stimulus. It need hardly be added that restricted,
sharply focused discharge zones may be instrumental
in recognizing a single localized peripheral event and
in more complex discriminations as well.
suMM.\RY. The single unit studies at several stations of
the somatic afferent system have produced a consider-
able mass of data concerning the relation of a dis-
charge of a single cell to the quantitative parameters
of the peripheral stimuli. For a population of cells the
data allow a reconstruction of the distribution ot
activity set up by a single brief peripheral stimulus
occurring in that population. However, no informa-
TOUCH AND KINESTHESIS
409
FIG. 1 2. Responses of a single neuron of ventrobasal thalamic nuclear complex of the cat to elec-
trical stimulation of skin of the contralateral foreleg. The stimuli were delivered at diflferent fre-
quencies per second which are indicated by the numbers on the left. Note reduction of modal \alue
and equilibration of response with increasing frequencies of stimulation, and the early silent period.
Stimulus artefacts are not visible. [From Mountcastle, V. B & | E. Rose, unpublished observa-
tions.]
tion is yet available which permits a complete descrip-
tion of the sequential changes in neural events brought
about by a natural stimulus in a completelv unanes-
thetized animal. Underlying studies of this type is the
assumption that perception of a local peripheral
event depends in the first instance upon a local zone
of cortical activity of abrupt onset, and that percep-
tion of more complex forms of stimuli (e.g. two-point
discrimination, form and contoiu" recognition, etc.)
may depend upon the interaction of many such zones
of activity. One of the problems in sensory physiology
at the present time is to determine in some detail the
patterns of cortical activity evoked by peripheral
stimuli of some spatial and temporal complexity. It
seems likely that single unit studies will advance the
solution of this problem.
KINESTHESIS OR SENSE OF POSITION .^ND
MOVEMENTS OF JOINTS
It is apparent that information concerning the
orientation of the bod\' in space and of the spatial
relations between its parts depends upon afferent
inputs from both somatic sensory and \estibular
receptors as well as from the visual apparatus. The
thesis is presented here that the somatic sensory com-
ponent, which we shall refer to as kinesthesis or the
sense of position and movement of the joints, depends
FIG. 13. Responses of a single neuron of the ventrobasal
thalamic nuclear complex of the cat to electrical stimulation of
the skin near the first digit of the contralateral forepaw, de-
livered at different frequencies. Note reduction of modal value
as frequency increases from 10 to 20 or more per sec. At
frequency of 40 per sec, or higher, the neuron responded to the
first stimulus of a train and failed to respond thereafter:
'cut-off' characteristic. Small deflections are stimulus artefacts.
[From Mountcastle, 'V. B. & J. E. Rose, unpublished observa-
tions.]
4IO
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
IMPULSES PER SECOND
100 I-
EXCITflTORY STIMULUS
^/4p-i-\^yi^
FIG. 14. Interacting effects of excitatory and inhibitory
peripheral stimuli upon the discharge rate of a single neuron of
area i of the postcentral gyrus of the monkey. Graph plots the
average frequencies of discharge of the neuron in each succes-
sive 400 msec, period. Neuron excited by internal rotation of
shoulder joint, indicated by upper bar, and inhibited by pres-
sure upon skin of the palm, indicated by lower bar; both contra-
lateral. Note that recovery from inhibition duplicates onset of
excitation, with rapid onset transient and decline to a less
rapid firing level. [From Mountcastle, V. B. & T. P. S. Powell,
manuscript in preparation.]
upon the receptor organs associated with the joints.
Activity set up in those receptors by the steady posi-
tion or movement of the joints is relayed through the
medial lemniscal system, in a topographical pattern
at each precortical relay and in the somatic sensory
cortex itself which is mutually interlocked with the
pattern representing the cutaneous sensory sheet.
Since this is contrary to the widely held belief that
kinesthesis depends as well upon afferent input from
muscle stretch receptors, the evidence for it will be
presented in some detail.
Mustif Sitetiii Receptors and h uiesthests
Evidence accumulates from recent research that
the rate of discharge of the stretch receptors of muscle
is not linearly or even constantly related to the length
of the muscle per se. Since the classical work of
Matthews (169) it has been known that the Golgi
tendon organs discharge afferent impulses at a rate
related to tension. The tension to which these recep-
tors are subjected depends upon the length of the
muscle, i.e. upon the joint angle, and upon the force
exerted h\ the muscle against its load h\ its active
contraction which in turn depends on the activity of
the alpha motoneurons. It follows that the number of
active Golgi organs and their rates of discharge are not
variables dependent solely upon the angle of the joint
or joints acro.ss which the muscle works; these recep-
tors cannot, therefore, inform reliably of joint posi-
tion.
The spindle organ receptors of muscle are subject
to even more complex influences. Matthews (169)
had shown that these receptors are excited by stretch
of the muscle but cease to discharge as the muscle is
shortened by alpha motoneuron action. They may be
completely silent when tension at the tendon is maxi-
mal. The work of Leksell (153) revealed, however,
that the smaller efferent fibers of the \entral root,
the gamma motoneurons, produce upon discharge an
increase in spindle organ activity, even when the
muscle shortens. These observations have been ex-
tended recently (102, 129-132, 144) and it is now
well known that the gamina efferents condition affer-
ent input from the spindles and thus play an important
role in \oluntary movement and reflex regulation.
More recently Granit and his colleagues (62, 103, 104)
have ciescriijed the central nervous control of the
gamma motoneurons and hence of spindle organ
discharge, and Eldred & Hagbarth (63) their reflex
regulation bv cutaneous afferents. Further details of
the function of the gamma efferent-spindle afferent
loop are presented by Eldred in Chapter XLI of this
work, and an excellent general review of the subject
is provided in the monograph by Granit (loi). The
important point in the present consideration is that
spindle activitv may varv from zero to ma.ximum
independenth' of the length or tension of the muscle;
these receptors, like the Golgi tendon organs, cannot
signal muscle length or joint angle.
These facts alone are impressive for the argument
that stretch receptors of muscle are not likely to in-
form of joint position. Complementary to them is the
experimental oiiservation of Lloyd & Mclntyre (160)
that the large stretch afferents from muscle do not
project upwards in the dorsal cokmins but relay in the
column of Clarke-Stilling into a.scending systems
terminating in the cerebellum. This observation has
been confirmed and extended in an elegant series of
studies (128, 150-152, 163) which showed that group
I-a afTerents from muscle spindle organs relay into the
dorsal spinocerebellar tract. In addition, O.scarsson
(190) has reported that group I-b fibers from tendon
organs project upon the cells of origin of the ventral
spinocerebellar tract. Complementary also are the
negative observations that direct stretch of muscle
produces no detectable response in the postcentral
TOUCH AND KINESTHESIS
homologue of the cerebral cortex (182). Nor have
single unit analysis studies revealed any cells at levels
of thalamus or cortex which could he activated by
stretch of muscle (181; Mountcastle, V. B. & T, P. S.
Powell, manuscript in preparation; and Mount-
castle, V. B. & J. E. Rose, unpublished observations).
Data obtained from experiments in which the
system is activated by electrical stimulation of bared
muscle nerves are somewhat discordant. Mount-
castle et al. (182) reported that when the afferent
volley was confined to group I afferent fiijers (which
innervate the annulospiral endings and the Golgi
tendon organs), no responses were evoked in the post-
central homologue in anesthetized animals. Nor were
such responses observed when the stimulus strength
was increased to activate group II afferents (which
innervate the flower spray stretch receptors). They
did observe, again in anesthetized animals, that when
group III fibers of the muscle nerves were activated
cortical responses of long latency appeared. The
peripheral endings of group III afferents are thought
to lie bare nerve terminals and there is no evidence
that they are sensitive to mechanical changes in the
muscle; it seems safe to assume that these endings are
of no significance for position sense. Perhaps they,
together with the C-fiber afferents, mediate the sensa-
tions of muscle fatigue and pain. These observations
are in agreement with the observation that direct
stretch of muscle evokes no detectable response in
the cerebral cortex.
Some workers (84, 86, 171) find, on the other hand,
that cortical responses do appear when the afferent
volley is thought to contain the group II and possibly
group I components. Perhaps these discordant results
are due to the different muscle nerves used, for it is
known that some fibers from joint receptors, perios-
teum and deep fascia, may travel in some muscle
nerves and are of group II size (76, 225, 231-233).
Whatever the final answer, it is clear that muscle
stretch afferents are unlikely to play a role in position
sense for they are under control of the gamma efferent
loop and may discharge over their full frequency
range at any muscle length.
Innervation of Joints
The tissues in and aijout the joints clearly receive
a rich innervation; [the older literature on this matter
has been reviewed by Skoglund (225)]. This innerva-
tion, the receptor organs in the ligaments and the
joint capsules, and the functional properties of the
receptors have been intensively studied in recent
vears. The articular innervation in a variety of animals
and in man has been described by a number of
workers (16, 18, 28, 29, 75-81, 215, 216, 225, 279).
Afferent fibers from some joints have been shown to
travel in both muscle and cutaneous nerves. The
myelinated fibers vary in size between 2 and 16 n
and according to Gardner (76) the spectruin displays
definite peaks between 2 to 5 and 7 to 10 /i, while
Skoglund's measurements (225) suggest a unimodal
distribution around a peak at about 3 to 6 ju. Articular
nerves contain large numbers of unmyelinated fibers,
some of sympathetic origin, while others are un-
doubtedly afferent dorsal root C fibers. It is clear
then that articular nerves resemble in composition
purely cutaneous ones.
Joint Receptors and Their Discharge Patterns
Some recent histological studies indicate three types
of receptor organs in articular tissue (16, 18, 28, 76).
FIG. 15. Graph of the impulse frequency of a single afferent
neuron innervating the capsule of the knee joint of the cat.
Graph plots frequency of impulses against time as the joint is
moved through 10 degrees of flexion and back again, as in-
dicated by the dashed line. Note onset transient during move-
ment, adaptation to a more or less steady frequency of discharge
during steady joint displacement, rapid drop in frequency when
joint moves away from excitatory position, postexcitatory silent
period, recovery to resting' frequency of discharge, and almost
exact repetition of the pattern of discharge when the move-
ment is repeated. [From Boyd & Roberts (29).]
412
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOC3Y
FIG. i6. Lejl: Graphs of the impulse frequency in a single aflTercnt fiber innervating the capsule of
the knee joint of the cat, showing frequency of discharge against time during flexion at a rate of lo
degrees per sec. carried through three different angles: open triangles, lo degrees; open circles, 12
degrees; closed circles, 14 degrees. The upper curves show the frequencies of the impulses, the lower
ones the angular displacements from a position of 1 32 degrees of extension, where this receptor did
not discharge. Note that steady state frequency is higher for greater joint displacements. Right:
Similar graphs for the same afferent neuron during movements of the joint between the same posi-
tions at four different rates : closed triangles, 35 degrees per sec. ; closed circles, 1 7 degrees per sec. ;
open triangles, 10 degrees per sec; open circles, 6 degrees per sec. The displacements are indicated
by thin lines. Note that while onset transients differ, the steady impulse frequency in the final posi-
tion is the same in each case. [From Boyd & Roberts (29).]
By far the most common are the ' spray-type' endings
which resemble those described in the skin by Ruffini.
They are located in the connective tissue capsule of
the joints but not in its synovial lining membrane and
are supplied by myelinated fibers ranging in diameter
from 7 to 10 /i (225)- They are well fitted by location
and response properties to signal the steady position
of the joint and the direction, rate and extent of joint
movement (29, 225). They respond at low threshold
with a rapid onset transient as the joint moves in a
direction which causes their excitation (fig. 15). The
rate of discharge during the movement is a function
of its speed and extent (fig. 16); the steady state of
discharge at a given excitatory displacement is inde-
pendent of the rate at which the initial displacement
occurred (fig. i 7).
These .slowly adapting receptors .subserve angles of
aljout 15 degrees. For any given joint different mem-
bers of the population of receptors have their excita-
tory angles located at different positions along the
range of joint movement. Some have excitatory angles
placed at one end of this range, responding at maximal
rate at either full flexion, or full extension (figs. 17,
18). At least that is true for the knee joint of the cat
which has been most intensively studied, but there is
no reason to believe that qualitatively different condi-
tions exist in other joints or other species, including
man, for the articular innervation has been found to
be remarkably uniform in all species studied.
A second slowly adapting receptor resembling in
appearance the Golgi tendon organ has been found
associated with the ligaments of the joints, and has
been found to be innervated by fibers 7 to 10 fj in
diameter. This type is much less numerous than the
Ruffini type endings described above and possesses
similar discharge properties (16, 225). Very rarely,
first order afferents are observed which adapt very
quickly to joint movement which e.xcites them. Al-
though some disagreement exists (76) they are thought
to arise from modified \'ater-Pacinian corpuscles
TOUCH AND KINESTHESIS 4I3
M
40
30
20
J L_l I I L
-i50
to
30
20
-10
J I I I I I I
SO
60
70
90
90
100
w
120
130 140 ISO 160 170 180
degrees
FIG. 17 Lefl: Graphs of the impulse frequency in single afferent neuron innervating the capsule
of the knee joint of the cat, as the joint is moved in steps through the 'excitatory angle' for the
receptor, in opposite directions. After each small step of the movement the frequency is allowed
to reach an adapted rate. The two curves are almost mirror images. [From Skoglund (225).]
FIG. 18 Right: Graphs of impulse frequencies for eight single neurons innervating slowly adapting re-
ceptors in the capsule of the knee joint of the cat. The adapted impulse frequency is plotted against
position of the joint in degrees. Solid lines show values for five units in one experiment, dolled lines
show those for three units in another. The figure is not fully representative for the distribution of
endings which are successively activated during full movement since in general endings which cause
maximal adapted discharge rates are more numerous immediately before or at full flexion or full
extension than in the intermediate positions of the joint. The sensitive ranges (15 to 30 degrees) are
representative of the behavior of most endings. [From Skoglund (aas).]
located in the pericapsular connective tissue (225).
They are innervated by the largest afferents in the
articular nerves.
Central Projection of Joint Afferents
The evidence that receptors in and about joints
do indeed project into the lemniscal system was ob-
tained by gross electrode recording of the electrical
responses evoked in the ventrobasal thalamic complex
and the somatic sensory cortex by mechanical stimu-
lation of those tissues (182) and by electrical stimula-
tion of articular nerves (83, 86). Such experiments
indicate that the afferents from bones and joints form
together with afferents from cutaneous receptors a
common topographic pattern. Knowledge of this
projection has been greatly extended by single unit
studies. Some single elements in the ventral thalamic
414
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
nucleus and in the postcentral honiologue are acti-
vated by, and only by, movement of the joints (i8i;
and Mountcastle, \'. B. & J. E. Rose, unpublished
observations). The great majority of these neurons
respond not only to transient rotation of the joint to
IMPULSES PER SECOND
50
CORTICAL NEURON RESPONDING TO
MAINTAINED ROTATION OF SHOULDER JOINT
FIG. ig. Impulse frequency of a single neuron of area i of the
postcentral gyrus of the macaque, plotted continuously as
average frequency in each 400 msec, period. Neuron is a deep
joint unit. At onset of rotation of the contralateral shoulder
joint there is a rapid rise in discharge frequency which declines
slightly to a more or less steady rate of discharge during
steadily maintained joint rotation (period of stimulation in-
dicated by black bar). Note rapid fall of frequency when joint
is returned to its neutral position, and the postexcitatory period
of low frequency discharge. [From Mountcastle, V. B. & T. P. S.
Powell, manuscript in preparation.]
which they are related but continue to discharge
impulses steadily when the joint is held within the
excitatory angle, subserved by the unit (.see figs. 19,
20). They adapt as a rule very slowly. The onset
transient is a function of the degree and rate of joint
movement; the subsequent steady state of activity is
a function of joint angle only. In the cortex, as in the
periphery, excitatory angles for different neurons
related to a given joint are different, and some units
of the group are active at any joint position. Phasic
joint movements may recruit additional neurons,
increase the discharge frequency in some neurons
already active and decrease it in still others. From
this description a generality is once again confirmed;
the discharge patterns of central neurons of the lemnis-
cal system arc determined by those ot the peripheral
receptors to which the)- are linked.
It is an observation of interest that pairs of closely
related cells in the cerebral cortex may be reciprocally
related to a given joint. One of the pair is active and
the other silent as the joint moves in one direction, and
the reverse occurs when the movement alternates
(181) (fig. 20). Whether the reciprocity is due to
some central reciprocal inhibitory exent or simply to
alternate loading and unloading of appropriate groups
of receptors on the two sides of the joint is unknown.
In any case, it is likely that such a mutual interaction
could serve to increase the discriminatory capacity in
respect to the rate and extent of joint mo\ement.
90 -
o
■z. 80
O
a 70
q: 60
uj
'^ 50
tn
i 30
- 20
10
Reciprocolly Responding Cortical Cells, Recorded Simultaneously
Driven Respectively by flexiono — o ond extension •--•
of Contralateral Elbow
Peripherol Receptors Within Elbow Joint
I
\
FIG. 20. Impulse frequency graphs of two neurons of postcentral homologue of the cerebral cortex
of the cat. Discharges of the two units observed simultaneously at a single microelcctrodc position.
Units responded reciprocally to alternating flexions and extensions of the contralateral elbow.
Graphs plot continuously the average frequencies for each consecutive 400 msec, period. Impulse
frequency reaches zero for each unit when the joint reaches the position maximally excitatory for the
other unit. During fourteenth and fifteenth seconds the joint was held in steady extension, and the
extension unit fires steadily, while the flexion unit is almost completely silent. [From Mountcastle
(.81).]
TOUCH AND KINESTHESIS
415
The thesis that the sense of position and movements
of the joints is dependent upon joint receptors them-
selves fits well the clinical observations. However, we
shall not discuss here the extensive clinical and psycho-
physical data available on this subject; we refer the
interested reader to a series of articles by Goldscheider
collected in a book (99). His careful work and his clear
recognition of the joints as the source for kinesthetic
sensations are unfortunately usually forgotten or dis-
regarded in modern physiological texts perhaps
because he was satisfied to treat these sensations within
the concept of 'muscle sense' (^Muskelsinn).
Projections of Deij) Receptors Other Than in Joints
Studies of the modality properties of individual
neurons of the lemniscal system at thalamic and
cortical levels have shown a class of cells whose
peripheral receptive fields lie in deep fascia (181;
and Mountcastle, V. B. & J. E. Rose, unpublished
observations). These fields are of similar shape and
size as those for neurons driven from the skin (see fig.
7). The units are driven by very light mechanical
stimuli to the fascia, and the threshold for activity is
so low that even a very small displacement of the
overlying skin may evoke their discharge. They may
also be driven by pressure changes occurring in the
deep fascial compartments when the enclosed muscles
contract. It is reasonable to assume that this cla.ss of
neurons functions in the overall sense of touch-pres-
sure, for they respond to all but the very weakest of
stimuli impinging upon the skin overlying their own
fascial receptive fields.
Other neurons of this class are activated by direct
pressure upon the periosteum. What role they may
play in kinesthesis or some other aspect of deep sensi-
bility is unknown.
FUNCTIONAL ORG.^NIZ.^TION OF FIRST SOMATIC
CORTICAL FIELD
One of the central problems of neurophysiology at
the present time is to understand the functional
mechanisms of any given region of the cerebral cortex.
Investigators proceed on the premise that if they can
determine the patterns of neural activity entering a
cortical region, the modifications of those patterns
occurring across intracortical synaptic relays ('inte-
grative action') and the spatial and temporal patterns
of output from the region, they will then be able to
reconstruct with some insight the way in which the
particular cortical region operates. In the past few
years much effort has been expended to study the
response properties of single cells in the first somatic
field, the way these cells are activated from the thala-
mus, the relations of the unitary discharges to the
evoked slow cortical wave on the surface of the cortex
and in its depths and the relation of single cell dis-
charges to the cortical EEG (13, 14, 157-159), matters
recently reviewed by Albe-Fe.ssard (7). Recently
Mountcastle (181) has suggested on the basis of his
studies that a vertical group of cells extending across
all the cellular layers acts, as it were, as a functional
cortical unit. Three observations are the reasons for
this suggestion, a) The neurons of such a vertical
group are all related to the same, or nearly the same,
peripheral receptive field. This observation establishes
also that the topographical pattern present on the
surface of the cortex extends throughout its depth.
6) The neurons of such a vertical group belong as a
rule to the same modality group, i.e. they are acti-
vated by the same type of peripheral stimulus. This
implies that a small group of thalamocortical fibers
entering the cortex is activated by a single mode of
peripheral stimulation and in turn activates a narrow
vertical column of cortical cells. 0 All cells of such a
vertical column disrharge on the average at more or
less the same latency to a brief peripheral stimulus.
The discharges are thus grouped within the time limits
of a few milliseconds into an initial firing pattern. This
observation is based, however, only upon the first
response of cortical cells, the latency of which is
known to be sensitive to various parameters of the
peripheral stimulus.
The possibility that a vertical column of cells tends
to behave as a functional unit appears acceptable
anatomically both from the cytoarchitectural point of
view and as regards the connections of such a vertical
column as seen in the Golgi material (162). The sub-
pial dicing experiments of several cortical fields (226,
227) could also be interpreted to imply that a complex
cortical activity is still possible as long as the cortical
organization in depth is preserved.
It is, of course, not implied by these observations
that the cortex is organized into sets of isolated,
vertically oriented tissue prisms. It appears, however,
that at least for the incoming activity a columnar
vertical organization is of special significance.
SPINOTHALAMIC SYSTEM
In comparison to our knowledge of the lemniscal
system, that pertaining to the tactile activity of the
4i6
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
spinothalamic system is quite inadequate since many
basic questions concerning it are still not solved. As
we define the system it consists of the spinothalamic
tract arising in the posterior horns and of the bulbo-
thalamic tract originating in the spinal nucleus of the
fifth nerve. ^ The system is known to transmit impulses
provoked by painful and thermal stimuli but there is
adequate evidence as well that some tactile impulses
are also relayed through it.
Location of Tactile Fibers m Sjntuithalamic System
It is customary to distinguish within the spinotha-
lamic system of the spinal cord (though not in the
bulbothalamic tract) a ventral and a lateral spino-
thalamic pathw-ay. The first is assumed to conduct
tactile impulses, the second is known to be important
for arousal of painful and thermal .sensations. The
ventral spinothalamic tract is usually believed to lie
in the medial aspect of the anterolateral column.
Clinical experience in man indicates that some fibers
in this column must be concerned with touch since
tactile anesthesia results only if in addition to a de-
struction of a posterior column on one side a contra-
lateral injury is present .somewhere in the region of the
anterolateral column. On the other hand, only
partial impairment in tactile sensation occurs when
either of these columns is .selectively injured. In fact,
it has been frequently believed in the past that a
destruction of the anterolateral column alone does
not lead to any deficits in tactile sensations. Foerster
& Gagel (71), Foerster (70) and KroU (141), however,
using finer testing techniques were able to determine
some such deficits after anterolateral cordotomies.
- Similar to the uncertainty which prevails in respect to the
secondary trigeminal pathways arising in the main sensory
nucleus of the fifth nerve (sec p. 396), a considerable confusion
and controversy exists in regard to the central course of the
bulbothalamic tract. Wallenberg (259) who described this
pathway maintained that it ascends in the dorsolateral portion
of the reticular substance of the brain stem tegmentum. He
believed that it terminates in the region of the centrum medi-
anum and in the arcuate component of the ventrobasal com-
plex. Biirgi's observations (36) imply that some of these fibers
may end also in the n. lateralis posterior. Although Wallen-
berg's findings as to the course of this tract in the brain stem
have been repeatedly confirmed (93, 241), many observers
conclude that the bulbottialamic tract crosses to join the medial
lemniscus and separates from it again at the level of the mid-
brain to join the spinothalamic tract. We believe that Wallen-
berg's original description is likely to be correct and that con-
trary results are probably due to lesions involving the posterior
column nuclei. For a contrary view and the review of the litera-
ture on this subject see Biirgi (36).
The deficits are generally described as an increase in
threshold for tactile stimuli and a decrease in the
number of 'sensory spots' without any readily detect-
able iinpairment in the capacity to localize the
stimuli or to discriminate between them. These ob-
servations have been confirined at all levels of the
spinothalamic system by a number of subsequent
workers who were interested in this problem (58,
109-111, 256, 270, 274). A striking aspect of tactile
impairment is that tickle sensations disappear with
some lesions of the anterolateral column and that
with bilateral lesions severe disturbances of sensations
in the sexual sphere are present.
Even though it is established that the spinothalamic
system must relay some tactile impulses, any exact
definition of the fibers concerned and therefore the
very existence of a separate ventral spinothalamic
tract as a tactile component of the spinothalamic
system seems to be based mainly on suppositions.
Foerster & Gagel (71) snd Foerster (70) concluded
that fibers concerned with temperature lie dorsally
to the fibers concerned with pain in the lateral spino-
thalamic tract and they assigned on a hypothetical
ijasis the anterior column to touch and pressure.
Walker (255) modified this scheme and believed the
fibers concerned with touch to lie in the most medial
aspects of the anterolateral column and, although he
emphasized the apparent overlap, he retained the
basic sequence of separate fiber systems for tempera-
ture, pain and touch. Many recent observers stress
the apparent or real overlap of fibers concerned with
pain and temperature [for a review of the literature
see White & Sweet (273)], but they are usually non-
committal on the problem of touch. Apparently this
is so because touch deficits resulting from anterior
cordotomy, or tractotomies performed at the level of
the medulla, pons or midbrain are of little or no clini-
cal discomfort to the patients, because they are diffi-
cult to detect and evaluate without special tests, and
because many observers were primarily interested in
the problem of pain. In consequence, despite the very
large number of operati\e procedures performed in
man on the spinothalamic system there is still no con-
clusive evidence as to whether touch deficits, such as
they are, result from injury of a separate sector of the
spinothalamic tract or whether fibers concerned with
touch are modality specific but are intermingled with
other fibers of the system. Finally, it is possible that no
modality specific tactile fibers exist within the system.
The fact that after anterior cordotomies tickle sensa-
tions in the analgesic areas have been reported as
alwavs lost (70, 71), as almost always preserved (134)
TOUCH AND KINESTHESIS
4>7
or only sometimes lost (273) could perhaps be inter-
preted to mean that at least some degree of separation
exists between the fibers concerned with touch and
those relevant for pain. This could be expected if the
different observers differed in their routine sectioning
of the anterolateral column in regard to the extent
and the depth of the cut. However, more exact work
is needed before one can conclude that the classical
notions in respect to touch hold true for the spino-
thalamic system.
Origin of Spinothalamic System
The knowledge that large cutaneous fibers are
activated by mechanoreceptors and that painful and
thermal stimuli usually activate small fibers was ob-
viously largely responsible for the deductions regard-
the origin of the ventral spinothalamic tract. This
tract is often conceived as originating solely from those
posterior horn cells which themselves are assumed to
be activated by the collaterals of the large myelinated
fibers of the medial division of the posterior root. The
lateral spinothalamic tract, on the other hand, is
pictured as originating from cells which are dis-
charged by the small fibers of the lateral division of
this root. The evidence at hand is clearly discordant
with such concepts since it is certain that tactile stim-
uli can activate A fibers of different sizes and since it
is probable that even some C fibers can be so activated
as well (see p. 394). It follows, therefore, that no cell
in the posterior horn which emits an axon into the
spinothalamic tract can be excluded at present as
potentially responsive to tactile stimuli. The evidence
secured with the retrograde degeneration method after
cutting the anterolateral column (71, 146, 147, 178)
implies that only the large apical, pericornual and
basal cells of the posterior horn give rise to the spino-
thalamic tract. The findings of Kuru (147) suggest
that the large cells just below the substantia gelatinosa
give rise to the ventral spinothalamic tract and hence
to the tactile component of the spinothalamic system
if, indeed, it is true that the fibers carrying touch are
running in a separate sector and if this sector lies
ventromedially to the other fibers of the system.
Curiously enough, no retrograde degenerations
(after cutting of the anterolateral column) were ob-
served in the suljstantia gelatinosa cells, which is one
of the reasons for suggesting that these cells may
actually represent a system intercalated lietween the
axons of the posterior roots and the cells of origin of
the spinothalamic system (194). However, more
evidence is needed to support this concept convinc-
ingly.
Termination of Spinothalamic System
Ever since the description of Edinger (61) there has
been general agreement (44, 47, 53, 82, 96, 100, 180,
204, 263) that the spinothalamic tract is easily
demonstrable in man and other primates. However,
despite early descriptions of both the spinothalamic
and the bulbothalamic components of this system in
the rabbit (139, 259, 260) douljts have Ijeen frequently
expressed as to whether the system actually reaches
the thalamus in forms other than primates. The system
is known to be composed mainly of small fibers (1 14)
and it seems right to assume that only a fraction of
them is actuall)' traceable with the Marchi technique
usually employed. It would appear that the poor
m\elination of the fibers accounts reasonably for the
failure of some workers to trace the system to the
thalamus although recently a claim has been made on
the basis of studies employing silver technique (173)
that, in comparison with the primates, actually
fewer fibers of the system reach the thalamus in sub-
primate forms. In any case it seems clear that the
spinothalamic system reaches the thalamus in all
mammals studied and specifically so in the cat (95,
I 78) which is used so frequently in modern research.
Although some fibers to the centrum medianum, to
the parafascicular nucleus and to the intralaminar
nuclei are often described, most workers are agreed
that the system ends mainly in the \entrobasal com-
plex of the thalamus. The spinal component is stated
to end in the external element; the Ijulbothalamic
component, in the arcuate element of this complex.
As far as the tactile system is concerned, the classical
concept assumes that the lemniscal and the spino-
thalamic systems converge upon the ventrobasal
complex and that from here on corticopetal pathways
are common to both.
It is possible that this concept may need a revision
since it seems appropriate to suggest that besides the
ventrobasal complex a region intercalated between
this complex and the medial geniculate i:)ody may be
a major terminal station for some spinothalamic
fibers. The reasons for this suggestion are as follows.
Many ol:)servers in the past have been greatly dis-
turbed by the scarcity of detectable terminations of
the spinothalamic fibers in the ventrol)asal complex.
It is clear from descriptions by most of the writers
4i8
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
cited that the spinothalamic tract can usually be fol-
lowed with fair ease up to the region immediately
medial to the medial geniculate body. It is the area
between this region and the ventrobasal complex
itself in which so many Marchi granules disappear
with the result that the number of terminations in the
ventrobasal complex is often only scanty. The point
to be made is that this area, which is morphologically
a part of the posterior nuclear thalamic group (209),
is the critical region under consideration.
In the cat; this region will remain essentially pre-
served after an extensive ablation of the suprasylvian
and lateral gyri and of the entire auditory region. It
will degenerate completely if in addition to this mas-
sive remoxal the second somatic aiVa is ablated as
well. Nevertheless, the removal of the second somatic
area alone will not cause any marked changes (209).
It appears then that the axons of this thalamic region
entertain connections (probably of collateral nature)
with the second somatic area. This conclusion is
harmonious with the findings of Knighton (138) who,
attempting to determine the thalamic relay nucleus
for the second somatic area, found that stimulation
of the posterior segment of what he beliexed to be the
n. ventralis posteromedialis activates the second
somatic field. From his drawings one can be fairly
confident that the actual locus of Knighton's critical
area was that segment of the posterior nuclear group
which is intercalated between the ventrobasal com-
plex and the medial geniculate. A similar interpreta-
tion applies, in our opinion, to the findings of Strat-
ford (235) who studied the corticothalamic projections
of the second somatic area by means of the strychnine
technique.
The evidence which suggests that the second so-
matic area may be activated by a thalamic grouping
other than the classical tactile thalamic region agrees
also with the findings of Woolsey & Wang (278) and
VVoolsey (personal communication) who determined
that after ablation of the first somatic area in an acute
or chronic e.xperiment the responses in the second
somatic area are not detectably affected.
It is tempting to assume that the second somatic
area is acti\ated solely by the spinothalamic system,
an assumption which, if true, could shed new light on
the function of this cortical region. This assumption,
however, implies that a destruction of both antero-
lateral columns should eliminate potentials evoked by
tactile stimuli in the second somatic cortex. While the
evidence in this respect is scanty, the findings at hand
imply that this is not the ca.se.
Topical Orgariiz'iti'in (if Spinothalamic System
We have already indicated that the a\ailable evi-
dence is inconclusive for deciding whether tactile
impulses are relayed within the spinothalamic system
in a separate spectrum of fibers or whether they are
transmitted partly or wholly by neurons which are
also utilized by discharges provoked by painful or
thermal stimuli. The existence of a specific tactile
pathway is inferred primarily from the observations
that thermal and painful .sensations may be affected
differentially by lesions of the spinal cord [for review
of literature see White & Sweet (273)]. The observa-
tions that such dissociations are not easily produced
even with shallow incisions into the spinothalamic
tract and that they are altogether rare or nonexistent
with extensive anterolateral cordotomies do not
militate, we believe, against the concept of separate
pain and temperature pathways as is occasionally
argued.
Regardless of how the spinothalamic system may be
organized in respect to different modalities of sensa-
tions, the evidence is conclusive that it is topically
organized in respect to the body surface. Thus, the
dermatomes are described as projecting in an orderly
fashion upon the cells of substantia gelatinosa (237).
It has been deduced early (196) and since amply con-
firmed by virtually all who perform anterolateral
cordotomies that fibers concerned with the caudal
portions of the body lie laterally to those related to
more oral skin areas at any level of the spinal cord.
The same basic sequence prevails in the medulla (57,
218, 219, 271), apparently in the pons, in the mid-
brain (257) and in respect to the terminations in the
thalamus (44, 47, 263) although the details may vary
somewhat at different levels.
Likewise, a topical organization of the trigeminal
fibers is well established. The anatomical evidence
indicates that the fibers of the mandibular, the maxil-
lary and the ophthalmic divisions of the fifth nerve
are arranged in a dorsoventral sequence in the spinal
tract [for reviews of the literature .see Astrom (19) and
Torvik (23B)], and this sequence has been confirmed
by electrophvsiological studies as well (172). In man,
the topical organization of this tract was inferred on
the basis of clinical observations (234) and these
deductions were proved substantially correct when
pain-relieving operations were introduced. Although
the opinions are not unanimous (64, 109, iii, 115,
133, 188, 202, 224), it is probable that in man, as in
others mammals, there is also a topical organization
TOUCH AND KINESTHESIS
4'9
of three trigeminal divisions in an orocaudal sequence.
The fibers of the mandit)ular division do not reach
as far caudally as do some fibers of the maxillary
division nor these as far as do some fibers of the
ophthalmic division. The clinical experience of some
observers (32, 273) led them to belie\e that the spinal
tract of the fifth nerve must be joined by some fibers
relevant for pain and temperature sensations from the
vagal, glossopharyngeal and intermedius nerves.
While this inference needs further confirmation, it
seems likely to be correct. The evidence in respect to
the ijulbothalamic tract is limited. Some data, how-
ever, clearly suggest that a topical organization of its
fibers exists here as elsewhere in the spinothalamic
system (55).
A statement that the spinothalamic system is
topically organized, but that nevertheless considerable
intermingling of fibers related to different segments of
the skin takes place, seems a fair reflection of the
opinions of the majority of neurosurgeons (272). This
conclusion is based primarily on the common experi-
ence that shallow cuts into the spinothalamic tract
tend to produce only transient analgesias of higher
segmental levels of the body and that in order to
secure lasting and complete effects a section as deep as
practicable is usually necessary. If the fibers concerned
with pain for all parts of the body were indeed known
to lie quite superficially, such observations would
constitute a proof for the existence of extensive over-
lap. In fact, however, the topographical position of
such fibers is quite obscure. If they should lie deep,
and if the transient symptomatology with shallow-
cuts results basically from contusion or compression
and not transection of the relevant fibers, the actual
o\erlap could be quite small. The important point is
that the data in respect to the spinal trigeminal tract
suggest that its topical organization is quite precise.
If the clinical evidence regarding extensive overlap
is not considered binding there is hardly any reason
to suppose that the entire spinothalamic system is
necessarily less precisely organized than is the system
of the medial lemniscus.
Ipsilateral Pathways of Spinothalamic System
For many decades it has been a belief, and this view
is still held frequently, that all the fibers of the spino-
thalamic tract originating in the cells of the posterior
horn cross to the opposite side and ascend within the
anterolateral column. With the introduction of cordot-
omy operations the view was advanced that in addi-
tion to a contralateral tract an ipsilateral component
of the spinothalamic system exists. Foerster & Gagel
(71) and Foerster (70) advocated this view and gave
several arguments for their belief The most cogent
were two observations: first, retrograde changes in
some cells of the posterior horn occur on the side of
the cord lesion (in addition to widespread changes on
the contralateral .side); and second, .some deficits of
tactile (and pain) sensations are demonstrable on the
side of the operation.
Anatomically there are .some reasons to believe that
an uncrossed spinothalamic tract exists, for some
cells of the posterior horn emitting a.xons into the
anterolateral column of the same side have iieen
described (27, 156, 201) and the occurrence of ipsi-
lateral retrograde changes after appropriate cord
lesions has been confirmed (147, 178). The observa-
tion that electrical stimulation of anterolateral column
may evoke pain on the same side (236) and the rare
occurrence of pain which is relieved by an ipsilateral
cordotomy militate for the existence of the ipsilateral
tract. Since the electrophysiological evidence in the
cat and monkey is concordant with the findings in
man it can be inferred that an ipsilateral as well as a
contralateral spinothalamic tract presumably exists
in all mammals.
SOME FURTHER OBSERV.JiTIONS ON SOMATIC
SENSORY SYSTEM
Relaying of Somatic Afferent Impulses
If the reasonable assumption is made that it is via
the main sensory afferent pathways that electrical
stimulation of the sensory nerve evokes early responses
in the first and second somatic cortical fields it appears
a simple matter to determine the location of the
relevant paths in the cord or brain stem by appro-
priately placed lesions in these structures. However
simple this method may be in principle it has proved
itself quite difficult in practice for it yielded occasion-
ally contradictory results in the hands of difTerenl
workers and often inconsistent results in the hands of
the same observers.
Thus, Bohm (25) and Bohm & Petersen (26)
found in their experiments that selective sectioning
of the posterior columns abolished responses in the
somatic areas I and II (SI and SII). Bohm concluded
rather boldly that the discharges in the anterolateral
column are not relayed to the cortex. Gardner and
his colleagues (83-86), on the other hand, who de-
voted much work to this problem, arrived at conclu-
420
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
sions much more in accord with other data ahhough
some of their findings are puzzhng. First of all, they
established that the potentials evoked in the contra-
lateral SI and SII (contralateral in respect to the
stimulated nerve) can be relayed both through the
ipsilateral dorsal column and through the contra-
lateral anterolateral one. This is, of course, expected
from the classical studies. However, such potentials
seem to be relayed as well through the anterolateral
column on the side of the stimulated nerve. While
electrophysiological evidence concerning the existence
of an ipsilateral pathway is, as already mentioned,
quite in harmony w'ith other data, the finding that
the discharges in this tract can relay also to the contra-
lateral cortex is anatomically not at all self-evident.
Thus, despite some ofjservations to the contrary it
must be assumed that destruction of an antero-
lateral column causes only ipsilateral terminal degen-
erations in the thalamus. Likewise it is doubtful
despite repeated affirmative reports that spinotha-
lamic fibers actually cross partly within the posterior
commissure. The latter doubt is reinforced by findings
of Gardner & Morin (85) which imply that all cross-
ings of sensory paths must take place below the mid-
brain. It appears then that, if the contralateral cortex
is indeed activated via the anterolateral column of
the same side as the stimulated nerve, the route by
which this takes place is yet to be determined.
In preparations in which the anterolateral column
of the same side was the only column available for
conduction the contralateral cortical potentials were
sometimes not evokable, and if evoked sometimes
displayed longer latencies than in the intact animals
(83). This suggests perhaps that other than the
classical pathways might have been involved in the
transmission of the discharges.
There is only fragmentary information available in
regard to the ipsilateral responses in SII. It might be
reasonable to expect that such responses are con-
ducted through the ipsilateral spinothalamic path-
way. However, out of three animals (83) in which this
path was presumably cut the ipsilateral cortical
responses disappeared in only one. Clearly, more data
are needed before any conclusions can be drawn.
The question of the existence of an ipsilateral path-
way from the nuclei of the posterior column to the
ventrobasal complex aroused considerable interest.
Several workers (26, 51, 116) using sectioning tech-
niques concluded that such a pathway exists. How-
ever, in our opinion both the anatomical and the
functional evidence (see p. 400) implies rather defi-
nitelv that such conclusions must have been in error.
The problem of whether discharges evoked by
stimulation of the afferent nerve may ascend within
the spinal cord by other than the dorsal column or
spinothalamic pathways has been considered re-
peatedly (41, 91, 176) and some evidence has been
adduced that this may be the case. Morin (176) pro-
posed that one such pathway runs in the dorsal part
of the lateral column and that it synapses in the nu-
cleus cervicalis lateralis. A crossing to the other side
is believed to take place at the upper cervical levels.
N. cervicalis lateralis, however, has been asserted
(205, 206) to relay exclusively to the cerebellum, a
finding strongly contested by Morin & Catalano
(177)-
In summary it appears that observations of evoked
potentials after sectioning various fiber tracts have
yielded thus far only limited data. The important
finding is that impulses from both sides of the body
are conducted in each anterolateral column. Some
equivocal or contradictory results may be due in part
to the difficulties in distinguishing in acute experi-
ments the shock due to the acute lesion itself from the
results of destruction of the relevant fibers. It is also
possible that a massive electrical stimulation of the
nerve might contribute to some confusing findings.
Whatever the reasons may be for the difficulties
encountered, much more systematic work is needed
with this technique.
Centrijugal Pathiva\s Impinging Upon Sensory
Somatic Synaptic Regions
It is implicit in many present day concepts concern-
ing the organization of the central nervous system that
synaptic regions situated orally in a pohsynaptic
chain of an afferent system are capable of modulating
the \ery inflow which arouses their activity. However
well founded such ideas may be, no rigorous proof has
thus far been offered for the existence of such circuits
in the somatic sensory system, although recently
suggestive evidence to this effect has been ad\anced.
Thus, Brodal et al. (34) and Walberg (248) have
described direct Ijilateral corticofugal connections to
the sensory trigeminal elements and to the gracile and
cuneate nuclei, arising not only from the sensorimotor
area but from all major cortical regions as well. The
former connections would clearly represent a ' feed-
back' system. It is certainly unexpected that virtually
all cortical regions should affect the essential compo-
nents of the projectional tactile system in a basically
identical fashion. The lack of any somatotopical
organization of the projection arising in the somatic
TOUCH AND KINESTHESIS
421
fields is puzzling since all synaptic regions of the
lemniscal system including the postcentral cortex are
in fact organized topically quite precisely.
Electrophysiological evidence indicates that repeti-
tive electrical stimulation of the sensoriinotor cortex
may depress the postsynaptic response which is
evoked in the following regions: a) in the trigeminal
nucleus by stimulation of the infraorbital nerves (i 25);
b') in the posterior column nuclei by stimulation of the
posterior columns (217); and (r) in the anterolateral
column by stimulation of the contralateral dorsal
roots (112). A destruction of the midbrain reticular
formation (presumably the destruction of the mid-
brain tegmentum), on the other hand, was observed
to enhance the postsynaptic response in the trigeminal
nucleus when the infraorbital nerve was stimulated
(126). In harmony with the latter observation King
et al. (137) observed recentK' that responses recorded
in the internal capsule to stimulation of the peripheral
nerve displayed a reduced amplitude but also a de-
crease of the latent period when an EEG arousal was
induced by repetitive electrical stimulation of the
sciatic nerve, of the midbrain reticular formation or
of the centrum medianum and n. centralis lateralis.
How to interpret these findings may be left an open
question since, except for the work of King el al. (137),
no quantitative data have been thus far offered to
substantiate an effect which manifests itself bv influ-
encing the test response only quantitatively. It is,
however, doubtful that the effects produced bv stimu-
lation of the sensorimotor area could have been
mediated by the pathways proposed by the Norwegian
workers since, if this were so, one could have expected
indiscriminate effects from stimulation of anv cortical
region in either hemisphere, which apparentk did
not occur.
Activation of Brain Stem Reluiilar Formation by
Sensory Somatic Discharges
In 1949, Moruzzi & Magoun (179) reported that
electrical stimulation of the medial portions of the
medulla, of the pontine and midbrain tegmentum,
and of the dorsal hypothalamus and subthalainus
produces generalized changes in the EEG which
appear identical with those which result when the
animal is aroused from sleep or alerted to attention.
They suggested, therefore, that the central core of
the brain stem represents an ascending activating
system, the activity of the system being essential for
wakefulness, the depression of this activity producing
normal sleep or somnolence. A great deal of effort
has been expended in recent years, particularly by
the research group of Magoun, by the group of
Moruzzi in Italy and by Bremer and his colleagues, to
substantiate this concept — which was suggested by the
early work of Bremer (30, 31) — and to determine the
functional organization of the reticular ascending
system and the sources of its inflow.
Just to what extent and in which sense one can
consider the reticular activating system as a functional
unit (it is certainly not a unit morphologically) is at
present still conjectural. Basic as this question may be
for considerations of sensations in general, we shall not
discuss it further since the present status of the prob-
lem is presented in detail in Chapter XLII of this
work. However, we shall consider briefly the evidence
regarding the activation of the brain stem by somatic
sensory afferents since the available evidence suggests,
we ijelieve, a departure from conclusions usually
reached on this subject.
Little is known about actisation of brain-stem
groupings by natural tactile stimuli. One may pre-
sume, however, that activity aroused by electrical
stimulation of a nerve (it was usually the sciatic nerve
which was stimulated) reflects, at least partially,
activity aroused by tactile stimulation as well.
In a series of papers the C^alifornia workers (72-74,
229, 230) concluded that, in addition to the medial
lemniscal system, there exists in the brainstem a
medially located, multisynaptic path, conducting
centripetally, which is fed by collaterals arising from
virtualh the entire length of the medial lemniscus.
They felt that this medial system must be composed
of a multisynaptic chain of neurons since in compari-
son with the potentials in the lemniscal system those
evoked in the reticular formation displayed much
longer latencies and longer recovery time and were
more sensitive to anesthetics. It is likely that the
California workers understand by the medial lemnis-
cal system, not only the system which we have defined
under that term but also the spinothalamic tract.
Nevertheless, all their data pertaining to the classical
pathways seem to refer to the medial lemniscal system,
as we understand it, and there is little doubt that
collaterals of the classical medial lemniscal pathway
are believed to activate the reticular ascending system.
While it is, of course, possible that the reticular
potentials are indeed of medial lemniscal origin, it
appears more likely that they are evoked, at least
predominantly, through activation of the antero-
lateral columns in the spinal cord rather than of the
medial lemniscus. There are several reasons for this
belief. First of all there is little anatomical evidence
42-2
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
that the fibers of the medial lemniscus emit any sub-
stantial number of collaterals. Ramon y Cajal (201)
was emphatic in this respect and believed that only a
few collaterals were given off to the region of the red
nucleus and a somewhat larger number to the pretec-
tal region. He seems to have been hesitant in respect
to the medial lemniscal contribution to the mamillary
peduncle. Other workers occasionally described some
collaterals to other regions as well but there seems to
be no convincing evidence that the medial lemniscus
gives off any substantial number of collaterals below
the midbrain. Matzke (170) recently stressed that the
medial lemniscus does not decrease perceptibly in
size from its origin to its termination.
The situation is different for the fibers arising in the
posterior horns and ascending in the anterolateral
column. We have considered thus far exclusively one
component of the group, the spinothalamic tract,
since it reaches farthest orally. However, it is well
known that there are other fibers accompanying the
spinothalamic tract which terminate below the thal-
amus and it is likely that at least some of them conduct
impulses evoked by cutaneous stimuli. The fact that
after anterolateral cordotomy only a small fraction of
the degenerating fibers reach the thalamus led, as
was discussed earlier, to doubts as to the existence of
the spinothalamic tract in some mammals. It appears
then that collaterals from the spinothalamic tract or
other anterolateral column fibers terminating at
lower levels could provide obvious pathways for
relaying sensory-somatic activity to the brain-stem
structures without any strain on the known anatomical
facts concerning the medial lemniscus.
Second, it has been shown that the brainstem
potentials evoked by stimulation of the sciatic nerve
occur bilaterally (230). This observation is quite in
harmony with the presumed existence of the ipsi- and
contralateral tracts in the anterolateral columns. On
the other hand, the occurrence of such ipsilateral po-
tentials would be rather puzzling if they were medi-
ated by the lemniscal system since, despite some
protestations to the contrary, there is, we believe, no
evidence for existence of an ipsilateral lemniscus aris-
ing in the posterior column nuclei.
Third, it has been shown that the potentials evoked
in the ascending reticular system by stimulation of the
sciatic nerve possess substantially longer latencies than
do responses recorded at virtually any level of the
lemniscal system (73). It is not at all clear why this
should be so if a collateral inflow for the ascending
activating system were indeed available almost at all
levels from the medial lemniscus. If, on the other
hand, these potentials were evoked by mediation of
predominantly small fibers of the anterolateral col-
umns their long latencies could be readily understood
even if the number of intercalated synaptic regions
was quite small. That some potentials in the brain
stem are, as could be expected, relayed through the
anterolateral column has been shown recently by
Collins & O'Leary (54). These workers studied a
small region in the midbrain which was activated
when smaller fibers (gamma and delta groups) of the
radial or sciatic nerves were excited. They could show
that the midbrain potentials survived (in contrast to
the potential evoked in the ventrobasal complex) a
destruction of the homolateral posterior column
(homolateral to the stimulated nerve) but were
abolished (again in contrast to the potentials evoked
in the ventrobasal complex) when the contralateral
anterolateral column was destroyed. It may be em-
phasized that the midbrain potentials displayed much
longer latencies than did the potentials evoked in the
medial lemniscal system, and in contrast to the latter
were sensitive to anesthetic agents.
In summary, it appears that the sources of the
sensory somatic inflow which activate the various
brain stem structures are not yet established une-
quivocally. The evidence at hand seems to imply that
the potentials recorded by the California workers in
the reticular activating system relay mainly or solely
through the anterolateral columns and the tracts aris-
ing from them rather than through the posterior
column and the medial lemniscal system. However,
these are indirect conclusions and it would \x desir-
al^le to test them experimentally.
Cortical Fields Olliir Than the Primary Receiving Area
Which Are Activated by Tactile Stimuli
We ha\e thus far proceeded on the assumption
that, among all the discharges in the central nervous
system which are provoked by cutaneous and deep
stimuli, only tho.se which occur in the medial lem-
niscal or spinothalamic systems are relevant for the
arousal of tactile and kinesthetic sensations. Clinical
evidence suggests that this is likely to be so for all the
synaptic regions below the cortical le\el. For the cor-
tex itself the situation is less clear mainly because one
is uncertain as to the extent of the cortical fields which
are directly activated by the subcortical components
of the classical systems. There is, of course, no doubt
that the postcentral region in primates or its homo-
logue in other mammals (which can be defined as the
projection field of the ventrobasal complex of the
TOUCH AND KINESTHESIS
423
thalamus) is the chief cortical representative of the
medial lemniscal system. As such it must be in some
way critically involved in the elaboration of tactile
and kinesthetic sensations, and we have already con-
sidered some functional properties of this field. Never-
theless, there is evidence available that this region is
not the e.xclusive recipient of all the discharges trans-
mitted through the medial lemniscal and spino-
thalamic relays. While the evidence to this effect is
fragmentary and much more work is needed to eluci-
date the details the general picture which emerges
seems to be as follows. The postcentral family of fields
(areas i to 3 of primates) appears to represent a focal
region for tactile and kinesthetic activity. This
activity is undoubtedly based primarily on the inflow
from the ventrobasal complex. .Surrounding this core
region is a belt of cortical fields which receive, apart
from any connections they may have with the post-
central region itself, some sensory somatic inflow
directly from the thalamus. It is convenient to con-
sider the evidence under several headings.
.^NATOMic^L EVIDENCE. Most of the cclls of the ventro-
basal complex are definitely known to project exclu-
sively upon the postcentral region, and it seems likely
that all do so. Assuming this to be true, it follows that
if impulses evoked by tactile stimuli are transmitted
directly from the thalamus to some fields surrounding
the postcentral region, they must be relayed through
thalamic nuclei other than the ventrobasal complex.
In fact evidence is available that a thalamic element
intercalated between the ventrobasal complex and the
medial geniculate body projects upon the second
somatic field (see p. 418). It seems probable further
that this element may be a terminal station for some
spinothalamic fibers. Whether other thalamic ele-
ments of the ventral or posterior nuclear groups which
partly surround the ventrobasal complex receive some
medial lemniscal or spinothalamic fibers is not clear.
It is tempting to speculate that for some this may be
true since, if this were so, a number of electrophysio-
logical observations would be readily understandable.
ELECTROPHYSIOLOGICAL EVIDENCE. It has been known
since the early days of the evoked potential technique
that the extent of the cortical areas activated by sen-
sory somatic stimuli may vary with the anesthetic
state. In deeply pentobarbitalized animals it is usually
the classical first and second somatic fields which are
activated by natural tactile stimuli. Under different
anesthetic conditions, with no anesthesia at all, or
when such drugs as chloralose are used, potentials
may appear in other regions as well, sometimes only
when nerve volleys are used as stimuli (i, 8, 9, 14, 38,
39, 84, 92, 142, 165, 167, 276). [Other references are
given by Buser (37).]
In the cat, which was most extensively studied,
such additional regions in which potentials evoked by
sensory somatic stimuli are likely to appear most
consistently are the precentral homologue, the an-
terior portion of the lateral gyrus and the suprasylvian
gyrus. It is known that a removal of the first somatic
area (38, 278) does not abolish e\oked potentials in
the second .somatic field. Recently it has been shown
by Albe-Fessard & Rougeul (8) that responses in the
lateral and the suprasylvian gyri are likewise not
abolished by such a removal. Similar evidence has
been offered (84, 142, 165) in respect to potentials
evoked in the precentral region of the monkey by
stimulation of the afferent nerves.
The fact that such potentials tend to appear under
special conditions of stimulation or when the excita-
bility of neurons is enhanced by drugs hardly di-
minishes the significance of the phenomenon if
transcortical spread from the postcentral area can be
excluded. Since this was done for several regions sur-
rounding this area the conclusion seems warranted
that, under certain conditions at least, some sensory
somatic discharges may relay to other regions of the
neocortex without mediation of the primary receiving
field.
EXPERi.MENT.\L psvcHOLOGic.vL EVIDENCE. The elec-
trophysiological evidence suggests then rather strongly
that not only the postcentral region but also a belt of
fields around it may be of significance for the capacity
of the animal to appreciate and handle sensory somatic
information. Nevertheless, it is reasonable to expect
somatic area I to be the central region of the somes-
thetic system. The problem is to determine the exact
role played by the different fields in the somesthetic
capacity of the animal since it is obvious that these
fields cannot by any means be functionally equivalent.
Unfortunately only a small number of studies is avail-
able on the ability of an animal to perform somesthe-
tic discrimination tasks after ablations of the post-
central field or other cortical regions. A systematic
analysis has not proceeded very far perhaps because
of the confusion which was created by the finding that
simple somesthetic discriminations are still possible or
can be relearned after removal of the first somatic
field. The studies of Ruch & Fulton (210), who re-
viewed the older literature on the subject, although
severely handicapped by lack of anatomical controls,
424
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
were suggestive that this might be so in primates.
Recent findings in rat (283, 285, 286), cat (284) and
dog (10, 11) provide acceptable evidence for this
statement. Ablations of somatic areas I and II to-
gether led to findings which may but need not be
discordant. In the rat (283, 286) discrimination of
roughness can apparently be relearned and form
discrimination need not be lost after such ablations.
Likewise form can be discriminated satisfactorily by
the monkey with some retraining (143), even though
a severe loss of tactile acuity is evident when placing
reactions or grasp reflexes are tested. On the other
hand, in the cat (284) and dog (i i) a persistent in-
ability of the animal to discriminate somesthetic
stimuli has been reported after such combined re-
movals. The findings in the cat can be dismissed since
they are based on studies on one animal only. The
findings of Allen on the dog require some comment.
It appears from his description that the actual cortical
removals exceeded considerably the anatomical limits
of SI and SII. This might but probably does not
account for Allen's divergent findings. What seems to
be a more probable explanation of his results is that —
in contrast to all other obsersers here considered who
used a pair of discriminanda differing only in weight,
roughness or form — Allen alone employed a differ-
ential conditioning technique to test the somesthetic
defects of his animals. The response of the animal
consisted of lifting his foreleg to a positive stiinulus
and not lifting it to a negative one. The positive and
negative stimuli were respectively a light stroking of
the iwck with the grain and against the grain or a
light stroking with the grain once a second (positive)
and three times a second (negatixe). The chief defect
observed was the inability of the operated animals to
withold the foreleg response when negative stimuli
were applied. The response to positive stimuli was
retained without impairment. In short, after the oper-
ations the animals tended to lift the leg to both the
negative and po.sitive stimuli and could not be re-
trained to make the differentiation. Since the task .set
by Allen for his animals was quite difi"erent and prob-
ably more subtle than those set by the other observers,
the different results need not imply contradictory
findings.
Even though older anatomical and physiological
views have often held that the precentral and post-
central regions somehow form a functional unit of a
higher order, it is only recently that the effects of
postcentral and precentral ablation upon the somes-
thetic capacity of the monkey have been tested with
modern techniques. As already mentioned, Kruger &
Porter C'43) found no permanent deficits in somes-
thetic form discrimination after remo\al of the somatic
areas I and II in their monkeys even though a severe
tactile impairment of the limbs could be reasonably
inferred to be present. Likewise, there was a perfect
retention of the learned habit if the precentral gyrus
alone was removed despite the .severe motor deficits
in the limbs. However, if both these regions were re-
moved jointK on one side the two animals tested
could not be trained to discriminate with the contra-
lateral hand a three dimensional figure ' L' from its
in\ersion. However, a \isual discrimination task could
be carried out utilizing that limb. Since this work re-
ports permanent deficits, further studies along these
lines are urgently needed. The reported lesions ex-
tended farther caudally than the anatomical limits of
areas i to 3. It remains to be determined whether an
inclusion of at least a part of the parietal region is
necessary to produce permanent discrimination def-
icits.
The knowledge that some tactile responses from the
ipsilateral side of the body reach the ipsilateral cortex
(although we believe this is not true for the first
somatic field) could suggest that learning; of at least
simple somesthetic discriminations takes place simul-
taneously in both hemispheres. Stamm & Sperry's
(22B) results are, therefore, somewhat surprising. In
their cats the discrimination of form, softness and
roughness performed with one paw had to be com-
pletely relearned only if the corpus callosum was
sectioned. Clearly more data are needed to substanti-
ate and further elucidate this problem.
The last set of available data we wish to consider
pertains to findings after lesions of the parietal cortex.
It was already suggested b\ the older work (21 1-2 13)
that parietal lesions may produce some deficits in the
capacity to discriminate somesthetic cues even though
the animals could usually relearn the tasks. Such
deficits after ablations of the parietal cortex which
spared the postcentral region itself were definitely
established by Blum (23), Blum et al. (24) and Pribram
& Barry (199). Blum et al. (24) made the tentative
suggestion that processes which determine the somes-
thetic discrimination capacity of the animal take place
outside the postcentral region itself and specifically in
the parietal region. The available findings hardly per-
mit an evaluation of this suggestion. The data at hand
are as yet too few in number, too limited in scope and
not sufficicntU systematic with respect to .some corti-
cal fields which are probably or possibly relevant.
Some important observations, therefore, are subject
to different interpretations. For example, the im-
TOUCH AND KINESTHESIS
425
portant finding of all workers that the removal of the
postcentral region does not necessarily lead to any
early or permanent deficits in somesthetic discrimina-
tions indicates strictly only that the postcentral region
is not the sole cortical recipient and distributor of all
the corticopetal tactile activity. This, of course, is also
apparent from the electrophysiological considerations.
Whether, however, such findings indicate in any way
that the postcentral cortex is not relevant for processes
determining the somesthetic discrimination capacity
of the animal is another question. The anatomical and
electrophysiological evidence leaves hardly any douijt
that it must be relevant. The experimental psycho-
physical data are indicative that the postcentral region
need not always be essential. It seems reasonable to
consider the possibility that the answer may lie in the
nature of the somesthetic task which the animal is
trained to perform. If the somesthetic cues used in the
experiments differed crudely from each other (and
certainly most of them did so), it is possible that any
somatic sensory inflow which reaches the cortex after
removal of the postcentral region still contains enough
information to enable the animal to perform the task.
It seems probable that the unique role of the first
somatic field will become apparent if the animal is
asked to perform a task requiring the highly detailed
and complex information which, as it appears, is
available only to the primary receiving field. If this
were so the postcentral cortex would be necessary for
any tactile or kinesthetic discrimination task of suffi-
cient complexity. Whether it alone is ever sufficient
for learning of such a discrimination is yet 10 be de-
termined. The chances are that the answer to this
question will depend on what the animal is asked to
do with the information it has available.
CONCLUDING REM.ARKS
It may be useful to discuss at the conclusion of this
chapter experimental work which appears necessary
for the clarification of some ideas regarding tactile and
kinesthetic sensations.
In the section dealing with the neural events in the
peripheral fibers it has been pointed out that a re\ival
in some form of the basic concepts of Head may be-
come advisable. What is well established is that
specific tactile receptors exist; what can be deduced
from some observations but what is bv no means vet
demonstrated is that generalized receptors, presum-
ably responding to all modes of cutaneous stimulation,
may exist as well. It seems futile to denv or ignore
the convincing evidence regarding the specificity of
some tactile receptors; it is probably too much to
expect, on the other hand, that all experimental find-
ings will yet become understandable within the frame-
work of von Frey's concepts. It seems probable that
the clouds over the classic concepts are real and that
further work will establish the existence of generalized
(in addition to the specific) receptors which will
probably reopen the question of the existence of
epicritic and protopathic sensibility.
Assuming that this development will take place the
problem will be to determine to what extent the
medial lemniscal and the spinothalamic systems are,
respectively, activated by these two types of receptors.
As far as the tactile activity is concerned there is
hardly any doubt that specific receptors activate the
medial lemniscal system. The available evidence indi-
cates that this system could represent the tactile (and
kinesthetic) epicritic system. The fundamental ques-
tion as to whether this system can be activated as well
by nociceptive and thermal stimuli must remain un-
answered at the moment. In anesthetized animals
only mechanical stimuli activate the medial lemniscal
system. It is, however, not known whether this repre-
sents the true state of affairs or whether such findings
are caused by anesthesia. The spinothalamic system
could be the obvious representative of the protopathic
system if the latter should exist. What little is known
about its tactile activity is compatible with the idea
that generalized receptors activate it. It is this system
which — in sharp contrast to the medial lemni.scal
system — seems to distriijute, together with other tracts
arising in the posterior horns the sensory somatic
activity throughout the brain stem. An extensi\'e inter-
locking between the medial lemniscal and the spino-
thalamic systems occurs in two places. The first is the
synaptic region of the posterior horns where the
lemniscal activity plays upon the cells of origin of the
spinothalamic system; the .second is the ventrobasal
complex of the thalamus where the spinothalamic
activity in turn interacts with the medial lemniscal
system. However, nothing at all is known as to the
meaning of these interactions. From clinical studies it
is clear that sensations of pain, temperature and
tickle, and those accompanying sexual excitement de-
pend upon the integrity of the spinothalamic .system.
Although this knowledge has been gained on large
human material, very little is known for certain about
the functional organization of the system, not even
whether or not its fibers are modality specific. It is
obvious that a number of basic problems of sensation
could be profitably explored in man in connection
426
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
with the frequently performed pain-relieving opera-
tions. Unfortunately such problems seem to be seldom
of interest to clinical observers.
In regard to kinesthetic sensations considerable
progress has been achieved in recent years. First of
all, it is now apparent that the sense of position and of
movements of the joints depends solely on the appro-
priate receptors in the joints themselves. There is no
need to invoke a mysterious ' muscle' sense to explain
kinesthetic sensations, and to do so runs contrary to all
the known facts concerning the muscle stretch re-
ceptors.
A second point is that kinesthetic activity is relayed
in the medial lemniscal system, as could have been
expected from clinical experiences in man. Cells con-
cerned with kinesthetic activity are intermingled at
each synaptic level with the cells concerned with the
activity evoked by tactile receptors, and the two
groups are arranged in one common representation
pattern. The individual cells retain, as far as is known,
their modality specificity at least to the first stage of
cortical activation.
A third fact of great interest is that receptors from
bones, periosteum, deep fascia and sheaths of tendons
activate the medial lemniscal system in exactly the
same fashion as do the tactile skin and joint receptors.
Whether kinesthetic and deep stimuli activate also the
spinothalamic system is unknown.
At present the conclusion must be that touch, pres-
sure, kinesthesis and deep sensibility are all very
closely related. Yet this is not at all apparent from
introspective observations, at least not for touch and
kinesthesis. It seems likely that more will have to be
known about cortical handling of the neural activity
evoked \)y sensory stimuli before one can approach
such problems on other than a purely speculative
basis.
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CHAPTER XVIII
Thermal sensations
YNGVE ZOTTERMAN 1 Department of Physiology, Veterindrhogskolan, Stockholm, Sweden
CHAPTER CONTENTS
STRUCTURE OF RECEPTIVE FIELD
Structure of Receptive Field
Topography of Thermal Senses: Cold and Warm Spots
Depth of Thermal Nerve Endings
Identification of Thermal Receptors
Afferent Nerve Paths
Conditions for Thermal Sensations
Conduction of Heat in Skin
Relation Between Temperature Change Recorded in Skin
and Thermal Sensation
Paradoxical Sensations
Thermal After -Sensations
Sensation of Hot'
Electrophysioiogy of Thermal Nerve Fibers
Specificity of Nerve Fibers in Mammals
Thermal Receptors in Cold-Blooded Animals
Quantitative Relations Between Temperature Movements
and Nerve Fiber Discharge
Methods
Discharge at constant temperature
Cold fibers
Warm fibers
Response of thermal receptors to temperature changes
Cold fibers
Warm fibers
Paradoxical discharges
Effect of temperatures above 47 °C
Intracutaneous gradient
Response of mechanoreceptors to thermal stimulation
Influence of Nonthermal Agencies
Theoretical Considerations
Central Threshold
Excitation Mechanism of Thermal Receptors
The different sensations of cold and warmth are produced by
stimulation of separate specific nerve end-organs in the skin.
Magnus Blix 1882 (9).
Topography of Thermal Senses: Cold and ]Varm Spots
SINCE THE DISCOVERY by Blix (9, I o) ol" cold and warm
spots from which adequate or electrical stimuli elic-
ited cold and warm sensations, respectively, numerous
authors have described the distribution of cold and
warm spots in the skin as well as in the mucous mem-
branes of man. In general cold spots are far more
numerous than warm spots, but the relation between
the density of the two kinds of temperature sensitive
spots varies a good deal in different areas. Hensel (45)
in his review emphasizes the great errors inherent in
finding these thermal spots by using punctiform
stimuli such as Blix's cone affords. The highest density
of thermosensitive spots is found in some areas of the
face. Particularly sensitive to thermal stimulation are
the eyelids and the lips. The forehead is very cold-
sensitive but only moderately sensitive to warmth.
The hairy parts of the head, the patellar region and
the tongue are very slightly sensitive to warmth. The
conjuctiva bulbi and the periphery of the cornea
possess cold sensitivity but do not respond to warmth.
Careful investigations on the distribution of tempera-
ture spots have been made for the whole body by
Rein (72) and Goldscheider (32), for the genital or-
gans by Hauer (39), Speiser (81) and Beetz (6), for
the eye by Strughold & Karge (84) and Strughold &
Porz (85), and for the mucous membranes of the
mouth and the nose by Rein (72), Strughold (83),
Schriever & Strughold (jS) and Hirsch & Schriever
(59). In these papers as well as in Goldscheider's re-
view (32) topographical charts of temperature spots
will be found. In table i the mean density of cold
and warm spots is given for different areas of the body
surface. The high temperature sensitivity of the tri-
43'
43^
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
TABLE I Distrihiitinn (if Warm nrul Cold Spots
in Human Skin*
Forehead
Nose
Lips
Other parts of face
Chest
Abdomen
Back
Upper arm
Forearm
Back of hand
Palm of hand
Finger dorsal
Finger volar
Thigh
Calf
Back of foot
Sole of foot
Cold Spotst
Warm Spots}
5-5-8
8-13
I
16-19
8.5-9
1-7
9-10.2
0-3
8-12.5
7-8
5-6-5
6-7-5
0.3-0.4
7-4
0-5
1-5
0.4
7-9
1-7
2-4
1.6
4-5-5-2
0.4
4-3-5-7
5-6
3-4
* Number per cm-.
t After Strughold & Porz (85).
I After Rein (72).
geminal area which in man is directly exposed to all
weathers no doubt has special importance.
Concerning the thermal sensitivity of animals our
knowledge is very scarce and scattered. Until recently
cold-blooded animals were not believed to possess any
specific thermoceptive organs. Sand (77) using elec-
trophysiological methods discovered that the Loren-
zinian ampullae of Raja reacted to cooling. The
Lorenzinian ampullae of the elasmobranchs are
situated laterally in the region of the head and con-
sist of a group of small mucous cysts lying subcu-
taneously. They are supplied by afferent fibers from
the facial nerve.
The facial pits of the pit viper (Crotalidae), which
originally were believed to function as mechano-
ceptors specialized for the detection of air vibrations,
were clearly shown by Noble & Schmidt (70) through
behavioral experiments to detect the body tempera-
ture of the snakes' prey. They proved that snakes
with the other principal sense organs of the head
nonfunctional can still strike correctly at moving ob-
jects and can discriminate between warm and cold
ones as long as the pits are uncovered. The organ
consists of a small pit about 3 mm in diameter covered
by a membrane 15 /z thick. This thin membrane is
the innervated sensory surface. Leading off from
microelectrodes, steel needles with tip diameter of
al)out 3 to 7 ;u inserted into the membrane, Bullock
& Cowles (12), Bullock & Diecke (13) and Bullock &
Faulstick (14) pro\ed that the afferent nerve endings
serv-e as infrared receptors. They are, so far as we
know at pre.sent, the most densely distributed warm
receptors and the most effective organ for infrared
detection within the animal kingdom. In mammals
cold sensiti\ity seems to be located particularily on
the bare parts of the nose and on the tip of the
tongue. More details are not available as yet.
Depth of Thermal Nerve Endings
The fact that the reaction time for warmth is con-
sistently longer than that for cold suggested that the
warm receptors should be located deeper in the skin
than the cold receptors (87, 91). This assumption had
many proponents (i, 26, 27, 72). Bazett et al. (5)
calculated the depth of the thermal receptors in the
prepuce. The skin was stretched out into a flat sheet
by means of small ijari^less fish-hooks. Sensitive spots
belonging to one layer of skin could thus be stimu-
lated from either side of the double fold. The rate of
transmission of the temperature wave through the
fold was determined by thermoelectrical recording;
the value obtained of about i mm per sec. is in agree-
ment with more recent measurements of Hensel &
Zotterman (55). From this figure and the reaction
time of the subject so stimulated it was possible to
estimate the depth of the receptors.
The average depth of the warm receptors was thus
found to be 0.3 mm. For the cold receptors the aver-
age depth was computed to somewhat less than 0.17
mm. The depths of the receptors for cold and warmth
computed in this way were in good agreement with
the average depth of the Krause and the Ruftini type
of end organ respectively as determined histologically.
This and other previous methods based upon the
subjective reaction time to thermal stimuli must be
subject to rather large errors because a great number
of uncontrollal)le reactions take place between the
application of the stimulus and the conscious action
of the subject, the time of which is many times longer
than that of the actual peripheral events occurring in
the thermal receptors themselves.
By using the method of recording the spike poten-
tials in the specific cold fibers Hensel et al. CoO
developed a method of physiological depth determina-
tion which eliminates the errors of the methods previ-
ously used. The method has been used for determining
the depth of the cold receptors on the tip of the tongue
of the cat and the dog but can of course in principle
be applied even to human suijjects.
THERMAL SENSATIONS
433
The principle of the method consists of determining
by means of small rectangular temperature steps the
threshold temperature change, d„ for the cold recep-
tors. A large well-defined cold pulse was applied then
to the surface by means of a special thermode de-
scribed in figure 14; then the lapse of time, /, from
the beginning of the pulse until the appearance of the
first cold fiber spike was measured. The tiine, t, is
composed of the "thermal latency,' te, the time which
the cold needs to penetrate into the receptor layer,
and two constants: the nerve conduction time, <„, of
the cold fibers and the physiological latency, /r, of the
cold receptor. For the thermal latency, te, from which
the depth of the receptor can be calculated, we
obtain
te
tr-
When the thermal diffusion coefficient, a, of the living
skin is known, it is possible to calculate to what depth
the threshold temperature change, d„ has proceeded
within the time, te- This depth is the depth of the
receptor. By means of a double beam cathode ray
oscillograph for simultaneous recording of the electric
response from the cold fibers and the temperature of
the surface of the tongue, the beginning of the tem-
perature course was easily determined with an ac-
curacy of ±0.002 sec.
Figure i shows a record of the discharge of cold
spikes from a strand of the lingual nerve of the cat in
response to a sudden cooling from 38 to I5°C and
rewarming. Simultaneously the temperature of the
silver bottom of a thermode on the tongue was re-
corded by the second beam. After an interval, / =
0.023 sec., from the beginning of the cooling, the first
action potential from the cold fibers appeared. On
rewarming, the last cold fiber spike disappeared after
an interval of 0.027 ^^c. from the beginning of the
rewarming. The determinations of / were repeated
several times for each preparation. As was shown by
Zotterman (96) the shorter the interval, /, the larger
the temperature steps. For the preparation of figure
I, for example, values of / between 0.015 ^^^- (for
steps from 38 to 5°C) and 0.07 sec. (for steps from 38
to 34°C) were obtained. For the sum of the two con-
stants /„ and tr an interval of about 0.006 sec. was
computed. The latency of the cold receptors, about
0.003 to 0.005 sec, is obtained by comparing the
intervals, /, at large and small temperature steps.
Using this value of /r we obtained exactly the same
depth at all temperature steps; at larger values of tr
the values of the depth were too small compared to
the values computed when using medium or small
temperature steps. From about 70 separate measure-
ments on six cats the following values were obtained :
Relatise
threshold - -
Average depth
of receptors
Dispersion
0-5
o. It mm
0.18 mm
0.20 mm
±0.015 n^"^ ±0.015 "^"^ ±0.018 mm
The physiological depth determinations of the cold
receptors are in good accordance with the histological
observations made on serial slides from the same area
of the cat tongue. The epithelium of the papillae has
a height of 0.05 to 0.08 mm. The musculature of the
tongue starts with a rather sharply defined border
line at a depth of about 0.3 mm. Closely above the
musculature of the tongue there is a well-developed
net of blood vessels. Thus, according to these deter-
minations, the cold receptors are situated subepi-
thelially partly in the papillae and particularly at their
base or just beneath them.
.^
"l
Cooling
\ ' 1
-Nil liiiiikifcu^ 'iiiiiite i
"Rewarming
1 '
iO°C
50
10
20
't , 1
II
■ 1 1 1
0
,T
r 1 I
FIG. I . Simultaneous records of cold potentials in a fine strand of cat lingual nerve and of tempera-
ture of silver bottom of thermode on tongue during sudden cooling from about 40° to I5°C and
rewarming. Lejt temperature scale for cooling, right scale for rewarming. Time, 50 cps. [From Hensel
434
HANDBOOK OF PHYSIOLOGY ^ NEUROPHYSIOLOGY I
Identification of Thermal Receptors
Since the recording of spike activity of single
thermal nerve fibers by Zotterman and co-workers
(22, 52, 96), there can be no doubt about the speci-
ficity of cold and warm nerve endings in the mammals
as these thermal receptors discharging into func-
tionally isolated nerve fibers responded to cooling and
warming, respectively, but not to mechanical stimu-
lation. The abundance of information about the func-
tion of the thermal receptors obtained in recent years
from electrophysiological investigations has, howev-er,
not been followed by any corresponding widening of
our knowledge of the morphological structure of the
receptors. The old attempts to identify the receptors
histologically h\ e.xcision of human skin beneath the
cold and warm spots, respectively, failed almost en-
tirely [see von Skramlik (92)]. The statement in most
textbooks that the Krause end bulbs are believed to be
the receptor for cold and the Ruffini end organ that
for warmth were based on histological studies by von
Frey (91) and Strughold & Karbe (84) on sensory
end organs within the cold sensitive periphery of the
cornea. After mapping the cold spots on the conjunc-
tiva bulbi, Strughold & Karbe dropped methylene
Ijlue into the eye and found a very good topographical
correlation between the cold spots and the blue
stained end bulbs observed in the corneal microscope.
Similarly Bazett et al. (5) in their attempt to identify
the end organs for temperature and touch in the pre-
puce injected methylene blue intra-arterially. They
described seven different types of end organs, among
which end bulbs of the Krause type were distributed
in good agreement with the cold spots. Their average
number was about 15 per cm- compared with 6 to 12
for the cold spots, but some of the end bulbs were so
close together that their number obviously must
exceed that found by mapping the cold spots. Further,
there are reasons to believe that some nerve fibers
branch and supply more than one end organ. Spots
sensitive to warmth in the prepuce are few in number
(one or rather less per cm-). The distribution of the
Ruffini end organs agreed fairly well with that of the
warm spots.
Whether the Krause end bulbs are the receptors
for cold in other parts of the skin is still uncertain
since conventional histological methods have failed to
reveal any end bulbs of the Krause type in the skin
underlying the cold spots. Recently Lele et al. (65)
maintained that, in limited areas of the skin (as opposed
to mucous membranes) in which encapsulated nerve
endings are abundant (the palm of the hand, sole of
the foot and parts of the dorsum of the digits), the
diversity in size and configuration of their cellular
and neural elements is such that any classification of
encapsulated endings in the skin becomes purely
arbitrary. On the other hand they draw attention to
the fact that in both glabrous and hairy skin en-
sheathed nerve fillers arising from the cutaneous nerve
ple.xus give rise at all levels in the skin (from the
stratum granulosum of the epidermis to the junction
of the dermis and the subcutaneous tissues) to a wide-
spread series of fine naked axoplasmic filaments
which interweave but do not fuse with one another.
These unencapsulated nerve endings cannot be dis-
tinguished from one another on morphological
grounds; they can be distinguished only by the fact
that they are situated in a different stratum of the
skin and thus lie among different tissue elements.
Thus the morphologically nonspecific nerve endings
found beneath the epithelium should be reduced in
temperature and therefore be stimulated by cooling
of the skin. The deeper endings situated close to the
lilood vessels are generally heated up by the blood so
that a positive temperature gradient between the
ending and the axons should be the usual mode of
stimulation. According to Lele et al. the temperature
modes are related not to the stimulation of morpho-
logically specific endings, but to the manner in which
nonspecific nerve endings of fibers in the skin are
stimulated. These unencapsulated endings should
thus, according to these authors, be looked upon "as
universal receptors which give rise to bursts of action
potentials, the pattern of which is related to the way
in which the stimulus affects the skin." Consequently
they also maintain that Johannes Miiller's 'law of
specific energies' and the thesis that there are specific
nerve terminals which subserve specific sensory
modalities is unsupported.
The absence of encapsulated nerve endings does,
however, not exclude the possibility of functional
specificity. The tongue of the frog does not contain
any such endings although it contains afferent fibers
responding specifically to touch, salt and water (98).
In recent years it has often been suggested that the
capsule of an end organ, for example in a Pacinian
corpuscle, protects the nerve ending from being
damaged when the organ is subjected to strong and
lasting mechanical stimulation as in the beak of a
wood pecker. The capsule should thus have nothing
specifically to do with the energy transformation.
This would imply that the specific process of transfor-
mation should be inherent in the morphologically non-
specific naked nerve endings or in the structures
where these are situated. The sensation experienced
THERMAL SENSATIONS
435
upon stimulation of the nerve ending may be more
closely correlated with the most usual mode of stimu-
lation— which, for the superficially situated 'cold'
endings, is cooling of the skin. The discharges from
these endings are then transmitted to specific cells of
the cortex the activity of which will be labelled cold.
So far it is easy to follow the idea of Lele et al. (65).
But when these authors maintain that the thermal
nerve endings respond even to mechanical and noxi-
ous stimuli they diverge from the experimental evi-
dence, in that the activity of single temperature fibers
of the cat and the dog cannot be influenced by me-
chanical stimulation of their receptive field at least
within reasonable limits of stimulus strength. The
nonspecific response of certain mechanoceptive fibers
to cooling, as demonstrated by Hensel & Zotterman
(53), requires a sudden temperature rise of more than
8°C. Since the cold fibers from the facial region of the
cat which have been more closely studied (46) do not
behave differently from those of the tongue, there can
be hardly any doubt that these fibers possess endings
which are specifically stimulated when the layer of
the skin in which thev are situated is cooled.
Afferent Nerve Paths
Judging from the relative spike height Zotterman
(96) suggested that the cold fibers of the tongue of the
cat were fairly thin myelinated fibers belonging to the
6-group of the class A fibers according to Gasser &
Erlanger's nomenclature (fig. 10). Direct measure-
ments of isolated single cold fibers from the saphenous
nerve of the cat by Maruhashi et al. (68) gave diam-
eters of 1.5 to 3 ti. These fibers showed a punctiform
receptive field and were the smallest of the myelinated
fibers. They were sensitive neither to light touch nor
to pinprick. As the warm fibers give rise to spikes of
somewhat higher amplitudes, they are considered to
be of slightly greater diameters (54, 96).
The central course of the temperature fibers in
man is only roughly known. After entering the spinal
cord via the dorsal roots the thermal fibers form a
lateral division which enters the dorsolateral fasciculus
or the tract of Lissauer. The fibers ascend only one to
three segments before terminating in the substantia
gelatinosa Rolandi, a cell column capping the poste-
rior horn with a .seemingly uniform texture containing
small cell bodies only and with no large myelinated
fibers traversing it. The axons of its small cells cross
the cord in the anterior gray commissure and ascend
in the lateral spinothalamic tract (76). In syringo-
myelia the fibers crossing in the narrow space of the
anterior gray commissure are often destroyed which
leads to a well-known clinical syndrome characterized
by loss of pain, warmth and cold on both sides of the
body at the level of the segments involved while the
sense of touch and pressure is preserved. In some
patients there may be a dissociation between the
degree of impairment of heat and cold sensation.
According to Haggqvist (36) as well as to Bailey &
Glees (3) the majority of the fibers in the spinothalamic
tract are 2 to 4 /x in diameter, 35 per cent are 4 to 6 /i
and only a few fibers run up to to fi in diameter. Thus
the dimensions of thermal and nociceptive peripheral
fibers seem to be preserved in the second order of
neurons. The spinothalamic tract is .so organized that
fibers ascending from the caudal region are pushed
outwards by the accretion of crossing fibers at each
successive segment (93). Fibers from the cervical
part are thus situated most anterior and medially.
This arrangement seems to maintain the topographi-
cal organization of the fibers into the cortical projec-
tion.
The small-sized temperature fibers of the trigeminal
nerve follow the course of the pain fibers after entering
the brain stem into the elongated spinal nucleus which
extends through the medulla to meet the substantia
gelatinosa Rolandi (28). Division of this tractus
spinalis of the trigeminal nerve, the trigeminal tractot-
omy of Sjoqvist, in the medulla leads to an analgesia
and also to a fairly complete thermal anesthesia in
the opposite half of the face as well as to failure of
tickling sensations (79, 97). The exact localization of
the third thermoceptive neurons in the thalamus is
not known. The spinothalamic tract fiiaers from dififer-
ent levels of the spinal cord terminate in the postero-
ventral nucleus of the thalamus but in doing so they
interdigitate so much that the original peripheral
topography of fibers mediating different modalities
seems to be regained. In the ventral nuclei of the
thalamus the finer topographical organization has
been worked out by studying degeneration of the
fibers in the medial lemniscus and the spinothalamic
tract (13) but a still more detailed map was obtained
by Mountcastle & Henneman (69) by studying the
electric response appearing in the thalamus on stimu-
lation of points on the body surface. The body surface
is projected onto the thalamus, specifically onto the
posteroventral nucleus which is the only part in which
stimulation of the skin evoked any electric response, in
such a way that the head is represented posteromedi-
ally, the tail anterolaterally, the back superiorly and
the feet inferiorly. According to Ruch (76) this
topography manifested in the thalamic terminations
436
HANDBOOK OF PHYSIOLOCV
NEUROPHVSIOLOOV I
/\ "w <i»>i«*»OMll*U^wi<WWWi>il»»«>»*»»>*»
Q iV^i^owt-iAt^vUiW^K^y^*^*^^^*^^"**' ^M^MAyfif^'^*'^
>MAMMMMAMMAWM«MWWMnW^MWMW«WM*MWWMIWW(MM«inM^
ImV
FIG. 2. Cortical cell responding specifically to cooling of the
tong\ie (cat). A, water of 1 1 °C and B, water of 37 °C were
applied to the tongue (signal on lower beam). Time, 50 cps.
C and D show the same cell responding to electrical stimulation
of the tip of the tongue. .S', stimulus artifact. Note that the
first spikes do not appear until the falling phase of the primary
cortical response. Time, 5 msec. Negativity upwards in all
records. [From Landgrcn, S-, personal communication.]
of sensory systems is preserved in the thalamocortical
projections. The medially situated arcuate nucleus
receiving impulses from the face projects near the
Sylvian fissure. The lateral part of the posterolateral
nucleus, receiving impulses from the leg, projects
near the mid-line. The projection from the arm is
intermediate in both thalamus and cortex. As far as
anatomical studies have revealed, the sensory body
surface is projected upon the postcentral gyrus with
spatial relations preserved but in an opposite direction
compared with that in the thalamus. Lacking any
direct evidence of the localization of the third thermal
neuron in the thalamus we have to suppose that the
original peripheral topographical organization of the
thermal units is regained at this level.
Electrical stimulation of the somesthetic areas of
the cortex made on conscious patients (16, 71) gives
rise to localized sensations. The most usual responses
are numbness, tingling and a feeling of movement
and only more rarely warmth and cold are experi-
enced. When recording from single cortical cells in
the cat by means of fine microelectrodes, Cohen et al.
(15) have found cells in the tongue sensory area which
respond specifically to cooling of the tip of the tongue
but not to mechanical or taste stimuli. Further investi-
gations by Landgren (63) show that in response to
cooling of the tongue cortical cold cells produce a
discharge, the latency, frequency and duration of
which is dependent upon the strength of the thermal
stimulus. The shortest recorded latency of the specific
cortical cold cells to an electric .shock to the tongue
was 0.015 sec. compared to 0.005 ^ec. of a cortical
touch cell within the same area. The shortest latency
recorded to cooling of the tongue was about 0.02 sec.
(fig. 2). The receptive fields of the specific cold cells
were limited to the tip or the lateral edge of the
tongue. Besides these specific cells other cells were
found which responded to mechanical as well as to
thermal stimuli, occasionally also to taste stimuli.
These nonspecific cortical cells showed much longer
latencies (0.08 to 0.30 sec.) which suggests that they
cannot be primary. So far only one cortical cell
responding specifically to warming the tongue was
found. It thus looks as though the thermosensitive
imits are represented in the cortex topographically in
much the same way as on the surface of the body. The
fact that we have found in the somesthetic cortical
areas cells which respond specifically to cold or to
warmth does not exclude the possibility that there are
peripheral afferent neurons which respond to thermal
as well as to mechanical and noxious stimuli. Such
neurons can, however, scarcely contribute to the
specific thermal discrimination. For that purpose we
have to reckon with the activity of specific peripheral
neurons finally activating specific cortical neurons.
All previous speculation of a possible frequency code
is not only incompatible with Johannes Miiller's
law of specific sensory energies as currently conceived
but also with recent electrophysiological investiga-
tions of the impulse traffic in sensory nerve fibers.
Although many have looked for facts indicating some
kind of frequency code there is to date very little
evidence that frequency modulation in the sensory
nerve can influence anything but the intensity of the
cortical events underlying the sensation. This opinion
will not be changed if nerve fibers are found with
endings which are not strictK functionally specific.
Some of the unmvelinated afferent cutaneous fibers
are most probably acti\ated by strong abnormal
stimulation as well as by inechanical stimulation.
The interference of these fibers with the activity
of more strictly specific fibers inay very well under-
lie such cutaneous sensations as hot and tickling
which possess something more than one sensory
quality. No nerve endings are aijsolutely specific as
they are all excitable by electrical stimulation or by
strong mechanical or chemical stimulation. Thus
when we speak of specific nerve endings from a func-
tional point of view, we refer only to such sensory
end organs as are specific within reasonable limits.
THERMAL SENSATIONS
437
CONDITIONS FOR THERMAL SENSATIONS
The variety of opinion concerning the conditions
for thermal stimulation, which until lately has charac-
terized the discussion of the temperature senses ever
since Weber presented his famous theory in 1 846, was
to a great extent dependent upon imperfections in the
physical methods used in studying the thermal move-
ments in the skin as well as upon the use of subjective
reports as an indicator of the stimulating eflTcct. The
main problems in the physiology of the thermal senses
have been the question of whether temporal tempera-
ture changes or the absolute temperature levels were
the adequate stimulus and the intimately connected
question of the physical or physiological interpreta-
tion of adaptation.
Conductiiin of Heal in Skin
While the majority of writers have on the whole
accepted Weber's opinion that the temporal diflfer-
ential quotient of the temperature change represents
the adequate stimulus, there are others who like
Hering (58) have given attention to the influence of
the prevailing temperature in itself (37). Thunberg
stated in 1905 in Nagel's Handhucli that this question
cannot be settled until the physical constants of the
external layers of the skin are so well known that the
thermal exchange in the skin can be computed quanti-
tatively. Following the work of Bazett et al. (5),
Hensel (42, 43) succeeded in developing methods
for the determination of intracutaneous temperature
at exactly localized depths, a very fine thermocouple
being introduced through a thin cannula or through
an intracutaneous punctured channel.
Further, Hensel (43) constructed a precision-flow-
calorimeter for measuring the steady heat flow given
oflf from small skin areas. The Stromungskalorim-
eter — a flat cylindrical measuring chamber through
which water of constant temperature flows with con-
stant velocity — is placed on the skin above the two
thermocouples which are situated at different depths.
The amount of heat given off is then obtained from
the flow velocity and temperature difference between
inflowing and outflowing water. The mean error of
the method is as low as about ±0.001 cal. per cm-
per sec.
The thermal movement in nonstationary conditions
depends not only upon the thermal conductivity of
the tissue but also on its specific heat and density.
The determining constant, the thermal diffusion
coefficient, a, is obtained by the following equation :
where X (calories per cm per sec. per degree) repre-
sents the thermal conductivity, C (cal. per gm per
degree) the specific heat, and p (gm per cm-*) the
density of the substance. As the determination of C
and X are problematic in the living skin, Hensel C44)
elaborated a method for direct determination of the
diffusivity, a. By means of the above described thermo-
electrical methods the temperature movements were
recorded at diflferent depths of the skin when rectangu-
lar temperature pulses were applied to the surface by
the application of metal bodies of constant tempera-
ture. From the curves obtained the diffusivity, a,
could be determined in that the curves for various
values of a were constructed and it was found at
which value of a the computed curve best fitted the
recorded curve. For human skin in depths up to 2
mm the values for a varied from 0.0004 to 0.0018
32
M
ss
a,
S
21
^com'/iK —^fioiiiiK.-^joae'hK. -
»
Time
-VlvK
ill''.'
fimse
FIG. 3. Recorded intracutaneous temperature change at a
depth of 0.6 mm on application of a thermode at I7°C on the
skin at 33.5^0. A distinct cold sensation persisted throughout
the whole experiment although the rate of change after 3 rnin.
fell below the minimum value of o.oo25°C per sec. given by
Gertz for the maintenance of a cold sensation. [From Hensel
(42)-]
438
HANDBOOK OF PHYSIOLOGY --' NEUROPHYSIOLOGY I
30
Temperature G
FIG. 4. 'Adaptation periods' (the time until the temperature sensation disappears) as a function
of the stimulus teinperature when using constant temperature for stimulation. The adaptation
periods become longer as the stimulus temperature departs from the indifferent temperature
(32.5''C). Broken lines indicate periods as function of the stimulus temperature after which the intra-
cutaneous temperature change at a depth of i mm has fallen below values of 0.2 "C per sec. and of
o.o°C per sec. The adaptation periods do not at all coincide with the subsidence of the intracuta-
neous temperature change. [From Hensel (42).]
cm- per sec. according to depth of the layer and the
cutaneous circulation.
By theoretical as well as by experimental investiga-
tion Hensel (44) showed that changes in the blood
flow in the skin exerts much less influence upon the
diff'usivity (the thermometric conducti\ity) than it
does upon the thermal conductivity.
Relation Between Temperature Change Recorded in
Skin and Thermal Sensations
Using the methods descrilsed above Hensel (43, 44)
made thorough investigations of the relation between
the thermal sensations reported by the subject and the
actual temperature movements in the skin when well
defined thermal stimulation was applied to the skin.
In confirmation of earlier workers, Heilbrun (41)
and Hensel (42) demonstrated that thermal sensa-
tions still persisted when the temperature of the skin
had reached a constant level. With the above de-
scriljed method Hensel recorded the temperature
movements at a depth of 0.6 mm when a rectangular
thermal step, t, was applied. As will he seen in figure
3, the rate of thermal change had gone down below
the value of 0.0025° P^r ^^c. which Gertz (30) had
found to be the minimum rate necessary to maintain
a thermal sensation, .\fter 20 min., when the tempera-
ture had been practically constant for some minutes,
there was still reported a diminishing but quite dis-
tinct cold sensation.
In figure 4 the adaptation period (interval from
the stimulus application until the disappearance of
thermal sensation) and the interval until the tempera-
ture change stopped is plotted against the tempera-
ture applied to the skin. At temperatures below 20°C
and above 40°C constant sensations appear. Hensel
(42) found that the adaptation requires a longer time
the more the temperature of the stimulus diverges
from the temperature of the skin. But the cessation of
the thermal sensation and the intracutaneous tempera-
ture changes do not coincide, as the sensation usually
considerably outlasts the intracutaneous temperature
movement. This is particularly the case at extreme
temperatures.
THERMAL SENSATIONS
439
K/iK
0,03
0.0!
0.01
J L
^T .
32 33 30 35 36 37 3S
Temperature 6
—is-
»C ft
FIG. 5. Rate, d^/d/, of the intracutaneous temperature change
at the subsidence of the warm sensation as a function of the
prevalent temperature. (Forearm, skin temperature 3 1 °C,
thermode area of 20 cm^.) It will be seen that smaller values of
d9/d< are necessary for maintaining a warm sensation, the
higher the prevailing temperature. [From Hensel C4J).j
The rate (d0/d/) of the intracutaneous temperature
change at the moment of the subsidence of the warm
sensation is shown in figure 5. Thus, the rate of temp-
erature change beUeved necessary to maintain a sen-
sation diminishes the more extreme the temperature
until at certain threshold temperatures it attains the
value of o. Outside this threshold value a constant
temperature acts as a stimulus eliciting a steady
thermal sensation.
The experiments of Gertz (30) on the effect of
approximately linear changes of temperature have
been repeated using more accurate methods by
Hensel (42). As will be seen from figure 6, the thermal
sensations pass successively through all grades of sen-
sation from cold to warmth, although the rate of
change (d9/dO is kept constant. If at any stage of the
procedure the temperature change is allowed to stop
(d9/d< = o), the thermal sensation in question at
once becomes definitely weaker.
With uniform rates of change of diff'erent slope the
time factor (adaptation) will produce a shift of the
threshold in such a way that the slower the rate of
change the more will the sensory threshold be trans-
ferred to the extreme regions of temperature. A
typical experiment is illustrated in figure 7 from
which it must be concluded that in the determination
of the thresholds for warmth and cold there must
exist a mutual relationship between two factors: the
prevalent temperature and the temporal slope (AQjAl)
of the intracutaneous temperature change.
Figure 8 gives a graphical description of the mutual
relationship between the prevalent temperature and
the temporal differential quotient, d9 d/, in relation
to thermal .sensations. The points of the curves repre-
sent average values from a great number of experi-
ments. As will be seen, temperature changes of
-|-o.ooi° per sec. and —0.001° per sec. are still effec-
tive at temperatures above 38° and below 25°. Out-
u
i2
I-
<
a: so
u
a.
2
u
^ 28
26
LUKEWARM
+ 0. 45 C/MIN
LUKEWARM
INDIFFERENT
COOL
COLD
.INDIFFERENT
COOL
0.87 °C/MIN
COLD
I . I . I ■ I ■ I ■ ' ■ ' ' ■ 1
10 20 30 40 50 60 70 80 90 100 MIN
TIME t
FIG. 6. Course of the temperature sensation at rectilinear warming and cooling of the foot in an
ultrathermostate according to Hoppler. [From Hensel (45).]
440 HANDBOOK OF PHVSIOLOGV ^ NEUROPHVSIOLOCY 1
f-C^OOSJ'/set:
'■0,02°l%iz
— Thermode temperature
Skin temperature 0. 5mm
10 min 11
Time t
FIG. 7 Position of the warmtli and cold thresholds on the forearm at rectilinear temperature
changes of different directions and slopes (thermode area of 20 cm-). The slower the rate of change,
the more distant from the indifferent temperature (33.4°C) the thresholds lie. [From Hensel (42).]
Zi
29
30
31 32 33 3¥ 35
Temperature 9
37
31 "C 33
FIG. 8- Position of warm and cold thresholds in relation to the rate of temperature change, dfl/d/,
and the temperature 9 of the skin. Broken lines, threshold sensation; solid line, distinct sensation. Initial
temperature in all experiments, 33.3°C. [From Hensel (42)-]
THERMAL SENSATIONS
441
side this temperature region the required slope
dd/dt sinks further until it finally attains a zero value,
i.e. where the temperature level itself is sufficient for
elicitation of the sensation.
When the temperature change starts from different
temperature levels (adaptation temperature), the
thresholds for the warm .sensation will reach different
values (see fig. 9). With a constant rate of change of
0.0017° P^i" sec. it is thus found that the threshold for
warmth will depend upon the initial temperature to
which the receptors have been adapted. The lower
this initial temperature, the greater the heating has
to be in order to elicit a sensation of warmth. For the
cold sensation it is the other way when initial tem-
perature is lowered. Here the cooling necessary
becomes less and less intense until the temperature
region is reached where a steady cold sensation ensues.
For higher initial temperatures, the opposite holds.
Here the cold receptors for equal cold steps become
less sensitive the higher the initial temperature is
taken (23, 37, 42).
It has long been recognized that the stimulated
area and thus the number of stimulated thermal re-
ceptors must be of great importance in the production
t-i
U
(U
£
H
37
"C
3f
35
3V
33
32
3!
30
29
26
2S
25
W*
w*
W+ warm threshold
W++ distinct warmth
Time t
J L
J
8 min 70
FIG. 9. Warm thresholds on forearm exposed to a rectilinear
increase of temperature of o.oi7°C per sec. from initial tempera-
tures of 25°, 30° and 35°C. (Thermode area, 20 cm^.) [From
Hensel (45).]
of thermal sensations, although for long periods the
use of more or less punctiform stimuli has been preva-
lent. The temperature sense in life situations is affected
o\er much of the body surface as Hensel (45) em-
phasizes. This is inter alia seen from the fact that the
cold and warm spots were not discovered until modern
times (9), although they can be detected by the most
simple devices.
Investigations on the temperature sensations when
the whole body surface was exposed have been made
by Marechaux & Schafcr (67). In a climate chamber
of the type used by Wetzler & Thauer the subjects
were exposed to approximately linear increases of the
temperature with a slope of o.ooi to o.oi°C per sec.
As the temperature of the chamber rose, the skin
temperature of the different parts of the body rose
relatively linearly. The average rate of the skin tem-
perature rise during the most rapid rises amounted
to 0.0015 to 0.003° per sec. and during the slowest
rise to less than o.ooi ° per sec. Starting from a general
coolish sensation the sensation of warmth appeared
regularly in the following order: forehead-abdomen-
hand-foot, in agreement with the investigations on
more limited areas carried out i)y Gilsbach (31) and
Hensel (42). The sen.sations produced appeared in this
order: cold-indifTerent-faintly warm-distinctly warm.
Table 2 shows the warmth threshold temperature
with slow rise of the chamber temperature. As will
be seen it is not possible even with an extremely slow
rate of temperature rise at less than 0.001° per sec.
to avoid the production of a sensation of warmth when
the temperature of the skin is aijove 35°C. The region
of thermal indifference when the whole body is con-
cerned is thus limited to a small region between about
32 to 35°C. Previous investigations of Rein & Strug-
hold (73, 74), Stein & von Weizsacker (82), Bohnen-
kamp & Pasquai (11), Hardy & Oppel (38) and
Herget et al. (57) have all shown that there is a marked
decline in the threshold when the number of stimu-
lated sen.sory spots is increased.
Besides the temporal temperature gradient (dd/dt)
a spatial temperature gradient (d^/d*) has been
widely discussed. Ebbecke (26) observed that the
release of blood flow into a previously clamped and
cooled limb elicited an intense and unexpected .sensa-
tion of cold. This led him to suggest that a cold sensa-
tion is produced by a temperature difference in the
skin at the border line of the epidermis and the cutis,
while a warmth sensation is produced by a tempera-
ture difference at the border line between the cutis
and the subcutis, the direction of the temperature
gradient being immaterial. This idea was confuted
442 HANDBOOK OF PHYSIOLOGY ^^ NEUROPHYSIOLOGY I
TABLE 2. Threshold '] emperatiiri's Jul Warmth During Healing of Body in Climate Chamber*
Rate of Increase
degrees/sec.
Forehead °C
Abdomen °C
Hand °C
Foot -C
Integrated Skin Temp. °C
O.OOI
0,002-0.003
34.8±o.3
34-7±o.5
34-5±o.6
34.8±o.8
3i-7±i->
3'-5±i-9
3i-5±i-i
3i-5±i.9
34.2±o.6
34-3±o-94
* Average values from 8 experiments [From Marechaux & Schafer (67).]
by Goldscheider & Hahn (33) who showed that .sub-
cutaneous injections of saline of I3°C ehcited a dis-
tinct cold sensation while injections of 50°C saline
elicited a sensation of warmth, whereas according to
Ebbecke's view a sensation of warmth should have
been produced in both cases.
From further experiments in which the tempera-
ture change and the change of the spatial gradient
ran in opposite directions, Hensel (42) concluded that
the intracutaneous temperature gradient or its tem-
poral change cannot be the decisive condition for the
production of a thermal sensation but the simple
warming or cooling of the receptors, independent of
the intracutaneous temperature gradient, is deter-
minative. Bazett & McGlone (4) also observed that
cooling from the lower surface of a double fold of the
skin of the prepuce led to a sensation of cold in the
upper surface. In their further investigations, carried
out to test the validity of Ebbecke's spatial gradient
hypothesis, they observed that sensations of intense
warmth or heat were found to be induced on release
of stasis in a limb maintained before, during and after
stasis in a bath at the blood temperature level, so that
on release no changes in temperature occurred and
no thermal gradient was established. This warm
sensation they attributed to a chemical stimulus
derived from metabolic processes particularlv in
muscle tissue by means of a substance that varies in
concentration both during asphyxia and as a result
of temperature changes in a manner similar to that
of acid.
According to Lewis et al. (66) and Zotterman (95)
the sensation of tingling which occurs after the release
of the blood flow to limbs in which the circulation has
been arrested is attributable to an excitation of fibers
in the nerve trunk in the area of compression. The
sensation of tingling after release of the blood flow
can be greatly enhanced by hyperventilation and its
appearance can be entirely prevented by breathing
1 2 per cent carbon dioxide in oxygen (29). The sensa-
tion of warmth upon release has, however, a quite
different time course from that of tingling which
appears after a latency of 30 to 60 sec, and the sensa-
tion of warmth which is immediately experienced
upon release is therefore most likely due to a stimula-
tion of the receptors in the periphery, as Bazett &
McGlone assumed. The only direct knowledge of the
influence of ischemia on thermal receptors comes
from Hensel (47) but is limited to the behavior of cold
receptors. He noticed that ischemia abolished within
a few minutes the steady discharge of the cold fibers.
Upon release of the blood flow the discharge immedi-
ately reappeared reaching the initial frequency within
15 to 30 sec. In the same way as the steady discharge
disappears during ischemia, the excitability of the
receptor to cold increases is gradually paralyzed.
Although Lele et al. (65) repudiate "the spatial
intracutaneous gradient theory which is based upon
the assumed presence of specific encapsulated thermal
receptors" on anatomical as well as on physiological
grounds, they maintain that the thermal sensations
reported in the presence of an absolutely constant
surface skin temperature are due to a difference in
temperature between different strata of the skin in
which the terminals of the unencapsulated nerve
endings and their nerve trunk lie. They suggest that
the unencapsulated endings give rise to propagated
disturbances when a difference of temperature exists
between stem axons and terminals and that they are
so arranged that the skin l)ehaves as a thermopile
type of 'bolometer' rather than as 'thermometer'.
They believe that the anatomical arrangement of
these unencapsulated nerve terminals in the skin is
such that it is likely that different teinporospatial
patterns of action potentials will be evoked from the
same area of skin when the temperature is raised or
lowered. The patterns evoked will not be due to the
fact that certain receptors have specific properties not
possessed by others but due to the fact that numerous
nonspecific receptors are disposed in different strata
of the skin which are not at the same temperature.
They further maintain that these endings, which sub-
serve warm and cold sensibility can, if stimulated in
the appropriate way, give rise to other sensations not
associated with the thermal modality such as touch,
prick, itch and sharp pain.
THERMAL SENSATIONS 443
This opinion is quite incompatible with the electro-
physiological findings of Zotterman (96), Hensel &
Zotterman (52, 54) and Hensel (45, 46) that cold
and warmth are subserved by specific peripheral
neurons which are relatively inexcitable by mechani-
cal stimuli. Hensel's thermoelectrical recordings show-
that a metal thermode through which water flows
quickly dominates entirely the temperature condi-
tions in the superior layers of the skin. The blood
temperature has little or no effect. At a constant
thermode temperature at 3o°C or above, no appreci-
able temperature change was observed in the layer of
the cold receptors in the tongue when the blood flow-
was arrested or released. The release of the blood flow
to the tongue which previously had been ischemic for
some minutes gave rise to an immediate return and
enhancement of the steady discharge from the cold
receptors previously paralyzed by the ischemia. The
Ebbecke phenomenon can thus not be explained by
thermal changes but by chemical changes induced by
the ischemia. The effects of ischemia occur equally at
all temperatures between 20 and 32 °C and afso when
there is no thermal effect of the blood flow. They
must all be due to oxygen lack (47).
Paradoxical Sensations
Striimpell (86) described patients with neurological
diseases displaying specific anesthesia to cold and
reported a very distinct heat sensation when the skin
was touched by pieces of ice. The reverse was less
often found, i.e. that heating the skin produced a
sensation of cold. In 1895 von Frey (91) definitely
established that the stimulation of single cold spots
with heat above 45°C caused a sensation of cold which
he named 'paradoxical cold sensation.' The existence
of a paradoxical cold sensation has been generally
accepted, while the corresponding paradoxical warm
sensation still is under debate. Lehmann (64), Al-
rutz (i) and later Rein (72) failed to produce any
paradoxical sensation of warmth. Thunberg (8g)
suggested in 1905 that this most likely is caused by
the fact that the intensive cooling evokes a very in-
tense cold sensation which masks the paradoxical
sensation of warmth which in Striimpell's case of cold
anesthesia was obtained unmasked. Recent electro-
phy.siological studies (22) reveal that warm fibers
actually respond to rapid cooling of 8 to i5°C but
this has more the character of an off discharge of a
phasic nature since it soon fades away. This behavior
of the warm receptors or the peripheral parts of the
warm fiber endings explains why this paradoxical
discharge of warmth is more difficult to detect (cf.
page 44B).
7 liermal After-Sensations
Weber (94) had great difficult\- in interpreting the
phenomenon of the 'persisting cold sensation' experi-
enced for instance when a cold metal object which has
been pressed for about half a minute against the skin
of the forehead is removed. In this famous experiment
a cold sensation is thus experienced while the tempera-
ture of the receptor layer of the skin is gradually
warming which according to Weber's theory should
lead to a sensation of warmth. Weber himself sug-
gested that this cold .sensation was due to a further
spread of the cooling to surrounding parts of the skin,
a view which had been already rejected by Hering
(58) because of the inadequate spread of the cooling
compared to the marked rewarming of the cooled
area. Alrutz (2) and Holm (60) suggested that the
persisting cold sensation was due to paradoxical
stimulation of the cold receptors by their sudden
rewarming by the blood. The interpretation of
Weber was again refuted by Holm (60) who anes-
thetized the cooled area of the skin leaving the sur-
rounding area intact. In spite of normal thermal
sensibility in the surrounding zone, no sensation of
cold appeared. Further, Bazett & McGlone (4) re-
corded the .skin temperature below the cooled area
and proved that the cold after-sensation coincided with
an actual rewarming of the skin although they believed
as Weber that in their case the sensation could be
attributed to a spread of the cooling to the surround-
ing skin.
More recently Hensel (42) has recorded the actual
course of the intracutaneous temperature movement
below as well as outside the thermode. He demon-
strated that the spread of cooling to adjacent parts of
the skin is very slight, the quantitative relation be-
tween the rewarming of the cooled area and the cool-
ing of the surrounding being 18:1 at the time of the
most intensive cold after-sensation.
Thus the cold after-sensation cannot be explained
by a subsequent spread of cooling. At low skin tem-
peratures a cold sensation can be present even when
the temperature of the .skin is gradually rising. This
cold sensation is just a normal cold sensation due to
the low temperature of the receptor layer of the skin.
Electrophysiological studies of the activity of the cold
fibers in the cat (cf. page 446) very substantially
supports the view that the cold receptors at low tem-
peratures are displaying a steady discharge which
444
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
increases in frequency as the temperature slowly rises
from 15 to '25°C.
Sensation iij 'Hot'
Alrutz (2) suggested that the sensation of hot was a
mixed sensation of warmth and 'paradoxical' cold
although it is a subjectively simple sensation not
divisible by introspective analysis and is qualitatixely
different from the sensations of cold and warmth.
Thunberg (87), Kiesow (62) as well as Trotter &
Davies (90) criticized this theory of Alrutz, main-
taining that the paradoxical cold sensation can
readily be apprehended and that the applied heat
even stimulates other sensory fibers in the skin. Hacker
(35) observed, however, in an experiment on him.self
in a traumatized region of the skin where no cold
spots but numerous warm spots were found that no
sensation of hotness was obtained but only of warmth.
Goldscheider (32), however, rejected Alrutz' inter-
pretation because the sensation of hot is felt most
strongly in regions where the warmth sensibility
is particularly good and not in regions where the
cold sensibility is comparatively stronger than that
of warmth.
Kaila (61) described an experiment on thermal
receptors of the penis in man which greatly strengthens
the original view of Alrutz (2). Usually the tip of the
penis does not possess any sensibility of warmth while
cold and pain is easily evoked. When the tip of the
penis is dipped into water of 40°C, the subject experi-
ences a rather unplea.sant painful sensation; this
temperature does not act on the cold receptors. If,
however, the temperature is raised to 45°C, an intense
sensation of cold is produced as this temperature
stimulates the cold fibers. The sensation is, however,
not really painful. When now a greater part of the
penis is dipped into the water at 45 °C, warm recep-
tors are also stimulated and a specific .sensation of
pleasant heat appears.
This simple experiment is an example showing
how simultaneous stimulation of different receptors
can evoke the sensation of a specific quality in which
it is not possible to recognize the elementary sensa-
tions which each of the specific receptors involved
produce. Thus, when we speak of 'hot' as an elemen-
tary sen.sation, as Alrutz did, or as a 'fusion' the dis-
tinction is fictitious because the integration ma\' ise
effected deeply below the 'threshold of consciousness."
Head (40) maintained that this occurred as early as
the first synapse. For further analysis see page 452.
ELECTROPHYSIOLOGY OF THERM.\L NERVE FIBERS
In recent years the function of the thermal recep-
tors has been subjected to more objective investigation
by the comijination of effective methods for recording
the temperature and the action potentials from the
nerve fibers involved.
Specificity of .Nerve Fibers in Mammals
The first recording of the specific electric response
to thermal stimulation was made by this writer in
1936. He was generally able to see leading off from a
fine branch of the lingual nerve a number of small
action potentials with spike heights I3 to ifo of that
of the largest spike potentials elicited by touching the
tongue (fig. 10). When the tongue is washed with
warm water these small spikes disappear to return
shortly if the tongue is laid free in the air at room
temperature. A faint draft over the tongue increases
the number of impulses, and a sudden fine stream of
air from a syringe on the receptive field elicits a dis-
■■^W^"**^*V*^*^^<^
FIG. 10. ^4. Microphotograph of lingual nerve preparation.
Magnification, 685. Largest fibers measure 10 ^ in diameter.
.\lsheimer-Mann stain. B. Record from the same preparation
showing the ratio between the spike heights of cold and touch
impulses. The irregular discharge of the small cold spikes is
due to the exposure of the tongue to air. The four large spikes
were elicited by touching the tongue with a brush. [From Zot-
terman (96).]
THERMAL SENSATIONS
445
tinct volley of small spikes. When the current of air is
forceful enough to make a noticeable deformation on
the tongue, larger spikes appear among an increased
number of small ones (fig. 1 1 B'). If the air in the syringe
is successively warmed, a point is reached when the
air stream does not elicit any small spikes, while the
large ones still appear as soon as the pressure is raised
sufficiently to occasion a noticeable deformation on
the surface of the tongue.
When one drop of hot water (8o°C) is applied to
the tongue, two types of spikes may be observed be-
sides the large spikes signalling the impact of the water
drop (fig. 11^). A careful examination of the record
reveals two types of spikes of which one derives from
warm fibers and the other, a somewhat smaller and
apparently more slowly conducted spike, derives from
a pain fiber. In this way it was possible to show that
cold and warmth as well as pain are mediated in
specific nerve fibers (96).
Thermal Receptors in Cold-Blooded Animals
Electrophysiological investigations by Sand (77)
on single fibers from the Lorenzinian ampullae of
Raja showed that the receptors when kept at constant
temperature were discharging continuously at a
steady rate which varied with the prevailing tempera-
ture. Cooling caused an immediate increase in the
frequency while warming led to the reverse eff"ect.
Recent investigations by Hensel (49, 50) on Scyllium
have confirmed Sand's original discovery in all
details. At constant temperature the steady discharge
in single fibers reaches a maximum of about 65 im-
pulses per sec. at about 20°C. The temperature limits
for steady discharge were 2 to 34°C. In this range of
temperature, sudden cooling produces in single fibers
a rapid increase in frequency up to 180 impulses per
sec. followed by rapid adaptation to a low steady rate
of discharge. The ampullae react definitely to a
change in temperature of o.o5°C. Warming produces
an immediate decrease or abolition of the discharge
which then slowly attains a new steady value. The
ampullae are not sensitive to mechanical stimulation
and they thus behave qualitatively in every respect
like the cold receptors of mammals. Quantitatively
they appear to be even more sensitive.
The remarkable infrared receptors of the facial pits
of the pit viper (Crotalidae) have been extensively
studied recently by Bullock & Diecke (13). The nerve
fibers from the facial pit usually show a continuous
nonrhythmic discharge in the absence of environ-
mental change. The adequate stimulus for increa.sing
this activity is a relative increase in the influx or a
decrease in the efllux of radiant energy in the middle
and long infrared bands. Relative increases in efflux
or decreases in influx reduce or inhibit the steady
discharge. No response is obtained to sound vibration,
a number of chemicals or heat-filtered light, but
JiriUM
»IHhl|ll l> IW>B , II (If
Mtl"*'*'!! t 'I
• ■ — * *
C .J t it * . . I'l I'
■ iii»|>tiii>UtiM>>itiiiHui
oi imiminiiiMNiiiiiiimiiiiM i\\\\\
• ^ t.4 I, > H \t> > »4->^-»^»VWV*-»'
FIG. 1 1. Afferent spike potentials from different sensory fibers of a fine strand of the cat lingual
nerve obtained by applying different stimuli to the tongue. A. The effect of a drop of water at I4°C
falling on the tongue. B. First, the effect of a faint puff of air, which does not cause any visible de-
formation of the surface, followed by the effect of a stronger puff of air which makes a definite defer
mation. C. A drop at 8o°C falling upon the tongue. D. The effect of pressing a pointed rod into the
tongue. E. Squirting hot water (6o°C) over the tongue. [From Zotterman (96).]
446
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
change in temperature by conduction from ambient
media and mechanical deformation of the sensory
membrane, do stimulate. It is concluded that these
are minor or incidental in some fibers. Direct measure-
ment of the change in temperature of water flowing
over the membrane necessary to elicit a response gave
values of 0.003 to o.oo5°C.
Thus the nerves of the facial pit organs of rattle-
snakes are composed of an essentially homogeneous
population of warm fibers behaving principally as do
mammalian warm fibers. But for the receptors of the
pit organ the normal stimulus is chiefly radiant and
not conducted heat, and several anatomical properties
adapt it to a high sensitivity in terms of caloric flux.
Dodt (19) describes discharges from the glosso-
pharyngeal nerve of the frog in response to tempera-
ture changes in the tongue of more than 3°C even in a
temperature range below I5°C. This response appears
only to warming, never to cooling. The response of
these fibers to heating the tongue resembles in many
ways that of mammalian warm fibers as well as that
of the pit organ of the rattlesnake. Further experi-
mental analysis is, however, necessary to decide
whether this response to heating the tongue of the
frog is due to the stimulation of nociceptive fibers
or of more or less specific warm fibers.
Qiiantitative Relations Belwem Temperature
Movements and Nerve Fiber Discharge
By use of well defined and thermoelectrically con-
trolled thermal stimuli applied to the tongue of the
cat, it has been possible to work out the fundamental
relationships between the temperature and the activ-
itv of the thermal fibers. This work has principally
been carried out in the writer's laboratory in a series
of investigations by Hen.sel, Dodt and co-workers.
METHODS. For quantitative studies of cold receptors
we have used fine strands of the cat's lingual nerve
containing only one or a few cold fibers. Preparations
containing single or a few warm fibers are best ob-
tained from the chorda tympani of the cat. [For the
operative technique see Zotterman (96), Hensel &
Zotterman (53) and Dodt & Zotterman (22).] For
thermal stimulation we used a metal thermode, open
at the top, which had a free outflow on one side (fig.
12). The thermode had a gold-plated silver i)ottom of
20 X 30 mm and a thickness of o. i mm. From above,
two constantly flowing jets of water at diff^erent
temperatures were directed on to the bottom of the
thermode in such a way that the jets could suddenly
FIG. 12. .\ppaiatus for applying rapid temperature changes
to the surface of the tongue. Th, thermode; li, silver bottom;
n'l and Ti'2, water jets of different temperatures; 0\ and O2,
outflows; S, switch; arrow, movement of switch; A, axis of
switch; Ti and To, thermocouple wires; J, junction in bottom
of thermode; /., lead strip. [From Hensel et al. (51)-]
be interrupted. In this way it was possible to produce
very rapid and exact temperature changes of the
gold-plated silver foil. Soldered on the thermode
bottom was a thermocouple with a diameter of 0.05
mm which enabled us to record the true temperature
changes of the silver foil. Because of the rapid temper-
ature change, which could exceed 300°C per sec,
the temperature was recorded either by a micro-
galvanometer of Moll or by the second beam of the
double beam cathode-ray oscillograph which was
used for recording the action potentials. The thermode
was adjusted on the tip of the tongue which rested on
a cork plate. It can easily be shown both mathemati-
cally and experimentally that a constant temperature
is reached in the receptor layer of the skin only
negligibly later than at the surface of the tongue. In
many experiments thermocouples were inserted to
different depths into the tongue in order to record the
temperature within the mucous membrane.
DISCHARGE .\T CONST.ANT TEMPERATURE. Cold fibers.
When the thermode is adjusted at a constant tempera-
ture the frequency of the cold spikes attains a constant
final value after a short interval. A record from a
nerve preparation containing two cold fibers (one
giving diphasic, the other monophasic spikes) will be
seen in figure 13. The thermode was previously kept
for a long time at a constant temperature of 34°C.
Even at this temperature there was present a steady
discharge of the monophasic fiber at a rate of 9 im-
THERMAL SENSATIONS 447
3»
•c B
IL I I I I I
i*r'c
Ur'C
»r'C
Fig. 13
\n I iiiiniiiiii|i|iiii mm I
i I I i i i I I M
Kl I I M i I I I I I I M I I
I I I
■itiiiiiiiiiiiiii
I I I
U5'
Fig. 14
itiiiutiliMiiMiKilMiilitiiHinihiiilliiiliiiitiliilllhiiMilltnini
iitKMnnHiiiiiiiiiiiiiMilliuiiiiti
W.5'
IMIIiliiiliiiiiiMiiiiiMiiiil(liiililiiiiM(iiiiuiUi(ttiiiiihiiiiitniiiiniiiiiniiiMitMiniMiiiiiiMiiiiiiiiMii
*2r'c 397'
37
■ IMIIII
I tl II 1 1 II II III II nil II II I II M) Mil nil It IMMI II I
lllllllllllllllll
*2
r'c 38.0'
ItlhlHniUltMIMIMIIUIIIIIIIMNtlHIMIIIIIIlMIMlMMlillllllllMll IIIM tlllnlllMMMtt lliilllilllllllllll
33.2'
I 1 I 1 I I I I
null Mil MM It II Mil nil II Mil til 111 Mil II I
ifr'C 25.5«
I I I I I M I i I lU I I I I I
JL
,i 1 , 1,1 1 I II I I i
FIG. 13. Spike potentials from two cold fibers recorded on cooling the tongue of the cat from
34° to 32 °C. .4, the temperature drop; B, after i min. , C, after 2 min.; D, after 4 min.; E, after 15
min. [From Hensel & Zottcrman (54).]
FIG. 14. .Spikes recorded from a single cold fiber (cat) at different constant temperatures.
Time marks, 50 cps. [From Hensel & Zotterman (54).]
pulses per sec. from which the three spikes can be
seen before the coohng starts (fig. 1 3). The thermode
was then quickly cooled down to 32°C. Immediately
the frequency of the monophasic fiber rose to 35
impulses per sec. and simultaneously there was a
discharge of thesecond diphasic fiber which, however,
after a few seconds ceased again, while the discharge
of the first fiber adjusted itself to a final constant fre-
quency which after i min. attained a value of 9.3
impulses per sec. After that there is practically no
more change. The cold receptor goes on discharging
at a fairly regular rhythm for minutes or even hours
with remarkable constancy if the temperature of the
surface of the tongue is kept constant.
Figure 14 gives an example of the discharge of a
single cold fiber after adjustment to a constant final
value of frequency at different constant temperatures.
At a temperature of 4i.3°C there is no discharge in
this fiber while already at a constant temperature of
40.5°C there is a low frequency of about i impulse
per sec. The upper limit at which a steady discharge
of the cold fiber appears, called the steady threshold
temperature for this particular cold fiber, lay between
41.3° and 40.5°C, i.e. above the ordinary blood
temperature. At this temperature (38°C) the fre-
quency of the steady discharge was 5 impulses per sec.
and the maximum about 3o°C. Below this tempera-
ture the steady discharge declines and at lower tem-
peratures the discharge generally becomes irregular,
occurring in beats of two or three impulses. Between
15° and io°C the average discharge increases again
(17) to disappear entirely between 12° and io°C.
No steady discharge of any cold fibers has been seen
at a temperature below 8°C.
The diagram in figure 1 5 shows the steady dis-
charge of a cold fiber as a function of the temperature.
The experiiTient was conducted in such a way that
the frequency was determined at definite teinperature
steps from warm to cold. After reaching the lowest
temperature — in about 2 hr. — the impulse frequency
448
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
10 r- Jmp/iec
5 -
from 40 - 20 C
.. 20 - 40 C
25
10
i5
•C ♦<?
FIG. 15. Impulse frequency of the steady discharge of a single
cold fiber as a function of the temperature of the tongue surface.
The frequencies were first measured at temperature steps from
40° to '20°C and then again in reverse order. [From Hensel &
Zotterman (54).]
was recorded once again when the temperature was
raised in the same steps as before. It is seen that the
points lie on the same curve. Even after hours of
experiments exposing the receptors to widely difTering
temperatures, the steady di.scharge appears with the
same frequency when the temperature of the tongue
is restored to the initial value. The impulse frequency
of the steady discharge of the cold receptors thus
depends entirely on the temperature.
The steady discharge of cold fibers shows a maxi-
mum frequency of about 10 impulses per sec. The
site of this inaximum on the temperature scale varies
in different fibers between 20° and 34°C, while the
upper and lower temperature liinits in extreme cases
reach 10° and 41 °C. The total frequency of cold
impulses in the nerve, which is the sum of the dis-
charges from the single cold fibers, reaches its inaxi-
mum (fig. 16) at a temperature between 15 and 20 °C
(54)-
Warm fibers. Judging from the relative spike height
the fibers inediating warmth were conceived to be
somewhat larger in diameter than the cold fibers (96).
Preparations containing only warm fibers display a
steady discharge to constant temperatures between
20° and 47°C. In single filler preparations the fre-
quency of this steady discharge varies in a consistent
manner with the temperature, although the maxi-
mum discharge as well as the upper and lower tem-
perature limits vary somewhat (fig. 17). The max-
imum usually was found between 37.5° and 40°C.
At higher temperatures the steady discharge falls ofT
rather steeply. Above 47°C and below 20°C no steady
discharge was noticed. The maximum frequency
varied in single warm fiber units between 1.5 and 3.7
impulses per sec. (23). The discharge was never as
regular as that of the cold fibers which may depend on
the comparatively low frequency and also on the
possibility that the warm fibers may divide peripher-
ally to supply more than one end organ.
The low sensitivity of warm receptors to tempera-
tures between 20° and 30°C aho has an important
bearing on the interpretation of Weber's phenomenon
of persisting cold sensation (cf. page 443). When the
cold object is removed from the skin there is a distinct
pause in the cold sensation due to the postexcitatory
depression of the cold receptors. When the cold sensa-
tion then slowly reappears, although the temperature
of the skin is gradually rising, there will be very little
interference from the scattered warm receptors. Thus
the steady discharge of impulses from the cold recep-
tors which display their maximum sensitivity in just
this temperature range 25° to 30°C will stand out still
more conspicuously.
Jmplc,ec
100 r-
— o— Single fiber
— •- 4-5 fibers
Itl 10-20 fibers
55 'C ^
FIG. 16. Total impulse frequency of the steady discharge in
different preparations of the cat lingua! nerve as a function of
the temperature of the tongue surface. [From Hensel & Zotter-
man (54).]
THERMAL SENSATIONS
449
^'"Plsec
a
7
—
6
—
5
—
4
—
3
—
2
—
1
— o— Single fibers
_o— Two fibers
50 °C
Fig. 17. Graph showing frequency of the steady discharge of different single and dual warm
fiber preparations as a function of the temperature of the tongue surface. [From Dodt & Zotterman
(23)-]
RESPONSE OF THERMAL RECEPTORS TO TEMPERATURE
CHANGES. For the investigation of the influence of
temporal changes in temperature on the impulse fre-
quency, rapid changes from one constant temperature
level to another constant level were used. A purely
rectangular shape of the temperature rise curve could
not be obtained as the equalization of the receptor
temperature takes a certain time, but a very rapid
adjustment to a constant value was ensured.
Cold fibers. Sudden cooling of the tongue produces,
as is seen in figure 18, a rapid discharge of the cold
fibers which quickly declines to the final value of the
steady discharge characteristic of the prevalent tem-
perature. The maximum response of a .single cold
fiber seen when applying a very rapid cooling from
40° to 2°C was 140 impulses per .sec. which is about
15 times as high as the maximum frequency recorded
at a constant temperature.
In contrast to the steady discharge, the frequency
of which is determined solely by the temperature, the
maximum frequency at temperature changes is not
so much dependent on the initial or final temperature
as on the rate of the temperature change (dd/di).
Rapid cooling can thus produce a discharge from cold
receptors even in a rather warm temperature region
above the upper temperature limit of the steady dis-
charge as is shown in figure 18.
The maximum rate of discharge of the cold fibers
in response to rapid cooling is, however, not exclu-
sively determined by the rate of cooling (dd/di), as
is evident from figure igi?. Applying equal tempera-
ture drops of 2°C at various initial temperatures, it
was found that identical intracutaneous temperature
changes elicited different grades of excitation in the
cold receptors depending upon the range of tempera-
ture within which the change occurred.
Rapid warming of the cold receptors to a constant
temperature leads to an immediate cessation of the
steady discharge. If this temperature lies below the
upper temperature limit of the steady discharge, the
impulses reappear and adjust themselves at a fre-
quency corresponding to the prevailing temperature
(fig. 19). The length of this pause caused by warming
the cold receptors depends upon the rate of warming
and the range of temperature. Thus, while rapid
cooling leads to an 'overshooting' excitation of the
cold receptors, rapid warming of these receptors
produces an 'overshooting' inhibition.
If the warming is small or follows at a relatively
low rate, the cold impulses may not disappear at all
but occur only at another frequency. Thus cold im-
pulses were shown to appear even during warming of
the cold receptors. This offers a ready explanation of
Weber's 'persisting cold' sensation (cf page 443)
that below a certain temperature cold sensations may
occur even when the temperature of the receptor
layer of the skin is rising. The objection ba.sed on the
spread of the cooling to surrounding parts of the skin
was quite pointless in these experiments since, when
thin nerve preparations are used, the receptive field
450
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
sec 50
FIG. i8. Impulse frequency of a single cold fiber in the cat
lingual nerve during induction of rapid temperature changes
in the tongue. A, From 32° to 30°C; B, from 40° to 38°C; C,
from 42° to 40°C; D, from 44° to 42 °C. Cooling starts at time
zero. [From Hensel & Zotterman (54).]
of the cold fibers is far smaller than the surface of the
thermode in contact with the tongue. The cold recep-
tors involved can thus be influenced only by the
temperature changes below the thermode and not at
all bv any spread of cooling outside the thermode.
]\'arm fibers. The discharge of the warm fibers in
response to thermal stimuli displays essentially the
same characteristic features as does that of the cold
fibers but in the reverse order. Thus rapid warming
to a constant level produces an overshooting discharge
after which the discharge adjusts itself fairly quickly
into an irregular steady rhythm. The initial volley
(fig. 20) appears after latencies varying from 0.15 to
0.55 sec. which was taken as indicating that the
warm receptors were situated at varying depths in the
tongue. Short latencies were observed particularly
for temperature rises from ;57° to 40°C, whereas
latencies for corresponding rises in the range of 25°
to 35°C were considerably longer. The discharge of a
single warm receptor displays a much higher initial
frequency compared with that of a cold receptor
exposed to a corresponding drop in temperature, and
the sequence of impulses thereafter is interrupted by
sudden pauses in the discharge. The mean value of
the frequency falls, however, in an exponential way
as does the discharge of the cold receptors.
Figure 21 shows simultaneous records from a
strand of the chorda tympani (above) and from a
strand of the lingual ner\-e (below). The former
preparation contained warm fibers only while the
lingual strand possessed cold fibers and one touch
fiber. At a constant temperature of 23 °C there is a
steady discharge of cold fibers in the lingual prepara-
tion (below) while hardly any spikes are recorded
from the chorda strand. When the temperature was
raised to 38.5°C, a discharge of the warm fibers
occurred while the steady discharge of the cold fibers
disappeared. A quick return of the temperature to
23°C produced a small oflf-efTect from the warm
fibers at the same time as the cold fibers started their
firing. When this procedure was repeated after 6 sec.
(fig. 21), hardly any change in the response could be
noticed. If however the temperature was raised to
44.8°C, a certain difiference in the warm fiber response
was noticed. First of all, the sudden rise elicits a much
stronger initial frequency of warm impulses. Secondly,
when the temperature dropped there appeared a
Time t
FIG. 19. Graphs showing .-J, impulse frequency of the steady
discharge of a single cold fiber ; B, frequency of a sudden tem-
perature drop at different temperatures. [From Hensel (48).]
THERMAL SENSATIONS
451
A 40 °^
' .I»>1*.HW|M||B I \
i*-^
¥m w^
iuiuij.g£'..jniiiiu»iiaiiiiuiiiiiuiiiu»i»»HitiMUiiiuiituiJi»'M"MiillllllllttUllMlHii l««iii'i'i»"i'''«iui!ilWIII«wwwm
B
45\ OC
^
•^
^U^
^4^
^
iM^
iijiUtaiiyijtiuu)itiiuiiiuiiiiiMHii)iiiiuujiuuiuuuiuuiiuyiu)u^^^^ ifiiiiiiiiiiiiiiiifiiiiiiiiiiiiiiiMtwmim
'^
^m^
■!■
iiijiiu J5 Liidiiiii'':ii)uiiuuiiiJuy[MUUUiiM muuiuuuiuuyiuuiuiHiiuuuuuuiiu
FIG. 20. Records showing the warm fiber response to sudden heating and cooling of the cat tongue
at different levels. .4, temperature rise, 14.2° to 38.6°C, latency 0.55 sec. B, 25.3° to 38.6°C, latency
0.46 sec. C, 30° to 38.6°C, latency 0.42 sec. D, 34.4° to 38.6°C, latency 0.47 sec. The latency of the
off-effect, 'paradoxical warmth,' varied between o.io and 0.15 sec. [From Dodt & Zotterman (23).]
A ^"^.
hMPViMMMMi
H MM>»4«|ii(
'I >l I I
Q 40 ^
NupT I li I Hill ^ »(i»liih III iK»|fi I I ij
"2**
C 45 OC
I i ii0»if<mniii^ I III iiw(i'»»M
MM
•gi*?^
iiiiiiiii!iMiiiiiiiriiiiiiiiiiiiriiii!iMiMihMMiMiiiiiiiiiii'iiiiiiiiiiitiiiiiMtiiiiiiiiiiiiiiiiiiiiiiMiiiiiiiiniiiiniiniiiiniiiniiiuiiiiiii
FIG. 21. Simultaneous recording from a warm fiber preparation of the chorda tympani and a
cold fiber preparation of the lingual nerve. A and B, a rise from 23° to 38.5°C and back; C and D,
from 23.8° to 44.8°C and back. B and D are recorded 6 sec. after the previous record. [From Dodt
& Zotterman (23).]
Strong off-discharge from the warm fibers. As can be
seen in figure 21, this effect occurred after a very short
latency, much shorter even than that of the cold fiber
discharge. When the heating was repeated within 6
sec, the initial warm fiber response to heating to
44.8°C each time was very much reduced while the
off-effect from the warm fibers remained almost
unchanged.
This off-effect of the warm fibers was observed
whenever the temperature dropped about 8° to
I5°C. It is more conspicuous the more rapid the
change in temperature, but it appeared even at
452
HANDBOOK OF PH'iSIOLGGV
NEUROPHYSIOLOGY I
rather slow rates of temperature change. The response
soon fades away when the temperature is kept below
20°C and is thus always of a phasic character in con-
trast to the steady paradoxical discharge of cold fibers
when exposed to constant temperatures above 45°C.
The fact that the latency of the warm fiber response to
sudden cooling is only about a third of the shortest
latency of its discharge to warming induced Dodt &
Zotterman (23) to consider whether the former re-
sponse of the warm fibers is due to an excitation of the
warm receptor or to its nerve fiber. As was originally
shown by Bernhard & Granit (7) rapid cooling of a
nerve trunk excites class A fibers directly and such a
rapid cooling also stimulates the endings of mechano-
ceptive fibers (53). This nerve fiber discharge in every
respect is of the same character as the discharge of
warm fibers to cooling. It has a relatively short
latency, the length of which varies with the rate of
cooling; the discharge is phasic, i.e. there is no steady
discharge. When, however, the thermode was placed
on the other side of the tongue where the more central
part of the lingual nerve runs closely under the sur-
face, no discharge of the warm fibers could be seen
when this surface was suddenly cooled from 45° to
25°C.
An old question in the field of sensory physiology
is whether sensation is in part due to direct stimula-
tion of the .sensory nerve fibers as well as of the recep-
tors. In the function of thermoreception this question
is, as we have seen, of particular importance. For that
reason Dodt (18) made a thorough study of thermo-
sensitivity of A fibers in the lingual nerve and com-
pared the responses in specific cold, warm and
mechanoceptive fibers upon thermal stimulation of
the surface of tongue and of the lingual nerve, re-
spectively. He found that all three types of afferent
fibers were phasically excited by local cooling of the
nerve trunk. In mechanoceptive fibers this occurred
whenever the temperature drop was of a sufficient
magnitude, regardless of the final value, the effect
being optimally elicited when the nerve was at an
initial temperature between 35° to 40 °C. Cold fibers,
however, were excited only when the nerve trunk was
cooled to below a certain threshold value of about
20°C. Warm fibers were mixed in their reactions,
some responding like mechanoceptive fibers, others
having a distinct threshold. Warming of the nerve
trunk never led to excitation of sensory A fibers.
The cold and the mechanoceptive fibers could be
blocked by low and high temperatures, the cold fibers
being blocked below 16° to 25°C and above 50° to
52 °C, whereas the thresholds in mechanoceptors were
in both types of block 5° to 8°C lower.
Cold fibers, excited by cooling the nerve to tem-
peratures insufficient to cause blocking, show follow-
ing the phasic excitation an impulse-free interval, the
duration of which varies directly with the length of
the excitatory burst and inversely with the back-
ground frequency of impulses coming from the recep-
tor.
These findings suggest that under physiological
conditions normal and paradoxical sensations of cold
are due to the stimulation of the thermal receptors or
the nerve fibers included in the end organ and never
to a direct stimulation of their myelinated nerve
fibers.
PAR.^DOXic.'^L DISCHARGES. When the temperature of
the tongue is raised above 45 °C, a steady discharge of
cold fibers is produced (24). This impulse activity
increases slowly and attains a level corresponding to
the prevailing temperature. This paradoxical dis-
charge begins at 45 °C and a maximum frequency of
7 to 7.5 impulses per sec. is attained at 5o°C. The
lower threshold temperature of this paradoxical dis-
charge lies about 5°C above the upper limit of the
usual range of temperature within which the cold
receptors display a steady discharge (fig. 22). Para-
doxical excitation of cold receptors at temperatures
below 45°C does not occur. Thus the cold sensation
which appears after a rise in the skin temperature
from 20° to 35°C as described by Thunberg (88) is
not due to any paradoxical excitation but to a reap-
pearance of the usual steady discharge of cold fibers
when the temperature approaches the final value of
FIG. 22. Graphs showing impulse frequency of the steady
discharge of a single cold fiber iopen circles) and of a single warm
fiber QfiUed circles') as a function of the temperature of the recep-
tors within the range of 10 to 50°C. [From Zotterman (99).]
THERMAL SENSATIONS
453
35°C. This phenomenon is only another example of
'persisting cold sensation' (cf. page 443). The low
sensitivity of the warm receptors and the relatively
high sensitivity of the cold receptors between 20° and
30°C has an important bearing on our interpretation
of the Weber phenomenon of persisting cold sensation.
When a cold object is removed from the skin, there is
an obvious pause in the cold sensation due to the
postexcitatory depression of the cold receptors. When
the cold sensation then slowly reappears, although the
temperature of the skin is gradually rising, there will
be very little interference from the rather scattered
warm receptors. Thus the steady discharge of im-
pulses from the cold receptors which display their
ma,\imum sensitivity in just this temperature region,
25° to 30°C, will stand out still more conspicuously.
The question concerning the real existence of a
paradoxical warmth sensation brought about by cool-
ing has been the subject of much discussion C72). The
reason for this is now quite obvious. We have to con-
sider not only that cooling of the skin stimulates
numerous cold receptors and that the ensuing cold
sensation thus will mask the paradoxical warmth
sensation ijut also the fact that the 'paradoxical'
response of the warm fibers is of phasic character and
soon fades away.
Thus we can conclude that the paradoxical sensa-
tion of cold experienced when the skin is heated to a
temperature between 45° and 50°C has its ph)'siologi-
cal analogy in a steady discharge of specific cold
fibers.
The paradoxical warmth sensation which generalh
is masked by an intense cold sensation has its counter-
part in a phasic discharge of specific warm fibers to
the cooling.
Effect of temperatures above 47°c. The fact that
the steady discharge of the warm receptors generalh
disappears at a temperature above 47°C must mean
that above this temperature the quality of sensation
which generally is described as hot has little to do
with the feeling of warmth (cf. page 444). Alrutz'
(2) suggestion that the sensation of heat was a mixed
sensation of warmth and paradoxical cold must be
revised to some degree. When the skin is suddenly
heated from 35° to 50°C, there occurs first a sudden
transient discharge of warm fibers accompanied by a
paradoxical cold fiber discharge which continues as
long as the temperature is kept at this level. To this
paradoxical discharge of cold fibers a discharge of
pain fibers is gradually added (96, 97). Skouby (So)
has recently found that the subjective pain threshold
lies at temperatures of 47. i ° to 48.5°C. Thus it can be
concluded that, when temperatures of above 47 °C are
applied and after the temperature change in the skin
has ceased, the sensation of heat then experienced is
the resultant of a mixed inflow of paradoxical cold
and pain impulses. This sensation is thus initiated only
by warm and paradoxical cold impulses and to the
persisting paradoxical cold discharge, pain impulses
are gradually added as the temperature is kept at a
constant value above 47 °C. At still higher tempera-
tures the heat will destroy the fibers. Heating the skin
to more than 50°C very quickly not only inactivates
the mechanoceptive fibers in the tongue (96) but
also causes the steady paradoxical discharge of the
cold fiber to disappear leaving the signalling duty
entirely to pain fibers. This course of events was fully
confirmed by recent experiments of Dodt (19).
intracut.anequs gradient. In order to investigate
the importance of the intracutaneous temperature
gradient for the stimulation of the thermoceptors
Hensel & Zotterman (55) recorded the action poten-
tials from the cold fibers of the lingual nerve of the cat
when cold stimuli were applied to the tongue so as to
cause negative or positive intracutaneous temperature
gradients (cf. page 446). The nerve preparations
chosen were those containing cold fibers supplying
only the upper surface of the tip of the tongue. In order
to produce negative or positive temperature gradients,
the tongue was cooled from either the upper or the
lower surface, respectively, the temperature on both
sides of the tongue being recorded thermoelectrically.
The cooling of the upper surface immediately gave
rise to a strong discharge of cold spikes which instantly
disappeared on rewarming (fig. 23). On cooling of
the lower side no impulses appeared at first ijut within
1.5 to 3 sec, when the cold had penetrated the tongue
and reached the upper surface, cold impulses appeared
with increasing frequency. On rewarming of the lower
surface the cold impulses persisted at first until the
upper surface was also warmed again. In some experi-
ments the cooling of the receptor laser was produced
by injecting cold solutions into the lingual artery.
This way of cooling produced the same cold receptor
discharges as cooling the surface. The participation
of deep thennoreceptors could be entirely excluded
in these experiments, and the arrest of the blood flow
in the tongue had no primary influence on these
findings.
These experiments demonstrate that the stimulation
454
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
37
29
] I I iiiiir rilif(»i)*iiM>Wiil>liii|iMiiill«»iil»iiMiilil>MNII'lll<ll
sf
vc B
29'-
■^^— *— * I ii>ii I iiimiiiiiiiiiii I mill
('Weber's deception'Ji. The pressure sensation caused
by cooling the skin has been the subject of thorough
examination by later workers. Kiesow (62) con-
firmed the existence of 'Weber's deception' and also
succeeded in provoking sensations of pressure by
application of ether and chloroform to the skin, and
Goldscheider & Hahn (33), experimenting with vari-
ous solutions and with cooled air, came to the conclu-
sion that the mcchanorcccptors could be stimulated
by cooling.
FIG. 23. .Simultaneous records of cold impulses from receptor
field on upper surface of cat tongue and of temperature of both
surfaces. A, on cooling of the upper surface; B, on cooling of
the lower surface; a, temperature of the upper surface; b, tem-
perature of lower surface. Time marks, 1 5 cps. [From Hensel &
Zotterman (55)-]
of the cold receptors does not depend upon the direc-
tion or slope of intracutaneous temperature gradient.
Thus temperature gradients between blood vessels
and the receptors, which were suggested as the ade-
quate stimulus, cannot be decisive since arrest of the
circulation for a minute or so did not notably change
the results obtained by the retrograde temperature
gradient.
RESPONSE OF MECH.iiNORECEPTORS TO THERM.'^L STIMU-
LATION. When the tongue of the cat or dog is cooled,
it is generally possible only to record small cold spikes
in the lingual nerve, whereas the large touch and pres-
sure spikes cannot be elicited by cooling. However, in
a few cases cooling also sets up relatively large spikes
in the lingual nerve. Hensel & Zotterman (53) investi-
gated this phenomenon further and demonstrated that
these larger spikes derived from mechanoceptive
nerve fibers. These large spikes usually appear only
with severe cooling and disappear within a few seconds
at a constant low temperature, whereas small cold
spikes appear with slight cooling and persist at con-
stant temperatures for long periods (fig. 24). It was
shown that this activity of mechanoceptive fibers
could not ije due to secondary mechanical stimulation
of the pressure receptors by local vasoconstriction nor
to stimulation of the nerve trunk by cooling. It is only
medium-sized mechanoceptive fibers (8 to 10 /li)
which were stimulated by cooling the surface; the
larger pressure fibers (12 to 15 m) were not excited.
These findings offer a ready explanation for the
well-known phenomenon first described by Weber (94)
that cold weights seem heavier than warm ones
Injiiience of Nonthermal Agencies
That menthol evokes cold .sensations when applied
on the tongue as well as on the skin is a well-known
experience which has been exploited in manifold ways.
It has likewise long been known that these cold sensa-
tions are not caused by physical cooling of the skin or
the mucous membranes but by some chemical action
directly on the cold receptors (32). Hensel & Zotter-
man (56) recorded the discharge of cold fibers after
the application of menthol solutions upon the tongue
using well defined thermal stimulation.
^ *0r',
tiipiiiiiiii iiniiiiiiiiiiiijutiiiiiiiiiyyiimy
""""""""""" '""" ■'■■ """ ■"""■" """■
■tOOuV
..MJJJ.I.L:;
III., 1
tiiMliiiiiimiHifc
C^X'C
50
JHlMtwaAid&iii«^4«t«ittjate
MMlwilllikMiiLd^^
£*0
50
tmtt^u^mttmJm^iikiii^ditmdtiMithit
FIG. 24. Records from a thin strand of the cat lingual nerve
obtained on applying mechanical and thermal stimuli to the
tongue. The Ihin line shows the temperature of the surface of the
tongue. A, pressure; B, cooling from 41° to 22°C; C, cooling
from 41 ° to 26°C; D, cooling from 41 ° to 2()°C; E, cooling from
41° to 32 °C. Time marks, 50 cps. [From Hensel & Zotterman
(53)-]
THERMAL SENSATIONS
455
'Mill iMIlllllllllllMMIIIIIIIIIIlllllllinillllllllllllllllhllllllllllllMlllllllllllllMllUlllinilllllllll
*oi'c Menthol 1 10.000
tei4yiUitiiiiiiitiiiiiiiiiiliiiiiiililuijiiii>iiiiiiiii
iiiiiiiiiiitiiiiiiiilliiniiii
'<: Menthol 1 10.000 ,, , , , i , ,
iyilMUmiiiJ.4 11 111 iUiJ " lioUL
iiiiiiiiiiiiiiiiiMiiiiiiiiiiiiMiiiiiiiiiiiiiiiiiiiniiiiiiiiiiiiiiiuiinihiiiiiiiiiiiiiiiiiiiiiHiiiiiiiiiihiiiiiiiii
•wr-f Menthol 1 10.000
f"- 1 1 -[-M 1 ' ■■^'^^^"'^ i.ii.iii>iiiy.y.ti
lillllllillinliMilinliii
FIG. 25. Action potentials from cold and warm fibers in a
thin strand of the cat lingual nerve after the application of
menthol solution to the tongue. Under the action of menthol
(i : 10,000) there is at 40°C strong discharge of cold libers which
disappears on warming, to be followed by discharge from a
warm fiber. [From Hensel & Zottcrman (56).]
substances into the skin produced an increased num-
ber of cold spots, Dodt el al. (21) investigated the
effect on single thermal fibers. Minute amounts of
acetylcholine shift the temperature range of the steady
discharge of cold fibers towards the warm side and
increase definitely the rate of the steady discharge of
the receptors inside the normal range of temperature.
Larger amounts produce a depression of the steady
discharge and a narrowing of the temperature range
recorded. Corresponding results were found with
warm fiber preparations.
Dodt (20) has recently investigated the influence
of carbon dio.xide on the thermal receptors. An in-
crease of the pClOa reduced the rate of the steady dis-
charge of cold receptors, whereas it caused an in-
crease of the steady discharge of warm receptors. The
regulating structures will thus, under the action of
carbon dioxide, receive a false picture of the actual
thermal conditions in the periphery which will lead
to a fall of the rectal temperature without any sub-
jective discomfort.
Aqueous menthol solutions of 1:10,000 lead to
strong steady discharge of the tongue cold receptors
at constant warm temperatures at which without
menthol there is no discharge (fig. 25). At lower
temperatures at which the cold receptors are steadily
discharging without menthol, this substance produces
a great increase of the steady cold impulse frequency.
Further studies of Dodt el al. (21) of the effect of
menthol on single fibers showed that menthol exerts
an effect, not only on the cold fiber activity in the
usual temperature range between about 10° and 38°C,
but also on the paradoxical cold fiber discharge
between 45° and 5o°C. In agreement with Gold-
scheider these authors observed that inenthol sensi-
tizes the warm fibers also.
The effect of menthol on the cold and warm fibers
can be completely compensated for by sudden heating
and cooling, respectively, or by keeping the tongue
at a constant higher and lower temperature, respec-
tively. These measures can cause the cold and warm
impulses provoked by menthol to disappear entirely.
Thus it is not simply the question of a chemical
'inadequate' stimulation of the thermal receptors but
of a sensitization of the thermal effect. The threshold
of the menthol effect lies between the concentrations
of I : 1 ,000,000 and 1 : 500,000.
Following the finding of Bing & Skouby (8) that
the introduction of small amounts of cholinergic
THEORETICAL CONSIDERATIONS
Cenlral Threshold
From the sensory physiological studies it appeared
that three factors are governing the occurrence of a
thermal sensation: a) the absolute intracutaneous
temperature, d, 6) the rate of change of the intra-
cutaneous temperature, dd/dl, and 0 the area F, the
extension of the stimulated field.
So far as the conditions for the occurrence of a
thermal sensation can jje expressed in physical-
thermal terms, the excitation mechanism can be repre-
sented by a three-dimensional system of thermal-spa-
tial-temporal factors which arc mutually dependent
on each other and to a great extent exchangeable.
The threshold condition can thus be expressed as fol-
lows:
E 3 i(e,dS/dt, F)
where E is the abstraction class of the sensation, 3
the implication sign of a probability implication (75).
A sensation of cold, for example, would thus occur
when a) d is low, b~) the rate of cooling, dO/dl, is
sufficient, and c) the receptive field has a certain area
(42).
The recordings of the action potential from periph-
eral cold fibers show that the total number, n, of im-
456
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
pulses which in the lime, /, arrive at the central organ
also is a function of these three factors,
^3 0(e,de/d/,F)
i.e. the value of n/t becomes greater when a) the
temperature is lower, A) the rate of cooling is greater
and c) when the receptive field is enlarged — i.e. when
the number of stimulated cold receptors is increased.
The rate of «// is nothing else but the central threshold
which thus can be written,
E3^
c
The results of the sen.sory-physiological studies are
thus in very good accordance with those obtained
from electrophysiological investigations on the specific
thermal fibers.
The declining impulse frequency at constant tem-
perature is the so-called "physiological adaptation' of
the thermal sense recorded objectively. As Hensel
(42) concluded from his sensory-physiological studies,
it should be more correct to avoid the use of the partic-
ular words, adaptation or change of excitability in
order to express the temporal decrease of the excita-
tion under a constant stimulus, as these expressions
lead to a conception of a specific process separated
from excitation. Adaptation is then assumed when a
temporal change of the excitation occurs while the
stimulus is kept constant. But this depends upon the
definition of stimulation. When as in the thermal
sense the temperature (9) is the stimulus, adaptation
appears at constant stimulation. If, however, the
stimulus is the rate of temperature change, dS d<,
there will be no adaptation during constant stimula-
tion. According to the usual definition, adaptation is
therefore nothing else than an indirect description of
the time factor of a sense organ based on its response
to a specific mode of stimulation.
At constant temperature of the skin, the magnitude
of nit is dependent upon the temperature and the
area of the skin. If the thermal receptors were evenly
distributed, the thermosensible tonus would thus be a
direct function of the integral skin temperature. This
is, however, not the case as some parts, especially the
trigeminal area, display a much greater density of
thermal receptors and are thus likely to exert a more
dominant influence upon the thermoregulation of the
body. It is very likely that the central threshold of
conscious cold sensations lies at a higher level than the
threshold of the thermal receptor discharge (34, 54),
which implies that a certain part of the afferent
thermoregulatory inflow occurs below the threshold
of our consciousness.
Excitation Alecfianism of 1 hernial Receptors
The fact that there is a distinct discharge of im-
pulses from thermal receptors when there is a com-
plete temperature equilibrium between the two sides
of the receptor layer, i.e. when the spatial as well as
the temporal temperature gradient is zero, shows that
this activity does not depend upon any exchange of
thermal energy. Thus there must occur in the recep-
tors, processes — probably of a chemical nature —
which are governed by temperature without any
external exchange of energy in the skin.
For this reason it is not practicable to express the
thresholds of the temperature sense — in analogy with
the eye and the ear — in terms of a thermal energy.
The course of the receptor discharge at constant
temperatures and particularly the effect of tempera-
ture changes suggests that we have to deal with at
least two interacting processes, one exciting and one
inhibiting. We can thus, according to Sand (77),
assume that the frequency of the steady discharge of
the cold receptor, n, is dependent upon the difference
between two temperature dependent processes, E and
/. The difference between these should give the im-
pulse frequency, n (45, 54).
FIG. 26. Graphs illustrating discharging mechanism of a
cold receptor. Abscissae, skin temperatures; ordinates, rates of
impulse discharge. In the lower left is a plot of the steady
discharge of a cold receptor assuming that the frequency of dis-
charge (n) is a function of the difference between two tempera-
ture dependent processes E and 7 (jibove'). On the right is illus-
trated the time course of the effect of sudden cooling from a
temperature of fli to one of ^2 and back to ffi. The intersection of
the curves of E and / gives the upper threshold temperature
9o of the cold receptor. [From Zotterman (100).]
THERMAL SENSATIONS
457
These functions E and / seem to resemble exponen-
tial functions with different constants as follows:
When the temperature 6 = 6,,, n = o. l( a < l3,
we obtain curves as shown in figure 26 where the
difference curve, n, resembles the experimental curves
of the steady discharge obtained from single cold
fibers.
In the above equation only the temperature de-
pendence has been considered. The time dependence
can, however, be included in the equation in a manner
which rather closely describes the "adaptive' part of
the response of thermal receptors, i.e. the response to
sudden temperature changes. The equation can be
written:
n = A[(a, - e--")£ - (6, - e"'^')/]-
The constants are dependent upon the previous
excitatory level of the thermal receptor. Figure 26
shows how these functions can be used to predict the
behavior of a cold receptor at a sudden drop in tem-
perature from di to d-i and back again. For further
details and the computation of the constants see
Hensel (45).
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CHAPTER XIX
Pain
WILLIAM H. SWEET j Department oj Surgery, Harvard Medical School, Boston, Massachusetts
CHAPTER C:ONTENT,S
Pain as a Sensation with Its Own Peripheral and Central
Nervous Apparatus
Stimulus, Sensation, and Their Measurement
Mechanical Stimuli
Correlation with Tissue Damage
Heat
Electricity
Distention of Viscera
Arterial Constriction with Ischemia and Arterial Dilatation
Inflammation
Quantitation of Severity of Pain
Animal Versus Human Subjects in Pain Studies
End Organs for Pain
Normal Skin
Cornea
Abnormal Skin
Special Cutaneous Sensory Endings
Deeper Somatic and Visceral Receptors
Terminal Sensory Plexuses
Peripheral Sensory Nerve Fibers
Single Fiber Studies
Fiber Diameters and Pain Conduction
Double Pain Responses or Second Pain
Pain in Abnormal Anatomical States at Periphery
Division of Cutaneous Nerves
Hyperalgesic State After Trauma
Chemical Excitants of Pain
Posterior and Anterior Roots
Pain and Autonomic Nervous System
Sympathetic Nerv^es
Parasympathetic Nerves
Spinal Cord
Medulla Oblongata
Mesencephalon
Thalamus
Cerebral Hemispheres
Stimulation
Lesions
Evoked Potentials
Second Sensory Area in Man
Reaction to Pain
Indifference to pain
Pain asymbolia
Reactions after operations on frontal lobes
Conclusion
Endocrines and Pain
Itching and Tickling
Pain and Inhibition
Referred Pain
THE NATURE AND RANGE of the sensations covered lay
the word ' pain' elude precise definition. Aristotle (8)
equated pain with unpleasantness whether arising
from outside the body, within the body or within the
' soul' (as when one feels miserable). ' Pain or un-
pleasantness' stood for him as the opposite to 'pleasure'
and he considered every action to be "accompanied
by pleasure and pain." For Spinoza (65) pain was a
focal form of sorrow which he called one of the three
primary emotions. Pain, which he thought of as the
emotion opposite to "pleasurable excitment," he
"related to a man when one of his parts is affected
more than the others; melancholy, on the other hand,
when all parts are equally afl^'ected." As scientists now
tend to u.se the word, ' pain' contains the Spinozistic
implication that the unpleasant feeling is specifically
referred to some place or places in the body. In any
case it is this more localized kind of pain which is
more amenable to physiologic study in contradis-
tinction to diffuse states of unpleasantness.
But from the standpoint of the physician it is neces-
sary to analyze and treat every type of disagreeable
feeling of which people complain. It matters not
whether the individual tags it by the label 'pain'. Thus
in the area of the face which has undergone trigeminal
denervation about 5 per cent of the patients have
severe annoying sensations which they may call
aches, but often they are at a loss for words to describe
459
460
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
the peculiar sensation so extraordinary and un-
matched by any of their previous experiences. Vet
many so afflicted find the feelings sufficiently intoler-
able to seek major surgery for relief Certainly such
sensations are reasonably classified as an unusual form
of pain, and the elucidation of the mechanism of
severe unpleasantness referred to an anesthetic area in
the presumed absence of an organic central lesion re-
mains one of many challenE^es to the neurophysi-
ologist.
Pain may be arbitrarily divided into two main
elements, the initial sensation and the reaction to that
sensation. As Beecher (15) has emphasized, the signifi-
cance of the pain to the individual plays a major role
in determining the extent of the second reactive com-
ponent of the feeling. Thus he found that only 32 per
cent of 1 50 war-injured men had pain severe enough to
require a narcotic, whereas 83 per cent of 150 male
civilians undergoing surgery involving much less
trauma required narcotics. For the soldier the war
wound marked the end of a gravely hazardous form of
life, whereas no such compensation and, at worst,
serious problems beset the operated civilian. Beecher
interpreted the differing degree of complaint in these
two settings as indicating "that the reaction or
processing phase is very often of more importance in
suffering than is the original sensation." Indeed the
original sensation as well may appear as a symptom
of protest, as from the person who develops a ' sick
headache' at will; or the pain may come as a conse-
quence of previous conditioning as in 'a painful
memory.' Contrariwise, various cerebral deficiency
states result in a reduced reaction to afferent impulses
for pain which would normally evoke a lively response.
In this essay we shall devote most of the discussion
to the sensation of pain as evoked by specific stimuli
to sensory endings or pathways, recognizing, how-
ever, the vast importance of the psychological com-
ponent of the response and the virtual impossibility of
separating this from the primary awareness of pain.
PAIN AS A SENSATION WITH ITS OWN CENTRAL
AND PERIPHERAL APPARATUS
The validity of searching for a special sensory
mechanism concerned wholly or mainly with pain
requires inquiry. The physiologist has not sought out
specific nervous pathways subserving pleasure, the
philosopher's antipode to pain; is it sensible to look
for pain pathways? One can answer promptly that it
is and has proved eminently fruitful to do so because
certain stimuli to certain areas almost invariaiilv
bring on pain in man, whereas the same constancy of
relationship in no way applies to pleasure. One may
venture to state that even the amorous male with the
most Ca.sanovian success has not developed a form and
site of stimulus which constantly evokes pleasure in
his partner, thous^h in the absence of a criticallv re-
ported series this can be no more than the author's
disgruntled surmi.se.
Erasmus Darwin (53, pp. 121 and 125) thought pain
to be the consequence of any excessive stimulation and
a result of exaggeration of sensations of heat, touch,
sight, taste or smell. This intensive theory of pain in
one modification or another has found many sup-
porters. And we can scarcely disagree with William
James' (134) conclusion that it is certain that sensa-
tions of every order which in moderate degree are
rather pleasant than otherwise become unpleasant
when their intensity grows too strong. For example, in
1934 Nafe (198) drew attention to the fact that when
smooth muscle was in spastic contraction at the
extremes of heat and cold, 52°C and 3°C respectively,
there was pain. At levels intermediate between these
there was only a sense of warmth or coolness. As
stimulation became more intense with a rise in tem-
perature the quality of the sensation was altered from
warmth, to heat, to pain; all mediated he thought bs-
the same peripheral equipment and integrated at the
thalamocortical level. More recently Gooddy (104)
has argued that "any nervous pathways are potential
pain pathways," i.e. that any pathway may provide
"the impulse patterns that are associated with the
perception of pain. " In certain patients successive
operations on peripheral nerves, posterior roots, spinal
cord, thalamus and cerebral hemispheres may all fail
to give permanent relief from pain. From such series
of events, infrequent though they are, Gooddy reaches
the extreme point of view that "unless the whole
nervous system is destroyed, the abnormal patterns
(evoking pain) gradually establish themselves anew.
The most clear-cut evidence to the contrary, that
at least some pain is to be regarded as a particular
form of sensation with its own pathways and not
merely an intensification of other forms, is provided
by patients with a lesion confined to the anterior
quadrant of the spinal cord. This usually deprives
them of the capacity to feel pain in response to a wide
variety of noxa previously painful, yet proprioceptive
and light touch sensibility are virtually unimpaired.
This is the typical finding after the operation of
anterolateral cordotomx. Although thermanesthesia
PAIN
461
is usually present along with analgesia, a rare patient
after such a cordotomy may show only the former
without the latter or vice versa, indicating that there
are special pathways for pain and others for tempera-
ture sensation which are nearly, but not precisely, co-
extensive (296, p. 259). Schiff (238) one century ago
made the fundamental observation that lesions of the
spinal cord in rabbits, sparing only the posterior
columns, resulted in animals which would make a
number of responses to touch whereas they would ig-
nore presumably painful deep stimuli. He recognized
the similarity between this state and the clinical con-
dition of analgesia without anesthesia to touch, de-
scribed in man both by Beau and by Vieusseux [ cited
by Schiff (238), p. 253].
Such data, though, do not prove that impulses for
pain and touch may not use the same fibers in pe-
ripheral nerves and there has been no histologic cor-
relation between lesions of certain types of peripheral
nerve fiber and a disassociated loss of touch or pain.
Although such loss may occur in leprosy — the Bacillus
leprae typically attacks only the peripheral and not
the central nervous system — a focal degeneration of
dorsal funiculi has also been seen in this disorder by
Wilson (301, fig. 92, p. 753). Hence a purely periph-
eral lesion may not be taken for granted here as the
explanation of a loss of pain without touch or the
reverse. However, conduction by peripheral nerves
can become impaired in such fashion that a differ-
ential loss of various forms of sensation occurs. Thus
Herzen (127) was the first to note that pressure on a
human peripheral nerve, the sciatic, caused initially
loss of touch sensibility, shortly thereafter that of cold,
much later that of warmth and finally of pain. Gold-
scheider (102) in the same year likewise observed a
differential loss of sensory modalities, although in a
different order, when a branch of a peripheral nerve
was cocainized. He thought cold was blocked first,
then, in sequence, warmth, pain and pressure. Modifi-
cations of the first method of compression or asphvxia
of the nerve and of the second, pharmacologic block,
have since been used extensively in a study of the
specificity of nerve fibers for single modalities of
sensation. Unequi\ocal proof that one peripheral
fiber is devoted to but one type of sensory modality,
pain, touch, cold or warmth has not been advanced
as yet. The evidence bearing on this and on the ques-
tion of special sensory end organs for pain will be pre-
sented later. Before studying the nervous system itself
we may properly consider the tactics used in arousing
its responses.
STIMULUS, SENSATION AND THEIR MEASUREMENT
Mechanical Stimuli
Quantitative assessment of pain involved, of course,
measurement both of stimulus and sensation. In the
earliest tactics one pricked the surface to be tested
with needle points mounted either in fibers which
bent at a calibrated force or on a calibrated spring — a
method which remains the best for many clinical
physiological studies.
Correlation with Tissue Damage
The adequate stimulus for pain, whether it is me-
chanical, thermal, electrical or chemical, is poten-
tially or actually productive of tissue damage. Hence,
the immediate zone of reception on which the stim-
ulus is acting soon becomes modified in serial determi-
nations at the same site. Thus Lewis (171, p. 106)
pointed out that, if the skin of the front of the forearm
is pricked with a needlejust hard enough to cause pain,
most ofthe.se pricks will subsequently show signs of tis-
sue damage in the form of little circles of redness. Ther-
mal radiation in order to evoke pain requires an en-
ergy (expressed in millicalories per second per square
centimeter) which is 2000 times that of the threshold
for warmth. In fact. Hardy et al. (118, pp. 23, 53),
the workei-s responsible for these figures, state that the
thermal radiation threshold for ' pricking pain' lies at
a skin temperature of roughly 45°C, which is likewise
the threshold temperature range for the production of
skin damage, according to Moritz & Henriques (192).
In agreement with this Benjamin (18) finds the
threshold for the production of a cutaneous flare by
heat is very clo.se to the pain threshold.
Heat
Nevertheless thermal radiation which eliminates
simultaneous contact and pressure sensations has
formed the basis for much of the modern work on pain
thresholds since the description by Hardy et al. (115)
of their 'dolorimeter.' This apparatus permits control
of the intensity and duration of applied heat and its
measurement by a radiometer. With critical, careful
use of this instrument so arranged as to provide a
radiation time of 3 sec, it is their contention that the
pain threshold is constant from person to person and
in the same individual from time to time. The three in-
vestigators were the initial subjects and they studied
themselves nearly every day for almost a year, di-
462
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
reeling the heat to an area of the forehead thoroughly
blackened with India ink and obtaining values which
all fell within ± 1 2 per cent of the mean. They describe
the subject's experience as follows: "The sensation is
one of warmth, heat and burning which seems to
"swell' and then to "draw together' into a prick at the
end of the third second. Minimal after-sensations of
heat and burning pain are common." This they call
the pricking pain threshold. Bigelovv et al. (26) also
identified another threshold — that for "burning pain.'
This on the forehead is, they say, about 20 to 30 meal,
lower than the pricking pain threshold. When these
workers extended their measurements to 1 50 individu-
als about the same mean intensity of stimulus, 0.21 gm
cal. per sec. per cm-, evoked ' pricking pain' with a
maximal variation of ± 1 5 per cent.
This uniformity is said to persist throughout a 24 hr.
period of enforced wakefulness (241) in women before,
during and after labor (135), and over much of the
body surface (i 18). But Wolfl & Goodell (304) also
state that, if the subject is unable to concentrate on the
testing procedure or "to maintain a detached, un-
prejudiced attitude" because of fatigue, lethargy, sug-
gestibility or other reason, then the pain threshold
varies greatly and is unpredictable.
A number of workers have been unable to confirm
the described uniformity of pain threshold in these
painfully collected data. Chapman & Jones (40)
found the theshold of 200 normal subjects to vary
much more widely — from —40 per cent to -I-50 per
cent. Others who have reported inconstancy of
thresholds by this technique include Clausen & King
(44), Leduc & Slaughter (160), Schamp & Schamp
(237) and Slaughter & Wright (252). Benjamin (20)
agreed that the tactic of painting the skin with India
ink resulted in absorption of nearly all (94 per cent)
of the incident heat and it^ transmission into the skin
by conduction, but found pain sensitivits' in the palm
less than in the forearm. Whyte (297} has advanced
this cogent criticism: the validity of the method de-
pends on the contention of Oppel & Hardy (203) that
the rise in skin temperature produced by radiant heat
is proportional to thermal intensity. If this were true,
then at the increa.sed radiant heat thresholds for
morphine described by Wolff ?< al. (306) extrapolation
of their curves would indicate that the skin tempera-
tures would have reached about 54°C. The actual fore-
head temperatures of Whyte's subjects at the pricking
pain threshold were about the same before and after
morphine, ranging from 46.2 to 47.5°C. From this
Whyte logically concludes that an increase in sweating
or in blood flow to the skin may have occurred follow-
ing the morphine rather than the presumed increase
in nervous threshold. Beecher and associates have also
been sharp critics of the contention that consistent
thresholds are obtainable by the method. Denton &
Beecher (63) found that an operator widely experi-
enced in the radiant heat method, who was called in
to correct their failure to get consistent data, was able
to do so as long as he knew what drug had been ad-
ministered; he failed when he did not know. They
interpreted this to be a consequence of unconscious
guidance by the operator of the subjective response he
was seeking. Much space has been devoted to con-
sideration of this single technique in order to point out
the difhculties of precise measurement of a sensation
as threatening to the individual as pain.
Electricity
Electrical stimulation has also been used to test
cutaneous sensation. The threshold feeling, according
to Bishop (27), varies depending upon the special
sensitivity of the skin spot tested. Using a condenser
discharge deli\'ering a spark when the point of the
stimulating needle was about 0.5 mm from the .skin,
he was able to stimulate without mechanical contact.
With this device he found spots "mediating ordinary
touch or light pressure" and others inducing the sensa-
tion of prick "which becomes pricking pain on a
stronger stimulation." But he says that a "single
stimulus applied to a single prick spot at the threshold
is not painful but elicits a tactile experience usually
accompanied by a faint aura of itch. This tactile
sensation is not associated with a feeling of pressure.
. . . On the other hand a single threshold stimulus
applied to a touch ending is experienced as a slight
tap." Distinctions between a tactile sensation with and
one without pressure, and between a prick and prick-
ing pain, certainly do not lend themselves to quantita-
tive analysis. Mueller et al. (ii^i), seeking to develop
an electrical method for the testing of pain threshold,
found the most clear-cut end point to be the sensation
of prick but, in critical electrical measurements, they
found the prick to occur during breakdown of skin
impedance .so that the electrical quantity was not
purely an index of threshold pain but was dependent
on the dielectric properties of the skin. Beecher (16)
after a thorough re\ iew of the whole proijlein of the
measurement of pain of both 'experimental' and
'pathological' types concludes that "no con\incing
demonstration has yet been given that the pain
PAIN
463
threshold is a constant from man to man or from one
time to another in a given man." He attributes the
variability to the 'psychic reaction component' rather
than the 'original sensation.' Precise determinations of
pain threshold find perhaps their greatest practical
utility in the pharmacologic appraisal of analgesic
agents — a subject beyond our scope. To me it appears
that firmer conclusions are tenable when one works
with stimuli in animals and man which, in normal
man, consistenth' evoke unequivocal and unalloyed
pain. The subsequent discussion will seek to emphasize
such work.
Other methods for the stud\' of pain either deliber-
ately evoked or arising in pathological states will now
be considered.
Distention of Viscera
Incision into and passing a needle through skeletal
mu.scle are almost painless, and the abdominal
viscera exposed under local anesthesia may be cut,
torn or burned as long as the parietal peritoneum and
roots of the mesentery are not stimulated (164). These
viscera are capable of initiating impulses for pain upon
the appropriate stimulus, however, and it was Len-
nander (165) who demonstrated that it was distension
of the human kidney pelvis which was painful. Hurst
(131) extended this principle, that distension is the
pain-evoking stimulus for hollow viscera, to studies of
the alimentary canal. Davis et al. (54, 56) have applied
the same tactic to studies of the gall bladder. Rapid
expansion of the capsule of solid organs like the li\er
and kidney also hurts.
Arterial Constriction with Ischemia and Arterial Dilatation
Both arterial constriction or occlusion to the point
of ischemia and severe arterial dilatation at times
associated with excessive pulsation in a part are pro-
ductive of pain. Sutton & Lueth (257) thought that
myocardial anoxia was the physiological stimulus for
cardiac pain when they found that lightly anesthetized
dogs gave responses suggestive of pain when a coronary
artery was occluded by a ligature. Gorham (107) con-
firmed these results and added the ob.servation that if
three ligatures were placed in the wall of the coronary
artery so that divergent traction on them would tend
to distend the vessel, responses of 'pain' also occurred.
The headache of migraine is one of the better studied
examples of a pain probably brought on by arterial
dilation. Wolff, a prominent exponent of this view,
summarized the e\idence for it in 1948 C303, pp. 265
to 288). Histamine produces, among other effects,
painful distension of arteries and presents a means of
evoking headache experimentally, although this
differs from that seen in migraine in at least eight
respects according to W'olff (303, pp. 289 to 290). The
reverse situation, ischemia as a cause of pain, is seen
both in intermittent claudication affecting especially
the lower limbs and in cardiac angina. Lewis, Picker-
ing and Rothschild have developed a testing pro-
cedure (171, p. 97) involving voluntary manual grip-
ping movements at the rate of i per sec. developing a
tension of 20 to 28 lb. Such movements, normally
painless for many minutes, soon cause pain if the
circulation to the arm is stopped by inflation of a
proximally placed cuff. Lewis (170) initiated and
Kellgren (140) followed with another type of test, the
injection of hypertonic saline into muscles, tendons,
ligaments and joints to provide and permit the analysis
of pain from these deeper structures.
Inflammation
Inflammation, arising from disease or produced
experimentally, is apparently another process whereby
previously painless stimuli appear to become painful;
this is true for skin (i 72), for deeper somatic structures
(150) and for the viscera (142). Thus the inflamed
appendix hurts when pinched, but not the normal
appendix.
Excellent summaries of various experimental
methods appear in Hardy et al. (118, Chapter III)
and in Beecher (16, Section V); Lewis (171, Chapter
I) gives a useful catalogue of the effective stimuli for
each of the pain-sensitive tissues of the body.
Qjiantitation 0/ Seventy of Pain
The purely subjective character of pain has given
rise to great difficulty in efforts at quantitation, but
Hardy et al. (118, p. 156) have thought that trained
observers can distinguish as many as 2 1 different
degrees of pain, from zero to maximum, arising from
radiant heat. That is to say, there were 21 steps or
'just noticeable differences (jnd's)' as the amount of
radiant heat was increased. They suggested a unit for
pain sensation, a ' dol' equivalent to the sum of 2
jnd's; pain of ceiling intensity has a value of lo''^
'dols.' Armstrong et al. (9) have found their trained
464
HANDBOOK OF I'HVSIGLOGV
NEUROPHYSIOLOGY I
group able to distinguish at least 8, possibly up to 16,
units of pain intensity when a chemical excitant of
pain is applied to the exposed base of a canthardin
blister.
ANIMAL VERSUS HUMAN SUBJECTS IN PAIN STUDIES
VVaterston (284) has pointed out that one's natural
repugnance to investigating pain in man must be
overcome because of " the \alue and importance . . .
of the information which can be thus obtained and by
this means only." The final and conclusive arbiter on
all questions relating to any sensation must i^e man
experiencing that sensation and able to describe it in
words; this is particularly true of pain which by defi-
nition must have .some degree of affective component
of unpleasantness. I should agree without reservation
with Hardy et al. (116, p. 2) that " the verbal report of
the instructed subject is the most reliable evidence that
the pain threshold has been reached." But it has
seemed logical to many to assume that a maneuver
which consistently evokes pain in man and pro\okes
in him some form of motor response when pain is felt
may Ije used in animals and the motor response of the
creature taken as an end point indicative of pain. Un-
fortunately this conclusion is not without pitfalls.
Such reasoning led Gerard (95, p. 335) to make a
series of successively more rostral incisions into the
spinal or descending trigeminal tract in cats, each
incision about 1.5 mm rostral to the previous one.'
She began at the midbulbar level at the obex and
ascended until stimulation of the cornea no longer
elicited the " pain reflexes' of struggling, pupillary
dilatation and rise of arterial pressure. Not until the
cut reached the midpontine area did corneal stimula-
tion fail to evoke such reflexes, .so she naturally con-
cluded that the pain fibers from the cornea terminate
just below this point. But in man all such fibers termi-
nate much lower, in fact all below the obex, because
cutting of all of the descending trigeminal tract at this
level produces enduring analgesia of the entire first
division trigeminal sensory zone (75; 296, p. 457}. It
is possible that collaterals from corneal pain fibers
may evoke reflexes without awareness of pain in both
cat and man, and that these come off at more rostral
levels than the obex; or it may be that the specific
anatomy in cats difiers from man. In either event
lesions needed to stop 'pain reflexes' in the cat were
' The trigeminal nerve enters the upper pons and one bundle
of its fibers descends the length of the pons and medulla into
the uppermost cervical segments, so the more rostral the in-
cision the more toward the periphery the tract was being cut.
decidedly diflx-rent from those required to stop pain in
man.
Recently Goetzl c^/. (too) found upon stimulation
of the tooth pulp in unanesthetized cats and rabbits a
rise in arterial pressure and a decrease in volume of
the leg, spleen and kidney, whereas the reverse
changes in arterial pressure and organ volume oc-
curred when such stimuli were delivered to anes-
thetized animals. They concluded from these ob.serva-
tions that the ability of the stimulus to produce a rise
in arterial pressure depended upon actual perception
of pain by the animal. Such a conclusion has dubious
validity in \iew of Gerard's erroneous deductions from
the rise of arterial pressure in her cats.
Animal experiments in the spinal cord have cor-
related even more mi.serably with work in man.
Cadwalder & Sweet (37}, after careful pre- and post-
operative studies in dogs, found behavior after antero-
lateral cordotomy which they considered evidence of
incomplete loss of cutaneous pain sensibilit\' along
with severe ataxia of the hind legs. Their post-mortem
material demonstrated incisions of the type which pro-
duce total cutaneous analgesia and no ataxia in man.
They quoted the work of six prexious groups who ob-
tained divergent results from similar animal work;
three of the other groups had been unable to demon-
strate any definite cutaneous sensory change in their an-
imals after anterolateral cordotomy. Even in monkeys
Mott (195) found no evidence of any loss of pain sensa-
tion after either unilateral or bilateral division of the
anterior halves of the cord. In the cat Karplus &
Kreidl (138) were unable to eliminate rostral response
to painful stimuli applied to the hind legs even by
complete hemisections, one on each side of the thoracic
cord, five or more segments apart. Only when the
incisions bisecting the cord were four segments apart
or less did noxa to the legs fail to e.xcite a response.
From this they deduced that pain is transmitted by
short chains of neurons crossing the cord from side to
side. The conclusion froin all these studies is that the
bulk of somatic pain-conducting axons in manv
mammals including monkeys do not maintain a fixed
position in the anterolateral columns of the cord.
Happily from the standpoint of easy surgical relief of
pain this position is usually the case in man. However,
if one had only reflex l)eha\ior in man as a guide one
might still be confu.sed. Thus, when one of my pa-
tients, after cordotomy, stepped on an upturned nail,
the analgesic leg briskly withdrew. C^urious as to why
the leg jumped, he discovered the heavy nail in the
sole of his foot; he was consciously aware only of some
local tina;linsf.
465
Br* • •
-v.r
_■ ^■* *
r
< i
i
. *■ ^ « » *i
««
FIG. I. Naked axons and terminals in
the cornea of the monkey, stained with
methylene blue. .1. Beaded axons ram-
ifying in the basal part of the epithelium
(X 240). B. Epithelium only which has
been stripped off substantia propria.
Beaded nerve fibers are terminating ex-
tracellularly in end beads passing be-
tween cells in the middle third of the
epithelium (X 400). [From Zander &
Weddell (313).]
At a number of areas in the human body pain has
been said to be the only sensation ehcitable in the
normal state. If this be true, it has seemed especially
reasonable to excite such areas in animals and study
the concomitant nervous behavior on the assumption
that it may be correlated with pain perception.
Appropriate stimulus of the most intensively studied
such area, the cornea, has however been shown clearly
to evoke other sensations than pain and will be dis-
cussed more fully. Even so, pain is the dominant and
by far the most readily provoked sensation upon
corneal stimulus in man and, in general, animal ex-
periments in which the stimulus used would surely
bring on pain in a normal man have been useful,
especially in analysis of action potentials in nerves.
Indeed Beecher(i6) considers that a more dependable
relationship has been established between the action
of powerful narcotics and the 'experimental pain
threshold' in animals than in man.
END ORGANS FOR PAIN
Normal Skin
The finding by Goldscheider (loi) of points on the
skin particularly .sensitive to painful stimuli and of
other spots which could be stuck painlessly with a
fine needle has been followed by efforts to locate a
particular end organ, the nervous receptor for pain.
vonFrey's (273, 274) exhaustive studies with calibrated
hairs and thorns led him to insist on a distinction be-
tween the spots in which the sole threshold response to
a point stimulus was a sense of pain and those in which
it was a sense of pressure. Nerves end in the skin in a
wide variety of complex patterns or specialized end or-
gans (see other chapters for discussion), but the over-
whelming majority of the fibers in the skin terminate
both in epidermis and dermis without specialized
groupings of cells about them, merely as fine naked
freely ending axoplasmic filaments in an extracellular
position. They interweave i:)ut do not fuse with one
another (288). In the corneal epithelium such termi-
nals are "disposed in depth throughout its whole
extent," as well as "throughout the whole extent of
the .substantia propria." [See Zander & Weddell's
(313) thorough original studies and analysis of the
massive literature on the subject.] Figure i illustrates
the appearances in two types of preparation. Weddell
and others (personal communication) have also noted
a gross variability from week to week in the number of
clusters of corneal naked nerve endings simulating in
appearance a Krause's end bulb, an observation
which indicates that the normal nerve endings may be
in a constantly changing dynamic state.
The multitudinous plexiform endings have been
correlated with the multiplicity of ' pain points' found
466
HANDBOOK OF PHVSIOLOGV
NEUROPHYSIOLOGY I
on examination with calibrated thorns. Strughold
(256) found up to 200 per cm^ and Woollard (307),
testing sensation over a small area of his own thigh
after removal of each of a succession of thin slices of
skin, found pain to be the most superficial as well as
the most extensive in depth of the modalities tested.
In one region of his own epidermis which was es-
pecially sensitive to a needle tip he saw histologically
a plexus of finely beaded nerve fibers. Woollard et al.
(310) examined a biopsy of human skin taken just
distal to an ulcer made 8 days earlier with solid carbon
dioxide. Pain was the only sensation elicitable from the
tissue and the subsequent microscopic examination
revealed only fine naked nerve terminals. However,
when Foerster & Boeke (cited in 77, p. 16) examined
sections of skin in man following division of cutaneous
nerves and beginning regeneration, they found in
areas from which pain was the only type of sensation
no free intraepithelial nerve endings. The positive
findings of the previous authors are probably more
significant. Despite the density of the pain points there
are, however, spots analgesic to pain. Tindall &
Kunkle (265) find that these are still demonstrable
both during induced erythema (with lowered thresh-
old) and during experimental ischemia (with raised
threshold). They conclude that the analgesic spot
represents a gap in the fiber network rather than a
pain fiber with an unusually high threshold. The
great ease with which pain is elicited from the cornea,
the tympanic membrane and the dental pulp — all
structures probably supplied only with delicate free
filamentous nerve terminals and no specialized nerve
endings — has convinced most workers that such
endings can initiate nervous impulses giving rise to
pain. [For the neurohistology of the tympanic mem-
brane see Wilson (300).]
There has been less agreement as to whether or not
other modalities of sensation might be evoked via
these delicate nerve endings. Waterston (283) actu-
ally believed that the nerves of the normal epidermis
mediate only touch, since he could slice this tissue
painlessly from himself with a razor. In the skin
shavings he saw nerve fibers ending in loops and fine
arborescent figures. In Woollard's (307) detailed de-
scription of his similar studies he says that, when the
first 5x22 mm slice of his skin was cut, he felt pain
only at four previousy mapped 'pain spots'. But he
must have felt touch during the rest of the slicing
process and this is likely to have been mediated, at
least in part, by the other fine nerve terminals in the
epidermis. Personal repetition of studies with cali-
brated hairs and needle points along with a review of
much of the voluminous literature on cutaneous sensa-
tion led us in 1955 (296, p. 10) to record agreement
with Goldscheider's (loi) original observation — that
the threshold sensation to minimal stimulation with a
minute pointed needle is one of touch at the great
majority of all spots on the skin of the body. This I
noted even in areas specifically recommended by von
Frey (274) for eliciting pain in preference to touch,
such as the skin over the eyelids, the biceps brachii
and the clavicle. Consequently, the cutaneous sense of
touch being even more widespread than that of pain,
it .seems likely that proper stimulus to many or even
any of the most widespread endings, the fine un-
myelinated type, elicits normally a sense of touch.
Cornea
Because the great majority of anatomists find only
such fine endings in the cornea its sensation has been
much tested. General teaching since von Frey (273)
and in agreement with Lewis (171) has been that one
may evoke only pain from the cornea. Since even a
speck of grit on the normal eyeball is so intensely
painful, repeated reports in the literature that a sense
of touch may be elicited from the cornea found little
general acceptance. However, many normal people
do in fact descrilje only a sense of touch without pain
or annoyance when a wisp of cotton rests on the
cornea.
Lele & Weddell (163) have recently summarized 40
publications on corneal sensation and have carried out
a series of critical experiments which may well become
a cla.ssic of well-controlled study in the complicated
field of sensation. In 25 of the 40 earlier publications
the various authors record a feeling of touch upon
corneal stimulation, and Lele & Weddell obtained
this response invariably from each of 10 subjects when
a fine nylon suture was brought into contact with the
cornea. Reports of each subject never "included even
a suggestion of pain". Contrariwise, a heavier nylon
thread touching the cornea caused invariably a blink
and a report of sharp pain. In their further studies a
jet of air at warm, cold or neutral temperature, a warm
or cool copper cylinder, or an infrared beam of radi-
ation was applied to and restricted to the cornea. The
stimulus excited an appropriate sensation of tempera-
ture in the overwhelming majority of instances.
From such findings it seems likely that the fine
naked nerve endings in the surface layers of the body
are capable of setting up impulses which will enaijle a
467
man to distinguish not only a potentially noxious from
a harmless stimulus — pain from touch — but warmth
and cold as well.
Ahn
il Skin
There are, however, areas of abnormally innervated
skin in man from which only pain can be aroused.
Weddell (285) studied biopsies of such skin from a
patient with a lesion of the sciatic nerve and from a
patient with a plastic tube pedicle of the abdominal
wall. On histologic examination he saw in each speci-
men only fine nerve fibers giving rise to superficial
nerve nets with beaded endings.
Special Cutaneous Sensory Endings
Discussion of the functions of the elaborate cu-
taneous sensory nerve endings of Meissner, Ruflini and
Krause and of the deeper such endings, the Vater-
Pacinian corpuscles and neurotendinous endings of
Golgi is germane to our theme only to point out that
many of them have a long slender 'accessory fiber'
(Reniak fiber or Timofevew fiber) with a fine un-
myelinated naked nerve ending similar to those in
the cornea. Assuming that the most elaborate forms
of sensory nerve terminal subserve some specialized
function such as touch,, warmth or coolness, does ex-
cessive stimulation of such a receptor cause pain as
well, and if so i's that pain mediated via impulses in the
accessory fiber? VVoollard (308), in support of this
hypothesis, has illustrated an 'accessory' fiber derived
from what he calls the 'subepidermal pain plexus'
terminating at a Krause's end bulb. Lavrenko (158}
and K0I0S.SOV have shown that the.se accessory
fibers are not connected with the sympathetic system;
their specific association with pain remains at the
moment a speculation. Trotter & Davies (270) re-
garded the sensation of 'hot' as a combination of
warmth and pain, the sensation of 'cold' likewise would
combine coolness and pain. With increasing thermal
difference the sense of temperature disappears and
pain alone is perceived. (See above for comments of
Nafe on sensations arising from smooth muscle.)
Elucidation of all the mechanisms of the combined
forms of sensation is a task for the future; but one can
say that the 'intensive' theory of pain is right to this
extent, that sufficiently pronounced mechanical and
thermal stimulation of fine unmyelinated nerve end-
ings will cau.se pain.
Deeper Somatic and Visceral Receptors
Correlation of deeper somatic and visceral re-
ceptors with particular types of pain or other sensa-
tion is likewise in an elementary stage. Free unmye-
linated nerve endings occur in serous membranes, the
subserous coat of gut, intermuscular connective
tissue, tendon surface and substance, deep fa.scia and
periosteum — from all of which the suitable stimulus
evokes pain. [For specific references see White &
Sweet (296, p. 15).] The plexus of nerve fibers is
much better developed in the adventitia and mu.scu-
laris of arteries than of veins, according to Dogiel (66).
This finding correlates well with the severe pain com-
monly felt on arterial puncture in man in contrast to
the absence of or minor pain on venepuncture (283).
Terminating also in clo.se relation to capillary walls
are fine unmyelinated endings derived from sheathed
stem fibers of dorsal root origin described by Weddell
et al. (288). Their afferent function is further .sug-
gested by Landis' (151) observation in man that pain
occurred when his micropipette penetrated these tiny
channels.
TERMINAL SENSORY PLE.XUSES
The nerve fibers ramifying in the subcutaneous
tissue and skin are so interwoven as to give the im-
pression of a continuous net or syncytium, but even in
densely innervated areas such as the cornea Zander &
Weddell (313) have never seen fusion between
daughter axons originating from neighboring nerve
fibers, although they have occasionally seen nets
formed by fusion of daughter axons arising from the
same parent fiber. Even though the stem nerve fiber
from one dorsal root ganglion cell supplies a large
area of skin, the capacity to perceive and localize pain
correctly to a single spot is well known. It appears to
be mediated by the multiple innervation of each 'spot'
by branches from different stem fibers. Thereby a tiny
area of skin gives ri.se to a pattern of excitation differ-
ing enough from its neighbor to permit localization
and two-point discrimination. This disposition of stem
nerve fibers was first seen by Bethe (23) at the sensory
end organs of frog tongue. Boring's (30) penetrating
analysis of sensation in his own forearm after deliber-
ate division of a cutaneous nerve led him to the same
concept. Weddell (285, 286) was the first to demon-
strate histologically in human skin biopsies that a spot
of skin especially sensitive to one modality of sensation
was in fact supplied by two or more nerve fibers
468
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
approaching from different directions. Moreover, in a
patient with partial interruption of an ulnar nerve
associated with impaired sensiijilit}-, a shavina; of skin
3 cm^ from the dorsum of the hand in the hyper-
sensitive zone revealed in one area a single well-
stained nerve fiber amid other unstained and pre-
sumaiily degenerated fibers. This fiiaer terminated in a
net immediately beneath the epithelium, covering a
roughh- circular area of 0.75 cm in greatest diameter.
This distance corresponded to the limen of two-point
discrimination for pain in a similar normal area. The
observation suggests that the appreciation of the dual
nature of .such stimulus requires the separation of the
points by about the diameter of the terminal net of
each fiber supplying the zone in question.
PERIPHERAL SENSORY NERVE FIBERS
Single Fiber Studies
Adrian (i, pp. 81-go) was the first to record electri-
cal impulses from individual sensory nerve fibers in
animals following a variety of peripheral stimuli. He
and Zotterman promptly established that the spike
potentials from a single axon are uniform in duration
and amplitude, i.e. that the axon's impulse has an
all-or-nothing character. Moreover the>- showed that
no particular frequency of the discharge is character-
istic for pain. Thus a needle prick evokes a discharge
which \aries between the usual limits for a number
of types of stimuli of around 5 to 100 per sec. in each
nerve fiber. Adrian pointed this out as e\idence that
pain is not the result of excessive stimulation of any
type of receptor; if it were, one would expect a uni-
formly high rate of discharge. In confirmation of the
conclusion that high frequenc\' of discharge is not
necessarily correlated with pain Adrian el al. (2) re-
ported that puffs of air at high frequency directed to
the skin of a frog would produce fiber discharges up
to 300 per sec. Such stimuli did not seem to hurt un-
anesthetized frogs.
Echlin & Fessard (72) have also found in cats that
they can drive receptors at frequencies o\er 400 per
sec. so as to record synchronous afferent discharges
from proximal points on nerves. The effective stimulus,
a powerfully vibrating tuning fork placed against the
skin over the bone of the til)ia or ankle, would not
cause pain in man — further e\idence that high fre-
quency of discharge in a sensory receptor or nerve
need not give rise to pain in an afferent pathway not
ordinarily concerned therewith.
Adrian however did note in animals that the dis-
charge following; the painful stimulus of a heavy needle
prick was prolonged up to 20 sec. The discharge after
a light needle prick likely to evoke only a .sense of
touch in man lasted ijut 0.2 sec. or less (fig. 2). The
initial frequency of the discharge was however the
same with each type of stimulus. Although at the time
of his writing the naked terminations of nerves were
presumed to be exclusively receptors for pain, it
would, as he said, "make for economy if one and the
same nerve fiber could be used to signal nonpainful
stimulation by a brief discharge and painful stimula-
tion bv a much longer one." He would account for
the difference in sensation by a breakthrough of the
long discharge into areas of the central nervous
system inaccessible to its shorter counterpart. Such a
mechanism would not preclude another apparatus for
touch with particular receptors and fibers such as the
nerve roots around hair follicles. In addition to pro-
longed discharge the pain receptors and fibers, as
studied at the cornea for example, also show slow
adaptation, i.e. they continue to transmit pain im-
pulses as long as the noxious stimulus is present.
Studies of single afferent fibers in the cat by Maru-
hashi rl al. (185) are mentioned later.
FIG. 1. .Action potentials in cat's cutaneous nei'\e in response
to touch and pain. Needle on weighed leser lowered on to the
skin and allowed to rest there. .-1. Weight on needle 3 gm,
very brief discharge. B. Weight on needle 43 gm, continued
discharge. C Weight on needle 99 gm, continued discharge.
The 3 gm weight on needle used by Adrian for tracing A would,
he says, be on human skin the stimulus for the sensation of
contact. The discharge of impulses lasted about 0.2 sec. At
weights above 20 gm a distinct prick' is felt on human skin.
Discharges as in tracings B and C lasted as long as 20 sec.
[From Adrian (i).l
469
Tower (267) has shown that stimuli to various por-
tions of the field of ramification of the same fiber
produce different responses in that one fiber; this intro-
duces another variable in the data presented to the
brain increasing the likelihood of precise spatial
discrimination peripherally. She worked in the corneo-
conjunctival region of the cat using a preparation con-
taining but one to three fibers. The stimuli with hairs,
needles or glass rods were nearly all well above
threshold and would presumably have caused pain at
the human cornea. She made oscilloscopic recordings
of the action potentials from the preparation, noting
that one isolated nerve fiber yielding fairly large im-
pulses fanned out over roughly one fourth of the
cornea and some of the adjacent sclera. "Low thresh-
old and slow adaptation characterized the central
region of the terminal fields of individual fibers, and
rapid adaptation more than high threshold, the
peripheral parts." A strong stimulus near the center
of the field of a fiber might push the frequency of the
response nearly to the limit permitted by the re-
fractory properties of the fiber, namely about 500 per
sec. In general the frequency, duration and rate of
adaptation of impulses within the field of one fiber
were determined by site as \vell as by intensity of
stimulus. When many fibers remained active, the
normal situation of course, their fields overlapped in a
fashion inextricable to the experimenter. But, pre-
sumably, the brain of the subject uses all this informa-
tion, analyzing signals from fibers excited minimally
which encircle fibers excited more vigorously to
achieve better localization. The frequency of dis-
charge in the most excited fiber would still re\eal the
intensity of the stimulus.
Fiber Dicinietcrs and Pain Conduction
Gasser (90) and his collaborators also have amassed
evidence correlating physiological with anatomical
properties of nerve fibers (see his Nobel Lecture,
1946). Their classification is based on the duration
and form of the three components of the action po-
tentials in the fibers — the initial negative spike, then
the negative and finally the positive after-potentials.
Their 'A' fibers embrace all of the medullated fibers
in somatic nerves and some in the visceral nerves as
well. The 'A' fibers are divisible into five subgroups
designated in order of diminishing diameter by the
letters alpha through epsilon. The velocity of con-
duction in these fibers varies directly with the di-
ameter of the axon, ranging between go to 115 m
per sec. for the largest fibers 16 to 20 ju in diameter
and around 10 m per sec. in the smallest myelinated
fibers 2 to 4 M in diameter (fig. 3). They have called
the unmeduUated fibers in sensory nerves 'C fibers;
these have a diameter of 2 /x or less and conduct at
from 0.6 to 2 m per sec. Each component of a 'C
fiber's action potential lasts much longer than the
corresponding part of the action potential of an A'
fiber. The action potentials in most of the medullated
fibers of visceral nerves difier so much from either of
these that they have been placed in a separate cate-
gory and called 'B' fibers. L'sually a single elevation is
present with no \isible negative after potential.
Gasser & Erlanger found no such fibers in the dorsal
roots.
The more recently introduced designations of
Lloyd (i 78) are also in current use. His Group I fibers
from 20 to I 2 M are seen only in muscular branches
of nerves; Group II fibers from 12 to 6 ju are seen infre-
quently in muscular branches but present a larae
peak in cutaneous ner\'es; Group III fibers mainly
from 4 to 3 /i correspond to 'A' delta and occur in
nerves to both mu.scle and skin; and Group IV' are
unmyelinated or G fibers.
Of the numerous efforts in animals to correlate
pain with certain nerve fibers, the early experiment of
Ranson & Billingsley (219) is still one of the more
widely cited. As the posterior rootlets enter the spinal
cord they divide into a lateral bundle of fine, mostly
unmyelinated, fibers and a medial bundle of large
fibers. These authors found that after .section of the
small (lateral) fibers stimulation of the remainder no
longer evoked the pain reflexes' of struggling, altered
breathing and arterial pressure, whereas after section
of the large (medial) fibers these reflexes persisted.
More specifically pain impulses have been associated
both with the delta-epsilon 'A' fibers and with the 'C'
fibers. The most direct evidence of as.sociation of pain
with impulses in delta-epsilon fibers was obtained by
Heinbecker et al. (i 25) from the cutaneous nerves of a
man's leg which was later amputated. No sensation
was evoked at operative exposure of the nerves until
stimuli at a frequency of 1 2 per 5 sec. caused grimacing
and a verbal report of unequivocal pain (as if he were
being whipped). At the efl"ecti\e stimulus parameters
there was a clear-cut delta elevation in the action
potential from a companion nerve in the leg, but no
'C' fiber activity. The threshold for the 'C' fiber eleva-
tion in this nerve was five times as high. Earlier
Bishop & Heinbecker (28) had established in animals
that the thresholds of response to electrical stimula-
tion of fibers in peripheral nerve trunks varied in-
versely with the fiber diameter. So in their study in
470 HANDBOOK OF PHVSIOLOG\' ^ NEUROPHYSIOLOGY I
0.5 msec. 1.0
16-6.5 At
1.5
2.0
2.5 3.0
4.5-2.5/x
3.5
6.5-4.5/0.
FIG. 3. Action potential form in a human sensory nerve. This curve was calculated from the fiber
distributions. Inset graph, upper right, gives fiber distribution for the medial cutaneous nerve as
fiber diameters. Beneath the curve is indicated the position of the axon potentials according to
diameters of fibers, not axons. [From Gasser (8g).]
man, since no pain had been caused by weaker
stimuli activating fibers conducting more rapidly and
at lower threshold than the delta-epsilon group, the
authors thought these fibers were specific in their
pain-producing power. Almost as direct evidence to
nearly the same effect has been secured by Brookhart
et al. C34) from the tooth pulp in cats and man, a
structure chosen because of the assumption that pain
is the only sensation experienced when it is stimulated.
These workers saw in the cats the unmyelinated
terminal arborizations join to form a.xons 1.5 to 6 /n
in diameter with a median at 3 yu; the axons were
nearly all invested with a myelin sheath, a fact already
observed in human tooth pulp by Brashear (33).
Brookhart et al. found that strength-duration curves of
responses upon tooth pulp stimulation in both cat and
man were similar to tho.se obtained for 'A' gamma-
delta fibers in the cat's saphenous nerve and markedly
different from the 'A' alpha and 'C fibers in the same
nerve. The index of excitation in the cat was the
action potential recorded from the saphenous or
trigeminal nerve and in man was the minimal sensa-
tion of pain. The conduction velocity of the responses
in the cat's mandibular ner\e ranged from 30 to 45 m
per sec, putting them well into the 'A' gamma group.
[The delta component conducts at 15 to 20 m per
sec, according to Gasser (89).]
The strength of stimulus required to produce 'C
fiber activation in vivo has not been attained in critical
human study, but Clark et al. (42) have shown that
activity in these fibers also is correlated with nocicep-
tive reflexes. Thus in deeply anesthetized animals a
stimulus exciting 'C plus 'A' fibers was followed by
much larger reflexes than one exciting only 'A' fibers.
Moreover the 'A' fiber conduction was not necessary
for the production of reflexes which could still be
evoked after block of all W fibers by a pneumatic
cuff surroimding the ner\e. Zotterman (315) recorded
47'
only 'A' delta and 'C fiber activity from the saphenous
nerve of a cat when the corresponding skin was burned
by a special stimulus applied without mechanical de-
formation of the surface. He obtained similar records
upon etching the skin with acids. Maruhashi et al.
(185) have recently studied preparations of single
afferent fibers in the cat so that their conclusions as to
fiber size are derived from direct measurement. They
found one group of large and another of small
'nociceptive' fibers in the range 3 to 1 1 m- Activity in
such fibers was evoked by a pin prick or strong pull on
a hair. The receptive field of a fiber in the toe pad was
2 X 2 to 3 X 3 mm; it was about 10 times larger in a
hairy area. The extent of the field was clearly defined
and within it the receptive spots were densely dis-
tributed. Following the stimuli used in the.se studies
the impulse discharges were phasic and ended in about
0.2 sec. ; but if a scalded area was stimulated mechani-
cally a protracted after-discharge was present in both
small myelinated and unmyelinated fibers.
Double Pain Responses or Second Pa/n
From the foregoing type of ob.servation it has been
concluded that pain is conducted in meduUated 'A'
fibers at 15 to 45 m per sec. and in unmyelinated 'C
fibers at less than 2 m per sec. The gap between the
two groups of impulses is conceivably sufficient to
permit a perceptible differentiation between the slow
and the fast group and, indeed, long before the speeds
of conduction in sensory nerves were known a double
pain response to a single stimulus was described by
many observers. Thus Rosenbach (225) in 1884 and
Gad & Goldscheider in 1892 (86) thought the re-
sponse to a pin was an immediate sensation of prick
followed after an interval without sensation by a
second prick. Thunberg (264) investigated what he
considered to be two separate prick sensations with a
great difference in reaction time between the two.
Zotterman in 1933 (3 14) first associated the 'second'
pain with 'C fiber conduction. He confirmed the
observation by Lewis el al. (173) that a compression
cuff around the arm blocking the circulation causes
early paralysis of the sense of touch, alters the pain
sense, but does not cause analgesia even after arrest
for 40 min. These two groups of workers fell in line
with Ga.sser & Erlanger's (91) conclu.sion that arrest
of the blood flow to the nerves causes a progressive
loss of their function in accordance with the character
of the fiber. The first fibers blocked are those in the
'A' delta elevation; with progression of asphyxia the
larger medullated 'A' fibers are next affected; finally
after even the largest fibers are no longer conducting
the 'C fibers are blocked. Zotterman, using his com-
pression cuff to switch off all the 'A' fibers, found that
the pain which persists is felt only after a delay, and
his measurement of the time of this delay agreed well
with the reaction time for 'second' pain recorded by
Thunberg. The conduction velocity in the sensory
fibers (calculated from the reaction time) was not lower
than 0.5 m per sec. which is only slightly below the
conduction rate of the slowest 'C fibers in mammalian
nerves observed by Erlanger & Ga.sser. Upon checking
the differences in time of appearance of the second
pain in relation to the site stimulated, Lewis &
Pochin (174) found the expected shorter time when
thigh rather than toe was the area pricked. Thus
calculated, the rate of conduction in the limb of the
second response was again at the 'C fiber speed of
0.5 to I m per sec. Confirmatory evidence of this con-
cept has arisen from studies upon cocainization of
nerve fibers. Gasser (89) found this drug blocked the
'C fibers in his animals early, and then blocked the
medullated A' fibers in the same way as asphyxia,
i.e. beginning first with the smallest. He points out
that "it is misleading to state that asphyxia blocks the
large fibers first, while cocaine blocks the small fibers
first." But cocaine does block the 'C' group before the
'A' group, and corresponding with this Lewis &
Pochin (174) found that in man "cocaine reduces and
ultimately abolishes the second pain response, before
it similarly affects the first pain response." They are
both agreed that there are great difficulties with any
further attempt to correlate in a clear-cut way sensory
function and fiber size, that the fibers belonging to
different modalities must be widely distributed
throughout the various fiber sizes and that there seems
to be little possibility of associating any one sensation
with an elevation in the electroneurogram. Sinclair &
Hinshaw (248, 249), after an extensive study of com-
pression and pressure block of peripheral nerves in
man, subscribe wholeheartedly to the notion that
such association is impossible. Even after a large
number of experiments with procaine they found it
impossible to generalize as to the order of loss of the
various modalities of touch, pain, warmth and cold
since by suitable adjustment of the experimental con-
ditions "almost any desired order of sensory loss may
be recorded."
Lewis (171) and Gasser (89) are agreed that both
the fast and slow impulses evoke the same quality of
sensation. Lewis adds that brief noxious stimulation
produces the sensation of 'pricking' and that a pro-
longed no.xious stimulation elicits a sense of 'burning.'
472
HANDBOOK OF PHYSIOLOGY ^^ NEUROPHYSIOLOGY I
Hardy et al. (i i8,p. 133)011 the other hand think there
are two different quahties of pain independent of
the duration of stimulation, that 'pricking' pain is
predominantly "fast' and primarily conveyed by
myelinated fibers, whereas 'burning' pain is pre-
dominantly 'slow' and conveyed by unmyelinated
fibers. Sinclair & Hinshaw (248, 249) had made a
similar statement, but had added that "in the experi-
ence of pin prick, the factor which determines whether
the subject reports a feeling of pain or not is probably
not the initial prick conveyed by fast fibers, but what
we may term 'unpleasantness' which arrives subse-
quently by the slower fibers." They also state that
"after the slow unpleasantness is removed in pressure
blocks there is a period when it is exceedingly difficult
to determine whether a pin prick should be reported
as 'sharp' or as 'sharp and painful'."
Landau & Bishop (150) have extended the analysis
of pain sensation by the techniques of differential
block by cuff pressure and procaine to subcutaneous
tissue, periosteum, muscle and fascia. They elicited
pain by both electrical stimulation and chemical in-
flammation. They concluded that the presumably 'C
fiber pain is "of slower onset, but of severer and more
penetrating character and of longer after-effect."
Periosteum, muscle and veins were found to be sup-
plied by fibers of both types, whereas inflammatory
pain from the subcutaneous injection of turpentine
and from bee stings, as well as the pain following in-
jection of 5 per cent sodium chloride solution, was
assigned almost entirely to activity in 'C fibers. De-
tailed consideration of their results reveals some in-
consistencies, however; thus with procaine block to
these deep endings which should block 'C before
delta fibers "only a partial loss of deep pain results
before prick is blocked." The pricking pain should
have been the last to go if the authors' hypothesis were
to be fully confirmed.
Further evidence that two different qualities of pain
may result from different types of responses of the
same peripheral nerve was obtained by Pattle &
Weddell (206) in an experiment which included
direct exposure of one of VV'eddell's own digital nerves.
The threshold sensation following single graded con-
denser shocks to the ner\-e was a "pain of unpleasant
quality like a wasp sting." This response occurred at
all strengths of shock from o. i to 6 ^f capacity of con-
denser. But the discharge of a condenser of 7 nf
capacity "produced a long-lasting, severe, aching
pain, which was completely different in quality from
the wasp sting reaction." The reaction time from
stimulus to closure of an electrical contact b\' the sub-
ject was exactly 1.27 .sec. for each type of pain, how-
ever. The study was carried out on a nerve in which
only a few fibers appeared to be responding to stimuli
following injection of the local anesthetic procaine
which produced complete insensitivity of the whole
distal phalanx of the finger. The two types of pain
here are however manifestly different from the experi-
ences recorded in experimental studies on double pain
from the intact skin.
An astute maneuver to measure the conduction
time for human pain sen.sation which eliminates the
time from cerebrum to motor response has been de-
scribed by Gordon & Whitteridge (106). The alpha
rhythm of the human EEG can be disturbed by un-
expected stimulus to the skin and in individuals in
whom this response was clear-cut these workers
found that the time between painful stimulus and
alpha interruption averaged about 0.25 sec. at both
normal fingers and toes. The delay was much greater
when the iiase of finger or toe was compressed for an
hour or more by a cuff occluding its blood supply.
It averaged 1.04 sec. from the asphyxiated finger
and 1.40 sec. from the asphyxiated toe. In the latter
state they measured the fiber conduction time for
the 'second' pain at about i m per sec.
Sinclair & Hinshaw (248, 250) and Sinclair (247)
have put forward some sharp and cogent criticisms
of much of this work on double pain and 'second'
pain, pointing out that a delay between stimulus
and perception of pain also occurs in procaine blocks,
a situation in which the slowly conducting fibers
are supposed to fail first. Critical scrutiny of the data
obtained during the asphyxia caused by cuff com-
pression also leads to doubts regarding the original
interpretation.
Thus, Lewis & Pochin's (174) average figures in
two subjects for appearance of second pain upon pin
prick of a normal finger and toe and for appearance
of delayed pain after a cuff block were about the same
at 1.2 sec. But when each subject is considered
separately, there is a statistically significant differ-
ence in both of them between the control and as-
phyxial readings. Moreover, Lewis & Pochin (174)
found after cuff asphyxia that the latency of the pain
response, the reaction time, rises abruptly from 0.3
sec. to be constant at 1.5 sec. Sinclair & Hinshaw
(250) have recorded delays much in excess of this
figure up to 5 sec. — longer than would be required
for conduction from finger to brain of any normal
'C fiber. Ashby (11) has likewise pointed out many
recorded instances of much longer delays in tabes,
and I have seen one such striking patient who showed
PAIN
473
a delay greater than 3 sec. upon stimulation of the
forearm. If the delayed pain under abnormal con-
ditions such as asphyxia is indeed pure 'C fiber pain,
then the abrupt rise in latency from 0.3 to 1.5 sec.
described by Lewis & Pochin is consonant with the
final failure of conduction in 'A' delta fibers. How-
ever, Wortis el al. (312) did not confirm this abrupt
change; they found delays in the pain response at
intervals during asphy.xial compression studies in
man to vary upon stimulus to the foot from o.g to
1.7 sec. Another major criticism rests upon the fact
that reaction time to pain is influenced greatly by
the intensity of the stimulus, there being a hyperbolic
decrease in time with increasing intensity according
to Pieron (212) and Eichler (73). In general the in-
tensity of stimulus has not been maintained constant
in the studies tending to identify delated pain under
abnormal conditions with second pain under normal
conditions. Even the less complex sensation, touch,
exhibits a reaction time which \aries in\ersely with
the intensity of the stimulus. It also varies with
the cross sectional area of the stimulus and changes
from day to day, from subject to subject and from
testing site to testing site (162). Likewise thermal stim-
uli even when ineasured from the threshold intensity
rather than from an absolute zero show the same
type of variation as shown by Lele & Sinclair (161).
Since the reaction time represents the sum total for
initiation of conduction, for actual conduction over
both afferent and efferent paths, for perception and
judgement and for synaptic transmission, the assump-
tion that changes in the reaction tiine are due to
changes only in afferent conduction rate would
seem unwarranted.
It will be noted that much of the work on second
pain and double pain in nerve fibers has been car-
ried out in abnormal situations of ischemia, pharma-
cologic insult or disease. Weddell et al. (289) have
suggested that the delay in these abnormal conditions
need not depend on the existence of two discrete
groups of fibers conducting at different rates and that
the delay could occur in the central rather than the
peripheral nervous system as a consequence of sim-
plification of the impulse pattern reaching the brain.
Such an explanation fits more satisfactorily with the
observation of gross variability in the delay and its
occurrence with all maneuvers depressing conduction.
However, such an explanation does not account
for the occurrence of second pain under normal con-
ditions. I have never personally been able to con-
vince myself that I could perceive two separate pains
in response to a single noxious stimulus even after
following Gasser's (89) prescription of flipping the
back of my finger against a hot incandescent light
bulb or metal hot water faucet. Weddell (personal
communication) has had the .same trouble. And
it has been a mystery to us how Thunberg (264)
and Lewis & Pochin (174) could measure such pre-
cise reaction times for a .sensation we could not con-
sistently discern.
It was with some relief that I read of Jones' (137)
experiments. When she applied a rigidly mounted
needle algesimeter calibrated in 0.25 gm steps to
three different spots on the dorsal forearm of each
of eight subjects, not one of them reported a double
pain after any stimulus. (The point of the needle had
been sharpened under a microscope to minimize the
stimulation of pressure sensation.) The needles were
not held by hand, as one infers was done b\- previous
investigators, because the pain stimulus might vary.
In another effort to elicit double pain she permitted
the needle to remain at the site evoking a response.
These 'adaptation trials' were carried out at the
threshold for pain, i gm above threshold, and in
four highly practiced subjects at 2 gm abo\e threshold.
The pain did not vary in a smooth way; instead "the
course of adaptation showed fluctuations; in about
one-fifth of the trials there were only two peaks
which naive observers might po.ssibly have inter-
preted as double pain." The four experienced
subjects looked carefully for possible double pain,
and with suprathreshold stimuli they reported it
twice out of 20 trials; in two other trials there were
other types of double sensation, one of cold and
pain and another of pressure and pain. The possi-
bility exists that a suprathreshold stimulus may
excite two discrete receptors sequentially and Jones
suggests this interpretation of the results. Woollard
et al. (310) had already correlated 'first pain' with
penetration of the needle point into the epidermis
and "second pain' with attainment by the point of
dermal levels. This they did by measuring on the
needle the depth at which each sensation was pro-
voked and then correlating this with an actual histo-
logic study of the skin in that area.
Thresholds to the pain upon electrical stimulus
with a square-wa\e pulse from a Grass stimulator
were also studied by Jones in 120 trials on each of
the four experienced subjects. No double pain and no
single delayed pains were felt. Jones regards this
form of stimulus as well suited to analysis of the double
pain hypothesis because if more than one receptor is
stimulated they are all stimulated simultaneously.
She points out that no experimenter has reported
474
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY
double pain with a single electric stimulus. Heat,
on the contrary, one of the more effective stimuli
in eliciting double pain, does continue to penetrate
deeper into the tissues and to stimulate more remote
receptors even after the stimulus is removed. Landau
& Bishop (150) also found in eight normal, unpreju-
diced subjects "only three who could recognize a
second pain response when the skin was tested with
heat or brief mechanical stimuli." They ascribe the
failure of brief stimuli to evoke delayed pain to a
masking effect of the pricking pain. In any event it
would seem to me that, since 'C fiber activation in
animals requires a much more powerful stimulus,
Jones' studies at threshold levels and up to 4 gm
above threshold may never have activated these
fibers.
It would thus appear that the whole suljject of
pain conduction by nerve fibers of specific size is
worthy of careful review. The technique of Dawson
& Scott (58) of recording nerve action potentials
through the intact skin in man may increase the feasi-
bility of securing the crucial information. The method
has already yielded valual)ie data on this score in
the hands of Magladery et al. (183) who have found
that the ischemia of cuff occlusion has a generalized
depressant effect on the conduction in both afferent
and efferent "A' fibers in peripheral nerve trunks
in man. They studied oscilloscopic records of the
action potentials and correlated these with serial
sensorimotor examinations as the cuff was inflated
and deflated. Thus 17 min. after the onset of ischemia
voluntary power was still relatively normal. But
recognition "of all forms of .sensory stimuli except
those producing deep pain was diminished." With
this one exception, no subject found one sensory
modality impaired disproportionately to another.
Figure 4 taken from their work shows the steady re-
duction in the potential from the rapidly conducting
fibers as the ischemia continued. No "C fiber poten-
tials appear in this record, obtained after a "maximal
single shock' to the ulnar nerve in the low forearm
with recording over the ulnar nerve above the elbow.
In an important study in man by Collins, Randt &
Nulsen (unpublished observations), the exposed sural
nerve is being stimulated distally while action poten-
tials are recorded oscilloscopically from a more
proximal position. .Such studies immediately precede
and follow therapeutic incisions into the pain path-
ways of the spinal cord. Reporting on the five pa-
tients thus far studied, they say tentatively that the
sensation corresponding to an 'A' gamma-delta
elevation on the oscilloscope has been equivocal —
not clear-cut pain. But at the first intimation of "C
fiber activation the patients have had severe pain;
this has been the case also even if 'A' fiber conduction
was profoundly depressed by local cooling of the
nerve.
In relation to double pain an effort has been made
to generalize even more widely regarding sense
organs supplied by nerve fibers of significantly
varying diameters by Katsuki fl al. (139). They say
that the thin fibers carry impulses from receptor
elements of lower threshold to physiologic stimuli
with a lower rate of adaptation, a lower maximal
frequency of discharge and a greater tendency to
continuous or spontaneous firing. Bullock (36) has
drawn attention to the applicability of this principle
to nine different sense organs, the thin fibers supply-
ing the more sensitive and tonic, the thick fibers the
more discriminating and phasic receptors. However
his attempt to bring pain fibers into this concept
stands up only in the roughest way under close
scrutiny. He cites Maruhashi ft al. in his support,
i)ut these workers actualh' describe distinct tonic
or phasic behavior mainly in two groups of small
myelinated nociceptive fibers in the toad all within
FIG. 4. Nerve action poten-
tials in man following maximal
single shocks to ulnar nerve in low
forearm. Surface recording over
ulnar nerve above elbow. Pres-
sure cuff on upper forearm in-
Hated to 200 mm Hg. Top record,
before ischemia; lower records, the
stated number of minutes after
onset of ischemia. Time: i and
5 msec. [From Magladery et al
(183).]
475
the range of 3 to 5 /x in diameter. Moreover the
group responding tonically had a higher maximal
frequency of discharge than that responding in phasic
fashion. In line with Bullock's thought, however,
was the finding in both these groups of lower ma.xi-
mal frequency than in the large myelinated nocicep-
tive fibers 6 to 9 // in diameter. These generally gave
a phasic discharge to light pin prick, ending about
0.2 sec. after the onset of the stimulus. It is apparent
that useful generalizations from the welter of facts
before us regarding pain and impulses in nerve
fibers are difficult.
P.'MN IN .'>iBNOR.M.-\L A.N.-\TO.MICAL STATES AT PERIPHERY
Dtv
oj Cutaneous Nerves
Both the quality and the degree of pain sensi-
bility become altered following injury to nervous
pathways concerned with its conduction. The most
painstaking and best controlled studies of the changes
have been made by investigators who divided and
then sutured the cut ends of one or more cutaneous
nerves in themselves. They then followed the sensory
status during the period of recovery. These workers
included Rivers & Head (223), Trotter & Davies
(270), Boring (30), Sharpey-Schafer (245) and Lanier
et al. (157). AH but the first group tended to agree
with Trotter & Davies that "the changes consequent
upon depriving a piece of skin of its nerve supply
are distributed in a central area of absolute lo.ss,
surrounded by a zone of much less loss which is
slight toward the periphery and deepens toward the
center." They also observed that the "defect of sensi-
bility to pain is precisely similar in character and dis-
tribution to the defects in sensibility to cold, to heat
and to touch." In addition, Trotter & Davies found
that there was an altered quality to many sensory
stimuli on the tenth to twelfth postoperative day,
lasting up to the sixth or eighth week. This developed
in spotty, irregular fashion largely peripheral to the
analgesic zone in the previously hypalgesic or so-
called intermediate zone. Later a more extensive
area of altered quality of sensation came on when
regeneration began.
In the first 'hyperalgesic' stage they found that
pain after pinprick has an abnormally unpleasant
quality, radiates diffusely, tends to provoke a motor
response, is poorly localized or may be a persistent
severe burning which may reappear spontaneously
afterwards. Two point discrimination is reduced in
the area and touch, although evoked only by stimuli
normally above the threshold, may then have a pain-
ful quality. In the later stage of regeneration the same
qualitative abnormalities can be elicited from the
previously analgesic zone. These abnormal features
may persist for many months and then gradually
decline. In general these reports have been well con-
firmed but their significance remains widely debated
and the mechanisms of production obscure. The
names applied to the situation have been as varied as
the hypotheses; 'hyperpathia', 'intensification", 'dyes-
thesia', 'over-reaction' and 'paradoxical pain' have
been used. Hyperalgesia is probably the least appro-
priate term since it implies a lowered threshold to
pain which is in fact usually not the case in this
condition.
The development of the early phase of hyperpathia
was correlated by Pollock (214) with the ingrowth
of fibers from the adjoining peripheral nerves for two
reasons: a) the early hyperpathia (and the other re-
covery of sensation) appears long before regenerating
fibers could reach the skin; and b) such .sensation
is not lost if the regenerating nerve trunk is cut a
second time. Weddell and as.sociates (285) have in fact
demonstrated unmyelinated fibers growing out from
the intermediate into the originally anesthetic zone
using methylene blue stain in man. More recently
Weddell and associates (personal communication)
have acquired evidence that a denervated sector of
the cornea is reinnervated from three sources of nerve
supply.
Head & Sherren (122) hypothecated that the nor-
mal sensations were mediated by 'epicritic' groups of
nerves and that the abnormal qualities ensued only
when 'protopathic' fibers were excited. Their com-
plex formulation completely failed to fit the facts
brought out h\ each of the succeeding workers who
studied their own sensations before and after de-
liberate cutaneous nerve section. Cobb (46) in his
work on patients with peripheral nerve injuries after
World War I drew attention to the fact that Head's
alleged areas of dissociation of sensibilities arose
from comparing stimuli which were not quantita-
tively equivalent. He found, for example, that the
areas of sensory loss were coextensive if one used a
soft brush to test cutaneous touch and a needle point
at 15 gm pressure for pain. .Sufiice it to sav that
despite the cogency of the criticisms of all of these
workers it has required the devastating verbal scythe
of Waishe (282), giving incisiveness to his keen
critical powers, to .sweep from the literature favorable
reference to the 'protopathic' and 'epicritic' nervous
476
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
systems of Head and associates. We are still left with
the necessityof explaining the above abnormal features
of the sensory response. Boring (30, p. 92) agrees
with Head to this extent: the abnormal sen.sory in-
tensity is achieved by the removal of an inhibition.
More recently Landau & Bishop have identified the
type of pain which they consider to be tran.'Oiitted
over normal 'C fibers with the 'protopathic' forms of
sensation of Head et al. (121) and conclude that
block of delta-pain fiber responses releases "the per-
ception of 'C fiber pain in the otherwise normal
subject."
An alternative explanation has been put forward
by Weddell et al. (289) on the basis of their histologic
studies of human skin at 39 sites from which the
above abnormal qualities of pain were induced.
Control studies were made at 20 other sites in cutane-
ous scars from which the pain did not have the ab-
normal unpleasant quality. In the former group the
nerve nets and terminals were isolated from their
neighbors instead of interweaving with them as
occurs normally, and as was seen in those reinner-
vated scars which showed no abnormal quality in
the senations aroused from them. Normally, as Bor-
ing (30, p. 95) first deduced, "single sensory spots are
innervated by more than one nerve fiber and the
multiple innervation is projected upon the central
nervous system as multiple excitations." Weddell
(285) demonstrated this, correlating neurophysio-
logic with clinical findings, and Weddell >i al. (289)
conclude that the complex pattern of impulses arising
from such multiple innervation is essential to the
normal quality of pain "of everyday experience,"
whereas if only a single pain fiber or terminal is ex-
cited then the pain is of characteristic unpleasant
quality. This conclusion, that reduction in the den-
sity of innervation of an area will cause alteration in
the quality of pain, has likewise been reached inde-
pendently by Livingston (177). In a patient recover-
ing from an injury to the median nerve at the wrist
there was one area in which pain was of normal t>'pe
until one of the main nerve trunks was blocked with
procaine, whereupon pinprick became peculiarly
unpleasant. This state was exacerbated when two
of the three nerves were blocked simultaneously.
Weddell et al. (289) have also studied the alterations
in pain sensibility in themselves upon compression of
the upper limb with a sphygmomanometer cuff.
They found the first change to appear was a rela-
tively abrupt alteration in the quality of the pain
upon a needle prick; when fully de\eloped at ai^out
the thirtieth minute of compression the prick caused a
"singularly unpleasant sensory experience," a slow
swelling burning sting lasting for as long as 10 sec.
and giving ri.se to a withdrawal reflex difficult to
control. There was also an increasing interval be-
tween the application of the stimulus and its per-
ception. They concluded that these typical features
of 'unpleasant pain' were to be correlated with a
gradual reduction in the number of fibers conducting
impulses as the compression continued.
Isolation of the pain nets appeared to have no
eflfect on the threshold of pain sensibility. In a num-
ber of biopsies these workers saw abnormal appear-
ances of the nerve endings, ellipsoidal expansions
which they called growth cones. The lowest thresholds
to pain occurred in their patients in whom such
growth cones lay just beneath the basal layer of
epidermis. In such cases the mere passing of a camel's
hair brush across the area was painful.
Foerster had earlier (77) .suggested that the peculiar
abnormalities of sensation (his hyperpathia) arose
from the stimulation of an isolated 'pain point.'
The .similarity between this explanation and that of
Weddell et al. is only superficial, however, because
Foerster contended that as soon as other senory
modalities such as touch and pressure were felt the
hyperpathia began to recede, a viewpoint which is
.simply not substantiated by the observations of
others. The sites at which pain has the abnormal
quality are not directly correlated with anesthesia to
touch. Figure 5 shows the results of an examination
in which more spots hypersensitive to pinprick were
in fact found outside of the anesthetic zone. Simi-
larly Lanier et al. (157) in their study found an area
in which, although touch sensibility was perfect, pain
sensibility was diminished and unpleasant pain
could be elicited from this region.
Figure 5 also illustrates another observation of
Trotter & Davies (270, p. 170), namely that such
patterns of 'hyperalgesia,' as they called it, were
associated with veins. They say that often the skin
over the vein itself was the most sensitixe part of the
patch. Although Cobb also thought that "these
painful spots were usualh' along the course of a super-
ficial vein," the explanation of this is unclear. Trotter
& Davies originally regarded the hyperalgesia as a
"secondary process due to the presence of some
irritating substance produced as the result of the divi-
sion and degeneration of the nerve."
But, in the light of another 17 years of rumination
on the subject. Trotter (269) thought that the lack
of complete insulation of regenerating nerve fibers
would explain the raised threshold to stimuli and the
477
^ \
\\
r- -^,
FIG. 5. Hyperpathia in relation to anesthesia following section of a cutaneous nerve. Examina
tion 34 days after division of middle cutaneous ner\e of thigh. VVttkin Ike continuous line: anesthesia
to camel's hair brush. Within the dotted lines: two areas abnormally sensitive to pin. Broken lines show
course of superficial \-eins; spots marked X show maximal sensitisity to pin prick. [From Trotter &
Davies (270).]
exaggerated explosive type of response upon effectual
stimulation. Accompanying this concept was his
notion that many types of fiber in their poorly in-
sulated regenerating phase may conduct impulses
giving rise to pain, since he presumed that pain was
the only sensation evoked from the uninsulated, i.e.
naked, unmyelinated end organs. He goes on to say,
"With the advance of regeneration the fibers serving
touch, heat and cold, become once more connected
with end-organs, and then their insulation, by the
junction of the neurilemma with the capsule of the
end-organ, can be completed. The completely insu-
lated fiber, having lost its teinporary resemblance to
the pain fiber, becomes once more sensitive to the
finer stimuli and ceases to yield exaggerated re-
sponses." Later work already discus.sed which demon-
strates the capacity of naked unmyelinated endings
to transmit impulses concerned with touch cuts the
ground from under the latter part of this reasoning,
but the concept of lack of insulation has become more
appealing since the work of Granit et a!. (109).
These investigators showed that a generalized break-
down in 'insulation' occurs at the site of injury to the
sciatic nerve in cats. This is so striking when the nerve
is cut across that impulses set up in spinal ventral
(motor) rootlets are transmitted to the sensory fibers
at the cut and can be picked up via an oscilloscope
from the dorsal (sensory) rootlets of the same seg-
ment. Such an 'artificial synapse' or 'fiber interac-
tion' also develops at the crush of a knot tightened
around a nerve and even appears from time to time
after moderate pressures of 50 to iio gm against a
nerve insufficient to stop conduction beyond the
point of compression. Granit et al. have assumed
that pain fibers would be among the most easily
excited by fiber interaction. These observations
clearly present a mechanism whereby impulses trav-
ersing one fiber may abnormally pass to many at a
site of injury, thereby pennitting abnormal central
excitation.
478
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
Hyperalgesic State After Trauma
We may now consider the special studies of Lewis
(171) on the hyperalgesic state provoked in skin by
controlled scratching, heat, freezing, ultraviolet
light, or chemical or electrical irritation. These
varied forms of trauma all produce a skin which is
hyperalgesic in the strict sense of the word, i.e. a
lighter needle prick will cause pain from it than from
corresponding normal skin. In addition, an effective
prick gives unusually intense, diffuse and long-lasting
pain. Spontaneous pain is present which is worsened
by relatively small amounts of warmth, more marked
cooling or light contacts such as those from clothing.
The zone of hyperalgesia gradually spreads after the
injury — for example five minutes of faradization of
the skin a little above the wrist provoked the above
change over an area 18 cm long with a maximal
width of 7 cm, an extent achieved within 1 1 min.
(171, p. 69). The soreness in the area lasted several
hours. Some days later repetition of the stimulation
procedure led to nearly the same pattern of hyper-
algesic zone. In general, such zones tend to corre-
spond to the entire area of a cutaneous nerve, as
shown by their agreement with the area of sensory
elimination after anesthetic block of the nerve trunk.
Moreover, direct stimulation of the cutaneous nerve
trunk or any of its smaller branches will evoke the
typical hyperalgesic pattern. Lewis advanced the
view that a pain-producing substance developed at
the site of injury which, by stimulus to local nerves,
provoked the reaction over the whole arborization
of a single cutaneous nerve. He also hypothecated
that such reactions must be mediated by a new and
distinct system of fibers which he called 'nocifensor'
nerves. He was especially led to this conclusion by the
fact that the pain terminals arising from a single
nerve fiber have never been demonstrated histo-
logically to cover so large an area as, e.g. 7x18
cm on the forearm. Maruhashi et al. (185) have come
close to this electrophysiologically however. They
found individual afTerent fibers in the cat innervating
oval areas ranging from 3x5 to 5x9 cm. Such
fibers to which they give the special designation 'wide
receptive fibers' were abundant in all skin nerves
examined; they ranged from 2 to 5 /j in diameter.
These fibers are probaljly not identifiable with the
nocifensor system since afferent impulses can be
evoked in them by 'extremely light touch' to the
skin or to a hair in the fiber's large receptive field.
Moreover such responses persist in areas 'deaffer-
ented' by excision of five lumbar root ganglia 3 to
4 wk. before the experiment. On the contrary the
post-traumatic hyperalgesia of Lewis disappears
from zones denervated by posterior rhizotomy. In
the absence of any anatomical demonstration of an
entirely different system of fibers specialized to medi-
ate the hyperalgesic spread, this concept of nocifensor
fibers has won little support. Walshe (282) and
White & Sweet (296, p. 96) may be consulted for
further arguments /)/o but mainly con.
CHEMIC.'\L EXCIT.XNTS OF P.MN
The concept that chemicals liberated at the site
of injury provoke pain has been supported experi-
mentally by Lewis (171, pp. 113 to 115). His extracts
of freshly excised human skin caused pain when in-
jected in tiny quantities intradermally. He thought
the substance was not histamine since he found
this to give itching rather than pain when it was
pricked into the skin even in such high concentra-
tion as 1:30. Rosenthal (226), however, found that
"as little as fifty-four molecules of histamine" in-
jected intradermally will cause pain, and in a series
of papers with several collaborators has presented
evidence that histamine or a similar substance is the
chemical mediator for cutaneous pain. Moreover
Habgood's (113) analyses of the substance liberated
upon antidromic stimulation of frog cutaneous nerve
pointed toward histamine or an 'H-substance.' In
addition he demonstrated that the chemical so
produced could often evoke spontaneous discharge
from an adjacent nerve twig (fig. 6). That a similar
phenomenon may take place in man is intimated by
Foerster's observations upon stimulation of distal
ends of divided posterior roots at operation. This
provoked burning pain in the skin which was elimi-
nated by division of adjoining posterior roots. If
then antidromically-induced liberation of a chem-
ical which stimulates nerve endings will activate a
separate but overlapping sensory unit, a wide area
would be involved by a continuation of this process.
The extent of the spread would tend to increase with
the extent and .severity of the original injur\-. .^nd
since Lewis had already obtained hyperalgesia by
antidromic stimulation of cutaneous nerves in man,
its explanation would not require either a separate
system of nocifensor nerves or the wide receptive
fibers of Maruhashi et al. (185).
The technique of applying fluids to the exposed
base of a blister caused by cantharidin or heat, de-
veloped by Keele and his a.ssociates, has enabled
PAIN
479
Skin
T
Stimulating C
electrodes (^
Recording
IQ electrodes
I
^^j^ L^^ 1^^^ ^|u^ k
FIG. 6. Double nerve preparation from frog's skin show-
ing chemical transmission of impulse from one nerve to the
other. Antidromic stimulation of the peripheral end of one
cutaneous nerve was often evoked by electrical stimulation
of an adjoining cutaneous nerve with an overlapping field,
the responses appearing either during or after the antidromic
stimulation. The nature of the discharges is shown in the pho-
tograph of an action potential. Vertical while lines are synchro-
nous with shock aitefact and are go msec, apart; a succession
of two fast spikes appears 3 to 4 msec, later ; then one fast, four
slow, one fast and two slow impulses regularly succeed in the
recording electrodes following each stimulus to the other nerve.
Direct conduction from one nerve trunk to the other and
spread of current could be excluded. [From Habgood (i 13).]
them to study effectively the pain produced by
chemical.s. The method has given them more con-
sistent results than intradermal injection or pricking
of the skin through a drop of solution on it. They have
demonstrated that tiny amounts of three identified
substances found in tissues provoke pain when applied
to the area exposed after removal of blistered skin.
Both acetylcholine and histamine in concentrations
of io~^ gm per ml, and 5-liydro.\ytryptaminc (sero-
tonin) even in amounts as low as io~* gm per ml
cause pain. The time of onset and duration of the
pain are different and characteristic for each of the
three. The two latter substances have already been
associated with injured tissue, serotonin with platelet
breakdown. Saline extracts of rat and human skin
made by these workers were found to contain 5 x io~^
gm per ml of histamine and to cause prolonged pain
when applied to a blister base. Histamine alone in
such concentration caused only itching.
The Keele group has found an additional pain-
producing substance (PPS) in the blister fluid itself
as well as in human plasma, serum and protein-rich
inflammatory fluids obtained from pleural, peri-
toneal, joint or hydrocoele cavities (10). The PPS
shows the peculiar behavior of appearing in these
fluids only after they are 'activated' by contact with
glass; but following activation the capacity to evoke
pain declines rapidly to less than 10 percent of the
peak within an hour at room temperature. The pain-
producing activity of PPS correlates well with ability
to cause contraction of the isolated rat uterus. By
applications of this convenient method as well as
by other tests they showed PPS to be different from
serotonin and histamine and to resemble the poly-
peptide Ijradykinin more closely than any other sub-
stance yet tested. Bovine bradykinin produced pain
in man indistinguishable from that of PPS in concen-
trations as low as io~^ gm per ml. A continuation
of this type of study may lead to knowledge of the
actual substances which are stimulating pain endings
in vivo. In general the minutiae of the mechanisms
whereby stimuli are transduced into nervous impulses
remain wide open for investigation.
POSTERIOR AND ANTERIOR ROOTS
The distribution of the nerve fibers transmitting
pain via each posterior root has been largely worked
out for the cutaneous supply. Various diagrams of
these so-called dermatomes obtained by a number
of methods have been collected by White & Sweet
(296, pp. 26 to 30); such data are more fragmentary
for the deeper structures (296, pp. 22 and 23). The
possibility that afferent fibers may also enter the
cord by way of the anterior roots has continued to
be supported by bits of evidence over the past 75
years. White & Sweet (296, pp. 31 to 36) have col-
lected and analyzed their own and others' data on
this subject. Studies not mentioned in that account
include those of Maruhashi el al. (185), who measured
the .size of small myelinated fibers they found asso-
ciated with ganglion cells on the course of ventral
roots in cats. These practically coincided with their
afferent fibers "with wide receptive field" (discussed
above), and they regard it as "certain that these
fibers provide an exception to the Bell-Magendie
law." However, these fibers were stimulated by
touch rather than noxious maneuvers. We were un-
able to find a) record of any patient in whom an-
terior rhizotomy stopped pain unassociated with
muscle spasm, i) report of altered response to ob-
jective sensory tests after anterior rhizotomy or c)
written account of failure to stop pain by posterior
rhizotomv followed by success af*er a later anterior
48o
HANDBOOK OF PHYSIOLGG"!'
NEUROPHYSIOLOGV
rhizotomy. We are hence without positive evidence
that pain impulses in clinically significant numbers
transverse the anterior roots to enter the spinal cord in
man.
P.MN .AND .AUTONOMIC NERVOUS SYSrE.VI
This system of nerves was defined by Langley (155)
as efferent and distinguished from the somatic ner-
vous system by a peripheral synapse. He was will-
ing to regard as autonomic afferent fibers only "those
which give rise to reflexes in autonomic tissues and
which are incapable of directly giving rise to sensa-
tion." He considered all other afferent fibers somatic.
We have since his time become progressively more
aware that most of the nerves of gross anatomy named
"autonomic' contain pain fibers. This is true in vir-
tually all of the sympathetic and pelvic parasympa-
thetic nerves to the torso; the distribution of these
insofar as they are known has ijeen diagrammatized
by White [see figs. 127, 130, 131, 133 and 134 in
White & Sweet (296)]. Evidence for the presence of
pain fibers in these nerves has been gleaned both
upon stimulation and after denervation. These vis-
ceral pain fibers differ from autonomic efferents in
their probable nonstop course through the para-
vertebral ganglia to enter the posterior roots of the
spinal nerves.
Sympathetic Nerves
The concept that the efferent sympathetic path-
ways leave the cord only from the lowermost cervical
to the upper lumbar segments and enter the sym-
pathetic chain via the white rami communicantes is
so well-established that it has led to ready acceptance
of Langley's statements that the afferent fibers
travelling with the sympathetic nerves also return
impulses to the spinal cord only by way of these white
rami. Thus in one study (156) leading toward this
conclusion he deduced that sensory fibers of the cat's
major accelerator nerve, the chief sympathetic nerve
to the heart, entered the cord only by the top 5 white
rami. He found in general that stimulation of the
central ends of the gray rami produced "no observable
physiological effect" in cats (155). Largely by histo-
logic study of degenerating myelin after section of
various nerves he concluded that the cell bodies of the
afferent fibers travelling with the sympathetic nerves
are only in the posterior root ganglia of the nerves
with white rami. For example, upon section of the
cervical sympathetic trunk below the superior cer-
vical ganglion he found complete degeneration of
the fibers rostral to the cut and extending up to the
ganglion C'SS)- This conclusion unfortunately rested
on the misconception that there are no nonmedullated
afferent fibers (i 54) which we now know to be wrong.
His histologic studies would have failed to demon-
strate degeneration in these. Ranson (218) reached
the same conclusions, again relying heavily on micro-
scopic studies of myelin degeneration. He said,
"Histologically it is possible to trace sensory fibers
through the sympathetic system because of their rela-
tively large size." These statements were all made
before the 'C fiber days of Gasser and Erlanger,
and the conclusions reached from them require modi-
fication not only because of that work but also be-
cause of later observations in man.
To begin with the neck, we point first to Leriche
& Fontaine (168) who studied pain in 10 operations
on nine patients by faradic stimulation to the superior
cervical ganglion and to the rami communicantes
of the second and third cervical nerves. The pain
was referred mainly behind the ear and to all the
teeth in the lower jaw. Stimulus to the trunk just
below the ganglion caused pain of similar locus which
was often very intense and might even last several
days. Leriche (167) explained this on the basis of
stimulation of vasomotor fibers in the area of pain
rather than ascribing it to direct stimulation of af-
ferent fibers in the sympathetic nerves. Foerster et al.
(79, p. 147) likewise produced pain upon stimula-
tion of the cervical sympathetic trunk at every
operation thereon undertaken under local anesthe-
sia. The pain was referred somewhere to the ipsilat-
eral side of the neck or head. But they added the ob-
servation that stimulus to the caudal cut end of the
cervical sympathetic trunk likewise caused pain of
the same severity and distribution. From this they
concluded that the stimulus was indeed to afferent
fibers directly and that these were entering the spinal
cord lower down. Frazier's (82) results on stimulation
both to carotid vascular plexuses and superior
cervical ganglia were less consistent, but in three of
four patients upon stimulation at some point in the
above zones pain was described in the ipsilateral
head or neck. Peet (209) has also produced pain in
the trigeminal zone "in a number of patients" upon
electrical stimulation of the superior cervical ganglion.
To determine the mechanism of this pain Davis
& Pollock (55) carried out a series of experiments in
cats. They found no evidence of pain on stimulation
of the intact cervical sympathetic trunk, and Langley
PAIN
481
(152) and Cleveland (45) found none on stimulation
of the caudal end of this trunk after it had been cut
below the superior cervical ganglion. These represent
another instance in which studies in man yield results
relative to pain opposite to conclusions drawn from
work in animals. However, the cats of Davis &
Pollock behaved as though in pain upon stimulation
of the superior cervical ganglion rather than of the
trunk below it and they continued to do .so after: a)
all its branches were cut except those to the carotid
plexus, b) the posterior roots of the upper 12 spinal
nerves were cut and r) the trigeminal posterior root
and the upper 1 1 spinal anterior roots were cut.
Only when /) was combined with trigeminal posterior
rhizotomy were the pain responses stopped. Since
Davis & Pollock accepted the evidence of Langley
and Ranson that there are no afferent pathways in
the cervical sympathetic trunk, they explained their
findings on the basis that they were setting up efferent
sympathetic impulses. These were presumed to pro-
duce a peripheral effect which in turn stimulated the
ordinary accepted sensory pathways.
Helson (126) reported critical sen.sory measure-
ments on patients of Frazier who had undergone
trigeminal denervation of the second and third divi-
sions. He found that such patients reacted violently
if a hot cylinder was kept on the face more than a
few seconds. But in three patients in whom thoracic
sympathectomy had been added to the trigeminal
rhizotomy he could sear the skin with a hot cylinder
and evoke only a sense of pressure. Hence he agreed
with Foerster et al. Cyg) that the cervical sympathetic
nerves contain afferent fibers.
During our own stimulations of the sympathetic
nerves in the neck, pain occurred in 9 of to indi-
viduals, init it was not elicited from all portions of
the trunk or superior cervical ganglion when small
bipolar electrodes with points less than i mm apart
were used, whereas an effective stimulus (at similar
voltage) applied to almost any point on a nerve of
the cervical plexus caused pain. The details of the
respon.ses are summarized by White & Sweet (296,
pp. 84 to 89); we concluded that there must be great
variation in the distribution of pain fibers within the
cervical sympathetics in man which would account
for Frazier's vacillating opinion as to whether or not
they were present at all (82). However the appearance
of pain upon stimulus to central ends, either of cut
peripheral sympathetic branches or of cut gray rami
communicantes, made it clear that true afferent
fibers do occur in them. Activation of efferent sympa-
thetic fibers with subsequent conduction via cranial
sensory fibers in nervus trigeminus or intermedins
could be excluded as the mechanism of pain in such
instances and in another patient in whom the fifth,
seventh and eighth cranial nerves had been divided.
That the sensory inflow back to the cord is not
confined to the white rami communicantes was fur-
ther shown in fi\e other patients in our series in
whom stimulus to each member of one or more
pairs of rami elicited pain. In several of these each
end of each cut ramus was stimulated; pain was
elicited only from the end toward the spinal nerve.
The pain came immediately upon stimulation, was
obtained at about the .same threshold and had the
same reference as that from the intact ramus. One
is unable to distinguish the white from the gray
ramus in anv given pair, but our results indicate
that the pain afferents travellino with the sympathetic
are not restricted to the portals of entrance to the
central nervous system u.sed by the efferent sympa-
thetic fibers, i.e. the white rami from C8 to the upper
lumbar area. Instead pain afferents may perhaps
reach the spinal cord via any of the gray or white
rami.
The presence of many pain fibers in the cardiac
and splanchnic branches of the sympathetic trunk
has been widely demonstrated by stimulation. Can-
non (38) buried electrodes in contact with the vagus
or splanchnic nerves in cats. After the wound was
healed stimulation of the latter nerves made the
animals restless and the presence of pain was in-
ferred. Vagal stimulation caused only respiratory
effects. White et al. (295) thought they relieved
experimental cardiac pain in dogs by resection of the
upper four thoracic ganglia and Davis et a!. (54)
concluded that the pain of their animals on disten-
sion of the gall bladder was stopped by splanchnicec-
tomy. Balchum & Weaver (13) reached the same
conclusion regarding the pain of gastric distension
in the 158 dogs they studied. Leriche & Fontaine
(168) provoked pain in the heart and precordial
region by stimulation of the lower pole of the stellate
ganglion in two patients. In a third patient who had
never had angina pectoris, faradization of the stellate
ganglion seemed to bring on an intense anginal
attack. In at least three other individuals with clinical
angina an attack has been elicited during dissection
at the stellate ganglion [Jonnesco and Bouchard
cited in (168); (167, pp. 375 to 376)]. The effective-
ness of upper thoracic sympathectomy in eliminating
afferent fibers for pain from the heart is attested by
two large series of patients relie\ed thereby of severe
482
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
angina pectoris, reported by Lindgren & Olivecrona
(176), and by White & fiiand (294).
Electrical stimulation of the central end of the cut
great splanchnic nerves produced some of the more
painful experiences seen in man by Foerster (77,
p. 32). When the patient is under spinal anesthesia
pain upon splanchnic stimulation is referred some-
where in the chest above the level of analgesia,
according to Adson (3) and Leriche (166). On the
other hand, in patients in whom we have stimulated
the central stump of the greater and lesser splanchnic
nerves under local anesthesia the pain has always
been referred to the ipsilateral abdomen. Such pain
appeared at the same low threshold without delay
and was of about the same intensity as that evoked
from the twelfth intercostal nerve several centimeters
lateral to the rami communicantes (296, p. 83).
Such pain also ensued upon stimulation of the twigs
of origin of the greater and lesser splanchnic nerves
from the sympathetic trunk and from their rostral
cut ends. From all of these nerves no sensation oc-
curred upon high voltage stimulation of their caudal
cut ends.
Bilateral sympathectomy from the midthoracic
through the third lumbar ganglia and including
the splanchnic nerves from the T7 ramus to beyond
the celiac ganglion (performed for hypertension)
yielded a series of patients for study of abdominal
visceral sensation by Ray & Neill (221). They found
the pain sense absent in these patients in the stomach,
intestine (except the rectum), extrahepatic biliary
tract, pancreas, kidney and ureter. The stimuli for
pain included distension by balloons of hollow viscera,
and traction and faradic stimulation of all the
structures mentioned. Studies after unilateral sym-
pathectomy revealed a homolateral afferent supply
for kidney, ureter, the two sides of the colon and pos-
siblv the gastric mesentery; the remaining organs
had a bilateral supply. Bentley & Smithwick (22)
had shown earlier that balloon distension of the duo-
denum and jejunum was no longer painful after
thoracolumbar sympathectomy and splanchnicec-
tomy. Bentley (21) stopped the pain evoked by
transfixing an exposed duodenal ulcer with a needle
when he procainized the splanchnic nerves. Numer-
ous other animal and experimental studies confirm
that the pain afTerents from the abdominal viscera
travel with the sympathetic nerves, and a substantial
number of patients with pain arising in these viscera
have been relieved by appropriate sympathectomy
according to White & Sweet (296, pp. 652 to 676).
Gernandt & Zotterman (96) have made a con-
tribution not readily feasible in man by recording
oscilloscopically from the splanchnic nerve and from
fine strands of mesenteric nerve in the cat. Slight
pressure or touch to the small intestine gave no elec-
trical impulses but pinching the gut or the mesentery
produced delta fiber impulses conducted at up to
20 m per sec. and much slower impulses in 'C fibers
conducted at 0.5 to 2 m per sec. These authors con-
cluded that intestinal sensibility is similar to that of
skin deprived of its fast conducting afferents.
In the limbs the presence of afferent fibers in the
sympathetic supply is less consistently demonstrable
by stimulation in man, especially in the lower limb.
However Leriche & Fontaine (168), Foerster et al.
(79) and Harris (119) all record examples of pain
referred to the upper limb upon stimulus to the in-
ferior cervical or stellate ganglion. The author has
seen one patient in whom electrodes applied to the
first and second thoracic ganglia caused immediate
pain in the entire ipsilateral arm and in whom this
response recurred upon stimulation of the caudal
end of the sympathetic trunk after section below the
T2 ganglion — evidence that direct afferent fibers
were stimulated. Similar evidence for the lower limb
has been cited by Foerster et al. (79, p. 154) and by
Echlin (71). White & Sweet have never .succeeded
in evoking pain in the leg by stimulation of the lumbar
sympathetic trunk or rami. But the type of pain
known as causalgia which may follow trauma to
nerves especially in the limbs is consistently stopped
by sympathectomy. This fact is extensively docu-
mented in table XIV of White & Sweet (296, p. 369).
A possible explanation other than the elimination of
direct afferent pathways in the sympathetics has been
suggested by Doupe et al. (68), namely that at the
site of injury artificial synapses appear permitting
tonic efiferent impulses in sympathetic nerves to excite
somatic afferents for pain. If this is true the fiber
interaction phenomenon of Granit et al. (109) has
major clinical significance. Relevant also are experi-
ments of Walker & Nulsen (280). They applied a
chronic pull-out electrode to the sympathetic chain
between the T2 and T3 ganglia and divided the
trunk below this electrode in 12 patients. Onh- in the
three who had causalgia did any pain appear in the
arm and hand on stimulus postoperatively. In the.se
three there was a consistent pattern in which the
pain appeared only 4 to 20 sec. after the start of
stimulus, usually a few seconds after piloerection
over the whole upper limb. Maximal pain was not
reached for 15 to 30 sec; then, despite continuation
of the stimulus, it slowly faded and disappeared 15
483
to 30 sec. after its peak. Although the sequence of
events is too slow to suggest fiber interaction, efferent
sympathetic discharges had apparently set up pain
impulses at the periphery.
We are not aware that any observer has reported
decreased appreciation of pinprick in man after
sympathectomy, but van Harreveld & .Smith (272)
thought that extensive thoracicoabdominal sympa-
thectomy produced additional loss of pain from the
skin in seven of eight lower thoracic and upper lum-
bar segments studied in the cat. They isolated a
dermatome by cutting three spinal nerves above and
three below the one they left intact. The borders of
this dermatome as determined by the motor respon.se
to pinching proved constant. After the sympathec-
tomy there was then an added loss of .sensitivity to
pinching in a small often triangular zone at the
cranioventral side of the dermatome. They sug-
gested that these sympathetic afferents might go to
the blood vessels of the skin.
Parasympathetic Nerves
Of the cranial autonomic nerves we shall mention
only the vagus. That this carries afferent fibers from
the trachea and bronchi is suggested by the finding of
Morton et al. (193) who relieved the pain and cough
of bronchogenic carcinoma by section of the homo-
lateral vagus below its recurrent laryngeal branch.
The presence of other afferent fibers perhaps from
the thoracic esophagus is intimated by the observa-
tions of Grimson et al. (112). Their patients under
spinal anesthesia experienced 'heartburn' and pain
referred to the neck when the vagus was stimulated
three inches above the diaphragm. Stimulation at or
below the diaphragm caused no pain, so the vagi
probably carry no such fibers from the abdominal
viscera. This was also the conclusion of Cannon in
his cats (38).
The problem of pain conduction by afferent sacral
parasympathetic fibers is discussed by White &
Sweet (296, pp. 671 to 674).
On balance it is our impression that afferent fibers
for pain are to i)e found in so many of the autonomic
nerves in man that no useful purpose is served by
regarding these as comprising a purely efferent ner-
vous system, the more so since a numl:)er of the con-
siderations which led to the development of this con-
cept by Ga.skell & Langley have been shown to be
invalid.
SPIN.AL CORD
Upon entry into the spinal cord the posterior root
filaments divide into a lateral bundle of fine fibers
and a medial bundle of large fibers. The small lateral
fibers bifurcate at once into two short branches one
of which passes rostrally, the other caudally, for a
few segments in the dorsolateral fasciculus or zone of
Lissauer (marginal zone of Waldeyer). Each branch
gives off collaterals which pass into the posterior
horn, according to Bok (29, p. 534). We have re-
ferred to the work of Ranson &. Billingsley (219)
in cats which places the pain fibers in the lateral
bundle. Hyndman (132) has contended that incision
into this zone in man produces an area of analgesia
without complete loss of touch sensation. R. W. Rand,
E. J. Penka and W. E. Stern, however, made in two
patients a total of 15 electrolytic lesions in the zone
of Lissauer and were unable to detect any sensory
changes attributable thereto. They made an even
more extensive series of rostrocaudal lesions in this
zone in a monkey, 10 in number, i mm deep from
the C6 through Ti cord segments. Examination
post-mortem showed the lesions extending but little
beyond the desired zone of destruction which had
produced analgesia only of the ulnar aspect of the
ipsilateral forearm and hypalgesia of the ulnar area
of the hand. Because of the above-mentioned rostro-
caudal fanning of the fibers, it is not surprising that
an extended continuous lesion is required to produce
any demonstrable sensory loss.
The posterior root fibers terminate around : a) the
posteromarginal or perlcornual cells which lie
around the entire margin of the posterior horn, A)
the more centrally placed cells of the nucleus pro-
prius of the posterior horn and c) small cells lying
within the substantia gelatinosa which caps the nu-
cleus proprius, as shown in figure 7. Pearson (207)
from studies of his Golgi preparations of spinal
cords of human babies finds that these small cells
in the substantia gelatino.sa may intervene between
some of the primary afferent terminals and the
larger cells which lie in the nucleus proprius and in
the pericornual regions. The latter two groups of
cells give rise to the major crossed ascending af-
ferent pathways in the cord. Pearson hypothecates
that the primary afferent fibers which end directly
in relation to the.se latter cells would be likely to
give rise to 'fast pain,' whereas those cells contain-
ing a sinall intercalated neuron of the substantia
gelatinosa might be those evoking 'slow pain.'
The pericornual cells are middle-sized ganglion
484
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
FIG. 7. Termination of pain fibers of the posterior root in
human spinal cord. Large fiber A passes through the substan-
tia gelatinosa to terminate near a cell of nucleus proprius.
Small fiber C ends within substantia gelatinosa in relation to
either: a pericornual cell, a cell of nucleus proprius, or a small
cell within the substantia gelatinosa. Long axons crossing in
the anterior commissure and ascending the cord arise from the
nucleus proprius or pericornual group. [Modified from Pear-
son (207).]
cells lying in three main groups around the margin
of the posterior horn, a special group at its dorsal
tip, a reticular or lateral group adjoining the pos-
terolateral column of white matter and an inner
medial group adjoining the posterior white column.
These extend the full length of the cord, and Kuru
concludes that they give rise to the pain and tem-
perature fibers (149, pp. 10 and 11). He has studied
the retrograde cell degeneration in the posterior
horns of patients who have had anterolateral cor-
dotomy, with attention to those who have had in-
complete analgesia and thermanesthesia below the
expected level. He found a striking correlation be-
tween the segments of the cord showing chromatoly-
sis of the pericornual cells and the dermal segments
showing loss of pain and temperature sensation. The
patients in whose pericornual cells below the level
of operation he saw the greatest chromatolysis also
had the greatest degeneration in the lateral spino-
thalamic tract. The larger cells occupying the more
centrally placed nucleus proprius of the posterior
horn were not degenerated unless the anterior white
columns were cut. They did show chromatolysis,
however, in three patients whose incisions included
the anterior white matter. In the.se three patients he
traced degeneration in a distinct ventral spino-
thalamic tract, which he did not associate with loss
of pain and temperature.
Anatomical details as to the number of segments
required for crossover of the pain fibers through the
anterior commi.s.sure, the likelihood of some fiJDers
remaining uncrossed and the consistency with which
fibers from a given area of the body occupy a par-
ticular portion of the opposite anterior quadrant
of the cord are of great importance to the surgeon
seeking to relieve pain but need not engross us here.
White & Sweet (296, pp. 37 to 45) may be consulted
for details.
Although the association of pain fibers with tho.se
for temperature in the anterior white quadrant is a
close one there are a number of recorded results of
dissociation of loss of pain from that of temperature.
Analgesia to pinprick with little or no thermanes-
thesia was recorded following small, fractionally
enlarged incisions for anterolateral cordotomy by
Wilson & Fay (299) in one of two cases, by Stookey
(255) in four cases, by Grant (no) in one case and
by Foerster & Gagel (80) and Kuru (149) in 3 of 30
cases. The converse state of severe hypothermesthesia
with preservation of normal pain sense has also
been recorded by Frazier & Spiller (83) in a pa-
tient with a midcervical cord tumor. The paucity
of .such observations indicates that there usually are
not two distinct bundles of fibers for pain and tem-
perature, but the fact that such dissociation can oc-
cur suggests that individual fibers are concerned
with impulses either for pain or for temperature.
Such a thought is further intimated by the observa-
tion of Sweet (259) that bipolar electrical stimula-
tion within the anterior half of the cord in man
elicited responses purely of temperature (usually
heat) in 46 per cent of the responses in which any
subjective sensation occurred. The usual response
was one of pain with or without a burning quality
in 54 per cent of 200 stimulations
A number of factors have conspired to make
physiologic studies of pain in the central nervous
system even more difficult than those of the periph-
eral somatic and autonomic systems. As mentioned
earlier, pain pathways in the cords of animals ap-
pear to be more difTusely distributed and to ascend
by multiple relays with cro.ssing and recros.sing of
PAIN
485
fibers. Furthermore, although the experience of
pain is a more compelling usurper of conscious at-
tention and tends to evoke more obvious motor
activity than touch, pressure or the movement of a
limb, these latter stimuli are accompanied by far
more conspicuous signs of electrical activity appear-
ing at a lower threshold. This is of course due to the
fact that the latter modalities tend to traverse larger
fibers and the recorded potential is in approximately
linear relation to the diameter of the fiber, as shown
by Gasser & Grundfest (92). Hence but few workers
have carried their studies into the difiicult realm of
analysis of the smaller late potentials from noxious
stimuli.
There are several facts which indicate that pain
impulse conduction within the cord ma\' invoke
unmyelinated as well as myelinated fibers. In the
painstaking study of Haggqvist (i 14) 17,000 fibers in
a single cross section of a young woman's cord at
the T3 .segment were measured. Samples were
counted from each of the zones numbered in figure
8. Forty-two per cent of all the fibers in the whole
cross section measured 2 ixor less in diameter, whereas
in the anterolateral zones 6 and 7, the division of
which would yield contralateral analgesia, 55 per
cent and 61 per cent, respectively, of the fibers were
of this small diameter.
Most of the histologic studies of fiber tracts in-
cluding those for pain have relied on myelin or its
degeneration products, but it would be a coincidence
if the unmyelinated pain pathways were coexten-
sive with pathways we can see in such stains as the
Swank-Davenport (258) modification of the Marchi
method. And indeed we shall see that in the brain
. .y?^.
1 i M S 6 T S t t& 11 a II n IS ti 17 IS // 20 Vfi
FIG. 8. Fiber sizes in the spinal cord. Cross section at T3 segment in which Haggqvist measured
diameters of 17,000 fibers and subdivided the white matter into 14 zones on the basis of differing
constellations of fiber sizes. The histogram below and to left indicates the percentage of fibers of
each diameter in the entire hemisection. In the regions ventral and ventromedial to the anterior
horn fibers less than 2 n constitute 43 to 45 per cent of total. Since this is about the general average,
these studies give no clue that the pain fibers lying here preponderate over tiny fibers with other
functions. See te.xt for different deductions with respect to zones 6 and 7. [From Haggqvist (i 14).]
486
HANDBOOK OF PHVSIOLOGV
NEUROPHYSIOLOGY I
Stem the position of the pain pathways correlates
poorly with the position of Marchi degeneration in
spinotectal and spinothalamic fibers.
Impulses from somatic nerves were traced into
the anterolateral column of the cat's spinal cord by
Collins & Randt (49). They studied with 10 m tip
microelectrodes the responses evoked from stimula-
tion of contralateral sciatic or superficial radial
nerves, and compared these with the responses to be
seen in the ipsilateral dorsal column. Velocities of
impulses were compared for the two loci both in the
peripheral nerve and in the cord. The responses in
the anterolateral quadrant were related to the
gamma component in the nerve. In the peripheral
nerve they traveled at about 34 m per sec; in the
cord they averaged 24.9 m per sec. ranging from 19
to 33 m per sec. The dorsal column impulses while
in the peripheral nerve traveled at about 85 m per
sec. and slowed down to an average of 50.5 m per
sec. in the cord. The typical anterolateral potential
had slow rising and falling phases with superimposed
spike activity which was maximal at the peak of
the slower potential. The maximum voltages were
from 50 to 75 Mv, the total duration was 30 to 40
msec. The ratios of threshold potentials in the
anterolateral column to the dorsal column were
2.6:1 for a 5 msec, shock, corresponding closely to
the ratios of these potentials in peripheral nerve of
2.4:1. The anterolateral column potentials traverse
this portion of the cord throughout its length as
shown by their abolition in a cervical lead following
thoracic anterolateral section (which leaves intact
the cervical dorsal column potential).
Impulses from autonomic nerves were traced into
the anterolateral column of the cord of rabbits, cats
and dogs by Amassian (5). He recorded with micro-
electrodes the responses excited by stimulation of the
splanchnic nerve. When this was increased to 15 v.
with a o. I msec, shock a large fraction of 'A' gamma-
delta fibers in the nerve was excited. A barrage of
spikes could then be seen bilaterally in the antero-
lateral region of the cord clo.se to the gray matter.
Its long latency of 1 1 to 13 msec, and much greater
duration of 25 msec, distinguished it from the pos-
terior column wave. There is a striking similarity
between these potentials and those recorded after
stimulation of somatic nerves from almost the same
spots in the cord, the splanchnic responses a bit
medial to those from the somatic nerves. The high
voltage required provoked reflex movements of the
body wall, but such motor actixity did not then set
up the whole potential in the anterolateral column
because this was only partially reduced when the
movements were stopped with </-tubocurarine.
Amassian is appropriately cautious about correlat-
ing this pathway with that subserving visceral pain
in man. Both clinical and experimentally induced
pain in gastrointestinal and urinary viscera is usually
stopped in patients by anterolateral cordotomy on
the side opposite a laterally placed viscus. So the
crossover of splanchnic pain fibers appears to be
more complete in man than the fibers from which
Ama.ssian was recording. Visceral aff"erent path-
ways in the cat had already been shown to be in-
completely crossed by Spiegel & Bernis (253) who
found that stimulation of the central end of one
splanchnic nerve caused 'pain responses' until both
anterolateral columns were destroyed.
The following evidence indicates that impulses for
pain may not ascend the cord exclusively via a single
fiber running in the anterior or anterolateral white
matter to reach the brain stem, a) Vigorous stimula-
tion, as with bipolar electrodes at 100 or more v.,
consistently causes pain in an area apparently de-
nervated by full anterior quadrant section as judged
by analgesia to pinprick and to a variety of other
forms of experimentally induced pain (296, p. 45).
King's (141) careful measurements revealed that
threshold voltage values for pricking pain on the
analgesic side were only 40 to 50 per cent greater
than on the normal side. That the pain impulses are
not entering the cord at levels above the cordotomy
incision, having moved rostrally along sympathetic
pathways in the paravertebral trunks or along the
aorta, is reasonably certain because the finding is
the same following high cervical cordotomy. 6)
Direct bipolar electrical stimulation applied to the
surface of the posterior and posterolateral columns
of the cord in man causes severe tingling sensations
like an electric shock. Foerster & Gagel (80) de-
scribed such responses; we confirm that at low
thresholds (of less than o.oi v. in our hands) applica-
tion of the electrodes to the fasciculus cuneatus
causes reference to the ipsilateral leg or pelvis, and
to the fasciculus gracilis causes reference to the
ipsilateral arm. At higher thresholds one evokes
similar responses contralaterally from the surface of
the posterolateral column of white matter. That
such pathways are rarely used in pain of clinical
cause is clear from the high percentage of patients
relieved of pain by anterior quadrant section. Pos-
sibly these observations have in fact no physiologic
significance, and electrical stimulus to the exposed
spinal cord may be a condition for which there is no
PAIN
487
physiopathologic counterpart. <) That the dorsal
columns may, however, even if only rarely, carry
impulses causing clinical pain seems a tenable hy-
pothesis from the results of Browder & Gallagher
(35). Their operative division of the dorsal column
relieved, in three of four patients, pain referred to a
phantom lower limb which seemed to be in a dis-
torted posture. Moreover, tingling sensations per-
haps like those evoked on posterior column stimula-
tion may occur in the analgesic limb after cordotomy
upon an unusually no.xious event, such as running
a nail into the foot.
.MEDULLA OBLONGATA
The primary afferent neurons for pain and tem-
perature arising from the face and head via tri-
geminal, nervus intermedius, glossopharyngeal and
vagal routes collect in the descending or spinal
trigeminal tract and terminate near cells in the
lower part of the nucleus of that tract. The cells in
this position extending froin about the obex down-
ward were called by Winkler the nucleus gelatinosus
tractus spinalis (302, pp. 51 to 59) because they
resemble those of the substantia gelatinosa Rolandi
of the spinal cord. Olszewski's (202^ more recent
careful study of the nucleus in man and monkev is
in general agreement. Section of the descending
tract at about the level of the obex usually produces
trigeminal analgesia as well as severe hypalgesia of
the deeper areas of the face and head supplied by
the afferent fibers in the seventh, ninth and tenth
cranial nerves; so the correlation of the 'subnucleus
gelatinosus' of Olszewski with pain and temperature
function seems likely. Evidence on these points as
well as on the finer details of topographic localization
of the fibers from various portions of the head and
face within the tract and their termination in the
nucelus are summarized by White & Sweet (296, pp.
457 to 466).
The locus of spinothalamic fibers ascending from
the secondary afferent neinons of the cord as de-
termined by Marchi stain is illustrated in figure 9.
4lh Ventricle
Bulbo-
T ha 1 om I
Troct
Spinocerebellar
Troct
Lot erol
Spi notholo mic
Troct
Mediol Lcnniicoi
nttrior Oliv*
FIG. 9. Degeneration in the spinothalamic and bulbothalamic tracts at level of the inferior olive.
The Marchi degeneration in the lateral spinothalamic tract (including spinotectal fibers) is that
seen by Kuru in a patient all of whose pain fibers in the anterior half of the cord below C4 segment
had degenerated. We show the locus of the bulbothalamic tract as that area of absence of Weigert-
stained fibers described by Wallenberg in a patient who had post-mortem a softening in the ventral
two-thirds of the descending trigeminal tract and its nucleus. The ictus had occurred 5 years earlier;
the infarct it produced was of maximal size at the level of the obex, i.e. about the rostral end of the
nucleus for pain fibers. We have referred to the secondary afferent pathway from this area as the
bulbothalamic rather than trigeminothalamic tract since it probably includes the area of nervus
intermedius, glossopharyngcus and vagus as well as trigeminus. [Modified from Kuru (149).]
488
HANDBOOK OF PHYS!OL(jnV
NEUROPHYSIOLOGY
The figures of other workers, such as Goldstein (103),
Foerster Sc Gagel (80, p. 24), Walker (276), Rasmus-
sen & Peyton (220), Gardner & Cuneo (87) and
Poirier & Bertrand (213), are in general agreement.
Although such degeneration has provided a subpial
signpost to the localization of the pain fibers, it has
failed utterly to intimate their full extent. This was
first shown by clinical plus post-mortem studies of
the lesions after thrombosis of vessels supplying the
bulbar brain stem. These deductions were fully
confirmed by the pioneering surgical work in man of
Schwartz & O'Leary (242, 243^, and of White (293)
and by subsequent surgeons, Crawford (50) and
D'Errico (64). Findings with respect to pain pro-
voked by stimulation at operation were checked
against depth of incision, postoperative analgesia
and, at times, later post-mortem studies. These show
that the pain fibers coming up from the cord occupy
a much wider area just dorsal to the inferior olives
extending 6 to 7 mm deep and continuing medially
in the midst of the bulbar reticular formation nearly
to the medial lemniscus. The quintoth^lamic or
secondary afferent trigeminal fibers tend to lie in
the more medial part of this area and to extend more
dorsally as well (D'Errico). McKinley & Magoun
(186) have shown from depth recording of action
potentials in cats that there is indiscriminate mixing
of the fibers from the three trigeminal divisions in
this area, whereas the grouping of fibers related to
trigeminal peripheral divisions is clearer in the de-
scending trigeminal tract and nucleus, as shown by
McKinley & Magoun (186) and Harrison & Corbin
(120). Subsequent work in man has also shown that
a discernible tendency to layering in the cord of
the fibers from specific sections of the body becomes
less consistent in the medulla.
More work is especially necessary on the course
of pain fibers from face and head once thev start
up the brain stem There is some evidence from
Wallenberg (281) that these fibers separate into
two deep bundles as they move rostralh'. To the
illustration from Kuru (fig, g) has been added an
indication of Wallenberg's notion of the location of
the.se secondary fibers from the face at the mid-
bulbar level.
Numerous fibers ascending from the cord move
medially to terminate in the reticular formation of
pons and medulla; their possible significance will i^e
considered in the next section.
MESENCEPH.\LON
In the upper pons and midbrain pain fibers again
become more superficial and hence more accessible
to special analysis and surgical section in animals
and man. Here their precise extent and location is
less well-known than in the cord and medulla be-
cause of the smaller numbers of studies. In general,
the fibers occupy a zone extending dorsallv and
medially for about i cm from the lateral messn-
cephalic sulcus. One example will suffice to indicate
some of the unresol\-ed discrepancies. Walker (278),
the major pioneer in this field, following a trigeminal
lesion in the monkey places the Marchi degenera-
tion in the lower midluain in a narrow zone 1 to 2
mm deep beginning right at the surface and ex-
tending dorsally a few millimeters from the lateral
mesencephalic sulcus (fig. 10). Wallenberg (281)
and van Gehuchten (271) working with the same
method in raijbits found the degeneration exclu-
sively in a much more medial position, and Wallen-
berg confirmed his impression in studies of degenera-
tion in a patient (281). Moreover the spinothalamic
tract demonstrable in Marchi stains at the level of
the superior coUiculus in man has dwindled to a
tiny bundle. Having identified the bundle in Marchi
stains, Glees & Bailey (99) then counted the fibers
in this region in normal Weigert preparations; they
found onl\ aijout 1500 fibers. Of these two-thirds
were 2 to 4 yu in diameter; most of the remainder
measured about 4 to 6 /x; they were all in a small
compact group only aijout 0.65 mm- in cross-sec-
tion.
However, figure 10 also illustrates the area of
surgical destruction in the largest lesion figured by
Walker (278) which did not produce complete
analgesia on the opposite face and lower limb (al-
though it did on the torso and upper limb). Yet the
lesion essentially blankets all of the variously de-
scribed zones of niNelin degeneration. It is again
apparent that we need to know more about the
unmyelinated fibers and perhaps about the role of
relays of neurons in conduction of pain impulses.
The marked decrease in size at the upper mid-
brain of the Marchi-stained ascending afferent
bundle following extensive cordotomy has long
been shown to be due to departure from it of ventral
spinocerebellar, spinoreticular and spinotectal fibers.
The earlier descriptions, such as those of Foerster &
Gagel (80), were confirmed by Morin el al. (190)
who were the first to suggest that the spinoreticular
PAIN 489
Beginning of Brochium
of Inf. Coliiculus
Lot. Sp
Nucleus of Inf. Coliiculus
FIG. I o. Pain pathways in the mesencephalon. On the left side are shown : the lateral spinotlialamic
(inchiding spinotectal) tracts as seen in Marchi degeneration after thoracic cordotomy in man by
Rasmussen & Peyton (220), Gardner & Cuneo (87) and Glees C98); and the bulbothalamic tract
as seen by absence of Weigert stained fibers seen following infarct by Wallenberg (281, legend to
fig. 1 2). On the right side are shown, diagonal hatching, secondary afferent pathways in monkey as
seen in Marchi degeneration : the upper medial area after mid-line myelotomy at L5 to 7 ; the lower
lateral area after lesion in spinal trigeminal nucleus according to Walker (278). Crosshatching: Lesion
in man which produced contralaterally a severe hypalgesia to pin prick on face, analgesia on upper
limb and torso and hyperpathia on lower limb (277).
component might influence the perception of pain by
effecting changes in cortical excitabiUty via the
reticular formation. Moruzzi & Magoun (194) had
shortly before demonstrated the widespread cortical
activation from electrical stiinulation in the ventro-
medial bulbar reticular formation. Now that stains
for axonal degeneration are available Mehler el al.
(188) have shown in monkeys, following antero-
lateral cordotomy, that there is indeed "a massive
fine-fibered, diffuse, medial spinoreticular system"
passing to 1 1 of the nuclei in the pontobulbar reticu-
lar formation. They also saw in the midijrain fine
spinotectal fibers passing to the lateral part of the
central gray inatter, the nucleus intcrcoUicularis and
deep strata of the superior coliiculus. Bowsher (31)
studied four patients following thoracic, cervical or
bulbar division of pain pathways using the silver
stains for axonal degeneration either of Glees (97)
or of Nauta & Gygax (199). His results show a strik-
ing similarity to those of the previous authors in
monkeys.
Perhaps these spinotectal fibers, or bulbothalamic
continuation paths from spinoreticular fibers, are
responsible for a sharp spike potential found in the
medial inidbrain by Collins & O'Leary (48). When
they stimulated the sciatic or superficial radial nerve
in cats, they evoked the potential in a discrete region
of the reticular substance dorsal to the rostral part
of the red nucleus and lateral to the oculomotor
nucleus. A relationship to pain was intimated by
these facts: a) the potential was activated from
peripheral axons of the gamma-delta group, the
fastest of which were conducting at 45 m per sec. ;
A) its pathway was principally \'ia the ventrolateral
490
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
sector of the cord contralateral to the nerves; c) it
was increased in amplitude by such painful maneu-
vers as spinal root manipulation; and a') it was
promptly depressed by a deepening of anesthesia
toward a surgical level.
By his special technique of stimulation Delgado
(62) has also obtained in monkeys evidence that the
inferomedial part of the mesencephalic central gray
matter is concerned with pain. The lateral part of
the mesencephalic tegmentum in the region occupied
by the spinothalamic tract and trigeminal lemniscus
has yielded similar responses. Delgado has im-
planted tiny multilead electrodes and then stimu-
lated via external leads from these after the wound
is closed and the animal is relatively free to move
about. At the aforementioned points stimulation
evokes the same sort of complex response that the
normal monkey makes to a peripheral annoyance
such as pinching his tail. Moreover in monkeys in
which such responses had been elicited electrically
the animal developed "conditioned anxiety,' i.e. as
soon as placed on the stimulation stage he screeched,
bit and tried to escape. This did not happen in mon-
keys in which purely somatic motor or autonomic
effects had been elicited. Hence Delgado assumed
that the sensations evoked from the mesencephalic
zones were painful and were remembered.
The possible significance of these pathways may
be considered in relation to curious sensory changes
which rarely appear following thoracic or cervical
cordotomy, perhaps more often after bulbar spino-
thalamic tractotomy for pain and in many patients
after mesencephalic tractotomy. Dogliotti (67), the
first surgeon to divide pain pathways in the mid-
brain, reported that his three surviving patients had
"diffused disagreeable sensations" in the half of the
body contralateral to the incision. As described by
Drake & McKenzie (69), in all six of their patients
after the operation in the midbrain there was anal-
gesia and thermanesthesia throughout the opposite
side of the body and head for 3 to 15 days after
operation. Then pinprick, deep pressure or thermal
stimuli in all six patients and even light touch in
one of them caused deep diffuse poorly-localized
agonizing pain with strong withdrawal and grimac-
ing. In three of the patients there was spontaneous
burning pain in some part of the formerly analgesic
area. Drake suggests that the impulses causing these
pains traverse a secondary route via relay in the
reticular formation which is not cut by the incision
in the midbrain. Walker (279) had already noted
"the diffuse, disagreeable sensation which may be
elicited by cold, extreme heat or pinprick, especially
by repeated stimulation" in some of his patients
after mesencephalic tractotomy. He suggested that
spinotectal tracts may be carrying such painful
impulses to higher centers. Bowsher (31) also pointed
out that bulbothalamic and tegmentothalamic tracts
running in the reticular formation are separate from
direct spinothalamic fibers between the level of the
inferior olive and the thalamus. He suggests that the
direct spinothalamic system transmits impulses for
pain which is felt at once, is sharply localized and
does not outlast the stimulus. He attributes to the
medially placed .spinoreticulothalamic system the
diffuse poorly-localized pain with an appreciably
slower conduction time which does outlast the stimu-
lus. Since mesencephalic incisions in man have
missed these fibers, this explanation would account
for the type of persistent pain shown by such patients.
One further observation of Drake & McKenzie
also fits in with this concept. One of their patients
preoperatively had had severe pain in the face.
Mesencephalic tractotomy replaced the original
pain by a diffuse facial burning sensation. Division
of all of the primary pain pathways from the face
by bulbar trigeminal tractotomy then gave complete
relief — perhaps because reticulothalamic pathways
could no longer be activated.
TH.'^L.AMUS
The fibers for touch and proprioception in the
medial lemnisci mix with those for pain and tem-
perature as they all terminate at the thalamic level.
In man when vascular lesions destroy the nucleus
ventralis posterolateralis severe sensory loss is found
in the contralateral limbs and trunk; the facial
fibers terminate in the nucleus ventralis postero-
medialis (200, 229}. These inferences from human
material have been confirmed and extended by the
more critical studies on Marchi material in lower
primates carried out by Clark (43) and Walker
(275, pp. 63 to 93). Moreover Walker's (275, p.
1 72) observations using the same technique have
revealed that these same thalamic nuclei project in
corresponding fashion to the postcentral gyrus of
the same cerebral hemisphere. The nucleus ventralis
posteromedialis sends fibers to the lowest or facial
sector of the postcentral gyrus, and the most lateral
parts of the nucleus ventralis posterior project to the
superior part of the gyrus.
Foerster & Gagel (80), Rasmussen & Peyton
491
(220} as well as Gardner & Cuneo (87) have been
able to follow only a few degenerating spinothalamic
fibers beyond the midbrain and into the thalamic
nucleus ventralis posterolateralis after thoracic
cordotomy in man. By the same Marchi method
Glees (98) insists that the degeneration after such an
operation is not in the posteroventral portion of the
lateral nucleus but dorsal to it; he sees the terminat-
ing fibers lying close to the nucleus lateralis posterior.
Using stains for a.xonal degeneration Mehler (187)
has found that true spinothalamic fibers to the nu-
cleus ventralis posterolateralis constitute 30 per cent
of the ascending afferent fibers in the chimpanzee.
Moreover he also saw terminations in these thalamic
nuclei : parafascicularis, paracentralis and the small-
celled component of the nucleus centralis lateralis.
Bowsher (31) studying four patients following
thoracic, cervical or bulbar spinothalamic tractotomy
by either the a.xonal degeneration stain of Glees or
that of Nauta found 'a large amount of degenera-
tion' in the nucleus ventralis posterolateralis on the
side of the surgical lesion as well as a little in the
same nucleus on the other side. The fibers reach the
contralateral thalamus by way of the dorsal part of
the posterior commissure. Moreover Bowsher found
terminations in the relatively large nucleus centrum
medianum of man not hitherto described even in
lower primates. He also saw a few degenerating fibers
in the rostral part of the thalamic reticular nucleus.
Although there are numerous careful studies of
thalamic action potentials evoked by electrical
stimulation of afferent nerves these have been cor-
related mainly with touch and have dealt largely
with the potentials conducted by the fastest fibers
presumably related to touch or proprioception.
However Gaze & Gordon (93, 94) recorded simul-
taneously the electrical activity of single neural
units in the thalamus and the compoimd action po-
tential from the saphenous nerve after stimulation
of this uncut nerve in the cat and monkey. Having
found an active thalamic unit, the investigators
then sought to determine the form of cutaneous
stimulus which would cause it to fire. The units
responding to electrical stimulus of alpha, beta or
gamma saphenous nerve fibers usually responded
also to light touch. Only a few of them required
strong mechanical stimuli. These comprised 80 per
cent of the total of 63 thalamic units found, whereas
only I 7 per cent responded to the stronger electrical
stimulus required to activate saphenous delta fibers.
Six-sevenths of these required stronger stimuli like
squeezing, pinching, tapping or pricking to activate
them. Three units were found which responded to
stimulation of saphenous 'C fibers, but the cutane-
ous stimulus which would fire them was not identi-
fied. The mean latencies — knee to thalamus — were
23, 47 and 630 msec., respectively, for the three
groups. Some representation ipsilateral as well as
that contralateral to the stimulated nerve was found
in the monkey thalamus. There was no anatomical
segregation among the different types of unit de-
scribed and there was likewise a huge overlap be-
tween regions for face, forelimb and hindlimb both
in cat and monkey, responses from the face even
being obtained in the leg area. Upon subtraction of
the peripheral conduction time from the total la-
tency one obtained a central conduction time in-
cluding synaptic dela\' averaging 15 m per sec. for
the alpha, beta, gamma group, 7.9 m per sec. for the
delta groups and 0.66 m per sec. for C fibers.
Dclgado's (62) monkeys with chronic implanted
electrodes also exhibited behavior suggesting pain
when the thalamic nucleus ventralis posterior was
stimulated. However, electrical stimulation within
the thalamus of conscious man as reported by
Talairach et al. (260) and by Hecaen et al. (124) did
not cause actual pain, although the centrum me-
dianum, the nucleus ventralis posteromedialis and the
nucleus medialis dorsalis were the presumed sites of
stimulation in five of their patients. Nevertheless the
making of electrical lesions mainly in the region of
the centrum medianum caused hypalgesia to anal-
gesia over varying extents of the contralateral half
of head, limbs or torso along with reduction or
elimination of the clinical complaint of contralateral
pain. In agreement with the observations that the
medial lemniscus terminates close to this area there
were in these patients also varying degrees of contra-
lateral loss of touch, position and vibratory sen.se
and stereognosis.
Following thrombosis of the thalamogeniculate
artery in man there is typically an extensive de-
struction of the posterior part of the lateral nuclear
mass of the thalamus which contains the nuclei
receiving fibers from the general afferent systems and
projects to the postcentral gyrus of the cerebral
cortex. This lesion produces among other signs a
transitory complete contralateral hemianalgesia as
part of the classical thalamic syndrome of Dejerine
& Roussy (61). This sign soon gives way to painful
sensations upon noxious stimulation; later these
occur upon milder stimulation such as touch, vibra-
tion, pressure or sound; and finally there may ap-
pear a state of spontaneous, constant or paroxysmal
492
HANDBOOK OF PHYSIOLOGY
NEITROPHVSIOLOGY I
pain on the affected side which no longer requires a
discrete external stimulus for its appearance. The
unpleasant sensations, often worse than those after
the operation of mesencephalic tractotomy a) are
diffuse and peculiarly disagreeable, h} come on only
after a latent period of i or more sec, c) are localized
with gross errors, (f) may appear only at a high
threshold and i) persist after the stimulus is removed.
It is not yet known whether permanent hemianal-
gesia is produced by a sutliciently massi\e lesion to
destroy all of the presently described thalamic nu-
clei of termination of somatic and visceral afferent
pathways. From many of the published descriptions
one cannot l)e certain that even the whole nucleus
ventralis posterior has been destroyed. Walker's
careful report illustrates preservation of some of
the nucleus ventralis posterolateralis in his patient
(279, p. 81). Nor do we know if a complete lesion
would preclude the appearance of the frightful con-
tralateral dysesthesias and pain of the thalamic
syndrome. Now that many more nuclei of termina-
tion for spinothalamic fibers have been found in
man by Bowsher it .seems even more likely that the
thalamic lesions recorded to date leave intact por-
tions of the pain pathways. Their relation to the
distortion of pain sensation remains to be elucidated.
CEREBR.AL HE.MISPHERES
The parts of the cerebrum known to be concerned
with pain have been established by a variety of con-
trived and spontaneous irritations and destructions.
Stinndatidn
Foerster (77, pp. 141 to 144), one of the early
workers to explore extensively in man the responses
to electrical stimulation of the cerebral cortex, found
the usual response from the postcentral gyrus or
superior parietal lobule to consist of contralateral
paresthesias, occasionally so strong as to be painful.
The sensations were referred to a comparativelv
small area of the body on stimulus to the postcentral
gyrus, whereas from the less excitable superior
parietal lobule a response when obtained was re-
ferred "more or less to the entire half of the body."
Although the majority of the responses are referred
to or near the body surface, visceral pain is also
represented in the postcentral gyrus. 'Cardiac pain'
and severe abdominal pain have been reported when
areas for the upper and lower trunk respectively
were stimulated (78, p. 363). The response inay be
complex, especiallv when a lesion affects the stimu-
lated area. As a part of one such long complicated
response to stimulation of the postcentral gvrus,
Krause and Schum (78, p. 363) provoked frightful
pain referred ipsilaterally to an upper liinb.
Penfield and his associates have given us the most
complete maps of cerebral localization based on the
technique of cortical stimulation. Penfield & Boldrey
(210) found that such stimulus of the cerebral surface
rarely causes frank pain, in fact in only 1 i out of 462
responses. But nearly half of the reports were of
'tinglins;' or 'electricity,' which at least raises the
question of activity in pain pathways. The great
majority of the points on the superolateral surface of
the hemisphere from which a stimulus elicited sensa-
tion are in the postcentral gyrus, but many are in
the precentral gyrus, and a few lie anterior or pos-
terior to these two gyri. Penfield & Boldrey obtained
no ipsilateral .sensory responses but the reference was
at times bilateral for the face, tongue and eyes.
Bilateral pressure sensations encircling the torso
were noted by Foerster.
In the subcortical white matter the limited ex-
plorations thus far carried out have yielded to
Hecaen et al. (124) an area in the parietal lobe deep
to the gyrus cinguli in which weak electrical stimuli
provoked violent localized lightning-like pain.
Patients with severe pain elsewhere in the body,
upon cortical stimulation, seem especially prone to
feel pain often akin to the clinical complaint. Thus
Horrax (129) elicited pain upon strong electrical
stimulation of the postcentral gyrus in three of four
patients suffering from painful states. Erickson et al.
(74) recorded similar results in three of five patients
afflicted with either a painful phantom limb or the
syndrome of thalamic pain. Both patients with pain
probleins described by White & Sweet (296, pp. 334
to 337 and p. 413) had pain upon stimulation of the
postcentral gyrus, and in one case even more severe
pain occurred upon stimulation of the precentral
gyrus. This patient's spontaneous pain in each
phantom finger was stopped dramatically as the
appropriate area of the postcentral gyrus was in-
jected subpially with procaine. Lewin & Phillips
(169) reproduced preoperative pain — either a part
of an epileptic seizure or a painful phantom — upon
stimulation of the postcentral gvrus in three of three
patients and secured relief by removal of this area
of the cortex.
Cortical and subcortical lesions have also pro-
vided irritative foci giving rise to pain, a) as an aura
PAIN
493
to or part of a focal seizure; A) as a more continuous
pain; or c) as a dysesthesia appearing only when the
surface of the body was stimulated. Michelsen (189)
reviews earlier reports and adds five new cases of
his own. Paroxysmal abdominal pain as a form of
epilepsy has now been reported in several series of
patients. O'Brien & Goldensohn (201) summarize
the earlier work and add their own observations
which indicate that in at least some of these patients
organic cerebral lesions cause attacks of pain pri-
marily referred to the abdomen, whereas in other
patients the pain is secondary to abnormal gastroin-
testinal motility.
Lesions
Destruction of appropriate cortex and subcortical
white matter may also cause hypalgesia, rarely
analgesia. One of the early reports implicating the
cerebral cortex with pain perception is Dejerine &
Mouzon's (60) account in 191 5 of a war casualty
whose small cortical wound produced loss of pain
sensibility in the contralateral arm. Kleist (14J, pp.
426 to 428) collected 24 patients wounded in World
War I in whom a localized parietal lesion brought
about disturbances mainly in pain and thermal
senses. In eight of these, hypalgesia was the only
sensory loss. He noted analgesia changing dining
convalescence at times to an abnormally increased
appreciation of stimuli, a hyperpathia. He ventured
without confirmation post-mortem a precise place-
ment of the cortical area for pain and temperature
sensations in the posterior bank of the central fis-
sure— in Brodmann's narrow fields 3a and 3b.
Russell (233) after a study of men wounded in
World War H reached essentially identical conclu-
sions on all of the above .scores. Davison & Schick
(57) have also described two patients with hyper-
pathia combined with hypalgesia in whom autopsy
revealed only cortical and subcortical lesions, com-
pletely sparing the thalamus.
Foerster (78, p. 146) pointed out that the sub-
normality in pain sensation after removal of the post-
central gyral representation for a limb soon returns
virtually to normal; but subtle changes such as a
reduction in the number of pain points or an increase
in their threshold persisted for years in seven patients
studied by Kroll (147). As early as 1909 Horsley
(130) had noted that even after removal of the
'whole arm centre' in both precentral and postcen-
tral gyri the pain sensation was 'notably diminished'
though not abolished. Marshall (184) ably sum-
marizes the earlier work and adds studies on 12 more
war-injured patients examined 5 to 34 years after-
ward. In some area contralateral to a shallow cere-
bral wound, all experienced slight or no pain when
tested both with a heavy pin jab and by injection of
0.2 cc of 6 per cent sodium chloride into the muscles
in an effort to provoke deep pain. He showed clearly
the possibility of protracted focal severe disturbance
of appreciation of pain from such lesions. Both he
and Russell have commented on the anomalous
situation that an extensive cortical injury may leave
pain sensibilit\- intact, whereas a small cortical wound
in part of the same area in another patient mav pro-
duce hypalgesia.
That a massive area of the cerebral cortex may in
some way be associated with irritating sensation was
shown by Dusser de Barenne and his collaborators
(70) in experiments in lower primates. For example
when they applied strychnine locally over a few
square millimeters of the cortex anywhere over about
the posterior half of the frontal lobe or the anterior
three-quarters of the parietal lobe of the chimpan-
zee, they set up a diffuse irritation in face, arms or
legs, depending on the area of cortex to which the
drug was applied. The animal licked or scratched
the skin of the zones concerned for about 30 min.
more vigorously contralateral than ipsilateral to the
side of the placement of the drug. The electrocortico-
gram showed "strychnine spikes' within this extensive
sensory region, according to Bailey et al. (12).
The ipsilateral cerebral representation of pain
intimated lay these studies is further suggested bv
the.se facts. Total hemispherectomy in man does not
produce complete contralateral analgesia, but such a
degree of cortical removal in the macaque and
chimpanzee provokes almost complete degeneration
in every thalamic nucleus except those in the medul-
lary laminae which do not project to the cerebral
cortex (279). This leaves the ipsilateral thalamus and
cerebral cortex as the most likely sites mediating
pain perception following hemispherectom\-. Some
individuals, e.g. Evans' patient reported by Walker
(279), show but little disturbance of appreciation of
pinprick anywhere except for some delay in response,
whereas in two patients of Dandy (52) there was
said to be loss of all contralateral cutaneous sensation
below the face with a varying but lesser lo.ss in the
face. Gardner et al. (88) have recently given a resume
of the findings in their own and the earlier reported
cases. They found a striking and constant retention
of all modalities of sensation in the trigeminal area
both in patients whose operation was for infantile
494
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY 1
hemiplegia and in those who had tumors. This ex-
tensive bilateral cortical representation for facial
sensation including pain is consonant with the well-
known similar motor representation. On the average
the tumor patients showed the greater deficit, the
lesion having been present a shorter time in a more
adult brain. The contralateral parts showed an im-
pairment of appreciation and localization of a sharp
point, which increased progres><i\ely in the following
sequence: face, trunk, thigh, upper arm, leg, fore-
arm, foot and hand. A delay in the appreciation of
all stimuli on the paralyzed side was short in the
trigeminal area and longest in the distal parts of
the limbs. Pain elicited from the abnormal side was
more disagreeable than that from the normal side.
Cold and hot stimuli were painful and could not be
differentiated. When a pin was applied simultane-
ously to similar sites on the two sides, there was
consistent extinction only below the elbow and knee
on the paretic side.
Evoked Potentials
The somatic sensory areas I and II of the cerebral
cortex of many mammals including monkeys have
been outlined on the Ijasis of cortical electrical
potentials evoked by tactile stimuli to the body
surface (311). There has i^een very little work to
determine in animals the cerebral representation for
painful stimuli; but in continuation of our assump-
tion that 'A' gamma-delta impulses may be asso-
ciated with pain, we shall summarize the work of
Amassian (5, 6) on the cortical respon.ses evoked
from such fibers in the splanchnic nerves of car-
nivores. From tiny areas on the cortex at the junction
of leg and arm representation in both sen.sory areas
I and II in the dog and cat, he found brief initially
surface-positive waves. These were obtained from
both sensory areas contralaterally and from the
ipsilateral area II in the cat when only splanchnic
'A' beta fibers were excited, as shown in figure 11.
At much higher voltage, when 'A' gamma-delta
activation was also visible in the record from the
splanchnic nerve, a small deflection appeared on the
returning limb of the primary response in area I
as the only early cortical evidence of presumed
activity of pain fibers. There was no change in the
primary response from area II. Activation of the
gamma-delta fibers also evoked a late secondary
response generalized over the cortex. In the monkey,
Ruch et al. (232) were able to find a splanchnic
representation only in cortical area I.
0.13v.
3.8 V.
FIG. 1 1 . Splanchnic A gamma-delta fibers and cerebral
evoked potentials. Stimulating electrodes on splanchnic nerve
distally. Upper records obtained with stimulus 0.13 v.; there is a
maximal primary response from cortical area 1 Qupper /efl~) with
no A gamma-delta discharge on the neurogram of the sym-
pathetic trunk O'Pper right^. Lower records obtained with stim-
ulus 3.8 V. and pulse duration i msec, the A gamma-delta
group is active (^second wave, lower right'), but the only cortical
correlate therewith is a small deflection on the returning limb
of the primary response (lower lejl). [From Amassian (5).]
A somewhat similar type of study has been carried
out in the cat by Mountcastle et al. (196) working
with nerves to muscle. They monitored oscilloscopi-
cally the ventral root instead of the stimulated
exposed nerve and took as evidence of excitation of
the Group III fibers, i.e. "the delta pile,' the ap-
pearance of a late polysynaptic spinal cord reflex in
the ventral roots. Only at stimuli .sufficiently intense
to excite these fibers did they evoke potentials in
the contralateral cerebral cortex. Responses were
seen in both somatic areas I and II; they were of
higher amplitude in area II. Their latency at 18 to
19 msec, was about twice that of cortical potentials
seen upon stimulation of adjacent cutaneous nerves.
Because the small myelinated fibers in these muscle
nerves are from i to 8 /x in diameter and conduct
up to 40 m per sec, it was thought that their im-
pulses might include some of nociceptive character.
Second Sensory Area in Man
Penfield & Rasmussen (211) have shown in man
that sensation can be evoked from the secondary
sensory area at the lowest part of the postcentral
gyrus extending into the superior lip of the Sylvian
fissure to include part of the parietal operculum.
PAIN
495
Only a few of the reported sensations ha\e been de-
scribed as 'pricking.' However, Biemond (25) has
described a remarkable case in which a complex of
small confluent foci of softening was found in the
cortex and white matter of the right parietal opercu-
lum (see fig. 1 2) and in the cortex of the insula. This
lesion had been as.sociated with severe hypalgesia
over the entire left half of the body, as well as with
a constant deep 'drilling' pain throughout this area
worsened by any local stimulus. The senses of touch,
proprioception, attitude, stereognosis, vibration,
graphesthesia and discrimination were all intact ! In
figure 12 one sees also retrograde degeneration of a
fiber bundle passing into the posteroventral nucleus
of the thalamus where a marked cellular loss had
occurred. This loss was worse in the caudal portion
of the nucleus in which the spinothalamic fibers
principally terminate. He also reports two other
less striking but similar patients in whom the findings
in life and at autopsy also suggest that the second
sensory area is related to the 'conscious pain sensa-
tion.'
A review of the earlier literature discloses that the
lesion in Davison & Schick's (57) case 10 was largely
in the second sensory area but with involvement also
of the superior temporal and insular cortex. The
sensory findings, similar regarding pain to those in
Biemond's (25) case i, included spontaneous and
touch-evoked pains — although in this patient touch,
vibration and stereognosis were impaired also. This
case report, made before Adrian had described the
second sensory area, may in retrospect be taken as
confirmation of such an area in man and as adding
evidence that it is especially concerned with the
sense of pain.
NUCLEUS LATERALIS
THALAMI
NUCLEUS MEDIALIS
THALAMI
NUCLEUS CENTRUM
MEDIANUM
NUCLEUS VENTRALIS
POSTEROMEDIALIS AND
POSTEROLATERALIS
_____CORPUS GENICULATUM
MEDIALE
CORPUS GENICULATUM
LATERALS
FIG. 12. Pain and the second sensory area in man. Fine diagonal hatching: areas of softening in the
parietal operculum and cortex of insula; these extended in varying degree from (he corona] plane
of the anterior commissure in front to that of the lateral geniculate body behind Heavy diagonal
hatching: retrograde degeneration of fiber bundle as seen in Weigert-Pal stain for myelin, passing
into posteroventral nucleus of thalamus via posterior part of internal capsule. Heavy dots: marked
cellular loss in nucleus ventralis posteromedialis and posterolateralis, especially in caudal portion
01 nucleus. [Based on data from Biemond (25).]
496
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
Remtton to Pain
The complexities of the cerebral mechanisms re-
sponsible finalK for normal appreciation of and reac-
tion to pain are at present lara;ely beyond our
knowledge.
Using the radiant heat method of Hardy et ai
(115), Chapman (39) studied thresholds to 'pain
perception,' i.e. the subjective end point signalled by
the patient; and to 'pain reaction,' the first objective
evidence of withdrawal, such as wincing, seen by the
examiner. He found that a group of psychoneurotic
patients, while presenting abnormal pain perception,
showed an abnormally low threshold for pain reaction.
INDIFFERENCE TO p.AiN. The Contrary state, indif-
ference to pain, has been seen temporarily in periods
of severe emotional stress or in hypnosis, or over longer
periods of time in hysteria, psychosis and posten-
cephalitic states, and in mental defectives. In the
latter two groups no eflTort has been made to correlate
any particular lesions of the brain with this s\ mptom.
An extraordinary and rare phenomenon, described
as 'a congenital insensiti\ity to pain' of many types,
may occur in people otherwise apparently nearly
normal. A detailed perusal of the case reports is re-
quired to appreciate the severity and \ariety of the
injuries and noxious stimuli which such indi\iduals
have repeatedly sustained without pain (32, 51, 59,
81, 136, 148, 224, 236). Seven other case reports
are cited by Madonick (182), although his own case,
I think, belongs in the mental defective group men-
tioned above. A feature common to nearlv all of these
indi\iduals has been their ability to distinguish with
fair or great accuracy between the point and head of
a pin or between slight differences of temperature.
Yet they are indifferent to violent jaijs and extremes
of temperature and their utter lack of suffering is
their striking characteristic. Boyd & Nie's (32) phrase
"congenital universal indifference to pain" more
clearly indicates the person's beha\ior and that
the abnormality is central rather than peripheral. A
number of them do experience discomfort upon cu-
taneous electrical stimulation at high levels, morbid
distension of viscera, or other extreme noxa. The
brain of no such person has yet been studied histo-
logically, but the occurrence of various types of
seizures or minor mental defect in several of them
intimate that an organic lesion is present.
PAIN ASYMBOLIA. A State with slight similarity to the
foregoing has been described by Schilder & Stengel
(239) as 'pain asymbolia,' the situation in which there
is "no analgesia in the common sen.se, but the psvchic
reaction to the sensation is absent." They (240) have
observed this symptom in 10 patients with acquired
organic cerebral disease and ha\e implicated the
anterior part of the lower part of the dominant
parietal lobe. Autopsies on three of the patients
showed \'arious lesions of which the\- thought the
common denominator was involvement of the supra-
marginal gyrus. However in these patients there was
a concomitant sensory aphasia which made appraisal
difficult, and at least in soine of them there was a
"dulling of the appreciation of pain" as well as an
insufficient pain reaction. Moreover this dullness ex-
tended to a lack of concern over threatening gestures
made toward the patient, intimating a general dis-
turbance of the capacity to appreciate danger.
Rubins & Friedman (230) have contrif)uted four
more patients in whom this general clinical picture
was present and in two of whom operati\e findings
placed the lesion mainly in the dominant inferior
parietal region. Although these patients recognized
a pin as sharp, they did not withdraw from either
painful stimuli or threatening gestures. But thev also
showed mild perceptive and more se\ere amnestic
aphasia, right-left disorientation, inaljility to repro-
duce postural attitudes in space, Gerstmann's svn-
dromc and idiokinetic apraxia. Hence, the 'asymbolia
for pain' is b\- no means the isolated phenomenon
seen in the syndrome of congenital indifference
to pain. Hecaen & de Ajuriaguerra ('''3). adding a
case report, note that in a number of other recorded
patients as well as theirs the lesion extended into the
posterior inferior part of the frontal lobe.
.\n e\-en greater variety of locus of lesion was seen
by VVeinstein et al. (290) in 15 patients with pain
asymbolia who did not have any aphasia. Such a
group was .selected for a special study of personalit\-,
and many of the patients had lesions in the non-
dominant hemisphere. Their heedlessness of noxious
stimulation was often accompanied b\ inattention to
disabled parts, by muteness, by hypokinesia or by
depression. The authors considered all of these symp-
toms as to some extent an implicit denial of illness,
perhaps related to actual \erbal denial of illness or
anosognosia. They considered such behavior related
more to the personality background of the patient
than to any specific lesion in the brain, and thought
the premorbid personality of patients with 'pain
asymbolia' was characterized by the habitual use of
withdrawal and axoidance in stressful situations. It
is apparent that the attribution of a depres.sed reac-
PAIN
497
tion to all noxa to a sharply focal cerebral lesion has
dubious validitv.
REACTIONS AFTER OPERATIONS ON FRONTAL LOBES.
The modifications in the reaction of the individual
to painful or distressing states provoked by removal of
cortex or division of white fibers in the anterior two-
thirds of the frontal lobe remain to be considered.
Such lesions in an otherwise normal brain diminish
the general reaction to constant pain of organic cause,
such as advancing cancer, as well as the reaction to
such psychological suff"ering as may be occasioned by
the knowledge of impending death, an obsessive com-
pulsive psychoneurosis or psychotic agitated depres-
sion. But the price paid for such relief includes in-
ability to experience keen pleasure as well, i.e. there
is a flattening of all affect and the de\elopment of a
more or less apathetic state. In addition a wide variety
of evidences of mental deficit may appear. The
greater the area of frontal lobe removed or deprived
of its normal connections by division of white matter,
the greater the deficit. When most of the frontal white
matter of a normally functioning human brain is
transected bilaterally in the coronal plane just an-
terior to the lateral ventricles, there is often a serious
disturbance of intellect and personality, as described
by Rylander (234), Freeman & Watts (84, pp. 360
to 374), and Krayenbiihl & Stoll (146). In an oc-
casional patient these defects are mild enough to
permit the indi\idual to return to his work and
retain for years a useful degree of pain relief (84, pp.
367 to 368; 205, pp. 452 to 453).
In an effort to secure a fruitful result with re.spect
to pain but to preserve the personalit\, small lesions
have been made. A total division of the white fibers
on one side only, according to Koskoff c/ al. (145) and
Scarff (235), produces a lesser deficit from which
there is usually much recovery, unfortunately accom-
panied pari passu by return of pain. No significant
difference in result re pain has been noted between
division of fibers contralateral or ipsilateral to one-
sided pain or between operations in the dominant or
nondominant hemisphere. Bilateral inferior quadrant,
bilateral medial or inferomedial lesions (i 1 1), removal
of various small portions of the frontal lobes
bilaterally, i.e. topectomy (216) or undercutting of
various parts of the frontal cortex (244) have all been
performed. Such patients have as yet been less thor-
oughly studied in relation to the correlation between
locus of lesion and relief of pain, but the general
pattern is similar in all. Contrary to the situation in
pain asymbolia, the lobotomized patient's reaction
to individual noxious stimuli is, if anything, increased.
He jumps at pinpricks and needle punctures and
responds in the Hardy-Wolff-Goodell pain-threshold
apparatus by wincing and pulling his hand away at
a lesser stimulus after operation than before it, ac-
cording to Chapman et al. (41). The general experi-
ence amply confirms Freeman & Watts' observations
(84, pp. 371 and 372) that such events as rectal dila-
tation or childbirth are distressing to lobotomy pa-
tients. Moreover, following lobotomy when questioned
about their preoperative pain they are likely to state
that it is 'just as bad as ever' or "terrible." Yet they
ha\e few or no spontaneous complaints of pain, ask
for little or no medication even if narcotic addiction
appeared to be a problem before operation and are
far less miserable even when mentation is almost
normal. Patients with significant mental deficits may
deny pain on direct questioning or even forget about
the illness which is causing the pain. LeBeau (159,
pp. 134 to 135 and pp. 226 to 290} and White &
Sweet (296, pp. 287 to 333) summarize earlier reports
and give accounts of their own experiences.
The behavior of the patients suggests that per-
sistence either of noxious physical stimuli or dis-
turbing thoughts sets off in the normal frontal lobes
a potentiating mechanism which becomes a major
factor in the total suffering of the person. That this
mechanism may be to some extent specific to the
frontal lobes is illustrated by the failure of bilateral
anterior temporal lobectomy to modify the reactions
to pain (296, p. 319).
That the mechanism may involve the diffuse
thalamic projection system of Morison & Dempsey
(191) is suggested by the following experiments. The
thalamic nuclei of the macaque monkey giving rise
to this projection system are the .same ones which
recei\'e afferent impulses of .somatic and visceral origin
from the reticular activating system lying in the
medial brain stem (85, 254). These impulses are dis-
tributed in certain thalamic association nuclei mainly
to the frontal lobe anterior to areas 4 and 6. Magoun
and associates have suggested that it is disturbance
of the diffuse thalamic projection system which
diminishes the aff^ective component of sensorv per-
ception and deprives pain of its unpleasantness, the
characteristic state following a frontal lobotomy,
cortical undercutting or corticectomy. Since the
dorsomedial nucleus of the thalamus is one of the
main association nuclei for the diffuse thalamic
projection system this explanation would also account
for the similar condition following operative destruc-
498
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
lion of this nucleus. Thus Orchinik ti al. (204), work-
ing with patients of Spiegel & VVycis in whom dorso-
medial thalamotomy had been done, found reduced
fearfulncss of emotionally charged situations of many
types. Yet there were "no changes in intellectual
functioning, as measured by a standardized test."
Conclusion
Despite all of the foregoing data we are still unable
to say what level of the brain must be attained or what
constellation of nuclei and fibers must be active if
pain is to be perceived. And not only do we not know
the mechanisms involved in conversion of awareness
of pain to the more grievous state of real suffering,
we are uncertain as to the site and e.xtent of lesion
required to preclude the appearance of suffering.
ENDOCRINES .AND P.AIN
The recent introduction of total hypophysectomy
in man as a palliative treatment for advanced cancer
of the breast has provided an incidental and imex-
pectedly great reduction in or abolition of the pain
in many of the patients so afflicted. Luft & Olivecrona
(180) saw these favorable effects in 19 of 24 women
in their series, and B. S. Ray has stated that his
results are similar. The relief of pain occurs promptly
after operation and is not due to cortisone since it
continues when the drug is stopped. It has not been
correlated with subsidence of tumor and has oc-
curred both in patients who did and in others who did
not give objective evidence of remission, as well as in
patients who had either subtotal or complete hy-
pophvsectomy. These obserx^ations open for considera-
tion the po.ssibility that endocrine potentiation of
nervous function is implicated in the full develop-
ment of pain.
ITCHING AND TICKLING
In addition to the various sensations under the
heading of pain discussed already there remain for
consideration 'itch' and 'tickle.' .Although the decisi\e
feature of the stimulus which will lead it to provoke
an itch is unclear, the nature of the sensation, i.e. the
desire to scratch, is universally understood. An
abundance of evidence now exists to indicate that
itching is closely related to cutaneous pain. In a
number of disorders involving a loss of pain with
presersation of touch and proprioception, the capacity
to itch in the analgesic zone was long ago shown to be
lost (4, 266). This was fully confirmed in a recent
study by Arieff ?/ al. (7) i)oth in patients with radicular
and in those with cord lesions causing the dissociated
decrease or loss in appreciation of a pinprick as pain-
ful. Itch disappears and reappears along with pain
perception in the reversible states of asphyxial nerve
i^lock (174, 175) and of local anesthesia (227, 263).
Rothman (227) has also noted that the converse
is true, i.e. that sensitivity to pain and itching may be
preserved in patients in whom there were zones of
complete tactile anesthesia. He has also reported
itching independent of the sense of temperature.
Zotterman (315) interpreted .some of his animal
experimental results to indicate that peripheral af-
ferent impul.ses mediating itching traverse C fibers,
but the crucial proof was lacking, namely that the an-
imal tended to scratch a zone from which C fiber po-
tentials were arising.
As one moves into the central nervous svstem the
correlation of itching with pain continues; it may be
followed first with the central portion of the pain
fibers of the primary afferent neuron. Thus operative
di\ision of the descending trigeminal tract in the
medulla oblongata \ielded complete trigeminal
analgesia and thermanesthesia in a patient who had
before operation such extreme itching that he
scratched out all the hair in the left anterior quadrant
of his scalp. Postoperatively the itching stopped and
the hair grew back (296, pp. 459 and 512). Likewise
division of pain fibers at the secondary afferent neuron
by section of the anterior quadrant of the cord has
stopped even itching of pathologically .severe origin
and intensity. This was first noted in Sicard &
Robineau's patient (^4^) and in Banzet's (14) case
21, each with bilateral kraurosis vulvae. Further
examples are mentioned by White & Sweet (296,
p. 261). Bickford C'^4) produced itching by puncturing
histamine solutions into the normal skin; a protracted
itch followed the use of a 1:15 dilution. In five pa-
tients, including one with a cordotomy whose spinal
lesion caused loss of pain to pin while touch was pre-
served, he could not evoke itching from the analgesic
skin. Hyndman & W'olkin (133) were likewise imable
to provoke itching by application of itch powder
(from Miuuna pruriens) to the analgesic areas after
cordotomy. Control areas of normal sensation did itch.
There is one discordant observation by Taylor
(261). His patient with generalized bilateral itching
continued to have this svmptom in the analgesic zone
following unilateral bulbar spinothalamic tractotomy.
499
But the itching postoperatively seemed 'deeper in' on
the side which no longer felt a pin as sharp. No men-
tion was made as to whether or not pain from deeper
structures was stopped by this operation. There is
also the possibility that the itching in this patient
was of central origin since he felt it everywhere and
had no primary skin disease. Intense itching appears
to have been provoked by stimulus to the brain in
cats upon intracisternal injections of morphine,
physostigmine, pilocarpine or acetylcholine Ci44)>
and upon intraventricular injection of diisopropyl-
fluorophosphate (DFP) or physostigmine (76). A
centrally induced itch probably does not require
intact spinothalamic pathways to achieve conscious
recognition.
Investigations of the sense of tickle suffer from the
difficulty one has in describing the sensation. For
Pritchard (217) and Foerster (78) it is 'itching of the
weakest intensity' and corresponding to this concept
Rothman (228) describes the after-sensation following
light strokes, firm strokes and burning stimuli on the
skin as tickle, itch and burning pain, respectively — all
mediated by 'C fibers, he says. These speculations
lack factual support. Foerster & Gagel (80) and Bick-
ford (24), pursuing the subject into the spinal cord,
found tickle sensation ab.sent in the analgesic area
after cordotomy; but patients of Feet (208), Hyndman
& VVolkin (133) and White & Sweet (296, p. 261)
said they could still be tickled in such areas. It .scarcely
seems worth fussing about.
PAIN AND INHIBITION
Head & Sherren (122) first described, and Foerster
(77, p. 28) later confirmed, that division of a cu-
taneous sensory nerve lowers the threshold to pain in
the underlying deep tissues, indicating that the super-
ficial system exerts a moderating influence on the
threshold and intensity of deep pain.
Zotterman (315) was one of the first to hypothecate
a peripheral inhibiting mechanism on pain within
a single nerve. He found only 'C fiber discharge in
the after-stimulation period when itching occurs. The
relief of itching by rubbing suggested to him an
inhibiting action of fast 'A' fibers on the slower 'C
fibers. Landau & Bishop (150) have extended this
concept to account for at least some of the features of
hyperpathia seen in lesions of peripheral nerves. They
attribute the sensation upon pinprick after partial
asphN'xial compression of nerve to elimination of
'delta fiber pain.' The pricking pain then changes, is
more intense, more persistent and of a different and
burning quality — the result they say of release of the
central effect of 'C fiber activation normally masked
by activity of the delta fibers. We have already dis-
cussed objections to the concept that pricking and
burning pain are mediated ijy delta and 'C fibers,
respectively. However in those explanations of hyper-
pathia following central lesions which attribute this
state to isolated action of spinoreticulothalamic,
spinotectal or other relay routes, there is also implicit
the notion that the divided direct spinothalamic
pathway normally activated by the same stimulus
exerts an inhibiting action on the 'over-response.'
A number of obser\ations point to an inhibiting
interaction between rival stimuli resulting in decrease
of pain. Thus Bender (17) found that causalgic pain
following peripheral nerve injury was relieved by im-
mersion of the opposite normal hand in water, and
Graham et al. (108) abolished experimentally-induced
itching on the skin of the back by pinprick in the
same dermatome on the anterior chest. Hardy et al.
(i 17) demonstrated another form of inhibition of one
pain by another in the experimental situation of
procaine block to a nerve trunk. Stimulation of the
trunk proximal to this site then provokes a zone of
hyperalgesia. Repeated pinpricks in this area, how-
ever, cause its borders to shrink; the investigators
suggest that a central inhibition is occurring.
Further evidence for central inhibitory mechanisms
for pain has been adduced by Foerster (77, pp. 77
and 78). In two patients with intramedullary cord
lesions he made operative incisions into portions of
the posterior columns; a severe cutaneous hyperpathia
ensued limited to those areas corresponding to the
incised pathways. He attributed this to removal of a
mechanism inhibiting pain inherent in the normal
pathways for touch and proprioception. In view of
the extensive incisions into normal dorsal columns
without such sequel reported by Browder & Gallagher
(35), Pool (215) and White & Sweet (296, p. 407),
Foerster's explanation of his results is no longer
tenable. His surgery may have exacerbated effects of
the original lesion in gray matter or nearby postero-
lateral white matter. Regarding the latter possibility,
Foerster (77, pp. 79 and 80) has cited the evidence of
Fabritius and Brown-Sequard that lesions in the
deep posterolateral white matter provoke hyperpathia,
i.e. that there is a corticofugal pain inhibiting path-
way in this region.
An extraordinary patient has recently been well
studied by Trent (268). Nearly four years after injury
to the left temporoparietal cerebrum the man began
5O0
HANDBOOK OF I'HYSIOLOGY
NEUROPH-l'SIOLOGY 1
to have pain in his right upper limb, maximal in
thumb and axilla. This on examination proved to be
accompanied by "hyperalgesia to pin prick, hyper-
esthesia to warm and cold" and intense pain from a
vibrating tuning fork when applied over sharply
defined areas of the limb and chest. Both the spon-
taneous pain, and the abnormal responses to pinprick,
temperature and vibration were completely and im-
mediately stopped by pressure on the anterior surfaces
of the tips of the medial four right fingers; later, pres-
sure only on the tips of fingers four and five sufficed
to stop the pain. The inhibitory mechanism did not
tend to fatigue and the patient could and did keep
away the pain by keeping his fingers clenched to a
fist. The purely clinical observations gave no clue to
the mechanism of such inhibition.
The converse situation in which pain exerts an
inhibitory effect on simultaneous perception of non-
painful stimuli has been studied by Benjamin (19).
He found that several forms of experimental pain all
increased the thresholds of hearing over the total
tonal range, flicker fusion, vibration at 60 cps and
contact heat. The mean threshold raising efifect was
generally proportional to intensity of pain.
REFERRED P.iiIN
Under a variety of circumstances pain arising from
impulses in one structure, usually deeply placed such
as a viscus, is referred wholly or partly to some other
area, usually superficial. The paucity of nerve endings
in the deep tissues and the small volume of conscious
sensation normally arising from these protected areas
allow lesser opportunity for the cerebral cortex to
build up a pattern of the internal image of the body
as detailed as that of the surface. And indeed the
cerebral mechanism for so doing is much smaller, as
witness the tiny cerebral cortical area of splanchnic
representation found by Amassian (5). If then noxious
stimuli arising from deep structures converge upon the
same neuron as such stimuli from the skin, the sensory
centers may refer the origin of the stimulus to the far
more frequent site of such origin — namely the skin.
That the peripheral neuron itself may be one of the
sites of the convergence has been suggested by Sin-
clair et al. (251). The bifurcation of a single parent
axon into two limbs, each passing into a different
nerve trunk, has been demonstrated in fish by Wern0e
(292), in amphibia by Adrian et al. (2) and probably
in mammals by Lloyd (179), but not yet in man.
However, the phenomena of summation, inhibition
and irradiation — all demonstrable in connection with
referred pain — are more readily explicable on a
central basis. Hence Weddell himself (287) is inclined
to place the mechanism for referred pain mainly in
the central nervous system.
Ruch (231) has drawn attention to one likely site
of convergence of visceral and cutaneous afferents,
namely the cells of the secondary afferent neuron in
the posterior horn, because he finds many more 'pain
fibers' in the posterior roots than axons in the spino-
thalamic tracts. If it is true that there are more
primary than secondary afferent fibers potentially
concerned with pain, then two of the former, one
from a viscus, the other from skin, may well terminate
in relation to a single dorsal horn cell. E.\citation of
the pool of such cells from a viscus ma\- then result in
erroneous reference to the skin.
Physiologic evidence for confluence of cutaneous
and deep afferent pathways upon a single neuron
has been acquired by demonstration of firing of the
central neuron by either the cutaneous or the deep
sensory nerve. Proof that it is indeed the same neuron
responding is enhanced by the finding of 'occlusion,'
i.e. that after excitation of the central neuron from
one peripheral source there elapses an 'unresponsive
period' during which it cannot be excited from the
other peripheral source. Such convergence upon single
neural units in the thalamic nucleus ventralis postero-
lateralis of the cat has been found by MacLeod (181)
specifically related to delta afferent fibers in the
splanchnic nerves and hence presumptively related
to pain. In fact the majority of the cells responding to
splanchnic delta afferents also responded to stimulation
of the skin, usually that of the trunk but at times that
of limbs or tail. Such thalamic cells were present both
ipsilateral and contralateral to the splanchnic
stimulus. The duration of the 'unresponsive period'
of the pathway depended upon which peripheral
field was stimulated first, and the response to stimu-
lation of one of the fields was at times intermittent
while that from the other field was consistent. Hence
MacLeod, cited by Gordon (105), considered it un-
likely that the confluence occurred peripherally in
branches of the primary afferent neuron.
Widen (298) has also studied in similar fashion
delta afferent fibers projecting to the anterior lobe of
the cerebellum. This region was excited by stimu-
lation of either a lower intercostal nerve or the
splanchnic delta fibers and a high degree of occlusion
between them was found. Although these studies are
less clearly related to referred pain because of the
lack of correlation between the cerebellum and con-
50I
scious sensation, they provide another example of
convergence of probable visceral pain and somatic
afferent fibers upon a single central neuron.
Clinical observations have revealed that an added
state, that of hyperalgesia or even tenderness upon
pressure, may be seen in the area of skin to which
pain is erroneously referred. Sinclair el al. (251) have
explained this, in their peripheral theory, on the
basis of antidromic impulses moving down the cu-
taneous branch of the parent axon (after stimulation
of the visceral branch) to excite secondarily endings
of other overlapping nerve fibers, perhaps via metabo-
lites (171, p- 80). Wolff & Hardy (305) after studying
referred pain and hyperalgesia in experiments on
themselves favor the theory that an increasing central
excitatory state presumably in the spinal cord is
evoked by an increasing barrage of afferent stimuli.
They noted, for example, that placement of the
fourth finger in ice water caused pain which spread
gradually from the immersed digit to those contiguous
to it. They thought the referred pain did not develop
quickly enough to he accounted for on the basis of
branching primary afferent axons. Moreover pro-
cainization of the digital nerves in the painful finger
out of the ice water did not stop the pain. It should
have done so if antidromically conducted stimuli
had produced an irritating metabolite or were other-
wise secondarily activating adjoining nerves.
However, the spread of a central excitatory state
would account for the varying findings following pro-
cainization of the cutaneous area of referred pain and
hyperalgesia. Procaine injection may stop these
manifestations (291), perhaps because it diminishes
the excitatory state at central cells by \irtue of stop-
ping subthreshold impulses from the skin, but a
variety of forms of experimental pain will break
through and cau.se referred pain within or around
the anesthetic zone of .skin when the stimulus becomes
more intense. These were the findings of Theobald
(262) with respect to referred suprapubic pain caused
by faradization of the uterus, and of Jones & Chap-
man, cited by White & Sweet (296, p. 74) relative to
the cutaneous pain of experimental jejunal disten-
tion. In some studies procainization of the cutaneous
area of reference did not stop the pain at all; this
was the experience of Woollard et al. (309) whose
direct stimulation of the phrenic nerve caused shoulder
pain, and of McLellan & Goodell, cited by White &
Sweet (296, p. 74) who distended ureters causing
pain in loin and groin. These results can all be ex-
plained by assuming that the central excitatory state
from such visceral stimulation was in itself adequate
to discharge the mechanism pertinent to cutaneous
reference. Such increase in the central excitatory level
may also arise from an increase in impulses from the
cutaneous area. Thus Cohen (47) describes two pa-
tients with attacks of cardiac anginal pain never
referred to the arm in question until in one instance
the inan fractured his elbow and in the other a
blistered area developed after a vesicant plaster to the
elbow region. Then both patients' anginal attacks
included reference to the injured elbow.
Still another form of erroneous reference of pain
may occur after injury to central pathways concerned
therewith. Ray & Wolff (222) have studied four
patients after anterolateral cordotomy in whom
noxious stimuli of high intensity in the analgesic area
induced pain of low intensity referred to the same or
nearby segments on the opposite normally innervated
side. The stimuli included squeezing of muscle, deep
pressure against a diseased hip joint and application
of heat at 80° to 90°C. The authors pointed out that
some of the collaterals of entering primary afferent
fibers proceed to synaptic relation in the posterior
horns with internuncial neurons whose axons cross
in the most dorsal part of the posterior commissure
to terminate about cells in the posterior horns of the
other side. The foregoing observations suggest that
with sufficient background of facilitation and sufficient
intensity of stimulation such indirect chains may
transmit impulses which eventually excite the intact
spinothalamic tract on the other side and are referred
to the side opposite that stimulated. Inherent in this
explanation is the assumption that with both spino-
thalamic pathways functioning before operation, there
was some form of interference with the internuncial
polysynaptic transmission. That such internuncial
relays extend longitudinally in the cord as well is
indicated by our observations (296, p. 257) and those
of Holbrook & de Gutierrez-Mahoney (128). We all
found that some patients after cordotomy may refer
pain to a much more rostral segment than that under-
going intense stimulation, still either in the analgesic
area or above it; the pain experienced was much
milder than that produced in normal circumstances
by such stimuli. In both types of incorrect reference
of the origin of impulses traversing less direct path-
ways, the patient interprets them as though they had
travelled only the customary direct route.
We may well close this chapter with a quotation
from Foerster & Gagel (80). "Pain has a vital sig-
nificance; it is no wonder then that those physical
processes associated with the psychic experience of
pain have the broadest anatomical basis. The im-
502
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
pulses leading to pain penetrate to and upwards within
the central nervous system by a thousand devious
routes. The wisdom of nature, which has placed pain
as the guardian over life and health, has provided
it with many paths and many back doors." Even the
main avenues and mechanisms for pain are still
poorly understood; the task of the neurophysiologist
in this field lies largely before him.
R ri F E R E N C E S
3
4
5
6
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9
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'9-
■20.
21.
22.
■^3-
24-
25-
26.
27-
28.
30.
3'-
32-
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CHAPTER XX
The sense of taste
CARL PFAFFMANN [ Psychology Department, Brown University, Providence, Rhode Island
CHAPTER CONTENTS
Receptor Anatomy
Neuroanatomy
Receptor Mechanisms
Functional Characteristics
Sensitivity and Mechanisms of Stimulation
Sour
Salty
Sweet
Bitter
Electric taste
Parameters of Stimulation
Temperature
Area and duration
Reaction time
Adaptation
Intcnsitivc Relations
Behavioral Effects
THE SENSE OF TASTE, as distinct from the other chemo-
ceptors, olfaction and the so-called common chem-
ical sense, is associated with specialized receptor
organs, the taste buds, which in land-inhabiting ver-
tebrates are located in the mouth. In aquatic animals
and insects chemoreceptors may be distributed o\er
the body surface or on special appendages (68, 152,
197). In man taste stimulation is associated with the
sensation qualities of salty, sour, bitter and sweet.
Of the three chemoceptors, common chemical
sensitivity is the least differentiated and rcc|uires
relatively high concentrations for stimulation. Indeed,
the distinction between chemical sensitivity of the
mucous membranes or moist skin surfaces and general
pain sensitivity has been questioned (60, 112, 161).
Some chemical irritants may be classed as lachryma-
tories or suffocants (144), depending upon their sites
of action, but this may be a differentiation largely
because of the surrounding structures. A familiar
dissociation of taste and smell often occurs in the
temporary anosmia during the common head cold.
Under normal circuinstances, exclusive stimulation
of taste can be insured by placing dilute odorless
solutions on regions of the tongue possessing taste
buds. But many stimuli will activate all three senses
with varying degrees of overlap.
The chemical senses are often classed among the
lower sen.ses (198) perhaps because of simplicity of
morphology, relative paucity of information con-
veyed and relative unimportance in the sensory life
of man. Indeed, the loss of taste is hardly as incapaci-
tating as the loss of vision or hearing, at least to civ-
ilized man. At the same time, the chemical senses
mediate such adaptive functions as food selection or
the rejection of noxious stimuli, particularly in the
case of lower organisms where dramatic examples
may be cited (104, 177).
RECEPTOR AN.^TO^n•
The taste buds in man and other mammals are
located primarily on the edges and dorsum of the
tongue, and adjacent .surfaces of the upper margin
of the gullet, epiglottis, soft palate and pharynx (124,
150, 198). On the tongue, taste buds lie in the upper
surface of the mushroom-shaped fungiform papillae,
in the grooves of the foliate papillae, which are a set
of three to eight folds at the side of the tongue near
the base and in the circular trench of the vallate
papillae which form a chevron-like row of from 6 to
15 papillae on the dorsal surface of the base of the
tongue (see fig. i). The slender keratinized filiform
papillae over most of the dorsuin contain no taste
receptors. In certain animals like the rodents, taste
buds occur on the anterior hard palate, especially in
and around the nasoincisor ducts (i 15).
507
5o8
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
FIG. I. Dorsal surface of the tongue partially dissected to
show the nerves to the posterior part. The circumvallate (C),
fungiform (F«) and filiform (F;) papillae are shown. The
foliate papillae QFo} are not clearly visible in this view since
they are on the lateral surface of the tongue. Taste buds occur
in C, Fo and not in Fi. [From Warren & Carmichael (199).]
in diameter al the thickest part. In a wide variety of
species these values range from 27 to 1 15 m for length
and 14 to 70 M for width. Two kinds of cells have
been described, a) the thicker supporting cells and
ft) the more slender gustatory cells from which a fine
terminal hair projects into the taste pore, but these
may be different stages in the age or functional state
of but a single type (124). During maturity a con-
tinuous process of atrophv and growth maintains the
population of receptor cells at a relatively stable level.
In children, taste buds are more widely distributed
o\er the hard palate, soft palate, pharyngeal walls
and fungiform papillae of the middorsum of the
tongue. In the adult, fungiform papillae are restricted
to the sides and edges of the anterior tongue (198).
Each fungiform papilla contains 3 to 4 taste buds.
Taste i)uds of the circumvallate papillae show a
marked atrophy in old age (i i). The total numijer of
taste buds in man is probai^ly of the order of 10,000.
It has been suggested that in humans the taste papil-
lae reach full development at puberty and remain so
until the age of 45 when regressixe changes set in (4).
In aniiuals atrophic changes followed castration but
could be reversed by hormone replacement therapy
(5). Such atrophic changes, howe\'er, do not appear
to diminish taste sensitivity in a preference test (184;
Warren, R. P. & C. Pfaflfman, unpuiilished oi)serva-
tions). In man the decrease in number of taste buds
with age is correlated with a decrease in sensitivity.
Young adults recognized sugar solutions at a lower
mean threshold, 0.41 per cent (0.012 m) compared
to 1.23 per cent (036 m) for elderly subjects (179).
The taste cell is a modified epithelial cell. The
taste buds degenerate and disappear entirely after
FIG. 2. Golgi preparations of taste buds and associated nerve endings. A. Taste cells and a 'sus-
tentive' element. B. Nerve endings, sense cells not shown (after Retzius). [From Crozier (62).]
Taste buds are goblet-shaped clusters of cells
oriented vertically in the epithelial layer with a small
pore opening to the mucosal surface (fig. 2). Human
taste i)uds measure from 60 to 80 ^i in length and 40 fx
section of the taste afferent fibers. When nerve fibers
regenerate to the periphery, taste buds also regenerate
('49. 152)-
Intrageminal nerve fibers arise from a subepithelial
network of fibers to enter the taste bud. Here they
branch a number of times to entwine about and
make contact with the surface of both the taste and
supporting cells. Two to three nerve fibers may enter
each bud and each fiber may connect with one or
more sense cells. Extrageminal nerve fibers with fine
terminations also arise from the same network of
fibers to innervate the surrounding epithelium (124).
NEURO.^NATOMY
The lingual nerve to the anterior two thirds of the
tongue subserves touch, temperature, pain and taste.
The taste aflferent fibers leave this nerve in a small
strand, the chorda tympani nerve, which passes
through the middle ear cavity close to the tympanum
to enter the brain stem as part of the seventh cranial
nerve. In some instances an alternative pathway via
the greater superficial petrosal nerve seems indicated
(63, 145, 188). The chorda tympani nerve also con-
tains the efTerent fibers for salivation, and tempera-
ture and tactile sensory fibers. The taste fibers are
moderately small myelinated fibers less than 4 /i in
diameter (70, 205). In the chorda tympani nerve of
the cat, 18 per cent of the afferent fibers are unmye-
linated (less than 1.5 /i) and the remaining are
myelinated, ranging from 1.5 to 6.0 // in diameter
(77). Taste fibers from the posterior tongue travel in
the glossopharyngeal and those from the larynx and
pharynx in the vagus (see fig. 3).
The gustatory fibers of the seventh, ninth and
tenth nerves run into the tractus solitarius together
with its nucleus in the medulla. This tract extends
from the posterior two thirds of the fourth ventricle
caudally to the closed part of the medulla where it
lies dorsal to the central canal, but the fibers of the
seventh and ninth nerves terminate in the rostral
portion of the nucleus (172). Insulated wire elec-
trodes inserted into the medulla at this locus yield
potentials when chemical stimuli are applied to the
anterior tongue region (95). A response to the tactile
stimulation occurs when the solution flow Ijegins,
but the response is brief compared with the con-
tinued discharge to taste solutions. Responses from
the anterior tongue tactile stimulation and anterior
tongue taste stimulation can be recorded from the
same electrode loci using a 40 /z insulated wire elec-
trode. Taste and the somatosensory pathways are
closely related at this level.
Lesions in the anterior nucleus solitarius produce
degeneration in fibers of the opposite ascending
Greater superficial
petrosal n.
VII n.
Otic ganglion
Petrous ganglion
Chorda tympani n.
THE SENSE OF TASTE 509
.Gasserian ganglion
V2
Sphenopalatine
ganglion
•Tongue
FIG. 3. The nerve supply to the tongue. The solid tines indi-
cate the most common pathways for the taste impulses. The
broken tine indicates an alternative path from the chorda tym-
pani believed to exist in a limited number of cases. [Modified
from Gushing, 1903 and Schwartz & Weddell, 1938; from
Pfaflrmann(i6i).]
medial lemniscus close to the fibers of the ventral
trigeminothalamic pathways (7, 81). Lesions in the
region of the medial lemniscus produced by a stereo-
taxic instrument were associated with elevated thresh-
olds in a two-bottle preference test with quinine
solutions (155).
Patton & Ruch following BSrnstein (30) have
emphasized that the central pathways for taste are
closely associated with the somatosensory systems for
the face which at the level of the thalamus synapse
medially in the arcuate nucleus (182). Degenerating
fibers following lesions in the region of the nucleus
.solitarius were found in the arcuate nucleus (81), and
retrograde degeneration was noted in the medial
part after ablation of the cortical taste area (82).
Destruction of a large portion of the arcuate nucleus
in the monkey was followed by an elevation in the
quinine preference threshold (157). Unilateral im-
pairment of gustatory and cutaneous sensitivity has
been reported following unilateral tumor of the
medial part of the arcuate nucleus opposite to the
sensory disturbance (3). The failure to find tactile
representation in the ventromedial nucleus in spite
of the fact that it adjoins the tactile representation of
the inner mouth and tongue of the medial part of
the ventrobasal complex led to the suggestion that
taste as well as interoceptive fibers may terminate in
the ventromedial complex (146, 182). Monkeys with
ageusia resulting from cortical ablation showed lesions
in the \'entromedial complex (13). Taste-sparing
cortical lesions of the inferior Rolandic cortex are
iio
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY
associated with severe degeneration throug;hout the
arcuate nucleus except for the dorsomedial tip (155).
The close association of taste pathways with the
somatosensory and also motor mechanisms appears
to hold true at the cortical level. Bremer (31) showed
that ablation of the masticatory cortex in rabbits is
associated with a taste deficit. Changes in the elec-
trocorticogram from this same area were observed in
unanesthetized rabbits when quinine solutions were
placed on the tongue (72). A corresponding area on
the orbital surfaces of the rat ijrain (25) was identi-
fied by the e\oked potential method following elec-
trical stimulation of the chorda tympani and glosso-
pharyngeal nerves. This corresponds to the region
from which masticatory movements could be elicited
by electrical stimulation (130) and thus is a sensory
motor area. Ablation of this area in the rat led to an
elevation of the two-bottle preference thresholds for
quinine .solutions. No taste deficits were noted in two
animals in which most of the neocortex except for the
combined chorda tympani and ninth nerve receiving
areas was removed. Further studies of the deficits
produced by cortical aijlation indicate that under
certain high drive states no apparent taste deficit
can be demonstrated. A thirsty normal animal and
a thirsty animal with a cortical lesion will show the
same aversion to quinine. Both have higher thresholds
for quinine than the normal animal with water pres-
ent ad libitum. Thus, the removal of the cortical
taste area does not make the animal ageusic but in-
stead renders the animal less discriminating in an ad
liijitum situation (23, 24).
The chorda tympani nerve area of the rat and cat
lies in the face somatic area (156, 201). Much of the
surface-positive cortical response to electrical stimu-
lation of the chorda tympani is due to the tactile af-
ferent fibers in that nerve. It has not been possible to
record an evoked cortical potential with gross sur-
face electrodes with adequate taste stimulation. How-
ever, ultramicroelectrodc probings in the tactile
tongue area of the cat did yield single units that re-
sponded to taste but not to touch or temperature.
Other units in this area showed convergence of tactile,
thermal and gustatory impulses (128). The taste units
appeared to be less chemically specific than the single
afferent fibers for they responded to almost all types
of gustatory stimulation Cso)-
In monkeys and chimpanzees, lesions of the face
motor and sensory areas along the free surface of the
lower Rolandic cortex did not produce taste deficits
in preference tests (155). Taste deficits occurred only
when the lesions involved the buried opercular and
parainsular cortex. Bagshaw & Pribram (13) have
shown that the insular and anterior supratemporal
as well as parainsular cortex all must lie included to
lead to an elevation of threshold. Some elevation of
threshold followed ablation of the operculum plus
insula, but not with restricted ablation of the insula
or insula and anterior supratemporal plane.
In man, a series of patients with bullet wounds of
the inferior postcentral region showed reduced gusta-
tory and tactual sensibility of the tongue (30). Pen-
field & Boldrey (159) elicited gustatory sensations in
conscious human patients by electrical stimulation
of the lower end of the postcentral gyrus. Thus, the
evidence implicates the region of the cortex of the
operculum, insula and supratemporal plane of the
temporal lobe.
Patton (155) notes that not only is there the close
approximation of the taste to the somatosensory
system but that taste localization fits into its orderly
topographical arrangement. Taste does not have a
special primary cortical receiving zone with exclusive
gustatory functions.
REGEPTOR MECHANISMS
Functional Characteristics
No simple relation can be established between
chemical stimuli and taste quality except perhaps in
the case of acid. Equally sour concentrations of
hydrochloric, sulfuric, nitric, phosphoric and acetic
acids are said to be indistinguishable from each other
when odor is excluded (56); but sucrose, dextrose
and lactose do not ha\e exactly the same taste (44);
and stimuli that elicit the bitter taste can be dis-
criminated from each other. The taste qualities of in-
organic salts are complex and only sodium chloride
has a pure saline taste, yet in threshold solutions this
is variously reported as .sweet or bitter (173, 181).
The tongue surface is not uniformly sensitive to
punctate stimulation. The middorsum is insensitive
to all tastes. Sweet sen.sitivity is greatest at the tip,
sour at the sides, bitter at the jjack, while salt sen.si-
tivity is relatively homogeneous but greatest at the
tip (96). Indi\idual papillae have been found to
react exclusively to salt, to sweet or to sour, or to
come combination of two, three or four of the basic
taste stimuli (120). Certain drugs have a differential
effect on sensitivity. Gymnemic acid, an extract of
the leaves of an Indian plant Gynmema sylvestre, reduces
sensitivitv for sweet and bitter but leaves salt and sour
THE SENSE OF TASTE
relatively uninfluenced (191). Such observations led
to the view that taste consisted of four different
modalities, salt, sour, bitter and sweet, each with its
particular type of receptor even though no obvious
histological diflferences distinguished taste buds from
different regions of the tongue (147).
Electrophysiological studies show that the chorda
tympani nerve discharge elicited by taste solutions
on the tongue, varies with concentration above the
threshold. In figure 4 the basic taste stimuli can be
ranked in order of effectiveness: quinine, hydro-
chloric acid, sodium chloride, potassium chloride and
400.
300 _
ZOO.
3 -2
LOG MOLAR CONG
FIG. 4. Height of integrator deflections to stimuli of differ-
ent concentrations in one cat preparation. Ordinate gives de-
flections in arbitrary units. [From Pfaffmann (164).]
sucrose but the exact order or magnitude of response
\aries with species. In rodents (rat, guinea pig and
hamster) sodium chloride is more effective than
potassium chloride, whereas in carnivores (raccoon,
cat and dog) the converse is true. There is very little
response to sugar in the cat, somewhat more in the
rat and still more in the hamster and guinea pig. The
quinine response is better in the cat than in the rat
or rabbit (21, 163).
A typical single fiber discharge from the rat chorda
tympani is shown in figure 5 (164). The threshold
varies from unit to unit so that as concentration in-
creases there is an increase both in the number of
units active and in the frequency of discharge. The
fiber in figure 5 also responded to hydrochloric acid
and potassium chloride. A wider sample of the 'spec-
trum' of sensibilities of different fibers in the rat
chorda tympani is shown in figure 6. The pattern of
sensitivity varies from fiber to fiber. Although some
elements (.4 and fi) are relatively specific, others
(especially /) have a broader sensitivity. These dif-
ferent sensitivities cannot be readily grouped into the
basic four types of classical theory. Studies (121) in
which micropipettes have been inserted into the
individual cells of the taste bud show the same kind
of sensitivity pattern in the receptor cells thernseh-es.
This important observation disposes of the possi-
bility that the overlapping sensitivities of single fibers
of the chorda tympani result from the branching of
fibers and termination upon more than one type o
1.0
-liiM—L
• r»>-ii'iiM> n I'lr^i'iiO ' i~ Wi 1J._. _i,».|iii
■C'^»»<^
rJiiiiiiL.liilJl.l..Jl.J,.>i
ni^^f^^^Wv*
J,,.L.i.i,, I ...UlLiLL L.
iirQii - If^ ill UililJ.L [1 liii ■■|J--1- ^ J, \^--i I -I'll* '|-1|-| ■ -I - I - -\ i.'~\\
.03
^^"^^^■^^^W^ri^iiJ^ LJ*^^— V ■^^^'W'U^^ ^
*pJ-i ^.LLLL l'y*.»*>* ^u.^^ L .1 ■ ■' /
l^i^«i tft^^if^t^ ^i.>^iy»>^>»>iOx^^»J>vt^|^»W>i>^>«iX^
.01
.003
4«M^^B«i^i»4irflMM
MMMtavNwl^«Mb«N
.001
inpi|i->^ii i<liiU>>
HzO
RAT No CI Series
I I
.1 sec.
FIG. 5. Response of a single element from the rat sensitive to NaCl. This element also responds
to HCl and KCl. Responses to quinine and sucrose were insignificant. [From Pfaffmann (164).]
512 HANDBOOK OF PHYSIOLOGY ^^ NEUROPHVSIOLOGV
FREQ
40-
RAT
SINGLE ELEMENTS
(01)
M
1
(3)
03N
.IM IM
OIM
1.0 M
HCI
KCI NaCI
Qu
Sue
.03N
HCI
IM
KCI
.1 M
NoCI
OIM
Q u.
1.0 M
Sue.
03N
H CI
IM
KCI
.1 M
NaCI
OIM lOM
Qu. Sue.
FIG. 6. Bar graphs summarizing frequency of response during the first second to fi\'e standard
taste solutions in nine different single fiber preparations in the rat. Sucrose of 0.3 m was used as
test solution in eleinents D and /, 0.01 M HCI in element /. In all other cases concentrations are
as shown on abscissa. Cross-hatehrd bar graph superimposed on figure for element E shows relative
magnitude of integrator response for test solutions. Figures in parentheses give magnitudes in arbi-
trary units. Note that only elements D and G resemble the response of the total nerve. [From Pfaff-
mann (164).]
receptor cell. The proijlcm of chemical specificity is
one of specificity within the individual cells, i.e. to
different sites or loci on the cell membrane.
The specificity of the receptor unit cannot be ade-
quately described by the response to only one con-
centration of a test stimulus. Figure 7 shows that
fiber B (the same as fiber B in fig. 6) can be stimu-
lated by sodium chloride at concentrations of o. i m
and higher. This might be labelled as a salt-sugar
unit. Since gymnemic acid applied to the tongue
leads to a clear-cut decrement in the response to sugar
with no change for sodium chloride, it appears that
only the sucrose sites on the cell is blocked, not the
'salt-sucrose' cell itself. The differential suppression of
sugar sensitivity, often cited as evidence for separate
modalities of taste, can be equally well encompassed
by a theory of specific sites on the cell membrane.
The two fibers, A and B of figure 7, respond to
ijoth sodium chloride and sucrose, but A is more
reactive to sodium chloride and B is more reactive to
THE SENSE OF TASTE
513
n
N.C, f^\
sue ^0
30.
1
1
1
1
A
1 T
/ 1
B / /
JO.
/
1
/ /
/ /
■0.
1
/
/
/
/
/
sue.
/,
L^
/ /
/ >
/ /
6 ^^ HoCl
-
—* 1 1
S -2 -1
0 1
0
_2
-1 0
TABLE I . Fiber Type Response"*
FIG. 7. Graph comparing relative specificities of two dif-
ferent elements in rat. Each is sensitive to NaCl and sucrose
(as well as other stimuli). Element A is relatively more sensitive
to NaCl; B is relatively more sensitive to sucrose. Ordinate
gives frequency in the first second of discharge. [From Pfaff-
mann (164).]
sucrose. At all concentrations of sodium chloride, the
frequencies in .-1 are higher than that in B; at all
concentrations of sucrose, B is greater than A. .Such
a two-fiber system, therefore, signals sodium chloride
when A is greater than B and sucrose when B is
greater than A.
Thus different information may be convened by the
same nerve fiber depending upon the activity in a
second parallel afferent fiber. From figure 7 it can be
seen that a discharge of 6 impulses in B with no ac-
tivity of .-1 is correlated with, that is, signals .05 m
sucrose. A discharge of 6 impulses in B plus a dis-
charge of 32 impulses in A is correlated with or
signals o. i m sodium chloride. Intensity would be
correlated with an increase in overall frequency of
discharge.
Such a model may be expanded by adding more
fibers to provide a greater variety of combinations of
discharge pattern. If sensory quality depends upon
such patterns, we might expect quality of sensation
to change as the afferent population is reduced, for
example when the stimulus concentration approaches
threshold. Such changes in quality are well known
(see table 3).
The further discovery that in certain species water
alone leads to an increase in afferent acti\ity (136,
164, 206) provides still another dimension by which
discrimination can be mediated. Thus, a decrease in
stimulus concentration will be as.sociated with an in-
crease in afferent activity. The base line or 'zero'
taste, therefore, is not provided by pure water but
Stimulus
'Water'
Fiber
'Salt'
Fiber
'Acid'
Fiber
'Qui-
nine'
Fiber
Sensation
Evoked
H;0 (salt <o.03 m)
+
0
0
0
-^
water
NaCl (0.05 m)
0
+
0
0
-^
salt
HCl (pH 2.5)
+
+
-1-
0
-.
sour
Quinine
+
0
0
+
— >
bitter
* According to Cohen et al. (49).
perhaps by the natural environment of saliva. Cohen
el al. have elaborated the pattern concept with a
schema (shown in table i) incorporating the water
receptor (49). This elaborates the earlier model de-
scribed by Pfaffmann (160), but it is not clear that
such 'typing' best describes the taste receptor spectrum
(75). Increasing concentrations, for example, may
bring in other stimuli so that a wider sampling of
stimuli might change the 'types.'
It is clear from recent electrophysiological evidence
that the taste receptors do not always fall into four
basic receptor types corresponding to the basic taste
qualities. The individual sensory cells are differen-
tially sensitive to chemicals, probably because of dif-
ferences at sites on the cell membrane. The chemical
specificity of the taste cell can best be described as a
cluster of sensitivities which varies among different
receptor cells. Any one cell is reactive to a varving
degree to a number of different chemical stimuli,
many of which fall in two or more of the four classical
basic taste categories.
Sensitivity and Mechanisms of Stimulation
SOUR. It has long been known that the sour taste is
associated with the hydrogen ion and that, in a rough
way, the degree of sourness is related to the degree of
dissociation. Strong acids (fully dissociated) are more
sour than equinormal solutions of a weak acid like
acetic (114, 174)- Neutralizing the acid eliminates
the sour taste, but not all acids are sour. Amino acids
are sweet and picric acid is intensely bitter.
Inspection of taste threshold data often reveals wide
discrepancies from one investigator to another. Table
2 summarizes selected data on the acid lower thresh-
olds. The range of \ariation among different refer-
ences cited is shown, such variation being probably
partly the result of valid individual differences among
subjects and partly the result of differences in meth-
ods of determining thresholds. Threshold may be
given as a sensitivity measure, i.e. the minimum con-
5'4
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
TABLE 2. Acid Thresholds in Man {in .Normal Concentrations)
Substance
Formula
Mol.
Wt.
Median
Range
n
Ref.«
Hydrochloric
HCl
36-5
.0009
.00005-. 01
(.0)
a, c,
b.g
Nitric
HNO.
63
.001 1
.001-. 0063
(4)
g
Sulfuric
H2SO,
98
.001
. 00005- • °02
(5)
a, c,
g
Formic
HCOOH
46
0
.0018
. 0007- . 0035
(3)
f.g
Acetic
CH3COOH
60
.0018
.0001-. 0058
(9)
a, c,
b, d, e, f
Butyric
CH3(CH0:COOH
88
.0020
. 0005- . 0035
(2)
f.g
Oxalic
COOHCOOH-aH.O
126
. 0026
.0020-. 0032
(2)
f. g
Succinic
COOH(CH,)iCOOH
118
.0032
.0016-. 0094
(3)
f,g
Lactic
CH.CHOHCOOH
90
.0016
.00052-. 0028
(4)
b, f,
g
Malic
HOOCCH(OH)CH..C:OOH
'34
.0016
.001 3-. 0023
(3)
b, g
Tartaric
HOOC(CHOH),COOH
H,0
168
.0012
.000025-. 0072
(8)
a, b
d, e, f, g
Citric
(COOH)CH;C(OH)(COOH)CH2COOH
192
.0023
.00 1 3-. 0057
(4)
b, g
f.g
This table is based on values cited in von Skramlik C198) and certain more recent studies. Data from earlier literature in
other compilations were not incorporated because of frequent errors of computation observed therein or uncertainties of
method or technique of e.xperimentation. Values shown are the median of several values, the number being shown in column
n. The ranges of values are also reported. Hahn's (90) values of .003 .V for all acids (except butyric and malic acids) were
not included in this table.
* a, Cragg (59); b, Fabian & Blum (74); c, Gibson & Hartmann (83), d, Hopkins (iio); e, Knowles et at. (123); f, Taylor
(195); g, (Paul and Bohnen, Corin, Richards, Heymann, Richet, Renqvist) cited by von Skramlik (198).
centration at which a difference from water can be
detected or as a recognition threshold, i.e. where the
quahty can be recognized. The former are usually
lower.
Weak organic acids appear more sovir than would
be expected from their degree of dissociation. At
threshold, the hydrogen ion concentration of acetic
acid is less than that of hydrochloric acid. Liljestrand
(135) found that the pH of weak organic acids at
threshold ranged from 3.7 to 3.9, for strong mineral
acids from 3.4 to 3.5. The findings of equal pH (ap-
pro.ximately 4.4) for organic and inorganic acids (59)
or equal normality of .003 n for all acids (89) are at
variance with the more common result of different
pH and different normalities at threshold (12, 26,
114, 158, 174, 195).
Cragg C58) noted that subjects with a more alkaline
saliv'a required more concentrated hydrochloric acid
solutions to match an acetic acid standard. The sour
taste of buffers and of solutions of the monobasic
salts of organic acids can be detected at pH values
which are lower than those of inorganic acid solutions
(12, 135, 158}. Buffer solutions held in the mouth
retain the sour taste longer than does plain acid. The
pH of acetic acid changes less than the pH of hydro-
chloric acid after being held in the mouth.
The relative stimulating efficiency of suprathresh-
old concentrations studied by means of equal sourness
matches between different acids and the standard,
hydrochloric acid, is shown in figure 8. On the basis
of hydrogen ion concentration, the organic acids
acetic, carbonic, tartaric, lactic and acetylactic acids
were all more sour than hvdrochloric acid (16, 103,
158).
These effects are not clue solely to the buffering
action of saliva. When acid solutions are applied by
a flow system applicator so that the saliva is
thoroughly rinsed off, equal afferent nerve discharge
was not achieved with equal pH, ecjual normality or
molarity (20). Figure 9 shows the magnitude of
response in the chorda tympani discharge produced
by different acids of the same pH.
Thus, some basic physiological mechanism com-
plicates the relation between sourness and acidity.
Richards (174) suggested that the hydrogen ions
might react with some substance on the receptor
surface so that, as these ions in a solution of the organic
acid were taken up, further dissociation would re-
place them. Others (103) refer to the potential as well
as actual hydrogen ion concentration as a deter-
miner of sourness. Kenrick (116) and Beatty & Cragg
(16) noted that the amount of phosphate buffer
(pH 7) necessary to bring equisour concentrations of
different acids to a pH 4.4 was proportional to the
sourness defined by the normality of an equisour
hydrochloric acid solution. Ostwald & Kuhn (151)
noted a parallel between the sourness and the swell-
ing of gelatin in different acids. Sourness has been
attributed to the rate at which the acid penetrates
the cell or intracellular spaces (61) or to adsorption
on the cell surface (195)-
Acid stimulation of the integument of lower organ-
THE SENSE OF TASTE
515
/ 2 3
Homentrvtion der SHuren.
5 6 7
Mi III mo/ in II
[HJCHiCOOH
(H-)COOHCH(OH)CII(0/I)COOH
fl^Hi C03> 1— I
FIG. 8. Equal sourness matches. Ordmates give concentrations of HC:l required to match the sour-
ness of other acids at concentrations shown on the abscissae. Broken lines give hydrogen ion concen-
trations of weak acid and salts. [From Paul-Munchen (158).]
FIG. 9. Integrated response of the rat chorda tympani nerve to hydrochloric, citric, formic, ox-
alic, acetic and hydrochloric acids ^reading from left to rig/it') at pH 2.5. Duration of response, 10 to
20 sec. [From Beidler (20).]
5i6
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY
TABLE 3. The Taste of Salts at Different Concentrations*
X
a.
NUMBER OF C ATOMS
-t-
FIG. 10. pH required to elicit a constant reaction time in
the sunfish, for hydrochloric acid and a series of normal ali-
phatic acids of increasing carbon chain length. [From ."Mlison
(8).]
isms (fish, frogs, barnacles, mollusks, worms) is
probably due to the general sensitivity and thus
simpler than in the case of taste. Stimulation by
mineral acids in this case is determined by pH, but
normal aliphatic acids stimulate at lower hydrogen
ion concentrations, the efficacy increasing systemat-
ically with increasing chain length (8, g, 54, 55)
(see fig. 10). Similarly, the nonpolar parts of the
molecule in a series of n aliphatic alcohols add to
stimulating efficiency with increasing number of
carbon atoms (53). The same holds for a series of
alcohols and glycols for taste in man and in insect
chemoception (66). In the insect studies a wider
sampling of organic molecules was employed. Stimu-
lation appeared to be associated with increasing
lipoid solubility attendant upon increased chain
length and the introduction of functional groups that
reduced water solubility (65, 68, 6g). The hydrogen
ion is clearly an important determinant of the sour-
ness of acids, but it alone does not determine stimu-
lating efficiency.
s.\LTY. All substances with a s<ilty taste are soluble
salts composed of positive and negative ions in the
solid (crystalline) state which dissolve in water to
Droduce a solution of these ions. Sodium chloride is
M
NaCl
KCl
0.009
no taste
sweet
O.OIO
weak sweet
strong sweet
0.0 J
sweet
sweet, perhaps bitter
0.03
sweet
bitter
0.04
salt, slightly sweet
bitter
0.05
salty
bitter, salty
0. I
salty
bitter, salty
0.2
pure salty
salty, bitter, sour
I .0
pure salty
salty, bitter, sour
* From R
engvist (173).
the only substance said to possess the 'pure sahy taste'
except that the threshold concentrations of this salt
taste sweet (see taljle 3). Other salts display the same
phenomenon but yield complex salty tastes at supra-
thresholcl values.
Both the anion and cation contribute to the taste
quality and to the stimulating efficiency (80). Thus,
whereas .04 m sodium chloride is distinctly salty,
sodium acetate of the same concentration has no
salty taste. In a series of sodium salts, the quality of
the taste elicited will vary with the anion. A similar
effect can be noted in a chloride series with different
cations. In a series of halides of the monovalent
alkali metals (plus ammonium) the low molecular
weight (below iio) salts are predominantly salty in
taste, while the higher molecular weight (over 160)
salts are bitter (122). Salts of heavy metals such as
mercury have a metallic taste but some lead salts,
especially lead acetate (sugar of lead), and beryllium
salts are sweet.
The thresholds for different salts ha\c been vari-
ously reported to be equimolar for the cation (92),
for halogen salts (84), inversely related to the molecu-
lar weight (80), directly related to cation mobility
(79). Table 4 shows the median values ba.sed on a
sampling of a numljer of different threshold studies in
man.
von Skramlik (198) attempted to specify objectively
the complex taste of salts by means of the following
taste equation : .'Y = .v.^ -|- yB -\- zC -\- vD in which
>■'
and v are molar concentration values and .-1
stands for sodium chloride; B, quinine sulphate; C,
fructose; D, potassium tartrate; and .A' is the molar
concentration of the salt being matched. Although
indi\idual differences among subjects are clearly
apparent in the matches, certain trends or consist-
encies can be noted.
The degree of saltiness of a series of salts is given
b> the ratio of m NaCl/M 'salt' required to match the
THE SENSE OF TASTE
5'7
TABLE 4. Salt Thresholds in Man (in Molar Concentrations)
Substance
Lithium chloride
Ammonium chloride
Sodium chloride
Potassium chloride
Magnesiiun chloride
Calcium chloride
Sodium fluoride
Sodium bromide
Sodium iodide
Formula
LiCl
NH4CI
NaCl
Mol. VVt.
42.4
53-5
58.5
Median
025
004"
01''
oy
017
015"
KCl 74.6
MgCb 95.23
CaClj 110-99
NaF 42 . 00
NaBr 102.91
Nal 14992
* a, Cox & Nathans (57); b, Fabian & Blum (74); c, Frings (79)
et al. (123): g, Richter & MacLean (181); h, von Skramlik (198): i, Hober & Kiesow (106).
» Mean value. '' Sensitivity threshold. ' Recognition threshold.
'^ Hahn (92) has reported one subject with a threshold for NaCl of less than 13 X io~'m. This is difficult to
value is far beyond the values commonly reported.
Range
. 009- . 04
.001-. 009
. 00 I - . 08
■OO3-.085
.001 -.07
.003-. 04
. 002- . 03
.001-. 04
.008-. 04
. C04- . I
3
8
10
6
3
1
2
3
d, e, g<i
g. h
h, i
005
024
028
; d, Hopkins (no); e, Janowitz & Grossman (in), 1, Knowlcs
terpret for the
TABLE 5. Mean Salt Qjioticnt (M NaCl/M 'Salt')
for Different Salts*
NH,
K
Ca
Na
Li
Mg
CI
2.83
1.36
1.23
1 .00
0.44
0.20
2.44
0.54
0.77
0.57
Br
..83
I .16
0.91
0.79
SO,
1.26
0.26
1-25
o.oi
NOi
1.03
o. 14
0.17
0.23
HCOi
0.23
Quotients show the molar concentration of NaCl required
to match the saltiness of the comparison salt.
* From von Skramlik (198).
saltiness ignoring all other components. Table 5
showing the mean values for each of several series of
salts gives the following cation series in the case of the
chlorides: NH4 > K > Ca > Na > Li > Mg.
This closely resembles the series found (79) in a
comparative study of rejection thresholds in animals
and detection thresholds in man. Frings' (79) attempt
to relate a single property, cation mobility, to the
stimulating efficiency of electrolytes across all species
is premature in view of the demonstrated species
differences in sensitivity based on electrophysiological
study (21, 163). The typical series for carnivores;
NH4 > Ca > Sr > K > Mg > Na > Li may be
contrasted with that for the rat; Li > Na > NH4 >
Ca > K > Sr > Mg which is typical of the rodent
cla.ss. The differences in the relation of sodium to
potassium in the two orders is striking. Sodium is
very effective in rodents but relatively ineffective in
carnivores, whereas potassium is relatively ineffective
in both. Beidler ?< al. (21) have pointed out that the
sodium/potassium ratios in the red blood cells are
high (16. 1 ) for carnivores and low- (0.12) for rodents,
perhaps indicati\'e of a species difference in the
physicochemical make up of the membranes of the
receptors. The seriation NH3 > K > Na > Li found
in the withdrawal reaction of the frog and other
lower arjuatic forms when these solutions are applied
to the integument is probably due to the less dif-
ferentiated common chemical sensitivity (52, 109,
153)-
The anion series based on tabic 5 for sodium salts
is SO4 > CI > Br > I > HCO3 > NO:,. Among
invertebrates the following seriation has been de-
scribed; I > Br > NO3 > CI. In the chorda tympani
of the rat, the anion has a much smaller effect than
the cation but the following series can be noted:
CI = Br > NO;, > citrate > SO, > CO., (18).
Such ionic .seriations (variously called Hofmeister
series, lyotropic series, etc.) can be demonstrated in a
number of other phenomena as the penetration into
cells or adsorption on surfaces (105). Beidler (19) has
recently developed a theory which provides some basis
for choosing among these possibilities. His basic
taste equation is:
C
R
Rt„ IlRn
where C equals the concentration of the stimulus, R
is the response magnitude of chorda tympani dis-
charge, Rm is the maximal response magnitude and
A' is an equilibrium constant. A plot of C/R against
C yields a straight line with a slope equal to i/Rm
and a y intercept equal to i/K'Rm- The equation is
similar to Langmuir's adsorption isotherm and to the
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
o.e
0.7-
0.6-
0.5-
0.4-
0.1-
0.2
0.4
0.6
0.8
1.0
FIG. II. Ratio of molar concentration and magnitude of integrated cliorda tympani response
plotted against molar concentration of stimulus. Explanation in text. [From Beidler (19).]
equation expressing the i^inding of ions by proteins.
The equation describes the responses to different
organic sodium salts (see fig. 11). From the low values
of AF, the change in free energy, the relative inde-
pendence of response magnitude of temperature or
pH, the conclusion is drawn that the ions are loo.seiy
bound to the taste receptor surface by a nonenzymatic
process much like that which occurs in the binding
of ions by proteins or naturally occurring polyelec-
trolytes, such as nucleic acid or polysaccharides (19).
Such binding may be the initial step in a series of
reactions leading ultimately to stimulation of the
receptor and depolarization of the associated afferent
nerve fiber. Species differences are attributed to dif-
ferences in the detailed configurations of the reacting
molecular sites on the receptor surfaces.
SWEET. The sweet taste appears to be associated
primarily with organic compounds, except for certain
inorganic salts of lead and beryllium. The aliphatic
hydroxy compounds which include alcohols, glycols,
sugars and sugar derivatives constitute one of the
better known classes. Other stimuli are aldehydes,
ketones, amides, esters, amino acids, sulfonic acids,
halogenated hydrocarbons, etc. A sampling of thresh-
old values for the commoner sweet stimuli is £;iven in
table 6.
The complex relations between structure and the
.sweet taste cannot be adequately explained by any
present systematization (sO- Oertly & Myers C148)
listed a number of sweet-producing molecular ar-
rangements and postulated that, to be sweet, a .sub-
stance must contain a 'glucophore' and an 'auxogluc'
Examples of their analysis are given in table 7. How-
ever, saccharin and dulcin are but two of the many
exceptions.
In an homologous series, the taste of the members
often changes from sweet to bitter with increase in
molecular weight. In the higher members of an
homologous series, it is said (144) that taste eventually
disappears when the products become insolufjie. On
the other hand, as previously noted, an increa.se in
molecular weight associated with increasing chain
length in an homologous series is paralleled by a
decrease in water solubility and an increase in taste
stimulating efhciency. This was shown for alcohols
and glycols at threshold (66). Some (62) have hy-
pothesized that sweetening power is often a.ssociated
with low water solubility, but numerous exceptions
make this a difficult rule to maintain.
The importance of the spatial arrangement of the
molecule is strikingly clear in the case of homologues
in which small changes may produce striking dif-
THE SENSE OF TASTE
519
TABLE 6. Sweet Thresholds in Man (in Molar Concentrations)
Substance
Formula
Mol. VVt.
Median
Range
n
Ref
Sucrose
CijHe.Ou
342.2
.01 t
■>7t
. 005- .016
.012-. 037
3
7
a, c, e
a, b, d
Glucose
CcHi.Oe
180. 1
.08
■04-09
3
a, b, f
Saccharin (sodium)
CO
/\
CeH, N
\/
SO2
Na
+
2H2O
241 .1
.000023
. 00002- . 00004
3
f. g
Beryllium chloride
BeClo
80.0
.0003
a, f
Sodium hydroxide
NaOH
40. 1
.008
.002-. 01 2
b, f
* a, Fabian & Blum (74); b, Biester & Wood (27); c, Schutz & Pilgrim (186), d, Janowitz & Grossman; e, Richter & Camp-
bell (179); f, von Skramlik (198); g, Warren, R. W. & C. Pfaffmann (unpublished observations).
t Detection threshold.
J Recognition threshold.
TABLE 7. Possible Structural Basis for Sweet Taste*
Glucophore
Auxogluc
Glycol
CH.OH— CHOH
H—
Glycerol
CHoOH— CHOH
CH2OH
Glucose
—CO— CHOH
CHcOH
Glycine
COOHCHNH2—
H—
Chloroform
— CCI3
H—
Ethyl nit
•ate
— CHONO2
CH3
* According to
Oertly & Myers (148).
ferences in ta.ste. For example, of the homologues of
w-nitroaniline, which is sweet, only 2-nitro-p-toluidine
is sweet.
Sweet
NO2
Sweet
NO2
Tasteless
NH,
NH.,
NO,
NH.,
CH,
CH3
Very shghtly bitter
NH,
NO,
CH,
Saccharin is one of the better known physiologi-
cally inert synthetic sweetening agents. The salts of
saccharin, especially the sodium salt crystallose, are
sweet presumably due to the anion
■N-
-SO,
-CO
Where substitution of the hydrogen in the imide
group occurs to form .^''-methyl saccharin, the com-
pound is tasteless presumably because ionization
cannot occur,
CO.
-SO,
.NCH,.
Several other intensely sweet substances are dulcin,
cyclamate (Sucaryl) and the 4-alkoxy-3-amino-
nitrobenzenes. The n propyl derivative of the latter
class, called P-4000, is said to be the sweetest known
compound but its use as a synthetic sweetening agent
is limited by its toxicity (29, 131).
Stereoisomerism is of significance in taste as in
other physiological systems. In fact, one of the earlier
examples of the biological significance of optical
activity was provided by asparagine of which the
dextro forin is sweet, the levo form tasteless. Freshly
prepared solutions of alpha D glucose are sweeter
than beta D glucose which predominates in solution
after mutarotation has occurred (44).
Mention has already been made of the selective
and reversible action of certain drugs like gymnemic
acid which reduces sensitivity to sweet and bitter but
520
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
leaves salt and sour unaffected (191). The effect may
be demonstrated most simply after chewing a few of
the dried leaves. A similar action is described for
verba santa, an extract of the leaves of Eriodicyton
calif ornicum. Topical application of w^eak concentra-
tions of cocaine depress taste in the order, bitter >
sweet > salt > sour. Stovaine in proper concentra-
tions will eliininate sweet and Ijitter and reduce
sensitivity to salt and acid followed by hypergeusia
for salt. Cocaine ageusia may be followed ijy hyper-
geusia for sweet and bitter. The Sudanese plant
Bumelia duliifica is said to change sweet and bitter to
sour.
The extract from the Gvnimmn leaves, after purifi-
cation and recrystallization, yields a white powder
with a melting point of i99°C and a molecular weight
of 805. This appears to be a glycoside which yields
glucose, arabinose and a small quantity of glucuro-
nalactone upon hydrolysis. The hydrolysate has no
effect on taste. Other sul^stances in the crude extract
do not influence the inhiljitory action. Not only is
the sweet taste of such diverse substances as sucrose
and saccharin suppressed, both are equalh' reduced
in sweetness, i.e. at suprathreshold levels equal sweet-
ness matches remain unchanged (Warren, R. M. &
C. Pfaffmann, unpublished observations).
The differential action of this drug is clearly shown
in the electrical activity of the chorda tympani nerve
(fig. 12), although the effect does not last as long as
the perceptual effect in man. A similar reversible ef-
fect can be produced by the salts of heavy metals,
silver and mercury, but not by arsenic, arsenous acids
or potassium ferricyanide. This suggests competitive
blocking of a mechanism which is nonenzymatic (88).
These results are in striking agreement with those
obtained in invertebrate contact chemoception (67,
68). The evidence from functional studies contra-
indicates an enzymatic process in stimulation gener-
!i!SO
>eo.
3
r-^
10 MIN.
i-i .1 No CI
•—» .1 sue.
T r
TIME (mir )
1 r
l-IO min H
FIG. 12. Differential suppression of taste response to sucrose
(«/<r.) and sodium chloride (chorda tympani discharge) by
gymnemic acid after 10 min. application to surface of tongue.
[From Hagstrom (88).]
ally in spite of the demonstration of enzymes in the
neighborhood of taste cells (14).
Action potential studies have shown that an indi-
\idual afferent receptor neural unit might respond
not only to sugar but also to a salt like .sodium chlo-
ride. Thus, specificity to a chemical agent must be
specificity of sites within or on the individual sense
cells. Presumably, different sites are specifically
sensiti\e to sugar on the one hand and salt on the
other (in addition to a wide variety of other sub-
stances). Gymnemic acid does not block the receptor
cell as a whole but onl\' the sucrose site.
Threshold and suprathreshold ecjual-sweetne.ss com-
parison methods have been employed to study rela-
tive sweetness of different stimuli. Although the
exact values may vary from experimenter to experi-
menter, the relative order of sweetness among the
sugars, for example, is the same. In equimolar con-
centrations the order of sweetness is: sucro.se > fruc-
tose > maltose > glucose > lactose (44). The rela-
tion between concentration and sweetness changes
with concentration (see fig. 13). There are very wide
differences in the stimulating efficiency of sweet
stimuli. Close to threshold, saccharin is 500 to 700
times less concentrated than sucrose of equal sweet-
ness. As yet there is no indication why .some syn-
thetic agents are so effective. In general, the available
evidence suggests that the initial step in sweet stimu-
lation ma\' be a process like that already elaborated
for salts. The response to sugar is resistant to enzyme
poisons and pH change but not to surface active
competiti\e inhibitors.
BITTER. Bitter, like sweet, is elicited by members of
many chemical classes and is often found in associa-
tion with sweet and other taste qualities. Increasing
molecular weight of inorganic salts is associated with
increasing bitterness (see p. 516). An increase in
length of the carbon chain of the organic molecules
may he associated with a change from sweet to Ijitter.
Many sweet substances have a concomitant bitter
taste or aftertaste (e.g. saccharin). This douiile or
multiple taste quality is especially apparent as the
stimulus moves from the front to the back of the
tongue where bitter sensitivity is especially developed.
The best known class of bitter substances is the
alkaloids which are complex nitrogenous compounds,
often highly toxic, such as quinine, caffeine, strych-
nine and nicotine (144). Nitro compounds are often
bitter (such as picric acid) especially if three or some-
times two nitro groups are present. The following
groups are often associated with bitter taste : (NO2) >
THE SENSE OF TASTE ^2 1
- 0.075
E 0.050
S 0.025
0.050 0 075 0 100
Gram-mol per cent
0125
0150
FIG. 13. Curves showing the concentrations at which different substances taste as sweet as various
concentrations of sucrose. Gram-mol per cent is ' fo the value of the molar concentration. [From
Cameron C44).j
TABLE 8. Bitter Thresholds in Man (in Molar Concentrations)
Substance
Quinine sulphate
Quin ine hydrochloride
Strychine inonohydrochloride
Nicotine
Caffeine
Phenyl thiourea (PTC)
tasters
nontastcrs
Urea
Magnesium sulfate
(Epsom salt)
* a, Blakeslee (28); b, Hanig (96); c, Harris (99); d, Hartmann (of. 48); e, Harris & Kalmus (100); f, Kiesow (118); g, Parker
& Stabler (154); h, Richter & Clisby (180); i, Schutz & Pilgrim (186); j, Setterfield, Schottl & Snyder (cf. 48): k, von Skram-
lik (198).
t Modes.
Formula
Mol. \Vt.
Median
Range
n
Ref
(C2oH,,N.002H.,S04
746.90
. 000008
.0000004-. 0000 ! I
3
b,
f, k
CaciHo4N.,0,HCl
360.88
.00003
. 000002- . 0004
3
g.
k
C2,H.,.,N.>0;HCI
370-75
, 00000 1 6
I
k
C5H4NC4H7NCH:,
1 62 . 2
.0000 1 9
I
k
CsHioN^Ot!
.94.1
.0007
.0003-. 001
2
i,
k
CeHsNHCSNH.
I 52 . 2 I
. 00002 t\
.oo8t /
f. 0000002 to
I >-oi7
6
a.
c, d,
CO (NHO2
60. I
. 12
. 116-.13
2
c,
k
MgSOi 7H2O
246.49
.0046
.0042-. 005
2
k
2, =N, =N= — SH, — S— , — S— S— , and — CS— .
Some typical threshold values for the human are
shown in table 8.
The importance of structure and specific chemical
grouping is shown by the phenomenon of 'taste blind-
ness,' a specific relative insensitivity to a number of
S
substances possessing the y NC — group. Phenylthio-
carbamide (PTC) is widely used as a test for 'taste
blindness.' The actual distribution of taste-blind
individuals found depends upon the manner of ad-
ministering the PTC;, the percentages of 'nontasters'
in Caucasians having been variously reported to be
between 3 per cent and 40 per cent. A graded series
of solutions yields no sharp cutoff at one threshold
concentration but rather a bimodal distribution.
This deficiency is inherited as a Mendelian reces-
sive characteristic. Evidence for such taste defects
were found in anthropoid apes (28, 48, too). Rats,
however, rejected PTC solutions with no evidence of
the defect. PTC is intensely toxic to the rat when
administered by stomach tube. This property was
utilized in the preparation of a rat poison "Antu'
from a chemically related but tasteless compound
C178, 180).
S
\ "
The inability to taste y NC — may be overridden
by other chemical groups as in thiourea, NH2CSNH.2,
522
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOCi' I
which is sour to ail persons. Many of the substances
with whicli taste blindness may be demonstrated are
antithyroid compoimds (99). Taste blindness is not
correlated with sensitivity for other bitter stimuli or
the other taste qualities. This suggests a high degree
of specificity for the particular chemical linkage to-
gether with some feature of the receptor mechanism.
An attempt has been made to relate taste blindness
to solubility of PTC in saliva (47). In view of the
specificity of the linkage this does not seem to be a
likely explanation.
The fact that sweet and bitter sensitivity are often
associated in the case of certain stimuli and that
both tend to be inactivated by the action of drugs or
narcotic agents led one in\estigator to propose that
both depend upon the action of a single receptor
mechanism (194). Of all the taste mechanisms, that
underlying bitter sensitivity is least well understood.
ELECTRIC TASTE. That electric currents can stimulate
the sense of taste has been known almost since the
discovery of electricity. \'olta noted, for example, a
sour taste when a circuit with two dissimilar metals
made contact with the tongue. Such taste is elicited
not only at the make and ijreak of current but by
the steady flow as contrasted with the more familiar
stimulation of nervous tissue by short duration pulses.
Anodal unipolar stimulation of the tongue with an
indifTerent electrode elsewhere on the body elicits a
sour taste; cathodal stimulation yields a complex
alkaline quality but, at cathodal break, sour is re-
ported (198).
Early investigators often employed metallic polariz-
able electrodes. With an inert electrode like platinum,
the following electrolytic change occurs when current
flows through a weak salt solution. Electrons are
introduced at the cathode toward which the positive
hydrogen and sodium ions are attracted. A higher
voltage is usually required to discharge the Na ion
so that H ions are discharged and H2 is liberated,
ae + 2H2O -^ 2OH- + H..
leaving Na+ and OH" ions. At the positive pole
electrons come primarily from the OH~ ions which
by their discharge leave an excess of H+ ions.
4OH-
2H,0 + O2 + 2e
These together with the remaining CI" ions form a
dilute solution of hydrochloric acid. These chemical
effects would appear to account for the sour taste at
the anode and alkaline taste at the cathode. In addi-
tion there is movement of cations toward the cathode
and anions toward the anode with a resulting change
in concentration in the vicinity of the electrodes.
With a nonpolarizable reversible electrode, electron
transfer at the electrode is derived from the reaction
Ag ^ Ag+ -f e. No discharge of OH" or H+ ions
occurs. There is no electrolysis, l)ut the subject still
reports sour at the anode (40). Further work is de-
sirable in view of one preliminar)- report that the
anode produces a salty taste when a carefully con-
structed reversible electrode is utilized C71).
In general two hypotheses have been proposed to
account for the electric taste. The first is the chemical
theory in which it is belie\ed that taste buds are
stimulated by the concentration of ions resulting from
electrolysis. Thus the sour of the platinum electrode
is said to be due to the excess of hydrogen ions. The
appearance of the same taste with a reversible elec-
trode suggests the second \iew, namely that direct
depolarization of the taste membrane occurs by
virtue of the ionic transfer in the cell and across the
cell membrane. In both cases, of course, the pa.ssage
of current is an electrochemical reaction.
Direct stimulation of the nerve fibers so that the
receptor organ itself is 'by-passed' can be ruled out,
at least for direct current anodal currents. The taste
threshold current is lower for the anode than the
cathode, which is the reverse of the relation found
for direct nerve stimulation. Furthermore the eleva-
tion of threshold after the topical applications of
tetracaine was much greater for the anode than the
cathode, suggesting that the anode stimulated the
more superficial receptor but that the cathode stimu
la ted the deeper nerve fibers. The strength duration
curses of taste indicate a longer time constant for
the anode than the cathode (38, 40).
Electrophysiological recordings of the single taste
fibers show that anodal polarization of the tongue
surface causes a discharge like that to chemical stimu-
lation, except that the latency to the electrical stimulus
is approximately 5 to 7 msec, whereas that to chemi-
cal stimulation is approximately 35 to 50 msec. (160).
Thus the anodal electrical stimulus appears to act
via the receptor cell but with a much shorter latency
as though some initial step were by-passed.
The discharge to a steady anodal current continues,
after an initial decrement, as long as the current flows.
The same magnitude of cathodal current, however,
causes an immediate inhibition of activity which lasts
as long as the current flows. Upon break of the
cathodal current, there follows a transient burst of
THE SENSE OF TASTE 523
activity. Other sense organs appear to show the same
polarity relations, e.g. the tactile receptors of the
frog skin and photo receptors of the Limulus eye,
suggesting that these effects are not specific to taste
(138, 139). These effects are just opposite to those
seen in the axon where anodal block and cathodal
excitation are found.
Studies of alternating current stimulation support
the view that the receptor ceil mediates the electric
taste at low frequencies from 30 to 50 cps at which
sour predominates. The low frequencies presumably
can stimulate the receptor organs with their slower
time constants. High frequencies around 1000 cps
elicit a more complex bitter taste. The high fre-
quencies may stimulate ti.ssues with faster time con-
stants, i.e. the nerve fibers themselves (41).
Intermittent square wave stimulation has been
employed in studies of the so-called 'flicker fusion' of
taste. The original studies (6) purporting to demon-
strate gustatory flicker fusion at frequencies between
125 and 350 cps have not been confirmed Cii3> i 70j
183), although it is true that something akin to fusion
can be reported. The effect appears to be largely a
tactual phenomenon which can be demonstrated in
regions of the mouth and lips where no taste buds are
found (170). Reports of true taste fusion (38) occur
with extremely low frequencies in the range of from
0.3 to 10 cps.
Parameters of Slimiilaliori
TEMPERATURE. The rate of most chemical reactions
is increased by a rise in temperature. Early work
showed that taste was optimal in a middle range
variously reported between 10° and 20°C, 20° and
30°C and 30° and 40 °C. At the extremes of 0° or
50 °C the tongue is nearly insensitive especially after
it has been immersed in solution (198). Komuro
(125) studied intermediate values and reported a
drop in threshold with temperature rise from 10° to
30°C, with some suggestion of an increase beyond
30 °C for all stimuli. Chinaglia (46) found no change
in threshold but did find a change in reaction time.
The interpretation of reaction time data is somewhat
equivocal because, in another study (143), no corre-
lation was found between reaction time and thresh-
old for sodium chloride over a wide temperature
range.
Goudrian (86) showed that the apparent taste
intensity of sugar solutions increased with increasing
temperature between 10° and 40°C. Acid showed a
FIG. 14. The effect of temperature on taste thresholds for
sodium chloride, quinine sulphate, dulcin and hydrochloric acid.
The ordinate gives the thresholds in arbitrary units. The value
of one unit on the ordinate differs for each of the four sub-
stances, as shown by the key in the figure. For example, one
unit for NaCI equals 0.0005 P^'' cent. [From Hahn (93).]
similar but not as regular or as striking a change.
Salt and quinine fell in intensity with an optimum for
salt at io°C. The optimum for quinine was less con-
sistent.
One of the better controlled studies is that of Hahn
& Gunther (gi) on absolute thresholds at different
temperatures using the 'Geschmackslupe.' This device
restricts the flow of solution to a specified region of
the tongue so that a preadapting flow of water at the
same temperature can be employed (see fig. 14).
Sugar sensitivity increases, salt and quinine decrease
and acid is unaffected by temperature rise. The
greatest deviations occurred with different sweet
stimuli. Glycol showed little change with tempera-
ture whereas beryllium salts and other sugars followed
the sucrose curve. Certain acids showed slight up-
turn at either temperature extreme and different
salts showed a flattening out or even a fall beyond
37°C. With different bitter stimuli there was only an
increase in slope. Hahn & Gunther's values do not
include the extremes which cause insensitivity. If
extended, their curves would probably have shown
a rise in threshold at the low and high values.
524
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
One study among recent ones on the temperature
effect using an electrophysiological method reported
no change in response magnitude for sodium chloride
at temperatures of 20°, 25° and 30°C (19)- Another
study with the larger temperature range found only
a 10 per cent variation in magnitude response between
20° and 30°C, but larger effects outside these limits
with sodium chloride (i). There was a sharp rise
from 15° to an optimum of 22 °C with a gradual
fall from 22°C tb 37°C and a greater drop at 45 °C.
Since a fall in neural response magnitude is equiva-
lent to a rise in threshold, the electrophysiological
results are in agreement with the human data showing
that sodium chloride sensitivity falls off with tem-
perature rise, particularly above 22°C.
In interpreting the temperature effects it should be
remembered that biological systems have a normal
functional range beyond which biological arrest usu-
ally occurs. With extreme cooling or excessive heating
there may be irreversible changes (22). Thus bio-
logical systems with a mid-temperature region of
optimal function, in general, yield U-shaped functions.
It was the optimal range with which earlier workers
were concerned. The more careful study of systematic
changes within normal limits shows clearly that
temperature increase does not increase all taste
sensitivity. There is no simple temperature coefficient
in the usual sense.
AREA AND DURATION. Stimulation of single papillae
or of a limited area of the tongue by a single drop of
solution usually results in higher thresholds or less
intense suprathreshold tastes than does tasting by the
whole mouth (44, 198). The expression IS'^ = K
approximately describes the relation between thresh-
old intensity, /, and surface area, S, with exponents
of 0.73 for sodium chloride, 0.6 for citric acid, 0.93
for sucrose, and i .42 for quinine hydrochloride.
Threshold decreases with areas up to 60 to 90 mm-.
A similar relation also holds for the apparent in-
tensity of suprathreshold solutions (43)-
The relation between threshold and stimulus dura-
tion can be expressed as t = C/i" where / is duration,
i is threshold and C is a constant. For sodium chloride
and citric acid, n equals 1.5, for sucrose n equals 2.0.
A similar relation with shorter durations holds for
the electric taste (33). Similarly the apparent in-
tensity of suprathreshold solutions depends upon
duration. With long durations, the sensation of taste
waxes slowly, reaching a maximum for quinine in '8
to 10 sec. and for salt in 4 to 5 sec. With electric
taste the 'build-up' time is i to 1.5 sec. C42).
REACTION TIME. Most early workers report that bitter
yields the longest, and salty the shortest times with
sugar and acid intermediate (198). Because the
stimulus intensity influences reaction time (169), it is
necessary to specify this parameter. One recent study
(32, 34) utilized a flow system in conjunction with
an electrical measurement of the solution flow at the
tongue surface or onset of current, in the case of the
electric taste. Reaction times vary with different
qualities and within the same quality. Reaction time
is longest at threshold and shortest at the higher in-
tensities, often by a factor of three or more. It seems
reasonable, in \ icw of the uneven distribution of
sensitivity over the tongue surface, that reaction time
for different stimulus classes would vary with the
region stimulated. This parameter has not been in-
vestigated, however. An increase both in the area of
stimulated surface or of hydrostatic pressure of the
solution against the tongue surface decrea.ses reaction
time to some extent (108).
Adaptation
The continued flow of taste solution over the tongue
leads to a diminution in subjective intensity and an
elevation of the absolute threshold which is propor-
tional to the intensity of the adapting stimulus (see
fig. 15). The rate and form of the adaptation curve
within the same quality may vary with different
FIG. 15. Adaptation and recovery curves for NaCl. The
ordinate indicates the threshold concentrations. The course of
adaptation to three concentrations of NaCl, 5, 10 and 15 per
cent, is shown for an adaptation period of 30 sec. and a re-
covery period of 30 sec. The unadapted threshold is 0.24 per
cent. [From Hahn (92). j
THE SENSE OF TASTE
0^0
Stimuli, l)ut the recovery curves tend to have the
same shape (92). Subthreshold stimuli may elevate
the threshold in a similar manner but to a lesser de-
cree. Adaptation by acid adapts the sour taste for
other acids, but in the case of bitter and sweet stimuli
cross adaptation within these respective qualities may-
occur only between some but not all stimuli. More
striking, however, is the case of salt where no cross
adaptation was found among 24 inorganic salts
studied (94).
It has commonly been assumed that sensory adapta-
tion reflects the exhaustion of some receptive sub-
stance in the cell in a manner analogous to the
bleaching of visual purple by light. The combination
of the stimulus with such a receptive substance was
assumed to be necessary for stimulation (129), and
further that all stimuli eliciting the same quality
would be mediated by the same receptor substance
so that cross adaptation would result. Such a mecha-
nism for the salts would require 24 different receptive
substances in the taste cell. Hahn rejected this notion
and hypothesized a specific inhibition of the cell re-
ceptor membrane (change in permeability) for the
adapting stimulus only. The receptor cell itself was
not rendered inexcitable (94). Analogous results were
found in recent electrophysiological studies (20). No
cross adaptation between calciuin chloride and so-
dium chloride for example, was found, even though
the single fiber analysis shows that calcium chloride
and sodium chloride affected the same peripheral
fiber and receptor cell (75).
Bujas has pointed out that the subjective intensity
of taste does not always parallel the peripheral process.
Maximal subjective intensity develops only after the
stimulus has been acting for some seconds. During
this 'buildup' period, however, the receptor sensi-
tivity is falling as shown by the rise in threshold.
Subjective intensity begins to fall off^ only later,
showing that the magnitude of sensation is probably
the result of a central and peripheral process working
in opposition (37). Beidler has noted that the main-
tained steady discharge for sodium chloride in the
electrophysiological record is at variance with the
complete disappearance of salt sensation reported
for all but the strongest concentrations in the human
observer (2, 39, 127). This points to a process of
central adaptation.
Adaptation to sucrose or sodium chloride enhances
sensitivity to stimuli eliciting other qualities. Adapta-
tion by quinine enhances sensitivity to sour and salt,
but adaptation by hydrochloric acid does not affect
the other qualities (64, 140). It is well known that
distilled water appears sweet following a weak acid.
The recent finding that water acts as a stimulus for
certain taste endings and that the magnitude of such
discharge can be modified by prior treatment with
acids or other chemical stimuli suggests a peripheral
locus for some of these effects (136, 164).
A positive after taste, i.e. persistence of the same
taste quality after withdrawal of the stimulus, has
been attributed usually to residual taste particles in
the mouth or to slow dcsorption from the receptor
surface.
Interaction when two disparate areas of the tongue
are stimulated has been reported. Weak acid or sugar
solutions were said to reduce the threshold for salt
on the opposite side (119). An enhancement of salt
sensitivity occurs with weak sugar solutions but
inhibition or elevation of salt threshold occurs with
stronger sugar concentrations. Such effects with
stimulation of disparate sensory surfaces must have a
central origin. Successive contrast effects of a similar
nature also have been described (36, 198).
Unfortunately, there have been few systematic
studies of masking and interactions with taste mix-
tures, except for efforts to duplicate complex tastes
by mixing four components. One well-known inter-
action is the reduction of sourness by the addition of
sugar or other sweetener. This has been studied by
the electrophysiological method. The discharge of a
nerve strand to a mixture of 10 per cent sucrose and
an acid of pH 2.5 showed only an increase compared
to the response to the sugar or acid individually (10).
There was no peripheral inhibition. Such sour-sweet
interaction, therefore, must have a central locus.
Intensitive Relations
Differential sensitivity (A/ /) as found by different
investigators is summarized in table 9. Values from
i/io (10 per cent) to i i (100 per cent) with a
modal value of i '5 (20 per cent) have been reported
depending upon the intensity level, amount of stimu-
lus, criterion of judgment, etc., employed. Constancy
of A/// with intensity has been reported by some,
whereas others reported a decrease in differential
sensitivity at the high or low intensities, but the
change in these latter instances was relatively small
(approximately 10 times) compared with the too to
1000 times change found for vision and hearing. High
differential sensitivity for one taste quality is not
correlated with high sensitivity for others, and dif-
ferences between subjects may be greater than the
526
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOG\' I
TABLE 9. Differential Thresholds {Al/I)
in Taste Modalities
No. of
Subjects
Sweet
(Sucrose)
Salt
(NaCl)
Bitter
(CaSeine)
Sour (Cit-
ric Acid)
•
OS
2
2
6-8
6
2
10
9'
3.1
5' (e.gj
4-8'V3.7/
I
5-8
I
6.6
I
3.8
6.7
I
7.15
3
I
4-5
I
6.7
4-7
I
3-3
I
5-2
I
4-5
e
b
f
c
g
§
d
a
h
Range in
individ-
ual sub-
jects
I I
8 2
I I
10 2.5
I I
6.7 1. 15
I I
II 1.6
h
Median
fraction
Median
ratio
I
5
20%
I
6.6
15%
I
4
25%
I
4.8
21%
* a, Beidler (20); b, Bujas (35); c, Fodor & Happisch
(76); d, Holway & Hurvich (107); e, Kopera (126); f, Lem-
berger (133); g, SanduUah (185); h, Schutz & Pilgrim (186).
t Saccharin. | Quinine.
§ Krogh & Jensen cited in (126). Values obtained by
Keppler (117) were much lower than most values obtained
by above authors and have been omitted from the table.
differences in the same subject for different intensities
or qualities (186).
Attempts to measure or scale subjective taste in-
tensity have employed different methods. One is the
summation of just noticeable difference steps (JND's).
In one study, successive JND steps were determined
for two sweet substances, crystallose (sodium sac-
charin) and sucrose so that stimuli falling at equal
JND steps abo\e threshold could be specified (133).
These concentrations, however, were not equallv
sweet when directly compared. At high concentra-
tions, saccharin became relatively less sweet than
sucrose of an equal JND scale \alue. As in the case
of other modalities, the JND summation scale is not
a valid scale for subjecti\e magnitude (193). This is
also true when cross quality comparisons, e.g. salti-
ness versus sweetness, are carried out (35).
Another method, analogous to the equal loudness
measurement in hearing, utilizes the direct match
between one solution and an arbitrarily selected
set of standards (44, 158). For sweetness, a series of
sucrose solutions is often used; for sourness, hydro-
chloric acid, etc. This does not give taste intensity
directly, onK the relati\e taste effectiveness of dif-
ferent substances in eliciting equal taste intensities.
In recent years, a number of direct scaling methods
have been developed, stemming from the work in
audition. In one series of studies (17, 134) the frac-
tionation method showed that subjectise magnitude
increased directK with the physical concentration, a
special case of Stevens' general psychophysical law,
^ = s", where ^ is sensation, s is stimulus intensity,
and n is an exponent, the exponent in this case being
equal to one (193). Other studies using similar
methods found that taste intensity increased as an
exponential function of stimulus concentration, so
that the exact relation between taste intensity and
stimulus concentration is yet to be established (187).
Glucose is less sweet, molecule for molecule, than
sucrose. Furthermore the ratios of concentrations for
equal sweetness of the two sugars change with concen-
tration. Sweetness does not increase equally with
concentration for both (137). That this depends upon
some basic receptor mechanism is suggested by the
fact that the electrophysiological response in the
chorda t\nipani nerve of at least one species, the rat,
follows a rather different course for glucose than for
sucrose as shown in figure 16 (89).
These relations also bear upon another effect, the
so-called 'supplemental action' in mixtures of two or
inore sweetening agents. When glucose and sucrose
solutions are mixed, for example, the sweetness of
the mixture is greater than would be predicted by the
simple addition of the equivalent sweetness values of
each component stated in terms of the equisweet
sucrose solution. W hen such mixtures are computed
in terms of the equLsweet glucose concentrations,
however, the sweetness of the mixture is the sum of
the components. There is simple additixity with no
supplementary action (44). If it is assumed that the
magnitude of nerve impulse discharge determines
directly the magnitude of taste, i.e. sweetness, we
note that the sensory effect for glucose is nearly
linearly proportional to concentration, but for sucrose
it is cur\ ilinear, i.e. negatively accelerated. A graphi-
cal solution of the addition of 0.2 m glucose and 0.2
THE SENSE OF TASTE
527
sue a GLUC_
100-
UJ
to
z
0
^"^ •SUCROSE
a.
/ ^---^
<n
/' ^^^"^
80-
^>^
u.
y' a GLUCOSE
SO-
0
/ol B /
UJ
0
3
/ / .- 0 MALTOSE
K
/ / /' '-''
40-
H
0
•/ / y
<
20-
/
/ y'
"^tJ.^ ,-- DISCHARGE
MOLAR CONCENTRATION
0 —
1 1 1 1 1 1 1 1 1 1
value to match .34 sucrose. There is no supplemental
action by this computation. The apparent supple-
mental action with one set of transformations but not
the other is due to the attempt to add arithmetically
one linear to one nonlinear function. This example,
although derived theoretically from the electrophysio-
logical response curves, can be matched almost
exactly by empirical data from psychophysical ex-
periments on man (44). Further study of taste mixtures
by the electrophysiological method is desirable. The
additive analysis presented in figure 16 is theoretical
except that the response curves for the individual
sugars are based upon experimental points.
BEH.^VIOR.^L EFFECTS
FIG. 16. Response of rat chorda tympani nerve to different
concentrations of different sugars. The dashed line SUC. &
GLUC is the summated response to be e.xpected when sucrose
solutions are added to 0.2 M glucose. See text for discussion.
(From Hagstrom, E. C, unpublished observations.)
M sucrose solutions in a mixture can be made from
figure 16 by adding the sucrose curve to the response
of 0.2 M glucose at A, so obtaining the dotted line.
The total sensory effect of the mixture should be the
sum of the two functions at point B. B equals 62
units, a magnitude of nerve discharge that could be
produced either by .34 sucro.se or .94 glucose, indi-
vidually. The empirical match to the original mixture
can be stated as:
.2G + .2S = .34S
CO
In sucrose equisweet solutions where .2G = .04.S, the
equation (/) becomes
.04S -|- .2S = (sucrose match)
C^).
But since the arithmetic sum of .04S -\- .2S is .24
and not .34 (a difference of .10) there is supplemental
action. That is, the empirical match shows a stronger
sucrose concentration than could be predicted by
the simple addition of equisweet sucrose solutions
(i.e. the mixture is sweeter). Setting equation (/) in
terms of glucose where .2S = .74G we have:
.2G -(- .74G = .94G (and .94G = .34S).
The arithmetic sum of .2G -|- .74G equals exactly
.94G which is the same as the equivalent glucose
Taste stimulation is most directly related to food
taking and the rejection or avoidance of noxious
stimulation. Hence, the manifold of four basic tastes
of salt, sour, bitter and sweet can be reduced to two
behavioral classes, acceptance 01 rejection. Certain
substances are rejected in all concentrations; others
may be accepted at low but rejected at high concen-
trations; still others may be accepted at all concen-
trations. Acceptance or rejection may also be in-
fluenced by postingestion effects, by the metabolic
condition of the organism and by past conditioning
or learning. Thus taste is only one of several determi-
nants of appetitive behavior.
Richter (177) in his classical studies of self-selection
demonstrated that the animal's behavior was a part
of "'the total adjustive mechanism working toward the
constancy of the internal en\ironment. " The adrena-
lectomized rat will increase the intake of salt solution
to such a degree that it not only survives but gains
weight. It is significant that the albino rat under
normal conditions, i.e. when not salt hungry or
hormone deficient, displays a striking preference for
sodium chloride and other sodium salts (15, 176, 203).
This behavior is exaggerated after adrenalectomy as
evidenced by a lowered preference threshold and
greater intake of all salt solutions above threshold
in preference to water. An excess of .salt in the diet
reduces the preference and may even wipe it out,
leaving only an aversion over the entire stimulus
range. Figure 1 7 summarizes these behavioral phe-
nomena together with a plot of the magnitude of the
afferent nerve discharge of the chorda tsmpani nerve
in the rat. The solid line curves show the relative
preference in per cent (cc salt 'cc salt -|- cc H2O)
under four conditions: adrenalectomized, normal (jV),
528
HANDBOOK OF PHYSIOLOGY'
NEUROPHYSIOLOGY I
with 5 per cent extra salt in diet and lo per cent
extra salt. The basic preference-aversion response
(TV) is shifted systematically by these changes in
salt need. In the normal animal, the preference
threshold lies above the concentration at which a
discharge of nerve impulses can be detected. In the
adrenalectomized rat the preference and electro-
physiological thresholds are more nearly equal. The
normal animal thus appears to taste the salt but does
not ingest it. The adrenalectomized rat takes the
salt solution when he can taste it (165).
The neural response curve of the receptor appears
to be a stable properly of the taste bud. The threshold,
i.e. a minimum concentration necessary to elicit a
discharge of the taste receptors, is essentially the same
in normal and adrenalectomized rats (166). This has
been confirmed in studies using the conditioned reflex
method (.15, 98). Thus the change in self-selection
behavior cannot be explained by a peripheral change
in sensitivity of the taste receptors. Of similar import
is the finding of the constancy of the chorda tympani
response in insulin hypoglycemia (167). Insulin in-
jection typically leads to a striking increase in the
preference for sugar solutions in a free choice situa-
tion.
Richter has presented evidence that the compensa-
tory increase in intake fails when the sensory nerves
to the tongue are surgically removed (175). The
attenuation in preference behavior in the normal
animal after combined chorda tympani-ninth nerve
deafferentation further supports the view that taste
stimulation triggers the response to taste solutions
(162). A rat with an esophageal fistula will show the
salt preference even when the .solution does not enter
the stomach and cannot ha\e a metabolic effect (192).
At the same time the ingestion of water or salt solu-
tions can be modified by stomach loading by intuba-
tion with sodium chloride solutions which 'by-passes'
taste, but the effect is less than when the same amount
of .solution is taken by mouth so that the taste recep-
tors are stimulated (132). Thus both taste and intra-
gastric factors may influence drinking C204).
%
100.
80.
60.
40-
20-
0 r
-3
o es
-8.0
-1.5
-1.0
- .5
1
-2
NoCI LOG M Cone.
"T"
0
FIG. 17. A composite graph of the neural response (broken line) and the preference curves (solid
lines') for different concentrations of NaCI. The neural response curve (ordinate to the right) shows
the magnitude of the electrical activity in the chorda tympani nerve of a normal rat. Each open
circle is a measure of the integrated electrical activity (in milliamperes, ma.) of the discharge at
each concentration. The preference curves were obtained from four different groups of animals:
adrenalectomized (adren.), normal (.V), normal with 5 per cent additional salt in the diet (j'/c)
and normal with 10 per cent additional salt in the diet (/o%), respectively. Each point is the av-
erage preference (or aversion) indicated as a percentage (cc intake salt) -f- (cc salt -|- cc H-.O) at
each concentration. Each point is the average consumption for a 48-hr. period when both water
and salt solution were continuously available. Salt solutions were presented in ascending order of
concentration. [From Pfaflfmann (165).]
THE SENSE OF TASTE
529
The role of taste or other head receptor stimulation
can be uncovered if the postingestion factors can be
eliminated or minimized. In the brief exposure be-
havioral test which permits little ingestion, rats show
a preference for the higher of two concentrations of
sugar solution over a wide range of pairs. But such
equally accepted solutions are not equally ingested
in continuous drinking periods as brief as 20 min. in
which the higher concentrations are usually con-
sumed in lesser amounts (204). McCleary (^142) has
clearly demonstrated the role of intragastric osmotic
pressure in this effect.
In another behavioral test, the Skinner box with
sugar solutions as reinforcers, the rate of bar pressing
on an aperiodic reinforcement schedule is faster, the
higher the concentration of sugar (87). This schedule
provides relatively little drinking per response and
apparently minimizes postingestion factors. Further-
more, the concentrations of two different sugars,
glucose and sucrose found to give equal rates of re-
sponse, i.e. to have equal reinforcing value, corre-
spond to the equally preferred concentrations in the
short exposure test and to the equally sweet concen-
trations of these sugars for man. Thus, the direct
sensory taste effect appears not only to instigate in-
gestion but to be capable of reinforcing the acquisi-
tion of other responses leading to ingestion. The
usual measures of intake obscure the relation to
sensory stimulation because of postingestion effects.
The nutritional consequences of sugar stimulation
do not appear to be essential for such reinforcement.
Nonnutritive saccharin solutions can also serve as
reinforcers for the acquisition of a maze-running
habit (189). The degree of reinforcement appears to
be correlated with the amount of consummatory be-
havior elicited. Whether reinforcement power is de-
termined by the magnitude of the afferent excitation
per se or by the magnitude of the consummatory be-
havior elicited, is not yet clear.
The fact that certain taste stimuli control ingestion
directly appears to be biologically determined, for
nearly all organisms accept sugar solutions (78).
Although there is evidence that direct injection of
nutrient sugar into the blood stream may serve as a
reinforcer of learning, there is no evidence that the
"sweet tooth' depends upon the concomitant nourish-
ment. The drinking of nonnutritive saccharin solu-
tions shows no sign of extinction which would be ex-
pected if the preference for saccharin were acquired
by the association of the sweet taste with nourishment
(189).
The aversion to certain stimuli like bitter appears
to be relatively unmodifiable by experience. In one
experiment, guinea pigs two days post jiartum were
provided with a nontoxic but normally avoided
solution as the only source of fluid until three weeks
of age. This substance has an extremely bitter taste
for man. Following this early exposure, preference
tests showed that the avoided stimulus had been
rendered somewhat more palatable, but in a retest
three months later the effect had dissipated so that
there was no difference between the control and ex-
perimental animals. The aversion had not been
moderated by the early experience (168).
Thus the factors that control behavior in the taste
preference and related situations are becoming
clearer. Taste may trigger ingestion behavior but
alone does not accoimt for it. In many instances, feed-
ing behavior is directed toward the physiological
well-being of the organisms; but situations and
habits may exist which are contrary to the physiologi-
cal well-being. According to Young, "New habits
tend to form in agreement with bodily needs, but
established habits tend to persist as regulators of
food selection even when the food selections are out
of line with bodily needs." The limitations of self-
selection are well documented (85, loi, 204).
Certain of these basic principles appear to be valid
for man. Instances of enhanced salt craving reported
by Richter included the case of a small boy who
apparently compensated for adrenal insufficiency
with an excessive intake of table salt (177). Patients
in whom hypoglycemia had been produced for
therapeutic reasons were reported to find strong
sugar solutions more palatable than when blood sugar
levels were normal (141). The bizarre taste cravings
of pregnant women are well-known. The change is
not one of taste sensitivity but one of changed likes
and di.slikes (97). The metabolic disequilibria of
diabetic patients are often associated with strong
cravings for sweet, although to satisfy this would
run counter to the individual's well-being (i 77). Thus,
although metabolic changes may be important factors
in determining the hedonic value of a taste stimulus,
such changes do not always automatically lead to
self-corrective behavior.
The well-known fact that human subjects can taste
certain substances when injected intravenously ap-
pears to support the view that taste sensiti\ity can
be influenced by constituents in the blood stream
(102). As already noted, neither the adrenalectomized
nor hypoglycemic animal shows evidence of a change
in taste sensitivity when studied electrophysiologically.
In another study with this method, preliminary re-
530
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
+ 100^
! + 50^
S-50^
-100^
Stimulus Concentration
FIG. i8. Preponderance of pleasant' or unpleasant' judg-
ments in relation to the concentration of taste solution. Ordmale
gives per cent 'pleasant' minus per cent unpleasant.' The
abscissa is proportional to the concentration, the full length of
the base line standing for 40 per cent cane sugar, i . 1 2 per
cent tartaric acid, 10 per cent NaOl and 0.004 per cent quinine
sulphate (all by weight). [From Engel, as reproduced in
Woodworth (200).]
suits showed no impulse discharge following intra-
venous injection of taste stimuli (Beidler, L. M.,
personal communication). Further electrophysiologi-
cal studies of 'intravenous taste' are called for.
Sherrington (190) has noted that stimulation of the
contact sense organs often initiates a chain of responses
culminating in consummatory behavior. Taste along
with tactile stimulation of the mouth leads directly
to the retention, chewing and swallowing of food or
its expulsion. Strong affective or hedonic tone ap-
pears to he a basic property of 'nonprojicient' receptor
stimulation as compared with the more neutral conse-
quences of distance receptor stimulation.
Troland (196) divided receptor stimulation into
classes of innate biological utility. These were
nociception, associated with deleterious agents; bene-
ception, with stimuli of biological utility; and neutro-
ception, with stimuli of relatively neutral character.
Different tastes might fall in either the beneceptor
or nociceptor classes. These three classes correspond
closely to the neutral, unpleasant or pleasant affectiv-e
lone aroused by sensory stimulation (202).
Intensity as well as taste quality is a determiner of
hedonic rating as shown in figure 18 (73). Quinine
is mostly unpleasant and is increasingly so with in-
crease in stimulus concentration. Sucrose is mostly
pleasant but acid and salt are intermediate, showing
a rise in pleasantness to a maximum and then a fall
with increase in concentration. These hedonic curves
appear to resemble the preference cur\es found in
animal studies (.see fig. 16), particularh for salt and
quinine. Hedonic ratings of more complex tastes and
flavors can be obtained with human subjects by
means of rating scales, paired comparison judgments
and other similar tests. These have had wide practical
application in the food industry and the armed forces
for assessing the palatability of food and rations. Such
ratings can be reliable predictors of the actual accep-
tance in the field (171).
Acceptability of food by man, of course, is deter-
mined not alone by taste. Food habits, cultural con-
ditioning, immediate social pressures or other com-
plex psychological factors play a significant role in
acceptability. Acceptability is not a property of food.
The acceptance of food is a response of the organism,
and taste as one component in flavor may play an
important role in determining this response.
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CHAPTER XXI
The sense of smell
\V. R. A D E V \ Department nf Anatomy, University of Melbourne, Melbourne, Australia
CHAPTER CONTENTS
Olfactory Mucosa and Peripheral Receptor
Arrangement of C31factory Mucosa
Olfactory Bulb and Its Connections with Olfactory Mucosa
Essential Processes Involved in Olfactory Stimulation
Characters of Odorous Substances
Enzyme Theories of Olfaction
Radiation Theories of Olfaction
Methods of Odor Measurement
Subjective measurement techniques
Objective measurement techniques
Electrical Phenomena in Olfactory Bulb Accompanying Ol-
factory Stimulation
Patterns of Spontaneous and Induced Activity in Bulb and
Effects of Anesthesia
Spontaneous waves
Waves and unit activity accompanying olfactory stimula-
tion
Differential Excitation of Receptors
Differentiation of response in area
Temporal differentiation of response
Central Connections of Olfactory Bulb
Efferent Pathways From Olfdctory Bulb
Extent of Primary Olfactory Cortex
Neuroanatomical investigations
Electrophysiological investigations
Higher Order Olfactory Connections
Behavior Studies of Olfactory Mechanisms
At alt stages of corticat etaboratio7i an important function of
ttie olfactory cortex, in addition to participation in its own
specific way in cortical associations, is to serve as a non-specific
activator Jor all cortical activities.
C. J. HERRICK, 1933
WHILE THE IMPORTANCE of the olfactory sense is
greatly reduced in primates in comparison with other
telereceptor mechanisms, such as sight and hearing,
it can nevertheless provide significant information
about events possibly remote in space and time. In-
deed, olfaction may provide the only warning of
serious environmental hazards, and in man it retains
its importance in feeding and sexual functions.
There remain many baffling aspects to even the
most basic phenomena in the olfactory process, par-
ticularly in the mechanisms ins-olved in excitation of
the peripheral receptor and in the physiological
patterning of activity through which fine differences
in odors are presumably perceived.
OLF.\CTORV MUCOS.\ AND PERIPHER.XL RECEPTOR
Arrangement nf Oljactory Mucosa
The olfactor\- mucosa forms a restricted zone in
man, lying in the dorsal and posterior part of the
nasal cavity. To the naked eye it appears yellowish-
brown in comparison with the rest of the mucosa,
and it covers the upper parts of both the lateral wall
of the nasal cavity and septum, extending over a
total area of about 240 sq. mm (66). The olfactory
mucosa is a pseudostratified columnar epithelium
and, unlike the respiratory portion, has no distinct
basement meinbrane or cilia. It lines the surface of
nearly all the superior turbinate, a small part of the
middle turbinate and the upper third of the nasal
septum (fig. i).
Inspired air traverses the inferior meatus and
partially the middle meatus during normal breath-
ing, and the olfactory area is thus above the main
air current. Since a change in breathing, as in sniffing,
causes adequate eddying of air into the upper olfac-
tory area, it is apparent that aerodynamic factors
may be intimately concerned in determining thresh-
olds of excitability (56).
The olfactory receptors or hair cells are bipolar
535
53^
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
FR. S.
SPH. S.
FIG. I. Diagrammatic representation of the lateral wall of
the nasal cavity, indicating the general extent of the olfactory
epithelium (dotted). The main stream of inspired air passes
below the olfactory region. Secondary eddying of air currents
carries odors to the receptor region. Abbreviations: CR.PL.,
cribriform plate, perforated by the olfactory nerves, FR.S.,
frontal air sinus; I.T., .\I.T., S.T., inferior, middle and su-
perior turbinate bones projecting as ledges from the lateral
wall of the nasal cavity; SPH.S., sphenoidal air sinus.
and oval. When seen by light microscopy, they pos-
sess distally small terminal swellings from each of
which five to six olfactory hairs commonly arise. In
the rabbit, these cells are estimated to number 150,000
per sq. mm (35). Electronmicroscopy indicates that
the hairs are considerably more numerous, with up
to 1000 hairs per cell (23). Each hair is i to 2 /:i long
and o.i /a in diameter. In this way the surface area ex-
posed by the receptor cell is greatly increased (fig. 2).
Clark (32) points out, however, that near the pe-
riphery of the olfactory epithelium there is some
intermingling of olfactory receptors and ciliated
epithelial cells of the 'respiratory' region, and that
this may lead to misinterpretations in electronmicros-
copy of the olfactory hairs, which he considers to
be coarser and to remain untapered at their free ex-
tremities.
Removal of the olfactory bulb in the raljljit pro-
duces a very striking degeneration in 48 hr., with
almost complete removal of the debris of the mucosal
receptors within three days (33). However, only
about half the receptors degenerate after complete
removal of the bulb, the remainder persisting un-
altered up to six months after operation. The findings
do not support the concepts that the axons of the
residual elements may proceed to adjacent areas of
the olfactory epithelium, rather than to the ijulb, or
that they may give off collaterals sufficient to main-
tain the cells. The possibility is considered of a cen-
trifugal system of fiijers arising in the bulb and
proceeding peripherally to the mucosa.
The secretions of the numerous serous and mucous
glands in both the respiratory and olfactory regions
of the nose bathe the entire cavity in a liquid sheath
which is in a constant state of motion towards the
nasopharynx. This sheath may be of basic importance
in conveying odorous substances to the receptor cell,
since varying degrees of water and fat solubility in
the tissues of the mucosa may be related to the odorous
properties of a particular substance (see below).
The electrical responses of the olfactory mucosa of
the frog have been successfully recorded by Otto.son
(76). Odorous air blown into the nasal cavity evokes
a slow negative monophasic potential in the olfactory
mucosa (fig. 3). The response is obtained only from
the olfactory area of the mucosa and is not abolished
by cocaine in concentrations sufficient to paralyze
olfactory nerve fibers. It is abolished i^y small amounts
of ether or chloroform vapor, and it is inferred that
the response arises in the olfactory hairs. The ampli-
tude of the respon.se is, within certain limits, propor-
tional to the logarithm of the stimulus intensity.
Equal amounts of odorous material distributed in
different volumes of air evoke responses of equal
amplitudes. The shape and time course of the re-
spon.se is related to the strength of the stimulus. With
an increase of odor intensits' in the stimidating air.
HG. 2. Electronmicrograph of the surface of a human ol-
factory cell, showing a great number of thin finger -like processes
1.5 to 2.0 11 long. Magnification X 23,430. [From Bloom &
Engstrom (23).]
THE SENSE OF SMELL
537
FIG. 3. Rhytlimic waves superimposed upon the slow potential. Stimulus; amy] acetate. Volume
of stimulating air, 0.25 cc. Vertical line 5.0 mv. Time bar, i sec. [From Ottoson (76).]
FIG. 4. Rhythmic waves evoked by continuous stimulation of the olfactory epithelium. Stimulus:
0.1 mole butanol. Velocity of stimulating air stream, i.o cc per sec. Vertical line i.o mv. Time bar
0.5 sec. [From Ottoson (76).]
the potential rises at a faster rate, the crest of the
response broadens and the decay time lengthens. The
'wave form' of the stimulating air current is of great
importance in determining the shape and time course
of the response. The latency of the response to stimu-
lation with butanol of different stimulus strengths
varies from 0.2 to 0.4 sec.
Ottoson has found that during continuous stimu-
lation the evoked response in the olfactory epithelium
declines from the initial peak to a lower level which
continues throughout stimulation (fig. 4). The ampli-
tude of this residual response is lower at higher stimu-
lus intensities. With repeated stimulation at short
intervals, the first three or four responses are pro-
gressively diminished, with greater reductions at
higher stimulus strengths. The sensitivity of the
epithelium to different substances can be selectively
reduced by repetitive stimulation, and rhythmic
oscillations are often seen on the peak of the slow
response evoked by strong stimuli.
Olfactory Bulk and Its Conrnrllons with Olfactvry Mucosa
The olfactory nerve fibers arising from the hair
cells penetrate the overlying cribriform plate of the
ethmoid bone and enter the olfactory bulb. Electron-
microscopy of the olfactory nerves indicates a unique
appearance, with large numbers of very small nerve
fibers having a modal diameter of 0.2 n. They num-
ber six million from one side of the nasal septum in
the pig and are considerably more numerous from
the turbinates (45). There appears to be a one-to-
one relationship between receptor cells and axons.
Their conduction velocity in the pike is 0.2 m per
sec, thus resembling the last elevation in the C fiber
action potential in the frog's .sciatic nerv-e.
Within the outer layers of the bulb the fibers of the
olfactory nerves enter into the formation of glomeruli
(fig. 5). Each glomerulus is formed jointly by enter-
ing olfactory nerve fibers and also from the dendrites
of more deeply situated mitral and tufted cells. These
cells forrn the succeeding second order neurons on
the olfactory pathway. The arrangement is an excel-
lent one for spatial summation, since each glomerulus
in the rabbit receives impulses from 26,000 receptors
and passes this information through 24 mitral cells
and 68 tufted cells (15, 16). The axons of the 60,000
mitral cells form the bulk of the lateral olfactory
stria passing to higher olfactory centers.
Physiological and anatomical evidence confirms the
existence of a regional projection pattern from the
olfactory mucosa to the bulb. Impulses from the
538
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
OLF. N.F.
FIG. 5. General arrangement of the neural paths in the ol-
factory bulb. Fibers from the receptor cells are collected on
the surface of the bulb (OLF .„V.F.) and participate in the for-
mation of more deeply situated glomeruli iGLOM') which
also receive the dendritic processes of the mitral cells (^W) and
the tufted cells (T). Axons of mitral cells are mainly collected
into the lateral olfactory tract QLAT. OLF. TR.') and run to
the primary olfactory cortex. The finer axons of tufted cells
pass into the anterior limb of the anterior commissure, reach-
ing the opposite bulb where they synapse with deeply situated
granule cells (G). .■\xons of granule cells are directed peripher-
ally at least as far as the fields of the mitral and tufted cells.
OLF. VEjVT. represents the olfactory ventricle present in
lower mammals and continuous with the cerebral ventricular
system.
anterior and dorsal parts of the olfactory mucosa
reach the anterior parts of the iaulia, whereas the
ventral and posterior reE;ions of the mucosa project
to the posterior parts of the bulb (5). Although initial
anatomical studies (35) did not support a topographic
arrangement, more extensive investigations (31) have
confirmed the general arrangement suggested bv
Adrian. The upper part of the olfactory epithelium
projects mainly to the upper part of the bulb, and
lower areas of epithelium to lower regions of the
bulb; but anatomical evidence of an anteroposterior
organization of the projections is less definite.
ESSENTIAL PROCESSES INVOLVED IN
OLFACTORY STIMULATION
Characters nf Odorous Substances
No embracing picture can yet be advanced to
categorize all odorous substances, since many are
totally unrelated physically and chemically. Hill &
Carothers (54) observed a relationship between the
number of atoms in certain macrocyclic ring hydro-
carbon compounds and the nature of their odors.
Thus compounds with 13 atoms possess a cedar-like
odor, with 14, 15 or 16 atoms a musk-like odor, and
with 17 or 18 atoms a civet-like odor. For example,
pentadecanolide and decamethylene oxalate both
have musky odors.
-CO
(CH,)i4
(CHOi,
Pentadecanolide
O
- O
I
CO
!
CO
I
- o
Decamethvlene oxalate
Hill & Carothers suggest that, within wide limits,
the number of atoms in the ring, rather than the
identity of the reactive groups, is the significant fac-
tor. However, many anomalies have limited attempts
to extend this hypothesis. Moncrieff (68) has sug-
gested that to be odorous a substance must be volatile
and soluble in the tissues of the olfactory mucosa, the
latter property involving varying degrees of water
and fat solubility. The olfactory mucous membrane
exhibits considerable powers of adsorbing odorous
substances in the freshly isolated state, and this
sorptive property may be intimately related to proc-
esses of excitation in olfactory receptors (69). Mon-
crieff further suggests that the disposition of an ele-
ment in the electrochemical series may be correlated
with odorous properties, since only seven elements
are odorous (fluorine, chlorine, bromine, iodine,
oxygen as ozone, phosphorus and arsenic), and six
of these occupy the lowest places in the electrochemi-
cal series. The disposition of substitution groups in
organic compounds is of great significance in deter-
mining both strength and quality of odors. Legge
(64) has advanced the hypothesis that odorous sub-
stances may react with groups on the free surface of
protein and lipoprotein films, leading to the rupture
of a few bonds in incompletely spread proteins with
a consequent enorinous increase in their area. In view
of the role played by — S — S — groups in the main-
tenance of protein structure, the rupture of bonds
induced by odorous substances might explain the
high dilutions at which mercaptans can be detected.
On the basis of records from the olfactory bulb,
.\drian (10) has defined four groups of .substances,
and in each group has detected one substance capable
of evoking a discharge limited to a single one of the
units within the range of the electrodes. Acetone
THE SENSE OF SMELL
539
exhibits a high specificity in a group which includes
amyl and ethyl acetate. Benzene behaves similarly
in a group composed of aromatic hydrocarbons.
Octane is similarly active in a group of paraffin
hydrocarbons and heavy oils. Dipentane, cedarvvood
oil and eucalyptus oil (substances belonging to the
terpenes and related compounds) likewise give single
unit discharges.
The ability of various substances, including metal
surfaces, to adsorb and retain foreign odors has been
tested by Deininger & Sullivan (36). The great ma-
jority of metal surfaces not only pick up odors, but
also modify and distort them, often so severely as to
leave little suggestion as to the original contaminant.
This perversion of the perceived odor is not related
to the purity of the metal in the case of either copper
or aluminum.
Enzyme Theories of Olfaction
Alexander (11) has suggested that odor-producing
substances affect the catalyst balance of the olfactory
cells. This theory has been elaborated by Kistiakow-
sky (60) in an hypothesis that substances having odor
inhibit a reaction requiring a catalyst. These changes
in the concentration of reaction products would
cause excitation in specific receptor units. Sumner
(81) has criticized this concept on the grounds that
substances we smell, in the concentrations needed to
smell them, would not be likely to have any effect
on any known enzyme systems and would require an
array of enzymes with new and unusual properties
in the olfactory mucosa. Beidler (21) points out that
some substances are eff^ective olfactory stimuli in
concentrations as low as io~'' molar.
Even if an odorous substance should inactivate an
enzyme, thus causing a change in concentration of
certain substances, there is as yet no explanation as
to how this change in concentration could stimulate
olfactory nerves. Bourne (26) and El-Baradi & Bourne
(38, 39} have detected significant amounts of alkaline
phosphatase in the olfactory mucosa and in the taste
buds of the tongue and have observed that vanillin
inhibits this alkaline phosphatase. However, alkaline
phosphatase is widely distributed throughout the
body. Goldwasser, quoted by Sumner (81), suggests
that the energy needed to stimulate olfactory recep-
tors may come from Pauling's electrochemical energy
source deriving from the modification of bonding
angles within a molecule at the time that the molecule
goes into solution.
Radiation Theories of Olfaction
Theories of electromagnetic radiation or molecular
viljration in relation to olfaction have engaged luany
workers (20, 37, 74, 84, 90). However, there appears
to be little or no experimental foundation for the
concept that the essential properties of odor result
from radiations inherent in molecular behavior (73).
Indeed, a suljstance such as the deuteroxyl counter-
part of n-butyl alcohol has exactly the same odor as
the original «-lnit\l alcohol, although its infrared
adsorption spectrum is different (89). On the other
hand, certain (^/- and /-isomers diflfer in smell, although
their infrared spectra are identical. No evoked elec-
trical responses can ije recorded from the olfactory
mucosa if it is covered with a thin plastic membrane
which transmits infrared radiation but impedes con-
tact between the stimulating particles and the epi-
thelium. There is no indication that olfactory re-
ceptors can be stimulated unless the odorous material
is brought into contact with the epithelium (76).
Methods oj Odor Measurement
SUBJECTIVE ME.ASUREMENT TECHNIQUES. SourCCS of
error in the subjective assessment of odor quality
and intensity have been discussed in a historical sur-
vey by Wenzel (87). It is obviously difficult to con-
trol such factors as the force of the ob.server's inhala-
tion in methods invoking the ' sniff technique, nor
does the administration of the odorous substance by
a stream of air at constant pressure necessarily con-
trol mechanical factors in\'olved in the eddying of
air towards the olfactory receptors in the upper part
of the nasal cavity.
Only a few of the many subjecti\e methods will be
discussed here, since all appear to involve significant
possibilities of error in assessment of threshold, and
there are conflicting opinions as to their relative
merits. A number of early methods, typified by the
olfactometer of Zwaardemaker (90), involved sniffing
gradually increasing intensities of the odorous sub-
stance up to threshold concentration. In attempts to
obviate subjective sniffing, both injection of a blast
of air and a continuous stream of air have been tested
by Elsberg & Levy (40). They defined the absolute
olfactory threshold as the minimal blast of odorous
air capable of producing a sensation of odor. Although
the measurement so obtained is usually expressed in
terms of volume, Jerome (55) has suggested that these
threshold measurements are dependent on pressure
of the air Ijlast rather than on odor intensity. Jones
(56) has also found that aerodynamic factors, es-
540
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
pecially pressure, determine the threshold in the
blast injection technique and that the threshold so
determined is not related to odor concentration.
Since neither subjective sniffing nor the substitu-
tion of an air blast for the observer's own sniff dispose
of many of the difficulties in odor threshold measure-
ment, Wenzel (88) has studied the reliability of
threshold measurements during normal breathing
with the subject's head placed in a camera inodorata.
Here a plastic box encloses the subject's head, and
the hair and face can be covered with plastic to
eliminate their odors, leaving only the nostrils ex-
posed. A continuous stream of pure air to which
odors can be added is fed into the box. This method
is claimed to give satisfactory results in threshold
measurement without the need for prior training of
the subject.
It has been claimed that subjects can match odors
quantitatively by the use of a standard "sniff' tech-
nique, using as test substances two aliphatic homol-
ogous series, comprised of the alcohols butanol (CO
through duodecanol (Cii), and the acetate esters
hexyl (Ce) through duodecyl (C12), each prepared in
serial dilutions (19). No attempt was made in these
tests to instruct the subject in the technique of sniffing,
reliance being placed on the subject's existing habits.
Results were consistent in repeated trials, with odor-
osity decreasing as a function of molecular chain
length, and also with dilution, for both alcohols and
acetates.
Kuehner (61) has used an air-dilution method in
determining olfactory thresholds and stresses the
need to standardize the subject from day to day by
exposing him to standard vapor concentrations. Ex-
treme variations of sensitivity noted in individuals
make it impossible to take odor measurements over
extended periods without knowledge of the subject's
sensitivity at the time of sampling. One breath of
ammonia can reduce the sensitivity by 50 per cent
for 24 hr. At the onset of a head cold, the sensitivity
is sharply increased but later is depressed. A marked
temporary reduction in sensitivity follows excessive
drinking or smoking. Kuehner used air saturated
with xylene vapor as a reference odor and in a pro-
longed series of experiments with two subjects ex-
hibiting similar sensitivities found that its normal
odor level was 380 times greater than threshold.
Under the same conditions, nicotine saturated air to
3000 times the threshold intensity.
OBJECTIVE ME.\SUREMENT TECHNIQUES. Kuchner (6l)
claims that odorous substances are capable of react-
ina; with oxidants and that the resulting deodoriza-
tion is related to the amount of oxidant reduced.
While efforts to find reproducible concentrations of
individual odors in a complex, such as tobacco smoke,
were unsuccessful, it was found that certain oxidants
react with odor complexes in a reproducible manner,
thus confirming the earlier observations of Lang et al.
(62). Kuehner found a close uniformity in odor pro-
duction by tobacco artificially burned in this system
regardless of type, freshness and rate of combustion,
and established that tobacco smoked by humans
produced only 40 per cent of the odor level of that
'smoked' artificially, both in its reducing powers with
oxidants and as determined subjectively under room
conditions. This technique has been criticized by
Turk (85) on the grounds that cxidant methods,
which usually employ permanganates or eerie salts,
may be inadequate because of a lack of relationship
between quality or intensity of odorants and their
reactivity toward a chemical oxidant. Such methods
may indicate only the reducing or oxidizing qualities
of the extraneous atmospheric gases and vapors.
Turk (85) has used infrared adsorption spectra of
odorous substances as a means of qualitative analysis.
Different functional groups, such as aldehyde, alco-
hol and ester linkages, show typical infrared adsorp-
tion frequencies. Thus the infrared spectrum of a
mixture of compounds reveals information on the
types of individual compounds therein, and by this
means Turk has been able to detect vaporized mineral
oil as a component of apple aroma in commercial
apple storage rooms. It has already been mentioned
that this method may not be free from error, since
substances with similar odors may have different ad-
sorption spectra and vice versa (87, 89).
ELECTRICAL PHENOMEN.A IN OLF.ACTORY BULB
.ACCOMP.ANYING OLF.ACTORY STIMUL.ATION
Patterns of Spontanrous and Induced Activity in Bulb
and Effects of Anesthesia
The rhvthmic waxes that can be recorded from
the surface of the bull) have been extensively investi-
gated (4-10, 72, 86). Whereas Adrian's initial ex-
periments suggested rhythmic discharges in the bulb
svnchronously with each ijieath, later experiments
(5, 9) have shown that with filtered air no mechanical
stimulation occurs. Both spontaneous waves and
those which occur in response to strong olfactory
stimuli have been recorded in the bulb.
THE SENSE OF SMELL
541
FIG. 6. Intrinsic waves' recorded in the olfactory bulb in light thiopental anesthesia. A: No ol-
factory stimulus. Frequency, 100 /sec. B: Abolition of intrinsic rhythm by weak olfactory stimulation
with amyl acetate. C: In another preparation, strong stimulation with amyl acetate abolishes the
intrinsic rhythm with substitution of a slower induced rhythm. [From .\drian (5).]
SPONT.ANEnus WAVES. Thcsc are usually smaller and
less regular than waves evoked by olfactory stimula-
tion and are associated with persistent activity in the
cells of the bulb. They were described in the isolated
olfactory bulb of the frog (47). Their frequencies are
as high as 70 to 100 per sec (fig. 6). They are sup-
pressed in the mammal by deep anesthesia and they
accompany a persistent irregular discharge of axon
spikes in the deeper layers. In medium anesthesia
this discharge may be so large as to conceal any
change induced by a weak olfactory stimulus. This
continuous activity persists after complete destruction
of the olfactory epithelium and after isolation of the
bulb from the forebrain but ceases after interference
with the blood supply of the bulb.
Adrian (5) regards this activity as largely spon-
taneous or intrinsic, expressing the continuous break-
down and repair of cells not stabilized by deep anes-
thesia. Although mitral cells certainly take part in
this activity, there is some reason to suppose that it
may originate in cells with short axons (granule
cells) arranged in layers deep to the mitral cells. This
is suggested by the fact that the intrinsic waves can
exhibit considerably higher frequencies than the in-
duced waves. If the induced waves indicate the
maximum frequency of discharge of the direct olfac-
tory pathwa\', a higher rhythm probably has a dif-
ferent origin.
In the phase of recovery from deep anesthesia, the
bulb is quiescent unless stimulated, but a breath of
odorous air will produce a few waves accompanied
bv .scattered discharges in the mitral cells. \Vith
lightening anesthesia such a stimulus may start a
longer train of waves of gradually decreasing fre-
quency. Ultimately a stage is reached at which the
bulb reacts with a train of waves which may con-
tinue indefinitely. This phenomenon has been named
by Adrian the ' awakening reaction' of the bulb, and
it is suggested that in medium or light anesthesia the
granule cells have become capable of maintaining
themselves in continued activity and that their ac-
tivity leads to a continued discharge in the mitral
cell axons.
WAVES AND UNIT ACTIVITY ACCOMPANYING OLF.^CTORY
sTiMUL.-iiTiON. In such animals as the cat and rabbit,
strong olfactory stimuli elicit large sinusoidal oscil-
lations in the bulb, usually at a fixed frequency and
occurring only with each period of stimulation (fig. 7).
These large regular waves are produced only by
olfactory stimuli given at three or four times the
threshold concentration, and may appear at fre-
quencies of 50 to 60 per sec. against a silent back-
ground in moderately deep urethane anesthesia, and
at 10 to 15 per sec. under allobarbital or pentobarbi-
tal. Their frequency does not bear any relationship
to the quality or intensity of the stimulus.
In moderately deep allobarbital or pentobarbital
anesthesia, with the bulb exhibiting regular intrinsic
waves at a low frequency, an olfactory stimulus usu-
ally abolishes the waves at each inspiration. If the
stimulus is strong the gap in intrinsic activity may be
filled with induced waves. As anesthesia lightens, the
rhvthm becomes more firmlv established and the
542
HANDBOOK OF FHVSIOLOGY
NEUROPHYSIOLOGY I
FIG. 7- Induced waves develop in the olfactory bulb after commencement of the olfactory dis-
charge. Rabbit under deep urethane anesthesia breathing air containing amyl acetate. The upper
oscillograph tracing shows the waves from the surface of the bulb; the lower shows the axon spikes
from the white matter. Inspiration indicated by white line above. Time marker, o. i sec. [From
Adrian (5).]
waves may be merely reduced or scarcely altered
during stimulation. When the iaulb is quiet in very
deep anesthesia, a moderate olfactory stimulus sets
up a mitral cell di.scharge with each inspiration, but
no discharges are visible between inspirations. With
lightening anesthesia, evoked discharges appear
against a background of continuous irregular activity
which ultimately becomes so prominent as to obscure
entirely any change evoked by the stimulus. In very
light anesthesia the olfactory stimuli regain some
control over the mitral pathway, and both weak and
strong stimuli evoke an obvious increase in discharge
during each inspiration, with suppression of the
mitral discharges in the periods between each in-
spiration.
The complete suppression of intrinsic activity in
the bulb of the rabbit is seldom long maintained. The
return of activity takes place more slowly when the
smell is strong and the anesthesia light. Adrian (5)
suggests that the phenomenon offers an explanation
of olfactory adaptation as seen in man, although, as
mentioned above, records from the mucosa during
continuous stimulation indicate that at least some
adaptation occurs at the receptor level (76).
Records from the olfactory bulb in man show a
series of rhythmic waves at each inspiration while
breathing tincture of valerian and benzene, whereas
room air yields no response. No spontaneous waves
of the type seen in the rabbit have been noted in
man. Thiopental anesthesia abolishes all responses
(80).
Unit activity recorded with microelectrodes in the
olfactory bulb of a variety of animals favors the mitral
cells as the site of origin of the axon spikes, with
tufted cells and glomeruli possibly also contributing.
Where it is possible to record both wave and spike
components of the response, it is found that the fast
spikes are evoked first, followed by the waves, with
the spikes becoming synchronous with the waves as
the wave response develops (5, 72).
Differential Excitation of Receptors
DIFFERENTIATION OF RESPONSE IN AREA. Substances
soluble in water (e.g. amyl acetate, ethyl acetate,
ether, acetone) have a lower threshold for spike dis-
charges in the anterior part of the bulb, where mitral
cells synapse with fibers from the anterior and dorsal
parts of the mucosa (fig. 8). Conversely, substances
soluble in lipoids (e.g. pentane, coal gas and ben-
zene) have a lower threshold for spike discharges in
the posterior part of the bulb which receives fibers
from the posterior and ventral parts of the olfactory
epithelium (9, 10). This difference does not neces-
sarily imply a differential excitability of the receptors
at the front and back of the organ and may well re-
sult from structural factors, difference in the velocity
of the air current and in the composition of the sur-
face film through which molecules of odorous sub-
stance pass to reach the receptor surface.
In records from the middle part of the bulb (9)
there may be a single series of large spikes or a mix-
ture of large and small spikes (fig. 9). The single
series presumably represents a discharge from one
cell, whereas small spikes come from neighboring
units. Adrian found that at any one recording point
one substance in low concentration would give a
single series of large spikes. Each large spike thus
appears to have a special relation to a particular
stimulus. Units have been observed displaying this
specific sensitivity to such diverse substances as
trimethylamine, acetone, ethyl acetate, amyl acetate,
pentane, octane, xylol, petrol, clove oil, oil of euca-
lyptus and thick machine oil. Despite the improb-
abilitv of finding a few primary smells out of which
all others can be compounded, .Adrian (lo) has de-
fined four groups of substances with one substance in
each group most frequently evoking a single unit
discharge (see above). Strong concentrations of
odorants will bring in other units, but critical regions
will always exist where the concentration is only
THE SENSE OF SMELL
543
FIG. 8. Three records with double oscillograph system showing discharge from the oral and
aboral regions of the rabbit's olfactory bulb. In each record the upper tracing is from the oral region
and the lower from the aboral. The signal line shows increasing odor concentration. With acetone
(top record) the discharge is confined to the oral region, with paraflFin oil (bottom record) to the
aboral and with amyl acetate (middle record) discharge occurs in both regions. [From Adrian (9).]
just great enough to e.xcite and there the specific
excitation will always show itself.
TEMPORAL DIFFERENTI.\TION OF RESPONSE. Adrian (lo)
suggests that at the beginning and end of each respira-
tion the concentration of odorous substance is near
threshold values. Physical and chemical properties of
the substance will therefore determine the time course
of the response. The integrated outline or envelope
of the response as .seen in oscillographic records will
thus have a characteristic contour and a particular
smell might be identified from this outline. Volatility
and solubility in water both favor a rapid rise and
decline of the discharge, with little pensistence be-
tween one inspiration and the next. Thus the re-
sponse to amyl acetate has a shorter latency and a
more abrupt rise and fall than the longer latency
responses to pentane. Increasing concentrations affect
the areal differentiation but have no effect on the
temporal pattern. Patterns of temporal integration
have been recorded i^y the more elaborate techniques
of Mozell & Pfaffmann (72) in determining the
relative sensitivity of different parts of the mucosa
and bulb to amyl acetate and heptane (fig. 10).
Mozell (71) has determined the neural response
curve of the integrated spike discharge from four
points on the olfactory bulb as a function of concen-
tration of amyl acetate, heptane, ethyl ether and
benzene. Discharge strength and duration increased
approximately as a negatively accelerated function of
concentration. The curves reached their a.symptotes
in about i to 1.5 log units of physical concentration.
By contrast, the asymptote in other senses is not
reached until the intensities have been increased
several thousand times, or bv 4 to 6 log units. It is
suggested that this may account for the relatively
narrow range of suiyective odor intensity discrimina-
tion. This study confirms the existence of a relatively
gross anteroposterior spatial differentiation of re-
sponsive zones within the bulb for different substances.
Thus smells seem to be distinguished by a combina-
tion of detailed pattern and general region of excita-
tion (lo). Hainer et al. (52), in discussing an informa-
tion theory of olfaction, also emphasize the iinportance
of threshold phenomena in the conveyance of essen-
tial olfactorv information.
CENTR.'^L CONNECTIONS OF OLF.ACTORY BULB
Olfactory functions were originally ascribed to
many deep parts of the temporal lobe, including the
hippocampal gyrus and hippocampal formation, and
to certain regions of the frontal lobe, including the
cingulate area. Much of the early work in this field
can be seen in an English translation of certain works
of Ramon y Cajal (78). Experimental determination
of the sites of termination of the olfactory tract has
indicated a much more restricted distribution of these
fibers. Reviews by Brodal (27), Allison (15) and
Pribram & Kruger (77) have discussed the morpho-
logical aspects of this problem.
Efferent Pathways From Olfactory Bulb
The majority of the axons of the mitral cells run
caudally to be collected on the lateral and inferior
aspects of the olfactory peduncle, forming the lateral
olfactory tract or stria. In addition to the superficial
pathways, there is a centrally placed group of delicate
544 HANDBOOK OF PHYSIOLOGY ^ NEUROPHYSIOLOCn' I
•/^
K^< /\c«SSUs.
FIG. 9. Records from the middle region of the rabbit's olfactory bulb showing the differential
sensitivity of neighboring mitral units. In this case, acetone gives only large spikes; amyl acetate
gives large and small; and pentane gives only small spitces. [From .Adrian (9).]
ANTERIOR BULB
POSTERIOR BULB
AMYL HEPTANE
ACETATE
FIG. ID. Integrator records of the spike discharges from the
anterior and posterior areas of the olfactory bulb following
stimulation by heptane and amyl acetate. The responses indi-
cate a differentiation in both space and time. [."Kfter Mozell
& Pfaffmann (72).]
axons arising mainly from the tufted cells and trav-
ersing the anterior commissure to reach the opposite
olfactory bulb. The existence of a medial olfactory
stria conveying fibers from the bulb to the septal
area appears unlikely (40- Although the tuberculo-
septal tract is often stated to conve\ impulses from
the olfactory tubercle to the septum, this tract arises
largely in ihc nonolfactorv part of the olfactor\
tubercle (15).
Extent oj Primary Olfactory Cortex
NEUROA.N.ATOMiCAL INVESTIGATIONS. Removal of the
olfactory bulb in the rabbit (34) and monkey (67) is
follovvfed by degeneration of fibers running in the
lateral olfactory tract to reach the olfactory tubercle,
the frontal prepyriform cortex, the temporal prepyri-
form cortex, the cortical and medial amygdaloid
nuclei and the bed nucleus of the stria terminalis.
The general arrangement of these structures is shown
in figure 1 1 . An essentially similar distribution occurs
in the marsupial phalanger (i). No degeneration has
Ijeen seen in these studies in the hippocampal forma-
tion nor in the posterior pyriform cortex (entorhinal
area), nor is there evidence of a medial olfactory
tract establishing direct cingulate or septal connec-
tions.
Following inoculation of the olfactory mucosa of
rhesus monkeys with poliomyelitis virus, Bodian (25)
has found degeneration in the olfactory tubercle, the
nucleus of the diagonal band, the prepyriform cortex
and the periamygdaloid cortex. Some degeneration
also occurs in the hypothalamus, the mid-line thalamic
nuclei, the habenular nucleus and the globus pallidus.
No degeneration was .seen in the hippocampal forma-
tion or entorhinal area, nor in the lateral thalamus,
putamen or caudate nucleus.
THE SENSE OF SMELL
545
ELECTROPHYSIOLOGICAL INVESTIGATIONS. Responses
can generally be recorded in animals exposed to
olfactory stimuli from considerably wider areas than
those which neuroanatomical studies have indi-
cated as being directly connected with the olfactory
bulb. Changes in electrical activity have been reported
from the olfactory tubercle, the septal region, the
prepyriform and periamygdaloid cortex and from
the hippocampal formation (4, 14, 53, 65).
Direct electrical stimulation of the olfactory bulb
has provided clearer information than the use of
olfactory stimuli, since it allows some assessment of
the temporal sequence of spread and mav permit
inferences to be drawn concerning the structures in
monosynaptic connection with the olfactory bulb (22,
43. 58, 79)-
In the cat under pentobarbital anesthesia, the bi-
polar record from the prepyriform cortex (with the
lead electrode nearer the point of stimulation) shows
an initial fast negative spike with a latencv of 2.0
msec, and presumably resulting from conduction in
the olfactory tract. This is succeeded by a biphasic
response with an initial negativity peaking at 6 to 8
msec. In records from near the caudal border of the
prepyriform cortex the diphasic response appears as
a double negative wave. This second peak is elimi-
nated by repetitive stimulation, possibly from svn-
chronization of cortical activity, in such a way that
the same elements which previously fired separately
to produce two peaks discharge in unison to produce
a single larger response (43). This is supported by
anatomical studies in the primary olfactory cortex
of the mouse (75) which have disclosed intracortical
neuron chains possessing abundant and systematically
distributed cells with short axis cylinders within
these chains.
Similar records from the surface of the olfactory
tubercle in the cat indicate two negative waves with
latencies of 6.0 msec, and 1 1 .0 msec. Records in
depth show a single deflection peaking at 8.0 msec.
Surface records from the pyriform lobe usually show
two peaks, an initial diphasic wave with a latency of
8 to 10 msec, and a later deflection at 20 to 35 msec.
Since this late respon.se is not abolished by section of
the lateral olfactory tract but only by complete tran-
section of the prepyriform cortex, it is suggested that
the late response in pyriform cortex depends on trans-
cortical connexions between prepyriform and more
caudally placed pyriform cortical areas (43).
Potentials similar to those in the cat are obtained
in the monke\ from stimulation of the olfactorv
ALLIGATOR
MACAQUE
OLF. B
FR. PREPYR AREA
TEMP PREPYR
AREA
OLF TUB
AMYG- "I
ENTORHINAL AREA
FR PREPYR AREA
OLF TUB
TEMP. PREPYR AREA
AMYG
ENTORHINAL AREA
FIG. II. The comparative extent of the primary olfactory
cortex (shaded area) in alHgator, rat and monkey, indicating
the progressive reduction in the proportion of the cortical
mantle receiving fibers directly from the olfactory bulb in
higher vertebrates. Abbreviations: AMYG., amygdala; FR.
PREPYR. AREA, frontal prepyriform area; OLF.B., olfactory
bulb; OLF. TUB., olfactory tubercle; PREPYR. AREA, pre-
pyriform area; TE.M P. PREPYR. AREA, temporal prepyriform
area, [.-^fter .■\llison (15).]
bulb (58). A fast negative spike can be recorded in
the olfactory tract, along the lateral and medial
olfactory striae, from the rostrolateral portion of the
olfactory tubercle and tip of the hippocampal gyrus.
Second and third negative deflections appear after
7 to 1 1 msec, and 18 to 45 msec, in the olfactory
tract, the cortex of the posterior orbital surface of
the frontal lobe just external to the lateral olfactory
stria, the rostrolateral posterior of the olfactory
tuljercle, the limen insulae and the anterior end of
the hippocampal gyrus. In subjects under very light
chloralose anesthesia, Kaada also noted responses in
the posterior part of the hippocainpal gyrus, the hip-
pocampus and the septum lucidum.
Centrifugal influences may modify both the resting
and induced electrical activity of the olfactory bulb
(59). Stimulation of the prepyriform cortex, cortical
amygdaloid nucleus and olfactory tubercle is followed
by a depression of electrical activity in the bulb.
Similar effects follow high frequency stimulation of
the anterior commissure. These influences are thought
to be mediated through the granule cells of the bulb
and appear to exert tonic effects siinilar to those ob-
served in the modulation of spinal afferent path-
ways (51).
546
HANDBOOK OF I'HYSIOLOGY
NEUROPHYSIOLOGV I
FIG. 12. Diagrammatic representation of intricate pathways
through which the primary olfactory cortex may be brought
into relation with certain 'rhinencephalic' structures and cer-
tain regions of the diencephalon and midbrain. The stria
terminalis (S.T.^ arises in the amygdala and terminates in
part in the hypothalamus (HTP.'). The amygdala probably
also has more direct hypothalamic connections and is also
connected with the septum (SEPT.) through the diagonal
band of Broca (D.B.B.}. The fornix bundles may convey ac-
tivity in both directions between the hippocampus and the
septum, the anterior thalamus (.4) and hypothalamus, which
terminates partly in the mammillary body (-V/). The mam-
millary body establishes anterior thalamic connections through
the mammillothalamic tract. The hippocampus (HIPP.) is
reciprocally connected with the entorhinal area (E.NT.AREA).
The tegmental nuclei {T.N.') and the periaqueductal grey
matter of the midbrain (M.B.) may receive fibers from the
entorhinal area through the stria medullaris (S.M.) and
through the periventricular fiber systems. The tegmental
nuclei may also be reciprocally connected with the mammil-
lary body through the mammillotegmental tracts and the
mammillary peduncle.
Higher Order Olfactory Connections
It is apparent from anatomical and physiological
studies that the primary olfactory cortex is only in-
directly connected with many of the cortical and
subcortical regions included in classical accounts of
the rhinencephalon. This is supported by the long
latencies of responses recorded in the more remote
regions. In the cat under pentobarbital anesthesia,
whereas responses appear in the ventral part of the
head of the caudate nucleus after 3.5 to 12.0 msec,
and in the hippocampal gyrus, subiculum and an-
terior end of the hippocampus after 7.0 msec, slower
responses are seen in the ventral parts of the hippo-
campus only after 10 to 33 msec, and in the caudal
and dorsal regions of the hippocampus after 1 7 to
38 msec. Responses appear in the stria medullaris
after 17 msec, and in the inammillothalamic tract
after 25 to 34 msec (22).
Certain studies have emphasized the possible role
of such regions as the septum, the hippocampal
formation and the adjoining pyriform cortex in
mechanisms of alerting and emotional arousal. Al-
thotigh responses from olfactory stimulation can be
recorded in these regions, they are also accessible to
other sensory stimuli including those from tactile,
\isual and auditory modalities (46, 50, 57, 65).
Maclean ct al. (65) have recorded in the rabbit
regular rhythmic discharges at 13 to 20 waves per
sec. in the anterior pyriform cortex and in the hippo-
campal formation during respiration of smoke-filled
air. Similar responses were evoked by gustatory and
painful stimulation. They concluded that the hippo-
campus responds to olfactory stimuli in a less pre-
dictable manner and probably after a longer latency
than the pyriform area. They did not seek responses
in the posterior pyriform area (entorhinal area of
the hippocampal gyrus).
Although a great body of evidence confirms the
role of the anterior pyriform or prepyriform region
as the major primary olfactory cortical area, path-
ways from it to adjoining rhinencephalic structures,
such as the hippocampus, may well be circuitous
(fig. 12). Thus neuroanatomical studies have indi-
cated that the amygdaloid nuclei project largely via
the stria terminalis i^undles to the hypothalamus
(3, 42, 44). The hypothalamus in turn establishes
connections with midline and intralaminar thalamic
nuclei (30, 70). Here further relays may pass via the
fornix to the hippocampal formation (49, 50), and
ultimately such activity may reach the midbrain
tegmentum via the entorhinal area and the stria
medullaris (2). Stimulation of the amygdala (48) has
indicated widespread subcortical projections from
both corticomedial nuclei (forming part of the
primary olfactory corte.x) and from basolateral nuclei.
Short latency responses (presumably monosynaptic)
appear in o\crlapping primary projection fields
covering the basomedial part of the telencephalon
and adjoining rostral pole of the diencephalon. From
here responses pass by short multisynaptic relays
through secondary projection fields which include a
central core of grey matter stretching from the hypo-
thalamus to the midbrain tegmentum. Short latency
responses from the corticomedial group extend
caudally into the hypothalamus further than those
following basolateral stimulation, but no tegmental
responses follow stimulation of the corticomedial
nuclei. This study confirms the role of the stria tenni-
nalis as an important efferent pathway from the
amygdala to the hypothalamus.
THE SENSE OF SMELL
547
Behavior Studies of Oljactory Mechanisms
Excision of the olfactory bulb or damage to the
anterior limb of the anterior commissure in the rat
leads to a distinct impairment of olfactory discrimi-
nation. However, lesions involving; the septuin, the
hippocampus, the fimbria, the fornix, the amygdala
and the pyriform lobes are without efTect on dis-
crimination in tests involving the differentiation of
wood shavings scented with oil of anise and creo-
sote (82, 83). Brown & Ghiselli (28) also failed to
find any impairment of olfactory discrimination
after a variety of subcortical lesions. Experiments de-
signed to test the role in olfaction of pathways through
the anterior thalamic nuclei from the hypothalamus
to the cingulate cortex have not disclosed impaired
discrimination after total bilateral destruction of the
anterior thalamic nuclei and their radiations, with
additional involvement of the septum (63). In these
experiments removal of the olfactory bulbs per-
manently abolished the discrimination between the
odors of oil of wintergreen and of bread and milk,
indicating that the reaction was based upon olfactory
and not trigeminal stimulation. Cats are capable of
finding food by olfactory cues after lesions destroying
almost all the neocortex but leaving intact the an-
terior pyriform and periamygdaloid cortex (18).
Studies by Allen (12, 13) using conditioned re-
sponses have provided a more delicate measure of
olfactory powers than simple discrimination tests.
Using dogs, Allen subjected all animals to four tests
which in\olved establishment of a conditioned fore-
leg response to clove vapor, ability to transfer this
refle.x to the opposite foreleg, ability to establish an
absence of foreleg response to asafetida (negative
conditioned reflex) and differentiation between two
olfactory conditioned reflexes and, finally, ability to
select by smell w-hen blindfolded a paper package
containing meat from three paper packets of like
size and texture. Allen found that bilateral extirpa-
tion of the pyriform-amygdaloid areas abolished the
negative conditioned reflex, the animals raising the
foreleg to the odor of both cloves and asafetida after
cortical resection. Additional ablation of the hippo-
campal formation was without effect on the olfactory
performance, and in no case was the abilitv impaired
in the blindfold test.
In view of the close subjective relationship between
the senses of taste and smell, it might be expected
that these senses would activate the same or adjacent
cortical regions. Quantitative tests of the monkey's
preference for water over a bitter quinine solution
show, however, that the insularopercular cortex,
rather than the amygdaloid complex and pyriform
cortex, is primarily concerned in taste (17, 24).
Human studies indicate that taste perception per-
sists after complete destruction of the olfactorv nerves
(29)-
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CHAPTER XXII
Vestibular mechanisms
B. E. GERNANDT I Department of Physiology, University of Gothenburg, Gothenburg, Sweden
CHAPTER CONTENTS
Anatomy of Labyrinth
Crista
Macula
Innervation of Sensory Cells
Mode of Action of Vestibular Apparatus
Action of Semicircular Canals
Adequate stimulation
Inadequate stimulation
Caloric stimulation
Galvanic stimulation
Action of Otolith Organs
Labyrinthine Pathways and Reflexes
Ascending Fibers
Nystagmus
Cortical projection
Descending Tracts
Effects of Labyrinthectomy
THE INNER EAR Contains an auditory portion, the
cochlea, and a nonauditory portion for maintenance
of equilibrium and orientation in three-dimensional
space. The association of two apparently very differ-
ent functions in a single organ may at first seem
puzzling, but the explanation for this is found by
studying the past history of the ear. In this chapter
we are concerned only with the nonacoustic part
which we shall refer to as the vestibular apparatus or
the labyrinth. This lodges the three semicircular
canals and two little membranous sacs, the utricle
and the saccule. Their function is to respond to forces
of acceleration, retardation and gravitation. In lower
vertebrates, in fish and even in amphibians, the sac-
cule seems to play an auditory receptor role in the
absence of the cochlea. The labyrinthine function is
phylogenetically older than that of hearing.
The labyrinth is by no means the only sensory or-
gan concerned with the control of equilibrium. The
ability of terrestrial man and his close relatives among
the vertebrates to maintain equilibrium and orienta-
tion with respect to the environment also depends
upon the stream of afTerent impulses from other re-
ceptor systems. These are a) the eyes (perception of
spatial relationships), b) the interoceptors of the mu.s-
cles, tendons, joints and viscera and c) the extero-
ceptors of the skin (perception of position and move-
ment of the f^ody or changes in either function).
At the beginning of the nineteenth century Floin^ens
(34) published the first exact observations on the func-
tion of the semicircular canals of pigeons and raliijits.
He was able to induce forced movements of the head
and body and involuntary rhythmical, conjugate de-
viations of the eyes following injury to the canals.
Since then an immen.se amount of research work
has been carried out. The early part of this period
was characterized by the struggle to separate the
vestibular apparatus from partnership with the coch-
lea in the perception of sound and to attribute to it a
function quite unrelated to that of hearing. In 1870,
Goltz (46) was the first to arrive at the conclusion
that the semicircular canals were sense organs con-
cerned with maintaining equilibrium.
The use of cla.ssical histological methods and the
observation of equilibrium disturbances resulting
from operative interference with the internal ear
(section or extirpation) have in the past been the two
principal sources of knowledge concerning the struc-
ture and function of the laijyrinth, but the answers
given to various questions vary considerably in their
value. From this it was realized that knowledge of
behavior mechanisms in the normal subject was
necessary in order to understand the nature and sig-
nificance of defects associated with peripheral or cen-
tral injuries. Recording of electrical activity from
single fibers of the peripheral vestibular nerve or from
nuclei within the central nervous system of different
349
55°
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
species has added much to our understanding of the
function of the human labyrinth in spite of a number
of difficulties posed by the anatomical differences from
lower animals. Experiments on various members of
the animal kingdom have shown that some of the
responses will vary greatly from one species to another.
However, the use of electrophysiological techniques
for a more far-reaching study of the function, and the
refinement in recent years of the ultrastructural anal-
ysis made possible by the electron microscope may-
allow more precise experimental studies of the corre-
lation of function and structure. Some of our modern
ideas about this correlation rest firmly on experi-
mental facts; others, in the present incomplete state
of knowledge, are mere speculations. The remaining
ones ranee between these two extremes.
AN.-SiTOMY OF LABYRINTH
lar canal makes an angle of about 55°, open in front,
and with the posterior canal, an angle of about 45°,
open posteriorly (fig. 2).
The semicircular canals run from and open into
the utricle by means of five apertures, one being com-
mon to the superior and posterior canals. At one end
of each canal, near its junction with the utricle, is the
swelling known as the ampulla. The horizontal and
superior canals have the ampulla forward and the
posterior canal has it backward.
The utricle is the larger of the two sac-like struc-
tures. It has an irregularly oblong shape, slightly
compressed transversely. Its most caudal portion lies
posteriorly, wherefrom it slopes anteriorly and up-
ward (rostrally) at an angle of approximately 30°.
The utricle communicates with the utriculosaccular
duct and with the semicircular canals mentioned
above.
For understanding the function of the semicircular
canals, the utricle and saccule, a clear concept of their
anatomical position and their relationship to each
other in space is paramount.
The bony labyrinth comprises a series of ca\ities
tunneled in the compact petrous part of the temporal
bone. The whole memljranous labyrinth, consisting of
a system of thin-walled sacs and ducts with a clear
fluid, the endolymph, is enclosed within the osseous
labyrinth, separated from its wall by the perilymph.
In form it closely resembles the osseous labyrinth, ex-
cept in its middle portion (fig. i).
The membranous semicircular canals, three in
number for each ear, are eccentrically suspended by
fibrous strands in the osseous semicircular canals.
They are smaller in diameter than the osseous canals
and fill only about one fourth of the lumen. The
canals are named according to their orientation in
space, the horizontal (external, lateral), superior
(frontal) vertical, and posterior (inferior) vertical,
lying approximately at right angles to each other,
one for each major plane of the f)ody. Considering
the two labyrinths together (right and left sides of
the head), the two horizontal canals lie in the same
bodily plane and form what may be termed a synergic
pair. The synergic partner of the right superior
vertical canal is the left posterior \ertical canal. The
left superior canal is parallel to the right posterior
canal. The horizontal canal is slightly inclined down-
ward and backward, so that it forms an angle of
about 30° with the horizontal plane when the head is
erect. The sagittal plane with the superior semicircu-
PcriostGuTTv
jcmicirCLilar-
Carval
Utr.cle-
SacTjuIe"
Oval window
Ductus reumens "
Round window and
secondary tynipanic
>T\embrane
Aouoduct oF the " '
cochlea.
Subdural
ondoVmphatiC? sac
-Dura nnatrcr
Aqueduct of the
~ vestibule
-Endolyrnphatic
duGtr
Cochlear
duct
■ -^Helicoti-enna
— Peri09tCUTT\
5cala Cympani
Scala vestibuli
FIG. I. Diagram of ppiilymphatic and endolymphatic spaces
of the internal ear. [From Larsell (57).!
R.cochl.-sacc
FIG. 2. The innervation and structural relations of liuman
vestibular apparatus and cochlea. [From Hardy (52).]
VESTIBULAR MECHANISMS
551
The saccule is a small, pear-shaped sac situated in
the forepart of the vestibule. It lies below and medial
to the utricle. The long axis of this sac is very nearly
vertical; its dome-shaped portion is directed upward
and its bluntly tapered portion downward and slightly
posteriorly. From its posterior wall, a slender tube,
the endolymphatic duct, arises to extend through the
vestibular aqueduct into the cranial cavity; here it
terminates outside the dura mater o\cr the petrous
portion of the temporal bone in a blind pouch, the
endolymphatic sac. The endolymphatic duct and sac
serve as a drainage mechanism for the endolymph.
The ductus reuniens, finally, is a v'ery slender duct
which connects the saccule with the cochlear duct
(scala media) near its basal end.
The macula is covered by a mucous or gelatinous
substance which contains aragonite concretions (oto-
liths, otoconia) of calcium carbonate. The specific
gravity of the otoliths, which ranges from 2.93 to 2.95,
is thus greater than that of the surrounding endo-
hmph. It has been shown that the otoliths of the
utricular macula of mammals are of two, or perhaps
three, distinct grades of fineness, each kind being
situated in its own particular area of the receptor sur-
face, which thus has a mosaic arrangement (61).
The macula of the utricle is situated on its anterior
and medial walls, the two portions being joined at an
angle of 140°. When the head is in the normal posi-
tion, the macula of the utricle is in an approximately
Crista
The sensory epithelium in the ampullae of the
semicircular canals is collected into transverse crest-
like elevations — the cristae ampuHares — protruding
toward the lumen and firmly attached to their bony
foundations but free to swing at the other end. These
are the receptor organs of the canals. The height of
the crista corresponds to about one third the diameter
of the ampulla. The epithelium is composed of two
main types of cells, the hair (sensory) cells and the
nonsensory supporting cells. Recent electronmicro-
scopic studies have revealed two types of hair cells
that differ distinctly from each other both in structure
and innervation (121). One type of cells is bottle-
shaped, the other is more cylindrical (fig. 3). The
former is mainly localized to the summit and the latter
to the periphery of the cristae. The majority of them
have a sterocilial structure, though one process from
each cell has a kinocilium-like structure. The sensory
hairs, or cilia, project into a gelatinous mass, the
cupula, and there are found in a large number of
canals (55, 56; fig. 4). The cupula may be regarded
as a damped structure with a natural period, in the
case of the pike of about 20 sec. (106), and acts as a
spring-loaded over-critically damped torsion pendu-
lum (50). Its chemical structure is not yet fully
elucidated, but histochemical investigations conducted
in recent years suggest that sulphomucopolysaccha-
rides are important chemical constituents.
Macula
The receptor organs of the utricle and saccule are
called maculae. The sensory epithelium exhibits
again two kinds of cells, supporting and hair cells.
FIG. 3. The ultrastructural architecture of the cells and
nerve endings of the crista ampullaris (guinea pig). HC /,
bottle-shaped hair cell; HC II, cylindrical hair cell; SC, sup-
porting cell; St, sterocilia; AC, kinocilia; .V, nucleus; GA, Golgi
apparatus; IM, intracellular membrane system; VB, vesicular
body; NC, nerve calyx; RM, reticular membrane; M, mito-
chondrion; NE, nerve endings; BM, basement membrane;
jV/.V, myelinated nerve; LG, lipid granule; MV, microvilli.
[From Wersall (121).]
552
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
FIG. 4. Schematic three-dimensional diagram of one-half of
an ampullar crista. [From Wersall (121).]
horizontal position, with the otoliths King on the
hair cells. The saccular maculae are situated ob-
liquely, forming an angle of about 30° with the verti-
cal plane. Thus, when the head is in the erect posi-
tion, the otoliths of the saccule are placed laterally on
the hair cells, embedded in the substance that covers
them.
INNERVATION OF SENSORY CELLS
Impulses from the peripheral receptors to the
stations in the medulla are conducted by the \estibu-
lar branch of the eighth nerve. These fibers make up
inore than half of the nerve and number about 19,000.
Most of them are large myelinated fillers (10 to 15 m)
but there are also medium and fine fibers (i to 2 /x)
(28, 59, 86, 90, 91). In addition, a large number of
unmyelinated fibers with diameters between 0.3 and
I M have been described (121). Nerve fibers of vary-
ing diameter, as pointed out by Ramon y Cajal C90)
and Lorcnte de No (59), have a characteristic distri-
bution in each crista. Thus, the large fibers innervate
the central region, those of medium size are distrib-
uted to the lateral regions, while the fine fibers go to
the basal region.
Electronmicroscopic examination of the innerva-
tion of the sensory epithelium in the guinea pig by
Wersall (121} revealed two different types of nerve
endings. The bottle-shaped hair cells have a nerve
calyx enclosing the greater part of the cell, while the
nerve branches form loops around the basal part of
the cylindrical hair cells or terminate like btid-shaped
nerve endings (fig. 3). Stimulation of the former type
will give rise to impulses conducted mainly in one
nerve ending, the nerve calyx, and only in one nerve
fiber. The cylindrical hair cell, however, is usually in-
nervated by branches from several dififerent fibers;
and several hair cells, often at relatively great distance
from each other, are innervated by the same fiber.
The difference, in principle, between the innervating
characteristics of the two types of sensory cells may
be of physiological importance but no investigations
have, as yet, been able to re\eal clear!)' the significance
of the postulated different functions in the sensory
epitheliinu of the cristae anipullares.
Recently PetrofT (84) has published results of ex-
periments with sectioning of the eighth nerve that
might point to the existence of thin efferent fibers in
the vestibular nerve. Such recurrent or feed-back
connections of the auditory system have previously
been described. Thus Rasmussen (92, 93) has found
an efferent cochlear bundle that forms a plexus at
the margin of the osseous spiral lamina around the
afferent fibers. Galambos (35) was able to surpress
the expected inflow of auditory nerve activity to
normal acoustic stimuli by electrical stimulation of
these efferent fibers. The function of the vestibular
efferent fibers has not yet been studied.
The vestibular nerve has six main branches of
origin : one each from the posterior, superior and
lateral ampullae, and the utricle, and two from the
saccule. Galambos & Davis (36) have found In histo-
logical methods that the auditory nerve in the interval
from the internal meatus to the medulla contains
nerve cell bodies which probably belong to the coch-
lear nucleus and are therefore second-order neurons
in the auditory tract. There are reasons to believe
that corresponding second-order neuron cell bodies
can be found in the vestibular portion of the eighth
nerve (38).
MODE OF ACTION OF VESTIBULAR APPARATUS
Though there must be an intimate coordination
between activities of receptors situated in the ampullae
of the semicircular canals and those in the vestibular
VESTIBULAR MECHANISMS
553
sacs, the two sets of end organs are, as described,
clearly different in detailed construction and they
function in accordance with somewhat different
principles. Interpretation of the particular functional
role of the different sensory endings of the labyrinth
has been exceedingly difficult because of the minute-
ness of the organ and the extreme inaccessibility of
the structures. The recording of action potentials
from the peripheral nerve or from the central nervous
system in response to vestibular stimulation can, in
many cases, serve as a revealing index of the validity
of the older theories presented during the last century.
In addition, this technique has been of considerable
importance in furthering the study of the mode of
action of the labyrinthine sensory endings (i, 6, 27,
38,58,68,80,94,123).
Action oj Semnucular Canals
The semicircular canals respond to any one of the
following forms of adequate and inadequate stimula-
tion: a) rotation (angular stimulation) of the head in
a vertical, transverse or anteroposterior axis; ^) arti-
ficial mechanical stimulation; c) caloric, irrigation of
the ear with hot or cold water; and </) galvanic
stimulation.
ADEQUATE STIMULATION. The anatomical fact that
three semicircular canals are arranged in planes ap-
proximately at right angles to one another corre-
sponds with the conclusion that their function is
concerned with movements in the three dimensions.
It is generally accepted that the cristae ampullares
are receptors for the perception of rotatory move-
ments.
The position of the cupulae is influenced by an
increase or decrease of velocity of rotation, i.e. by
positive or negative angular acceleration, but they
are proi^ablv not influenced by linear acceleration
(1,53,81,88).
Several different theories have been presented dur-
ing the last century to explain the physical changes
in the canals resulting in stimulation of the receptor
cells (the hydrostatic, hydrodynamic and pressure
theories). Some arc today only of historical interest.
The literature for the first quarter of the twentieth
century has been fully reviewed (13, 78, 85, 122) and,
in addition, a number of reviews dealing with more
recent studies have appeared (32, 104, iio, 119).
According to the hydrodynamic theory of Mach,
Breuer and Clrum Brown, the only way in which the
elastic cupular ridge may be swayed, one way or
another, is by the flow of endolymph. Any change in
speed of rotation will cause a deflection of the cupula
and the hairs of the sensory cells by a movement of
the endolymph with a resulting differential push and
pull upon the hairs. Owing to inertia, the endolymph
of the involved pair of canals lags behind the progress
of the wall of its containing tube and therefore exe-
cutes a movement opposite to the direction of turn-
ing. The speed of endolymph movement in a semi-
circular canal during increa.sed acceleration and the
resulting deviation of the cupula have been calculated
(95, 96, 106, 108, 109). Steinhausen (107, 108, 109)
was able to demonstrate that the cupula, spreading to
the sides and reaching to the roof of the ampulla,
glides during its deflection in a swing-door fashion
with a minimum of endolymph leakage. Some authors
hesitate to accept the hydrodynamic theory because
of the capillary nature of the canals and the viscosity
of the endolymph (48, 73, 78). According to Maier &
Lion (77), however, endolymphatic circulation is
possible in the minute canals.
The hydrodynamic theory is strongly supported by
experiments with direct observations on the exposed
semicircular canals in fish. Through the injection of
Chinese ink into the canals of the pike, which are
relatively large and accessible, Steinhausen (107, 108,
109) was able to make visible the endolymphatic
current with its corresponding deflection of the cupula.
Dohlman (24) introduced a drop of oil into the canal
and the fish (cod) was rotated while the behavior of
the cupula was studied. As the rotation begins the
endolymph in the canal moves, as shown by the shift
in the position of the drop of oil, and the cupula
becomes bent over in the direction of the endolymph
movement (fig. 5). By using direct manometric meas-
urement he found cupular movement from pressure
changes equal to 0.05 ml of water (0.00004 gm)-
The most effective stimulus to each ampulla is rota-
tion of the head in the plane of its canal. But angular
acceleration about any axis that lies obliquely to this
plane may also tend to disturb the internal liquid
(69, III). A more or less combined stimulation of the
ampullar cristae may be expected by movements of
the head in any one of the intermediate planes. The
utricle is shared by the three canals. Therefore, the
question arises whether this does not cause an inter-
ference between the canals. Indeed, when the fluid
in one canal is strongly affected by an acceleration,
part of it mav flow through into another canal. The
other canals arc, however, a shunt with a high re-
sistance, so that the leakage is small (17, 20); and,
for example, when angular stimulation produces
554
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY
FIG. 5. The ampulla and semicircular canal in the living
state before and during angular acceleration. The cupula,
situated on the top of the crista, traverses the entire lumen of
the ampulla. A, the cupula in its normal position; B, the cupula
during angular acceleration. Note the shift of position of the oil
droplet in the endolymph during acceleration. [From Dohlman
(24)-]
endolymph flow in the horizontal semicircular canals
placed strictly in the horizontal plane, no flow is
thought to occur in the vertical canals (30, 61).
Let us consider the case of rotation to the right
after adjustment of the head so that the two horizontal
semicircular canals, the synergic pair, are in the hori-
zontal plane. During such a rotation the left ampulla
is ' leading' its canal while the right ampulla is ' trail-
ing' behind its canal. The endolymph, owing to the
moment of inertia, will cause a deflection of the cupula
of the right horizontal canal in the ampuUopetal direc-
tion and an ampullofugal deviation of the cupula of
the left horizontal semicircular canal. When the rota-
tion is stopped, the two cupulae will be deflected in
the opposite direction owing to a backflow of endo-
lymph. Although movements of the endolymph stop
in about 3 sec, the cupula seems to take about 25 to
30 sec. to return to its resting po.sition. During this
time, the subject will experience a sensation of rota-
tion in the opposite direction. The stimulus to the
cristae obviously arises from the swinging of the cupula
set up by the endolymph. However, the cupula, being
elastic, returns to its original position if the speed of
angular stimulation becomes constant. Therefore, no
response to movements of steady velocity occurs be-
cause the endolymph, subject to the frictional influ-
ence of its enclosing walls, takes up the motion of its
canal and stimulation subsides.
The threshold for perception of angular accelera-
tion has been studied by various methods (rotating
chair, torsion swing, after-sensation time) and is now
rather well-established. The torsion swing appears to
be the most sensitive method for measuring this
quantity (49). The minimum value for the perception
of rotation varies with the indicator used and with
the method of computation. Mach (72) and Dodge
(22) found a threshold value of 2 ° per sec,- The prod-
uct of the time and the acceleration required to reach
the threshold of rotational .sensation is constant. Thus,
for reaching the threshold, the required acceleration
is the greater, the shorter the time of its action. The
lowest values reported for the human threshold are
0.2° per sec- (i 13) and 0.5° per sec^ (5, 23, 49)
Some experimental results have led to the conclu-
sion that the crista is a unidirectional receptor, capa-
ble of being stimulated only in one direction but
irresponsive to deflection in the opposite direction
(16, 70, 71, 78, 109, 123). Ewald (29) demonstrated
that an ampuUopetal cupular deviation in the hori-
zontal semicircular canals evokes a stronger reaction
than a corresponding ampullofugal deflection. In the
vertical canals the efl'ect of ampullofugal flow is more
marked. There is no explanation for this functional
diff'erence, between the horizontal and vertical canals,
a diff'erence emphasized repeatedly by many authors.
More recent experiments, however, speak in favor
of a bidirectional function of the semicircular canals
(14, 61). The clearest evidence comes from experi-
ments with electrical recording of the action poten-
tials set up in the primary receptor fibers under condi-
tions of natural stimulation (68, 69). By dividing the
intracranial portions of the different nerve branches
from the labyrinth into very slender filaments, it has
been possible to obtain o.scillographic records of the
action potentials occurring in response to various
kinds of stimuli, and under favorable conditions it is
possible to continue the process of subdivision until
only one or two sensory units are in functional con-
nection with the recording device. Ashcroft & Hall-
pike (6) and Ross (94) made the first successful
attempts to exploit this possibility, using frogs.
Mowrer (80) recorded from the vestibular nerve of
the common painted terrapin. Later Lowenstein &
Sand (68, 69) made similar recording from the dog-
fish and ray and Ledoux (58) from the frog. They
demonstrated a clear bidirectional response against a
background of a resting discharge which is present
even when the animal is in a state of absolute rest;
their findings are in complete agreement with the
assumption that the cristae are stimulated as a result
of positive and negative angular acceleration. In-
creases or decreases in the resting discharge rate of
the sensory cells in the crista are brought about by
the deformation of their hair processes during deflec-
tions of the cupula. In the horizontal canals excitation
occurs, and an increased impulse discharge can be
recorded when the cupula is deflected in an ampul-
■71;
VESTIBULAR MECHANISMS
555
lopctal direction, the stimulus being ainpullopetal
inertia movement of endolymph. With an increase of
stimulus strength a clear recruitment of sensory units
can be demonstrated. The maximum frequency is
evidently related to the acceleration, but o\\ ing to the
deceleration which follows it is impossible to say how
rapidlv the receptors would become adapted to the
stimulus. For the study of adaptive behavior, a con-
stant angular acceleration would have to be applied
for a protracted period of time. Some results suggest
that the receptors adapt slowly (i, 94) but Hallpike
& Hood (51) and Lowenstein (64) came to the con-
clusion that the end organs show considerable adapta-
tion under conditions of sustained cupular deflection.
An ampullofugal deviation of the cupula of the
horizontal canal inhibits the spontaneous impulse
activity. This demonstrates that a single receptor can
signal rotation in either direction instead of one direc-
tion only. In the vertical canals the discharge of
impulses is increased by angular displacements in
which the ampulla is leading__and an ampullofugal
deviation of the cupula is elicited. An ampullopetal
deviation will cause an inhibition. On cessation (or
deceleration) of the angular stimulation, changes
which are the reverse of the initial ones occur. If the
speed of rotation is maintained at a constant level,
the impulse frequency falls ofT until it has reached
the spontaneous rate.
Adrian (i) was the first to use a higher mammal,
the cat, for recording the discharge following varying
stimulation of the labyrinth. The activity was recorded
from the vestibular nuclei. Generally speaking, the
results obtained have not shown any marked difTer-
ence between the vestibular apparatus of the cat (i,
38) or rabbit (27) and that of the frog or the fish.
There are gravity receptors to signal the posture and
linear acceleration of the head, and rotation receptors
to signal the turning movements (fig. 6). Some differ-
ences are found, however, but they are probably due
to recording from second-order neurons (38). Units
associated with the receptors of the horizontal semi-
circular canal showed an increase in impulse fre-
quency in response to rotation toward the side of
recording, while rotation in the opposite direction
inhibited the activity. Sudden arrest of the rotatory
movement resulted in a reduction in impulse discharge
rate after ipsilateral and an increased discharge after
contralateral acceleration. This type of response is
interpretable on the basis of a mechanical tension-
release theory for the hair cells, excitation being; the
result of stress, inhibition of release. In addition to
this usual type of response, there were units which
showed an increased discharge in response to rotation
in both directions (i, 27, 38). Both the ampullopetal
and ampullofugal flow of endolymph had an excita-
tory effect. A mechanical tension-release theory
would seem to be still more natural for these units
than for units of the previous type (51). The hair cells
may be assumed to be pulled upon by the movement
of endolyinph and cupula in both directions. This
type of response appears in about 12 per cent of units.
An inhibitory effect of rotation in both directions has
been noted also during recording of the electrical
activity from second-order neurons. This inhibition
can hardly be regarded as due to a peripheral mech-
anism, a fact suggesting a difference in function be-
tween higher mammals and simpler organisms. An
inhibition in both directions of rotation should, how-
ever, not provide greater difficulties to a tension-
release theory than inhibition in one direction only.
In both cases we have to account for the nature of
the release by internal forces of tension for which so
far there is no evidence. Once impelled, by the
mechanical theory, to add unidirectional tensile
forces inside the receptive organ to account for these
findings, we might as well assume the existence of
structures pulling upon the hair cells in such a well-
balanced fashion that release follows when the cupula
swings either way. Alternatively, the mechanical
theory should be given up altogether in favor of the
assumption that the impulses recorded are from cell
bodies of second-order neurons, and that the pull on
certain hair cells sets up inhibition at the first synapse,
in the manner of the well-known retinal inhibition.
This alternative seems to be the more probable.
Another assumption is that these neurons may have
60
t^20
-
C)
l_ >
V
" 40
20
-
1^"
i , , , ,
^1
RoulM.n
FIG. 6. Diagram to illustrate average time course of impulse
discharge from a semicircular canal showing after-discharge and
silent periods when acceleration and deceleration are separated
by an intervzJ of steady rotation. [From Adrian (l)]
556
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
been in synaptic connection with path\va\s deri\cd
from the opposite labyrinth (65).
iNADEquATE STIMULATION. Thc icsults obtained by
using various forms of inadequate stimulation have
supported the assumption that the flow of endolymph
stimulates the cristae. Thus, the old experiment of
Ewald with his ' pneumatic hammer' illustrates how
the semicircular canals are stimulated. He was able
to stimulate each canal separately in a pigeon by in-
creasing or decreasing the pre.ssure of the endolymph.
Two small holes were made in an osseous semicircular
canal near its smooth end. The hole farther from the
ampulla was sealed with amalgam so as to block the
membranous canal completely. The pneumatic ham-
mer, a small metal cylinder with a moving piston, was
cemented in the hole between the plug and ampulla.
Compression or decompression of the endolymph
caused an ampullopetal and ampullofugal endolymph
flow, respectively. An increase in pressure in the hori-
zontal canals caused the head and eyes to move
toward the opposite side; decompression caused a
weaker reaction in the reverse direction. Compression
and decompression of the two vertical canals cause
similar movements, but the effect of ampullofugal
flow is more marked.
CALORIG STIMULATION. By this form of stimulation
movements in the endolymph are produced (7). On
irrigating the external auditory meatus with hot and
cold water, labyrinthine reactions appear becau.se
convection currents are provoked in the endolymph
of that semicircular canal which is placed in a vertical
position and changes in the pressure on the ampulla
result, cau.sing the cupula to bend. The direction of
the convection currents depends upon changes in the
specific gravity of the endolymph resulting from heat-
ing or cooling. Thus irrigating the car with cold
water causes currents toward the ampulla of a vertical
semicircular canal; on irrigation with warm water
the endolymph ri.ses. The effect of cold water is there-
fore the opposite of that of hot. The caloric test used
in clinical otology and physiological experiments has
the advantage over rotatory stimulation in that it
permits the examination of one ear at a time. If the
head is held in various po.sitions, any one of the three
semicircular canals can be stimulated; however, the
posterior canal, lying deep in the bone, is influenced
only slightly. Hot or cold water causes a greater
change in the temperature of the endolymph in the
part of the canal lying nearer to the external meatus
than in the part more deeply situated. The tempera-
ture change first reaches the horizontal canal (23).
When the head is inclined 60° backward, the
horizontal canals are brought into a vertical position.
Irrigation of the left ear of a subject with warm water
or the right ear with cold water produces involun-
tary, rhythmical conjugate deviations of the eyes
(nystagmus) to the right and a tendency to fall to the
same direction. The nystagmus appears after a short
latency and lasts for a varying time according, inter
alia, to the temperature employed and the duration
of the irrigation.
A direct effect of thermal stimulation upon the
peripheral nerve endings, in addition to the indirect
effect based on movements of the endolymph, can not
always be excluded (38). This is in accordance with
the assumptions made by Bartels (8) and Breuer (11)
that cold water may lead to a direct paralysis of the
nerve endings and by Spiegel & Aronson (102) who
found that the nystagmus due to continued caloric
stimulation was independent of the position of the
head.
GALV.-VNIG STi.MULATiON. Another way to elicit reflexes
from the labyrinth is by applying direct or alternating
currents to the ear. Galvanic polarization produces
impulse discharges similar to those occurring on nat-
ural rotatory stimulation (64). No movements of the
cupula will occur during this form of stimulation
(108). In the employment of this method of inade-
quate stimulation of the cristae or the peripheral
nerve fibers themselves, an electrode is placed on one
of the mastoids, another electrode on a distant part
of the body (monaural stimulation) or on the other
mastoid (binaural stimulation). In the latter case all
six canals will be stimulated owing to the current
spread. The galvanic stimulation will give rise to a
mixture of horizontal and rotatory eye movements.
When the cathode is on the right mastoid, the nys-
tagmus is to the right and vice versa. A reflex move-
ment of the head to the left will result if the cathode
of the circuit is applied to the right mastoid.
Action of Otolith Organs
The anatomical, physiological and physical factors
involved in the stimulation of thc maculae are some-
what different to those influencing the semicircular
canals. Breuer (12) realized that, although the endo-
lymph is not in motion when the head is at rest, we
nevertheless have a sense of position. He decided,
therefore, that the otoliths within the utricle and
saccule must be responsible for the static and posi-
tional sense. The mechanism of stimulation of the
receptors has been controversial. According to the
theory of Breuer, the gliding of the otoliths and bend-
ing of the hairs of the sensory cells caused by this
gliding during changes of the position of the head is
the stimulus. This theory has been rejected l)y later
workers (7, 78). The effective stimulus is now thought
to be the pull of gravity. The sensory cells will be
differentially stimulated in different positions of the
head since the otoliths will obey the law of gravity.
When the stimulation of the utricular maculae on
both sides is equalized, the sensation is that of normal
position, with the vertex of the head up and its base
down. Any disturbance of this equilibrium, as must
take place in a changed position of the head, neces-
sarily exerts a different pull of gravity upon the re-
ceptor structures. Experiments have demonstrated
that the utricle is the source of responses to gravity,
centrifugal force and linear acceleration (i, 63, 66,
67, 71, 94). By these various means of stimulation the
otoliths are made to change their relative orientation
with respect to the underlying macular surface.
Electrical responses recorded from the frog by Ross
(94) made it possible to distinguish between two types
of gravity receptors. One type responds when the
head is tilted out of the level position; the other type
signals only the return of the previously tilted head to
level. Cohen (15) describes four receptor types in the
lobster. Adrian (i) recorded the potentials appearing
in the vestibular nuclei of cats when the head is
tilted. In a lateral tilt, with the recording side lower-
most, the frequency of the discharge increased with
increasing tilting (fig. 7). In no case was there an
increase in frequency when the tilt was in the opposite
sense, i.e. raising the side under examination and
lowering the other. The frequency of the discharge
declined very slowly as an expression of a slow adapta-
tion of the receptors. It is interesting to note that the
responses of different stimuli (tilting, rotation) were
not found in the same parts of the vestibular nuclei.
This may well indicate some sort of functional locali-
zation within the nuclei.
The utricle appears to be the organ of major im-
portance in postural reflexes and in the differential
distribution of muscular tone in the various laby-
rinthine reflexes.
The function of the saccule is more obscure and
still imperfectly known. It can be destroyed on both
VESTIBULAR MECHANISMS 557
10 20
Inclinaticm in degrees
FIG. 7. Response of gravity receptors. Relation between tilt
of the head and frequency of discharge in units from several
animals. The degree of lateral tilt of the head is shown in the
upper inset. The impulses were recorded from the right side
while the head was being tilted to the right. [From Adrian (i).]
sides without disturbing labyrinthine reflexes, even in
the rabbit, an animal in which these reflexes are highly
developed. It has been considered that the saccule is
not an essential part of the vestibular mechanism but
rather an organ associated with the cochlea and de-
signed for the perception of vibrational stimuli (6, 94,
123). Vibrations acting upon the mass of otoliths
should thus transmit corresponding oscillations of
pressure to the ciliate cells. More recent experiments
by Lowenstein & Roberts (67) upon elasmobranchs
have presented evidence that the fibers conducting
iinpulses in response to vibrational stimuli are derived
from the anterior two thirds of the saccular inacula
(and the papilla basilaris and macula neglecta). In
higher vertebrates the saccule has probably lost its
auditory function. It is unlikely that the sound vibra-
tions transmitted from the oval window to the peri-
lymph are further propagated in that part of the
labyrinth represented by otolith organs and the three
semicircular canals. The only exception may be the
effect of very violent explosive sounds. The wave of
pressure in the endolymph and perilymph set up by a
sudden, very loud sound may be sufficient to stimu-
late the receptor cells of the semicircular canals, the
utricle and the saccule. The subjective sensation is
then one of vertigo, or of a sudden displacement in
.space. The reflex response to such stimulation is a
sudden movement of the head, such as normally tends
558
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
to compensate for an actual sudden change of position
in space (112, 115) The direction and character of
the movement depend upon which of the labyrinthine
sense organs are most strongly stimulated. The semi-
circular canals can become sensitive to acoustic
stimulation when they are artificialh' exposed to it, as,
for instance, after a fenestration operation (12, 45,
112, 114). This does not mean, however, that sound
perception is in the natural range of functions of the
semicircular canals.
L.^BYRINTHINE P.ATHW.^YS .AND REFLE.XES
The neural connections of the vestibular organ
consist of numerous chains of neurons, reciprocally
linked in many ways and ha\ing their synapses in
various anatomical nuclei. All the chains work in
intimate collal^oration and the final pattern of reflex
responses is attributable largeK' to the highly complex
integrating activity of the center (62). The labyrin-
thine function is automatic, carried out in a reflex
fashion, in other words, mostly below the level of
consciousness. The brain centers through which the
labyrinths elicit the various appropriate muscular
reactions of the head, body, limbs and eyes — the
righting, the postural and the ocular reflexes — repre-
sent an intricate mechanism. The nervous connections
of the vestibular apparatus with the brain are, as yet,
imperfectly known.
The impulses generated in response to stimulation
of the peripheral receptors pass for the most part to
Peiter's nucleus (the lateral \estibular nuclejis),
Schwalbe's nucleus (the niedial nuclejj.s!). Bechterew's
nucleus (the supfrior nucleus^ and Roller's nucleus
(the descending oi- spinal \ estibulaJL nuclettsy In
these nuclei originate, in turn, the ascending and
descending tracts. For all practical purposes these
four nuclei can be treated as a single functioning
entity. Some axons pass directly to the cerebellum
(2, 25).
The vestibular nuclei on each side of the medulla
are connected with each other. This connection may
be either direct (19, 31, 47, 90) or indirect by way of
the reticular formation. Ramon y Cajal (90) describes
a compact bundle of fibers within the vestibular
nerve which passes directly from the vestibular
(Scarpa's) ganglion across to the opposite side of the
bulb without synaptic relay in the ipsilateral vestib-
ular nuclei. Because these fibers spread out diffusely
after crossing the mid-line, he was uncertain whether
they terminate in the contralateral vestibular nuclei
or within the contralateral bulbar reticular formation.
Ascending Fibers
Fibers arising from the medial and superior vestib-
ular nuclei form the medial longitudinal fasciculus,
the fibers of which end in the nuclei of the oculomotor
nerves of the same and opposite sides. The tract is
phylogenetically one of the every early ones to
appear. It is present in cyclostomes and is known to
be an important reflex pathway in fish. Its position
and connections are very constant throughout the
vertebral series.
NYST.AGMUS. Thc position of the eyes is very markedly
influenced by stimulation set up in the labyrinth.
This is of obvious importance since, as the body
moves, compensation must be made b\' the eye
muscles in order that the gaze may remain fixed on
any object. In birds and reptiles most of the compensa-
tion is made by the neck muscles, and a head nystag-
mus appears during and after angular stimulation
(12). As the body turns the eyes swing slowly in the
opposite direction so as to maintain their fixation.
Having turned as far as possible, they swing quickly
back in the opposite direction to fix a new object which
in turn they follow by a slow deviation. The slow move-
ment in one direction is known as the slow component
of the nystagmus, and the quick movement in the
opposite direction is known as the quick component.
The reflex latency of the slow component is 50 to 80
msec. (21). The magnitude of the quick and slow
components is the same and by convention the direc-
tion of the nystagmus is designated as that of its quick
component. Thus, when the quick component of a
nystagmus is observed to be in the direction of the
subject's right, it is called a nystagmus to the right.
The movement of the eyes in nystagmus is in either
the horizontal, frontal or sagittal plane. These differ-
ent directions of the nystagmus can be easily demon-
strated in man by rotating him with eyes closed in a
revolving chair when different pairs of canals are
brought into their maximal po.sition (120). For
example, to stimulate the horizontal canals maximally
the head should be inclined forward about 30°. Dur-
ing rotation the quick component will be in ihe
direction of rotation. When the rotation is stopped a
postrotatory nystagmus will i)e ob.served; its quick
component is in the direction opposite to that of the
rotatorv movement. This is due to thc retardation of
VESTIBULAR MECHANISMS
559
the endolymph which causes a deviation of the
cupula, this time in the opposite direction. The post-
rotatory nystagmus occurs, and lasts as long as the
cupula needs to return to its starting position through
its elastic recoil.
Thus we have seen that the impulses from the laby-
rinth are able to act on the different ocular muscles in
an extremely precise manner. However, the details of
the reflex arcs are as yet obscure. The slow phase of
nystagmus is initiated from the labyrinth and has its
center in the vestibular nuclei from which impulses
are propagated, in part at least, through the inedial
longitudinal bundles to the eve muscles. The quick
component is entirely central. Its neural mechanism
must lie in the brain stem between and including the
nuclei foi'the third nerves and the_yestibular nuclei.
for nystagmus occurs after tran.sections of the brain
above and below these levels (i8, 60, 61). It is not
abolished by ablation of the cerebellum. Lorente de
No has located the cejUfiT for the rapid phase in the
reticular formation in the region of the abducens
nucleus. It has also been found that nystagmus could
still be produced after section of both medial longi-
tudinal bundles (60, 61, 98). This finding is supported
by experiments upon monkeys by Bender & Wein-
stein (9). There may be a double pathway from the
vestibular nuclei to the nuclei of the ocular nerves —
through the medial longitudinal bundle and through
the reticular formation.
CORTICAL PROJECTION. It Was previouslx' implied that
the vestibular apparatus had only subcortical projec-
tions. Recently, however, it has been well established
by the work of a number of investigators using electro-
physiological methods that the organ is represented
by a projection area in the cerebral cortex of the cat,
dog and monkey. Adequate stimulation (37, 39, 99,
1 01) — which is not easily graded or measured, nor
brief enough for mapping out the exact boundary of
the area — does not, in the light of more recent work,
seem to be useful. The use of brief electrical stimula-
tion of the vestibular nerve, in order to elicit a dis-
crete evoked cortical response, has been of greater
value (2, 54, 79, 117). The receiving area lies in the
anterior ectosylvian gyrus_and_tb£_ptQ§terior bank of
the anterior suprasylvian gyrus. The projection is
princitjallv contralateral, but stimulation of the
ipsilateral nerve activates a part of the same region.
The response to electrical stimulation of the peripheral
nerve occurs after a latency which suggests that the
projection is direct from the thalamic relav nuclei
(79)- " "' ^ '
The orderly features of the vestibular innervation
and the projection of the vestibular fibers in the
primary nuclei (i, 47, 103) have prompted the postu-
lation that each vestibular receptor organ has its own
exclusive representation on the cerebral cortex.
Cortical respon.ses to liminal electrical stimulation of
three accessible vestibular branches can be recorded
only from a more limited portion of the projection
area as a whole (fig. 8). Stimulation of the nerve from
the utricle of the cat evoked responses from the dor.sal
part of the area. Below and anterior to the latter
focus, responses to stimulation of the ner\e from the
crista of the horizontal semicircular canal were re-
corded, and above it the cortical projection of the
nerve from the superior crista was found (2) (fig. 9).
It has been demonstrated by neurotomy that the
corti^al__response to stimulation of the vestibular
apparatus requires neither an intact cerebellum nor
an intact_medial longitudinal fasciculus (4, 87). This
proves that there are other ascending \estibular path-
ways conducting the impulses. According to Wallen-
berg (i 16) a vestibulocortical pathway appears to run
parallel to the acoustic fibers (10). It should be noted
that available results also suggest the existence of a
corticovestibular connection, although it has been
impossible to trace one (33, too).
B
FIG. 8. Site of electrical stimulation ot branches of the ves-
tibular nerve. Ventrolateral view of the left \estibule, A before
and B after rcmo\ing the membranous labyrinth. Vestibular
nerve branches from the ampulla of the superior canal, /;
lateral canal, 2; and utricle, 4. The utricle is marked, 3, and
the saccule, j. In B three silver wires (black lines') are placed as
stimulating electrodes and are held in place by dental cement
attaching them to the cut edge of the bulla. [From Andersson
& Gernandt (2).]
560
HANDBf)OK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
fk:. 9. Responses of various cortical areas to vestibular
stimulation, recorded from points ;, 2 and 5 indicated on the
drawing of the brain. A:i, A:j and A:j from the utricle, B:i,
B-j and B:^ from the superior ampulla; C.i, C.jj and C.j from
the lateral ampulla before local strychninization. A.j, A.\f and
A:6 from the utricle; B:2, B:^ and B:6 from the superior
ampulla; C:2, C:^ and C':6 from the lateral ampulla after
strychninization. Time in lo msec, intervals. [From .^ndersson
& Gernandt (2).]
Descending Tracts
Through these connections vestibular impulses are
conveyed to the primary motoneurons of the spinal
cord. As far as origin and course are concerned the
vestibulospinal tract seems to be the less complicated
of the descending pathways. This tract, which origi-
nates, at least for the most part, from the large ' motor'
type cells of the lateral vestibular nucleus, descends
ventrally during its course in the medulla into the
aTUerior_Jmii£iilus of the s^jne side of the cord. As
stated, numerous anatomical connections exist between
the vestibular nuclei and the reticular formation, and
the fibers which constitute the reticulospinal tract
have been traced from here into the lateral andven-
tral parts of the spinal cord (82, 83). Descending fibers
forming the nigdial longilmjjnal fasciculus, being both
homolateral and contralateral, are derived from the
descending_ntcdial and lateral nuclei. Those fibers on
the contralateral side all terminate in the cervical
region, while those on the homolateral side may con-
tinue throughout the cord.
X'estibular and proprioceptive systems are both
known to be active in posture and locomotion;
streams of impulses arising from receptors in each of
these systems must converge to influence the activity
of the final common path. ."Ml reflexes which aim at
preserving the normal posture of the body are col-
lectively called 'postural reflexes' (26, 74, 75, 89);
these are considered in Clhapter XLI by Eldred in
this work. The hyperextension of the extremities of a
decerebrate animal can be modified by passively
changing the position of the head. The compensatory
movements of all four legs are elicited by the stimula-
tion of the otolith organ and the proprioceptors of the
neck muscles. These ' tonic labyrinthine' and ' tonic
neck reflexes' operate in the same direction and con-
sequently sum algebraically when both arc elicited.
The tonic labyrinthine reflexes can be studied .sepa-
rately after excluding the tonic neck reflexes by section
of the upper cervical dorsal roots or by fixing the head
so as to prevent any movements of it in relation to the
body. It is then possible to move the animal about in
different positions and thus ascertain the effects of the
labyrinths upon the distribution of tone. For example,
placing the animal on its back with the angle of the
snout approximately 45° ajjove the hori7.ontaJ_jTlane
cau.ses the extensor tone to become maximal; it is
minimal when the animal is in the prone position with
the angle of the mouth 45° below the horizontal axis.
When the head is brought into other positions by
rotation of the body around its transverse or longi-
tudinal axis, intermediate degrees of rigidity between
the two extremes result. These modifications in pos-
tural tone disappear if the labyrinths are destroyed.
More precise experiments have made it clear that the
reflexes are abolished by remosing the otoliths from
their maculae.
The ability to stay in an upright position is a uni-
versal property of man and higher animals. Five
principal groups of reflexes of a somewhat similar
type, responsible for the righting tendency, have been
separated. Each one of these factors alone may bring a
more or less normal upright position; but when they
collaborate, greater precision and promptness in
righting results. These responses can be studied in
decorticate animals in which their reflex nature is
quite apparent. One of them, which is dependent on
the hib\rinth, will be descrilied briefly. In an animal
blindfolded but with the labyrinths still intact the
head tends to assume the natural horizontal position
irrespective of the position in space of the remainder
of the body. The reflexes causing righting of the head,
initiated from the otolith organ, are called the
VESTIBULAR MECHANISMS
561
'labyrinthine righting reflexes'. The responding
muscles are those of the neck. The tonic labyrinthine
and righting reflexes are static ones and are not to be
confused with the vestibular reflexes which are pro-
voked by movements in space and initiated from the
semicircular canals.
Since the classical investigations of Magnus and
Sherrington upon the brain-stem influences on spinal
motor activity were published, some more recent
papers concerning the maintenance and control of
static and phasic postural activites have appeared.
Magoun and coworkers (76) have studied the role of
the brain-stem reticular formation with respect to
inhibition and facilitation of spinal motor activity.
The importance of the vestibular nuclei as an excita-
tory mechanism for the cord has also, in the light of
recent experiments, been reinvestigated (43, 44, 97,
105, 118).
It has been shown that the brain-stem reticular
formation receives impulses relayed from somatic and
auditory sensory structures. It is of interest from this
point of view to be able to add the vestibular organ
to the rest. By recording the impulse activity generated
in response to adequate vestibular stimulation from
isolated units in the reticular formation, it has been
demonstrated that the formation is connected with
both the homolateral and the contralateral vestibular
nuclei (42). Thus the reticular formation forms an
internuncial relay constituting a fundamental element
of the reflex arc. The bilateral distribution of impulses
from both labyrinths are changed in the relay into
excitatory and inhibitory impul.ses which influence
the motoneurons, i.e. the vestibular responses are
organized for reciprocal action on flexors and exten-
sors even when initiated from the reticular level C43).
Impulses conducted in the vestibulospinal tract
will encounter fewer synapses on their wav from
periphery to periphery than those in the reticulo-
spinal tract bv way of the reticular formation. It is
therefore possible to record a two-peak response to a
single vestibular shock stimulus from a whole ventral
root because the impulse volleys are transmitted along
separate paths having different nuclear delays (40).
The descending impulses occurring in response to
vestibular stimulation will influence the activity of
both alpha and gamma fibers. The small gamma
eflferents, however, are activated at a lower strength
of stimulation than are the alpha fibers (3).
In studying the effect of the proprioceptive im-
pulses upon the efferent discharge elicited by vestib-
ular stimulation and recorded from a ventral root, it
became obvious how strong and dominating this
FIG. 10. Effect of foot joint stimulation on vestibular root
response. In A is sliown a control response recorded from
ventral root L7. In B the response is augmented by manipula-
tion of the tarsometatarsal joints of the ipsilateral hind foot.
Time scale in msec. [From Gernandt el at. (40).]
proprioceptive control can be. The vestibular re-
sponse, however strong it may be, will be inhibited
by a muscular contraction (3). One kind of peripheral
stimulation found to facilitate the vestibular re-
sponse arises from manipulation of the joints of the
foot ipsilateral to the recording site (fig. 10). Rein-
forcement of the vestibular response by afferent
discharges arising from the foot joints will contribute
to the increased stability and strength of the corre-
sponding limb during standing, walking and jumping
C40).
The effects of vestibular stimulation upon strych-
nine autorh\thmic convulsive activity of the spinal
cord has been studied in decerebrated cats. Inhibition
of strychnine tetanus was obtained at all levels of the
cord by tilting the head or the whole animal to the
side, backward or forward. The inhibitory effect was
characterized by a progressive decrease in frequency
of the tetanic waves until a complete, but always
reversible, inhibition occurred (41).
EFFECTS OF LABVRINTHECTOMV
As mentioned above, a distinction is made between
two different functions of the vestibular apparatus.
One is concerned with recording the position of the
head in space, the other with reacting to any change in
the rate of movements. The former function is
mediated by the otolith organs, the latter by the
ampullary cristae of the semicircular canals. The
observation of equilibrium disturbances resulting
S62
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY
from operative interference with the different parts
of the labyrinth has been an important source of
knowledge concerning the function of the two sets of
end organs. It was Ewald who first drew attention to
a tonic action of the labyrinth. The operation of
double labyrinthectomy produces slackness of muscles
in various parts of the body. This has been \erified
by McNally & Tait (70) who were aijle to show that
denervation of the canals__did not interfere with
muscular tone, whereas denervation of the ujri£le.
did. The general effects of extirpation of the semicircu-
lar canals, so far as disturbances of equilibrium and
occurrence of forced movements are concerned,
resemble those resulting from operations upon the
cerebellum.
If the organ on one side is destroyed, an aljnormal
asymmetrical posture of the head and trunk results
ifrom the tjnequal influence of the laljvrinths on the
tnnf nf the nerk muscles of the two sides. The result
is a continuously acting righting reflex which causes
the trunk to be curved and makes the animal tend to
roll over and over. Cold blooded vertebrates are much
disturbed by unilateral ablation of the labyrinths.
Extirpation of the labyrinth in monkeys is followed by
nystagmus with the quick component towards the
normal side and rotation of head and neck to the
same side. Rabbits, cats and dogs are rather less
disturbed.
In man the effects are less enduring than in the
monkey. A sudden ablation or a rapid destruction of
one labvrinth causes a vertigo. \'estibular symptoms,
such as nystagmus, past pointing, tendency to fall and
vertigo, are frequently accompanied by symptoms
pointing to an involvement of the autonomic system.
Nausea and vomiting, lowering of_arteria! pressure,
tachycardia and recessive perspiration may occur in
the beginning. The intensity of the vertigo renders
the sufferer unable to maintain erect posture. \Vhen
examined in bed, the patient is poised in the least
uncomfortable position and resists any head move-
ment for fear that any alteration will increase the
vertigo and bring on a spell of severe nausea and vom-
iting. The face is pallid and the skin is clammy.
Diarrhea mav alternate with the vomiting. The
direction of the horizontal or rotatory nystagimis
present is always to the healthy side. The vertigo
likewise is to the healthy side. The distressing vestib-
ular symptoms subside gradually and a complete
reco\eyy from the vestibular disability usually occurs
at the end of one or two months.
A complete bilateral loss of vestibular function
does not produce the vestibular syndrome that is
found following an acute destruction of one labyrinth.
There is no nystagmus and novcrtigo. A disturbance
of equilibrium is always present and the patient, when
deprived of the visual sense, is unable to_mainiain
normal posture and locomotjon. When submerged in
water, he is disoriented and is as likely to swim down-
ward as upward in attempting to reach the surface.
These symptoms are permanent, although partial
compensation takes place.
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CHAPTER XXIII
Excitation of auditory receptors'
H A L L O W E L L DAVIS Central Institute for the Deaf, St. Louis, Missouri
C: H A P T E R CONTENTS
Introduction
Auditory Information
Range and Differential Sensitivity
Significance of Bitemporal Location of Ears
General Plan of Ear
Functional Anatomy and Acoustic Properties of Ear
Middle Eai-: Acoustic Impedance Matching
Tympanic Reflex
Frequency Characteristics of Ear
Mechanical Properties of Inner Ear Structures
Traveling Wave Pattern of Cochlear Partition
Fine Structure of Organ of Corti
Innervation of Hair Cells
Fine Movements of Organ of Corti
Blood Supply and Fluids of Inner Ear
Blood Supply
Fluids
Electric Responses of Inner Ear
Action Potentials
Intracellular Potentials
Endocochlear Potential
Cochlear Microphonic and Summating Potentials
Auditory Nerve Impulses
Volleys and Latencies
Single Fiber Activity
Efferent Inhibitory Action
Theory of Aural Action
Transmission of Auditory Information
INTRODUCTION
Auditory Information
THE EARS ARE SENSE ORGANS specialized for excitation
by airborne vibratory energy. They belong in the
' This work was supported by a contract between the Central
Institute for the Deaf and the Office of Naval Research. Re-
production in whole or in part is permitted for any purpose of
the United States Government.
general class of mechanoreceptors, together with the
organs of touch, pressure, stretch and equilibrium.
They are exteroceptors; the source of the acoustic
energy is in general external to the body. They serve
to transmit information concerning the character of
the physical source as revealed by the rates of vibra-
tion, the intensity, the epoch and the overall temporal
pattern of .such vibrations. The ears also give informa-
tion indirectly as to the direction from which the
sound waves arrive.
Range and Differential Sensitivity'
The lower frequenc\- limit of ' hearing' is usually
set arbitrarily anywhere from 20 to 50 cps. Hearing
merges gradually into sensations of touch, vibration,
'flutter', etc. The upper limit is about 20,000 cps in
young ears but falls off with age. Differences in fre-
quency of less than one per cent may be recognized.
The dynamic range is very great, covering more than
12 logarithmic units (120 db) on the scale of acoustic
energy (see fig. 6) from a lower limit close to the
physical background noise of thermal energy (Brown-
ian movement) up to limits set by acoustic injurv to
the sense organ. Differential .sen.sitivity for intensity is
in the order of magnitude of a tenth of a logarithmic
unit, i.e. one db. Absolute differences in time of ar-
rival of .sound wavesat the twoearsas small as 10 msec,
sensed in terms of the direction of the source, can be
detected by practiced observers.
One physiological problem of hearing is to under-
stand how the sense organ achieves such sensitivity,
dynamic range and discrimination. Another is the
means by which it encodes in nerve iinpulses the in-
^ See especially the papers of Stevens & Davis (11) and of
von Bekesy & Rosenblith (22).
565
566
HANDBOOK OF PHVSIOLOGV
NEUROPHYSIOLOGY I
formation necessary for the central nervous system to
achieve such discriminations. A third is the mecha-
nism by which the mechanical forces of acoustic
energy excite the nerve impulses in the sense organ.
Significance of Bitemporal Localion oj Ears
The location of the inner ears within the temporal
bone of the skull gives them excellent mechanical
protection. Certain details of anatomical architecture
seem to give special acoustic isolation from the inter-
nal sounds of the body, including the sound of one's
own voice (22). The location at the sides of the head
provides an acoustic baffle between the two ears that
insures the differences in intensity of sound waves and
in times of arrival that are the basis of the sensing of
direction of the incoming waves. The location in the
head also allows the use of scanning movements of
the whole head, which, in the human, replace the
separate movements of large external ears. Acous-
tically, the human auricle is an organ of little sig-
nificance.
GENERAL PLAN OF EAR
The external ear (fig. i) includes the canal which
extends diagonally inward about 27 mm (in man) to
the tympanic membrane. This partition, however,
belongs to the middle ear or 'ear drum.' The middle
ear is air-filled and is periodically ventilated for
equalization of air pressure by opening of the audi-
tory (Eustachian) tube. The latter connects with the
nasopharynx. A chain of three small bones, the ossi-
cles, in the middle ear form a system of mechanical
levers that connect the outer tympanic membrane
with a smaller inner opening, the oval window, into
the inner ear. A second opening from middle to inner
ear, the round window, is closed by the flexible
round-window membrane. As we shall see, the chief
acoustic function of the middle ear is to provide an
impedance match between the air of the external ear
canal and the fluid that fills the inner ear and thus
to deliver acoustic energy efficiently to the inner ear
where the sensory cells are located.
The auditory portion of the inner ear is a spirally
coiled canal, called the cochlea because of its snail-
like shape, within the temporal bone. It is fluid-filled
and it is divided along nearly its entire length by a
partition. This partition is actually a tube, the coch-
lear duct, which contains the sense organ proper,
namely the organ of Corti, and its accessory structure,
the tectorial membrane.
The coiled tube that contains the organ of Corti is
roughly triangular in cross section (fig. 2). One side is
formed by the fibrous, elastic basilar membrane,
which extends from the inner bony core of the coch-
lea, the modiolus, to the spiral ligament which lines
Auricle:
Cartilage
SCMICIRCULAR
MaLLELUS CANALS
VeSTIBULE
VeSTlBULAR N
Facial n
Cochlear m
Internal
auditory
canal
Cochlea
Mastoid tip
Cross section
OF eustachian tube
FIG. I. In this semidiagrammatic drawing of the ear, the cochlea has been turned slightly from
its normal orientation to show its coils more clearly. The opening for nerves through the bone to
the brain cavity of the skull is quite diagrammatic. The muscles of the middle car are omitted.
[From Davis (2).]
EXCITATION OF AUDITORY RECEPTORS
567
SCALA TYMPANI
(PERILTMPh)
FIG. '2. Cross section of the cochlear partition of the guinea pig in the lower part of the second
turn. [From Davis (5).]
the outer wall of the cochlear canal. The organ of
Corti lies on the basilar membrane. The second, ex-
ternal, side of the triangle is largely covered by the
stria vascularis, so called because it is richly provided
with capillaries. This thick layer of specialized cells
that face into the cochlear duct is thought to secrete
the fluid, the endolymph, that fills the duct. The
third side of the cochlear duct, Reissner'.s membrane,
is thin but double-layered. It extends from the edge
of the stria vascularis acro.ss to the modiolus and
separates the space within the cochlear duct, the
scala inedia, from the .scala vestibuli. The basilar
membrane separates the scala media from the scala
tympani. The scala vestibuli and scala tympani are
filled with perilymph, a fluid closely resembling cere-
brospinal fluid.
The cochlear partition, including both the basilar
membrane and Reissncr's membrane, ends a little
short of the apical end of the cochlear canal (fig. 3).
Here the scala vestibuli and the scala tympani join
through the helicotrema while the scala media ends
blindly. At the other end of the scala tympani is the
round window. The scala vestibuli opens into the
central chamber of the labyrinth, the vestibule, close
to the oval window. The length of the cochlear parti-
tion in inan, from its origin between the oval and the
round window to the helicotrema, is about 35 mm.
The sensory surface of the cochlea is thus a long
narrow ribbon, coiled in spiral form, mounted on an
elastic membrane between two fluid-filled channels.
This membrane is moved by the fluid which is driven
acoustically at the oval window by the last of the
ossicles, the stapes. The cochlear partition is the me-
chanical frequency analyzer of the ear.
FUNCTIONAL ANATOMY AND ACOUSTIC
PROPERTIES OF EAR
Onlv those anatomical features of the ear will be
described that are necessary for understanding how
the ear acts as an acoustic impedance matching sys-
tem, an acoustic frequency analyzer and a inechanical
stimulator. Anatomy and physiological acoustics will
be combined.
Middle Ear: Acoustic Impedance Malcliing^
The tympanic membrane is a light but fairly stiff
cone with an apical angle in man of about 135° and
^ See especially the papers of Stuhlman (13), von Bekesy &
Rosenblith (22) and \Ve\er & Lawrence (24).
568
HANDBOOK (JF PHYSIOLOGY ^ NEUROPHYSIOLOGY I
Perilymph
Malleus. Stapes
Vestibular
apparatus
Scala
vestibuli
External auditory meatus
Helicotrema
Scala tympani
membrane
Eustachian^
tube
FIG. 3. Schematic drawing of tlic liuman car. [From von Bekesy & Rosenblith (22).]
with flexible edges. It closes the external canal di-
agonally. The long process of the first of the ossicles,
the malleus, is attached radially to the inner surface
of the tympanic membrane from the apex of the cone
nearly to its upper edge (figs 4, 5). The similarity of
the tympanic membrane to the paper cone of a loud-
speaker or microphone is obvious and, like the cone
of a microphone, it moves in and out as a whole
when driven by sound waves — at least up to about
2000 cps. The malleus articulates with the second
ossicle, the incus, but, except perhaps at very high
intensities, the coupling between them is close and
they move as one. The malleus and incus are sus-
pended by ligaments in such a way that their only
free movement is a rotation around an axis that is
nearly tangent to the upper edge of the tympanic
membrane. The membrane and the two ossicles turn
on this axis as a unit. The rather large heads of
malleus and incus serve as a counterweight for their
long processes so that the center of gravity of the
whole unit is very close to its center of rotation. The
system is therefore not readily set in motion relative
to the head when the head itself vibrates. This re-
duces the sensitivity of the ear to bone-conducted
vibration.
The third ossicle, the stapes, nearly closes the oval
window with its "foot-plate," but a flexible annular
ligament allows it to swing like a door on an axis that
is tangent to the oval window at its posterior end. The
long process of the incus articulates with the head of
the stapes and drives the latter in a bell-crank type of
motion. When the foot-plate of the stapes moves, the
fluid of the inner ear moves with it. Although the
inner ear is a closed chamber, movement is possible
because of the yielding of the elastic round window
membrane (fig. 3). The latter thus moves in and out
in approximately opposite phase to the foot-plate of
the stapes.
The area of the human tympanic membrane is 50
to 90 mm^. The area of the foot-plate is about 3.2
mm'-. The amplitude of movement of the center of
each is about the same. In other words, there is very
little mechanical advantage in the lever system in
terms of amplitude of movement. The total force at
the oval window is about the same as at the tympanic
membrane, but it is concentrated in a smaller area;
therefore, the pressure exerted on the fluid is greater.
The overall system thereby matches the impedance
of the air almost exactly to that of the inner ear. As a
result, very little acoustic energy is reflected back
from the tympanic membrane and nearly all is de-
livered to the inner ear.
Tympiniii Riflrx
Two small muscles, tensor tsmpani and stapedius,
attach to the long process of the malleus and the neck
of the stapes, respectively. Each tends to rock its ossi-
cle into the cavity of the middle ear. The muscles are
thus mechanically antagonistic but they act syner-
gistically. They are fast striated muscles and probably
not normally in tonic contraction. They do contract
reflexly, with a latent period of about 10 msec, in
response to fairly strong sounds. They also contract in
EXCITATION OF AUDITOR\' RECEPTORS
569
.Axis ligaments,
Ear drum
Pivot
FIG. 4. Arrangement of
incus and malleus showing
how the mass is distributed
around the axis of rotation.
The maximum displace-
ment of the drum occurs
at its lower edge. [From
von Bekesy (18), after
Barany (i).]
' FIG. 5. The human
tympanic membrane turns
on an axis near its upper
rim. A fold on the lower
rim permits movement of
the rigid eardrum cone.
[From von Bekesy (18).]
response to mechanical stimulation in the car canal.
The refle.x contraction is not very well sustained The
contraction does not move the tympanic membrane
significantly in man, but the increased stiffness (and
perhaps damping also) of the ossicular chain reduces
the transmission of low-frequency and of very-high-
frequency sounds. The reflex seems to be primarily
protective.
Frequency Characteristics of Ear
The middle ear has a resonant frequency of vibra-
tion of about 1700 cps but its movements are quite
heavily, although not critically, damped. The reso-
nant frequency of the chain of ossicles is raised slightly
when the tympanic muscles contract. The external
ear canal has a resonant frequency at about 4000
cps, which gives an increase of sensitivity of about 10
db at this frequency. This resonance combines with
that of the middle ear to give an overall acoustic
frequency response of the ear that has a broad maxi-
mum from 800 to 6000 cps but which falls off rather
rapidly above 6000 and, less rapidly, below 800 cps.
The main features of the human threshold curve of
acoustic sensitivity are apparently determined very
largely by these acoustic properties (fig. 6).
Meclianical Properties oj Inner Ear Structures^
In the inner ear the basilar membrane widens
gradually from 0.04 mm at the stapes to 0.5 mm at
the helicotrema. Certain other measurements, such as
cross section of the cochlear canal and relative sizes
of certain types of cell in the organ of Corti, are also
graded from end to end; but the important variation
that allows the cochlea to act as a mechanical acoustic
analyzer is in the width of the basilar membrane. As
a result of this variation the stiffness ('volume elas-
ticity') of the cochlear partition varies by a factor of
at least 100 from one end to the other.
The cochlear partition has significant stiffness and
also inass. Contrary to earlier opinions it is not under
tension. When cut the edges do not retract. The move-
ments of the partition, like those of the middle ear,
are quite heavily, but not critically, damped. Because
of the gradation in stiffness and mass, different parts
of the basilar membrane have different resonant fre-
quencies, but the various parts cannot move as inde-
pendent resonators. The basilar membrane and the
organ of Corti on it are continuous structures. Their
elements are coupled to one another elastically and
also by friction. The endolymph and the perilymph
provide some of the friction.
Traveling U^ave Pattern nj Cochlear Partition''
An increase in pressure on the footplate of the
stapes caused by a sound wave sends a wave of
acoustic pressure up the cochlea with a velocity that
is determined by the laws of transmission of acoustic
' See especially the papers of von Bekesy (20) and von
B6kesy & Rosenblith (22).
'See especially the papers of Tasaki el at. (17), von Bekesy
(20, 21) and von Bekesy & Rosenblith (22).
570
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
100
I I I 1 1 III 1 — Ill
__ Bekesy '
""■^ .^"Pricking in middle ear" 10
T I I II I I ij
"I 1 — I I I I 1 11
160
|-140„
E
120 T
>.
T3
100 8
O
O)
-80 i
c
60 3
«
40 ■?
.5?
20
-0
100
Frequency m cps
10,000
FIG. 6. The threshold of audibihty and the threshold of feeling. MAP, minimum audible pressure
at the eardrum. MAF, minimum audible pressure in a free sound field, measured at the place
where the Hstener's head had been. [From Licklider (g).]
waves in a tube with a flexible wall. This velocity is
less than the velocity of sound in water but it is so
fast that the increase in pressure in scala vestibuli
relative to scala tympani is virtually simultaneous
throughout the length of the cochlea. The pressure
wave travels much faster than the phase velocity of
the traveling wave of mechanical movement that
occurs in response to this difference in pressure be-
tween the two scalae. An over-all net movement of
the cochlear partition towards scala tympani in re-
sponse to this differential pressure occurs because the
round window forms a flexible portion of the other-
wise rigid walls of the bony labyrinth. The round
window membrane bulges outward and thus allows
inward movement of the stapes. Inside the cochlea,
the cochlear partition bulges toward the round
window.
When the movement is very slow, some fluid also
flows through the helicotrema. But all parts of the
cochlear partition do not move with equal prompt-
ness. The relatively stiff portion in the basal turn
moves very nearly in phase with the driving force,
but the more flexible apical portions, particularly
those with a resonant frequency lower than the fre-
quency of the acoustic wave that is driving the parti-
tion, tend to lag behind. As the acoustic wave reverses
its pressure, the portion that is 'tuned' to lower
frequencies tends to overshoot and continues to lag
behind the driving force exerted on it by the acoustic
pressure in the fluid. Thus, because of the gradation
of stiffness, a traveling wave of displacement appears
on the cochlear partition (fig. 7). Furthermore, be-
cause of the continuity of the partition, the stifTer
portion, moving almost as a unit, drives the more
flexible portion.
The traveling wave increases in amplitude as it
moves apically and reaches its maximum near the
region where the resonant frequency of the basilar
membrane corresponds to the frequency of the driving
waves (fig. 8). The amplitude of movement falls off
rather rapidly beyond this point; also the phase lag
increases rapidly as the traveling wave moves on
toward the apex. The velocity of travel therefore
diminishes, and consequenth the wavelength of the
displacement pattern becomes shorter. A little distance
beyond the position of maximum amplitude there is
no significant movement at all. In the region of rapid
diminution of amplitude the phase lag amounts to a
full cycle or more.
If the driving frequency is increased, the position of
maximum amplitude moves toward the oval window;
if it is decreased, the maximum moves toward the
EXCITATION OF AUDITORY RECEPTORS
571
Flg.7
A<* = ^:200cps
\
\
— T
/
"~--
—
^
N
\
/
/ /
t'O
"~~-^^
^\. \
/
/ /
/ /
lo.
1 .. 1
. 1
1 1
1 1 1
\
1
[ 1 r
1
_l 0
20
22
24 26 28
Distance from stapes in millimeters
30
32
50 100 200 400 800 1600 2400 5000
Frequency in cps
FIG. 7. A traveling wave on the cochlear partition for a 200 cps tone. The solid line shows the
pattern at one instant, the line with short dashes a quarter of a period later. The envelope shows
the maximal displacement at each point. [From von Bekesy (19).]
FIG. 8. Resonance curves for si.x points on the basilar membrane. The solid curves represent
measurements by von Bekesy; the dashed curves, theoretical calculations by Zwislocki. [From von
Bekesy (22).]
apex (fig. 9). At about lOO cps in man, it is very close
to the helicotrema. At 2000 cps there is very Httle
movement beyond the mid-point of the cochlear par-
tition. The extreme basal end of the partition, how-
ever, moves in response to all frequencies within the
audible range.
The unsymmetrica! traveling wave pattern of
movement, with its rather flat maximum of amplitude
and its abrupt apical reduction in activity, has been
shown to be a necessary and predictable consequence
of the principles of acoustic resonance in a system
such as the cochlea with gradation of stiffness, mass,
damping and coupling (21, 26). The traveling wave
pattern has been reproduced in appropriate physical
models and it has been observed directly in the
cochlea under the microscope with stroboscopic illu-
mination (20) and inferred from electrical recordings
(17) (see fig. 15). It allows the cochlea to act as a
mechanical frequency analyzer because the extent of
activity and position of maxima vary as functions of
frequency. It introduces additional features, such as
asymmetry, progressive time and phase lag, and sig-
nificant longitudinal as well as transverse bending of
the cochlear partition, that contribute to the pattern
of neural excitation that results from the movements
of the partition.
Fine Structure of Organ of Corti^
The organ of Corti consists of sensory cells that are
known as ' hair cells' because of their tufts of hair-like
SOOcps 200 cps 100 cps
50 Cps
25 Distance from 3Q
stapes in millimeters
n
35
* = 0i d:^:::-
1 1
"^-^....^^^ "— — *-*.^
50 cps
^■^^^^ ^^ 100 cp?
\ \
N^ 200 cps\
300 cpN ^
' See especially the review by Davis (4).
FIG. 9. Amplitude and phase angle of movements of the
cochlear partition for four different frequencies as a function of
distance from the stapes. At 50 cps the partition moves sub-
stantially in phase throughout. [From von Bekesy (19).]
processes that extend into the scala media and sup-
porting cells. The tectorial membrane, in which the
outer ends of the hairs are imbedded, is an important
accessory structure (fig. 2). It is obviously the ana-
logue of the otolithic membrane of the utricle and of
the cristae of the semicircular canals, sense organs
that are sensitive to mechanical acceleration.
The ends of Deiters" cells that face the scala media
form a stiff but openwork plate, the reticular lamina.
The hair-bearing ends of the hair cells are firmly held
in the openings of this lamina; their opposite ends,
surrounded by the nerve endings of the auditory nerve,
rest in cup-like supports that are also part of Deiters'
cells. Between their upper and lower ends the external
hair cells hang free in a fluid-filled space. The so-
called ' rods of Corti' form, with the basilar membrane
572
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
on which they rest, a stiff triangular supporting struc-
ture for the inner end of the reticular lamina. The
outer edge of the lamina rests on a softer cushion of
Hensen's cells. The outer portion of the basilar mem-
brane, between Hensen's cells and the spiral ligament,
carries the lower cuboida! cells of Claudius.
The flask-shaped hair cells forming a single row
along the inner edge of the reticular lamina are known
as internal or inner hair cells. There are about 3500 of
them, each about 12 |i in diameter. The smaller (8 fi)
cylindrical external hair cells are arranged in three
or four rows external to the tunnel of Corti. There are
aiiout 20,000 of them in each ear.
Innervation of Hair Cells'^
The afferent neurons of the auditory nerve art-
bipolar cells. The cell bodies, about 28,000 in each
ear, are arranged in a long spiral ganglion parallel to
the organ of Corti but within the bony modiolus
Their axons pass inward to the hollow core and
thence, as the cochlear portion of the eighth cranial
nerve, through the internal auditory meatus, to the
cochlear nucleus of the medulla. The axon-like den-
dritic processes pass outward through the sieve-like
bony and fibrous habenula perforata into the organ
of Corti (fig. 2). They are myelinated up to the
habenula perforata. Some of them, the internal radial
fibers, pass directly to the internal cells and innervate
one to three cells. Others cress the tunnel of Corti to
the external hair cells. Some of these are radial fibers
with a restricted area of distribution but most of them
run apically or basally, or in both directions, for as
much as several millimeters as the external spiral
fibers. Each fiber innervates many external hair cells
but not cver\- cell along its course, and each cell
typically receives more than one nerve fiber. The
plan of innervation is illustrated in figure 10. The
ner\c endings around the lower ends of the hair cells
appear under the electron-microscope as well-devel-
oped structures rich in mitochondria.
In addition to the afferent fillers, an efferent olivo-
cochlear bundle from the contralateral olivary nu-
cleus runs lengthwise of the organ of Corti as the intra-
ganglionic bundle within the modiolus and just
peripheral to the spiral ganglion (fig. 2). These
efferent fibers distriiiute to the organ of Corti and
apparently innervate the hair cells, particularh' the
inner hair cells.
' See especially the papers of Dasis (4) and Wever (23).
Fine Movcmenis of Organ of Corti
The fine movements of the organ of Corti and the
tectorial membrane have been observed under the
microscope by stroboscopic illumination and described
in some detail by von Bekesy (20). In any one seg-
ment the basilar membrane, organ of Corti, tectorial
membrane, and usually Reissner's membrane also,
move in phase with one another. The basilar mem-
brane is fibrous and elastic, and basically it deter-
mines the traveling wave pattern of vibration de-
scribed above. The cells of Hensen form a soft cushion
supporting the stiffer plate of the reticular lamina.
The tectorial membrane is hinged like the cover of a
book along the edge of the limbus. It is composed of a
system of diagonal fibers and also a jelly-like sub-
stance It is a viscous elastic system that yields to slow
movements but is quite resistant to quick movements.
It returns rather slowly after being displaced.
Apparently, as the basilar membrane bulges 'up-
ward' or 'downward' (fig. 11), the stiff reticular
lamina tends to rock on the support of the rods of
Corti around an axis at the attachment of the basilar
membrane to the bony modiolus. The tectorial mem-
brane swings on its attachment to the limbus The
result is a shearing action between the tectorial mem-
brane and the reticular lamina (fig 12). The 'hairs'
arise from the cuticular plates of the hair cells which
are set firmly in the reticular lamina, and their outer
ends are firmly imbedded in the tectorial membrane.
Therefore, as the basilar membrane bulges, the hairs
are bent. The force of the movements of the cochlear
partition is rather efficiently concentrated on this
shearing action.
The movement described above is associated with
an approximately radial displacement of Hensen's
cells, as seen under the microscope, and a correspond-
ing radial or slightly diagonal bending of the hairs.
This movement is characteristic on the basal side of
the position of maximal amplitude. On the apical
side, however, due to the shorter wavelength of the
traveling wave and sharper longitudinal bending of
the basilar membrane, a longitudinal mo\ement pre-
dominates and the hairs are presumably bent longi-
tudinally instead of radially (fig. 13)
The exact significance of these different directions
of mo\cment in relation to the excitation of nerve
impulses by the hair cells is still a matter of specula-
tion, but the bending of the hairs is the final and
EXCITATION OF AUDITORY RECEPTORS 573
FIG. 10. Diagram of the innervation of the cochlea. The hair cells are indicated only in part.
The principal types of fibers and the bundles that they form aie: / and -', intraganglionic spiral
fibers; sa and 3a, internal spiral fibers; 4, external spiral fibers; j and 6, radial fibers. (Based on
observations of Retzius, Solovcov and Lorente de No.) Not shown are the relatively scarce un-
branched external radial fibers (Held). Type I is the continuation of the efferent olivocochlear
bundle. [From Wever (23).]
FIG. II. Movement of the cochlear partition, based on descriptions by von Bekesy. Explanation
in text. [From Davis (3).]
critical mechanical event that has been recognized in
the mechanism of stimulation. At this point the signif-
icant events apparently become electrical, for this
bending of the hairs seems to release energy in the
form of biolectric potentials and these potentials are
in all probability the important intermediate step in
the mechanism of excitation of the auditory nerve
fibers.
574 HANDBOOK OF PHYSIOLOGY ^ NEUROPHYSIOLOm' 1
RETICULAR
TECTORIAL
FIG. 12. Movement of the organ of Corti and the tectorial membrane, based on descriptions by
von Bekesy. The shearing action between two stifT structures, the tectorial membrane and the
reticular lamina, bends the hairs of the hair cells. [From Davis (s)-]
helicotrema
stapes
Hensen s
cells
longitudinal
vibrations
radial
FIG. 13. The distribution of radial and longitudinal vibra-
tion along the organ of Corti for stimulation with a tone, seen
through Reissner's membrane. [From von Bekesy (20).]
FLUIDS AND BLOOD SUPPLY OF INNER EAR*
Blood Supply
The cochlea is supplied by the cochlear artery
which enters the modiolus through the internal
auditory meatus. The spiral ganglion is richly sup-
plied with capillaries, and arterioles arch across the
roof of the .scala vestibuli to the spiral ligament. The
stria vascularis, facing the scala media, is, as its name
suggests, a veritable maze of small blood vessels with
many anastomoses. The limbus is fairly well supplied
with capillaries and a small arteriole often runs length-
wise on the tympanic surface of the basilar membrane.
' See especially the papers of Davis (4) and of Smith et al.
(.0).
The blood flow of the inner ear reflects, as would be
expected, major alterations in systemic circulation,
but it does not seem to be significantly aff^ected by
stimulation of the cervical sympathetic nerve.
Fluids
The perilymph, which fills the scala vestibuli and
the scala tympani, is chemically almost identical with
cerebrospinal fluid, and in fact the perilymphatic
space is anatomically continuous with the subarach-
noid space through the cochlear aqueduct. Essen-
tially the same fluid also permeates the modiolus, the
substance of the spiral ligament, and the tunnel of
Corti and other spaces within the organ of Corti. The
basilar membrane seems to be readily permeable to
ions, and, in contrast to Reissner's membrane, offers
little resistance to electrical current flow. The sensory
cells are probably nourished from the scala tympani,
not from the scala media.
The endolymph, which fills the scala media, differs
sharply from perilymph in its ionic content.
Unlike all other extracellular body fluids, it is high
in potassium and low in sodium. It more nearly
resembles intracellular fluid in this respect. Typical
analyses of endolymph, perilymph and cerebrospinal
fluid are given in table i. The endolymph has some-
times been described as 'viscous,' but this is probably
true onlv for certain fish and perhaps other lower
forms.
The endolymph is probably secreted h\ the stria
va.scularis. Whether it is also reabsorbed wholly or
onlv in part by the same structure is a matter of de-
bate. The saccus endolymphaticus, an intradural
extension of the endolymphatic system of the mem-
branous labyrinth, may participate in secretion, in
reabsorption or in both.
EXCITATION OF AUDITcmV RECEPTORS
0/0
TABLE I . Composition of Spinal Fluid,
Perilymph and Endolymph
Spinal fluid
Perilymph
Endolymph
Potassium
(mEq/1.)
4.2±o.5
4.8±o.4
i44-4±40
Sodium (mEq/1.)
1 52 . o± 1 . 8
150. 3±2 . I
I5.8±i.6
Chloride CmEq/1.) ^
122. 4±i .0
12 1 .5±i .2
107. i±i .4
Protein (mg %) ...
21 ±2
50 ±5
15 ±2
Results (means and standard errors of means) of analyses
of spinal fluid, perilymph and endolymph, made by Smith
et al. (10). The endolymph was collected from the utricle,
but cochlear endolymph gave similar although less reliable
results.
ELECTRIC RESPONSES OF INNER EAR'
Action Potentials
The final output of the inner ear is ner\e impulses
in the auditory nerve. If these impulses are well
enough synchronized into definite groups or volleys,
as in responses to clicks or to successive sound waves
of a low-frequency tone, the corresponding action
potential waves can easily be recorded. They appear
clearly when one electrode is on the round window
and the other on the neck, but special placements
are needed to record the action potentials without
contamination by the other electric responses of the
cochlea. With the u.sual electrode placements, the
potentials are recorded as the impulses pass through
the modiolus and just before they enter the internal
auditory meatus.
The action potentials represent the familiar all-or-
none 'spike' responses of nerve fibers. They show defi-
nite thresholds and are followed by refractory
periods. One consequence of the refractory period is
the phenomenon of 'masking.' The synchronized
action potentials in response to a click or tone of
moderate intensity are much reduced if a moderate
random noise is presented at the same time. The
noise stimulates the nerve fibers at random and the
refractory periods prevent the usual synchronized
responses of many fibers.
Other details of the nerve response in relation to
parameters of the stimulus will be given below. The
present point is that nerve action potentials are one of
' See especially the papers of Davis (3, 4) and of Tasaki el
al. (15, 16, 17) .
the electric responses of the ear and that they are in
all ways similar to 'axon spikes' elsewhere.
Intracellular Potentials
Nearly all cells show a negative intracellular poten-
tial. Explorations of the cochlea and the auditory
nerve with very fine microelectrodes reveal these intra-
cellular potentials, ranging from —60 or even —80
mv relative to the potential of the perilymph in large
cells such as Hensen's or Claudius' down to — 20 or
so in the cells of Reissner's membrane. The exact
value seems to be a function of the amount of injury
caused by the microelectrode, the greater the injury
the lower the value. The hair cells, like the nerve
fibers and supporting cells, are electrically negative
internally.
Endocochlear Potential
The interior of the scala media, the endolymph, is
electrically positive relative to the perilymph in the
scala vestibuli and the scala tympani, and to the spiral
ligament and extracochlear tissues in general. This
potential is -|-8o mv (fig. 14). It is encountered
abruptly at the point where the exploring electrode
enters the endolymphatic space, although a relatively
large (15 ju) electrode pushed through the stria vascu-
laris usually reaches this potential level in a series of
two or more steps. The change of potential in going
from the interior of a hair cell through its cuticular
layer into the scala media is from — 70 to -f-Bo, or
about 150 mv.
The endocochlear potential, formerly known as the
endolymphatic potential, is so designated because it
seems to be practically confined to the endolymphatic
space of the cochlea. The corresponding potential
within the utricle is not more than -I-5 mv. The endo-
utricular potential is hardly more than the difference
in potential found in the perilymph between the
helicotrema and the basal end of the scala vestibuli
or scala tympani. The latter potential gradient may
well be due to unequal leakage through Reissner's
membrane or other parts of the endolymphatic wall,
but in any case it implies a considerable continuing
current flow, dependent presumably on continuing
metabolic activity.
The endocochlear potential is in fact closely de-
pendent on an adequate oxygen supply It falls, re-
versibly, to a very low level at the stage of asphyxia
that is reached in extreme Cheyne-Stokes respiration
576
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
Reissner's
membrane
CELLS OF THE
ENDOLYMPHATIC
WALL
ENDOLYMPHATIC
SPACE
+ 80mV
STRIA
VASCULARIS
BLOOD
■' VESSELS
SPIRAL
LIGAMENT
BONE
FIG. 14. Distribution of the positive endocochlear potential'. The 'endolymphatic space' of the
scala media is shown in heavy outline. The negative intracellular potentials are also indicated. The
tectorial membrane is omitted and only one external hair cell is shown. [From Tasaki (16).]
(in anesthetized, moribund guinea pigs). Full recovery
requires only a few seconds after a large single gasping
inspiration. It is also abolished rapidly by injection of
cyanide or azide into the scala tympani or scala
media. It is not immediately affected by injection of
isotonic potassium chloride, choline chloride, or po-
ta.ssium glutamate into the scala tympani or scala
vestibuli. It does fail, although less rapidly than with
cyanide, following surgical injury to the scala media
or the injection into the scala media of a solution that
differs substantially in ionic content from the analytic
figures for endolymph given in table i.
The endocochlear potential is modified by displace-
ment of structures within the cochlear partition. Dis-
placement of the basilar membrane toward the scala
tympani, as by injection of fluid into the scala media
or an inward movement of the stapes, causes an in-
crease in the positive potential by as much as 5 or 10
mv. Movement in the opposite direction, as by out-
ward movement of the stapes, causes even greater
reductions in the potential. Movements of Reissner's
membrane alone are not effective, but movements of
the tectorial membrane relative to the reticular
lamina, when it is manipulated by a microneedle,
produce just such changes in potential. The changes
are related to displacement, not to velocity, and are
sustained as long as the displacement is maintained.
The source of the endocochlear potential has been
identified positively. It is the stria vascularis (6). The
changes in endocochlear potential described above
are clearly associated with the organ of Corti, almost
surely with the hair cells, but the resting positive
endocochlear potential is not generated there. Per-
haps a separate electric response to mechanical move-
ment occurs in the hair cells and simply adds to the
potential that is produced by the generator in the
stria vascularis, or perhaps the potential of scala
media is modified by a change of the electrical re-
sistance to the continual leakage current that must
flow from stria \'ascularis through the hair cells.
Cochlear Microphonic and Sumrnatino Potentials
The cochlear microphonic and two summating
potentials (positive and negative) are all electric
responses to acoustic stimulation. The cochlear micro-
phonic is linearly proportional, up to a limit, to the
displacement of the cochlear partition and thus,
indirectly, to the instantaneous acoustic pressure.
The microphonic thus reproduces the wave form of
EXCITATION OF AUDITORY RECEPTORS
577
the acoustic stimulus (fig. 15). The summatins; poten-
tials are proportional not to any instantaneous value
of the acoustic signal but to a root-mean-square value,
integrated over a very short time. Thus the summating
potentials reproduce appro.ximately the form of the
envelope of the original acoustic signal. The positive
and the negative summating potentials are opposite
in sign. They can be separated by the greater vulner-
ability of the positive summating potential to oxygen
lack and other injury and by the more apical site of
generation of the negative response. The range of
linear response of the summating potentials has not
yet been determined.
The cochlear microphonic is generated at the
cuticular surface of the hair cells. This is clearly
proved by exploration with microelectrodes. The
microphonic, and in all probability the summating
potentials also, seem to reflect the bending of hairs in
the appropriate direction. It is believed that, at
intensities high enough to evoke the summating poten-
tials, some kind o*^ mechanical rectifying or detector
action takes place in the inner ear to cause an asym-
BASAL
250 TURN n
APICAL
1000
2000
8000
PAIRED ELECTRODES, SCALAE VESTIBULI AND TyMPANI,
IN EACH TURN
FIG. 15. Cochlear microphonic responses to 'tone pips' of
various frequencies recorded simultaneously from the basal, the
second and the apical turn. The wave form of the acoustic sig-
nals is accurately reproduced. The time delay (phase difference)
between the second and apical turns and the basal turn demon-
strates the traveling wave pattern. The failure of 1000, 2000
and 8000 cps waves to reach the apical turn and of 8000 cps to
reach the second turn demonstrates acoustical analysis. The
displacements of the base line in the 8000 cps responses are
summating potentials. [From Tasaki (17).]
metrical, persistent one-way bend in the hairs of
certain cells. In some cases the bending is probably
across, in others lengthwise of, the organ of Corti.
[A theory that includes this and several other aspects
of the electrophysiology of the cochlea has recently
been published elsewhere (4).]
Both the cochlear microphonic and the summating
potentials are continuously graded responses, linearly
related, up to a limit, to the intensity of the acoustic
stimulus and with no true ' threshold' like that of all-
or-none action potentials. No evidence of anv all-or-
none response in the sen.sory cells or of a refractory
period has been found, even when the cochlear micro-
phonic was recorded from an electrode inside a hair
cell. Both the microphonic and the summating poten-
tials show very little or no fatigue or adaptation.
The cochlear microphonic 'appears', in the sense
that it reaches a root-mean-square value of a micro-
volt or thereabouts, at a much lower sound pressure
level than the summating potential (except at the
extreme high-frequency limit of response). The in-
crease is linear with the sound pressure level up to
about 90 db relative to 0.0002 microbar in the guinea
pig but varies somewhat with frequency. The response
then increases more slowly and usually goes through a
maximum. At low frequencies harmonic distortion
(peak limiting) occurs within the cochlea at even
lower levels than in the iTiiddle ear. For high fre-
quencies, however, the sinusoidal wave form of the
microphonic is maintained even when the increase of
amplitude with intensity has become nonlinear. This
curious behavior is in sharp contrast to the peak
limiting seen at low frequencies.
The summating potentials are not directly related
to the nonlinearity of the mechanism of the cochlear
microphonics although they may happen to first ap-
pear at sound pressure levels which lie near the
beginning of nonlinearity. With increasing intensity
the summating potentials do not reach a maximum
but continue to increase up to limits that are set only
by acoustic injury to the organ of Corti.
The cochlear microphonic, like the endocochlear
potential, is closely dependent on an adequate oxygen
supply. In anoxia both fall almost in parallel, and the
minor differences are well explained by the changes in
electrical resistance of Reissner's membrane, etc.,
which also occur in anoxia. This parallelism is a
strong argument for a cau.sal dependence of the micro-
phonic on the endocochlear potential, but neverthe-
less the microphonic may also be abolished by certain
injuries that leave the endocochlear potential un-
affected. Two such injurious procedures are a) injec-
578
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
tion of a high-potassium solution like endolymph into
the scala tympani (fig. i6), and b') poisoning with
streptomycin just sufficient to cause degenerative
changes in the hair cells.
Surgical injury or injections into the scala media of
solutions of ionic makeup substantially different from
endolvmph causes a depression of the cochlear micro-
phonic as well as the endocochlear potential, as in
anoxia but more slowly. The parallelism between the
endocochlear potential and cochlear microphonic
here holds in general but is not exact.
In complete anoxia, and continuing for an hour or
more post mortem, a small cochlear microphonic
remains. This residue may depend, in part at least,
on oxygen that diffuses to the basal turn through the
round window, but perhaps it is generated in part
by an anaerobic mechanism. This latter might be a
transducer action like that of a condenser microphone.
The primary aerobic cochlear microphonic, however,
apparently represents an amplifier action in which
energy from a pre-existing ' biological pool of energy,"
such as is suggested by the endocochlear potential,
is 'valved' or modulated by the mechanical bending
of the hairs. In any case the sustained changes in the
endocochlear potential noted above certainly repre-
sent a modulation of a biological source of energy and
not simplv a passive physical transducer mechanism.
The summating potential, as usually seen, is a dis-
placement of the base line of the oscilloscopic record
on which the cochlear microphonic is superimposed.
It is a paradoxical fact that, with mild anoxia, ab-
normal ionic concentrations, etc., as the cochlear
microphonic diminishes the negative summating
potential increases (see fig. i6). The diphasic effect
of anoxia, etc., is best explained by assuming a) that
there is a positive as well as a negative summating
potential, generated by a different set of sensory cells,
and ft) that the positive response is more sensitive to
anoxia than the negative. The negative summating
potential seems to be stronger, although higher in
'threshold' (of detection); only under more severe
anoxia or ionic injury does it weaken and finally
disappear. The positive summating potential is
attributed to the inner hair cells which are known to
be the more sensitive to anoxia. "^ With moderate
stimuli in a fresh preparation the positive summating
'° On the basis of more recent evidence (6), the negative
summating potential is attributed to the internal hair cells and
the cochlear microphonic and the positive summating potential
are attributed to the external hair cells.
ENDO-TYRODE IN SCALA TYMPANI
Cochlear
MlCROPHONIcl
AND .1
Summating/ I
Potential
Action /
Potential
STIMULUS
4 MSEC
9450 GPS
I MSEC
RISE TIME
-."^J^^fNUlC^
BEFORE
INJECTION
10 SEC
AFTER
90 SEC
AFTER
DC REMAINED CONSTANT at 75 MV
FIG. 1 6. A solution with high potassium and low sodium
concentration like endolymph injected into the scala tympani
depresses cochlear microphonic, summating potential and ac-
tion potential before affecting the endocochlear potentizd in
the scala media. Note the transient increase in summating
potential at lo sec. Downward deflections indicate the scala
vestibuli to be more negative relative to the scala tympani
{top tines^ or the cochlea more negative relative to the neck
(lower lines'). [From H. Davis, unpublished observations.]
Positive SP
Positive and Negative SP
0\^^r^
AP
TONE BURST
AP
8600 GPS
+ 20 DB
FIG. 17. Action potentials, cochlear micophonics and sum
mating potentials from the basal turn. An increase of 20 db in
stimulus intensity causes the negative summating potential
nearly to obscure the smaller positive response. Note Ni, No,
and Nt in the action potential response to the stronger tone
burst. [From H. Davis, unpublished observations.]
potential may dominate (fig. i 7) The reduction in
positive summating potential causes the apparent
increase in the opposing negative summating poten-
tial. The full sequence of changes may be even more
complicated and depends in its details on the initial
condition of the organ of Corti, the location of the
recording electrodes and the frequency of the tone
bursts used to elicit the responses.
EXCITATION OF AUDITORY RECEPTORS
579
AUDITORY NERVE IMPULSES'
Volleys and Latencies
The auditory ner\e responds to a single click with a
sharp, well-synchronized volley of action potentials,
conventionally designated 'Ni'. If the click is of moder-
ate strength, Ni is usuallv followed about i msec,
later by a smaller second vva\e, 'N)'; and with still
stronger clicks, a third still smaller wave, 'Nj', may be
seen (fig. 17). N5 and N3 are due largely to repetitive
firing in some but not all of the responding fibers, the
interval corresponding to the refractory period of the
nerve fibers.
The successive sound waves of a steady tone of
frequency below 4000 cps give rise to similar, although
smaller, volleys of action potentials. Between 4000
and 2000 cps the indi\iduai \'olleys are very small,
but the frequency of the tone is nevertheless clearly
reproduced in the action potential pattern, even
though no one fiber responds to every sound wave.
This pattern of occasional but synchronized response
to a regular but intermittent stimulus such as sound
waves is the basis of Wever's (23) 'vollev principle'
(fig. 18).
At very low frequencies in the guinea pig, both Nj
and N2 may sometimes be seen in response to each
sound wave, but both are rather dispersed in time.
At 1000 cps and below, the sharp initial portion of Nj
is initiated in the lower turns of the cochlea in which
the partition moves almost in phase as a unit. The
sharp initial 'spike' is followed by a more diffuse
' tail' of impulses from the inore apical regions.
Not only do different fibers have different latencies
of response due to the travel time of the traveling
waves but, as shown by studies of individual fibers,
the latency of each varies from one response to the
next. This variability leads to a less and less perfect
synchronization of the impulses as the frequency is
raised, and above 4000 cps no synchronization is
visible on the oscilloscope or audible by ear. At the
onset of a high-frequency tone burst, however, there
is a very well synchronized Ni, N2 and perhaps N3
(figs. 16, 17). The latency of Ni, the sum of the whole
group of fibers, is very stable in spite of the variability
among individual fibers. The latency shortens from 2
msec, or more near threshold to about i msec, as
intensity is increased. The shortest latency reported is
0.55 msec. The latency is a function of rise-time as
" See especially the papers of Davis (4) and of Tasaici
(14. 15)-
\AA/I\AA/
FIG. 18. Single-fiber spikes in two different fibers of the
auditory nerve induced by 1000 cps pure tones about 55 db
above human threshold. Lower Iracitig is sound stimulus recorded
through a microphone. Exposure was about .015 sec. [From
Tasaki (14).]
well as the intensity and perhaps also the frequency of
the acoustic signal.
The latency of the action potentials is attributed
chiefly to conduction time in the nonmedullated
dendritic iiranches in the organ of Corti. It is meas-
ured from the beginning of the cochlear microphonic
to the foot of the action potential spike, recorded as
the volley passes through the modiolus. (No latency
can be seen between mechanical displacement of the
cochlear partition and the cochlear microphonic.)
The response to a brief high-frequency transient
such as a click or the onset of a tone burst seems to be
determined by the wave-group as a whole as if a
rectifier-detector were operating in the ear. The
summating potential is proijably the electrical sign
of just such a mechanical detector action.
At lower frequencies, below about 3000 cps, each
sound wave acts more and more like an individual
stimulus. Excitation apparently occurs during the
'falling phase' of the cochlear microphonic, i.e. while
the .scala media (and vestibuli) is ijecoming more
negative relative to the scala tympani. This corre-
sponds to the phase of outward movement of the
stapes. The latency of responses to individual waves
can be reckoned consistently and logically from the
positive peak (in the scala media) of the cochlear
microphonic; but latency measurements are compli-
cated at low frequencies because of the progressive
time delay of the travelinc: wave.
Single Fiber Activity
Many of the above statements concerning latency
of response, all-or-none activity, etc., of auditory
58o
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
nerve impulses, derived originally from studies of the
whole-nerve action potentials, have now been con-
firmed or extended by studies of single fiber activity.
The auditory axons are 2.5 to 4.0 fi in diameter.
Tasaki succeeded in inserting hyperfine electrodes
into individual axons in the modiolus near the internal
auditory meatus while delivering brief tone bursts or
steady tones to the guinea pig (fig. 18). The spike
responses resembled those from myelinated fibers of
similar size elsewhere. Injury discharge was some-
times seen and also responses clearly related to the
auditory stimuli. The response to a brief burst or
click was often repetitive as shown in figure i g, some-
times outlasting the stimulus by 20 to 30 msec. The
minimum interval between impulses in such discharges
was I msec. 'Spontaneous' impulses, i.e. not correlated
with acoustic stimuli, were often seen in the same fibers
that also gave clear responses to sounds. No inhibition
of spontaneous impulses by acoustic stimuli was ever
seen.
Some fibers regularly tended to give single, others
repetitive responses. Some fibers had low thresholds;
others high. Most fibers were partially selective with
respect to frequency. Each showed a very sharp and
very stable cut-off frequency above which it failed to
respond even at high intensities of stimulation. At a
frequency only slightly below the cut-ofF the fiber was
most sensitive, but the rise in threshold with further
reduction in frecjuency was very gradual (fig. 19).
Nearly all fibers encountered had cut-ofFs above 1000
Response Area of a single auditory nerve fiber
- 0
>
2 -20-
3
S -40
-60
nil 11
m
III 111
III III
/
III III
— il 1
■1
II IIDt
III m 1
/
/
.11 II
1
II III
1 II
/
1. /
^
^
\
/
,1 '
-
1 -^
11/
1
1 1
1
1 '
J
1 1
2345 6 7 8KC
Frequency
FIG. 19. Repetitive responses of a single auditory fiber to
tone pips of different frequencies and intensities. Doited line
shows boundary of response area' of this fiber. [From Tasaki
(■4)-]
cps but in a few fibers a cut-off as low as too cps was
found. The 'response areas' mapped out by Tasaki
are much like those described earlier by Galambos
and Davis for units now known to be second order
(cochlear nucleus) neurons; but the high-frequency
cut-off is rather sharper, the low-frequency decline is
more gradual and inhibition of acoustic responses was
never observed.
During continued tonal stimulation an apparently
irregular discharge continued but at a gradually
diminishing rate. This is the phenomenon of adapta-
tion, for which there is also good psychoacoustic
evidence. The continuing discharge was superficially
irregular but aciually, except for a few (presumably
'spontaneous') impulses, all the impulses from a given
fiber fell in approximately the same phase relation to
the tonal stimulus and the cochlear microphonic as
explained above.
Concerning recovery from adaptation, fatigue, or
both, the information from psychoacoustics has con-
siderably outrun that from physiology. The recovery
curve of Ni of the composite nerve response is mono-
tonic, unlike the recovery curve of psychoacoustic
threshold. The partial depression of a second nerve
response depends both on the intensity of the first
click and on the duration of the interval following it,
and it outlasts by 10 msec, the refractory period of the
fillers.
The action potential threshold for clicks in guinea
pig or cat may be within an order of magnitude of
the human auditory threshold. With increasing power
(in decibels), Ni increases along a sigmoid curve,
reaches a nearly flat plateau and then, with fairly
strong stimuli, rises much more rapidly again. The
tendency of single units to group into high -threshold
and low-threshold classes may explain this nonlinear
behavior of Ni in the whole-nerve response. The maxi-
mum of response is uncertain, due to the onset of
'fatigue' or 'incipient acoustic trauma.'
Efferent Inhibitory Aetion'-
Stimulation in the medulla of the olivocochlear
tract of Rasmussen produces an inhibitory effect on
the action potential response to clicks. Nj is clearly
reduced, but the cochlear microphonic is not affected.
The effect is very specific with respect to the location
of the stimulating electrodes, and the middle ear with
its tympanic muscles is definitely not involved. The
reduction appears some 20 to 30 msec, after stimula-
'^ See especially the paper by Galambos (7).
EXCITATION OF AUDITORY RECEPTORS
581
tion has begun and increases up to about 250 msec.
Rather rapid stimulation, 30 to 40 shocks per sec,
is required. The optimal frequency is 100 cps. The
long latency and the need for repetitive stimulation
show quite clearly that this efferent inhibitory action
is not related to the temporal priority of nearly simul-
taneous bilateral signals. It is apparently an expression
of a rather general principle, namely central regula-
tion of the sensitivity of sense organs. The functional
relationships of this reduction in sensitivity are com-
pletely unknown.
THEORY OF AURAL ACTION'''
This author has suggested elsewhere a series of
possible mechanisms and interrelationships that,
taken together, offer a presently tenable working
hypothesis. This theory will be presented here in
brief for its value in unifying many varied experi-
mental observations, but the reader must recognize
that several assumptions, interpretations and opin-
ions, more or less plausible, are now added to the
experimental facts.
Acoustic energy is delivered to the inner ear by the
external and middle ears. The frequency characteris-
tics of the external and middle ear determine to a
large extent the shape of the curve of auditory sensi-
tivity. The impedance match provided by the tym-
panic membrane and ossicles between air and intra-
cochlear fluid is nearly perfect, except perhaps for
frequencies below 500 cps, and contributes to the
great absolute sensitivity of the ear. Other aspects of
the middle ear structure and function are chiefly
protective.
Acoustic pressure on the tympanic membrane
causes movement of the foot-plate of the stapes and
reciprocal movement of the round window membrane.
The fluid movements between these two windows
carry with them the elastic cochlear partition, but the
pattern of movement of this partition, determined
primarily by the graded stiffness of the basilar mem-
brane, is complicated. The pattern is a sequence of
traveling waves that move very rapidly at first, then
more and more slowly, as they travel toward the apex.
The amplitude increases gradually with travel to a
rather flat maximum and then falls off" quite sharply.
The positions of this maximum and of the cut-off
beyond it move toward the apex as the frequency is
reduced and toward the ba.se as the frequency is
" See especially tlie papers of Davis (3, 4).
raised. In this way the cochlea acts as a mechanical
frequency analyzer and the 'place principle' is estab-
lished as one element contributing to frequency dis-
crimination.
The traveling wave pattern is an expression of
pha.se differences in the movements of different seg-
ments of the cochlear partition. It is a necessary con-
sequence of the graded stiffness of the cochlear parti-
tion, of the varying ma.ss of fluid that moves with it
and of the rather clo.se coupling inherent in a continu-
ous membrane such as the cochlear partition. The
energy is transmitted in part through the fluid as an
acoustic wave and in part along the membrane from
segment to segment. The stiffer basal region, which
for' middle and low frequencies moves almost in
phase, tends to drive the more flexible apical portion.
The nearly-in-phase movements of the partition in the
basal turn in response to low-frequency sounds cause
nearly synchronous stimulation of impulses in many
nerve fibers. Thus the frequency principle ('volley
principle') contributes to the space-time pattern of
nerve impulses in spite of the large phase differences
that are a.ssociated with the fundamental traveling
wave pattern.
The movements of the partition in the traveling
wave pattern involve a bending of the basilar mem-
brane in two dimensions, both across and lengthwise.
The crosswise bending or bulging is sharpest at the
position of maximal amplitude, but it is also signifi-
cant for a considerable distance basally from the
ma.ximum. The longitudinal l)ending is sharpest in
the 'cut-off' region on the apical side of the maximum
and is probably negligible on the basal side.
As the basilar membrane, and the organ of Corti
with it, bulge one way or the other, there is a shearing
action between the stiff reticular lamina of the organ
of Corti and the stiff and viscous tectorial membrane
that lies in contact with it becau.se the tectorial mem-
brane pivots around a different axis, as illustrated in
figure 12. The shearing action bends the hairs of the
hair cells, which are attached both to the organ of
Corti and to the tectorial membrane. This bending
is the mechanical movement that is critical for stimu-
lation. Protection against too great bending probably
is provided by the attachment of tectorial membrane
directly to the outer and inner borders of the organ
of Corti.
The longitudinal bending causes longitudinal
vibratory mov-ements among the cells of the organ of
Corti and presumably bends lengthwise the hairs of
the cochlear partition. The external and internal hair
cells are not equally sensitive to radial and longi-
582
HANDBOOK OF PHVSIOLOOY
NEUROPHYSIOLOGY I
tudinal bending of iheir hairs (19a). The differential
stimulation of the two sets by the different directions
of bending allows possibilities, through inhibitory
neural interactions within the central nervous system,
of sharpening the 'place' aspect of frequency discrimi-
nation.
The large traveling waves are known to produce
eddies in the cochlear fluids on the apical side of the
position of maximal amplitude. The forces that pro-
duce eddies we beliexe also tend to cause an unsym-
metrical longitudinal shift or 'creep' of the tectorial
membrane relative to the organ of Corti. .Such a
shift would cau.se a one-way longitudinal bending of
the hairs. This is a mechanical rectifying action, and
it allows the cochlea to 'detect' efficiently and respond
with nerve impulses to high-frequency acoustic signals
above 2000 per sec. Just as the cochlear microphonic
is the electrical sign of a symmetrical vibratory bending
of the hairs, we believe the negative summating poten-
tial is the electrical sign of an asymmetrical, rectified
longitudinal shift. This shift is strongest on the apical
side of the position of ma.ximal excursion. The sus-
tained bend of the hairs presumably acts as a steady
stimulus to the hair cells that are affected, but com-
pared to the alternating shearing movements revealed
by the cochlear microphonic this mechanism is rela-
tively insensitive. The rectifying action, as revealed
by the negative summating potential, continues to
increase, however, after the vibratory movements,
and with them the cochlear microphonic, have
reached their maximum. The rectifying action, no
matter how it is produced, seems to be a mechanism
that significantly extends the dynamic range of the
ear.
The complete theory, as presented elsewhere, con-
siders the mechanism of limitation of crosswise bend-
ing (and with it the cochlear microphonic) in more
detail and it also includes a second rectifying action,
associated with the crosswise bending, that depends
on the viscous properties of the tectorial membrane.
This second mechanical rectifying action and conse-
quent one-way bias of the hairs is invoked as the basis
of the positive summating potential, but this extension
of the theory as well as a possible inhibitory action of
the positive summating potential is admittedly more
speculative than the postulate of the longitudinal
"shift' and its production of the negative summating
potential.
The association of the cochlear microphonic with
the bending of the hairs seems very well established.
The mechanism that connects the two is completely
obscure, however. A vague suggestion that the
mechanical distortion changes the electrical resistance
of the upper ends of the hair cells has been offered but
without supporting evidence (fig. 20). Whatever the
mechanism, the bending of the hairs is supposed to
account for not only the cochlear microphonic but
also for both of the summating potentials. But these
three electrical responses, it should be noted, are
observed phenomena, not theories.
Consideration of the extreme .sensitivity of the ear,
and afso the fact that the summating potential per-
sists indefinitely if a static displacement of the tectorial
membrane relative to the reticular lamina is main-
tained mechanically, leads to the conclusion that the
energy of the electrical responses is derived from the
metabolism of the tissues, not from the acoustic
stimulus. The latter .serves merely to 'valve' the flow
of energy from the biological source. The result is an
amplifier action in the sense organ prior to stimulation
of the nerve fibers.
The endocochlear potential has been hailed as the
obvious 'pool of biological energy' that is tapped by
a valving action of the hair cells (3). Its mechanism is
completely unknown but it seems to be a imicjue prop-
erty of the cochlea. Its analogue in the utricle is not
MODEL OF
COCHLEAR EXCITATION
"POLARIZED RtLA^f'
OR OTHER DETECTOR
THAT TRIGGERS THE
NERVE IMPULSE
FIG. 20. An electrical model of excitation of nerve impulses
in the cochlea. Additional batteries', not shown in the diagram,
are located at the cell membranes of the hair cells and of the
nerve endings. The return circuit from nerve endings to the
stria vascularis is not restricted to the narrow anatomical path
indicated in the diagiam but is diflfuse through all intervening
tissues except the scala media. [From Davis (3).]
EXCITATION OF AUDITORY RECEPTORS
5«:5
more than 5 mv at most. It is dangerous, therefore, to
ascribe to the endocochlear potential anything more
than an accessory function, namely to hyperpolarize
the cuticular surfaces of the hair cells and thereby
increase the sensitivity of the auditory detector. In
the utricle the negative intracellular potential of the
hair cells apparently must suffice as the ' pool of bio-
logical energy.'
The unique chemical composition of endolymph
does not necessarily imply a high positive potential.
The high potassium is present in the utricle; the po-
tential is not. The two are probably unrelated.
Perhaps the high potassium merely serves to maintain
the proper colloidal state and consequent viscosity
of the tectorial membrane!
The cochlear microphonic and the negati\e sum-
mating potential are believed to e.xcite directly the
nerve fibers in contact with the hair cells. Only a
passive role as electrical conductors is ascribed to the
nerve endings. There is no synapse-like delay in
excitation. The phase relation of neural excitation to
cochlear microphonic is correct for the electrical
theory. The current flows from hair cell into nerve
fiber and outward across the nerve membrane and
thus can e.xcite the nonmeduUated dendritic terminals
like one tremendous node of Ranvier or like non-
meduUated fibers elsewhere. Spatial .summation be-
tween the several hair cells attached to a given nerve
fiber is clearly possible, as is also a facilitating action
between summating potential and cochlear micro-
phonic. A neurohumoral step between hair cell and
nerve fiber is an acceptable addition to this simple
electrical theory.
Transmission of Auditory Injorrnalion^'^
We can now summarize the best present answers
to the questions implied in the introduction concern-
ing frequency and intensity discrimination and time
differences.
Frequency (pitch) discrimination, the core of
classical 'theories of hearing' (11, 23) is now con-
sidered to be a duplex function. We do not think of
either a place principle (von Helmholtz) or a periodic-
ity principle (Rutherford) but of a combined or du-
plex theory (Wever, Licklider).
The position of maximal stimulation, or more
probably the cut-off boundary of strong stimulation,
is certainly one part of the mechanism for identifica-
" See especially the papers of Davis (4), Licklider (8), von
Bekesy (21) and Wever (23).
tion of frequency, particularly of high frequencies.
The organ of Corti of the basal turn is essential for the
hearing of high tones. Surgical injuries combined with
behavioral tests in animals and disease in humans have
established this fact firmly. Partial section of the
auditory nerve may cause a complete high-tone hear-
ing loss. Injuries to the apical end of the cochlea may
cause a restricted low-frequency hearing loss but
complete loss of sensitivity for the low frequencies does
not occur. There is nevertheless a clear relation be-
tween frequency and position along the organ of
Corti. Fine frequency discrimination is still a problem,
however. The inaxima of the ' resonance curves' of the
cochlear partition (fig. 8) are much too flat, and the
'response areas' of individual nerve fibers (fig 19)
are too asymmetrical to account for the known facts
of frequency discrimination without some additional
hypothesis. A model in which the skin of the forearm
is exposed to traveling waves of tactile stimulation is
surprisingly effective, however, in giving a sharp suId-
jective location of the tactile sensation and in dis-
criminating changes of frequency by changes in this
location (21). The model reinforces the general
opinion that a neural interaction, involving inhibition
of the impulses from less strongly stimulated areas
must be involved. Such inhibitory interaction at the
level of the cochlear nucleus is already familiar.
Direct information as to the frequency of .sounds
below 4000 cps is al.so carried in the auditory nerve
by the volley principle. This information is believed
to contribute importantly to frequency discrimination
and to the sense of pitch (8, 23). Opinions differ as to
the upper frequency at which it ceases to be important
and as to how the space and the 'periodicity' prin-
ciples interact in the region of o\erlap. In any ca.se
the periodicity (volley) principle gains in importance
and the place principle loses as the frequency is
lowered.
Intensity discrimination and .subjective loudness
are usually attributed to the number of nerve impulses
per second traversing the auditory nerve. Recruitment
of additional fibers as intensity is increased is certainly
one mechanism of increasing this number, and faster
average rate of discharge per fiber is another. It is
possiiale also that certain high-threshold fibers con-
tribute more per fiber to loudness than do others, and
it is by no means necessary to assume that loudness is
a simple linear function of the total number of im-
pulses per second.
Temporal information and also the binaural differ-
ences in time utilized in auditory localization are
584
HANDBOOK t5F PHYSIOLOGY ^' NEUROPHYSIOLOGY I
obviously transmitted in the form of time differences
between volleys of impulses. In binaural localization
the volleys in homologous nerve fibers are the impor-
tant ones. The very small time differences that are
known to suffice show that there is a statistical con-
stancy in latencies, conduction times, etc., that is
remarkable in view of the variability in the behavior
of the individual unit. Here, as in fine discrimations
in general, more time is required, often with repeated
trials, for the best performance. The longer time al-
lows for more complete averaging out of minor vari-
abilities. This averaging out is primarily a function of
the central nervous system rather than the sense
organ. For frequency it allows very fine discrimination
when ample time is allowed or, alternatively, good
discrimination of time but with reduced discrimina-
tion for pitch when the duration of the stimulus is
verv short.
REFERENCES'*
1. Barany, E. Acta oto-taryng. Suppl. 26, 1938.
2. Davis, H. (editor). Hearing and Deafness: A Guide for Lay-
men. New York: Rinehart, 1947.
3. Davis, H. In: Physiological Triggers and Disconlinuous Rate
Processes, edited by T. H. Bullock. Washington : American
Physiological Society, 1957.
4. Davis, H. Physiol. Ret'. 37: i, 1957.
5. Davis, H., R. W. Benson, W. P. Covell, C. Fernandez,
R. Goldstein, Y. Katsuki, J. -P. Legouix, D. R. Mc-
AuLiFFE AND I. Tasaki. J. Acoust. Soc. Am. 25: 1 180, 1953.
6. Davis, H., B. H. Deather.\ge, B. Rosenblut, C. Fer-
N.^NDEZ, R. Kimura AND C. .\. Smith. Laryngoscope. 68:
596, 1958.
7. G.-iLAMBOs, R. J. Meurophysiol. 19: 424, 1956.
8. LicKLiDER, J. C. R. Experientia 7: 128, 1951.
9. LicKLiDER, J. C. R. In: Handbook oj Experimental Psy-
chology, edited by S. S. Stevens. New York: Wiley, 1951.
10. SnaxH, C. A., O. H. Lowrv and M.-L. Wu. Laryngoscope
64: 141. 1954-
11. Stevens, S. S. and H. Davis. Hearing, Its Psychology and
Physiology. New York : Wiley, 1 938.
12. Stevens, S. S., J. G. C. Loring and D. Cohen (editors).
Bibliography on Hearing. Cambridge : Harvard, 1 955.
13. Stuhlman, O. In: An Introduction to Biophysics. New York:
Wiley, 1943.
14. Tasaki, I. J. .Veurophysiol. 17: 97, 1954.
15. Tasaki, I. Ann. Rev. Physiol. 19: 417, 1957.
16. Tasaki, I., H. Davis and D. H. Eldredoe. J. Acoust. Soc.
Am. 26: 765, 1954.
17. Tasaki, I., H. Davis and J. -P. Legoui.x. J. Acoust. Soc.
Am. 24: 502, 1952.
18. von Bekesv, G. Akust. ^tschr. 6: i, 1941.
19 von Bekesv, G. J. Acoust. Soc. Am. 19: 452, 1947.
iga.voN Bekesv, G. J. Acoust. Soc. Am. 25: 786, 1953.
20. VON Bekesv, G. Ann. Otol. Rhin. & Laryng. 63 : 448, 1 954.
21. von Bekesv, G. Science 123: 779, 1956.
22. VON Bekesv, G. and W. .\. Rosenblith. In: Handbook of
Experimental Psychology, edited by S. S. Stevens. New York :
Wiley, 1 95 1.
23. Wever, E. G. Theory of Hearing. New York: Wiley, 1949.
24. Wever, E. G. and M. Lawrence. Physiological Acomtics.
Princeton: Princeton Univ. Press, 1954.
25. ZwisLOCKi, J. Acta oto-laryng. Suppl. 72: i, 1948.
26. Zv\tslocki, J. J. Acoust. Soc. Am. 25: 743, 1953.
'' Only general references, a few key papers, and the sources
of the figures reproduced in this chapter axe given. Fairly com-
plete bibliographies will be found in references (4) and (12).
CHAPTER XXIV
Central auditory mechanisms
HARLOW" W" . A D E S U. S. .\'aval School of Aviation Medicine, Pensacola, Florida
C: H A P T E R CONTENTS
INTRODUCTION
Introduction
Central Auditory Pathway
Cochlear Nuclei
Efferent Fibers from Cochlear Nuclei
Lateral Lemniscus and Its Nucleus
Inferior CoUiculus
Inferior Quadrigeminal Brachium
Medial Geniculate Body
Auditory Connections with Cerebellum
Reticular Activating System
Descending Fibers in Auditory Pathway
Auditory Cortex
Auditory Cortex in Primates
Topologic and Tonotopic Projection
Summary and Discussion of Topologic and Tonotopic Pro-
jection
Other Aspects of Central Auditory Function
Loudness
Laterality of Projection
Dispersion of Excitation, Recurrent Pathways and Inhibition
THE ASSIGNMENT IN THIS CHAPTER is to give an account
of the cell and fiber groups of the brain which are
more or less directly related to hearing. The coverage
of this area is not necessarilv uniform and probably
expresses a certain degree of the author's bias, not only
in choice of material but perhaps also in interpreta-
tion. The author, adinitting to an unspecified degree
of bias in both respects, finds it futile to offer apology
but instead suggests to the reader the additional study
of a recent review (32) and volume (log) to which
text and bibliographic references will be found. The
reference listing for this chapter is likewise not com-
plete, especially in a historical sense, and the reader
may remedy this deficiency by reference to the works
just mentioned and also to the recent Bibliography on
Hearing (98).
The history of research on the central auditory path-
way goes back only a few years into the last century,
not even as far as the study of other sensory systems.
The greater volume of significant work has been done
in the last three decades only. This history can be
divided into two phases which, while they began at
different times, have been largely concurrent. The first
necessarily concentrated on defining the neural struc-
tures which are primarily concerned with sound
stimulation and those showing fiber connections, more
or less direct, with the input from the cochlear nerve.
The early functional studies suffered, as we now know,
from the fact that the pathway of projection from ear
to cerebral hemisphere is bilateral with only slight
contralateral preference; consequently, clinical studies
of one-sided damage to the brain produce only meager
auditory deficits, and these can be demonstrated only
by very sensitive tests. For this reason, studv of central
auditory inechanisms lagged behind studies on other
sensory systems in which there is a great preponder-
ance of contralateral projection. It is only with the
advent of increasingly reliable physiological appara-
tus and the development of more sensitive behavioral
testing in the past 25 to 30 years, that tracts, nuclei
and cortical areas responsive to auditory stimulation
have been reliably defined. This definition continues
to be studied and revised, although attention to it
has gradually given way to studies of the qualities of
response rather than mere presence or absence of
response.
The anatomical aspect of the first phase of central
auditory study fared better than the functional and
as well as that of other neural systems. The original
work of Ramon y Cajal (75, 76), as far as the auditory
pathway is concerned, has been amplified and em-
585
586
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY
bellished but remains basic. The cellular and fiber
elements we traditionally consider as components of
the central auditory system with few exceptions are
the same as those which appear in Ramon y Cajal's
diagrams.
The second phase of research on the central audi-
tory pathway has concerned itself with the discovery
of correlates between the characteristics of sound
stimuli and the anatomicophysiologic mechanisms
activated by them. From the beginning, two qualities
of sound, frequency and intensity, have been the focal
points of efforts to discover the neural correlates of
hearing. There appear to be several interrelated
reasons for this and for the consequent preoccupation
with the pure tone stimulus in auditory research.
Perhaps the most compelling force has been the in-
fluence of von Helmholtz who, soon after the middle
of the nineteenth century, proposed the idea that the
cochlea functions as a selectively resonant system in
which tones of given frequency produce localized
resonance of the basilar membrane. The implication
of this is that the end organ functions as an analyzer
of sound and delivers to the brain patterns of excita-
tion which are already analyzed with respect to
stimulus frequency. Besides the influence of von Helm-
holtz is that resulting from the relative ease with
which pure tone stimuli can be controlled in terms of
the standard parameters, frequency and intensity.
As will be seen, the experimentalist's bemusement
with pure tone has had both an advantageous and
disadvantageous effect upon the course of central
auditory research. However the relative good and
bad may be evaluated, it is impossible to discuss
central auditory function either historically or cur-
rently without giving a great deal of attention to pure
tone studies.
There has been in recent years a growing trend
away from pure tone studies of the central auditory
system (at least in their simplest form). There are
three reasons for this: /) 'Click' stimulation has been
frequently used (where widespread rather than selec-
tive cochlear stimulation is desired) in order to avoid
the experimental consequences of the frequency
specificity which appears, at least to some degree, to
be characteristic of the projection pathway. 2) There
is difficulty in studying the higher auditory centers
by postablational hearing tests to separate the
operated from the unoperated animals unless sound
patterns more complex than pure tones or auditory
functions requiring more than acuity and frequency
discrimination are used. 3) There is a feeling among
some workers in audition that pure tone studies ignore
an essential temporal clement in hearing which is
introduced when clicks or other complex stimuli are
used.
With this introduction, we can proceed to examine
the available data relating more or less directly to
the beginnings of neurological explanation of some of
the simpler aspects of hearing as these are defined in
psychophysical terms. As we do so, it will become
apparent that few specific questions of this sort can be
authoritatively answered at this time. It will be
further apparent that, while considerable progress in
thinking about central auditory problems has occurred
in the last 25 years, few of even the earliest studies
during this period are altogether obsolete, although
interpretations and conclusions may be. Therefore,
perhaps the best approach to the problem will be a
semihistorical one in which we will attempt to de-
velop, summarize and evaluate current trends of
thinkine.
CENTR.-\L AUDITORY PATHWAY
To define as central auditory mechanisms all
neural elements which are activated by stimulation
of the organ of Corti would impose an impossible task
of description because sound stimulation may trigger
neural activity of far-reaching systems eventuating
finally in the activation of muscles. Consequently,
arbitrary limits must be imposed on the description,
if possible without causing a corresponding limitation
on our thinking of the con.sequences of sound stimula-
tion. One might choose, for example, to limit the
definition of central auditory mechanisms to the
classical pathway of Ramon y Cajal. This would
include fibers and nuclei through which may be
traced, anatomically, a clearly sequential series of
connections from the ganglion of Corti to the cerebral
cortex: cochlear nuclei, trapezoid body, superior
olivary nucleus, lateral lemniscus and its nuclei,
inferior colliculus. Inferior quadrigeminal brachium,
medial geniculate body and its fibers radiating to
the cortical auditory projection area. However,
strict adherence to the classical pathway would make
it impossible to explain .several phenomena observed
in experiments on the response of medial geniculate
body, cerebral cortex and cerebellum to soimd stimu-
lation. In the former case, for example, single neural
elements of the medial geniculate body may be found
with a latency of response far too long to be accounted
for by impulses which are transmitted via the tradi-
tional pathway; hence, these impulses must be carried
CENTRAL AUDITORY MECHANISMS
587
over a slower system, perhaps one not hitherto con-
sidered as auditory (36). A similar phenomenon has
been demonstrated in the cerebral cortex (25). In the
case of the ccrebelhim, the very fact that response to
sound may be evoked requires some addition to the
classical definition of central auditory mechanisms.
Finally, while they have been mentioned from time to
time for manv years, fibers coursing within the
classical pathway, but running perversely from rostral
to caudal instead of ascending, have been until re-
cently consistently ignored as functional units.
In considering the tracts and nuclei which we
classify as 'central auditory mechanisms', we should
keep in mind several functional requirements, some
of which are specificalK' auditory but others are of
more general neural significance, that is they are
functional requirements of any neural system. Taking
up the general requirements first, they have to do with
two closely related characteristics of neural systems:
/} the tendency for feed-back devices to occur, such as
recurrent collaterals by which any neuron mav by its
own discharge feed back into itself, or similar mecha-
nisms on a recurrent nucleus-to-nucleus basis, this
sort of device apparently serving to amplify the effect
of input into the system; and 1^) the apparent ability of
the system, by its own activity, to modify, modulate
or control that activity, a function which could be
served by the same kind of recurrent feed-back circuits.
The more specifically auditory requirements have
to do /) with the mechanisms by which sound is
analyzed with respect to frequency and intensity, and
the combinations and permutations of these, and the
manner in which these are impressed upon the
brain, and 2) with the arrangements by which the
activities of the auditory system impress themselves on
integrative mechanisms of the brain and ultimately on
motor systems through which responses to auditory
stimulation may be mediated. It has been common to
speak of this kind of function in terms of ' levels of
integration', as though integration of auditory infor-
mation could be classified as to its own complexity
and to the complexity of response called for, and each
category relegated to a particular rostrocaudal level.
This concept may have a very general kind of validity,
but it will become increasingly evident that its useful-
ness is questionable. It must be applied with great
caution, and the delegation of degrees of perceptual
judgment to one or another of the cell masses of the
central auditory pathway represents a pattern of
thinking which is more dangerous than helpful.
There appear to be significant differences between
the pathway of projection from sensory end organ to
cerebral cortex in the auditory system as compared
with other afferent systems, for example the somatic
sensory systems. The latter are characterized by a
second-order link with a thalamic nucleus, whereas
in the auditory the fibers reaching the thalamus are
at least third order, and there are probably relatively
few that are not of fourth, fifth or higher order. There
is, in other words, in the auditory pathway a more
complex and devious system of nuclear interruptions.
One factor leading to this situation must have been
that, since the cochlea and its central connections de-
veloped phylogenetically late as compared with other
sensory .systems, the ascending pathway had to be
constituted from such scattered elements as were still
open to modification in a neural matrix otherwise too
fixed in pattern to permit of a new through pathway.
Figure i shows diagrammatically the main features
of the known connections of the auditory pathway.
Cerebellar connections are not shown. Connections
with the reticular system are shown schematically.
These are actually not known in anatomical detail,
but some .such connections must be present according
to physiological evidence.
Cochlear Nuclei
The course and terminations of two types of den-
dritic processes of cells of the spiral ganglion of Corti
have been studied and described by several authors
(e.g. 28, 59, 75). Despite the rather elaborate differ-
entiation thus revealed in the end organ of hearing,
the course and terminations of the axons of the
ganglion cells show no such corresponding differenti-
ation; rather, the terminations display a pattern of
organization of a different sort. For practical purposes
then, our story of the central auditory pathway may
begin with a group of fibers, showing little differenti-
ation, entering the medulla at the inferior border of
the pons as the cochlear portion of the eighth cranial
nerve. Immediately the fibers begin to bifurcate and
the resultant branches to pass to their terminations in
dorsal and ventral cochlear nuclei (28, 75). Each
fiber is said to terminate on 75 to too cells of the coch-
lear nuclei. This being true, it must also follow that
each cell of the nucleus receives terminations from
many incoming fibers because the total number of
cochlear nucleus cells is only about 2.9 times the num-
ber of cells of the ganglion of Corti (22).
The cochlear nuclei are divisible each into several
parts. The organizational pattern in the dorsal coch-
lear nucleus is laminar, that in the ventral is not but
shows a similar degree of complexity and differenti-
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOOY I
FIG. 1. Main features of the known connections of the auditory pathways in the cat. .-1, medial
geniculate body; B, superior colliculus; C, inferior coliiculus; D, cochlear nucleus; E, superior olive;
F, cut section of brachium pontis; 2, corticopontocerebellar pathway; 3, recurrent fibers throughout
the auditory projection pathway; 4, commissure of Probst; j, brachium of inferior colliculus; 6,
commis.sure of inferior colliculus; 7, nucleus lateral lemniscus; 8, lateral lemniscus; 9, olive cochlear
bundle; ;o, cochlear nerve; //, trapezoid body; 12, reticular system (diffuse projection to cerebral
cortex).
ation. Both contain many cell types (28, 68) and
several types of axon endings. Of the former, some
are recognized as intranuclear short axon cells (28).
In the light of present knowledge, there is little evi-
dence to tell us what may be the functional signifi-
cance of this coinplcx organization or even its signifi-
cance in terms of distribution of efferent fibers from
the cochlear nuclei. Rose et al. (84) have recently
demonstrated a functional organization in terms of
frequency but have not yet tied this firmly to the
histological pattern. For the present, therefore, we
have little choice l)ut to ignore most of the organiza-
CENTRAL AUDITORY MECHANISMS
589
tional features of cochlear nuclei in describing the
efferent fibers which leave them, particularly as the
latter display a very great range of diameters (75).
Efferent Fibers from Coe/ileiir .Suelei
Three principal groups of fibers emanate from the
cochlear nuclei (13, 60). /) The dorsal (or superior)
acoustic stria leave the dorsal nucleus to pass through
the reticular formation under the medial longitudinal
fasciculus, and, upon crossing the mid-line, pass
ventrolaterally to the vicinity of the superior olivary
nucleus. 1^) The intermediate stria arises from the
dorsal part of the ventral cochlear nucleus, passes
over the restiform body and crosses the reticular
formation to the opposite side in an intermediate
position, j) Fil:)ers, which e.xceed in number the com-
bined total of the other two striae, arise in the main
body of the ventral cochlear nucleus, pass directly
medially \cntral to the restiform body, traverse the
ventral part of the reticular formation and cross the
mid-line as the trapezoid body (or \'entral stria).
The three striae tend to draw together in the \icin-
ity of the contralateral superior olivary nucleus where
many of them terminate. In the course of their passage
from origin to that point, there is a considerable dimi-
nution of fibers even before the mid-line is crossed
due to termination of some fibers in the reticular
formation and others in the ipsilateral superior olivary
nucleus (13). The latter are of .special interest insofar
as they provide an essential part of an anatomical
basis for ipsilateral rostral projection and possibly for
reflex connections at the medullary level.
A few fibers emanating from the cochlear nuclei
fail to be interrupted by synapses in either the ipsi-
lateral or contralateral superior olivary nucleus (13)
but turn rostrally and ascend through the pontine
medulla in company with third order fibers which
arise from the superior olivary nucleus, the combined
elements being called the lateral lemniscus. Appar-
ently all of the second order fibers which ascend in the
contralateral lateral lemniscus terminate in either
the nucleus of the lateral lemniscus or the inferior
coUiculus (13).
Lateral Lemniseus and its Nueleus
This tract ascends from the region of the superior
olivary nucleus to the inferior colliculus and, in part,
beyond, as the inferior quadrigeminal brachium, to
the medial geniculate body in the thalamus. Between
superior olive and inferior colliculus, the tract is com-
posed of at least two, and probably more, different
components, /) fibers having origin in the contra-
lateral cochlear nuclei (13) and 2) fibers taking origin
from the ipsilateral superior olivary nuclei (13, 33,
69, 71. 75)- It should be noted that since the superior
oli\e receives second order fibers from both ipsi- and
contralateral cochlear nuclei, the two components of
the lateral lemniscus listed above can actually be
sui^divided into three with respect to cochlear origin
of excitation carried by each: /) contralateral second
order, 2) contralateral third order and 3) ipsilateral
third order.
At this point it may be pointed out that our use of
'second order' and 'third order' is valid only if we
assume a single synapse in each successive nucleus,
for each chain of conduction as represented at one
single point by a fiber of the lateral lemniscus. This
a.s.sumption is neither necessary nor likely in view of
the complexity of the nuclei so far encountered. It
would seem more likely that a variable number of
links in such chains of conduction might be introduced
by the patterns of intranuclear conduction. Evidence
on conduction time to the cochlear nucleus, trapezoid
body and lateral lemniscus (5) indicates that there are
at least some conduction chains in the system which
are as direct as would be implied in speaking of second
and third order fibers in the lemniscus; however, the
protraction of the response to a very brief stimulus
would also make one suspect the presence of chains
with greater numbers of synapses.
The nucleus of the lateral lemniscus, unlike the
other nuclei so far discussed, is neither compact nor
does it show any recognizable organization. It con-
sists of scattered groups of cells lying among the fibers
of the tract. Some few of the tract fibers apparently
terminate in synapse with these cells, and in turn they
send their axons upward with the tract to termina-
tions in the inferior colliculus, probably both ipsi-
lateral and contralateral (by way of the commissure
of Probst).
Some fibers of the lateral lemniscus, of third order
or higher, pass lateral to the inferior colliculus and,
becoming part of the inferior quadrigeminal bra-
chium, continue with it to terminations in the medial
geniculate body (3, 51, 75). The greater number of
lemniscal fibers terminate in the inferior colliculus
(13. 75)-
Inferior Colluulus
The inferior colliculus (or posterior corpus quadri-
geminum) receives a few fibers which project without
590
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY
interruption from the contralateral cochlear nuclei,
many more from the ipsilateral superior olivary
nucleus and a few (proiaably) from the nucleus of the
lateral lemniscus, ipsi- and contralateral. The input
to this nucleus, therefore, represents a degree of diver-
sity and temporal dispersion still greater than that of
the superior olive and cochlear nuclei. This is demon-
strated by the relatively greater protraction of re-
sponse to brief stimuli than is seen in the more caudally
located stations of the pathway (5, 90).
The inferior colliculus is one of the most highly
organized and largest nuclei of the brain stem. In-
deed, its position, size, pattern of organization and
multiplicity of afferent and efferent connections would
make it seem more logical to consider it, together with
the superior colliculus, suprasegmental rather than a
brain-stem nucleus in the usual meaning. At any rate,
the organization and fiber connections are such that,
despite the fact that the inferior colliculus must func-
tion to some extent as a relay in the ascending audi-
torv pathway, its significance can by no means be
limited to its relay function. This will be discussed
further in a different context in a later section of this
chapter.
Inferior Qiiadrigermnal Braclnum
The colliculus, in addition to efferent pathways to
superior colliculus and pons (77), has, as its principal
route of discharge, the brachium of the inferior collic-
ulus (or inferior quadrigeminal brachium). This
tract is composed predominantly of fibers arising in
both ipsilateral and contralateral colliculi, those from
the latter passing through the commissure of the in-
ferior colliculus (ill). In addition, there is present
in the tract the group of lemniscal fibers, noted in the
preceding section, that bypasses the colliculus. The
entire brachium passes rostrally and .somewhat later-
ally to terminate in the medial geniculate body.
Medial Geniculate Body
The medial geniculate body is the thalamic nucleus
of the auditory pathway. It is described as having a
pars principalis compo.sed of small closely-packed
cells arranged in a laterodorsally curving band, and
a pars magnocellularis, lying medioventral to the
pars principalis and composed of large cells (10, 23).
There is some doubt that the magnocellular part
should be considered a part of the true auditory
thalamic relay, although the terminology which
makes it a part of the medial geniculate has been
generally accepted for many years.
The pars principalis appears to be fairly homogene-
ous with respect to cell size and distribution, except
for a slightly decreasing gradient of density from lat-
eral to medial aspects (85). Thus, there is none of the
conspicuous organizational complexity of the brain-
stem acoustic nuclei. The principal input to the nu-
cleus consists of the terminations of the inferior
quadrigeminal brachium. Other than these, the only
fibers reported as afFerents to the nucleus are recurrent
projections from the cortical projection area (62).
Aside from a small number of fillers which are dis-
tributed rather diffusely to other parts of the thalamus
(i) and a few which retrace the lower projection path-
way (i), the main efferent outflow from the medial
geniculate is the acoustic radiation. These fibers
proceed bv way of the posterior limb (sublenticular
portion) of the internal capsule to part of the superior
face of the superior temporal gyrus and adjacent
insular and parietal opercular cortex in primates and
the corresponding cortex in carnivors which lack a
true temporal lobe. Discussion of the projection areas
forms the subject matter of a later section of this
chapter.
As noted above, the medial geniculate, pars princi-
palis, shows little or no histologically demonstrable
organization; however, there is other evidence indicat-
ing that there is, nevertheless, at least a spatial type
of organization. This is inseparable from evidence of
similar organization in other parts of the auditory
system and a separate section will be devoted to spa-
tial and tonotopic aspects of the projection pathway.
Auditory Connections with Cerebellum
.Snider & .Stowell (95) in 1944 reported the hitherto
unknown fact that auditory stimuli (clicks) could
regularly evoke responses from the cortex of the
cerebellar \ermis in cats. In subsequent experiments
these findings were confirmed and the additional dis-
covery made that stimulation by light flashes also
elicits response in the same cerebellar area. The
responses to auditory stimulation occur with latency
so brief as to imply a fairly uncomplicated projection
from the periphery. At the time of the original ob-
servations, no such cochleocerebellar path was known.
Since then Niemer & Cheng (68) have deduced the
existence of a pathway by which the ventral part ot
the dorsal cochlear nucleus sends fibers to termina-
tions in the cerebellar \ermis. Their evidence consists
CENTRAL AUDITORY MECHANISMS
59'
in the observation of retrograde chromatolysis in that
nucleus as a consequence of destruction of the vermis.
The tectopontile tract described by Rasmussen (77),
which provides communication from the inferior
colHculus to the pons, would also seem a possible
avenue from auditory pathway to the cerebellum.
What may be the functional significance of such a
system is a proper but as yet unanswered question.
The further information that stimulation of the
audiovisual" area of the cerebellum may evoke re-
sponse in the cerebrocortical auditory area (94) and
that stimulation of the latter elicits response from the
former (42) may offer some help in answering the
question. One suggestion, which has been made
repeatedh' by one of the more ardent advocates of a
cerebellar contriljution to audition, is that the coch-
leocerebellocerebral pathwas pro\ides an alternative
pathway of auditory projection or integration (or
both) to the cerebral cortex which inay be implicated
in the preservation of auditory function after inter-
ruption of the regular cortical projection pathway.
This is neither a necessary nor a likely hypothesis.
The fact that the cerebellum receives an auditory
projection does not imply that it is implicated in the
psychological phenomenon of audition per se.
The cerebral connections to the cerebellum are
presumably those described b\' Mettler (62) as pro-
jecting from the cat's cerebral auditory area to the
pons froiTi which a pontocerebellar relay would be
the expected pattern. A cerebellocerebral pathway
from the cerebellar cortex to the cerebellar nuclei to
the thalamus to the cortex would be a plausible or
even probable explanation of the functional evidence
that the auditory area of the cerebellum projects to
that of the cerebral cortex. It is the more plausible
when we recall the similar type of anteriorly directed
projection of the brachium conjunctivum. The pattern
of interprojection of cerebellar and cerebral areas is
thus probably no different in relation to the auditory
than to any of several other functional systems. The
most likely explanation of cerebellar auditory (and
visual) connections, therefore, would seem to be that
these add the information of distance receptors to that
of contact and proprioceptive receptors as these may
modulate the cerebellar contribution to regulation of
motor patterns.
sumably at brain-stem levels. Certainly, it has been
demonstrated that arousal can be induced by auditory
stimuli in animals in which the standard acoustic
projection pathway has been bilaterally interrupted
(30, 57, 61, 96, 97). Thus, there is through the retic-
ular system another route from brain-stem acoustic
mechanisms to cerebral cortex, though this is of
general rather than specifically auditory distribution.
The ascending reticular system .seems to be a diffuse
and multisynaptic route, so the auditory and other
specific modalities of input tend to be swallowed up
in the more comprehensive functions of the ascending
reticular system. It is impossible to say to what ex-
tent, if any, this system may serve a specific sensory
function, though it would appear that this could not
be extensive in the light of what we know about
reticular function.
Descending Fibers in the Auditory Pathway
Fibers which proceed from rostral to caudal re-
gions, that is from higher to lower stations in the
auditory projection pathway, have been described at
all levels from the cerebral cortex to the cochlea. In
general these closely parallel the ascending system,
although they may bypass nuclei with greater free-
dom. They are better known anatomically than
physiologically with the possible exception of the
olivocochlear tract which was described by Rasmus-
sen (78-80). For a review of the available evidence
and current studies of the descending auditory path-
ways, the reader is referred to Chapter XXXI by
Livingston in this volume and to Galambos' recent
review (32, p. 502). He indicates that, for the first
time, a systematic anatomic study of these by ade-
quate degeneration methods is under way. While the
information is as yet meager, it is clear that a neural
system which provides a possible mechanism by which
the sensory system to which it belongs can achieve
some degree of .self-regulation may be of the utmost
importance in providing explanation of complex
functions, the means for which are not obviously
available in the organization of the afferent pathway.
.AUDITORY CORTEX
Reticular Activating System
Like other sensory systems, the acoustic makes its
contribution to the reticular activating system pre-
The development of knowledge of the cortical ter-
mination of the auditory projection system may be
said to have begun with the observations of Ferrier
(29) reported as part of a more general work in 1876.
592
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
Observations of the responses of cats to electrical
stimulation of the brain, such as movements of the
ears and turning of head and eyes, led Ferrier to
identify as auditory in function the ectosylvian region.
This area has remained the ' auditory area' ever since,
although the exact limits of the cortex so designated
have varied considerably with variations in method,
investigator and, presumably, also with variation in
the cat itself. For if there is one single incontrovertible
fact which has emerged from a long series of investi-
gations of this area, it is that a too faithful reliance
on the correspondence between visible brain markings
and functional significance in this or any other region
in this or any other animal is a trap for the unwary.
Ferrier's observations apparently satisfied everyone
for about 20 years because, for that period of time, no
other work appeared, either to contradict or to modify
Ferrier's conclusions. In 1899 Larionow (52) defined,
also from experiments on cats, remarkably precise
(though incorrect) boundaries of an S-shaped strip of
cortex coursing along the gyral crest beginning at the
middle ectosylvian gyrus, doubling back down the
posterior ecto.sylvian gyrus and redoubling around the
inferior end of the posterior suprasylvian sulcus for a
short distance. Larionow was the first, though not the
last, to see in his auditory strip a representation of an
'unfurled cochlea', an expression which has proved
attractive to several workers through the years. In-
deed, though Larionow unrolled his cochlea too far
back, there is a note of prophecy and a modest degree
of validity to the concept, as later events have shown.
A year prior to Larionow's report Vogt (104) had
pointed otit that the ectosylvian cortex of the carni-
vore is an area of early myelination. By the turn of
the century, therefore, the feline auditory area had
been located, though not precisely defined, by crude
functional methods; the same area had been shown
to have special histological characteristics and the
ideaof cochlear projection had been introduced. Thus,
the ideas which were to guide the future study of the
cortical auditory area were all present. The subse-
quent additions can be thought of as refinements and
variants of method, the advent of good electrical
recording methods during the 1930's constituting the
only radical departure since. Even this has been used
without much change in pattern of thinking until very
recently.
There are several ways in which one might trace
the development of knowledge of the auditory cortex.
In order to show how we have arrived at our present
knowledge and attitudes we will here adopt an ap-
proach which will be, in the main, sequential, but
will deviate from strict chronology by first defining
certain questions which were or might rea.sonably
have been asked at the beginning and considering the
successive steps which have been taken toward an-
swering these. Thus, departures from strict chronology
will be necessary when solutions to questions have
been found not in what at the beginning might have
tjecn logical sequence. More often than not this has
occurred when it was generally thought that, for
example, question i had been answered and one might
proceed to question 2, only to find in the cour.se of
investigation of question 2 that question i had not
been answered as fully as it had seemed.
Given the general location of a functional cortical
area, the next question is to determine the extent of
the area. This question has been asked at least tacitly
in nearly all investigations for over 50 years, even
when the stated central question of a particular study
was of a more esoteric nature. One reason which
makes this determination an almost mandatory start-
ing point for any study of the auditory cortex is that,
because of individual variation, there are no configur-
ative landmarks which can be relied on except in the
most general way; therefore, if the experiment pre-
supposes exact knowledge of extent of auditory pro-
jection, this must be determined for each animal as
the starting point.
The animal most frequently used in experiments on
the auditory area is the cat with the monkey (espe-
cially macaque) next most frequently; the dog has
been used in only a few cases. Unless otherwise
specified, the ensuing discussion may be assumed to
refer to the cat as the experimental animal. Figure 2
shows the standard lateral view of the cat brain which
will be used in subsequent figures in portraying the
auditory area maps of several studies.
Vogt's myelination time studies represented the
first application of a detailed morphological method
of study to the auditory cortex. Campbell (21) in 1905
produced the first careful study of the region by the
cytoarchitectonic method. Campbell's area is shown
in figure 3. (In this figure, the total extent of the
cortex considered to be auditory in function is shown
in each case. Each portrays the original data as
nearly as these could be projected from the original
publication to the standard view of the cat brain used
in all. Subdivisions are ignored for purposes of the
immediate discussion but will be considered in the
next section.) It is interesting to note that Campbell's
auditory area is the most extensive of any but the
latest published and is remarkably similar in some
respects to the total composite area which would ex-
CENTRAL AUDITORY MECHANISMS
393
press the current area of substantial agreement of
several authors.
In 1937, Kornmiiller (50) published the first map
of the cat's auditory cortex determined by recording
electrical responses to acoustic stimulation. His map,
seen in figure •], includes an area confined to middle
FIG. 2. Lateral view of brain of cat. FR, rhinal fissure; GEA.
anterior ectosylvian gyrus; GEM, middle ectosylvian gyrus,
GEP, posterior ectosylvian gyrus; GPA, anterior pseudosylvian
gyrus; GPP, posterior pseudosylvian gyrus; GSA, anterior
suprasylvian gyrus; GSM, middle suprasylvian gyrus; GSP,
posterior suprasylvian gyrus; SEA, anterior ectosylvian sulcus;
SEP, posterior ectosylvian sulcus; SP, pseudosylvian sulcus;
and SSAI, middle suprasylvian sulcus.
ectosylvian cortex. Between that time and 1941, two
other such maps were published. Bremer & Dow (17)
and Ades (i), using brief acoustic stimuli (clicks),
defined the area responsive to such stimulation largely
in the middle ectosylvian gyrus (fig. 4). The responsive
area of Bremer & Dow extends to the pseudosylvian
sulcus while that of Ades stops short of the sulcus.
Bremer & Dow studied the cytoarchitectonic char-
acteristics of the region also and found the somewhat
smaller area shown in the same figure to satisfy the
criteria of a sensory projection area. The study of
WooUard & Harpman (iio), in which they traced
Marchi degeneration after electrolytic lesions in the
media! geniculate body, defined the area shown in
figure 4 as the projection area of that nucleus. It is
interesting to note that the Woollard & Harpman
map, based on anatomical findings, corresponds more
closely with the Bremer & Dow electrical response
map than the latter does with their own cytoarchi-
tectonic map, which itself more nearly coincides with
Ades' electrical response map.
The maps of the feline auditory cortex derived from
the foregoing studies from 1933 to 1941 share the
common feature of being considerably more restricted
than the much earlier work of Campbell indicated.
They were at the time regarded as being reasonably
consistent with each other and probably substantially
valid in defining the " primary' auditory projection
area, the only point of disagreement being the exten
WOOLLARD
AND HARPMAN
1939
VOGT 1898
KORNMULLER 1933
BREMER AND DOW 1939
ADES 1941
FIG. 3 (top). Auditory area of cat as described by individuals named, shown by shaded areas.
All redrawn from originals on standard view.
FIG. 4 (bottom). Auditory area of cat as described by individuals named, shown by shaded
areas. All redrawn from originals on standard view. In the map of Bremer & Dow, electrical re-
sponses to clicks could be obtained over both the horizonlalh and verlicatly shaded arcaj ; cytoarchi-
tectonically, the vertically shaded area satisfied the criteria for a sensory projection area.
594
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
of the lateral (ventral) margin of the area. The pos-
terior ectosylvian cortex is the one part of the area
that none of these studies implicated as auditory in
function. This is a particularly curious circumstance
in the light of evidence which began to accumulate
rapidly the following year (1942) and which demon-
strated that the posterior ectosylvian cortex is most
definitely auditory.
Two virtually concurrent physiological studies ex-
tended the cortical sphere of auditory response to the
posterior ectosylvian gyrus in 1942 and 1943. Both
represented a departure from the preceding studies in
that functional subdivision or organization rather than
total extent of the auditory cortex became the princi-
pal theme although extension of the boundaries also
came as a by-product. Both these studies and later
ones which grew out of them demonstrated how much
the factor of adequate instrumentation may influence
validity of data. Ades (2) demonstrated what was then
termed a 'secondary' auditory area (see fig. 5) occupy-
ing most of the posterior ectosylvian cortex. The
experiments consisted in mapping the area responsive
to clicks, then applying strychnine to the ' primary'
area .so defined and remapping the responsive area
which now included the posterior ectosylvian. The
latter area was originally termed 'secondary' because
its response appeared to be dependent on and driven
by that of the 'primary' middle ectosylvian cortex.
This terminology was further motivated by a preoc-
cupation, dating from Campbell's time, with the
concept of primary sensory projection areas sur-
rounded by or adjacent to sensory 'association' areas.
Repetition of the same experiments with more nearly
adequate instruments (14, 48, 49) has demonstrated
that while the posterior ectosylvian, under the influ-
ence of strychnine, is driven by the middle ectosylvian,
its response is not wholly dependent on transmission
through the middle ectosylvian.
Wool.sey & VValzl (113) published a report (actually
a few months earlier than the one by Ades, though
imknown to the latter until after his own report was
in process of publication) which also extended the
auditory area to the posterior ectosylvian cortex and
also provided a basis for .subdivision of the total
responsive area but on a quite different basis than
that suggested by the strychnine experiments. The
experiments reported in this paper by Woolsey &
Walzl are worthy of special note, as they represent a
turning point in research on the auditory cortex which
provides the basis for the modern view point. They
employed a more adequate system of amplification
and recording than had previously been used. This,
together with stimulation of small groups of nerve
fibers in the exposed osseous spiral lamina of the
cochlea, afforded by far the most precise technique
yet brought to bear on the problem. In addition, the
results had great influence in dispelling the bemuse-
mcnt with the concept of primary and secondary
areas, which, while it may still have some degree of
validity, was in retrospect a concept which had done
little to advance, and possibly something to retard,
the development of understanding of cortical auditory
function.
Woolsey & VValzl stimulated electrically small local
groups of the exposed ends of cochlear nerve fibers in
the osseous spiral lamina and recorded the cortical
response. They were able to show that local stimula-
tion of such small groups of fibers elicited a similarly
localized response within the ectosylvian cortex. The
pattern of projection was an orderly one such that in
the more superiorly lying strip (fig. 5) stimulation at
the base of the cochlea evoked response anteriorly
while stimulation of the apex produced it posteriorly.
In the more laterally lying strip, the pattern is re-
versed so that the base of the cochlea projects pos-
teriorly and the apex anteriorly. These results were
ADES 1943
WOOLSEY
AND WALZL 1942
ROSE
AND WOOLSEY 1949
FIG. 5. .'\uditory area of cat as described by individuals named. .\\l redrawn from originals on
standard view. Ades: Vertical shading, 'primary area'; horizontal, secondary area.' Woolsey & Walzl:
Horizontal shading, A I; vertical, A II. Rose & Woolsey: Horizontal shading, EP; vertical, A II; cross-
hatched, A I.
CENTRAL AUDITORY MECHANISMS
595
confirmed by experiments reported by the same au-
thors (io8) in which the deficits in cortical response
to click stimulation were noted after local lesions in
the cochlea. These experiments then introduce in the
auditory cortex an organization based on an internal
integrity of the auditory projection pathway such that
the anatomical pattern of the cochlea seems to be
faithfully represented in the cortical receiving station.
A fuller discussion of this 'point-to-point' feature of
anatomical projection and its functional implications
will be found in another section of this chapter.
Woolsey & Walzl introduced the terminology by
which the two strips of auditory cortex noted in the
foregoing paragraph were designated respectively
'A r (the superior or dorsal strip) and 'A IF (the
inferior or lateral strip). When this organization of
the cortical auditory field was subjected to further
study involving, in addition to electrophysiological
methods, cytoarchitecture and retrograde degenera-
tion in the medial geniculate body following selective
extirpation of parts of the auditory cortex by Rose
(83) and Rose & Woolsey (85), a further revision of
the terminology became necessary. For, as their re-
sults showed, A I occupies a more limited area than
originally designated by Woolsey & Walzl (fig. 5) and
is the only part whose destruction leads to widespread
degeneration in the pars principalis of the medial
geniculate. Cytoarchitectonic study shows that A I
and A II differ from each other and the anterior parts
of both diflPer from the posterior. These findings lead
to the map presented by Rose & Woolsey (fig. 5) in
which the auditory area is now divided into A I, A
II, and EP, the latter being compounded of the pos-
terior parts of the original A I and A II. It will be
noted that these areas now show varying degrees of
correspondence to those of earlier studies. For ex-
ample, A I now is closely similar to the more restricted
electrically responsive area shown by Ades (i) and
Kormiiller (50) and to the cytoarchitectonic maps of
Bremer & Dow (17) and Waller (106). It also cor-
responds to the posteroinferior portion of Vogt's (104)
old map based on myelination time. A I plus A II
now resembles the electrical map area of Bremer &
Dow (17), the geniculocortical projection area of
Woollard & Harpman (iio), and corresponds with
somewhat lesser fidelity to the anterior part of the
Campbell (21) map. EP corresponds clo.sely to the
posterior ectosylvian 'secondary area' of Ades (2). It
would appear that the restriction of responsive area
shown in the earlier o,scilloscopic studies may have
been due to the relative weakness of responses in A II
(except at its anterior end) and in EP which were
not detected by the comparatively poor instruments
then available. The re-emergence of the EP area,
as it is now commonly called, plus the reaffirmation
by Kiang (49) that EP is to .some extent functionally
dominated by A I revives the question of the func-
tional significance of such a cortical interrelationship.
At this point, while it has become apparent that
the limits of the cortex which can be activated by
acoustic stimulation may not have been completely
and finally defined, it will be useful to depart briefly
from the development of this essentially anatomical
concept to consider some functional studies. These
are of interest not only as they contribute to correla-
tion of structure and function, but also as they reflect
on the extent and internal organization of the auditory
cortex.
The history of functional studies of the auditory
cortex is, to a great extent, a history of increasing
complexity of stimulus and experimental learning
situations. It is also a study in progression of con-
ceptualization of auditory function. It begins with the
experimenter striving for valid criteria to show simply
whether or not the experimental animal hears and
continues at present as a search for ways in which
auditory discriminative ability of animals can be
accurately assessed.
Some of the earlier efforts to estimate the cortical
contribution to hearing in animals took the form of
hearing tests of greater or lesser refinement, following
total or hemidecortication (12, 38). It was demon-
strated that the decorticate dog can still acquire a
crude conditioned response to sound although not
nearly as readily as an intact animal. Although the
animal could acquire the habit, his absolute intensity
threshold was higher by 70 db (38). Other workers
(12) were less impressed by the auditory deficit in
decorticate cats. The decorticate animal, however,
shows a general debility and inattentiveness which is
more impressive than an auditory or any other specific
sensory defect. This leads one to suspect that any test
of hearing in such a preparation may be contaminated
to a considerable degree by other deficits which have
more to do with general integrative capacity than
with hearing per se.
To avoid this difficulty, several workers resorted
to extirpations of, as they thought, specifically audi-
tory cortex. The theory was that if the cortical audi-
tory projection area is removed, then the entire
cerebral cortex is effectively eliminated from partici-
pation in any learning or conditioning process that
involves stimulation by sound. If this were so, then
any auditory function present before but absent after
396
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
operation couW be said to depend upon mediation
through the auditory cortex. (Of course, as we now
know, the geniculotemporal radiation is not quite the
bottleneck it was then supposed. It is not the only
avenue through which excitation aroused by sound
may reach the cerebral cortex, and it may not ije
the only effective avenue by which such excitation
can produce a specifically auditory cortical sign.) A
series of studies in which various aspects of hearing
were tested before and after auditory cortical extirpa-
tion were carried out beginning about 20 years ago.
These yielded results which were surprising because
of the difficulty encountered in seriously impairing
auditory function. Several specific studies are con-
sidered in the following paragraph.
The earlier workers in this area were convinced
that the intensity threshold of hearing for pure tones
constituted the proper initial criterion of cortical
auditory function. This led immediateh to apparent
discrepancies in results between different laboratories
and even different individuals in the same laboratories
(51, 58, 74) because, as ultimately became clear, the
factor of recovery time between extirpation of the
auditory cortex and retesting of thresholds is crucial.
Those who were retested within a very short time
showed varying degrees of threshold elevation, those
who waited several days or weeks before being re-
tested demonstrated little or no loss of acuity for pure
tones. Finally Girden (37) demonstrated that in the
dog, after incomplete lesions of the auditory cortex,
initial losses in acuity gave way with continued testing
and the thresholds returned nearly to preoperative
levels. Even then, the blame for discrepant results
tended to be fixed on differences in testing methods
and on the degree of completeness of destruction of
auditory cortex, the latter factor being complicated
further by differences in understanding of extent of
auditory cortex and by this kind of experiment it.self
being used as a criterion of determining that extent.
Kryter & Ades (51) demonstrated that ab.solutc in-
tensity threshold to pure tones does not rise appreci-
ably due to extirpation of auditory cortex in the cat,
even when the cortical lesions in some instances
extended considerably beyond the widest boundaries
suggested for the area. By this time, workers were
despairing of the intensity threshold to pure tone as a
reliable indicator of cortical auditory function. It be-
came apparent, in retrospect, that the confusion of
previous studies had occurred, at least in part, becau.se
simple acuity as measured in this way is simply not
dependent on cortical participation. It appeared logi-
cal then to .seek .some more complex manifestation of
auditory function which could be tested by a condi-
tioning method and which might prove to be de-
pendent on auditory cortex.
A series of studies directed toward that end began
in 1946 with the report of Raab & Ades (74) indicat-
ing that, while of interest in other respects, the func-
tion of discrimination of differences in intensity of
sound, measured in terms of difference limens, was
not the cortex-bound function .sought. This impression
was confirmed by Rosenzweig (87). The next obvious
point of attack was the ability of the animal to
discriminate between small differences in frequency
before and after extirpation of auditory areas. This
kind of study has been done by Butler et al. (20), by
Meyer & Woolsey (64) and by Allen (9). Before
discussing these studies, it is necessary to digress
briefly to note the addition of still another cortical
area which shows .signs ol auditory function.
In 1945, Tunturi (103) described in the dog an
area in which electrical response to auditory stimula-
tion could be evoked. This area lies outside any of
those previously described as auditory in the dog or
as homologous areas in the cat. It lies in fact partly
in the second somatic area (43). Also in 1945 Allen
(9) using Tunturi's map found that, whereas aljlation
of the traditional auditory areas temporarily impaired
but failed to destroy permanently the ability of dogs
to discriminate widely different frequencies, this
ability was permanently lost if the third auditorv area
of Timturi were also destroyed. Later studies on the
cat have confirmed the fact that auditory stimulation
elicits response in the second somatic area (15, 16,
65, 70)-
Meyer & Woolsey (64) trained cats to respond to
change in frequency of a gi\en tone at irregularly
spaced intervals in a series of 2 sec. tones which were
otherwise alike. Once the cats were trained, a rough
difference limen for frequency was determined. They
then extirpated, symmetrically, in \arying combina-
tion the following cortical areas: A I, A II, EP,
suprasylvian gyrus, temporal region (see fig. 6) and
the cerebellar tuber vermis. Following operation, the
animals were retrained and retested. It was foimd
that if A I, A II, EP and S II (second somatic area)
were completely destroyed on both sides, the animals
could no longer achie\e the frequenc\- discrimination.
No other combination of lesions had this efl'cct and
if remnants of A I and A II escaped damage, fre-
quency discrimination was maintained. Butler el al.
(20) used a basically similar plan but with what they
felt was a more reliable and critical method of testing.
In addition, they carefulK' analyzed the retrograde
CENTRAL AUDIT(JRV MECHANISMS
597
FIG. 6. Composite view of all areas of cat brain showing
auditory function. A I, first auditory area; A II, second auditory
area; EP, posterior ectosylvian area; S II, second somatic area;
IN, insular region; TE, temporal area.
thalamic degeneration in their cat.s. The rcsuhs in
this series of experiments differ from those of Meyer
& Woolsey in that ability to discriminate frequency
was not permanently impaired even after complete
lesions of A I, A II, EP and S II. Three significant
points in explanation of the apparent discrepancy
were offered by Butler et al. /) The testing methods,
as have already been mentioned above were different,
r) In the Meyer-Woolsey animals with loss of dis-
crimination, the lesions, though listed as including
A I, A II, EP and S II, actually extended ventrally
nearly to the rhinal fissure (unlike those of Butler et
al.^. j) In the latter group, the posterior part of the
medial geniculate, pars principalis, consistently es-
caped degeneration, although it was also noted that
the nearer to the rhinal fissure the lesion approached,
the farther posterior crept the degeneration in the
medial geniculate. Thus, the tissue lying before and
behind the p.seudosylvian sulcus, hitherto largely im-
mune to implication in the auditory cortical sphere,
began to take on a most suspiciously acoustic flavor.
That this trend is essentially correct has been demon-
strated in recent experiments by Neff and his group
and in the recent critical analysis by Rose & Woolsey
(86) of thalamic degeneration resulting from lesions
of the several subdivisions of auditory and apparently
related cortex singly and in combinations.
Diamond & Neff (24) trained cats to respond to
change in a simple tonal pattern. A three-tone se-
quence, for example, of low-high-low was presented
repetitively for a variable number of tiines and then
changed abruptly to high-low-high, at which point
the animal, in the course of trairiin^, learned to
respond (by moving across the middje of a shuttle
bo.x) to avoid shock. Extirpation qf A I failed to
disturb the habit of discriminating tht; two patterns.
With extensive damage to A II and EF in addition to
-A I, the habit wa"; temporarily lost but could be re-
established by further training. If the destruction of
all three areas was complete, the tonal pattern dis-
crimination could not be re-established even with a
prolonged period of retraining. It is interesting to
note that even small remnants of tissue which could
be excited by sound, and which closely adjoined
ablated areas, were sufiicient to make possible retrain-
ing of the tonal pattern discrimination. In a second
series of experiments, Goldberg et al. (39), having
trained cats to both a simple frequency discrimination
habit and to the tonal pattern discrimination, now
extirpated bilaterally the region ventral to A II and
EP (insular and temporal cortex shown in fig. 6),
sparing A I, A II and EP as demonstrated by subse-
quent responsiveness to click stimulation and absence
of severe degeneration in the medial geniculate. The
results were quite surprising, both simple tone dis-
crimination and tonal pattern discrimination being
lost after operation. It proved possible to re-establish
simple discrimination in about the same time as that
required for original training. On the contrary, pat-
tern discrimination could not be relearned even with
prolonged retraining. The behavior of the animals in
the test situation was not visibly different from pre-
operative behavior and, since the frequency discrimi-
nation habit was relearned, one cannot attribute the
results to loss of learning capacity; rather the loss of
pattern discrimination seems to be a specific auditory
deficit.
Two salient features, then, emerge from the recent
work of Neff and his group. /) The insular and tem-
poral cortex of the cat are demonstrated to be of
crucial importance to at least some aspects of auditory
integrative function. 2) Discrimination of tonal pat-
terns (as distinguished from simple change in fre-
quency) appears to be cortically bound.
One cannot help recalling (at least this author
cannot) experiments in x'isual discrimination (4, 7) in
which somewhat similar results were obtained after
lesions of areas 18 and 19 and the temporal lobe in
the monkey. It suijsequently proved, however, that
losses of discriminative ability in the monkey were less
permanent if the monkey had been trained to learn
quickly many different visually-guided discrimina-
tions rather than just one (81, 82). Although the
evidence is insufficient, one cannot help but wonder
598
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
if the insular and temporal cortex of the cat ha\e a
significance to the cat's auditory function similar to
that of areas i8 and ig and the temporal cortex to
the monkey's visual function. Also, though prophecy
is a questionable if not dangerous indulgence for
ordinary people, one also wonders, given an animal
whose sophistication is augmented by the learning of
many rather than a single type of auditory discrimina-
tion, whether the particular habit (tonal pattern in
this case) would remain as firmly corticalizcd.
Rose & Woolsey (85) introduce in their study an
anatomical concept which goes a long way toward
clearing up at least one aspect of the interrelationship
between the subdivisions of the cat's auditory cortex
and also toward providing anatomical support for the
work of the Neff group. This is based on the shifting
pattern of degeneration observed in the medial genic-
ulate body as the cortical lesions are varied in pattern
to include one or more of the subdivisions (fig. 6
indicates the areas and the terminology applied to
them). It is considered that a cortical area receives an
essential projection from a given thalamic nucleus if
destruction of that area and only that area results in
marked degeneration in the thalamic nucleus. If, how-
ever, two cortical areas are considered and if destruc-
tion of neither of these alone causes degeneration in a
given thalamic nucleus, but simultaneous destruction
of both does lead to severe degeneration in that
nucleus, both cortical areas are said to receive sustain-
ing projections from the nucleus. On this basis, Rose
& Woolsey found that the only component of the
cortical auditory complex which receives an essential
projection from the medial geniculate (pars princi-
palis) is A I. Since, however, simultaneous destruction
of A I, A II, and EP result in much more profound
medial geniculate degeneration than does A I alone,
it is considered that both All and EP receive sustain-
ing projections from the geniculate pars principalis.
Even the combination leaves the posterior third of the
nucleus relatively unscathed. It is only when the
cortical destruction is extended ventrally to include
all of the cortex between A II and EP and the rhinal
fissure (temporal and insular cortex as shown in fig. 6)
that severe degeneration extends posteriorly to include
the entire pars principalis. There is, therefore, projec-
tion from the posterior sector of the pars principalis
to the temporal and insular cortex. That this is
probably a sustaining projection is attested by the
fact that the still limited evidence indicates insular
and temporal lesions alone fail to produce severe
posterior sector degeneration. Similarly, the pars
magnocellularis degenerates markedly only when A I,
A II, EP, insular and temporal area'* are all destroyed.
Both posterior pars principalis and magnocellularis
are largely preserved by the preservation of A I alone;
consequently, it would appear that both emit rather
widespread sustaining projections, but there is no
evidence as yet of emission of essential projections.
Finally, from the limited available evidence, the
anterior part of the posterior nuclear group of the
thalamus, in addition to the medial geniculate, must
be suspected of having auditory connections. The
critical evidence is lacking but this thalamic area,
lying between auditory and tactile nuclei, probably
sends a sustaining projection to S II, which itself has
ijeen shown to be excitable by auditory stimulation
(15, 16, 19, 65, 70). Moreover, this auditory excita-
bility, according to Rose & Woolsey (85), .seems to be
independent of medial geniculate-auditory cortex
activity since it appears even when the medial genic-
ulate body is profoundly degenerated. In contrast to
this conclusion, Priljram ft al. (73), noting an ap-
parently similar system in the monkey, maintain that
the responses in S II do drop out upon degeneration
of the medial geniculate, and so come to the conclu-
sion that the interconnection is by way of collaterals
from the medial geniculate. Until this conflict is re-
solved, therefore, the question of the essential connec-
tion of this thalamic nucleus and cortical area with
the cochlear projection pathway must be left open.
Returning briefly to efforts toward finding some
auditory integrative function which is corticalizcd in
the sense that the task cannot be accomplished with-
out cortical participation, the work of Neff f < al. (67)
deserves special attention. They trained cats to make a
response requiring localization of sound in space, cor-
rect performance being rewarded with food. Lesions
were then made in A I in .some cases and A I, A II and
EP in others. Bilateral destruction even of A I, if
complete, caused severe deterioration of performance
in the test situation. That this behavioral deficit was
specific to hearing was demonstrated by a normal
capacity to learn a problem in the same situation if it
were based on visual cues. As the authors point out,
while the auditory cortex must play an important role
in the function of localization of sound in space, it is
less clear what the nature of this role may be. The
evidence would allow several hypotheses but select
none of them. The authors list the following. /) Intact
auditory cortex is essential to learning the relationship
between auditory signal and food reward. 2) Intact
auditory cortex is essential for maintaining attention
to auditory signal, attention being defined as the
abilitv of the animal to orient toward the signal and
CENTRAL AUDITORY MECHANISMS
599
carry through its appropriately directed activity until
the full response of opening a door and obtaining; food
is accomplished, jj) Intact auditory cortex is necessary
for accurate localization of sound in space. As indi-
cated above, the data fail clearly to single out any of
these. This, incidentally, is a common finding in
behavioral experiments involving extirpation ot brain
tissue. It may be an inherent failing in all such ex-
periments. However, this is of more concern from the
standpoint of the neurology of learning than from that
of specifically auditory integration.
We cannot leave the subject of definition of the
auditory area without referring to the work of
Lilly (55, 56) who has introduced a new method
and a new dimension to this field of study. Using a
square array of 25 electrodes covering an area of
cortex of i cm'-, 25 amplifiers and glow tubes, each
channel serving one electrode, and photographing
at 128 frames per sec. the bank of glow tubes, Lilly
has been able to demonstrate the patterns of spon-
tanous electrical activity and those evoked by acous-
tic stimulation in the cat's auditory cortex. In this
fashion, the simultaneous cortical surface activity
can be recorded at 25 different zones and the changes
at each noted in time sequence. Thus Lilly has
demonstrated what he calls 'forms and figures' of
cortical activity which combine the dimensions of
time and space in a way not previously possible.
The array was placed across the upper end of the
posterior ectosylvian sulcus so that it covered part
of the junctional area of A I and A II with EP.
Lilly found that both spontaneous activity and the
response to clicks followed a definite, repeatable
pattern. Under deep anesthesia the response to clicks
would appear first in one corner of the array, spread
posteriorly to a boundary and there die out. Pos-
terior to the boundary (i.e. in EP) spontaneous
waves tended to originate and travel downwards
along the posterior ectosylvian gyrus; however,
under lighter anesthesia the response wave could
trigger the 'spontaneous' EP waves, and at still
lighter levels spontaneous waves were seen to origi-
nate in A I and travel across the border. In another
series of experiments on unanesthetized monkeys,
clicks set ofT waves of activity which were observed
to travel systematically over the sensorimotor cortex.
Thus, Lilly has at once made several interesting
points, some of which are of specific interest in the
development of knowledge of the cortical auditory
equipment and others are of even greater significance
to neurophysiological thinking in general. With
respect to auditory function, he has shown that there
is a certain validity to the accepted subdivision of
auditory cortex, albeit this may have been to some
degree overplayed in the past because most previous
workers (with one qualified exception in Bremer')
have used deeply anesthetized animals as the stand-
ard preparation. At the least, these studies present
the interrelationship of auditory subdivisions from a
new \iewpoint. He has further demonstrated that
the excitation of cerebral cortex which results from
acoustic stimulation may be (or perhaps always is)
considerably more widespread than is usually as-
sumed, tacitly at least, in the plan of auditory ex-
periments. This is somewhat disquieting from the
standpoint of planning an experiment to demon-
strate by electrophysiological method some facet of
cortical auditory function; howe\er, it is perhaps
potentially comforting in even greater degree to
those who work with behavioral methods and are
constantly confronted with the necessity of explain-
ing why an animal in which access to cortical in-
tegrative processes has presumably been denied to
the acoustic system (by remoxal of receptive areas)
can yet behave as though auditory stimulation still
held meaning for him.
From a more general \iewpoint, Lilly has neatly
demonstrated the restrictive elTect of anesthetization
on cortical activity with respect to both time and
space such that the functional separation of con-
tiguous areas tends to be exaggerated. It should be
an ample indication that while unguarded use of
anesthesia in electrophysiological studies of the
cortex may relieve some technical problems for the
experimenter, it may simultaneously furnish the
basis for an abundance of conceptual 'red herrings.'
Lilly's work suggests further, however, that the en-
lightened, controlled use of anesthesia may be of
most positive value in cortical studies by virtue of
its capacity to separate functional areas whose
boundaries tend to be inconspicuous in the waking
animal.
The reader will note that, having begun with a
hazy idea of the location and limits of the auditory
cortex of the cat, these gradually became sharply
defined through the years with improvement in
instrumentation, method and thinking. At several
points in this history, the matter seemed to have
been settled. Each time this has occurred, someone
' Bremer's encephale isole preparation falls short of qualifying
as equivalent to the intact preparation to the extent that it
interrupts part of the reticular input; however, it is different
from the deeply anesthetized animal to the extent that part of
the reticular system is intact.
6oo
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
assuming this to be true and predicating a new study-
on lliis assumption has, by his findings, introduced
some new confusion which has then required its
own gradual resolution. We have now arrived at an
interesting dilemma in which we recognize several
types of auditory thalamocortical projection to a
wide lateroventral extension of the auditory area
as first defined and, in addition, projection from
hitherto nonauditory thalamic nuclei to a cortical
area originally considered to belong to the somes-
thetic svstem but now known to be excitable also by
sound (and, indeed, Ijy the nonacoustic labyrinth
as well). Moreover, these latter-day auditory areas
seem to play essential roles in the mediation of
auditory-guided learned behavior. When we add to
this the findings of Lilly which tend to blur func-
tional if not anatomical boundaries, we begin to be
less impressed than we once were with the possi-
bility of singling out certain areas whose sole re-
sponsibility and exclusive prerogative lie in the
realm of auditory integration. On the other hand,
we must be equally careful to avoid the other horn
of the dilemma by keeping in mind that, however
dim the boundaries may become, the areas we call
auditory do respond differently to sound than do
other cortical areas and they do show differences
among themselves.
Auditory Cortex in Primates
The foregoing section was ba.sed almost entirely
on the brain of the cat. Comparable studies on the
primate brain are far fewer in number and com-
paratively lacking in the area of behavioral studies.
Otherwise, a history of developing knowledge of the
primate cortical auditory areas would parallel that
in the cat since neurophysiology traditionally uses
the cat for pilot experiments which, after trial,
modification and revision, can be applied to the
monkey. The history of monkey experiments reflects
the greater efficiency which is made mandatory by
the expense of buying monkeys out of the charac-
teristically meager operating budget for neurophys-
iological studies.
The early development of knowledge of the
monkey auditory cortex is similar to that of the
cat, often appearing in the same accounts, such as
those of Ferrier, Munk and Campbell. It will suffice
here to say that by the beginning of the twentieth
century, inference, extrapolation and inspired guess-
work, based on some knowledge of human and
carnivore brains, had implanted firmly and widely
the belief that the primate auditory area is located
somewhere in the superior temporal convolution.
Fortunately in view of this, the facts, as they subse-
quently accumulated, support this belief.
Aside from the cytoarchitectural studies of the
earlier neurologists, the modern investigation of the
primate auditory area may be said to begin with the
studies of Poliak in 1932 (72) based on Marchi
studies of monkey brains after lesions in the medial
geniculate body. He described the course and
terminations of the auditory radiations, defining as
the cortical projection area thus delineated the
greater part of the superior surface of the superior
temporal gyrus. The concentration of terminations
was greater posteriorly than anteriorly, the focal
zone coinciding with an elevation toward the pos-
terior end of the concealed face of the gyrus which
Poliak likened to Heschl's convolution in man.
Poliak described a lesser concentration of fibers
which reaches the lateral face of the superior tem-
poral gyrus.
Walker (105) and Clark (23), both using the
method of retrograde degeneration in the medial
geniculate body following lesions in the superior
temporal cortex, are in general agreement with
Poliak on the location of the projection area of the
medial geniculate; however, both outline a smaller
area confined to the posterior part of the superior
face of the gyrus. If the situation in the monkey is
similar to that found in the cat by Rose & Woolsey
(85), in which only A I of all the auditory region
receives essential projection, it would be expected
that only the corresponding area in the monkey
would be revealed by the retrograde degeneration
method. On the other hand, the Marchi method in
conjunction with medial geniculate lesions should in
addition demonstrate some of the fibers constituting
sustaining projections to a wider area. No study of
the primate auditory thalamocortical relationships
comparable to the Rose and \V'oolsey study of the
cat is available. There are, however, some hints de-
rived from several other studies that similar prin-
ciples may apply.
Electrophysiological efforts to map the primate
auditory cortex, like the comparable studies of the
cat, show the same sort of progression. They begin
with a limited area and, with improvement of in-
struments and methodology, expand and become
subdivided. There is, in the monkey, an additional
handicap which limited the accuracy of the early
studies. This arises from the fact the primate audi-
torv area, unlike the feline, lies almost entirely in
CENTRAL AUDITORY MECHANISMS
60 I
cortex concealed within the Sylvian sulcus, part of
it, in fact, facing inward toward the insula. This
makes necessary some special preparation in order
to gain access for the exploring electrode. Earlier
workers usually accomplished this by extensive re-
movals of the overhanging frontal and parietal
operculum, the latter of which, as later events have
shown, actually contains some auditory responsive
cortex. This was therefore missed until more re-
cently Pribram and his coworkers (73) were able to
expose the areas in question without major destruc-
tion of tissue.
The first electrophysiological demonstration of the
simian auditory cortex, bv Ades & Felder (6), used
click stimulation and the usual exploration for
cortical response. An area on the posterior part of
the superior temporal plane was found to Ije re-
sponsive; this is shown in figure 7. This area is larger
than those outlined by Cllark and by Walker but
confirms the general location. It is somewhat smaller
than the area shown by Poliak (72) to receive genic-
ulocortical fibers.
Licklider (53) and Licklider & Kryter (54), as-
suming the Ades-Felder definition of the auditory
area to be correct, explored it while stimulating with
short bursts of pure tone. They were able to demon-
strate a degree of specificity of various parts of the
area referable to frequency of stimulation. Bailey
et al. (i i) defined similar auditory areas from monkey
and chimpanzee, in each case confined to the supra-
FIG. 7. View of monkey brain with operculum cut away to
expose supratemporal plane. Horizontal shaded area shows 'click
map' of Ades & Felder (6); crosshaiched area within 'click map'
shows area determined by Walker by retrograde degeneration
to be medial geniculate projection area.
temporal plane, and confirmed the tonotopic dis-
tribution suggested by Licklider & Kryter. Walzl
(107) and Woolsey (112), using different methods,
also demonstrated a specificity of cochleocortical
projection in the same area but found, in addition,
a region of reversed order of projection on the upper
(parietal) bank of the sylvian fi.s.sure, thus extending
the boundaries of auditory cortex. The aspects of
these and other studies which relate to topical pro-
jection, localized response to different stimulus fre-
quencies or both will be considered in more detail
in a section dealing specifically with that aspect of
auditory projection.
The most extensive auditory area yet described
for the monkey is that of Pribram et al. (73). They
mapped the cortical areas from which electrical re-
sponse could be evoked by clicks, exposing the depth
of the Sylvian fissure and the insula by gently sepa-
rating the lips of the fissure and wedging them
apart in various ways. They do not relate in detail
the means by which damage to the rich vascular
tree of the middle cerebral artery was avoided;
however, this surgical tour de Jorce must have been
accomplished because the effects of severe heinor-
rhage and ischemia in the region supplied by this
vascular tree are not e\'ident in the results. The
corte.x of the posterior supratemporal plane, superior
temporal gyrus, insula and inferior parietal lobe all
yielded responses to clicks (fig. 8). On the basis of
latency of initial positive deflection and other cri-
teria, the authors identify (by inference or direct
statement) subdivisions of the total responsive area
with those of the cat as follows: /) the posterior
supratemporal plane with A I; j?) the anterior margin
of responsive area of supratemporal plane, posterior
insula and posterior inferior parietal operculum
with 'secondary' area of Ades & Bremer and, hence,
EP of Rose & Woolsey; and 3) the parietal opercu-
lum with S II. This analysis omits most of the re-
sponsive area of the posterior insula which corre-
sponds roughly to the 'second' auditory area (or
simian A II) of Walzl (107) and Woolsey (112). In
this regard the data of Pribram et al. furnish no
parallel to the Walzl & Woolsey data because the
definition of A I and A II in the lexicon of the latter
two authors hinges upon the presence in each of
cochlear projections of mutually opposite orienta-
tion.
Pribram et al. include data on retrograde degenera-
tion after lesions of the posterior supratemporal
plane but not of any other part of their responsive
area. So far as this goes, it confirms the impression
602
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
FIG. 8. A. Lateral view of monkey brain, the sylvian fissure spread to show area responsive to
clicks Cshaded') according to Pribram et at. (.Ti)- ^- Enlarged view of shaded part of ^. SL, short latency
area; PO, parietal operculum.
that the simian posterior supratemporal plane corre-
sponds to the feline A I inasmuch as in each case
destruction of the area leads to severe degeneration
of all but the caudal portion of the principal part of
the medial geniculate body. Pribram et al., however,
contrary to the findings of Rose & VVoolsey, are
quite positive in asserting that such a lesion and
consequent thalamic degeneration effectively elimi-
nates all conduction, not only to the simian counter-
part of S II but also to the other normally responsive
cortex of the ipsilateral hemisphere. From this they
conclude that the pathway to S II follows collaterals
from medial geniculate to some thalamic nucleus
which projects to S II. This impression gains credi-
bility from their oJKervation that the negating effect
of the lesion is not seen acutely (i.e. before conse-
quent geniculate degeneration has taken place)
but only some weeks later (i.e. after the effects have
been felt in the medial geniculate). This conflict,
except in the unlikely event it represents a species
difference, can be resolved only by full analysis of
the retrograde consequences of all combinations of
suspected subareas in each species combined with
electrophysiological delineation of responsive cortex
in each instance after time lapse to allow degenera-
tion and just before sacrifice. This is a large order,
but it is both legitimate and feasible.
The reader will note that in the discussion of the
primate auditory cortex, no functional counterparts
of the feline insular and temporal regions have
emerged. This probably represents merely a relative
shortage of information on the monkey, a lack which
may be filled in part by the additional information
we hope will accrue from the arduous future study
suggested in the last paragraph and in part from be-
havioral studies comparable to those in the cat. The
behavioral studies on the monkey so far available
are of little use inasmuch as they show no positive
loss of auditory capacity and the lesions are incom-
plete (26, 27). At the least, in the outlook on the
insular and temporal regions of the monkey, there is
reason to hope becau.se, if we accept the total area of
Pribram et al., a portion of the insula and all of the
lateral surface of the posterior superior temporal
gyrus are responsive to clicks but have not yet been
claimed for any other anatomical, electrical or func-
tional counterpart in the cat.
Finally, we may note that the definition of A II
in the monkey rests in part on published data (107,
116) but in even larger part on logical though less
well supported extension of that data. This is due,
at least in part, to relative inaccessibility. In this
connection, it may have been noted that of all the
subdivisions in the cat's auditory cortex, A II seems
to be the least firmly established. At no time since
the initial definition of A II has it been as clearly
valid an area as it was at that time. The experiments
of Kiang (49), which explore the whole region in
the cat by a combination of techniques, make the
distinction between A I and A II more nebulous
CENTRAL AUDITORY MECHANISMS
603
than it previously had seemed. It is possible this
region may prove to be, as Kiang suggests, a transi-
tional area or a fringe portion of A I.
TOPOLOGIC AND TONOTOPIC PROJECTION
An investigator entering upon the serious stud\
of the neural aspects of audition 25 years ago in-
evitably found that the single most engrossing topic
of study and speculation was that of the neurological
basis of pitch perception. This was not at that time
a new tendency., for von Helmholtz was in large
part responsible for initiating it many years before
by expressing the idea that the basilar membrane
of the cochlea resonated in different, narrowly re-
stricted regions to different frequenceis of .sound. It
followed that if the cochlea is thus an analyzer of
frequency, it must be reflected faithfully in the brain
in order to make the results of its analytical efforts
available to conscious processes. There was little
opportunity to test this hypothesis rigorously until
the advent, during the 1930's, of instruments which
would reliably measure the neural results of stimula-
tion by sounds. When this occurred, there was a
rapid increment of interest in auditory neurophys-
iology and, in natural consequence, in study of the
anatomy of the auditory pathway and of behavior
as related to audition. It was quickly established that
different parts of the cochlea do indeed respond dif-
ferently to different stimulus frequencies, though not
for the reasons nor in the manner which von Helm-
holtz thought, and this served to whet interest in the
central reflection of the phenomenon.
Another factor in the rapid acceleration of interest
in auditory neuroanatomy and neurophysiology was
the then recent demonstration of a very preci.se point-
to-point projection of the retina through the optic
tract and lateral geniculate body to the occipital
cortex. It was conceived that this sort of anatomical
arrangement might be characteristic of sensory projec-
tion systems in general. Certainly a similar orderliness
and topologic precision could be di.scerned in the
somesthetic system, in which the functional counter-
part of the visual field map was the body surface
map. Why not a projection of the organ of Corti
and a tonal map for the acoustic pathway?
The central auditory pathway, unfortunately for
those theories, is more complex in its multinucleate
interconnections than the visual or somesthetic path-
ways and it has not yielded easily to being fitted
into the same general scheme. Nevertheless, the nor-
mal anatomy of the system is not without some indi-
cations of orderliness and a variety of experimental
techniques has revealed even more. Likewise, on the
functional side, no easy uncomplicated scheme of
matching frequencies and fibers has presented itself.
It has gradually become evident that this system is
unicjue among sen.sory systems and presents problems
peculiar to itself; however, it has also become more
apparent that some relationship exists between ana-
tomical location and location in the audible spectrum.
Although it is somewhat awkward to do so, it will
be best to consider structural and functional localiza-
tion together, and the story will ije more coherent
if we largely ignore chronological sequence.
One of the more conspicuous features of the nerve
supply of the organ of Corti and the termination of
the cochlear nerve fibers in the cochlear nuclei is
their orderly anatomical dispositions. At their en-
trance into the cochlear nuclei, the cochlear nerve
fibers bifurcate along a curving line such that the
linear relationship of their origins in the cochlea from
apex to base is preserved (59, 75) with those from the
apex bifurcating lateroventrally, those from the base,
dorsomedially. The two branches of each fiber then
pass respectively to dorsal and ventral cochlear
nuclei and multiple terminations among the cells
of these nuclei. Single unit responses in the dorsal
cochlear nucleus to pure tone stimuli were shown by
Galambos & Davis (34, 35) to respond selectively
to tones of different frequency, each having its charac-
teristic frequency. Very recently. Rose et al. (84),
applying a similar microelectrode technique, ex-
plored the dorsal nucleus more systematically and
demonstrated an orderly pattern of frequency re-
sponse, the basic feature of which is that characteris-
tic frequencies of the single units vary systematically
from high at the medial (dorsal) edge to low at the
lateral (ventral) edge. Less complete data indicate
further that a similar arrangement is repeated in
each of the two divisions of the ventral nucleus.
If we accept for the moment that the base of the
cochlea is concerned with high frequency reception
and the apex with low (a concept which will need to
be qualified presently), the frequency distribution
in the cochlear nuclei corresponds to the pattern of
nerve terminations. This study affords the first step
toward an explanation of the as yet inexplicable mean-
ing of the elaborate organization of the cochlear
nuclei.
The story so far appears to be simple straightfor-
ward testimony in favor of the uncomplicated hy-
pothesis that each narrow segment of the organ of
6o4
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
Corti responds to a correspondingly narrow frequency
band and is connected by its own group of nerve
fibers to an isolated part of the cochlear nuclei.
True, upon arrival at the latter stadon, a rather dis-
quieting multiplication of the end organ seems to
take place such that the organ of Corti is projected
not once but several times to the nuclei, this being
accomplished by the systematic terminal branching
of the cochlear axons. There are, however, aspects
of this and related studies which are more fundamen-
tally disturbing to the hypothesis in its .simplest
form. In both the microelectrode studies cited in the
preceding paragraph, while the frequency response
band of a given nuclear element was extremely
narrow or punctate when the intensity of the stimu-
lus was near threshold, as the intensity was increased
the band became progressively wider, especially
toward the low end of the scale. (There was little or
no expansion of the response band to higher fre-
quencies, even at \ery high intensity.)
When information on microelectrode studies of
cochlear nerve fibers became available (99, 100, loi),
one of the more striking features was the exaggeration
of the principle just described for the second-order
units in the cochlear nucleus. The individual units
in the nerve also showed sharply restricted frequency
specificity at threshold intensities but, upon increasing
intensity, each fiber responded to a wider and wider
range of lower frequencies but not to higher. Instead
of responding each to its own frequency, therefore,
it would be more correct to say that each fiber re-
sponds to all frequencies up to its high frequency
limit and to none higher. This fits well with direct
observation by von Bekesy of cutoff points of vibra-
tion of the basilar membrane which vary with fre-
quency of stimulus and involve all of the membrane
up to the cutoff point (99, too).
If the feature of auditory nerve function just de-
scribed is true, then random partial lesions of the
nerve should not, as was once supposed, result in
hearing loss in the form of tonal islands but instead
in losses at the highest frequencies with smaller
lesions and a progressive high frequency loss as more
and more fibers are involved. Relatively few fibers
are stimulated by high tones, and so high frequencies
are most vulnerable since in the spiral course of the
nerve bundles also, it is inconceivable that any
appreciable lesion could miss these. Hence, in lesions
sparing only a few fibers, hearing should be preserved
only for tones at the low end of the spectrum (since
most or all fibers are sensitive to low frequencies,
and the lower tones are therefore relatively invul-
nerable to any but complete section of the nerve).
This is, in fact, the common finding in both animal
and human studies of this kind (41, 66, 91, 92, 93).
Studies of localized frequency response of neural
elements in stations lying between the cochlear nuclei
and the auditory cortex are relatively few in number,
although they are increasing currently. They rely
mainly on the microelectrode techniques. Such studies
have been made of the superior olivary nuclear com-
plex (33, 99), the inferior colliculus (99, 102) and
the medial geniculate body (31, 40). All of these
share with each other and with the studies on cochlear
nerve and nuclei the finding of elements which can
be activated by tonal stimuli; of others, already
discharging spontaneously, whose rate of (spike)
discharge is increased by tonal stimuli; and of still
others, already discharging, whose activity is in-
hibited by stimulation. An exception is seen in the
work of Tasaki & Davis (100, loi) who found no
fibers in the cochlear nerve whose acti\ity was
inhibited by stimulation.
The response band or area seems to undergo some
change in shape at successively higher stations. In
the nerve, it is characterized by a sharp high fre-
quency cutoff and a long extension into lower fre-
quency range. The cochlear nuclear elements show
high frequency cutoff nearly as sharp as nerve ele-
ments but with a lesser expansion of the area into
lower frequencies at higher intensities (31, 99, loi).
An abstract report of single unit recording from the
several subdivisions of the superior olivary complex
has just appeared (33), and a brief account of simi-
lar though less extensive experiments is included
together with those on other nuclei (99). There is a
greater variety of responsive units in these cell masses
than in the cochlear nuclei, their relati\e numbers
varving with location in the subdivisions and also
with other factors. Some units (from the reports it is
not clear what percentage) respond differentially to
tonal stimuli. The response area of a given unit
resembles closely those of cochlear nuclear units in
that the high frequency cutoff is still sharp and the
degree of extension into low frequency range about
the same as for the nucleus. Sumi et al. (99) report
that they found trapezoid elements responding to
tones over 20 kc situated rostrally, those to tones be-
low 300 cps caudally, and between these, 5000 and
3000 cps elements side by side. Thus there is indica-
tion of tonotopic localization of the projection thus
far.
The inferior colliculus (99, 102) shows some dif-
ferences and some similarities to the lower centei
CENTRAL AUDITOR^- MECHANISMS
605
with respect to single unit responses. The response
areas are much narrower than in the more caudally
situated nuclei. The threshold is just as sharp, but
one is less impressed with the high frequency cutoff,
there being some tendency for band width to widen
toward the higher as well as the lower tones with in-
crease in intensity, though the low tone bias is still
prominent. The inferior colliculus has not been sys-
tematically explored, so we do not know to what rela-
tive degree each part of this complex organ may be
populated with frequency-selective units. We can
only be sure that such units can l)e found in consider-
able numbers.
The medial geniculate body responsive elements
show, again, some similarities and some differences
to the situation in the medullary nuclei. While there
are many units which can be stimulated by pure
tones, there are also many which cannot, though the
latter group includes many units which do respond
to clicks, noise or both. Of those responding to pure
tones, it is noted the frequency ijands to which they
respond are broader at threshold than those of the
other nuclei. Furthermore, the bands widen, with
increasing intensity, almost equally toward higher
and lower tones. The available data offer us little
or nothing which would point to the existence of a
nuclear plan or map of frequency-specific areas;
however, this is really an open question which can
be .settled only by a more systematic survey of fre-
quency-biased (if not specific) units throughout the
nucleus.
A recent study of auditory cortical single unit
response to pure tone (25) has demonstrated some
units (few relative to brain-stem nuclei) which are
responsive to tonal stimuli (as well as others respon-
sive to other auditory stimuli). Tone-sensitive units
are said to be usually maximally sensitive within a
restricted frequency band, this band widening rela-
tively little as intensity increases. In the terms we
have been using, the response area follows the pro-
gressive tendency for narrowing of the band width
overall while widening it somewhat at threshold.
It should be emphasized that among the units sensi-
tive to any kind of auditory stimulus, which alto-
gether constitute less than 60 per cent of all units
identified, those sensitive to pure tone represent
only a small fraction. With respect to location of
frequency-specific units, the findings indicate that
those most sensitive to low frequencies predominate
in the posterior A I field and high frequency units
predominate in anterior A I, although in neither case
is the characteristic t\pe the exclusive frequency
sensitive type.
In review of the studies cited so far, it can be said
that the sharply restricted frequency specificity of
fibers for threshold intensity in the cochlear nerve
persists in units of the medullary auditory nuclei but
in the thalamus and cortex gives way to restricted
though broader bands of threshold sensitivity. On
the other hand, the very broad frequency response
for tones below the high frequency cutoff, characteris-
tic of the cochlear nerve fibers, diminishes steadily
in width as we ascend the pathway and the sharp
high frequency cutoff is lost. Thus, a given auditory
nerve fiber may respond at threshold only to 2000
cps tone (for example) and, with increasing intensity
may respond to all tones lower than 2000 cps, but will
respond to no higher tones, no matter how intense;
however, a cortical unit may respond at threshold
to a restricted band centering at 2000 cps but re-
spond at considerably higher intensity to a band not
much wider. From the situation in the cochlear nerve
where virtually all fibers are sensitive to tonal stim-
uli, we go to that in the cortex where only a fraction
of the total elements are tone sensitive. Although we
do not have very exact information on the percentage
of tone-sensitive elements at all levels, the indications
are that there is a proportional decrea.se, but no ac-
tual numerical decrease, and, more probably, some
increase of elements whose prime preoccupation has
to do with stimulus frequency.
Postponing for the moment any interpretation of
the microelectrode studies, let us turn to other studies
in which the basic questions have to do with overall
specificity of projection rather than that of indi\idual
fibers or cells of the pathway. Both types of evidence
will have to be incorporated into any effort at inter-
pretation.
We have followed the upward progress of single
tone-sensitive elements of the projection pathway
and noted that through the several synapses and proc-
essing centers, a certain change in character of rela-
tive frequency sensitivity has occurred together with
a dispersion of these elements among others which
seem to have different concerns. It would now be
well to examine the overall situation to determine if
there is, indeed, any pattern of anatomical or ph\sio-
logical integration which can be discerned by correla-
tion of elements or groups of elements at one end of
the system with those of the other. Several relevant
studies on cat, dog and monkey at once present them-
selves.
Let us consider first those primarily concerned with
6o6
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
anatomical integrity of projection. We have in the
report of Woolsey & Walzl (11:5) a pure example
of anatomical study of the neural projection of the
cells of the spiral ganglion to the cortical projection
area, by physiological means uncontaminated by the
mechanical characteristics of the end organ. The only
element of control lacking will he apparent as the
experiment is briefly described. The procedure was:
/) to expose the cochlear duct by removal of the ex-
ternal bony cap.sule, in the process of which the organ
of Corti and basilar membrane were removed to
expose the ends of the peripheral processes of the
ganglion cell in the free border of the osseous spiral
lamina; and 2) to stimulate by brief electric shocks
small groups of these fibers while exploring the sus-
pected cortical areas for the responses and map these.
The only methodological fault (which was unavoid-
able) is that, while the stimulus is electrically and
geographically speaking quite localized, not all of
the nerve fibers at any such local spot are. Some of
them innervate only the inner hair cells immediately
beyond the position of the stimulating electrode,
but the rest innervate more widespread groups of
outer hair cells, and the latter, to an unknown de-
gree, mav extend the cortical response area of a given
point or perhaps blur its edges.
On the basis of these experiments, Woolsey &
Walzl postulated a double cortical projection area
(A I and A II as they have since come to be called
and have been referred to in this chapter). Within
A I, they found the basal end of the cochlea to project
to the anterior part of A I and the apical to posterior
A I, with intermediate cochlear stations projecting
in orderly fashion between. A II showed a similar
pattern except it was inverted, so that the basal
cochlea is represented in posterior A II, the apical
in anterior A II; however, it was less easy to trace
the intermediate loci between these two focal regions.
Part of this difficulty could be due to the fact the evi-
dence is limited to the half of each cochlear spiral
which can be surgically exposed, while the situation
on the still inaccessible obverse turns must be logi-
cally inferred without demonstration
We know from the foregoing that there is a direct
relation of cochlear region to cortical area. Inferen-
tially, we can postulate further from this work that
high tones (basal cochlea) should e.xcite anterior A I
and posterior A II, while low tones should be repre-
sented in posterior A I and anterior A II. This has
been experimentally tested by several investigators.
The recent work of Erulkar et al. (25), using the micro-
electrode method, has alreadv i)een mentioned.
With macroelectrode techniques, the cortical re-
sponse to sustained pure tones (or noise for that mat-
ter) is less conspicuous than one might have thought,
and it is difficult to evaluate reliably for purposes of
mapping areas excitable by sound. This applies to
the sound after it has been turned on during what
Rosenblith calls a quasi-stationary state, the prefix,
'quasi', in this case representing the overwhelming
burden of our ignorance of the continuously changing
' backgroimd' electrical activity, and the ways it may
be influenced to change further by sound. The same
handicap does not apply to the onset response to
an\- kind of sound stimulus (onset can be seen as a
high-voltage wave response, due presumably to
arrival at cortex of a surge excitation), a fact which
has been capitalized in the use of clicks, which are
brief complex noises, and of tonal pips, which are
brief pure tones in which the frequency characteris-
tics are established and brought to threshold intensity
within a very few cycles. Response to tonal pips has
been used to map frequency-sensitiv'e cortical areas
and so has another method, the evoked strychnine
spike technique. The latter depends upon the fact
that a small part of the auditory cortical area can be
.sensitized with strychnine so that onset response of a
tone to which the area is normally sensitive evokes a
strychnine spike which, unlike the response of the
untreated cortex, is so characteristic it cannot lie
lost in the background activity.
In earlier efforts at mapping the auditory cortex
with respect to differential frequency sensitivity,
both in cat and monkey, the tonal pip and tonal on-
set methods were used, recording from the un-
treated auditory cortex in anesthetized animals.
In the cat (53), Licklider found that rough focal areas
of maximal response to higher or lower frequencies
could be found which are in general agreement with
the more recent stud\' of Hind (44)- Licklider felt
the situation could be better described in terms of
gradients rather than restricted tonal foci because
of the extensive overlapping.
Hind (44), using the evoked strychnine method,
presented more extensive data and extended the fre-
quency range studied. (It should be noted that the
technique was originalh' worked out by Tunturi
(103) and applied to study of the dog's auditory
cortex. Tunturi's work will not be described here
because, while in general agreement with others,
the comparison of data on dog and cat is troublesome
due to configural differences in the brain. We will,
therefore, to conserve space and avoid confusion,
confine the discussion to the cat studies which are
CENTRAL AUDITORY MECHANISMS
607
more useful by virtue of wide comparability with
others.) Hind found areas showing predilection for
higher and lower frequencies. There is general
agreement with Licklidcr's frequency map but,
whereas the latter's highest tested frequency was 8
kc. Hind's study goes as high as 50 kc. Furthermore,
Hind found two high frequency areas, namely an-
terior A I and posterior AH, and two low frequency
areas, namely posterior A I and anterior A H. On
both A I and A H, the area between high and low-
could be spoken of only as middle frequency range
area, the data permitting no finer gradation. Hind's
findings seem to agree with those of Woolsey &
Walzl (113). Together, they indicate a broad cor-
respondence between cochlea and cortical projection
on the one hand and stimulus frequency and cortical
frequency .sensitivity on the other. Let us note that
the data do not permit us to think here of a finely
tuned system.
It is interesting to note that Hind was able, at each
cortical point studied, by varying both frequency
and intensity of stimulus, to outline areas of response
which look very much like those of single units in the
microelectrode studies. The focus of threshold fre-
quency is not as sharp, and the response area widens
rapidly both up and down the scale.
Similar studies to those in the cat are available for
the monkey and the results, which will not be pre-
sented in detail, are similar. Woolsey (112) and Walzl
(107) repeated on monkeys their earlier experiments
on cats with similar results (cf. preceding section).
Licklider & Kryter (54) described a pattern of fre-
quency representation showing low frequencies to-
ward the anterior part of the auditory area of the
supratemporal plane (refer to fig. 8 for orientation)
grading to high frequencies most posteriorly. This
general arrangement was confirmed by Bailey et al.
(11). Kennedy (47) explored the monkey's temporal
region according to the same general plan as in Hind's
study on the cat. She found no widespread response
to tonal stimuli comparaijle to that responsive to
clicks described by Pribram et al. (73), although she
confirmed their findings with click stimulation.
Kennedy did find the presumptive monkey A I
area of the supratemporal plane respon.sive to tonal
onset which, enhanced by strychnine, yielded fre-
quency intensity thresholds for each point similar
to those of Hind. Her composite map of frequency
representation generally confirms but also extends
(with respect to both area and frequency range)
the study of Licklider & Kryter. It also considerably
sharpens the picture for the monkey and shows the
pattern to conform to a plan of concentric octave
bands, each oriented from medial to lateral. As in
the cat, the overlapping of frequency range areas is
at least as impressive as their .separation, but the gen-
eral trend is perhaps more cleAr-cut than in the cat;
howe\'er, Kennedy shows no A II and this helps to
to make the results look cleaner as compared to
Hind's.
Summary and Discussion of Tupalogic
and Tonotopic Projection
It can be taken as settled that a degree of frequency
specificity is characteristic of some of the neurons of
the central acoustic system. In numbers, the.se vary
from a great many elements in the cochlear nerve,
through progressively diininishing percentages of
the total at intermediate recording stations, to an
undetermined but certainly small proportion of
elements in the auditory cortex. We must also reduce
the term 'specificity' to its real proportions, a quali-
fication which has often not been made in interpre-
ting this kind of data. The term really applies well
only if we are talking about threshold intensity and,
even with this qualification, it applies best to the
more caudally situated recording stations rather than
to the thalamus or cortex. A second aspect of this
specificity has to do with the manner and degree of
expansion of the respon.se area with increasing in-
tensity. At the nerve, and to an only slightly lesser
degree in the cochlear nuclei, the direction of the ex-
pansion is strictly toward the lower part of the scale
and in degree is so wide as to make us think that some
fibers are stimulated by high tones, many by inter-
mediate tones and virtually all by low tones, given a
stimulus of sufficient intensity. As we ascend this
changes, so that among those cortical elements which
are sensitive to tone each, though less sharply tuned
at threshold, is comparatively greatly restricted in
range of frequency sensitivity even at quite high
intensity and expansion of response area is both
up and down the scale. Thus, while 'attention' to the
parameter of frequency is evident froin cochlea to
cortex, the original coding of this information, im-
posed by the mechanical characteristics of the coch-
lea, is changed, perhaps in the cochlear nuclei, per-
haps aided by the superior olivary complex, perhaps
even more gradually, so that in the more rostral
parts of the pathway, tone-sensitive elements are in
one way even more frequency-selective than those in
the nerve.
We have spoken of progressive dispersion of tone-
6o8
HANDBOOK OF PHYSIOLOGY ^ NEUROPHYSIOLOGY I
sensitive elements in tiie upper reaches of the audi-
tory pathway. This may be a misleading term. What
we really mean is that such elements become less and
less predominant from the standpoint of numbers,
or to state it another way, there is a progressively
increasing proportion of elements which have no
direct concern with the parameter of stimulus fre-
quency. Many of these, however, do respond (as do
all the tone-sensitive units) to complex sounds (e.g.
clicks, noise) encompassing wide bands of the audible
spectrum. We do not know why this is true but, within
the bounds of known facts, it is not difficult to en-
vision a theoretical switching system by which tone
and noise sensitive and only noi.se-sensitive elements
would come to exist in parallel. We know that the
cochlear nuclei contain at least three projections or
replicas of the organ of Corti. According to the micro-
electrode evidence (84), these retain the original
coding of the cochlea; however, in the output of the
nuclear neurons, there is no inherent constraint to
preserve the original coding pattern. If, in the ensu-
ing relays, we picture one group of cells each of which
receives approximately equal synaptic terminations
from all parts of one cochlear replica, it would pre-
sumably be responsive to summated volleys from a
sufhciently wide band of the replica, regardless of
position on the replica, and would therefore be re-
sponsive to stimuli of frequency bands of a given
minimal width, regardless of position on spectrum,
but not to narrow bands or pure tones. A second group
of cells, each receiving sufficiently concentrated synap-
tic terminations from a restricted part of the cochlear
replica, would respond to stimuli of frequency bands
of narrow proportions or e\en to pure tones. If in
succeeding relays the units of the second group began
to overlap each other somewhat, we would expect to
find the kind of changes which in fact ha\e been found
in the response area of successively higher single
auditory units, namely some widening at threshold
but without a corresponding widening at higher in-
tensity where small differences are insignificant.
That the units showing sensitivit\' to the various
segments of the audible spectrum retain, in the main,
their positions relative to each other in the ascent to
the cortex is evident, although there is also reason
to believe there is some degree of dispersion. This is
in accord with the observation, direct or incidental
by a variety of methods of many in\estigators on
several segments of the auditory pathway and on the
whole pathway from cochlea to cortex, that the ar-
rangement of auditory elements, though often intri-
cate with respect to nuclear organization, is always
orderly and maintains spatial relationships quite
faithfully. Macroelectrode studies of relative sensi-
tivity of diflTerent regions of the auditory cortex con-
firm the impression that, relatively at least, tone-
sensitive elements of similar frequency range tend
roughl) to group, though not to segregate themselves,
and maintain an orderlv relationship to elements of
different frequency characteristics. These studies
also accord well with those which demonstrate projec-
tion of the cochlea to the cortex in a recognizable
pattern.
The less careful reader might, at this ]3oint, feel
we have established a good case for the primary rela-
tionship of frequency specificit}' and anatomical order
and for these conjointly as the prime organizational
feature of the auditory system. It must be re-empha-
sized that frequency tuning of auditory neural ele-
ments and of the o\erall grouping of these as meas-
ured by electrical response is relatively fine only at
threshold intensity and at higher intensity is an even
less con\incing feature when compared to the pre-
cision of the psychophysical phenomenon of pitch
discrimination to which, presumably, we must relate
it. We can only suppose that the neurophysiological
facts so far known reveal to us only a part of the pic-
ture.
Efforts to translate the anatomicophysiological
phenomenon of tonotopic projection into terms of
hearing in animal experiments have been discourag-
ing but possibly needlessly so. There is good reason
to believe the meager success of such ventures is the
consequence of having asked the wrong questions,
these in turn growing out of unwarranted assumptions.
One doulile assumption of this sort is that pitch dis-
crimination, of necessity, must depend upon intact
auditory cortical function because it is a 'complex'
auditory function. Neither part of this is necessarily
true. Compared to deficits of human auditory func-
tion resulting from temporal lobe lesions, pitch dis-
crimination would be on the simple side. Deficits
in human subjects are not conspicuous unless they
involve actual auditory aphasia or unless the patient
is subjected to rigorous testing which goes far beyond
routine audiometry. It might also be pointed out
that it is impossible to prove the presence of a com-
plex auditory deficit such as auditory aphasia unless
one can first establish that basic perception is essen-
tially intact. The only auditory function which seems
to have been clearly tied to the cortex in aniinals,
namely discrimination between two three-tone pat-
terns, would appear off hand to be of a very diflTerent
order of integrati\c complexity than aphasia. Sup-
CENTRAL AUDITORY MECHANISMS
609
posing, for argument, that pitch discrimination is a
'complex function', it still does not follow that the
auditory cortex is the only or even the best neural
matrix in which the discrimination may be made.
If we consider the possibility that a kind of signal to
noise ratio operates between frequency-sensitive and
nonfrequency-sensitive elements, then the auditory
cortex affords the poorest ratio of any part of the sys-
tem. Finally, the animal behavioral experiments may
be clouded to the extent that the learning and reten-
tion and conditioned response aspects of the method
are neurologically inseparable from the purely audi-
tory aspects.
OTHER .ASPECTS OF CENTRAL AUDITORY FUNCTION
If it is apparent that the auditory system contains
a tonotopic organizational pattern, it is equally ap-
parent it is not filled by this pattern. Like many paths
through a jungle, this tonotopic path through the
auditory system has been found only because it was
suspected and sought. It is also well to consider the
jungle where other matters may be equally signifi-
cant. By far the greater number of neural elements
in the system cannot be demonstrated to have any-
thing to do with this parameter (frequency) of the
acoustic stimulus. Such has been the preoccupation
with it, however, that any discussion of audition is
inevitably dominated by it. Nevertheless, some in-
vestigative attention has, in fact, been otherwise
directed and more should be. The remainder of the
chapter will be devoted to several other aspects of
central auditory function which have received some
and require more attention.
Loudness
The neurophysiological correlates of loudness
probably cannot be altogether divorced from those
of pitch, althoua;h the subject was avoided almost
entirely in the preceding section. The main reason
for this was the desire to a\oid confusion of issues in
an area where much more is known of one side of the
issue than of the other. A second, and hardly less
compelling reason, howeser, is the status of our ideas
about the neural mediation of loudness which is
currently as or more confused than at any time in
recent years.
Traditionally, loudness has been regarded, rather
vaguely, as being expressed in terms of quantitv of
excitation. Whereas frequency was supposed to in-
volve the appropriate restricted group of fibers,
loudness was supposed to be expressed in terms of a
greater or lesser proportion of the total cross .section
of pathway excited. With the realization that, at
least with respect to the cochlea, the total amount of
end organ being stimulated and total number as well
as site of origin of nerve fibers are involv^ed in the
analysis of frequency, it became apparent that the
same device could not be used simultaneously for the
factor of loudness, at least in a simple way. The pos-
sibility exists, however, that some interaction be-
tween inner and outer hair cells may lie at the bottom
of the mechanical aspect of loudness. Whatever may
be the cochlear, nerve and cochlear nuclear corre-
lates of loudness, if the hypothesis proposed in the
preceding discussion relative to a frequency recoding
function of the nuclei is at all correct, the mediation
of loudness might also take a different form in the
ascending pathway.
It would probably be a mistake to suppose that
loudness could be subserved by any of the possible
upward projecting patterns without the addition of a
factor of selective neural inhibition by recurrent ele-
ments. There is little evidence to call upon in this
respect, and the possible significance of such elements
will be discussed below in more general terms. For
the moment, we can only exercise caution in theoriz-
ing about the mediation of loudness, bearing in mind
that there is a large factor of relativity inherent in
the concept and hoping that further investigation
of the cochlear end organ will yield some suggestion
as to direction.
Laterality of Projection
One of the more distinctive features of the central
acoustic system, as contrasted to other .sen.sory sys-
tems, is its tendency to bilateral reduplication and
its bewildering array of commi.s.sural opportunities.
It is obvious the system begins with two ears which
are situated on opposite sides of the head, the open-
ings of the external auditory meatuses 180° apart
in terms of direction of orientation, plus or minus
what few degrees of bias may theoretically be im-
posed by the presence of the pinna. This immediately
suggests the possibility that source and direction of
sound may be perceived in part as a consequence of
the relative time of arrival or loudness or both of
signal for the two ears. From psychophysical studies,
it is clear that directionality is one of the properties
of sound perception. It is not the function of this
chapter to go extensively into the analysis of direc-
6io
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
tionality as a function of binaural interaction; how-
ever, whatever may be the mechanism of such interac-
tion, it is our concern to discuss whether, to what
extent and by what means binaural interaction is
reflected in the anatomicophysiologic organization
of the central acoustic mechanisms. The evidence
relevant to these questions is limited but does yield
some useful information which we will examine
presently.
A second question has to do with the extent to
which each ear is bilaterally represented in the pro-
jection pathway. This question is probably not alto-
gether separable from that of the central reflection
of binaural interaction, although in certain contexts
it may be. For this reason, discu.ssion of the two ques-
tions will overlap, especially from the anatomical
point of view.
The crucial anatomical problem in any theory of
bilateral interaction must be the opportunity for
side-to-side communication. There is no dearth of
such opportunities in the auditory pathway. Crossing
occurs at the trapezoid body, the earliest opportunity
since this begins at the level of entrance of the cochlear
nerves. The trapezoid crossing seems to provide not
only the first but also the most essential crossing for
maximum representation, both quantitative and
qualitative, of the left ear in the contralateral hemi-
sphere and vice versa (5). It is also at this level
that the superior olivary complex, by virtue of its
bilateral input from cochlear nuclei, provides many
of the ascending fibers of the lateral lemniscus which
represent either ear. Thus the basically bilateral
projection of this system has its anatomical foundation
almost at the level of entrance of the nerves.
Fibers of the lateral lemniscus cross at the somewhat
diffuse commissure of Probst, just below the inferior
colliculus. No functional significance of this commis-
sure has been demonstrated (5).
A third opportunity for crossing of auditory nerve
fibers occurs at the commissure of the inferior collicu-
lus. The significance of this crossing appears to be
largely local, carrying fibers from colliculus to oppo-
site colliculus or, at most, to opposite medial genicu-
late (i 1 1). Its function with respect to the pathway as
a whole, as measured by the influence of its presence
or absence on cortical response to stimulation of the
contralateral ear, seems to be negligible (5, 90).
The cortical auditory area, like other cortical areas,
communicates by strong connections with its counter-
part on the opposite hemisphere by way of the corpus
callosum (62; also Ades, H. \V.., unpublished ob-
servations). The functional significance of this with
special reference to audition is not clear.
A problem which particularly stimulated some of
the early modern research in audition, and on which
incidental observations have since been made, is
that of the bilateral representation of each cochlea.
This has been tested, more or less adequately, in
various ways (5, 13, 18, 45, 46, 63, 88, 108, 113).
Functionally, the results have generally indicated
some difference but usually so small as to make it
difficult to detect an effect on acuity of even the de-
struction of one ear. Most of the observations on cor-
tical electrical response to contralateral versus ipsi-
lateral and bilateral stimulation of the ears have
revealed some small difference in representation.
Similar results have been differently interpreted,
apparently depending upon the point of view of the
individual investigator more than on any other fac-
tor. One could sum up by saying the difference in
representation of the two ears at one cerebral hemi-
sphere is often statistically different Ijut probably
not practically different.
In a more ingenious way, however, Rosenzweig
(89) has succeeded in demonstrating that, while
quantitatively the difference in the effect of the two
ears on the cortical area may appear nearly equal
when one ear is stimulated at a time, there is never-
theless a more significant difference when the position
of the stimulus is varied with respect to the two ears
simultaneously stimulated. He found that when a
sound is presented at one side, the cortical response
s greater at the contralateral than the ipsilateral
hemisphere — the farther to the side, the greater the
difference. When the sound is in the median plane,
the cortical activity is equal at the two hemispheres.
Here we have, then, a clear correlation between audi-
tory localization and differential response of right
and left cortical auditory areas. We know, however,
from the work of Neff rf al. (67) that auditory localiza-
tion is a function which is not abolished by destruc-
tion of the cortical areas. In a second group of ex-
periments, Rosenzweig & Wyers C90) found some
evidence for binaural interaction in the inferior
colliculi, although not of the same kind as in the cor-
tex.
Other than the studies cited briefly in the foregoing,
the evidence on the bilaterality of auditory function
is relatively scanty. The system has been more often
than not treated without regard for, or with only
incidental attention to, this structural and functional
feature.
CENTRAL AUDITORY MECHANISMS
6X1
Dispersion of Excitation, Recurrent
Pathways and Inhibition
In this final section, the author would like to take
up as a group certain considerations which have
been touched upon in earlier sections of this chapter
and by other authors. Presumably, these should ul-
timately apply to the elucidation of central auditory
functions but are at present speculativ-e and little
supported by evidence. They must for the present
be spoken of in general terms. The evidence which
will be cited is more by way of justifying the specula-
tion than of supporting a theory; indeed, we have no
complete coherent theory to offer but only a number
of facts, some connected, some possibly connected,
and some suggestions of things which should be con-
sidered in future investigations.
One of the distinguishing features of the auditory
system is the multiplication of elements at succes-
sively higher nuclear stations in the pathway (22).
Coupled with this are the twin physiological phe-
nomena of temporal dispersion of electrical response
to brief (click) stimuli and amplification of response
(5, 25, 32, 36). In this case, amplification takes the
form of increased amplitude of response and tem-
poral dispersion of extending the duration of response
if, for example, we compare these factors from coch-
lear nuclei to medial geniculate body. The simplest
way of accounting for these phenomena is by assum-
ing the amplification to be the consequence of the
larger number of units available to be fired in the
larger, more rostral nucleus, and the temporal dis-
persion to be the consequence of the multisynaptic
connections which result in a lateral lemniscus com-
posed of several different orders of fibers. There are
additional possibilities which might contribute to
both phenomena. Each nucleus traversed contains
within itself the neural matrix requisite (quantitatively
speaking) to an internal temporal and spatial dis-
persion process in addition to that we are attributing
to the pathway as a whole. The inferior colliculus
constitutes, in one sense at least, a tract parallel to
the lemniscal fibers which pass directly to the medial
geniculate; lemniscal fibers diverge to the colliculus
and fibers from it reconverge on the main path at
the medial geniculate, providing a possible feed-back
device which might augment the dispersion processes.
We also know, howe\'er, from many electrophysio-
logical studies that amplification and temporal dis-
persion are only two of the things which may happen
to a burst of activitx' in the auditorv system aroused
by so simple a stimulus as a click. The response may
also be reduced in amplitude or obliterated by pre-
ceding or simultaneous auditory stimuli of the same
or different type, depending upon where, when and
how strong the two are relative to each other and upon
where the recording is done. We may, at this point,
recall the recurrent fibers mentioned in the early
description of the pathway as still another feed-
back portion of a complex input to a given nucleus.
When we recall that stimulation and inhibition are
equally possible consequences of the firing of one
neuron into another (depending on conditions at a
given instant), we must realize the term "feed back'
as used here may be positive or negative with respect
to the whole or a part of the pattern being processed
in a given nucleus at a given time.
To make concrete the rapidly growing po.ssibilities
in the foregoing paragraphs, there is evidence, cited
by Galambos (32) in a discussion of inhibition, that
inhibition, intranuclear or that provided by recur-
rent fibers or both, may in the cochlear nuclei act
to restrict the frequency range to which a given unit
responds. He further indicates that other studies are
in progress, both anatomical and physiological which
we can hope will lead to an expansion of this factual
nucleus.
We are not constrained to limit the possibilities of
selective inhibition or other forms of modulation to
the elements of the traditional projection pathway.
It has already been pointed out in discussing the retic-
ular formation that the auditory system feeds in some
way into the brain-stem reticular system and thereby
exerts its influence, in common with other sensory
systems, upon the status of general cortical activity
quite independently or indeed in the absence of an
intact auditory projection pathway. Adey et al. (8)
have recently demonstrated also that various cortical
areas (including, as it happens, A I in the cat) fire
freely back into the brain-stem ascending reticular
system. There are many indirect suggestions in the
literature which would lead one to believe that this
system also may fire into the specific afTerent path-
ways. This would provide a reciprocal arrangement
at brain-stem levels which would permit interaction
not only, in this ca.se, between the auditory system
and the cortex via the reticular system but also be-
tween the auditory and other sensory systems.
Any, all or none of the foregoing connections may
exist and work in any, all or none of the ways sug-
gested. But one thing is clear, namely that the central
6l2
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
nuclei of the auditory system must operate on a plan
which is far more complex than the simple projection
pathway in terms of which we often speak. There is no
reasonable doubt that each nucleus processes the
information it receives from an input, complex both
as to sources and patterns, in relation to events which
have occurred or are occurrins; in centers above and
below, auditory and nonauditory. It seems most
unlikely that substantially further progress will be
made toward explaining the facts of audition in
neurophysiological terms without considering the
intrinsic and extrinsic neural processes by which ex-
citation aroused by sound is modulated in the central
auditory system.
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CHAPTER XXV
Vision — introduction
H. K. HARTLINE | Rockefeller Institute for Medical Research, New York City
WE ARE INDEED 'CHILDREN OF THE SUN'. The ultimate
dependence of li\ing organisms on solar enersy is
probably one reason why animals came to evolve
highly specialized sensory receptors for exploiting the
sun's radiations. And since the green plants utilize
wavelengths in that part of the solar spectrum reach-
ing the earth's surface in greatest amount, it is not
surprising that the receptors evolved by plant-eating
animals and their predators also should operate in
roughly the same range of wavelengths, which we in
consequence call visible light.
Wavelengths of visible light are small compared
with the size of the bodies of most animals and of
many significant objects in their surroundings. Hence
light reflected, scattered and absorbed in varying
degrees by objects in an animal's environment makes
an ideal physical agent for providing information
about that environment. This possibility has been
exploited by nearly all animal forms to a remarkable
degree.
It is appropriate that a neurophysiologist taking up
the study of vision should begin with a consideration
of the extraordinary diversity in which eyes have
evolved in 'lower' animal forms. An intimation of
this diversity is given in the Milnes' chapter on in-
vertebrate photoreceptors. Missing from this hand-
book is a comparable discussion of the eyes of the
vertebrates, which, though of but a single type,
nevertheless show a great variety of ingenious adap-
tations to meet special needs. Fortunately, this de-
ficiency is easily remedied by reference to Walls'
excellent and highly readable hook. The Vertebrate
EyeCn')-
Of the great variety of visual organs that the animal
kingdom has developed, many are no mean per-
formers. Our own eyes, for all their defects, are
excellent physical instruments, all the more remark-
able for being constructed, by embryological magic,
out of gristle and jelly. Yet man need not think he
has the best of all possible eyes. He terms the short
wavelengths 'ultraviolet', but they are visible to at
least some insects. Polarized light elicits the entoptic
phenomenon known as ' Haidinger's brushes', the
orientation of which reveals the direction of the
plane of the light's polarization. A few individuals
are said to be able to perceive these brushes when
viewing the blue sky with unaided vision. But as far
as is known to the author, no race of men has utilized
this as a sky compass, comparable to the use made
by many of the arthropods of their ability to sense
the plane of polarization of sky light. Man's eyes are
remarkably sensitive; they can detect approximately
loo quanta, but many nocturnal vertebrates un-
doubtedly have a lower effective threshold. Our
visual acuity is surpassed by that of some other ani-
mals, especially the acuity of birds of prey. Yet for
all of this, man is at no very great disadvantage
merelv because the visual apparatus of other animals
surpasses his own in some special directions. His
visual equipment is not over-specialized, and it does
many things very well.
Interest in light and vision dates back to antiquity.
Nearly everyone has heard of the quaint idea of the
Greeks, that light is an intangible ray-like emanation
from the eye itself, exploring tactually the surround-
ings. (Indeed, if we were to assume that sensation
could result only if such emanation were absorbed by
what we term luminous objects, this idea would not
be easy to disprove; in physics the optical principle
of the reversibility of path is often invoked in theo-
retical discussions.) With a history of many interesting
misconceptions, a sound understanding of the nature
of light and the structure and function of the eye
gradually emerged. By the time of Kepler many of
615
6i6
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
the essentials of physiological optics were beginning
to be clear. In the first few chapters of his book, The
Retina, Polyak (ii) summarized in scholarly and
interesting style the early history of this subject, from
the Greeks and Arabs through Medieval to Modern
times.
As the science of optics developed, it took two
paths. On the one hand, the physics of light emerged.
Optics through most of its history depended ulti-
mately on visual observations made by the human
eye as the final detecting and measuring instrument.
Only relatively recently have physicists been able to
replace human vision to ad\antage by the photo-
graphic plate and by elaborate photoelectric detecting
and recording devices. The laws of reflection and re-
fraction were first derived by simple visual operations,
conducted in a scientific manner. This history is
discussed in some detail in a recent paper by Ratliff
(13). Combined with the lens maker's art, the physics
of lenses and mirrors developed into our present day
geometrical optics. Physical optics is based on the
observation of the maxima and minima detected by
the eye in interference and diffraction patterns, and
by brightness changes produced by polarization op-
tics. Photometry was, and still is to some extent,
dependent on the ability of a human observer acting
as a null device to detect very small inequalities in
brightness in an illuminated field. Even color vision,
properly a subject belonging to physiology, has
fascinated physicists from the time of Newton, when
it formed the basis for the emerging science of spec-
troscopy. As these physical sciences developed, they
in turn were applied to the eye itself, and physiologi-
cal optics resulted.
Physiological optics had its great flowering in the
last century, with the epochal work of v'on Helm-
holtz. In its essentials and in many of its details, the
physics of the dioptric system of the human eye was
put into satisfactory shape by Helmholtz, and is em-
bodied as part of a broad study of visual physiology
in his three monumental volumes Handbuch der
Physiologischen Oplik (16).
Physiological optics is by no means a finished sub-
ject, as shown plentifully in Fry's chapter. Even the
physics of the eye, narrowly defined, invites creative
effort today. In a broad sense, physiological optics is
often taken to include most of visual physiology.
Perhaps this is too broad a definition, but it is wise
to avoid drawing arbitrary boundaries to this field.
Photosensitivity, that essential property that makes
a visual organ possible, is conferred upon the special-
ized receptor cells of an eye by their possession of
certain chemical substances that can absorb light
(and therefore are pigments) and undergo photo-
chemical change. This reaction must be such as to
initiate a change of events in the irritable mechanism
of the receptor, leading to the transmission of nervous
influences along the optic pathwav.
The \isual pigment of the retinal rods of the verte-
brate eye was discovered by Boll and carefully in-
\estigated by Kiihne nearly a hundred years ago.
The essential importance of ' visual purple' or " rho-
dopsin' in \ision was questioned for many years be-
cause of two misconceptions. First, it was argued
that since no such pigment could be observed in the
cones, none was there. True, the pigment of the cones
is different from, though closely related to, that of
the rods, and it is more diflicult to detect; but modern
methods are adequate for its detection in the cones
and its extraction and study in vitro. The second, and
less obviously fallacious argument was that the visual
purple in a retina bleached on exposure to light, and
yet photosensitivity remained. It was not realized
that the restorative processes (already described by
Kijhne) would operate in light as well as darkness,
and would lead to a'stationary state' in which a small
but significant amount of visual pigment would be
present in the receptor for indefinitely long periods.
Even in bright light, an active turnover of visual pig-
ment, with photolysis and regeneration, takes place
continually, and photosensitivity, while reduced, is
still present. The clear, quantitative formulation of
these ideas by Hecht in his classic studies of the
photosensory mechanism of the clam, Mya, opened
a new era of visual physiology. Before the advent of
modern biochemistry, Hecht applied these ideas of
photolysis, regeneration and the stationary state to
ijasic \'isual phenomena such as light and dark adap-
tation, inten.sity discrimination and flicker. The
experiments that he and his colleagues performed
using animals and with human observers, and the
theories they devised to explain their results, still
play a fruitful role in the field of visual physiology (9).
But by now it has become clear that Hecht's ideas,
while basically sound, were oversimplified, and need
to be reworked in the light of more recent biochemical
developments.
At the present time, the significance of visual purple
and the photosensitive substances related to it is
firmly established. The biochemistry of these visual
pigments is one of the most actively pursued and
most exciting topics of receptor physiology, as amply
VISION INTRODUCTION
617
demonstrated in Wald's chapter. The pro£!;ress that
has been made in the study of chemistry of the primary
photosensitive substances of the rods and cones of the
vertebrate retina, and the receptors of a few inverte-
brates, is indeed impressive.
It was a significant step when the visual pigments
could be extracted from their loci in the outer limbs
of the rods and cones, and bleached and resynthe-
sized in vitro. Another important step has now been
taken by Rushton and his colleagues (14), who have
succeeded in measuring the bleaching and regenera-
tion of visual pigments of both rods and cones in the
living eye, as described in Wald's chapter. Operating
on the principle of the ophthalmoscope, a sensitive
photoelectric device is used to measure the light re-
flected back through the retina of a human subject.
Rushton's studies are providing a link between the
biochemical knowledge of the visual pigments, and
the physiology of the living retinal receptors.
Biochemistry alone is not sufficient to solve the
problem of the photoreceptor. In the living eye,
visual pigments are part of highly organized cellular
systems. New concepts of the fine structure of visual
receptor cells are emerging from recent cytological
investigations. In the developing vertebrate retina,
the rods and cones originate as ciliated epithelial
cells from the neural tube. [This subject has been
reviewed by Detwiler (2) and by Walls (17).] The
cilia becoine transformed (i) into the outer segments,
which are long stacks of doui^le-membrane disks
(15). Remnants of the original ciliary structure re-
main visible to electron microscopy in the com-
pletely developed receptors (i, 12). In arthropods, the
osmium-staining ' membranes' take the form of
densely packed microvilli of the surfaces of the retinula
cells, so that the rhabdom has a structure resembling
a honey-comb (4, 10, 18). Rhodopsin is present only
in the outer segments of the rods, and, as Wald
points out in his chapter, constitutes a large fraction
of their bulk. Prcsumaijly a similar arrangement of
visual pigment holds for the cone outer segment
and for the invertebrate rhabdomere as well. These
cytological facts will have to be taken into considera-
tion in any theory of the receptor mechanism.
.•\ photoreceptor is a transducer of light energy
into nervous action. The first step, the photochemical
change in a specific visual pigment, is now quite
familiar. The later steps, ultimately resulting in
nervous excitation that is transmitted in the afferent
nerve fibers, are almost completely unknown. Wald
and Granit in their chapters have indicated some of
the possibilities that are to be considered [see also
(5) and (7)]. Presumably at least some of these proc-
esses in the photoreceptor are not basically different
from those occurring in any other cell of the nervous
svstem. Indeed, it would not be surprising if the
entire photosensitive mechanism were the result of
but a comparatively minor modification of a funda-
mental irritable structure of a cell. The photosensi-
tivitv of some ganglion cells, as discussed in the
Milnes' chapter, and the fact that peripheral nerves
can be photosensitized by dyes (3) makes this a not
unreasonable expectation.
The final outcome of the excitatory processes ini-
tiated by light is the generation of trains of nerve
impulses in the fibers of the optic pathway. Whether
all photoreceptor cells themselves — the rods and
cones in the vertebrate retina, the retinula cells in
the arthropod compound eye, for example — actually
generate trains of discrete impulses in their own fibers
is not established; but some primary receptor cells do,
and so do neurons closely associated with the recep-
tors. Optic nerve fiber activity consists of the rhyth-
mic succession of propagated ' all-or-none' disturb-
ances typical of the activity of all neurons concerned
with transmitting influences rapidly over large dis-
tances. Studies of the discharge of impulses in single
optic nerve fibers have shown that many of the
familiar phenomena of vision have their origin in
properties of the receptors, or of the retinal neu-
rons (6).
Intimately associated with the excitation of the
visual mechanism are comparatively slow electrical
changes measurable grossly as the retinal action po-
tentials. These are discussed in Granit's chapter. As
a result of studies employing microelectrodes that
are small enough in some instances to penetrate
single cells and record electrical activity from within
them, the .significance of various components of the
retinal action potentials is gradually becoming clearer.
It seems likely that an integral link in the excitatory
process is a change in electrical polarization of cellu-
lar structures, brought aijout somehow by the photo-
chemical system of the receptor. As in other parts of
the nervous system, these electrical changes, because
of the local current flow they engender, result in the
initiation of relaxation oscillations in cellular mem-
branes which, conducted, are the trains of nerve
impulses that constitute the sensory message to the
higher centers.
An eye is more than a simple mosaic of photore-
ceptor elements. The histological complexity of the
6i8
HANDBOOK OF PHYSIOLOGY ^ NEUROPHYSIOLOGY I
vertebrate retina and of the compound eye of insects
is ample evidence that, in the more highly developed
eyes, sensory information from the transducer ele-
ments is acted upon almost immediately by highly
organized ganglionic structures. The physiological
studies that bear out this expectation are reviewed in
Granit's chapter, where the conception of the retina
as a nervous center is thoroughly developed. In the
vertebrate retina, excitatory and inhibitory influences
spread and converge, and interplay in a complex
manner to generate patterns of optic nerve activity
that are much more than mere copies of the patterns
of light and shade on the receptor mosaic. Even in
more primitive eyes, simple interactions of receptor
units take place (8) that serve to accentuate certain
significant features of the stimulus pattern, at the
expense of exact fidelity of reproduction. Integrative
nervous processes begin \ery early indeed in the
visual pathway. More than this, Granit's chapter
reveals that the visual receptor organ, like other
sense organs, is under a certain amount of centrifugal
control from the higher nervous centers. This new
development in neurophysiology is already having
far-reaching effects on ovn- understanding of sensory
physiology.
With the study of the physiology of the higher visual
centers of the brain, taken up in Hartley's chapter,
visual physiology merges with other branches of
neurophysiology. In this area, contributions come
from workers not primarily concerned with vision,
for brain physiology involves the integration of all
forms of neural activity that govern the organism's
behavior. Quite properly, many references to the
physiology of the visual centers will be found scat-
tered in other chapters throughout this work.
In the analysis of central nervous system mecha-
nisms, extensive u.se has been made of experimental
animals in which parts of the brain have been ab-
lated, fiber pathways interrupted or specific areas
stimulated artificially. The resulting modifications of
behavior then reveal important physiological rela-
tionships. Applied to the visual system, such studies
require more than a casual familiarity with specific
principles of retinal physiology and with overall
visual performance. This is brought out in Hartley's
chapter. Especially in the field of animal behavior it
should be emphasized that great advances have been
made recently by experimental psychologists. Ani-
mal behavior can now be controlled more effecti\ely
and studied with greater precision than was possible
only a few years ago. The present day neurophysiolo-
gist must master these powerful new techniques or
work in close collaboration with colleagues who have
mastered them.
The aim of the studies that have been outlined
above and taken up in detail in the chapters that
follow is to understand vision. This broad aim can
be expressed quite explicitly, so far as many ol the
behavioral manifestations of vision are concerned.
The reactions of intact animals to stimulation by
light and the reports of human observers in response
to visual presentations have been studied by truly
scientific methods for many years. Experimental
psychology provides a vast amount of very detailed
and very precise information about just how animals
do react, what human subjects do report, in carefully
controlled visual experiments. Students of visual
phenomena have not neglected the analysis of their
observations in attempts, often very successful, to
provide an understanding of underlying mechanisms.
Indeed, many such mechanisms are now being veri-
fied by direct neurophysiological experimentation.
Psychological studies of vision are vitally important
to the visual neurophysiologist, for it is this field of
science that sets many of his ultimate problems. No
matter how far we may progress in the analysis of
the neurophysiological mechanisms of the visual
pathway, our task of acquiring .scientific understand-
ing will not be complete without the complementary
act of synthesizing our detailed knowledge into a
coherent whole.
REFERENCES
1. DeRobertis, E. J. Biophyi. & Biochem, Cylol. 2, .Supple-
ment: 209, 1956.
2. Detwiler, S. R. Vertebrate Photoreceptors . Experimental
Biology Monographs. New York: MacMillan, 1943.
3. Fessard, a. Recherches sur I'Activite Rytlmiique des NerJ
holes. Paris: Hermann, 1936, p. 130.
4. Goldsmith, T. H. and D. Philpott. J. Biophys. & Bio-
chem. Cylol. 3: 429, 1957.
5. Granit, R. Receptors and Sensory Perception. New Haven;
Yale Univ. Press, 1955.
6. Hartline, H. K. Harvey Lectures Ser. 37: 39, 1942.
7. Hartline, H. K., H. G. Wagner and E. F. MacNichol,
Jr. Cold Spring Harbor Symp. Qiiant. Biol. 17: 125, 1952.
8. Hartline, H. K., H. G. Wagner and F. Ratliff. J.
Gen. Physiol. 39 : 65 1 , 1 956.
9. Hecht, S. Physiol. Rev. 17: 239, 1937.
10. Miller, W. H. J. Biophys. & Biochem. Cytol. 3: 421, 1957.
11. PoLVAK, S. L. The Retina. Chicago: Univ. Chicago Press,
194" •
VISION — INTRODUCTION
619
12. Porter, K. R. H an n Lectures fict. 51: 175, 1957.
13. Ratliff, F. In: Psychology: A Study oj a Science (vol. 4),
edited by S. Koch. New York: McGraw Hill. In press.
14. RusHTON, W. A. H. AND F. W. Campbell. Nature, London
174: 1096, 1954.
15. SjoSTRAND, F. S. J. Cell. & Comp. Physiol. 42: 15, 1953.
16. VON Helmholtz, H. Handbuch der Physiologischen Optik,
III Auflage. Hamburg and Leipzig: L. Voss, 1909. (Eng-
lish transation, J. P. C. Southall (editor). Menasha, Wis-
consin: Banta, 1924- 1925.)
17. \Vali5, G. L. The Vertebrate Eye and its Adaptive Radiation.
Bloomfield Hills, Michigan: Cranbrook Press, 1942.
18. WoLKEN, J. J., J. Capenos AND A. TuRANO. J. Biophys. &
Biochem. Cytol. 3; 441, 1957.
CHAPTER XXVI
Photosensitivity in invertebrates'
LOR us J. MILNE2
MARGERY M I L N E^
Durham, .h'eiv Hampshire
CHAPTER CONTENTS
Photosensitivity in Unicellular Organisms
Cells Without Obvious Photoreceptors
Cells With Obvious Photoreceptors
Photosensitivity in Multicellular Organisms
Photosensitivity Mediated Without Obvious Receptors
Ganglionic photosensitivity
Peripheral photosensitivity
Photosensitivity Mediated Through Unicellular Eyespots
Photosensitivity Mediated Through Multicellular Eyes
Compound eyespots
Ocelli or simple eyes
Compound ocelli or aggregate eyes
Stemmata
Compound eyes
Camera-style eyes in moliusks
Camera-style eyes in annelids
Camera-style eyes in arthropods
Phenomena Related to Stimulus Intensity
Pigment Migration Within the Eye
Spectral Sensitivity and Color Vision
Form Perception and Pattern Recognition
EYE-MINDED MAN IS proDC to forgct that the fundamen-
tal irritability of protoplasm includes a sensitivity to
radiant energy in the spectral region he knows as
light. An eye is a specialization with which a multi-
' Contribution from the Scripps Institution of Oceanography,
La Jolla, California, New Series No. 967. The information in
this chapter has been assembled with the aid of research grants
from the .American Academy of .\rts and Sciences, the Ameri-
can Philosophical Society, the E.xplorers Club and the Society
of the Sigma Xi.
' Professor of Zoology, University of New Hampshire.
^ Recently Visiting Professor of Biology, Northeastern Uni-
versity, Boston, Mass.
cellular animal may gain additional information from
a light stimulus. Usually it is a device allowing a
central nervous system to be better informed about
events in the surrounding environment. An eye im-
plies a nervous mechanism of some kind, but the
converse is not true.
In photosensitivity the initial event is absorption
of photons — the quanta of radiant energy — by some
substance which is altered by this addition. When
compared to thermal reactions, most photochemical
changes appear to be in a class by themselves charac-
terized by temperature coefficients so small that they
are described as 'temperature-independent.' Through
the temperature range within which living things are
active this is correct enough.
Since only the absorbed energy is effective in pro-
ducing a photochemical change, every photosensitive
mechanism must contain a chemical substance which
can trap photons. When the concentration of such a
substance is high enough so that a few per cent of
incident photons are absorlied, we may detect the
absorption as an opacity and recognize the absorbing
substance as a pigment.
So far none of the pigments found to be responsible
for photosen.sitivity in living systems are neutral in
their absorption. They are not gray but colored be-
cause they absorb most at one wavelength and less
at others. This feature determines the spectral sensi-
tivity of the system.
For an animal to be informed continuously regard-
ing the radiant energy reaching its surface, it must
be able to produce continuously the pigment which
is altered by the absorption of photons. In the dark
this production would be expected to decrease in
rate until the pigment reached a maximum concen-
621
622
HANDBOOK OF PHVSIOLOGV
NEUROPHYSIOLOGY I
tration. Simultaneously the mechanism would attain
its maximum sensitivity to light energy. In continuous
illumination the system should reach an cquiliijrium
such that the rate at which the pigment is altered by
absorbed energy is equal to the rate at which the
pigment is produced. The time required to reach
maximum concentration in the dark has been found
to be several times as great as that required to reach
an equilibrium in continuous illumination. The
former is a measure of dark adaptation and the latter
of light adaptation.
Since radiant energy arrives a quantum at a time
and, according to Einstein's law of photochemical
equivalence, is absorbed only at the rate of one quan-
tum per molecule affected, this initial step in photo-
sensitivity has a statistical character. At low intensities
of light, so few molecules may capture a photon in a
given time that the organism ignores the scattered
events. At a slightly higher intensity of stimulation,
the frequency of capture would rise. If the lower
limits for response to light are explored with a test
flash of constant duration, some definite intensity
level can be found at which a sensation of light is
obtained 50 per cent of the time. At a slightly lower
intensity, the response is obtained perhaps 30 per
cent of the time. At a slightly higher intensity, per-
haps 80 per cent of test flashes elicit a response. Both
subjective and objective measurements of this kind
show a range in 'frequency of seeing.' Some value,
such as 50 per cent, can be defined as threshold.
Variation in response at threshold may be entirely
attributable to variations in the quantum content
of test flashes. Whether one molecule of pigment
modified in a brief time (such as o. i sec.) is enough to
trigger the entire photosensitive mechanism is still
unsettled (10, 77, 97, 213). Different nervous systems
may require several molecules of pigment to be al-
tered almost simultaneously. In any case it is clear
that photosensitivity has an efficiency approaching
the theoretical limit of one quantum and one mole-
cule.
Relatively few pigments are so unstable that a
single photon can produce a chemical change. A
photon simply lacks the amount of energy required
to start most chemical reactions. From this it might
be expected that photons with the largest content of
energy would be most important in photosensitivity.
In the wavelength band visible to the human eye,
that giving the sensation of violet consists of photons
with about double the energy of those in the red.
Ultraviolet includes photons with an energy content
double that of photons in the violet; but the seem-
ingly transparent media of terrestrial vertebrate eyes
ab.sorb the ultraviolet before it reaches the photo-
sensitive retina. Aquatic organisms are shielded from
ultraviolet by the water around them. Except under
laljoratory conditions, only the terrestrial arthropods
(such as insects) appear to be stimulated visually by
wavelengths shorter than 400 m/x.
The photosensiti\e pigments extracted from in-
vertebrate and vertebrate eyes (152, 153, 276, 277)
appear consistent in having their eflTective maximum
of absorption between 400 and 700 m/z — well within
the spectrum visible to man (fig. i). Indirect evidence
is available to indicate that the corresponding pig-
ment or pigments in insects may be more affected by
the ultraviolet components of sunshine than by energy
absorbed at a secondary absorption maximum in the
human range. Hence it is apparent that the chemical
adaptations which permit photosensitivity in aquatic
life and terrestrial vertebrates are related less to the
energy content of the photons than to the wave-
lengths of radiant energy which penetrate most
deeply into seas (480 mju) and lakes (560 m/ii). Sensi-
tivity to ultraviolet seems to have come secondarily
as a gain when some arthropods became both ter-
restrial and diurnal.
For extraction of photosensitive pigments in suf-
ficient quantity for spectrophotometric analysis, con-
siderable masses of photosensitive tissue are needed.
So far this requirement has limited direct study to the
large eyes of squids (20, 21, 65, 150, 229) and the
stalked eyes of euphausiid crustaceans (143) which
can be cut from hundreds of specimens taken with
plankton nets. Most other invertebrates are either
too small or too difficult to catch in adequate num-
bers for a biochemical approach. In consequence
other avenues of investigation have been necessary
for studying their photosensitivity.
The most valid approach is beset with technological
difficulties. It consists of inserting microelectrodes
into photosensitive cells and recording electrical events
which follow stimulation of the cells by light. These
changes in electrical potential clearly demonstrate
the peripheral origin of nervous activity in visual
systems (90) and suggest that depolarization of the
photosensitive cell is responsible for initiating nerve
impulses in its associated nerve fiber (177).
With some invertebrate eyes it is possible to study
impulses in surviving nerve fillers emerging from
photosensitive cells (88, 89, 281, 286). Far easier and
more widely applicable is the less informative pro-
cedure of applying an electrode to the corneal surface
of an intact eye and examining the gross potential
PHOTOSENSITIVITY IN INVERTEBRATES
623
400 424
491 500
575 585 600
648
700 m^i
ultra-
violet
vio-
let
blue
green
yei-f
llow:
orange
red
Infra-
red
410
A
A
A
A
A
463
491
522
562
620
470
520
580
600
650
FIG. I. The absorption maxima of extracted and synthesized photosensory pigments range across
much of the spectral range visible to man. Commonly accepted boundaries (jop) and representative
centers {holtom) of appropriate wavelengths of light arc shown for each hue sensation. Photosensory
pigments include: 463, euphausiopsin (Kampa, 1955); 491, rhodopsin (Kiihne, 1877) and cephalop-
sin (Bliss, 1948); 5.^2, porphyropsin (VVald, 1937); 5^.2, iodopsin (Wald, 1937); and 620, cyanopsin
(Wald, 1953).
changes which accompany illumination of the organ
(6, 7, 87). Excised surviving eyes can be studied in
the same way although without gaining from them
any additional information (56, 211, 212).
Far more unknowns arc encountered in trying to
learn about an animal's photosensitivity from its be-
havior either under laboratory conditions or undis-
turbed in its natural habitat. Yet the vast bulk of
physiological investigations on invertebrate vision
employ methods of this type. In them one advantage
can be seen : the reactions of the whole animal — even
in an artificial environment — must be closer to its
responses in normal life. By observing behavior, some-
thing more of the role of vision in ordinary situations
can be gathered. Isolated measurements of electrical
potentials are far more difficult to interpret on an
ecological basis.
By far the most hazardous approach to photosensi-
tivity in animals is also the commonest. It is decep-
tively easy to examine their photosensory structures
anatomically and histologically and to infer how these
structures may be used. Valuable evidence can cer-
tainly be obtained as to limitations imposed by struc-
ture; but without careful experimentation with li\ing
individuals, there is no way to be sure that the aniinal
exploits its photo.sensory mechanism in its daily life.
In most groups of in\'ertebrates the best that can
be done in summarizing findings on photosensitivity
is to relate the anatomical and behavior studies. This
is approached most simply on a structural basis or on
a taxonomic framework (31, 77, 142, 193, 216, 269).
PHOTOSENSITIVITY IN UNICELLULAR ORGANISMS
Since both receptor and eff"ector are component
parts of the same cell in protozoans, photosensory
specializations are more limited than among meta-
zoans. Responses to light seem correspondingly re-
stricted to movements of the whole cell or of its loco-
motory structures, such as flagella.
Cells Without Obvious Photoreceptors
There is no a priori reason to assume that the re-
sponses to light found in amebas need correspond to
those in such flagellates as Peranema. In the former, an
increase in intensity of illumination is usually fol-
lowed by retraction of pseudopodia. The rate of
locomotion of amebas appears to be afifected signifi-
cantly by the intensity of continued illumination.
Initially the rate is modified by the state of dark
adaptation of the cell (183). Hertel, who investigated
the ultraviolet to 280 m// as a stimulus (104), postu-
lated that the radiations catalyzed the release of
hydrogen peroxide within the cell and that these
chemical changes accounted for behavior. Mast &
Stahler (183) believed, instead, that the light pro-
duced a physical change in the elastic strength of the
plasmagel, inhibiting the formation of pseudopodia.
624
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
In Peranema the whole cell, including its flagellum,
appears to he sensitive to light (238, 239). A gradient
can be detected from a minimum in the posterior end
to a maximum in the flagellum. Even detached flagella
will respond to increased illumination by bending,
but no recovery seems possible. Hence both the re-
ceptor and effector substances must be widely dis-
tributed in the protoplasm, but the recovery phase
depends upon transport of additional materials into
the flagellum from the cell body where they are
elaborated.
Cells With Obvious Pholoreceplors
Definite organelles called stigmata are present in
many flagellates and seem associated with a localized
photosensitivity. Some stigmata are ball-like masses
of opaque red or black pigment. This is the case in
Euglena where the stigma is close to the double base
of a single flagellum and must shade the flagellar
bases from radiations reaching the cell from straight
ahead. If it is assumed that shading allows the flagel-
lar mechanisms to operate at full speed and illumina-
tion from the side inhibits the lashing movement, then
the polarity of swimming movements with respect to
a point source can be explained rather simply.
Cup-shaped and spoon-shaped stigmata are usual
among colonial flagellates such as Gonium and Volvox.
The concavity of the stigma is associated with the
hypersensitive protoplasm and may be lined with a
reflecting layer which serves as a concave mirror and
concentrates the light at a focal point with the photo-
sensitive region. Both Gonium and Volvox stigmata
possess a lens as well. In Volvox the size of the stig-
mata decreases with distance of the cell from the an-
terior pole of the colony, and all stigmata are placed
so as to face outward and slightly toward the an-
terior pole. The two flagella of each cell beat in dif-
ferent modes and at unlike rates according to the
direction from which light reaches the stigma. Mast
worked out the paths of the reflected and refracted
rays (180, 182) but did not identify the functional
connection between the photosensitive mass in the
stigmatic area and the locomotor mechanism at the
flagellar bases. It is clear, however, that when a Volvox
colony is illuminated only from directly ahead on its
axis of symmetry, every cell receiving radiations does
so in ways which lead to symmetrical beating of the
flagella. Under these circumstances the entire colony
revolves on its axis and, unless the light intensity is
excessive, approaches the source while so rotating.
Unilateral illumination, by contrast, appears to
modify flagellar movements on the illuminated side
while vigorous beating on the shaded side gradually
turns the colony until its axis is directed toward the
source.
Mast (182) presented generalizations concerning
the form and function of stigmata in unicellular and
colonial flagellates, without mentioning the most re-
markable of them all. In Pouchetia and related dino-
flagellates, the lens associated with the stigma is
enormous and spherical. The resemblance to a multi-
cellular eye in these unicellular organisms is striking.
No experimental work has been reported which
might show the use to which Pouchetia puts this
striking organelle.
PHOTOSENSITIVITY IN MULTICELLUL.'^R ORG.ANISMS
With multicellularity a metazoan might be ex-
pected to show pronounced localization of photo-
sensitivity into obvious eyes. Some metazoans manage
quite well and respond to light without obvious
specializations of this kind. Others, although equipped
with eyes, seem to ignore visual cues for considerable
parts of their life histories.
Photosensitivity Mediated Without Obvious Receptors
To this phenomenon the phrases 'dermoptic sense'
and "dermal photosensitivity' have often been ap-
plied (e.g. 133-135, 201). Table i indicates the
taxonomic groups in which a generalized response of
this kind has been demonstrated. Often a failure to
recognize the presence of this photosensory system in
animals with eyes has led to wrong conclusions con-
cerning the effects of unilateral blinding.
Ganglionic Photosensitivity
In 1934, Welsh (290) and Prosser (218) discovered
independently that the abdominal ganglia of the
crayfish were photosensitive, permitting the animal
to respond to light even after its eyes had beeti re-
moved. Hess (113) found the same sensitivity in
abdominal ganglia of the shrimp Crangon and the
spiny lobster Panulirus but learned that photosensory
cells were scattered along nerves in such remote
parts of the body as the uropods. The role of gangli-
onic photosensitivity in controlling locomotor ac-
tivity of the intact animal has received some con-
sideration (232). Probably it is more important at
the time of molt, before the new exoskeleton has de-
PHOTOSENSITIVITY IN INVERTEBRATES
62 =
TABLE I. Structural and Functional Aspects of Photoreceptors as Presently Known
in the Various Taxnnomic Groups of Invfrlehrales
Reoresentatlon
a = all
1 = larval
m = most
s = some
v = noted
0 >
S >
— tn
fi
Stigmata (Intracellular
organelles) also
General photosensitivity
Neuronal photoreceptors
Unicellular eyespots
Compound eyespots
Ocelli = simple eyes
Compound ocelli
Stemmata
Compound eyes (ommatldia)
Camera-style eyes
Retina direct
Retina inverted
Pigment-cell Iris diaphragm
Muscular iris diaphragm
Tapetum
Migratory eye pigments
Muscular shift of lens
Hydraulic shift of retina
Muscular shift of retina
Muscular reshaping of lens
' Ladder retina '
Binocular field
Color vision
PROTISTA
Mastigophora
S
Sarcodlna
a
Cillata
a
COELENTERATA
Hydrozoa
V s s m s
Scyphozoa
V m 8 a
Anthozoa
V
CTENOPHORA
V
PLATYHELMDJTHES
Turbellarla
V m s s n
1 s
Trematoda
V s
NEMERTINEA
V s s n
1
ASCHELMINTHES
Rotlfera
V m s a
Gastrotrlcha
V m s a
Kinorhyncha
V m
Nematoda
V s a
_
BRYOZOA
V
MOLLUSCA
Amphlneura
V m a
Gastropoda
V s s m E
8 S 8 S 8
Pelecypoda
V V 1 s s s m (
i S 8 S
Cephalopoda
V a a
am 8 ?
ANNELIDA
Archiannellda
V m
Polychaeta
V s s s 8 m s
i B B
Ollgochaeta
V V
Hlrudlnea
V m
CHAETOGNATHA
V m
1
TARDIGRADA
V m
OhreCHOPHORA
V a a
AHTHROPODA
U
Branchiopoda
V m m a
m 8 s
Ostracoda
m ma
m 8
Copepoda
m m 8 a
m 8
Branchlura
m ma
m
Clrrlpedia
m 1 a
a
Malacostraca
V V s ma
ass s 8
Trllobita
m m ?
?
Xlphosura
a a a
8
Eurypterlda
m m ?
?
■g
Scorpionida
V m a
S
Pseudoscorplonlda
V m a
8
Phalanglda
V m
a s
Acarlda
V 8 a
Araneida
V m m
8 8 S
Solpuglda
8 a
8
Pycnogonlda
m
a
Chllopoda
V m 8 m
8 8
Dlplopoda
V 8 8 m
8
t
1
Ametabola
V s m a
S
Hemlmetabola
V 8 m a
m s s
Holometabola
1 1 8 8 8 m a
m a 8 8 8
ECHINODERMATA
Crlnoldea
V
Holothuroldea
V V
Asteroldea
V 8 8
Echinoldea
V
Ophluroldea
V
HEMICHORDATA
V V 1
CHORDATA
Urochordata
V V T
a
Cephalochordata
V a
626
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
veloped its pigmentation and while light can pene-
trate more readily into the viscera.
Peripheral Photosensitivity
The degree to which light responses can be localized
into effective behavior patterns without structural
specialization of photoreceptors is certainly shown in
the echinoid echinoderms. With the Mediterranean
urchin Centrosteplianiis, von Uxkiill found fairly rapid
adjustments in orientation of the spines according to
the direction from which the body was shadowed
(275). A more detailed study of the Caribbean
Diadema by Millott (i 88-1 91) confirmed von Uxkiill's
findings on behavior and established the fact that no
special photoreceptor cells are present at the ends of
the twigs from the radial nerves where these enter
the dermis. Yet the entire body surface appears
photosensitive, only the spines themselves lacking this
type of irritability. The radial nerve must be intact
for the responses to follow local stimulation. Even a
kind of dark adaptation is present through concentra-
tion of pigment in dermal chroma tophores, permit-
ting more light to penetrate to the level in the skin at
which the nerve twigs lie.
With another Caribbean urchin Millott was able
to duplicate some of the spectacular findings of Dubois
(59) on European Strongylocentrotus. Both echinoids
have the habit of partially covering the aboral sur-
face with debris picked up from the adjacent bottom.
The Caribbean Lvtechinus inhabits the coral reefs and
boulder-strewn beaches to the limit of wave action
at low tide and appears to use bits of coral as ballast
in this buffetted zone; but if a narrow beam of light
is directed on any portion of the aboral surface, the
urchin transfers these opaque objects (or any bits of
seaweed within reach of tube feet and pedicellariae)
into the path of the beam, using them as a parasol.
Urchins at greater depths, where the light is less in-
tense, seem to carry debris only while sunlight is
reaching them on the bottom (191).
Perhaps the best example of an extreme sensitivity
to shadows was found by Millott with Diadema. When
a single urchin was placed in a finger bowl of sea
water under a checkerboard of electric lamps, it
would rapidly point many spines in the direction of
any single lamp in the pattern when this one was
temporarily turned off. Identification of the direction
in which so minor a change occurred must be medi-
ated through an inherent polarity with maximum
sensitivity to light reaching the body surface at right
angles, as well as through the general roundness such
as Nagel postulated (201) (fig. 2 right~).
A general photosensitivity with less striking re-
sponses has Ijeen demonstrated in other echinoderms:
in the entire aboral surface of the sessile (and swim-
ming) crinoid Antedon (163); over the whole body of
the holothurians Synaptula (203) and Holothuria (41);
o\er the aboral surface of asteroids from which the
ocellatc tips of the arms had been removed (258, 297);
and in the ophiuroid Ophiocoma (37). Crozier found
a difference (41) between the behavior of Holothuria
and Thyone in that the latter holothurian mo\cd away
from a light source as an echinoid might — any angle
of the body in advance. Holothuria, by contrast,
showed a functional polarity, swinging around until
the mouth was farthest from the stimulating light
before moving off in this orientation.
Responses to light where no receptors seemed
specialized toward sensiti\ity to radiations have been
reported in blinded and intact members of many
phyla: in the hydrozoan medusa Gonionemus (200); in
luminescent ctenophores Beroe (122) and Mnemiopsis
(197); in blind turbellarians (165); in blind rotifers
(263, 264); in nematodes (104); in oligochaetes (no,
III, 114, 161) with identification of neuronal photo-
receptors in which photo.sensitivity was localized; in
the polychaete Mercierella (228); in the leech Hirudo
(234); in bryozoans, both as larvae (Pectinatella) and
adults QLophopus'), through kinetic responses of nega-
FIG. 2. Curvature of the body surface can provide an animal
having general photosensitivity with a means for identifying
the direction from which a light stimulus comes. Neither lamp
A nor shadow B have a directional significance for a flat photo-
sensitive tissue (/f/O; but in a cylindrical or spherical organism
(jigtiO quite different cells are illuminated by the two sources,
A and B. [After Nagel; from Milne & Milne (193).]
PHOTOSENSITIVITY IN INVERTEBRATES
627
live sign (179); in various pelecypods (201) but
particularly Mya (94, 96, 148, 166); in the gastropod
Helix on the basis of photosensitivity in spite of a gap
found in the optic nerve from the tentacular eye
(306); in the hemichordate Dolichoglossus (39, 11 1,
112); and in the adult urochordates Ascidia (93) and
Ciona C96).
Photoreceptors in the skin of a soft-bodied animal,
such as an oligochaete, vary greatly in degree of ex-
posure depending on the extension and contraction
of the superficial tissues in locomotion. In Perichaeta,
Harper (85) found that a negative response might be
shown to low-intensity illumination w-hen the worm
was tested while extended, yet the same test applied
while the worm was contracted might lead to a posi-
tive response.
Quite a few eyeless invertebrates (particularly
hydroid coelentcrates and turbellarians) react posi-
tively to sunlight without giving proof that they are
themselves photosensitive. These organisms harbor
mutualistic algae (green 'zoochlorellae' or brownish
green 'zooxanthellae') which carry on photosynthesis
when illuminated. A response to chemical changes
accompanying photosynthesis could account for the
behavior of the animal partner in many instances.
Even when the invertebrate possesses eyes as well as
mutualistic algae, the role of vision in photic re-
sponses becomes suspect until pro\ed definitely.
Translucent bodies which stud the exposable por-
tion of the mantle in the giant clam Tridacna were
described as eyes until Yonge (305) cleared up the
misunderstanding. He found that these structures are,
instead, an adaptation permitting daylight to reach
deep levels of the mantle tissue where large numbers
of mutualistic algae grow. Tridacna appears to depend
for food primarily upon the success of the enclosed
algae. It raises the plants in mantle greenhouses, and
the supposed eyes are merely illuminators in the roof!
Photosensitivity Mediated Thrmigh Unicellular Eyespots
Addition of a cup of opaque pigment beside a
photosensory cell seems but a small step in evolution
but still a move toward development of an eye. This
addition permits the receptor to be more definite as
to the direction from which a stimulating light comes
than when its own greater sensitivity to radiation
passing along its axis is the sole means for differentia-
tion. When photosensory inechanisms consist of a
single receptor cell and an associated pigment mass,
the term eyespot is useful — although earlier authors
have used the word far more loosely. Often a lens is
associated with an eyespot, providing still more dis-
criminatory possibilities and perhaps increasing the
structure's sensitivity by gathering in more light.
Eyespots are present in such turbellarians as Pro-
rhynchus (^14.4) and in a number of parasitic trematodes,
particularly at various larval stages of digenetic
forms. Some trematode cercaria possess them; so does
the miracidium of Fasciola. Instances of apparent de-
generation have been identified (70), although no
evidence has been given that would indicate a cor-
responding loss of sensitivity. In many nemertineans,
one or more pairs of eyespots are present (123), but
whether negative responses to radiation found in
Lineus (194, 195) depend upon functional eyespots
has not been proved. By ingenious experiments,
Viaud has been able to distinguish between photo-
sensitivity in rotifers mediated by their eyespots and
those elicited on the basis of a general sensitivity
(260-264). Eyespots are the only photoreceptors
identified in archiannelids (125) and some poly-
chaetes (i 17, 237). They are characteristically present
in tardigrades (43) and larval hemichordates (243,
245). They are scattered along the nerve cord of
cephalochordates (116, 141, 204), and appear to be
the sole mechanism allowing response to radiations
(204); possibly degenerate eyespots, devoid of pig-
ment cups, were described by Joseph (141).
Pliotosensitii'ity Mediated Through Multicellular Eyes
COMPOUND EYESPOTS. Another small step toward ef-
fective vision consists of the grouping together of
unicellular eyespots, forming them into an organized
cluster with radially divergent axes. Structures of this
kind — compound eyespots — have been reported in but
three groups of organisms with no indication that
they are part of an evolutionary sequence.
Both solitary and compound eyespots project from
the mantle margin of pelecypods in the genera Area
(fig. 6) and Pectunculus. In A. noae a specimen 8.5
cm long had 235 of these sensory clusters. Neither
Patten (206) nor Kiipfer (159), however, indicated
the degree to which the compound eyespots were
used in a visual way.
The annelids Potamilla and Branchiomma (fig. 6)
bear compound eyespots on the main stems of the
cephalic branchiae (3, 27). Each sensory unit is
isolated from its neighbors by pigment cells. Yet the
known reactions of these polychaete worms seem no
628
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
more complex than those of other genera in which
the structure of photoreceptors is simpler (267).
The other group of invertebrates with compound
eyespots conceals its photoreceptors so well that they
were unknown before 1946. Most maggots (larval
flies, insect order Diptera) give strong negative re-
sponses to any but very dim illumination, and many
can orient themselves with remarkable accuracy.
Yet it remained for Bolwig (22) to locate the photo-
sensory structures using microdissection. He found a
small group of rounded cells somewhat anterodorsal
to the supraesophageal ganglion. In early first-instar
lar\ae these cells are not fully developed; neither is
photosen,sitivity. By the second instar, the cell group
is well organized but not yet surrounded i^y opaque
tissues; these larvae orient well, apparently bv dis-
criminating the faint shadow of their own translucent
bodies. In the third instar, the growth of the pharyn-
geal .skeleton provides an opaque cup around the
compound eyespot without blocking the light from
anterior directions; these larvae will follow the vec-
torial resultant path between two light sources. With
later development, both overgrowth of the pharyn-
geal skeleton and increased opacity of the body re-
duce the accuracy of orientation and raise the thresh-
old for response.
Eyes of types other than compound eyespots agree
in having a layer of photosensory cells, i.e. a retina.
It may line a pit (fig. 3, left") or lie below a lens (fig.
3, right). Where the retina consists of many cells so
close to the dioptric elements that no clear image
seems possible, the term ocellus (simple eye) may be
applied. If a similar retina is remote enough from
the dioptric system that a reasonable image is cast
upon it, the phrase camera-style eye seems preferable;
camera-style eyes usually have an accessory mecha-
nism permitting accommodation. If the retina con-
sists of only a ring of receptor cells, clustered around
the pro.ximal end of the dioptric system like sections
of a citrus fruit, the structure is an ommatidium.
Ordinarily ommatidia are grouped into a compound
eye with the optic axes of the individual units diverg-
ing from one another on a quasiradial plan. Ocelli
may also be grouped as compound ocelli, or 'aggre-
gate eyes.' A puzzling intermediate between an ocel-
lus and an ommatidium is found in the larvae of
some holometabolous insects; for this structure the
word stemma is useful.
OCELLI OR SIMPLE EYES. OcelH with large lenses are
located around the rim of many coelenterate medusae,
but the degree to which their photosensiti\ity is used
— PIGMENT CELLS
FIG. 3. A pigment-surrounded cup lined with photoreceptor
cells (/(>//), a cuticular lens above the retina (jrighl'), or a com-
bination of the two, are characteristic of true eyes. .\ narrowing
of the cup's aperture improves the ability of an eye to dis-
criminate between events at A and B but reduces the amount
of light admitted. A lens provides an aid to discrimination and
also can collect more light, hence increasing the organ's sensi-
tivity. [After Nagel; from Milne & Milne (193).]
to modify responses arising from a general responsive-
ness to light has never been established (e.g. 200).
Nerve fibers from these eyes communicate with the
diffuse nerve net and may be part of a much more
direct .sensory-motor mechanism than is found among
animals with a highly developed nervous system.
Shallow and deep pigment cups without lenses are
the characteristic ocelli in turbellarians. Their num-
ber ranges from one pair to many and their size from
minute to relatively large. No phylogenetic pattern
is discernible, and no correlation has been made with
habits or habitat (133). Best known are the con-
spicuous ocelli of Planaria in which a pigment cup
open lateralis' conceals the distal ends of the receptor
cells (fig. 4). Hesse (115) related the visual field of
each ocellus to the behaxior of the intact flatworm.
Taliaferro (249) found in addition that receptors in
the posterior and ventral portions of each pigment
cup arc invoked in responses wherein the animal
turns toward the eye of that side, whereas stimulation
of the remaining receptor cells is followed by a turn
in the opposite direction.
Amono nemertineans (123) and rotifers (263, 264)
the presence of ocelli rather than eyespots has been
noted in se\eral genera. But no special significance
has been sttributed to the more complex photosensory
mechanism.
So wide a variation in ocellar structure is present
PHOTOSENSITIVITY IN INVERTEBRATES
629
PLANAR I A
DORSAL
EPITHELIUM
MEDIAL
( IN CROSS SECTION )
FIG. 4. The dorsal ocelli of the turbellarian flatvvorm Planaiia consist of opaque pii^ment cups
open laterally, concealing the distal ends of photoreceptor cells. Shadowing of the photoreceptors
by the pigment cups differs in horizontal illumination according to the orientation of the worm
Qeft). Each receptor cell (right) is most sensitive to radiations passing through it parallel to the
long axis of the portion within the pigment cup. [.After Hesse; from Milne & Milne (193).]
among the many eye-bearing members of the phyla
Annelida, Mollusca and Arthropoda that it is tempt-
ing to arrange them in parallel .series (i 17, 193, 237).
A phylogenetic basis for this series would be valuable
(fig. 5), Ijut no correlation has been found between
form of ocelli and other structural features or with
the normal habitats occupied. Hence it seems prob-
able that the variation has no Ijroader implications,
and the parallels in embryonic de\elopment are
fortuitous.
The several paired ocelli on the prosiomium of the
polychaete Nereis are of a single structural type with
a cuticular lens over a cupped retina (162, 199).
The most anterior pair mav mediate negative re-
sponses to light and the others positive responses
(105); an asymmetry of the retina in the anterior
pair appears to adapt them to forward and lateral
vision, whereas the other ocelli are directed more
vertically upward (199). Brand (24) reported that
the behavior characteristic of unilaterally blinded
Nereis is shown even when any single ocellus is left
intact on the operated side.
In the Atlantic palolo worm, the polychaete Eunice,
each segment bears a single mid-ventral ocellus, but
its function has not been found (in) since general
photosensiti\ity appears to account for responses
observed.
The ocelli of leeches appear to be the chief special-
ized sensory organs and in the first fi\e body .segments
occupy the positions corresponding to lateral-line
organs in more posterior regions. Each ocellus is al-
most cylindrical with its longitudinal axis at right
angles to the body surface; its nerve fibers connect
on the medial surface. Whether they are phylogeneti-
cally related to tactile elements (293) or can legiti-
mately be arranged in an evolutionary series (266)
has not been proved. Their function may be related
more to body pigment distribution (247) than to
kinetic responses. As Parker pointed out (205), mere
possession of photoreceptors does not imply that an
animal can see.
The abundant small ocelli of amphineuran mol-
lusks provide a comparable puzzle. An adult Cure-
pliium may have as many as 8500 of these structures,
perhaps 3000 in the most anterior plate of the shell
(198, 214, 215). Heath (92) traced their formation
and concluded that they must be functional even in
the adult. Crozier (40) could find only a general
photosensitivity, however, in Chiton. It was most
pronounced in the scaly girdle, where ocelli are lack-
630 HANDBOOK OF PHYSIOLOGY ^ NEUROPHYSIOLOGY
RANZANIDE5
SYLLIS
NEREIS
PHYLLODOCE
HAL/OTIS
PATELLA
SCUTUM
SECRETION
MUREX
LIMULUS
SCOLOPENDRA
DYTISCUS LARVA
— CUTICLE
\
SAGITTA
AND
TRANSVER
SECTIONS
FIG. 5. A comparative series showing degrees of development in ocelli of polychacte annelids
Qipper roiv), gastropod moUusks (^center row) and arthropods Qower row), the ocelli in longitudinal
section in all instances. No phylogenetic interpretation seems indicated. [Limulus after Demoll,
Scolopendra after Heymons, Dyliscus after Giinther, others after Hesse; from Milne & Milne (193).]
ing, and extended over the soft ventral surface of the
foot. Moreover, as the animal aged, its response to
light changed from negative to positive.
Among the pelecypods, Nagel (201) distinguished
a category of 'ikonoptic' organisms in which the
structure of the ocelli seemed suitable for producing
a poor image in the receptor cells. Potamides has a
single layer in the retina, Pecten (fig. 7, left) a double
layer; in both instances the ends of the receptor cells
are turned away from the lens so that the retina is
inverted (159, 209). Wenrich (291) investigated what
he believed to be image-formation in Pecten in terms
of the smallest white card intensely illuminated,
movement of which would produce a shell-closing
response in the scallop. A more probable explanation
for his observed fact is that, at the light intensity
used, the appearance or disappearance of the card in
the visual field furnished the minimum effective change
in brightness. Hartline (88) found by electrical means
that the distal (smaller) layer of retina mediates a
strong off-response, whereas the proximal layer dis-
charges nerve impulses whenever illuminated.
A remarkably gradual series can be arranged show-
ing sectional views of gastropod eyes (fig. 5, second
line), but the significance of the differences noted in
terms of photic responses by the intact animal may
be questioned (121, 216, 295). The sign of the re-
sponse appears to be altered by many other factors,
such as diet, wetness or dryness of the body surface
(196), and whether the animal is inverted or upright
(74). The role of general photosensitivity in these
reactions has not been segregated from the supposed
dependence upon vision through the ocelli.
On the basis of embryonic origins and neurologic
connections, Hanstrom (82) classified ocelli in arthro-
pods into three categories: a) the nauplian eyes of
crustaceans, the ocelli of insects, the median eyes of
trilobites, the ocelli of xiphosurans and the eyes of
PHOTOSENSITIVITY IN INVERTEBRATES
631
pycnogonids — all arising from a dorsal ectodermal
mass in the embryo; 6) the lateral ("secondary")
ocelli of modern arachnoids and all eyes of diplopods
and chilopods, arising through degeneration from
the ommatidia of compound eyes produced by the
lateral ectodermal mass of the embryo; and f) the
ventral ocelli of trilobites and xiphosurans and the
median ("primary") eyes of eurypterids and arachnids,
arising from a ventral ectodermal mass in the embryo.
No clear correlation can be noted between these
categories and the detailed anatomical features of
the ocelli in postembryonic life — features described
and illustrated with great care by Grenacher (81).
In many planktonic crustaceans the median ocellus
is the only eye present. Fundamentally it appears to
be a double structure, but fusion may be remarkably
complete. Many crustaceans which metamorphose
lose their ocelli as they grow. An extreme example is
found among barnacles (6g): newly hatched nauplii
have a bilobed median ocellus; a pair of compound
eyes appears at the metanauplian stage, only to be
extruded or to degenerate at metamorphosis; until
this time the median ocellus remains unchanged, but
then it separates into two, each half migrating into a
lateral position and continuing as the sole photo-
sensory specialization of the adult.
The ventral position of the median ocellus in
Branchipus, Artemia and other branchiopods, many
copepods, some trilobites and larval xiphosurans sug-
gests that inverted swimming may be an ancestral
habit. Inverted swimming is characteristic of Limulus,
Branchipus and Artemia, and probably was also of
trilobites. A median ocellus must be of help while
dorsal compound eyes are directed toward the bot-
tom rather than the sky. Persistent nauplian ocelli
are known in some decapod malacostracans. In
Artemia the ocelli can serve alone in mediating essen-
tially all normal adult responses to light stimulation
(171); exceptions, which depend upon function of
the compound eyes, are the visual following of females
by males and a convulsive reflex when a dark-adapted
animal is suddenly illuminated.
Waterman (281) has provided a convenient table
showing the groups of arthropods in which a median
ocellus is known. At the same time he presented
evidence from electrical recordings indicating that
messages pass along the optic nerve fibers from
Limulus ocelli comparable to those from the com-
pound eyes. Their use by the animars central nervous
system remains a mystery.
Eight ocelli or less are characteristic of spiders
(208); the arrangement and actual number varies
from one genus to another. One pair, the 'primary
eyes," are simpler in having a direct retina and no
tapetum, although the entire retina may be moved
within the body through the contraction of paired
muscles — perhaps in following the progress of prey
or potential mate. The 'secondary eyes" usually have
an inverted retina and often a tapetum; no move-
ments of the retina are possible. Nervous connections
to the two types of ocelli are consistent with this
difference in structure and with Hanstr6m"s generali-
zations (82). The role of vision is difhcult to demon-
strate (128-130, 217, 294) in spiders, except in jump-
ing spiders (127). These have been recommended as
ideal laboratory material because they seem so un-
aware of confinement.
Among centipedes and millipedes which have
ocelli, no responses to light ha\e been described
which could not be accounted for adequately on the
basis of a general photosensitivity in the body surface.
Two, or at most three, ocelli are present in many
insects (136, 137), but their role in normal living
habits has been a puzzle (23, 52, 53, 108, 118, 126,
224). When only the ocelli are exposed, insects usu-
ally behave as though completely blinded. Some show
responses which cannot be accounted lor on the basis
of general photosensitivity (25). Demoll & Scheuring
(52) found considerable correspondence between the
visual fields of the compound eyes and of the ocelli.
This discovery, together with the observation that
many insects with their ocelli covered respond more
slowly to events in the visual field of their compound
eyes, led to the notion that ocelli serve to measure
general intensity of illumination and to control the
level of tonic contraction in locomotor muscles.
Variation in proportion of parts and arrangement
of retinal cells seems to have little effect in determin-
ing the role of insect ocelli (167-170, 303, 304).
Some ocelli show a strong retinal astigmatism (fig. 5,
lower right'), those in some dragonflies (order Odonata)
being particularly pronounced (252). In the orthop-
teran Acridium the ocelli are dimorphic in that those
of the female alone show a double curvature on the
proximal surface of the corneal lens — like a bifocal
spectacle lens — producing two images at different
distances (253). No explanation is available.
Ocelli in which the components of three-part
lenses lie side by side, like the top of a clover-leaf
roll, are found in the larvae of many urochordates.
Mast (181) reported photosensory responses of this
type of larva until the time of metamorphosis when
the ocelli degenerate. Whether the remarkable lenses
indicate fusion from an originally triplicate ocellar
632
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY
cluster is not clear from embryological studies (78).
A comparable suggestion of multiple origin for the
one to three ocelli in pelagic salps has received no
support.
COMPOUND OCELLI OR AGGREGATE EYES. The grouping
of separate ocelli, each with its own retina and pig-
ment cup, into a pattern with roughly radial diver-
gence of the optic axes seems to have arisen inde-
pendently in many phyla through convergent
evolution. In coelenterates a number of scyphozoans
(cubomedusae) exhibit this arrangement (132). It is
characteristic of chaetognaths in which three ocelli
are clustered in each of two groups (120, 124).
Among arthropods, compound ocelli resemble a
compound eye in many millipedes and in males of the
insect order Strepsiptera (227, 246). The millipede
Narceus is hatched with only a single ocellus but adds
others in a triangular area on each side of the head
until a total of between 40 and 50 are present a few
instars before sexual maturity (32).
Many starfish (asteroid echinoderms) bear a cluster
of ocelli at the tip of their arms. Muscular movements
of the arm tissues can alter somewhat the relative
orientation of the separate ocelli (296), Ijut the form
of each photosensory unit appears fixed. A large
central dioptric body must serve to concentrate radia-
tions upon the receptor cells (242, 258), and photo-
sensory functions seems indicated by the slow action
potentials which develop upon illumination of the
ocellar area (90). Some movements related to the
direction of lateral illumination and of shadows have
been described, but at least some of these may be
due to a general photosensitivity in the dermis. The
presence of carotenoid pigments in the compound
ocellar tissues (192) could relate to a photosensitive
substance. Alternatively these pigments may serve as
filters which affect the spectral sensitivity of the
organism.
STEMMATA. In the larvae of many members of the
holometabolous insect orders, Neuroptera (j. lat^,
Coleoptera, Lepidoptera, Trichoptera, Diptera and
Hymenoptera, photosensory structures resembling
isolated ommatidia are present. They disappear at
metamorphosis and have no relationship to the
compound eyes of the adult stage. Their distinctness
from an ontogenetic standpoint led Landois (160) to
consider them as an independent type of eye; he
called them 'composite eyes,' but the term stemmata
has been approved more widely.
Anatomical details have been described for those
of a larval water beetle Acilius (236), a lepidopteran
caterpillar Isia (54, 55), a mosquito wriggler Cukx
(35) and several sawfly larvae (Hymenoptera) in a
comparative study by Cornell (36). For the cater-
pillar, Dethier considered the diopteric system and
found that a stemma with a one-part lens had an
effective aperture between f 0.5 and f/i.o, whereas
those with a three-part lens were slightly less spec-
tacular collectors of li»ht with effective apertures be-
tween i.o and 1.5. In all instances the caterpillar
stemma had seven receptor cells arranged at two
levels, a distal clump of three and a proximal group
of four. No matter whether the corneal lens was
simple or tripartite, only a single crystalline body was
below it, close to the distal group of receptor cells.
The stemmata were fi.xed in the firm head capsule
at such angles to each other that their fields did not
overlap. Dethier concluded that a coarse type of
mosaic vision was possible.
Many caterpillars show clear responses to distant
trees. Those of the nun moth Lymantria under ex-
perimental conditions will react to and approach
pillars and vertical stripes of paint (131), whereas
horizontal patterns seem to be ignored. Hundert-
mark, who explored this problem thoroughly, con-
cluded that dark vertical patterns stimulated the
larvae while their heads were being swung from side
to side — a characteristic gesture of these caterpillars.
Stimulation would then correspond to patterns cross-
ing the visual field of stemma after stemma, and the
astigmatism noted would have a basis in behavior
rather than in structure.
COMPOUND EYES. True compound eyes are restricted
to arthropods (fig. 6, lower right) and are represented
among crustaceans, trilobites, xiphosurans, euryp-
terids, inany fossil chilopods and diplopods, the
centipede Scutigera and close allies, and most insects.
Holometabolous insects possess them only as adults.
In all situations they present a much more eflfective
organization than compoimd eyespots or compound
ocelli Ijut show the same quasi-radial dixeraience of
visual units.
According to Hanstrom (82), all true compound
eyes arise from a lateral ectodermal mass in the
embryo. In following these embryonic steps toward
the final battery of ommatidia, Watase (278) recog-
nized no major variants in development. One rather
fundamental difference has been overlooked in these
and subsequent studies: in Limulus (and presumably
all xiphosurans, perhaps eurypterids as well), the
entire dioptric mechanism is molted. Other arthro-
PHOTOSENSITIVITY IN INVERTEBRATES 633
PELECYPOD (ARCA)
ANNELID (BRA NCHIOMMA )
PIGMENT CELL-
SENSORY CELL-
MANTLE
EPITHELIUM
OPTIC NERVE
CRUSTACEAN ( ASTACUS)
GANGLIA
CUTICLE
OPTIC NERVE
FIBER
SENSORY
/CELL
OPTIC NERVE
FIBER
FIG. 6. Quasiradial divergence of photosensory units is characteristic of both compound eyespots
and compound eyes. The former are exemplified by the pelecypod moUusk Area (upper right^ and
the polychaete annelid Branchiomma QeJC), shown in lengthwise and transverse section and in detail.
Each ommatidium of the compound eye Qower right, detaiO consists of a cuticular lens, additional
dioptric components on the ommatidial axis, a cluster of receptor cells whose nerve fibers penetrate
the basal membrane and an investing sheath of pigment cells. .At the extreme right are sections cut
through such an ommatidium at lesels as indicated. Commonly the optic nerve fibers pass to a
series of ganglia close to the eye Qower right, longitudinal section of crustacean eye and stalk). [Braji-
chiornn after Hesse, Area after Kijpfer, Astaciis after Giesbrecht; from Milne & Milne (193).]
pods which molt after acquiring compound eyes re-
tain most of the dioptric mechanism, shedding only
the corneal lens or a part of it.
There is reason to question that the con\entional
classification of arthropod ominatidia has a sound
phylogenetic basis. The term 'exoconc' is applied to
those of crustaceans, trilobites, and beetles of the
families Dermestidae, Elateridae and Lampyridae, in
which the dioptric parts consist of a molted corneal
lens and a nonmolted inward extension of corneal
secretion. Elsewhere special cone cells ('Semper's
cells') lie between the corneal lens and the receptor
cells, and provide dioptric function. In 'acone' om-
matidia the cone cells become transparent and refract
light; they occupy all of the space and are character-
istic of the insect orders Dermaptera, Heteroptera,
some Odonata, some Coleoptera and .some nemato-
cerous Diptera. In 'eucone' ommatidia the cone cells
secrete a solid 'crystalline cone' within themselves,
usually in such a wa\' that the cone-cell nuclei remain
distal to the cone; .sometimes an anuclear portion of
the cone cells lies proximal of the cone; this type is
characteristic of the insect orders Thysanura, CoUem-
bola, Orthoptera, Homoptera, Neuroptera, Trichop-
tera, Lepidoptera, Hymenoptera, some members of
Odonata, inost of the Coleoptera and some neinato-
cerous Diptera. The brachycerous Diptera are unique
in ha\ing 'pseudocone' ommatidia in which the cone
634
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
cells remain small and transparent but secrete distal
to themselves a fluid or paste extending to the corneal
lens and supposedly aiding in the refraction of light.
At the proximal end of the dioptric mechanism
within the ommatidium is a ring of receptor cells,
or two rings, one distal to the other. Two rings may
be more primiti\'e than one ring. In Limulus and some
others, an eccentric receptor cell lies outside the ring
but extends a terminal segment toward the dioptric
system in a position central to the ring of other recep-
tor cells. More commonly there is no eccentric cell,
and the ring of receptors secretes a translucent rod
in the core position as a rhabdom which conducts
light energy along the optical axis to the more proxi-
mal parts of the receptor cells.
In rendering these dioptric structures visiljle in
sections through a compound eye, it is customary to
bleach the pigment from the cells which sheath each
ommatidium. Exner (68) appears to have forgotten
the existence of this pigment mantle while tracing the
path of light rays, van der Horst (256) drew attention
to the pronounced diaphragmatic effect of the mantle
in many compound eyes, limiting the passage of light
to so small an aperture that no image could be pro-
duced at the receptor level. Under these circum-
stances an indi\'idual ommatidium could do no better
than serve as a photometer. Compound eyes which
are used in daylight operate in this way, with each
ommatidium isolated from its neighbors, and any
picture of the outside world a synthesized one in the
central nervous system, built on the mosaic of photo-
metric information coming from the indi\idual om-
matidia.
Notthaft (202) took the extreme view that each
ommatidium operated on an all-or-none principle.
Either a target was included in its visual field enough
to stimulate the receptor system, or not. Almost
certainly this view is too severe. In Limulus, where the
compound eye may be somewhat degenerate, the
optic nerve fibers lack lateral connections and gan-
glion cells for a distance from the eye sufficient that
electrodes can be applied and the response of indi-
vidual ommatidia studied (75, 89, 90, 286). In
juveniles, two or more nerve fibers per ommatidium
may carry nerve impulses when the eye is illuminated,
but in adults only one is conducting, seemingly the
one arising from the eccentric cell. A wide range of
sensitivity and of response is evident. But the function
of the 9 to 1 9 other receptor cells in each ommatidium
remains unknown. Both at threshold and under in-
tense illumination, the ommatidium discharges im-
pulses as a unit.
The directional sensitivity of single ommatidia in
the compound eye of Limulus has been evaluated using
the same electrical technique (282). Sensitivity is
highest on the optic axis and falls off to a tenth or less
for light sources 10 to 20 degrees on any side. The
effectiv-e aperture of the ommatidium from a physio-
logical point of view is thus to 40 degrees for high
sensitivity and to 180 degrees for response to stimuli
as much as four log units above threshold intensity.
Yet the maximum angular separation of Limulus
ommatidia is about 15 degrees, the minimum 4 to 5
degrees. Hence the overlap of visual fields of neigh-
boring units must be extensive and the acuity which
might be predicted (as Notthaft did) on the basis of
number of ommatidia is probably not realized. Since
the dioptric mechanism of the Limulus ommatidium
is somewhat different from that of most other arthro-
pods, however, these findings may not apply widely.
Acuity may be far better elsewhere in the phylum.
The compound eye seems particularly efficient in
detecting movements in its total visual field. This
can be demonstrated under field conditions (34) or as
a sensitivity to flickered light in the laboratory (298-
301). When plotted on a probability grid, flicker-
fusion curves are like visual-acuity curves in being
essentially straight lines (298, 299). This may be due
to a normal statistical distribution of sensitivities
among the ommatidia; or it may arise through the
recruitment of progressively more ommatidia in a
convex eye as the intensity of stimulus rises. Crozier
& W'olf (42) believed that the latter was the limiting
factor in the crayfish Camharus.
The intensity difference required for flicker detec-
tion by arthropods is greater than that for the human
eye. At optimum intensity the honeybee requires one
stimulus to be 25 per cent greater or less than the
other (298, 299). For the fly Drosophila the difference
must be of the order of 225 per cent (98, 99). For
man 1.5 per cent is adequate in good illumination.
Hence the visual field of the arthropod eye contains
a gray scale with far fewer than the 500 steplike
increments between black and white detectable by
the human eye.
Evaluation of stimuli effective with a compound
eye is more satisfactory if it can be made from elec-
troretinograms rather than kinetic responses of the
entire animal. Electrical records of this kind are pos-
sible either with a surviving eye (56) or an intact
animal (87). Antrum & Stocker (7) learned with this
technique that insects show two \ery different ranges
in flicker detection. The fly Calliphora, the wasp Vespa
and the honeybee Apis responded to rates as high as
PHOTOSENSITIVITY IN INVERTEBRATES
635
200 per sec, better than five times the performance
of the human eye. In the cockroach Periplaneta and
the grasshopper Tachycines, by contrast, any flickering
rate higher than 5 or 10 per sec. was e\idently fused
and interpretated as a constant stimulus. The authors
postulated that in the orthopterans an after-image
was present, a phenomenon lacking in the dipterans
and hymenopterans.
For the fly Calliphora the electroretinograms show
that the effective angle of view of each ommatidium
is about twice as great in the horizontal plane as in
the vertical (6). Hence a target remains for a longer
time within the visual field if it is moving horizontally;
summation can permit its detection at a lower thresh-
old than would be found in the same target moving
vertically. The structural basis for astigmatism of this
kind can be found in the dimensions and divergence
of ommatidia. Ommatidia facing downward com-
monly are relatively shorter and have larger lenses
than those facing upward; usually they diverge from
one another more strongly. Antrum (6) generalized
that in all insects which fly well the angle of view of
each ommatidium in the horizontal direction is
about twice that in the vertical.
In Apis the situation is somewhat more complex
(i i). The radius of curvature of the bee eye is smaller
in the transverse plane than in the frontal, with a
ratio near 2.5 to i. The angle between ommatidia is
regularly greater in the transverse than in the frontal
plane, with a ratio of difference reaching about 2 to i .
In consequence maximum acuity lies in a plane in-
clined 65 degrees to the sagittal, and in this plane
only in an arc from 47 degrees behind the anterior
margin of the eye to 49 degrees ahead of the pos-
terior margin.
The extremes of difference in dimensions and
angular separation among ommatidia in a single
compound eye are met in some deep-sea crustaceans
and in insects belonging to the orders Homoptera
(287), Ephemeroptera and Diptera (57, 58). In most
of these the region with short ommatidia and large
lenses is confined to one part of the eye, and the por-
tion with long ommatidia, slight divergences and
fine lenses forms a sort of 'turban' toward the top of
the head. In many instances the owner of such a
'divided' eye is a predator. However, Radl (221)
concluded that it indicated a duality of embryonic
origin and proposed a "duplicity theory.' Zavfel
(308) extended this into a triplicity theory, but later
workers have not supported either hypothesis.
de Serres (53) appears to have been the earliest to
experiment with arthropod vision by painting over
all or part of a compound eye with black varnish. He
found many of the postural changes which became
classic demonstrations of the 'muscle tonus' theory in
rather recent texts of physiology. Light intensity,
interpreted through the compound eyes, w-as be-
lieved to control the tonus of muscles involved in
posture and locomotion. 'Circus' movements of uni-
laterally blinded arthropods were explained on this
basis.
At the same time de Serres pointed out the 'false
pupil' seen as a shifting dot or line in many living
compound eyes. Ewing (66) described it more fully
and concluded correctly that it represents ommatidial
pigment visible in those few ommatidia facing an
observer's eye. In cylindrical compound eyes, such as
the stalked ones of the crab Ocypoda, it takes the form
of a vertical line which follows the observer or camera
lens through as much as a 360-degree field of view.
Duges (60) noted that a false pupil can be seen
simultaneously in the two compound eyes of many
insects and suggested that they must have binocular
vision. Demoll (47), working from sections of com-
pound eyes, showed the extent of these binocular
fields. It is easy to assume that binocular vision is
important to predaceous arthropods and that they
snatch for prey when the proper ommatidia in the
two eyes are stimulated simultaneously by an object
placed symmetrically in the binocular field. Distance
estimation is evidently good in both naiad and adult
stages of most members of the insect order Odonata
(i, 8, 50), among the dipteran family Asilidae (185)
and in tiger beetles.
The adaptaiaility of the neural components in the
eye-brain team appears to have been underestimated.
In a matter of hours or days, the postural peculiarities
and circus movements of unilaterally blinded arthro-
pods often disappear entirely. Partially blinded odona-
tan naiads can adapt their behavior to approach
prey monocularly, pivot and seize at the appropriate
instant (i, 8). Whether marginal ommatidia can
participate in this versatility has been questioned (9).
It would be interesting to know whether variations in
adaptability correspond to the zones found in the
Notonecta eye (172), since in this heteropteran insect
kinetic responses seem related to specific areas of the
compound eye. Certainly ommatidia can serve in un-
usual reflexes (2191 220) but limitations may still be
present.
Many, perhaps most, arthropod eyes show a sensi-
tivity to the plane of polarization of light from the
sky. Something of the kind has been suspected for
many years to account for the homing ability of vari-
636
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
ous hynienopteran insects. Wolsky C302) sought in
vain to find an analyzer function in tiie corneal lenses
of the coarse compound eyes of land isopod crusta-
ceans, von Frisch credited the actual demonstration
of polarization sensitivity to Autruni, although von
Frisch's own reports (271, 272) antedate any of
Autrum's published comments on the subject, von
Frisch has found in the honeybee's '.sky compass' a
basis for the ability of one bee to communicate to
another by dancing within the dark hi\e the direction
to a discovered supply of food (273).
Since von Frisch used an octagon of Polaroid film
cut into svmmetrically fitted equilateral triangles, it
was natural that he should parallel this with the ring
of receptor cells in each insect ommatidium. When
the octagon was held toward the blue .sky, some one
diagonal was darkest, another lighest. The former
corresponded to Polaroid triangles the axes of which
were transverse to the plane of polarization in the
sky area seen through the plastic. Possibly an image
of comparable type was cast upon the ring of receptor
cells and information of this kind interpreted ijy a
single ommatidium.
In the dipteran VohueUa, a ring of eight receptor
cells and birefringence with extinction of one ray
were reported (186), but the reality of the phe-
nomenon described is open to question. Certainly
each ommatidium may vary in its response to light
as the plane of polarization of incident radiation is
rotated around its optic axis, as may occur in Limulus
(279, 280, 282, 283) or in Drosoplula (244). But struc-
tural asymmetries of dioptric components in indi-
vidual ommatidia and the oL)liquit\ with which
many ommatidia in each eye meet the outer surface
seem more responsible for the sensitivity found to the
plane of polarization. The extent to which polarized
light is available as a cue useful in arthropod naviga-
tion both in air and in water has been described by
Waterman (280, 285). It has been shown experimen-
tally (12) to be significant in the free beha\ior of
fresh-water planktonic crustaceans.
In the earliest comprehensive account of the arthro-
pod compound eye, Grenacher (81) recognized a
difference in the distribution of pigment cells accord-
ing to whether the organism was a day-active type
or a crepuscular and night-active organism. In most
of the latter, the pigment is not extended as a sheath
isolating each ommatidium from the next but is
clumped in such a way that light could pass obliquely
from ommatidium to ommatidium. Exner (67, 68)
traced the ray paths, and showed by diagrams how
light entering many ommatidial lenses could be re-
fracted and fall on the receptors of a central visual
unit. Grenacher's terms apposition' type for the eye
with isolated ommatidia and 'superposition' type for
the eyes used in dim illumination have been retained.
The same ommatidium may function alone by day
and in concert by night through migratory move-
ments of its pigment (145, 248). In crustaceans these
changes in the eye are often matched by alterations
in body color, the entire chromatophore system being
imdcr the control of hormones whose secretion is in-
fluenced by stimulation of the eyes by light (207).
The literature on this subject has become extensive
l)ut most of it centers on hormonal aspects. In insects
the corresponding shifts in ommatidial pigment may
be independent of hormones (44, 49).
Normal structure of compound eyes has required
extensive study because of the large numJDer of varia-
tions within the wealth of genera in the phylum
Arthropoda. Where possible, many writers on the
subject have attempted to correlate form with func-
tion (30, 31, 48, 51, 61, 62, 119, 250, 268, 269).
Numerous crustaceans bear their eyes on movable
eyestalks and show compensatory movements of these
when the animal or its visual field is rotated. Branchio-
pods show all gradations between a distinct pair of
compound eyes and indistinguishable fusion into a
single mass. The fused median compound eye of
Daphnia consists of al)Out 20 ommatidia and is some-
what unusual in that it can be rotated several degrees
within the body through the action of a series of
oculomotor muscles.
Ostracod compound eyes are commonly separate
if a median ocellus is present but fused if the ocellus
is lacking. Some lack compoimd eyes entirely. The
luminescent Cypndina, howe\er, has full)- developed
eyes.
Copepod compound eyes range from the median
fused structure of Cyclops and Calamis through genera
in which the two are completely separate. Branchiuran
compound eyes must be regarded as degenerate.
Argulus has four eye types present in each individual.
Barnacles ha\e compound eyes onl\ during the meta-
nauplian stage (69). .'\mong chilopods only Scuttgera
and related genera possess compound eyes (84). Here
each eye consists of not more than 200 ommatidia,
each with two rings of receptor cells as in the thysanu-
ran insect Lepisina.
Growth of compound eyes is inferred among trilo-
bites because of the gradual increase in number ot
ommatidia found to accompany increase in body
size within each species (226). In Limulus and other
xiphosurans, ijoth the number of ommatidia and the
PHOTOSENSITIVITY IN INVERTEBRATES
637
size of each increase at each moh (284), rapidly in
early ages and more slowly later on. The same is
true in crustaceans studied (14, 16, 149) and most
insects (16, 173). The stick insect Dixippiis is unusual
in adding no new ommatidia, although the total in-
crease in dimensions of each is 126 per cent and the
eye area doubles from hatching to maturity.
Development of the compound eye appears to de-
pend upon normality of the supraesophageal gan-
glion. Damage to this ganglion usually leads to failure
of the eye to differentiate. In Drosophila, however, the
various genetic mutants with degenerate eyes arise
through factors acting on the eye itself and not in-
directly through the nervous system (225). Degenera-
tion of compound eyes in cavernicolous arthropods
and deep-sea crustaceans is common and apparently
follows a similar genetic course influencing the eye
itself (83). Beddard (13) believed a relationship could
be seen between depth and degree of degeneration of
the compound eye, but so many instances of hyper-
trophy of these organs in deep-sea crustaceans have
been described that the generalization is unsafe.
Regeneration following injury to the compound
eyes seems possible in decapod crustaceans, although
the regenerated part is not an eye but an antennalike
organ. Trilobites alone are known to have regenerated
ommatidia (138), this being recognized in terms of
independence in the direction of the facet pattern in
areas set off by scar tissue.
CAMERA-STYLE EYES IN MOLLUSKS. The remarkable
convergence in anatomical organization between the
large eyes of some cephalopod moUusks and those of
vertebrate animals have led to frequent comment.
Hensen (102) investigated the embryonic steps lead-
ing to the cephalopod types of eye. In all the organ
arises as an invaginated vesicle. That of Nautilus is
unique in proceeding no farther and hence remaining
as a pinhole-camera eye (fig. 7, righl^.
In all other cephalopods the vesicle closes and
sinks below the body surface. The douijle layer of
tissue where the pinhole closed produces a pair of
planoconvex lenses in contact with one another, as
the sole structure focusing an image in these marine
organisms. Distal to the lens an encircling ridge arises
forming the muscular iris diaphragm (fig. 7, center^.
The whole eye sinks further below the surface at the
bottom of a fresh invagination the rim of which
closes over either partialh' or completely in forming
a transparent cornea. A number of genera retain an
open pore between the anterior chamber and the
outside world, and sea water washes the front of the
lens. In some genera an additional encircling ridge
forms around the eye, producing an approach to eye-
lids.
Deep-sea cephalopods often have eyes which are
amazingly hypertrophied, sometimes supported on
swi\eling turrets (33). In these a binocular field seems
probable, whereas in most surface and mid-water
cephalopods the visual fields are completely .separate.
The apparent absence of blind cephalopods must be
related to the number of kinds which bear lumines-
cent organs in the depths.
Most cephalopods have a slit pupil which closes
into a slightly hooked horizontal line. It is under
direct control from the central nervous system and
changes the degree of opening more in relation to
emotional conditions than it does refle.xly in relation
to light intensity (259). Muscles provide for accom-
modation of the lens (151, 164) and demonstrate their
action when the outer surface of the eye is stimulated
electrically (2, 101). In Octopus, at least, the resting
eye is myopic by 6 to 10 diopters, and accommoda-
tion is both positive for objects at clo.se range and
negative for distance (274).
Unlike the vertebrate eye, the cephalopod organ
has a direct retina. Its optic nerve fibers may emerge
from the eyeball as multiple bundles which fuse into
a common optic nerve. Around them are the four
oculomotor muscles which shift the eye in a wide
range of movements, including rotational ones (121,
25O.
Electroretinograms from cephalopod eyes (211,
212) has'e been as helpful as beha\ior in indicating
the role of vision in these animals. In all cephalopods
the nervous system is .so highly organized, with \ isual
cues related elaborately to tactile ones and perhaps
taste as well, that simple responses are rarely elicited.
Captise animals are seemingly aff"ected strongly by
their confinement, but will develop conditioned re-
sponses under skilful handling.
Camera-style eyes of quite different form are found
in some other mollusks. a) In the sand-eating pul-
monate gastropods Onchidium, Oncis and Peronina, the
dorsal surface of the body bears short wartlike projec-
tions each with a single eye or with from two to ses'cn
of them in an irregular cluster. Each eye is about 0.2
mm in diameter and has a two-part refractive body be-
tween the rather flattened cornea and the inverted
retina. The more distal refractive body alters in shape
when a muscular collar surrounding it contracts.
Presumably this is an accommodation mechanism.
Natural history observations on a Bermudan On-
chidium posses.sing eyes of this type suggest nothing
638
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
PECTEN
LOLIGO
NA U TIL US
FIG. 7. Mollusk eyes present a variety of optical systems. In the scallop Pectai Qejt), a cellular
lens concentrates light on two levels of inverted retina. The distal layer mediates only the oflT-responsc
leading to sudden closure of the shell valves. The proximal layer responds to steady illumination.
A reflecting tapetum (shown as opaque blocks basal to the pro.ximal retina) increases sensitivity and
contrast discrimination at low intensities of light. In the cephalopod NaulUus (rig/iQ, the eye becomes
functional and matures as a pinhole-camera organ at an embryonic stage passed through in the
development of all other cephalopod eyes. In the squid Loligo (center'), extrinsic muscles orient the
whole eye; intrinsic muscles provide both positive and negative accommodation and adjust the
aperture of the slit pupil. [Peclen after Kupfer, Loligo and Nautilus after Hensen; firom Milne &
Milne (193).]
which might not be due to general photosensitivity
(5)-
A) Clams of the genus Cardium bear small eyes on
short tentacles around the rim of the mantle. Each
eye has a cellular lens mass in which the refractive
index changes from distal to pro.ximal and may pro-
vide an image on the rather coarse inverted retina.
A cup-shaped extension of pigment cells surrounds
the lens material and narrows to a distal pupil. The
whole eye is invested in a muscular coat, the contrac-
tion of which alters the shape of the lens mass and
may serve in accommodation. Nothing is known of
the function of these eyes.
c) In the pelagic heteropods (gastropods) Ptero-
trachea, Carinaria and Atalania, one small eye is borne
projecting from the body contours on each side, like
the port and starboard running lights on a ship.
These highly modified eyes are directed forward and
must have a binocular field in front of the animal,
although no evidence has been presented to show
that the animal makes use of them in sighting on
objects of importance to it. Each eye has a large
spherical lens at considerable distance from a 'ladder
retina' with little ridges of receptor cells (fig. 8,
centei) and a muscle who.se contractions shift the lens
(109), perhaps as a fine adjustment for focus.
c.\MER.'^ -STYLE EYES IN ."ANNELIDS. Fairly conventional
camera-style eyes arc found in the pelagic polychaetes
Alciopa and Eupolvodonles. In the former (fig. 8, left)
the two eyes at rest diverge widely, but contraction
of three extrinsic muscles to each of them pro\ides a
basis for convergence, binocular vision and perhaps
distance estimation (45). In Eupolyodotites the eyes
face forward at rest (210). In all members of the
family Alciopidae, the eye structure is comparable
(79, 80). The large retina has direct receptors, a
secreted mass of two consistencies separating the
retina from the lens, an accommodation muscle (45),
and a secretory cell (107) which responds well to
electrical stimulation. Secretory action increases the
volume of the distal mass behind the lens and pushes
the lens forward, accommodating the eye for nearer
vision. Muscular contraction should operate in the
reverse sense. Unfortunately, no natural history de-
tails are available to indicate how and when these
worms use their remarkable eves.
PHOTOSENSITIVITY IN INVERTEBRATES
639
GASTROPOD
(PTEROTRACHEA i
CRUSTACEAN
(COPILIA )
VENTRAL VIEW
SECRETION ACCOMMODATION
MUSCLE
-OPTIC NERVE
FIG. 8. Camera-Style eyes are found in several phyla of invertebrate animals, but the mechanism
of accommodation varies considerably. In the polychaete annelid Atciopa it includes both a hy-
draulic system from a secretory gland, shifting the lens distally, and a muscle operating in the re-
verse direction (Jeft). In the gastropod mollusk Plerolrachea, a muscle pro\ides the basis for fine
focusing on a series of receptor clusters known collectively as a ladder retina' (center). In the copepod
crustacean Copilia, a small group of receptor cells at the focal point of the biconvex lens is shifted
both toward the lens and swung laterally by muscular contraction. In both the mollusk and the
crustacean the eyes apparently are useful only as sights but, like the annelid eyes with their extrinsic
musculature, may have a binocular field in advance of the body. [Alciopa after DcmoU; Plerolrachea
after Hesse; Copilia dorsal view after Giesbrecht, detail after Grenacher; from Milne & Milne (193).]
CAMERA-STYLE EYES IN ARTHROPODS. Still Icss Can bc
guessed as to the function of strangely simplified
camera-style eyes in the planktonic copepod crusta-
ceans known as corycacids. Copilia carries two of
them facing forward, widely separated in the body.
Sapphirina has a pair close together. In Corycaeus their
lenses are fused on the mid-line. Yet in all, the large
lens in the body surface (fig. 8, right) appears to focus
light on a little cluster of three or four receptor cells
surrounded by a pigment sheath. A long slender
muscle lengthwise at the side of the eye can shift the
receptor cluster with reference to the lens in a way
which may provide for both some accominodation
and soiTie sighting, perhaps in binocular vision.
Nothing is known of the habits which would suggest
a use for a visual mechanism of this kind.
PHENOMENA RELATED TO STIMULUS INTENSITY
Changes in the sensitivity and in the discriminatory
capacity of multicellular eyes are often based in part
upon other features in addition to photochemical
changes and such obvious adjustments as those of iris
diaphragms.
Pigment Migration within the Eye
A redistribution of pigment, either by active exten-
sion and contraction of pigment cells or by shifting of
pigment granules within the protoplasm of stationary
cells, follows changes in intensity of illumination on a
variety of eyes: in the ocelli of the gastropod Planorbis
(4, 241); in the stemmata of the lepidopteran cater-
640
HANDBOOK OF PHVSIOLOGV
NEUROPHYSIOLOGY I
pillar (235); in the ommatidia of crustaceans and
insects (15, 46, 248, 254, 289, 309); and in the retina
of cephalopod camera-style eyes (103, 106, 223). The
redistribution serves to reduce the proportion of in-
tense light reaching the receptor cells and to increase
the proportion of dim light passing to retinal level.
In most insects that are active by day the pigment
lies between the receptor cells when light intensity is
high, and migrates below the basement membrane
when the intensity is reduced. In mantid orthopterans
and sphingid lepidopterans the mechanism is more
like that in decapod crustaceans. During daylight the
pigment is spread parallel to the crystalline cones and
maintains isolation of one ommatidium from the ne.xt
in typical apposition-eye organization; at night the
pigment becomes concentrated distally, giving the eye
a far darker appearance and permitting it to function
on the superposition principle.
Either type of pigment movement may expose a
reflecting layer in the eye. This may be either a
'basement tapetum' which serves to increase sensi-
tivity and contrast at low light intensities by reflecting
nonabsorbed incident light back through the receptor
cells, or an 'iris tapetum' which reflects energy out of
the eye again before it has reached the receptor-cell
level. The latter is more developed among crustaceans
(291), although found in some insects as well. If a
basement tapetum is hidden by pigment movement
at higher intensities of light, it is an 'occlusible tape-
turn' analogous to that found in some fish. No regu-
larity is noticeable in either the chemical nature of
the reflecting pigment or its systematic position. In
Limulus the iris tapetum contains only guanine (146);
the closely-related .xiphosuran Tachypleus lacks a tape-
tum of any kind (284}; the crayfish Astacus has an iris
tapetum of uric acid (147); and the lobster Homarus
one in which uric acid is supplemented by at least
three additional substances, none of which is guanine
(146).
So far, tapeta have been recognized either from eye
histology or 'eyeshine' in only two phyla. Among
moUusks it is present in the pelecypods Pecten (233)
and Cardium (216). Among arthropods it is widespread
in crustacean and insect ommatidia, in the ocelli of
certain insects (216) and in the secondary ocelli of
many spiders.
Spectral Sfnsitivity and Color I 'isiun
Paralleling the spectral absorption characteristics
of the photosensitive pigment in a receptor system is
a spectral sensitivity shown through ner\e impulses or
responses in effector systems. With care an action
spectrum can be plotted showing the energy required
in a light stimulus at each wavelength in a series of
tests to find the threshold of response. This graph is a
spectral sensitivity curve; it regularly shows one or
more maxima. The only exception reported, Hydra'f.
response to light (91), appears to be a uniform reac-
tion at all wavelengths.
Even where two receptor systems are present in the
same eye, there is no a priori rea.son to expect them
to have different photosensitive pigments and hence
a single action curve. In many vertebrate eyes the rod
mechanism and the cone mechanism are known to
have different spectral sensitivities, evident as a
'Purkinje shift' in the wavelength of maximum sensi-
tivity and in the limits of the effective spectrum as the
intensity is altered — reduced until the cones are in-
active or raised until they dominate. A Purkinje
shift has been detected in only one invertebrate so far
(72), the fruit fly Drosopliita.
A dual mechanism in the eye and a Purkinje shift
does not indicate color vision; the dog has a Purkinje
shift yet is color blind. Color \ision depends upon dif-
ferential mechanisms in the brain to which nerve
impulses go separately from two or more unlike series
of receptors active in the same intensity range. Color
\ision enables an organism to distinguish between
radiant stimuli on the basis of inequalities of energy
content at diiTerent wavelengths rather than upon
intensity alone. A color-blind organism may distin-
guish between a series of grays but will confuse any
color with some one shade of gray since only intensity
discrimination is possible. The xiphosuran Limulus has
been shown to have the peripheral basis for color
vision (76) in that some ommatidia have greater
sensiti\ity toward longer wavelengths, .some toward
shorter \va\elengths; apparently this differential sen-
sitivity at the ommatidial le\el is not used by the
central nervous system since no discrimination be-
tween a spectral hue and a neutral .source seems pos-
sible except on an intensity basis.
Scarcely any two individuals, let alone any two
species, show the same range of spectral response. The
human eye is regarded as sensitive to wavelengths
from the extreme violet sensation at 400 m/i to the
extreme red at 700 niju. Many invertebrates are .sensi-
tive to wavelengths designated as ultraviolet (shorter
than 400 m/u), even when these are not a normal part
of their environment (as among aquatic organisms
which are protected from radiation of this type by the
spectral absorption characteristics of water). Many
insects, which are active in sunlight containing; ultra-
PHOTOSENSITIVITY IN INVERTEBRATES
641
violet, are more sensitive to this part of the solar
spectrum than to the region visible to man (17, 18,
1 74, 1 75). In consequence it becomes important for
man to learn more of what reflects ultraviolet, and
hence may be visible to insects though not to him
(26, 38, 175, 176).
Amebas travel as rapidly in the presence of radia-
tions of long wavelengths (red) as in darkness but are
increasingly sensitive as the wavelength of a stimulus
is shortened (86). Paramecium tends to swim upwards in
darkness, downward in light, and the direction is
altered most effectively by shorter wavelengths (73).
The platyhelminth Planaria has been studied ex-
tensively in responses to spectral distribution in light
stimuli. Erhardt (64) was able to account for earlier
claims (19, 115) that Planaria had color vision upon
intensity discrimination. Werner (292) concluded
that much of the flatworm's response to ultraviolet
arose through general photosensitivity and not the
eyes; but Merker & Gilbert (187) found only non-
directional kinetic responses when the eyes were
removed, compared to a definite orientation with a
single ocellus intact. They were able to plot the visual
fields of Planaria toward ultnn iolet and believed that
responses were to the wavelengths used (366 to 313
m/j) rather than any secondary fluorescence.
Two separate receptor systems were described for
the earthworm (255). One, mediating the shadow
reaction, was most sensitive in the yellow portion of
the spectrum and depended upon receptors distrib-
uted uniformly in the skin. The other, a more general
photosensitivity related to rate of locomotion and the
like, showed greatest sensitivity in the blue and was
most developed toward the two ends of the body. In
the leech Pisricola, pigment migration in surface chro-
matophores is an effector demonstration for which a
spectral action curve can be drawn (140).
Using the threshold for retraction of the siphon as
a kinetic cue to photosensitivity in the pelecypod Mya,
Hecht (95) obtained a spectral action curve with
limits somewhat short of those for the human eye.
Its maximum fell at 500 inn, suggesting that the
neuronal photoreceptors in the mantle tissue of the
clam have a photosensitive pigment similar to tho.se
extracted from organized eyes.
The fresh-water planktonic crustacean Daphnia ap-
pears to have at least three photosensory systems, one
with greatest sensitivity in the ultraviolet (257), one
in the yellow and the third in the blue. Only the
latter two can have much importance under natural
conditions (240). The response with maximum sensi-
tivity to yellow is a positive horizontal swimming
toward the radiant source. The response to blue is
negative. Baylor and Smith at the University of
Michigan have used the yellow and blue responses in
an underwater trap which catches a wide variety of
plankton organisms, crustaceans, acarid arachnids and
insect larvae. Possibly photosensory mechanisms of
this kind are involved in the \ertical migrations made
daily by many types of plankton, down during day-
light, up at night.
Although the arthropod cuticle transmits freely a
wide range of radiations from infrared to ultraviolet,
only certain fireflies (nocturnal Coleoptera) have been
found to respond to infrared stimuli (28). By painting
the eyes of various butterflies with a clear red lacquer,
Eltringham (63) was able to show that some kinds
flew about naturally — able to see in red light —
whereas others behaved as though blinded.
Sensitivity to ultraviolet is pronounced in most
insects, and shown by many lar\ae as well (139, 184).
Bertholf (17, 18) found a bimodal curve represented
the spectral sensitivity of the honeybee. The peak in
the ultraviolet was far higher than that in the spectrum
visible to man and explained why these insects re-
spond more to cues in ultraviolet components of sun-
light than to reflectances visible to man. Lutz (174-
176) examined the ultraviolet world of the insect and
was aljle to produce conditioned responses in tropical
hymcnopterans (175) to patterns in white paints when
one white reflected ultraviolet and another did not.
Conditioned responses in honeybees demonstrate
that these insects do have color vision (270, 273). They
can be trained to come for food to line spectra regard-
less of relative intensity (154-158). But a majority of
insects, particularly the night-active ones, probably
show no color vision, merely intensity discrimination
based on a simple spectral-.sensiti\ity curve (288).
This may be modified from one genetic strain to
another according to the eye pigments present and
changes in the eye structure itself (71).
A neural basis for color vision has been described
in insects (222, 230, 231); but whether even day-
active species, operating in good light, make use of
cues reaching them from differential mechanisms in
the ommatidia is a point which inust be established
separately for each kind.
Form Perceplinn and Pattern Recognition
If both the photosensory mechanism and the nerv-
ous system are sutticiently well organized and co-
ordinated, the animal can give evidence of an aware-
ness of surrounding events that is close to, if not
642
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
identical with, consciousness. Identification marks and
courtship gestures are significant in these terms. In-
sects which go habitually from one flower to another
of the same kind demonstrate this type of discrimina-
tion; efficient pollination often depends upon it.
To be useful in form perception and pattern recog-
nition, a photosensory mechanism must carry inten-
sity discrimination the further step of detecting simul-
taneously in small areas of the visible field the
differences in intensity which are significant. Several
types of acuities are involved, all of them properly
defined as the reciprocals of threshold intensities,
whether linear, areal or angular. How large must a
single object be to constitute an adequate stimulus?
How far apart must two objects be for the gap be-
tween them to be visible? Can an object, such as a
triangle, be significant in one orientation (say up-
right) but not another (say inverted}? Is alignment,
or motion or distance significant to the organism as it
views objects in the environment?
The camera-style eye and the compound eye appear
most competent to interpret the world in terms of
small differences in light intensity and to send mes-
sages to the central nervous system from which a
picture of the environment can be assembled. Even
for organisms with these eye types, pessimistic views
have often been expressed. Frequently they represent
inadequacy of experimental technique. "Absence of
evidence is no evidence of absence." Thus VVillem
(295) concluded terrestrial mollusks could detect the
presence of voluminous objects only when less than a
centimeter distant, but \on Buddenbrock (269) re-
ported compensatory movements of the eyestalks to a
rotating visual field much farther away. And various
workers (100, 258) have had difficulty satisfying
themselves that cephalopod mollusks respond to visual
cues in the absence of simultaneous tactile and gusta-
tory stimulation.
Plateau (217) obtained so few responses to the
stimuli he gave to captive spiders that he concluded
that they were essentially blind. Apparently some ob-
jects are recognized and others ignored, so that the
acuities possible are not always demonstrated (208).
No doubt Mallock (i 78) gave far too optimistic values
of resolution in spider ocelli since he used the out-
moded Rayleigh criterion in his calculations. Ho-
mann's estimates (127-129) correspond more closely
with observed reactions.
In.sect behavior seems to match reasonably well
with predictions based on measurement of eyes and
binocular fields (29, 47, 172, 173, 250, 307). Lack of
accommodation — an ability claimed for ommatidia
only once (265) — is of no significance in an apposition
eye since no image is formed (256), or in a superposi-
tion eye since image resolution has been sacrificed for
increa.sed sensitivity. The mosaic style of vision tends
to stress the importance of movement and find detail
only at very close range.
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CHAPTER XXVII
The image-forming mechanism of the eye
GLENN A. FRY | School of Optometry, The Ohio State University, Colimhus, Ohio
CHAPTER CONTENTS
Image Formation
GuUstrand's Schematic Eye and Its Refracting Mechanism
Formation of Image by Refracting Mechanism
Refracting Power of the Eye
Helmholtz Schematic Eye
Reduced Eye
Role of Pupil in Image Formation
Chief Rays
Blur Circles in Eye Free from Astigmatism
Astigmatism
Lines of Sight
Primary Line of Sight and Foveal Chief Ray
Pupillary Axis and Angle X
Size of Retinal Image
Refraction and Accommodation of the Eye
Refraction of the Eye
Accommodation
Static Refraction of the Eye
Correction for Ametropia
Specification of Amount of Accommodation in Play
Aphakia
Ocular Measurements
Indices of Media
Purkinje Images
Optic Axis of the Eye
Configuration of Front Surface of Cornea
Measurement of Internal Refracting Surfaces
X-ray Measurement of Axial Length of the Eye
X-ray Determination of Location of Second Nodal Point
Locating Conjugate Focus of Retina
Mechanism of Accommodation
Intraocular Mechanism of Accommodation
Ciliary Muscle Potential
Innervation Controlling Accommodation
Night and Sky Myopia
Visual Field
Retinal Illuminance
Light and Illuminance
Solid Angle
Luminance
Retinal Illuminance
Transmittance of the Eye
Stiles-Crawford Effect
Stray Light in the Eye
Blur of Retinal Image
Entoptic Phenomena
THE EYE PLAYS THE TRIPLE ROLE of gathering infor-
mation, coding it and relaying it to the brain. In
this chapter we are concerned only with the role which
the eye plays as an optical device in gathering in-
formation.
In trying to explain this role I have started with a
schematic e\e which is free from some of the defects
and complications of an actual eye. With this kind of
an eye one can explain how an image is formed and
what is meant by refracting power, refraction of the
eye, size of the retinal image, etc.
The eye is not like a telescope which can be taken
apart to find out how it works. Hence it is necessary
to develop approaches which are not needed with an
ordinary optical device. For example, the focal length
of an eye cannot be measured directly and we have to
substitute the concept of refraction to provide an
index of an eye's performance as an optical instru-
ment. An attempt will be made to explain how this
and other measurements are made on a living eye.
After explaining these basic concepts and methods of
measurement, consideration will be given to the
mechanism whereby the eye can change its focus.
The physiologist is by right inore concerned with
the response of the retina to light than the mechanics
of applying light to the retina, but there are some
special problems that arise in describing the stimulus
applied to the retina to which attention must be
given. In optics the word illuminance is used to de-
scribe the rate at which light is applied to the retina,
but the physiologist wants to call this stimulus inten-
647
648
HANDBOOK OF PHVSUJLOGV
NEUROPHVSIOLOGY I
sity. This is confusing because in optics the term
intensity is reserved to designate the candlepower of a
point source.
Furthermore, blur produces a pattern of illumi-
nance on the retina which is quite different from the
distribution of luminance in the visual field, and in
most cases it is the blur inherent in the image-
forming mechanism and not the structure of the
retina which limits the ability of the eye to resolve
fine detail.
Stray light in the eye also presents a proljlem. Al-
though the stray light is feeble in comparison with
the focused light which is applied to a small spot on
the retina, it still has to be reckoned with in relating
the light response of the pupil and the potential of
the electroretinogram to the pattern of stimulation
applied to the retina. We are dealing not only with
the small number of photoreceptors responding to
focused light but also with the millions of photo-
receptors responding to stray light.
This chapter also includes a section on entoptic
phenomena because they are used in various indirect
ways to help us understand how the eye gathers in-
formation.
The study of the image-forming mechanism of the
eyes has a long history because as soon as man began
to think about himself as something separate from
the external world, he assumed the reality of the
external world and began to wonder how he could
.see external objects. At first he supposed that images
were given off by objects and transmitted into the
eye. He reasoned that these images must be reduced
in size in order to get through the pupil. The discovery
of the small images reflected by the cornea led to the
belief that these images are responsible for \'ision, and
the lens and not the retina was assumed to be the
structure assigned to relay the images to the brain.
This view lasted for centuries. About the beginning of
the seventeenth century, Kepler (79, p. 116) dis-
covered and described how an image is formed by a
refracting surface. He then applied his concepts to
the eye to show how the refracting mechanism of
the eye must form an upside-down picture on the
retina. The pinhole camera which was invented about
the same time helped to demonstrate how an upside-
down image could be formed, and finally Scheiner
(79, p. 116) demonstrated the upside-down image
on the back of an excised eye.
.•\ijout this time attention was turned away from
the nature of the image on the retina to the mecha-
nism of accommodation by which the eye can change
its focus. From the time of Kepler to that of Young
C79> P- 158) various mechanisms were proposed in-
cluding change in length of the eye, change in the
curvature of the cornea, change in the position and
shape of the lens and change in the size of the pupil.
Young (86, p. 201; 79, p. 158) with a series of bril-
liant experiments at the beginning of the nineteenth
century showed that the lens provides the basis for ac-
commodation. Since then steady progress has been
made in understanding the various aspects of image
formation by the eye.
Helmholtz (79) has presented at the end of each of
his chapters an historical summary and a biljli-
ography which is useful to those interested in the
early history of the subject. There are other general
references that pertain to the early history (74, 77, 78).
IMAGE FORMATION
Giillstriind' s Schematit Eve and Its Refracting Mechanism
In demonstrating the principles of image forma-
tion by the eye, it is customary to substitute for an
/y_J. CILIARY BODY NX
CORNEA y^
K
\V-RETINA
*" if
lr\if' LENS CORTEX
^ OPTIC
^
\yL VITREOUS
Axis
AQUEOUSVvJ
wC\
IRIS
\\ LENS NUCLEUS /
7
FIG. I. Gullstrand's schematic eye, in which the dimen-
sions and indices are as follows:
mm
Thickness of cornea 0.5
Displacement of front surface of lens behind front
surface of cornea 3.6
Displacement of nucleus from front surfaceof lens . . 0.546
Thickness of nucleus 2.419
Thickness of lens 3.6
Index of refraction of cornea i . 376
Index of aqueous and vitreous i .336
Index of lens cortex 1 .386
Index of lens nucleus i .406
Radius of front surface of cornea 7.7
Radius of back surface of cornea 6.8
Radius of front surface of lens lO.o
Radius of front surface of nucleus 7 •9' '
Radius of back surface of nucleus ~5-7^
Radius of back surface of lens —6.0
THE IMAGE-FORMING MECHANISM OF THE EVE
649
actual eye a schematic eye such as Gullstrand's (79,
p. 392) which is illustrated in figure i .
The front and back surfaces of the cornea, the
front and back surfaces of the lens and the front and
back surfaces of the nucleus of the lens are the refract-
ing surfaces and constitute the refracting mechanism.
The spaces bounded by these surfaces are assumed
to be filled with homogeneous transparent media,
but differ from each other in having different indices
of refraction. The si.\ refracting surfaces of Gull-
strand's .schematic eye are assumed to be spherical
and centered on a common optic a.xis.
Ffirmation of Image by Refracting Meehanism
The refracting mechanism forms images of objects
placed in front of the eye. The simplest kind of object
that can be .so placed is a monochromatic point
source of light as shown in figure 2. The point source
Q. gives off rays which are incident at the cornea.
Because these rays diverge from the point Q_ this
point represents the focus of the incident rays. These
rays are said to exist in object space and the point
Q. is called an object point.
The pupil admits into the eye a certain number of
the rays diverging fron the point Q_, and after these
rays emerge into the vitreous they are said to exist in
image space. They converge at the point ()' which
represents the image point which is conjugate to Q_.
One can locate the image point corresponding to
a given object point by tracing two or more rays
through the refracting surfaces. Each ray entering
the eye is refracted or bent at each surface in accord-
ance with .Snell's law of refraction, illustrated in figure
3. The ray in the first medium which is incident to
the refracting surface makes an angle a with the
normal to the refracting surface at the point of inci-
dence. After it emerges into the second medium as
the refracted ray, it makes an angle a with the
normal. .Snell's law states that
n sin a = n' sin a'
where n represents the inde.x of refraction of the first
medium and n' the index of the second medium.
This method of locating an image point which in-
volves tracing rays from surface to surface is tedious,
and it is much simpler to locate first the so-called
cardinal points and planes and then use these to
locate the image point. For Gullstrand's schematic
eye one may compute for any given wavelength a
pair of nodal points N and N' , a pair of principal
points H and H' and planes, and a pair of focal
points F and F' and planes (.see fig. 4). The signifi-
cance of these points and planes will become obvious
as the discussion proceeds.
A ray incident to the front surface of the eye which
is directed through the first nodal point emerges into
the vitreous directed through the second nodal point
and parallel to the incident path of the ray, as shown
in figure 5. A second incident ray which passes
through the primary focal point F emerges into the
vitreous parallel to the optic axis. The emerging ray
is also directed through the points V and (". This is
true because an incident ray which is directed
through the point V in the primary principal plane
must emerge into the vitreous directed through the
point I' in the second principal plane which lies on
a line through V parallel to the optic axis. This is a
consequence of the fact that the principal planes are
the conjugate planes of unit magnification. A third
incident ray parallel to the optic axis emerges into the
vitreous directed through the secondary focal point
F'. All three of these rays which emerge into the
vitreous converge at the image point Q'. It is obvious
that once the cardinal points and planes are located
we can predict the location of the image of any object
point.
The cardinal points bear fixed relations to each
other so that once the principal points and one of
the focal points are given, the locations of the other
points can be immediately determined b>' means o
FIG. 2. Conjugate foci in object and image space.
650
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
the equation
H'F' = ^ (F//) = FjV = - (M'FO
n n
where n' is the index of the vitreous and n the index
of air.
SURFACE
FIG. 3. Snell's law of refraction.
Refracting Power of the Eye
Since the locations of principal points and the ratio
n'/n are relatively fixed from eye to eye and remain
relatively unchanged as a given eye accommodates,
the specification of the distance H'F' tells us prac-
ticalh' all we need to know about the refracting
mechanism of an eye. Instead of specifying this dis-
tance, which is known as the secondary focal length,
it is more usual to specify the refracting power F,
but
F = n'/H'F'.
The refracting power is expressed in diopters.
The refracting power of an eye is dependent upon
the curvature of the refracting surfaces and the indices
of the media. In all cases except for the back surface
FIG. 4. Cardinal points of the GuUstrand schematic eye. In this eye the secondary focus F' falls
0.387 mm behind the retina, i.e. the layer of photosensitive elements that respond to light. The
principal points //and //'are located 1.348 mm and 1.602 mm from the front surface of the cornea,
respectively. FH = M'F' = 17055 mm and H'F' = FJV = 22.785 mm. The ratio H'F'/FH is
equal to the index of the vitreous.
FIG. 5. Ray tracing.
0
M ^>^ H
^-^N^N' ^\f' **'
H' ^"~"'~~ „,,^^ \^
vl
V (
3'
THE IMAGE-FORMING MECHANISM OF THE EYE 65 1
of the cornea, an increase in curvature increases the
refracting power of the eye.
When we want to know how a change in index
affects the refracting power of the eye, we have to
approach the matter from a different direction. If we
introduce a thin layer of air between the adjoining
media, this will create two surfaces for each surface
except the first, and each medium will be bounded
on both sides by air. Introducing such layers of air
would not affect the direction of the refracted rays.
Figure 6 represents an exploded diagram showing
each medium bounded on both sides by air. These
elements form plus and minus lenses except in the
ca.se of the lens nucleus where a biconvex lens is
formed, and in the case of the vitreous where we
must deal with a single refracting surface. This analy-
sis of the optical system makes it easy to visualize
what happens when the index of a given medium
changes. An increase in index will increase or de-
crease the total power of the eye depending upon
whether the refracting effect of the particular element
is plus or minus.
Helmhollz Schematic Eye
Hclmholtz (yg, p. 152) made use of a somewhat
more simplified schematic eye than that employed
by Gullstrand. In the Helmholtz schematic eye the
cornea represents a single refracting surface at which
the aqueous adjoins the air. Furthermore the lens is
treated as having a uniform index throughout (see
fig- 7)-
The value which Helmholtz selected for the radius
of the front surface of the eye approximates the average
front surface of the cornea in the adult human eye.
The displacement of the lens from the front surface
of the eye also approximates the distance from the
front surface of the cornea to the front surface of the
lens as measured experimentally. The thickness of
the lens and the radii of curvature also appioximate
the actual values. The value of 1.338 given to the
CORNEA
CORNEA I CORTEX | CORTEX |
AQUEOUS NUCLEUS VITREOUS
FIG. 6. Exploded diagram of the Gullstrand schematic eye
showing the various elements with air spaces between them.
FIG. 7. The Helmholtz schematic eye
index of the aqueous and vitreous for sodium light.
(589 m|t) approximates the true value. A value
of 1.455 ^35 been selected for the lens because, if
the lens substance is assumed to have a uniform
index throughout, it gives the lens approximately the
same refracting power as an actual lens immersed in
vitreous. The indices selected by Helmholtz have
been adjusted by Laurance (54) from 1.338 to 1.333
(or J--Q and from 1.455 to 1.45 in order to give the
eye primary and secondary focal lengths of — 15 and
20 mm, respectively, which are round numbers.
The radii of curvature of the refracting surfaces,
their locations and the indices of the media constitute
the optical constants of the eye and are summarized
for the Helmholtz schematic eye in table i. All of
these values refer to sodium light (589 mix).
Reduced Eye
Helmholtz's schematic eye can be simplified still
further, as has been done by Laurance (54), by
using a single refracting surface as shown in figure 8.
The interior of this eye is filled with a medium which
has the same index throughout and is equivalent to
that of the vitreous of the Helmholtz schematic eye,
namely 1.333. The surface at which this medium
makes contact with the air in front of the eye is the
only refracting surface. The curvature of this surface
has been arbitrarily increased to compensate for
the absence of the lens so that the eye has the same
refracting power as the Helmholtz schematic eye.
In the reduced eye the two principal planes coin-
cide and are tangent to the front surface of the eye.
The two nodal points coincide at the center of curva-
ture of the front surface. The focal lengths are the
same as in the Helmholtz schematic eye, and for
most purposes the reduced eye is equivalent to the
Helmholtz eye. It is very useful for visualizing certain
652
HANDBOOK OF PHYSIOLOG\'
NEUROPHYSIOLOGY I
TABLE I . Optical Constants of the Helmholtz Schematic Eye
Distance from cornea to front of lens
I'hickness of lens
Radii of curvature:
Cornea
Front surface of lens . .
Back surface of lens
Indices of refraction (sodium light)
Aqueous i .333
Lens 1 .45
Vitreous 1 .333
■i-*^
mm
:3f^
mm
8
mm
0
mm
6
mm
FIG. 8. The reduced eye devised by Laurance.
aspects of image formation as will become ob\ious
later.
Role of Pupil in Image Formation
The pupil is an aperture in the iris which lies in
contact with the front surface of the lens. The pupil
varies in size because the muscles in the iris can make
it either contract or dilate. The pupil is important in
the formation of an image on the retina because by
changing its size it can aflfect the illuminance and the
blur of the image. It does this by limiting the size
of the ray bundle which enters the eye from each
object point. In terms of geometrical optics this
means that it serves as the aperture stop of the
system.
In order to understand the role of the pupil in
image formation, it simplifies matters to make use of
the imaginary entrance- and exit-pupils of the eye.
The entrance-pupil is conjugate to the real pupil
with respect to refraction at the cornea, and the exit-
pupil is conjugate to the entrance-pupil with respect
to the complete refracting mechanism of the eye. The
entrance-pupil is larger than the real pupil and lies
slightly in front of it. The exit-pupil lies behind the
real pupil and is not quite as lai-ge as the entrance-
pupil. The entrance-pupil is the pupil which we see
when we look at another person's e\e. This is the
pupil on which direct measurements can be made in
\isual experiments. Its position and diameter can be
directly determined. The positions and sizes of the
real and of the cxit-piipil have to be calculated.
Chief Rays
Another concept which is needed in explaining the
role of the pupil is that of a chief ray. The chief rav
of a bundle of rays entering the pupil of the eye from
a given object point is the one which is directed
through the center (0) of the entrance-pupil and
which, after refraction at the cornea, passes through
the center of the real pupil. After emerging into the
vitreous, it is directed through the center (0') of the
exit-pupil, as shown in figure 9.
Blur Circles in Eye Free from Astigmatism
The major role of the pupil is to limit the size of
the blur circles and ellipses formed on the retina when
an eye is out of focus. The schematic and reduced eyes
referred to above are all free from astigmatism for
object points close to the optic axis because the re-
fracting surfaces are assumed to be spherical and also
centered on the optic axis. In this eye free from
astigmatism, the bundle of rays from a given object
point emerges into the vitreous as a cone or pencil of
rays with the exit pupil forming the base and with the
rays coming to a focus at the apex as shown in figure
10. This point is called the optical image and may
lie on, in front of, or behind the retina. If the retina
intercepts the bundle at the optical image so that the
optical image falls on the retina, the retinal image in
terms of geometrical theory is a point image; but if
the optical image ()' falls in front of or behind the
retina, the retinal image at Q.' is an out-of -focus blur
circle. As is obvious from figure 10, the size of the
blur circle is determined by the size of the exit-pupil.
Astigmatism
The bundle of rays from a point source does not
always come to a focus at a point. The most common
deviation from this ideal is called astigmatism. Figure
I I illustrates an astigmatic bundle of rays emerging
from the exit-pupil. The planes which intersect at the
chief ray constitute the meridians of the bundle. The
vertical and horizontal meridians are the principal
meridians because the ravs come to a focus in these
THE IMAGE-FORMING MECHANISM OF THE EYE 653
Fig. 10
Fic. 9. Chief ray.
FIG. 10. Out-of-focus blur circle.
meridians. The rays in the vertical meridian focus at
Q,' and the rays in the horizontal meridian at QJ'.
Cross sections of the bundle at various distances
from the exit-pupil are also shown in the figure. The
cross section is in general elliptical but at Q,' it be-
comes a horizontal line and at QJ' a vertical line. At
one point in between it becomes a circle; and when
this part of the bundle is intercepted by the retina,
the effect is the same as throwing out of focus an
eye which is free from astigmatism.
There are two principal causes of astigmatism.
On the one hand the chief ray of the bundle may be
oblique to one or more of the refracting surfaces. On
the other hand one or more of the surfaces may be
toroidal, i.e. a given surface may be shaped like the
side of a barrel which is more curved in the direction
around the barrel than up and down. It is obvious
that in a multisurface system like the eye, there may
be many comijinations of toroidal and tilted surfaces
and it becomes impractical to try to analyze all these
various combinations.
In practice the resultant astigmatism is measured
and treated without analyzing the contributions
made by the separate surfaces. However, the toroidic-
ity of the cornea may be independently measured and
gross observations may be made of the tilt of the re-
fracting surfaces.
Lines of Sight
Object points which lie on the incident path of a
chief ray produce concentric blur circles or ellipses
on the retina, and because of this the incident path of
a chief ray is also called a line of sight.
Primary Line of Sig/it and Foveal Chief Ray
Of all of the lines of sight (or chief rays) which
converge at the center of the entrance-pupil, there is
CHIEF
RAY
CIRCLE OF
LEAST CONFUSION
FIG. 1 1. .-Xstigmatic blur ellipses.
one which is all-important in the use of the eyes. When
a person is told to fixate a given point with one of his
eyes while the other is covered, he points that eye
at the object. The pointing is not steady because the
eye is subject to a fine tremor and also weaves back
and forth and makes occasional jerks awa\' from the
object, but we can nevertheless think of the average
fixating position of the normal eye as one in which the
retinal image is centered on a given part of the retina
which falls somewhere near the center of the fo\'ea.
The chief ray which penetrates this point is the fo\eal
chief ray and the incident path of this ra\ is the pri-
mary line of sight.
Pupillary Axis am! Angle X
It is customary to specify the location of the fo\enl
line of sight in terms of its relation to the pupillary
axis which can be easily located by ol)jective methods.
The pupillary axis is a line normal to the front surface
of the cornea and directed through the center of the
entrance-pupil. It forms an angle X with the primary
line of sight which also passes through the center of
654
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
FIG. 12. The angle X.
the entrance-pupil. The pupillary axis is usually
about 5 degrees temporalward from the primary line
of sight, as appears in figure 12.
Size of Retinal Image
The chief ray concept is also useful in dealing with
the size of the retinal image of an external object. The
angle 7 subtended by two object points at the center
of the entrance-pupil 0 is called the visual angle; it
is the angle between the two lines of sight (see fig. 9).
The term "size of the retinal image' refers to the
linear distance between the retinal images M" and
Q," of the two object points M and Q,. When the eye
is out of focus, the retinal images are blur circles and
the size M"Q_" represents the distance between the
centers of the two blur circles formed on the retina.
If the angle y' subtended by the centers of the two blur
circles at the center of the exit-pupil is expressed in
radians,
linear separation of the
centers of two blur circles
y' = .
distance from the exit pupil to the retina
The ratio of 7' to 7 is one of the more important
constants of the eye. In the case of the Helmholtz
schematic eye
7'/7 = 0.81.
With this ratio and the distance from the exit-pupil
to the retina specified, one can compute the linear
separation of two blur circles on the retina for a given
value of 7.
The expression 'size of the retinal image' is often
misinterpreted to mean the size of the blur circle
formed by a single object point, but this is something
which is quite different from the linear separation
between the centers of two blur circles.
REFRACTION AND ACCOMMODATION OF THE EYE
The eye has an adjustable focusing mechanism.
The first section of this chapter has explained how the
eye forms an image of an object when the focusing
mechanism is fixed. This section describes how the
changes in focus may be described and specified.
Refraction of the Eye
If a given point on the primary line of sight pro-
duces a bundle of rays which comes to a point focus
on the retina, the eye is said to be focused for this
point. Another way of stating this is to say that the
object point producing the bundle is conjugate to
the retina.
The spectacle point 5 (14 mm in front of the cornea)
is used as the reference point for specifying the loca-
tion of the point R which is conjugate to the retina,
as represented in figure 13.4. Stating the distance
from R to S adequately describes the refractive state
of the eye, but it is customary to use the reciprocal of
this distance and call it the refraction of the eye. It
is measured in diopters when the distance RS is given
in meters.
When the eye is astigmatic, it is necessary to
specify separately the refraction in the two principal
meridians. To visualize this problem it is better to
start with a point on the retina penetrated by the
foveal chief ray and trace a bundle of rays back out
of the eye through the entrance-pupil. The line of
sight represents the chief ray of this bundle, and the
principal meridians are the planes which intersect at
right angles at the line of sight.
The o to 180 degree meridian which is the reference
meridian for the location of the principal meridians
lies in the plane of regard which is defined by the
centers of the two entrance-pupils and the point of
convergence of the two primary lines of sight. In figure
1 3^ the line of sight is perpendicular to the paper and
penetrates the front of the eye at A. The angles 0i and
-I4fnm
A. SPECTACLE POINT
FIG. 13. Reference points and planes for specifying the
refraction of an eye.
THE IMAGE-FORMING MECHANISM OF THE EYE
655
02 represent the counterclockwise angular displace-
ment of the principal meridians from the o to 180
degree meridian.
Accommodation
The refracting mechanism of the eye possesses the
ability of accommodating itself for different distances;
that is to say, the eye can focus on one object at a
given moment and on an object at a diflferent distance
a moment later. This represents a change in the re-
fractive state of the eye which is brought about by a
change in form of the lens and a slight movement for-
ward. The major part of this efTect is mediated by the
change in curvature of the front surface of the lens,
and it greatly simplifies our concept of how the eye
works if we assume that this is the only variable. If
as in the schematic eye the pupil is centered upon the
optical axis of the lens, chief rays through the center
of the pupil cross the axis at the front surface of the
lens and the refraction of such rays is not affected by
a change in curvature. There is therefore no change
in the ratio of 7' to 7.
Static Refraction of the E\e
When accommodation is relaxed, the point R for
which the eye is accommodated in a given meridian
is known as the far point Qmncliim remotum") for that
meridian. The reciprocal Qi/RS') of the distance from
the far point (R) to the spectacle point (5) is defined
as the static refraction of the eye and is measured in
diopters. The spectacle point corresponds to the back
surface of a spectacle lens and lies 14 mm in front of
the cornea. For all practical purposes it coincides
with the primary focal point.
Emmetropia is the condition in which the far
point lies at infinity and in which the static refraction
equals zero. Ametropia is the condition in which the
far point does not lie at infinity but at some finite dis-
tance either in front of or behind the spectacle point.
Myopia is the positive t) pe of ametropia in which the
far point lies at some finite distance in front of the
spectacle point. Hyperopia is the negative type of
ametropia in which the far point lies behind the
spectacle point.
When an eye is equally ametropic in all meridians,
it is said to have a spherical error of refraction which
may be either hyperopic or myopic. When the static
refraction differs in the various meridians, the eye is
said to have an astigmatic error of refraction.
Correction for Ametropia
That lens which will permit an ametrope to see
lines clearly in all meridians at 6 m with relaxed ac-
commodation is called the distance correction. The
myope needs a minus lens and the hyperope a plus
lens, as shown in figure 14. In each case the refracting
power of the lens is the same in all meridians and is
equal numerically to the static refraction but opposite
in sign. Myopia for example is a positive ametropia
which is neutralized with a minus lens.
A person with astigmatism requires a lens which
varies in power from meridian to meridian. Such a
lens has a toric or cylindrical surface on one side and
a plane or spherical surface on the other and is
equivalent to a combination of a spherical lens with
a cylindrical lens. The cylindrical lens compensates
the astigmatic component of the refractive error, and
the spherical lens compensates the residual spherical
component.
In designing a lens for a given person many com-
binations of surfaces may be used on the two sides
to provide the correction for the ametropia, and
other factors have to be considered in selecting the
particular curves to be used. The thickness and index
can also be varied although the glass normally used
has an index of 1.523 for sodium light. The lens may
be designed to compensate for its own aberrations, to
provide a specified amount of angular magnification
in addition to refracting power and to minimize re-
flections, and some consideration is always given to
breakage and weight on the face. Plastic lenses are
sometimes used instead of glass lenses.
The ordinary ophthalmic lens is mounted with its
back surface at or near the spectacle point 14 mm from
the cornea and with its optic axis passing through
the center of rotation of the eye.
A corneal contact lens is worn in contact with the
cornea, while the scleral type contact lens contacts
FIG. 14. Spectacle lenses for the correction of spherical
ametropia.
656
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
the sclera around the cornea with a thin fluid layer
between the contact lens and the cornea.
Specification of Amount of AccommodatKin m Play
Accommodation is measured in diopters and repre-
sents the reciprocal of the distance from the conjugate
focus of the retina to the spectacle point when the
distance correction is worn. Thus when the distance
correction is worn the accommodation must be re-
duced to its zero level in order to see a distant object
clearly.
The ma.ximal amount of accommodation that can
be elicited is called the amplitude of accommodation.
The nearest point for which the eye can accommodate
is called the near point of accommodation (^punctum
proxirnurtt). This varies with age as shown in figure 15.
At the age of about 40, the near point recedes rapidly
beyond the ordinary working distance of 33 to 40 cm.
\'arious sets of data relating amplitude to age have
been analyzed by Marg et al. (63). It is necessary to
compensate for this loss of accommodation with a
plus lens added to the distance correction. The added
plus lens power at the near point is usuallv pro\ided
in the form of a bifocal which has enough plus lens
power added in the segment to permit the eye to see
clearly at a given working distance with one half of
the accommodation held in reserve.
Ap/iafcia
When the crystalline lens is missing, the eye is
said to be aphakic. The lens may be surgically re-
moved, it may be congenitally absent, or it may be
dislocated so that it fails to cover the pupillary aper-
ture. Clear vision can still be obtained by means of a
lens mounted in front of it, but the eye no longer has
any power of accommodation. The range of clear
vision through any given lens is strictly a function of
the depth of the focus of the eye.
FIG. 15. Regression of the
near point of accommodation
with age. Based on Donder's
data (20). It is assumed that the
distance correction is worn.
20 30 40
iGE (YEARS)
OCUL.AR ME.ASUREMENTS
In the first section of this chapter reference was
made to the indices of the media and the curvature
of the refracting surfaces and their distances in front
ot the retina. In the second section, reference was
made to the distance from the conjugate focus of the
retina to the spectacle point and its use in specifying
refraction and accommodation. This section explains
how such quantities are actually measured.
Indices of Media
Each medium of the eye has been assumed to be
uniform in the schematic eye; but the cornea and the
lens have a definite microstructure and can be
treated as made up of layers of different indices.
The cornea has five different layers, the epithelium,
Bowman's membrane, the stroma, Descemet's mem-
brane and the endothelium. The index for the
epithelium has been found to be 1.416 and that for
the rest of the cornea, 1.372 (22, p. 728).
The index of the lens substance varies from 1.387
at the cortex to 1.406 at the center (22, p. 736). The
variation in index of the lens from the center to the
cortex affects its performance as an image-forming
device. The problem can be formulated by visualizing
a series of isoindical surfaces from the cortex to the
center. In a meridian section these surfaces probably
correspond to the course of the fibers as they arch
around the nucleus from the axis back to the axis
(79. P- 339)-
The index of the aqueous is 1.336 and that of the
vitreous is the same (22, p. 734).
The index measurements reported above ha\e all
been made with an Abbe refractometer which makes
use of the principle of total reflection.
Purkinje Images
The Purkinje images are important because they
provide us with many objective methods of studying
the configuration, tilt and location of the refracting
surfaces. The refracting surfaces of the eye can form
images both by reflection and refraction. Images in-
volving single reflection at the front and iiack surfaces
of the cornea and at the front and iiack surfaces of the
lens are known as the first, second, third and fourth
Purkinje images (86, p. 48). These images may be
seen bv an observer located in front of the eye.
THE 1M.\C;E-F()R.ML\G mechanism OF THE EYE
657
Optic Axis 0/ the Eye
It has been assumed in connection with the sche-
matic eye that the refracting surfaces are centered on
a common axis, but the extent to which this is true
in the case of an actual eye can be tested by observing
the Purkinje images of a point of light held close to
the observer's eye. The subject is then made to follow
a fixation target which is moved about until the
Purkinje images line up or at least until the third and
fourth ones line up. This puts the observer's eye on
the path of a ray of light which passes through the
lens normal to both surfaces, and the extent to which
the center of the pupil and the center of curvature of
the front surface of the cornea are displaced from the
optic axis of the lens can then be directly observed.
In general the optic axis (in so far a such an axis
exists) coincides with the pupillary axis, so that the
optic axis deviates temporalward from the primary
line of sight about 5 degrees and also about 2 degrees
downward (86, p. 77). For the purpose of specifying
this angle, it may be assumed that the two lines inter-
sect at the center of the entrance-pupil.
The optic axis does not necessarily coincide with
the anatomical axis of the eye which may be defined
as the line connecting the geometrical center of the
cornea (front pole) with the geometrical center of
the sclera (back pole). However, the optic axis
and the anatomical axis do approximately coincide
in the average eye. Theoretically the anatomical
axis of the eye should coincide with the line
normal to the cornea at its geometrical center.
This is called the geometrical axis of the cornea.
Coiifigmalion of Front Surface of Cornea
The central portion of the cornea is usually spherical
or toroidal. With a keratometer one can determine
whether the cornea is spherical or toroidal and, if it
is toroidal, the principal meridians can also be deter-
mined. Furthermore, one can measure the radius of
curvature in each of the principal meridians of a
toroidal cornea and in any meridian of a spherical
cornea.
The central portion of the typical cornea which
may be regarded as spherical or toroidal covers a
region about 4 mm in diameter and outside of this
area the curvature gradually decreases as the limbus
is approached. The center of the optical portion does
not necessarily fall at the center of the cornea (79,
p. 311 ; 86, p. 68).
The exact form of the peripheral portion of the
cornea can be investigated in a number of ways. One
can view the profile of the cornea with a microscope
or photograph the profile. One can examine it point
by point with an ordinary keratometer by using a
variable point of fixation. It can also be viewed with
a keratoscope or photographed with a photokerato-
scope. In this technique a reflected image of a series
of concentric circles is used. In one of the later models
(50) the concentric rings are arranged on a spherical
surface concentric with the eye so that the reflected
images cover the entire cornea. Another method is
that of sprinkling powder on the cornea and then
taking a stereophotograph which can later be ana-
lyzed like an aerial map. One can also take a mold
of the cornea as in fitting contact lenses and then
studv the configuration of the mold.
Measurement of Internal Refracting Surfaces
One can measure the position of the margin of the
iris with respect to the cornea and assume that this
lies in contact with the front surface of the lens (79,
p. 19, 334). The ophthalmophakometer (86, p. 80)
and the Blix ophthalmometer (79, p. 326) make use
of specular reflections at the surfaces to locate the
positions of the vertices and centers of curvature of the
surfaces. It is also possible to photograph the Purkinje
images (i, 2, 6, 45, 49, 94) and to calculate the radii
of curvature of the reflecting surfaces from this kind
of data.
Fincham (26, p. 38) used diffusely reflected light
to produce an optical section of the refracting surfaces,
and lay viewing with a microscope having a cali-
brated fore and aft movement he was able to measure
directly the apparent separations of the surfaces.
A similar arrangement can be used with a camera
replacing the microscope (26, p. 44). A projective
transformation of the photographic image gives a
cross section of the eye. This inethod has the ad-
vantage of showing not only the configurations of
the surfaces but also gives the internal structure of
the lens.
The measureiTients made on an internal surface
appl\- to the apparent surface viewed through the
refracting surfaces lying in front of the surface in
question. The concept of a thick mirror is helpful in
this connection. The center of curvature of the
apparent surface is the image of the actual center of
curvature formed by the refracting surfaces lying
in front, and the vertex of the apparent surface is
also the image of the vertex of the actual surface.
6^8
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
X-ray Measurement of Axial Length of the Eye
A sheet of X-rays is produced by passing X-rays
through two parallel slits, and the eye is held so that
this sheet of rays traverses the eye perpendicular to
the direction of regard, as shown in figure i6. Its
intersection with the retina is a circle and, since
X-rays so applied stimulate the retina, the subject
sees a circle of light. The size of the circle can be made
smaller and smaller by moving the sheet of rays
toward the back of the eye, keeping it always per-
pendicular to the direction of regard. It reduces to a
point as it becomes tangent to the retina. The distance
of the cornea from this plane can then be measured by
sighting on the profile of the cornea (23). (Care
must be taken to keep the X-rays from passing through
the crystalline lens.)
X-ray Determination oj Location of Second .Nodal Point
Two sheets of X-rays are produced by passing
X-rays from a source through one slit and these then
are passed again through two slits which are parallel
to the first slit as shown in figure 17. These two sheets
of rays are allowed to traverse the back of the eye
which is pointed with its optic axis -in a direction
parallel to the slits. Two distant object points are
adjusted so that their images fall on the two lines
on the retina stimulated by the X-rays. Knowing the
linear separation of the two X-ray images and
knowing the angular separation of the two optical
images at the second nodal point, one can compute
the distance from the second nodal point to the retina.
Locating Conjugate Focus of Retina
It is assumed in this section that the astigmatism
of the eye, if any be present, has been corrected and
that the experimenter is interested only in locating
the conjugate focus of the retina for the purpose of
determining the refractive state of the eye or the
amount of accommodation in play. In order to
simplify our problem let us consider absolute pres-
byopia in which the eye has a fixed focus. The same
thing occurs in an aphakic eye or in an eye which has
been temporarily paralyzed with a drug. In this
case a target is needed to control fixation and then
some subjective or objectiv'e means must be provided
for locating the conjugate focus of the retina.
Let us consider the subjective methods first. A
target consisting of a point, a line or a row of small
letters can be used for controlling fixation and lo-
cating the conjugate focus of the retina. The distance
can be varied or lenses may be placed in front of the
eyes. The natural pupil may be used or, if this has
been dilated, a diaphragm with a pupil of normal
size can be placed before the eye. The target must
be fine enough so that the subject can tell when
the focus is sharpest.
The Scheiner principle substitutes for the natural
pupil two small holes or two parallel slits. If a single
target is used the retinal image doubles when it is
out of focus (fig. 18). The doubling is easier to detect
when monochromatic light is used than when white
light is used; still better the two beams can be trans-
mitted through filters of different color. If the upper
and lo\ver halves of a vertical slit are seen through
different parts of the pupil displaced laterally from
Fig 16
Fig^l7 oPTK
FIG. 16. X-ray measurement o( the axial length of the eye. fig. 17. X-ray method of locating the second nodal point.
THE IMAGE-FORMING MECHANISM OF THE EVE
^59
each other, the two halves of the slit are seen out of
vertical alignment when the eye is out of focus
(fig. 19). Monochromatic light is used in this case.
Since the Scheiner technique makes use of only two
small parts of the pupil, it may yield a different
measure of accommodation than a measurement
based upon the full pupil. This is a function of the
spherical aberration of the eye. Consequently the
Scheiner principle is primarily useful in measuring
changes in accommodation.
The threshold principle involves having the target
(usually a line) disappear when it goes out of focus.
This test has the advantage that it can be used with a
normal pupil.
The retinoscope (skiascope) is an objective device
for determining the refraction of the eye. A small
mirror throws a beam of light on the eye from a
small source. The examiner looks through a small
hole in the mirror and observes the light reflected
from the retina back out of the eye. This makes the
pupil appear bright, and moving the mirror modifies
the distribution of the light in the pupil so that the
examiner can tell when the eye is out of focus for the
hole in the mirror. When the eye has a fixed focus,
the subject can control his fixation by fixating the
mirror image of the light source.
The coincidence optometer is another objective
device which is a very valuable means for the ob-
jective determination of the refractive state. In this
device an image is formed on the pigment epithelium
in contact with the retina, and the light difl'uscly
reflected from this surface forms an image in the
plane conjugate to the retina. This image is viewed
through an eye piece. The target and the focal plane
of the eye piece are kept at the same distance from
the subject's eye, but this distance can be varied to
locate the conjugate focus of the retina. The operator
may use blur as a criterion for the proper setting, or as
in Fincham's instrument (24, 27) a modification of
Scheiner's principle may be used. Fincham (un-
published observations) has also made use of a
photoelectric cell with a feed-back which auto-
matically focuses the instrument.
Campbell (15) has designed an optometer based
on the use of a photocell and Scheiner's principle
which automatically records changes in accom-
modation.
The indirect ophthalmoscope may be used like a
coincidence optometer except that the blood vessels
and demarcations on the retina are used instead of
an image of an external target focused on the retina.
In this way only the focus of the emerging beam is
involved in the measurement.
With the direct ophthalmoscope the refracting
mechanism of the subject's eye is used as a magnifier,
the focal length of which can be varied with the
auxiliary lenses mounted in the instrument.
The aberrations of the eye and the differences in
criteria as to what constitutes a focus create a problem
in trying to correlate the results obtained with sub-
jective and objective methods.
A technique known as the fogging method has been
developed for measuring the 'zero level' of ac-
commodation by manipulating the stimulus pattern
Fig 19
FIG. 18. Scheiner principle with doubling as the criterion of the retinal image being out of
focus.
FIG. 19. Scheiner principle with vernier displacement as the criterion, .\ssume that the upper
and lower halves of the slit are covered with polaroid with the axes at right angles, and that the
two holes in the viewer are also covered with polaroid with the axes crossed at right angles.
66()
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
to force accommodation to this level. A chart of
small letters is used to control fixation and to stimu-
late relaxation of accommodation. Plus lenses are
placed in front of the eye to relax accommodation and
then additional plus lenses are used to get below
the level to which accommodation can be relaxed.
This 'fogs' the eye. Once the eye is 'fogged' the plus
power is reduced to locate the level at which the
'fog' ends. This represents the 'zero lexel' of ac-
commodation. The measurement can be carried out
on the two eyes at the same time if they have pre-
viously been corrected for astigmatism and ani-
sometropia. The target is placed at a distance of
about 6 m to create an awareness of distance and
also to relax convergence if the test is binocular.
In many experiments it is necessary to stimulate
accommodation to various degrees. For most pur-
poses it suffices to use a single target with fine detail
to control fixation and accommodation. If the fine
detail is clearly visible, it is assumed that the eye is
in focus for the target. On the other hand it is often
desirable to find out whether the amount of ac-
commodation in play is leading or lagging behind
the stimulus. One target is used for stimulating
fixation and accommodation and, if both eyes are
used, it also serves as a convergence stimulus. An
independent target must be used to measure the
amount of accommodation in play. This target is
usually presented to one eye and a beam splitter is
used to superimpose an image of the measuring
target upon the stimulus target. The image of the
measuring target must be adjustable so that it can
be made to fall in front of or behind the stimulus
target. A single bright point source is a good meas-
uring target because it cannot compete with the
more complex stimulus target in controlling ac-
commodation. This is the principle underlyins; the
stigmatoscope.
The threshold principle (56; 57, p. 485; 73) may
be employed to avoid stimulating accommodation.
As long as the target is invisible, it cannot stimulate
accommodation and hence it is moved from the out-
of-focus position to the just-visible point. This is
clone from both directions to determine the limits of
the visible range. The mid-point is assumed to be
the point of best focus.
It is of interest to know what happens to ac-
commodation when the stimulus to accommodation
is fixed and the stimulus to convergence is \aried.
The Scheiner principle can be used to good advantage
in this kind of experiment because the changes in
accommodation can be continuously tracked by
having the subject adjust the target as the stimulus
to convergence is slowly decreased or increased CsO-
The Scheiner target avoids stimulating accommoda-
tion because the two beams entering the pupil are
narrow.
The skiascope (32) or the coincidence optometer
(30) may also be used in this kind of experiment to
measure the amount of accommodation in play.
However, the objective methods not only present
criteria problems (34). but also the additional
stimuli applied to the retina may affect the amount
of accommodation. This, of course, is avoided in
the case of the infrared skiascope (16, 49).
At low levels of illumination and in the presence
of an optically empty field of high luminance, ac-
commodation fluctuates. Westheimer (91) has been
successful in measuring these fluctuations using
intermittent exposure of a Scheiner target. The
subject reports at each exposure. This target not
only measures accommodation but also controls
fixation. Chin & Horn (16) observed these fluctu-
ations with an infrared skiascope.
An optically empty field at high luminance is pro-
\ided by Knoll's 'blob' (47) which is a luminous
patch with diffuse edges upon which the subject can-
not focus. It is small enough, however, so that fixation
can be controlled by looking at the center of the
'blob.'
Another problem is that of controlling convergence
without stimulating accommodation and at the same
time measuring the amount of accommodation in
play. The 'blob' described above or a blurred line
(58) can serve as a stimulus to convergence and the
threshold, momentary exposure or infrared principle
can be used in measuring the accommodation.
Tracking rapid changes in accommodation pre-
sents a special problem. Changes in the ciliary muscle
potential (76) can be used as an index of changes in
accommodation. Photographic records of the changes
in size of the third Purkinje image have also been em-
ploved (i, 6, 45). Campbell's automatic recording
optometer (15) should be useful for this purpose.
The amount of accommodation in play at a gi\en
moment following a stimulus to a change in accommo-
dation can be measured by presenting a momentary
exposure of a measuring stimulus at the selected time
(3. 4. ?)•
MECH.\NISM OF .\CCOMMOD.\TION
Intraucular Mechanism vj Aaommndiilion
Of all the structures which might be manipulated
to focus the eye, the lens alone fulfills this role. Young
THE IMAGE-FORMING MECHANISM OF THE EYE
66 I
(79, p. 158; 86, p. 201) proved that the lens;th of the
eye does not change with accommodation by placing
the front and back of one of his eyes between the jaws
of a clamp and noting that there was no change in
the pressure phosphene at the back of the eye as the
eye changed accommodation. The X-ray method of
measuring the length of the eye described abo\e is
now available for demonstrating this fact. Young also
showed that the cornea does not change its curvature
during accommodation by noting the reflections from
the front surface. He also immersed his eye in water
which has about the same index as the aqueous and
showed that the power of accommodation was not im-
paired. The final proof offered by Young that the lens
alone pro\ides the mechanism of accommodation is
the fact that the eye assumes a fixed focus when the
lens is absent.
Bv measuring the curvature of the front and back
surface of the lens and the distances of the two surfaces
from the cornea, Helmholtz 79, p. 143) showed that
the lens increases in thickness and moves forward
slightly, that the curvature of the back surface also
increases slightly but that the most important change
is in the curvature of the front surface of the lens.
Helmholtz believed these changes to be brought
aljout by a decrease in tension of the zonule which
attaches the lens to the ciliary body surrounding the
lens. The lens was regarded as a pliable body enclosed
in an elastic capsule. Such a body tends to assume an
ellipsoidal form when a centripetal tension is applied
all along its equator but tends to assume a more
spherical form when released from this tension.
Helmholtz believed that the release in tension on
the zonule required for accommodation is brought
about by a contraction of the ciliary muscle which acts
partly as a sphincter in reducing the diaineter of the
ciliary margin and partly as a system of radial fibers
pulling forward the choroid to which it is attached.
This increases the pressure of the vitreous on the back
side of the lens and neutralizes the tendency of the
lens to bulge on its back side. The mechanical pressure
of the iris on the peripheral part of the front surface
of the lens would help to increase the curvature of the
front surface.
Fincham (26, p. 42) has demonstrated in a patient
with aniridia that the mechanical pressure of the iris
is not an essential part of the mechanism of accommo-
dation. In this case he could observe the decrease in
diameter of the lens and of the margin of the ciliary
body during accommodation. Finchain (26, p. 50)
has described a person with an eye in which the lens
substance had been dissolved out of the capsule and
showed that when the other eve accommodated the
tension on the capsule decreased and left it free to
dangle. Hensen & \'oelkers (86, p. 199) demonstrated
the forward movement of the choroid during accom-
modation by inserting a needle through the sclera and
choroid near the ora serrata and then making the
ciliary muscle contract. The protruding part of the
needle moved backward as the choroid ino\ed
forward.
Young (86, p. 208) demonstrated that the spherical
aberration of the eye becomes partially corrected
when the eye accommodates and Tscherning (86,
p. 211) used the specular reflections from the front
surface of the lens to demonstrate that this was due
to a flattening of the peripheral part of the front sur-
face of the lens. The Helmholtz theory had not taken
this fact into account.
It remained for Fincham (26, p. 59) to demonstrate
that this is due to a variation in the thickness of the
capsule. The details of the theory of how an elastic
ellipsoidal inembrane having zones of varying thick-
ness from the pole to the equator affects the form of
the lens as a result of a change in tension of the zonule
have not yet been worked out.
Fincham (26, p. i 7) demonstrated the elastic force
of the capsule by puncturing the lens and noting that
the lens substance protruded through the capsule.
Also by direct experiment Fincham (26, p. 24) demon-
strated that the zonule behaves like an elastic mem-
brane. Furthermore, when the capsule of the lens is
removed, the lens assumes a form of its own in which
the decapsulated lens is more spherical (26, p. 65).
Hess (26, p. 52; 79, p. 398) observed that when a
maximal efTort of accommodation is made, tension on
the zonule is relaxed so that the position of the lens
in the eye is aflfected by gravity. This can be demon-
strated by showing that the amplitude of accommo-
dation is greater when the head points downward than
when it points upward. The lateral displacement of
the lens when the head is laid on one side or the other
can be demonstrated entoptically when there exists a
small opacity near the front or back pole of the lens.
Hess concluded from this finding that it may not be
necessary for the eye to make a maximal contraction
of the ciliary muscle in order to relax the lens com-
pletely from the tension of the zonule.
Lancaster & Williams (53) have shown that when
a maximal state of accommodation is maintained over
a period of time, the lens develops a set so that it can-
not immediately relax to the zero level of accommo-
dation. It takes several minutes to overcome this set.
Lancaster & Williams regarded this as evidence that
the lens is completely released from the tension of
the zonule at the maximum level of accommodation.
662
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY' I
However, in some subjects the same type of effect
occurs in lesser degree with submaximal amounts of
accommodation.
Duane (21) showed that in a youns; man it takes
the same time for homatropine to begin to take effect
as in an older man and argued from this that the older
man has the same excess of ciliary capacity above the
capacity of the lens to respond as the young man.
It is necessary to look in some other direction to
ascertain what fraction of the total ciliary contraction
a\ailable is required to produce a diopter of accom-
modation at different ages. The answer is to be found
in the study of the relation of accommodation to con-
vergence as described in the next section.
It remains to be determined whether the lens layers
become nonpliai)le one by one from the center out
with the cortical layers remaining relatively unaffected
or whether all la\ers get progressively less pliable
with age but with the hardening process more de-
veloped at the center than at the cortex. The role
played by the tensile strength of the indi\-idual fibers
must also be considered.
The slit lamp technique of observing or photo-
graphing the internal structure of the lens, if system-
atically used at different age levels, might throw some
light on this problem. It would also be important to
study at different ages the time characteristics of the
response of the lens to changes in tension of the
zonule (7).
Ciliary Muscle Potential
Schubert (76) has recently developed a method for
detecting and recording a potential which appears to
be generated by contraction of the ciliary muscle.
One electrode is applied to the .sclera o\er the ciliary
bodv and the other to some indifferent part of the
bod\-. Alpern (unpublished observation.s) has de-
scribed the relation of size of this potential to the
amount of accommodation in play. This new tech-
nicjue provides us with an opportunity to study the
lag of the response of the lens behind the changes in the
ciliary mu.scle.
Innervation Controlling Accommodation
Although the ciliary muscle is classified histologi-
cally as a smooth muscle and the branch of the third
nerve supplying it is identified as a part of the para-
sympathetic system, the ciliary muscle behaves in
many ways like a skeletal muscle. Marg et al. (64) have
demonstrated that in the cat the amount of accom-
modation elicited in response to a square wave gal-
\anic current applied to the ciliary ganglion is a func-
tion both of the strength of the current and the fre-
quency of the stimuli. A submaximal response of any
degree may be elicited.
Allen (2) has developed a method which can be
used in the cat or dog for comparing the lag of the
lens and the lag of the muscle. A faradic stimulus is
applied to the region of the ciliary muscle. A needle
pushed through the sclera into the choroid gives a
record of the muscle response, and motion picture
photography is used to measure the change in size of
the third Purkinje image.
When the eyes accommodate, they also converge
and the pupils constrict. This is known as the triad
response. The convergence part of the triad response
is called accommodative convergence because it is
associated with accommodation. It has to be differen-
tiated from fusional convergence which is a different
kind of response.
Allen (i) devised an arrangement for suddenly
switching from a stimulus at one distance to a stimulus
at a different distance. The stimuli were presented to
one eye only and the ensuing accommodative and
convergence responses were tracked with recording
devices. The accommodative response lags a little
behind the convergence response (see fig. 20) and
this may be due to the lag of the lens behind the re-
sponse of the ciliary muscle. The results confirm the
notion that the two types of responses are initiated
through a common center.
The triad response is probably always brought into
plav bv voluntary effort and it behaves like a postural
adjustment of the arm which may be raised to a given
level and held in that posture while the subject pays
primarv attention to .some other aspect of his behavior.
Under normal conditions of use of the eyes, the only
'^.46
E
E
~.53
UJ
M
u
".73
CONVERGENCE
-^ 3rd PURKINJE IMAGE SIZES
1 I I 1 1 L
O
.5 1.0
TIME (SECONDS)
IS
FIG. 20. Accommodative and accommodative convergence
responses to a change in the stimulus to accommodation. The
points represent sizes of the third Purkinje image measured in
successive frames of a motion picture record occurring at a
rate of 64 per sec. [From Allen (i).]
THE IMAGE-FORMING MECHANISM OF THE EYE
663
awareness of voluntary effort to readjust the triad
mechanism is an awareness of switching attention
from an object percei\eci to be located at one distance
to an object perceived to be located at another dis-
tance (60). As a matter of fact a readjustment of the
triad mechanism can be evoked when the subject is
in total darkness by ha\ing him switch his attention
from an imaginary far point to an imaginary near
point (47). The problem of focusing the eye, however,
is not quite this simple. If the subject starts by paying
attention to a given object, then covers one eye and
places a minus or plus lens in front of the other to
throw the image out of focus, and then concentrates
on the object or attempts to clear up the blur, the
object eventually comes into focus without the subject
perceiving any change in distance. We have yet to
learn whether this response is a result of the voluntary
effort to clear up the blur or a reflex response to the
blur which is akin to the reaction of an automatic
focusing device. Regardless of whether this accommo-
dative response to blur is voluntary or reflex, it ap-
pears to involve the same tie-up with convergence and
pupillary constriction as the accommodative response
to a change in the distance of attention. Considerable
attention is being devoted today to the problem of
whether the eye can detect ahead of time from some
aspect of a blurred image whether to increase or de-
crease accommodation to clear up the blur. Fincham
(28, 29) has investigated the response to blur and has
found evidence that the colored fringes on the target
resulting froin chromatic aberration determine the
direction of the response. Allen (6) has also investi-
gated what determines the direction of the response
when the subject is confronted with a blurred stimulus
with all cues of distance eliminated. In 19 of the 20
trials in which the response was recorded, the subject's
first response was in the right direction and in only
one trial did he make an initial response in the wrong
direction which had to be corrected by a second
adjustment. Astigmatism as well as chromatic aberra-
tion could provide the subject with a cue as to the
right direction.
It is possible that the cortical center which controls
the triad response transmits impulses simultaneously
to the centers in the midbrain controlling convergence,
accommodation and pupil constriction. On the other
hand it is entirely possible that the triad innervation
from the cortex is first transmitted to the center con-
trolling accommodation and relayed from there to
the centers controlling convergence and pupil con-
striction. This is possible because the brain-stem
center controlling accommodation never responds
without the simultaneous occurrence of a convergence
and a pupillary response. However, the accommoda-
tive response could not be mediated either through
the brain-stem center controlling convergence or
through the center controlling pupillary constriction
becau.se these same centers mediate other types of
pupillary and convergence responses which are not
associated with accommodation.
The same center in the midbrain which mediates
the pupillary part of the triad response also mediates
the pupillary response to light. It is assumed to be
located in the Edinger-Westphal nucleus.
Furthermore the brain-stem center which mediates
the convergence part of the triad response also medi-
ates fusional convergence. Both types of convergence
induce an excycloductive movement of the two eyes,
i.e. the two eyes rotate around their lines of sight with
the tops of the eyes turning outward. This indicates
that both types of convergence are mediated by the
same mechanism in the brain stem. There is no cyclo-
rotational movement associated with simple conjugate
movements of the eye to the right or left (5).
On the other hand there is ample evidence that the
brain-stem mechanism for accommodative and fu-
sional convergence receives innervation from two
different cortical centers in mediating these two types
of responses. Fusional convergence is a reflex response
to stimulation of disparate points of the two retinas.
This is probably a feed-back type of response in which
the eyes constantly tend to drift to the phoria position,
i.e. that which they would assume if one eye were
placed under a cover, but are brought back to the
fusion position by the retinal disparity resulting from
the drift.
Knoll (46) and Marg & Morgan (61, 62) have
demonstrated that a marked pupil constriction is
associated with a change in accommodation and ac-
commodative convergence, but the pupil response
associated with fusional convergence is almost negligi-
ble. The very fact that fusional convergence can be
manipulated without affecting accommodative con-
vergence is in itself evidence that it involves a separate
cortical mechanism.
Reese & Hofstetter (7;^) have reported a case
in which accommodation and accommodative con-
vergence were absent, but positive fusional conver-
gence was still operative. An ordinary concomitant
squinter may have a normal amount of accommoda-
tive convergence but a total absence of fusional con-
vergence.
The relationship of accommodative and fusional
convergence (8, 31, 33) at various levels of accommo-
664
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY
Q. 10 —
z
o
o
o
o
SPIKE
LIMIT OF
POS.FUS.CON.
0 50 100
CONVERGENCE (CENTRADS)
FIG. -i I . Relation between accommodation, accommodati\e
convergence and positive and negative fusional convergence in
a normal 20-year-o]d subject.
dation is shown in figure 2 1 . At each level of accommo-
dation the phoria position of the two eyes represents
the position of rest that the eyes assume when one of
them is covered. At the same level of accommodation
the two eyes can be made to converge toward or
diverge away from this position of rest in response to
stimuli upon which the two eyes can fu.se, and the
extent to which this can be done without changing
accommodation gives us the limits of fusional con-
vergence. The phoria line shows the relation between
accommodation and accommodative convergence
when the eyes are freed from fusion stimuli. The re-
ciprocal of the slope of this line is called the ACA ratio.
The 'spike' at the maximum level of accommodation
which indicates that an increased amount of con-
vergence can develop at that level was regarded by
van der Hoeve & Flieringa (87) as evidence that the
ciliary mu.scle can keep on responding after the lens
reaches its limit to respond, van Hoven (unpublished
observations) has shown in six subjects that this is not
the case. He paralyzed one eye with homatropine and
when the eye partially recovered, he measured the
phoria at various levels of accommodation for each of
the two eyes and he also measured the amplitude of
accommodation of each eye by measuring the ac-
commodative response at the maximum level of con-
vergence. He showed that the amplitude is strictly
proportional to the ACA ratio. This means that the
lens is responding to changes in contraction of the
ciliary muscle at the maximum level of accommoda-
tion. Hence it is the muscle and not the lens which
determines the maximum le\'el of accommodation.
Fincham (30) independently performed the same
kind of experiment except that he has also used
physostigmine. This gives a hypermaximal spike
which proves that the limit lies with the muscle or its
innervation but not with the lens.
One can explain the "spike" by assuming that the
ciliary muscle reaches the limit of its capacity to con-
tract before the cortical center controlling the triad
responses reaches the limit of its capacity to initiate
impulses.
The effect of age upon the ACA ratio is important
(8, 18, 30, 40). If the ACA were proportional to the
amplitude it ought to change as the amplitude
changes with age. The studies made so far have not
confirmed this relation. This raises the question
whether the connection between accommodation and
convergence is a matter of habit instead of dependence
on some fixed anatomical arrangement.
Morgan & Olmsted (67) have shown that stimula-
tion of the sympathetic supply to the eye produces a
relaxation of accommodation to the extent of about
0.75 D below what is commonly regarded to be the
zero level. Morgan (66) believed this eflfect to be
mediated by a change in blood volume of the ciliary
body, but Melton et al. (65) have demonstrated in a
ijloodless eye that the eflTect is still obtained. The
mechanism involved has yet to be identified.
Night and Skv Mvnjna
In total darkness and in the absence of a stimulus
to accommodation the refractive state of the eye comes
to rest at a higher level than occurs when the eyes are
looking at a test chart at 20 ft. (47; 48; 56; 57, p. 485;
71 ; 72; 84). The effect of low levels of illumination can
partly be explained (84, 89) by the aberrations of the
eye, but these explanations do not apply in sky
myopia (92). In sky myopia as well as in night myopia
an increase in accommodation of about i D above its
zero level is found to exist. Moreover, VVestheimer
(gi) has shown that under these conditions the ac-
commodation is not fixed but exhibits slow oscilla-
tions up to a diopter in amplitude. These fluctuations
have also been reported by Campbell (14) and by
Chin & Horn (16).
VISU.\L FIELD
The visual field of a gi\en eye is a conical space
with its apex at the center of the entrance-pupil which
contains the chief rays for all parts of the retina that
respond to light. In the ordinary use of the eyes a part
of the field of view is cut off h\ the nose, eyebrow and
cheek.
The direction of a point in the field of \ icw may be
specified in terms of its radial direction and eccen-
THE IMAGE-FORMING MECHANISM OF THE EYE 66=^
tricity from the primary line of sight. Objects in the
zero radial direction lie in the plane of regard to the
left of the line of sight. Other radial directions are dis-
placed clockwise around the line of sight and specified
in degrees from o to 360. This is the same kind of
notation as that used for cylinder axes mounted in
front of the eyes. Eccentricity represents degrees be-
tween the primary and secondary lines of sight.
The limits of the visual fields for the right and the
left eye are shown in figure 22. The combination of
the two monocular fields with their centers coinciding
represents the binocular visual field.
RETINAL ILLUMINANCE
In order for a person to see, it is necessary for
the photoreceptors to react to the light falling on them
b> generating impulses which can be transmitted
to the brain. The response of the photoreceptor is de-
pendent not only on the amount of light directed to-
ward it from the e.xit-pupil but also upon its struc-
ture and orientation with respect to the exit-pupil.
The amount of light falling upon a given photorecep-
tor is dependent upon the amount of light admitted
into the eye from the corresponding part of the field
of view and upon the transmittance of the eye. We
have in the eye not onlv the light which is focused by
the image-forming mechanism at or near the retina
but also a certain amount of stray light. These prob-
lems can all be treated in a quantitative way, although
it is necessary to introduce a few photometric con-
cepts and units. The units which have been used be-
long to the meter-kilogram-second system.
Light and Illuminance
Light is luminous energy, and a unit of this energy
is called a talbot. Illuminance is a term which is used
to describe the rate at which light is falling on a sur-
face from all directions. The statement that one lux
of illuminance is falling on a surface indicates that a
total of one talbot of light is falling each second from
all directions on a square meter of the surface.
Solid Angle
The simplest way to visualize a solid angle is to
consider a certain area on the surface of a sphere.
This area is said to subtend a certain amount of solid
270
RIGHT
FIG. ^2. Monocular and bioncular \'isual tields.
angle at the center of the sphere. It is measured in
steradians and is equal to the area of the surface
divided by the square of the radius.
Luminance
Luminance is a term which may be used to describe
the rate at which light is falling on the e\e from a
given direction. Consider any line of sight. The lumi-
nance in this direction as measured at the center of
the entrance-pupil represents the illuminance per unit
solid angle falling on a surface perpendicular to the
line of sight at the center of the entrance-pupil. One
unit of luminance is equal to one lux of illuminance
per steradian of solid angle.
Retiiuil Illuminance
The illuminance E (luxes) at a given point on the
retina corresponding to a given direction in the field
of view is given by the following equation,
E = BtA cos d/k
where
B = luminance in the given direction (nits),
/ = transmittance of the eye,
A = area of the pupil (//r),
9 = angle of incidence of the chief ray at the plane
of the pupil, and
666
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
A = a constant which represents the ratio of a
given area (m-) of the retinal image to the
corresponding solid angle (steradians) in the
visual field.
Since / and k are constants and since cos 6 in the
usual case may be assumed to be equal to unity,
Troland (85) proposed a unit of retinal illuminance
which he called the photon (now known as the tro-
land). The number of trolands at a given point on the
retina is equal to the number of nits multiplied by the
area of the pupil in square millimeters.
This unit is useful in an experiment in which an
artificial pupil is used, but should not be used when
pupils of different sizes are used unless the proper
allowance is made for the Stiles-Crawford effect.
Transmittance of the Eye
The spectral transmittance of the eye from the
cornea to the retina as measured by Ludvigh &
McCarthy (59) is shown by the dots in figure 23.
This includes consideration of the Icsses by reflection
and scatter at the surfaces as well as the losses by alj-
sorption and scatter in the media. In considering
foveal vision it is necessary to pay attention to the
brown or yellowish spot of macular pigment covering
the central 14-degree region of the retina which is
called the macula lutea. The transmittance of the
macular pigment in this region according to VVald
(88) is given by the circles in figure 23 and the curve
represents the product of the two transmittances
500 600
WAVELENGTH, rriM
FIG. 23. Spectral transmittance of the ocular media. The
circles represent the transmittance of the macular pigment, and
the dots the transmittance of the media from the cornea to the
retina. The curve represents total transmittance. [From Judd
(44)-]
giving the total transmittance of the ocular media.
The absorption in the ultraviolet region depends
largely upon the lens. In an aphakic eye enough ultra-
\iolet reaches the retina so that objects invisible to the
normal eye with ultraviolet illumination are easily
seen by the aphakic eye.
Maxwell's spot, which can be seen when the eye
alternates fixation from a gray surface to a purple
surface of the same brightness, is probably dependent
upon the macular pigment. Walls & Mathews (90)
believe it to be a function of the distribution of differ-
ent kinds of photoreceptors.
Polarization affects the amount of light reaching
the retina as shown by Haidinger's brushes which are
visible in looking at the blue .sky through a polaroid
filter. This polarization effect is attributed to Henle's
fibers (22, p. 806) which radiate from the center of
the fovea and connect the cones at the center of the
fovea with bipolar cells which are displaced toward
the edge of the fovea.
Stiles-Craivjoril Effect
Stiles & Crawford (83) have in\estigated the rela-
tive luminous efficiency of rays entering different parts
of the pupil. The results in the horizontal meridian
in a typical case are given in figure 24. Los.ses from
reflection and scattering at the refracting surfaces
and losses from absorption and scattering by the media
niav contribute to this effect but the most important
factor is the angle of incidence at the photoreceptors.
It is an effect which involves cones but not rods (82)
which are normally oriented. It is not affected by
polarization of the light (70). Phase diflFerences in two
beams entering different parts of the pupil (25) do
not affect the efficiency of the beams when thev are
combined again at the retina, and hence the eflfect
can be treated as if it were produced by a gradient
filter covering the pupil which has a high transmit-
tance at the center which tapers off at the edge.
Stra\ Li§lit in the Eye
There are .several sources of stray light in the eye
(10, 35, 36, 55, 81): fl) diffusion through the sclera and
iris (10, 75); 0 flare in the optical system (55), in-
cluding the light reflected from the iris to the cornea
and thence through the pupil to the retina, and also
part of the light difl"usely reflected by the retina
which mav be reflected back toward the retina by one
THE IMAGE-FORMING MECHANISM OF THE EYE
667
4 3 2 10 12 3 4mm.
DISTANCE FROM THE CENTER
OF THE PUPIL
FIG. 24. The Stiles-Crawford effect. Data for the horizontal
meridian of the right eye of B.H.C. (81). [From Fry (37).]
of the refracting surfaces; <) scatter by the media
(12, 35, 36, 41, 55, 81) including the halos(22, p. 801)
produced by diffraction associated with the micro-
structure of the lens and cornea; (f) diffuse reflection
from the pigment epithelium, choroid and .sclera
(19, 34), this light stimulating the photoreceptors in
passing back through the retina (halation), and then
passing through the vitreous to the other parts of the
retina (after reaching some other part of the retina a
part of the light may be further reflected); e) fluores-
cence of the lens (22, p. 820) and the retina (22,
p. 821) when exposed to ultraviolet light; and /) bio-
luminescence in the photoreceptors which Judd
(44, 69) has proposed may cause one of the images in
the sequence following a flash of light. [The 'blue arcs'
associated with the passage of impulses along ganglion
cell axons across the retina are explained by some
writers as a form of electroluminescence, but the evi-
dence favors the direct electrical excitation of the
underlying eleinents (68).]
In the actual use of the eyes a person is most likely
to run into the problem of stray light in connection
with the impairing effect of a peripheral glare source
on foveal vision. The effect of the glare source on a
given test object can be compared with the effect of
a patch of veiling luminance superimposed on the test
object (41, 42, 80). It is satisfactory to assume that
this effect is mediated by stray light (12, 35, 36, 81)
and hence the luminance of the veiling patch may be
used as a measure of the stray light. In figure 25 the
ratio of the veiling luminance By (nits) to the illumi-
nance E (luxes) in the plane of the pupil produced
by a glare .source is plotted as a function of the angle
d of the glare source from the primary line of sight.
Stray light is especially important in interpreting
the results of electroretinography (11, 13, 38, 93) and
pupillography (39). If the eye is exposed to a small
bright stimulus, the electrical potentials or the
pupillary response produced by the millions of ele-
ments feebly stimulated by stray light may completely
mask the response of the few elements stimulated by
focused light.
BLUR OF RETINAL IMAGE
The retinal image can be treated either as a geo-
metrical or as a physical image. In treating the image
of a monochromatic point source as a geometrical
image, one assumes that the rays from the point source
which pass through the pupil are uniforinly distrib-
uted across the pupil. These rays can be traced to the
retina and the illutriinance at any part of the image
is proportional to the concentration of rays at that
point.
In treating the retinal image as a physical image,
it is assumed that the light entering the eye is propa-
gated in the form of waves and diffraction is taken
into consideration.
The concept of a blur circle produced by throwing
the eye out of focus and of a ijlur ellipse produced by
astigmatism is based upon geometrical imagery. The
100
05° I"
e (DEGREES)
FIG. 25. The equivalent veiling brightness (Bv) of a glare
source at various glare angles (f). [From Fry (36).]
668
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
AR
_
+ 100
-
0
-
^
^
)
-1.00
-
/
/
2 00
/
3C
0
400
500
600
700 8a
X
FIG. 26. Chromatic aberration data of Wald & Griffcn
(89), cited by Fry (37). AR is the distance from the cornea to
the conjugate focus of the retina. X represents wave length.
[From Fry (37).]
-6 -5 -4 -3 -2 -I
BEST SPECTACLE CORRECTION FOR ZONE. DIOPTERS
FIG. 27. Spherical aberration of an eye with various amounts
of accommodation in play. [From Koomen et al. (52).]
light is assumed to be uniformly distributed over the
blur circle or blur ellipse. This approach to the prob-
lem of throwing the eye out of focus is usually quite
adequate.
Geometrical ray tracing is also adequate for
describing and defining aberrations, but in order to
evaluate the effect of aberrations upon the distribu-
tion of illuminance in the retinal image it is necessary
to deal with the physical image.
The a.xial chromatic aberration of the eye can i^e
measured by locating the conjugate focus of the retina
for different wavelengths of light. Figure 26 gives the
average data for the seven subjects of Wald & Griffin
(89) expressed in terms of an eye focused on a yellow
(589 mfx) point at infinit\-.
The spherical aberration of the eye can be expressed
in terms of the conjugate foci of the retina for different
zones of the pupil. Figure 27 shows the data of
Koomen et al. (52) for a typical eye for several dif-
ferent amounts of accommodation. Many arrange-
ments (9, 34, 43, 51, 52) have been used for measuring
the spherical aberration of the eye.
Chromatic dispersion (37, p. 89) of the eye is
dependent upon the axial chromatic aberration of the
eye and the lateral displacement of the pupil from the
incident ray directed through the primary nodal
point of the eye (see fig. 28). Blur produced by chro-
matic dispersion is akin to astigmatism in being
radially asymmetrical. Other aberrations in the
human eye, such as coma and radial and irregular
astigmatism, have not been extensively studied.
Figure 29 shows the effect of diffraction (37, p. 57)
upon the image of a monochromatic point source in
an eye free from aberrations and astigmatism and in
perfect focus. The geoinetrical image would be a point.
Reducing the size of the pupil increases the blur due
to diffraction and minimizes the effect of being out of
focus and the effects of chromatic and spherical aber-
ration. A pupil size of about 4 mm yields maximum
sharpness of \ision in an eve which is well-focused
(17)-
Once the distriljution of illuminance for a single
point is known, the distribution of illuminance on the
CHROMATIC
DISPERSION
OPTIC
AXIS
BLUE
AXIAL
CHROMATIC ABERRATION
FIG. 28. Dependence of chromatic dispersion on axial chro-
matic aberration and lateral displacement of the pupil.
FIG. 29. Disli iliution iit ilhiniinance across the center of the
phvsical image of a monochromatic point source in an eye free
from spherical aberration and astigmatism and focused for
the sharpest possible image.
THE IMAGE-FORMING MECHANISM OF THE EVE
669
on
POINT
LINE
BORDER
FIG. 30. Distributions of illuminance in the images of a point,
a line and a border, representing the same degree of blur.
retina may be calculated for any pattern. The index
of blur <j) proposed by Fry & Cobb (37, p. 33) pro-
vides a method of specifying the amount of blur
regardless of how it is caused. Figure 30 illustrates the
distribution of retinal luminance across the images of
a point, a line and a border. Although 4> may be de-
fined in terms of any one of these images, its meaning
is best comprehended in the case of a line. It repre-
sents the ratio of the area under the curve to the height
of the central ordinate. <t> has the advantage that for
any condition of observation it can be measured ex-
perimentally without analyzing the factors that
contribute to it.
ENTOPTIC PHENOMENA
Entoptic phenomena include the shadows on the
retina of opaque structures inside the eye and the
nonuniformities in the illumination of the retina pro-
duced b\ nonuniformities of index and surface
cur\ature.
A white surface \iewed through a pinhole held
near the primary focal point produces a shadow of the
iris on the retina. The irregularities in the margin are
clearly visible and changes in the size of the pupil
can be observed directly. The Broca pupillometer
(57, p. 237) is based on this method of viewing the
pupil. This method of viewing also makes visible spots
and folds in the cornea, star figures and incipient
cataracts in the lens, and opacities in the \itreous body
which give rise to the muscae volitantes. One can also
see images of the blood corpuscles in the retinal capil-
laries as white spots. If the pinhsle is oscillated back
and forth, one can observe shadows of the large and
also the minute blood \essels. The larger vessels form
a branched tree known as the Purkinje figure.
This Purkinje figure formed by the blood vessels
can also be \iewed !:>> illuminating a spot on the
sclera or by forming a small bright image on the
peripheral retina. By using two point sources, two
shadows can be produced whose angular separation
at the second nodal point can be measured. From this
one can determine the distance of the vessel in front
of the photosensitive elements.
Since the vessels move with the photosensitive ele-
ments, their shadows are not affected by the
micronystagmoid movements of the eye; this pro-
\ides a means of studying adaptation without in-
vohing micronvstagmoid mosements.
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79. SouTH.\LL, J. P. C. (editor). Helmholtz's Treatise on Physio-
logical Optics (translated from 3rd German ed.). Rochester;
Opt. Soc. Am., 1924, vol. I.
80. Stiles, W. S. Proc. Roy. Soc, London, ser. B. 104: 322, 1929.
81. Stiles, W. S. Proc. Roy. Soc, London, ser. B. 105: 131,
1929-
82. Stiles, W. S. Proc. Roy. .Soc, London, ser. B. 127: 64, 1939.
83. Stiles, W. S. and B. H. Crawford. Proc. Roy. Soc, London,
ser. B. 112: 428, 1933.
84. Tousey, R., M. Koomen and R. Scolnick. J. Opt. Soc
Am. 43:926, 1953.
85. Troland, L. T. Principles of Psychophysiology. New York:
Van Nostrand, 1930, vol. II, p. 62.
86. Tscherning, M. Physiological Optics, translated by C. Wei-
land. Philadelphia: Keystone, 1924.
87. van der Hoeve, J. and H. J. Flieringa. Brit. J. Ophth.
8: 97, 1924.
88. Wald, G. Science loi : 653, 1945.
89. Wald, G. and D. R. Griffin. J. Opt. Soc Am. 37: 321,
'947-
90. Walls, G. L. .\nd R. W. Mathews. .New .Means of Studying
Color Blindness and Normal Foveal Color Vision. Berkeley and
Los Angeles: Univ. California Press, 1952.
91. Westheimer, G. J. Opt. .Soc Am. 47: 714, 1957.
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93. Wirth, A. AND B. Zetterstrom. Brit. J. Ophth. 38: 257,
■954-
94. Wulfek, J. W. J. Opt. Soc. Am. 45: 928, 1955.
CHAPTER XXVIII
The photoreceptor process in vision'
GEORGE WALD [ Biological Laboratories, Harvard University, Cambridge, Massachusetts
CHAPTER CONTENTS
Chemistry of Visual Excitation
Rhodopsin
Porphyiopsin
lodopsin
Cyanopsin
Recapitulation
Role of Opsin in Visual Excitation
Physiological Correlations
Absorption Spectra and Spectral Sensitivity : Purkinje
Phenomenon
Visual Adaptation and the Bleaching and Synthesis of
Visual Pigments
Vitamin A Deficiency and Night Blindness
Nicotinamide
CHEMISTRY OF VISUAL EXCITATION
LIGHT INITIATES a ncrvous excitation in the outer
segments of the rods and cones which, transmitted
from one neuron to another to centers in the brain,
ends in exciting visual sensations. To achieve this
resuh probably the whole apparatus must be thrown
into activity; yet all of it waits upon and, to a degree,
retains the impress of the primary processes of ex-
citation in the receptor cells.
The general arrangement of these processes is clear
from first principles. Light to have any effect, chemi-
cal or physical, must be absorbed. The rods and
cones must therefore contain substances which absorb
visible light — hence pigments — and are changed
thereby so as to yield a nervous excitation. The photo-
' The investigations from this laboratory were supported in
part by the Rockefeller Foundation, the Office of Naval Re-
search, and the Public Health Service. The author wishes to
thank Dr. Ruth Hubbard for help with the preparation of
this manuscript.
.sensitive pigments must be continuously restored,
or vision would cease soon after a light went on.
The excitatory state must also be rapidly removed,
or vision would continue long after a light went off.
It would aid the economy of such a system if these re-
actions were coupled so as to complete a cycle but
this, though an advantage, is not essential. All
photoreceptor processes may therefore be formulated
as follows:
» Photosensitive pigment
-Excitatory product^
light
This is not only the basic arrangement for photo-
reception but, generalized to include stimuli other
than light, it must also be the form of all neural
excitation. Every irritable tissue must contain similar
arrangements for reacting with the stimulus, for
removing its effects and for restoring the original
system. One may therefore expect to meet the same
fundamental pattern of reactions at every level of the
\isual pathway; and the entire process of visual
excitation from rods and cones to cerebral cortex
may be conceived as a chain of such .systems. The
peculiar importance of the photoreceptor systems
rests, therefore, not on their intrinsic form but on
their unique sensitivity to light and their initial
position in the chain, by virtue of which certain of
their properties are imposed on the entire visual
response.
Four visual pigments are known : rhodopsin and
porphyropsin in rods, and iodopsin and cyanopsin
in cones. All of them are built upon a common plan.
They are all carotenoid-proteins — proteins bearing
carotenoid chromophores to which they owe their
color and sensitivity to light. The rhodopsin system
will be described in some detail since it provides the
671
672
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
model for all the others. Once this system is under-
stood, the others emerge as simple variants upon a
common theme.
Rhudo/isiii
Franz Boll discovered the red pigment rhodopsin
in the rods of frogs in 1876 (5). It is characteristic
of the rods of marine fishes and land \ertebrates
(62). There is no evidence (hat it is ever found in
cones.
Some years ago rhodopsin was shown to par-
ticipate in a cycle of the following skeletal form (56) :
Rhodopsin
/■
Vitamin A + opsin <
('visual white')
\Ught
\
(orange intermediates)
\
Retinene + opsin
('visual yellow')
Rhodopsin bleaches in the light through orange
intermediates to a mixture of the yellow carotenoid,
retinene, and the colorless protein, opsin (fig. i).
The retinene is then converted to colorless vitamin
A. Rhodopsin is resynthesized on the one hand from
retinene and opsin, on the other from vitamin A
and opsin.
Morton has shown that retinene is vitamin A
aldehvde (3):
CH,
CH;,
C CH, CH,,
y \ hh|hhh|hh
HjC C— C=C— C=C— 0=C— C=C— C— OH
I II H
\ /
c
Vitamin A
FIG. I. .Absorption spectra of bullfrog
rhodopsin and of the product of its
bleaching in aqueous digitonin solution,
pH 5.55- Rhodopsin possesses three ab-
sorption maxima: the a-band, mainly
responsible for the spectral sensitivity of
rod vision; the ^-band, which, like a-,
belongs to the prosthetic group; and
the 7-band, due to the protein opsin.
On bleaching, the a- and (3-bands are
replaced by the retinene band at about
385 m/i; the opsin band remains un-
changed. [From Wald (63).]
2 Z
2.0
1.8
1.6
14
l.i
1.0
0.8 -
0.6 -
0.4 -
0.2
Rhodops in
B ie ached product
200
400 SOO
600
THE PHOTORECEPTUR PROCESS IN VISION
673
CH,
CH,
B.C.
H,C
CH, CH;,
H H j H H H I H H
-C=C— c:=c— C=C— C=C— c=o
C— CH3
C
H.
Retincne
The retinene formed Ijv the bleaching of rhodopsin
is reduced to vitamin A by the enzyme, alcohol
dehydrogenase, working together with the coenzyme,
DPN. This process is readily carried out in free
solution (fig. 2). It involves only the transfer of
hydrogen from reduced DPN to the aldehyde group
of retinene, reducing it to the alcohol group of
vitamin A (4, 64, 75):
CsHjjCHO + DPN— H + H+
retinene
alcohol dehydrogenase
C,,H„CH,OH + DPN+
vitamin A
0.4 -
0.3 -
C
o
^0.2
Uj
07 -
0 -
1 1 1 1
/ taminAj-* — ref i nene j
Frog
apoemyme
+ DPN-H
300
400
Wavelength - mjj
FIG. 2. The reduction of retinene to vitamin .\. Retinene
was mixed in digitonin solution with the enzyme, alcohol
dehydrogenase, extracted from frog retinas, and with reduced
cozymase (DPN-H). A control mixture was also prepared
which differed only in that the enzyme had been kept at ioo°C
for 0.5 min. Both mixtures were incubated, then extracted
with hexane. The absorption spectra of the hexane extracts
are shown. The control mixture (^solid circles') contains unaltered
retinene; the mixture containing active enzyme (_open circles)
shows complete conversion to vitamin .\. [From VVald (64).]
DPN introduces a second \itamin into the chem-
istry of vision. Its active principle is nicotinamide,
the antipellagra factor of the \itamin B complex.
In the retina it is in the curious position of helping
to regenerate vitamin A.
This completes the degradative processes in vision.
Rhodopsin having been bleached by light to a mix-
ture of retinene and opsin, the retinene is reduced to
vitamin A. The problem now is to go back. Kiihne
already recognized this to be a dual problem (38).
He described a resynthesis of rhodopsiti from yellow
precursors (anagenesis) which was relatively rapid
and occurred not only in the intact eye but in the
isolated retina and even slightly in solution. In
addition there occurred a relatively slow synthesis
of rhodopsin from colorless precursors (neogenesis)
which Kiihne could ob.serve only in the intact eye
and which seemed to require the cooperation of the
pigment epithelium. These two processes can now
be identified with the synthesis of rhodopsin from
retinene and opsin, and from vitamin A and opsin.
The synthesis of rhodopsin from retinene and opsin
is a spontaneous reaction. It requires neither an
enzyme nor, as do most syntheses, an external source
of energy. One has only to bring a mixture of these
two substances into the dark to form rhodopsin
(67). Like all spontaneous reactions, it is an energy-
yielding process, which can therefore do work. The
work it does in vision is to force the oxidation of
vitamin A. The equilibrium between vitamin A
and retinene lies far over toward the side of re-
duction— toward vitamin A. In the dark, however,
opsin "traps' retinene, removing it to form rhodopsin,
so displacing the equilibrium in the oxidative di-
rection. The basic mechanism of rhodopsin synthesis,
therefore, is the energy-demanding oxidation of
vitamin A to retinene, coupled with the energy-
yielding condensation of retinene and opsin to form
rhodopsin (33, 76).
One important consequence of this arrangement
is that it is self-limiting. Vitamin A is oxidized to
retinene only as long as opsin is available to trap
the latter. Retinene therefore never accumulates.
When all the opsin in the visual receptors has been
converted to \isual pigments, the oxidation of vitamin
A automatically ceases.
The rhodopsin system in more detail therefore
has the form shown in figure 3. Rhodopsin is con-
verted by light to the orange-red intermediate,
lumi-rhodopsin. .\t temperatures above — 20°C
this goes on to form meta-rhodopsin; and with access
674
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
T^hodopsin
l,ghf
Lumi-rhodopiin
[.>-20°C.
Me ta - rhodops in
alcohof dehydrogenase
DPfJ-H
Vitamin A, i-Opsin -■ =^ Fietinene, -h Opsin
w
VtiarrtinAj from
pigment epithelium
and circufaiion
DVN-H
FIG. 3. Diagram of the rhodopsin system. [From Hubbard
& Wald (33).]
to water, meta-rhodopsin yields retinene and opsin
(74). The retinene is then reduced to vitamin A.
In the dark, the spontaneous combination of reti-
nene and opsin to form rhodopsin promotes the o.xi-
dation of vitamin A to retinene. This process is
aided Idv the influx of new vitamin A from the pig-
ment epithelium which obtains it from the blood
circulation, by the provision of DPN, the oxidant of
vitamin A, and by respiratory enzymes, which keep
DPN oxidized. All these factors acting in concert
sweep the system back toward rhodopsin (33).
It should be noted that light enters this scheme
directly at only one point, the conversion of rhodopsin
to lumi-rhodopsin. The other reactions follow from
this initial act but are themselves 'dark' reactions,
i.e. reactions which proceed equally well in light
or darkness.
Judging from figure 3, it should be possible to
assemble the rhodopsin system by mixing four sub-
stances in solution: vitamin A, opsin, alcohol de-
hydrogenase and DPN. The system has, in fact,
been put together using highly purified vitamin A,
crystalline alcohol dehydrogenase from horse livers
and DPN from yeast. The only component that
needs to be obtained from the retina, and indeed
from the outer segments of the rods, is opsin. This
mixture, placed in the dark, forms rhodopsin.
Brought into the light it bleaches, and replaced in
the dark it synthesizes more rhodopsin. It thus per-
forms in solution all the reactions of the rhodopsin
system (33).
However, in making up this mixture, not all
vitamin A is effective. \'itamin A, like other carot-
enoids, exists in a number of different molecular
shapes, cis-trans isomers of one another (47, 83, 84).
A.\\-trans vitamin A (fig. 4), the predominant isomer in
liver and blood (Wald, G. & P. S. Brown, unpub-
lished observations), is ineffective in rhodopsin
synthesis. Rhodopsin requires for its formation one
of the cis isomers of vitamin A (34).
According to theory, only two of the four side-
chain double bonds of vitamin A should be capable of
forming stable m-linkages, those marked 9 and 13
in figure 4. At the other double bonds, a cis linkage
encounters serious steric hindrance, and the molecule
must be twisted out of coplanarity. This interferes
with resonance and should consequently lead to a
lowered stability (42, 43). Only four geometrical
isomers of vitamin A or retinene were therefore
expected: a\\-trans, g-cis, I'^-cis, and 9, 12,-dicis (fig. 4).
Five cis-trans isomers of retinene, however, have
been identified and crystallized (10, 32, 39, 48):
CH,
CH,
ripC 4 f, t- L. t- *- \
1 I
CH,
a//-fran3
viiamin fi
^c-^'^X
H,C C ^C C
c c
reiinene
13 —CIS
(neo - a)
CH,
'3 »
CH,
Hx/^^v^N^N-
H,C C-CH, c^
1^, I
9 -as
ftso-a)
CHj ^C
CH,
CH,
H,C ^c c c
'1 I t^ I
H,C C-CHj
^C-^ CH,
h'-'^^-h
9,)3 -d^as
(iso - b)
CH, C
(4
FIG. 4. Unhindered geometrical isomers of vitamin .-K. Tiiis
molecule can assume the eis configuration only at double
bonds 9 and 1 3 without encountering serious steric hindrance.
At the other double bonds, groups come into conflict, and the
CIS configuration not only bends but twists the molecule.
[Modified from Hubbard & Wald (34).]
the al\-trans isomer, originally prepared by Ball et al.
(3); the three unhindered cis isomers — neo-a (i3-«.s-),
iso-a (g-m) and iso-A ((),\j,-dicis); and a hindered
cis isomer of the type which had been deemed im-
probable on theoretical grounds (fig. 5). This hin-
dered cis isomer, neo-A (ii-m), is the precursor of
rhodopsin (32, 39).^
The synthesis of rhodopsin proceeds in two stages.
First, vitamin A is o.xidized to retinene; then rctinene
couples with opsin. The first process is relatively
indiflferent to isomeric configuration. It is the coupling
of retinene with opsin that is isomer-spccific.
On incubation with opsin in the dark, neo-6
retinene yields rhodopsin, indistinguishable from
that extracted from the dark-adapted retina. On
similar treatment, iso-a retinene yields a very similar,
light-sensitive pigment, with its X„,,,s displaced about
13 m/i toward shorter wavelengths. This is called
iso-rhodopsin. The remaining isomers are inacti\e
(fig. 6).
When rhodopsin is bleached, the retinene which
emerges is a\\-trans. This must be isomerized to the
active isomer, neo-6, before it can resynthesize
rhodopsin. A cycle of cis-trans isomerization is there-
fore an intrinsic part of the rhodopsin system.
A single passage through this cycle is shown in
figure 7. On the left, a mixture of neo-A retinene and
cattle opsin in aqueous solution incubated in the
dark forms rhodopsin. On the right, the rhodopsin
formed in this way is bleached to a mixture of all-
Irans retinene and opsin. The extinction of retinene
which emerges on the right is much higher than that
which enters on the left. That is because the specific
extinction of a\\-trans retinene is higher than that of
the neo-i isomer.
The mechanism by which the eve converts all-
trans retinene, which results from bleaching rho-
dopsin, to nco-h retinene is not entirely clear. All-
trans retinene is isomerized to a mixture of cis and
tram isomers by simple exposure to light. This is a
second photochemical process in the rhodopsin
system. The eye tissues also contain an enzyme,
retinene isomerase, which catalyzes specifically the
interconversion of a\\-trans and neo-6 retinene, and
which is also light-sensitive (31). There probably are
additional mechanisms for converting aW-trans rcti-
nene or vitamin A to the neo-A isomer.
The rhodopsin system can therefore be formulated
^A si.xth isomer of retinene, called neo-c (11, lydicis"),
has since been synthesized by Oroshnik (39).
THE PHOTORECEPTOR PROCESS IN VISION 675
as follows (34) :
Rhodopsin
Neo-6 retinene -t- opsin -
-. W\-lrans retinene -|- opsin
[ (alcohol dehydrogenase, DPN)
J
Neo-A vitamin A -
; All-;raHf vitamin A
Vitamin A emerges from the bleaching of rhodopsin
as the free alcohol; yet the great bulk of the vitamin
H,C C
^^'\./
C-CH3
CH.
CHf
-%
^c'""
.'T.'^'^^'H
CH
CHg^OH
11 -cis (neo-b)
FIG. 5. The sterically hindered neo-b (11 -aV) isomer of
vitamin A, precursor of rhodopsin and iodopsin. [From Orosh-
nik e/ al. (40).]
0.3 __
O.Z.
0.1
0._
-0./-_
"1 1 1 \
opstn -f- retinene isomers
o a!I~iran5
• neoretinene a
9 neoretinGne b
e isoreiinene a
— o
C
wave length — m/^
400
450 500
550
600
FIG. 6. The products of incubating various geometrical
isomers of retinene with cattle opsin. Difference spectra are
shown — differences in the absorption spectra before and after
bleaching in the presence of hydroxylamine. A\l-lrans and
neo-a retinene yield no light-sensitive pigment. Neo-A retinene
yields rhodopsin; iso-a retinene, iso-rhodopsin. Iso-A retinene,
though itself inactive, isomerizes preferentially to iso-a which
yields iso-rhodopsin. [From Hubbard & Wald (34).]
676
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
FIG. 7. Synthesis and bleaching of
rhodopsin in solution (22.5°C, pH 7.0).
Left: A mixture of neo-A retinene and
cattle opsin was incubated in the dark,
and absorption spectra recorded peri-
odically, (/) at 0.3 min., (5) at 2.5,
(3) at 5, (^) at 10, (5) at 18, (ff) at 30,
(7) at 60, (<9) at 120 and (5) at 180 min.
The absorption band of neo-A retinene
(Xmax 380 m^i) falls regularly, while that
of rhodopsin (X„,ax 498 m^) rises. Righl .
The rhodopsin formed at the left (;) is
exposed to light of wavelengths >550
mil for various intervals, and the spec-
trum is recorded immediately after each
exposure. The total irradiations are: (2)
5 sec, (3) 10 sec, (^) 15 sec, (5) 30
sec, and (5) 120 sec. The residue was
exposed for 45 sec. longer to light of
wavelengths >440 mn (7). [From VVald
6 Brown (70).]
300 400 SOO 600 400 500
Wavelength- m/u
600
A stored in the eye (primarily in the pigmented
layers, choroid and pigment epithelium) is in the
form of an ester. Recently a cell-free enzyme system
has been prepared from cattle retinas and pigmented
layers which esterifies vitamin A in vitro (38). The
significance of this reaction for the visual cycle is
still obscure. It is, however, noteworthy that the
amount of vitamin A ester stored in the dark-adapted
eye is roughly equivalent to its rhodopsin content on a
molar basis, and that the neo-h isomer constitutes
about one-half of this store (37; VVald, G. & P. S.
Brown, unpublished observations).
Porphyropsin
The rods of vertebrates which li\e in, or better,
spawn in fresh water — fresh-water fishes, spaw^ning
lampreys, and certain larval and adult amphibia —
characteristically contain in place of rhodopsin a
purple light-sensitive pigment called porphyropsin
(62). Its X„i;,x in aqueous .solution ordinarily is close
to 522 niM (fig. 8). On bleaching, it yields a mixture
of opsin and a new retinene called retinenca, and
this in turn is reduced to a new vitamin A called
\itamin A-j. It was the analysis of this visual system
that led to the discovery of these carotenoids (57,
60). The structures of these substances have now been
established by total synthesis (13). They differ from
\itamin A and retinene' — sometimes called vitamin
Ai and retinenei — only in possessing an additional
double bond in the ring:
CH3
CH3
C CH., CH3
/\ hh|hhh|hh
H2C c— c=c— c=c— c=c— c=c— c-
1 II H
-OH
HC C— CH3
\ /
c
H
Vitamin A2
2 Throughout this discussion, the terms vitamin A and
retinene will be used synonymously with vitamin Ai and
retinenei.
THE PHOrORECEPTOR PROCESS IN VISION
677
CH,
H,C
HC
\
C
H
CH3
/
CH, CH;,
^ H H I H H H 1 H H
C— C=C— C=C— C=C— c:=c— c=o
II
C-CH3
Retinene.,
The properties of the porphyropsin system arc in
general precisely parallel with those of the rhodopsin
system. Alcohol dehydrogenase and DP\ catalyze
the equilibrium between retinenes and vitamin Ao
just as between retinenei and vitamin Ai (64). The
bleaching of porphyropsin yields an inactive form of
retineneo, apparently the dW-lrans isomer.
The geometrical isomers of retinenez have not been
investigated as thoroughly as those of retinenei.
Nii-trans retinene2 has been crystallized. Two cis
forms of retinene2 have been partially purified, though
not crystallized. These resemble in their spectro-
scopic properties respectively the neo-i and iso-o
isomers of retinenei. Neo-fe retinene^, when incubated
in the dark with opsin, yields porphyropsin, in-
distinguishable from that extracted from a dark-
adapted fresh-water fish retina; whereas iso-a retinene
treated similarly yields a comparable pigment, iso-
3.0
2.5 -
2.0 Y
C
.0
0
K
1.0
OS
0 -
1 \ — r
"Porphyropsin - yo//ow/ perch
• unbleached
o bleached
J L
J 1 1 1 ^_
\ L
300
400
£00
600
FIG. 8. Absorption spectra of porphyropsin and of the product of its bleaching (pH 7.0) from
the fresh-water yellow perch, Perca flavescens. This preparation was extracted with 2 per cent digi-
tonin from a suspension of rod outer segments, which had been previously hardened with alum,
and pre-e.\tracted with water and with petroleum ether. Porphyropsin, like rhodopsin, possesses
three absorption bands: the a-band about 522 m^ at, the /3-band at about 377 m/x, and the 7-band
(opsin) at about 280 m/i. On bleaching, the a- and /J-bands are replaced by the absorption band
of retineneo , at about 400 m^i. [From Wald, G., P K. Brown & P. .S. Brown, unpublished ob-
servations, i
678
HANDBOOK OF PHYSIOLOGY
NEURiil'in^iOLGGY I
008\- K
T — r
T
Lepomia op sin
o* n*o-b rei inQna^
• ■mo- ex rei tnanOi
J \
be formulated :
FIG. 9 Synthesis of poiphyropsin and iso-porphyropsin. The
neo-A and iso-a isomers of retinene; , partially purified, were
incubated with opsin from the sunfish, Lcpomis. The difference
spectra of the products are shown, measured in the presence
of hydroxylamine. The neo-6 isomer yields porphyropsin
(Xmai , 522 m^i), the iso-a isomer iso-porphyropsin (Xmax ,
507 m^)- [From Wald, G., P. K. Brown & P. S. Brown, un-
published observations.]
porphyropsin, with X^ax 507 m^ (hg- 9; Wald, G.,
P. K. Brown & P. S. Brown, unpublished obser-
vations).
In performing such syntheses it makes no difference
whether the opsin is derived from a fresh-water
fish, a frog or cattle. All these opsins when mixed
with neo-6 retinenej yield porphyropsin, while with
neo-/> retinenei they form rhodopsin. The pigments
obtained with cattle opsin lie at slightly shorter
wavelengths than those obtained with frog opsin:
'cattle porphyropsin' lies at X,,,.,^ 517 ni/j, while
'frog porphyropsin' has Xmax 5-;-^ ni/i. Cattle and frog
rhodopsins display similar differences: the former
has Xmax 498 m/i, the latter Xmax 502 m^i. Clearly
species differences in the opsin affect the X,„:,x of
the visual pigments.
The opsins of the rods that have been examined are
so closely related that they must be regarded as
belonging to the same family, the rod opsins or
scotopsins. The rhodopsin and porphyropsin systems
therefore share entirely the same proteins. Only their
carotenoids differ and those only by one double bond
in the ring. The porphyropsin system can therefore
Porphyropsin
Neo-A retinenco -|- scotopsin .KW-Uans retinene-j -\- scotopsin
[ (alcohol dehydrogenase, DPN)
Neo-A vitamin Ao
-^ All-(ra«i vitamin Aj
lodopsin
The first light-sensitive pigment of cone vision was
extracted from the chicken retina in 1937. It is a violet
pigment (Xmax 562 m/x) called iodopsin. The chicken
retina contains a few rods among a large predomi-
nance of cones and hence yields a mixture of iodopsin
and rhodopsin (58).
The carotenoids of the iodopsin system are identical
with those of the rhodopsin system, even to cis-trans
configuration. Only the opsin is different. The cone
opsins can be called photopsins. The replacement of
.scotopsin by photopsin changes the rhodopsin to
the iodopsin system (72) :
lodopsin
/ light
/ \
..\\\-lrans retinenei -f photopsin
Neo-A retinenei + photopsin
(alcohol dehydrogenase, DPN)
Neo-A vitamin Ai —
" All-trans vitamin .^i
From the light-adapted chicken retina one can
extract a colorless carotenoid-free mixture of the
proteins of rod and cone vision, scotopsin and pho-
topsin. On incubating this, or a wholly bleached
extract of chicken retinas, in the dark with neo-A
retinenei, one obtains a mixture of rhodopsin and
iodopsin indistinguishable from that extracted from
the dark-adapted chicken retina (fig. 10).
Just as iso-a retinenei yields iso-rhodopsin when
incuijated with rod opsin, it yields a similarly dis-
placed pigment, iso-iodopsin, on incubation with
cone opsin. The Xm.ix of iso-iodopsin is at about
515 m/i. The remaining isomers of retinene are in-
active (fig. 1 1).
Cya7}opsin
Rod opsin combines with nto-b retinenei to yield
rhodopsin, or with neo-6 retineneo to yield por-
THE PHOTORECEPTOR PROCESS IN VISION
679
0.4
-1 1
— 1 r- I ■ I 1 1 1 1 1-1-
Synthes/\s of phoiopigmGnts
~
from chicHen opsins-^
03
r^^^ •-*- ca/cLf/ated amount re^/nene _
4/
U
c
/o ftv • ° "'' ^"^055 retinene
0.d
k!i
/ \ \
V
0.1
-
\ \
-
X^^^ \.
0
-I L
1 1 1 1 I. -J \ \ \ L
500
700
FIG. 10. Successive syntheses of iodopsin and rhodopsin
in solution. An extract of chicken retinas was wholly bleached
with an orange nonisomerizing light to a mixture of all-/ra«j
retinene and rod and cone opsins. To this mixture just enough
neo-A retinene was added to regenerate iodopsin alone. This
amount had been determined by preliminary trial. Iodopsin
forms so much more rapidly than rhodopsin that its synthesis
is complete when that of rhodopsin has scarcely begun (cf.
fig. 2i). The absorption spectrum of the product, formed within
a few minutes in the dark, is shown with ^olid circles. Then a
small excess of neo-b retinene was added, and the mixture was
reincubated in the dark for 30 min. This yielded rhodopsin
(_open circles). [From VVald el al. (72).]
phyropsin. Cone opsin combines with neo-^ retinenci
to yield iodopsin. Clearly a fourth combination is
possible: cone opsin with neo-ft retinenej.
This synthesis was recently performed in our labora-
tory. It yielded a blue photosensitive pigment called
cyanopsin which absorbs maximally in the orange-
red, at about 620 m/z (7i)- Always heretofore knowl-
edge of a visual pigment had developed in the
sequence: recognition, extraction, analysis, synthesis.
With cyanopsin this history was reversed. A pigment
was synthesized in solution which had never been
identified in a retina. Had it a place in vision?
Where would one look? Obviously in retinas which
provide its ingredients: cones, hence photopsin; and
vitamin Ao. One might therefore look for cyanopsin
in a fresh-water fish possessing cones, or in the all-
cone retina of such a turtle as Pseudemys, which had
been shown to contain \itamin A2 CvO-
Some years ago Granit measured electrophysiologi-
cally the spectral sensitivity of cone vision in a fresh-
water fish, the tench, and in the European tortoise,
Testudo graeca (15, 16). His measurements are shown
as the points in figure 12; the line is the main ab-
sorption band of cyanopsin. There is little doubt
that cyanopsin is the pigment of cone vision in these
animals.
Recapitulation
This phase of the chemistry of visual excitation
ends on a very simple note. The visual systems which
have been studied involve the interaction of four
substances: a rod or cone opsin; the enzyme, alcohol
dehydrogenase; the coenzyme, cozyniase; and neo-6
Qii-cis) vitamin Ai or Aj. They can be summarized:
light
DPN+ I -\- rod opsin rhodopsin
vitamin A, . retinene, , 'ight
DNP-H [-f cone opsin . iodopsin
(alcohol dehydrogenase)
light
DPN"*" [ +rod opsin . porphyropsin
vitamin A2 retinene2 j light
^ cyanopsin
DPN-H
[-\- cone opsm -
In addition there are the four iso-pigments, the
carotenoid chromophores of which are stereoiso-
meric with those of the visual pigments. Since none
of the iso-pigments has yet been found in a retina,
they must for the present be regarded as artifacts.
How does the retina avoid forming them? Prelimi-
nary measurements indicate that traces of iso-a
vitamin A are present in liver oils, while in cattle
blood the iso-a isomer accounts for about 6 per cent
of the total vitamin A. No iso-a vitamin A has been
detected in the retina and pigment layers of the eye,
whereas the neo-b isomer is found only in the eye
(Wald, G., P. K. Brown & P. S, Brown, unpublished
observations). It is therefore likely that the eye actively
forms neo-6 vitamin A — presumably from the all-
trans isomer — and actively excludes iso-a vitamin A.
Role of Opsin ill I'isuai Exeilation
To this point the visual pigments have been dis-
cussed mainly from the point of view of their carot-
enoid components. Their properties, however, depend
greatly also upon the opsins. Though their color and
sensitivity to light are mediated principally through
the carotenoid prosthetic groups, almost everything
else derives from their character as proteins. Light
liberates retinene. Yet, like other carotenoids,
retinene is a bland, relatively inert substance, hardly
capable of initiating a nervous excitation. Further-
more, at physiological temperatures and pH it is
released relatively slowly as the last step in a chain
680 HANDBOOK OF PHYSIOLOGY ^ NEUROPHYSIOLOGY I
T
0.30 -
0.20
c
o
o ._
c
><
1 r
T
neor&iinene a
o //-trans reiinene
S'^nthes/s of iodops/ns
from sfGreo/somers
of retinenQ
/so- lodops/ n
/
/oolops/n
^ '• ^' necreiinene h
300
400 SOO
VMcxvelencjth-^ mjj
600
700
FIG. II. Synthesis of iodopsin and iso-iodopsin. In a chicken retinal extract, the iodopsin alone
was bleached with deep red light to a mi.xture of all-(ra;?.s retincne and photopsin. This product
was incubated in the dark with four geometrical isomers of retinene. The absorption spectra were
then measured against the red-bleached solution as blank. .\\\-trans and neo-a retinene synthesized
no photosensitive pigments, hence remained almost as added. Neo-i retinene formed iodopsin
C^inax 562 m^); iso-a retinene, iso-iodopsin (Xmax 510 m/i)- Both photosensitive pigments are ac-
companied by residues of unchanged retinene, primarily responsible for the absorption bands at
about 370 my.. [From Wald et al. (72).]
of reactions initiated by light (viz fig. 3 and text
above), whereas the nervous response, e\en in a
cold-blooded animal, appears within a fraction of a
second. Changes in the opsins therefore would seem
to offer richer possibilities.
Rhodopsin has been studied most in this regard.
Cattle rhodopsin has a molecular weight of about
40,000 and contains one molecule of retinene (30).
It has a molar extinction of 40,600 (69). The iso-
electric point of frog rhodopsin is at pH 4.47 and
goes to pH 4.57 on bleaching (7); cattle rhodopsin
is isoionic at pH 5.4 and goes to pH 5.5 on bleaching
(45). Neither cattle rhodopsin nor opsin contains
available N- or C-terminal amino acids (i).
The synthesis of rhodopsin from retinene and
opsin requires the presence of free sulfhydryl ( — SH)
groups on opsin. Conversely, the bleaching of rho-
dopsin liberates 2 or 3 — SH groups per molecule.
This is true equally for rhodopsins from cattle, frogs
and squid (68, 69). Exposure of rhodopsin to light
also immediately exposes an acid-binding group with a
pK of about 6.6, close to the pK of the imidazole
group of histidine (45). Furthermore, opsin is much
more readily denatured by acid and alkali, or heat,
than rhodopsin (31a, 46).
All of this means that the action of light on rho-
dopsin, in addition to splitting off carotenoid, pro-
foundly affects the reactivity of the opsin. In the
structural context of a rod outer limb, these or like
changes are probabh' the ultimate source of excita-
tion.
It is important to realize that rhodopsin is one of
the principal structural components of a rod. It
accounts for about 40 per cent of the dry weight of
THE PHOTORECEPTOR PROCESS IN VISION
68 1
7^
W
to
C OS
(1)
<o
o
06 -
0/S
C 0.2
0
• Cyanopsm absorption
Spectral sensiiivity.
<D 'tortoise
© trench
V^ave1enc)th-m)j
I I I I ^
soo
600
700
FIG. 12. The absorption spectrum of cyanopsin compared with Granit's electrophysiological
measurements of the spectral sensitivity of cone vision in a fresh-water fish, the tench, and in the
European tortoise, Testudo graeca. [From Wald et a/. (71).]
the outer segment of a frog rod, or about 60 per cent
of the nonlipid dry weight. In cattle rods, it accounts
for about 14 per cent of the dry weight of the outer
segment, or about 22 per cent of the nonlipid dry
weight (30). The outer segments of the rods and
cones are layered structures composed of several
hundred to several thousand layers, apparently of
protein, each about 40 to 160 A thick (52). The
membranes of the rod must be made in large part of
rhodopsin (or porphyropsin). A cone has much the
same construction, though in some cones the visual
pigments may compose a smaller fraction of the
membranes (65).
Two model systems have been described in which
the bleaching of rhodopsin in solution registers
directly as an electrical fluctuation (45, 68). Both are
based on the fact that light exposes ion-binding
groups on opsin, sulfhydryl groups in one case, an
acid-binding group with pK 6.6 in the other, which
aflTect the ion concentration in the medium. These
models show that rhodopsin has the capacity to
translate the absorption of a quantum of light into
an electrical event. The eflfective utilization of this
capacity depends entirely upon the structural frame-
work within which it occurs. A dark-adapted rod is
stimulated by the absorption of a single quantum of
light (6, 29, 44). The same probably is true of a
dark-adapted cone. One quantum of light is absorbed
by one molecule of visual pigment, and a rod or cone
is so peculiarly constructed that so small a change
can excite it.
PHYSIOLOGICAL CORREL.ATIONS
Every physiological function, normal and path-
ological, has its roots in biochemistry; conversely
every facet of biochemistry finds expression in the
properties and behavior of the organism. In a sense
the organism is a macroscopic representation of
certain of its component molecules, and one of the
principal tasks of physiology is to learn to read its
features in their features.
This is nowhere plainer than in \ision. The re-
actions initiated by light in the rods and cones in-
troduce a long train of nervous and s\naptic proc-
esses which end in visual sensations. The primary
events have been described in some detail. The
visual apparatus as a whole is largely concerned
with conducting the information they dictate. For
this reason many of the basic properties of vision
reflect simply and directly the properties of retinal
molecules.
It is of the highest importance to explore lhe.se
relationships. Needless to say, there is much more in
vision than photochemistry, or indeed than any of
682
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
the peripheral processes one can measure. Yet it is
important to learn how far one can come with these
if only to know that one must seek elsewhere for
what remains.
Absorption Spectra and Spectral Sensitivity:
Purkinje Phenomenon
The rise and fall of \isual sensitivity throughout
the spectrum is governed in the first instance by the
capacity of the visual pigments to absorb light of
various wavelengths, i.e. by their absorption spectra.
When properly corrected, the spectral sensitivity
should correspond closely with the absorption spectra
of the visual pigments.
For such a comparison, the spectral sensitivity
must be corrected for distortions caused by colored
ocular structures, in the human eye principally the
yellow lens and macula lutea and similar structures
in the eyes of other animals. The spectral sensitivity
also should be quantized. What is measured generally
is the relative energy at each wavelength needed to
evoke a constant response. The reciprocal of this is
the relative sensitivity, and this divided by the wave-
length is the sensitivity in terms of relative numbers
of incident quanta. This is the form in which spectral
sensitivity data can best be employed for the present
purpose.
The spectra of the visual pigments should be stated
in terms of percentage ab.sorption rather than ex-
tinction (cf 59). The point of this distinction is that
all extinction curves are simple multiples of one
another, whereas a percentage absorption curve has a
unique shape depending upon the actual value of the
absorption. However, extinction and percentage
absorption are almost exactly proportional to each
other up to 10 per cent absorption and depart only
slightly from proportionality up to aljout 20 per
cent absorption. All known cones and most rods seem
to have absorptions below this value. Extinction
therefore runs parallel with absorption for all cones
and for all but the more densely pigmented rods.
In the figures which follow, the absorption spectra
of the visual pigments have been plotted in terms
of relative extinction since the percentage absorption
usually is not known. This introduces appreciable
distortion only in comparison with frog rod \ision
(cf. fig. 14)-
Figure 13 shows the comparison between the
absorption spectra of chicken rhodopsin and iodopsin,
and the spectral sensitivity of rod and cone vision in
the pigeon. It would, of course, be preferable to com-
pare the spectral sensitivity of the chicken, but
in the absence of accurate data measurements on the
closely related pigeon have been used. They were
obtained by inserting microelectrodes into the retina,
following removal of the lens and cornea (11, 19).
The pigeons were either dark-adapted i to 2 hours
following the operation, or were light-adapted. At
each wa\elength, measurements were made of
the energy needed to evoke a constant electrical
response. The reciprocal of the energy, the sensi-
tivity, was quantized by dividing by the wavelength.
The scotopic sensitivity agrees very well with the
absorption spectrum of rhodopsin. The photopic
sensitivity however is displaced about 20 m/i toward
the red from the spectrum of iodopsin. This displace-
ment must be caused in large part by the brightly-
colored oil globules which lie in the cones of chickens
and pigeons in the position of color filters (79, 80).
The displacement seems larger than the color filters
of the chicken retina should cause and may mean
that many of the electrophysiological measurements
happened to fall within the 'red field' of the pigeon
retina, the dorsotemporal quadrant in which deep
red oil globules predominate.
The shift of spectral sensitivity toward the red as
one goes from scotopic to photopic conditions, from
rod to cone vision, is the well-known Purkinje
phenomenon. Except for the distortion just alluded
to, this is accurately mimicked in solution by the
absorption spectra of rhodopsin and iodopsin.
This comparison gains special force when made
with retinas which do not possess obviously colored
filtering pigments. In figure 14 the absorption
spectra of chicken rhodopsin and iodopsin are
compared with the spectral sensitivities of rod and
cone vision in the frog, snake, guinea pig and cat,
measured with electrical procedures by Granit and
co-workers. The scotopic data agree very well with
the absorption spectrum of rhodopsin. The photopic
sensitivities agree so well with the absorption spec-
trum of iodopsin that it seems probable that this is
the major pigment of cone vision in the frog, snake
and cat.
Figure 14 shows that when colored ocular struc-
tures do not intervene, the Purkinje phenomenon
emerges quantitatively from the absorption spectra of
rhodopsin and iodopsin. In essence it in\olves
nothing more than the transfer of vision from de-
pendence on the absorption spectrum of rhodopsin
in dim light to that of iodopsin in bright light.
THE PHOTORECEPTOR PROCESS IN VISION
683
1.2
1.0
0.8 -
0.6-
9 0.4 -
0.2
O -
-
1 — 1 — \ — 1 — \ — I I ■-
ChicKen visual picfmenis vs.
P'9^
-1 — \ — I I
on retinaj sens/
— ^ — \ r-." '
t/v/ty
1
-
/
/
^-^
—
-
rhodopsin^^l
/
/
e
\
-
-
/ /
V
\
, \^/odops/n
-
scoiopic Yv
sensitivity J
//
\
\
\ sensitivity
/ /
\
\
-
/7
/ /
•\
\
\
\
-
-
f^ * j/
/ /
\
\\
-
-
^r
y
\
\
V
-
1 \ \ L_
Wavelength -
_J , 1 1 —
-mjj
^^
._.•__
XL
- I-
' , '^ ?
400
soo
6O0
700
FIG. 13. Absorption spectra of chicken rhodopsin and iodopsin, compared with the spectral
sensitivities of dark- and Hght-adapted pigeons. The latter were measured electrophysiologically
and are plotted in terms of the reciprocals of the numbers of incident quanta needed to evoke a
constant electrical response. The scotopic data are from Donner (11), the photopic data from the
same source (^barred circles') and from Granit (19) (open circles'). The scotopic sensitivity agrees well
with the absorption spectrum of rhodopsin. The photopic sensitivity is displaced about 20 m^
toward the red from the absorption spectrum of iodopsin, owing in large part to the filtering action
of the colored oil globules of the pigeon cones. [From Wald (72).]
FIG. 14. The absorption spectra of chicken rhodopsin
(Xmax 502 m/i) and iodopsin (Xmax 562 my.) compared with the
scotopic and photopic sensitivities of various animals. The
lines show the absorption spectra of the visual pigments, the
points electrophysiological measurements of spectral sensitivity
(quantized). Scotopic data: frog (22); cat (12); guinea pig
(18). Photopic measurements; frog (17); snake (20); cat (21).
[From Wald et al. (72).]
Figure 15 shows this same comparison for the
human eye. The spectral sensitivities were measured
in the periphery of the aphakic (lensless) eye, to
avoid distortions otherwise introduced by the yellow
pigmentations of the lens and macula lutea (61, 63).
The scotopic sensitivity agrees well with the ab-
sorption spectrum of rhodopsin, but the photopic
sensitivity is displaced about 20 m/x toward the blue
from iodopsin. This is hardly surprising, for the
human photopic sensitivity is believed to be a com-
posite function, the resultant of the spectral sensitivi-
ties of at least three classes of cone needed to account
tor trichromatic vision. These seem to possess maxima
at about 450, 550 and 590 mix (2, 53). Iodopsin, or a
clo.sely related pigment, may function as the middle
member of this trio, but this must cooperate with at
least two other cone pigments to provide the mech-
anism of normal color differentiation.
Finally, in figure 16, such a comparison is shown
for the vitamin A2 eye of a fresh-water fish, the tench.
The spectral sensitivities, scotopic and photopic,
684
HANDBOOK OF PinSlOI.OCV -^ NEUROPHYSIOLOCJY I
\ \ 1 \ \
ChicHen : o iodopsin
• rhodopsin
Human lensless peripheral
vision: O cones
• nods
rhodopsin
rod vision
1 — I — I — I — r
1.2 -
1.0
p 0.8
5
§ 0.6
o
u
l5
0.2-
0-
I r
iodopsin
cone vision
400
500
600
700
FIG. 15. Absorption spectra of chicken rliodopsin and iodopsin compared with the spectral
sensitivity of human rod and cone vision. The spectral sensitivity measurements were made in a
peripheral field in the aphakic (lensless) eye to avoid distortions caused by the yellow pigmenta-
tions of the lens and macula lutea. They represent as close an approximation to the sensitivities
of the naked rods and cones as can be achieved in the living eye (cf. 61, 63). The scotopic (rod)
sensitivity agrees with the absorption spectrum of rhodopsin over most of its course. The photopic
(cone) sensitivity is displaced some 20 m^i toward the blue from the absorption spectrum of iodopsin;
it represents the resultant of the spectral sensitivities of at least three groups of cones concerned
with color vision. [From VVald li at. (72).]
measured electrophysiologically, are shown as large
circles. The lines and small circles show the ab-
sorption spectra of porphyropsin and cyanopsin.
The photopic sensitivity agrees very well with the
absorption spectrum of cyanopsin; but for reasons
which are still obscure, the scotopic sensitivity is
displaced about 10 m/i toward the red from por-
phvropsin. The corneas and lenses had been remo\ed
from these preparations; possibly some yellow pig-
mentation in the retina or a trace of blood in the
ocular fluids may account for this discrepancy,^ In
animals having vision based upon \itamin A.., the
' Recently it has been shown that the absorption spectra of
visual pigments in silu lie about 7 mix toward the red from their
positions in solution (ga, 70a).
Purkinje shift is unusually large: about 90 m/z,
from about 530 m/x in the scotopic eye to about 620
mix in the photopic eye. This is consistent with the
large displacement between the absorption spectra
of porphyropsin and cyanopsin.
It can be concluded that the spectral sensitivities
of rod and cone vision, and hence the Purkinje
phenomenon, derive directly and quaiititati\ely
from the absorption spectra of the \isual pigments.
Visual Adaplalion and the Bleaching and
Synthesis of Visual Pigments
It has been believed for many years that soine
simple relation connects the visual threshold, or
THE PHOTORECEPTOR PROCESS IN VISION
68 n
}.0 -
^
t oQ- porphyropsin^
C
c
o
■ ^04
Q
02-
0
1 \ \ 1 \ \ 1 \ \ \ \ \ \ \ I \
T'orphyropsin, cyanopsin, and spectral sensitivity of the tench
scotopic
-sensitivity
cyanopsin
photopic
sensitivity
A L
_L
_L
A L
SOO 600
Wavelengrt/i - m/j
700
FIG. 1 6. Absorption spectra of porphyropsin and cyanopsin Clines, small circles^ compared with
the spectral sensitivities of rod and cone vision in a fresh-water fish, the tench (broken line, large
circles'). The spectral sensitivities were measured electrophysiologically by Granit (i6) in opened
eyes from which cornea and lens had been removed. The photopic sensitivity agrees well with the
absorption spectrum of cyanopsin, but the scotopic sensitivity is displaced about lo mM toward
the red from porphyropsin, perhaps because of some yellow pigmentation in the retina or oculai"
fluids.
better its reciprocal, the visual sensitivity, with the
concentration of visual pigment. It has been as-
sumed that in a steady illumination the visual pig-
ments bleach to steady levels, maintained thereafter
by regenerative processes. Simultaneously the visual
sensitivity falls to a steady state value; this is light
adaptation. Conversely, in the dark the vi-sual pig-
ments are synthesized to their maximal concentra-
tions. Simultaneously the sensitivity rises to a maxi-
mum; this is dark adaptation.
Lately it has become apparent that whatever
relation obtains between visual sensitivity and con-
centration of visual pigment is not as direct as
simple proportionality. On the contrary, the bleach-
ing of a very small fraction of rhodopsin in dark-
adapted rods results in an extraordinarily large fall
of sensitivity (51). Parallel 'light adaptations' con-
ducted on a human subject and on a solution of
cattle rhodopsin in a water model of the human eye
show that, to a first approximation, the bleaching
of 0.006 per cent of the rhodopsin lowers the visual
sensitivity 8.5 times; and the bleaching of 0.6 per
cent of rhodopsin lowers the sensitivity 3300 times
(65). Conversely the resynthesis of the last small
fraction of rhodopsin must raise the sensitivity
greatly. Indeed much of light and dark adaptation
in the rods seems to involve the first small fraction of
rhodopsin to be bleached, and the last small fraction
to be resynthesized (cf. 23, 24).
Recently Rushton and his co-workers have suc-
ceeded by a most ingenious procedure in measuring
directly the rise and fall of visual pigment in the
living human eye (8, 49, 50). This permits a direct
comparison between the rates of bleaching and syn-
thesis of photosensitive pigments and the course ol
light and dark adaptation. For measuring rhodopsin,
the method depends on comparing the reflection
from the retina of a blue-green light strongly ab-
sorbed by rhodopsin with an orange light scarcely
absorbed by rhodopsin. No change of retinal re-
686
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
flectance was detected on illuminating such rod-free
areas as the fovea or the optic disc. On light-adapting
areas known to contain rods, increases in the re-
flectance of blue-green light were recorded, ap-
parently caused by bleaching rhodopsin. The vari-
ation in magnitude of this effect along the horizontal
meridian, from nasal to temporal, can be correlated
with the distribution of rod density (fig. 17).
When the eye is exposed to light, the rhodopsin
content falls exponentially to a steady state level at
which the rate of bleaching is balanced by the
regeneration rate. As might be expected, the rho-
dopsin content at the steady state decreases as the
level of illumination is raised (fig. 18). The time
course of bleaching roughly parallels the course of
light adaptation of human rod vision (cf. 73). Fol-
lowing light adaptation, the rhodopsin concentra-
tion rises regularly in the dark (fig. 18) and ap-
proaches a maximum value in about thirty minutes
(50), in good agreement with the time required for
human rod dark adaptation (fig. 19).
The course of bleaching and rcsynthesis of rhodopsin
in the human retina, measured in this way, agrees
with the course of human light and dark adaptation
only when the latter is plotted in terms of log sen-
sitivity. It is the logarithm of the visual sensitivity
that rises and falls with time much as does the con-
centration of rhodopsin. A theory has been proposed
which accounts for this relationship (65, 72). The
rod is viewed as a compartmented structure. Each
compartment contains a large quantity of rhodopsin
and is discharged by the absorption of a first quantum
of light. The residual rhodopsin of a discharged
160
'■120
80
•
•
- ..
■ III
■5
s.
0
•
\ r °^\
•
1 8* 1 1 1 1 1
50
-fO 30
•Nasal
10 0 10
Degrees
20 30 40
— Temporal
FIG. 17. Distribution of rhoclop.sin den.sity in the human
retina. Circles: measurements of rhodopsin density at tlie points
shown along the horizontal meridian. Line: rod density per
mm'' in the same region. [From Campbell & Rushton (8).]
i
i
. 1
.x--^'^^
-
V
1 /^"^
'
-
/
\^
_
/
/
/
y 100
1
10
Time (mm)
FIG. 18. Bleaching and resynthesis of rhodopsin in the
human retina 15 degrees temporal to the fovea. Open circles:
On exposing the eye successively to lights of increasing bright-
ness (i, 5 and 100 units, where i unit = 20,000 trolands),
the rhodopsin content falls each time to a new steady-state
level at which the rate of bleaching is balanced by the regenera
tion rate. Filled circles: In the dark, rhodopsin regenerates.
Complete recovery (not shown in figure) takes about 30 min.
(50). [From Campbell & Rushton (8).]
compartment continues to absorb light and to
bleach but can no longer contribute to excitation.
A rod is rendered wholly inexcitable when each of
its compartments has absorbed at least one quantum
of light, i.e. when in each of its compartments at
least one molecule of rhodopsin has been bleached.
In this way the bleaching of very little rhodopsin
can lead to a high state of light adaptation^. This
hypothesis, pursued mathematically, leads to the
expectation that the logarithm of the visual sensitivity
should be appro.ximately proportional to the con-
centration of visual pigment (72).
The same relationships appear to hold for cones.
Rushton (49) has recently modified his method to
measure cone pigments in the human fovea. He
finds that in the dark, following exposure to a bright
light, cone visual pigment is resynthesized much more
rapidly than rhodopsin (fig. 20). The course of
synthesis parallels human cone dark adaptation (fig.
19). It has long been known that in man and many
other animals the cones dark-adapt much more
rapidly than the rods. In the human eye the dark
^ The term bleach is here used loosely to in\oK'e the entire
chain of eflfects that follows the absorption of light by rho-
dopsin. The first such effect is the production of lumi-rhodopsin;
then by thermal reactions meta-rhodopsin (still without literal
bleaching); and finally a mixture of all-/ran.f retinene and opsin.
The excitation process probably depends upon the first of
these steps, the change to lumi- or at most mcta-rhodopsln.
THE PHOTORECEPTOR PROCESS IN VISION 687
8
—I
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-| 1 1 \ r 1 1 1 1
-T" I I
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/
r
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/
/
-
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/
_
7
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-J —
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-+-
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-\ — i — \ — \ — \ — I — 1 — I — \ —
J \ \
4 L-
10
ts
20
2S
30
3S
40
FIG. 19. Dark-adaptation of the human eye measured in a peripheral area which contains both
rods and cones. The dark adaptation of the cones is completed within about 5 min., that of the rods
within about 45 min. [From VVald et al. (72).]
S 01
V
Q
30 sec bleachinq
with strong orange liqht
Subject J WHD
FIG. 20. Bleaching and resynthesis of visual pigments in
the human fovea. Initial values after dark adaptation. Fol-
lowing a 30 sec. bleach with strong orange light, the density
is at first very low but rises rapidly in the dark. Recoscry is
complete in 6 min. [From Rushton (49).]
adaptation of the cones is complete within 4 to 6
min., while that of the rods continues for over 45
min. The dark adaptation of a peripheral area of the
human retina containing rods and cones is shown
in figure 19. It is plotted in terms of log sensitivity
(-log threshold) the better to expose its relationship
to the rise of \isual pie;ment concentration.
Another approach to this problem has been made
by comparing the rates of synthesis of rhodopsin
and iodopsin in solution. Figure 10 above shows a
mixture of chicken iodopsin and rhodopsin made by
incubating nco-b retinene in solution with a mixture
of cone and rod opsins. The reason the visual pig-
ments form separately in this instance is that iodopsin
is synthesized with enormously greater speed than
rhodopsin, about 530 times as fast at io°C (72).
Figure 21 shows the synthesis of the two pigments in
solution at 23°C. The synthesis of iodopsin is com-
plete within 5 min., while that of rhodopsin continues
for well over an hour. The data are taken from the
same experiment as figure 10 but with rhodopsin
extinctions multiplied by 1.3. It is hardly necessary
to labor the clo.se relationship between these measure-
ments, the synthesis of human rod and cone pig-
ments in vivo, and the course of human dark adapta-
tion, cone and rod. Again, however, what parallelism
obtains involves the comparison of log sensitivity
with the concentration of the visual pigments.
One must conclude from all these measurements
that light and dark adaptation have their primary
source in the bleaching and resynthesis of the visual
pigments of the rods and cones. To be sure, more
central phenomena — changes in the sensitivities of
688
HANDBOOK OF PHYSIOLOGY ^ NEUROPHYSIOLOG\- I
—I 1 1 1 1 1 \ 1
Synthesis of photo pigmerrts
from chicMen opsins + retinene
O.S -
0.4
03
0 2
0.1
a -
I I r
rhodopsin (SOOm/i )
iodopsin fS60mp)
Time in diarK~nninutas
A L
J \ L
;o
20
30
FIG. 2 1. Synthesis of iodopsin and rhodopsin in solution from a mixture of chicken opsins and
neo-i retinene. 23°C. This is the same experiment as shown in figure lo but with the rhodopsin
extinctions multiplied by 1.3. At this temperature, iodopsin synthesis is complete within 2 to 3
min., whereas rhodopsin synthesis still continues after 35 min. [From W'ald C72).]
neurons and synapses along the optic pathways —
may also play a role. Of this possibility as yet very
little is known. In general, nein-al adaptations are
relatively rapid; if they enter at all, they should
probably be completed during the earliest stages
ot visual adaptation. They probabh' are responsible
al,so for only a minor portion of the range of \isual
adaptation. As a first approximation, light and dark
adaptation seem to reflect the fall and rise of visual
pigment; and specifically it is the log sensitivity which
runs parallel with pigment concentration.
I iliiiiiiii A Deficiency and .A'lghl Blindness
Probably the earliest symptom of \-itamin A de-
ficiency in man and other animals is the rise of visual
threshold known as night blindness. Because night
vision is associated with the rods, it was once thought
that dietary night blindness, so called to distinguish
it from the idiopathic or congenital disease, is a
failure specifically of rod \ision. The first experi-
mental studies of human night blindness, however,
showed at once that in \itamin A deficiency cone
vision deteriorates with rod \ision, and both recover
together on administration of \itamin A (figs. 22, 23)
(26, 27, 77).
The realization that both iodopsin and rhodopsin
are synthesized from the same form of vitamin .\
oflfers a substantial theoretical basis for this relation-
ship. To he sure, iodopsin has not been demonstrated
in human cones; if present, it is presumably ac-
companied by at least two other cone pigments
needed to account for normal human color vision.
\'et the observation that on administration of \itamin
.■\, or carotene, night blindness is repaired as quickly
and completely in the cones as in the rods (fig. 23)
implies that the human cone pigments as a group
are probabh' synthesized from vitamin A. Just as
rhodopsin and iodopsin are constructed by joining
the same prosthetic group to different opsins, so the
cone pigments responsible for human color vision
may well be composed of the same retinene com-
bined with a variety of different opsins.
The opsins ha\e been altogether a neglected coiti-
poncnt in the etiology of dietary night blindness.
This disease and its cure have been thought of too
much in terms of the removal and replacement of
\itamin A, particularly since vitamin A was shown
to be a precursor of rhodopsin. This preconception
may be the source of some of the embarrassments
that have attended the experimental study of night
blindness: a) on beginning a vitamin A-deficienl
THE PHOTORECEPTOR PROCESS IN VISION
689
diet, some subjects immediately begin to become
night-blind, whereas others show no effects, visual
or otherwise, for many months; and //) on admin-
istration of vitamin A to night-blind subjects, some
^
1
' '
1
7rot«nt \
Con
»
1 ,
s_^^
>— ^
/-
""i^
/]
\
—
*
> '
u
<
>
I
fiods
Ox'
^
«o
0,
^
--
, •
»
I'^iJfS,";
•\
i 1
10 10 30-0 10 iO JO
pre-diet -DAYS -on diet
FIG. 22. Thresholds of completely dark -adapted cones
and rods during 30 days of heavy vitamin .\ administration
(Jejt) and during 30 days on a vitamin .'\-deficient diet (jight").
Open and closed circles show thresholds of right and left eyes,
respectively. On the thirtieth day of the deficient diet, one
dose of vitamin A was administered; both rod and cone thresh-
olds returned to normal. On the thirty-second day, the subject
was again slightly night-blind and was given a dose of carotene,
again both cone and rod thresholds returned to normal.
[From VVald et al. C77).]
are cured completely within several hours, whereas
others retain some degree of night blindness for
months while recei\ing a high dosage of vitamin A.
Figure 22 shows the rapid type of onset of night blind-
ness, figure 23 the rapid type of cure. Unfortunately
the other type of result is observed at least as often
(28, 35, 66).
One must distinguish an acute from a chronic
syndrome in \itamin A deficiency. The results of a
current study ot vitamin A deficiency in the rat are
summarized in figure 24 (cf. 12a). When an animal
is placed on a vitamin A-deficient diet, the liver stores
slowly lose \itamin A until the liver has been emptied.
Up to this time the blood level remains normal, but
now it sinks within a few days to zero. To this point
the rhodopsin content of the retina has remained nor-
mal, but now this too falls, marking the beginning of
night blindness. For about three weeks longer the opsin
level stays normal. Then it too begins to fall; at the
same time the retina deteriorates anatomically, and
the animal loses weight and displays other overt signs
of vitamin A deficiency. All these disorders are reversed
by administration of \itamin A.
The role of vitamin A as the precursor of visual
pigments seems almost trivial coinpared with its
general role in maintaining the integritv of the
tissues. The mechanism of this action is still com-
pletely obscure. In vitamin A deficiencv, various
tissues all over the bod\ begin to deteriorate, the
ao )oo
mi n i/fes
FIG. 23. The cure of night-blindness with carotene. Following a standard light adaptation, the
measurement of dark adaptation shows both cone and rod plateaus to lie abose their normal range
(enclosed within the upper and lower pairs of broken lines^. After dark adaptation was completed, 20,000
International Units of carotene in oil were administered in gelatin capsules orally. For 12 to 14
min. the rod threshold remained constant; then it fell rapidly to normal. Immediate repetition of
the standard adaptation procedure showed both cone and rod plateaus to have entered their normal
ranges. [F'rom Wald & .Steven (78).]
690
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
too -
80-
V 60
o
0)
0
R,
Vitamin A
deficient rats
live
5 6 7 8
WeeKs on diet
FIG. 24. Vitamin A deficiency in the rat. Blood vitamin .\
(CD) falls precipitously as liver stores of vitamin .-^ (S) are
exhausted. At this point, the rhodopsin content of the dark-
adapted eye (O) begins to decline, presumably because not
enough vitamin .\ is available to convert all the opsin of the
rods to rhodopsin. About three weeks later, opsin itself (•)
begins to disappear, its concentration from then on paralleling
the decreasing rhodopsin content. Disappearance of opsin
may in part be responsible for the degeneration of rods and
cones associated with chronic vitamin .-\ deficiency. [From
Dowling & VVald (12a).]
retina among others (36, 54). Johnson has reported
that after 7 to 13 weeks of vitamin A deprivation in
young rats, the rods in the retinal fundus exhibit
marked changes. Many outer segments have dis-
appeared and those that remain stain aljnormally.
As the deficiency progresses, the inner segments of
the rods also degenerate, then successively the ex-
ternal limiting membrane and outer nuclear layer,
the pigment epithelium, the outer molecular layer,
and the inner nuclear layer. These changes progress
much faster in the central retina than toward the
periphery. Outer segments of rods which have suffered
only slight degenerative changes seem to repair
considerably within 24 hours of vitainin A therapy.
Even rods which have degenerated completely
appear to regenerate within 10 to 18 weeks of \itamin
A administration.
The rod outer seginent is composed in considerable
measure of rhodopsin (see above). A loss of opsin
might therefore profoundly damage its structural
integrity; long before such changes are visible in
the micro.scope they might become detectable physi-
ologically as night blindness. In any case, night
blindness clearly involves far more than the simple
decline of \itamin A concentration in the retina.
It introduces, particularly in prolonged deficiency,
deep-seated anatomical changes and these might
repair only very slowly.
In addition to deficiency in the diet, any inter-
ference with the flow of vitamin A to the retina, or
with its uiilization by the tissues can be expected to
react on the visual threshold. This appears to be the
case in certain chronic liver diseases (cf. 41). Bile
is needed for the absorption of both carotene and
\itamin A (25). In obstructi\e jaundice, in which
bile fails to reach the intestine, vitamin A deficiency
and hence night Ijlindness may develop in spite of a
diet adecjuate to meet normal requirements. In ad-
dition to producing the bile, the li\er is the principal
storage tissue for vitamin .\. It is not surprising
therefore that liver disorders may affect the extent,
and apparently in some instances also the rate, of
dark adaptation.
Recently it has been shown that the wall of the
intestine is probably the principal site for the con-
version of carotene to \itamin A (14, 55). It is not
unlikelv that conditions exist in which some failure
of this process leads to \isual disturbances.
Even when the diet is adequate, and the liver and
intestine are performing their functions, this may
not yet be enough. \'ision depends, not merely on
\itamin A, but on a particular shape of vitamin A,
the nco-h isomer. This is not ordinarily present in
the food, so that other isomers of vitamin A obtained
in the diet must be converted into this special con-
figuration. The neo-fe isomer is continuously lost
in the bleaching of the visual pigments and must be
continuously replaced for vision to persist. It is not
impossible that there exists a visual disorder that
has its source in a failure to isomerize vitamin A.
Furthermore, the fact that \itamin A is stored in the
eye as an ester, which must presumably be hy-
drolyzed before entering the \isual cycle, constitutes
another point at which \isual processes are vulnerable
to metabolic failure.
It has repeatedly been suggested that retinitis
pigmentosa, a degenerative disease which attacks
primarily the layer of rods and cones, is due to some
THE PHOTORECEPTOR PROCESS IN VISION
691
local failure in the supply or effective utilization of
vitamin A (9, 81, 82). The lesions at one stage of
vitamin A deficiency resemble somewhat those in
retinitis pigmentosa. The layer of rods and cones is
the first to deteriorate in vitamin A deficiency, and
such deterioration is characteristic of the disease.
In more advanced vitamin A deficiency, however,
the inner retinal layers also succumb, while remaining
apparently intact in retinitis pigmentosa. It is con-
ceivable that these symptoms are due to a local
failure in vitamin A metabolism which is not ap-
parent elsewhere in the eye tissues.
The participation of vitamin A in the processes
of visual excitation therefore introduces a whole
series of special relationships. It renders vision de-
pendent upon an ecological factor, the nutrition,
and upon the entire network of internal arrangements
that govern the absorption, metabolism and trans-
port of vitamin A throughout the body.
.\ icotinamide
A second \itamhi plays a basic role in the \isual
processes: nicotinamide, the anti-pellagra factor of
the \itamin B complex and the active principle of
DPN, which is the coenzyme of the alcohol dehy-
drogenase system. Without this factor vitamin A
presumably cannot be oxidized to retinene, a neces-
sary step in the synthesis of rhodopsin and iodopsin.
Are there visual symptoms in pellagra? Is there,
for example, some disturbance of dark adaptation
in this disease? None has been reported; but it might
be well to examine carefully the visual beha\ior of
pellagrins with these considerations in mind.
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CHAPTER XXIX
Neural activity in the retina
RAGNAR GRANIT 1 Nnhel hulitute for Neurophysiology, KaroUnska Instituli-t, Stockholm, Sweden
CHAPTER C: O N T E N T S
Outline of Retinal Histology
Electroretinogram (ERG)
Neural Patterns
Stimulus Correlates
Centrifugal Control
ERG of Man: Its Clinical Use
OUTLINE OF RETINAL HISTOLOGY
THE RETINA consists of a surface layer of receptors,
the rods and cones (fig. i), joined to a nervous center
which delivers an organized message in terms of im-
pulses through the optic nerve. The great works of
Ramon y Cajal (123, 124) and Polyak (122) should
be consulted for details. The anatomy of the eye and
retina throughout the vertebrates has been ably
discussed by Walls (146). There is also a recent brief
summary by Willmer (147).
In lower vertebrates it is not always easy to dis-
tinguish rods from cones (38, 146). In mammals rods
end in knobs and cones in dendrites, but in frogs both
types of receptor have dendritic terminals. Rods are
generally more elongated and slender than cones but
this criterion breaks down in some lizards and birds
and in the fovea of the primates in which the elongated
cones look like rods. Walls emphasizes that the outer
cone segment is enclosed by a tubular process from
the pigment epithelium cell oppo.site to it and holds
this criterion to be universal and never found in rods.
Differentiation between rods and cones seems pos-
sible by electron microscopy, at least in some species
(132, 133, 134, 135). It has even been possible to
distinguish two kinds of rods in guinea pigs (135)
which would agree well with the electrophysiological
observations on blue sensiti\ity existing in this spe-
cies which has almost no cones. Photodichroism, an
orientation of the light-absorbing molecules serving
to aid absorption, has been observed in the rods (36,
1 29). The fresh cones, viewed end on, light up when
the micro.scope is focused on the outer limbs which
thus seem to serve as a focusing device operating by
total internal reflection (138). This observation may
explain why a pencil of light entering at an angle is
dimmed if it enters cones, the Stiles-Crawford effect
(136).
Double cones and twin cones have been described
in fish but since these types do not occur in mammals,
they have attracted little attention, physiological work
rather tending to settle on universal characteristics.
Schwalbes green' rods found in frogs have recently
been observed to contain a special blue-absorbing
photosensitive substance (37) and ma\' well be more
general than one had thought.
The rods are integrating organs and converge in
large numbers towards the bipolar dendrites. Bipolars
in their turn converge towards the ganglion cells
which give rise to the optic nerve fibers. In man there
are some 125,000,000 rods as against 800,000 to 1,000,-
000 optic nerve fibers. Since man has only 4 to 7 mil-
lion cones, it is clear that the amount of convergence
is far less for them; this criterion seems to be general
throughout the animal kingdom, signifying that
cones, on the whole, are more discriminative, while
rods are more integrative and designed to serve as
collectors of light quanta in the dark (92, 127). The
fundamental observation that rods actually do dom-
inate the eyes of nocturnal animals and that an in-
creasing number of cones is characteristic of diurnal
habits was made by Schultze (131) on the basis of
extensive histological studies. This, and later psycho-
physical work by Parinaud (117), Konig (99) and
693
694
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOCn- I
i
B
m
^n -I
/ it n
f c
e
4/
t
FIG. I. A. Types of cones from the leopard frog, Rana pipieris (c); the snapping turtle, Chelydra
serpentina (</); the marsh hawk, Circus hudsoniits (c); and from the circumfoveal eminence of man
(/). B. Types of rods from the goldfish, Carassius auratus (/); the leopard frog, a common or 'red'
rod ((/); the leopard frog, a so-called green' rod of Schwalbe (f); the flying squirrel, Glaucomys
V. volans (/); and from the temporal side of the macula lutea of man C?)- [From Walls (146).]
von Kries (145) led to the concept of a duplex retina
for scotopic and photopic vision, respectively. Most
eyes from this point of view are 'mixed', that is they
contain two organs in one. When, at about the same
period, Boll's (24) discovery of the light-sensitive
visual purple (rhodopsin) was made and ably elab-
orated by Kiihne (loi), Konig (99) and their col-
laborators, this gave further support to the duplicity
theory. Visual purple has been found only in the
outer limbs of the rod. A historical review of this
development is available (69).
In the external plexiform layer, between the recep-
tors and bipolar cells, there are lateral connections,
the horizontal cells (fig. 2), joining cones, each of
which is embraced by a dendritic basket, to a larger
group of rods and cones. There are several baskets
to each horizontal cell and axons up to 0.8 mm in
length have been found (123). The arrangement sug-
gests a starting loop or positive feedback for general
facilitation.
Polyak's (122) classification of bipolars is of interest
because it is based on primates. There is, in the foveal
area, the midget bipolar which is individual or private
for a single cone. In the periphery each midget bi-
polar receives impulses from a small number of cones.
At the opposite end it articulates with a midget
ganglion cell by an axodendritic synapse, yet this
midget system is not wholly isolated. Mop bipolars
also run to the midget ganglion but this contact is
axosomatic. These together with all the other bipolar
types belong to the diffuse variety which receive a
large number of receptors. The mop bipolars possess
a kind of dendritic tuft, smaller in the fovea than in
the periphery and forming a receptaculum for rod
and cone pedicles. Its axosomatic projection is a crude
shallow basket touching one or more ganglion cell
NEURAL ACTIVIT"!' IN THE RETINA
695
FIG. 2. A. Scheme of the structures of the primate retina as revealed by the method of Golgi.
The layers and the zones are designated as follows: (/) pigment layer; (,2-a) outer zone and (^-A)
inner zone of the rod and cone layer; (5) outer limiting membrane; (_4-a) outer zone and (^-A)
inner zone of the outer nuclear layer; (is-a) outer zone, (j-A) middle zone and (j-c) inner zone
of the outer plexiform layer; (5) inner nuclear layer with its four zones; (7) inner plexiform layer;
C5) layer of the ganglion cells; (9) layer of the optic nerve fibers; and (/o) inner limiting membrane.
The nerve cells are designated as follows: (a) rods, (A) cones, (r) horizontal cells, (d, e, f, A) bi-
polar cells, (i, /) so-called 'amacrine cells', (m, n, 0, p, i) ganglion cells and 00 'radial fibers' of
Miiller. In this scheme the nervous elements are reduced to their essentials, with, however, the
characteristic features of each variety preserved — the location of the cell bodies, the size, the shape,
and the spreading of the dendrites and of the axis cylinders — and with the synaptic contacts pre-
sented accurately. [From Polyak (122}.]
B. The structure of the primate retina reduced to its essentials, including the synopsis of the
propagation of the retinal impulses from the photoreceptors to other parts of the retina, to the
brain, and from the brain back to the retina (direction indicated by the arrows). The marking
of the layers and the zones the same as in A. Labeling of the cells: (a. A) rods and cones, the pho-
toreceptors where the nervous impulses are generated by physical 'light' (in the scheme only the
left group of the photoreceptors is assumed to be stimulated by light); (c) horizontal cells which
transmit the impulses to the surrounding rods and cones; (_d, c, /, A) centripetal bipolar cells of
the mop, brush, flat and midget varieties, which 'transmit' the impulses from the photoreceptors
to the ganglion cells, the bipolars serving as 'analyzers'; (i) centrifugal bipolar cell, a variety of
the 'amacrine cells,' which probably receives the impulses from the centripetal bipolars from the
ganglion cells, and also from the brain by way of the centrifugal or efferent fibers (/) and trans-
mits them back upon the photoreceptors (a. A); (/) an 'amacrine cell' which possibly intercepts
a part of the bipolar impulses and spreads them over the surrounding territory; and (m, n, 0, p, j)
ganglion cells which receive impulses from the centripetal bipolars and transmit them to the brain
along their axon called 'optic nerve fibers.' [From Polyak (122).]
bodies. The brush and flat bipolars reseinble each
other and occur everywhere in the retina from the
fovea to the ora serrata. They have large dendritic
territories. Their most interesting properties seem to
be: a) a "reciprocal overlapping of each of the den-
dritic territories with its own kind" (122) and 6)
axodendritic articulations with the ganglion cells.
The midget system also intermingles with this wide
a.xodendritic or plexiform (inner plexiform layer)
network. The basic pattern consists of bipolar ter-
minals, ganglion cell dendrites and the Golgi type II
of cells called amacrines. Similar large plexiform net-
works with Golgi type II of cells are found elsewhere
in the nervous system, including the cortex of the
cerebellum.
The ganglion cells, for physiological correlations.
696
HANDB(50K OF PHYSIOLOGY ^ NEUROPHYSIOLOGY I
can be divided into two types, large and small, with
two extremes, giant and midget. It is doubtful
whether the midget system occurs in the common
laboratory animals. The dendritic expansions of the
giant ganglion cells may be "from 250 to 350 n across
and probably more" (Polyak).
The system of amacrine cells (i.e. cells without
axons) seems highly organized. This, according to
Ramon y Cajal, is particularK true for the stratified
ones (Polyak's knotty amacrines) which form five to
seven layers in the inner plexiform network. Their
dendritic arborizations are similarly stratified at cor-
responding levels. There are also giant amacrines
(Polyak's tasseled amacrines) some of which spread
a 'daddy longlegs' mop extending over i mm above
the plane of the ganglion cells. Polyak has also de-
tected axons running from amacrine cells towards the
pedicles of the receptors and regards them as bipolar
cells conducting backwards. This raises the question
of whether amacrines appear to lack axons merely
because of difficulties in staining.
In this microcosm of a nervous center that we call
a retina, the inner plexiform layer, as we have seen,
is the meeting ground of three major systems and thus
a critical region. It is difficult to imagine this layer
to be wholly self-controlled lay the chance play of
light and shadow. And, as a matter of fact, this is the
very region to which the centrifugal fibers of Ramon
y Cajal (123) and Dogiel (50) were found to project.
Ramon y Cajal studied them in the retina of the dog
(fig. 3), while Dogiel worked on birds. They seem
to be difficult to stain and their origin is unknown,
yet Ramon \ Cajal did not hesitate to postulate a
central origin rather than to describe them as re-
current collaterals. Some centrifugal fibers are held
to go as far as to the outer plexiform layer.
The briefest path in the retina clearly is disynaptic :
receptor-bipolar-ganglion. A more fundamental issue
seems to be the question of whether bipolar cells
make axosomatic or axodendritic connections with
the ganglion cells. Conduction is slow in dendrites
(104) so that axo.somatic latencies are likely to be
shorter. In the probable absence of midget cells in
the common laboratory animals, the size of the
ganglion cell is likely to be an important property
because the larger the cell, the greater the probability
of axodendritic activation in the inner plexiform
layer. Actually the ganglion spikes in the cat's retina
fall into two main categories, large and small, the
small ones as a rule having brief latent periods. The
larger the spike caused by illumination, the later it
tends to be discharged and the lower its absolute
threshold to light. This is the author's general im-
pression, not a result of systematic analysis.
If, in the cat's eye, one proceeds to send an anti-
dromic (backward) shock into the optic nerve and
places a microelectrode on the blind spot (74), the
volley recorded consists of an early large and a later
small group of spikes, similar to those recorded ortho-
dromically at the central end of the optic nerve (22,
23, 107). The maximal conduction velocities of its
fillers are 70 and 23 m per sec, respectively (22). Two
main fiber sizes (as judged from the conduction veloci-
ties) suggest two main groups of sizes of ganglion cells.
This is further evidence for subdi\'iding the spikes into
two main categories.
At the blind spot the optic nerve loses its myelin
sheath and so conduction suddenly slows down as the
antidromic impulse enters the fibers running across
the retinal surface (74). Precise measurements by
Dodt (42) gave mean values of 2.9 and 1.7 m per
sec. for large and small spikes, respectively. The large
spikes (see below) are the ones most easily influenced
by centrifugal tetani (74) as also seems probable con-
sidering their wide dendritic expansions within the
inner plexiform layer.
Another interesting point is that, on account of the
slow conduction across the retinal surface, the im-
pulses from the peripheral portions of the retina may
i^e delayed by 4 to 6 msec, as compared with those
arising in the region around the blind spot. This is of
technical interest because it means that, unless special
precautions are taken in studying retinal brain pro-
jections by evoked potentials, these are likely to be
mainly determined i)y the fibers around the blind
spot. Phvsiologically the delayed conduction means
that, with a moving retina, space coordinates stand
a good chance of being transformed into time co-
ordinates. The eye always makes small oscillations
in fixation (39, 125).
ELECTRORETINOGR.KM (eRG)
The electroretinogram is a polyphasic mass re-
sponse (fig. 4) with specific cornea-positive deflections
at the onset and cessation of illumination. Standard
leads in electroretinography are between the cornea
and an 'indifferent' point on the body or behind the
bulb (in the case of eyes excised from cold-blooded
NEURAL ACTIVITY IN THE RETINA
69/
FIG. 3. .1. Retina of the dog showing cone axons (n); rod axons (A); types of bipolars (c-c). of
which e is Ramon y Cajals cone bipolar; ganglion cells (m, n); ascending nerve fiber 0); and cen-
trifugal fibers (j). B. Details of structure of ganglion cells (B, C and E") and of connections made
by centrifugal fibers (a). [From Ramon y Cajal (123).]
animals). The ERG was discovered by Holmgren (94,
95). The literature has been twice summarized by the
author (69, 73), the first time with a full historical
review. Some of the more important classical papers
are those of Kiihne & Steiner (102, 103), Gotch (60,
61), Piper (119, 120, 121), Einthoven & Jolly (53),
Frolich (56), Chaffee et al. (31), Chaffee & Hampson
(32), Hartline (85), Adrian & Matthews (3) and
Kohlrausch (98).
The ERG (which in such animals as cats and frogs
reaches maximal cornea-positive values around i mv)
begins with a small negative dip, the a-wave, then
goes positive, the 6-wave. If stimulus intensity is suf-
ficiently high, there follows a very slow cornea-positive
secondary rise or c-wave and, at the cessation of il-
lumination, another positive hump, the off-effect or
(/-wave (see fig. 4). There is some doubt as to whether
the c-wave occurs in cone eyes. In mixed eyes it is not
found in the state of light adaptation (144). Noell
(114) appears to hold that it is always present but
sometimes compensated for i3\ an opposite negative
potential of similar slow characteristics. There is no
reason to believe any of the ERG waves to be absent
in any kind of vertebrate eye; but they are very dif-
ferently developed with respect to .size and rate of rise
and they vary with the experimental conditions so
that, for instance, in rod eyes the (/-wave is small or
missing. The ERG has generally been thought to
consist of components integrated in complex inter-
ference pictures. These are reasonably well-known
6g8 HANDBOOK OF PHYSIOLOGY ^ NEUROPHYSIOLOGY I
50 cy/5ec.
.■^.■■..^■^.
O.SmV
...,I,„.I.,,.I....I-.I..,.I....I.„.Im..(,....
I
0 0.5 7.0 sec.
•Mt||Ul!lM"'<"'<"mM'>>'*MlMlf)(iif|M<
)l(llllllllil)lllltlllllUIII>ttlHttllltl>i<liii.
03 nN
0.5 TO sec
FIG. 4. Elcctroretinograms from various types of retinas. A. Cone retina of the cold blooded
horned toad, Phyronosoma, showing a large diphasic (/-wave. [From Chaffee & Sutcliffe (33).] B.
Mammalian cone retina of the squirrel, Sciurus carolinensis leucotis, with marked a-wave and narrow
pointed b- and (/-waves (calibration: 0.5 mv; time, i sec). [From Arden & Tansley (8)] C. Cat
eye, dark-adapted, exposed to two flash durations at an intensity of about 700 meter-candles;
(!-wave is just visible, A-wave shows fast oscillation, followed by a drop below base line before the
c-vjavc begins; (/-wave or off -effect appears as a retarding of fall of response at cessation of illumi-
nation. [From Granit (73).] D. Guinea pig eye, dark-adapted, exposed to light intensity of about
goo lux, showing a definite (j-wave and indication of double ft-wave; in this eye the c-wave or sec-
ondary rise tends to be the most prominent phase of the response. [From Granit (73).] E. Gecko
eye illuminated with an intensity of 1J50 meter -candles; the first record represents 3.8 sec. illumi-
nation after i min. in the dark, the second record 2.8 sec. illumination after 2 min. in the dark
(time marks 0.2 sec. apart). [From Dodt & Heck (47).] In records, A to E illumination periods
are indicated by shift in the signal line.
for many types of eyes in different conditions. The
reviews referred to should be consulted, supplemented
with recent work (i 1 1, 114).
The problems of electroretinography have centered
around the following main issues; a) differentiation
of rod and cone ERG's, b') analysis of the transition
from rod to cone dominance in mixed retinae, c) at-
tempts to split the ERG into component responses,
d') comparisons between the ERG and the discharge
in the optic nerve and e") attempts to localize com-
ponents of the ERG to specific structures in the
retina. Under this heading also fall the recent experi-
ments with penetrating capillary microelectrodes of
the Gerard-Ling type. Finally as /) should be men-
tioned a steadily expanding literature on electroretin-
ography in man from descriptive, theoretical and
clinical points of view. All these aspects cannot be
discu.sscd with full attention to detail. Leading refer-
ences will, however, be given within all of them.
The pure cone ERG's illustrated in figure 4 (.4 and
B) are from the horned toad (33) and a squirrel (8)
and are essentially alike. These types were called
Trctinograms (69), as long as there were no pure cone
mammalian ERG's available. The cone eyes of
squirrel species (8, g, 25) have since provided the
evidence necessary for identifying the I-type with the
cone ERG in mammals as well as other animals.
There is no secondary rise or c-wave. Cone ERG's are
often negative in between the h- and c/-waves (cf.
fig. 4.-I). They also tend to have large a-waves. The
rod ERG's (C and Z)) are from guinea pig and cat
eyes, the former having a practically pure rod retina,
the latter with cones corresponding roughly to the
number found in the human peripheral retina. The
ERG labeled E is from the pure rod retina of the
gecko (47). It diflfers from that of the guinea pig in
showing a (/-wave at 'off.' Now guinea pigs afso have
off-di.scharges in their optic nerves (a very striking
feature of cone eyes) and so the absence of the corre-
sponding (-/-wave in their ERG suggests that elements
responding at 'off' are fewer in number than in cone
eyes and many other types of rod eyes (cf. 69). In the
ERG of the cat (C), for instance, the d-wavc is re-
duced to a plateau, or a retardation at 'off' in the
drop of potential towards the base line. Walls (146)
holds the rods of the gecko to be transmuted cones.
The a-wave seems to occur in all retinae, provided
the light intensity is sufficiently high to elicit it.
By changing state of adaptation from scotopic to
photopic it is also possible to demonstrate in mixed
eyes that the on-off differentials, the a- and rf-waves,
become faster, the rf-wave in addition Ijecoming
NEUR.I1L .ACTIVITY IN THE RETINA 699
Dog Rabbit
Fio. 5. A comparison of the electroretinogram of the red
Irish setter and tlie rabbit. The upper tracing in each record
gives the electroretinogram and the lower, the time mark.
The Ught is 'on' when the time tracing is displaced upwards.
The record shows that the normal positive c-wave of rabbits
is replaced by a negative potential in dogs. Time mark: 0.5 sec.
Calibration: 50 ^v. [From Parry el al. (118).]
larger than before (41, 46, 80, 113). This is conven-
iently done by using flickering light. Rod ERG's
tend to flicker with repeated positi\e i-waves, while
in cone ERG's a-waves and rZ-waves (see below) also
take part in the response to intermittent illumination.
By varying stimulus intensity from the threshold
upwards it can easily be shown that both the b- and
the rf-waves consist of several components of different
rates of rise and of different size though complete sep-
aration may be diflicult to achieve. Systematic atten-
tion to this problem was first given in two papers on
the frog eye (78, 84) and, by varying state of adapta-
tion and wavelengths, the authors could show that
some components belonged to rods (slow ones) and
some to cones. Similar differentiations for the human
eye were followed by Motokawa & Mita (iio) and
Adrian (i, 2). Variations in duration (149) and in
rate of rise of the stimulating light (126) have recently
been found to be convenient methods of separating
scotopic and photopic components. (This matter is
further considered below.)
Deteriorating ERG's tend to become cornea-nega-
tive, but in many animals the negative phase is also a
normal feature of the response and then is always
found to succeed the cornea-positive A-wave (see fig.
4.4). In fact, a large negative phase occurs fairly
generally in high intensity ERG's and, after light-
adaptation, also in rod eyes. Figure 5 illustrates the
ERG of a dog (118) which obviously contains a slow
negative component not visible in the ERG of the
rabbit inserted for comparison. Noell's (114) work is
of particular interest from this point of view, as has
been discussed by Granit (73).
The common occurrence of slow or semistationary
negative phases during illumination has led most
700 HANDBOOK OF PHYSIOLOGY ^' NEUROPHYSIOLOGY
III
FIG. 6. Components of the cat ERG: PI, PII and PHI. The two alternatives for PII drawn
on the basis of experimental results. [From Granit (64).]
workers to assume that the ERG is an algebraic sum
of component processes of opposite signs. The methods
used for analysis have been based on variations of
stimulus intensity, duration and state of adaptation
as well as on direct interference with the ERG by
chemical agents and asph\xia. For an orientation in
this field the reader is referred to the detailed discus-
sion by Granit (69) supplemented by more recent
work (7, III, 114). The three components of the
author's analysis (fig. 6) are based on many observa-
tions in the classical literature (quoted in the intro-
duction) and certain of his own experiments (64, 80)
and have served for some time now as a summary and
a starting point for further work.
There is general agreement about the existence of a
slow cornea-positive component such as PI which is
responsiiile for the secondary rise or (-wave (see also
114, 144). This requires fairly high intensity and not
too short exposures. There is much evidence to show
that the cornea-negative a-wave is the first .sign of
illumination (cf. 3, 34, 69) and that it passes over into
a slower negative phase which is often submerged
below a mainly cornea-positive rcspon.se but is some-
times visible. The component PHI appears to survive
damage to the retina better than the other ones. Noell
(114) uses poisoning with iodate to produce it in the
rabbit's eye. It has been suggested (69, 73) that the
negative PHI consists of two components, one fast
and the other slow. This view has been elaisorated in
consideraijle detail by Noell (114), particularly with
regard to the slow phase.
A con\cnient way of making the retina respond
quickly to illumination by a fairly pure negative ERG
is to drop potassium chloride solution into the opened
bulb (83, 139). This is a well-known depolarizing
agent and accordingly the remaining cornea-negative
response to light cannot itself be a depolarization of
already depolarized structures. The cornea-positive
PII, however, is likely to represent depolarization by
light. Both components are increased by running a
polarizing current across the bulb, inside negative,
and are decreased by reversal of this current (18, 28,
76). A negative ERG can be made positive Ijy drop-
ping alcohol into the bulb (19).
At cessation of illumination PHI returns towards
the base line of the record (the .so-called resting po-
tential discussed below), first rapidly, then more
slowly. At least in the isolated state the slow returning
phase may appear as a kind of 'remnant negativity.'
[There are apparently still slower changes of poten-
tial, both negative and po-sitive (see 114), than the
ones generally counted as belonging to the ERG
proper.] At the same time the cornea-positive PII
ends at cessation of illumination, either by returning
to the base line or even going below it or else contrib-
uting to the rf-wave that otherwise would have been
due merely to interference between PII and PHI.
There is evidence for both alternatives in the litera-
ture according to the view of Granit (73). Further
experimentation with different eyes seems necessary
to establish the dominant event in difierent types of
eye (see 6, 82, 113, 141).
In considering questions of this kind it is necessary
never to forget that the ERG is a mass response re-
corded at a distance from the sources generating its
potential. VVirth & Zcttcrstrom (150) illuminated the
cat's eye through perspex cones applied directly onto
the retina and found that illumination of an area of
20 mm- was necessary for maximal responses. Con-
sidering that the diameter of the rods is 0.D02 mm,
there is ample margin for a large variety of elementary
component responses to complicate the issue. A gen-
eral analysis can merely aim at describing dominant
features. Localized leads and localized light projec-
tions on the retina are necessary for a study of details.
If one illuminates through a glass electrode applied
directly onto the retina (20), the individual retino-
grams are very different in different places.
There are a number of interesting features by which
the cornea-positive PII and the cornea-negative PHI
of the general analysis differ from one another. Figure
7.-I, which illustrates for the frog retina the effect of
reilluminating at different times after cessation of
illumination (46, 80, 112), shows that the cornea-
NEURAL ACTIVITY IN THE RETINA
701
negative a-wave now is greatly increased and maximal
when the off-effect has reached full size. The retina
seems to show no refractoriness but is immediately
ready to re-establish the level of negativity charac-
teristic of that particular state of adaptation and
stimulus strength. The cornea-positive PI I (6-wave)
behaves very differently. It fails to appear until some
time has passed, as can also be very clearly seen with
the cat retina (Z)) which is dominated by this com-
ponent.
Figure 8 shows the full analysis of an experiment of
this kind. The dotted lines represent the effects of the
individual flashes of reillumination, d is the rf-wave
control; h, the level of the A-waves; a, that of the a-
waves. Assuming a and b being generated in the same
structures, it is difficult to understand why the former
response is immediately ready to be re-established
while the latter refuses to behave in the same fashion.
Part of this difference has been found to be due to
the b- and ^/-waves sharing generators in the sense
that the one leaves refractoriness for the other (82).
In recent attempts to assign the origin of the ERG
to definite retinal structures, experiments of this type
have been neglected altogether. Yet, they seem to
contain essential information about the components
of the ERG which no discussion of these problems can
neglect. Perhaps this is the place for pointing out that
the ganglion cells definitely seem to be excluded as
sources of the ERG. From time to time since 1933 the
author has stimulated antidromically the optic nerve
of frogs and cats while recording the ERG in order
FIG. 7. Effect of increasing the interval between two stimuli
on the electroretinogram of different types of retinae: .4, frog;
D, cat. Uppermost curve of each series shows the uninterrupted
off-effect. Short vertical lines indicate the beginning of re-
illumination. Time marking: o.i sec. [From Granit (65).]
U U-l 0-2
FIG. 8. Off-effect or (/-wave given by d in the frog ERG. Reillumination by single flashes elicits
the potential changes (a- and i-waves) shown in dotted lines, a and b trace maxima of a- and i-waves
respectively. Note that curves b and a are drawn through peaks of b and a waves at different
times of re-illumination and thus show that the a-wave reappears at once and is increased while
the 4-wavc requires a long time for recovery. [From Granit c& Riddell (80).]
702
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
400r
300-
200
e"ioo
O O
X
0
200
400
600
800 0-
FIG. g. Effect of a Hash, supcrimposfd on the off-discharge
in the frog's optic nerve, plotted as average spike frequency
in impulses per sec. against time in msec. Dotted line, off-
discharge control. Continuous line, diminution in frequency
(inhibition) caused by a flash, indicated by the horizontal black
line, delivered at the height of the off-effect. [From Granit &
Therman (8i).]
to determine whether the latter could be influenced.
This has never been the case (76). Yet it is possible to
influence both the discharge of ganglion cells and
their level of depolarization by such means (74).
Further, glaucoma with optic nerve atrophy is asso-
ciated with a normal ERG (96, 114).
The question of how the ERG correlates with the
discharge through the optic nerve can be profitably
attacked by studying what happens in the nerve when
these large a-waves are induced on top of the ofT-
discharge. Figure 9 shows that there is inhibition of
the off-discharge (81) and this was confirmed by
Granit & Helme (76). This experiment provided the
main argument for the view that PHI is concerned
with inhibition rather than with excitation. The cor-
nea-positive PII was held to signify excitation. The
general likeness between the cornea-positive retino-
gram and the variation of the discharge-frequency
through the optic nerve, first pointed out lay Adrian
& Matthews (3, 4, 5), supports the same inference
(fig. 10). Granit & Therman (81) could find no eff"ect
in the optic nerve discharge corresponding to the
large c-wave of the dark adapted eye.
In this connection the effect of alcohol on the frog
retina is particularly interesting (19). The left record
in figure 1 1 shows the light adapted ERG of a frog.
A drop of alcohol into the opened bulb makes it
change as shown in the right record. The upper
record shows the change of the a-wave under alcohol.
In this final stage it looks like the ERG of the fully
dark adapted retina and, like the latter, has a small
d-wavc and responds only to slowly flickering light.
Even an ERG made largely negative by potassium
200-
FiG. 10. Variation in impulse frequency of the eel optic
nerve during stimulation. [From Adrian & Matthews (3).]
1
^
FTP
FIG. II. Effect of alcohol on frog ERG. Top record: diminu-
tion of a-wave during alcohol treatment. Left: Light-adapted
ERG with reillumination on top of the rf-wave. Right: Same
experiment after alcohol. Time, 0.2 sec. Light signal above
time record. [From Bernhard & Skoglund (ig).]
chloride turns positive after alcohol. The interpre-
tation of these changes is that alcohol diminishes PHI
and augments PII, which agrees with the interpreta-
tion of the similar changes with state of adaptation.
However, still more interesting from the present point
of view is what happens in the test with reillumination
in which, after alcohol, the negative a-wave will now
be very small or absent. The experiment showed that
the corresponding inhibitory pau.se in the discharge
also was curtailed. The authors held their result to
support the view that PHI (or what now may be
called fast PHI) was inhil)itory, i.e. as confirming
the view that excitation and inhibition was charac-
terized ijy opposite deflections of the ERG.
In this volume the vision of invertebrates is treated
in Chapter XX\"I by Milne and Milne. It is neverthe-
less of considerable interest here to mention the recent
experiments of MacNichol & Benolken (105) with
Hartline's so-called lateral inhiljition in the plexus of
nerve fibers behind the Limulus ommatidia (9O. By
means of interconnections in this plexus, illumination
of one ommatidium suppresses the discharge of
another (91). Now, MacNichol cS: Benolken find that
alcohol removes this lateral inhibition re\ersil)ly.
For a final allocation of the retinal component po-
tentials to definite structures (receptors or bipolar
NEURAL ACTIVITY IN THE RETINA
703
cells), it will be necessary to use nonpolarizable pene-
trating microelectrodes. Such work was initiated by
Tomita (141, 142). Instead of a review of arguments
from general electroretinographic work for which the
author's summary (69) may be consulted, a brief dis-
cussion of the results obtained by such niicromcthods
is given.
Tomita"s work was criticized and ignored by Otto-
son & Svaetichin (i 16) on the grounds that his pene-
trating microelectrodes were held to be too coarse.
Tomita has since (142) repeated his experiments with
the Ling-Gerard type of microcapillaries, used by
Svaetichin, and confirmed his previous results. At the
same time Brindley (28, 29, 30) has also published a
careful study using the same technique. Ottoson &
Svaetichin's conclusions as far as fundamental ques-
tions are concerned were: a) that slow potentials of
the ERG type are obtained in the receptors only;
this has since been definitely refuted by Brindley (30)
and by Tomita & Torihama (142), who found large
potential changes mirroring the ERG in the bipolar
layer; b) that rods respond only with positive, and
cones only with negative retinograms [cf. also Svaeti-
chin (137)], disproved by Granit (73) as well as by
Forbes ft al. (55) and Brindley (29); c) that the resting
potential of the retina is a receptor potential (115),
since refuted by Brindley (28); tt) that, from the fact
that cocaine slowly attacks the ERG but immediately
stops the discharge of impulses through the optic
nerve, it is possible to conclude that the ERG is a pure
receptor potential [from Kiihne & Steiner (102)
onwards the number of agents capable of blocking the
impulse discharge without much effect on the ERG
has been slowly multiplying, yet without suggesting
to anyone such far-reaching conclusions] ; e) that from
the size of sudden potential gradients of the order of
20 to 30 mv within the fish retina (approached from
the receptor end) it is po.ssible to assume that the
electrode recorded intracellularly from single cones.
Now Brindley (28) has shown that there are charac-
teristic steps in the radial resistance to a penetrating
microelectrode, the largest one across the external
limiting membrane (see below), and extracellular
spike potentials of the order of 40 to 60 mv have been
recorded by Granit & Phillips (79) by the same tech-
nique at the surface of the cerebellar Purkinje cells.
Furthermore, an extracellular retinal microelectrode
has been shown by Brindley (30) and Tomita & Tori-
hama (142) to pick up its response from very distant
illuminated regions. This is, of course, what one must
expect. Light intensities and techniques of illumina-
tion are hardly ever mentioned in the papers by
Svaetichin & Ottoson but this, in itself, suggests that
the whole retina or a large fraction of it was illumi-
nated. Focal microillumination would be needed for
localized responses and there is in its favor the further
advantage that absence of a response within the bi-
polar layer shows whether damage has occurred (30,
142). Such damage probably explains why Ottoson
& Svaetichin have missed the response inside the
retina. In fact, Brindley (30) describes two types of
responses in excised frog eyes of which the .second
agrees with the pictures of Svaetichin. This type
Brindley holds to be characteristic of local damage
because it alone is seen when the focal intraretinal
response is absent. These remarks may suffice to show
why it is felt that Ottoson & Svaetichin have under-
rated the analytical difficulties of the work they set
out to do. For this reason individual good observa-
tions in their work, perhaps unjustly, lose their sig-
nificance to a reviewer and can only be rescued by
those who have undertaken microelectrode work with
the same structure and thus can evaluate them criti-
cally against a background of specific experience.
Apparently retinal neurons do not differ from other
neurons, all of them producing potential changes.
Both Brindley and Tomita have arranged their ex-
periments for comparison of precise focal microil-
lumination around the microelectrode tip with illu-
mination of larger areas. Unless an electrode within
the bipolar area responds to focal illumination with a
reponse of the intraretinal type, the region around
this electrode is not likely to be in a normal state.
Brindley suggests that this condition is due to dam-
age of the external limiting membrane. The inside
focal response has a maximum among the bipolar
cells at a depth of 1 00 to 1 40 yii from the ganglion side.
The large ERG elicited by general illumination is
always obtained and tends to be positive. The two
authors differ in that Tomita's response to diffuse
light reverses sign within the inner nuclear layer,
going from positive at the ganglion side to negative
at the receptor side of the retina, while Brindley finds
more variability in this regard. Now, is the focal
response inside the retina identical with the ERG?
Obviously this response is physiologically important
but both Brindley and Tomita argue against identi-
fication. In the reviewer's opinion it is impossible at
the present stage of our knowledge to be certain as to
whether or not bipolar cells contribute to the ERG.
Tomita, for instance, finds no focal response within
the receptor layer. This is no crucial objection to a
localization in the receptors, nevertheless it is a fact
to be considered. Brindley holds the focal response to
704
HANDBOOK OF I'HYSKJLOGV
NEUROPHYSIOLOGY I
be caused by sources located tangentially within the
retina and suggests, on the basis of electrical con-
siderations too involved to discuss, that "only the
rods and cones contribute substantially to the a-, b-
and (/-waves of the electroretinogram, although cells
belonging to the inner nuclear layer can produce
large electrical changes of similar time course" (30).
He himself finds this hypothesis "somewhat surpris-
ing." Tomita localizes the same response to the
bipolar layer with some contributions from other
retinal layers, in particular the inner portion of the
receptors [cf. also Noell (114)].
Particularly interesting are Brindley's (28) meas-
urements of the passive electrical properties of frog
retina for radial fields and currents and the method
applied to make such measurements possible. The
largest step takes place at around 230 fx from the
ganglion side and is of the order of 270 fi. This is
Brindley's R-membrane which he pro\isionally identi-
fies with the external limiting membrane. Its capacity
is about 40 /i F. Across this memi^rane also is the largest
step or component of the resting potential of the
retina. Electron microscopy (134, 135) has led to the
view that the external limiting membrane consists
of rings or collars around the receptor base (inner
segment), a fact difficult to harmonize with the high
resistance and capacity if it really can be assumed
that there has been no shrinkage in Sjostrand's
preparations.
These papers are thought-provoking and serious
attempts to lay bare the considerable difficulties in
arriving at evidence for final conclusions and thus
form a structure of knowledge upon which further
work can be built. There is a large body of informa-
tion about the ERG as influenced by alcohol, potas-
sium, state of adaptation, etc., which will have to be
experimentally applied to microelectrode analysis be-
fore a final conclusion can be reached.
The crucial point in the present position is the
identification of the R-membrane, it being highly
unlikely that any intracellular potentials in the retina
ever have been recorded. The recent findings by
McNichol et al. {105a) show that the former cone-
potential of Svaetichin actually is obtained below the
layer of rods and cones and Tomita (141a) has shown
that it can be obtained with electrodes far too big to
penetrate individual cells successfully. However, the
observations on effects of different wavelengths in fish
seem interesting independently of present assumptions
m
oft
11
pJ I I I
oft
— I
.d_L
.1 I I llllllllllllll I II Mill II I I I I I
FIG. 12. Diagiain illustrating tliree libers in the optic nerve
firing spontaneously and their responses to illumination as
described in text. [From Granit (73).]
and also confirm the demonstration of dominators
and narrow-banded modulators in this eye (65a).
NEUR.\L P.^TTERNS
Work on the spike discharge from the retina started
with the classical papers by Adrian & Matthews
(3, 4, 5) who used the long optic nerve of the eel
Conger for a study of the massed discharge. The dis-
covery of different discharge types was a consequence
of Hartline's (86) successful attempts to split the
frog optic nerve. This he did at the point where it
enters the blind spot and is already naturally split
into fibers coming from different parts of the retina.
The types are shown in the schematic figure 12 in
which account also is taken of the microelectrode
records from mammals (see 69, 73) in which one
often finds more activity between onset and cessation
of light than in the frog and less stability of response
types. Some fibers (/ in fig. 12) respond to onset of
light, others (2) are inhibited by onset of light and
instead discharge at 'ofT." The majorit\- of them dis-
charge to both onset and cessation of light (j). Re-
illumination during the off-discharge inhibits it, as
shown by 2h. It should be realized that, since the
optic nerve fibers represent highly differentiated con-
vergence structures, there are in actual practice al-
most as many discharge types as there are optic nerve
fibers. Nevertheless the types illustrated show ap-
proximately what happens. The inhibition of the
ofT-discharge, as stated, coincides with the large
negative o-wave on top of the off-effect described
NEURAL ACTIVITY IN THE RETINA
705
above. In most eyes there is some spontaneous firing,
generally greater in the scotopic state.
The salient point with regard to the general prob-
lem of response types is, as shown by Granit (71, 72)
and Kuffler (100), that the retina contains two an-
tagonistic systems, the on-system and the off-system,
which, when made to clash on to the same ganglion
cell, are mutually exclusive. One system is excited by
light (the on-system), the other is inhibited by light
(the off-system) and the latter behaves as if the longer,
within limits, the duration during which inhibition is
piled up, the more did this favor the subsequent
off-discharge. Thus, during the time the off-discharge
is inhibited by light something happens that makes
it prone to respond when ultimately light is exchanged
for darkness. Short exposures tend to give very brief
off-effects. When a definite off-effect is seen in the
ERG, e.g. in frogs, it also behaves similarly.
The anatomical convergence means that each
fiber has a receptive field, first measured by Adrian
& Matthews (3, 4, 5) and shown to be of the order of
I mm in the eye of the conger eel, then more pre-
cisely with the single-fiber technique by Hartline
(87). Figure 1 3 shows the exploring spot used by
him and the field sizes obtained in the frog eye when
stimulus strength was varied. Just as convergence
varies from fiber to fiber, so do the dimensions of the
receptive fields. In cats Kuffler (100) found them
beautifully organized so that sometimes the on-,
sometimes the off-effect occupied the center, the
opposite response then occupying its periphcrv and
on-off-responses occurring between the two. This
provided Kuffler with a good opportunity to make
on- and off-spots of the receptive field clash in \arious
combinations and thus elegantly to demonstrate the
antagonism between the two systems relative to the
ganglion discharge. A very complete discussion of
receptive fields and on-off systems has been given by
Granit (73). Both principles of organization recur in
the central structures to which receptors in other
sense organs project.
Why then is the lining of receptors inside the e)e
connected to an intricate nervous center just behind
it, while other receptor systems mostlv have their
first neural organization at the spinal cord level?
Apparently receptors cannot do much by themselves;
their mes.sagcs must be organized somehow for dis-
crimination and integration; and, since the little
brain behind the rods and cones moves with the eye,
it can because of its place in the retina aid better in
the interpretation of the ever-changing boundaries of
FIG. 13. Chait of the receptive field of a single optic nerve
fiber of the frog. Each fine encloses a retinal region within which
the exploring spot light (relative size shown above left) — the log
of the intensity is given on the line — produced a response from
the fiber. On each line the indicated intensity was the threshold;
the set of curves constitutes a contour map of the distribution
of the retinal sensitivity to light with reference to this par-
ticular fiber. [From Hartline (89).]
light, darkness and color out of which the visual
world is synthesized. The eye, as stated above, is
never still and, if by artificial means the image is kept
stationary (39, 125), it tends to fade out quickly,
as if it needed the on-off differentials sharpening up
contours during oscillations. Movement of an object
or a point across the retina will light up a trail of on-
off sparks, as well shown by Barlow (15, 16) in frog
experiments set up to illustrate the biological sig-
nificance of such factors for perceprion. Apparently
also, it is necessary for this highly developed organ
not to be forced to one single mode of working in
coping with a range of illumination from dusk to
bright sunlight. It has been shown that the receptive
fields of the retina vary in width with state of adapta
tion (17).
From what has l)een stated it is clear that at least
within a receptive field interaction can occur, as
first shown by Adrian & Matthews (5) and then
studied in detail by Hartline (87, 88). When spike
frequency or latency is used as an indicator, area and
intensity are found to he interchangeable within the
field, whether from excitation or inhibition being
unknown. These facts provide a likely explanation
of the many old psychophysical observations on the
interchangeability of area and intensity in vision.
From what has been stated it will be realized that
on-off interaction adds to the complexity so that over
7o6
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
a large range of intensities the on-off ratio will undergo
considerable variation. This variation has been held
to support a mechanism of discrimination based on
the overlapping receptive fields. Overlapping recep-
tive fields, less elaborated than in the retina, also
occur in other sense organs. These principles have
been discussed at some length by Granit (73).
Many problems of retinal neurology have been
clarified by Hartline's work on the much simpler
Limulus eye, to which students of the verteljrate retina
are advised to give careful attention. This in par-
ticular applies to the recent important analysis of the
lateral inhibition (90) in the neural network below
the ommatidia, because the suppression of the dis-
charge of one ommatidium by its illuminated neigh-
bor is clearly a mechanism of contrast. In the frog
retina Barlow (15, 16) has found the discharge from
a receptive field to be inhibited by illuminating retinal
regions just outside it.
There are other aspects to the problem of inhibition
than those connected with the organization ot the
receptive fields. There is, for example postexcitatory
inhibition (73) and the generalized inhibition recently
described Ijy Dodt (43).
STIMULUS CORRELATES
The average electroretinographic response is
roughly proportional to the logarithm of stimulus
intensity. However, since most retinae contain two
organs in one (rods and cones) and the ERG's of
rods and cones do not relate similarly to stimulus
intensity in addition to differing in latency and rate
of rise (see above), too much should not be made out
of this general logarithmic relationship. It does, how-
ever, suggest that the elementary generator potentials
of which the total response is made up tend to be
logarithmically related to stimulus intensity, and this,
whenever they have been recorded, actually is the
case [cf. the discussion by Granit (73)]. In Limulus
the spike frequency emanating from the excentric cell
of a single ommatidium is logarithmically related to
stimulus intensity meaning that the level of om-
matidial generator potential, at least when stabilized,
is directly proportional to spike frequency [the cor-
responding relation for muscle receptors has been
described (97)]. Many single fiber preparations rep-
resenting receptive fields in frogs (86) and mammals
(67) have shown a general logarithmic relation to
stimulus intensity, superimposed, as it were, upon
on-off complexities. The overall effect of an assembly
of cells is likely to follow this rule which, of course, is
nothing but the well-known Fechner law looked at in
a diflferent way [for a full discussion, see Granit (73)].
The retina is a detector of so-called visible light
which is visible because photochemical substances
within the rods and cones absorb energy and trans-
form it into a form appropriate for stimulation. Most
color theories have assumed that different kinds of
cones are provided with photochemical substances ad-
justed for absorption of light within different parts of
the spectrum but the only substance known until
fairly recently was Boll's visual purple or rhodopsin
in the rod outer limbs, and these organs, on the
duplicity theory, were assumed to be color blind.
This was the situation until some experiments with
the electroretinogram (78, 84) definitely proved that
the frog light-adapted eye showed distributions of
spectral sensitivity that required a minimum of three
cone substances to be intelligible. This has since been
confirmed in many other types of experiments with
different eyes. In light-adapted frogs and in the cone
eyes of the turtle, Forbes et al. (55) showed that, if
they were illuminated by two 'white' lights, these
could be exchanged without influencing the ERG but
that certain pairs of colored lights never could be
exchanged, whatever their intensity ratio, without a
specific electroretinographic color response. Japanese
workers (62, 63, 140) using frogs studied the multiple
off-effects and wavelets on top of the off-effect, men-
tioned above, and found evidence for a representation
of differential spectral sensitivity in the different crest
times of such wavelets. There was a minimum of three
humps appearing in the order red, green and blue,
as also shown in the recent work of Heck & Rendahl
(93). A similar order had previously been observed
bv Donner (51) working with the spike frequency-
time differentials of single ganglion cells in the cat
retina and by Motokawa and his group (108, 109,
143). There is a critical review of Motokawas work
by Gebhard (59). Motokawa's measurements were
based on the rate of rise of retinal sensitivity to a
brief polarizing current after preillumination with
different wavelengths.
Recent work with the human electroretinogram is
definite in showing that the ERG contains com-
ponents of different color sensitivity, even in the light-
adapted state (10, II, 93, 130). HowcNcr, all work
with a mass response such as the ERG suff"ers from
the difficulty of isolating the spectral components in a
quantitative way.
Color vision as an electrophysiological problem
contains two different aspects: a) the primary sensi-
NEURAL ACTIVITY IN THE RETINA
707
tivity distributions of individual receptors and b) their
representation in the organized message dehvered by
the ganglion cells through the optic nerve. The latter
delivers the information which the striate area has to
interpret and so problem b is as important as prob-
lem a. The act of interpretation itself is at the moment
beyond the reach of electrophysiological approach.
Solution of the first problem requires more reliable
microelectrode records of individual receptor po-
tentials than is found in any paper hitherto presented.
Our most definite quantitative data are still the ones
obtained from individual optic nerve fibers of animals
(66, 68, 6g, 73). It is necessary to understand how a
spectral distribution is defined in order to comprehend
the color problem. A simplified presentation of this
question can be given in the following way.
Assume that a color-sensitive substance absorbs light
along a spectral distribution curve represented in
every wavelength by S\. Dependent upon the lamp
used and upon other properties of the spectrum (e.g.
slit width, diffraction) each of these wavelengths tested
represents an amount of energy E\. Finally, again,
each of the wavelengths tested elicits an effect Lx. It
is immaterial now if this effect is considered in terms
of a receptor potential, a spike frequency or as per-
ceived brightness. This efTect L>, will be proportional
to the sensitivity Sx and the amount of energy Ex so
that Lx = Ex-Sx. In order to measure Sx which is the
function we want to study and which clearly is .Sx
= Lx/Ex we must first of all measure Ex of the spec-
trum used (which should be of a high degree of
purity). The next step is to set up the biological ex-
periment so that the physiological effect Lx is kept
constant in every wavelength. Then, with Lx and
Ex known, the equation can be solved, i.e. Sx can be
calculated. It is proportional to i/Ex. For c|u;)ntita-
tivc work it is therefore not enough to keep the energy
E of the spectrum constant and measure the physio-
logical effect L, even though such results may have
indicative value and can be approximately corrected if
the relation between E and L initially has been meas-
ured over the working range for each wavelength.
Very serious errors can also be introduced by filters
of which even the best have narrow color bands over
one or two log units only. Therefore spectra should
be used for quantitati\e work. A good method is to
mea.sure i/Ex for a constant response (Lx) such as
the threshold. This was the method employed in the
experiments on the discharge from indi\idunl nerve
fibers.
These results, for which a large number of different
species of animals were used, some with pure cone
%
80
/
'\
/
\
y
■10
I
7
\
?n
/
\
>
^
0 450
0 500
0-550
mO 700
FIG. 14. Photopic dominator curves of the frog ( ) and
the snake Tropidonotus natrix (• •). Equal quantum in-
tensity spectrum. Sensitivity plotted against wavelength.
[From Granit (66).]
retinae, others with mixed retinae (after light-
adaptation), led to the dominator-modulator con-
cept. The optic nerve fibers were found to deliver two
types of curves, broad-band dominators and narrow-
band modulators. Figure 14 shows photopic domina-
tors of the snake cone eye and the light-adapted frog
eye which are of interest because the photochemical
systems of these eyes seem to he very similar to our
own. Actually their photopic dominators agree very
\\ell with the average photopic distribution of sensi-
tixity of the human eye. When the mixed eye is
dark-adapted, the same fiber that previously gave a
photopic doiuinator now gives a scotopic one with
b
maximum around 5000 A which agrees with the
sensitivity distriljution of visual purple or rhodopsin.
We recall that Polyak (122) had shown that both
rods and cones converge towards the saiue ganglion
cell. Thus the dominators are the carriers of the
Purkinje shift of retinal sensitivity with state of adap-
tation. In man the point of maximum shifts from
5560 to 51 00 A, just as in frogs and cats. The photo-
chemical aspects will be discus.sed elsewhere in this
volume (Wald, Chapter XXVIII), but it deserves to
be pointed out that dominators in various systems
have been synthesized by Wald out of vitamin A
aldehydes and rod and cone proteins with the aid
of various enzymes and that these synthesized prod-
ucts have absorption spectra in good agreement with
the experimental results obtained from optic nerve
fibers [see also the summaries by Granit (73, 75)].
Examples of modulators from different animals are
7o8
HANDBOOK OF PHYSIOLOGY
NEl'R0PH^■S10L0Cn•
100
%
80
60
40
20
/
■(
>•
W/
N
\
■
■
/
.A
' \j?
IK % j\
[\
\
■
f
■
/
%
i.\\
•
■
/
/
r\^'\/
\
■ ". 1
\ \
1
V
■
450
500
550
600
650
r
FIG. 15. Modulator curves. Doli, rat; broken line, guinea pig;
continuous line, frog; O O, snake. Equal quantum intensity
spectrum. Sensitivity plotted against wavelength. [From
Granit (66).]
given in figure 15. The modulator at 5000 A was
obtained after light-adaptation from the rat, an ani-
mal with rod eyes. In the dark-adapted state it had
been a dominator of the ordinary rhodopsin type. It
is by no means rare to find, in practically pure rod
eyes such narrow curves with ma.ximum around 5000
A, when visual purple activity has been suppressed
by light-adaptation. The other modulators very
clearly occupy three regions of predilection which
have recurred since in many other measurements.
The narrowest modulators ever seen were found by
Donner (52) in the pigeon cone retina where they
also occurred in three regions of predilection and
shifted slightly towards wavelengths which are long
compared with those of frogs. Donner suggested that
this shift was due to colored oil globules. Modulators
have also been obtained by selective adaptation to
different wavelengths as well as by electrical polari-
zation.
A much debated question is whether these modu-
lators represent the more or less pure absorption
curves of photochemical substances or are products
of neural interaction based, for instance, on a mini-
mum of three broad-band curves. The simplest basis
for such interaction would obviously be overlap of
liroad-ljand curves, such as those of Dartnall C35)>
the pathways of one set of cones synaptically sup-
pressing or e.xciting those of the neighbor cones with
which they overlap in spectral sensitivity. As to such
interaction, it is true that it has been shown to e.xist
(43, 71), especiallv b\' polarization methods (70), but
this does not necessarily constitute proof that it
actually did occur under the circumstances of thresh-
old experiments of the type used to establish the
concepts. On the other hand, retinal photochemistry,
though highly developed in many interesting experi-
ments by several workers [see Wald's summary in
Chapter XXVIII of this volume; also Granit (73,
75)], has not yet reached the point when it would be
possible to state that narrow-band photochemical
substances do not occur in living retinae. The most
that could be said is that broad-band curves seem to
be easier to demonstrate. Further work will no doubt
solve this problem.
Much work has lately been devoted to the study of
the action of intermittent or flickering light. In
general, rod eyes have been found to fuse flicker at
lower values than cone eyes. In a mixed eye in the
dark adapted state rod sensitivity is high, for example
in the frog retina with roughly equal numbers of rods
and cones. Fusion frequency of the ERG to a light
of some 2000 lux in this animal will then be around
7 to 10 flashes per sec. But if this light is allowed to
shine for a while so as to light-adapt the eye, the
fusion frequency will soon rise to values around 20
flashes per sec. Now why could not the faster cones
also participate in tlie dark-adapted state and raise
the fusion frequency to their higher rate? Why was
light-adaptation necessary, particularly if the ERG
is a pure receptor affair and not influenced by inter-
action? Perhaps the reply is that interaction does
occur so that highly sensitized rods suppress the
cones, as was suggested by Granit & Riddell (80)
when they made this experiment. They also demon-
strated that the flickering wavelets change character
as light-adaptation proceeds and, besides, are dif-
ferent in rod and cone eyes. The same changes can
be seen in the ERG of man (41).
Figure 16 is from experiments with ERG in guinea
pigs, cats and pigeons (45, 49) and shows a graph of
fusion frequency against light intensity in double
logarithmic plotting. Clearly there are two branches
of the curve in cats and guinea pigs. Much evidence,
presented in Granit's summary (73), goes to show
that the lower branch is a scotopic and the steeper
portion a photopic function. The less the number of
cones (their being far fewer in guinea pigs than in
cat.s), the higher the intensity at the kink of the curve.
The pigeon with cone dominance in the ERG has
no low-intensity branch but the curve rises steeply to-
wards values as high as around 1 30 per .sec.
Records from the large retinal ganglion cells of
cats have shown (54) that fusion frequenc\' is pro-
NEURAL ACTIVITY IN THE RETINA
709
750r Fusion frequency
iriashesf^^,
100 ~
50
Light intensity
10
100
1000
10000
FIG. 16. Double logarithmic plot of fusion frequency of the
electroretinogram against stimulus intensity in meter candles.
O, cat; C, guinea pig (two animals); •, pigeon. [From
Granit (73).]
20'
SOcylsec
FIG. 17. Evcephale isole given
curare. Collicular stimulating
electrodes on contralateral side
at depth H 2 in Horsley-Clarke
coordinates. C, controls with test
light of 3 lux alone. /, and 18-20
show first and three last records
of stimulation period 22 sec. in
duration, at a rate of 47 per sec.
Note, no driving, as shown by
isolated shock artifacts; after-
wards diminution of spike fre-
quency. Sweep interval in sec.
[From Granit (74).]
portional to impulse frequency set up by the indi-
vidual flashes just before the moment of fusion when
impulse frequency still can be measured. Fusion it-
self is defined as the flicker frequency at which effects
of individual flashes on the spike frequency are no
longer discernible. Flicker and fusion in electrical
records has recenth' been discussed by Granit (73).
CENTRIFUG.AL CONTROL
The inner plexiform layer, which forms a network
of dendrites between ganglion cells and bipolar cells
densely interspersed with amacrine cells, also re-
ceives the terminals of the centrifugal fibers (.see fig.
2). Their central station in the brain is unknown.
However, experiments have shown that it is possible
to obtain diff'erent kinds of centrifugal effects on the
ganglion cell discharge (44, 74). These are partly
excitatory, partly inhibitory but quite often mixed,
excitation followed by inhibition, and generally re-
quire an array of antidromic stimuli to the optic
nerve before a definite effect is noticed. This is not
surprising. We are best informed about centrifugal
effects from the brainstem to the muscle spindles (77)
through the so-called gamma neurons and these too
mostly require iterative stimulation. Similarly the
suppression of the cochlear nerve discharge (58) by
stimulation of the centrifugal olivocochlear bundle is
fully developed only after it has been stimulated for
about half a second at the optimal rate of 100 per sec.
The effect on the retina is very .similar independently
of whether the site of stimulation is the optic nerve
where it is spread out in the pretectum or the brain-
stem reticular substance. In the former case there is,
of course, also driving of the ganglion cells by anti-
dromic stimulation which seems to facilitate excita-
tory components on the driven cells. On the other
hand, from lower portions of the optic nerve inhibi-
tory effects are quite common. When the effect is
excitation, it tends to be an increase of level of excita-
bility so that a greater number of impulses are dis-
charged between 'on' and 'off. The on-off' differ-
entials tend to disappear in this general outburst.
Again, when the final result is suppression, the whole
effect of light is suppressed. An inhibitory effect from
the brainstem reticular formation is shown in figure
17. High-frequency on- or off-bursts cannot be much
altered by centrifugal stimulation.
Recently further work by Dodt (44) on the rabbit
eye has led to the actual demonstration of a centrifu-
gal spike picked up in the retina. This spike is from
8 to 20 msec, delayed with respect to antidromic im-
pulses recorded from the ganglion cells. These also
are positive-negative and much larger than the cen-
trifugal spikes which are purely negative as if they
started below the recording electrode itself. It is
710
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
impossible to elicit the ccntriiugal spike by light. It
is at the moment too early to put forth a theory of
the role of centrifugal control.
ERG OF M.^N: its CLINICAL USE
erg's of man have been recorded from the very
earliest time of electroretinography but the first really
good records were published by Hartline (85). The
work gradually got under way, particularly when
the first more differentiated responses separating
rods and cones were published by Motokawa &
Mita (no) and Adrian (i, 2) and when Karpe (96)
started clinical electroretinography. In 1956 this
subject gathered a large number of European con-
tinental and British students of the human ERG to a
first symposium in Hamburg (128). The contriljutions
to this symposium provide a convenient introduction
to the literature of electroretinography, particularly
in its clinical aspects.
Since in man it is impossible to open the eye and
use microillumination of selected spots and, at the
same dme, the dominant phase of the human ERG
is a rod response requiring dark-adaptation, the
question of whether the ERG is a generalized re-
sponse to stray light or is focally elicited has created
considerable interest. Contributions to this discus-
sion by Fry & Hartley (57), Boynton & Riggs (27),
Asher (13), Boynton (26), Wirth & Zetterstrom
(150), Marg & Heath (106) and Brindley (29) should
be consulted. There is general agreement that stray
light is unavoidable at the strength needed for an
ERG to be recorded in the human eye, i.e. from the
cornea; in particular, clinical work shows that evi-
dence of large scotomata may fail to appear in the
ERG (96). In cats, as stated, an area of 20 mm-
must be illuminated for a maximum ERG (150).
With regard to localized focal stimuli in opened eyes
of animals and whether they can interact or not,
opinions still differ (29, 106).
Much recent theoretical work on the human ERG
has been devoted to the identification of its various
deflections and components, particularly with regard
to rods and cones (12, 14, 21, 40, 41, 48, 130, 148),
and to a study of its sensitivity to colored lights (as
mentioned above).
The clinical values are both diagnostic and prog-
nostic. Karpe (96) initiated the work iiy bringing
together the data necessary for establishment of
normal standard values for the b-wave and for de-
fining a number of fundamental pathological types
of initial deflections. There has since been much
systematic work done, and in many eye hospitals
recording of the ERG is a routine procedure, not
only when the eye media are opaque but also for
the prognosis of varieties of tapetoretinal degenera-
tions, to decide whether treatment should be surgi-
cal or not, in children (151), etc. It seems that early
changes in the ERG or failure of such changes when
the ophthalmoscopic picture suggests a pathological
retina are of considerable prognostic value.
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CHAPTER XXX
Central mechanisms of vision
S. HOWARD BARTLEY | Department of Psychology, Michigan State University, East Lansing, Michigan
CHAPTER G O N T E N I S
Types of Data
Commonality in Modes of Study
Phenomena of Vision
Phenomena of the Optic Pathway
Brain waves; spontaneous and evoked
Optic pathway
Cortical response
Activation of cortex by stimulation of radiation
Activity in regions other than optic cortex
Cortical localization
Properties of dendrites
Visual Phenomena to be Explained
Gross Response to Gross Intensity Relations
Area of Target
Brightness
Flicker and Fusion
Brightness Enhancement
Bilateral Functions
Brightness Contrast
Visual Movement
Color Vision
THE PRESENT CHAPTER, devotcd to Central mechanisms
of vision, must deal with two diverse sets of phe-
nomena. One set comprises the phenomena that,
taken together, we call vision. The other is the group
of neurophysiological phenomena that constitute the
activities of the central end of the optic pathway. The
visual phenomena must be considered first, for they
are the items to be accounted for, if possible, by what
we know about the optic pathway and its associated
systems.
Vision is the behavior of the organism that stems
more or less directly from optic pathway activity.
Vision includes both the introspective (the experien-
tial) and the motor. Visual behavior in question is
divisible in still another way. Part of it is the immedi-
ate discriminatory reaction which we call visual per-
ception. Perception is not only experiential but also
motor in expression. Another part of behavior is in
the form of imagery, etc., that is, a function of the
visual mechanism when the eye is not stimulated.
Material appropriate in the discussion of central
visual mechanisms stems first from what we know
about visual phenomena in accord with the definition
of vision just given and from what we have found out
from direct investigation of the activity of the entire
optic pathway. We may also legitimately include cer-
tain inferences that seem to be necessary to bridge the
gaps in our knowledge and to provide a basis for
further investigation.
TYPES OF D.«iTA
In this portion of the chapter we must specify, at
least in general, the kinds of phenomena with which
we shall deal. They are of two kinds so diverse that
they generally are dealt with in entirely separate dis-
courses. The one class is visual and includes the ex-
periential outcomes of the action of the optic pathway
activated by photic radiation. The other class of
phenomena is neurophysiological. The task of the
present chapter seeins to be one of relating the two
classes of phenomena.
Commonality in Modes of Study
The fundamental requirement in relating vision to
the various phenomena in the optic pathway is for
the two sets of events to be initiated by the same ex-
ternal event (stimulus). In this way, one can .say that
7'3
714
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
a given visual end result is occasioned upon such and
such events in the bodily mechanism involved.
It is fortunate that the same stimulus conditions
can and have been used to study the behavior of the
two categories of events. This is to say that not only
are photic stimuli used in both cases, but the very
same manipulations are used and seem effective in
giving us the data we need.
The following remarks have to do with modes of
studying both vision and the neural mechanisms that
underlie them. Vision can be studied only in the intact
or near-intact animal. Neurophysiological mecha-
nisms can be studied in the reduced animal and in
animal preparations. Vision is to be studied only by
use of retinal stimulation with photic radiation.
Neurophysiological mechanisms (including central
mechanisms) may be studied by stimulating either
the retina or by eliminating it and stimulating the
optic nerve directly by electrical energy, or by directly
stimulating regions farther along in the pathway. The
electrical method provides for stricter control than
the photic and, though 'unnatural' in the temporal
pattern of impulses delivered, the central end of the
pathway is helpful in analyzing the nature of the
mechanisms involved. Eliminating the retina elimi-
nates the selective feature^ employed by it in pro-
ducing the optic nerve discharge. The retina selects
or emphasizes certain channels in the optic nerve
according to the distribution of the discharge into the
various channels in keeping with its own principles of
divergence and convergence in its neural circuits.
Virtually no discharge initiated by the retina involves
all channels simultaneously. They are activated in
temporal succession of some sort or another.
When the optic nerve is stimulated directly
(electrically), all available channels may be activated
together in time and thus a very different reception
of the afferent input may occur at the stations along
the pathway. To discover just how nearly alike the
two forms of stimulation, in effect, can be is a matter
of empirical test.
At this point, it may be appropriate to point out
one of the more salient features of the retina-initiated
optic nerve discharge, namely that it is composed of
three temporal orders, a) One is the maintained dis-
charge, a series of impulses lasting throughout the life
of the photic impingement on the retina. 6) Another
is the on-off discharge, occurring at the beginning and
also at the termination of the photic impingement,
c) The third type is the off discharge, occurring only
following the termination of impingement. There are
certain visual end results that seem to be explained
on the basis of these differences. The retina is also
responsible for an unexpected end result, the seeing
of two flashes when the photic impingement (pulse)
is brief, moderate in intensity and singular, owing to
the fact that the two sets of sense cells do not have
the same latency.
Modes of study in\olve not only the two forms of
setting up the optic nerve message but also manipula-
tions in the photic impingements themselves. In
general, three forms of timing may be employed : a)
single i-solated stimuli; /;) paired stimuli, in which the
two members of the pair are variously separated in
time; and r) trains of stimuli, often called intermittent
stimulation. In intermittent stimulation, time inter-
vals between stimuli may be varied, and the ratio
between the stimulus (pulse) duration and the length
of the cycle of intermittency may also be varied.
These three forms of manipulation have turned out
to be much more than empty differences in form of
stimulation as will be seen later. The use of method
a provides for a response from a resting system, at
least as far as intended activation is concerned.
Method b proxides for the determination of the effect
of the first stimulus on the second, or otherwise stated
it provides for discovering how long it takes for the
reacting system to complete its response and reassume
status quo. Method c provides for still another aspect
of the reacting system to become manifest. Since the
optic pathway consists of a number of parallel chan-
nels, each with finite limits in the rate at which it can
be reactivated, it is possible that, when a whole train
of stimuli is dcli\ered at a rate beyond which single
channels can repeatedly respond, a redistribution of
the relationships between repeated pulses and the
responses to them occurs as stimulation progresses.
Phenomena of Vision
The phenomena of vision are the items to be ulti-
mately accounted for, hence it is necessary that we
have in mind what they are. Vision consists in the
appreciation of the surrounds via the use of the eye,
the nervous system, and in turn the effector muscles.
The feature of the environment to which response is
made is, of course, photic radiation. The dimensions
involved are spatial, intensive and temporal. Hence
it could easily be supposed that these w-oujd be the
experimental variables to be used.
In vision a field is responded to in terms of intensive
components that, when they evoke experience, are
perceived as lightness and darkness of various degrees.
These qualities need not be stable but may be per-
CENTRAL MECHANISMS OF VISION
715
ceived as appearing and disappearing. \'ision is also
response to spatial rclationsiiips of radiation origi-
nating in various directions from the eye. When these
relationships are experienced, we see objects at various
locations, manifesting various inovements and assum-
ing various directions from us. We are also visually
responsive to manipulations in timing of radiation
coming from various parts of the field. When this
response is in the form of experience, events are seen
as occurring in succession, or together in time, and
lasting for various durations. Photic radiation may
also be differentially responded to in terms of its
wavelength. The experience then is of color, hue,
saturation and brightness.
It is meant to be clear to the reader that vision,
i. e. perceptual response, may occur in the form of
clear immediate experience, in the form of inarticulate
gross incipient reactions or in the form of articulate
differential motor responses. In the last analysis, the
sharp dichotomizing between the experiential and the
motor is only one of the possible ways of dealing with
beha\ior. It would seem that when one looks carefully
at the kinds of behavior which the human manifests,
it is more appropriate to postulate a kind of spectrum
of kinds rather than two opposite kinds with no form
intervening between them.
The following are some of the essential types of
problems which we must handle as best we can with
our present information and interpretations, a) The
first problem is that of seeing various brightnesses,
i) Next we have the problem of seeing continuously.
It is known that many neurophysiological processes
are discontinuous. Were these the only processes we
could discover in the nervous system, the problem of
getting continuity from discontinuity would seem to
be a cardinal one. We are beginning to learn of sus-
tained activity or sustained state of potential, and
this may help a great deal, c) This is followed by the
problem of differential response to various parts of the
space field, since response to the field as a whole is
not what would be expected were the response to iso-
lated parts either independent or summative. d) The
problem of fine resolution is the question of how
closely adjacent parts of the field are seen as separate.
i) Finally, we have the problem of differential re-
sponse to various parts of the spectrum — both local
response to an isolated part of the field and response
to the whole field.
While the problems that ha\e just been listed are
fundamental, they are in the form of generalizations
and cannot be dealt with as directly and as concretely
as is the case when particular visual phenomena are
chosen. For most of our considerations, we have chosen
phenomena that are fairly specific but stand for the
broader classes to which they belong.
The first general phenomenon appropriate for men-
tion is that of gross response to the simplest major
intensity differentiations in the field. This is the
response merely to one large part of the field as more
intense than the others.
W'hereas the foregoing item may be thought to
have to do with brightness, brightness is an experi-
ence. It and any overt response that seems to be
related to it in an experimentally approachable way
had better be put in a class by themselves. Hence, in
the present category, we refer to the higher order re-
sponses to intensity relations in the stimulus field.
These responses would be expected to be based on
cortical function, whereas those in category above may
be subcortical.
The observer experiences undulations of darkness
and lightness in temporal sequence. This is flicker. At
high rates of intermittent stimulation this experience
is lost, a fact implying that the neural or some other
mechanism is unable to keep pace. Differential re-
sponse to the intermittent stimulation of the optic
mechanisms of subhuman species also are quite
common and manifest many close parallels or simi-
larities to the quantitative features of the experiential
responses of the human subject.
Brightness enhancement is another feature of
human experiential response. It is the case in which
intermittent stimulation results in a higher brightness
than continuous stimulation of the same intensity.
Bilateral functions involving the use of the two eyes
result, of course, in a different input into the central
nervous system than the involvement of one eye alone.
It has been found that both the experiential and the
oculomotor outcomes differ in the two cases.
Brightness contrast occurs when fields made up of
certain patterns and intensities of radiation are pre-
sented. They are reacted to in ways not predictable
from the separate local intensities of the parts of the
field. These parts are not independent in effect nor
are the results simply additive when they are interde-
pendent. The major phenomena in this category are
often known as brightness-contrast phenomena.
Visual movement creates complexities. Portions of
the visual field are not stable. They quickly appear
and disappear as segregated portions that may or may
not undergo spatial displacement. When movement
is seen under conditions where no visual target ele-
ments are displaced, it has been customary to call the
movement 'apparent movement.' When displace-
7i6
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
ment is involved, the movement is said to be 'real.'
Again it may be said that subhuman species respond
in motor ways so as to indicate they are differentially
sensitiv-e both in cases of displacement and in cases of
stationary localization of targets.
Color vision is the name given to the fact that both
human and some subhuman species give evidence of
being differentially sensitive to various portions of the
visible spectrum. Color as an experience may also be
exoked in the human by nonspectrally selected radia-
tion, hence the color end result stems also from condi-
tions of nonspectral selection.
Phenomena of the Optic Palliivnx
BRAIN waves: spontaneous and EVOKED. One of the
major considerations in dealing with the neurophysi-
ology of central phenomena, 'brain waves,' for exam-
ple, is the assignment of their origin. All the activities
which we deal with can be put into two classes : those
that occur when no intended peripheral input to the
brain is involved (spontaneous activity), and the spe-
cific activity that occurs when known inputs are
delivered through intended stimulation (specific or
evoked responses).
What do the characteristic waves found in the
record of spontaneous activity represent? What ele-
ments produce them? There are two quite obvious
alternative possibilities. One is that these rhythmic
patterns of potential are the summed record of the
primary impulses of unit neuronal responses occurring
somewhat out of phase and producing wave envelopes
of much longer duration than the unit impulses them-
selves. The second alternati\e is that the recorded
waves are the manifestations of slower longer-lasting
processes that are more nearly similar in duration to
the recorded waves than would be the case in the first
alternative. These waves would apparently be some-
thing like after-potentials in elements where activity
would fall short of the kind of discharge that produces
spikes. Bishop & Clare (21) believe that the first al-
ternative is preferable in accounting primarily for
spontaneous activity. They believe that this activity
may incidentally include slower potentials suggested
in the second alternati\ e. As for e\oked responses, the
slow surface-negative portions may be an example of
a slow potential of the character suggested in the
second alternative.
Whichever alternative may operate, the next ques-
tion is whether the spontaneous and the evoked activi-
ties as the result of well-controlled peripheral stimula-
tion occupy the same cortical elements. Of course,
there are two alternatives here. At first, it was inferred
that they did not, but it has later appeared possi-
ble that the two activities share at least some common
elements (15, 21).
The conclusions just given are in line with the find-
ings of Adrian & Moruzzi (i). They reported that
groups of impulses were discharged via axons in the
pyramidal tract in unison with the alpha cycle of the
motor cortex. Thus it appears that whatev-er may be
said about the cortical waves them.selves, impulse
volleys are associated with them. Primary impulses of
cortical cells are involved in spontaneous activity.
The conclusions are also consistent with the finding
of Bartley (4) that, following the cortical response to
the afferent input via the optic nerve and radiation,
the cortex is refractory to a second stimulus, the de-
gree depending upon elapsed time. The moment of
full recovery coincides with the point at which the
alpha-like portion of the typical evoked response
de\elops. This alpha-like portion may be spoken of as
a sequel to the specific response (21) or be considered
as a less specific but true portion of the response. The
conclusions are also in line with Bishop's (18) finding
that responses to stimulation of the optic nerve waxed
and waned in such a way as to imply that the sponta-
neous alpha wave left a depression of the same tem-
poral character as the evoked response just mentioned
(4).
Interpretations that may be added in this connec-
tion are those of Bremer (31), Eccles (40), and Gastaut
el al. (42). The first of these attributed spontaneously
occurring rhythmic potentials in connection with
excitability changes, plus axon discharges to account
for the brain waves observed in 'resting' records. The
second supposes that the activity in the cortex can be
interpreted as being analogous to that in the spinal
cord where neuronal activity involves reco\ery from
depression. The interpretation is that rhythmicity
results from successive re-excitations following periods
of depression. Apparently closed neural chains form
the sources of the re-excitations. The third, in study-
ing what is ordinarih- called photic driving of the
cortex, inferred that the spontaneous cycle is an ex-
pression of refractoriness following discharge.
OPTIC pathway. The optic pathway consists of: a)
the tract, including the optic nerve; />) the relay nuclei
of the lateral geniculate, the pretectal area and the
superior colliculus; c) the radiation to cortex, and
paths to thalamus and tectal area; and d) the projec-
tion areas including the cortical, thalamic and tectal
CENTRAL MECHANISMS OF VISION
717
projections. In addition to these, there are e) the
association areas. Just where to delimit the visual sys-
tem is problematic, depending upon how one views
neural functions.
Omitting retinal structures, the first way station is
the geniculate body. Saggitally, the dorsal nucleus of
the lateral geniculate body of the cat possesses three
layers : A, Aj and B. The middle layer has been further
diflferentiated by Rioch (62). Layers A and B receive
terminals of tract fibers of the contralateral retina.
The middle layer, Aj, is the terminus of fibers from
the homolateral retina. It would seem that the de-
velopment of binocular vision has involved increased
stratification of the dorsal nucleus of the geniculate.
The rabbit nucleus possesses scarcely any, if any, and
those of monkey and man present six layers. Part of
the process of development seems to have involved an
increase in homolateral representation of the retina.
There are four groups of fibers in the optic tract
(24). These groups distribute to four different regions
and are unlike in range of cross-section size and in
conduction rate. The fastest conducting groups inner-
vate layers A and A] of the lateral geniculate. These
fibers relay to the projection area of the striate cortex.
CORTEX]
PRETECTAL.
THALAMUS
GENICULATE
CULUS
FIG. I. Diagram to indicate distribution of optic activity to
structures beyond the optic tract. The first relay neurons in the
geniculate, pretectal area and colliculus are indicated for four
tract components. Neurons for projection are represented in
the striate cortex, lateral nucleus of thalamus and tectum.
From the striate cortex paths are indicated to elaborative
structures of opposite cortex, association cortex, pulvinar, etc.
In cortex a short-axon cell is inferred on the basis of other
work to relay the impulse from afferent fiber to pyramid cell.
[From Bishop & Clare (24).]
The next slower group synapses in layer B of the
geniculate, and relays to the lateral nucleus of the
thalamus. The third group goes to the pretectal area
and the fourth group terminates in the superior col-
liculus. Figure i is Bishop & Clare's schematization
of these connections. (See also figs. 2 and 3.)
The conduction rates step down by ratios of one
half from group to group. Neither in the frog nor the
cat, for example, can four distinct fiber-size maxima
be demonstrated. No qualitative sensory differences,
such as are found to be correlated with fiber size in
the somesthetic system, have yet been found in the
visual system. Sensation is likely mediated by the
direct path to the cortex via the large fiber group.
Strong stimulation of the contralateral optic nerve
elicits two definite spikes, sometimes followed by a
prolonged diminishing potential recordable just prior
to the dorsal nucleus of the lateral geniculate. The
second spike is propagated at about one half the rate
of the first, and the threshold of its elicitation is about
•2}/^ times as high as for the first. Corresponding to
these two spikes, there are two postsynaptic spikes
manifested by the cells and axons of the dorsal nucleus
(27, 28).
Single shocks to the optic nerve induce complete
cortical responses even when such stimuli are weak
enough to activate onK the large-fiber group, in-
ducing the first of the two tract spikes. The time of
arrival at the cortex of the response to the second
group of radiation fibers does not tally with any of
the prominent spike components of the cortical record.
Instead, the activity induced in layer B of the genicu-
late is propagated to the lateral nucleus of the thala-
mus. It first emerges when stimuli just strong enough
to elicit the second spike are used, and thus the
activity is not a response induced there by activity
coming back from the cortex.
When records are obtained from the postsynaptic
elements in the geniculate, the response to the first
tract spike from the contralateral eye arises mainly
from layer A and the response to the second spike
from layer B. Thus the ensuing responses from the
activation by the first tract spike reach the cortex,
and those from the second spike reach the thalamus.
This represents a functional differentiation of the two
geniculate layers. These two lasers are also different
histologically (59), but we do not yet know the sig-
nificance of the difference.
The response of the middle layer Ai to the stimu-
lation of the homolateral optic nerve is mainly to the
first tract spike. When occasionally a second post-
synaptic spike is elicited, its threshold is the same as
7IO HANDBOOK OF PHYSIOLOGY ^ NEUROPHYSIOLOGY' I
Jt^ ^^'^^^^-.V-'^-'-'V-BP*
J I IL.
Fv_l
1
FIG. 2. Postsynaptic responses following single stimuli to the optic nerve from the pretectal area
(records i to 3), from the colliculus (i? to ;o) and from both (^ to 7). The presynaptic responses
are usually too low to detect. Time scale is in 10 msec, intervals. In each column the first record
is below threshold for the major responses to be recorded but nearly maximal for the second tract
spike. For record 2, stimulus strength is 1.5 times that for ;, for 3 it is twice. For 5 to 7, strengths
are 3, 5, and 6 times that for 4. For g to 10, strengths are 3 and 5 times that for 8. Ratios of thresh-
olds depend materially upon durations of square-wave pulse stimuli, the ratios increasing with
shorter duration of pulses. First column: Records from electrodes, one at the surface above pretectal
area and one below surface. The wave form varies widely with different positions of electrodes, and
the spikes recorded here are not usually as prominent. Second column: Critical electrode in anterior
border of superior colliculus where it evidently recorded activity both of pretectal character (with
latency of 7 msec, shown in l\\e first column) and of colliculus type (latency 11 msec, third column^
Reference electrode in the medial geniculate body. Note growth of second potential in records 6
and 7 as a wave starting beyond the crest of the first (starts marked by vertical lines) when stimulus
strength is increased. Third column: The second only of the two waves of record 6 is recorded from a
critical electrode just below the surface of the colliculus proper against a reference electrode at a
distance. Critical electrode negative. Record 8 is at higli amplification, q and 10 at one quarter of
this amplification. [From Bishop & Clare (24).]
the first response. Layers A and Ai arc homologous in
function, both being activated by the first tract spike
and both relaying to the cortex. Both retinas, how-
ever, send fibers to each colliculus, though many more
arrive from the contralateral retina than from the
other (24, 59).
Bishop el al. (29) and Bishop & McLeod (30) also
have studied the response of the lateral geniculate
body, finding it repetitive under the conditions used.
They attribute repetitiveness to origins outside the
geniculate, possibly to excitation over reverberatory
circuits leading back from the cortex. Such paths have
not been established anatomically.
The responses of structures beyond the relay nuclei
(the cortex, the lateral thalamic nucleus and the
tectum) differ from those up to and including the relay
nuclei. Instead of being mainly spikes, they are ex-
tended responses involving complex pictures of chains
of neurons, each link active in turn.
In the cat, it is at present feasible to distinguish
histologically only three fiber-size ranges in the optic
tract. The large-size group includes fibers ranging
from 8 to 12 /j, and these pass only to the dorsal
geniculate nucleus and are included in the first of the
four functional groups of fibers already mentioned.
The middle histological group with fibers ranging
from 4 to 8 |i also makes up some of those in the first
functional group as well as some in the second spike
group. The small-fiber group constitutes the fibers in
the third and fourth functional groups. Although the
CENTRAL MECHANISMS OF VISION 719
^.^^
5
^
^\^~^.f-»\^A^
ffA
/Vvv>v^
FIG. 3. Responses from the lateral nucleus of the thalamus to the second postsynaptic volley
from dorsal nucleus of the geniculate with single optic nerve stimuli. The first record in each column
was from a stimulus just below threshold for the second postsynaptic spike as recorded from the
dorsal nucleus. Strength of stimulus for record 2 was 5 times that for / ; for 4, 3.5 times that for 3;
for 6, 2.5 times that for j. Record 7 is a duplicate of (J at 1.5 and higher amplification. In the second
column the cortical record appears on the second oscillograph beam. In the third column the response
consists of a sequence of brief spikes. Time scale for thalamic records in i o msec, intervals. Latency
of response cannot be accurately determined but is not over 6 msec. Form of response varies widely
with location of electrodes and with depth below the surface of the thalamus, and varies considerably
at one locus following identical stimuli. All records presented were from a critical electrode in the
dorsal or dorsolateral region of the lateral nucleus approximately at the level of the anterior tip
of the dorsal nucleus of the geniculate. The reference electrode v/as deeper in the thalamus or in
white matter lateral to it. [From Bishop & Clare (24).]
locations of the fiber groups in the cross section of the
tract are known (24), it is not necessary to delineate
them here.
CORTICAL RESPONSE. The cortical response of the cat
to a peripheral input as simple as it is possible to
deliver is exceedingly complex. The simplest pattern
may be shown by the recorded events in the optic
cortex following single stimuli to the stump of the
optic nerve. The afiferent radiation fillers conduct
impulses mainly to the fourth layer of the cortex.
Activity, of course, immediately spreads to the other
cortical layers. This is pictured in the record as a
sequence of three definite spikes interpretable as indi-
cating that three groups of cell bodies are discharging
in sequence (20). More intimate examination (23) of
the early part of the response shows that a second spike
sequence also occurs. It, of course, is less prominent
than the one just mentioned. In the record, the second
series (the small spikes) alternates with the first. The
authors have reason to infer that the sinall spikes
represent the short-axon cells of the cortex. These
cells do not possess long apical dendrites as do the
pyramid cells. Their axons are short and mingle with
the adjacent pyramid cells. It is supposed that they
conduct activity from one group of pyramids to
another.
The model of activity that Clare & Bishop (37)
suggest is as follows and is pictured in figure 4. Af-
ferent radiation fibers first activate the short axon cells
of the fourth layer of the cortex. These, in turn, in-
nervate a group of pyramid cells at about the same
cortical level. These cells discharge into their axons.
The main branches of these leave this level of the
cortex via the subcortical white matter, activating
other parts of the central nervous system. The pyra-
mid-cell axons possess recurrent branches that arbor-
ize within the cortex activating a second group of
short axon cells. Tiicse, then, activate a second group
of pyramidal cells. This alternation occurs until the
sequence first mentioned has been completed. Since
the synaptic periods between each two successive
spikes is less than i msec, the transmission is thought
to be from axon to cell body.
When activation of the pyramidal cells is intense
enough, the dendrites of these cells are definitely in-
volved. When so, they conduct their effects toward
their terminals. Clare & Bishop (37) state that this
produces the slow wave sequence typical of the re-
sponse of the visual cortex. If stimulation is slight.
720
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
pyramidal cells may become active without activity
of their apical dendrites resulting. They suggest the
possibility that in normal cortical iiehavior dendritic
activation is minor. Activation of dendrites via paths
in addition to the afferent radiation must also be con-
sidered, although in the present case the radiation
impulses form the major component.
Neurons e.xert their influences on their surrounds
by way of their axon discharges, but neurons may re-
no. 4. Possible pattfins oi activation of neurons in the corte.x.
The afferent radiation axon entering; at right activates the
Golgi cell 6'i, the axon .-1 of which in turn activates the pyram-
idal cell Pi at its cell body and induces a brief spike response.
.\ recurrent branch of the axon of Pi is shown activating G^,
which in turn activates P,; etc., accounting for the alternate high
and low spike sequences of the response. Circuits from other
sources are able to activate the dendrites of Pi and set up slow
wave responses. B is such a circuit ending along the apical
dendrite, C ending at its terminals and D ending on the basal
dendrites. [From Clare & Bishop (37).]
ceive their effects either through cell body synap.ses or
through their dendritic synapses. Activation through
cell body synapses has been considered to require
more than a single impulse. The required number
may reach the cell body via several branches of one
axon synap.sing with the given cell body, or via several
axons, or several impulses via one axon. The above
mentioned authors deduce that when a cell body is
intensely activated, its continued firing for a time
after input has ceased depends upon the beha\ior of
dendrites. These dendrites were activated bv the cell
body and now in turn are reactivating the cell body
or, as we might say, keeping it active. The dendritic
contribution acts like a steady current stimulus to the
cell body.
What has already been said in describing the initial
spikes in the nerve has been interpreted as picturing a
sequence of activations from lower levels in the cortex
to the surface. A slow surface positive wave associated
with the spikes is another component of the response.
A negative wave immediately follows the positive one,
and it is found in the lower third of the cortex, proba-
bly originating in layer IV. Prior to this negative
wave, there is another negative wave. It occasionally
shows up in a normal record and becomes the most
conspicuous part of a record under strychninization in
which case it occupies the whole depth of the cortex.
Not only do the two negative waves seem to have dif-
ferent origins, but the late negative wave is belicxed
to arise from cells other than those responsible for the
positive components in the record. The first negative
wave is attributed to conduction from cell bodies via
apical dendrites toward the surface of the cortex.
When not present in the normal record, its absence is
a sign that such conduction is not induced by cortical
stimulation. In weakly strychninized preparations,
before any detectal:)lc effect is produced upon the
surface positive components, the response represented
by the negativity in question is made evident. When
large positive responses are induced, they are followed
immediately by the early negativity. Lower responses
are characterized by a delay between the positive and
negative waves. In these records, the two negative
waves are distinguishable.
Bishop & Clare (20) interpret the early positive
wave as representing the activity of the basal dendrites
of the neurons of which the spikes indicate the activity
of cell bodies. In figure 5 is presented the diagram
given by Bishop & Clare to indicate the nature and
origin of the five components of the cortical response
of the cat. Figure 6 shows the findings of Bishop &
O'Leary (25) on the rabbit. In both the cat and the
rabbit, the final component of the response may
repeat several times at the rate of the alpha rhythm.
Chang & Kaada (33) also analyzed the cortical
response to optic nerve stimulation. The description
is much like the one we have just given. Some of their
interpretation was different from that of Bishop's
laboratory. The authors did point out, however, that
it is only the slow waves of the various components
of the response that are reduced by agents affecting
the cortex. This is in line with findings of Bishop's
laboratory over the years.
CENTRAL MECHANISMS OF VISION 72 1
CORTEX UPPER
CORTEX MIDDLE
CORTEX LOWER
OPT. RADIATION
THALAMUS
/W
MSEC
14 OPT. NERVE
FIG. 5. Left: Tentative inferences concerning the origin of cortical responses drawn from experi-
mental data. Roman numerali at lejl indicate conventional cortical layers and furnish a scale of depth.
Numerals / to J refer to cortical spikes; ,-1+ refers to underlying surface-positive waves; B— refers
to late surface-negative wave which appears to arise from lower layers of cortex, .4— represents the
early surface-negative wave only occasionally seen well-developed in normal cortex but large under
strychnine where it becomes the most prominent potential clement of the record. [From Bishop &
Clare (20).!
FIG. 6. Right: Diagram of responses of the optic pathway of the rabbit. At least four elements of
the response, following the activation of the optic nerve, can be distinguished in some records although
any two adjacent elements, each presumably complex, may be confluent in a single response. The
last of these four may be repeated several times at inter\-als of about 0.2 sec. following a single
shock. There is a discharge of the corticofugal fibers during at least the first of these repetitive cortical
discharges which appears to facilitate the thalamic neurons to a second discharge from the optic
nerve. This is indicated by the Ims' vertical arrows pointing downward. (Abscissae, time; ordinates,
voltage.) [From Bishop & O'Leary (25).]
Chang attributes deflections 2, 3 and 4 in his record
to the activities of three different geniculocortical
pathways and suggests that they may conduct the
respective impulses of trichromatic vision. He uses to
support this interpretation the findings of Pieron (60)
to the effect that latencies for seeing the three funda-
mental colors are different. This is thought to be
evidence that the impulses signalling these travel at
independent and different velocities.
We prefer to follow Bishop & Clare (19, 20, 23),
Clare & Bishop (37) and Bishop & O'Leary (25, 26).
Bishop & Clare (19) made it a point to check the
findings of Chang & Kaada in regard to the kind of
potentials found in the geniculocortical radiation and
found onK a single and rapidly conducting spike.
When a later tract spike resulting from use of higher
stimulus strengths is elicited, it represents impulses
distributed mainly to the pulvinar, pretectal area and
colliculus. Hence they conclude that all the successive
spikes up to five in number, except the first one, that
can be recorded from the cortex represent groups of
neurons active within the cortex itself.
Bishop & Clare (22) stimulated the optic and
parietal cortex in cats at various depths below the
surface. They found that when the cortex is stimu-
lated at the surface, the response obtained from two
electrodes, one at the surface and the other at any
depth, is a simple negative wave. When stimulation is
presented i:)elow the surface, a diphasic wave with its
initial phase surface-positive is obtained. When
stimulation is presented half way or more down
through the cortex, first a single and then two or
three short spikes are manifested in the response. These
are comparable to those elicited from activation of
the radiation pathway. As the radiation terminals are
approached, the complete cortical response to pe-
ripheral afferent stimulation is simulated. This pro-
cedure is thus a way of showing the transition from
direct cortical stimulation to the indirect or pe-
ripheral.
The main difference between direct and indirect
stimulation, in addition to the possible simultaneous
activation by the direct stimulus of elements that
respond successively to indirect stimulation, pertains
722
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
. A^sAAa/\x\^
FIG. 7. Diagrammatic reconstruction of typical records, led
from surface to white matter, by addition of what are inferred
to be their chief potential components, a. Diphasic response
assignable to conduction along apical dendrites when these only
are activated below the surface of the cortex; negative phase
is early negative component, b. Summation of surface-positive
potentials inferred to be caused by activity of successively
activated basal dendrites at successively higher levels of the
cortex, f. .Spike sequence detectable in responses to near-
threshold stimulation of the optic nerve, later responses of
which are usually obscured following stronger stimuli, d. Slow,
presumably diphasic process arising from deeper layer of cor-
tex, the second phase of which appears as a late negativity in
many respon.ses. /. From addition of all four of above com-
ponents, a reconstruction of a record of response to optic nerve
stimulation which shows considerable early negativity. 2.
Similar reconstruction of response to direct stimulation fairly
deep in the cortex, but above layers V and VI, eliminating
component d\ negative phase of diphasic component a is
exaggerated, as appears to be the case in records from direction
stimulation, and the first spikes are telescoped. 3. Reconstruc-
tion as in ;, but for record showing minimal or no early nega-
tivity, from which therefore component a is eliminated. [From
Bishop & Clare (22).]
to the way the apical dendrites behave (see fig;. 7).
When these structures are directly activated from the
region of the neuron's cell bodies, the dendrites
always conduct toward the surface of the cortex.
When indirectly activated, by way of the radiation,
this conduction often does not materialize, even fol-
lowing maximal optic ner\e stimulation. It generally
fails in connection with very weak stimulation. They
deduced that in normal (nonsynchronou.s) activation
conduction does not occur from cell ijody to apical
dendrite. On the other hand, supposedly when a
sufiicient number of dendrites are activated, some
kind of mutual facilitation provides for antidromic
conduction.
These authors believe that when strychnine or any
other convulsive drug is applied, the spike manifesta-
tion is primarily the indication of a conducted re-
sponse in apical dendrites. The essence of the convul-
sive state lies both in the heightened irritability of the
dendrites and in the mutual facilitation and activa-
tion to the point of a massive and well synchronized
discharge.
The cortical response, recorded from leads from
brain surface to white matter, is a composite
(summation) of many primary sources of potential.
The response to a single brief stimulus to the optic
nerve producing a volley of impulses may produce a
record that is an inadequate representation of cortical
function in normal behaxior. The brief stimulus pro-
duces a degree of synchronization that, in itself, is an
artificial distribution of impulses from the start. This
sort of volley could be considered more appropriate
for producing con\ulsions than for the usual response
(23). One of the justifications for this, however, aside
from procedural necessity, is that the normal ob.ser\er
can make a visual discrimination from such stimuli
which are shorter than might ordinarily be thought
efTective. Actually, for certain comparisons between
perceptions very short pulses of photic stimulation are
found usable and analytically helpful. Of course,
none of such stimuli is actually as brief as the electric
shocks used.
While the investigations of Bishop & Clare cited in
this chapter indicate a general propagation of mass
impulse from cell to cell upward from the neighbor-
hood of the terminals of afferent fibers and apparently
downward also to lower cortical layers, the norma!
stratification may be less sharp than has been de-
scribed. Apparently, as more and more minute
regions are explored with closely located microelec-
trodes, an increasing heterogeneitv in the directions
CENTRAL MECHANISMS OF VISION
723
of propagated impulses becomes evident. Marshall
^55) has shown a remarkable degree of temporal
summation of the optic pathway to be recordable at
the geniculate. Bishop & Clare (19, 20) have done
likewise for the effects manifested at the cortex. The
latter authors have pointed out that, with graded
stimulation, a large effect reaching the geniculate
neurons is required to produce even a threshold re-
sponse in them. Furthermore, supraliminal activity
of the afferent radiation is needed to produce a thres-
hold response at the corte.x. Increasing the strength of
stimulation upward from this level prolongs the corti-
cal response with its spikes and waves.
They also point out that weak stimulation is, in
effect, the stimulation that fails to produce much
spatial summation. In normal activity of the optic
pathway, this lack of summation ought to be charac-
teristic and, accordingly, lead to incomplete or brief
cortical responses. But the fact that normal stimula-
tion is characteristically prolonged rather than ab-
breviated to a very small fraction of a second, would
provide for temporal summation that ought to com-
pensate for the lack of the spatial variety. Relevant to
this, Chang (32) has demonstrated the extreme effec-
tiveness of 'potentiation' by photic stimulation of the
retina of responses to individual brief stimuli at the
geniculate. This steady photic stimulation seemed to
maintain a raised level of excitation and this made
incidental impingements more effective. We know
that exceedingly weak excitation of the retina trans-
mits something to the cortex. Not only does this slight
effect get through to the cortex but certain effects
from adjacent cortical areas are afso produced in
order that the activity in the visual cortex be given
a context that would provide meaning for the terminal
input. Bishop & Clare (23) describe well how the
experimental conditions of the laboratory emphasize
the effects of spatial interaction at the expense of what
may occur via temporal interaction.
From their work and knowledge of cytoarchitec-
ture, Bishop & Clare (23) depict the kind of interac-
tion between cortical elements that would plausibh'
occur. The description is as follows. The elements in
the cortical network can be suppo.sed to constitute a
system of both parallel and series connections. Each
afferent channel (fiber) at any given synaptic level
would be in connection with a number of postsynaptic
elements, the arrangement involving definite over-
lapping. This would be the parallel set of connections.
In addition to this, elements at each synaptic level
send axons to the next higher level, and this provides
series connections. The authors suggest two further
features of the system. Afferents from sources collateral
to the visual projection system surely connect at some
or all levels. What they call 'jumpers' may be in-
volved. These are collaterals affecting more than a
single synaptic level. An example may be the recurrent
axons of the pyramidal cells. Some authors have
reported afferent radiation fibers terminating not only
at the usual layer IV but also at the two successive
layers above it. Bishop & Clare inject an additional
assumption, namely, that the mass of impulses tra-
versing the one-step circuits are more effecti\e than
those involving a jump of two or three synapses.
Perhaps the latter pathways should be considered to
need assistance even to fire the synapses. The activity
just suggested is pictured in figure 8, schematized in
figure 9. The evidence for the scheme consists in a
double series of spikes, ones of low amplitude alter-
nating with ones of high amplitude when certain sub-
maximal records are obtained from potentiometer
leads and from electrodes subtending only small frac-
tions of the total cortical depth. The timing of the
spikes is about i .4 msec, between those of the same
series, and 0.7 msec, between any two of the alternate
series. Bishop & Clare's suggestion is that this double
series is made up of pyramidal cells alternating in dis-
charge with short axon cells (Golgi II). Since the
latter cells are oriented in random fashion, their
potentials would tend to be registered by the leads as
lower in amplitude. The pyramids extend in a single
direction. This description diflfers from that of Thomas
& Jenkner (66) in which records were interpreted as
evidencing repetitive firing of the same cells.
ACTIVATION OF CORTEX BY STIMULATION OF RADIATION.
Instead of initiating activity in the optic pathway by
stimulating the optic nerve, it is possible to eliminate
the geniculate and stimulate the radiation and note
the cortical effects. By stimulating at this site. Bishop
& Clare (23) found that the same cortical response
was obtainable as when the cortex is stimulated
through the geniculate. Certain features of cortical
response must be independent of the geniculate cycle.
To single stimuli constant in intensity, the initial
cortical response spike attributable to radiation axons
was constant in amplitude. Throughout a period of a
few milliseconds, the specific response to a second
stimulus manifested only slight diminution of ampli-
tude in its positive pha.se. The early negative wave of
the second response was depressed nearly to the
vanishing point, and this effect covered the whole de-
7'24 HANDBOtm OK I'HNSIOLOGV ^ NEHROPHYSIOKOCY 1
FIG. 8. Records of cat optic cortex to show minor spike series. ;. Total corte.x, stimulation of
radiation above the geniculate. 2. Same, but stimulation of the optic nerve; negativity failed to
dc\elop in a weak response, and between each pair of spikes there occurs a minor disturbance.
3. Radiation stimulus; potentiometer balance to accentuate first minor spike. 4. Like .:? (in a differ-
ent cat), a subma.ximal response of total cortex thickness showing a succession of spikes at half the
intervals of major sequence. 5. Balanced record showing first and second minor spikes. 6 and 7.
.Stimulus at the radiation, different fractions, similarly balanced. 5 to 7. From same cat as / to 3.
8. Weak response like 4 (from a different cat), showing double sequence. Major spike intervals
marked on 4 and 8 were obtained from other records of the respective preparations of fonn of
record 1. g. Total cortex, submaximal stimulus to radiation, like -', first and second minor spikes
recorded. 10. Balanced record accentuating second of these. 11. Maximal response, lower ampli-
fication, same cat. 12. Total cortex. 13. Record as in 12 but balanced to accentuate the first and
second minor spikes. 14. Same as /j but at half the stimulus strength and recorded at twice the
amplification. [From Bishop & Clare (23).]
pression period. Negativity representing antidromic
conduction via apical dendrites toward the cortical
surface appears to be depressed more easily by prior
acti\ity than the other features of response.
In the period of depression, the base line slowly
became negative during which responses to second
stimuli were diminished. Following the depression, the
positive phase of the specific cortical responses to
second stimuli returned to normal amplitude.
Clare & Bishop, from these and other results, con-
cluded that most of the features of the cortical re-
sponse can be attributed to the excitability cycle of
the cortex itself. On the basis of this information on
the cortical cycle and Marshall's (55) analysis of the
geniculate cycle, cortical responses to optic nerve
stimulation were studied.
The degree of depression in the geniculate response
to a second stimulus \aries greatly from one animal
to another as well as to varying intensities of optic
nerve stimulation. Aside from the possibilitv that some
ol the \ariatioii may be due to anesthesia differences,
the variability may arise from the contextual or back-
grotmd excitation upon which the activation is super-
imposed.
If two stimuli are delivered very close together, a
single suprama.ximal response may occttr. Even when
an initial maxiiual stimulus is invoK'ed, there seem to
be a number of elements that were not activated but
only possibly excited subliminalh . These can be
acti\ated by the second stimulus, hence producing a
supermaximal response to the paired shocks. This
principle is more pronounced when the shocks are
submaximal. The facilitation period soon ends and
beyond it a period of depression ensues. It may last
as long as 5 sec.
We may inject here the idea that this period may
possibly bring about perceptual (\isual) end results
simtilating adaptation in the retina. Some of the many
visual experiments labeled those of adaptation have
to do with short term effects. The various experiments
CENTRAL MECHANISMS OF VISION
/-'5
of Schouten and Ornstein, and of Fry and colleagues
are the ones referred to.
Clare & Bishop (34) noted that even during the
deepest depression, a second stimulus may find that
a first one, though maximal, may have left some ele-
ments that were not stimulated. This is as if at no time
can any stimulus deliverable to the optic nerve fire all
channels in the radiation pathway. The opposite ex-
treme of this may take place. A second stimulus may
cause a large geniculate response at any instant fol-
lowing a maximal first one. From this, they infer that
many, though not all, elements represented in the first
response are likewise involved in the second. When
the second stimulus is made weaker, the second re-
sponse manifests first a more marked diminution than
when the first stimulus is applied alone. Ultimately,
the response disappears completely at a stimulus
strength otherwise able to elicit a large response if not
preceded by an earlier stimulus. If, now, the first
stimulus is diminished the response to the second
grows, indicating the acti\ation of elements not ac-
tivated by the first stimulus.
ACTIVITY IN REGIONS OTHER THAN OPTIC CORTEX.
Clare c& Bishop (35) studied the activity of a portion
of the lower half of the medial wall of the suprasylvian
gyrus in the cat. This is an area responding only sec-
ondarily to activity in the striate cortex. They re-
corded from this area, first to optic nerve stimulation
and second to direct electrical stimulation of points in
the striate area itself.
They found that this region responds quite similarly
to the striate area, but with an amplitude about one
eighth or less. The response with all its components
appears about i msec, later than does the striate
response, when the activation is induced by the
impulses in the optic nerve. The response to striate
stimulation is late by only a very short conduction
time. Experimentation showed that this region was
fired by the discharge of the second major spike of the
optic cortex response to optic nerve stimulation,
which is to say, the activity of the pyramids in layer
IV and probably in layer II. This activity probably
represents an association area interrelating acoustic
and optic activities.
Jasper et al. (48), utilizing repetitive activation pro-
ducing local convulsive acti\ity in ihe striate cortex
of the monkey, did not disclo.se active pathways acro.ss
the cortex from striate to parastriatc and other areas.
They did find activity transmitted to the pulvinar.
When this region is activated by direct experimental
m
'iXTXt
FIG. 9. Schematic diagram of
cell network suggested by analy-
sis of spike responses. Solid l,„es:
A, afferent radiation; B to D
sequence of cell groups. Differ-
ences between short a.xon cells
and pyramids are ignored in the
interest of diagrammatic sim-
plicity. Dashed lines: Collateral
■jumpers' impinging on cells fall-
ing later in sequence than next
adjacent cell. Dotted lines: Affer-
ents from sources other than
geniculate. Axons leaving the
cortex are omitted. Lines ending
blindly indicate synaptic con-
nections similar to those repre-
sented. This fundamental as-
sumption is required to render
the diagram functionally applica-
ble; insofar as impulses at syn-
apses are equivalent, a minimal
number (more than one) is re-
quired to fire a cell at which they
arrive simultaneously. From A simultaneous impulses arrive
at B and C. B will be activated if .-1' fires with A, and C will
not until activated by synchronous firing of B and B', or A and
B, etc. Activated by a synchronous volley of impulses from ra-
diation fibers, a simple succession of synchronized discharges
should ensue. Activated by a barrage of impulses from same
source, a much more scattered discharge should result, owing
to arrival of impulses at each level over different paths Qsolid
and dashed /m«), and with different delays. Arrival of im-
pulses from other sources {dotted lines') should further mod-
ulate the patterns. [From Bishop & Clare (23.))
stimulation, it was found to activate areas of corte.x
alongside the optic cortex.
Marshall et al. (57}, on the other hand, in exploring
the cat's cortex found an area of the cortex over-
lapping with the acoustic cortex. From it, they were
able to obtain response both to the acoustic and to
optic stimuli. Bishop & Clare (24) found that the
relay fibers responding to the second spike in the
optic tract terminate in the thalamus.
Chang & Kaada (33) interpreted the three spikes
of the cortical record following single shock stimula-
tion as attributable to separate groups of fibers from
the thalamus. They assume that each of the three
spikes is followed in turn by a surface positive wave,
but that these three longer-lasting effects sum in the
record to a single surface positive wave. Bishop &
Clare (19) re-examined the matter. To do this, they
recorded the impulses in the radiation directly, fol-
lowing optic nerve stimulation, using diphasicity as a
criterion for propagation in radiation fibers. It was
726
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
from this technique that they found only one spike
conducting in the radiation from geniculate to cortex
and that this was the relay from the first spike in the
optic tract prior to the geniculate.
There are possibly three subcortical pathways the
activities of which directly or indirectly affect the
optic cortex in a demonstrable way. There is, of
course, the direct relay path, the optic pathway itself;
the collateral path of the brain stem to association
nuclei in the thalamus (65); and possibly a collateral
circuit from thalamic relay nuclei to others in the
thalamus to the cortex (38, 47).
Bishop & Clare (24) describe a bundle of fibers
lea\ing the pulvinar and terminating in the temporal
lobe of the cortex. When the optic nerve is stimu-
lated, a weak and extended discharge is recorded in
this bundle. The activation of the bundle was pre-
sumably from ijrain-stem or thalamic nuclei re-
sponding to optic tract activation. The exact origin of
the discharge is not yet known, but its temporal
features tally with the pretectal or lateral nucleus.
CORTICAL LOC^Liz.^TiON. Hartley (4), using photic
stimulation of the retina in which two discrete retinal
areas were tested, showed that one part of the cortex
responded maximally to the activity in one retinal
area A, and another part of the optic cortex responded
ma.ximally to another retinal area B. Stimulation of
A would not usually activate the cortical area re-
sponding to B, and \ice versa. When any sign of
response under these conditions was detected, it was
merely an irregular train of indefinite waves.
When A and B were stimulated simultaneously,
the corresponding cortical areas did not manifest any
summation. The responses were simply of the usual
size. On the other hand, when the two stimuli were
separated by an interval of 150 to 175 msec, the
respon.se to the second was enhanced; and if the inter-
val was lengthened, a value could be found at which
inhibition or depression of the second response was
manifested.
At a retinal point C, intermediate between A and
B, responses to both stimuli were recordable, both
responses being discernible when enough temporal
separation was allowed for the two response waves to
be seen in two parts of the record. When simultaneous,
the record representing the response to the two retinal
areas was a single wave larger than either of the two
responses individually recorded.
In one experiment, for instance, cortical point C
later came to respond only to the stimulation of the
second retinal area. At first, the two stimuli produced
an enhanced result when simultaneous. When the
two were separated by about 15 msec, the entire
response almost disappeared. This continued to be
the case as the separation was made considerably
greater. It did not matter which of the two stimuli
was delivered first. When finally the first retinal area
failed to produce a response of its own, it still could
augment B, when applied simultaneously, and reduce
the size of B, when definitely out of phase with it. Still
other examples of the interaction of cortical areas
were obtained.
Since this material relates not only to cortical locali-
zation but also to the visual experience of movement,
it will lie discussed in the section on that subject.
PROPERTIES OF DENDRITES. Stimulation of the cortex
at various depths has led Clare & Bishop (36, 37) to
make certain inferences about the behavior of cortical
dendrites. These were given in the section devoted to
the cortical response. The following is a statement of
the picture they paint of the behavior of the various
parts of the neuron. In referring to intercortical paths
that terminate only on apical dendrites of pyramidal
cells, they found cases in which only the terminal por-
tions near the cortical surface are activated. When
the dendrites are activated indirectly by way of these
paths, or directly by artificial stimuli, dendritic con-
duction is not of the all-or-none type. The conduction
occurs more readily away from the cell body than in
the reverse direction. Its rate is less than i m per sec.
After initial indirect activation, a stimulus finds the
dendrites activatable at all times later than the abso-
lutely refractory period of the axons involved. Follow-
ing a 20 msec, facilitation period, depression sets in
and the sign is positive. The authors inferred that, in
general, the depression following neuron activation is
attributable mainly to its dendrites. Apical dendrites
manifest no refractoriness, and so later activation sums
with the first. Continuous negativity may be perpetu-
ated by repetitive stimulation. All that would be re-
quired to produce waves of potential of any temporal
proportions would be modulation of stimulation of the
dendrites. The authors suggest this principle in the
production of the waves of the cortical record.
The influence of a neuron on its surrounds is
brought about only through the impulses it causes to
be discharged by the cell body into its axon. These
effects are variously distributed via the ramification
of axon branches. Activation of the neuron may occur
via two avenues. The one is by way of cell-body
synapses; the other by way of dendrite synapses. These
CENTRAL MECHANISMS OF VISION
727
two avenues ought to affect the pattern of axonal dis-
charge from the cell.
The conditions applying to activation of the neuron
via cell-body synapses are as follows. More than one
impulse must be delivered to the cell body in order
to activate it. When the discharge is once set up, it is
of the all-or-none type. The impulses required for cell-
body activation may arrive via a single axon branch,
or via several of them, provided that they arrive
within the required time limits.
As just implied, when once set into action, the cell
body discharges once or more without receiving fur-
ther activation. The authors (36, 37) infer that, when
once a cell body is .set into action, its action may be
sustained by its own dendritic activity. They say that
the cell body once sufficiently activated can activate
its own dendrites, and they in turn can sustain activity
in the cell body. The duration of the dendritic impulse
seems to be of the order of 15 msec. This length of
time provides for the dendrites acting like a steady-
current stimulus to the cell body while it builds and
discharges .several times.
In cases of stimulation of dendrites only, the den-
drites do not exhibit all-or-none conduction to the
cell body which, therefore, would not be expected to
be activated. It is presumed that some effect, never-
theless, would be exerted by dendrites upon the cell
body by reason of the excited state of one and un-
excited state of the other. The various excitations
induced in dendrites would sum. The authors sup-
pose it proble that, if the dendrites are excited from
enough converging sources, they might begin to con-
duct and activate cell bodies. The role of the dendrite
seems to be to rai.se the level of excitation of the cell
body and thereby lower its threshold to influences
arriving via axons impinging on it. The chief charac-
teristic of dendritic action is its graded character in
contrast to the all-or-none manifestations of cell body
and axon. This provides for a great deal moie flexi-
bility and variety in action than a system limited to
all-or-none activity.
VISUAL PHENOMENA TO BE EXPLAINED
Gross Response to Gross Intensity Relations
One of the major considerations in the study of vision
and its mechanism is the question of what characteris-
tics of vision require the striate cortex and what charac-
teristics are demonstrable when the cortex is removed.
It has been found that in some animals response to
gross intensitv relations in the stimulus field are re-
acted to in the absence of the occipital cortex. This
is not at all surprising in the light of what we know
about the bifurcation of the optic pathway, some
fibers going to cortex and some going to motor
centers that are subcortical, and in the light of our
findings on pupillary responses which parallel Fech-
ner's paradox (see the subsequent section on bilateral
functions). It would seem possible that the structuring
of response to gross flux differences could occur in the
motor sphere and in the sensory spheres somewhat
parallel to each other, according to our interpretation
of the parallelism described in connection with Fech-
ner's paradox. If one of the two channels were to be
destroyed, the other might be able to mediate an end
result. With the cortical channels destroyed, motor
behavior of some effective kind might still be able to
be exhibited. With the motor channel destroyed, one
could experiment only on man, for he alone could tell
whether experiential reactions to intensive features
of stimulation were altered. We should not expect
them to be in gross situations.
The following are some of the characteristics of the
ijehavior of monkeys in response to visual stimuli
when their occipital cortices are removed, eliminating
the geniculostriate systems, as described by Kliiver
(50). In such animals, the eyelid reflex to photic
stimulation is abolished permanently. The pupillary
reflex to photic stimulation is retained, however. The
sudden appearance of a stationary or moving photic
source does not elicit a turning of the head or eyes
towards it, although movements of the head and eyes
are elicited by nonphotic stimuli.
Conjugate movements of the eyes are not destroyed;
neither does destruction of the superior coUiculi
abolish such movements in response to stimulation of
the cortical eye fields. Visual placing reactions are
lost. Nevertheless, animals rarely bump into objects
when they are left to themselves or are not excited.
When the bilaterally decorticate monkey is in a
limited familiar habitat, its behavior in jumping,
swinging and climbing is so readily executed that
the unsuspecting observer would suppose the animal
to be normal. Variation in the position of some fa-
miliar object in its cage elicits considerable fumbling
until the animal's hands come into contact with it.
Such a monkey can respond discriminatively to the
more or less intense of two photic sources whether they
are indefinitely present orappear suddenly, or whether
their presentation is simultaneous or successive. Re-
sponses to weak photic stimuli have demonstrated
that the ai:)solute threshold in the occipitally operated
728
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
90
80
60
m
_i
(9
Z
1
1
«40
20
\
\
\
V"?
,^''
V
V
^
-^
.
30 MSEC
40
50
IMPLICIT TIME
60
70
FIG. lo. The relation between implicit time of the rabbit's
cortex and the visual angle of the target. Note break in curves
at or near 20 degrees. This suggests that the increase in target
size beyond this point does not involve further spatial summa-
tion at the retina, and that further reduction in implicit time
is a continuation of the effect from increasing the intensity of
incidental stray illumination of the retina. [From Hartley (3).]
monkey is not essentially different from that of the
normal monke\- or of man.
The decorticated monkey responds differentially to
two equally intense and equally large targets if their
distances from the eye are quite different. This is to
say, the animal is able to use differences in total flu.x
as a factor. This reaction, like the others in which
familiarity with the stimulus is ab.sent, has to be
learned rather than immediately apprehended.
Responses to targets differing in shape, preopera-
tively established, are lost through the remosal of the
occipital lobes. Neither can new differential responses
be learned if the new targets are compact and do not
differ greatly in any dimensional respect. A decorti-
cate animal, taught to respond to a target having a
greater amount of flux, will continue to do so regard-
less of whether the flux is continuous or intermittent.
Thus a source with an on-off rate of 4 per sec. is
equivalent to a continuous one just so long as the
total flux per second is the same.
Color vision is permanently lost in the decorticate
animal. Kliiver would say, from his many studies,
that brightness vision is destroyed in the animal
without occipital cortices. What such an animal does
is to respond on the basis of total flux.
Area of Target
When a photic source (target) subtending some
known \isual angle at the eye is used as a stimulus, the
resulting response of an animal may be that which we
could call the perception of brightness, or it may be
simply the response to the stimulus as total flux.
Brightness is the response to flux per unit area of
target, and may be expressed as an experience or as
a differential motor response on the i^asis of flu.x per
tmit area. It is not difficult to determine which of the
two possible responses is being made when the human
is a subject, and not too difficult when certain sub-
human species are being tested. It is a little more
uncertain when inferred in some cases such as from
the cortical response to photic stimulation of the
retina.
The experiments of Hartley (3) on manipulating
the target area to measure the implicit time of the
cortical response will be presented here. Implicit time
is the time elapsing between the beginning of stimulus
and the peak of the initial large wave of response. In
this investigation, target area was varied from i to go
degrees of visual angle. Throughout this range incre-
ments in visual angle reduced implicit time of the
cortical response. One of the significant findings was
that the relation between target area and implicit
time was not a simple function throughout the range
used as was the function of target intensity. To explain
this, it was pointed out that the image of the target
on the retina was not the only site of retinal stimula-
tion. The retina as a whole received stray radiation
as well as focused radiation. Thus the cur\e showing
the relation between implicit time and stimulus area
is a composite of the increasing spatial summation
within the image and the increasing intensits' of stray
photic flux on the retina as a whole.
If the target area operates as just indicated, one
ought not to expect the resulting curves relating area
to implicit time and intensity to implicit time to
coincide. .Since spatial interaction and stimulus in-
tensity are both varied when target area is manipu-
lated and stimulus intensity alone when photic in-
tensity is manipulated, the curve for the former would
lie to the left of the latter. Thus, if interaction (spatial
summation) would operate over part of the range of
target manipulation and not over the whole range,
then a break in the response curve would be expected.
This is what resulted, as appears in figure 10. In all
CENTRAL MECHANISMS OF VISION
729
experiments in which the target was increased beyond
about 20 degrees, a break in the curve appeared. The
question of how far across the retina spatial summa-
tion may operate has been dealt with by Adrian and
others. To say the least, spatial summation has come
to be considered to possess definite limitations. The
limiting subtense in this investigation seemed to be in
the region of 20 degrees. The curve in each experi-
ment shows that when targets of broad angular sub-
tense are reduced in size, the implicit time is length-
ened. This continues until the target is reduced to
about 20 degrees and then, fairly quickly, implicit
time becomes much shorter than expected for further
target area reductions.
While the present investigation offered no way to
eliminate the stimulation out.side the retinal image, it
did present evidence of the operation of two stimulus
components (increase in image area and increase in
stray radiation intensity). The same evidence demon-
strated that the two factors operated at different rates.
In the demonstration that two factors were in opera-
tion, the author showed intensity per unit area of
retinal image was involved in determining implicit
time. Thus it can be said it was not merely flux as
such that produced the response as recorded but that
the response was in a way a brightness response.
While it was not doubted that the rabbit has bright-
ness \ision, it was a question from the beginning as
to whether it could be demonstrated by the neuro-
physiological experiments of the kind being per-
formed.
Bnglitness
The experience of brightne.ss or a motor response
based on the same principle is something different
than the response to mere flux differences in two
major portions of the photic field. Brightness is the
result of manipulation of intensity per unit area of
visual target. Hence an area can be seen as brighter
than another even though the total flux of the first
area is less than that of the second. This would be the
case if the flux per unit area were greater. Kliiver's
monkeys, devoid of the geniculostriate system, gave
no evidence of being able to do this. They could learn
to distinguish between two equal-sized and equally
intense targets when one was removed to a greater
distance than the other, in which case its retinal
image was smaller. A lesser total flux on the retina
for it than for the near target was thus invoked.
Kliiver states that he does not see any evidence in the
behavior of cats and other animals that would indicate
that they can distinguish brightness at subcortical
levels.
Electrophysiological experimentation upon the re-
sponse of the optic pathway has not been of such a
nature as to make the needed distinctions between
response to total flux and to flux per unit area. One
way to extract evidence on this point is to try to com-
pare certain perceptual responses with the electro-
physiological ones and make what deductions we can.
It now seems as though certain comparisons be-
tween brightness in perception and the amplitude of
the response to specific brief stimulation can be made.
In a later section we deal with brightness enhance-
ment. In it we are comparing the experience that is
evoked by steady continuous stimulation with one
that is evoked by intermittent stimulation. So long as
we keep the two areas equal, certain justifiable com-
parisons between the intensity needed in both cases
to produce equally bright surfaces can be made.
Many of the conditions for producing the various
levels of effectiveness of the intermittent stimuli seem
to be the very same as tho.se similarly varying the
amplitude of the cortical response to such stimuli.
Since continuous steady stimulation produces noth-
ing in the extended record of cortical activity, the
amplitude of which we can measure, we are prevented
from making the same amplitude-brightness compari-
sons for steady photic impingements. With the con-
crete evidence at present available, we seem unable to
go beyond the gross comparison just described. Per-
haps we do not know enough regarding the measure-
ment of steady states and the relation of steady states
in one part of the cortex to those in others. Steady
states seem, at the present state of our knowledge, to
be quite dead and processless. To explain some things,
however, they seem to be just what is required. (For
further discussion of cortical response to continued
peripheral stimulation, see the later section on bright-
ness enhancement.)
Flicker and Fusion
When a series of photic pulses is delivered to the
retina, the experience is flicker, except when the rate
of delivery reaches a critical value. Obviously, the
intact human and even certain subhuman species can
distinguish between an intermittent and a steady
photic source. This is true at least down to arthropods
and crustaceans. How the discrimination is accom-
plished must differ in detail at the various phylo-
genetic levels. It would seem from Kliiver's observa-
tions that a monkey, clepri\-ed of the geniculocortical
73"
HANDBOOK OF PHYSIOLOGY
NEUROFHYSIOLOGY 1
apparatus, can not distinguish between a steady
source and one the intermittency of which is as low as
4 cps, just so long as the total flux per unit time is the
same in the two cases. Hence, although much has
been said about the photochemical basis for flicker
and its elimination, the ultimate crucial point of de-
termination of critical flicker frequency (c.f.f.) appears
to be in the cortex.
Durinc flicker, the activity in the optic nerve waxes
and wanes with sufficient amplitude and at such rates
that the cortical activity may also vary in its temporal
aspects in significant ways. It has been noted that
whereas the response of the optic pathway up to and
including the postsynaptic elements in the lateral
geniculate body are ijrief and spike-like, response
beyond this is somewhat extended in time and in-
volves certain complexities absent in its precursors.
This in itself would be a kind of e\'idence for believing
that the cortex cannot respond at the same high rate
as the peripheral mechanisms.
Be this as it may, a rate can be attained that re.sults
in the perception of uniform continuous light. The
point at which this is reached (c.f.f.) is also known as
the fusion point. All rates above this maintain fusion.
This means that at the fusion point any temporal
undulations in cortical activity that may occur are so
slight as to be of no ultimate effect.
Talbot found that when fusion was reached, the
level of perceived brightness of the light field was less
than for a continuous and uniform stimulus of the
same intensity. The effect is as if the input instead of
being intermittent were uniform and spread evenly
throughout the cycle. Thus, if the PCF (pulse-to-
c)cle-fraction) is one-half, the level of brightness is
one-half. Whereas those devoted to photochemistry
have shown how this effect might be attributed to the
manner in which photochemical systems react to
photic impingements, certain features of the behavior
of the optic pathway have been overlooked. One of
these is the way the neuroretina behaves. It rearranges
the temporal distribution of the sense-cell discharge
effects of the retina. Since we are not dealing pri-
marily with peripheral respon.ses, we cannot go into
this matter further. Needless to say, the cortex must
take a hand in even the determination of critical
flicker frequency and the Talbot effect (7, 8).
Since the Talbot effect represents the simplest
possible smoothing-out result from a waxing and
waning stimulus, we can suppose that the cortex
operates on the simplest principle in that respect.
The following investigations in which cortical re-
sponse was elicited by stimulation of the retina rather
than electrical stimulation of ilic optic nerve was used
to give some information relative to the mechanisms
at work in flicker and fusion. Bartley (3-5) measured
the latency of the cortical response to various forms of
photic stimulation. One of the factors varied was the
duration of a "dark' interval. When these intervals
were very short, the off-response to the termination of
the photic pulse and the on-response to the beginning
of the succeeding pulse were both evident in the
record when the interval was as short as 1 2 msec.
When this interval was shorter than the implicit time
of the ofl'-response, the resumption of stimulation
did not preclude the appearance of the off-response,
nor the appearance of the on-response to the begin-
ning of the next pulse. Since 12 msec, compare to the
interval between pul.ses when pulse frequency is 40
per sec, if the pulse-to-cycle fraction is one-half, it
would seem as though under the conditions dealt
with, Bartley was reaching the point called critical
flicker frequency in hmnan flicker experiments.
The implicit times of the on- and off-responses are
not equivalent. It would .seem from the results (4, 5)
that for similar conditions the implicit times of the
on-response are shorter than those for the off-response.
Thus, as the 'dark' interval in the cycle is made
shorter and shorter, the off-response to the termina-
tion of the one pulse and the on-response to the be-
ginning of the succeeding pulse finally becomes con-
current. This might be one factor iit ijringing about
fusion in flicker experiments, since in some way these
two responses might counteract each other at some
final level in the cortex.
That the two forms of response (on and off) could
be concurrent is to be understood from the finding of
Bartley that the two responses occupy separate chan-
nels all the way from the retina to the cortex. One of
the evidences for this was the finding that an on-
response can follow an off-response as clo.sely as 1 2
or fewer msec, whereas an on-response to a second
stimulus cannot follow unless the two are at least 80
msec, apart. Electrograms of the retina have been
interpreted as showing that a second pulse presented
shortly following the termination of the first will
inhibit the off-response to the first. Bartley (4) showed
in a number of ways that phenomena that were de-
tectable in the cortical record are not discernible in
the electroretinogram recorded under the same con-
ditions. It would thus seem logical to rely on the
cortical record in cases where differential responses in
the electroretinogram fail to show up.
Bartley also measured the implicit time of cortical
on-re.sponse when duration was the variable (2) and
CENTRAL MECHANISMS OF VISION yjl
,0N OFF
»-
CO
en
>
•-
o
u
>
<
-I
til
e
'PHOTIC PULSE
I SEC
200%
100%
Fig.12 >
^
X
\ BRIGHTNESS OF STEADY SOURCE
50%
B ^^^^^
o
0
PHOTIC PULSES PER SECOND
0
10
20 30
40
FIG. II. The cortical response of the rabbit to intermittent stimulation of the eye in which the
photic pulse occupied one quarter of the cycle. Note responses both to onset and to termination
of the photic pulse. [From Bartley (9).]
FIG. 12. Brightness enhancement, the greater relative effectiveness of intermittent stimulation
than of steady stimulation at lovkf photic pulse rates. This is shown in curve A but not in curie B.
B shows the effect under some conditions of weak stimulation. [From Bartley (7).]
when area of the target was a variable (3). For varia-
tion in duration of photic pulse to affect implicit time,
it must be as short as 4 or 5 msec, for targets with
luminosities as great as 2400 candles per square foot,
and which subtend 6 or 7 degrees. Increasing area
reduced implicit time and thus would be expected
to work in the direction of raising critical flicker
frequency.
Jasper (46) recorded potentials from the occipital
cortex in man following pulse rates of 55 to 60 per sec,
and thus was near the critical flicker frequency under
the conditions. This was not interpreted as being a
demonstration of driving the cortical alpha rhythm
beyond its normal 8 to 1 3 per sec. frequency. He found
that the amplitude of the waves at 20 per sec. was
about one-half of what it was at 10 per sec, and waves
at 40 per sec. were about one-fourth as high as those
at 10 per sec. A further \ery crucial observation also
supporting his interpretation of the impossibility of
driving the cortex was the following. As the stimulus
rate was slowlv increased, there were stages at which
the waves would undergo what he called desynchroni-
zation. For example, at frequencies of from 14 to 15
per sec, this would happen and the result would in-
clude a shift in amplitude so that at from 18 to 20
per sec, the amplitude would drop to one-half the
height up to that time.
Halstead and colleagues (44, 45, 67) reported that
although the dominant brain waves (alpha) in the
monkey could be 'driven' up to rates comparable to
critical flicker frequency only, the pathway prior to
the cortex could follow input intermittencies beyond
the c.f.f. Obviously, the records of Halstead and col-
leagues manifest waves at the rates indicated and
thus, in essence, tally with those of Jasper. Whether
this is driving depends upon one's definition of the
term. A standard definition has not yet been put into
the literature.
The foregoing tallies with Hartley's observations
and his alternation of response theor\ (which is con-
sidered in the section on brightness enhancement).
For example, one observation (3) was that if the rate
of intermittent retinal stimulation suddenly delivered
to the retina was definitely above 5 per sec. (the rab-
bit's alpha rate), the following would occur. A large
cortical response to the first pulse would appear. No
response to the second pulse would result. Then, the
responses to the following few pulses would wax and
732
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY
wane or be entirely absent in random order. Finally,
all pulses would be responded to by equal waves but
of a reduced size, the amplitude in keeping with the
rate. If the rate was high the amplitude would be low,
and vice versa. This irregular initial period was
looked upon as a reorganization period during which
redistribution of the various retina-to-cortex channels
responsive to successive stimuli was brought about so
that all stimuli were responded to.
Hartley (9) obtained a very definite cortical off-
response as well as an on-response in the rabbit when
using a .slow photic pulse rate and a pulse-to-cycle-
fraction of I to 4. The results are pictured in figure 1 1 .
In it, the shape and temporal characteristic of the
wave following the off-response would suggest that it
is the usual final slow component of a typical cortical
response or, in other words, an alpha wave. If this be
the case, then it is suggested that the off-response may
institute an alpha series in the same sense as it can be
said that a brief electric stimulus to the optic nerve
mav do so. The fact that an off-response is at all
discernible in the cortical record makes the supposi-
tion that the off-response plays a role in controlling
critical flicker frequency all the more plausible.
Brightness Enhancement
When intermittent photic stimulation is used at
rates below those producing the experience of steady
light (i.e. at subfusional pulse frequencies), it may
become more effective than steady stimulation in pro-
ducing brightness. This increased effectiveness we call
'brightness enhancement' which is pictured in figure
12. With intense pulses, effects such as shown in
/
K
0 MSEC
200 400
INTERVAL BETWEEN SHOCKS TO OPTIC NERVE
FIG. 13. The cycle of rcsponsixcnt'ss ot the optic cortex of
the rabbit as determined by paired stimulation. [From Hartley
(4)-]
curve A will occur. With weaker photic radiation,
results shown in curve B will occur. While it is to be
taken for granted that photochemical processes in
sense cells play their usual roles in determining the
magnitude of afferent input over the optic nerve,
they do not account for the nature of brightness en-
hancement. We must look to neurophysiological proc-
esses for this.
It will be seen from the diagram in figure 12 that
the effectiveness of intermittent stimulation increases
as pulse rate is reduced, and that under some condi-
tions it becomes maximum in the human in the region
of 10 pulses per sec. This region is the peak and still
slower rates result in reduced effectivenesses. One
might well start off with these findings and make
various manipulations of pulse rate, pulse-to-cycle-
fraction, pulse intensity, etc., to further one's under-
standing of brightness enhancement in general. The
study of Ijrightness enhancement has not proceeded
on this ba.sis. The work that has provided the impetus
for brightness enhancement investigation lay in the
findings of neurophysiology of the optic pathway. On
this account, it may well seem much clearer to the
reader were we to describe behavior of the visual re-
sponse apparatus before continuing to deal with
brightness enhancement.
Bishop and Hartley, in their study of cortical re-
sponse to precise stimulation of the optic nerve in the
rabbit, disclosed a number of temporal and intensive
features of the behavior of the cortex. Bishop (18) first
demonstrated the rhythmicity for the cortex in rela-
tion to peripheral stimulation. Stimuli presented to
the optic nerve at intervals without regard to cortical
events produced random-sized responses. He showed
that stimuli could be tuned to the cortex, so that all
responses would be essentially the same; either all
small, all large or all medium-sized, depending upon
the phase to which the input was tuned. He showed
that if the first stimulus in a train was maximal, that
it would, in effect, 'drive' the cortex. This is to say,
it would be able to start oflT a sequence of cortical
consequences having the properties of the natural
rhythm but shifted somewhat in time from it. Subse-
quent closely-following stimuli would obey the laws
of the rhythmicity but according to the shifted timing.
Hartley (4) mapped the nature of the rh\thm by
using paired stimuli systematically varied in their
separation. He found that the size of a second maximal
stimulus to the optic nerve did not produce a cortical
response the same size as the first until the temporal
interval became equal to the cortical period found by
the means earlier discovered. The findings of Bartley
CENTRAL MECHANISMS OF VISION
733
(4) are shown in figure 13, in which it is indicated
that the rhythm could be followed through at least
about two cycles. Since maximal stimuli were used, it
was inferred that the behavior of the optic nerve as a
whole represented the way the single parallel channels
in it react. This deduction rested upon the idea that
all parallel channels in the nerve were activated
simultaneously. This cycle represented the rhythm of
single channels while being the rhythmicity of the
system as a whole under these conditions.
The more specific portion of the evoked response to
brief stimulation is followed by a long-lasting surface-
negative potential (14). It is during this time that a
.second brief peripheral impingement evokes either no
response or else one of reduced amplitude ('25). The
repetition of the cycle implied here may be demon-
strated at the frequency of the spontaneous alpha
sequence. Use of repetitive stimulation at twice alpha
frequency (4) showed that an original inability of the
system to respond at intervals half the alpha value
slowly changed into submaximal response following
each stimulus. The shift was as if the channels avail-
able for response became differently distributed in
time, so that finally part were ready to respond at the
presentation of one stimulus and the other part at the
presentation of the succeeding stimulus. .Stimulation
at higher multiples of the alpha rate resulted in what
appeared to be a further redistribution, such that
each stimulus was responded to in some degree but,
of course, more weakly than when rates were slower
(see fig. 14).
This phenomenon could be expected to have a
parallel in perceptual response. Whereas a certain
rate of intermittent stimulation (c.f f) is required to
obliterate flicker fully once the visual system is ex-
posed to a considerable number of photic pulses, an
even slower rate may fail to be responded to as indi-
vidual pulses at the very onset of the stimulus train.
Wilkinson (68) studied this problem and found that
the rate at which the first few pulses were seen as indi-
\idual flashes or produced flicker was much below
the rate at which the pulses could still produce definite
flicker after the train had progressed for awhile. The
perceptual responses to the first few pulses manifested
some of essentially the same irregularity as was mani-
fested in the cortical response (4) under the same
conditions.
In some cases, as in the rabbit, the long-lasting
surface-negative wave is replaced by a series of
briefer waves (25). Something like this was observed
in the cat by Bishop & O'Leary (26). Prior to the
onset of the depression following a specific cortical
response, it was found that a short period of facilita-
tion to a second stimulus occurs in the radiation re-
sponse (27). For example, as the strength of an initial
stimulus is increa.sed, the response of the radiation
increases more rapidly than does the tract response.
With a second stimulus, it and the first, being 'maxi-
mal' for the tract, may elicit a larger radiation re-
sponse than a single stimulus. Even below maximal, a
second stimulus is typically more effective than the
first when falling within the short time limits implicit.
This indicates that spatial and temporal summation
are operative in the geniculate even with "maximal
stimuli.' This, although indubitable, is inconsistent
with the idea of a one-to-one fiber channel from retina
to cortex in the functional sense. It is consistent with
the theory of partially shifted overlap suggested by
Lorente de No (53). Similar results were reported by
Marshall & Talbot (56).
Facilitation may occur also at the cortical level. The
matter is far more complex, however, for at least two
reasons. In the first place, the t\pe of facilitation just
described for the geniculate occurs at each cortical
synapse. That is, facilitation builds up step by step
at each synapse in the sequence, even though the
facilitation at each synapse in the cortex may be no
greater than the geniculate synapse facilitation. The
I 2 3 4 5 6 7 e 9 10 II 12 13 14 15 16 17 18
REORGANIZATION OF RESPONSE OF CORTEX TO INTERMITTENT STIMULATION
FIG. 14. The response of the optic cortex of the rabbit to rapidly repeated stimulation of the
optic nerve. At first the pulses are delivered more frequently than the corte.\ is able to respond.
Later to this same rate, the several channels capable of being activated become distributed in
time in such a way that no single channel needs to respond to successive pulses for there to be a
cortical response. [From Hartley (4).]
734
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY
second reason is that the size of the cortical response
varies independently from the amplitude of the re-
sponse of the geniculate, owing to the phase of the
spontaneous alpha rhythm that is involved at the
time. The greater responses are elicitable during the
final surface-positive phase of the cycle (i8).
The depression phase following activation of a
pathway may be a more general thing than merely a
phenomenon of the optic pathway. Such a phenom-
enon was dealt with by Pitts (6i) in respiratory func-
tion. Phasic fluctuations of response to a second click
stimulus have been observed in the auditory tract by
Ro.senzweig (63).
As an extension of the description of the phasic
nature of cortical activity both spontaneous and
evoked, and thus as a furtherance of the understanding
of the mechanisms that possibly underlie brightness
enhancement, we shall describe the changes in spon-
taneous activity of the cortex following a single optic
nerve stimulus.
The spontaneous picture in the rabbit and cat dif-
fers (21). Whereas in the rabbit extended periods of
alpha wave activity are t\pical, in the cat similarh
dealt with one may find short trains of alpha waves,
but more often this is replaced by a continuous rapid
sequence of low-amplitude waves varying in fre-
quency from 20 to 80 per sec. This sort of sequence
tends to appear during the intervals between the
"spindles' of alpha wave activity.
If stimulation is presented during this fast-wave
activity, the cortex undergoes a characteristic altera-
tion. The waves just mentioned disappear and slowly
come back over a period of from 100 to 200 msec. At
the end of this period, the amplitude of these waves
mav be far above normal in some cases. Sometimes
the waves may coalesce into longer waves as if two
or more had summed. These may be of a higher am-
plitude and are frequently diphasic. The whole se-
quence, in amplitude variation and in temporal
features, often presents the over-all envelope of the
typical alpha wave.
In the rabbit also, the t\pical alpha wave may be
replaced at times by three or more peaks with the
same over-all duration as the alpha wave (26). The
differences in the two animals presumably consists in
a smoother summation in the one than the other,
rather than in the presence or absence of the alpha
cycle. The depression cycle in both animals seems to
be a recovery from the peripheral input and a return
to spontaneous activity.
When submaximal rather than maximal stimuli are
u.sed, the response to a second stimulus of a pair is
le.ss depressed. The spontaneous activity is also less
depressed. The amplitude of the specific response
during the depression period is a function of depres-
sion in both the geniculate and cortex, but the re-
covery in the cortex seems to be dependent upon
events in the cortex alone.
The basic picture of how the overall systems must
react to intermittent inputs was summarized by
Bartley (6) in what he called the "alternation of re-
sponse' theory. The essentials of the theory are as
follows, a) There is a fixed number of parallel channels
in the optic pathway from eye to brain. 6) These
channels can be activated simultaneously or they can
be activated according to the various temporal distri-
butions, f) Certain maximally intense, but abrupt and
brief, stimuli may activate all available channels while
submaximal stimuli do not. d') Any given single chan-
nel from eye to cortex cannot be reactivated until it
has recovered. This requires about 0.2 sec. for the
rabbit and o. i sec. for man. i) The period represented
in the cycle is of the same length as the animal's alpha
rhythm. In fact, it is the alpha rhythm, as was indi-
cated in the work of Bartley (15). /) Brief stimuli de-
livered at the alpha rate would be expected to produce
maximal brightness effects, g) Not only must the
stimuli be intense (maximal or in the upper range of
intensity) but they must be relatively brief, else they
would involve not only the initial activation of chan-
nels but also the reactivation of the same channels or
the activation of still others, tending to spread the
over-all activity out in time and reduce the number of
channels participating in the responses at any single
instant. /;) Since the available channels, as has already
been said, may be activated not only in unison but
also in various temporal distributions, various patterns
of the latter would result in corresponding levels of
sensory brightness. This is to say that with continuous
stimulation the activity of the available channels be-
comes uniformly distributed throughout the cycle.
There would be as many channels going into action
at all instants as are going into rest. This would pro-
vide for continuous uniform visual (sensory) response
to continuous illumination. In fact, sensory continuity
and steadiness may result before the full uniformity of
channel activity is achieved.
Bartley (11, 12, 13, 16, 17) and colleagues ha\e
performed a number of sensory experiments, and in
all cases the expectations of the alternation of response
theory have been met.
It may be said, then, that in brightness enhance-
ment and in the group of findings in regard to the
way in which the optic pathway is able to react to
CENTRAL MECHANISMS OF VISION
735
timing of input, we ha\c one of the more fully docu-
mented sets of the relationship ijciween sensory be-
ha\ ior (perception) and neurophysiology of the
central nervous system.
In the foregoing, it has been shown that stimulus
conditions for obtaining various brightnesses and
those for obtaining various amplitudes of cortical
response are the same, but much still remains to be
worked out. For example, the comparison seems to
pertain to the quantitative features of continuous
over-all brightness and the amplitude of a momentary
feature of cortical activity, namely the specific brief
response. As yet, there is no characteristic of recorded
electrical response of the cortex to indicate the level of
cortical activity in response to a continued peripheral
stimulus. It is as if we are confined to dealing exclu-
sively with momentary and brief effects in the central
nervous system. They can be dealt with because they
represent an observable change from previous or from
subsequent activity as a reference. Continued stimula-
tion does not result in any characteristics of prolonged
cortical activity that lend themselves to useful quanti-
fication. One approach to this is, of course, the com-
parison of the appearance of the ongoing cortical
activity during stimulation with activity in the absence
of an intended experimental input. This, as was
implied, does not give anything to quantify in a
direct way. The chief difference between cortical
records in the two sets of conditions seems to be the
disappearance of certain forms of wave-like activity
in the 'active' record. Various studies on 'blocking'
the alpha rhythm are relevant here (64). They were
also relevant in the earlier section on brightness.
Jasper & C^ruikshank (49) studied the electro-
encephalograms of human subjects exposed to a cross-
target in a room in which this was the only photic
stimulation. They ascertained the change in the cor-
tical activity picture to the sudden exposure to the
target and the subsequent sequence of changes that
followed. They found the following: a) an occasional
and \aried short detectal)lc cortical effect arising in a
few milliseconds easily confused midst the features of
the alpha rhythm; A) 'blocking' of the alpha rhythm
after a latency of 160 to 520 msec. ; c) gradual irregular
reco\ery of the alpha rhythm if the stimulus continued
for more than 3 to 5 sec. ; dj the emergence of a second
dubious positive effect that, since it followed the
termination of exposure to the target, could be called
an 'off' effect; i) sometimes a second 'blocking,' this
time of the recovered rhythmic activity, following
cessation of the stimulus;/) a continued depression or
'blocking' effect during; the existence of reported
afterimages; g) a partial recovery toward the usual
amplitude of alpha waves between successive after-
images; and //) a final total recovery of the normal
alpha activity following the final afterimage. This
recovery typically would begin as a train of small
waves of higher frequency than those of the alpha
rhythm. The amplitude of the alpha waves might even
increase for a while before the full prior status quo
would be reached. Here we have a set of results
seeming to bear upon several matters: the nature of
the cortical activity during continued stimulation,
and the fact that one can detect cortical response
during afterimages as being different than when they
are absent. Others have been interested in the latency
of the blocking effect, but we shall forego listing the
authors or the exact latencies found.
To further the understanding of what constitutes
the cortical response to continued stimulation, certain
reference conditions for inactivity will have to be
discovered. From these comparisons can be made.
One of the possible leads in this direction may be the
study of dendritic behavior. We have progressed from
the exclusive concern with and ability to record
spike-like, momentary, conducted all-or-none activity.
The activity of dendrites seems to fall into the category
of sustained potentials (36, 37). While sustained states
seem to be 'inactive' ones, since we cannot detect
them as ongoing processes, this static aspect may be
only the over-all aspect of the whole complex of
activities that is in operation, thus for us an 'illusion.'
When we realize that what is happening in any
mass of central nervous tissue is a combination of
\arious orders of process, having many origins and
sustaining conditions, we may find added use, in our
concept, for sustained states. They may be the sub-
strata for the interplay of more highly particularized
items of activity that occur differently and play dif-
ferent roles during one level of sustained potential
than during another. It thus might become possible
to conceive of the level of sustained dendritic potential
in crucial areas as being the correlate of the experi-
ential or motor outcome in the ultimate response
called perceptual behavior.
In essence, the idea of a sustained state, varying in
significance or potency according to its level, is
nothing new. We have long had it in the central
excitatory state and in the central inhibitory state of
Sherrington. But, to understand the sustained state as
being inherent in a neuron rather than in some sort of
a chemical matrix outside it is very different. In
dendritic activity, we may now have a basis for sus-
tained potentials as an activity of neurons themselves.
736
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
Bilateral Fiinclions
In viewing a single visual target, both sides of the
optic pathway are generally involved. When corre-
sponding portions of the two retinas receive photic
radiation from this target, the results are as follows.
If the photic flux is unequal to the two retinas, the
surface seen will, of course, be singular but will not
look as bright as though viewed by the eye receiving
the greater radiation. That is, summation does not
take place. This is Fechner's paradox. If, instead,
equal radiation is received by both eyes, the result is
summative. The brightness is greater than when one
or the other eye views the target alone. Fechner
did not make a full study of this matter. DeSilva &
Hartley C39)> snd Fry & Hartley (41) manipulated
stimulation so as to provide curves showing this func-
tion under a wide range of conditions (see fig. 15).
Hartley (lo) later studied a correlate phenomenon of
Fechner's paradox, namely the way the pupil behaves
under comparable conditions of stimulation. The
same pattern of quantitative response was demon-
strated. This is to say that if one eye alone is presented
successive increments of photic radiation, the pupil
constricts step by step. The same occurs in the un-
stimulated eye. Then, if the flux to the first eye is held
at the final high level and step by step the flux to the
second eye is increased from zero upward to the level
for the first eye, at first, the paradoxical reversal of
effect occurs. Instead of constricting further, the two
pupils begin to dilate. They continue to do so as
further steps of increment are added to the second eye.
Finally, the paradox reaches a peak and further incre-
ments begin to cause constriction. When finallv both
eyes are receiving equal amounts of radiation, the two
pupils have constricted more than when the final level
of radiation was directed to the one eye alone. This is,
in quantitative pattern, the very thing that happens
in perception.
It was also shown that the essentials of the paradox
are manifested when noncorresponding points of the
two eyes are involved and finally when two targets of
differing inten.sity are imaged on two parts of a
single retina.
It is not too startling to find the parallel between
the perceptual and the motor phenomena when once
it is remembered that the two end results stem from
the same input, namely the discharge of the optic
nerve. The same pattern of input must go to the
geniculate and to the superior coUiculus. In our illus-
tration we have two simple aspects of the respective
categories of response. Were we to try to compare
other aspects of motion and perception (experience),
we would be hard put to find modes of quantification.
That is to say, it would be very difficult, if not impos-
sible, to find convincing quantitative parallels in limb
movement and in the concurrent perception of color
or position of a seen object. Vet there must be rational
(lawful) relations between what an organism sees and
where it reaches to grasp the object seen.
Binocular relations of other sorts are Ijroughi out in
other perceptual phenomena. If two fields differing in
texture or color as seen separately are presented, one
to the one eye and the other to the second eye simul-
taneously, the result may not be a fused single stable
field but rather a single field that alternates in texture
or color. This is called l^inocular ri\alry. Some times
this ri\alry in lightness is replaced by a curious effect
called 'luster.' Further analysis shows this luster to be
a transparent light field behind which is a dark field.
FIG. 15. Binocular summation and
subtraction in response to photic stim-
ulation. The subtractive effect is Fech-
ner's paradox. Top line indicates the seen
brightness when both eyes are presented
equal intensities. Horizontal line ('one
eye alone') indicates the seen brightness
when only one eye is exposed to the
target. The curve shows the relative seen
Ijri^htncsscs when one eye is exposed to
the full intensity of the target and the
second eye is exposed to various frac-
tions of full intensity shown on the hor-
izontal axis. [From Da Silva & Bartlcy
(39).]
BOTH
EYES
u>
>
/
<n
111
ONE EYE
ALONE
z ^
111
Sw
>
>
V
"*
1-
s.
U— """^
0
>
111
u.
11.
Ill
111
>
p
1.
-1
Ul
K
1/16 1/8 1/4 1/2 3/4 7/8 15/16
RELATIVE AMOUNT OF ILLUMINATION PRESENTED SECOND EYE
CENTRAL MECHANISMS OF VISION
737
It is as if one can be seen through the other. This con-
current existence of the two fields is best brought out
when one uses a temporal alternation of the targets for
the two fields. Thus when the over-all binocular tar-
get is made up of a steady annulus surrounding an
intermittent disk, luster eventuates when the intensity
of the annulus is one-half that of the positive phase of
the disk. Whether it shows up or whether one sees
simply light and dark alternating is dependent partly
upon the rate of stimulus intermittency. As one slowly
shifts the rate, one can watch the phenomenon
emerge.
Rivalry can occur even when the target \iewed as
first described constitutes only a small part of the
visual field. Ri\alry in this case occurs when the field
surrounding the target is of medium brightness and
the target seen via one eye is white and via the other is
black. Apparently the neural contour processes for
the two targets interact in some way that involves some
sort of alternation, thus bringing about the rivalry (8).
It has been shown by Graham (43) that the abso-
lute light threshold is no lower for the two eyes than
for one. This finding, though it might be unexpected,
is in line with the supposition of summation at a
common central region, as found by Fry & Hartley
(41). The latter pointed out that two thresholds must
be recognized : a) the minimal radiation required to
activate either of the two converging pathways, and
A) the minimal frequency of impulses reaching a com-
mon central region to produce postsynaptic activity.
The perceptual end result does not occur unless one
or the other of the two pathways delivers the threshold
frequency. If in either one of the two the minimum is
reached, there is no lowering of the first threshold by-
adding a stream of impulses via the other converging
pathway.
Brightness Contrast
Whereas the foregoing illustration (Fechner's para-
dox and its pupillary analogue) was meant to demon-
strate intensive effects based upon the interaction of
the two sides of the visual apparatus, it also exemplifies
brightness contrast inasmuch as it has to do with
adjacent as well as corresponding areas of the two
retinas and with adjacent portions of a single retina.
Brightness contrast pertains to adjacent portions of
the \isual target, but to explain it relevant adjacent
portions of the visual apparatus must be dealt with.
It would seem that whatever neural mechanism will
account for Fechner's paradox will go a long way in
accounting for brightness contrast.
I isual Movement
Brightness contrast, a spatial phenomenon, is a con-
figurational one. The same principle would seem to
apply to both perceptual and neurophysiological
phenomena described in temporal terms. One order
of temporal phenomena in perception is the experi-
ence of movement. Very often the crucial neural con-
ditions underlying movement have been thought to
be retinal and neuroretinal. These cannot be given
space here. Be it sufficient to say that in this category
lie .some of the conditions for apparent visual move-
ment. Apparent movement is defined as phenomenal
(experienced) movement that is elicited by visual
targets that do not undergo displacement. Real move-
ment is the movement stemming from targets that do
undergo displacement.
Despite all the patterning produced in the retina,
there is still much left for the cortex to do. The cortex
probably plays a part in making the end product
resulting from optic nerve discharge under conditions
of target displacement often very similar to that ob-
tained with target fixity. We know that the perceptual
end results, in some cases, are indistinguishable.
Since in beta movement (the form of apparent
movement in which two spatially discrete targets are
used) there is a temporal gap between the two portions
of stimulation, the cortex was \ery definitely Ijrought
in by early workers to account for it. Supposedly some
sort of spatial-temporal coalescence of the afferent
discharge into the cortex was finally achieved in cor-
tical activity much like that produced by the periph-
eral input from real-mo\'ement targets. An early form
was called a short-circuit theory, but never has a
theory been worked out to the point of being con-
N'incing. It would seem that in the recent establishment
of the nature of dendrite acti\ity, we have an essential
tool for this purpose. Until recently, any theorist
wishing to account for certain more persistent effects
(those lasting up to seconds, minutes or longer) had
to rely upon purely hypothetical processes such as
those described by Kohler (51) or upon reverberative
circuits. Now it would seem that with the demonstra-
tion that some tissue does maintain potential and not
merely conduct potential \ia a fleeting impulse, cer-
tain more slowly changing active relations between
tissue elements or central nervous regions are made
more concretely thinkable.
The investigation (4) described in an earlier section
on cortical localization is relevant here. Actually, the
stimulus conditions used in this investigation were
the very ones that produce apparent visual movement
738
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
in the human subject, namely the exposure of two
restricted local targets separated by an interspace and
presented in sequence. To go with this target arrange-
ment from conditions that are not productive of
apparent movement to those that are is simply to
adjust timing and spatial separation for the given
intensity used (Korte's laws). In this investigation
timing and spatial separation were manipulated, and
it was demonstrated that cortical responses to two
separate targets could be recorded at two separate
cortical locations in the rabbit and that various inter-
action effects were obtainable when space separations
were reduced and when the delivery of the stimuli
was made close together in time. The elements of a
study of apparent movement were demonstrated. The
in\estigation did not go far enough to determine the
conditions under which the rabbit responds to two
stimuli as to a single moving target. A conditioning
experiment would ha\e Ijeen necessary for this. Thus,
if the rabbit could be 'conditioned to apparent move-
ment,' the cortical experiments, carried further than
Bartley (4) was able to do, could possibly have given
a picture of some of the cortical e\ents involved in
seeing movement.
Color Vision
No consideration of vision should bypass what is
called color vision, the difTerential response to the
spectrum. In discussing color vision, there is very
often some confusion as to what is really meant, owing
to the fact that the stimulus differentiators may lie
not only at the periphery but also in the central ner-
vous system, and owing to the possibility of setting up
diflferent criteria for color response. There are actually
si.x items to keep in mind and make clear in a dis-
cussion of color vision. They will be mentioned here
to set matters straight, a) There is the question of the
existence of color sense cells and the number of kinds
of such cells in the species in question, i) Often this
discus.sion takes the form of whether some of the cells
are differentially sensitive to the spectrum and some
not sensitive (cones and rods). All of these matters
have been studied on an anatomical basis, c) There is
the question of directly or indirectly recording elec-
trical responses to answer the questions in a and h.
d) There is the problem of obtaining differential con-
ditioning of overt responses to the spectrum in the
species in question, e) In human subjects, there is the
study of color experience. /) There is the realization
of the possibility that any species might possess a
well-developed spectral analyzer of which it can make
little or no use. For example, the eye of a rabbit or a
cat or a monkey may be quite like that of a human,
but this does not mean that in any or all of these cases
there is the same color experience. In fact, we know
nothing of subhuman experience in any case.
For our purposes here, we want to know the role
played by central mechanisms in either muscular dif-
ferential response to the spectrum or in the production
of various color experiences. Obviously, even though
we credit the retina in both its photochemical and
neural mechanisms as being a keen analyzer and thus
providing the central nervous system with a differen-
tiated message, the central apparatus must also, in a
way, be an analyzer, else it cannot make differential
use of the message. The requirement of an analyzer
applies both to the center and the periphery. This is
made apparent to those possibly more difficult to
convince by the fact that color experiences can be
predictably elicited by nonspectral stimuli. Certain
alternations in intensity of stimulation as produced by
a rotating disk with high- and low-reflecting ('white'
and 'black') portions are sufficient to produce color
experience. The central apparatus responds to this
nonspectral presentation in the same fashion as to
certain spectral presentations.
The foregoing phenomena taken together, or many
of them taken alone, lead us to the conclusion that
for much of what we call vision we must include the
central mechanisms that are not visual, else we have
nothing that can be called vision. It is customary to
call the surrounding areas association areas, but we
see that their function is not to associate rigid units of
activity each of which plays a single role but rather
to participate in the overall differentiation of activity
we call response.
Cortical as well as retinal responses to spectral stim-
ulation (200 msec, in length) have been recorded by
Lennox & Madsen (52). Simultaneous records from
the cortex and retina were compared in wa\e form,
amplitude and latency. The spectral points involved
were 'blue' (445 m^i); 'green' (560 m^); 'yellow' (575
mti); and 'red' (620 mti).
The recordable threshold of the cortex lay about
one logarithm below the retinal threshold. The on-
response of the cortical potential consisted in a di-
phasic wave, initially surface-positive. At low and
moderate intensities, the positive response was double.
At high intensities the initial phases contained four
or five spikelets.
Increasing stimulus intensity decreased the latency
of both the retinal and cortical responses and in-
CENTRAL MECHANISMS OF VISION
739
creased their amplitudes. The spectral composition of
the stimulus affected shape, amplitude and latency.
The two components of the positive response were
most marked in response to 575 and 620 m|i stimuli.
The amplitude of the cortical response to the 445 m/j
stimulus was greater than to the 560 m/i stimulus
when in the retina the two were the same. The la-
tency of the cortical response to the 445 m/j stimulus
was longer than for the greater wavelength when
under the same circumstances the latencies were the
same at the retina. The final conclusion was to the
effect that variation in the cortical responses were not
solely determined at the periphery.
The same two authors, Madsen & Lennox (54),
studied cortical response to spectral stimuli still fur-
ther. In this Study, the anterior, mid and posterior
optic cortices were compared by means of simulta-
neous recording. The double positive on-response
mentioned earlier was found in the posterior and mid
cortex. The response from the anterior cortex was
single. The maximum of the wave corresponded to
the latency of the second peak of the double waves
found in mid cortex within a value of from 2 to 5
msec. Latencies on the anterior cortex were signifi-
cantly longer than in posterior cortex, and the rate of
reduction in latency with increase in intensity was
more rapid. The authors attributed the difference in
latency between the anterior and posterior cortex to
the absence of the first positive peak of the on-re-
sponse in the anterior cortex.
The latency of responses to the 445 m/i stimulus
was shorter at the anterior position and that for red
was longer than at the posterior position. The ampli-
tude for the cortical response to the 445 m/z stimulus
was relatively greater at the anterior than at the
posterior cortical position.
The types of cortical respon.ses obtained by these
authors indicates that the cortex of the cat does re-
spond differentially to spectral stimulation. In direct
contrast to this, we have recent evidence for thinking
that the o\er-all response of the cat (its overt beha-
vior) does not utilize the differentials of cortical
response just described. Meyer et al. (58) were unaijle
to condition the cat differentially to the photic radia-
tion passed by three Wratten filters (23A, 'red'), (47,
'blue') and (61, 'green'). One thousand trials were
used for each of the comparisons of filter 23A with
61, and 47 with 61. As a check, a pure intensity
comparison was used and conditioning was accom-
plished in 200 trials. This led the authors to believe
that the cat does not possess color vision.
The fact that differential cortical responses to spec-
tral stimulation can be detected and yet the same spe-
cies cannot be taught to respond differentially in its
overt behavior is a concrete example of the principle
which we stated earlier in this section. It is an exam-
ple of why we need to be quite definitive in what we
mean when we use the term color vision.
To clarify matters, one had better never speak of
color vision in subhuman species. If the animals in
question can be trained to respond differentially to
various parts of the spectrum, we can call the beha-
vior overt spectral vision. Color vision is a term that
should be reserved for the description of human ex-
perience. If neurophysiological experiments indicate
differential response to the spectrum by any or all
sense cells, then it should simply be called spectral
response. Vision is not a term to apply to sense cell
behavior. Thus we have three categories of behavior
to talk about, spectral response, spectral vision and
color vision, and it is in the interests of clarity that we
use three terms.
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CHAPTER XXXI
Central control of receptors
and sensory transmission systems
ROBERT B. LIVINGSTON
National Institute oj Menial Health and National Institute of Neurological
Diseases and Blindness, National Institutes of Health, Bethesda, Maryland
CHAPTER CONTENTS
Control of Receptor Acti\ ity
Sympathetic Influence on Touch Receptors
Efferent Control of Invertebrate Stretch Receptors
Efferent Control of Mammalian Stretch Receptors
Remote Central Control of Stretch Receptors
Control of Activity in Special Sense Afferents
Auditory Nerve Activity
Optic Nerve Activity
Olfactory Bulb Activity
Control of Central Sensory Relays
Spinal Ascending Relays
Dorsal Column and Other Bulbar Relays
Thalamic Relays
Cephalic Interaction Systems
Corticipetal Projection Systems
Cortical Interaction Systems
Corticifugal Influences on Brain-Stem Mechanisms
Organization of Centrifugal Sensory Control Mechanisms
Transactional Mechanisms Relating to Sensory Control
Systems
Sensory Attention, Habituation and Conditioning
Auditory Habituation
Auditory Conditioning
Shifts of Attention
Visual Responses
Beha\ior and Neurophysiology
Interpretations
Summary
IT IS A VER"!' OLD NOTION, which needs often to be
repeated, that our sensory pathways are subject to
error and hence may yield distorted sensations. This
idea was succinctly stated three centuries ago by
Descartes,' in point of fact, these essentially neuro-
physiological considerations provided the cornerstone
of his philosophy of universal doubt. Nonetheless,
little attention has been given to the possibility that
the central nervous system may itself be able to
exercise some measure of direct control over the
traffic of nerve impulses ascending sensory pathways.
Recent experimental evidence indicates that such
central influences do exist and can modify sensory
input patterns all the way from receptors to whate\er
end point is chosen — from peripheral sense organs to
at least the sensory cortex. Much additional study
needs to be given to particular features of this mech-
anism, but already the implications are far-reaching.
Sensory impulses can apparently be interfered with
at their point of origin and at synaptic junctions as a
result of activity taking place in certain remote parts
' "I have learned from some persons whose arms or legs have
been cut off, that they sometimes seemed to feel pain in the part
which had been amputated, which made me think I could not
be quite confident that it was a certain member which pained
me, even although I felt pain in it. . . . In the same way, when
I feel pain in my foot, my knowledge of physics teaches me that
this sensation is communicated by means of ner\es dispersed
through the foot, which being extended like cords from there
to the brain, when they are affected in the foot, at the same time
affect the inmost portion of the brain which is their extremity
and place of origin, and there excite a sensation of pain repre-
sented as existing in the foot. ... If there is any cause which
excites, not in the foot but in some part of the ner\es which are
extended between the foot and the brain, or even in the brain
itself, the same action which usually is produced when the foot
is detrimentally affected, pain will be experienced as though it
were in the foot." Rene Descartes, Discourse on Method, 1637.
741
742
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
of the nervous system. This interference inxoKes an
active process that is usually inhibitory. In the waking
state, the sensory pathways seem ordinarily to be
under a tonic inhibitory influence; evidenth a good
deal of the potential content of sensory experience is
being continuously reduced or eliminated within the
initial stages of sen.sory integration. Inasmuch as
activity along sensory pathways appears to be modifi-
able to some extent according to an animal's en\iron-
mental experience and according to its overtly ex-
pressed direction of attention, the interference with
sensory transmission appears to be regulatory and to
constitute a goal-seeking physiological mechanism.
These findings call for some adjustment of current
physiological, psychological and philosophical con-
cepts relating to perception. Most such concepts have
been based upon a) physiological findings deri\ed
from an examination of anesthetized animals, findings
which usually reveal the activities of only a few parts
of the nervous system at a time, and A) behavioral
evidence obtained with waking unanesthetized ani-
mals in which the nervous system is treated as a whole.
Some degree of closure between these two experi-
mental realms of .science was apparently achieved 30
years ago. Adrian and other physiologists discovered
that the strength of a stimulus necessary to elicit
action currents in peripheral sensory nerves of anes-
thetized animals was approximately equal to that
found by psychologists for threshold perception in
attentive human subjects (4, chapter VI}. Compa-
rable stimuli, again in anesthetized animals, were then
found to yield evoked cortical responses that were
localized to certain 'sen.sory receiving' areas of the
cortical mantle (59). Detailed analysis in anesthetized
animals of activity taking place within various relay
stations between the peripheral nerves and the cortex
re\-ealecl that the spinal (80), brain-stem (60) and
thalamic synaptic relays (69} were quite reliable in
their transmission of evoked signals.
Naturally such findings led to an interpretation
that the sen.sory nerves and the central ascending
paths reliably convey to the cortex whatever messages
are generated by the sensory end organs. It was argued
that only when the impulses reach the cortex are they
then accessible to such p.sychological factors as habit-
uation, focus of attention, suggestion, etc., long known
to intervene in sen.sory perception. The cortex was
believed to be only the first stage in the integration
of sensation from sense data (7, pp. 39, 40, 62). This
view fitted well with the traditional conception of
hierarchical supremacy of the cortex — notions de-
ri\ecl partly from the recognition of its topmost loca-
tion, enormous areal extent, anatomical complexitv,
phylogenetic recency, etc., and partly from the mo-
mentum of theoretical conceptions of Pa\lo\- and
others who assigned most psychological functions to
the cortex (64).
^ et for more than 50 years anatomists have recog-
nized that certain nervous pathways enter sensory
nuclei and relay stations from above, and that nearly
all .sensory systems have eff"erent fibers passing from
the neuraxis to receptor organs. When the indi\idual
anatomical features of these centrifugal projections
are grouped together, they appear to constitute a
series of descending neuronal cascades which con-
ceivably might have an influence upon ascending
sensorN impul.ses. These descending and efl"erent sen-
sory projections ha\e usually been considered piece-
meal and few conceptual generalizations are available.
Perhaps the most prophetic of these appears in an
interpretive discussion of neuropathology by Brouwer
in 1933: ". . . We accept that there is also a cen-
trifugal side in the process of sensation, of \ision, of
hearing, and so on. I believe that a further anahsis
of these descending tracts to pure sensory centers will
also help physiologists and psychologists to under-
stand some of their experiences" (10, p. 627).
CONTROL OF RECEPTOR .ACTIVITY'
Sympalhetif Iiifluemt' nii Touch Receptors
Single touch receptor activity in isolated skin areas
of the frog can be facilitated in stimulation of the
sympathetic nerve supply to that region (56). Activity
in these receptors can also be facilitated by the local
application of epinephrine or norepinephrine, or by
introducing these hormones into the circulation.
Thus, individual receptors are evidently subject to
generalized as well as local sympathetic influences.
Sympathetic ner\e influences have alreadv been
shown to be facilitatory to transmission across the
neuromuscular junction (see 56 for references); their
effects on touch receptor acti\it\- therefore appear to
be parallel and to place the peripheral sensory as well
as peripheral motor portions of the reflex arc under
some degree of central control. By \irtue of these in-
fluences, the reflex arcs relating to touch should no
longer be considered such simple units of neuro-
physiological and behasioral systems. Since appar-
ently all sensory receptors receive sympathetic fibers,
it is perhaps not too extra\agant a generalization to
suppo.se that all of them may be found susceptible to
this kind of central interference.
CENTRAL CONTROL OF RECEPTORS AND SENSORY TRANSMISSION SYSTEMS
743
Efferenl Cunlinl nf Irivetiehrale Stretch Rcajitors
Another central control mechanism relating to
peripheral afferent nerve discharge has been dem-
onstrated in crustacean stretch receptors by Kuffler &
E\zaguirre (49)- They have shown that the stretch-
sensitive muscle afferent in the crayfish tail is itself
innervated by an efferent inhibitory ner\e fiber which
can diminish or arrest the activity of the afferent fiber.
The afferent ner\e discharge that is ordinarily elicited
by a given muscle stretch can be decreased or oblit-
erated depending on the rate and number of impulses
delivered to the inhibitory fiber. Presumabh' this sort
of control can be effected by central ganglia in the
intact cravfish.
Efferenl Crjiitrol oj Mainmalnin Stretch Receptors
The rate of discharge of the large mammalian
muscle-spindle afferent apparentK' depends upon the
degree of tension developed by a small intrafusal
mu.sclc fiber contained within the spindle. This intra-
fusal fiber can be passively stretched or relaxed along
with lengthening or shortening of the surrounding
skeletal muscle. In addition, it has its own motor con-
trol by way of the small ventral root gamma efferents
(40, 50-52). Thus, the discharge of spindle afferents,
which play such an important role in proprioception,
is determined both by the state of the skeletal muscle
and by the rate of discharge of the gamma efferents.
The gamma efferents enable the spindle afferents
to have a full range of discharge rates for any given
muscle length, the end result being a better accom-
modation of different loads and rates of movements.
It can readily be appreciated that this peripheral
feedback or loop-gain system provides an exceedingly
important measure of central control over sensory
input.
Remote Central Control of Stretch Receptors
Granit & Kaada (30) discovered that the gamma
efferents controlling muscle-spindle afferents are in
turn regulated by a number of remote central struc-
tures. As shown in figure i, muscle-spindle discharges
are readily accelerated by stimulating the mesence-
phalic and diencephalic reticular formation — the
brain-stem facilitatory region of Magoun (28, 30).
When these structures are activated, a mu.scle-spindle
afferent will continue to show facilitation for up to
half a minute or more following discontinuation of
the brain-stem excitation. Similar but less uniform
13
16
FIG I. Effect of brain-stem reticular (midbrain tegmentum)
stimulation on a gastrocnemius muscle spindle afferent dis-
charge. Above: Contraction of 134 gm at low myograph sensi-
tivity to demonstrate silent period of the large muscle spindle
afferent unit. Initial tension throughout, 52 gm. Light Dial-
chloralose anesthesia. / to ./: Control before reticular stimula-
tion. 5 to //: During stimulation. 12 to 31: After stimulation.
Consecutive sweeps at 2 sec. intervals. Myograph (M) alongside
film. Distance M-B (base line) corresponds to 10 gm. Note that
stimulation of the brain-stem reticular formation, without
altering the muscle tension, accelerates the spindle's rate of
firing and that this effect persists more than half a minute.
[From Granit & Kaada (30).]
744
HANDBOOK (JF PHYSIOLOGY
NEUROPHYSIOLOGY I
effects are elicited by stimulating the motor cortex,
the anterior lobe of the cerebellum, the habenular
complex and the head of the caudate nucleus. Inhibi-
tion of spindle activity is readily elicited by stimula-
tion of the medial part of the bulbar reticular forma-
tion— the brain-stem inhibitory region of Magoun
— and by excitation of the anterior lobe of the cere-
bellum (17; 28, p. 103; 30). Eldred has painstakingly
extended the exploration and anahsis of these remote
central spindle afferent control mechanisms (16).
Granit & Kaada showed that gamma efferent
activity is facilitated by reticular stimulation at
strengths considerably below those which will elicit a
discharge of the large skeletal-muscle (alpha) moto-
neurons. Hence, motor facilitation by brain-stem
mechanisms appears to take place first through an
activation of the gamma efferents controlling sensory
input from the muscle spindles, and then bv both the
direct descending influences which act upon the large
motoneurons and the continuing indirect influence of
brain-stem control over muscle-spindle afferent dis-
charges which act back upon the same motor units.
As in other sensory control systems, the gamma effer-
ents appear to be normally under a tonic inhibitory
influence from above.
In each example, the frog tactile receptor, the
muscle stretch receptor in Crustacea and the mam-
malian muscle-spindle afferent, there is evidence for
efferent neuronal systems which exercise an important
controlling effect upon the initiation of afferent nerve
impulses. In the case of the muscle spindle, at least,
the efferent fibers are in turn under the control of
certain remote central mechanisms. The principle of
central control of afferent activity is equally applicable
to the special senses.
CONTROL OF ACTIVIT\- IN SPECIAL SENSE AFFERENTS
Auditory Nerve Activity
For many years a compact bLuidlc of libers traveling
with the eighth cranial nerve pair was considered to
be afferent (65, vol. I, figs. 319, 324). In a series of
critical anatomical studies, Rasniussen proved that
these are really efferent fibers. They arise in the
vicinity of the superior olive and terminate within the
contralateral cochlea (67, 68). Rasmussen's efferent
fibers appear to make contact with the afferent audi-
tory fibers as these pass from the hair cells to the
spiral ganglion. Some of the efferents may pass
directly to the inner hair cells but this point is un-
LEFT 0-C
CUT
/t^tN""*^
LEFT STAPEDIUS
CUT
FIG. 2. Suppression of auditory nerve response by olivococh-
lear and stapedius mechanisms. A. Control auditory nerve
responses to click applied to each ear, right recording above
left. B. Suppression of both left and right responses with shocks
at 100 per sec. delivered to the decussation of the olivocochlear
bundle in the floor of the fourth ventricle. This high frequency
of stimulation tetanizes the stapedius muscle so as to eliminate
interference from that source (see E below). C. Following
transection of the left olivocochlear bundle, the suppression
shown in B occurs only on the right. D. .Another control re-
sponse showing that lesion made between B and C has not
interfered with auditory nerve response from either ear. E.
Single shocks to same medullary location 1 3 msec, prior to test
clicks suppress the eighth nerve responses from either ear
(stapedius effect). F. Following cutting of the tendon of left
stapedius muscle the suppression shown in E is seen only on
the right. [From Galambos (26).]
settled. Galambos has recently shown, as illustrated
in figure 2, that stimulation of the medulla in the
region of the superior olive, and along the course of
the olivocochlear bundle, will cause a suppression of
auditory nerve responses elicited by standard click
stimulation (26). Such suppression does not occur
following division of the olivocochlear bundle at a
point peripheral to the locus of stimulation. The
CENTRAL CONTROL OF RECEPTORS AND SENSORY TRANSMISSION SYSTEMS
745
suppression reappears if the stimulus is reapplied
peripherally to the point of division of the bundle.
Rasmussen's efferent fibers are therefore evidently
capable of suppressing activity in auditory afferents
either at or near the point of impulse origin within the
cochlea.
Optic j\erve Activity
Granit, by stimulating the midbrain tegmentum,
induced a lasting augmentation of the frequency of
firing of individual ganglion cells in the retina,
whether the latter were spontaneously active or were
made active by test flash illumination (29). Occasion-
ally, from the same general region, inhibition is
elicited. Both the facilitatory and inhibitory effects
appear to be conveyed by fine efferent fibers described
by Ramon \ Cajal and others (e.g. 65, vol. II, fig.
211, p. 366). Dodt, by stimulating the optic tract in
rabbits, elicited small, late-appearing retinal spikes
which are unlike antidromic spikes; these he inter-
preted as due to impulses conveyed along the cen-
trifugal fibers to the retina (15)- The exact central
origin of such centrifugal fibers is not yet determined.
These efferent effects upon retinal activity are most
readily initiated by stimulation of the reticular forma-
tion of the midbrain and are reliably obtained only in
animals lacking central anesthesia (29, 39).
Olfactory Bull) Activity
The anterior commissure contains cflerent fibers,
described by Ramon y Cajal and others (e.g. 65, vol.
II, p. 664, figs. 423-425; 66, p. 12), which apparently
arise in basal rhinencephalic areas and pass out to the
olfactory bulb. These and similar fibers coming from
the opposite bulb are believed to terminate on granule
cells and in the periventricular and external plexiform
layers. In this location they have access to the synaptic
junction between receptor-cell terminals and bulbar
neurons. Kerr & Hagbarth (46) studied the effects of
exciting this centrifugal system upon the electrical
activity of the olfactory bulb, both in the resting state
and following olfactory stimulation. Excitation of the
anterior commissure, the prepyriform cortex, the
cortical amygdaloid nucleus and the olfactory tubercle
induces a diminution of olfactory-bulb activity. Ef-
ferent fibers apparently exercise a tonic inhibitory
influence upon the olfactory bulb since the addition
of central anesthesia or a surgical division of the an-
terior commissure is followed by an augmentation of
olfactory-bulb activity.
CONTROL OF CENTRAL SENSOR"!' REL.AYS
Spinal Ascending Relays
Magoun observed in 1950 (58) that the "study of
descending influences of the reticular formation has
so far been preoccupied entirely with the pronounced
effects exerted upon the discharge of spinal motor
neurons. It would be of considerable interest to
know whether or not these generalized reticulospinal
influences are capable also of altering the transmission
of afferent impulses within the cord." The effect of
centrifugal influences upon the synaptic relay of im-
pulses from dorsal root fibers to second order ascend-
ing neurons was first tested by Hagbarth & Kerr in
■954 (sO- Using cats immobilized with curare and
lacking central anesthesia, they applied test shocks to
individual lumbosacral dorsal roots and analyzed the
effects of intervening (conditioning) excitation applied
elsewhere in the central nervous .system. They found
that stimulation in either the inhibitory or facilitatory
zones of the reticular formation diminishes or abol-
ishes responses being conveyed within both the ventral
and lateral funiculi of the spinal cord. The relayed
response in the dorsal columns is also affected although
the primary dorsal column spike, representing con-
duction along primary afferent fibers, is unaltered.
Stimulation of a number of other parts of the central
nervous system, the sensorimotor cortex, the second
somatic sensory area, the anterior part of the cingulate
gyrus and the anterior vermis of the cerebellum, has
similar but less pronounced effects. An example of
this is shown in figure 3.
When central anesthetics are administered, there is
an augmentation in amplitude of the relayed re-
sponse as compared to preanesthetic levels (fig. 4).
Additionally, if the spinal cord is divided in the cer-
vical region in animals without central anesthesia, a
similar 'release' appears, resulting in an increase of
amplitude in the second order neuron responses to a
standard dorsal-root volley (31). Evidently in anes-
thetized animals the high amplitude of .sensory-e\oked
responses recorded within the classical sensory path-
wa\s is due to the anesthetic having interrupted a
tonic descending inhibitory influence.
Dorsal Column and Other Bulbar Relays
Excitation of the brain-stem reticular formation
induces a prolonged depression of transmission
through the dorsal column relay nuclei (39, 71). A
moderately intense i-sec. stimulation causes a rapid
746
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
onset and slow decay of depression, affecting impulses
being relayed to the internal arcuate fibers. The ini-
tial spike of impulses arri\-ing via the dorsal columns
is not affected. Not only is the relayed response of the
dorsal column nuclei modified, but the background
activity of reticular neurons at the same level is af-
fected, although with a different time course, by the
same conditioning reticular stimulation. On the intro-
duction of central anesthetics or the production of a
mid-line pontine lesion, there is a notable increase in
amplitude of evoked responses pa.ssing through the
dorsal-column nuclei, indicating that ordinarily there
"^^^^W^^^
'^«^'^^%/\.'^ - - -
I M I I I I I r r
I r I r I I I I I I I I I I
10 msec.
FIG. 3. Cerebellar inllucnces on .spinal sensory transmission.
Responses are elicited by stimulation of the right dorsal root
L7, and recorded from the left ventral column of the spinal
cord {upper beam') and left sensory cortex (lower beam)- Inter-
current stimulation is applied to the ventral part of the anterior
vermis of the cerebellum. Test responses recorded (/) prior to
cerebellar stimulation, (.?) during cerebellar stimulation, (j)
I sec. and (4) 3 sec. after termination of cerebellar stimulation.
Dorsal columns of spinal cord were sectioned at L4. [From
Hagbarth & Kerr (31).]
I I t I I I I
5 m sec .
FIG. 4. Release' of tonic descending inhibitory influences by
anesthesia and by cord transection. Curarized cats without
central anesthesia. Top row: Left ventral column response to
feeble L7 dorsal root stimulation (^4) before, and (B) after
injection of 45 mg chloralose per kg. BoUom row : Effect of high
cord section on left ventral column response. A before, and B
1 hr. after transection. In each experiment the stimulus in-
tensity and location were kept constant; the dorsal columns
had been transected at the L4 level. [From Hagbarth & Kerr
(30-]
is a tonic descending inhibitory influence acting upon
this relay station.
Impulses being relayed through the spinal root of
the trigeminal nerve in response to test shocks applied
to the ophthalmic branch of the trigeminal are also
diminished by stimulation of the brain-stem reticular
formation (36). Sensory-evoked responses in the adja-
cent reticular formation are sometimes depressed for
more than a minute even though the trigeminal nu-
clear response is only transiently affected. Stimulation
of the sensorimotor cortex will also bring about active
inhibition of the trigeminal synaptic relay, as appears
in figure 5.
Jouvet & Dcsmedt report that stimulation of the
mesencephalic reticular forntation will cause a marked
reduction in amplitude of auditor\-e\oked responses
recorded from the dorsal cochlear nucleus (44). This
occurs even when the electrical responses recorded
from the round window in response to the same
sensorv stimuli are unaffected. They conclude that
CENTRAL CONTROL OF RECEPTORS AND SENSORY TRANSMISSION SYSTEMS
747
0 m sec
peaks of facilitation, holds for the thalamic relay of
c\'oked responses during barbiturate anesthesia or
following lesions placed in the brain-stem reticular
formation. These alterations result from the 'release'
from a tonic inhibitory reticular influence which evi-
dently modulates the thalamic relay nuclei during
wakefulness (48). Other evidence indicates that stim-
ulation of the brain-stem reticular formation will
affect the lateral geniculate as well as retinal relays of
photically-evoked responses (39). Apparently evoked
responses to the same flash signal may be augmented
in the retina and yet depressed in the thalamus.
Altogether, these experiments suggest that each of
the major stations which relay afferent impulses
within the spinal cord, medulla and thalamus appears
to be susceptible to interference by inhibitory influ-
ences, and that these influences are tonically active
in the unanesthetized animal.
FIG. 5. Sensorimotor cortex inHuence on trigeminal relay
and brain-stem reticular formation responses to infraorbital
nerve stimulation. Curarized cats without central anesthesia.
A. Bulbar recording from left spinal fifth tract. Afferent tri-
geminal response following stimulation of the left infraorbital
nerve (/) before, (2) during, (j) 3 sec. after and (^) 6 sec. after
repetitive stimulation of right sensorimotor cortex (100 per
sec. for 3 sec). In this record the trigeminal response is com-
posed mainly of a secondary wave, the primary spike being
hardly visible as an initial notch. B. Recording from the right
side of the midbrain reticular formation. Reticular response
evoked by infraorbital stimulation (i) before, (2) 13 sec. after
and (3) about 20 sec. after repetitive stimulation of right sen-
sorimotor cortex (100 per sec. for 3 sec). [From Hernandez-
Peon & Hagbarth (36).]
the inhibitory effect is probaljly taking place at the
level of the central (dorsal cochlear nucleu.s) relay.
Thalamic Relays
Recently the brain-stem reticular formation has
been found capable of altering synaptic transmission
through thalamic relay nuclei. In animals without
central anesthesia, test-evoked responses being con-
veyed through the somatosensory relay (from the
medial lemniscus to the internal capsule) develop a
shortened latency and duration and a reduced ampli-
tude during brain-stem activation (48). The peaks of
facilitation that otherwise appear during recovery
following a relayed volley are likewi.se obliterated.
The converse, i.e. a long latency, high amplitude and
prolonged duration response followed by succes.sive
CEPHALIC INTERACTION SYSTEMS
Cortuipiial Prnjulum Systtmi
In addition to the primary somcsthetic sensory re-
sponses which are highly resistant to deep anesthesia,
there are the so-called 'secondary' responses which
have longer latency, are more widespread and are
somewhat less resistant to anesthesia (5, 20). These
have been shown to be independent of the classical
medial lemniscus pathway and to be dependent
upon structures lying in the medial part of the
cephalic brain-stem (14, 62). These secondary re-
sponses are recorded well beyond the ijoundaries of
the classical somesthetic receiving cortex and may
even be of higher amplitude in the surrounding asso-
ciation cortex (33, 42, 43, 76, 77, 79).
A number of additional studies have extended the
analysis of the somesthetic secondary response and
have found what appear to be analogous .secondary
responses relating to the auditory and visual systeins
as well. Recent studies, illustrated in figure 6, of
Buser & Borenstein may be taken as exemplary of
current insight into these mechanisms (i i)." Primary
- Recent work confirms that the 'secondary discharge' of
Forbes & Morison (20), observed in rather deeply anesthetized
cats, probably involves a different mechanism from that re-
sponsible for the 'reponses sensorielles secondaires' of Buser cSi.
Borenstein (11), observed in animals lacking central anesthesia.
Drs. Evarts and Fleming (personal communication) have
established that by recording from implanted electrodes in the
visual receiving cortex of the cat they can demonstrate a dis-
748
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY
FIG. 6. Cortical zones showing reinforcement of responses
between two heterogeneous sensory stimuh. Cats curarized,
without central anesthesia or with a light dose of chloralose.
When two heterogeneous stimuli occur nearly simultaneously,
certain cortical loci outside of the primary receiving areas
show an interaction between the two stimuli (potentially the
effect is either facilitatory or inhibitory but is most readily ident-
ified if facilitatory). Auditory and somesthetic reinforcement in
,-1, visual and somesthetic in B; auditory and visual in C. The
principal primary receiving areas are outlined by dolled lines.
GSP, posterior sigmoid gyrus; C, coronal gyrus; SSA and SSM,
anterior and middle suprasylvian gyri; LAT, lateral gyrus;
ESM, middle ectosyl\ian gyrus. [From Buser & Borenstein
(")•]
and secondary response systems arc differendated by
being a) independent in pathway (lemniscus and
medial brain-stem reticular formation), i) different
in susceptibility to anesthetic agents (primary re-
sponses are highly resistant, secondary responses are
more vulnerable to barbiturate anesthesia), <) differ-
ent in latency (for primary somesthetic responses,
approximately 8 to lo msec, as compared with those
for secondary responses, approximately 40 to 80 msec.)
and d) different in areal extent on cortex (primary
localized to classical sensory projection area, second-
ary extending widely into association cortex where
the modalities belonging to the different sensory
systems overlap each other).
There is an important functional distinction be-
tween the classical sensory pathways and the ascend-
continuity of secondary responses during the application of
increasing increments of barbiturate anesthesia. An early
secondary response which can be discerned when conditions
are favorable in the completely unanesthetized cat disappears
with light stages of anesthesia (pentobarbital, 15 mg/kg), and
a much larger secondary response appears at a deeper stage of
anesthesia (30 mg/kg) and after a substantially longer latency.
ing brain-stein reticular system. French & Magoun
(22) found that monkeys with bilateral destruction of
the classical lemniscal pathways in the midbrain are
still aroused from sleep by sound and touch stimuli.
When the reticular formation in the midbrain is
destroyed, however, leaving the classical ascending
sensory pathways intact, the monkeys remain in coma,
even though sensory evoked potentials can be re-
corded in the auditory and somesthetic receiving
cortices. Central anesthetics block conduction in
certain extralemniscal pathways, and this undoubt-
edly represents an important basis for their action as
anesthetics (23). These facts underline the importance
to sensory evoked arousal, and presumably to sensa-
tion in general, of the extralemniscal pathways.
Cortical Intrrarlion Sysli'ms
High frequency stimulation of the brain-stem retic-
ular formation yields a generalized reduction in de-
gree of synchronization among cortical neurons (63).
The effect on the electrocorticographic patterns imi-
tates the desynchronization that takes place during
natural arousal. It has been shown that brain-stem
activation is accompanied by an increase in the rate
of discharge of neurons throughout the cephalic brain-
stem, including the diffusely projecting thalamic
system (57). As is well known, almost all individual
cortical loci are reciprocally related to points that are
symmetrically placed on the opposite hemisphere, as
though in mirror image of each other. Chang dis-
covered, as shown in figure 7, that when one records
evoked potentials from a given cortical locus, an
intervening stimulation of the homotopically related
point on the opposite hemisphere will modify the
evoked response (12, 13). von Euler & Ricci (81)
have analyzed this capacity for interference with pri-
mary cortical sensory-evoked responses on the part of
separate cortical inputs. By stimulating the classical
thalamic relay nuclei and recording the primary
evoked cortical responses, these investigators could
then add conditioning stimuli to the contralateral
homotopic cortical point. They find, as did C^hang,
that these systems converge and interact within the
sensory cortex (81). Afferent impulses arriving in the
sensory cortex are known to interact there with non-
specific impulses from the thalamic recruiting system
(43). Moreover, recruiting responses recorded from
the cortex are found to be altered during behavioral
alerting to sound stimuli (18).
All of these facts sulxstantiate the general principle
that within the cortical receiving areas, as at each of
CENTRAL CONTROL OF RECEPTORS AND SENSORY TRANSMISSION SYSTEMS
749
%
120
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100
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. •••
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•
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•
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20 40 60 80 100 120 140 160 i80 200
msec.
FIG. 7. Time course of blocking effect of callosal potential on positive and negative components
of primary auditory response. Abscissae: Time after delivery of stimulus on contralateral cortex
for callosal potential. Ordinatcs: Magnitude of auditory response expressed as percentage of control.
Dots represent positive component and circles, negative component. Note that stimulation of the
contralateral homotopic cortical locus modifies, by its callosal connections, the sensory-evoked
response in a primary receiving area. [From Chang (13).]
the Other stations along the sensory pathways, the
character and e.xtent of sensory-evoked responses are
subject to intervention by activities taking place else-
where within widespread regions of the brain.
Corticifugal Influences on Brain-stem Mechanisms
Bremer & Terzuolo (9) showed that stimulation of
the cortex in cats without central anesthesia will in-
duce electrocorticographic evidence of arousal. Jasper
and co-workers (41), working with monkeys, had
earlier shown a spread of localized cortically-induced
after-discharges into the brain stem. It has subse-
quently been observed, in monkeys without central
anesthesia, that single shock stimuli delivered to spe-
cific regions of the cortex will yield evoked potentials
throughout a wide zone of the cephalic brain stem
(1-3, 21). This zone is generally coextensive with the
brain-stem region within which sensory responses from
different sensory systems appear to converge. Blocking
and facilitating interaction takes place in this general
region among the various combinations of cortically
and peripherally initiated signals (8, 21, 36, 70).
Examples appear in figures 8 and 9. The corticifugal
projections not only interact with other signals con-
verging upon the brain stem but also with signals
intrinsic to the reticular formation, i.e. signals gen-
erated within and recorded from the brain-stem retic-
ular formation itself (2), as may be seen in figure 10.
The same corticifugal systems are known to be capable
of initiating electrocorticographic (73) and behav-
ioral C72) arousal, presumably by virtue of their con-
nections with the cephalic brain-stem reticular forma-
tion.
It can be seen that not only are input and output
patterns modifiable within the cortex, but the cortex
itself can also modify activity taking place within the
ijrain stem and thereby possibly have an indirect in-
fluence back upon sensory patterns as these are ini-
tiated and relayed at lower levels.
Organization of Centrifugal Sensory Control Mechanisms
Up to this point we have described mainly how
activity in each of the sensory neurons linking to-
gether a given classical ascending sensory pathway
750
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
i*iiAMi^**«i*MMiitiii*iita^*iMMlMMi^i^MW«M«4i
sAAAAAAAAA/VWNAAA/VX/WWXAAy
lioo^V 25/sec noo^V
FIG. 8. Inhibition of reticular unit discharges by stimulation
of the cerebellum and augmentation of reticular unit dis-
charges by sensory stimulation. Encfphale isote preparation,
without cential anesthesia. For each strip, the top line registers
an electroencephalographic tracing recorded from the fronto-
temporal regions of a hemisphere; the lower line indicates unitary
spike discharges picked up from the median bulbar reticular
formation by a microelectrode. A. .Activated electroencephalo-
gram and continuous high frequency discharge of the reticular
unit. B. Total inhibition of the unit by positive polarization of
the anterior vermis of the cerebellum (0.5 ma); EEG trace not
modified. C. Immediately after discontinuation of the cere-
bellar polarization. D. Same as C a few seconds later. Tlie
reticular unit reappears (C) and progressively increases in
discharge frequency (D); during the early part of this period,
slow high-amplitude waves appear in the EEG. E. Some
minutes later, an intense tactile stimulation (brisk rubbing of
the bridge of the nose) causes the appearance of a multiple
reticular discharge (including recruitment of new units), and
an increase in frequency of EEG waves. [From Mollica et at.
(6.).]
is subject to some degree of interference according to
the state of activity in other parts of the nervous
system. Now, is it possible to define somewhat more
specifically the relationship between the classical
sensory paths and these other parts? No final inter-
pretations are warranted since the data are as yet
incomplete for any one sensory system. Nonetheless,
in each sensory system there can be identified certain
centrifugal sensory control mechanisms which bear
close analogy with structural or functional aspects of
one or another of the other sensory systems. Generali-
zations that might not be permitted for one system
alone seem to gain in strength when all of them are
examined together.
Paralleling the classical succession of ascending
neurons appears a descending system which links the
same nuclear relay stations from above downward.
Although analogous centrifugal projections have been
identified anatomically for many individual parts of
other sensory systems, the auditory pathway probably
po.ssesses the most completely documented succession
of descending fibers. These pursue a course in reverse
direction that roughly parallels the ascending; audi-
tory pathway. They pass step-by-step downward from
the auditory cortex to the medial geniculate body and
inferior colliculus, thence to the lateral lemniscus and
trapezoid body and to the superior olive where they
are succeeded by the olivocochlear efferent bundle.
As Galambos says, "It is unlikeh that these descend-
ing fiber .systems — some reasonably powerful, some
weak — perform no function in audition. What this
function might be will unfortunately continue to re-
main entireK' speculati\e until more anatomical and
physiological data become available. One can hazard
a guess, however, that the solution of certain problems
of hearing resides as much in the understanding of
the function of these descending pathways as in the
knowledge of the ascending ones" (25, p. 503). Pre-
sumably centrifugal fiber projections which belong to
the visual, somesthetic and olfactorv svstems mia;ht
B
W*/<-^;
10 m sec
10 nri sec
FIG. 9. Influence of hypothalamic and toe pad stimulation
on sciatic nerve responses elicited within the brain-stem reticu-
lar formation. Recording from the right side of the midbrain
reticular formation in a curarized cat without central anes-
thesia. A. Sciatic responses, (/) before, (.?) during, (3) 8 sec.
after and (^) 20 sec. after repetitive stimulation in the right
hypothalamic region (50 per sec. for 3 sec). B. Sciatic response
(/) before, (s) during and (3) 10 sec. after pinching the toe pads
of right hind limb (ipsilateral to reticular recording site).
[From Hernandez-Peon & Hagbarth (36).]
CENTRAL CONTROL OF RECEPTORS AND SENSORY TRANSMISSION SYSTEMS
751
STIMULATION
POINT "A"
'^/'^^''»'''■'%^^*^
RETICULAR
RESPONSE
POSTERIOR
TO ANTERIOR
RETICULAR
RESPONSE TO
CORTICAL
STIMULATION
MULATtON
POINT "B"
SHOCK
INTERVALS
4 MS
12
20
25
31
39
48
59
93
rv/'^flv^Nw^
D^V
*\Nv^
\|L/Vv,sM****M
»/|^,.^S,.VSv^
' /V,^^>^''**^
'1 J-^^-mA^N^
^^^M-^-H^^*^
^^/^v^***'*N
*^v^
COMBINED
CORTICAL
a
RETICULAR
STIMULATION
SHOCK
INTLRvaLS
4 MS
[yx/'^s^
p/w^*^
p^/^-^^-^,-
/y/irv^
fW^.^^^S.^PV-^Mi*
20
25
31
39
48
59
93
FIG. 10. Coiticifugal inHuences
upon a conduction pathway in
the brain-stem reticular forma-
tion. Responses recorded from
bipolar electrodes in the anterior
brain stem show effects of single
cortical shocks on volleys ascend-
ing from a test stimulation site
in the posterior brain stem. Left
column: Effects of cortical shocks
applied to point 'A' on the
medial surface of the monkey
hemisphere. Right column: Effects
on the same pathway of shocks
applied to a more anterior
cortical site, point 'B". Note that
ascending brain-stem volley is
facilitated when cortical shock is
delivered to point 'A' 31 msec.
prior to posterior brain stem test
shock, whereas facilitation from
point 'B' occurs at 9 and again
at 48 msec, at which moments
the brain-stem pathway is being
inhibited from point 'A'. This
illustrates the principle that a
number of cortical sites can exert
a controlling influence on ascend-
ing systems intrinsic to the brain
stem, thereby being able, pre-
sumably, to interfere with mecha-
nisms involved in sensation.
[From Adey el at. (i).]
752
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
play an analogously important, but as yet undefined,
role in the perception of each of these modalities.
It is generally accepted that the classical ascending
sensory pathways connect directly or indirectly with
the brain-stem reticular formation (78). Rasmussen
reports that the centrifugal auditory projection sys-
tem also sends branches into the same general region
(personal communication). It may be by virtue of
such collateral connections to the brain-stem reticular
formation that most sensory pathways and certain
zones of the cerebral cortex have indirect reciprocal
relations with the cerebellum (6, 32, 74, 75). Each of
the cerebral and cerebellar cortical areas which is
capable of exercising an eflfect upon impulses trans-
mitted along the classical ascending sensory pathways
possesses projections to the brain-stem reticular for-
mation. Moreover, stimulation of the brain-stem re-
ticular formation is known to evoke very notable
sensorv control effects. This much is highly suggestive.
But whether the descending sensory projections which
parallel the classical ascending sensory pathways and
the cerebral and cereljellar projections into the brain
stem each have an influential access to the ascending
sensory transmission systems must await definitive
experimental proof.
To these considerations should be added the fact
that there is really no physiological boundary between
central sensory and motor mechanisms. Each central
pattern for the initiation of movement has its neuronal
repercussions upon central sensory patterns, and each
performed movement introduces alterations in sensory
input patterns. In this way sensory and motor systems
are inextricably bound together both internally and
externally.
Transactional Mechanisms Relating to
Sensory Control Systems
It is now possible to identify six extensive, mutually
interacting systems: a) the classical ('lemniscal')
ascending sensory pathways projecting finally upon
the classical sensory receiving areas of the cortex, b~)
the parallel ('extralemniscal') ascending sensory
pathways which reach more widespread regions of
the cortex by way of the brain-stem reticular forma-
tion, f) the classical ('pyramidal') descending motor
pathways projecting directly from cortex to lower
motoneuron aggregations, ctj the parallel ('extra-
pyramidal') motor pathways which descend to the
motor nuclei indirectly by way of the basal ganglia
and the brain-stem reticular formation, e) the brain-
stem reticular formation which is known to exert
modifying influences upward upon both the cerebral
and cerebellar hemispheres and downward upon both
sensory and motor synaptic relays, and /) the cen-
trifugal sensory control mechanisms which may in-
volve fibers coursing in reverse direction parallel to
the classical ascending sensory pathways and which
may also implicate projections from cerebral and
cerebellar loci through the brain-stem reticular for-
mation.
The interdependence of these six systems is obvious.
Evidently they are all knit together by the brain-stem
reticular formation which could not be efTectively
studied in animals with central anesthesia. Because
of this experimental limitation, antecedent concep-
tions had to deal with relatively independent sensory
and motor systems which were more stable, imperious
and reliable in their handling of signals than is the
case in the unanesthetized brain.
Since collaterals from the classical ascending
pathways influence the reticular formation and the
reticular formation in turn modifies the initiation and
transmission of impulses along the classical sensory
pathways, since both of these systems interact with
each other again in the sensory receiving cortex,
since the reticular formation by way of the diffusely
projecting thalamic nuclei modifies activity generally
throughout the cortex and the cortex in turn modifies
activity within the reticular formation, since the cere-
bellum is similarly linked both ways with the brain-
stem reticular formation, etc., one can begin to
visualize the extent of abstraction imposed by the
experimental isolation of only a few elements of this
entire complex. Moreover, it is not possible to de-
fine how such a 'transactional mechanism' (55) might
operate on the basis of any single experimental ap-
proach. By adding evidence from studies that in-
corporate both neurophysiological and behavioral
techniques, it is possible to add a new dimension
to the conception of the mechanisms involved in
the central control of sensorv transmission.
SENSORY ATTENTION, HABITU.ATION AND CONDITIONING
Auditory Habituation
By means of electrodes implanted within the dorsal
cochlear nucleus, Galambos, Hernandez-Peon and
their associates have recorded potentials elicited by
acoustic stimulation during the course of behavioral
studies on unanesthetized cats. Responses to the same
tone pip show modest fluctuations in amplitude and
CENTRAL CONTROL OF RECEPTORS AND SENSORY TRANSMISSION SYSTEMS
753
CONTROL -^■fft^^y-^ /r^-y^J^' /^,■'/v^-V./' ,Vv/>V
CLICKS ALONE J
HABITUATION ,■ v*'>u,i i /iv«.,r «. jA ,m . .
CLICKS ALDNE'^-^^''^W*^^-^^' ^Vs-^/^^.>V
AFTER 600 ,-,«..• v ,
CLICK- SHOCKS''*.'^^**^ ^-^^.A^I^V •'/^aN^",>/. ,vv^^
DEHABITllATION ' . '
AFTER 1100 /V-^-Wj".' '^v"-^ V^V^.^vV-yVA/
CLICK -SHOCKS ' -•
REHABITUATION
AFTER 1800 >'-V^V-Nwir-JV*V.'; •''.v^N/-.a/rAfwwV^
CLICKS ALONE
0.9 SEC.
SO>iV
FIG. II. Modification of amplitude of click-evoked responses
in dorsal cochlear nucleus according to experience of the
animal. Unanesthetized cat with recording electrodes im-
planted in the dorsal cochlear nucleus. Amplitude of responses
elicited by clicks repeated every second gradually declines over
many trials. The animal exhibits behavioral as well as electro-
physiological evidence of habituation to the click stimuli. After
habituation, if weak electric shocks are applied to the foreleg
of the same animal in temporal association with the clicks, the
click -evoked responses gradually become increased in ampli-
tude. The dehabituation' can occur within only a few trials if
sufficiently powerful shock stimuli are applied, as shown by
Galambos et al. (27). The dehabituation' is plastic in the sense
that the amplitude of the click -evoked responses declines once
more after the shock stimuli are discontinued. This kind of
modification of sensory-evoked responses has been taken as an
objective evidence of conditioning. [Modified from Jouvet &
Hernandez-Peon (45).]
undergo periods of waxing and waning. If the same
tone signal is repeated many times, the amplitude of
the evoked dorsal cochlear nucleus responses tends
gradually to become reduced to a new lower level,
although the fluctuations still persist (27, 37, 38, 45).
The authors refer to this as auditory 'adaptation' or
'habituation.' If the tone is shifted up or down in
pitch, the ev'oked potentials return to a higher ampli-
tude once more, but rehabituation can be established
to the new tone signal. After habituation to a particu-
lar tone has been thoroughly established and the tone
is then associated with a nearly simultaneous signal,
such as an electric shock to the foreleg or across the
chest, a high amplitude cochlear response will re-
appear. This has been referred to as 'dehabituation'
(35). After discontinuation of the electric shock, a slow
rehabituation to the auditory signal takes place (27,
45), as is shown in figure 1 1 .
Auditory Conditioning
These fluctuations in amplitude of the responses
recorded within the first central relay stages along the
auditory pathway may be reflected by roughly parallel
shifts in the animal's behavior. When first introduced
to the test-tone signals, an animal attentively alerts to
each tone pip. As electrographic evidence of habitua-
tion occurs, the animal shows less behavioral evidence
of devoting attention to the acoustic signals. When
habituated and then given an unconditioned electric
shock in association with the tone signals, the animal
behaves as if it has suddenly acquired an increased
interest in the associated tone. Growth in behavioral
evidence of attention usually takes place a few trials
in ad\ance of the growth in amplitude of the evoked
dorsal cochlear response, but the modified
(conditioned) cochlear response lasts approximately
as long, during e.\tinction trials, as the overtly ex-
pressed attention. The electrophysiological plasticity
in response of the nervous system has with some justi-
fication been taken as an objective indication of con-
ditioning.
Using electrical shocks applied across the chests of
cats, Galambos et al. (27) have found that only ten
or twentv such unconditioned stimuli, applied in asso-
ciation with clicks to which the cats had previously
become thoroughly habituated, were sufficient to
cause electrographic as well as behavioral evidence of
conditioning. Simultaneous recordings made in the
cochlear nucleus, auditory cortex, hippocampus,
septal area and head of the caudate nucleus show that
electrographic changes associated with this kind of
conditioning may occur at several difTerent levels
along the auditory pathway and in regions other than
the classical auditory system. Cycles of associated be-
havioral and electrophysiological evidence for condi-
tioning and extinction can apparently be repeated
indefinitely. [Galambos et al. (27) may be consulted
for additional evidence and commentary on condi-
tioning in relation to modifications of electrical
activity in the brain. This subject is also discussed by
Galambos in Chapter LXI of this work.]
Shifts of Attention
Recording from electrodes implanted in the dorsal
cochlear nucleus of the cat before habituation had
754
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
been established, Hernandez-Peon et al. (38) have
tested the effects on auditory-evoked potentials of
distraction by visual and olfactory stimuli. As may be
seen in figure 12, when mice in ajar are placed before
the experimental animals, or when fish odors are
blown into the cage through a tube, the formerly high
amplitude auditory responses are immediately re-
duced in amplitude. The effect is as if the cats had
suddenly shifted from a naive to an 'habituated' state
with reference to the auditory test-signal responses.
But when the mice are removed or the odor blowing
stopped, and after the cats are apparently relaxed
once more, the evoked auditory potentials return
again to their initial high level of amplitude. The
duration of the reduced auditory potentials corre-
sponds closely with the period when the animals are
distracted by the nonacoustic signals.
Visual Responses
Using electrodes implanted in the brain-stem reticu-
lar formation, optic tract, lateral geniculate body and
optic radiation, Hernandez-Peon et al. (39) were able
to analyze the effects of intercurrent brain-stem stimu-
lation on the relay of flash-evoked responses through
the retina and lateral geniculate body. When light
flashes are reiterated over an extended period of time.
the flash-evoked responses at each point along the
visual pathway tend to diminish in amplitude. This
suggests that there is a mechanism of habituation
operating in the visual system. .Stimulation of the
brain-stem reticular formation or behavioral distrac-
tion by nonvisual stimuli is associated with a reduc-
tion in amplitude of the nonhabituatcd photic re-
sponse.
Behavior and Xeurophyswlogy
Although these studies are quite recent, and only
a few aspects of a potentially very rich field have been
touched upon, certain features merit special comment.
It is evident that the activity taking place along at
least the auditory and visual pathways, and possibly
the olfactory and somesthetic sensory systems as well,
is vulnerable to systematic intervention in accordance
with previous experience (habituation) and shift of
attention (distraction) (11, 45 and other pertinent
chapters in 19). It is inferred, but not yet firmly estab-
lished, that these dynamic changes in activity within
the sensory paths are accomplished by some mecha-
nism involving the brain-stem reticular formation.
The evidence is as follows: «) activation of the i)rain-
FIG. 12. Modification of click-evoked
responses in the cochlear nucleus during
'attention' in the unanesthetized cat. Re-
cording from implanted electrodes in
the dorsal cochlear nucleus in an ani-
mal prior to habituation to click signals
delivered every second. Photographs are
simultaneous vi'ith potential recordings
opposite. Top and bottom : Cat is relaxed;
the click responses are large. Middle:
While the cat is visually attentive to
mice in a jar, the click responses are
diminished in amplitude. [From Her-
nandez-Peon el al. (38).]
,...,.,-.^^,,^,^.,^,.,...-v,^ -v.-^^V'^WJ^y^^-
■■Xy-v^
,V.^^^,X'VvAv-
'■ — y ■
[lOOuv
.^V^y/M^^^-
,y»i-»M
y^,
0 500
t_i ■ • ' •
M SEC
CENTRAL CONTROL OF RECEPTORS AND SENSORV TRANSMISSION SYSTEMS
755
Stem reticular formation in unanesthetized animals
has an effect on nonhabituated acoustic- or flash-
evoked responses that is similar to distraction of atten-
tion by extraneous stimulation of the same animals;
A) distraction of attention by extraneous sensory stimu-
lation may very likely have its effect, as does arousal,
by activation of the brain-stem reticular formation;
f) animals given barbiturate anesthesia (known to
interfere with activity in the brain-stem reticular for-
mation) cannot be habituated; d) if animals are
habituated prior to being anesthetized, the sensory-
evoked potentials change from habituated (reduced)
amplitude to the initial prehabituated height but
typical habituated responses reappear following re-
covery from the anesthetic; e) in habituated animals,
a lesion restricted to the pontine or mesencephalic
brain-stem reticular formation is followed by perma-
nent 'release' from the habituated pattern.''
Recently, Fuster (24) has reported that monkeys
trained to do difficult tachistoscopic discriminations
between two similar objects show improved perform-
ance in both their speed of response and percentage
of correct choices when the test exposure is preceded
by a very brief electrical shock applied to the mesen-
cephalic brain-stem reticular formation. More pro-
longed stimulation in the same brain-stem location
interferes deleteriously with both the reaction time
and percentage of correct choices. These findings
imply an alteration of visual sensory or possibly judg-
mental processes as a result of brain-stem activation.
Although there is no way of being certain, in Fuster's
experiments, where the effect takes place, it is possible
that such changes occur within the first few synapses
along the visual pathway. This might be inferred from
the experiments of Granit (29) and Hernandez-Peon
et al. (39) cited above. More convincing evidence for
improvement in the kind of differentiation demanded
by tachistoscopic discrimination is reflected in experi-
ments by Lindsley (53). He finds that two flashes
which are placed close enough together to produce a
^ .\ note of caution. Much has been learned within the last
few years which assigns important functions to the brain-stem
reticular formation.' It must be remembered, however, that
this region may well contain several functional systems. The
studies of Adey, Amassian, Haugen, Moruzzi and their asso-
ciates imply that this is the case (2, 8, 34, 47, 61). In the first
stages of interpreting the functions of so large and complex a
region of the brain, it is natural that somewhat overgcneralized
and sweeping conclusions may be alluring. This does not deny
the reliability of observations made to date but implies that,
when this complex skein of reticular neurons becomes better
understood, a greater precision in the localization and charac-
terization of its functions may be possible.
single large-humped electrical wave in the lateral
geniculate body are, on stimulation of the brain-stem
reticular formation, separated into a two-peaked
himip.
Taken as a whole, all of these behavioral experi-
ments reinforce the neurophysiological evidence that
the sensory pathways are relatively plastic rather than
fi.xed in the transmission of impulses generated by a
particular stimulus. Sensory transmission is apparently
modifiable in accordance with waking experience.
Moreover, the brain-stem reticular formation evi-
dently plays an important role in the government of
such neuronal plasticity.
I\'TERPRET.\TIONS
Remarkable changes take place within sensory
circuits when one shifts from the u.se of anesthetized
animals to animals without central anesthesia. In the
anesthetized state the classical sensory pathways con-
vey high amplitude .signals with great reliability and
consistency, and there is little activity within the
brain-stem reticular formation. Clortical responses to
sensory stimuli are greatly amplified and tend to be
confined to the classical sensory receiving areas. In
the waking brain, without central anesthesia, the
classical sensory pathways convey signals that are less
reproducible from one moment to the next. Indeed,
over a period of some minutes or hours there may be
remarkable alterations in the size of evoked responses
to a given stimulus. In addition, there are widespread
responses elicited throughout extensive cortical and
subcortical regions. It seems obvious now that the
classical sensory pathways and cortical projection sys-
tems, no matter how necessary they might be to per-
ception, are not in themselves .sufficient for perception.
The extralemniscal sensory pathways, coursing
through the brain-stem reticular formation and
diffusely projecting thalainic nuclei, appear to have a
general function of providing an integrative back-
ground or context for perception. Their contribution
in this respect may be likened usefully to the organi-
zational contribution in movement and behavior that
is made by the descending extrapyramidal projec-
tions. They may be thought to provide a general
.sensory awareness and feeling tone comparable to the
background of excitability and motor tone generated
by the extrapyramidal system. Nonetheless, they may
convey more specific sense data too. Haugen &
Melzack (34), for example, report persuasive evidence,
soine of which appears in figures 13, 14 and 15, that
756 HANDBOOK OF PHYSIOLOGY ^ NEUROPHYSIOLOGY I
FIG. 13. Short and medium latency response areas of brain stem and thalamus responding to
tooth pulp stimulation. Narrow vertical stripes identify the trigeminal lemniscus (medial lemniscus)
which has a short latency and a dominantly contralateral projection. Horizontal stripes mark the
trigeminobulbothalamic path (spinobulbothalamic), with short latency and bilateral projections.
Stippled areas mark the ascending portion of the central tegmental fasciculus (dorsal secondary
trigeminal pathway), with medium latency and bilateral projection. Diagonal stripes designate the
Eiscending path within the central grey which possesses medium latency and bilateral projections.
The reticular formation yields widespread responses characterized by long latency and bilateral
character. The relevant structures are indicated on the leftside of each level. Recording sites (except
within reticular formation) are shaded on the right side. Abbreviations : BC, brachium conjunctivum;
BIC, brachium of inferior colliculus; CE, centralis; CG, central grey; CM, center median; CTF,
central tegmental fasciculus; DBC, decussation of brachium conjunctivum; DM, dorsalis medialis;
H, habenula; HIP, habenulointerpeduncular tract; IP, interpeduncularis; LG, lateral geniculate,
LP, lateralis posterior; MG, medial geniculate; ML, medial lemniscus; MLF, medial longitudinal
fasciculus; .\''/?,red nucleus; Pet/., peduncle; PL, parafascicularis; Pul., pulvinar; P]\ periventricular
area; Py, pyramidal tract; SBT, spinobulbothalamic tract; .S'C, superior colliculus; .S'.V, substantia
nigra; Sbf., subparafascicularis; STh, subthalamicus, TBT, trigeminobulbothalamic tract; TL,
trigeminal lemniscus; TO, optic tract; VL, ventralis lateralis; VPL, ventralis postcrolateralis; VP,
ventralis posterior; VPM, ventralis posteromedialis; VTT, ventral tegmental nucleus of Tsai; and
^I, zona incerta. [From Kerr et al. (47).]
particular portions of the reticular pathways may con-
vey signals essential to pain perception.
It is clearly established that, whatever may be con-
tributed by upward-streaming sensory-evoked im-
pulses, the central nervous system possesses an im-
portant downstream sensory control mechanism
which also undoubtedly contributes to the perceptual
content. The ner\ous system possesses some mecha-
nism whereby the amplitude of sensory-evoked re-
sponses, and hence the number or synchrony of units
responding, can be greatly modified. This mechanism
exerts an effect within each of the classical sensory
pathways, altering the initiation of impulses or their
transmission through the entire succession of sensory
CENTRAL CONTROL OF RECEPTORS AND SENSORY TRANSMISSION SYSTEMS
757
synapses. There is good e\idence, too, that this
mechanism is discharged by way of the brain-stem
reticular formation; the action might originate there
or perhaps elsewhere within the cerebral and cerebel-
lar hemispheres, but it undoubtedly funnels through
and may be significantly modified by the reticular
formation. The end effect of this mechanism may be
facilitatory or inhibitory, but in many central relays
it appears to be predominantly inhibitory. The
mechanism clearly depends upon an active process;
its effect can be interrupted by transection of the
neuraxis above the level of testing, by deep anesthesia
and, more specifically, by the placement of a lesion
in the central core of the brain-stem reticular forma-
tion. The dynamic operation of this mechanism ap-
pears to be responsible during wakefulness for
fluctuations in the amplitude of sensory-evoked
responses.
Beha\ioral studies, too, indicate that this mecha-
FiG. 14. Evoked potentials following tooth pulp stimulation
recorded from three loci at the same mesencephalic level. ^tI.
Recorded from the portion of the central tegmental fasciculus
ascending alongside the periaqueductal grey. B. Recorded from
the pathway within the intermediolateral portion of the central
grey. C, Small early response followed, after a long latency, by
a second longer discharge, recorded from the region of the
decussated brachium conjuncti\-um. Note differences in the
time scale. Note also that, although all three of these individual
loci may be considered parts subsumed within the general
regional designation of the brain-stem reticular formation and
each is a bilaterally represented pathway, they are nonetheless
distinguished from one another by differences in latency, am-
plitude and duration of response. [From Kerr el al. (47).]
nism plays a dynamic role during wakefulness. Here
its operational effect is usually a reduction of sensory
signals, an effect that is active in inverse relation to
the degree of attention or interest enlisted by that
particular stimulus. The mechanism seems to be less
active (to inhibit less) when a stimulus is novel or
when a stimulus is given special significance, as by its
association with an important unconditioned stimu-
lus. The mechanism appears to be more active (to
inhibit more) in relation to signals arising from stimuli
to which habituation has been developed and other
stimuli, even though not rendered ineffective by
habituation, from which attention has been with-
drawn.
Briefly, this sensory control mechanism appears to
provide the perceptual processes with an active or-
ganizing principle, including an element of purpose,
which tends to select and modify sensory messages
within the earliest stages of their trajectory. If overt
behavior may be assumed to provide a cogent index
for the interpretation of telos, then this sensory control
mechanism is designed to diminish the engagement
of higher centers with those signals that have the least
significance to the individual.
A mechanism operating in this way requires that
incoming signals be identified and given significance.
How might this identification and attachment of value
come about? Only partial answers can be provided at
this time. Continuous electrographic recordings from
multiple sites indicate that, when a behaving animal
encounters a new situation, at first a very large terri-
tory of the brain is drawn into a novel activity. As the
experience is repeated many times, there develops a
significant economy in terms of the extent of brain
involvement. Perhaps recognizable signals can eventu-
ally be reduced to a quite small number of impulses,
representing minuscule abstractions of reality. Perhaps
recognizable identity can be established e\en before
the sensory-evoked impulses have time to ascend ail
the way to cortex and back. Something of a parallel
sort appears to take place within motor circuits as one
proceeds from the execution of a complex novel move-
ment to that same movement when it is established
as an ingrained motor habit. There is evidently an
analogous economization and automatization of
neuronal activity in relation to the habituated act as
finally executed.
The attachment of value to such identified signals
could presumably come about quite naturally through
the activation, pari passu, of certain portions of the
brain's primary reinforcement systems (see Chapter
LXII l)y Stellar in this work). .\ number of the struc-
758
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
FIG. 15. Effect of nitrous oxide on long latency bilateral reticular formation responses to tooth
pulp stimulation. Although the lemniscal response to tooth pulp stimulation is not perceptibly
aflfected by nitrous oxide-oxygen inhalation, responses elicited within both ipsilateral and contra-
lateral reticular formation practically disappear after 5 min. of such inhalation. Recovery is nearly
complete 15 min. later. [From Haugen & Melzack (34).]
tures implicated in both positive and negative rein-
forcement undoubtedly participate in the central inte-
gration of both sensory and motor mechanisms. These
structures are anatomically linked with the extra-
lemniscal, diffusely projecting and extrapyramidal
systems as well as the phylogenetically older parts of
the cortex and brain stem.
There has long been a quest to know how nerve
signals might be 'read' and how they might be gi\en
'value.' We are now certainly closer to knowing where
such events take place even though the how is still
unanswered. Clearly the cortex is not the first step in
sensory integration. During wakefulness sensory inte-
gration is taking place continuously and dynamically,
beginning with the farthest afferent outposts. This
involves an erosion of information that originally
started into the nervous system and an intrusion of
influences which are based upon the animal's previous
experience as well as its momentary disposal of atten-
tion. This implies that there is a reduction and distor-
tion of sensor\-cvoked signals from the acttial nature
of the stimulating world. Perhaps 'value' is likewise
inserted into the complex at these early stages of
sensory integration. Certainly significance to the
organism appears to be a guiding principle with
respect to the operation of sensory control mecha-
nisms, hence a survival of incoming impulses in the
unanesthetized brain would appear to he jnima Jacie
evidence of their significance.
In order to bridge the gap between neurophysi-
ology and psychology, it is necessary somehow to
determine the neuronal mechanisms underlving be-
havior. A principal difliculty appears with the at-
tempt to interpret the fimction of the whole out of its
parts. Whereas the beha\ ior of separate parts could
be made out from an analysis of the interaction of one
part with another, these parts will not add together
in any simple fashion to account for the beha\ior of
the whole. There ha\e been recent attempts to char-
acterize the differences between linear cause-and-
effect relationships and the more inxolved dynamics
of a large number of mutually interdependent systems
in simultaneous action (55). The authors use the term
'trans-action' to signify the latter kinds of operations
and to contrast them with more limited 'interaction'
systems. .Attempts ha\e been made to interpret some
of the transactional mechanisms invoked in \isceral
sensation and emotional expression (54).
SUMM.XRY
Recent experimental evidence, drawn largely from
the studv of animals without central anesthesia, indi-
cates that the nersous .system is much more plastic in
CENTRAL CONTROL OF RECEPTORS AND SENSORY TRANSMISSION SYSTEMS
759
its action than previously believed. XN'hat may be
taken for sensory pathways, because they convey
sensory-evoked signals in a centripetal direction, turn
out to be more variable and more widespread in their
transmission of impulses in the waking state. The in-
creased variability seems to be due to active inter-
ference by a centrifugal mechanism. The widespread
distribution of sensory-evoked impulses allows a more
elaborate intermingling of sensory with other signals
throughout various parts of the brain. Experimental
evidence favors a lessening of our ccjnceptual isolation
of sensory from motor and other central mechanisms.
The nervous system appears to be made up less of
independent linear pathways than of mutually inter-
dependent loop circuits which stitch together the
\arious parts of the brain into a functional whole.
Along ascending as well as descending projections,
the brain-stem reticular formation and the cerebral
and cerebellar systems linked closely with it seem to
modulate impulse traffic in a continuous action that
modifies the composition of perceptive as well as pro-
jective neural patterns. The losses and distortions of
signals brought about by this mechanism favor the
conclusion that some teleological mechanism is at
work; this appears to be designed to diminish the in-
volvement of higher centers with signals that have
little immediate significance for the animal. Thus,
sensory signals appear to be subject not only to error,
in the sense projected by Descartes, but also to some
purposive central control. A further examination of
these mechanisms will help us to understand many
problems of absorbing interest in neurology, psychia-
try, psychology and philosophy.
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INDEX
Index
ACA ratio: sec Accommodation
Acceleration stimuli: see Equilibrium
Accommodation, 654-656, 660-664
ACA ratio
definition, 664
accommodative convergence and, 664
age and, 664
convergence and, 662
definition, 656
innervation controlling, 662
lens and, 660
limiting factor, 664
mechanism, 660
night myopia and, 664
phoria and, 664
pupils and, 662
refracting mechanism and, 655
response to blur, 663
.Scheincr principle and, 659
sky myopia and, 664
threshold level and, 97
with fixed stimulus, 660
zero level, 659
Accommodative convergence: see Con-
vergence
Acetylcholine
see also Cholinergic transmitter; Trans-
mitter substances; Cvu'arc; Neuro-
muscular transmission ; Parasym-
pathin
arousal and, 1 79
as pain excitant, 479
as transmitter substance, 1 39, 1 55,
166, 179, 200, 230
characteristics, 231
competition with curare, 210
depolarization and, 210
electrically inexcitable membrane and,
■55
intermittent release, 207
mode of action, 2 1 o
mollusc muscle and, 248
sodium and, 210
substances blocking, 139
thermoreceptors and, 455
Action potential
see also Evoked potential
abolition, 100
absolute refractory period and, 308
activity and, 378
auditory nerve, 575
axoplasm, longitudinal current and,
103
current theories, 1 1 7
excitability and, 99
giant axon, 84
junctional activity and, 205
membrane
definition, 84
membrane potential, 100
time course and, 103
monophasic, 77
muscle in invertebrates, 242
Na theory and, 1 18
non-linear phenomena, 95
polarizing current and, 1 1 2
prolonged abolition, loi
retina, 617
temporal relation to membrane cur-
rent, 104
Adaptation
see also Photic adaptation; Scoptic
adaptation
definition, 125
double pain and, 473
in pain receptors and fibers, 468, 473
in thermal receptors, 456
retinal receptive fields and, 705
taste sense and, 524
to touch-pressure, 403
vestibular mechanism and, 555
Adrenaline : see Epinephrine
Adrenergic transmitter, 218-230
see also Epinephrine; Norepinephrine;
Dopamine; Isopropylnorcpincph-
rine; Catechol amines; Transmitter
substances
biosynthesis of, 220-222
characteristics, 218, 220
dopamine as, 229
763
epinephrine as, 140, 179, 218, 229
exhaustibility, 227
identification of, 218-220
iproniazide and, 224
isopropylnorepinephrine as, 229
other than norepinephrine, 228
release, 222-227
removal of, 227, 228
remote effects, 225
stimulus frequency and, 222
storage, 221
After-discharge
classification, 312
cortical, thalamic connections, 307
decamethoniuni iodide, 306
definition, 305
isolated cortex, 306
medullary pyramid, 306
rhythmic, 307
specific neuronal circuits and, 307
types, 305
After -potential
definition, 1 15
fiber type and, 1 15
membrane resistance and, 1 1 5
negative, 1 15
Age
electroencephalogram, human
beta activity, 297
delta activity, 296
theta activity, 297
lens structure and, 662
taste bud distribution and, 508
Alcohol dehydrogenase
visual pigments and, 673
Alkaline phosphatase
in olfactory mucosa, 539
All-or-none response, 64, 76, 79
conversion to graded, 168
lack in protozoa, 370
Alteration of response theory: see Vision
Aluminum cream
lesions due to, 351
764
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
Ametropia
correction, 655
definition, 655
Amino acids
action on synapses, i 77
7-Aminobutyric acid
action on synapses, 177
inhibitory synapses and, 162
mode of action, 1 78
Amygdala
lesions in, 351
stimulation of, 351
Analeptics
electrical discharge and, 340
Anesthesia
auditory cortical activity and, 599
brain excitability and, 308
hyperpathia and, 477
medial lemniscal system and, 406
olfactory bulb activity and, 541, 542
reticular formation inhibition and, 745
sensory pathways and, 752, 755
sensory responses and, 747
sensory somatic stimuli and, 423
Anesthetics
central neuron escitability and, 389
Angular acceleration
threshold for perception of, 554
Annelids
see also Invertebrates
eye, camera style, 638
Anoxia
cochlear microphonic and, 577
cochlear summating potential and, 578
convulsions
reticular formation and, 339
theory, 344
d.c. potential and, 318
EEG and, 339
pre- and postsynaptic potentials and,
302
Aphakia
definition, 656
ultraviolet light and, 666
Appetitive behavior
see also Behavior; Self-selection studies;
Conditioned reflex
taste and, 527
Aqueous humor
index, 656
Arterial pressure
brain excitability and, 308
Arteries
volume change and pain, 463
Arthropods
see also In\ertebrates; Insects; Crusta-
ceans
camera style eyes in, 639
compound eye
polarization plane of light and, 636
cone cells in eyes, 633
muscle innervation, 240
neuromuscular transmission in, 240
ocelli in, 630
polarized light and, 636
.Asphyxia
blocking of nerve fibers and, 471, 472
d.c. potential and, 318
Atropine
mode of action, 233
Attention
neural mechanism of, 753-759
reticular formation and, 367
Audition, 565-612
see also parts of the ear and related terms
acuity
auditory cortex and, 596
pure tone threshold and, 596
central mechanisms of, 585-612
decortication and, 595
descending fibers and, 591
interaction with visual impulses, 3 1 1
invertebrate, 381, 382
range of, 565
temporal information
transmission of, 583
theory of, 58 1 -584
Auditory conditioning
experimental production, 753
Auditory habituation, 752, 753
Auditory cortex, 591-609
see also Central auditory function
anatomical area, 592
cochlear representation in, 594, 606
evoked potentials
distraction and, 754
hearing acuity and, 596
integrative function, 598
localization of sound in space, 598
medial geniculate and, 598
periodic excitability change, 309
postexcitatory depression and, 309
primary and secondary, 594
refractory period, 308
species differences in, 592
thalamic nuclei and, 598
third area, 596
tonal pattern discrimination, 597
tonotopic projection in, 603
topological projection in, 603
.\uditory habituation
experimental production, 752
Auditory localization
transmission of, 583
Auditory nerve, 579-581
action potentials, 575
central control, 744
efferent fibers in, 744
efferent inhibition, 580
frequency response, 580
impulses in, 579
latency in, 579
parallel ascending and descending
pathways, 750
recruitment and, 31 1
single fiber activity in, 579
volley principle in, 579
Auditory reception
in man and insects, 374
Autonomic nervous system
see also Parasympathetic nerves; Sym-
pathetic nervous system
neuroeflTector transmission in, 215-235
pain and, 480-483
Axon
see also Nerve fibers
function, 59
membrane as condenser, 85
squid, as cable, 85
Axoplasm
longitudinal current in, 103
Barbiturates
brain excitability and, 308
corticopetal system and, 389
refractory period and, 308
synaptic block and, 301
Basilar membrane : see Cochlea
Bechterew's nucleus
equilibrium and, 558
Behavior
see also Self-selection studies, Appetiti\e
behavior; Conditioned reflex
attention and, 752-755
neuronal mechanisms of, 754-759
olfaction and, 547
response to light, 728
cells with photoreceptors, 624
cells without photoreceptors, 623
reticular formation and, 755
taste and, 527
Binaural stimulation
definition, 556
Bitter taste
modification by experience, 529
substances giving, 520
Body temperature
EEG, alpha activity and, 296
Brachium of inferior coUiculus: see In-
ferior quadrigeminal brachium
Bradykinin
as pain excitant, 479
Brain
see also Central nervous system; Spinal
cord; individual parts of the brain
electrical activity of, 255-258, 279-297,
'^99-3'^. 3 '5-360, 716-727
evoked potentials of, 299-312
excitability
afferent impulse inflow and, 310
factors affecting, 308
moisture
excitability and, 308
rliythmic activity
generation of, 280
INDEX
76:
harmonic and relaxation oscillators,
281
oscillators, 281
responsiveness to stimuli, 283
simple harmonic motion, 280
spontaneous, 279, 282, 283
Brain potentials, 255-258, 279-297, 299-
312,315-360,716-727
characteristics
functional significance, 256
nature, 255
neuron characteristics affecting, 257
rhythmicity of, 258
Brain rhythms : see Electroencephalogram
Brain stem reticular formation: see Re-
ticular formation
Brightness
definition of, 715
measurement of, 729
nature of, 729
Brightness vision, 729, 732-735, 737
see also Vision
contrast
definition of, 715
decortication and, 728
enhancement
description of, 732
neurophysiological explanation, 732
Buffer solutions
taste of, 514
Bulbar relays: see Medullary oblongata
Burning pain: see Pain
Calcium
end plate potential and, 208
Caloric stimulation
of endolymph, 556
Carbon dioxide
thermoreceptors and, 455
Catechol amines
see also Norepinephrine; Epinephrine;
Dopamine; Isopropylnorcpineph-
rine; Adrenergic transmitter; Trans-
mitter substances
remote effects of, 225
urinary excretion of, 225
Caudate nucleus
convulsion inhibition by, 344
Central auditory function, 585-612
see also Auditory cortex
dispersion of excitation, 61 i
frequency specificity, 607
functional requirements, 587
inhibition, 61 1
lateral lemniscus and nucleus, 589
laterality of projection, 609
loudness and, 609
recurrent pathway, 61 I
Central excitatory state: see Central
nervous system
Central inhibitory state: see Central
nervous system
Central ner\ ous system
axons
potentials from, 268
control of triad response, 663
excitatory state
depolarizing p.s.p.s and, 164
field currents in, igi
inhibitory state
hyperpolarizing p.s.p.'s and, 164
microelectrode studies in, 262
micropipette techniques in, 263
motoneurons
recording from, 271
neurons
excitability states, 389
for kinesthesis, 414
primary sensory fibers
recording from, 270
single fiber isolation, 262
single units
activity, 261-276
identification, 267
Cephalopods
see also Invertebrates; Molluscs
pupil in, 637
Cerebellum
auditory pathway and, 590, 591
Cerebral cortex
ablation, pain and, 493
afferent impulse interaction, 310
anemia
d.c. potential and, 318
auditory projection system and, 591
corticifugal sensory control, 749-752
d.c. potentials in, 315-327
excitability of, 310, 311
functional unity of vertical columns,
415
interaction systems in, 310, 748
isolated
after-discharges, 306
lesions in epilepsy, 349
pain and, 492-498
piriform stimulation, 351
postcentral homologue
patterns, 402
reticular control of afferents to, 747-749
somesthetic area
electrical stimulation of, 436
strychnine and, 340
taste representation in, 510
thermosensitive units in, 436
visual mechanisms in, 719-727
Chemical energy
receptor excitation by, 124
Chemical stimuli
taste and, 510
Chemical transmission
see also Transmitter substances
anatomy, 2 r6
versus electrical, 2 1 7
Chemoreceptors
invertebrate, 375, 376
temperature changes and, 376
Choline acetylase
characterization, 232
Cholinergic transmitter, 230-233
see also Acetylcholine; Transmitter
substances. Curare; Neuromuscular
transmission; Parasympathin
acetylcholine as, 139, 155, 166, 179,
200, 230
biosynthesis, 231, 232
characteristics, 230, 231
mechanism of release, 232
parasympathin, 233
release of, 232, 233
removal of, 233
storage, 232
Cholinesterase
inhibition, 233
Cholinesterase inhibitors
mode of action, 180
Chromaffin cells
storage of hormones in, 221
Ciliary muscle
as limit to accommodation, 664
as skeletal muscle, 662
muscle potential, 662
Cocaine
blocking of nerve fibers, 471
blocking of sensation by, 394
second pain response and, 471
Cochlea
see also Audition; Ear
as mechanical frequency analyzer, 571
basilar membrane, width of, 569
bilateral representation of, 610
blood supply, 574
cortical representation of, 594, 606
efferent control of, 744, 745
excitation of, 565-584
generator potential, 130
Cochlear ner\es
tone frequency response, 604
Cochlear nuclei
anatomy, 587
efferent fibers from, 589
Cochlear potentials, 575-579
injury and, 577
microphonics
anoxia and, 577
characteristics, 576
summating
anoxia and, 578
characteristics, 576
Coelenterates
see also Invertebrates
effector structures in, 370
neuromuscular transmission in, 249
Cold
effect on endolymph, 556
766
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
Cold-blooded animals
thermal receptors in, 445
Cold fibers
see also Thermal fibers
discharge, 446
and temperature, 447
paradoxical discharge, 452
temperature change and, 449
Cold receptors
depth in cat tongue, 43JJ
Cold sensation: see Thermal sensation
Colliculi, inferior
heaving and, 589, 590
Color experience
with non-spectral stimuli, 738
C'olor vision
definition, 716
description of, 738
electrophysiology of, 706
in cat, 739
in decorticate animal, 728
in lower animals, 706
problems related to, 738
Conditioned reflex
see also Behavior; Self-selection studies;
Appetitive behavior
as test for auditory function, 596
Conditioning nerve impulse: my Nerve
impulse, conditioning
Conduction, 75-1 19
see also Nerve impulse; Transmission
external resistance and, 1 06
narcosis and, i 14
polarized fiber, i 1 1
retinal, 696
safety factor, 108
saltatory, 106
model, 109
velocity
determination of, 103
of nerve fibers, 78
Cones
arthropod, 633
electroretinogram and, 699
flicker fusion and, 708
histology of, 693
modulators in, 708
visual pigments in, 671
Convergence
accommodative
accommodation and, 664
fusional
innervation of, 663
relation of accommodative and fu-
sional, 663
Convulsions, generalized, 329-360
see also Pentylenetetrazol seizures;
Strychnine convulsions; Epilepsy;
Anoxia, convulsions
cortical potentials and, 322, 323
cortical theory, 333
eclectic theory, 333
electrical discharge, 338
duration of, 343
propagation of, 350
factors producing, 338
inhibition, 343
mechanism of discharge, 334
neuronal exhaustion, 343
produced by analeptics, 340
reticular formation and, 335, 340
subcortical theory, 332
unified concept, 338
without loss of consciousness, 339
Cornea
configuration, 657
indices of layers, 656
pain and, 465
pain receptors in, 466
Crista
anatomy of, 551
Critical flicker frequency: see Flicker
Critical potential
frequency of the discharge and, 128,
13-i
Crustaceans
see also Invertebrates
muscle
end-plate potentials, 243
inhibition in, 244
innervation, 240
slow and fast potentials, 241
neiu'omuscular transmission in, 240,
243, 244
Curare
see also Cholinergic transmitter; Acetyl-
choline; Transmitter substances;
Neuromuscular transmission ; Para-
sympathin
arthropod neuromuscular transmission
and, 244, 247
competition with acetylcholine, 210
end-plate potential and, 203
transmission and, 149
C'litaneous sensations
see also Thermal sensations; Tactile
system; Skin receptors; Touch-
pressure system
activity in fibers of different size, 394
concept of Head, 391
pattern theory, 390
sensory recovery after section, 475
theories of, 390, 391
Cyanopsin
see also Visual pigments
as visual pigment, 678
photopic sensiti\'ity and, 684
Dark adaptation
liver disorders and, 690
pigment resynthesis and, 686
D.C. potentials, 315-327
anoxia and, 318
asphyxia and, 318
convulsoid discharge and, 322
cortical anemia and, 318
definition, 315
evoked potentials and, 319
factors affecting, 315
human scalp, 326
origin, 326
polarization and, 316
recording of, 316
on conventional EEG, 317
recruiting responses and, 320
shift
ECG and, 319
spreading depression and, 323
stimiUation multisvnaptic path and,
326
strychnine and, 321
veratrine spikes and, 321
Uecamethonium
after-discharge and, 306
effect on synapses, 1 79
Dcfacilitation
definition, 157
Deiter's nucleus
equilibrium and, 558
Dendrites
see also Nerve fibers
activity of, 735
behavior in optic cortex, 726
function, 59
potentials from, 273
sustained potentials and, 735
Depolarization
see also Postsynaptic potentials; Po-
larization
acetylcholine and, 210
critical, 95
postsynaptic potential during, 158
threshold, 95
Diencephalon
chemical stimulation of, 335
electrical stimulation of, 334
origin of generalized discharges, 334
Diffuse thalamic projection system: see
Thalamus, diffuse projection system
Diphosphopyridine nucleotide
visual pigments and, 673
Direct current potentials: see D.C. po-
tentials
Dol
as measure of pain, 463
Dopamine
see also Catechol amines. Norepi-
nephrine, Epinephrine; Isopropyl-
norepinephrine; .Adrenergic trans-
mitter; Transmitter substance
as adrenergic transmitter, 229
Dorsal columns
see also Spinal cord
nuclei
INDEX
767
pathway to ventrobasal complex, 400
patterns in, 398
patterns of medial lemniscal system in,
397
relays
reticular formation and, 745
Dorsal root reflex
electrical activation, 192
DPN: see Diphosphopyridine nucleotide
Drugs
taste sensitivity and, 5 1 o
Ear
see also Audition; Cochlea
acoustical properties, 567-574
anatomy, 566-575
electrical responses of, 575-578
fluids of, 574, 575
frequency characteristics, 569
receptor excitation in, 565-584
Ebbecke phenomenon : sec Thermal sensa-
tions
Eel electroplaques
electromicroscopy of, 151
Eighth cranial nerve ; see Auditory nerve
Electric taste
production of, 522
Electrical stimulus
afferent discharges and, 128
cortical somesthetic area and, 436
double pain and, 474
EEC and, 348
paired
postexcitatory depression and, 309
partial epilepsy and, 348
through microelectrodes, 274
vestibular nerve and, 559
Electrocardiogram
steady potential and, 319
Electroencephalogram, 255-258, 279-297
see also Electroencephalogram, human
absence type petit mal and, 337
alpha acti\'ity
visual blocking, 735
amygdaloid lesions and, 35 1
anoxia, 339
cortical lesions and, 349
critical flicker frequency and, 731
epileptic seizures and, 329
focus and epileptogenic lesions, 354
local application of strychnine, 348
localized electrical stimulation and, 348
models, 280, 281
partial epilepsies and, 331, 357, 358
seizure in multiple relay systems and,
359
SP shift and, 319
Electroencephalogram, human
see also Electroencephalogram
alpha activity, 284, 287
activation, 292
afferent signals and, 289
blocking, 289, 735
body temperature and, 296
distribution, 286
efferent signals and, 294
identification, 287
implanted electrodes, 293
LSD 25 and, 289
origin, 294
pain and, 472
psychotechnical tests and, 289
synchronization and, 292
theta with, 285
beta activity
age and, 296
complexity, 287
delta activity
age and, 296
disease and, 296
theta with, 285
theta activity
age and, 296
variation, 287
Electrogenesis
cellular, 154
electrically excitable, 154
electrically inexcitable, 154-156, 159
sustained, 156
postsynaptic membrane and, 156
synaptic
chemicals and, 163
drug inactivation, 1 76
transducer action and, 189
Electromagnetic energy
receptor excitation by, 124
Electroneurogram
elevations related to sensation modality,
394
Electroretinography, 696-704, 710
see also Retina
alcohol and, 702
arthropod eye and, 635
characteristics, 697
clinical use, 710
cone, 699
damage to retina and, 700
glaucoma and, 702
photopic adaptation and, 699
retinal type and, 698
rod, 699
scoptic adaptation and, 699
source of response, 701, 703
standard leads, 696
stimulus intensity and, 706
stray light in, 667
Emmetropia
definition, 655
Endocochlear potential
characteristics, 575
source of, 576
Endocrines
pain and, 498
Endolymph
composition, 574
flow in semicircular canal, 553
movement due to caloric stimulation,
556
Endolymphatic potential : see Endo-
cochlear potential
End-plate potentials, 202-209
calcium and, 208
characteristics, 203
conditioning nerve impulses and, 208
curare and, 203
definition, 149, 202
in absence of action potential, 205
in crustacean muscle, 243
inhibition and, 244
magnesium and, 208
mammalian muscle fiber, 206
miniature, 207
uncurarized muscle and, 204
Ephaptic transmission, 190-194
see also Transmission ; Synaptic trans-
mission
as model of synaptic transmission, 190
compared to synaptic, 149
evolution, 194
excitation, 190
nerve cords, 192
polarized, 192
unpolarized junction, 192
Epicritic system
criticism of, 475
sensory mechanism, 391
Epilepsies, partial
anatomical lesions, 353
characterization, 330
diffuse, 359
discharges
character of, 357
diffuse, 358
erratic, 353
localized EEG in, 357
mode of propagation of, 356
neuronal, 355
requirements for propagation of, 356
distinction of two varieties, 357
EEG changes in, 331
etiology, 331
experimental, 348
generalized convulsions, 357
localized, 359
physiopathogenesis, 354
physiopathology, 347
predisposing factors, 355
rhinencephalic, 350
secondary generalization, 352
subcortical origin, 352
Epilepsy, 329-360
see also Convulsions, generalized;
Pentylenetetrazol seizures; Strych-
nine convulsions; Anoxia, convulsions
clinical picture, 329
768
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
cortical lesions in, 349
degenerative
reticular formation and, 342
EEG changes, 329
focus
behavior of allied centers and, 356
functional, 331
organic, 331
postdischarges
characteristics, 349
cortical, propagation, 350
transmission, 353
zones for, 349
psychomotor
characterization, 330
Epilepsy, grand mal
characterization, 330
cortical theory, 333
eclectic theory, 333
electrical discharge
causes of, 342
mechanism of, 334
electrical discharge and, 338
experimental production, 332
pentylenetetrazol seizures and, 341
physiopathology, 331
reticular neurons in, 342
subcortical theory, 332
Epilepsy, partial: see Epilepsies, partial
Epilepsy, petit mal
absence type, 336, 346
EEG in, 337
characterization, 330
myoclonic, 33'j, 346
experimental production, 336
thalamus and, 337
Epinephrine
iee also Catechol amines; Norepi-
nephrine; Dopamine; Isopropylnor-
epinephrine; Adrenergic transmitter;
Transmitter substances
acetylcholine and, 210
as transmitter substance, 140, 179, J 18,
229
differentiation from norepinephrine,
218
release in hypoglycemia, 226
Equilibrium
see also Vestibular mechanism
control in invertebrates, 382
senses affecting, 549
Evoked potentials, 299-312
after-effects, 319
anatomical studies and, 300
antidromically produced, 304
apical dendrites, 304
auditory cortex and, 599
compared to spontaneous, 299
components, 300
cortical
mechanism, 303
pain and, 494
definition, 299
distraction and, 754
electrical signs, 304
electrical stimulation of vestibular
nerve and, 559
excitability changes and, 308
external milieu and, 302
internal milieu and, 302
latent period, 301
lateral geniculate and, 325
olfactory bulb and, 541, 545
periodic, 307
presynaptic differentiation from post-
synaptic, 312
repetitive stimulation and, 301
sensory localization and, 300
synapse and, 304
Excitation
axonal, 94-100
mechanism of, in thermal receptors,
456
neuronal, 273-276
quantitative aspects, 129
transmission of energy, 1 37
Excitatory synapses: see Synapse, excita-
tory
Eye, 615-759
see also Vision, Retina; Cornea
accommodation of, 654-656, 660-664
as optical device, 647
axial chromatic aberration in, 668
axial length, x-ray measurement, 658
image formation in, 647-691
internal refracting surfaces
measurement, 657
measurements in, 656
optic axis, 657
Purkinje figure in, 669
reaction to stimuli, 366
refracting mechanism, 654-656
accommodation and, 655
refracting power, 650
refraction of, 654
schematic
exploded, 651
Gullstrand, 648
Helmholtz, 651
reduced, 651
second nodal point
x-ray location, 658
sensitivity to ultraviolet, 64 1
spectral transmittance, 666
spherical aberration, 668
static refraction, 655
stray light in, 667
visual pigment in, 617
migration of, 640
Eye, camera style
definition, 628
in annelids, 638
in arthropods, 639
in molluscs, 637
Eye, compound
in arthropods, 631, 633
polarization plane of light and, 636
Eye, multicellular
photosensitivity in, 627
Eyespots
composition, 627
simple and compound, 627
unicellular, photosensitivity, 627
Facilitation
definition, 168
heterosynaptic, 185
homosynaptic, 184
neuromuscular junction and, 250, 251
of nerve impulse, 1 84
Fasciculation
explanation, 164
Fechner"s paradox
brightness contrast and, 737
definition, 736
Field currents
central nervous system and, 191
First somatic cortical field
fimctional organization, 415
somesthetic discrimination and, 425
tactile and kinesthetic activity and, 423
Flicker
definition of, 715
description of, 729
detection
by arthropods, 634
EEG driving and, 731
frequency
cortical relation, 730
fusion
in cone eyes, 708
in rod eyes, 708
Foveal chief ray
definition, 653
Foveal vision : see Vision, foveal
Frequency discrimination
transmission of, 583
Frontal lobectomy
pain responses and, 497, 498
Fusion
description of, 729
Fusion point
definition of, 730
Fusional convergence : see Convergence
GABA ; see -, -aminobutyric acid
Galvanic stimulation
of labyrinth, 556
Ganglia
photosensitivity in, 624
Gastropods
see also Invertebrates
ocelli in, 630
Generator potential
complex organs, 1 30
definition, 130
INDEX
769
desensitization and, 157
during sustained depolarization, 158
receptor development of, 1 27
Geniculate body
lateral
vision and, 717
medial
auditory cortex and, 598
auditory pathway and, 590
recruitment in, 311
Geniculate response
to optic nerve stimulation, 724
Grand mal epilepsy: see Epilepsy, grand
mal
Gravity receptors
in otoliths, 557
Gravity stimuli: see Equilibrium
Gustatory fibers ; see Taste
Habituation
inhibitory efferent pathways and, 757
Hair cells : see Olfactory receptors
Hearing: see Audition; Cochlea
Heat
double pain and, 474
eflfect on endolymph, 556
Heat conduction
skin and, 437
Histamine
as pain excitant, 478
Historical development, 1-58
concepts
accommodation, 648
acetylcholine, 215
adrenergic transmission, 221, 225
all-or-nothing law, 23, 24
auditory cortex, 600
auditory projection to cortex, 591
central auditory mechanisms, 585
cerebral localization, 46
cerebrospinal fluid, 30
chemical transmission, 24, 215
conditioned reflexes, 53, 55
correlation of sound stimuli and
auditory mechanism, 586
curare, 199
development scientific method, 1-4, 9
electrical transmission, 14, 20, 22, 23
electroencephalography, 49, 51, 284
epilepsy, 51, 333
epinephrine, 215
evoked potentials, 49
ganglia, 33
image formation in eye, 648
inhibition, 36
irritability, !2
medulla oblongata, 34
membrane theory, 1 1 7
motor cortex, 47
motor function, 27, 28, 48
muscle electrophysiology, 19
neuromuscular junction, 24
neuron theory, 59, 149
nicotine, 199
norepinephrine, 217
pain, 459, 460
pain fibers, 480
Pfl tiger's law of contraction, 1 13
pupillary reflex, 42
reciprocal innervation, 7
reflex activity, 25, 30, 32, 34, 36
reflex arc, 35, 40, 42
reflex excitation, 40
reflex inhibition, 37, 40
refractory period, 39
respiratory center, 34
reticular formation, 42 1
science of optics, 6 1 6
seat of the soul, 2, 4, 8, 28
semicircular canals, 553
sensory function, 27, 28, 48
spinal cord, 25
spinal shock, 33
stepping reflex, 35
sympathetic trunk, 42
sympathins, 219
synapse, 38
contributors
Accademia del Cimento, 5
Adrian, 24, 255
Altenburg, 52
Aristotle, i
Auburtin, 46
Bacon, 3
Baglivi, 9
Ball, 616
Bartholow, 48
Hartley, 255
Beck, 50, 255
Beevor, 48
Bell, 28, 36, 42
Berger, 51, 255, 279, 284
Bernard, 21, 199
Bernstein, 23, 148
Bichat, 28
Bishop, 255
Borelli, 5
Bouillaud, 45
Bowditch, 23, 76
Boyle, 7
Bemer, 255
Breruer, 37
Broca, 46
Cabanis, 47
Caldani, 47
Cannon, 219, 225
Caton, 49, 225
Croone, 7
Gushing, 49
Cybulski, 255
Dale, 215, 230
Danilewsky, 52, 255
Davis, 52
Descartes, 5, 31
Dieter, 26
Dixon, 230
du Bois-Reymond, 22, 148
EUiott, 24, 215
Erianger, 24
Ewins, 230
Fernel, 2, 31
Ferrier, 48
Fischer, 52, 255
Fleischl von Marxow, 255
Flourens, 44
Foerster, 49, 52
Fontana, 23, 47
Forbes, 39
Fritsch, 47
Galen, i
Gall, 43
Galvani, 17
Gaskell, 38
Gasser, 24
Gerard, 255
Gerlach, 38
Gibbs, 52
Gilberd, 3
Gilbert: see Gilberd
Glisson, !2, 32
Goltz, 46
Gotch, 24
Gozzano, 255
Hales, 32
Hall, 34
Haller, 1 1, 47
Hamill, 230
Harvey, 4
Hecht, 616
Helmholtz, 23, 26, 75, 616
Hering, 37, 39
Herringham, 30
Hitzig, 47
Horsley, 48
Humboldt, 18
Hunt, 230
Jackson, 48, 54
Jasper, 255
Keen, 48
KoUiker, 27
Kornmiiller, 255
Krause, 148
Kronecker, 37
Kiihne, 24, 148, 201, 616
Laycock, 54
Legallois, 34
Lennox, 52
Lewes, 55
Loewi, 25, 215
Lower, 7
Lucas, 24
Luciani, 45
Magendie, 29, 42, 44, 45, 47
Matteucci, 19
Matthews, 255
Mayo, 42
770
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
Mayow, 7
Monro, 14
Miiller, 20, 34
Newton, 8
Pavlov, 55
Penfield, 49
Pfliiger, 22
Plato, 40
Praudicz-Neminsky, 255
Piochaska. 2
7. 33
Purkinje, 26, 261
Remak, 26
Rolando, 44, 47
Rosenblueth, 219, 225
Rosenthal, 38
Ruffini, 30
Schaefer, 48
Schneider, 42
Schwann, 26
Sciamanna, 48
Sechenov, 52, 54
Sherrington, 30, 35, 36, 39, 40, 56,
148, 149
Soemmering, 27, 41
Spencer, 54
Taveau, 230
Tiirck, 30
Ukhtonisky, 149
Unzer, 33
Vesalius, 3
von Gerlach : see Gerlach
von Haller : see Haller
von Helmholtz ; see Helmholtz
von Humbolt: see Humbolt
von Kolliker: see KoUiker
von Soemerring : see Soemerring
Waldeyer-Hartz, 27
Waller, 26
Walter, 52
Wang, 255
Wedensky, 39
West, 36
Whytt, 32, 41
Willis, 7, 31, 41
Winslow, 31
Young, 648
Hofmeister series: see Taste threshold
Hot sensation : see Thermal sensations
5-HT: see 5-Hydro.\ytryptamine
5-Hydroxytryptamine
as pain excitant, 479
as transmitter substance, 1 79
mollusc muscle and, 248
Hyperalgesia
trauma causing, 478
Hyperopia
definition, 655
Hyperpolarization : see Postsynaptic po-
tentials, hyperpolarizing
Hypoglycemia
epinephrine release and, 226
Hyperpathia
anesthesia and, 477
Hypothermia
pre- and postsynaptic potentials and,
302
Illuminance
delinition, 647, 665
Image formation, 647-691
see also Eye; Vision; Retinal image
astigmatism and, 652
lines of sight and, 653
pupil and, 652
pupillary axis and, 653
refracting mechanism and, 649
size of retinal image and, 654
Implicit time
definition of, 728
of flicker, 730
relation to stimulus area, 728
Inferior colliculus
auditory fibers in, 589
Inferior quadrigeminal brachium
auditory pathway and, 590
Inflammation
pain and, 463
Inhibition
afferent in medial lemniscal system, 408
auditory nerve and, 580
as distinct from occlusion, 310
central nervous system and, 188
central paths for, 70, 7 1
crustacean muscle and, 244
end-plate potential and, 244
membrane potential and, 245
muscle membrane and, 245
pain and, 499, 500
pathways
central, 70
interneurons of, 7 1
referred pain and, 500
retina and, 706
seizures and, 344, 346
sensory neuron, 379
sodium ions and, 70
strychnine tetanus and, 561
synaptic mechanism of, 68-70
transmitters for, 71-72
Inhibitory synapses: see Synapse, inhibi-
tory
Injury
hyperalgesia and, 478
pre- and postsynaptic potentials and,
302
response of cochlear potentials, 577
Injury potential
components, 326
d.c. recording and, 316
Insects
see also Invertebrates
binocular vision, 635
eye sensitivity to ultraviolet, 641
muscle
multiterminal innervation, 247
slow and fast contraction, 246
units in, 245
neuromuscular transmission in, 245
receptor cells in, 373
retina in, 631
sense organs in, 373
Integrative activity
synapses and, 182
utility of electrical inexcitability, 187
Intensity discrimination
transmission of, 583
Intensity-time relation: see Strength-dura-
tion relation
Interneuron
definition, 272
Invertebrates
see also Unicellular organisms; Pelecy-
pods; Multicellular organisms; In-
sects; Gastropods; Crustaceans;
Coelenterates ; Cephalopods; Arthro-
pods; Annelids; Molluscs
axon conduction, 1 1 1
chemoreceptors in, 375
color sision, 640
form perception, 641
hearing, 381
mechanoceptors, 380
muscle
conduction, 250
end-plate potentials, 243
responses, 174
non-photic receptors, 369
pattern recognition, 641
Purkinje shift, 640
receptor cells in, 371, 375
response to dynamic stimuli, 382
response to static stimuli, 382
sense organs compared with verte-
brate, 374
spectral sensiti\ity, 640
squid axon as cable, 85
statocysts in, 382
stretch receptors
efferent control of, 743
tactile sense, 380
thermoreceptors, 379
true receptors, 371
tympanal organs, 382
vibration sense in, 380
lodopsin
see also Visual pigments
bleaching and resynthesis, 687
photopic sensitivity and, 682
Ionic hypothesis, 62-65, 93, 94, 118, 119
explanation of properties of nerve
fibers, 64
refractory period and, 64
synaptic transmission and, 63
INDEX
771
Ionic pump
Na, K concentrations and, 60, 62
Iproniazide
adrenergic transmitter and, 224
removal of catechol amines and, 227
Ischemia
pain and, 463, 474
resistance of nerve fibers to, 395
thermal receptors and, 442, 443, 453
Isopropyl isonicotinyl hydrazine ; s^f Ipro-
niazide
Isopropylnorepinephrine
see also Catechol amines; Norepineph-
rine; Epinephrine; Dopamine; Adre-
nergic transmitter; Transmitter sub-
stance
as adrenergic transmitter, 229
Itching
see also Pain
as related to pain, 498, 499
intracisternal injection of drugs and,
499
intraventricular injection of drugs and,
499
Joint receptors
central projection, 413
discharge patterns of, 411
Ruffini type endings, 412
J oints
innervation of, 411-415
sensations from, 409-415
Kinesthesis, 388-390, 395-415
central neurons for, 414
definition, 388
description of, 409
invertebrate receptors for, 376-379
joint receptors and, 41 i
muscle stretch receptors, 410
postcentral fields and, 423
sites of receptors, 410
Kinesthetic systems, 387-426
central classification, 396
central representation, 395
Krause end bulbs
as cold receptors, 434
Labyrinth: see Vestibular mechanism
Labyrinthectomy
compensation, 562
eff'ects of, 561
species differences, 562
Latency
explanation, 163
factors determining, 166
Lateral lemniscus: see Central auditory
function
Lens
see also Aphakia
accommodation and, 660, 664
age and, 662
as limit to accommodation, 664
nature of capsule, 661
substance
index, 656
Light
spectral distribution, 707
unit of energy, 665
Light intensity
pigment migiation and, 640
Light, response to : see Behasior
Li\er disorders
dark adaptation and, 690
Local response : see Subthreshold response
Longitudinal current
of axoplasm, 103
space and time patterns of, 1 04
Loudness
transmission of, 583
LSD 25: see Lysergic acid diethylamide
Luminance
definition, 665
Luster
conditions for, 737
Lux
definition, 665
Lyotropic series
taste threshold, 5 1 7
Lysergic acid diethylamide
alpha activity and, 289
Maculae: see Otolith organs
Magnesium
end-plate potential and, 208
p.s.p. and, 167
Malononitrile
steady potential and, 318
Marsilid : see Iproniazide
Maxwell's spot
definition, 666
Mechanical energy
receptor excitation, 123
Mechanical pressure
pre- and postsynaptic potentials and,
302
Mechanoreceptors, 380-383, 387-426
see also Audition ; Ear
discharges from, 392
invertebrate, 380
response to thermal stimulation, 454
specificity of, 391
Medial lemniscal system, 396-409
anatomical definition, 396
direct bulbocortical pathways, 400
direct spinocortical pathways, 400
joint receptors projection in, 413
modality components, 403
path from dorsal column nuclei to
\entrobasal complex, 400
patterns
in dorsal column nuclei, 398
m projection, 397
in response of neurons, 405
in thalamic relay nucleus, 399
physiological properties, 397 ,
response, anesthesia and, 406
reticular activating system and, 42 1
touch-pressure and, 403
Medulla oblongata
bulbar relays
reticular formation and, 745
pain fibers in, 487, 488
Medullary pyramid
collateral activity of fibers, 306
Membrane action potential : see Action
potential
Membrane current
space and time patterns of, 104
temporal relation to action potential,
104
Membrane potential
action potential and, 95, 100
constant inward current and, 1 1 2
definition, 102
graded responsiveness and, 168
long polarizing currents and, i 1 2
membrane conductance and, 103
membrane current and, 93
membrane resistance and, 89
postsynaptic potential and, 161
rate of accommodation and, 127
sodium potential, [68
space and time patterns of, 1 04
spatial distribution
action potential and, 103
threshold, 94
stimulus duration and, 96
transducer action of synaptic mem-
brane and, 156
true refractory period and, 309
variation with brief voltage pulse, 1 00
Membranes
electrogenic evolution, 165
excitable and inexcitable, 154, 155
impedance during activity, 90
permeability at receptors, 143
resistance and after-potential, 1 15
Menthol
cold sensation due to, 455
Mesencephalon
hearing and, 589, 590
pain fibers in, 488
remembered pain from stimulation, 490
Metrazol : see Pentylenetetrazol
Microelectrodes
damage due to, 270
double-barrelled, 275
identification of position, 267
micropipettes as, 263
recording from
axons, 268
motoneurons, 271
772
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
primary sensory fibers, 270
stimulation through, 276
types, 262
Micropipettes
as electrodes, 263
electrical properties, 265
preparation, 263
Modulators, visual : see Vision
Molluscs
see also Invertebrates
eye, camera style in, 637
muscle
acetylcholine and, 248
relaxation in, 247
neuromuscular transmission, 247
Monaural stimulation
definition, 556
Monoamine oxidase
distribution in cells, 228
removal of catechol amines, 228
Motoneurons
definition, 272
model for initiation of impulses, 274
single unit activity of, 271-272
threshold level, 68
Muscle
catch-mechanism theory of contrac-
tion, 247
conducted action potential, 239
dual responses of, 1 75
innervation of, 200-202
junctional receptor function, 209-212
multiterminal innervation, 239, 242,
247
neuromuscular transmission, 199-253
polyneuronal innervation, 24!
reciprocal innervation of, 181
smooth
innervation, 2 1 7
tetanus theory, 247
Muscle, invertebrate : see Invertebrates
Muscle potentials
ciliary muscle, 662
in molluscs, 249
Muscle spike: see Spike potentials
Myelinated fiber; see Nerve fibers, mye-
linated
Myopia
correction for, 655
definition, 655
night
accommodation and, 664
sky
accommodation and, 664
Narcotics
cflFect on nodes, 1 1 4
Nerve excitability: see Nerve fibers
Nerve fibers
A, B and C, 469
A, conduction in, 393
after-potentials of, i 14-1 17
blocking by
asphyxia, 471, 472
cocaine, 471
C, conduction in, 394
conduction in, 102-1 14
clectrotonic state, 1 1 i
excitability
determination, 99
relation to threshold, 98
explanation of properties, 64
group I-IV, 469
interaction, 82
myelinated
as cable, 86
potential field of impulse, i i i
peripheral, cutaneous, 393
potentials from, 273
recovery curve of, 80
repetitive firing, 116
constant current and, 127
impulse interval, 127
membrane potential and, 1 1 7
nerve accommodation and, 127
sensorimotor cortex, 42 1
sensory receptors and, 127
rhythmical activity, 1 1 5
saltatory conduction in, 1 06-1 13
specificity of thermal response, 444
temperature and activity, 446
threshold of, 94-100
unit activity of, 269, 270
Nerve impulse, 75-119
see also Conduction; Transmission
afferent discharges
modification of, 128
along uniform axon, 102
character, 79
conditioning
end-plate potential and, 208
external resistance and, 106
facilitation of, 184
generation of, 70
importance of local circuit, 102
insulating air gap and, 108
membrane conductance of, 89-94
multiplication, 82
nodes of Ranvier and, 109
potential field, 1 1 1
propagation, 62
rate of conduction
fiber diameter and, 78
refractory period of, 80
saltatory conduction of, 1 06-1 13
site of initiation, 135
sodium theory of, 62-65, 93, 94, wi
119
spatial summation and, 186
summation, 130
two-way conduction, 81
velocity, 103
volume conductor
potential field calculation and, 105
Weber-Fechner law, 1 26
Nerve net
coelenterates, 249
scyphozoans, 252
Neuromuscular junction
morphology, 200
Neuromuscular transmission, 199
see also Cholinergic transmitter : Acetyl-
choline; Transmitter substances;
Curare; Parasympathin
anticholinesterases and, 210
autonomic, 215-235
chemical theory, 200
electrical theory, 200
in coelenterates, 252
in crustacean muscle, 243
in insects, 245
mechanism of, 211
skeletal, 1 99-2 1 2
substance affecting, 199
temperature and, 2 1 1
Neuron
see also Pyramidal neurons; Sensory
neurons; Motoneurons and parts of
the neuron
action in evoked potential, 303
after-discharge of, 305-308
autorhythmicity, 308
differences in excitability, 1 7 1
epileptic state in, 342
excitation of, 273-276
excitatory, 71
impulse initiation in, 304
inhibitory, 71
internal structure, 60
interneuron single unit activity, 272,
273
invertebrate, 239-253
mechanisms and behavior, 758
membrane of, 61-65
model for initiation of impulses, 274
morphology, 59-61, 257
postactivity excitability of, 308-3 1 1
single unit activity of, 261-276, 305
soma
potentials from, 273
Neurons, axon : see Axon ; Nerve fibers
Neuron, dendrites : see Dendrites
Neuron theory : see Historical develop-
ments, concepts
Neuron physiology, 59-254
Neiu'onal surface membrane
electrical diagram, 62
function of, 59
physiological properties, 61
potential across, 62
resting potential, 62
structure, 60
transport across, 60
INDEX
773
Neurotransmitters: see Transmitter sub-
stances
Nicotinamide
visual excitation and, 691
Night blindness
opsins and, 688
vitamin A and, 688
Night myopia : see Myopia
Nodal membrane: see Nodes of Ranvier,
membrane
Nodes of Ranvier
membrane
threshold stimulation and, 96
role in conduction, 109
threshold at, 87
Non-photic receptors
in invertebrates, 369
Nonpolarizing competitive inhibitors: see
Synaptic inactivators
Noradrenaline: see Norepinephrine
Norepinephrine
see also Adrenergic transmitter; Epi-
nephrine ; Isopropylnorepinephrine ;
Dopamine; Transmitter substances;
Catechol amines
acetylcholine and, 210
as transmitter substance, 218
characterization, 1 78
content in autonomic nerves, 220
differentiation from epinephrine, 218
other adrenergic transmitters and, 228
release, 222
storage, 221
Nystagmus
characteristics of, 558
reticular formation and, 559
vestibular mechanism and, 558
Occipital cortex : see Visual cortex
Occlusion
of evoked potential
as distinct from inhibition, 310
definition, 310
Ocelli
classification, 630
definition, 628
insect
retina in, 631
Ocular muscles
action of vestibular mechanism on, 559
Odor measurement
methods, 539
Odorous substances
characteristics of, 538
chemical elements and, 538
Olfaction, 535-548
behavior and, 547
eflferent control of receptors for, 745
enzyme theories, 539
olfactory mucosa and, 535
radiation theories, 539
receptors for, 535
species specialization in, 374, 376
stimulus intensity and response, 536
Olfactory bulb
anesthesia and, 541, 542
awakening reaction of, 54 1
central connections, 543
central control, 745
efferent pathways, 543
electrical activity in, 540
evoked potentials from, 545
inhibitory efferent fibers, 745
olfactory mucosa and, 537
organization of, 537
patterns of activity in, 540
removal of, 544
spatial sumnnation in, 537
spike discharge from, 544
spike potentials from, 545
spontaneous activity, 540
Olfactory cortex, 543-547
electrophysiological investigation, 545
primary aiea, 544
relation to rhinencephalon, 546
Olfactory mechanisms
behavior studies and, 547
Olfactory mucosa
alkaline phosphatase in, 539
arrangement of, 535
connections with olfactory bulb, 537
smell sense, 535
Olfactory receptors
anatomy of, 535
degeneration after olfactory bulb re-
moval, 536
differentiation of response, 542
innervation, 572
Olfactory response, 366
area differentiation, 542
temporal differentiation, 543
Ommantidia: see Eye, compound
Opsin
see also Visual pigments
in visual excitation, 679
night blindness and, 688
reaction with free sulfhydryl, 680
Optic cortex: see Visual cortex
Optic nerve
central control, 745
discharge
retinal-initiated, 714
electrical stimulation, 714
fiber
activity of, 617
spatial summation in, 723
stimulation
cortical areas responding, 725
geniculate response to, 724
temporal summation in, 723
Optic pathway
anatomy of, 716
direct and indirect stimulation, 721
interaction of elements in, 723
phenomena in, 716
radiation
cortex and, 723
spatial summation in, 723
temporal summation in, 723
Optics, physiological, 647-691
Organ of Corti
movements, 572
structure, 571
Otoliths
anatomy of, 551
gravity stimulation, 557
stimulation of, 556
Pacemaker
artificial and natural, 1 1 7
definition, 1 16
Pain, 459-502
see also Itching
abnormal anatomical states and, 475
abnormal innersation for skin, 467
adaptation to, 468
alpha rhythm and, 472
arterial constriction and, 463
arterial dilatation and, 463
asymbolia, 496
autonomic nervous system and, 480
burning, 462, 472
central inhibition of, 499
chemical excitants of, 478
corneal stimulus and, 465
cortical ablation and, 493
cortical evoked potentials from, 494
cutaneous
referred pain and, 501
definition, 459
diffuse thalamic projection system and,
497
distention of \'iscera and, 463
double response, 47 1
histological correlates, 473
due to cortical or subcortical lesions,
492
due to mechanical stimulation, 467
due to thermal stimulation, 467
end organs, 465
endocrines and, 498
experimental subjects for, 464
fibers mediating, 468-475
frequency of discharge and, 468
frontal lobectomy and, 497
in second sensory area, 495
indifference, 496
inflammation and, 463
inhibition and, 499
ischemia and, 463
length of discharge and, 468
multiple innervation and, 476
parasympathetic nerves and, 483
774
HANDBOOK OF PHYSIOLOGY
NEUROPH\'S10L00Y I
perception
reticular formation and, 736
pricking, 472
threshold, 462
quantitation, 463
reaction, 496
reaction time to, 473
receptors, 465-467
referred, 499-502
injury to central paths and, 501
summation, 500
reflexes
lesions inhibiting, 464
related to itching, 498
related to tickling, 498
remembered after inesencephalic stim-
ulation, 490
representation in cerebral hemispheres,
493
second response to, 47 1
significance to individual, 460
somatic and visceral receptors, 467
sympathetic nerves and, 480
tissue damage and, 461
Pain, conduction; see Pain fibers, con-
duction
Pain fibers
association with temperature fibers, 484
conduction, 472
diameter and, 469
ischemia and, 469
in anterolateral column, 486
in anterior roots, 479
in cerebral hemispheres, 492
in medulla oblongata, 487
in mesencephalon, 488
in posterior roots, 479
in second sensory area, 495
in spinal cord, 483
in thalamus, 490, 491
insulation and, 477
myelinated and unmyelinated, 485
specificity for pain, 461
Pain threshold
constancy, 462
electrical stimulation, 462
nerve nets and, 476
thermal radiation and, 461
Parasympathetic nervous system
cholinergic transmission in, 230-233
pain and, 483
Parasympathin
see also Cholinergic transmitter
role in cholinergic transmission, 233
Partial epilepsy: see Epilepsies, partial
Pattern recognition: see Vision
Pelecypods
see also Invertebrates
ocelli structure in, 630
Penis
warmth receptors in, 444
Pentylenetetrazol
pharmacological efTects on synapse, 1 75
Pentylenetetrazol seizures
see also Convulsions generalized. Strych-
nine convulsions j Epilepsy; Anoxia,
convulsions
anoxic convulsions and, 340
cortical reactivity, 340
grand mal epilepsy and, 341
strychnine convulsions and, 340
Pericorpuscular synaptic knobs : see Sy-
napse, pericorpuscular knobs
Perilymph
composition, 574
Peripheral receptive fields: see Sensory
systems
Petit mal epilepsy: we Epilepsies, petit
mal
Pfliiger's law of contraction: see Historical
development
Phasic receptors
excitation of, 1 29
summation, 130
Phoria : see Accommodation
Photosensitivity
efficiency of, 622
in ganglia, 624
in multicellular organisms. 624
in unicellular organisms, 623
peripheral, 624
Pia-ventricular potential: see DC. po-
tentials
Picrotoxin
synaptic transmission and, 1 78
Piriform cortex: see Cerebral cortex
Pitch: see Frequency discrimination
Polarization
see also Depolarization; Postsynaptic
potentials
d.c. potentials and, 316, 327
Polarized light : see Arthropods
Postcentral cortex : see First somatic cor-
tical field
Postdischarges : see Epilepsy
Posterior nuclear thalamic group : see
Thalamus, posterior nuclei
Postexcitatory depression
definition, 309
factor affecting, 309
Postsynaptic membrane: see Synapse,
postsynaptic membrane
Postsynaptic potentials, 65-71, 150-190
anatomical considerations, 302
anoxia and, 302
changes in amplitudes, 189
character and nature of transmitter,
166
definition, 149
depolarizing, 1 73
central excitatory state and, 164
hyperpolarization and, 189
properties of, 151
spatial considerations, 182
during depolarizing, 158
electrical stimulation and, 153
excitatory, 65, 152
factors effecting, 167
generation site, 150
genesis of, 1 66
gradation of, 167
hyperpolarizing, 151, 158
central inhibitory state, 164
depolarization and, 189
spatial considerations, 182
hypothermia and, 302
inhibitory, 69, 152
interrelation with spikes, 152, 170
mechanical pressure and, 302
mode of spread, 165
nature, 150
pyramidal neurons and, 303
reversal of, 1 60
species differences in, 171
standing
electrotonic effects, i8g
nonpropagated, 164
transfer to electrically excitable mem-
brane, 168
trauma, 302
types of, 151, 172
Postural reflexes
role of utricle in, 557
vestibular mechanism and, 560
Potassium
conductance, 62, 118
excitation and, 62-65, '''^' ''9
Potassium potential
resting potential and, 168
Potassium theory
evidence against, 118
resting potential and, 1 1 7
Prepotential
definition, 304
Presynaptic impulse
effects on postsynaptic region, 1 63
Presynaptic membrane: see Synapse, pre-
synaptic membrane
Presynaptic potential
anatomical considerations, 302
anoxia and, 302
definition, 149
hypothermia and, 302
latency, 162
mechanical pressure and, 302
trauma and, 302
Primary line of sight
definition, 653
Primary receiving area: see First somatic
cortical field
Proprioceptive: see Kinesthetic
Protopathic system
criticism of, 475
sensory mechanism, 391
INDEX
775
Protoplasm
differential irritability, 369
Pulvinar
sensory sy terns, correlation and, 31 1
Pupil
astigmatism and, 652
axis
definition, 653
cephalopods, 637
chief ray and, 652
entrance and exit, 652
image formation and, 652
Pupillography
stray light in, 667
Pure tone threshold : see Audition
Purkinje images
see also Vision
importance of, 656
Purkinje phenomenon
see also Vision
description, 682
Pyramidal neurons
collateral activity of fibers, 306
postsynaptic impulse in, 303
Receptor cells
electrical responses, 165
functional components, 165
generator potential and, 127
in higher invertebrates, 37 1
in insects, 373
in invertebrates, 375
lines of research, 365
reaction to stimuli, 366
Receptor potential, 130-135
absolute magnitude, 134
definition, 130, 393
depression of, 1 35
duration of stimulus, 134
from different receptors, 131
impulse initiation and, 132
latency and, 1 29
nerve terminals, 1 30
phasic behavior, 131
procaine and, 136
size of the exciting displacement, 133
sodium lack and, 1 36
source of energy, 143
stimulus and, 1 32
summation and, 134
threshold
depression and, 135
tonic behavior, 131
velocity of the displacement and, 133
Receptors, 123-144
see also various types of receptors
adaptation of, 124, 125, 144
central control of, 741-759
definition, 123
discharge frequency of, 126-128
electronmicroscopy of, 141
excitation of, 123, 129, 130
excitation reduction and, 126
initiation of impulse, 142
invertebrate
nonphotic, 369-383
photic, 621-642
junctional, 209
minute structure of, 141, 142
potentials of, 130-135
repetitive firing, 127
role, 123
sensitivity and time factors, 124
sodium lack and, 136, 137
specific sensitivity, 1 24
time course, 129
tonic, 126
transmitter action on, 139-141
Recruitment
repetitive stimulation and, 31 i
Reflexes
see also individual reflexes
synaptic determinants of, 147-194
Refraction, 654-656
coincidence optometer, 659
indices of
measurements, 656
retinoscope and, 659
Refractory period
barbiturates and, 308
ionic hypothesis and, 64
visual cortex, 308
Repetitise firing : see Nerve fibers
current theories, 117
definition, 83
equilibrium potential and, 162
external K concentration and, 1 1 7
potassium potential and, 168
Reticular activating system; see Reticular
formation
Reticular formation
activation, 42 1
anoxic convulsions, 339
ascending sensory paths and, 752
as functional unit, 42 1
as origin of generalized convulsions,
335
ascending sensory paths and, 752
attention and, 367
auditory pathway and, 591
behavior and, 755
bulbar relays and, 745
cerebral afferent systems and, 747-749
control of afferent paths by, 745-747
dorsal column relays and, 745
efferent effects upon retinal activity,
745
efferent pathways and, 757
hearing and, 591
inhibition of spinal relays, 746
medial lemniscal system and, 42 1
pain perception and, 756
rapid phase of nystagmus and, 559
role in tonic and clonic spasms, 340
sensory system, correlation and, 3 1 1
spinal ascending relays and, 745
spinal motor activity and, 561
spinothalamic tract and, 421
stretch receptors and, 743
vestibular stimulation and, 561
Retina, 665-669, 671-710
see also Cones; Rods; Electroretin-
ography; Ocelli
action potentials from, 617
conduction across surface, 696
conjugate focus, 658
damage and ERG, 700
efferent control of, 745
electrical activity of, 696-704, 710
entoptic phenomena, 669
histology of, 693-696
illuminance of, 665, 669
inhibition in, 706
neural activity in, 693-710
on-system and off-system in, 705
receptive fields and adaptation, 705
spike discharge, 704
stimulation
cortical localization and, 726
type and ERG, 698
vitamin A and, 68g
Retinal image, 647-691
see also Image formation
blur, 667
size, definition, 654
Retinene
see also Visual pigments
rhodopsin and, 674
Retinitis pigmentosa
vitamin A and, 691
Rhinencephalon
EEG and electrical stimulation of, 351
epilepsy, partial and, 350
olfactory cortex and, 546
Rhodopsin, 672-676
see also Visual pigments
adaptation and, 686
anagenesis, 673
as visual pigment, 672
bleaching and resynthesis, 686
changes during vision, 672
neogenesis, 673
retinene and, 674
scoptic sensitivity and, 682
synthetic system, 674
vitamin A and, 672, 674
Righting reflex
mechanism of, 560
Rods
see also Retina
electroretinogi'am and, 699
flicker fusion and, 708
histology of, 693
modulators in, 708
sensitivity of, 699
visual pigments in, 671
776
HANDBOOK OF PHYSIOLOGY
NEUROPHYSIOLOGY I
Roller's nucleus
equilibrium and, 558
Rotation
perception of, 554
Ruffini end organs
as warm receptors, 434
Saccule
anatomy of, 551
function, 557
Saltatory conduction: see Conduction,
saltatory
Salty taste
substances giving, 3 1 6
Scheiner principle
accommodation and, 659
Schwalbe's nucleus
equilibrium and, 558
Sceptic adaptation
electroretinogram and, 699
retinal sensiti%ity in, 699
Second sensory area
conscious pain sensation, 495
in man, 494
Second somatic area
relation to spinothalamic system, 418
Seizures, general : see Convulsions, gen-
eralized; Epilepsy
Self-selection studies
see also Behavior, Appetitive behavior.
Conditioned reflex
intragastric osmotic pressure and, 529
taste and, 527
Semicircular canals, 553-556
action of, 553
adequate stimulation to, 553
anatomy of, 550
bidirectional function, 554
endolymph flow in, 553
functions, 549
hydrodynamic theory, 553
inadequate stimulus, 556
stimulation of, 553-556
Sensorimotor cortex
repetitive stimulation and, 42 1
Sensory cortex: see Sensory systems
Sensory nerve fibers
direct stimulation of, 45*2
peripheral, 468
Sensory neurons
inhibition of, 379
scheme for proprioception, 379
Sensory plexuses
cutaneous, 467
subcutaneous, 467
Sensory reaction time: see Sensory systems
Sensory systems, 365-759
see also Receptors; specific systems
central control of, 741-759
correlation, 3 1 1
cortex
periodic excitability change, 309
electrophysiological methods, 389
interaction in, 752
pathways
anesthesia and, 752, 755
as determined by lesions, 420
central control of, 741
peripheral receptive fields
projection upon central neurons, 405
size, 404
receptors, see Receptors
reticular formation and, 421
stimulus intensity
reaction time and, 473
Sensory units
description, 123
patterns of information, 1 25
receptise fields, 125
steady states and, 1 26
Serotonin : see 5-Hydroxytryptamine
Skin
abnormal pain innervation, 467
analgesic spot, 466
as thermopile bolometer, 442
conduction of heat, 437
sensations from, 390-394
sensory plexuses in, 467
temperature gradient in, 453
thermosensitive areas, 43 1
Skin receptors
reaction to stimuli, 366
Skin temperature
change and adaptation, 439
Sky myopia : see Myopia
Smell: see Olfaction
Smooth muscle : see Muscle
Sodium conductance
membrane potential
changes and, 62
Sodium ions
acetylcholine action and, 210
receptor potentials and, 136, 137
relation to excitation, 62-65,93,94, 1 18,
"9
relation to inhibition, 70
Sodium potential
membrane potential and, 168
Sodium theory
action potential and, 118, 119
proof of, 62-65
Solid angle
definition, 665
Somatic afferent systems: see Sensory
systems
•Somesthetic discrimination
postcentral cortex and, 425
Sound stimulation
of labyrinth, 557
Sour taste
electric current and, 523
pH and, 513
Spatial summation
in olfactory bulb, 537
m optic nerve, 723
in optic pathway, 723
synaptic, 66
Spike potentials
antidromic, 67
invertebrate muscle
quarternary ammonium compounds
and, 244
IS spike, 67
SD spike, 67
Spinal cord
see also Dorsal columns
anterolateral column and pain fibers,
486
ascending relays
central control of, 745-747
reticular formation and, 745
association pain and temperature fibers,
484
lesions, pain and, 464
neurons, periodic excitability, 310
pain fibers in, 479, 483-487
Spinothalamic system, 415-419, 484-492
as sensory path, 415
ipsilateral pathways, 419
modaUty organization, 418
origin, 4 1 7
pain paths in, 484-492
posterior nuclear thalamic group and,
418
reticular activating system and, 42 1
second somatic area and, 148
tactile fibers in, 416
termination, 417
topical organization, 418
Spreading depression
conditions for production, 324
cortical maturity and, 324
d.c. changes and, 323-325
species variation, 324
spikes and, 67
Static stimuli: see Equilibrium
Statocysts
invertebrate, 382, 383
Steady potential: see DC. potentials
Stiles-Crawford effect
definition, 666
Stray light
eye and, 648
pupillography in, 667
source for eye, 667
Strength-duration relation
anatomical determinants, 98
Blair's equation for, 97
formula, 98
Stretch receptors
central control of, 743, 744
efferent control of, 743
Striate cortex
see Visual cortex
INDEX
777
Strychnine
EEG and, 348
inhibition of transmission, 71
partial epilepsy and, 348
postexcitatory depression and, 309
synaptic transmission and, 1 75
tetanus, 561
Strychnine convulsions
see also Pentylenetetrazol seizures;
Convulsions, generalized; Epilepsy;
Anoxia, convulsions
cortex, reactivity, 340
electrical discharges during, 339
reticular discharge during, 339
theory of, 344
Subthreshold response
action potential and, 98
area hypothesis, 98
membrane potential and, 98
spatial factor
time course and, 98
theory, 76
Sugars
order of sweetness, 520
Summation: see Spatial summation.
Temporal summation; Pain; Ner\e
impulse
Sweet taste
effect of drugs, 520
molecular structure and, 518
order in sugars, 520
stereoisomerism and, 519
substances giving, 518
Sympathetic nervous system
adrenergic transmission in, 218-229
pain and, 480-483
touch receptors and, 742
Sympathins
see Adrenergic transmitter
Synapses, 147-194
comparative physiology of, 1 71-175
definition, 150
electrically excitable and unexcitable,
192
electrogenesis by, 153-165
electrotonic effects across, 163
excitability, 65
function, 60
inhibitory, 65
strychnine and, 71
tetanus toxin and, 71
integrative activity, 182
membrane
augmented responsiveness, 169
chemical sensitivity, 163
postsynaptic, definition, 60
transducer action, 154, 157, 161
pericorpuscular knobs
postsynaptic discharge and, 303
pharmacological properties, 175-182
postsynaptic membrane
sustained electrogenesis and, 156
postsynaptic potentials, 150-175
presynaptic membrane
function, 60
spatial interrelations, 182
structure of, 61
transmitter specificity, 181
Synaptic activators
characterization, 1 75
mode of action, 163, 180
Synaptic block
barbiturates and, 301
repetitive stimulation and, 301
Synaptic delay
definition, 170
explanation, 170
Synaptic electrogenesis: see Electrogenesis
Synaptic inactivators
characterization, 163
mode of action, 1 80
Synaptic inhibitors
characterization, 175
Synaptic membrane: see .Synapse, mem-
brane
Synaptic transmission, 147-194
see also Ephaptic transmission. Trans-
mission
chemical, 150
compared to conduction, 149
compared to ephaptic, 149
effectiveness of, 183
electric current and, 67
events in, 165
integrative function of, 182-190
Tactile activity
postcentral fields and, 423
Tactile fibers
in spinothalamic system, 416
Tactile stimuli
definition, 388
fibers of different size and, 393
specificity of receptors, 391
Tactile system
see also Touch -pressure system; Cu-
taneous stimuli; Skin receptors
central representation, 395
Talbot
definition of, 665
Talbot effect
description of, 730
Taste, 507-547
adaptation, 524
cross, 525
enhanced sensitivity and, 525
area stimulated, 524
behavior and, 527
buds
anatomical sites, 507
chemical stimuli and, 510
CNS pathways, 509
deficit
ablation or section and, 510
definition, 507
duration of stimulus, 524
effect of mixtures, 526
fibers
pathway to CNS, 509
sensitivity pattern, 51 1
ingestion and, 529
intensity relations, 525
reaction time, 524
receptor anatomy, 507-509
receptor mechanisms, 510
reinforcement of conditioning by, 529
self-selection studies and, 527
sensiti\'ity
drugs and, 510
influence of blood constituents, 529
mechanisms of stimulation, 513
species differences, 51 1
specialization in animals, 376
specificity
drugs and, 520
sites on cell membrane, 512
temperature and, 523
Taste blindness
chemical structure and, 52 1
inheritance, 52 1
Taste threshold
cation series, 51 7
measures of, 513
sodium salts anion series, 517
Temperature
brain excitability and, 308
change
thermal receptors and, 449
gradient
spatial and temporal aspects, 442
nerve fiber activity and, 446
taste sense, 523
Temperature sensibility: see Thermal
sensations
Temporal information : see Audition
Temporal summation
in optic nerve, 723
in optic pathway, 723
Tetanus toxin
inhibition of transmission, 71
Tetraethylammonium chloride
action potential and, 101
Thalamocaudate inhibitory system: see
Thalamus
Thalamic relay nucleus: see Thalamus,
relay nuclei
Thalamus
caudate inhibitory system and, 344
diffuse projection system
pain and, 497
nuclei
auditory cortex and, 598
pain fibers in, 490
petit mal and, 337
posterior nuclei
as part of spinothalamic system, 418
778
HANDBOOK OF PH'lSIOLOOY '
NEUROPHYSIOLOGY I
relay nuclei
pathway to dorsal column n\iclci, 400
patterns in, 399
reticular formation and, 747
tactile area
patterns, 401
thermoreceptive neurons in, 435
Thermal energy
receptor excitation by, 1 24
Thermal fibers, 444-455
see also Cold fibers
association with pain fibers, 484
discharge, 446-453
discharge and temperature, 447, 448
latency to cooling, 452
paradoxical discharge, 452
temperature change and, 449, 450
Thermal receptors, 431-457
acetylcholine and, 455
adaptation, 456
afferent ner\'e paths of, 435
carbon dioxide, 455
cold-blooded animals, 445
depth in skin, 432
excitation mechanism, 456, 457
identification, 434
intracutaneous temperature gradient,
453
invertebrates, 379, 380
ischemia, 442, 443, 453
location of, 431-435
paradoxical responses, 443
specificity of fibers, 444
temperature change and, 449
Thermal sensations, 431-457
central threshold for, 455
cold
non-thermal causes of, 454
paradoxical, 452
Ebbecke phenomenon, 443
hot, 444
temperature change in skin, 438
topography, 43 1 , 432
warmth
paradoxical, 453
Weber's deception, 454
Weber's phenomena, 453
Weber's theory, 437, 443
Thermal thresholds
temperature change and, 440
Threshold membrane potential ; see Mem-
brane potential
Threshold receptor potential: see Re-
ceptor potential
Tickling
as related to pain, 498, 499
Tonal pattern discrimination
auditory cortical ablation and, 597
Tone frequency
response to, by cochlear ncrscs, 604
Tonic labyrinthine reflexes
action of, 560
otoliths and, 560
Tonic neck reflexes
action of, 560
otoliths and, 560
Touch-pressure system, 387-426
see also Cutaneous sensations; Tactile
system; Skin receptors
adaptation in, 403
in deep fascia, 415
medial lemniscal system and, 403
Touch receptors
invertebrate, 380
sympathetic influence, 742
Transducer action
synaptic membranes and, 154, 156, 157,
161
synaptic electrogenesis and, 189
tactile receptors and, 380
Transmission
see also Ephaptic transmission; Synaptic
transmission; Nerve impulse; Con-
duction
nerve conduction and, 62, 65
between neurons, 65
electrical versus chemical, 2 1 7
integrative activity and, 149
neuromuscular, 199-253
autonomic, 215-235
invertebrate, 239-253
skeletal, 199-235
postsynaptic potential and, 149
Transmission, autonomic neuroeffector :
see Transmitter substances; Chemical
transmission
Transmittance, spectral
eye and, 666
Tiansmitter substances
ee also Adrenergic transmitter; Cho-
linergic transmitter
action Ca on, 153
action Mg on, 153
blood content of, 234
characterization, 178
crustacean, 243
desensitization at synapse, 157
excitatory, 7 1
histamine, 141
identification, 178
inhibitory, 71
insect, 247
localized action, 181
mode of action, 166, 180, 233
molluscs, 248
requirements, 1 79
synaptic specificity, 181
urine content of, 234
Triad response
definition, 662
Tympanic membrane
function, 568
Tympanal organs
in invertebrates, 382
Tympanic reflex
characterization, 568
Ultraviolet light
aphakic eye and, 666
eye sensitivity to, 641
Unicellular organisms
photosensitivity in, 623
Utricle
anatomy of, 550
function, 557
Vestibular mechanism, 549-562
see also Equilibrium; Labyrinthectomy
action on ocular muscles, 559
adaptation, 555
anatomy of labyrinth, 550
ascending pathways from, 558-560
caloric stimulation. 556
connections with brain, 558
cortical projection, 559
destruction of, 561, 562
discharge after stimulation, 555
galvanic stimulation, 556
mode of action of, 552
muscle contraction and, 561
nystagmus and, 558
postural reflexes and, 560
receptor cells, 552
reticular formation and, 561
reflexes from, 558-561
sound stimulation of, 557
Vestibular nerve
electrical stimulation of, 559
origin, 552
Vestibular nuclei
connections, 558
fiber paths from, 558
Vestibulospinal tract
anatomy of, 560
Vibration sense
human, 374
insect, 374
invertebrate, 380
Vibrational stimulation
of utricle, 557
Vision, 617-759
see also Brightness vision; Image forma-
tion; Retinal image; Eye; Retina;
Cones; Rods
alternation of response theory, 734
apparent movement, 737
binocular rivalry, 737
brightness contrast and, 737
central mechanisms, 713-739
modes of study, 7 1 4
color vision, 738, 739
cortical facilitation, 733
cortical on-off responses, 730
definition of, 713, 714
flicker, 729-732
INDEX
779
foveal
macula lutea and, 666
geniculate facilitation, 733
implicit time and stimulus area, 728
modes of study, 7 1 4
modulators
as absorption curses, 708
in cones and rods, 708
movement, 738
description of, 715
pattern recognition, 641
primary line of sight, 653
problems of, 715
real movement and, 737
retinal image formation and, 647-691
solid angle and, 665
striate cortex and, 727
sustained potentials
apparent movement and, 738
dendritic activity and, 735
sustained potentials in, 729, 735
triad response, 662
Visual accommodation : see Accommoda-
tion
Visual cortex, 719-725
ablation in monkey, 727
activation of neurons in, 727
dendrite behavior in, 726
latency to spectral stimuli, 739
periodic excitability change, 309
postexcitatory depression and, 309
refractory periods, 308
response to stimuli, 719, 738
retinal stimulation and, 726
subcortical pathways to, 726
Visual excitation
absorption spectra and, 682
chemistry and, 671, 679
enzymes and, 673
nicotinamide and, 691
opsin in, 679
spectral sensitivity and, 682
vitamin A and, 691
Visual fields
definition of, 664
limits, 665
Visual pigments, 671-691
ief also Cyanopsin; lodopsin; Opsin;
Retinene; Rhodopsin
adaptation and, 684
alcohol dehydrogenase, 673
chemistry of, 67 1
cones and, 67 1
cyanopsin as, 678
DPN and, 673
in eye, 617
porphyropsin as, 676
rhodopsin and, 672, 678
rods and, 67 i
\isual sensitivity and, 685
Visual purple : see Rhodopsin
Visual system, central, 713-739
bilateral function in, 736
cortical response to stimuli, 719
habituation
experimental production, 754
interaction with auditory impulses, 31 1
receptors
organization of, 705
recruitment in, 311
sensitivity
visual pigment and, 685
spatial summation, 723
spectral stimulation and, 738
stimulus area
and implicit time, 728
temporal summation, 723, 724
Vitamin A
night blindness and, 688
retinal integrity and, 689
retinitis pigmentosa and, 691
rhodopsin and, 672, 674
visual excitation and, 691
visual pigments and, 676
Vitreous humor
index, 656
Volume conductor ; see Ner\"c impulse
Warm fibers
see also Thermal fibers
discharge, 448
discharge and temperature, 448
latency to cooling, 452
temperature change and, 450
Warm threshold: see Thermal thresholds
Warmth sensation : see Thermal sensations
Weber-Fechner law: see Nerve impulse
Weber's deception : see Thermal sensations
Weber's phenomenon: see Thermal sen-
sations
Weber's theory : see Thermal sensations
Wedensky inhibition
definition, 159
explanation, 159
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