COLUMBIA LIBRARIES OFFS1TE HEALTH SCIENCES STANDARD HX64088448 QP34 .H831 1911 A text-book of physi RECAP Hi|;}|{lj!|i|ifwiiili|ii;j;:B Columbia SlntoersttpVMv in tije Citp of Jleto §9orfe COLLEGE OF PHYSICIANS AND SURGEONS Reference Library Given by * J82-^ Digitized by the Internet Archive in 2010 with funding from Columbia University Libraries http://www.archive.org/details/textbookofphysio1911howe A TEXT-BOOK OF PHYSIOLOGY FOR MEDICAL STUDENTS AND PHYSICIANS BY WILLIAM H. HOWELL, Ph.D., M. D., Sc. D., LL.D. PROFESSOR OF PHYSIOLOGY IN THE JOHNS HOPKINS UNIVERSITY, BALTIMORE jpourtb JEDition, Cborougbls IReviseD PHILADELPHIA AND LONDON W. B. SAUNDERS COMPANY 1911 Copyright, 1905, by W. B. Saunders and Company. Reprinted February, 1906, September, 1906, and January, 1907. Revised, reprinted, and recopy- righted August, 1907. Reprinted January, 1908, and October, 1908. Revised, reprinted, and recopyrighted August, 1909. Reprinted January, 1910, and July, 1910. Revised, reprinted, and recopyrighted August, 1911. Copyright, 151 1, by W. 1!. Saunders Company. Registered at Stationers' Hall, London, England. PRINTED IN AMERICA PRESS OF W. E. SAUNDEHo COMPANY PHILADELPHIA PREFACE TO THE FOURTH EDITION. A new edition of a text-book implies that the author has made diligent search through the literature of the subject to find what new facts have been discovered, what new views have been advanced, and what old views have been discarded. Every- one who is familiar with the great output of experimental work in physiology will appreciate the difficulties confronting an author who makes such an effort, and will be inclined, let us hope, to deal leniently with him as regards his sins of omission. Truly, the ever-widening boundaries of physiological literature make it more and more difficult for any one individual to gain a familiar knowledge not only of the highways, but of all the many by-ways, along which enthusiastic workers are following their investiga- tions. One is tempted to conclude that the effort to cover the whole field must be futile, and that some other plan should be devised to furnish the student and general reader with a reliable summary of the knowledge and tendencies of the time. There is, for instance, the possibility that the general text-book may be replaced by a series of small monographs, dealing each with a separate part of the subject — that is to say, a small text-book on circulation by one author, another by a different writer on respiration, and so on. It is quite possible that such a plan might be very successful, but it is perhaps more probable that it would fall to the ground between the errors of excessive detail, on the one hand, and lack of continuity, on the other. At the other extreme the plan of a text-book which shall contain only the bare elements or outlines of physiology, with little discussion and no attention to the trend of contemporary investigation, has been tried and has not proved successful. Such a book spreads before the student an arid array of statements, dry and dogmatic in form, and more or less characterized by the lifelessness and 1 2 PREFACE. the lack of suggestiveness that usually go with a categorical treatment. No doubt text-books of these two and of other types will be written. It is, in fact, desirable that experiments of many kinds shall be made, but at present, so far as the author can judge, the larger amount of usefulness is likely to attach to the general text- book compiled by a single writer. This belief has at least served to encourage the present author in attempting a task which he is conscious cannot be discharged so successfully as to escape all criticism. So far as his duties as a teacher and investigator have permitted, he has made an earnest effort to keep this book in the current of the advancing tide of physiological knowledge. W. H. Howell. August, 1911. PREFACE. In the preparation of this book the author has endeavored to keep in mind two guiding principles: first, the importance of simplicity and lucidity in the presentation of facts and theories; and, second, the need of a judicious limitation of the material selected. In regard to the second point every specialist is aware of the bewildering number of researches that have been and are being published in physiology and the closely related sciences, and the difficulty of justly estimating the value of conflicting results. He who seeks for the truth in any matter under discussion is often- times forced to be satisfied with a suspension of judgment, and the writer who attempts to formulate our present knowledge upon almost any part of the subject is in many instances obliged to present the literature as it exists and let the reader make his own deductions. This latter method is doubtless the most satis- factory and the most suitable for large treatises prepared for the use of the specialist or advanced student, but for beginners it is absolutely necessary to follow a different plan. The amount of material and the discussion of details of controversies must be brought within reasonable limits. The author must assume the responsibility of sifting the evidence and emphasizing those con- clusions that seem to be most justified by experiment and obser- vation. As far as material is concerned, it is evident that the selection of what to give and what to omit is a matter of judg- ment and experience upon the part of the writer, but the present author is convinced that the necessary reduction in material should be made by a process of elimination rather than by con- densation. The latter method is suitable for the specialist with his background of knowledge and experience, but it is entirely unfitted for the elementary student. For the purposes of the latter brief, comprehensive statements are oftentimes misleading, or fail at least to make a clear impression. Those subjects that are presented to him must be given with a certain degree of full- ness if he is expected to obtain a serviceable conception of the facts, and it follows that a treatment of the wide subject of physi- ology is possible, when undertaken with this intention, only by the adoption of a system of selection and elimination. The fundamental facts of physiology, its principles and modes 3 4 PREFACE. of reasoning are not difficult to understand. The obstacle that is most frequently encountered by the student lies in the com- plexity of the subject, — the large number of more or less dis- ' connected facts and theories which must be considered in a dis- cussion of the structure, physics, and chemistry of such an intri- cate organism as the human body. But once a selection has been made of those facts and principles which it is most desirable that the student should know, there is no intrinsic difficulty to prevent them from being stated so clearly that they may be comprehended by anyone who possesses an elementary knowledge of anatomy, physics, and chemistry. It is doubtless the art of presentation that makes a text-book successful or unsuccessful. It must be admitted, however, that certain parts of physiology, at this par- ticular period in its development, offer peculiar difficulties to the writers of text-books. During recent years chemical work in the fields of digestion and nutrition has been very full, and as a result theories hitherto generally accepted have been subjected to crit- icism and alteration, particularly as the important advances in theoretical chemistry and physics have greatly modified the attitude and point t of view of the investigators in physiology. Some former views have been unsettled and much information has been collected which at present it is difficult to formulate and apply to the explanation of the normal processes of the animal body. It would seem that in some of the fundamental problems of metabolism physiological investigation has pushed its experi- mental results to a point at which, for further progress, a deeper knowledge of the chemistry of the body is especially needed. Cer- tainly the amount of work of a chemical character that bears di- rectly or indirectly on the problems of physiology has shown a re- markable increase within the last decade. Amid the conflicting results of this literature it is difficult or impossible to follow always the true trend of development. The best that the text-book can hope to accomplish in such cases is to give as clear a picture as possible of the tendencies of the time. Some critics have contended that only those facts or conclu- sions about which there is no difference of opinion should be pre- sented to medical students. Those who are acquainted with the subject, however, understand that books written from this standpoint contain much that represents the uncertain compromises of past generations, and that the need of revision is felt as fre- quently for such books as for those constructed on more liberal principles. There does not seem to be any sound reason why a text-book for medical students should aim to present only those conclusions that have crystallized out of the controversies of other times, and ignore entirely the live issues of the day which are PREFACE. 5 of so much interest and importance not only to physiology, but to all branches of medicine. With this idea in mind the author has endeavored to make the student realize that physiology is a growing subject, continually widening its knowledge and read- justing its theories. It is important that the student should grasp this conception, because, in the first place, it is true; and, in the second place, it may save him later from disappointment and distrust in science if he recognizes that many of our conclu- sions are not the final truth, but provisional only, representing the best that can be done with the knowledge at our command. To emphasize this fact as well as to add somewhat to the interest of the reader short historical resumes have been introduced from time to time, although the question of space alone, not to men- tion other considerations, has prevented any extensive use of such material. It is a feature, however, that a teacher might develop with profit. Some knowledge of the gradual evolution of our present beliefs is useful in demonstrating the enduring value of experimental work as compared with mere theorizing, and also in engendering a certain appreciation and respect for knowledge that has been gained so slowly by the exertions of successive generations of able investigators. A word may be said regarding the references to literature inserted in the book. It is perfectly obvious that a complete or approximately complete bibliography is neither appropriate nor useful, however agreeable it may be to give every worker full recognition of the results of his labors. But for the sake of those who may for any reason wish to follow any particular subject more in detail some references have been given, and these have been selected usually with the idea of citing those works which themselves contain a more or less extensive discussion and litera- ture. Occasionally also references have been made to works of; historical importance or to separate papers that contain the experi- mental evidence for some special view. TABLE OF CONTENTS. SECTION I. THE PHYSIOLOGY OF MUSCLE AND NERVE. PAGE Chapter I. — The Phenomenon op Contraction 17 The Histological Structure of the Muscle Fiber, 18. — Its Appearance by Polarized Light, 19. — The Extensibility and Elasticity of Muscular Tissue, 20. — The Inde- pendent Irritability of Muscle, 22. — Definition and Enumeration of Artificial Stim- uli, 24. — The Duration of the Simple Muscle Contraction, 25. — The Curve of a Simple Muscle Contraction, 26. — The Latent Period, 27. — The Phases of Short- ening and Relaxation, 27. — Isotonic and Isometric Contractions, 27.— Maximal and Submaximal Contractions, 2S. — Effect of Temperature upon the Simple Con- traction, 29. — Effect of Veratrin on the Simple Contraction, 31. — Contracture, 32. — Fatigue, the Treppe, and Effect of Rapidly Repeated Stimulation, 34. — -The Wave of Contraction and Means of Measuring, 35. — Idiomuscular Contractions, 36.— The Energy Liberated during a Muscular Contraction, 36. — The Propor- tional Amount of this Energy Utilized in Work, 37. — The Curve of Work and the Absolute Power of a Muscle, 38. — Definition of Tetanus or Compound Con- traction, 41. — The Summation of Contractions, 42. — Discontinuity of the Proc- esses of Contraction in Tetanus, 43. — The Muscle-tone, 43. — The Rate of Stimu- lation Necessary for Complete Tetanus, 44. — The Tetanic Nature of Voluntary Contractions, 45. — The Ergograph, 47. — Results of Ergographic Experiments, 49. — Sense of Fatigue, 50. — Muscle Tonus, 50. — Rigor Mortis and Rigor Ca- loris, 52. — The Occurrence and Structure of Plain Muscle Tissue, 55. — Distinctive Properties of Plain Muscle, 55. — The General Properties of Cardiac Muscular Tissue, 57. — The Contractility of Cilia and Their General Properties, 57. Chapter II. — The Chemical Composition of Muscle and the Chem- ical Changes of Contraction and of Rigor Mortis 60 The Composition of Muscle Plasma, 60. — The Proteins of Muscle, 61. — The Carbohydrates of Muscle, 62. — Phosphocarnic Acid, 63. — Lactic Acid in Muscle, 63. — The Nitrogenous Extractives of Muscle, 64. — Pigments of Muscle, 64.— Enzymes of Muscle, 64. — Inorganic Constituents of Muscle, 65. — The Chemi- cal Changes in Muscle during Contraction, 65. — The Chemical Changes during Rigor Mortis, 69. — The Relation of the Waste Products to Fatigue, the Chemical Theory of Fatigue, 69. — Theories of the Mechanism of the Contraction of Muscle, 71. Chapter III. — The Phenomenon of Conduction. Properties of the Nerve Fiber 76 General Statement Regarding Property of Conductivity, 76. — Structure of the Nerve Fiber, 76. — Function of the Myelin Sheath, 77. — Chemistry of the Nerve Fiber, 78. — The Nerve Trunk an Anatomical Unit Only, 80. — Definition of Afferent and Efferent Nerve Fibers, 80. — Classification of Nerve Fibers, 81. — The Bell-Magendie Law of the Composition of the Anterior and the Posterior Roots of the Spinal Nerves, 82. — Cells of Origin of the Anterior and Posterior Root Fibres, 84. — Origin of the Afferent and Efferent Fibers in the Cranial Nerves, 84. — Independent Irritability of Nerve Fibers, Artificial Nerve Stimuli, 85. — Du Bois-Reymond's Law of Stimulation by the Galvanic Current, S7. — Electro- tonus, 88. — Pfliiger's Law of Stimulation, 89. — The Opening and the Closing Tetanus, 91. — Mode of Stimulating Nerves in Man, 91. — Motor Points of Muscles, 92. — Physical and Physiological Poles, 94. Chapter IV. — The Electrical Phenomena Shown by Nerve and Muscle 96 The Demarcation Current, 96. — Construction of the Galvanometer, 98. — Con- struction of the Capillary Electrometer, 101. — Non-polarizable Electrodes, 101. — Action Current or Negative Variation, 103. — Monophasic and Diphasic Action Currents, 104.— The Rheoscopic Frog Preparation, 106. — Relation of Action Current to the Contraction Wave and Nerve Impulse, 107. — The Elec- trotonic Currents, 108. — The Core-model, 109 » TABLE OF CONTENTS. PAGE Chapter V. — The Nature of the Nerve Impulse and the Nutri- tive Relations of Nerve Fiber and Nerve Cell Ill Historical, 111. — Velocity of the Nerve Impulse, 112. — Relation of the Nerve Impulse to the Wave of Negativity, 114. — Direction of Conduction in the Nerve, 115. — Effect of Various Influences on the Nerve Impulse, 117. — The Fatigue of Nerve Fibers, 118. — The Metabolism of the Nerve Fiber during Functional Activity, 120. — Theories of the Nerve Impulse, 121. — Qualitative Differences in Nerve Impulses, 124. — Doctrine of Specific Nerve Energies, 124. — Nutritive Relations of Nerve Fibers and Nerve Cells, 125. — Nerve Degeneration and Regeneration, 126. — Degenerative Changes in the Central End of the Neuron, 128. SECTION II. THE PHYSIOLOGY OF THE CENTRAL NERVOUS SYSTEM. Chapter VI. — Structure and General Properties of the Nerve Cell 130 The Neuron Doctrine, 130. — The Varieties of Neurons, 132. — Internal Structure of the Nerve Cell, 135. — General Physiology of the Nerve Cell, 136. — Sum- mation of Stimuli in Nerve Cells, 139. — Response of the Nerve Cell to Varying Rates of Stimulation, 140. — The Refractory Period of the Nerve Cell, 140. Chapter VII. — Reflex Actions 142 Definition and Historical, 142. — The Reflex Arc, 142. — The Reflex Frog, 144.— Spinal Reflex Movements, 144. — Theory of Co-ordinated Reflexes, 146. — Spinal Reflexes in Mammals, 147. — Dependence of Co-ordinated Reflexes upon the Excitation of the Sensory Endings, 147. — Reflex Time, 148. — Inhibition of Reflexes, 149. — Influence of the Condition of the Cord on its Reflex Activities, 151. — Reflexes from Other Parts of the Nervous System, 151. — Reflexes Through Peripheral Ganglia, Axon Reflexes, 152. — The Tonic Activity of the Spinal Cord, 154. — Effects of the Removal of the Spinal Cord, 155. — Knee-jerk, 156. — Reinforcement of the Knee-jerk, 156. — Is the Knee-jerk a Reflex Act? 158. — Conditions Influencing the Extent of the Knee-jerk, 160. — The Knee-jerk and Spinal Reflexes as Diagnostic Signs, 161. — Other Spinal Reflexes, 161. Chapter VIII. — The Spinal Cord as a Path of Conduction 163 Arrangement and Classification of the Nerve Cells in the Cord, 163. — General Relations of the Gray and White Matter in the Cord, 165. — The Methods of Determining the Tracts of the Cord, 165. — General Classification of the Tracts of the Cord, 166. — The Names and Locations of the Long Tracts, 168. — The Termination in the Cord of the Fibers of the Posterior Root, 169. — Ascend- ing or Afferent Paths in the Posterior Funiculi, 170. — Ascending or Afferent Paths in the Lateral Funiculi, 173. — The Spinal Paths for the Cutaneous Senses (Touch, Pain, Temperature), 175. — The Homolateral or Contralateral Con- duction of the Cutaneous Impulses, 177. — The Descending or Efferent Paths in the Anterolateral Columns (Pyramidal System), 179. — Less Well-known Tracts in the Cord, 181. Chapter IX. — The General Physiology of the Cerebrum and Its Motor Functions 183 The Histology of the Cortex, 184. — The Classification of the Systems of Fibers in the Cerebrum (Projection, Association, and Commissural), 185. — Physio- logical Deductions from the Histology of the Cortex, 187.- — Extirpation of the Cerebrum, 189. — Localization of Functions in the Cerebrum, Historical, 191. — The Motor Areas of the Cortex, 194. — Differences in Paralysis from Injury to the Spinal Neuron and the Pyramidal Neuron, 196. — Voluntary Motor Paths Other than the Pyramidal Tract, 197. — The Crossed Control of the Muscles and Bilateral Motor Representation in the Cortex, 197. — Are the Motor Areas Exclusively Motor? 198. Chapter X. — The Sense Areas and the Association Areas in the Cortex 200 The Body-sense Area, 201. — The Course of the Lemniscus, 203. — The Center for Vision, 205. — Histological Evidence of the Course of the Optic Fibers, 205. — The Decussation in the Chiasma, 207. — The Projection of the Retina on the Occipital Cortex, 208. — The Function of the Lower Visual Centers, 210. — The Auditory Center, 210. — Course of the Cochlear Nerve, 211. — The Physiological Significance of the Lower Auditory Centers, 212. — Motor Responses from the Auditory Cortex, 214.— The Olfactory Center, 214. — The Olfactory Bulb and its Connections, 215. — The Cortical Center for Smell, 216. — The Cortical Center for Taste, 216. — Aphasia, 217. — Sensory Aphasia, 219. — The Association Areas, 221. — Subdivision of the Association Areas, 223. — The Development of the Cortical Areas, 224. — Histological Differentiation in Cortical Structure, 227. — Physiology of the Corpus Callosum, 228. — Physiology of the Corpora Striata and Thalami, 229. TABLE OF CONTENTS. 9 PAGE Chapter XI. — The Functions of the Cerebellum, the Pons, and the Medulla 231 Anatomical Structure and Relations of the Cerebellum, 231. — General State- ment of Theories Regarding the Cerebellum, 235. — Experiments upon Ablation of the Cerebellum, 236. — Interpretation of the Experimental and Clinical Re- sults, 237. — Conclusions as to the General Functions of the Cerebellum, 239. — The Psychical Functions of the Cerebellum, 241. — Localization of Function in the Cerebellum, 241. — The Functions of the Medulla Oblongata, 242. — The Nuclei of Origin and the Functions of the Cranial Nerves, 243. Chapter XII. — The Sympathetic or Autonomic Nervous System . . . 248 General Statements, 248. — Autonomic Nervous System, 249. — The Use of the Nicotin Method, 250. — General Course of the Autonomic Fibers Arising from the Cord, 250. — -General Course of the Fibers Arising from the Brain, 251. — General Course of the Fibers Arising from the Sacral Cord, 253. — Normal Mode of Stimulation of Autonomic Iserve Fibers, 253. Chapter XIII. — The Physiology of Sleep 255 General Statements, 255. — Physiological Relations during Sleep, 255. — The Intensity of Sleep, 256. — Changes in the Circulation during Sleep, 258. — Effect of Sensory Stimulation, 261. — Theories of Sleep, 262. — Hypnotic Sleep, 265. SECTION ILL THE SPECIAL SENSES. Chapter XIV. — Classification of the Senses and General State- ments 266 Classification of the Senses, 266. — The Doctrine of Specific Nerve Energies, 268. — The Weber-Fechner Psychophysical Law, 270. Chapter XV. — Cutaneous and Internal Sensations 273 General Classification, 273. — Protopathic, Epicritic, and Deep Sensibility, 273. — The Punctiform Distribution of the Cutaneous Senses, 275. — Specific Nerve Ener- gies of the Cutaneous Nerves, 276. — The Temperature Senses, 277 .— The Sense of Pressure, 278. — The Threshold Stimulus and the Localizing Power, 279. — The Pain Sense, 281. — Localization or Projection of Pain Sensations, 281. — Reflected or Misreferred Pains, 282. — Muscular or Deep Sensibility, 282. — The Quality of the Muscular Sensibility, 284. — Sensations of Hunger and Thirst, 285. — The Sense of Thirst, 287. Chapter XVI. — Sensations of Taste and Smell 288 The Nerves of Taste, 288. — The End-organ of the Taste Fibers, 290. — Classi- fication of Taste Sensations, 290. — Distribution and Specific Energy of the Fundamental Taste Sensations, 291.— Method of Sapid Stimulation, 292. — The Threshold Stimulus for Taste, 293. — The Olfactory Organ, 293.— The Mech- anism of Smelling, 294. — Nature of the Olfactory Stimulus, 295. — The Qualities of the Olfactory Sensations, 295. — Fatigue of the Olfactory Apparatus, 297. Delicacy of the Olfactory Sense, 297. — Conflict of Olfactory Sensations, 299. — Olfactory Associations, 299. Chapter XVII. — The Eye as an Optical Instrument. Dioptrics of the Eye 300 Formation of an Image by a Biconvex Lens, 300. — Formation of an Image in the Eye, 303. — The Inversion of the Image on the Retina, 305. — The Size of the Retinal Image, 306. — Accommodation of the Eye, 307. — Limit of the Power of Accommodation and Near Point of Distinct Vision, 310. — Far Point of Dis- tinct Vision, 311. — The Refractive Power of the Surfaces in the Eye, 311. — Optical Defects of the Normal Eye, 312. — Spherical Aberration, 313. — Abnor- malities in the Refraction of the Eye, Myopia, 314. — Hypermetropia, 314. — Pres- byopia, 315. — Astigmatism, 316. — Innervation and Control of the Ciliary Muscle and the Muscles of the Iris, 318. — The Accommodation Reflex and the Light Reflex, 320. — Action of Drugs upon the Iris, 322. — The Antagonism of the Sphincter and Dilator Muscles of the Iris, 323. — Intraocular Pressure, 324. — The Ophthal- moscope, 325. — Retinoscope, 327.— Ophthalmometer, 328. Chapter XVIII. — The Properties of the Retina. Visual Stimuli and Visual Sensations 330 The Portion of the Retina Stimulated by Light, 330.— The Action Current Caused by Stimulation of the Retina, 331. — The Visual Purple, Rhodopsin, 332.— Extent of the Visual Field, Perimetry, 334. — Central and Peripheral 10 TABLE OF CONTENTS. PAGE Fields of Vision, 335. — Visual Acuity, 337. — Relation Between Stimulus and Sensation, Threshold Stimulus, 339. — The Light Adapted and the Dark Adapted Eye, 340. — Luminosity or Brightness, 341. — Qualities of Visual Sensations, 341. — The Achromatic Series, 343. — The Chromatic Series, 344. — Color Saturation and Color Fusion, 344. — The Fundamental Colors, 345. — The Complementary Colors, 345. — After Images, Positive and Negative, 346. — Color Contrasts, 347. — Color Blindness, 348. — Dichromatic Vision, 349. — Tests for Color Blindness, 350. — Achromatic Vision, 351. — Distribution of Color Sense in the Retina, 351.— Functions of the Rods and Cones, 352. — Theories of Color Vision, 354. — Entoptic Phenomena, 360. — Shadows of Corpuscles and Blood-vessels, 360. — Shadows from Lens and Vitreous Humor, 361. Chapter XIX. — Binocular Vision 362 Movements of the Eyeballs, 362. — Co-ordination of the Eye Muscles, Muscular Insufficiency and Strabismus, 364. — The Binocular Field of Vision, 365. — Corres- ponding or Identical Points, 365. — Physiological Diplopia, 367. — The Horopter, 368. — Suppression of Visual Images, 368. — Struggle of the Visual Fields, 369. — Judgments of Solidity, 369. — Monocular Perspective, 370. — Binocular Perspect- ive, 371. — Stereoscopic Vision, 372. — Explanation of Binocular Perspective, 374. — judgments of Distance and Size, 374. — Optical Deceptions, 375. Chapter XX. — The Ear as an Organ for Sound Sensations 378 The Pinna or Auricle, 379. — The Tvmpanic Membrane, 379. — The Ear Bones, 380. — Mode of Action of the Ear Bones, 381. — Muscles of the Middle Ear, 383.— The Eustachian Tube, 384.— Projection of the Auditory Sensations, 384. — Sensory Epithelium of the Cochlea, 385. — Nature and Action of the Sound Waves, 386. — Classification and Properties of Musical Sounds, 387. — Upper Harmonics or Overtones, 389. — Sympathetic Vibrations and Resonance, 391. — Functions of the Cochlea, 391. — Sensations of Harmony and Discord, 395. — Limits of Hearing, 395. Chapter XXI. — Functions of the Semicircular Canals and the Vestibule 397 Position and Structure of the Semicircular Canals, 397. — Flouren's Experi- ments upon the Semicircular Canals, 398. — Temporary and Permanent Effects of the Operations, 399. — Effect of Direct Stimulation of the Canals, 409.— Effect of Section of the Ampullary or the Acoustic Nerve, 401. — Is the Effect of Section of the Canals due to Stimulation? 401. — Theories of the Functions of the Semicircular Canals, 401. — Summary of the Views upon the Function of the Semicircular Canals, 404. — Functions of the L'triculus and Sacculus, 405. SECTION IV. BLOOD AND LYMPH. Chapter XXII. — General Properties of Blood. Physiology of the Corpuscles 408 Histological Structure of Blood, 408. — Reaction of the Blood, 409. — Specific Gravity of the Blood, 411. — The Red Corpuscles, 412. — Condition of the Hemo- globin in the Corpuscles, 412. — Hemolysis, 413. — Hemolysis Due to Variations in Osmotic Pressure, 414.— Hemolysis Due to Action of Hemolysins, 415. — Nature and Amount of Hemoglobin, 418. — Compounds of Hemoglobin with Oxygen and Other Gases, 420. — The Iron in the Hemoglobin, 421. — Crystals of Hemoglobin, 422. — Absorption of Spectra Hemoglobin and Oxyhemoglobin, 423. — Derivative Compounds of Hemoglobin, 427. — Origin and Fate of the Red Cor- puscles, 429. — Variations in the Number of Red Corpuscles, 431. — Physiology of the Blood Leucocytes, 433. — Variations in Number of the Leucocytes, 435. — Functions of the Leucocytes, 435. — Physiology of the Blood Plates, 436. Chapter XXIII.— Chemical Composition of the Blood Plasma; Coagulation; Quantity of Blood; Regeneration after Hemorrhage 439 Composition of the Plasma and Corpuscles, 439. — Proteins of the Blood Plasma, 441. — Serum Albumin, 441. — Paraglobulin (Serum Globulin), 442. — Fibrino- gen, 443. — Less Well-known Proteins of the Blood, 445. — Coagulation of Blood, 445. — Time of Clotting, 446. — Preparation of Solutions of Fibrinogen, 447. — Preparation of Thrombin, 448. — The Action of Thrombin on Fibrinogen, 449. — The Influence of Calcium, 450. — The Influence of Tissue-extracts, 450. — Theory of Coagulation, 451. — Why Blood Does Not Clot Within the Vessels, 453. — Metathrombin, 454. — Intravascular Clotting, 454. — Means of Hastening or of Retarding Coagulation, 455. — Total Quantity of Blood in the Body, 458. — Regeneration of the Blood after Hemorrhage, 459. — Blood Transfusion, 460. TABLE OF CONTENTS. 11 PAGE Chapter XXIV. — Composition and Formation of Lymph 462 General Statements, 462. — Formation of Lymph, 463. — Lymphagogues of the First Class, 465. — Lymphagogues of the Second Class, 466.— Summary of the Factors Controlling the Flow of Lymph, 468. SECTION V. PHYSIOLOGY OF THE ORGANS OF CIRCULATION OF THE BLOOD AND LYMPH. Chapter XXV. — The Velocity and Pressure of the Blood Flow . . 471 The Circulation as Seen Under the Microscope, 471. — The Velocity of the Blood Flow, 472. — Mean Velocity in the Arteries, Veins, and Capillaries, 475. — Cause of the Variations in Velocity, 477. — Variations of Velocity with the Heart Beat or Changes in the Blood-vessels, 477. — Time Necessary for a Complete Cir- culation of the Blood, 478. — The Pressure Relations in the Vascular System, 479. — Methods of Recording Blood-pressure, 479. — Systolic, Diastolic, and Mean Arterial Pressure, 483. — Method of Measuring Systolic and Diastolic Pressure in Animals, 485. — Data as to the Mean Pressure in Arteries, Veins, and Capillaries, 486. — Methods of Determining Blood-pressure in the Large Arteries of Man, 490. — Normal Arterial Pressure in Man and its Variations, 496. — The Method of Determining Venous Pressures and Capillary Pressures in Man, 497. Chapter XXVI. — The Physical Factors Concerned in the Produc- tion of Blood-pressure and Blood-velocity 501 Side Pressure and Velocity Pressure, 501. — The Factors Concerned in Producing Normal Pressure and Velocity, 504. — General Conditions Influencing Blood- pressure and Blood-velocity, 505. — The Hydrostatic Effect, 506. — Accessory Factors Aiding the Circulation, 508. — The Conditions of Pressure and Velocity in the Pulmonary Circulation, 509. — Variations of Pressure in the Pulmonary Circuit, 510. Chapter XXVII.— The Pulse 512 General Statement, 512. — Velocity of the Pulse Wave, 513. — Form of the Pulse Wave, Sphygmography, 515. — Explanation of the Catacrotic Waves, 517. — Anacrotic Waves, 518. — The Kinds of Pulse in Health and Disease, 519. — Venous Pulse, 520. Chapter XXVIII.— The Heart Beat 525 General Statement, 525. — Musculature of the Auricles and Ventricles, 525. — The Auriculoventricular Bundle, 528. — Contraction Wave of the Heart, 531. — The Electrical Variation, 533. — Change of Form during Systole, 535. — The Apex Beat, 536. — Cardiogram, 537. — Intraventricular Pressure during Sys- tole, 538. — The Volume Curve and the Ventricular Output, 540. — The Heart Sounds, 543. — The Third Heart Sound, 545. — Events Occurring during a Cardiac Cycle, 546. — Time Relations of Systole and Diastole, 547. — Normal Capacity of Ventricle and Work Done by the Heart, 547. — Coronary Circulation during the Heart Beat, 549. — Suction-pump Action of the Heart, 551. — Occlusion of the Coronary Vessels, 553. — Fibrillar Contractions of Heart Muscle, 553. Chapter XXIX. — The Cause and the Sequence of the Heart Beat. Properties of the Heart Muscle 555 General Statement, 555. — The Neurogenic Theory of the Heart Beat, 557.— Myogenic Theory, 558. — Automaticity of the Heart, 560. — Action of Calcium, Potassium, and Sodium Ions on the Heart, 561. — Connection of Inorganic Salts with the Causation of the Beat, 563. — Maximal Contractions of the Heart, 564. — Refractorv Period of the Heart Beat, 564. — The Compensatory Pulse. 566. — Normal Sequence of the Heart Beat, 567. — Tonicity of the Heart Muscle, 570. Chapter XXX. — The Cardiac Nerves and Their Physiological Action 573 Course of the Cardiac Nerves, 573. — Action of the Inhibitory Fibers, 573— Analysis of the Inhibitory Action, 575. — Effect of Vagus on the Auricle and the Ventricle, 577. — Escape from Inhibition, 577. — Reflex Inhibition of the Heart Beat, the Cardio-inhibitory Center, 578. — The Tonic Activity of the Cardio-inhibitorv Center, 579. — The Action of Drugs on the Inhibitory Appara- tus, 581. — The 'Nature of Inhibition, 581. — Course of the Accelerator Fibers, 583. — Action of the Accelerator Fibers, 585. — Tonicity of the Accelerators and Reflex Acceleration, 585.— The Accelerator Center, 587. 12 TABLE OF CONTENTS. PAGE Chapter XXXI. — The Rate of the Heart Beat and Its Variations under Normal Conditions 588 Variations in Rate with Sex, Size, and Age, 588. — Variations through the Extrinsic Cardiac Nerves, 589. — Variations with Blood-pressure, 589. — With Muscular Exercise, 590. — With the Gases of the Blood, 591. — With Temperature of the Blood, 591. Chapter XXXII. — The Vasomotor Nerves and Their Physiological Activity 594 Historical, 594. — Methods Used to Determine Vasomotor Action, 595. — The Plethysmograph, 596. — General Distribution and Course of the Vasoconstrictor Nerve Fibers, 598. — Tonic Activity of the Vasoconstrictors, 601. — The Vaso- constrictor Center, 601. — Vasoconstrictor Reflexes, Pressor and Depressor Fibers, 603. — Depressor Nerve of the Heart, 606. — Vasoconstrictor Centers in the Spinal Cord, 607. — Rhythmical Activity of the Vasoconstrictor Center, 607.— -Course and Distribution of the Dilator Fibers, 608. — General Properties of Vasodilator Fibers, 609. — Vasodilator Center and Reflexes, 609. — Vasodila- tation Due to Antidromic Impulses, 611. — Regulation of the Blood-supply by Chemical and Mechanical Stimuli, 612. Chapter XXXIII. — The Vasomotor Supply of the Different Organs 014 Vasomotors of the Heart, 614. — Vasomotors of the Pulmonary Arteries, 615. — Circulation in the Brain and Its Regulation, 616. — Arterial Supply, 616. — Venous Supply, 617. — The Meningeal Spaces, 618. — Intracranial Pressure, 620. — Effect of Changes in Arterial Pressure upon the Blood-flow through the Brain, 622. — The Regulation of the Brain Circulation, 623. — Vasomotor Nerves of the Head Region, 626. — Of the Trunk and the Limbs, 627. — Of the Abdominal Organs, 627.— Of the Genital Organs, 628.— Of the Skeletal Muscles, 628.— The Vaso- motor Nerves to the Veins, 629. — The Circulation of the Lymph, 630. SECTION VI. PHYSIOLOGY OF RESPIRATION. Chapter XXXIV. — Historical Statement. The Organs of Exter- nal Respiration and the Respiratory Movements 632 Historical. 632. — Anatomy of Organs of Respiration, 636.— Thorax as a Closed Cavity, 636. — Normal Position of the Thorax, 637. — Inspiration by Contraction of the Diaphragm, 638. — Inspiration by Elevation of the Ribs, 639. — The Muscles of Inspiration, 640. — Muscles of Expiration, 640. — Quiet and Forced Respiratory Movements, Eupnea and Dyspnea, 641. — Costal and Abdominal Types of Res- piration, 642. — Accessory Respiratory Movements, 643. — Registration of the Respiratory Movements, 643. — Volumes of Air Respired, Vital Capacity, Tidal Air, Complemental Air, Supplemental Air, Residual Air, Minimal Air, 615. — Size of the Bronchial Tree, 647.— Artificial Respiration, 647. Chapter XXXV. — The Pressure Conditions in the Lungs and Thorax and Their Influence upon the Circulation (>49 The Intrapulmonic Pressure and Its Variations, 649.— Intrathoracic Pressure, 650. — Variations of, with Forced and Unusual Respirations, 651. — Origin of the Negative Pressure in the Thorax, 652. — Pneumothorax, 653. — Aspiratory Action of the Thorax, 653. — Respiratory Waves of Blood-pressure, 654. Chapter XXXVI. — The Chemical and Physical Changes in the Air and the Blood Caused by Respiration 058 The Inspired and Expired Air, 658. — Physical Changes in the Expired Air, 658. ■ — Injurious Action of Expired Air, 659. — Ventilation, 660. — The Gases of the Blood, 662. — The Pressure of Gases, 665. — Absorption of Gases in Liquids, 665. — The Tension of Gases in Solution, 667. — The Condition of Nitrogen in the Blood, 669.— Condition of Oxygen in the Blood, 669. — Condition of Carbon Di- oxid in the Blood, 671. — The Physical Theory of Respiration, 672. — Gaseous Exchanges in the Lungs, 673. — Exchange of Gases in the Tissues, 675. — Secre- tory Activity of Lungs, 675. Chapter XXXVII.— Innervation of the Respiratory Movements. ti77 The Respiratory Center, 677. — Spinal Respiratory Centers, 678. — Automatic Activity of the Respiratory Center, 679. — Reflex Stimulation of the Center, 679. — Afferent Relations of the Vagus to the Center, 681. — The Inspiratory and Inhibitory Fibers of the Vagus, 683. — Respiratory Reflexes from the Larynx, Pharynx, and Nose, 684. — Voluntary Control of the Respiratory Movements, TABLE OF CONTENTS. 13 PAQB 685. — Nature of the Respiratory Center, 685. — Respiratory Centers in the Mid- brain, 687. — Automatic Stimulus to the Respiratory Center, 687. — Cause of the First Respiratory Movements, 690. — Dyspnea, Hyperpnea, and Apnea, 691. — Innervation of the Bronchial Musculature, 694. Chapter XXXVIII. — The Influence of Various Conditions upon the Respiration 695 Effect of Muscular Work on the Respiratory Movements, 695. — Effect of Varia- tions in the Composition of the Air, 696. — High and Low Barometric Pressures, Mountain Sickness, Caisson Disease, 697. — The Respiratory Quotient and Its Variations, 699. — Modified Respiratory Movements, 701. SECTION VII. PHYSIOLOGY OF DIGESTION AND SECRETION. Chapter XXXIX. — Movements of the Alimentary Canal 703 Mastication, 703. — Deglutition, 703. — Nervous Control of Deglutition, 707. — Anatomy of the Stomach, 708. — Musculature of the Stomach, 709. — Move- ments of the Stomach, 710. — Effect of the Nerves on the Movements of the Stomach, 713. — Movements of the Intestines, 714. — Peristaltic and Pendular Movements of the Intestines, 715. — Nervous Control of the Intestinal Move- ments, 718. — Effect of Various Conditions on the Intestinal Movements, 719. — Movements of the Large Intestines, 719. — Defecation, 721. — Vomiting, 724. — Nervous Mechanism of Vomiting, 725. Chapter XL. — General Consideration of the Composition of the Food and the Action of Enzymes 727 Foods and Food-stuffs, 727. — Accessory Articles of Diet, 729. — Enzymes, Historical, 730. — Reversible Reactions, 732. — Specificity of Enzymes, 734. — Definition and Classification of Enzymes, 735. — General Properties of Enzymes, 736. — -Par- tial List of Enzymes, 738. — Chemical Composition of the Enzymes, 739. Chapter XLI. — The Salivary Glands and Their Digestive Action. 740 Anatomy of the Salivary Glands, 740. — Histological Structure, 742. — Com- position of the Secretion, 743. — The Secretory Nerves, 744. — Trophic and Secre- tory Nerve Fibers, 746. — Histological Changes during Activity, 748. — Action of Drugs upon the Secretory Nerves, 750. — Paralytic Secretion, 751. — -Normal Mechanism of Salivary Secretion, 752. — Electrical Changes in Glands, 753. — Digestive Action of Saliva, Ptyalin, 753. — Conditions Influencing the Action of Ptyalin, 754. — Functions of the Saliva, 755. Chapter XLII. — Digestion and Absorption in the Stomach 756 Structure of the Gastric Glands, 756. — Histological Changes during Secretion, 757. — Method of Obtaining the Gastric Secretion and Its Normal Composition, 758. — The Acid of Gastric Juice, 760. — Origin of the HC1, 761. — Secretory Nerves of the Gastric Glands, 762. — Normal Mechanism of the Secretion of the Gastric Juice, 763. — Nature and Properties of Pepsin, 765. — Artificial Gastric Juice, 767. — Pepsin-hydrochloric Digestion, 767. — The Rennin Enzyme, 769. — Digestive Changes in the Stomach, 771. — Absorption in the Stomach, 772. Chapter XLIII. — Digestion and Absorption in the Intestines. . . 775 Structure of the Pancreas, 775. — Composition of the Secretion, 776. — Secre- tory Nerve Fibers to the Pancreas, 776. — The Curve of Secretion, 777. — Nor- mal Mechanism of Pancreatic . Secretion, 778. — Secretin, 779. — Enterokinase, 779. — Digestive Action of Pancreatic Juice, 780. — Significance of Tryptic Diges- tion, 782. — Action of the Diastatic Enzyme (Amylase), 784. — Action of the Lipolytic Enzyme (Lipase, Steapsin), 784. — The Intestinal Secretion (Succus Entericus), 786. — Absorption in the Small Intestine, 787. — Absorption of Car- bohydrates, 789. — Absorption of Fats, 790. — Absorption of Proteins, 791. — Digestion and Absorption in the Large Intestine, 793. — Bacterial Action in the Small Intestine, 794. — Bacterial Action in the Large Intestine, 795. — Physio- logical Importance of Intestinal Putrefaction, 795. — Composition of the Feces, 796. Chapter XLIV. — Physiology of the Liver and Spleen 79S Structure of the Liver, 798. — Composition of Bile, 798. — The Bile Pigments, 800. — The Bile Acids, 801. — Cholesterin, 803. — Lecithin, Fats, and Nucleo- albumins, 803. — Secretion of the Bile, 804. — Ejection of the Bile — Function of the Gall-bladder, 805. — Occlusion of the Bile-ducts, 807. — Physiological Im- portance of Bile, 807. — Occurrence of Glycogen, 808. — Origin of Glycogen, 809. — Function of Glycogen, Glycogenic Theory, 811. — Glycogen in the Muscles and Other Tissue, 813.— Conditions Affecting the Supply of Glycogen, 814. — Formation of Urea in the Liver, 814. — Physiology of the Spleen, 815. 14 TABLE OF CONTENTS. PAGE Chapter XLV. — The Kidney and Skin as Excretory Organs 818 Structure of the Kidney, 818. — The Secretion of Urine, 819. — Function of the Glomerulus, 821. — Function of the Convoluted Tubule, 823. — Action of Diu- retics, 825. — The Blood-flow Through the Kidneys, 826. — The Composition of Urine, 828. — The Nitrogenous Excreta in the Urine, 829. — Origin and Signifi- cance of Urea, 830. — Origin and Significance of the Purin Bodies (Uric Acid, Xanthin, Hvpoxanthin), 833. — Origin and Significance of the Creatinin and Creatin, 836! — Hippuric Acid, 838. — The Conjugated Sulphates and the Sulphur Excretion, 838. — Secretion of the Water and Inorganic Salts, 839. — Micturition, 840. — Contractions of the Bladder, 841. — Nervous Mechanism of Micturition, 843. — Excretory Functions of the Skin, 844. — Composition of Sweat, 845. — Secretory Fibers of Sweat Glands, 846. — Sweat Centers, 848. — Sebaceous Secre- tion, 848. — Excretion of Carbon Dioxid through the Skin, 849. Chapter XLVI. — Secretion of the Ductless Glands — Internal Secretion 850 Internal Secretion of Liver, 851. — Internal Secretion of the Thyroid Tissues, 851. — Extirpation of Thyroids and Parathyroids, 852. — Function of the Para- thyroids, 852. — Function of the Thyroid, 854. — Cyon's View of Function of Thyroid, 856. — Function of Thymus, 856. — Structure and Properties of Adrenal Bodies, 857. — The Chromaphil Tissues, 859. — Function of Adrenal Bodies, 861. — Pituitary Body, 863. — The Pineal Body, 866.— Internal Secretion of Testis and Ovary, 867. — Internal Secretion of Pancreas, 869. — Internal Secretion of Kidney, 871. SECTION VIII. NUTRITION AND HEAT PRODUCTION AND REGULATION. Chapter XLVII. — General Methods. History of the Protein Food 872 General Statement, 872. — Nitrogen Equilibrium, 872. — Carbon Equilibrium and Body Equilibrium, 874. — Balance Experiments, 874. — Respiration Cham- ber, 874. — Effect of Non-protein Food on Nitrogen Equilibrium, S75. — Nutritive History of the Protein Food, 876. — Tissue Protein and Circulating Protein, 876. — Amount of Protein Necessary in Normal Nutrition, 878. — Intermediary Metabol- ism of Proteins and Nucleo-proteinx, 881. — Specific Dynamic Action of Pro- teins, 884. — Nutritive Value of Albuminoids, 885. Chapter XLVIII. — Nutritive History of Carbohydrates and Fats 888 The Carbohydrate Supply of the Body, 888. — Intermediary Metabolism of the Carbohvdrate in the Body, 889. — Regulation of the Sugar Supply of the Body, 890. — Diabetes, 891. — Functions of the Carbohydrate Food, 893. — Nutritive Value of Fats, 894. — Intermediary Metabolism of Fats, 895. — Origin of Body Fat, 897. — Origin of Bodv Fat from Food Fat, 898. — Origin of Body Fat from Carbohvdrates, 898. — Source of Fat in Ordinary Diets, 899. — Cause of the Formation of Fat, Obesity, 899. — General Functions of Fat, 900. Chapter XLIX. — Nutritive Value of the Inorganic Salts and the Accessory Articles of Diet 901 The Inorganic Salts of the Body, 901. — Effect of Ash-free and Ash-poor Diets, 902. — Special Importance of Sodium Chlorid, Calcium, and Iron Salts, 902. — The Condiments, Flavors, and Stimulants, 905. — Physiological Effects of Alcohol, 906. Chapter L. — Effect of Muscular Work and Temperature on Body Metabolism; Heat Energy of Foods; Dietetics 910 The Effect of Muscular Work, 910.— Effect of Sleep, 913.— Effect of Variations in Temperature. 913. — Effect of Starvation, 914. — The Potential Energy of Food, 915.— Dietetics, 919. Chapter LI. — The Production of Heat in the Body; Its Measure- ment and Regulation; Body Temperature; Calorimetry; Physiological Oxidations 924 Historical Account of Theories of Animal Heat, 924. — Body Temperature in Man, 925.— Calorimetry. 927. — Respiration Calorimeter, 932. — Heat Regulation, 932.— Regulation of Heat Loss, 932. — Regulation of Heat Production, 935. — Existence of Heat Centers and Heat Nerves, 936. — Theories of Physiological Oxidations, 938. TABLE OF CONTENTS. 15 SECTION IX. PHYSIOLOGY OF REPRODUCTION. PAGE Chapter LIT — Physiology of the Female Reproductive Organs . . 944 General Statement, 943. — The Graafian Follicle and the Corpus Luteum, 944. — Menstruation and Puberty, 946. — Structural Changes in the Uterus during Menstruation, 947. — The Phenomenon of Heat in Lower Animals, 947. — The Relation of the Ovaries to Menstruation, 948. — Physiological Significance of Menstruation, 950. — Effect of the Menstrual Cycle on Other Functions, 951. — Passage of the Ovum into the Uterus, 952. — Maturation of the Ovum, 953. — Fertilization of the Ovum, 955. — Implantation of the Ovum, 957. — Nutrition of the Ovum — Physiology of the Placenta, 958. — Changes in the Maternal Organism during Pregnancy, 960. — Parturition, 961. — The Mammary Glands, 961. — Con- nection between the Uterus and the Mammary Glands, 962. — Composition of Milk, 964. Chapter LIII. — Physiology of the Male Reproductive Organs. . 966 Sexual Life of Male, 966. — Properties of the Spermatozoa, 966. — Chemistry of the Spermatozoa, 96S. — The Act of Erection, 969. — Reflex Apparatus of Erection and Ejaculation, 9i 1. Chapter LTV. — Heredity; Determination of Sex; Growth and Senescence 962 Definition of Heredity, 972. — Evolution and Epigenesis, 962. — Theory of Mu- tations, 974. — The Mendelian Law, 975. — Determination of Sex, 976. — Growth and Senescence, 979. APPENDIX. I. — Proteins and Their Classification 986 Definition and General Structure of Proteins, 986. — Reactions of Proteins, 9S8. — Classification of Proteins, 990.— The Albumins, 990. — The Globulins, 990.— The Glutelins, 991. — Alcohol-soluble Proteins (Prolamines), 991. — Albuminoids. 991. — Protamins and Histons, 991. — The Conjugated Proteins, 992. — The Derived Proteins, 993. II. — Difusion and Osmosis 993 Diffusion, Dialysis, and Osmosis, 993. — Osmotic Pressure, 993. — Electrolytes, 995. — Gram-molecular Solutions, 995. — Calculation of Osmotic Pressure in Solutions, 995. — Determination of Osmotic Pressure by the Freezing Point, 996. — Application to Physiological Processes, 996. — Osmotic Pressure of Proteins, 997. — Isotonic, Hvpertonic, and Hvpotonic Solutions, 997. — Diffusion or Dialysis of Soluble Constituents, 998. — Diffusion of Proteins, 998. Index 999 A TEXT-BOOK PHYSIOLOGY. SECTION I. THE PHYSIOLOGY OF MUSCLE AND NERVE. CHAPTER I. THE PHENOMENON OF CONTRACTION. The tissues in the mammalian body in which the property of contractility has been developed to a notable extent are the mus- cular and the ciliated epithelial cells. The functional value of the muscles and the cilia to the body as an organism depends, in fact, upon the special development of this property. The muscular tissues of the body fall into three large groups, considered from either a histological or a functional standpoint, — namely, the striated skeletal muscle, the striated cardiac muscle, and the plain muscle. These tissues exhibit certain marked differences in properties which are described farther on. In each group, moreover, there are certain minor differences in structure which are associated with differences in properties; thus, skeletal muscle from different re- gions of the same animal may show variations in rapidity of contraction, and this variation goes hand in hand with an obvious difference in histological structure. Similar, perhaps more marked, differences are observed in the plain muscular tissue of various organs. The muscular tissues from animals belonging to different classes exhibit naturally even wider variations in proper- ties, and these differences in some cases are not associated with visible variations in structure. 2 17 18 THE PHYSIOLOGY OF MUSCLE AND NERVE. The Structure of Skeletal Muscle. — This tissue makes up the essential part of the skeletal muscles by means of which our voluntary movements are effected. Each muscle fiber arises from a single cell and in its fully developed condition may be regarded as a multinuclear giant cell. It is inclosed entirely in a thin, structureless, elastic membrane, the sarcolemma. The material of the fiber is supposed to be semifluid or viscous when in the living condition; it is designated in general as the muscle plasma. There is on record an interesting observation by Kiihne* which seems to demonstrate the fluid nature of the living muscle substance. He hap- pened, on one occasion, to find a frog's muscle fiber containing a nematode worm within the sarcolemma. The animal swam readily from one end of the fiber to the other, pushing aside the cross bands, which fell into place '#f. Fig. 1. — A cross-section of muscle fiber of rabbit. The bundles of fibrils are dark; the intervening small amount of sarcoplasm is represented by the clear spaces. — {Kolliker.) Fig. 2. — Cross-section of two muscle fibers of the fly: Ms, The columns of fibrils; Sp, the sarcoplasm. — (Schieffer- decker.) again after the animal had passed. At one end, where the fiber had been injured, the worm was unable to force its way. The muscle substance at this point was dead and apparently had passed into a solid condition. The fact that the cross bands were displaced only temporarily by the movement and fell back into their normal position would indicate that they may have a more solid structure. Disregarding the nuclei, the muscle plasma consists of two different structures: the fibrils, which are long and thread-like and run the length of the fiber, and the intervening sarcoplasm. The fibrils consist of alternating dim and light discs or segments, which, falling together in the different fibrils, give the cross-striation that is characteristic. In mammalian muscles the fibrils are grouped more or less distinctly into bundles or columns (sarcostyles), between which lies the scanty sarcoplasm. The relative amount of sarcoplasm to fibrillar substance varies greatly in the striped muscles of different animals, as is indicated in the accompanying * Kiihne, " Archiv fur pathologische Anatomic," 26, 222, 1863. THE PHENOMENON OP CONTRACTION. 19 illustrations. The evidence from comparative physiology indi- cates that the fibrils are the contractile element of the fiber, while the sarcoplasm, it may be assumed, possesses a general nutritive function. Among mammals there are certain muscles in which the amount of sarcoplasm within each fiber is relatively large, and this sar- coplasm, having the granular structure common to undifferentiated protoplasm, interferes with the clearness of striation of the fibers. Fibers of this latter sort are usually of a deeper color than those in which the sarcoplasm is less abundant, and the two varieties have been designated as the red (more abundant sarcoplasm) and the pale fibers. Muscles containing chiefly the less clearly striated red fibers, for example, the diaphragm and the heart, are charac- terized physiologically by a slower rate of contraction and by a relatively small suscep- tibility to fatigue. The so-called red and pale fibers may occur in the same muscle. The separate fibrils, like the entire fiber, show two kinds of substance, the alter- nating dim and light bands, and these two materials are obviously different in physical structure as seen by ordinary light. When examined by polarized light, this difference becomes more evident, for the dim substance possesses the property of double refraction. When the muscle fiber is placed between crossed Nicol prisms the dim bands appear bright, while the light bands remain dark, as is shown in Fig. 3. From this standpoint the material of the light bands in the normal fibrils is spoken of as isotropous, and that in the dim bands as anisotropous. The anisotropic material of the dim bands consists of doubly refracting positive uniaxial particles, and Engelmann has shown that such particles may be discovered in all contractile tissues. The inference made by him is that this anisotropic substance is the contractile material in the pro- toplasm, the machinery, so to speak, through which its shorten- ing is accomplished. Engelmann supports this conclusion by the statement that during contraction the size of the dim bands Fig. 3.— To show the appearance of the dim (anisotropic) and light (isotropic) bands at rest and in contraction, as seen by ordinary and by polar- ized light. The figure rep- resents a muscle fibril (beetle) in which the lower portion has been fixed in a condition of contraction. — {Engelmann.) 20 THE PHYSIOLOGY OF MUSCLE AND NERVE. increases at the expense of the material in the light bands.* This theory is indicated in the schema given in Fig. 3. The relative changes in appearance of the anisotropic and isotropic bands during the phase of contraction, which are shown in the figure, may be explained on the assumption that the anisotropic sub- stance absorbs or imbibes water from the isotropic layer. Engel- mann has used such an assumption as the basis for an attractive theory of the shortening of the muscle (p. 71). Unfortunately, the histological changes indicated in Fig. 3 have not been wholly corroborated by later observers. Hiirthlef states that during contraction the anisotropic band may shrink to less than one-half its width, while the isotropic layer shows no change. He finds in this appearance a confirmation of the view that the anisotropic substance constitutes the active contractile material of the muscle, but there is no evidence, he thinks, to support the assumption that the change in the anisotropic layer is due to imbibition of water from the isotropic layer or from any other source. Fig. 4. — n. Curve of extension of a rubber band, to show the equal extensions forequal increments of weight. The band had an initial load of 17 gms., and this was increased by increments of 3 gms. in each of the nine extensions, the final load being 44 gms. The line joining the ends of the ordinates is a straight line. 6, Curve of extension of a frog's muscle (gastrocnemius). The initial load and the increment of weight were the same as with the rubber. The curve shows a decreasing extension forequal increments. The line join- ing the ends of the ordinates is curved. The Extensibility and Elasticity of Muscular Tissue. — Muscular tissue, when acted upon by a weight, extends quite readily, and when the weight is removed, it regains its original form by virtue of its elasticity. In our bodies the muscles stretched from bone to bone are, in fact, in a state of elastic tension. If a muscle is severed by an incision across its belly the ends retract. The * Biedermann, "Electro-physiology," vol i, translated by Welby, and Engelmann, "Archiv fi'ir die gesammte Physiologic," is, 1. tHiirthlc, "Archiv f. d. ges. Physiologic," 126, 1, 1909. THE PHENOMENON OF CONTRACTION. 21 extensibility and elasticity of the muscles add to the effective- ness of the muscular-skeletal machinery. A muscle that is in a state of elastic tension contracts more promptly and more effec- tively for a given stimulus than one which is entirely relaxed. Moreover, in our joints the arrangement of antagonists — flexors and extensors — is such that the contraction of one moves the bone against the pull of the extensible and elastic antagonist. It would seem that the movements of the skeleton "must gain much in smoothness and delicacy by this arrangement. The physical advantages of the extensibility and elasticity of mus- cular tissue are evident not only in the contractions of our volun- tary muscles, but, as we shall see, in a striking way also in the circulation, in which the force of the heart beat is stored and economically distributed by the elastic tension of the distended arteries. The extensibility of muscular tissue has been studied in comparison with the extensibility of dead elastic bodies. With regard to the latter it is known that the strain that the body undergoes is proportional, within the limits of elasticity, to the stress put upon it. If, for instance, weights are attached to a rubber band suspended at one end, the amount of extension of the band will be directly proportional to the weights used. If the extensions are measured the relationship may be represented as shown in Fig. 4, the equal increments in weight being indicated by laying off equal distances on the abscissa, and the resulting extensions by the height of the or- dinates dropped from each point. If the ends of the ordinates are joined, the result is a straight line. When a similar experiment is made with a living muscle it is found that the extension is not proportional to the weight used. The amount of ex- tension is greatest in the beginning and decreases proportionately with new increments of weight. If the results of such an experiment are plotted, as above, representing the equal increments of weight by equal distances along the abscissa and the resulting extensions by ordi- nates dropped from these points, then upon joining the ends of Fig. 5. — Curve given by Marey to show the effect upon the extension of muscle caused by increasing the load regularly to the point of rupture : From o to a the extension of the muscle decreases as the weight increases, giving a curve concave to the abscissa, ox ; at a the limit of elasticity is passed and the muscle lengthens by in- creasing extensions for equal increments; at x rupture (750 gms. for frog's gastrocnemius). 22 THE PHYSIOLOGY OF MUSCLE AND NERVE. the orclinates we obtain a curve concave to the abscissa. At first the muscle shows a relatively large extension, but the effect becomes less and less with each new increment of weight, the curve at the end approaching slowly to a horizontal. If the weight is increased until it is sufficient to overcome the elasticity of the muscle the curve is altered— it becomes convex to the abscissa, or, in other words, the amount of extension increases with increasing increments of weight up to the point of rupture, as shown in the accompanying curve* (Fig. 5). Haycraftf calls attention to the fact that under normal conditions the physio- logical extension of the frog's muscles in the body is equal to that produced by a weight of 10 to 15 gms., and that when the excised muscle is extended by weights below this limit it follows the law of dead elastic bodies, giving equal extensions for equal increments of weight. It is only after passing this limit that the law stated above holds good. It should be added also that the amount of deformation exhibited by a muscle or other living tissue placed under a stress varies with the time that the stress is allowed to act. The muscle is composed of viscous material, and yields slowly to the force acting upon it. In experiments of this kind, therefore, the weights should be allowed to act for equal intervals of time. It has been shown that the extensibility of a muscle is greater in the contracted than in the resting state. The curve of extension described above for skeletal muscle holds also for so-called plain muscle. This latter tissue forms a portion of the walls of the various viscera, the stomach, bladder, uterus, blood-vessels, etc., and the facts shown by the above curve enter frequently into the explanation of the physical phenomena exhibited by the viscera. For instance, it follows from this curve that the force of the heart beat will cause less expansion in an artery already distended by a high blood-pressure than in one in which the blood-pressure is lower. The Irritability and Contractility of Muscle. — Under normal conditions in the body a muscle is made to contract by a stimulus received from the central nervous system through its motor nerve. If the latter is severed the muscle is paralyzed. We owe to Haller, the great physiologist of the eighteenth century, the proof that a muscle thus isolated can still be made to contract by an artificial stimulus — e. g., an electrical shock— applied directly to it. This significant discovery removed from physiology the old and harmful idea of animal spirits, which were supposed to be generated in the central nervous system and to cause the swelling of a muscle during contraction by flowing to it along the connecting nerve. But to remove a muscle from the body and make it contract by an artificial * See Marey, " Du mouvement dans les fonctions de la vie," 1868, p. 284 t Haycraft, "Journal of Physiology," 31, 392, 1904. THE PHENOMENON OF CONTRACTION. 23 stimulus does not prove that the muscle substance itself is capable of being acted upon by the stimulus, since in such an experiment the endings of the nerve in the muscle are still intact, and it may be that the stimulus acts only on them and thus affects the mus- cle indirectly. In a number of ways, however, physiologists have found that the muscle substance can be made to contract by a stimulus applied directly to it, and therefore exhibits what is known as independent irritability. The term irritability, according to modern usage, means that a tissue can be made to exhibit its peculiar form of functional activity when stimulated, — e. g., a muscle cell will contract, a gland cell will secrete, etc., — and inde- pendent irritability in the case under consideration means simply that the muscle gives its reaction of contraction when artificial stimuli are applied directly to its substance. This conception of irritability was first introduced by Francis Glisson (1597-1677), a celebrated English physician.* Subsequent writers frequently used the term as synonymous with contractility and as applicable only to the muscle. But it is now used for all living tissues in the sense here indicated. A simple proof of the independent irritability of a striated muscle is obtained by cutting the motor nerve going to it and ' stimulating the muscle after several days. We know now that in the course of several days the severed nerve fibers degenerate completely down to their terminations in the muscle fibers, and the muscle, thus freed from its nerve fibers by the process of degeneration, can still be made to contract by an artificial stimulus. The classical proof of the independent irri- tability of muscle fibers was given by Claude Bernard, the great French physiologist of the nineteenth century. He made use of the so-called arrow poison of the South American Indians. This substance or mixture of substances is known generally under the name curare; it is prepared from the juices of several plants (strychnos) (Thorpe). The poisonous part of the material is soluble in water, and Bernard showed that when such an extract is injected into the blood or hypodermically it paralyzes the motor nerves at their peripheral end, so that direct stimulation of these nerves is ineffective. Direct stimulation of the muscle substance, on the contrary, causes a contraction, f We are justified, therefore, in saying that skeletal muscle possesses the properties of independ- ent contractility (Haller) and independent irritability (Ber- nard). By the former term we mean that the shortening of the muscle is due to active processes developed in its own tissue, by the latter we mean that the muscular tissue may be made to enter into contraction by artificial stimuli applied directly * See Foster's "History of Physiology," p. 287. f " Lecons sur les effets des substances toxiques et medicamenteuses," 1857, pp. 238 et seq. 24 THE PHYSIOLOGY OF MUSCLE AND NERVE. to its own substance. This latter property cannot be said to hold for ay the tissues. Whether a nerve cell or a glancl cell may be made to enter into its specific form of activity by the direct appli- cation of an artificial stimulus is still an undetermined question. Artificial Stimuli. — If we designate the stimulus that the muscle receives normally from its nerve as its normal stimulus, all other forms of energy which may be used to start its contraction may be grouped under the designation artificial stimuli. Experi- ments have shown that a contraction may be aroused by mechani- Fig. 6. — The induction coil as used for physiological purposes (du Bois-Reymond pattern): .4, The primary coil; B, the secondary coil; P', binding posts to which are at' tached the wires from the battery, they connect with the ends of coil .4 : P", binding posts connecting with ends of coil B, through which the induction current is led off; H, the slide.. with scale, in which coil B is moved to alter its distance from A. cal stimuli, — for instance, by a sharp blow applied to the muscle; by thermal stimuli, — that is, by a sudden change in temperature; by chemical stimuli, — for example, by the action of concentrated solu- tions of salts, and finally by electrical stimuli. In practice, how- ever, only the last form of stimulus is found to be convenient. The Fig. 7. — Schema of induction apparatus. — (Lombard.) b represents the galvanic battery connected by wires to the primary coil, A. On the course of one of these wires is a key (k*) to make and break the current. B shows the principle of the secondary coil, and the connection of its two ends with the nerve of a nerve-muscle preparation. When the battery current is closed or made in A, a brief current of high intensitv is induced in B. This is known as the making or closing shock. When the battery current is broken in A, a second brief induction current is aroused in B. This is known as the breaking or opening shock. mechanical and thermal stimuli cannot be well applied without at the same time injuring the muscle substance, and the same is prob- THE PHENOMENON OF CONTRACTION. 25 ably true of chemical stimuli, which possess the disadvantage, more- over, of not exciting simultaneously the different fibers of which the muscle is composed. Electrical stimuli, on the contrary, are applied easily, are readily controlled as regards their intensity, and affect all the fibers simultaneously, thus giving a co-ordinated contraction of the entire bundle, as is the case with the normal stimulus. For electrical stimulation we may use the galvanic current taken directly from the battery, or the induced or so-called faradic current obtained from an induction coil. Under most conditions the latter is more convenient, since it gives brief shocks, the strength and number of which can be controlled readily. The form in which this instrument is used in experimental work in physiology we owe to du Bois-Reymond; hence it is frequently known as the du Bois-Reymond induction coil. Experimental physiology owes a great deal to this simple and serviceable in- strument. A figure and brief description of the apparatus are appended (Figs. 6 and 7). Simple Contraction of Muscle. — Experiments may be made upon the muscles of various animals, but ordinarily in physiolog- ical laboratories one of the muscles (gastrocnemius) of the hind leg of the frog is employed. If such a muscle is isolated and connected with the terminals from an induction coil it may be stimulated by a single shock or by a series of rapidly repeated shocks. The contraction that results from a single stimulus is designated as a simple contraction. In the frog's muscle it is very brief, lasting for 0.1 second or less; but in this, as in other respects, cross-striated muscular tissue varies in different animals,* as is shown by the accompanying table, which gives a general idea of the range of rapidity of contraction: DURATION OF A SIMPLE MUSCULAR CONTRACTION. Insect 0.003 sec. Rabbit (Marey) 0.070 " Frog 0.100 " Terrapin 1.000 " The series may be continued by the figures obtained from the plain muscle, thus: The involuntary muscle (mammal) 10.00 Foot muscle of slugf (Ariolimax) 20.00 The duration of the simple contraction varies considerably in the muscles of different parts of the same animal. Thus, according to Cash, the hyoglossal muscle in the frog requires 0.205 to 0.3 second, while the gastrocnemius takes 0.12 second; in the tortoise the pectoralis major requires 1.8 seconds, the * Cash, "Archiv f. Anat. u. Physiol.," 1880, suppl. volume, p. 147. f Carlson, "American Journal of Pysiology," 10, 418, 1904. 26 THE PHYSIOLOGY OF MUSCLE AND NERVE. omohyoid only 0.55 second; in the rabbit the soleus (a red muscle) requires 1 second, the gastrocnemius (a pale muscle) 0.25 second. On examining into these differences it may be shown that the variations bear a relation to the special functions of the muscles. Rapidity of contraction and maintenance of contraction are two properties which are capable of being altered by the processes of adaptation, either together or independently, to suit the needs of the organism. The distribution of the pale and red muscles in such an animal as the rabbit bears out this idea. It will be remembered also that these two varieties show a difference in histological structure (p. 19). The Curve of Contraction. — When a contracting muscle is attached to a lever this lever may be made to write upon a smoked surface and thus record the movement, more or less magnified according to the leverage chosen. If the recording surface is sta- tionary the record obtained is a straight line and indicates only the extent of the shortening. If, however, the recording surface is in movement during the contraction the record will be in the form of a curve, which, making use of the system of right-angled co-ordinates. Fig. 8. — Curve of simple muscular contraction. will indicate not only the full extent of the shortening, but also the amount of shortening or subsequent relaxation at any moment during the entire period. To obtain such records from the rapidly contracting frog's muscle it is evident that the recording surface must move with considerable rapidity and with a uniform velocity. A curve of this kind is represented in Fig. 8. C represents the axis of abscissas and gives the factor of time. A vertical ordinate erected at any point on C gives the extent of shortening at that moment. Below the curve of the muscle is the record of the vibrations of a tuning fork giving 100 double vibrations per second; that is, the distance from crest to crest represents an interval of T-j7 of a second. Three principal facts are brought out by an analysis of the curve: I. The latent period. By this is THE PHENOMENON OF CONTRACTION. 27 meant that the muscle does not begin to shorten until a certain time after the stimulus is applied. On the curve the stimulus enters the muscle at S, and the distance between this point and the beginning of the rise of the curve, interpreted in time, is the latent period. II. The phase of shortening, which has a definite course and at its end immediately passes into III., the phase of relaxation. The Latent Period. — In the contraction of the isolated frog's muscles as usually recorded the latent period amounts to 0.01 sec, but it is generally assumed that this period is exaggerated by the method of recording used, since the elasticity of the muscle itself prevents the immediate registration of the movement. By improve- ments in methods of technique the latent period for a fresh muscle may be reduced to as little as 0.005 or even 0.004 sec. Under the conditions in the body, however, the muscle contracts against a load, as when lifting a lever; hence, we may assume that normally there is a lost time of at least 0.01 sec. after the stimulus enters the muscle. In addition to the latent period due to the elasticity of the muscle it is certain that a brief amount of time actually elapses after the stimulus enters the muscle before the act of shortening begins ; some time is taken up in the chemical changes and the effect of these changes in putting the mechanism of con- traction into play (see below on the Theory of Muscle Contractions). The latent period varies greatly in muscles of different kinds, and in the same muscle varies with its conditions as regards temperature, fatigue, load to be raised, etc. The Phases of Shortening and of Relaxation. — In the normal frog's muscle the phase of shortening for a simple contraction occu- pies about 0.04 second, while the relaxation may be a trifle longer, 0.05 sec. In muscles whose duration of contraction differs from that of the frog the time values for the shortening and the relaxation exhibit corresponding differences. As we have seen, the appearance of the muscle fiber when viewed by polarized light indicates that during the phase of shortening the most marked physical change occurs in the anisotropic band. Whatever may be the nature of this change, it is evidently a reversible one. After reaching its maximum it proceeds in the opposite direction, the particles return to their original position, and a relaxation occurs. Many conditions, some of which will be described below, alter the time necessary for these processes, that is, the duration of the simple contraction. It is noteworthy that it is the phase of relaxation which may be most easily prolonged or shortened by varying conditions. Isotonic and Isometric Contractions. — In the method of recording the shortening of the muscle that is described above the muscle is supposed to con- tract against a constant load which it can lift. Such a contraction is spoken of as an isotonic contraction. If the muscle is allowed to contract against 28 THE PHYSIOLOGY OF MUSCLE AND NERVE. a tension too great for it to overcome — a stiff spring, for instance — it is prac- tically prevented from shortening, and a contraction of this kind, in which the length of the muscle remains unchanged, is spoken of as an isometric contraction. A curve of such a contraction may be obtained by magnifying greatly, by means of levers, the slight change in the stiff spring against which the muscle is contracting. Such a curve gives a picture of the liberation of energy within the muscle during contraction. The usual oval form of dynamometer employed to record the grip of the flexors of the fingers gives an isometric record of the energy of contraction Df these muscles. •t^B Fig. 9. — Effect of varying the strength of stimulus. The figure shows the effect upon the gastrocnemius muscle of a frog of gradually increasing the stimulus (breaking induction shock) until maximum contractions were obtained. The stimuli were then decreased in strength and the contractions fell off through a series of gradually decreasing submaximal contractions. The series up and down is not absolutely regular owing to the difficulty of obtaining a regular increase or decrease in the stimulus. (The prolongations of the curves below the ba.se line are due to the elastic extension of the muscle by the weight dur- ing relaxation.) Effect of Strength of Stimulus upon the Simple Contraction. — The strength of electrical stimuli can be varied conveniently and with great accuracy. When the stimulus is of such a strength as to produce a just visible contraction it is spoken of as a minimal stimulus and the resulting contraction as a minimal contraction. Stimuli of less strength than the minimal are designated as sub- minimal. If one increases gradually the intensity of the electrical current used as a stimulus without altering its duration, beginning with a stimulus sufficient to cause a minimal contraction, the result- ing contractions increase proportionally up to a certain maximum beyond which further increase of stimulus, other conditions remain- ing the same, causes no greater extent of shortening. Contrac- tions between the minimal and the maximal are designated as submaximal.* (See Fig. 9.) * Fick, " Untersuchungen iiber elektrische Nervenreizung," Braun- schweig, 1864. THE PHENOMENON OF CONTRACTION. 29 Effect of Temperature upon the Simple Contraction. — Varia- tions in temperature affect both the extent and the duration of the contraction. The relationship is, however, not a simple one in the case of the frog's muscle upon which it has been studied most fre- quently. If we pay attention to the extent of the contraction alone it will be found that at a certain temperature, 0° C, or slightly below, u* ij~/( n i% if .30 •"V'l'inuuiiiuuunimn'.' • -} a>- at j* • 3'0 s( a» Fig. 10. — Curve showing the effect of temperature. The temperatures at which the contractions were obtained are indicated on the figure. In this experiment a large resis- tance was introduced into the secondary circuit so that changes in the resistance of the muscle itself due to heating could not affect the strength of the stimulus. the muscle loses its irritability entirely. As its temperature is raised a given stimulus, chosen of such a strength as to be maximal for the muscle at room temperatures, causes greater and greater contractions up to a certain maximum, which is reached at about 5° to 9° C. As the temperature rises beyond this point the con- tractions decrease somewhat to a minimum that is reached at about 15° to 18° C. Beyond this the contractions again increase in extent to a second maximum at about 26° to 30° C, this maxi- mum being in some cases greater, and in others less than the first maximum. Beyond the second maximum the contractions again decrease rather rapidly as the temperature rises until at a certain temperature, 37° C, irritability is entirely lost (Fig. 10). If the tem- perature is raised somewhat beyond this latter point heat rigor makes its appearance, and the muscle may be considered as dead. The re- lationship between temperature and extent of contraction, therefore, may be expressed by a curve such as is represented in Fig. 11, in which there are two maxima and two points at which irritability is lost. The second maximum indicates a fact of general physiological in- terest,— namely, that in all of the tissuesof the body there is a certain high temperature at which optimum activity is exhibited, and if the temperature is raised beyond this point functional activity becomes 30 THE PHYSIOLOGY OF MUSCLE AND NERVE. more and more depressed. The point of optimum effect is not iden- tical for the different tissues of the same animal, much less so for those of different animals, but the fact may be emphasized that in no case do protoplasmic tissues withstand a very high temperature. Fig. 11. — Curve to show the effect of a rise of temperature from 0° C. to 38° C. upon the height of contraction of frog's muscle. The first maximum at 9° C, the second at 28° C. Beyond 38° C. the muscle lost its irritability and went into rigor mortis. rti J° 10' 15' 20' 2S' J"" JJ" 3r jr ir Fig. 12. — Curve to show the effect of a rise of temperature from 5° C. to 39° C. upon the duration of contraction of frog's muscle. The relative dura- tions at the different temperatures are represented by the height of the cor- responding ordinates. Functional activity is lost usually at 45° C. or below. The duration of the contraction shows usually in frogs' muscles a simple relation- ship to the changes of temperature. At low temperatures, 4 or 5° C, the contractions are enormously prolonged, particularly in the phase of relaxation ; but as the temperature is raised the duration of the contractions diminishes, at first rapidly, then more slowly, to a certain point — about 18° to 20° C, beyond which it remains more or less constant in spite of the changes in extent of shortening. The relationship between duration of contraction and temperature may therefore be expressed by such a curve as is shown in Fig. 12, in which the heights of the ordinates represent the relative durations of the contractions. Muscles from different frogs show considerable minor variations in their reactions to changes in temperature, and we may suppose that these variations depend upon differences in THE PHENOMENON OF CONTRACTION. 31 nutritive condition. In this, as in many other respects, the reac- tions obtained from so-called winter frogs after they have prepared for hibernation are more regular and typical than those obtained in the spring or summer. Effect of Veratrin. — The alkaloid veratrin exhibits a peculiar and interesting effect upon the contraction of muscle. A muscle taken from a veratrinized animal and stimulated in the usual way by a single stimulus gives a contraction such as is exhibited in the accompanying curve (Fig. 13). Two peculiarities are shown by the curve: (1) The phase of shortening is not altered, but the phase of relaxation is greatly prolonged. (2) The curve shows two summits, — that is, after the first shortening there is a brief relaxation followed by a second, slower contraction. The cause of this second shortening is not known. Biedemann has sug- gested that it is due to the presence in the muscle of the two kinds of fibers — red and pale — which were spoken of on p. 26, and that Fig. 13. — Curve showing the effect of veratrin. the veratrin dissociates their action, but this explanation, ac- cording to Carvallo and Weiss,* is disproved by the fact that muscles composed entirely of white or red fibers show a similar result from the action of veratrin. It would seem more probable, therefore, that two different contraction processes are initiated by the stimulus, one much more rapid than the other. Many other facts in physiology speak for this general view that a muscle may, according to conditions, give either a quick contraction (twitch) or a more slowly developing contraction, with a prolonged phase of relaxation. This latter feature constitutes the characteristic peculiarity of the curve of a veratrin contraction. A somewhat similar effect is produced by the action of glycerin, nicotine, etc. We have in such substances reagents that affect one phase of the contraction process without materially influencing the other. As regards the veratrin effect, it becomes less and less marked if the muscle is made to give repeated contractions, but reappears after a suitable period of rest. The peculiar action of the veratrin is, therefore, antagonized seemingly by the chemical products formed during contraction. * "Journal de la physiol. et de la path, generate," 1899. 32 THE PHYSIOLOGY OF MUSCLE AND NERVE. Contracture.— The prolonged relaxation that is so character- istic of the veratrinized muscles may be observed in frog's muscle under other circumstances, and is described usually as a con- 3 a ■S3 >.J2 dition of contracture. By contracture we mean a state of maintained contraction or, looking at it from the other point of view, a state of retarded relaxation. THE PHENOMENON OF CONTRACTION. 33 This condition is often exhibited in a most interesting way when a muscle is repeatedly stimulated. In some cases it develops at the beginning of a series of contractions, as is represented in Fig. 14, which pictures the phenome- non as it was first described.* In other cases it appears later on in the curve, Fig. 15. — Effect of repeated stimulation; complete curve, showing late contracture. The muscle was stimulated by induction shocks at the rate of 50 per minute. The separate contractions are so close together that they can not be distinguished. preceding or following the development of the state of fatigue. Whenever it occurs the effect is to hold the muscle in a state of maintained contraction, on which is superposed the series of quick contractions and relaxations due to the separate stimuli. When the condition develops early in the functional activity of the muscle (Fig. 14) further activity usually causes it to disappear, Fig. 16. — Effect of repeated stimulation, curve showing no contracture or very little. The muscle was stimulated by induction shocks at the rate of 50 per minute. A very slight contracture is shown in the beginning, but subsequently the contractions show only a diminished extent, the rate of relaxation remaining apparently unchanged. and the condition of the muscle as a mechanism for prompt shortening and relaxation is improved. We have in this fact apparently an indication of one way in which the "warming up" exercise before athletic contests may be of value. When the contraction appears late in the series of contractions * Tiegel, "Pfluger's Archivfur die gesammte Physiologie, " etc., 13, 71, 1876. 3 . 34 THE PHYSIOLOGY OF MUSCLE AND NERVE. it is usually permanent, that is to say, it wears off only as the muscle relaxes slowly from fatigue. Toward the end of such a series the muscle is often practically in a state of continuous contraction, a condition which would nullify its ordinary use in locomotion. It seems possible that certain conditions of tonic spasm or cramps which occur during life may involve this process, for example, the temporary cramp that sometimes attacks a player in athletic games, or the curious spasmodic condition known as intermittent claudication, in which, apparently as a result of insufficient circulation, the muscles on exercise are thrown into a state of tonic contraction. From the physiological standpoint the phenomenon of contracture when compared with that of the simple contraction indicates the possibility that two different contraction processes may take place in muscle, one involving the state of tone and, therefore, the length and hardness of the muscle, the other con- trolling the movements proper. This suggestion has been made by a number of authors * on various grounds. It has been suggested by some that there are two different contractile substances in muscle, one giving the usual quick contraction, shown as a "twitch," the other the slower contraction, which exhibits itself as tone or contracture. It would be equally as permissible to suppose that there are two kinds of chemical processes which may occur in muscle, one which occurs with explosive suddenness and causes the "twitch," and one which takes place slowly and causes the maintained contraction shown in contracture. This latter point of view is supported by the work of Hill, referred to below, which shows that during contracture there is a constant production of heat — that is to say, the condition is one really of maintained or continuous contraction, and not simply a case of a retardation of the physical processes of relaxation. The Effect of Rapidly Repeated Contractions. — When a muscle is stimulated repeatedly by stimuli of equal strength that fall into the muscle at equal intervals the contractions show certain features that, in a general way, are constant, although the precise degree in which they are exhibited varies curiously in different animals. Such curves are exhibited in Figs. 14, 15, and 16, and the features worthy of note may be specified briefly as follows : 1. The Introductory Contractions. — The first three or four con- tractions decrease slightly in extent, showing that the muscle at first loses a little in irritability on account of previous contractions. This phenomenon is frequently absent. 2. The Staircase or u Treppe." — After the first slight fall in height has passed off the contractions increase in extent with great regularity and often for a surprisingly large number of contractions. This gradual increase in extent of shortening, with a constant stimulus, was first noticed by Bowditch upon the heart muscle, and was by him named the phenomenon of "treppe," the German word for staircase. It indicates that the effect of activity is in the beginning beneficial to the muscle in that its irritability steadily increases, and the fact that the same result has been ob- tained from heart muscle, plain muscle, and nerve fibers indicates that it may be a general physiological law that functional activity leads at first to a heightened irritability. According to Lee,f * See especially Uexkull, " Zentralblatt f. Physiologic," 1908, 22, 33; also Guenther, "American Journal of Physiology," 1905, 14, 73. t See "American Journal of Physiology," 1907, 18, 267. THE PHENOMENON OF CONTRACTION. 35 the " treppe " in muscle is due to an initial increase of irritability set up by the chemical products formed during contraction. 3. Contracture. — This phenomenon of maintained contraction has been described above. In frogs' muscles stimulated repeat- edly it makes its appearance, as a rule, sooner or later in the series of contractions; but there is a curious amount of variation in the muscles of different individuals in this respect. 4. Fatigue. — After the period of the " treppe " has passed, the contractions diminish steadily in height, until at last the muscle fails entirely to respond to the stimulus. This progressive loss of irritability in the muscle caused by repeated activity is designated as fatigue. It will be considered more in detail under the head of Compound Muscular Contractions and in Chapter II. The curve obtained in an experiment of this kind illustrates in a striking way one of the general characteristics of living matter, namely, that every effective stimulus applied to it leaves a record, so to speak. The muscle in this case is in a changed condition after each stimulus, as is indicated by the difference in its re- sponse to the succeeding stimulus. While it cannot be said that a similar effect has been shown in all tissues, still the evidence in general points that way, and some of the complicated phenomena exhibited by living matter, such as memory, habits, immunity, etc., are referable in the long run to this underlying peculiarity. Lee has discovered the interesting fact that while in frog's muscle, as a rule, fatigue is accompanied by a prolongation of the curve, especially of the phase of relaxation, this does not hold for mammalian muscle. In the latter muscle the successive contractions become smaller as fatigue sets in, but their duration is not increased. The Contraction Wave. — Under ordinary conditions the fibers of a muscle when stimulated contract simultaneously or nearly so, and the whole extent of the muscle is practically in the same phase of contraction at a given instant. It is comparatively easy to show, however, that the process of contraction spreads over the fibers, from the point stimulated, in the form of a wave which moves with a definite velocity. In a long muscle with parallel fibers one may prove, by proper recording apparatus, that if the muscle is stimulated at one end a point near this end enters into contraction before a point farther off. Knowing the difference in time between the appearance of the contraction at the two points and the dis- tance apart of the latter, we have the data for determining the velocity of its propagation. In frog's muscles this velocity is found to be equal to 3 to 4 meters per second, while in human muscle, at the body temperature, it is estimated at 10 to 13 meters per second. Knowing the time it takes this wave to pass a given point (d) and its velocity (v), its entire length is given by the 36 THE PHYSIOLOGY OF MUSCLE AND NERVE. formula I = vd. In the frog's muscle, therefore, with a velocity of 3000 mm. per second, and a duration of, say, 0.1 second, the product (3000X0.1 =300 rams.) gives the length of the wave or the length of muscle which is in some phase of contraction at any given instant. Under normal conditions the muscle fibers are stimulated through their motor plates, which are situated toward the middle of the fiber, or perhaps one muscle fiber may have two or more motor plates, giving two or more points of stimula- tion. It follows, therefore, from this anatomical arrangement and the great velocity of the wave that all parts of the fibers are in contraction at the same instant and, indeed, in nearly the same phase of contraction. Under abnormal conditions muscles may exhibit fibrillar contractions; that is, separate fibrils or bundles of fibrils contract and relax at different times, giving a Hickering, trembling movement to the muscle. Idiomuscular Contractions. — In a fatigued or moribund muscle mechan- ical stimulation may give a localized contraction which does not spread or spreads very slowly, showing that the abnormal changes in the muscle prevent the excitation from traveling at its normal velocity. A localized contraction of this kind was designated by Schiff as an idiomuscular contraction. It mav be produced in the muscle of a dying or recently dead animal by localized mechanical stimulation, as by drawing a blunt instrument — e. g., the handle of a scalpel — across the belly of the muscle. The point thus stimulated stands out as a wheal, owing to the idiomuscular contraction. The Energy Liberated in the Contraction. — When a muscle contracts, energy is, as we say, liberated in several forms, and can be measured quantitatively. First there is a production of heat, which is indicated by a rise in temperature of the muscle. According to Heidenhain, the temperature of the frog's muscle is increased in a single contraction by 0.001° C. to 0.005° C. Larger muscles, such as those of the thigh of the dog, when repeatedly stimulated may cause a rise of temperature of from 1° to 2° C. The thermometer does not, of course, measure the amount of heat produced, but only the temperature of the muscle. Heat is esti- mated quantitatively in terms of calories. By a calorie is meant the quantity of heat necessary to raise 1 gm. of water 1° C. Knowing the specific heat and weight of muscle, we can readily calculate the number of calories produced. Thus, if a frog's muscle weighing 2 gms. shows a rise of temperature of 0.005° C. from a single contraction the production of heat in calories is given by multiplying the weight of the muscle by its specific heat, 0.83, to reduce it to an equivalent weight of water, and this product by the rise in temperature: 2 X 0.83 X 0.005 = 0.0083 calorie. The fact that muscular exercise increases the produc- tion of heat in the body is a matter of general observation. Making THE PHENOMENON OF CONTRACTION. 37 use of a very sensitive thermo-couple, Hill* has been able to register the production of heat in an excised frog's muscle. In the case of a simple contraction or twitch, the production of the heat is practically instantaneous, indicating an underlying chemical change of explosive suddenness. When the contraction is pro- longed, as in the case of " contracture," or conditions of "tone," there is a correspondingly slow production of heat, which must be referred to chemical changes of a more deliberate character. Second. Some electrical energy is developed during the contrac- tion. The means of detecting and measuring this energy will be described in a subsequent chapter. Considered quantitatively, the amount is small. Third. Work is done if the muscle is al- lowed to shorten during the contraction. By work is meant external or useful work — that is, the muscle lifts a weight or over- comes an opposing resistance. If a muscle contracts against a weight too heavy to be lifted, or a resistance too strong to be over- come, it does no external work, although, of course, much energy is liberated as heat or, as it is sometimes called, internal work. The work done by a muscle during contraction is measured in the usual mechanical units, by the product of the load into the lift. That is, if a muscle lifts a weight of 40 grams to a height of 10 millimeters, the work done is 40 X 10 = 400 gram-millimeters, or 0.4 grammeter. We can in calculations convert external work into heat or internal work by making use of the ascertained mechanical equivalent of heat, according to which 1 calorie = 426.5 grammeters of work. The work, 0.4 grammeter, supposed to be done in the above experiment, would be equivalent, there- fore, to 0.4 -=- 426, or about 0.001 of a calorie. The Proportion of the Total Energy Liberated that may be Utilized in Work. — All of the energy liberated in the muscle has its origin in the chemical changes that follow upon stimulation. We assume that these changes are such that complex molecules are broken down, with the formation of simpler ones, and that some of the so-called chemical or internal energy that holds together the atoms in the complex molecule is liberated and takes the three forms described above. The chemical changes occurring in the muscle during contraction are complex and not entirely understood, but the significant ones from our present standpoint are oxidations which destroy some of the material in the muscle, with the forma- tion of carbon dioxid and water and the liberation of heat. It is a matter of interest to inquire as to the proportion of the total heat energy which may be converted into useful work and the conditions under which the optimum amount of work may be realized. Regarded from this standpoint, the muscle may be * Hill, "Journal of Physiology," 40, 389, 1910. 38 THE PHYSIOLOGY OF MUSCLE AND NERVE. considered as a piece of machinery comparable, let us say, to a gas engine. In the latter the heat generated by the explosive chemical change is converted partially into external work by a properly adapted mechanism — and in a well-constructed engine as much as 15 to 25 per cent, of the total energy may be obtained as work. In the muscle there is also a mechanism of some kind, not as yet understood, by means of which a part of the energy liberated may be converted into work. Experiments made by Fick with frogs' muscles indicate that the proportion of the total energy which under optimum conditions may be utilized as work is, in round numbers, from 25 to 30 per cent. Chauveau,* in experiments made upon the elevator of the upper Up in the horse, found a pro- portion of only 12 to 15 per cent. The last observer points out that this proportion must vary greatly for different muscles and for muscles in different animals, while for the same muscle it will vary with the extent and duration of the contractions and other conditions. From experiments made upon dogs in which a meas- ured amount of work was done and in which the energy changes were estimated from the oxygen absorbed and carbon dioxid eliminated, Zuntz f calculates that somewhat more than $ of the total chemical energy liberated in the muscles may be applied to external work, the other § taking the form of heat. Similar ex- periments made by the same observer J upon men have indicated that the muscles work most economically in lifting the weight of the body, as in mountain-climbing. In this form of muscular work he estimates that from 35 to 40 per cent, of the heat energy- yielded by the material oxidized in the body may take the form of external work. When the muscular work performed was effected by the muscles of the arms and upper part of the body, as in turning a wheel, a smaller yield (25 per cent.) was obtained. It appears from these figures that the muscular machine is an especially efficient one as regards the amount of external work that can be obtained from the oxidation of a given amount of material, and Zuntz has shown, in the work previously referred to, that this efficiency may be increased by training; that is, by the repeated use of a group of muscles a more economical application may be made of the liberated energy in the performance of work. The Curve of Work and the Absolute Power of a Muscle. — The statements in the preceding paragraph prove that the muscle, judged from the standpoint of a machine to do work, compares most favorably in its efficiency with machinery of human construction. But it should be borne in mind that in this as in other respects the properties of cross-striated muscular tissues vary greatly. In some * Chauveau, " Le travail musculaire, etc.," Paris, 1891. t Zuntz, "Archiv f. d. gesammte Physiologie," 68, 191, 1897. X Zuntz and Schumberg, " Physiologie des Marsches,*' Berlin, 1901. THE PHENOMENON OF CONTRACTION. 39 animals or individuals it is a much more efficient machine than in others. This fact is indicated by our general experience regarding Fig. 17. — To show the decrease in extent of contraction of the gastrocnemius muscle of a frog with increase in load. In the first contraction, to the right, the load was 14.2 gms. At each successive contraction the load was increased by 5.3 gms. With a load of 182 gms. the lever gave only the slightest indication of a shortening, and this may have been due to some lateral movement. Fig. 18. — The curve of work obtained by plotting the results shown in Fig. 17. The initial contraction was made with a load of 14.2 gms., and the work done in gram-milli- meters is represented by the ordinate erected at this point. The maximum work was done with a load of 88.6 gms., and the absolute power of this particular muscle was found to be equal to 182 gms. variations in muscular strength in different individuals, and is proved more precisely by direct experiments on single muscles. A frog's 40 THE PHYSIOLOGY OF MUSCLE AND NERVE. muscle may be isolated and the extent of its contractions and the work done may be estimated directly. Under such conditions it will be found that, while the height of the successive contractions diminishes as the load increases (see Fig. 17), the work done — that is, the product of the load into the lift — first increases and then decreases. For example : Work Done in Gram -millimeters Load in Grams. Lift in Millimeters. Load X Lift. 5 27.6 138.0 15 25.1 376.5 25 11.45 286.25 35 6.3 220.5 A series of experiments of this kind furnishes data for con- structing a curve of work by plotting off along the abscissa at equal intervals the equal increments in load and erecting over each load an ordinate showing the proportional amount of work done. The curve has the general form indicated in Fig. 18. Three facts are expressed by this curve: First, that if the muscle lifts no weight no work will be done; this follows theoretically from the formula W = L H, in which TF represents the work done, L the load, and H the lift. If either L or H is equal to zero the product, of course, is zero; that is, no external work is done; the chemical energy liberated in the contraction takes the form of heat. Under such circumstances the amount of heat given off from the muscle should be greater than when a load is lifted. In accordance with this fact it is found that a muscle lifting a light load gives off more heat during the contraction than when lifting a heavier load. Second. There is an optimum load for each muscle with which the greatest proportion of work can be obtained. Third. When the load is just sufficient to counteract the contraction of the muscle no work i? done, H in the above formula being zero. This amount of load measures what Weber called the absolute power of the muscle. As will be seen from the above curve, it is measured by the weight which the muscle cannot lift and which, on the other hand, cannot cause any extension of the muscle while contracting. Or, in more general terms (Hermann), the absolute power of a muscle is the maximum of tension which it can reach without alteration of its natural length. This absolute power can be measured for the muscles of different animals and for convenience of comparison can then be expressed in terms of the cross-area of the muscle given in square centimeters. Weber has shown that the absolute power of a muscle varies with the cross-area, since this depends upon the number of constituent fibers whose united contraction makes the contraction of the muscle. Expressed in this way, it is found that the absolute power of human muscle is, size for size, much greater than that of frog's muscle. For in- THE PHENOMENON OF CONTRACTION. 41 stance, the absolute power of a frog's muscle of 1 square centimeter cross-area is estimated at from 0.7 kilogram to 3 kilograms, while that of a human muscle of the same size is estimated by Hermann at 6.24 kilograms. Taken as a whole, the human muscle is a better machine for work, but it seems possible, although exact figures are lacking, that the absolute power of the muscles of some insects reckoned for the same unit of cross-area would be much greater than in human muscle. COMPOUND OR TETANIC CONTRACTIONS. Definition of Tetanus — When a muscle receives a series of rapidly repeated stimuli it remains in a condition of contraction as long as the stimuli are sent in or until it loses its irritability from the effect of fatigue. A contraction of this character is described as a compound contraction or tetanus. If the stimuli follow each other with sufficient rapidity the muscle shows no external sign of relaxation in the intervals between stimuli, and if its contractions are recorded upon a kymographion by means of an attached lever a curve is obtained such as is shown at 5 in Fig. 19. A con- traction of this character is described as a complete tetanus. If, however, the rate of stimulation is not sufficiently rapid the mus- cle will relax more or less after each stimulus and its recorded curve, therefore, will present the appearance shown in 1, 2, 3, and 4 of Fig. 19. A tetanus of this character is described as an incom- plete tetanus. It is obvious that according to the rate of stimu- lation there may be numerous degrees of incomplete tetanus, as shown in Fig. 19, extending from a series of separate single con- tractions, on the one hand, to a perfect fusion of the contractions, a complete tetanus, on the other. Tetanic contractions present two peculiarities in addition to the mere matter of duration, which is governed, of course, by the duration of the stimu- lation: First, the more or less complete fusion of the contrac- tions due to the separate stimuli. This, as stated above, is the distinctive sign of a tetanus. Second, the phenomenon of sum- mation in consequence of which the total shortening of the muscle in tetanus may be considerably greater than that caused b}r a maxi- mal simple contraction. Summation. — The facts of summation ma}' be shown most read- ily by employing a device to send into the muscle two successive stimuli at varying intervals. If the second stimulus falls into the muscle at the apex of the contraction caused by the first stimulus, then, even if the first contraction is maximal, the muscle will shorten still farther; the first and second contractions are summatecl, giv- ing a total shortening greater than can be obtained by a single stim- ulus (see Fig. 20). The extent of the summation in such cases varies with a number of conditions, such as the intervals between the 42 THE PHYSIOLOGY OF MUSCLE AND NERVE. stimuli, the relative strengths of the stimuli, the load carried by the muscle, etc. Taking the simplest conditions of a moderately loaded muscle' and two maximal stimuli, it is found that the greatest sum- Fie 19 —Analysis of tetanus. Experiment made upon the gastrocnemius muscle of a froe to show that by increasing the rate of stimulation the contractions, at first separate mf f use Tore and mo^ threoughga series of incomplete tetani (2, 3, 4) into a comple e tetanus (5) in which there is no indication, so far as the record goes, of a separate effect tor eacn Stimulus. mation occurs when the stimuli are so spaced that the second contrac- tion begins at the apex of the first. If the stimuli are closer together, so that, for instance, the second contraction follows shortly after THE PHENOMENON OF CONTRACTION. 43 the first has begun, the total shortening is less, and the same is true to an increasing extent as the second contraction falls later and later in the period of relaxation after the first contraction.* If Fig. 20. — Summation of two successive contractions. Curve 1 shows a simple con- traction due to a single stimulus, the latent period being indicated at the beginning of the contraction. Curve 2 shows the summation due to two succeeding stimuli. instead of two we use three successive stimuli, falling into the muscle at proper intervals, a still further summation occurs. In this way the total extent of shortening in a muscle completely tetanized may be several times as great as that of a single maximal contraction. The Discontinuous Character of the Tetanic Contraction — The Muscle-tone. — In complete tetanus the muscle seems to be in a condition of continuous uniform contraction; the re- corded curve shows no sign of relaxation between stimuli and no external indication, in fact, that the separate stimuli do more than maintain a state of uniform contraction. It can be shown, how- ever, that in reality each stimulus has its own effect, and that the chemical changes underlying the phenomenon of contraction form an interrupted series corresponding, within limits, to the series of stimuli sent in. The clearest proof for this belief is found in the electrical changes that result from each stimulus, and the facts relating to this side of the question will be stated subsequently in the chapter on The Electrical Phenomena of Muscle and Nerve. Another proof is found in the phenome- non of the muscle-tone. When a muscle is stimulated directly or through its motor nerve a musical note may be heard by applying the ear or a stethoscope to the muscle. The note that is heard corresponds in pitch, up to a certain point, with the num- ber of stimuli sent in, — that is, the muscle vibrates, as it were, m * Von Kries, "Archiv fur Physiologie," 1888, p. 537. 44 THE PHYSIOLOGY OF MUSCLE AND NERVE. unison with the number of stimuli, and, although the vibrations are not sufficient to affect the recording lever, they can be heard as a musical note. This fact, therefore, may be taken as a proof that during complete tetanus there is a discontinuous series of changes in the muscle the rate of which corresponds with that of the stimulation. The series of electrical changes corresponding with the series of stimuli sent in may be made audible by applying a telephone to the muscle. Making use of this method, Wedenski* has shown that the ability of the muscle to respond isorhythmically to the rate of stimulation is limited. In frog's muscle the pitch of the musical tone may correspond with the rate of stimulation up to about 200 stimuli per second. In the muscle of the warm-blooded animal the correspondence may extend to about 1000 stimuli per second. If the rate of stimulation is increased beyond these limits the musical note heard does not correspond, but falls to a lower pitch, indicating that some of the stimuli under these conditions become ineffective. It should be added that the high figures given above for the correspondence between the stimuli and the muscle-tone hold good only for entirely fresh preparations. The lability of the muscle quickly becomes less as it is fatigued; so that in the frog, for instance, the correspondence in long-continued contractions is accurate only when the rate of stimulation does not exceed 30 per second. The Number of Stimuli Necessary for Complete Tetanus. — The number of stimuli necessary to produce complete tetanus varies, as we should expect, with the kind of muscle used and in accordance with the rapidity of the process of relaxation shown by these muscles in simple contractions. The series that may be arranged to demonstrate this variation is quite large, extending from a supposed rate of 300 per second for insect muscle to a low limit of one stimulus in 5 to 7 seconds for plain muscle. The frog's muscle goes into complete tetanus with a rate of stimulation of from 20 to 30 per second. Inasmuch as the rapidity of relaxation of the muscle is much retarded by certain influences, such as a low temperature or fatigue, it follows that these same influences affect in a corresponding way the rate of stimulation necessary to give complete tetanus. A frog's muscle stimulated at the rate of 10 stimuli per second may record an incomplete tetanus, but if the stimulus is maintained for some time the tetanus finally becomes complete in consequence of the slowing of the phase of relaxation, or, what is probably the truer way of looking at the matter, in consequence of the development of that condition of maintained contraction which has been spoken of above as contracture. * Wedenski, " Du rhythme museulaire dans la contraction normale," "Archives de physiologic," 1891, p. 58. THE PHENOMENON OF CONTRACTION. 45 Voluntary Contractions. — After ascertaining that muscles may give either simple or tetanic contractions one asks naturally whether in our voluntary movements we can also obtain both sorts of contractions. In the first place, it is obvious that most of our voluntary movements are too long continued to be simple contractions. The time element alone would place them in the group of tetanic contractions, and this is the usual conclusion regarding them. In voluntary movements a neuromuscular mechanism comes into play. This mechanism consists, on the motor side, of at least two nerve units or neurons and the muscle, as indicated in the accompanying diagram (Fig. 21). If in ordi- nary voluntary movements the muscular contractions are tetanic, we must suppose that the motor nerve cells discharge a series of nerve impulses through the motor nerve into the muscle. The contraction of voluntary muscle has been investigated, therefore, in various ways to ascertain whether there is any objective indi- cation of the number of separate contractions that are fused together to make this normal tetanus. In the first place, the normal movements of the muscles have been recorded graphically by levers or tambours. The records thus obtained show that our usual contractions are not entirely complete tetani — that is, there is an indication in some part of the curve of the single con- tractions that are being fused. According to most observers,* these records show that our normal contractions are com- pounded of single contrac- tions following at the rate of 10 per second, or, in other words, the motor neurons discharge about 10 impulses per second into the muscle. The so-called natural muscle- tone has been used for the same purpose. When one places a stethoscope or lays his ear upon a contracting muscle a low tone is heard, the pitch of which corresponds with 40 vibrations per second. It was formerly assumed that this note does not represent the actual rate of stimulation of the muscle, since the number is higher than that obtained by some other methods. A rate of 35 to 40 vibrations per second corresponds to the resonance tone of the external ear and it is possible that the real muscle tone may have a lower pitch, and that the ear picks * Horsley and Schafer, " Journal of Physiology," 7, 96, 1886. Fig. 21. — Schema to show the innerva- tion of the skeletal (voluntary) muscles: 1, the intercentral (pyramidal) neuron; 2, the spinal neuron; 3, the muscle. 46 THE PHYSIOLOGY OF MUSCLE AND NERVE. out by its own resonance one of the overtones. Helmholtz made use of a simple and direct method to determine this point. He utilized the principle of sympathetic vibrations, according to which a vibrating body will be set into movement most easily by vibrations that correspond in number to its own period. Helmholtz attached to the muscle watch springs that had different periods of vibration, and found that when the muscle was contracted the spring that vibrated 20 times per second was set into most active movement. He concluded, therefore, that the muscle receives 20 stimuli per second in ordinary con- tractions and that the tone that is heard, 40 vibrations per second, represents the first overtone. The whole subject has been reinvestigated more recently by employing the "string galvanometer" (see p. 100) to record the number of electrical Fig. 22. — The upper curve shows the vibrations of the "string" of the string gal- vanometer during voluntary contraction of the flexor of the fingers. Each vibration is due to an electrical oscillation in the muscle (action current). These oscillations occur at the rate of 50 per second, as may be seen by reference to the lower curve, the breaks in which indicate fifths of a second. This fact would indicate, therefore, that in the voluntary con- traction we have a tetanus composed of single contractions following at the rate of 50 per second — (From Piper.) variations occurring during a voluntary contraction. Since each separate stimulus to a muscle causes a distinct electrical variation, it is evident that if we can record the number of such variations per second we shall have almost conclusive evidence as regards the number of simple contractions which enter into the production of voluntary tetanus. The string galvanometer lends itself to this purpose better than any form of electrometer yet devised, and Piper,* by the use of this instrument, finds that in voluntary contractions of the flexor muscles of the arms or fingers the number of electrical variations follow at the rate of 47 to 50 per second. Increase in strength of contraction in these muscles causes no change in rate, although a corresponding variation in the intensity of the electrical changes is observed. * Piper, Pfliiger's " Archiv f. d. ges Physiologie," 1907, 119, 301. Zeitschrift f. Biologie," 1908, 50, 393, and 504. Also THE PHENOMENON OF CONTRACTION. 47 When different muscles are studied by this method, quite a marked difference in rate is obtained. Piper reports such observations as the following: M. deltoideus, 58 to 62; M. gas- trocnemius and M. tibialis anterior, 42 to 44; M. quadriceps femoris, 38 to 41 ; M. masseter, 88 to 100, and M. temporalis, 80 to 86. Assuming that these figures represent the rate of dis- charge of nerve impulses per second by the nerve cells from which arise the motor fibers to the muscles named, it is evident that the various spinal and cranial motor centers may possess quite widely different rhythms, although for each particular center the rate is more or less fixed. Among the motor centers thus far studied it will be noted that the cells of the N. trigeminus possess the highest rate of discharge. There has been much discussion as to whether or not we can obtain simple as well as compound contractions by voluntary stimulation of our muscles. It has been pointed out that in very rapid contractions, such as occur in the trilling movements of the fingers in playing the piano, the duration of the separate contractions is so brief as to suggest that they may be of the order of simple contractions. Direct investigation of such movements by the older method of recording with levers (von Kries) or by the newer method of photographing the electrical oscillations shows, on the contrary, that even the shortest possible voluntary contractions are brief tetani made up of a short lasting series of contractions fused together. In all probability, therefore, our motor centers, when- ever they are stimulated by a so-called act of the will, discharge rhythmically a series of nerve impulses. As we shall see later, it is possible that certain of these centers, when stimulated reflexly, may discharge a single nerve impulse and thus arouse a simple muscular contraction (see Knee- kick). The Ergograph. — Voluntary contractions in man may be re- corded in a great many ways, but Mosso has devised a special in- strument for this purpose, known as the ergograph. It has been much used in quantitative investigations upon muscular work and the conditions influencing it. The apparatus is shown and described in Fig. 23. The person experimented upon makes a series of short contractions of the flexor muscle of the middle finger, thereby lifting a known weight to a definite height which is recorded upon a drum. In a set of experiments the rate of the series of contractions — that is, the interval of rest between the contractions — is kept constant, as also is the load lifted. Under these conditions the contractions become less and less ex- tensive as fatigue comes on, and finally, with the strongest voluntary effort, the contraction of the muscles is insufficient to lift the weight. In this way a record is obtained such as is shown in Fig. 24. 48 THE PHYSIOLOGY OF MUSCLE AND NERVE. In such a record we can easily calculate the total work done by obtaining the product of the load into the lift for each contrac- Fig. 23. — Mosso's ergograph: c is the carriage moving to and fro on runners by means of the cord d, which passes from the carriage to a holder attached to the last two phalanges of the middle finger (the adjoining fingers are held in place by clamps) ; p, the writing point of the carriage, c, which makes the record of its movements on the kymographion ; w, the weight to be lifted. Fig. i?4. —Normal fatigue curve of the flexors of the middle finger of right hand. Weignt 3 kilograms, contractions at intervals of two seconds. — (Maggiora.) tion and adding these products together. By this means the capacity for work of the muscle used can be studied objectively THE PHENOMENON OF CONTRACTION. 49 under varying conditions, and many suggestive results have been obtained, some of which will be referred to specifically.* It should be borne in mind, however, that the ergograph in this form does not enable us to compute the total work that the muscle is capable of performing. It is obvious that when the point of complete fatigue is reached, as illustrated in the record, Fig. 24, the muscle is still capable of doing work, that is external work, if we replace the heavy load by a lighter one. For this reason some investigators have substituted a spring in place of the load,f giving thus a spring ergograph instead of a weight ergograph. Although with the spring ergograph every muscular contraction is recorded and the entire work done may be calculated, it also possesses certain theo- retical and practical disadvantages, for a discussion of which refer- ence must be made to the authors quoted. The weight ergograph has, so far at least, given us the most sug- gestive results. Among these the following may be mentioned: (1) If a sufficient interval is allowed between contractions no fatigue is apparent. With a load of 6 kilograms, for instance, the flexor muscle (M. flexor digitorum sublimis) showed no fatigue when a rest of 10 seconds was given between contractions. (2) After complete fatigue with a given load a very long interval (two hours) is necessary for the muscle to make a complete recovery and give a second record as extensive as the first. (3) After complete fatigue efforts to still further contract the muscle greatly prolong this period of complete recovery, — a fact that demonstrates the injurious effect of straining a fatigued muscle. (4) The power of a muscle to do work is diminished by conditions that depress the general nutritive state of the body or the local nutrition of the muscle used; for instance, by loss of sleep, hunger, mental activity, anemia of the muscle, etc. (5) On the contrary, improved circulation in the muscle — produced by massage, for example — increases the power to do work. Food also has the same effect, and some particularly interesting experiments show that sugar, as a soluble and easily absorbed foodstuff, quickly increases the amount of muscular work that can be performed. (6) Marked activity in one set of muscles — the use of the leg muscles in long walks, for example — will diminish the amount of work obtainable from other muscles, such as those of the arm. It is very evident that the instrument may be used to advantage in the investigation of many problems connected with gymnastics, dietetics, stimulants,^ medicines, etc. * Mosso, "Archives italiennes de biologie," 13, 187, 189; also Maggiora, 1890, p. 191, 342. Lombard, "Journal of Physiology," 13, 1, 1892. f Franz, "American Journal of Physiology," 4, 348, 1900; also Hough, ibid., 5, 240, 1901. % Schumberg, "Archiv f. physiol.," 1899, suppl. volume, p. 289. 4 50 THE PHYSIOLOGY OF MUSCLE AND NERVE. A point of general physiological interest that has been brought out in con- nection with the use of the ergograph calls for a few words of special mention. Mosso found that if a muscle — e. CH2 CHOH * Halliburton, "British Medical Journal," 1907, May 4 and 11. Also "Folia Xeuro-Biologica," 1907, i., 38, and " Biochemistry of Muscle and Nerve," Philadelphia, 1904. 80 THE PHYSIOLOGY OF MUSCLE AND NERVE. The fact that lecithin and cholesterin usually occur together has suggested that they have some physiological connection. It has been supposed, for example, that they act as a check upon each other. Lecithin under certain conditions favors hemolysis of red corpuscles, or the action of lipase on fat, while cholesterin inhibits both of these activities. No application of this antagonistic rela- tionship is possible at present in the case of the myelin sheath. Cerebrosides or Cerebrogalactosides. — This name is given to a group of bodies containing nitrogen, but no phosphorus. In the myelin they are found in connection with and possibly in com- bination with the lecithin. They belong to the group of glucosides, that is, on hydrolytic decomposition they give rise to a carbo- hydrate group, in this case galactose . Fatty acids and a nitrogenous base also result from this decomposition. The cerebroside material obtained from the white matter has been named specifically cerebrin or phrenosin, but little is known of its exact structure. Union of Nerve Fibers into Nerves or Nerve Trunks. — The assembling of nerve fibers into larger or smaller nerve trunks re- sembles histologically the combination of muscle fibers to form a muscle. Physiologically, however, there is no similarity. The various fibers in a muscle act together in a co-ordinated way as a physiological unit. On the other hand, the hundreds or thou- sands of nerve fibers found in a nerve may form groups which are entirely independent in their physiological activity. In the vagus nerve, for instance, we have nerve fibers running side by side, some of which supply the heart, some the muscles of the larynx, some the muscles of the stomach or intestines, some the glands of the stomach or pancreas, and so on. Nerves are, therefore, anatomical units simply, containing groups of fibers which have very different activities and which may function entirely independently of one another. As a nerve-trunk is con- stituted it consists chiefly of the connective tissue binding the fibers together. It is estimated (Ellison) that in the median nerve the connective tissue forms 63 per cent, of the whole trunk, while myelin sheaths make up 28 per cent., and the axis cylinders only 9 per cent. Afferent and Efferent Nerve Fibers. — The older physiologists believed that one and the same nerve or nerve fiber might conduct sensory impulses toward the central nervous system or motor im- pulses from the central nervous system to the periphery. Bell and Magendie succeeded in establishing the great truth that a nerve fiber cannot be both motor and sensory. Since their time it has been recognized that we must divide the nerve fibers connected with the central nervous system into two great groups: the efferent fibers, which carry impulses outwardly from the nervous system THE PHENOMENON OF CONDUCTION. 81 to the peripheral tissues, and the afferent fibers, which carry their impulses inwardly, — that is, from the peripheral tissues to the nerve centers. Under normal conditions the afferent fibers are stimulated only at their endings in the peripheral tissues, in the skin, the mucous membranes, the sense organs, etc., while the efferent fibers are stimulated only at their central origin, — that is, through the nerve cells from which they spring. The difference in the direction of conduction depends, therefore, on the anatomical fact that the efferent fibers have a stimulating mechanism at their central ends only, while the afferent fibers are adapted only for stimulation at their peripheral ends. Classification of Nerve Fibers. — In addition to this funda- mental separation we may subdivide peripheral nerve fibers into smaller groups, making use of either anatomical or physiological differences upon which to base a classification. For the purpose here in view a classification that is physiological as far as possible seems preferable. In the first place, experimental physiology has shown that the effect of the impulse conveyed by nerve fibers may be either exciting or inhibiting. That is, the tissue or the cell to which the impulse is carried may be thereby stimulated to ac- tivity, in which case the effect is excitatory, or, on the contrary, it may, if already in activity, be reduced to a condition of rest or lessened activity; the effect in this case is inhibitory. Many physiologists believe that one and the same nerve fiber may cam- excitatory' or inhibitor}- impulses, but in some cases at least we have positive proof that these functions are discharged by separate fibers. We may subdivide both the afferent and the efferent sys- tems into excitatory and inhibitory fibers. Each of these sub- groups again falls into smaller divisions according to the kind of activity it excites or inhibits. In the efferent system, for instance, the excitatory fibers may cause contraction or motion if they ter- minate in muscular tissue, or secretion if they terminate in glandu- lar tissue. For convenience of description each of the groups in turn may be further classified according to the kind of muscle in which it ends or the kind of glandular tissue. In the motor group we speak of vasomotor fibers in reference to those that end in the plain muscle of the walls of the blood-vessels; visceromotor fibers, those ending in the muscular tissue of the abdominal and thoracic viscera; pilomotor fibers, those ending in the muscles attached to the hair follicles. The classification that is suggested in tabular form below depends, therefore, on three principles: first, the direc- tion in which the impulse travels normally; second, whether this impuLse excites or inhibits; third, the kind of action excited or inhibited, which in turn depends upon the kind of tissue in which the fibers end. 6 82 THE PHYSIOLOGY OF MUSCLE AND NERVE. Efferent Afferent Excitatory Inhibitory Excitatory Inhibitory < Secretory Inhibito-mo- tor In hi bi to-se- cretory Sensory Reflex Inhibito-re- flex Motor. Vasomotor. Cardiomotor. Visceromotor. Pilomotor. Salivary. Gastric. Pancreatic. Sweat. Subdivisions corresponding to the varieties of mo- tor fibers above. Subdivisions corresponding to the varieties of se- cretory fibers above. Visual. Auditory. Olfactory. Gustatory. Pressure. Temperature. Pain. Hunger. Thirst, etc. According to the efferent fibers affected. Inhibitory effects upon the conscious sensations are not demonstrated. The reflex fibers that cause unconscious reflexes are known to be inhibited in some cases at least. That the final action of a peripheral nerve fiber is determined by the tissue in which it ends rather than by the nature of the nerve fiber itself or the nature of the impulse that it carries is indi- cated strongly by the regeneration experiments made by Langley.* For instance, the chorda tympani nerve contains fibers which cause a dilatation in the blood-vessels of the submaxillary gland, while the cervical sympathetic contains fibers which cause a constriction of the vessels in the same gland. If the lingual nerve (containing the chorda tympani fibers) is divided and the central end is sutured to the peripheral end of the severed cervical sympathetic, the chorda fibers will grow along the paths of the old constrictor fibers of the sympathetic. If time is given for regeneration to take place, stimulation of the chorda now causes a constriction in the vessels. The experiment can also be reversed. That is, by suturing the central end of the cervical sympathetic to the peripheral end of the divided lingual the fibers of the former grow along the paths of the old dilator fibers, and after regeneration has taken place stimulation of the sympathetic causes dilatation of the blood- vessels in the gland. These results are particularly instructive, as vasoconstriction is an example of the excitatory effect of the nerve impulse, being the result of a contraction of the circular muscles in the vessels, while vasodilatation is an example of inhibitory action, being due to an inhibition of the contraction of the same muscles. Yet obviously these two opposite effects are determined not by the nature of the nerve fibers, but by their place or mode of ending in the gland. Separation of the Afferent and Efferent Fibers in the Roots of the Spinal Nerves. — According to the Bell-Magendie discovery, * Langley, "Journal of Physiology," 23, 240, 1898; ibid., 30, 439, 1904; "Proceedings Royal Society," 73, 1904. THE PHENOMENON OF CONDUCTION. 83 the motor fibers to the voluntary muscles emerge from the spinal cord in the anterior roots, while the fibers that give rise to sensa- tions enter the cord through the posterior roots. These facts have been demonstrated beyond all doubt. Magendie discovered an apparent exception in the phenomenon of recurrent sensibility. When the anterior root is severed and its peripheral end is stimu- lated only motor effects should be obtained. Magendie observed, however, upon dogs that in certain cases the animals showed signs of pain. This apparent exception to the general rule was after- ward explained satisfactorily. It was shown that the fibers in question do not really belong to the anterior root, — that is, they do not emerge from the cord with the root fibers; they are, in fact, sensory fibers for the meningeal membranes of the cord which are on their way to the posterior roots and which enter the cord with the fibers of the latter. Since the work of Bell and Magendie it has been a question whether their law applies to all afferent and efferent fibers and not simply to the motor and sensor}' fibers proper. The experimental evidence upon this point, as far as the mammals are concerned, has accumulated slowly. Various authors have shown that stimulation of the anterior roots of certain spinal nerves may cause a constriction of the blood-vessels, an erection of the hairs (stimulation of the pilomotor fibers), a secretion of sweat, and so on, while stimulation of the posterior roots in the same regions is without effect upon these peripheral tissues. One apparent excep- tion, however, has been noted. A number of observers have found that stimulation of the peripheral end of the divided posterioi roots (fifth lumbar to first sacral) causes a vascular dilatation in the hind limb. The matter has been particularly investigated by Bayliss,* who gives undoubted proof of the general fact. At the same time he shows that the fibers in question are not efferent fibers from the cord passing out by the posterior instead of the an- terior roots. This is shown by the fact that they do not degenerate when the root is cut between the ganglion and the cord, as they should do if they originated from cells in the cord. Bayliss's own explanation of this curious fact is that the fibers in question are ordinary afferent fibers, but that they are capable of a double ac- tion: they can convey sensory impulses from the blood-vessels to the cord according to the usual type of sensory fibers, but they can also convey efferent impulses, antidromic impulses as he desig- nates them, to the muscles of the blood-vessels. In other words, for this special set of fibers he attempts to re-establish the view held by physiologists before the time of Bell, — namely, that one and the same fiber transmits normally both afferent and efferent impulses. An exception so peculiar as this to an otherwise general rule cannot be accepted without hesitation. It is possible that * Bayliss, "Journal of Physiology," 26, 173, 1901, and 28, 276, 1902. 84 THE PHYSIOLOGY OP MUSCLE AND NERVE. future work may give an explanation less opposed to current views than that offered by Bayliss. Cells of Origin of the Anterior and Posterior Root Fibers. — The efferent fibers of the anterior root arise as axons or axis cjdinder processes from nerve cells in the gray matter of the cord at or near the exit of the root. The motor fibers to the voluntary muscles arise from the large cells of the anterior horn of gray matter; the fibers to the plain muscle and glands, autonomic fibers according to Langley's nomenclature, take their origin from spindle-shaped nerve cells lying in the so-called lateral horn of the gray matter.* According to the accepted belief regarding the nutrition of nerve fibers, any section or lesion involving these portions of the gray mat- ter or the anterior root will be followed by a complete degeneration of the efferent fibers. In the case of the fibers to the voluntary muscles this degeneration will extend to the muscles and include the end-plates. In the case of the autonomic fibers the degenera- tion will extend to the peripheral ganglia in which they terminate, involving, therefore, the whole extent of what is called the pre- ganglionic fiber (see the chapter on the autonomic nerves and the sympathetic system). The posterior root fibers have their origin in the nerve cells contained in the posterior root ganglia. These cells are unipolar, the single process given off being an axis cylinder process or axon. It divides into two branches, one passing into the cord by way of the posterior root, the other toward the periph- eral tissues in the corresponding spinal nerve in which they form the peripheral sensory nerve fibers. It follows that a section or lesion of the posterior root will result in a degeneration of the branch entering the cord, this branch having been cut off from its nutri- tive relationship with its cells of origin. The degeneration will in- volve the entire length of the branch and its collaterals to their terminations among the dendrites of other spinal or bulbar neurons (see the chapter on the spinal cord). After a lesion of this sort the stump of the posterior root that remains in connection with the posterior root ganglion maintains its normal structure. On the other hand, a section or lesion involving the spinal nerve will be followed by a degeneration of all the fibers, efferent and afferent, lying to the peripheral side of the lesion, since these fibers are cut off from connection with their cells of origin, while the fibers in the central stump of the divided nerve will retain their normal structure. Afferent and Efferent Fibers in the Cranial Nerves.— The first and second cranial nerves, the olfactory and the optic, contain only afferent fibers, which arise in the former nerve from the olfac- tory epithelium in the nasal cavity, in the latter from the nerve cells in the retina. The third, fourth, and sixth nerves contain only efferent fibers which arise from the nerve cells constituting * Herring, "Journal of Physiology," 29, 2S2, 1903. THE PHENOMENON OF CONDUCTION. 85 their nuclei of origin in the midbrain and pons. The fifth nerve resembles the spinal nerves in that it has two roots, one containing afferent and the other efferent fibers. The efferent fibers, consti- tuting the small root, arise from nerve cells in the pons and mid- brain, the afferent fibers arise from the nerve cells in the Gasserian ganglion. This ganglion, being a sensory ganglion, is constituted like the posterior root ganglia. Its nerve cells give off a single process which divides in T, one branch passing into the brain by way of the large root, while the other passes to the peripheral tissues as a sensory fiber of the fifth nerve. The seventh nerve may also be homologized writh a spinal nerve. The facial nerve proper consists of only efferent fibers, which arise from nerve cells constituting its nucleus of origin in the pons. The geniculate ganglion, attached to this nerve shortly after its emergence, is similar in structure to the Gasserian or a posterior root ganglion. Its nerve cells send off processes which divide in T and constitute afferent fibers in the so-called nervus intermedins or nerve of Wrisberg. The eighth nerve consists only of afferent fibers which arise from the nerve cells in the spiral ganglion of the cochlea, cochlear branch, and from those constituting the vestibular or Scarpa's ganglion, the vestibu- lar branch. Both of these ganglia are sensory, resembling the posterior root ganglia in structure. The ninth nerve is also mixed, the efferent fibers arising from the motor nucleus in the medulla, while the sensory fibers arise in the superior and petrosal ganglia found on the nerve at its emergence from the skull. The tenth is a mixed nerve, its efferent fibers arising in motor nuclei in the me- dulla, the afferent fibers in the nerve cells of the ganglia lying upon the trunk of the nerve at its exit from the skull (ganglion jugulare and nodosum). The eleventh and twelfth cranial nerves contain only efferent fibers that arise from motor nuclei in the medulla. It will be seen from these brief statements that in all the nerve trunks of the central nervous system — that is, the spinal and the cranial nerves— the cells of origin of the efferent fibers lie within the gray matter of the brain or cord, while the cells of origin of the- afferent fibers lie in sensory ganglia outside the central nervous system, — namely, in the posterior root ganglia for the spinai nerves, in the ganglion semilunare (Gasseri), the g. geniculi, the. g. spirale, the g. vestibulare, the g. superius and g. petrosum of the glossopharyngeal, and the g. jugulare and g. nodosum of the vagus. These various sensory ganglia attached to the cranial nerves corre- spond essentially in their structure and physiology with the posterior root ganglia of the spinal nerves. Independent Irritability of Nerve Fibers. — Although the nerve fibers under normal conditions are stimulated only at their ends, the efferent fibers at the central end, the afferent at the peripheral end, yet any nerve fiber may be stimulated by artificial 86 THE PHYSIOLOGY OF MUSCLE AND NERVE. means at any point in its course. Artificial stimuli capable of affecting the nerve fiber — that is, capable of generating in it a nerve impulse which then propagates itself along the fiber — may be divided into the following groups: 1. Chemical stimuli. Various chemical reagents, when applied directly to a nerve trunk, excite the nerve fibers. Such reagents are concentrated solutions of the neutral salts of the alkalies, acids, alkalies, glycerin, etc. This method of stimulation is not, however, of much practical value in experimental work, since it is difficult or impossible to control the reaction. 2. Mechanical stimuli. A blow or pressure or a mechanical in- jury of any kind applied to a nerve trunk also excites the fibers. This method of stimulating the fibers is also difficult to control and has had, therefore, a limited application in experimental work. The mechanical stimulus is essentially a pressure stimulus, and the difficulty lies in controlling this pressure so that it shall not actually destroy the nerve fiber by rupturing the delicate axis cylinder. Various instruments have been devised by means of which light blows may be given to the nerve, sufficient to arouse an impulse, but insufficient to permanently injure the fibers. The results ob- tained by this method have been very valuable in physiology as con- trols for the experiments made by the usual method of electrical stimulation. It may be mentioned also that under certain condi- tions— for instance, at one stage in the regeneration of injured nerve fibers mechanical stimuli may be more effective than electrical, that is, may stimulate the nerve fiber when electrical stimuli totally fail to do so. 3. Thermal stimuli. A sudden change in temperature may stimulate the nerve fibers. This method of stimulation is very ineffective for motor fibers, only very extreme and sudden changes, such as may be obtained by applying a heated wire directly to the nerve trunk, are capable of so stimulating them as to produce a muscular contraction. On the other hand, the sensory nerve fibers are quite sensitive to changes of temperature. If a nerve trunk in a man or animal is suddenly cooled, or especially if it is suddenly heated to 60° to 70° C, violent pain results from the stimulation of the sensory fibers in the trunk, while the motor fibers are apparently not acted upon. We have in this fact one of several differences in reaction between motor and sensory fibers which have been noted from time to time, and which seem to indicate that there is some important difference in structure or composition between them. 4. Electrical stimuli. Some form of the electrical current is be- yond question the most effective and convenient means of stimulat- ing nerve fibers. We may employ either the galvanic current — that is, the current taken directly from a battery — or the induced current HE PHENOMENON OF CONDUCTION. 87 from the secondary coil of an induction apparatus or the so-called static electricity from a Leyden jar or other source. In most experi- mental work the induced current is used. The terminal wires from the secondary coil are connected usually with platinum wires im- bedded in hard rubber, forming what is known as a stimulating elec- trode. (See Fig. 30.) By this means the platinum ends which now Fig. 30. — Stimulating (catheter) electrodes for nerves: 6, Binding posts for attachment of 'wires from the secondary coil; s, insulating sheath of hard rubber; p, platinum points laid upon the nerve. form the electrodes, anode and cathode, can be placed close together upon the nerve trunk, and the induced current passing from one to the other through a short stretch of the nerve sets up at that point nerve impulses which then propagate themselves along the nerve fibers. The induction current is convenient because of its intensity, which overcomes the great resistance offered by the moist tissue ; be- cause of its very brief duration, in consequence of which it acts as a sharp, quick, single stimulus or shock, and because of the great ease with which it may be varied as to rate and as to intensity. On account of the very brief duration of the induced current it is dif- ficult to distinguish between the effects of its opening and closing. The Stimulation of the Nerve by the Galvanic Current. — When however, we employ the galvanic current, taken directly from a bat- tery, as a stimulus, we can, of course, allow the current to pass through the nerve as long as we please and can thus study the effect of the closing df the current as distinguished from that of the open- ing, or the effect of duration or direction of the current, etc. Du Bois-Reymond's Law of Stim- ulation.— When a galvanic current is led into a motor nerve it is found, as a rule, that with all moderate strengths of currents there is a stimulus to the nerve at the moment it is closed, the making or closing stimulus, and another when the current is broken, the breaking or opening stimulus, while during the passage of the current through the nerve no stimulation takes Fig. 31. — Schema of the arrange- ment of apparatus for stimulating the nerve by a galvanic current: 6, The battery; k, the key for opening and closing the circuit ; c, the commutator for reversing the direction of the cur- rent; + the anode or positive pole; — the cathode or negative pole. 88 THE PHYSIOLOGY OF MUSCLE AND NERVE. place: the muscle remains relaxed. We may express this fact by saying that the motor nerve fibers are stimulated by the mak- ing and the breaking of the current or by any sudden change in its intensity, but remain unstimulated during the passage of cur- rents whose intensity does not vary. The Anodal and Cathodal Stimuli. — It has been shown quite con- clusively that the nerve impulse started by the making of the current arises at the cathode, while that at the breaking of the current begins at the anode, or, in other words, the making shock or stimulus is cathodal, while the breaking stimulus is anodal. This fact is true for muscle as well as nerve, and possibly for all irritable tissues capable of stimulation by the galvanic current. This important generalization may be demonstrated for motor nerves by separating the anode and cathode as far as possible and re- cording the latent period for the contractions caused respect- ively by the making and the breaking of the current in the nerve. If the cathode is nearer to the muscle the latent period of the mak- ing contraction of the muscle will be shorter than that of the break- ing contraction by a time equal to that necessary for a nerve impulse to travel the distance between anode and cathode. If the position of the electrodes is reversed the latent period of the making con- traction will be correspondingly longer than that of the breaking contraction. It is very evident from these facts that when a current is passed into a nerve or muscle the changes at the two poles are different, as shown by the differences in reactions and properties of the nerve at these points. Bethe has shown that a difference may be demonstrated even by histological means. After the passage of a current through a nerve for some time the axis cylinders stain more deeply than normal at the cathode with cer- tain dyes (toluidin blue), while at the anode the}7 stain less deeply. Electrotonus. — The altered physiological condition of the nerve at the poles during the passage of the galvanic current is designated as electrotonus, the condition round the anode being known as anelectrotonus, that round the cathode as catelectrotonus. Elec- trotonus expresses itself as a change in the electrical condition of the nerve which gives rise to currents known as the electrotonic currents, — a brief description of these currents will be given in the next chapter, — and also by a change in irritability and con- ductivity. The latter changes were first carefully investigated by Pfiiiger, who showed that when the galvanic current, or, as it is usually called in this connection, the polarizing current, is not too strong there is an increase in irritability and conductivity in the neighborhood of the cathode, the so-called catelectrotonic increase of irritability, while in the region of the anode there is an anelec- trotonic decrease in irritability and conductivity. These opposite variations in the state of the nerve are represented in the accom- THE PHENOMENON OF CONDUCTION. 89 panying diagram. Between the two poles — that is, in the intrapolar region — there is, of course, an indifferent point, on one side of which the irritability of the nerve is above normal and on the other side below normal. The position of this indifferent point shifts toward the cathode as the strength of the polarizing current is increased. In other words, as the current increases the anelectrotonus spreads more rapidly and becomes more intense, and the conductivity in this region soon becomes so depressed as to block entirely the passage of a nerve impulse through it. The changes on the cathodal side are not so constant nor so distinct. It has been shown,* in fact, that if the polarizing current is continued for some time, the ' heightened irritability at the cathode soon diminishes and sinks below normal, so that in fact at the cathode as well as at the anode the irritability may be lost entirely. If the polarizing current is very strong this depressed irritability at the cathode comes on practically at once. Moreover, when a strong current that has been passing through a nerve is broken the condition of depressed irritability at the cathode persists for some time after the opening of the current. Pfluger's Law of Stimulation.- — It was said above that when a galvanic current is passed into a nerve there is a stimulus (catho- dal) at the making of the current and another stimulus (anodal) Fig. 32. — Electrotonic alterations of irritability caused by weak, medium, and strong battery currents: A and B indicate the points of application of the electrodes to the nerve, A being the anode, B the cathode. The horizontal line represents the nerve at normal irri- tability; the curved lines illustrate how the irritability is altered at different parts of the nerve with currents of different strengths. Curve r/1 shows the effect of a weak current, the part below the line indicating decreased, and that above the line increased irritability; at xx the curve crosses the line, this being the indifferent point at which the catelectrotonic effects are compensated for by anelectrotonic effects; y- gives the effect of a stronger current, and Vs, of a still stronger current. As the strength of the current is increased the effect becomes greater and extends farther into the extrapolar regions. In the intrapolar region the in- different point is seen to advance, with increasing strengths of current, from the anode toward the cathode. — (Lombard.) at the breaking of the current. This statement is true, however, only for a certain range of currents. Of the two stimuli, the making or cathodal stimulus is the stronger, and it follows, therefore, *Werigo, "Pfluger's Archiv," 84, 547, 1901. See Biedermann, " Elec- trophysiology," translated by Welby, vol. ii, p. 140. 90 THE PHYSIOLOGY OF MUSCLE AND NERVE. that when the strength of the current is diminished there will come a certain point at which the anodal stimulus will drop out. With weak currents there is then a stimulus only at the make. On the other hand, when very strong currents are used the stimuli that act at the two poles set up nerve impulses whose passage to the muscle may be blocked by the depressed conductivity caused by the electro- tonic changes. Whether or not the stimulus will be effective in causing a contraction in the attached muscle will depend naturally on the relative positions of the electrodes, — that is, on the direction of the current in the nerve. In describing the effect of these strong currents we must distinguish between what are called ascending and descending currents. Ascending currents are those in which the direction of the current in the nerve is away from the muscle, a position of the poles, therefore, in which the anode is closer to the muscle. In descending currents the positions are reversed. Pfliiger's law of contraction or of stimulation takes account of the effect of extreme variations in the strength of the current and is usually expressed in tabular form as follows: The letter C indicates that the nerve is stimulated and causes a contraction in the attached muscle, and 0 indicates a failure in the stimulation (weak currents) or a failure in the nerve impulse to reach the muscle owing to blocking (strong currents) . Fig. 33. — Schema to show the arrangement of apparatus for an ascending and a descending current: A, ascending; D, descending. Ascending Current. Making. Breaking. Very weak currents . . C O Moderate " . . . .C C Very strong " ....O C Descending Current. Making. Breaking. c o c c c o The effects obtained with the strong currents are readily under- stood if we bear in mind the facts stated above regarding electro- tonus. When the current is ascending the stimulus on making starts from the cathode, but cannot reach the muscle because it is blocked by a region of anelectrotonus in which the conduc- THE PHENOMENON OF CONDUCTION. 91 tivity is depressed. The stimulus on breaking takes place at the anode and the impulse encounters no resistance in its passage to the muscle. With the descending current the cathode lies next to the muscle and the making or cathodal stimulus of course causes a contraction. On breaking, however, the impulse that is started from the anode is blocked by the depressed irritability in the cathodal region, which, as has been said, comes on promptly with strong currents and persists for a time after the current is broken. The Opening and the Closing Tetanus. — While the du Bois-Reymond law stated above expresses the facts as usually observed upon a nerve-muscle preparation, there are a number of observations which indicate that the excitation at the anode and the cathode during the passage of a current may give rise to a series of stimuli instead of a single stimulus. Thus with sensory nerves it is well known that the stimulation, as judged by the sensations aroused, continues while the current is passing instead of being limited to the moment of making or of breaking of the current. In this respect, as in stimulation by higli temperatures, the sensory fibers differ apparently from the motor. When a galvanic current is passed through the ulnar nerve at the elbow sensations are felt during the entire time of passage of the current. But in an ordinary nerve-muscle preparation it is also fre- quently observed that at the moment of opening the current a tetanic con- traction, persisting for some time, is obtained instead of a single twitch. This phenomenon is known as the opening tetanus or Bitter's tetanus, and Pfliiger has shown that the continuous excitation proceeds from the anode, since in the case of a descending current division of the nerve in the intrapolar region brings the muscle to rest. In the same way it frequently happens that upon closing the current through a nerve the muscle, instead of giving a twitch, goes into a persistent tetanic contraction. The tetanus in this case is designated as the closing or Pfliiger's tetanus. Both of these phenomena are observed, especially, when the irritability of the nerve is for any reason greater than normal. It should be added that the opening and the closing tetanus may be observed also in a muscle when the galvanic current is passed through it. Stimulation of the Nerves in Man. — For therapeutic as well as diagnostic and experimental purposes it often becomes desirable to stimulate the nerves, particularly the motor nerves, in man. We may use for this purpose either the induced (faradic, alternat- ing) current or the direct battery current (galvanic or continuous current) . In such cases the electrodes cannot be applied, of course, directly to the nerve; it becomes necessary to stimulate through the skin, and the so-called unipolar method is employed. The unipolar method consists in placing one electrode, the active or stimulating electrode, over the nerve at the point which it is desired to stimulate, while the other electrode, the inactive or indifferent electrode, is applied to the skin at some more or less remote part, usually at the back of the neck. The indifferent electrode is made large enough to cover several square centimeters of the skin, and one may conceive the threads of current as passing from it into the moist tissues of the body, and thence to the active electrode. As the threads of current condense to this latter electrode they pass through the motor nerve which lies under it, and if sufficiently in- 92 THE PHYSIOLOGY OF MUSCLE AND NERVE. tense, will stimulate the nerve. The arrangement is represented in the accompanying schema (Fig. 34), showing the disposition of the electrodes for stimulating the median nerve. At the indifferent electrode the sensory nerves of the skin are of course stimulated, but no motor response is obtained, as no motor nerve lies immediately under the skin. Moreover, the large size of this electrode tends to diffuse the current and thus reduce its effectiveness in stimulating. The active or stimulating electrode is small in size, particularly when induction currents are employed, so that the current may be condensed and thus gain in effectiveness. The dry surface of the skin is a poor conductor of the electrical current, and to reduce the resistance at the points at which the electrodes come in contact Fig. :^4. — Schema to show the unipolar method of stimulation in man. The anode, -f, is represented as the stimulating pole, applied over the median nerve. The cathode, — , is the indifferent pole. with the skin each is covered with cotton or chamois skin kept moistened with a dilute saline solution. Motor Points.— By means of the unipolar method nearly every voluntary muscle of the body may be stimulated separately. All that is necessary, when the induced current is used, is to bring the active electrode as nearly as possible over the spot at which the muscle receives its motor branch. A diagram showing these motor points for the arm is given in Fig. 35. In the same way the THE PHENOMENON OF CONDUCTION. 93 nerves of the brachial plexus and other nerve trunks may be stimulated very readily through the skin. 'When the induction current is used no distinction is made between the cathodic and anodic effects. When, however, the battery current is employed M. dcltoideus — Verv. fnuscrtloculaneuM M* biceps brachii M. br.tch Internuj Fig. 35. — Motor points in upper extremity. one may make the stimulating electrode either anode or cathode, and under these circumstances a marked difference is observed in the strength of the current that it is necessary to use to get a response. With the battery or galvanic current, in fact, one may distinguish four stimuli, the closing and the open- ing shock when the stimulating electrode is cathode and the closing and the opening shock when it is anode. The con- tractions resulting from these four stimuli are designated usually as follows: The cathoclol closing contraction, C C C; the cathodal opening contraction, C 0 C; the anodal closing contraction, A C C ; and the anodal opening contraction, A O C. If the minimal amount of current necessary to give each of these contractions is measured in milliamperes by means of a suitable ammeter, 94 THE PHYSIOLOGY OF MUSCLE AND NERVE. it will be found that the four stimuli are of different efficiencies. The usual relationship is expressed by the sequence C C C > A C C > A 0 C >C 0 C, although this sequence is subject to some individual variation. Certain pathological or traumatic lesions that cause the degeneration of the nerves may be revealed by the use of these methods of stimulation. The nerve trunk under such circumstances fails to respond to either form of stimulus, induced or galvanic. The muscle, on the other hand, while it fails to respond to induction shocks, is stimulated by the galvanic current and, indeed, may show an increased irritability toward this form of stimulus, although the contractions are more sluggish in character than in a muscle with a normal nerve supply. Certain qualitative changes in the reaction of the muscle to the galvanic current may also be noticed, for instance, the A C C is sometimes obtained with less current than the C C C. This qualitative and quantitative change in reaction to the galvanic current, and the loss of irritability to the induced cur- rent, constitute what is known as the reaction of degeneration. =*& Sc^^* 0$$ ±IA_ \M mm n Fig. 36. — Two schemata to show the relation between the physical and the physio- logical electrodes or poles. Each schema represents the forearm with the median nerve, ia. In / the stimulating electrode is the cathode; the threads of current which have started from the anode (the indifferent electrode) placed elsewhere, converge to this pole. Where these threads enter the nerve we have a series of physiological anodes, a', where they leave, a series of physiological cathodes, c. In // the stimulating electrode is the anode. The threads of current leave this pole to traverse the body toward the indifferent electrode (cathode). Where they enter and leave the nerve we have, as in the first case, physio- logical anodes and cathodes, now, however, on the opposite sides of the nerve. Distinction between Physical and Physiological Poles. — The facts stated above seem to show, at first sight, that by the unipolar method we may obtain both an opening and a closing shock at either the cathode or anode, — a result which is in apparent contradiction to the general law that the making or closing stimulus occurs only at the cathode and the breaking or opening stimulus only at the anode. This apparent contra- diction is readily explained when we remember that in the THE PHENOMENON OF CONDUCTION. 95 unipolar method the active electrode rests upon the skin over the nerve, and that the threads of current radiating from this point enter the nerve at one point and leave it at another. Evidently, therefore, so far as the nerve is concerned, there will be an anode where the current is considered as entering the nerve and a cathode where it leaves it, so that under the active electrode, whether this is physically an anode or cathode, there will be, as regards the nerve, a series of what may be called physiological cathodes and anodes. The closing shock arises at these cathodes, the opening shock at the anodes. The position of the series of anodes and cathodes will vary according as the active electrode is an anode or cathode, as is indicated in the accompanying diagram (Fig. 36). CHAPTER IV. THE ELECTRICAL PHENOMENA SHOWN BY NERVE AND MUSCLE. The Demarcation Current. — Our definite knowledge of the electrical properties of living tissue began with the celebrated in- vestigations of du Bois-Reymond* (1843). When a muscle or nerve is removed from the body, and, in the case of the muscle, when one tendinous end is cut off, it is found that the cut end has an electrical potential differing from that of the uninjured longi- tudinal surface of the preparation. Following the usual nomen- clature, the cut end is electronegative as regards the longitudinal surface. If, therefore, the longitudinal surface is connected by a conductor with the cut; surface a current will flow from the former to the latter, as is indicated in the accompanying diagram. Fig. 37. — Schema showing the course of the demarcation current in an excised nerve, when a point on the longitudinal and one on the cut surface are united by a conductor. While the direction of the current through the conductor con- necting the two points is from the longitudinal to the cut surface the current may be considered as being completed in the opposite direction within the substance of the muscle or nerve, as shown in the diagram. We may, in fact, consider an excised nerve or muscle as a battery, the cut end representing the zinc plate and the longitudinal surface the copper plate. Within the battery the direction of the current is from zinc to copper, from cut end to longitudinal surface; outside the battery the direction is from copper to zinc, from longitudinal to cut surface. If two wires are connected with the muscle or nerve the end of the one attached to the longitudinal surface will represent the positive pole or anode, the end of the one attached to the cut end will represent the cathode * "Untersuchungen iiber thierische Elektricitiit," du Bois-Revmond, 1848-1860. 96 ELECTRICAL PHENOMENA. 97 0 or negative pole. On joining the ends of the wires a current will pass from positive to negative pole. A current of this character from an excised nerve or muscle is, of course, small in amount and to detect it one must make use of a delicate electrometer of some sort (see below). Du Bois- Reymond considered that the difference in electrical potential which gives rise to this current exists normally in the muscle, although masked by an opposite condition in the tendinous ends, and he therefore spoke of the currents as the natural muscle or natural nerve currents. It has since been shown by Hermann that this view is incorrect; that the perfectly normal uninjured muscle or nerve has the same electrical potential throughout and will therefore give no current when any two points are con- nected by a conductor. Moreover, the completely dead muscle or nerve shows no current. The difference in poten- tial that is found in the excised nerve or muscle is due, according to Hermann, to the fact that at the cut end the nerve or muscle is injured. The chemical changes that take place as a result of the injury make the tissue electronegative as regards the un- changed living substance elsewhere. For this reason Hermann described the current as a demarcation current; others have called it the current of injury. The nature of the changes at the injured end are not known. It is inter- esting to note that Bernstein * has shown that the electromotive force of the muscle current increases with the temperature, a fact which leads him to conclude that the difference in potential between the longitudinal and cut surface of the muscle depends upon a difference in concentration of the electrolytes. The muscle, in fact, acts after the manner of a "concentration cell." Such a difference in concentration may pre-exist in the normal mus- cle, or, according to the view adopted above, is developed as the result of injuring one end of the muscle. It may be supposed that the injury causes changes which result in the formation of new organic or inorganic electro- lytes and thus increases the concentration at that point. From what is known of the chemical changes in muscle it is safe to assert that there is an increased production of lactic acid at the injured end, and it is probable that other electrolytes may be liberated in diffusible form. With this increased concentration at the injured area a development of electric potential might be expected, owing to the probability that the cations (H, K, Na, Mg, Ca) will diffuse off more rapidly and thus leave the injured end with a negative charge. Experiments made by Urano and von Frey on muscle juice squeezed out of the muscle fibers under high pressure have shown that when it is diffused against sugar solutions it loses its K and Mg more rapidly than the P04 and S04. * "Pfliiger's Archiv," 1902, 92, 521. 7 Fig. 38. — Schema showing the principle of construction of the galvanometer: M, The mag- net suspended by a thread; B, the battery, with the wires lead- ing off the current encircling the magnet. yb THE PHYSIOLOGY OF MUSCLE AND NERVE. Means of Demonstrating the Muscle Current. — The demarcation current and other electrical conditions to be described require especial appara- tus for their study. To detect the existence of a current physiologists use either a galvanometer or a capillary electrometer. The galvanometers employed are of several types, the Kelvin reflecting galvanometer, the d'Arsonval form, and more recently the "string-galvanometer" of Einthoven. The principle of the galvanometer lies in the fact that a magnetic needle is deflected when an electrical current passes through a wire in its vicinity. If a magnetic needle is swung by a delicate thread so as to move easily, it will come to rest in the magnetic meridian with its north pole pointing north. If now a wire is curved round it, as shown in the accompanying diagram (Fig. 38), and a battery current is sent through this wire, the needle will be deflected to the right if the current passes in one direction and to the left if it passes in the opposite direc- tion. The movement of the needle is an indication of the presence and direction of the electrical current in the wire. The extent of deflection of the needle may be used to measure the strength of the current by ascertaining Fig. 39. — D'Arsonval galvanometer as modified by Rowland. the amount of deflection caused by a standard battery. The effect of the current upon the needle increases with the number of turns of wire, so that delicate galvanometers constructed upon this principle are spoken of as high resistance galvanometers, the great length of wire used making, of course, a high resistance. Instead of having the coil through which the current passes kept in a fixed position and the magnet delicately swung or poised, the reverse arrangement may be used — that is, the coil may be swung between the poles of a fixed magnet. Under these circumstances, if a current is sent through the coil, this latter will move with reference to the magnet . A galvanometer con- structed on this principle is designated as a d'Arsonval galvanometer, after the physiologist who first employed this arrangement. In the d'Arsonval form the magnet is fixed while the coil of wire through which the current passes is swung by a very delicate thread of quartz, silk fiber, or phosphor- bronze. The principle of the arrangement is shown in the accompanying diagram (Fig. 40) and one form of a complete instrument in Fig. 39. A large horseshoe magnet (n, s) is fixed permanently and between the poles is swung a coil (c ) of delicate wire, the two ends of the wire being connected with binding posts in the frame of the instrument. The coil is held in place below by a delicate spiral. In Fig. 40 it will be seen that the delicate thread suspending ELECTRICAL PHENOMENA. 99 the coil carries just above the coil a small mirror, m, and a plate of thin mica or aluminum. The mirror is deflected with the coil, and when viewed through the telescope pictured in Fig. 39 the image of the scale above the telescope is reflected in this mirror. As the coil and mirror are twisted by the action of the current passing through the former the reflection of the scale in the mirror is displaced. By means of a cross hair in the telescope the angle of deflection may be read upon the reflected scale. The aluminum vane back of the mirror makes the system dead-beat, so that when a deflection is obtained Fig. 40. — Diagram of struc- ture of the d'Arsonval galvanom- eter, c is the coil of fine wire through which the current is passed. It is swung by a fine thread of phosphor-bronze so as to he between and close to the poles — (ji) north pole, and (s) south pole — of the magnet. Just above the magnet the thread car- ries a mica or aluminum vane to which is attached a small mirror. The scale of the instrument is re- flected in this mirror and is observed through the telescope shown in Fig. 38. Fig. 41. — Schema of capillary electrometer arranged to show the demarcation current in muscle {Lombard) : a, The glass tube containing mercury and drawn to a fine capillary below; c, the receptacle containing mercury by raising which the mercury can be driven into the capil- lary of a; f, a vessel with glass sides containing mercury below, and above dilute sulphuric acid into which the capillary of a dips; E, the micro- cope for observing the mercury thread in the capillary; to, the muscle; g and h, the wires touching the longitudinal and cut surfaces of the muscle. The current flows as indicated by the smaU arrows ; d, the capillary thread of mercury as seen under the microscope. the system comes quickly to rest with few or no oscillations. If the coil of wire contains sufficient turns, enough to give a total resistance of two to three thousand ohms, and the poles of the magnet are brought very close to the coil, the instrument may be given a delicacy sufficient to study accurately the muscle and nerve currents. In such an instrument the effect of the earth's magnetism may be neglected and the galvanometer may be hung upon any support without reference to the magnetic meridian. The movable system of this galvanometer possesses considerable inertia, so that it will not indicate accurately the presence or extent of very brief electrical currents such as have to be studied in physiology in some cases. 100 THE PHYSIOLOGY OF MUSCLE AND NERVE. For purposes of this kind the string-galvanometer or the instrument knows as the capillary electrometer is employed. The String-galvanometer. — In this instrument a very delicate thread of silvered quartz or of platinum is stretched between the poles of a strong magnet, as is represented in the diagrams given in Figs. 42 and 43. The b--~ Fig. 42. — One form of the string-galvanometer : E, The electromagnet; b, the projection microscope; F, a screw for varying the tension of the thread. — (Edehnann's Catalogue.; u Fig. 43. — Schema to show the relation of the thread to the magnets in the string- galvanometer : A A, The delicate thread of silvered quartz or of platinum, stretched between the polar pieces (PP) of an electromagnet. When a current passes through AA, the thread shows a movement. The ends of the magnets are pierced by holes, seen in P\, through which the movements of the thread may be watched by means of a microscope or be pro- jected upon a photographic plate. — (After Einthoven.) metal poles of the magnet are pierced by holes, so that the thread may be illuminated by an electric light (Nernst lamp) from one side, and on the other the shadow of the thread may be thrown upon a screen after being magnified by a microscope (see Fig. 42). With this arrangement the thread shows a ELECTRICAL PHENOMENA. 101 3 lateral movement whenever a current is passed through it. The instrument may be made of great delicacy so as to detect very minute currents, and, moreover, it has the very great advantage of responding accurately to rapid changes in potential. If the shadow of the thread is allowed to fall upon sensitized paper properly adjusted upon a rotating surface, its movements may be photographed and a permanent record be thus obtained (see Fig. 22 for an example of such a photographic record showing the electrical changes in a contracting muscle) . The Capillary Electrometer. — The principle of the construction of the capillary electrometer is illustrated in Fig. 41. A glass tube, a, is drawn out at one end into a very fine capillary, the end of which dips into some diluted sulphuric acid contained in the vessel (/). At the bottom of this vessel is a layer of mercury connecting with a wire, g, fused into the glass vessel. The tube a is partially filled with redistilled mercury, which pene- trates for a short distance into the capillary. By means of pressure applied from above c, the mercury can be forced through the capillary. Then by diminishing the pressure the mercury can be brought back into the capillary a certain distance, drawing after it some of the dilute sulphuric acid. The mercury in tube a is connected with the other pole of the battery by a wire fused into its wall and dipping into the mercury. By regulating the pressure on the mercury the point of contact be- tween the thread of mercury and the sulphuric acid in the capillary, d, can be brought to any desired position. An equilibrium is then established which will remain constant as long as the conditions are not changed. If now the circuit from a battery or other source of electricity — for example, the excised nerve or muscle — is closed, the current entering by wire g, if this represents the anode, traverses the sulphuric acid and mercury in the capillary and returns by the wire h. At the moment of the establishment of the current the equilibrium of forces that holds the mer- cury at a certain point in the capillary is disturbed, the end of the mercury thread moves upward with the current for a certain distance, depending on the strength of the current and the delicacy of the capillary. If the current be passed in the opposite direction the mercury will move downward a certain distance. The meniscus of contact moves up or down with the direc- tion of the current, owing, it is supposed, to a change in the surface tension at this point. The capillary tube as used for physiological purposes is too small for the movements of the mercury to be detected with the eye. It is necessary to magnify it either with a microscope or a projection lantern. Ordinarily the electrometer is so made that it can be placed upon the stage of the microscope and the capillaries be brought into focus at the meniscus, as shown in d, Fig. 41. By means of proper apparatus the movement can be photographed and thus a permanent record be obtained of the direc- tion and extent of movement of the mercury. Non-polarizable Electrodes. — In connecting a muscle or nerve to an elec- trometer or galvanometer it is necessary that the leading off electrodes — that is, the point of contact between the wires and the muscle or nerve — shall be iso-electrical and non-polarizable. By iso-electrical is meant that the two electrodes shall have the same electrical potential, and it is obvious that the leading off electrodes must fulfil this condition approximately at least, since otherwise the current obtained from the muscle or nerve could not be attrib- uted to differences in potential in the tissue itself; it would be shown by any other moist conductor connecting the two electrodes. Two clean platinum electrodes would fulfil this condition. A more serious difficulty is found in - -2 Fig. 44. — To show the structure of a non- polarizable electrode: 1, The pad of kaolin or filter paper moistened with physiological sa- line (NaCl, 0.7 per cent.) (this is placed on the tissue) ; 2, the sat- urated solution of zinc sulphate; (3) the_ bar of amalgamated zinc. 102 THE PHYSIOLOGY OF MUSCLE AND NERVE. the polarization of metallic electrodes. Whenever a metal conductor and a liquid conductor come into contact there is apt to be polarization. What takes place may be represented by the following diagram, in which a current is supposed to be passing + A >■ + + + + Na Na Na Na CI CI CI CI <- between the poles A and C through a solution of sodium chlorid. During the passage of the current the cations, Na, with their positive charges move toward the cathode; at the cathode the free sodium ion acts upon the water, HHO, forming NaOH and liberating hydrogen, which gives its charge to the cathode and accumulates upon it in the form of gas. The anions, CI, with their negative charges move toward the anode; there the chlorin acts upon the water, forming HC1 and liberating oxygen. In conse- quences of these chemical actions at the poles an electromotive force is de- veloped at the cathode which diminishes the current passing from A to C. It is obvious that in quantitative studies of the electrical currents of animal tissues polarization will destroy the accuracy of the results; the demarcation current will show a diminution due not to changes in the nerve, but to physi- cochemical changes at the leading off electrodes. To prevent polarization du Bois-Reymond devised the non-polarizable electrodes consisting of zinc terminals immersed in zinc sulphate. Theoretically any metal in a solution of one of its salts may be used, but experience shows that the zinc-zinc sulphate electrode is most nearly perfect. Each electrode where it comes into contact with the tissue is made of one of these combinations. Various devices have been used. For instance, the electrode may be constructed as shown in the diagram (Fig. 44). A short glass tube of a bore of about 4 mms. is well cleaned — one end, which is to come into contact with the nerve — is filled, as shown, by a plug of kaolin made into a stiff putty with physiological saline solution of NaCl (0.7 per cent.). The kaolin should have a neutral reaction and unless good kaolin is obtainable it is better to use a plug made of clean filter paper macerated in physiological saline and packed tightly into the end of the tube. Above this plug the tube is filled in for a part of its length with a saturated solution of zinc sulphate into which is immersed a bar of amal- gamated zinc with a copper wire soldered to its end. With a pair of such electrodes the conduction of the current through the nerve or muscle to the metallic part of the circuit may be represented as follows: Zn > + + + + + + + Zn Zn Na Na Na Zn Zn S04 S04 CI CI CI S04 S04 Zn -< The liquid part of the circuit comes into contact with the metallic part at the junction of Zn and ZnS04. At the cathode it may be supposed that the Zn cation instead of acting upon the water and liberating hydrogen, deposits itself upon the zinc electrode; at the anode the sulphion (S04) attacks the zinc instead of the water, forming ZnS04. In this way polarization is prevented, and by the construction of the electrode the living tissue is brought into contact only with the plug of kaolin moistened with physio- logical saline. _ Such electrodes are indispensable in studying the electrical phe- nomena of living tissues, and also in all investigations bearing upon the polar effects during the passage of an electrical current from a battery. Ordinarily, however, when it is only desired to stimulate a nerve or muscle, metal (plat- inum) electrodes are employed. ELECTRICAL PHENOMENA. 103 The Action Current or Negative Variation. — Du Bois-Rey- mond proved that when the excised muscle or nerve is stimulated its demarcation current suffers a diminution or negative variation. If, for instance, the excised nerve gives a demarcation current suf- ficient to cause a deflection in the galvanometer of 50 mms., then if the nerve is stimulated by a series of induction shocks the galva- nometer will show a lessened deflection, say, one of 40 mms. The negative variation in this case is equal to 10 mms., on the scale of the galvanometer used. It has been shown that this negative varia- tion is due to a current in the opposite direction whose strength, in the example given, relative to that of the demarcation current is as 10 to 50. Frequently the phenomenon of the negative varia- tion is known also as the action current. The explanation given for this action current is that the nerve or muscle when excited takes on an electrical condition which is negative as regards any unexcited or less excited portion of the nerve. The effect upon the demarcation current is illustrated in the accompanying diagram. The demarcation current in a nerve is led off to a galvanometer by electrodes placed at b and c. When the nerve is stimulated at a the excitation set up passes along the nerve, and wherever it may be that portion of the nerve is thrown into an electronegative condi- tion. When this condition reaches a point at which it can influence the galvanometer — that is, when it reaches b, it will dimmish the difference in potential that exists between b and c, and therefore reduce the current flowing from b to c. _j_ Bernstein* has shown that this neg- ative condition moves in the form of a wave. That is, at any point the nega- tivity grOWS to a Fig 45.— Schema to indicate the method of detecting moyimnrr nnrl thpn the action current in a stimulated excised nerve: b and c, iiittJLiiiium ctiiu men the leading off electrodes, one on the longitudinal, one on diminishes. More- tne cut surface; the demarcation current passes through the galvanometer, gr, in the direction of the arrows; a, stimu- OVer, it travels at a lating electrodes from induction coil ; the stimulus causes a . „ . . . , negative condition, — which passes along the nerve ; when deiinite Velocity this reaches bit causes a partial reversal of the demarca- 1 • i • • i tion current, giving the negative variation or action cur- which is easily rent. measured. Accord- ing to his experiments, the velocity of this wave in the frog's motor nerve is from 25 to 28 meters per second, and the length of the wave is about 18 mms. Hermann, on the contrary, be- lieves that, in the excised nerve at least, the length of the wave may be greater, reaching perhaps 140 mms. * Bernstein, " Untersuchungen iiber den Erregungsvorgang im Nerven und Muskelsysteme," Heidelberg 1871. 104 THE PHYSIOLOGY OF MUSCLE AND NERVE. These figures will vary naturally for the nerves of different ani- mals or for different nerves in the same animal, for it must always be remembered that nerve fibers, whose functions in general are so similar, differ much in obvious microscopical structure and probably more widely in their chemical composition. Using an analogy that is familiar, we may say that when a stimulus acts upon a living nerve a wave of electronegativity spreads from the stimulated spot and travels in wave form witl a definite velocity, just as water waves radiate from the spot at which a stone is thrown into a quiet pool. A similar phenomenon occurs in muscle fibers when stimu- lated, but the negative condition travels over the muscle fiber at a slower speed, 3 to 4 meters per second in frog's muscle, and with a wave length, according to Bernstein, of only 10 rams. This wave of negativity in the muscle begins during the latent period and, therefore, precedes the actual shortening at any point, as shown in Fig. 48. This phenomenon of a negative electrical condition traveling over the nerve or muscle and giving us an active current when led off through a galvanometer is of the greatest physiological impor- tance, particularly in the study of nerves. It has been shown that in the nerve this wave of negativity marks the progress of the wave of excitation, and, since we can study its progress by means of the galvanometer or capillary electrometer, we can thus study the excitability and conductivity in nerves when removed from con- nection with their end-organs. That the negative wave, or the action current that it gives rise to, is an invariable sign of the passage of an excitation or nerve impulse is shown by the facts that it is absent in the dead nerve, and that in the living nerve it is produced by mechanical,* chemical, f and reflext stimulations, as well as by the more usual method of electrical stimulation. Herzen has claimed that under certain conditions of local narcosis the nerve fibers when stimulated may give an action current, but no muscle con- traction,— a fact which if true would seem to show that the excitation wave or nerve impulse and the wave of negative potential are not associated invariably. This result, however, has been denied by other competent observers (Wedenski, Boruttau). Monophasic and Diphasic Action Currents. — According to the conception of the action current given above, it is evident that it should be obtained upon stimulation when a living normal nerve is connected at any two points of its course with a galvanometer or capillary electrometer. The detection of the current under such * Rteinach, "Pfliiger's Archiv," 55, 487, 1894. tGrutzner, "Pfliiger's Archiv," 25, 255, 1881. % Boruttau, " Pfliiger's Archiv," 84 and 90, 1901-1902. ELECTRICAL PHENOMENA. 105 conditions offers more difficulties, because it is diaphasic, as will be seen from the accompanying diagram (Fig. 46). The figure represents a normal nerve led off to the galvanometer from two points, b and c, of its longitudinal surface. As these points in the uninjured nerve have the same potential, no current is shown by the galvanometer. If the nerve is stimulated at a by a single stimulus, a negative condition or charge passes along the nerve. When it reaches the point b, there will be a momentary current through the galvanometer from c to b; as the charge passes on to c, this point in turn will become negative to b, and there will be a momentary current through the galvanometer in the other direction. The diphasic current that occurs under these con- ditions cannot be detected by the ordinary galvanometer, even when a series of stimuli is sent into the nerve at a, since the movable system in this instrument has too much inertia to respond to such quick changes in opposite directions. With the more mobile string-galvanometer or capillary electrometer the diphasic currents have been demonstrated successfully. In laboratory investigations one of the leading off electrodes, c, is usually placed on the cut end of the nerve. Under this con- dition the action current becomes monophasic and shows itself as a negative variation of the demarcation current. This difference is due to the fact that a negative condition upon excitation depends upon a living condition of the nerve, and it cannot, therefore, affect the nerve at the electrode c if this latter is placed upon the cut end where the nerve is dead or dying. It will affect only the electrode b, and give only the monophasic current, which can now be shown by the usual galvanometer, provided a series of stimuli is thrown in at a. Fig. 46. — Schema to show the arrangement for obtaining a diphasic action current. The arrangement differs from that in Fig. 42 only in that both leading off electrodes, b and c, are placed on the longitudinal surface. No demarcation current is indicated. When the nerve is stimulated at a the negative charge reaches b first, causing a current through the galvanometer from c to b. Subsequently it reaches c and causes a second current in the opposite direction from b to c. The Positive Variation. — It happens not infrequently that when one electrode is placed upon the cut end, the nerve upon stimulation with a series of induction shocks gives a positive instead of a negative variation of the demarcation current. This result is usually explained as being due to a pre- dominance of the anelectrotonic currents (see below), but Wedenski has con- tended recently that it is due to a peculiar condition of excitation in the nerve 106 THE PHYSIOLOGY OF MUSCLE AND NERVE. at the cut end, a condition to which he gives the name of parabiosis. When this phenomenon occurs it can usually be avoided by making a fresh section at the end of the nerve. Detection of the Action Currents by the Rheoscopic Frog Preparation or by the Telephone. — The motor nerve of a nerve- muscle preparation from a frog is so extremely irritable to electrical currents that it may be used instead of a galvanometer to detect the action currents in a stimulated muscle. A nerve-muscle prep- aration used for this purpose is known as a rheoscopic preparation. The way in which it is used is indicated in the accompanying diagram, b represents the rheoscopic preparation, its nerve being laid upon the muscle whose currents are being investigated, a, so as to touch the cut end (x) and the longitudinal surface (g). When a is stimulated, either directly or through its nerve, as represented in the diagram, the negative charges that pass along the muscle fibers of a with each stimulus cause action currents that will be led off through the nerve of b from x to g. If the nerve is in a sensitive con- dition it will be stimulated by the action currents and thus a series of excitations will be sent into b corresponding exactly in rate with the artificial stimuli given to the nerve of a. The rheoscopic preparation may be used very beautifully to demonstrate the action current in the contracting heart muscle. If the nerve of b is laid upon the exposed beating heart of an animal, the muscle of b will give a single twitch for each beat of the ventricle. An- other interesting method of detecting the action currents, particu- larly in nerves, is by means of the telephone. Wedenski has made especial use of this method, the telephone being connected with Fig. 47. — Schema to show the arrangement of a rheoscopic muscle-nerve preparation: b. The rheoscopic muscle-nerve preparation, the nerve being arranged to touch the cut sur- face and the longitudinal surface of the muscle, a, whose action currents are to be detected. When the nerve of a is stimtilated each contraction of this muscle is followed by a contrac- tion of b, since each contraction of a is accompanied by an action current which passes through the nerve of b and stimulates it. the nerve in place of the galvanometer. The method has obvious advantages in the fact that it may be used with a nerve to which the muscle is also attached, so that the excitation processes in the nerve and their effect upon the muscle may be studied simul- taneously. ELECTRICAL PHENOMENA. 107 Relation of the Action Current to the Contraction Wave in Muscle and to the Excitation Wave (Nerve Impulse) in Nerve. — The action current or, to be more accurate, the moving negative charge which gives rise to an action current when two points of the muscle are led off to a galvanometer, has been shown by Bernstein to precede the wave of contraction in muscle; that is, in a stimulated muscle fiber the electrical change at any point precedes the mechanical process of shortening. When studied by means of the string-galvanometer it would seem, according to the curve reproduced in Fig. 48, that in a simple Li I i h ■t? ! : ! ' ' i ' I Fig. 48. — Photograph of the electrical variation in the frog's gastrocnemius muscle during a simple contraction, as given by the string-galvanometer : a, The electrical curve, showing two waves ; 6 (retouched to make it distinct), occurring during the latent period. This is followed by a smaller but longer wave, which begins at the moment of shortening of the muscle ; c, the break in this line indicates the moment of stimulation ; d, the curve of contraction of the muscle ; k, vibrations of a tuning-fork at the rate of 100 per second. — {Judin.) muscular contraction two electrical waves pass over the muscle: first, a quick extensive change in potential which occurs during the latent period and marks probably the passage of the wave of excitation; second, a slower wave accompanying the proc- ess of shortening. Paying attention only to the first of these waves, we may suppose that the electrical change is an indication of the excitation or possibly constitutes the excitation that sets up the chemical change of contraction, or else that the change in electrical potential is caused by the chemical change of contraction and precedes the mechanical result of shortening, since the latter process will have a certain latent period. It has been shown, indeed, by Demoor that a completely fatigued muscle may still 10S THE PHYSIOLOGY OF MUSCLE AND NERVE. conduct an excitation (muscle impulse), although unable to con- tract, and the same fact has been demonstrated by Engelmann for the heart muscle. In the nerve the action current, or the negative change causing it, has been considered as simultaneous with or possibly identical with the nerve impulse. The velocity of the two is identical; the action current is given whenever the nerve is stimulated, and, so far as experiments have gone, the nerve cannot enter into activity without showing an action current, — that is, without showing a moving electrical charge. Whether this electrical charge constitutes the nerve impulse or is simply an accompanying phenomenon will be discussed briefly in the paragraph upon the nature of the nerve impulse in the following chapter. The Electrotonic Currents. — In speaking of the effect of passing a galvanic current through a nerve attention was called to the fact that the condition of the nerve is altered at each pole. At the anode there is a con- dition of decreased irritability and con- ductivity known as anelectrotonus ; a t the cathode, in the beginning, at least, a condition of in- creased irritability known as catelec- trotonus. In addi- tion to these changes in the physiological properties of the nerve there is a change also in its electrical condition at each pole, of such a character that if the nerve is led off from two points on the anode side a current will be indicated. The current can be obtained at a considerable distance from the anode, and is known as the anelectrotonic current, while the electrical condition in the nerve that makes it possible is designated as anelectrotonus. A similar current can be led off from the nerve on the cathode side for a considerable distance beyond the cathode; this is known as the catelectrotonic current, and the electrical condition leading to its production as catelectrotonus. Within the nerve these electrotonic currents have the same direction as the battery or polarizing current, as is shown in the diagram (Fig. 49), The terms anelectrotonus and catelectrotonus are used, therefore, in physiology to designate both the physiological and the elec- Fig. 49. — Schema to show the direction of the elec- trotonic currents in an excised nerve: P, The battery for the polarizing current sent into the nerve at + , the an- ode, and emerging at — , the cathode; g', galvanometer arranged with leading off electrodes to detect the anelec- trotonic current, the direction of which is indicated by the arrows (in the nerve it is the same as that of the po- larizing current) ; g, galvanometer similarly arranged to de- tect the catelectrotonic current. The anelectrotonic and catelectrotonic currents continue as long as the polarizing current is maintained. ELECTRICAL PHENOMENA. 109 trical changes around the poles when a battery current is led into a nerve. Whether the physiological and the electrical changes have a causal connection or are two independent phenomena is at present undecided. Bethe* has recently shown that during the passage of the polarizing cur- rent the neurofibrils in the axis cylinder lose at the anode their power of stain- ing with certain basic dyes (e. g., methylene blue), while at the cathode the affinity for these dyes is increased. He assumes, that in the neurofibrils there is an acid substance — fibril acid — and that at the anode the combination with this body and the neurofibrils is loosened; hence the loss of staining power. At the cathode the reverse change takes place. He assumes further- Fig. 50. — To show the action of the core-model: p, The polarizing current; g' and g, the galvanometers with leading off electrodes to detect the anelectrotonic and eatelec- trotonic currents, respectively. more, that when the affinity between neurofibril and fibril acid is increased at the cathode an electronegative ion is liberated (anion), while at the anode at the time that the combination between fibril and fibril acid is dis- sociated an electropositive ion (cation) is liberated. In this way he constructs an hypothesis of a complex of neurofibril, fibril acid, and electrolyte which is capable of accounting for the electrotonus, both as regards the electrical and the physiological phenomena, and which refers both phenomena to a single reaction in the nerve. Another explanation of the electrotonic currents which has been much discussed is that first developed by Hermann, f This author constructed a model consisting of a conductor surrounded by a less conductive liquid sheath, and showed that such a model is capable of giving the electrotonic currents. This model may be made as represented in the accompanying diagram, of a glass tube A-B, through the middle of which is stretched a platinum wire, P, the rest of the tube being filled with a saturated solution of zinc sulphate. The glass tube is provided with vertical branches by means of which a polarizing current, p, can be sent into the solution of zinc sulphate and the electrotonic currents be led off to galvanometers, g' . g, on ■each side. Under these conditions a current similar to the anelectrotonic current can be detected on the side of the anode (g') and one equivalent to the catelectrotonic current on the side of the cathode (g). The explanation given to these currents is that as the threads of current pass into the platinum core there is a polarization at the surface between the core and the zinc sul- phate solution which extends to a considerable distance on each side of the electrodes and causes diffusion currents from sheath to core. It is these threads of current that may be led off as electrotonic currents. Hermann suggested that in the nerve we have a structure essentially similar to that of the core model. He thought that the axis cylinder might be considered ■as representing the core and the myelin the less conductive sheath corre- sponding to the zinc sulphate solution. Others (Boruttau) have suggested that * Bethe, " Allgemeine Anatomie u. Physiol, des Nervensystems," Leipzig, 1903. f Hermann, " Handbuch der Physiologie," vol. ii, p. 174. 110 THE PHYSIOLOGY OF MUSCLE AND NERVE. the neurofibrils in the axis cylinder may represent the core or cores and the sur- rounding neuroplasm the sheath, thus providing for the possibility of electro- tonic currents in non-medullated fibers. As a matter of fact, the non-medul- lated fibers in mammals give very slight electrotonic currents compared with the medullated fibers.* According to the "core-model" explanation, the electrotonic currents represent a purely physical phenomenon, which is dependent, however, upon a certain structure of the nerve. That is, a completely dead nerve will not show these currents, although an anesthetized nerve, in the mammal (Waller) at least, continues to show them, and, according to Sosnowsky, excised rab- bits' nerves kept in a moist atmosphere may show them for several days. While the core-model hypothesis has led to much investigation in physiology and has been made the basis for a purely physical explanation of the nerve impulse, it is still very uncertain whether it furnishes any positive informa- tion concerning the processes that actually take place in the living nerve wheD submitted to the action of electrical currents or other artificial stimuli. * Alcock, " Proceedings Royal Society," 1904, 73, p. 166. CHAPTER V. THE NATURE OF THE NERVE IMPULSE AND THE NUTRITIVE RELATIONS OF NERVE FIBER AND NERVE CELL. The question of the nature of the nerve impulse has always aroused the deepest interest among physiologists. It has consti- tuted, indeed, a central question around which have revolved vari- ous hypotheses concerning the nature of living matter. The impor- tance of the nerves as conductors of motion and sensation was apparent to the old physiologists, and the nature of the conduction or the thing conducted was the subject of many hypotheses and many different names. For many years the prevalent view was that the nerves are essentially tubes through which flows an ex- ceedingly fine matter, of the nature of air or gas, known as the animal spirits. Others conceived this fluid to be of a grosser struc- ture like water and described it as the nerve juice. With Galvani's discovery of electricity the nerve principle, as it was called, became identified with electricity, and, indeed, this view, as will be ex- plained, occurs in modified form to-day. Du Bois-Reymond, after discovering the demarcation current and action current in muscle and nerve, formulated an hypothesis according to which the nerve fibers contain a series of electromotive particles, and by this hypothesis and the facts upon which it was based he thought that he had established that " hundred-year-old dream" of phys- icists and physiologists of the identity of the nerve principle and electricity. His theory to-day has fallen into disrepute, but the facts upon which it was based remain, as before, of the deepest importance. In the middle of the nineteenth century those who were not convinced of the identity of the nerve principle with electricity believed, nevertheless, that the process of conduction in the nerve is a phenomenon of an order comparable to the trans- mission of light or electricity, with a velocity so great as to defy measurement. But in this same period a simple but complete experiment by Helmholtz demonstrated that its velocity is, as compared with light or with electrical conduction through the air or through metals, exceedingly slow. — 27 meters per second. Modern views have taken divergent directions; the movement or excitation that is conducted along the fiber has been named 111 112 THE PHYSIOLOGY OF MUSCLE AND NERVE. the nerve principle, the nerve energy, the nerve force, the nerve impulse. As the latter term is less specific regarding the nature of the movement, and emphasizes the fact of the conduction of an isolated disturbance or pulse, it seems preferable to employ it until a more satisfactory solution of its nature has been reached. The Velocity of the Nerve Impulse.— The determination of the velocity of the nerve impulse was first made by Helmholtz* upon the motor nerves of frogs. His experiment consisted in stimulating the sciatic nerve, first, near its ending in the muscle Fig. 51. -Record to show the method of estimating the veloc tyof the nerv e imp ulse in a motor nerve. The experiment was made upon a ner^muscle pr ef™XlumVy£ frog, the contractions bring recorded upon the rapidly moving plate , of a Pe™ulum «££ graph. Two contractions were obtained, the first a) when the .nerve '™*f 'f™^ the near the muscle, the second (b) when the nerve was stimulated as far as] possible inm™ muscle The latent period of the second contraction was longer, as shown by the dbtance between the curves measured on the line x The value of this c hsta ace in t lme is^ ob ta ned hv reference to the record of a tuning fork vibrating 100 times per secon,a'nv;^'V* ^J^, on the lower line. In the experiment the length of a tuning fork wave (0.01 "■)"•* mm^, the distance between the two muscular contractions was '3.35 mms anjcityof tte tance between the points stimulated upon the ^^ef^^^ ^^J^f^l 16 m) nerve impulse in this experiment was 49 dividedby (oWff X T?o) or 30716 mms. {6V., lom.j per second. and second, near its origin from the cord, and measuring the time that elapsed in each case between the moment of stimulation and the moment of the muscular response. It was found that when the nerve was stimulated at its far end this time interval was longer and since all other conditions remained the same this dif- ference in time could onlv be due to the interval required for the nerve impulse to travel the longer stretch of nerve. In the accom- * Helmholtz, " Muller's Archiv f. Anat. u. Physiol.," 1852, p. 199. NATURE OF THE NERVE IMPULSE. 113 panying figure the record of a laboratory experiment of this kind is reproduced. Knowing the difference in time and also the length of nerve between the points stimulated, the data are at hand to calculate the velocity of the impulse. The velocity varies with the temperature. According to Helmholtz, this variation lies between 24.6 and 38.4 m. per second for a range of temperature between 11° and 21° C. For average room temperatures we may say that in the motor nerves of the frog the impulse travels with a velocity of 28 to 30 meters per second. Similar experiments have been made upon man and other mammals. Helmholtz stimulated the median nerve in man at two different points and recorded the resulting contractions of the muscles of the thumb. By this means he obtained an average velocity of 34 m. per second, but others, making use of the same method, have reported varying results. Quite recently Piper* has applied the string- galvanometer to the investigation of this point. Using the unipolar method, he stimulated the median nerve with induction shocks, the active electrode being applied at the elbow and at the axilla at a distance apart of from 160 to 170 mm. The muscular response was recorded not by registering the con- traction, but by means of its action current. "When the stimulus was applied at the elbow the interval between the stimulation and the electrical response averaged 0.00442 second; at the axilla the interval was 0.00578 second. The difference, namely, 0.00136 second, gave the time necessary for the impulse to travel over 160 to 170 mm. of nerve, and indicated a velocity of 117 to 125 m. per second. It is interesting to recall that only six years before Helmholtz's first pub- lication Johannes Miiller had stated that we should never find a means of determining the velocity of the nerve impulse, since it would be impossible to compare points at great distances apart, as in the case of the movement of light. " The time," said he, " required for the transmission of a sensation from the periphery to the brain and the return reflex movements of the mus- cles is infinitely small and unmeasurable." The mode of reasoning by which Helmholtz was led to doubt the validity of this assertion is interesting. He says (" Midler's Archiv," 1852,330): "As long as physiologists thought it necessary to refer nerve actions to the movement of an imponderable or psychical principle, it must have appeared incredible that the velocity of this movement could be measured within the short distances of the animal body. At present we know from the researches of du Bois-Reymond upon the electro- motive properties of nerves that those activities by means of which the con- duction of an excitation is accomplished are in reality actually conditioned by, or at least closely connected with an altered arrangement of their material particles. Therefore conduction in nerves must belong to the series of self- propagating reactions of ponderable bodies, such, for example, as the con- duction of sound in the air or elastic structures, or the combustions in a tube filled with an explosive mixture." One of the first fruits, therefore, of the scientific investigation of the electrical properties of the nerve fiber was the discovery of the important fact of the velocity of the nerve impulse. * Piper, "Archiv f. d. ges. Physiologie," 1908, 124, 591. 114 THE PHYSIOLOGY OF MUSCLE AND NERVE. Numerous efforts have been made to determine the velocity of the nerve impulse in medullated sensory fibers. The results have not been entirely satisfactory. The end-organ in this case is the cortex of the cerebrum, and its reaction consists in arousing a sensation, or a reflex action. Neither end-reaction can be meas- ured directly. Attempts have been made to determine it indi- rectly by noting the time of a voluntary muscle response for sensory stimuli applied to the skin at different distances from the spinal axis. In such cases the sensory impulse travels to the cord, thence to the brain, and the return motor impulse travels from brain to cord and then by the motor nerves to the muscle used for the re- sponse. The results of this method have been discordant, owing probably to the fact that the central paths from two different points on the skin are not identical. It is usually assumed — without, however, very convincing proof — that the velocity of the impulse in the medullated afferent nerve fibers is the same as in the efferent fibers. A large number of observations are on record which show that the velocity varies greatly in the nerves of different animals. In the mammal, according to Chauveau, the velocity for the non-medullated fibers is only 8 meters per second; in the lobster it is 6 meters per second; in the octopus, 2 meters; in the olfactory (sensory) nerve of the pike, A meter, and in the anodon, only yt5 meter per second. Relation of the Nerve Impulse to the Wave of Negativity. — A fact of great significance is that the velocity of the impulse in the motor nerves of the frog corresponds exactly to the velocity of the wave of negativity as measured by Bernstein. Evidently the two phenomena are coincident in their progress along the fiber, and physiologists generally have accepted the existence of an action cur- rent as a proof of the passage of a nerve impulse. This belief is strengthened by the fact that, as stated above, the negative wave ac- companies the nerve impulse not only when the nerv e is stimulated by electrical currents, but also after mechanical, chemical, or reflex stimulation. The question has been raised as to whether this elec- trical phenomenon accompanies the normal nerve impulse, — that is, the nerve impulse that originates in the nerve centers, in the case of motor nerves, or in the peripheral sense organs in the case of sen- sory nerves. In regard to the latter relation we have positive evi- dence that when light falls upon the living retina an electrical distur- bance is produced by the visible rays of the spectrum,* and there is every reason to believe that the passage of visual impulses along the optic nerve is accompanied by an electrical change. With regard to normal motor impulses, the evidence is also positive that motor discharges from the central nervous system are accompanied * Consult Gotch, "Journal of Physiology," 31, 1, 1904. NATURE OF THE NERVE IMPULSE. 115 by a wave of electrical potential. This fact may be shown by stimulating the motor areas in the cerebral cortex and testing the efferent nerves, such as the sciatic, for an action current; or by stimulating a posterior root on one side in the lumbar region and testing the sciatic nerve on the other side with a galvanometer.* Moreover, all influences that alter the velocity or strength of the nerve impulse affect the intensity of the action current in the same manner. It is believed generally, therefore, that the electrical charge is an invariable accompaniment of the excitatory wave, and the demonstration of an action current in a nerve is tantamount to a proof of the passage of a nerve impulse. Direction of Conduction in the Nerve. — The fact that under normal conditions the motor fibers conduct impulses only in one direction — i. e., toward the periphery — and the sensory fibers in the opposite direction — that is, toward the nerve center — suggests, of course, the question as to whether the direction of conduction is conditioned by a fundamental difference in structure in the two kinds of fibers. No such difference in structure has been revealed by the microscope, although in two respects at least it will be re- membered that the sensory nerve fibers react differently from the motor fibers — namely, in the fact that they are readily stimulated by high temperatures and that during the passage of a galvanic current of constant strength they are stimulated continuously in- stead of only at the opening or closing of the current. These latter differences, however, may rest simply upon a difference in irrita- bility and have no bearing upon the question in hand. It is the accepted belief in physiology that any nerve fiber may conduct an impulse in both directions, and does so conduct its impulses when the fiber is stimulated in the middle of its course. An entirely satisfactory proof for this belief is difficult to furnish unless the conclusion in the preceding para- graph is admitted, — the conclusion, namely, that the electrical change is a necessary and in- variable accompani- ment of the nerve Fig. 52.— Schema to show the arrangement for proving . T . the propagation of the negative charge in both directions: impulse. It IS not a. The stimulating electrodes; g and g', galvanometers j'm ij. -l i i with leading off electrodes arranged to show the negative difficult tO Show by variation on each side. means of a galva- nometer that when a nerve trunk is stimulated the negative charge spreads in both directions from the point stimulated and * Gotch and Horsley, "Phil. Trans., Royal Soc," London, 1891, vol. 182 (B), and Boruttau, " Pfliiger's Archiv," 1901. 116 THE PHYSIOLOGY OF MUSCLE AXD NERVE. gives an active current on either side, as indicated in the accom- panying diagram. This fact holds true for motor or for sensory fibers. The older physiologists attempted to settle this question in a more direct way, but by methods which later experiments have proved to be insufficient. They attempted, for instance, to unite a motor and sensory trunk directly, to cut the hypoglossal (motoi ) and the lingual (sensory) and suture, say, the central stump of the lingual to the peripheral stump of the hypoglossal. If stimu- lation of this latter trunk, after union had been established, gave signs of sensation it was considered as proof that the efferent hypo- glossal fibers were now conducting afferently. We now know that in such a case the old hypoglossal fibers degenerate completely, and the new ones that are eventually formed in their place are out- growths from the lingual stump, or at least are not the old efferent fibers, and hence experiments of this kind are not so conclusive as they seemed to be at the time when it was supposed that severed nerve fibers can unite immediately, by first intention, without previous degeneration. A similar objection applies to Paul Bert's often quoted experiment. Bert implanted the tip of a rat's tail into the skin of its back. After union had taken place the tail was severed at the base, and the stump now attached to the back was tested from time to time as to its sensibility. Sensation returned slowly. At first it was indefinite, but by the end of a year was apparently normal. Modification of the Nerve Impulse by Various Influences — Narcosis — Temperature. — The strength of the impulse and its velocity may be modified in various ways: by the action of temperature, narcotics, pressure, etc. Variations of tempera- ture, as stated before, change the velocity of propagation of the impulse, the velocity increasing with a rise of temperature up to a certain point. So also the irritability as well as the con- ductivity of the nerve fiber is influenced markedly by tem- perature. If a small area of a nerve trunk be cooled or heated, the nerve impulse as it passes through this area may be increased or decreased in strength or may be blocked entirely. Different fil:°rs show somewhat different reactions in this respect; but, speaking generally, the limits of conductivity in relation to temperature lie between 0° C. and 50° C. Cooling a nerve to 0° C. will in most cases suspend the conductivity, but this function returns promptly upon warming.* By this means we can block the nerve impulses in a nerve trunk for any desired length of time. The exact relationship between the temperature of the nerve and the velocity of the impulse has been studied carefully with the object of determining the temperature coeffi- * Howell, Budgett, and Leonard, "Journal of Physiology," 16, 298, 1894. NATURE OF THE NERVE IMPULSE. 117 dent. It has been shown by van't Hoff that the velocity of chemical reactions is increased twofold or more for each rise of 10 degrees in temperature, that is, the temperature coefficient for chemical reactions lies between 2 and 3. On the other hand, with most physical processes the temperature coefficient for the same range of temperature lies around 1 or between 1 and 2. Snyder* finds, on comparing the velocities of the impulse at different temperatures, that they follow van't Hoff's law for chemical reactions, that is, the velocity is approximately doubled by a rise of 10° C. in temperature within physiological limits, velocity at Jn or, expressed in more general terms, = 2. This velocity at Tn effect of temperature on the velocity of the impulse is shown graphically in Fig. 53. Anesthetics and narcotics,! such as ether, Fig. 53. — Figure to show the effect of temperature on the velocity of the nerve impulse. At each temperature two contractions of the gastrocnemius were recorded, one when the nerve was stimulated close to trie muscle, one when it was stimulated further away (44 mm.). The horizontal distance between the curves as they rise can be expressed in time by refer- ence to the tuning-fork vibrations (200 per second) given below. For intervals of 10° C. it will be seen that the velocity, as indicated by the reciprocals of the distances between the pairs of curves, indicates a coefficient of two. — {Snyder.) chloroform, cocain, chloral, phenol, alcohol, etc., may be applied locally to a nerve trunk, and if the application is made with care the conductivity and irritability may be lessened or suspended entirely at that point, to be restored again when the narcotic is removed. It is an interesting fact that the conductivity of the nerve may be suspended also by deprivation of oxygen, J — that is, by local suffocation or asphyxia. A nerve fiber sur- rounded by an oxygen-free atmosphere will slowly lose its conductivity, and this property will be restored promptly upon the admission of oxygen. Compression of a nerve will also suspend its conductivity without permanently injuring the * Snyder, "American Journal of Physiology," 22, 179, 1908. t Frohlich, "Zeitschrift f. allgemeine Physiol.," 3, 75, 1903. % Baeyers, ibid., 2, 169, 1903. 118 THE PHYSIOLOGY OF MUSCLE AND NERVE. fibers, provided the pressure is properly graduated. Lastly, as was explained in a preceding chapter, the conductivity of the nerve may be increased or decreased or suspended entirely by the action of a galvanic (polarizing) current. This method of sus- pending conductivity temporarily has been frequently employed for experimental purposes, the arrangement being as represented in Fig. 54. The Question of Fatigue of Nerve Fibers. — An important question in connection with the nature of the nerve impulse has been that of the suscep- tibility of the nerve fibers to fatigue. The obvious fatigue of muscles and of nerve centers has been referred to the accumula- tion of the products of metabolism of their tis- sues or to the actual consumption of the en- ergy-yielding material in them. Functional activ- ity in these tissues im- plies the breaking down of complex organic material (catabolism) and the setting free of the so-called chemical energy. The potential, chemical or internal energy of the compound is liberated as kinetic energy of heat, etc. It has been accepted, therefore, that, if the nerve fiber could be demonstrated to show fatigue as a result of functional activity, this fact would be probable proof that the conduction of the im- pulse is associated with a chemical change of a catabolic nature in the substance of the fiber. Experimental work, however, has shown that under normal conditions the nerve fiber shows no fatigue. The experiments made upon this point have been nu~ merous and varied. The general idea underlying all of them has been to stimulate the nerve continuously, but to interpose a block somewhere along the course of the nerve so that the impulses should not reach the end-organ. This precaution is necessary because the end-organ — muscle, gland, etc. — is subject to fatigue, and must therefore be protected from constant activity. From time to time or at the end of a long period of stimulation the block is removed and it is noted whether or not the end-organ — for in- stance, the muscle — gives signs of a stimulation. The removable block has been obtained by the action of a polarizing current, by cold, by narcotics, by curare, etc. Using curare, for instance, \5 Fig. 54. — Schema to show the method of block- ing the nerve impulse by means of a polarizing cur- rent: a, The stimulating electrodes; b, the battery, the current of which is led into the nerve. The de- pressed irritability at both anode, +, and cathode, ; — , prevents the nerve impulse started at a from reaching the muscle. NATURE OF THE NERVE IMPULSE. 119 Bowditch* found that the sciatic nerve might be stimulated continu- ously by induction shocks for several (four to five) hours without complete fatigue, since as the curare effect wore off the muscle whose contractions were being recorded (M. tibialis ant.) began to respond, at first with single and finally with tetanic contractions. The curare in this case may be supposed to have blocked the nerve impulse at the motor end-plate and thus protected the muscle from responding until the lapse of several hours, although the nerve was under stimulation during this entire time. This experiment has since been repeated by Durig, f who has made use of the fact that the effects of curare can be removed within a few minutes by the salicylate of physostigmin. Durig stimulated the nerve for as much as ten hours and then upon removing the curare block found from the contraction of the muscle that the nerve was still conducting. EdesJ and others have shown that the same result is obtained when the nerve is tested by a capillary electrometer instead of by the response of an end-organ. Under such conditions the nerve exhibits an undiminished action cur- rent, although constantly stimulated by tetanizing shocks from an induction apparatus. Brodie and Halliburton § have found that the non-medullated fibers in the splenic nerve can also be stimulated for many hours without losing their power of conduction, — that is, without showing fatigue. Many other observers have obtained similar results, which have confirmed physiologists in the belief that the nerve fibers may conduct impulses indefinitely, or, in other words, that their normal functional activity may be carried on continuously without fatigue. If this belief is entirely correct it would place the nerve fibers in a class by themselves, since all other tissues that have been studied show evidence of fatigue when kept in continuous functional activity. Moreover, if this belief is entirely correct it would imply that the conduction of an impulse in the nerve fiber is not associated with a consumption of material, a metabolism, and in this respect also the functional activity of the nerve would be placed in contrast with that of other organs. It must be remembered, however, that, although the above ex- periments demonstrate the practical " unfatigueableness " of nerve fibers under ordinary conditions of stimulation, there are some reasons to make us hesitate in supposing that in these structures functional activity is entirely without a depressing effect upon irritability. In the first place it has been shown that the nerve exhibits the phenomenon of a "refractory period." That is to say, for a certain brief interval after stimulation it is * Bowditch, "Journal of Physiology," 6, 133, 1885. t Durig, "Centralblatt f. Physiol.," 15, 751, 1902. t Edes, " Journal of Physiology," 13, 431, 1892. g Brodie and Halliburton, " Journal of Physiology," 28, 181, 1902. 120 THE PHYSIOLOGY OF MUSCLE AND NERVE in a non-irritable condition. If two stimuli be applied to a nerve with a very brief interval between (0.006 sec. or less, according to the temperature), the second stimulus is ineffective so far as can be determined by the response of an attached muscle or by means of a capillary electrometer.* It may very well be that in this case the lack of response to the second stimulus is due to a short-lasting fatigue from the first stimulus. This point of view is strengthened by the fact that, when the irritability of the nerve is greatly depressed by narcotics, f this critical interval is much lengthened; two stimuli with a rate of more than 10 per second may give an effect only for the first stimulus, and, indeed, in a nerve treated with yohimbin the refractory period may extend over two seconds (Tait). Garten has shown that one nerve, the olfactory of the pike, when stimulated by induction shocks, with an interval between the stimuli of as much as 0.27 sec, gives evidence of fatigue, since its action current, as measured by the capillary electrometer, diminishes in extent quite rapidly, and recovers after a short rest. J So also it has been found that while a nerve deprived of oxygen, by keeping it in an atmosphere of nitrogen, loses its irritability after a certain time, this event occurs much more rapidly if the nerve is stimulated constantly. § This fact would suggest that some oxygen is consumed during functional activity, and that the ability of the nerve under normal circum- stances to escape the results of fatigue may be due possibly to the fact that the supply of oxygen is sufficiently abundant to oxidize promptly the fatigue substances formed during activity. Does the Nerve Fiber Show Any Evidence of Metabolism During Functional Activity? — The functional part of a nerve fiber in conduction is the axis cylinder, and, indeed, probably the neurofibrils in the axis cylinder. The mass of this material, even in a large nerve trunk, is small (about 9 per cent.), and its chemistry is but little known. The efforts that have been made to prove a metabolism in the nerve fiber during activity have been directed along the lines indicated by what is known of muscle metabolism. In a muscle during contraction heat is produced, the substance of the muscle shows an acid reaction, and among the products formed carbon dioxid gas is perhaps the most prominent. Efforts to show similar reactions in stimulated nerves have been unsuccessful. Rol- leston|| investigated the question of heat production with the aid of a delicate bolometer capable of indicating a difference of tempera- * Gotch and Burch, "Journal of Physiology," 24, 410, 1899. t Frohlich, "Zeitschrift f. allgemeine Physiol.," 3, 468, 1904. t Quoted from Biedermann, "Ergebnisse der Physiologie," vol. ii, part ii, p. 129. 3 Thorner, "Zeitschrift f. allg. Physiologie," 8, 530, 1908. Rolleston, "Journal of Physiology," 11, 208, 1890. NATURE OF THE NERVE IMPULSE. 121 ture of go^o0 C. The frog's sciatic was used, but no increase in temperature during stimulation could be demonstrated. Xo change in reaction can be obtained by means of the usual indicators for acidity. Waller has given some experiments to show that car- bon dioxid is produced during activity, but they are far from being conclusive. His line of argument is as follows: He has found that the action current of a nerve that is being stimulated is increased by the presence of very slight amounts of carbon dioxid, higher percent- ages causing again naturally a decrease. This reaction for the pres- ence of carbon dioxid is apparently a very delicate one. When now a normal nerve is stimulated, its action current after some minutes of tetanic stimulation is increased in the same way as would happen if a little carbon dioxid was passed over it. He con- siders that this temporary increase in the action current is due to the formation of carbon dioxid from a functional metabolism. More positive evidence for the occurrence of a nerve metabolism during activity is found in the fact, already alluded to, that oxygen plays a part in maintaining the irritability of nerves. An excised frog's nerve loses its irritability in an atmosphere deprived of oxygen and regains it promptly when oxygen is again supplied. When stimulated in an atmosphere free from oxygen the nerve shows signs of fatigue, while in the presence of oxygen activity is maintained, one may say indefinitely, under continuous stimulation. These facts warrant the belief that oxygen is used by the nerve during activity, and presumably it is used in this as in the other tissues to produce physiological oxidations. An additional fact which points in the same direction is the high value of the temperature coefficient for nerve conduction, which has been referred to above. Bearing these two general considerations in mind, we can hardly escape the conviction that the functional activity of the nerve fiber is connected with a chemical reaction of some kind, most probably a reaction in which some material in the nerve undergoes oxidation. Views as to the Nature of the Nerve Impulse. — The older con- ceptions of the nerve principle, while they varied in detail, were based upon the general idea that the nervous system contains a matter of a finer sort than that visible to our senses. This matter was pictured at first as a spirit (animal spirits), and later as a mate- rial comparable to the luminiferous ether or to electricity. Since the discovery that the nerve impulse travels with a relatively slow velocity and is accompanied by a demonstrable change in the electrical condition of the nerve, many different views regarding its nature have been proposed. In discussing the matter it is evident that two perhaps different phenomena have to be consid- ered, namely, the act of excitation by natural or artificial stimuli 122 THE PHYSIOLOGY OF MUSCLE AND NERVE. and the act of propagation or conduction. Formerly, it was held in a general way that the nerve impulse depends upon the breaking down of some unstable substance within the axis cylinder. It was assumed that this sensitive and unstable material is upset by the energy of the stimulus at the point stimulated, and that the energy thus liberated acts upon contiguous particles, and so the disturb- ance is propagated along the nerve as a progressive chemical change which in a very general way may be compared to the pas- sage of a spark along a line of gunpowder. A fundamental ob- jection to such a view is the absence of proof regarding the con- sumption of material in a nerve during activity, as has been ex- plained in the preceding sections. Quite the opposite point of view has also been held, namely, the idea that the nerve impulse is a purely physical process, which involves no chemical change and no using up of material. Various suggestions have been offered as to the character of this physical change, but the one that is perhaps most worthy of consideration identifies the nerve im- pulse with the negative electrical charge that is known to pass along the fiber. It is assumed that this electrical charge consti- tutes the nerve impulse, and to explain its occurrence and propaga- tion from a physical standpoint it has been supposed that the nerve fiber has a structure essentially similar to the " core conduc- tor " (see p. 109), in that it contains a central thread surrounded by a liquid sheath of less conductive material. The central thread may be supposed to be the axis cylinder and the less conductive sheath the surrounding myelin, or, perhaps, to follow another sug- gestion that fits the non-medullated as well as the medullated fibers, the central threads are represented by the neurofibrils within the axis cylinder and the surrounding sheath by the perifibrillar substance. That the axis cylinder is a better conductor than the myelin sheath has been indicated by the microchemical researches of Macallum. This observer has shown that in the axis cylinder the chlorids exist in greater concentration than in the surrounding sheath.* The point of importance is that, with a core model (see Fig. 50), consisting of a glass tube with a core of platinum wire and a sheath of solution of sodium chlorid, 0.6 per cent., electrical phenomena can be obtained similar to those shown by the stimulated nerve. If an induction current, serving as a stimulus, is sent into one end of such an artificial nerve and from the other end two leading off electrodes are connected with a galvanometer, then we can demonstrate by means of the galvanometer that an electrical charge is propagated along the model at each application of the stimulus. And, as such a moving electrical disturbance is the only objective * Macallum, "Proceedings of the Royal Society," 1906, B. lxxvii., 165. NATURE OF THE NERVE IMPULSE. 123 phenomenon known to occur in the stimulated nerve, it has been assumed that it constitutes the nerve impulse. When this electrical disturbance reaches the end-organ, — the muscle, for instance, — it initiates the chemical changes that characterize the activity of the organ. This kind of theory makes the nerve impulse an electrical phenomenon, and assumes that the nerve fibers have become differentiated to form a specifie kind of conductor, the efficiency of which depends upon its having a structure similar to that of a " core conductor." Other theories of a physico-chemical character have been proposed especially to explain the initial excitation caused by a stimulus and the electrical phenomena responsible for the action current. Nernst has supposed that the electrolytes contained in the axis cylinder lie within membranous partitions which are impermeable to the passage of certain ions. When an electrical current is passed through a nerve, it is conveyed of course by the dissociated elec- trolytes, and in consequence of the impermeable character of the septa, there will be a concentration of positively charged ions at one face of the membranes and of negatively charged ions at the other. When the concentration of the ions reaches a certain point, excitation occurs. The nature of the excitation under such circumstances has been further imagined by Hill, who suggests that some sensitive substauce, presumably a colloid, exists in the nerve in combination with certain ions. This combination is in an unstable or critical state, and when, in consequence of a stimulus of any kind, the concentration of ions in combination with it is increased, it breaks down and this act constitutes the excitation, which is then propagated along the nerve. This author has treated his assumption mathematically to ascertain how far it accords with the known facts of the stimulation of nerves with electrical currents. It should be added that these and, indeed, all specific theories of the nature of the nerve impulse are, at present, matters for discussion and experiment among specialists. We are far from having an explanation of the nerve impulse resting upon such an experimental basis as to command general acceptance.* Qualitative Differences in Nerve Impulses and Doctrine of Spe- cific Nerve Energies. — Whether or not the nerve impulses in vari- ous nerve fibers differ in kind is a question of great interest in physi- ology. The usually accepted view is that they are identical in character in all fibers and vary only in intensity. According to this view, a sensory nerve — the auditory nerve, for instance — car- * For a summary of the literature upon the nature of the nerve impulse consult Boruttau, "Zeit. f. allg. Physiologie, " 1, 1, Sammelreferate, 1902; Biedermann, "Ergebnisse der Physiologie," vol. ii, part ii, 1903; Hering, "Zur Theorie der Nerventhatigkeit," 1899; Hill, "Journal of Physiology," 40, 190, 1910, and Lucas, ibid, p. 224. 124 THE PHYSIOLOGY OF MUSCLE AND NERVE. ries impulses similar in character to those passing along a motor nerve, and the reason that in one case we get a sensation of hearing and in the other a contraction of a muscle is found in the manner of ending of the nerve, one terminating in a special part of the cortex of the cerebrum, the other in a muscle. From this standpoint the nerve fibers may be compared to electrical wires. The current conducted by the wires is similar in all cases, but may give rise to very different effects according to the way in which the wires ter- minate, whether in an explosive mixture, an arc light, or solutions of electrolytes of various kinds. We have in physiology what is known as the doctrine of specific nerve energies, first formulated by Johannes Mil Her. This doctrine expresses the fact that nerve fibers when stimulated give only one kind of reaction, whether motor or sensory, no matter in what way they may be stimulated. The optic nerve, for instance, gives us a sensation of light, usually because light waves fall on the retina and thus stimulate the optic nerve. But if we apply other forms of stimulation to the nerve they will also, if effective, give a sensation of light. Cutting the optic nerve or stimulating it with electrical currents gives visual sensations. On the identity theory of the nerve impulses the specific energies of the various nerves — that is, the fact that each gives only one kind of response — is referred entirely to the charac- teristics of the tissue in which the fibers end. If, as has been said, one could successfully attach the optic nerve to the ear and the auditory nerve to the retina then we should see the thunder and hear the lightning. The alternative theory supposes that nerve impulses are not identical in different fibers, but vary in quality as well as intensity, and that the specific energies of the various fibers depend in part at least on the character of the impulses that they transmit. On this theory one might speak of visual impulses in the optic nerves as something different in kind from the auditory impulses in the auditory fibers. With our present methods of investigation the question is one that can not be definitely decided by experimental investigation; most of the discussion turns upon the applicability of the doctrine to the explanation of various conscious reactions of the sensory nerves. So far as experimental work has been carried out on efferent nerves, it is undoubtedly in favor of the identity theory. The action current is similar in all nerves examined; the reactions to artificial stimuli are essentially similar. Moreover, nerves of one kind may be sutured to nerves of another kind, and, after re- generation has taken place, the reactions are found to be deter- mined solely by the place of ending (see p. 82). The Nutritive Relations of the Nerve Fiber and Nerve Cell. — In recent times in accordance with the so-called neuron doctrine NATURE OF THE NERVE IMPULSE. 125 (see p. 130) even- axis cylinder has been considered as a process of a nerve cell, and therefore as a part, morphologically speaking, of that cell. However this may be, there is excellent experimental evidence to show that the physiological integrity of the axis cylinder depends upon its connection with its corresponding nerve cell. This view dates from the interesting work of Waller,* who showed that if a nerve be severed the peripheral stump, containing the axis cyl- inders that are cut off from the cells, will degenerate in a few days. The process of degeneration brought about in this way is known as secondary or Wallerian degeneration. The central stump, on the contrary, remains intact, except for a short region immediately contiguous to the wound, for a relatively long period, extending perhaps over years. Waller, therefore, spoke of the nerve cells as forming the nutritive centers for the nerve fibers, and this belief is generally accepted. In what way the cell regulates the nutrition of the nerve fiber throughout its whole length is unknown. Some of the cells in the lumbar spinal cord, for instance, give rise to fibers of the sciatic nerve which may extend as far as the foot, and yet throughout their whole length the nutritive processes in these fibers are dependent on influences of an unknown kind, emanating from the nerve cells to which they are joined. These influences may consist simply in the effect of constant activity; that is, in the conduction of nerve impulses, or there may be some kind of an actual transferal of material. This latter idea is supported by the interesting fact, which we owe to Meyer, that tetanus and diph- theria toxins may be transmitted to the central nervous system by way of the axis cylinders of the nerve fibers. By means of his method Waller investigated the location of the nutritive centers for the motor and sensory fibers of the spinal nerves. If an anterior root is cut the peripheral ends of the motor fibers degenerate throughout the length of the nerve, while the fibers in the stump attached to the cord remain intact; hence the nutritive centers for the motor fibers must lie in the cord itself. Subsequent histo- logical work has corroborated this conclusion and shown that the motor fibers of the spinal nerves take their origin from nerve cells lying in the anterior horn of gray matter in the cord, the so-called motor or anterior root cells. If the posterior root is cut between the ganglion and the cord, the stump attached to the cord degener- ates; that attached to the ganglion remains intact, and there is no degeneration in the nerve peripheral to the ganglion (Fig. 55). If, however, this root is severed peripherally to the ganglion degenera- tion takes place only in the spinal nerve beyond the ganglion. The nutritive center, therefore, for the sensory fibers must he in the pos- terior root ganglion, and not in the cord. This conclusion has also ♦Waller, "Muller's Archiv," 1852, p. 392; and "Comptes rendus de l'Acad. de la Science," vol. xxxiv., 1852. 126 THE PHYSIOLOGY OF MUSCLE AND NERVE. been abundantly corroborated by histological work. It is known that the sensory fibers arise from the nerve cells in these ganglia. By the same means it has been shown that the motor fibers in the cranial nerves arise from nerve cells (nuclei of origin) situated in the brain, while the sensory fibers of the same nerves, with the exception of the olfactory and optic nerves which form special cases, arise from sensory ganglia lying outside the nervous axis, such, for Fig. 55. — Diagram to show the direction of degeneration on section of the anterior and the posterior root, respectively. The degenerated portion is represented in black. instance, as the spiral ganglia of the cochlear nerve, or the gan- glion semilunare (Gasserian ganglion) of the fifth cranial nerve. Nerve Degeneration and Regeneration. — When a nerve trunk is cut or is killed at any point by crushing, heating, or other means all the fibers peripheral to the point of injury undergo de- generation. This is ,an incontestable fact, and it is important to bear in mind the fact that the definite changes included under the term degeneration are exhibited only by living fibers. A dead nerve or the nerves in a dead animal show no such changes.* The older physiologists thought that if the severed ends of the nerves were brought together by sutures they might unite by first intention without degeneration in the peripheral end. We know now that this degeneration is inevitable once the living continuity of the fibers has been interrupted in any way. Any functional union that may occur is a slow process involving an act of regeneration of the fibers in the peripheral stump. The time required for the degeneration differs somewhat for the different kinds of fibers found in the animal body. In the dog and in other mammalia the degeneration begins in a few (four) days; in the frog it may require from thirty to one hundred and forty days, depending upon the season of the year, although if the frog is kept at a high temperature (30° C.) degeneration may proceed as rapidly as in the mammal. In the dog it proceeds so quickly that the process seems to be simultaneous throughout the See Van Geliuchten, " Le Nevraxe," 1905, vii., 203. Fig. 56. — Histology of a degenerating nerve fiber. Fig. 57. — Embryonic fibers in a regenerating nerve. Fig. 58. — A newly developed fiber in a regenerating nerve fiber. NATURE OF THE NERVE IMPULSE. 127 whole peripheral stump, while in the frog, and, according to Bethe, in the rabbit, it can be seen clearly that the degenerative changes begin at the wound and progress peripherally. The fibers break up into ellipsoidal segments of myelin, each containing a piece of the axis cylinder, and these segments in turn fragment very irregu- larly into smaller pieces which eventually are absorbed* (Fig. 56) . The central stump. whose fibers are still connected with the nerve cells undergoes a similar degeneration in the area immediately contiguous to the wound, but the degenerative processes extend for only a short distance over an area covering a few internodal segments. Although the central ends of the fibers remain sub- stantially intact, it is interesting to find that the nerve cells from which they originate undergo distinct changes, which show that they are profoundly affected by the interruption of their norma) connections (see p. 129). In the peripheral end the process of regeneration begins almost simultaneously with the degenerative changes, the two proceeding, as it were, hand in hand. The regen- eration is due to the activity of the nuclei of the neurilemma! sheath. These nuclei begin to multiply and to form around them a layer of protoplasm, so that as the fragments of the old fiber disappear their place is taken by numerous nuclei and their surrounding cytoplasm. Eventually there is formed in this. way a continuous strand of protoplasm with many nuclei, and the fiber thus produced, which has no resemblance in structure to a normal nerve fiber, is described by some authors as an " embryonic fiber"'; by others as a "band fiber" (Fig. 57). In the adult animal the process of regeneration stops at this point unless an anatomical connection is established with the central stump, and. indeed, such a connection is usually established unless special means are taken to prevent it. The central and peripheral stumps find each other in a way that is often remarkable, the union being guided doubtless by intervening connective tissue. Forsmannsf has emphasized this peculiar attraction, as it were, be- tween the peripheral and the central ends, giving some reason to believe that it is a case of chemotaxis or chemotropism. When the ends of the nerves were given very unusual positions by means of collodium tubes into which they were inserted they managed to "find" each other. Moreover, he states that a central stump, if given an equal opportunity to grow into two collo- dium tubes, one containing liver and the other brain tissue, will chose the latter, a fact which would indicate some underlying chemical attraction or affinity in nerve tissue for nerve tissue. A directive influence of this kind depending upon some property connected with chemical relationship is desig- nated as " chemotaxis." If the central and peripheral stumps are brought together by * See Howell and Huber, "Journal of Physiology," 13, 335, 1892; also Mott and Halliburton, " Proceedings Royal Society," 1906, B. lxxviii., 259, and Cajal, "Trabajos del laboratorio de investigaciones biologicas (Univ. of Madrid)," vol. 4, 119, 1906. fForsmanns, "Zeigler's Beitrage," 2<, 216, 1902. 128 THE PHYSIOLOGY OF MUSCLE AND NERVE. suture or grow together in any way, then, under the influence of the central end, the " band fiber " gradually becomes transformed into a normal nerve fiber, with myelin sheath and axis cylinder (Fig. 58). It is possible that this result is due to local processes in the band fiber stimulated by nutritive influences of some kind from the central stump, but more probably there is an actual down- growth of the axis cylinders from the central- ends. In support of this latter view, it may be said that the outgrowth of the new axis cylinders from the old ones present in the fibers of the central stump has been followed more or less successfully by a number of histologists. From a practical standpoint it re. interesting to note that this influence of the central stump may be exerted months or even years after the injury to the nerve. The peripheral stump after reaching the stage of " band fibers " is ready, as it were, for the influence of the central end, and cases are on record in which a secondary suture was made a long time after the original injury, with the result that functional activity was restored to the nerve. Bethef has thrown some doubt upon this view, for he has shown appar- ently that in young mammals (eight days to eight weeks) the regeneration of the fibers in the peripheral stump does not stop at the stage of " band fibers," but progresses until perfectly normal nerve fibers are produced, even though no connection is made with the central stump. It should be added, however, that the fibers so formed do not persist indefinitely unless they become con- nected with the central stump. If this connection fails to take place, the newly formed fibers will degenerate after an interval of some months. Still, the fact, if true, that in the young fiber the regeneration is corrfplete seems to indicate definitely that the axis cylinder may arise independently of the fibers in the central stump. Whether or not Bethe's observations upon the autoregeneration of the axis cylinders in the severed nerves of young animals can be accepted is at present doubtful, the balance of evidence seems to indicate that what he took for autoregenerated fibers were really fibers which grew into the de- generated trunk from the surrounding tissue. (For discussion with refer- ences see Barker, "Journal of the American Medical Assoc," 1906, Stefan- owska, "Journal de Neurologic," 1906, Nos. 16-19, and Halliburton, "British Med. Journal," May 11, 1907.) Degenerative Changes in the Neuron on the Central Side of the Lesion. — According to the Wallerian law of degeneration, as originally stated, the nerve fiber on the central side of the injury and the nerve cell itself do not undergo any change. As a matter of fact, the central stump immediately contiguous to the lesion undergoes typical degeneration and regeneration similar to that described for the fibers of the peripheral stump. The immediate degenerative changes in the fibers in the central stump were supposed to extend back only to the first node of Ranvier, — to affect, there- fore, only the internodal segment actually injured. Later it was found that the degeneration may extend back over a distance of several internodal segments. This limited degeneration on the central side must be considered as traumatic, — that is, it involves only those portions directly injured by the lesion. The central * Bethe, "Allgemiene Anat. u. Physiologie des Nervensystems," 1903. NATURE OF THE NERVE IMPULSE. 129 end of the fiber in general was supposed to remain intact as long as its cell of origin was normal. It was thought at first that after simple section of a nerve trunk, in amputation, for instance, the nerve cells and central stumps remain normal throughout the life of the individual. Dickinson, however, in 1869 * showed that in amputations of long standing the motor cells in the anterior horn of the cord decrease in number and the fibers in the central stump become atrophied. This observation has been corroborated by- other observers, and it is now believed that after section of a nerve chronic degenerative changes ensue in the course of time in the central fibers and their cells, resulting in their permanent atrophy. We have, in such cases, what has been called an atrophy from disuse. A fact that has been discovered more recently and that is perhaps of more importance is that the nerve cells do undergo certain definite although usually temporary changes immediately after the section of the nerve fibers arising from them. It has been shown that when a nerve is cut the corresponding cells of origin may show distinct histological changes within the first twenty-four hours. These changes consist in a circumscribed destruction of the chromatin material in the cells (chromatolysis), which in a short time extends over the whole cell, so that the primary staining power of the cell is lost (condition of achromatosis) (see Fig. 63). The cell also becomes swollen and the nucleus may assume an excentric position. These retrogressive changes continue for a certain period (about eighteen days). After reaching their maxi- mum of intensity the cells usually undergo a process of restitution and regain their normal appearance, although in some cases the degeneration is permanent. According to other observers a number of the cells in the spinal cord and spinal ganglia undergo simple atrophy after section of their corresponding nerves, and some of the nerve fibers in the central stumps may also show atrophy, while others undergo a genuine degeneration, which, however, comes on much later than in the peripheral stumps. It seems evident that the behavior of the cells and fibers on the central side of the section is not uniform; atrophy rather than degeneration is the change that is prominent, and this atrophy in some neurons occurs early, while in others it is apparent only after a long interval of time. An explanation of this variation in the reaction of the nerve cells and their disconnected central stumps cannot yet be given. On the peripheral side of the section, as stated above, the de- generative changes are complete and affect all of the fibers. t * " Journal of Anatomy and Physioloogy," 3, 176, 1869. t Nissl, "Allgemeine Zeitschrift f. Psychiatrie," 48, 197, 1892. Also Bethe, loc. cit., and Ranson, " Retrograde Degeneration in the Spinal Nerves," The Journal of Comparative Neurology and Psychology, 1906, xvi., 265. 9 SECTION II. THE PHYSIOLOGY OF THE CENTRAL NERVOUS SYSTEM. CHAPTER VI. STRUCTURE AND GENERAL PROPERTIES OF THE NERVE CELL. The Neuron Doctrine. — Since the last decade of the nineteenth century the physiology of the nervous system has been treated from the standpoint of the neuron. According to this point of view, the entire nervous system is made up of a series of units, the neurons, which are not anatomically continuous with each other, but communicate by contact only. It has been taught also that each neuron represents from an anatomical and physiological standpoint a single nerve cell. The typical neuron consists of a cell body with short, branching processes, the dendrites, and a single axis cylinder process, the axon or axite, which becomes a nerve fiber, acquiring its myelin sheath at some distance from the cell. According to this view, the peripheral nerve fibers are simply long processes from nerve cells. Within the central nervous system each neuron connects with others according to a certain schema. The axon of each neuron ends in a more or less branched " terminal arborization," forming a sort of end-plate which lies in contact with the dendrites of another neuron, or in some cases with the body of the cell itself, the essentially modern point of view being that where the terminal arborization of the axon meets the dendrites or body of another neuron the communication is by contact, the neurons being anatomically independent units. It is usually ac- cepted also as a part of the neuron doctrine that the conduction of a nerve impulse through a neuron is always in one direction, that the dendrites are receiving organs, so to speak, receiving a stimulus or impulse from the axon of another unit and conveying this impulse toward the cell body, while the axon is a discharging process through which an impulse is sent out from the cell to reach another neuron or a cell of some other tissue. The neuron, so 130 PROPERTIES OF THE NERVE CELL. 131 far as conduction is concerned, shows a definite polarity, the con- duction in the dendrites being cellulipetal, in the axons, cellulifugai. The neuron doctrine, so far as the name at least is concerned, dates from a general paper by Waldeyer,* in which the newer work up to that time was summarized. The main facts upon which the conception rests were furnished by His (1886), to whom we owe the generally accepted belief that the nerve fiber (axis cylinder) is an outgrowth from the cell, and secondly by Golgi, Cajal, and a host of other workers, who, by means of the new method of Golgi, demonstrated the wealth of branches of the nerve cells, particularly of the dendrites, and the mode of connection of one nerve unit with another. The view that these units are anatomically independent and on the embryological Fig. 59.- -Motor cell, anterior horn of gray matter of cord. From human fetus (Lenhos- sek) : * marks the axon ; the other branches are dendrites. side are derived each from a single epiblastic cell (neuroblast) has proved acceptable and most helpful; but the validity of this hypothesis has been called into question from time to time. As was stated on p. 128, Bethe has claimed that in young animals the nuclei of the neurilemma! sheath may regenerate a new nerve fiber containing axis cylinder and myelin sheath, and this fact, if true, at once brings into question the hitherto accepted belief that the axis cylinder can be formed only as an outgrowth from a nerve cell. Some histologists — Apathy, Bethe, Nissl — have also attacked the most fundamental feature of the neuron doctrine — the view, namely, that each neuron represents an independent anatomical element. These authors contend that the neurofibrils of the axis cylinder pass through the nerve cells and enter by way of a network into direct connection with the neurofibrils * "Deut. med. Wochenschrift, " J.891, p. 50. 132 PHYSIOLOGY OF CENTRAL NERVOUS SYSTEM. of other neurons (see Fig. 64). The neurofibrils form a continuum through which nerve impulses pass without a break from neuron to neuron. Ac- cording to this conception, the ganglion cells play no direct part in the con- duction of the impulse from one part of the nervous system to another; the neurofibrils alone, and the intracellular and pericellular networks with which they connect, form the conducting paths that are everywhere in con- tinuity. In the explanation given below of the activities of the nervous system, the author, following the usual custom, makes use of the neuron doctrine, since it is at present impossible to say whether or not the newer views of the continuum of neurofibrils will be corroborated. While the physiological facts remain the same whichever view prevails, there can be no doubt that the point of view of the physiologist would be greatly changed if the present simple conception of a series of neurons of a definite polarity as regards conduction were replaced by the more complex schema of inde- pendent neurofibrils and a central reticulum in which a basis for polarity and definite paths of conduction is lacking.* The Varieties of Neurons. — The neurons differ greatly in size, shape, and internal structure, and it is impossible to classify them with entire success from either a physiological or an anatomical standpoint. Neglecting the unusual forms whose occurrence is limited and whose structure is perhaps incompletely known, there are three distinct types whose form and structure throw some light on their functional significance: I. The bipolar cells. This cell is found in the dorsal root gan- glia of the spinal nerves and in the ganglia attached to the sensory fibers of the cranial nerves, the ganglion semilunare (Gasserian) for the fifth cranial, the g. geniculi for the seventh, the g. vestibu- lare and g. spirale for the eighth, the g. superius and g. petrosum for the ninth, the g. jugulare and g. nodosum for the tenth. The typical cell of this group is found in the dorsal root ganglia. In the adult the two processes arise as one, so that the cell seems to be unipolar, but at some distance from the cell this process divides in T, one branch passing into the spinal cord via the posterior root, the other entering the spinal nerve as a sensory nerve fiber to be distributed to some sensory surface. Both processes become medullated and form typical nerve fibers. That these apparently unipolar cells are really bipolar is shown not only by this division into two distinct fibers, but also by a study of their development in the embryo. In early embryonic life the two processes arise from different poles of the cell, and later become fused into an ap- parently simple process (Fig. 60). The striking characteristics of this cell, therefore, are that it gives rise to two nerve fibers, and that it possesses no dendritic processes. On the physiological side these cells might be designated as sensory cells, since they appear to be associated always with sensory nerve fibers. * For discussion, see Barker, "Journal of the American Medical Associa- tion," 1906, and Retzius, "Proceedings of the Royal Society," 1908, B. vol. lxxx., 414. PROPERTIES OF THE NERVE CELL. 133 The nerve cells found in the sensory ganglia exhibit, as a matter of fact, a number of different types, some of which possess short dendritic processes. These histological variations cannot as yet be given a physiological signifi- cance, but their occurrence certainly seems to indicate a possibility that the sensory ganglia may have a much more varied physiological activity than has been attributed to them heretofore. For a description of these ganglia and a classification of their cells under eight different types con- sult Cajal in Ergebnisse der Anat. u. Entwickelungsgeschichte, vol. xvi., 1906. So far as' the sensory fibers of the spinal and cranial nerves are concerned, it is worth noting also that all of them arise from cells lying outside the main axis of the central nervous system. It has been a question whether the sensory impulses brought to the ganglion cells through the peripheral process (sensory Fig. 60. — Bipolar cells in the posterior root ganglion. Section through spinal gan- glion of newborn mouse (Lenhossek) : a, The spinal ganglion ; b, the spinal cord ; c, the posterior, d, the anterior root. fiber) passes into the body of the cell before going on to the cord or brain, or whether at the junction of the two processes it simply passes on directly to the cord. According to the histological structure there is no apparent reason why an impulse should not pass directly from the peripheral to the central process at the junction, but whether or not this really occurs and the relation of the ganglion cell to the conducting path are questions that must be left unsettled at present. II. The multipolar cells. The processes of these cells fall into two groups: the short and branching dendrites with an inner structure resembling that of the cell body, and the axon or axis cylinder process (Fig. 59). According to the structure of this last process, this type may be classified under two heads : Golgi cells of the first and the second type. The cells of the first type are charac- 134 PHYSIOLOGY OF CENTRAL NERVOUS SYSTEM. terized by the fact that the axon leaves the central gray matter and becomes a nerve fiber. This nerve fiber within the central nervous system may give off numerous collaterals, each of which ends in a terminal arborization. By this means the neurons of this type may be brought into physiological connection with a number of other neurons. This kind of nerve cell is frequently described as the typical nerve cell. Golgi supposed that it rep- resents the motor type of cell, and this view is, in a measure, borne out by sub- sequent investigation. The distinctly motor cells of the central nervous system — such, for instance, as the pyramidal cells of the cere- bral cortex, the anterior horn cells of the spinal cord, the Purkinje cells of the cere- bellum— all belong to this r& ' \-r/& &V^-' 'M mm. x%\ &>M Fig. 61. — Golgi cell (second type). The axon, a, divides into a number of fine branches. — (From Obersteiner, after Andriezen.) Fig. 62. — Normal anterior horn cell (Warrington), showing the Nissl granules in the cell and dendrites: a, The axon. type. But within the nerve axis most of the conduction from neuron to neuron, along sensory as well as motor paths, is made with the aid of such structures, the dendrites being the receptive or sensory organ and the axon the motor apparatus. The Golgi cells of the second type (Fig. 61) are relatively less numerous and important. They are characterized by the fact PROPERTIES OF THE NERVE CELL. 135 that the axon process instead of forming a nerve fiber splits into a great number of branches within the gray matter. Assuming that in such cells the distinction between the axon and the den- drites is well made and that as in the other type the dendrites form the receiving and the axon the discharging apparatus, these cells would seem to have a distributive function. The impulse that they receive may be transmitted to one or many neurons. They are sometimes spoken of as intermediate or association cells. Internal Structure of the Nerve Cell. — Within the body of the nerve cell itself the striking features of physiological signifi- cance are, first, the arrangement of the neurofibrils, and, second, the £\ Fig. 63. — Anterior horn cell fourteen days after section of the anterior root {Warring- ton) : To show the change in the nucleus and the Nissl granules, beginning cbromatolysis. presence of a material in the form of granules, rods, or masses which stains readily with the basic anilin dyes, such as methylene blue, thionin, or toluidin blue. This latter substance is spoken of as the "chromophile substance," tigroid, or more frequently as Nissl's granules, after the histologist who first studied it success- fully. These masses or granules are found in the dendrites as well as in the cell, but are absent from the axon (see Fig. 62). Little is known of their composition or significance, but their presence or ab- sence is in many cases characteristic of the physiological condition of the cell. After lesions or injuries of the neuron the material may become dissolved and diffused through the cell or may decrease in amount or disappear, and it seems probable, therefore, that it repre- sents a store of nutritive material (Fig. 63). The non-staining material of the cell, according to most recent observers, contains neurofibrils which are continued out into the processes, dendrites as well as axons. These fibrils may be regarded as the conducting structure along which passes the nerve impulse. The arrangement of these fibrils within the cell is not completely known, the results obtained varying with the methods employed. A matter of far- 136 PHYSIOLOGY OF CENTRAL NERVOUS SYSTEM. reaching importance on the physiological side is the question of the existence of an extracellular nervous network. Most recent histoiogists agree in the belief that there is a delicate network surrounding the cells and their protoplasmic processes. This pericellular net or Golgi's net is claimed by some to be a ner- vous structure connecting with the neurofibrils inside the cell and forming not only a bond of union between the neurons, but possibly also an important intercellular nervous structure that may play an important role in the functions of the nerve centers. This view is represented schematically in Fig. 64. According to others, this network around and outside the cells is a supporting tissue simply that takes no part in the activity of the nerve units. Fig. 64. — Bethe's schema to indicate the connections of the pericellular network: Rz, A sensory cell in the posterior root ganglion ; the fibrils in the branch that runs to the cord are indicated as connecting directly with the pericellular network of the motor cells, Gz. General Physiology of the Nerve Cell. — Modern physiologists have considered the cell body of the neuron, including the den- drites, as the source of the energy displayed by the nervous system, and it has been assumed that this energy arises from chemical changes in the nerve cell, as the energy liberated by the muscle arises from the chemical changes in its substance. It would follow from this standpoint that evidences of chemical activity should be obtained from the cells and that these elements should exhibit the phenomenon of fatigue. Regarding this latter point, it is believed in physiology that the nerve cells do show fatigue. The nerve centers fatigue as the result of continuous activity, as is evident from our personal experience in prolonged intellectual or emo- tional activity and as is implied in the necessity of sleep for re- cuperation and the rapidity with which functional activity is lost PROPERTIES OF THE NERVE CELL. 137 on withdrawal of the blood supply. Objectively, also, it has been shown in the ergographic experiments (see p. 50) that the well- known fatigue of the neuromuscular apparatus possibly affects the nerve centers as well as the muscle. Assuming that the nerve cells are the effective agent in the nerve centers, such facts indicate that they are susceptible to fatigue under what may be designated as the normal limits of activity. But we have no very direct proof that this property is possessed universally by the nerve cells nor any indication of the probable differences in this regard shown by nerve cells in different parts of the central nervous system. It seems probable that under normal conditions — that is, under the influence of what we may call minimal stimuli — some portions of the nerve centers remain in more or less constant activity during the day without showing a marked degree of fatigue, just as our muscles remain in a more or less continuous state of tonic con- traction throughout the waking period at least. Doubtless when the stimulation is stronger the fatigue is more marked, because the processes of repair in the nerve centers can not then keep pace with the processes of consumption of material. In general, it may be held that every tissue exhibits a certain balance between the processes of consumption of material associated with activity and the processes of repair. If a proper interval of rest is allowed, the tissue will function without exhibiting fatigue, as is the case with the heart and the respiratory center. If, however, the stimu- lation is too strong or is repeated at too rapid an interval, then the processes of repair do not keep pace with those of consumption, or the products of functional activity are not completely removed, and in either case we have the phenomenon of fatigue, that is to say, a depression of normal irritability. The point of importance is to determine the differences in this respect between the different tissues. Our actual knowledge on this point as regards nerve cells is quite incomplete. Evidence of a probable chemical change in the nerve cells during activity is found also in the readiness with which the gray matter of the nervous system takes on an acid reaction.* In the fresh resting state it is prob- ably alkaline or neutral, but after death it quickly shows an acid reaction, due, it is said, to the production of lactic acid. Its resemblance to the muscle in this respect leads to the inference that in functional activity acid is also produced. Mosso states that in the brain increased mental activity is accompanied by a rise in the temperature of the brain, f His experiments were made upon individuals with an opening in the skull through which a * Langendorff, "Centralbl. f. d. med. Wiss.," 1886. See also Halliburton, "The Croonian Lectures on The Chemical Side of Nervous Activity," 1901. t Mosso, ."Die Temperatur des Gehirns," 1894. 138 PHYSIOLOGY OF CENTRAL NERVOUS SYSTEM. delicate thermometer could be inserted so as to lie in contact with brain. So also the facts briefly mentioned in regard to the Nissl granules give some corroborative evidence that the activity of the nervous system is accompanied by and probably caused by a chemical change within the cells, since the excessive activity of the nerve cells seems to be accompanied by some change in these granules, and in abnormal conditions associated with loss of func- tional activity the granules undergo chromatolysis, — that is, they are disintegrated and dissolved. Obvious histological changes which imply, of course, a change in chemical structure, have been observed by a number of investigators.* All seem to agree that activity of the tissue, whether normal or induced by artificial stimulation, may cause visible changes in the appearance of the cell and its Fig. 65. — Spinal ganglion cells from English sparrows, to show the daily variation in the appearance of the cells due to normal activity: A. Appearance of cells at the end of an active day; B, appearance of cells in the morning after a night's rest. The cytoplasm is filled with clear, lenticular masses, which are much more evident in the rested cells thai; in those fatigued. — (Hodge.) nucleus. Activity within normal limits may cause an increase in the size of the cell together with a diminution in the stainable (Nissl) substance, and excessive activity a diminution in size of the cell and the nucleus, the formation of vacuoles in the cell body, and a marked effect upon the stainable material. Hodge has shown that in birds, for instance, the spinal ganglion cells of a swallow killed at nightfall after a day of activity exhibit a marked loss of substance as compared with similar cells from an animal killed in the early morning (Fig. 65). Dolley f also states that in * See especially Hodge, "Journal of Morphology," 7, 95, 1892, and 9, 1, 1894. { Dolley, "American Journal of Physiology," 25, 151, 1909. PROPERTIES OF THE NERVE CELL. 139 the dog the cerebellar cells exhibit a definite series of changes in the chromatic substance, both that within the nucleus and that within the cytoplasm (Nissl's granules) following upon prolonged muscular activity or after such conditions as shock or anemia. If these conditions are extreme, the chromatin material may be entirely removed from the cells, and this he interprets as an indica- tion of a functionally exhausted cell. It must be remembered, however, that our knowledge of the nature of the chemical changes that occur in the cell during activity is very meager. Presumably carbon dioxid and lactic acid are formed as in muscle, and we know that oxygen is consumed. Enough is known perhaps to justify the general view that the energy exhibited by the nervous system is derived, in the long run, from a metabolism of material in the nerve cells, a metabolism which consists essentially in the splitting and oxidation of the complex substances in the protoplasm of the cell. Summation of the Effects of Stimuli. — In a muscle a series of stimuli will cause a greater amount of shortening than can be obtained from a single stimulus of the same strength. In this case the effects of the stimuli are summated, one contraction taking place on top of another, or to put it in another way, the muscle while in a condition of contraction from one stimulus is made to contract still more by the following stimulus. In the nerve fiber such a phenomenon has not been demonstrated. The strength of the nerve impulse can be determined only by means of the effect on the end-organ, — e. g., the muscle, — in which case the properties of the end-organ must be taken into account, or by the aid of the electrical response. Now, when a nerve is stimulated so rapidly that the second stimulus falls into the nerve before the electrical change due to the first stimulus has passed off, the second stimulus, instead of adding its effect to that of the first, simply has no effect at all; it finds the nerve unirritable and by the time that the nerve regains its irritability, it has returned to its condition of rest.* According to this result, we should expect that a summation of the effects of rapidly following stimuli is not possible in the case of the nerve fiber in the sense in which summation occurs in a muscle fiber, that is to say, the addition of a new state of activity to an already existing state of activity. On the other hand, according to the physico-chemical theories of nerve excitation it is possible that a single ineffective stimulus, which did not in itself cause a concentration of ions sufficient to produce an excitation might, if repeated, bring about such a concentration and thus be converted to an effective stimulus. In the nerve cell it is usually taught * Gotch and Burch, "Journal of Physiology," 24, 410, 1899, and 40, 250, 1910. 140 PHYSIOLOGY OF CENTRAL NERVOUS SYSTEM. that the power of summation is a characteristic property. It is pointed out that, while a single stimulus applied to a sensory nerve may be ineffective in producing a reflex response from the central nervous system, a series of such stimuli will call forth a reaction. In this case it is assumed that the effects of the suc- ceeding stimuli are summated within the nerve cells through which the reflex takes place, and, generally speaking, it is assumed in physiology that the nerve centers are adapted by their power of summation to respond to a series of stimuli or to continuous stimu- lation. The best examples of this kind of action are obtained perhaps from sensory nerves, in which case we judge of the intensity of the cell activity by the concomitant sensation, or by a reflex response. Response of the Nerve Cell to Varying Rates of Stimula- tion.— The various parts of the neuromuscular apparatus — namely, the nerve cell, the nerve fiber, and the muscle fiber — have different degrees of responsiveness to repeated stimuli, and this responsiveness varies, moreover, for the different kinds of mus- cles and of nerve fibers, and, probably for the different kinds of nerve cells. The motor cells of the brain and cord discharge their impulses under normal stimulation at a certain rhythm which was formerly supposed to average about 10 per second, but is now estimated as varying between certain wide limits, perhaps from 40 to 100 per second (p. 47). For any particular group of these motor cells the evidence indicates that it has a prac- tically constant rate whatever may be the intensity of the stimulus — and, indeed, when artificial stimulation is used and the rate is varied, the evidence that we have so far appears to show that the nerve cells do not discharge in a one to one correspondence with the rate of stimulation, as is the case, within limits, for muscle and nerve fibers. On the contrary, under such circum- stances the discharge from the nerve cells takes place in a rhythm characteristic of the cells and independent of that of the stimula- tion.* From this point of view we must look upon these nerve cells as possessing fundamentally a rhythmic activity, as in the case of the heart. There is no doubt, however, that some at least of the motor cells of the spinal cord can be stimulated by a single stimulus so as to respond with a single discharge instead of a rhyth- mical series of discharges. As will be described below, the knee- kick is a simple muscular contraction, not a tetanus, which is aroused by reflex stimulation of the corresponding motor cells in the spinal cord. The Refractory Period of the Nerve Cell. — It will be recalled that the nerve fiber exhibits what is called a refractory period for a * Horsley and Schafer, "Journal of Physiology," 7, 96, 1886. PROPERTIES OF THE NERVE CELL. 141 brief interval (0.002 to 0.006 sec.) after it is stimulated. During this period it is not irritable to a second stimulus. The same phenomenon is exhibited to a marked degree by the heart muscle and likewise by many nerve cells. In the motor nerve cell which shows the property of discharging a series of impulses with rhythmic regularity it may be supposed that the refractory period is marked, and indeed is connected probably with the rhythmic character of the cell's activity. But in this as in other properties it is certain that there are great differences in the many varieties of nerve cells found in the central nervous system. While those that act rhyth- mically have probably a relatively long refractory period, others may exhibit a period of unirritability but little longer than that shown by the nerve fibers. In the case of the reflex motor centers in the lumbar spinal cord of the frog it is stated (Langendorff) that a second stimulus falling at an interval of 0.04 sec. after the first is effective. The refractory period of these cells is less, therefore, than this interval. CHAPTER VII. REFLEX ACTIONS. Definition and Historical. — By a reflex action we mean the involuntary production of activity in some peripheral tissue through the efferent nerve fibers connected with it in consequence of a stimulation of afferent nerve fibers. The conversion of the sensory or afferent impulse into a motor or efferent impulse is effected in the nerve centers, and may be totally unconscious as well as invol- untary,— for instance, the emptying of the gall-bladder during digestion, or it may be accompanied by consciousness of the act, as, for example, in the winking reflex when the eye is touched. The application of the term reflex to such acts seems to have been made first by Descartes* (1649), on the analogy of the reflection of light, the sensory effect in these cases being reflected back, so to speak, as a motor effect. The attention of the early physiologists was directed to these involuntary movements and many instances were collected, both in man and the lower animals. Their invol- untary character was emphasized by the discovery that similar movements are given by decapitated animals, — frogs, eels, etc. Some of the earlier physiologists thought that the reflex might occur in the anastomoses of the nerve trunks, but a convincing proof that the central nervous system is the place of reflection or turning-point was given by Whytt (1751). He showed that in a de- capitated frog the reflex movements are abolished if the spinal cord is destroyed. Modern interest in the subject was excited by the numerous works of Marshall Hall (1832-57), who contributed a number of new facts with regard to such acts, and formulated a view, not now accepted, that these reflexes are mediated by a spe- cial set of fibers — the excitomotor fibers. In describing reflexes the older physiologists had in mind only reflex movements, but at the present time we recognize that the reflex act may affect not only the muscles, — voluntary, involuntary, and cardiac, — but also the glands. We have to deal with reflex secretions as well as reflex movements. The Reflex Arc. — It is implied in the definition of a reflex that both sensory and motor paths are concerned in the act. Ac- * See Eckhard, "Geschichte der Entwickelung der Lehre von den Reflex- erscheinungen," " Beitriige zur Anatomie u. Physiologic," Giessen, 1881, vol. U. 142 REFLEX ACTIONS. 143 cording to the neuron theory, therefore, the simplest reflex arc must consist of two neurons: the sensory neuron, whose cell body lies in the sensory ganglia of the posterior roots or of the cranial nerves, and a motor neuron, whose nerve cell lies in the anterior horn of gray matter of the cord or in the motor nucleus of a cranial nerve. The reflex arc for the spinal cord is represented in Fig. 66. The arc may, however, be more complex. The sensory fibers entering through the posterior roots may pass upward through the entire length of the cord to end in the medulla, and on the way give off a number of collaterals as is represented in Fig. 67, or they may make connections with intermediate cells which, in turn, are con- nected with one or more motor neurons (Fig. 68). According Fig. 66. — Schema to show the connection between the neuron of the posterior root and tha neuron of the anterior root, — the reflex arc. to these schemata, one sensory fiber may establish reflex connections with a number of different motor fibers, or, a fact which must be borne in mind in studying some of the well-known reflex activities of the cord and medulla especially, a sensory fiber carrying an impulse which eventually reaches the cortex of the cerebrum and gives rise to a conscious sensation may, by means of its collaterals, connect with motor nuclei in the cord or medulla and thus at the same time give origin to involuntary and even unconscious re- flexes. Painful stimulation of the skin, for example, may give us a conscious sensation of pain and at the same time reflexly stimulate the vasomotor center and cause a constriction of the small arteries. The fact that in this case two distinct events occur does not necessitate the assumption that the impulses from the skin are carried to the cord by two different varieties of fibers. 144 PHYSIOLOGY OF CENTRAL NERVOUS SYSTEM. It may well be that one variety of sensory neuron, the so-called pain fibers, effects both results, because of the opportunities in the cord for connections with different groups of nerve cells. The Reflex Frog. — The motor reflexes from the spinal cord can be studied most successfully upon a frog in which the brain has been destroyed or whose head has been cut off. After such an operation the animal may for a time suffer from shock, but a vigorous animal will usually recover and after some hours will Fig. 67. — Kolliker's schema to show the direct reflex arc. It shows the pos- terior root fiber (black) entering the cord, dividing in Y. and connecting with motor cells (red) by means of collater- als. Fig. 68. — Kolliker's schema to show the reflex arc with intercal- ated tract cells. Posterior root fiber, black; intercalated tract cell, blue; motor cells, red. exhibit reflex movements that are most interesting. The funda- mental characteristics of reflex movements in their relations to the place, intensity, and quality of the stimulus can be studied with more ease upon an animal whose cord is thus severed from the brain than upon a normal animal. In the latter case the connec- tions in the nervous system are more complex and the reactions are therefore less simple and less easily kept constant. Spinal Reflex Movements. — The reflex movements obtained from the spinal cord or from other parts of the central nervous system may be divided into three groups by characteristics that are physio- logically significant. These classes are: (1) Simple reflexes, or those in which a single muscle is affected. The best example of REFLEX ACTIONS. 145 this group is perhaps the winking reflex, in which only the orbic- ularis palpebrarum is concerned. (2) Co-ordinated reflexes, in which a number of muscles react with their contractions so grad- uated as to time and extent as to produce an orderly and useful movement. (3) Convulsive reflexes, such as are seen in spasms, in which a number of muscles — perhaps all the muscles — are con- tracted convulsively, without co-ordination and with the pro- duction of disorderly and useless movements. Of these groups, the co-ordinated reflexes are by far the most interesting. They can be obtained to perfection from the reflex frog. In such an animal no spontaneous movements occur if the sensory surfaces are entirely protected from stimulation. A sudden stimulus, however, of sufficient strength applied to any part of the skin will give a definite and practically invariable response in a movement which has the appearance of an intentional effort to escape from or remove the stimulus. If the toe is pinched the foot is withdrawn — in a gentle manner if the stimulus is light, more rapidly and violently, but still in a co-ordinated fashion, if the stimulus is -strong. If the animal is suspended and various spots on its skin are stimulated by the application of bits of paper moistened with dilute acetic acid the animal will make a neat and skillful movement of the corresponding leg to remove the stimulating body. The reactions may be varied in a number of ways, and in all cases the striking features of the reflex response are, first, the seemingly purposeful character of the movement, and, second, the almost mechanical exactness with which a definite stimulus will give a definite response. This definite relationship holds only for sensory stimulation of the external integument, the skin and its organs. It is obvious, in fact, that a muscular response can be effective only for stimuli originating from the external surface. Stimuli from the interior of the body exert their reactions, for the most part, upon the plain musculature and the glands. The convulsive reflexes may be produced by two different means : (1) By very intense sensoiy stimulation. The reflex response in this case overflows, as it were, into all the motor paths. A variation of this method is seen in the well-known convulsive reaction that follows tickling. In this case the stimulus, although not intense from an objective standpoint, is obviously violent from the standpoint of its effectiveness in sending into the central nervous system a series of maximal sensory impulses. (2) By heightening the irritability of the central nervous system. Upon the reflex frog this effect is obtained most readily by the use of strychnin. A little strychnin injected under the skin is soon absorbed and its effect is shown at first by a greater sensitiveness to cutaneous stimulation, the slightest touch to the foot causing its withdrawal. Soon, however, the response, instead of being orderly and adapted to a useful end, becomes 10 146 PHYSIOLOGY OF CENTRAL NERVOUS SYSTEM. convulsive. A mere touch of the skin or a current of air will throw every muscle into contraction, and the extensors being stronger than the flexors the animal's body becomes rigid in extension at every stimulation. The explanation usually given for this result is that the strychnin, acting upon some part of the nerve cells, increases greatly their irritability, so that when a stimulus is sent into the central nervous system along any sensoiy path from the skin it apparently radiates throughout the cord and acts upon all the motor cells. This latter supposition leads to the interesting con- clusion that all the various motor neurons of the cord must be in physiological connection, either direct or indirect, with all the neurons supplying the cutaneous surface. The further fact that under normal conditions the effect of a given sensory stimulus is manifested only on a limited and practically constant number of the motor neurons seems to imply, therefore, that normally the paths to these neurons are more direct and the resistance, if we may use a somewhat figurative term, is less than that offered by other possible paths. Muscular spasms are observed under a number of pathological conditions, — for instance, in hydrophobia. We are at liberty to assume in such cases that the toxins produced by the disease affect the irritability of the cells in much the same way as the stiychnin. Theory of Co-ordinated Reflexes. — The purposeful character of the co-ordinated reflexes in the frog gives the impression to the observer of a conscious choice of movements on the part of the brainless animal. Most physiologists, however, are content to see in these reactions only an expression of the automatic activity of a mechanism. It is assumed that the sensory impulses from any part of the skin find, on reaching the cord, that the paths to a certain group of motor neurons are more direct and offer less resistance than any others. It is along these paths that the reflex will take place, and we may further assume that these paths of least resistance, as they have been called, are in part preformed and in part are laid down by the repeated experiences of the indi- vidual. That is, in each animal a definite structure may be sup- posed to exist in the cord; each sensory neuron is connected with a group of motor neurons, to some of them more directly than to others, and we may imagine, therefore, a system of reflex apparatuses or mechanisms which when properly stimulated will react always in the same way. And, indeed, in spite of the adapted character of the reflexes under consideration their automaton-like regularity is an indication that their production is due to a fixed mechanical arrangement. Whether or not the reactions of the nervous system in such cases are accompanied by any degree of consciousness can not be proved or disproved, but the assumption of such an accom- paniment does not seem necessary to explain the reaction. REFLEX ACTIONS. 147 Spinal Reflexes in the Mammals. — Experiments upon the lower mammals show that co-ordinated reflex movements may be ob- tained from the cord after severance of its connections with the brain. Sherrington* has described a simple operation by which the head may be removed from an anesthetized cat and the animal be kept alive for a number of hours. Stimulation of the skin in such an animal calls forth numerous definite reflexes, such as flexion or extension of the legs, the scratching movements of the hind legs, stretching movements, etc. Or the spinal cord may be severed in the thoracic region, below the origin of the phrenic nerves, and the animal, with care, can be kept alive for months or years. In such an animal reflex movements of the hind legs or tail may be ob- tained readily from slight sensory stimulation of the skin. The knee-jerk and similar so-called deep reflexes are also retained. But it is evident that these movements are not so complete nor so distinctly adapted to a useful end as in the frog. The muscles of the body supplied by the isolated part of the cord retain, however, a normal irritability and exhibit no wasting. In man, on the contrary, it is stated that after complete section of the cord the deep reflexes, such as the knee-jerk, as well as the skin reflexes, are very quickly lost. The muscles undergo wasting and soon lose their irritability.! The monkeys exhibit in this respect a condition that is somewhat intermediate between that of the dog and man. It seems evident from these facts that in the lower animals, like the frog, a much greater degree of independent activity is exhibited by the cord than in the more highly developed animals. According to the degree of development, the control of the muscles is assumed more and more by the higher portions of the nervous system, and the spinal cord becomes less important as a series of reflex centers, its functions being more dependent upon its connections with the higher centers. Dependence of Co-ordinated Reflexes upon the Excitation of the Normal Sensory Endings. — It is an interesting fact that when a nerve trunk is stimulated directly in a reflex frog — the sciatic nerve, for instance — the reflex movements are disorderly and quite unlike those obtained by stimulating the skin. It is said that if the skin be loosened and the nerve twigs arising from it be stimulated, an operation that is quite possible in the frog, the re- sponse is again a disorderly reflex, whereas the same fibers stimu- lated through the skin give an orderly, co-ordinated movement. The difference in response in these cases is probably not due to any peculiarity in the nature of the sensory impulses originating in the nerve endings of the skin, but more likely to a difference in their strength and arrangement. When one stimulates a sensory nerve * Sherrington, "Journal of Physiology," 38, 375, 1909. t See Collier, " Brain," 1904, p. 38. 148 PHYSIOLOGY OF CENTRAL NERVOUS SYSTEM. trunk directly, — the ulnar nerve at the elbow in ourselves, for in- stance,— the resulting sensations are markedly different from those obtained by stimulating the skin areas supplied by the same nerve; we have little or no sensations of touch or temperature, only pain and a peculiar tingling in the fingers. In such an experiment the stimulus applied to the trunk affects more or less equally all the contained fibers, whereas in stimulation of the skin itself the effect upon the cutaneous fibers of pressure, temperature, or pain pre- dominates and presumably it is these fibers that normally are con- nected in an efficient way with the reflex machinery in the nerve centers. Reflex Time. — Since nerve centers are involved in a reflex movement, a determination of the total time between the appli- cation of the stimulus and the beginning of the response gives a means of ascertaining the time needed for the processes within the nerve cells. Helmholtz, who first made experiments of this kind, stated that the time required within the nerve centers might be as much as twelve times as great as that estimated for the conduction along the motor and sensory nerves involved in the reflex. Most observers state that the time within the center varies with the strength of the stimulus, being less, the stronger the stimulus. It varies also with the condition of the nerve centers, being lengthened by fatigue and other conditions that depress the irritability of the nerve cells. By reflex time or reduced reflex time we may designate the time required for the processes in the center, — that is, the total time less that required for transmission of the impulse along the motor and sensory fibers and the latent period of the muscle con- traction. For the frog this is estimated as varying between 0.008 and 0.015 sec. In man the reflex time usually quoted is that given by Exner for the winking of the eye. He stimulated one lid electrically and recorded the reflex movement of the lid of the other eye. The total time for the reflex was, on an average, from 0.0578 sec. to 0.0662 sec. He estimated that the time for transmission of the impulse along the sensory and motor paths, together with the latent period of the muscle, amounted to 0.0107 sec. So that the true reflex time from his determinations varied between 0.0471 and 0.0555 sec. Mayhew,* using a more elaborate method, obtained for the total time a mean figure equal to 0.0420 sec. If Exner's correction is applied then the true reflex time according to this de- termination is equal to 0.0313 sec. In a series of experiments made upon frogs, in which the efferent response to stimulation of the afferent fibers of the sciatic nerve was measured by the electrical variation in the muscle involved, Buchanan finds that the delay in the cord, when the reflex was on the same side, was * Mayhew, "Journal of Exp. Medicine," 2, 35, 1897. REFLEX ACTIONS. 149 equal to 0.01 to 0.02 sec. If the reflex was on the crossed side about double this time was consumed in the cord. This delay of the velocity of transmission of an impulse in the nerve centers is a factor which must vary somewhat in different parts of the nervous system. It has been shown that in certain cases, at least, when strong stimuli are used the latent period of a reflex is not greater than would be accounted for by transmission through the nerve fibers and by the latency of the muscular contraction. Thus Franyois Frank, in an experiment in which the gastrocnemius muscle of one side was made to contract reflexly by stimulation of the afferent root of a lumbar nerve on the other side, records a latent period of only 0.017 sec. Evidently in such a case there was no perceptible delay in passing through the nerve centers of the lumbar cord. Inhibition of Reflexes.— One of the most fundamental facts regarding spinal reflexes is the demonstration that they can be depressed or suppressed entirely — that is, inhibited — by other im- pulses reaching the same part of the spinal cord. The most sig- nificant experiment in this connection is that made by Setschenow.* If in a frog the entire brain or the cerebral hemispheres are re- moved, then stimulation of the exposed cut surface — for instance, by crystals of sodium chlorid — will depress greatly or perhaps inhibit entirely the usual spinal reflexes that may be obtained by cutaneous stimulation. On removal of the stimulating substance from the cut surface by washing with a stream of physiological saline (solution of sodium chlorid, 0.7 per cent.) the reflex activities of the cord are again exhibited in a normal way. This experiment accords with many facts which indicate that the brain may inhibit the activities of the spinal centers. In the reflex from tickling, for instance, we know that by a voluntary act we can repress the muscular movements up to a certain point; so also the limited control of the action of the centers of respiration and micturition is a phenomenon of the same character. To explain such acts we may assume the existence of a definite set of inhibitory fibers, arising in parts of the brain and distributed to the spinal cord, whose function is that of controlling the activities of the spinal centers. In view of the fact, however, that there is no independent proof of the existence of a separate set of inhibitory fibers within the central nervous system — that is, a set of fibers whose specific energy is that of inhibition — it is preferable to speak simply of the inhibitory influence of the brain upon the cord, leaving unde- cided the question as to whether this influence is exerted through a special set of fibers, or is brought about by some variation in * Setschenow, " Physiologische Studien uber d. Hemmungs-Mechanismen f. d. Reflexthatigkeit im Gehirn d. Froscb.es/' Berlin, 1863. 150 PHYSIOLOGY OF CENTRAL NERVOUS SYSTEM. the time relations, intensity, or quality of the nerve impulses. Regarding the fact, however, there can be no question, and it constitutes a most important factor in the interaction of the dif- ferent parts of the nervous system. It is possible that this factor explains why a normal frog gives reflexes that are so much less constant and less predictable than one with its brain removed. A similar inhibition of spinal reflexes may be obtained by simul- taneous stimulation of two different parts of the skin. The usual reflex from pinching the toe of one leg may be inhibited in part or completely by simultaneous stimulation of the other leg or by direct electrical stimulation of an exposed nerve trunk. A similar interference is illustrated, perhaps, in the well-known device of inhibiting an act of sneezing by a strong sensory stimulation from some part of the skin — for instance, by pressing upon the upper lip. The importance of the process of inhibition in the normal movements of the body is illustrated strikingly by the phenomenon known as reciprocal innervation, which has been investigated chiefly by Sherrington.* This observer has found that when a flexor muscle is stimulated reflexly there is at the same time a relaxation or loss of tone in its antagonistic extensor, which is explained as being due to an inhibition of the motor cells of the extensor in the cord. Reflex stimulation of the extensor is accompanied similarly by an inhibition of the tone of the antagonistic flexor. This phenomenon has been demonstrated not only for reflex stimulation of the cord but also for voluntary movements (Athanasieu) and for electrical stimulation of the cortical centers. The motor centers of the muscles surrounding the joints are apparently so connected in pairs that when one is excited the center of the corresponding antagonist is inhibited. This reciprocating mechanism dis- appears under conditions, such as strychnine-poisoning, in which, according to the usual belief, the irritability of the centers is greatly increased. A relationship quite comparable to the reciprocal innervation, although working in only one direction, is exhibited by the peripheral nerve plexuses in the intestinal canal in the so-called law of the intestines (see p. 715). A brief statement of the more or less unsatisfactory theories of inhibition is given in connection with the inhibitory action of the vagus nerve on the heart beat (see p. 581). It should be added, however, in this connection, that stimulation of the cord, and probably of other parts of the nervous system, from two different sources may result not only in an inhibition of the reflex normally occurring from one of the stimuli, but under some circumstances ♦Sherrington, "The Integrative Action of the Nervous System," 1906, p. 84. REFLEX ACTIONS. 151 may give an augmentation or reinforcement of the reflex. A striking example of this augmenting effect is given below in the paragraph upon the knee-kick. Influence of the Condition of the Cord on its Reflex Ac- tivities.— The time and extent of the reflex responses may be altered greatly by various influences, particularly by the action of drugs. The effect in such cases is usually upon the nerve centers, — that is, upon the cells themselves or upon the synapses, that is to say, the connections between the terminal arborization and the dendrites — the process of conduction within the sensory and motor fibers being less easily affected. A convenient method of studying such influences is that employed by Tiirck. In this method the reflex frog is suspended, and the tip of the longest toe is immersed to a definite point in a solution of sul- phuric acid of a strength of 0.1 to 0.2 per cent. If the time between the immersion and the reflex withdrawal of the foot is noted by a metronome, or by a record upon a kymograph, it will be found to be quite constant, provided the conditions are kept uniform. If the average time for this reflex is obtained from a series of observations it is possible to inject various substances — such as strychnin, chloroform, potassium bromid, quinin, etc. — under the skin, and after absorption has taken place to determine the effect by a new series of observations. So far as drugs are concerned the results of such experiments belong rather to pharma- cology than to physiology. The method in some cases brings out an interesting difference in the effects of various kinds of stimulation. Strychnin, for instance, as was stated above, increases greatly the delicacy of the reaction to pressure stimulation. At one stage in its action before the convulsive responses are obtained the threshold stimulus is greatly lowered, — mere contact with the toes causes a rapid retraction of the leg; whereas in the normal reflex frog a relatively large pressure is necessary to obtain a similar response. At this stage in the action of the strychnin the effect of the acid stimulus, on the contrary, may be markedly weakened so far as the time element is concerned. If the action of the strychnin is not too rapid, it is usually possible to find a point at which the time for the reflex is diminished, but this effect quickly disappears and the period between stimulus and response becomes markedly lengthened at a time when the slightest mechanical stimulation gives a rapid reflex movement. This paradoxical result may depend pos- sibly upon the variety of nerve fiber stimulated by the two kinds of stimuli or may be connected with the fact that the acid stimuli may bring about inhibitor}- as well as excitatory processes in the cord. Reflexes from Other Parts of the Nervous System. — Nu- merous typical reflexes are known to occur in the brain. The 152 PHYSIOLOGY OF CENTRAL NERVOUS SYSTEM. reflex effects upon the important centers in the medulla, such as the vasomotor center, the respiratory center, and the cardio- inhibitory center, the winking of the eye, sneezing, the light reflex upon the sphincter muscle of the iris, and many other similar cases might be enumerated. All of these reactions will be described and discussed in their proper places. The conscious reactions of- the brain are not included among the reflexes by virtue of the defi- nition which lays stress upon the involuntary characteristic of the reflex response, but it should be remembered that, so far as the nervous mechanism is concerned, these conscious reactions do not differ from the true reflexes. When we voluntarily move a limb the movement is guided and controlled by sensory impulses from the muscles put into action. The fibers of muscle sense from these muscles convey sensory impulses through a chain of neurons to the cortex of the brain and there the impulses doubtless affect and set into action the motor neurons through which the movement is effected. So far as we know, the discharges from the efferent neuron of the brain are not really automatic, but are conditioned or originated by stimuli from other neurons; so that the activities of the brain are carried on by a mechanism of one neuron acting on another, just as in the case of the reflex arc. The added feature of a psychical factor, a reaction in consciousness, enables us to draw a line of distinction between these activities and those of so-called pure reflexes; but the distinction is perhaps one of convenience only, for, although the extremes may be far enough apart to suit the definition, many intermediate instances may be found which are difficult to classify. All skilled movements, for instance, such as walking, singing, dancing, bicycle riding, and the like, — although in the beginning obviously effected by voluntary co-ordination, nevertheless in the end, in proportion to the skill obtained, become more or less entirely reflex, — that is, involuntary. In learning such movements one must, as the saying goes, establish his reflexes, and the result can hardly be understood otherwise than by suppos- ing that the continual adjustment of certain sensory impulses to certain co-ordinated movements results in the formation of a more or less complex reflex arc, a set of paths of least resistance. Reflexes through Peripheral Ganglia — Axon Reflexes.— Many attempts have been made by physiologists to ascertain whether or not reflexes can occur through the peripheral nerve ganglia, lying outside the central nervous system. With regard to the posterior root ganglia, it has usually been supposed that they cannot exhibit reflexes. When the posterior root con- necting such a ganglion to the cord is severed, then, according to our usual conception, the cells in the ganglia are cut off from all connections with the peripheral tissues by efferent EEFLEX ACTIONS. 153 paths. This usual view may not, however, be correct. On the physiological side we have the fact (see p. 83) that stimu- lation of certain of the posterior root ganglia undei such cir- cumstances does give peripheral effects on the blood-vessels, causing a vascular dilatation in a certain region. On the histological side Cajal* and others have shown that some of these cells are provided with a pericellular nerve network, which is an afferent path so far as the cell is con- cerned, while the axon of the cell con- stitutes an efferent path. Whether these cells form a special group of efferent cells lying within the sensory ganglion, or whether they are sensory cells discharging into the cord and stimulated reflexly through the nerve network as well as through the peripheral process of the axon, cannot be said. The subject is one full of interest to physiology. In the ganglia of the sympathetic nerve and its appen- dages and in the similar ganglia contained in many of the organs the nerve cells have dendritic processes, and, so far as their histology is concerned, it would seem possi- ble that in any ganglion of this type there might be sensory and motor neurons so connected as to make the ganglion an independent reflex center. Numerous experiments have been made to determine experimentally whether reflexes can be obtained through such ganglia. Perhaps the most successful of these experiments have been made upon the inferior mesenteric ganglion. This ganglion may be isolated from all connections with the central nervous system and left attached to the bladder through the two hypogastric nerves (see Fig. 287). If now one of these nerves is cut and the central stump is stimulated, a contraction of the bladder follows. Obviously in this case the impulse has traveled to the ganglion and down the other hy- pogastric nerve; the reaction has every appearance of being a true reflex. Nevertheless, Langley and Anderson, f who have studied the matter with especial care, are convinced that in this * Cajal, " Ergebnisse der Anat. u. Entwickelungsgeschichte, " vol. xvi., 1906. t Langley and Anderson, "Journal of Physiology," 16, 410, 1894. Fig. 69. — Sohema to show idea of an axon re- flex: The preganglionic fiber, a, sends branches to two postganglionic fibers, 6, c. If stimulated at x the impulse passes backward in a direction the reverse of normal and falling into b and c gives a pseudoreflex effect. 154 PHYSIOLOGY OF CENTRAL NERVOUS SYSTEM. and similar cases we have to do with what they call pseudo- reflexes or axon reflexes. The idea underlying this term may be explained in this way: Every sympathetic ganglion is connected with the central nervous system, brain and cord, by efferent spinal fibers, preganglionic fibers, which terminate by arborization around the dendrites of the sympathetic cells. The efferent fibers arising from the latter may be designated as post- ganglionic fibers. These authors give reasons to believe that any one preganglionic fiber, a, Fig. 69, may connect by collaterals with several sympathetic cells. If such a fiber were stimulated at x, then the impulse passing back along the axon in a direction the reverse of normal would stimulate cells b and c, giving effects that are apparently reflex, but which differ from true reflexes in that the stimulating axon belongs to a motor neuron. Under normal circumstances it is not probable that an effect of this kind can be produced. The Tonic Activity of the Spinal Cord. — In addition to the definite reflex activities of the cord, each traceable to a distinct sensory stimulus, there is evidence to show that many of its motor neurons are in that state of more or less continuous activity which we designate as tonic activity or tonus. There is abundant reason for this belief in regard to many of the special centers of the cord and brain, such as the vasomotor center, the center for the sphinc- ter muscle of the iris, the centers for the sphincter muscles of the bladder, the anus, etc. But the evidence includes the motor neurons to the voluntary as well as the involuntary musculature. In a decapitated frog the muscles take a definite position, and Brondgeest showed that if such an animal is suspended, after cut- ting the sciatic plexus in one leg, the leg on the uninjured side takes a more flexed position. The explanation offered for this result is that the muscles on the sound side are being innervated by the motor neurons of the cord. Inasmuch as a result of this kind cannot be obtained from a frog whose skin has been removed, or in one in which the posterior roots have been severed it seems evident that this tonic discharge from the motor neurons is due to a constant inflow of impulses along the sensory paths. The muscle tonus, in other words, is really a reflex tonus, which differs from ordinary reflex movements only in the absence of a sudden, visible contraction and in the more or less continuous character of the innervation. In the section on animal heat the importance of this constant innervation of the muscles as a source of heat i£ further emphasized. The idea of a more or less continuous but varying activity of the centers in the brain and cord in consequence of the continuous inflow of impulses along the sensory paths fits in very well with many facts observed in the peripheral organs, — REFLEX ACTIONS. 155 facts that will be referred to from time to time as the physiology of these organs is considered. Effects of Removal of the Spinal Cord. — Numerous investi- gators have sectioned the cord partly or completely at various levels. The general results of these experiments as regards loss of sensation or voluntary movement are described in the next section treating of the cord as a path of conduction to and from the brain. But attention may be called here to some of the gen- eral results obtained by Goltz* in some remarkable experiments in which the entire cord was removed with the exception of the cervical region and a small portion of the upper thoracic. In making this experiment it was necessary to perform the operation in several steps. That is7 the cord was first sectioned in the upper thoracic region and then in successive operations the lower tho- racic, lumbar, and sacral regions were removed completely. Very great care was necessary in the treatment of the animals after these operations, but some survived and lived for long periods, the digestive, circulatory, and excretory organs performing their functions in a normal manner. The muscles of the hind limbs and trunk, however, underwent complete atrophy, owing to the destruction of their motor nerves. The blood-vessels also were paralyzed after the first operations, but gradually their muscu- lature again recovered tone, showing that, although under normal conditions the tonic contraction of the vessels is under the in- fluence of nerves arising from the cord, this tone may be re-estab- lished in time after the severance of all spinal connections. Some of the specific results of these experiments, bearing upon the re- flexes of defecation, micturition, and parturition, will be described later. Attention may be called here to the general results illustrating the general functions of the cord. In the first place, there was, of course, a total paralysis of volun- tary movement in the muscles innervated normally through the parts of the cord removed, and a complete loss of sensation in the same regions, particularly of cutaneous and muscular sensibility. In the second place, the visceral organs, including the blood-vessels, were shown to be much more independent of the direct control of the central nervous system. While these organs in the experiments under consideration were still in connection with the sympathetic ganglia and in part with the brain through the vagi, still their connections with the central nervous system, particularly as regards their sensory paths and the innervation of the blood-vessels, were in largest part destroyed. The immediate effect of this destruction would have been the death of the animal if the care * Goltz and Ewald, "Pfluger's Archiv fur die gesammte Physiologie, " 63, 362, 1896. - 156 PHYSIOLOGY OF CENTRAL NERVOUS SYSTEM. of the observer had not replaced, in the beginning, the normal control exercised by the nervous system through the spinal nerves; but later this careful nursing was not required. While these organs, therefore, are capable of a certain amount of independent activity and co-ordination, they are normally controlled through the various reflex activities of the brain and cord. In the third place, it is noteworthy that the adaptability of the cordless portion of the animal was distinctly less than normal. Its power of preserving a constant body temperature was more limited than in the normal animal, and the susceptibility to inflammatory disturbances in the visceral organs was greatly increased. It seems evident, from these facts, that, although the animal was living, its power of adaptation to marked changes in the external or internal environment was greatly lessened, and this fact illustrates well the great general importance of the spinal cord and brain as reflex centers controlling the nutri- tion and co-ordinated activities of the body tissues and organs. This control is necessary under normal conditions for the success- ful combination of the activities of the various organs. A large part of this control is doubtless dependent upon the regulation of the blood supply to the various organs. The mechanism by which this is effected and the parts played by the cord and the brain (medulla oblongata), respectively, will be described in the section on Circulation. Knee-jerk. — Knee-jerk or knee-kick is the name commonly given to the jerk of the foot when a light blow is struck upon the patellar ligament just below the knee. The jerk of the foot is due to a contraction of the quadriceps femoris muscle. Accord- ing to Sherrington, the parts of this muscular mass chiefly concerned are the m. vastus medialis and m. vastus intermedius. In order to obtain the muscular response it is usually neces- sary to put the quadriceps under some tension by flexion of the leg. This end is achieved most readily by crossing the knees or by allowing the leg to hang freely when sitting on the edge of a bench or table. Under such circumstances the jerk is obtained in the great majority of normal persons, and this fact has made it an important diagnostic sign in many diseases of the spinal cord. The importance of the reaction for such purposes was first brought out by the work of Erb and Westphal * in 1875. Reinforcement of the Knee-jerk. — It was first shown by Jendrassik (1883) that the extent of the jerk may be greatly aug- mented if, at the time the blow is struck upon the tendon, a strong voluntary movement is made by the individual, such as squeezing the hands together tightly or clenching the jaws. This phenomenon * Erb and Westphal, " Archiv f. Psychiatrie," 1875, vol. v. REFLEX ACTIONS. 157 was studied carefully in this country by Mitchell and Lewis,* who ascertained that a similar augmentation may be produced by giving the individual a simultaneous sensory stimulation. They desig- nated the phenomenon as a reinforcement, and this name is gen- erally employed by English writers, although occasionally the term "Bahnung," introduced by Exner to describe a similar phenom- enon, is also used. It is found that by a reinforcement the knee- jerk may be demonstrated in some individuals in whom the ordi- nary blow upon the tendon fails to elicit a response. Bowditch and Warren f studied the phenomenon of reinforcement and brought out a fact of very great interest. They studied especially the time interval between the blow upon the tendon and the reinforcing act and found that if the latter preceded the blow by too great an inter- val then, instead of an augmentation of the jerk, there was a dimi- nution which they designated as negative reinforcement or inhi- bition. This inhibiting effect began to appear when the reinforcing act (hand-squeeze) preceded the blow by an interval of from 0.22 to 0.6 sec, and the maximum inhibiting effect was obtained at an 40- 30- Fig. 70. — Showing in millimeters the amount by which the "reinforced" knee-kick varied from the normal, the level of which is represented by the horizontal line at 0, "nor- mal." The time intervals elapsing between the clenching of the hands (which constituted the reinforcement) and the tap on the tendon are marked below. The reinforcement is greatest when the two events are nearly simultaneous. At an interval of 0.4 sec. it amounts to nothing; during the nest 0.6 sec. the height of the kick is actually diminished, while after an interval of 1 sec. the negative reinforcement tends to disappear: and when 1.7 sec. is allowed to elapse the height of the kick ceases to be affected by the clenching of the hand*. — (Bowditch and Warren.) interval of from 0.6 to 0.9 sec. Beyond this point the effect became less noticeable, and at an interval of 1.7 to 2.5 sec. the reinforcing act had no influence at all upon the jerk. These relations are shown in the accompanying curve (Fig. 70). These authors con- * Mitehell and Lewis, " American Journal of Med. Sciences," 92, 363, 1886. t Bowditch and Warren, "Journal of Physiology," 2, 25, 1890. 158 PHYSIOLOGY OF CENTRAL NERVOUS SYSTEM. firmed also the fact that a sensory stimulus, such as a gentle blast of air on the conjunctiva or the knee, may reinforce the jerk. The physiological explanation of the reinforcement, negative and posi- tive, is a matter of inference only, but the view usually held is that it is due to "overflow." That is, many facts, such as strychnin tetanus, indicate that the neuromuscular machinery of the entire eentral nervous system is more or less directly connected and that functional activity at one part may influence the irritability of the remainder, either in the direction of reinforcement (Bahnung) or inhibition. We may conceive, therefore, that when the hands are squeezed the motor impulses sent down from the cortex of the brain to the upper portion of the cord overflow to some extent, sufficient at least to alter the irritability of the other motor neurons in the cord. Experimental stimulation of the cortex has given similar results. Exner* found that when the motor center for the foot in the cortex of a rabbit was stimulated, the stimulation, even if too weak to be effective itself, caused an increase in the contraction brought about reflexly by a simultaneous stimulation of the skin of the paw, and furthermore if these stimuli were so reduced in strength that each was ineffective, then when applied together a contraction was obtained. In this case an ineffective stimulus from the cortex reaching the spinal cord increased the irritability of the motor centers there so that a simultaneous reflex stimulus from the foot, ineffective in itself, became effective. Is the Knee-jerk a Reflex? — The most interesting question in this connection is whether the jerk is a true reflex act or is due to a direct mechanical stimulation of the muscle. Opinions have been divided upon this point. Those who believe that the jerk is a reflex lay emphasis upon the undoubted fact that the integrity of the reflex arc is absolutely essential to the response. The quad- riceps receives its motor and sensory fibers through the femoral nerve, and pathological lesions upon man as well as direct experimental investigation upon monkeys prove that if either the posterior or anterior roots of the third and fourth lumbar spinal nerves are destroyed the knee-jerk disappears entirely. The oppo- nents of the reflex view explain this fact by the theory that* in order for the quadriceps to respond it must be in a condition of tonus. This tonus depends upon the reflex arc, the sensory impulses from the muscle serving to keep it in that condition of subdued contraction known as tone. On this view destruc- tion of the reflex arc renders the muscle less irritable, so that it will not respond by a contraction to the sudden mechanical exten- sion or pull caused by the blow on the tendon. The adherents of this view lay emphasis upon two facts: First, the knee-jerk is a * Exner, "Archiv f. die gesammte Physiologie," 27, 412, 1882. REFLEX ACTIONS. 159 simple contraction, and not a tetanus, and, generally speaking, the motor centers of the cord discharge a series of impulses when stimulated. In answer to this objection it may be said that while muscular contractions produced reflexly are usually tetanic, it does not follow that this is invariably the case. Sher- rington* has shown, for instance, that an undoubted reflex designated by him as the "extensor thrust," which also involves the extensor muscles of the hind leg, is very short lasting, requir- ing perhaps only i sec, and judged by this standard is as much of a simple contraction as the knee-jerk. The "extensor thrust" is a sharp contraction of the extensor muscles of the hind leg aroused by pressure upon the plantar surface of the hind foot. On the frog also a single stimulus applied to the central end of the divided sciatic nerve will call forth a reflex contraction, which is a twitch, and not a tetanus. Second, the time for the jerk — that is, the interval between the stimulus and the response — is too short for a reflex. The determination of this time has been attempted by many observers for the purpose of deciding the controversy, but unfortunately the results have been lacking in uniformity, although the best results from man indicate a latency between stimulus and response of 0.023 sec. after deducting the latent period of the mus- cle icself. Applegarth, making use of a dog with a severed spinal cord, obtained for the time of the knee-jerk an interval of 0.014 to 0.02 sec. ; Waller and Gotch, using the rabbit, found the time to be only 0.008 to 0.005 sec. Other figures would appear to indicate that the latent period is shorter the smaller the animal, a fact which in itself would imply that some factor other than the latency of the muscle itself enters into the time required. And if we accept the newer figures in regard to the velocity of the nerve impulse in mammalian nerves at the body temperature (see p. 113), there would seem to be sufficient time in all cases for the impulse to get to the cord and back. Several observers! have attempted to determine the time intervening between stimulus and response by using the string galvanometer to indicate the electrical response in the muscle, instead of attempting to record the contraction itself. According to Snyder, the time interval lies between 0.0113 and 0.015 sec, while Hoffmann's results give an interval of 0.019 to 0.024 sec. The calculations of both observers indicate that the time is sufficient for a reflex, and much too long for a direct excita- tion. In the case of the Achilles jerk, Hoffmann finds that it may be liberated by electrical stimulation of the n. tibialis and that under these circumstances there is first a deflection of the galvano- meter, due to direct stimulation of the gastrocnemius through * Sherrington, "The Integrative Action of the Xervous System," 1906. f Snyder, "American Journal of Physiology," 26, 474, 1910. Hoffmann, "Archiv f. Physiologie," 1910, 223. 160 PHYSIOLOGY OF CENTRAL NERVOUS SYSTEM. its motor nerve, and this is followed later by a second deflection, due to reflex stimulation. This latter accords in time interval with the Achilles jerk, and gives a new proof that the phenomenon is a genuine reflex. In view of these facts it would seem to be safe to conclude that the knee-kick and similar phenomena are reflexes, but reflexes in which a single nerve impulse is sent out from the cord, causing a simple contraction in the muscle affected. Conditions Influencing the Extent of the Knee-jerk. — The effect of various normal conditions upon the knee-jerk has been studied by a number of observers, particularly by Lombard.* The results are most interesting in that they indicate very clearly that the irritability of the spinal cord varies with almost every marked change in mental activity. During sleep the jerk disappears and in mental conditions of a restful character its extent is relatively small. In conditions of mental excitement or irritation, on the contrary, the jerk becomes markedly increased. Lombard ob- served also, in his own case, a daily rhythm, which is represented in the chart given in Fig. 71. It would seem from his experiments Fig. 71. — Lombard's figure to indicate the daily rhythm in the extent of the knee- jerk and the effect of mental stimuli. The ordinates (0-110) represent the extent of the kick in millimeters. Each dot represents a separate kick, while the heavy horizontal line gives the average extent for the period indicated. that the extent of the knee-jerk is a sensitive indicator of the relative state of irritability of the nervous system: "The knee- * Lombard, "The American Journal of Psychology," 1887, p. 1. See also article "Knee-jerk" (Warren), "Wood's Ref. Handbook of Med. Sci- ences," second edition, 1902. REFLEX ACTIONS. 161 jerk is increased and diminished by whatever increases and di- minishes the activity of the central nervous system as a whole." This general fact is supported, especially as regards mental activity, by observations on other similar mechanisms, — such, for instance, as the condition of the nervous centers controlling the bladder. Use of the Knee-jerk and Spinal Reflexes as Diagnostic Signs. — The fact that the knee-jerk depends on the integrity of the reflex arc in the lumbar cord has made it useful as a diagnostic indication in lesions of the cord, particularly, of course, for the lumbar region. It is mainly on account of its practical value and the ease with which it is ordinarily obtained that the phenom- enon has been studied so extensively. In the disease known as progressive locomotor ataxia the posterior root fibers in the pos- terior columns in the lumbar region are affected, and, as a con- sequence, the jerk is diminished or abolished altogether according to the stage of the disease. So also lesions affecting the anterior horns of the gray matter will destroy the reflex by cutting off the motor path, while in other cases lesions in the brain or the lateral columns of the cord affecting the pyramidal system of fibers may be accompanied by an exaggeration of this and similar reflexes. This latter fact agrees with the experimental results (see p. 149) upon ablation of the brain. After such operations in the frog and lower mammals at least the spinal reflexes may show a marked increase. Interruption of the descending connections between brain and cord at any point, therefore, may be accompanied by a strik- ing increase in sensitiveness of the spinal reflexes. The explana- tion usually given is that the inhibitor}" influences of the brain centers upon the cord are thereby weakened or destroyed. The Other Spinal Reflexes. — Various other distinctive reflexes through the spinal cord may be obtained readily, and since the motor cells concerned lie at different levels in the cord the presence, absence, or modified character of these reflexes has been used frequently for diagnostic purposes. In the first place there are a number of so-called deep reflexes which may be aroused by sensory stimulation of parts beneath the skin, such as the tendons, ligaments, and periosteum. Almost any tendon if stimulated mechanically may give a jerk of the cor- responding muscle, just as in the case of the knee-kick. Such reactions have been described and used in the case of the wrist- jerk, the jaw-jerk, the Achilles-jerk, etc. The last named is obtained by putting the foot into a position of dorsiflexion and then tapping the tendo calcaneus (Achillis). The result is a contraction of the gastrocnemius, causing plantar flexion of the foot. A variation of this reflex is the phenomenon known as ankle clonus. This is obtained by giving a quick forcible 11 162 PHYSIOLOGY OF CEXTRAL NERVOUS SYSTEM. dorsiflexion to the foot thus putting the tendon and muscle under a sudden mechanical strain. In some cases there results a rhythmical series of contractions of the gastrocnemius. A second group of reflexes may be obtained by stimulation of special points on the skin, the cutaneous reflexes. For example, the plantar reflex, which consists in a flexion of the toes when the sole of the foot is stimulated by tactile or painful stimuli. Under pathological conditions which involve a lesion of the pyramidal tracts in the cord this reflex is altered, the great toe being extended instead of flexed (Babinski's phenomenon). The cremasteric reflex consists in a contraction of the cremasteric muscle which raises the testis. It follows from stimulation of the skin on the inner side of the thigh at the level of the scrotum. The location of the motor centers of these and other similar- reflexes is shown in the accompanying illustration (Fig. 72). Fig. 72. — Diagrammatic representation of the lower portion of the human bulb and spinal cord. The cord is divided into its four regions: 1, Medulla cervicalis; 2, medulla dorsalis; 3, medulla lumbalis; 4, medulla sacralis. Within each region the spinal segments bear Roman numbers. On the left side of the diagram the locality supplied by the sensory (afferent) neurons is indicated by one or more words, and these latter are connected with the bulb or the segments of the cord at the levels at which the nerves enter. The afferent character is indicated by the arrow tip on the lines of reference. On the right-hand side the names of muscles or groups of muscles are given, and to them are drawn reference lines which start from the segments of the cord in which the cell-bodies of origin have been located. Within the cord itself, the designations for several reflex centers are inscribed in the segment where the mechanism is localized. For example, Reflexus scapularis, Centrum cilio-spinale, Reflexus epigastricus, Reflexus abdominalis, Reflexus cremastericus, Reflexus patellaris, Reflexus tendo Achillis. Centrum vesicale, Centrum anale (the last two on the left side of the diagram). (Donaldson, "Amer. Text-book of Physiology." from " I cones Neurologicse," Striimpeli and Jofcofc.) (cum Trigemino) Pharynx Oesophagus Larynx, Trachea Mm. pharyogis, palati Mm. laryngis Mm. linguae Oesophagus Regio occipitalis' Regio colli Regio nuchaa Regio humeri Regio Nervi radialis Regio N. mediant Regio N. ulnaris Regio femoris Regio cruris Fig. 72. CHAPTER VIII. THE SPINAL CORD AS A PATH OF CONDUCTION. In addition to the varied and important functions performed by the cord as a system of reflex centers controlling the activities of numerous glands and visceral organs as well as the so-called voluntary muscles, it is physiologically most important as a path- way to and from the brain. All the fibers, numbering more than half a million, that enter the cord through the posterior roots of the spinal nerves bring in afferent impulses, which may be continued upward by definite tracts that end eventually in the cortex of the cerebrum, the cerebellum, or some other portion of the brain. On the other hand, many of the efferent impulses originating reflexly or otherwise in different parts of the brain are conducted downward into the cord to emerge at one or another of the anterior roots of the spinal nerves. The location and extent of these ascending and descending paths form a part of the inner structure of the cord, which is most important practically in medical diagnosis and which has been the subject of a vast amount of experimental inquiiy in physiology, anatomy, pathology, and clinical medicine. In working out this inner architecture the neuron conception has been of the greatest value, and the results are usually presented in terms of these interconnecting units. The Arrangement and Classification of the Nerve Cells in the Gray Matter of the Cord. — Nerve cells are scattered throughout the gray matter of the cord, but are arranged more or less distinctly in groups or, considering the longitudinal aspect of the cord, in columns the character of which varies somewhat in the different regions. From the standpoint of physiological anatomy these cells may be grouped into four classes: (1) The anterior root cells, clustered in the anterior column of gray matter (1, Fig, 73). The axons of these cells pass out of the cord almost at once to form the anterior or motor roots of the spinal nerves. (2) The tract cells, so called because their axons instead of leaving the cord by the spinal roots enter the white matter and, passing upward or downward, help to form the tracts into which this white matter may be divided (2 and 3 of Fig. 73) . These tract cells are found throughout the gray matter, and, according to the side on which the axon enters into a tract, they may be divided into three subgroups : 163 164 PHYSIOLOGY OF CENTRAL NERVOUS SYSTEM. (a) Those whose axons enter the white matter on the same side of the cord, the tautomeric tract cells of Van Gehuchten. (6) Those whose axons pass through the anterior white commissure and thus reach the tracts in the white matter of the other side. These are known as commissural cells or the heteromeric tract cells of Van Gehuchten. They form one obvious means for crossed conduction in the cord, (c) Those whose axons divide into two, one passing into the white matter of the same side, the other pass- ing by way of the anterior commissure to reach the white matter of the opposite side — the hecateromeric tract cells of Van Gehuch- ten. (3) The Golgi cells of the second type — that is, cells whose 1/en.tral Fig. 73. — Schema of the structure of the cord. — After Lenhossek.) On the right the nerve cells; on the left the entering nerve fibers. Right side: 1, Motor cella, anterior column, giving rise to the fibers of the anterior root; 2. tract cells whose axons pass into the white matter of the anterior and lateral funiculi; 2, commissural cells whose axon.- pass chiefly through the anterior commissure to reach the anterior funiculi of the other side; 4, Golgi cells (second type;, whose axons do not leave the gray matter; 5, tract cells whose axons pass into the white matter of the posterior funiculi. Left side: 1, Entering fibers of the posterior root, ending, from within outward, as follows: Clarke's column, posterior column of opposite side, anterior column -ame side (reflex arc), lateral column of same side, posterior column of same side: 2, collateral- from fibers in the anterior and lateral funiculi, 3, collaterals of descending pyramidal fibers ending around motor cell- in anterior column. axons divide into a number of small branches like those of a dendrite. The axons of these cells, therefore, do not become medullated nerve fibers; they take no part in the formation of the spinal roots or the tracts of white matter in the cord, but terminate diffusely within the gray matter itself. (4) The pos- terior root cells lying toward the base of the anterior columns. These cells have been demonstrated in some of the lower verte- brates (petromyzon — chick embryo), but their existence in the mammal is still a question in some doubt; their axons pass out from the cord by the posterior root and they form the anatomical evidence for the view that the posterior roots may contain some SPIXAL COED AS A PATH OF CONDUCTION. 165 efferent fibers. Some of the groups of tract cells have been given special names — such, for instance, as the dorsal nucleus (Clarke's column). This group of cells lies at the inner angle of the posterior column of gray matter (5, Fig. 76), and forms a column usually described as extending from the middle lumbar to the upper dorsal region. The axons from these cells pass to the dorsal margin of the lateral funiculi on the same side to con- stitute an ascending tract of fibers known as the tract of Flechsig, or the fasciculus cerebellospinalis. General Relations of the Gray and White Matter in the Cord. — Cross-sections of the cord at different levels show that the relative amounts of gray and white matter differ considerably at different levels, so that it is quite possible to recognize easily from what region any given section is taken. At the cervical and the lumbar enlargements the amounts of both gray and white matter — that is, the total cross-area of the cord — show a sudden White mailer. Gray matter. Entire section. oo so 60 >'"^ NXomposile curves based on 4 Cases. 40 •JO --... 7^ tOO J 11 III D* y u Ynsra 1 D Dl E ranisanaxxixui n juiyyi nuiBrf Fig. 74. — Curves to show the relative areas of the gray and white matter of the spinal cord at different levels. — {Donaldson and Davis.) The Roman numerals along the abscissa represent the origin of the different spinal nerves. increase owing to the larger number of fibers arising at these levels. The white matter, and therefore the total cross-area, shows also a constant increase from below upward, due to the fact that in the upper regions many fibers exist that have come into the cord at a lower level or from the brain, those from the latter region being gradually distributed to the spinal nerves as we proceed downward. In the accompanying figure a curve is presented showing the cross- area of the cord and the relative amounts of gray and white matter at each segment. Tracts in the White Matter of the Cord, Methods of Deter- mining.— The separation of the medullated fibers of the cord into distinct tracts of fibers possessing different functions has been accomplished in part by the combined results of investiga- tions in anatomy, physiology, and pathology. The two methods that have been employed most frequently and to the best advan- tage are the method of secondary degeneration (Wallerian degen- 166 PHYSIOLOGY OF CENTRAL NERVOUS SYSTEM. eration) and the method of myelinization. The method of second- ary degeneration depends upon the fact that, when a fiber is cut off from its cell of origin, the peripheral end degenerates in a few days. If, therefore, a lesion, experimental or pathological, is made in the cord at any level, those fibers that are affected undergo degeneration: those with their cells below the lesion degenerate up- ward, and those with their cells above the lesion degenerate down- ward. According to the law of polarity of conduction in the neuron a descending degeneration in the cord indicates motor or efferent paths as regards the brain, and ascending degeneration indicates sensory or afferent paths. It is obvious that localized lesions can be used in this way to trace definite groups of fibers through the cord. If, for instance, one exposes and cuts the posterior roots in one or more of the lumbar nerves, the portions of the fibers entering the cord will degenerate, and the path of some of these fibers may be traced in this way upward to the medulla. The degenerated fibers may be revealed histologically by the staining methods of Weigert or of Marchi. The latter method (preservation in Midler's fluid, staining in osmic acid and Muller's fluid) has proved to be espe- cially useful; the degenerated fibers during a certain period give a black color with this liquid, owing probably to the splitting up of the lecithin in the myelin and the liberation of the fat from its combination with the other portions of the molecule.* The mye- linization method was introduced by Flechsig. It depends upon the fact that in the embryo the nerve fibers as first formed have no myelin sheath, and that this easily detected structure is in the central nervous system assumed at about the same time by those bundles or tracts of fibers that have a common course and func- tion. By this means the origin and termination of certain tracts may be worked out in the embryo or shortly after birth. The well-known system of pyramidal fibers, for instance, is clearly differentiated in the embryo late in intra-uterine life or at birth, owing to the fact that the fibers composing it have not at that time acquired their myelin sheaths. Flechsig assumes that the development of the myelin marks the completed structure of the nerve fiber and indicates, therefore, the time of its entrance into full functional activity. General Classification of the Tracts. — The tracts that have been worked out in the white matter of the cord have been classified in several ways. We have, in the first place, the division into as- cending and descending tracts. This division rests upon the fact that the axon conducts its impulses away from the cell of origin, and consequently those neurons whose axons extend upward toward the ♦See Halliburton, "The Chemical Side of Nervous Activity," London, 1901; "Croonian Lectures." SPINAL CORD AS A PATH OF CONDUCTION. 167 higher parts of the cord or brain are designated as ascending, since normally the impulses conducted by them take this direction. They constitute the afferent or sensory paths, and in case of injury to the fiber or cell the secondary degeneration also extends upward. The reverse, of course, holds true for the descending or motor paths. The tracts may be divided also into long and short (or segmental) tracts. The latter group comprises those tracts or fibers which have only a short course in the white matter, extending over a dis- tance of one or more spinal segments. Histologically the fibers of these tracts take their origin from the tract cells in the gray matter of the cord and after running in the white matter for a^distance of one or more segments they again enter the gray matter to terminate around the dendritic processes of another neuron. These short tracts may be ascending or descending, and the impulses that they conduct are conveyed up or down the cord by a series of neurons, each of whose axons runs only a short distance in the white matter, and then conveys its impulse to another neuron whose axon in turn extends for a segment or two in the white matter, and so on. These tracts are sometimes described as association or short associa- tion tracts, because they form the mechanism by which the activi- ties of different segments of the cord are brought into association. This method of conduction by segmental relays involving the par- ticipation of a series of neurons may be regarded as the primitive method. It indicates the original structure of the cord as a series of segments, each more or less independent physiologically. The short tracts in the mammalian cord he close to the gray matter, forming the bulk of what is known as the anterior and lateral proper fasciculi. The long tracts, on the contrary, are com- posed of those fibers, ascending or descending, which run a long distance, and, in fact, extend from the cord to some part of the brain. It is known, however, that, although the tracts as tracts extend from brain to cord, many of their constituent fibers may begin and end in the cord or in the brain, as the case may be. Some of the fibers of the long tracts are, there- fore, so far as the cord is concerned, simply long association tracts which connect different regions — e. g., cervical and lum- bar— of the cord by a single neuron, as the short asso- ciation tracts connect different segments of the same region. It is said that in these long tracts those fibers that have the shortest course lie to the inside — that is, nearest to the gray matter.* From the results of comparative studies of the different vertebrates we may conclude that the long tracts are a relatively late development in their phylogenetic history, and that in the most highly developed animals, man and the anthropoid apes, * Sherrington and Laslett, "Journal of Physiology," 29, 188, 1903; and Sherrington, ibid., 14, 255. 168 PHYSIOLOGY OF CENTRAL NERVOUS SYSTEM. these long tracts are more conspicuous and form a larger per- centage of the total area of the cord. A physiological corollary of this conclusion should be that in man the independent activity of the cord is less marked than in the lower vertebrates, and this deduction is borne out by facts (see p. 147). Specific Designation of the Long Spinal Tracts. — The tracts that are most satisfactorily determined for the human spinal cord are indicated schematically in Fig. 75. They are named as follows: In the posterior funiculus, 1. The fasciculus gracilis (column of Goll). 2. The fasciculus cuneatus (column of Burdach). Fig. 75. — Schema of the tracts in the spinal cord (Kolliker) : g, Fasciculus gracilis; b, fasciculus cuneatus ; pc, fasciculus cerebrospinalis lateralis ; pd, fasciculus cerebrospinalis anterior; /, fasciculus cerebellospinalis ; gr, fasciculus anterolateralis superficialis. In the lateral funiculus, 1. The fasciculus cerebrospinalis lateralis, known also as the lateral or crossed pyramidal tract. 2. The fasciculus cerebellospinalis, known also as Flechsig's tract. 3. The fasciculus anterolateralis superficialis, known ;dso as Gower's tract. 4. The lateral ground bundle (fasciculus lateralis proprius), made up chiefly of short association fibers. In the anterior funiculus, 1. The fasciculus cerebrospinalis anterior, known also as the direct or anterior pyramidal tract. 2. The anterior ground bundle (fasciculus anterior proprius). SPINAL COED AS A PATH OF CONDUCTION, 169 Of these tracts, the fasciculus gracilis, fasciculus cuneatus, fasciculus cerebellospinalis, and fasciculus anterolateralis super - ficialis represent ascending or sensory paths, while the lateral and anterior cerebrospinal or pyramidal fasciculi form a related descending or motor path. It will be convenient to describe first the connections and physiological significance of these tracts and then refer briefly to the other less definitely estab- lished ascending and descending paths. The Termination in the Cord of the Fibers of the Posterior Root. — All sensory fibers from the limbs and trunk 6 enter the cord through the posterior roots. Inasmuch as these roots are superfi- cially connected with the posterior funiculi. the older observers naturally supposed that this portion of the white matter of the cord forms the pathway for sensory impulses passing to the brain. That this sup- position is not entirely cor- rect was proved by experi- mental physiology. Sec- tion of the posterior fu- niculi causes little or no obvious loss of sensations in the parts below the lesion. Histological inves- tigation has since shown that only a portion of the fibers entering through the posterior root continue up the cord in the posterior funiculi; some and indeed a large proportion of the whole number enter into the gray matter and end around tract cells, whence the path is continued upward by the axons of these latter cells, mainly in the lateral or anterolateral funiculi. The several ways in which the posterior root fibers may end in the cord are indicated in Fig. 76. The posterior roots contain fibers of different diameters, and those of smallest size (1) are found collected into an area known Fig. 76. — Schema to show the terminations of the entering fibers of the posterior root : 1, Fibers entering zone of Lissauer and terminating in posterior column; 2, fiber terminating around a tract cell -whose axon passes into white matter of same side; 3, fiber terminating around a tract cell whose axon passes to opposite side ( commissural cell); 4, fiber terminating around motor cell of anterior column ( reflex arc); 5, fiber terminating in tract cell of dorsal nucleus; 6, fiber ("exog- enous) passing upward in posterior funiculus to terminate in the medulla oblongata. 170 PHYSIOLOGY OF CENTRAL NERVOUS SYSTEM. as the zone of Lissauer, lying between the periphery of the cord and the tip of the posterior column. These fibers enter the gray matter chiefly in the posterior column of the same side and end around tract cells. The larger fibers of the root lying to the median side fall into two groups: Those lying laterally (2, 3, 4) enter the gray matter of the posterior column and end in tract cells (2) whose axons are distributed to the same side of the cord, or in tract cells whose axons (3) pass to the other side through the anterior white commissure, or in the motor cells of the anterior column, thus making a typical reflex arc. Some of the fibers of this group may also pass through the posterior commissure, to end in the gray matter of the opposite side. The larger fibers lying nearest to the median line enter the fas- ciculus cuneatus and run forward in the cord, some of them (6) continuing upward to the medulla, and some of them (5), after a shorter course, turning into the gray matter to end in the cells of the dorsal nucleus. The axons of the cells in the dorsal nucleus in turn pass out of the gray matter to constitute the ascending path in the lateral funiculus, known as the cerebello- spinal fasciculus. This general outline of the mode of ending in the cord of the fibers of the posterior root is complicated further by the fact that these fibers are supposed to give off collaterals after entering the cord. The course of the typical fiber in the posterior root is represented in Fig. 67. According to this diagram, the root fiber, after entering the cord, makes a Y or T division, one branch passing downward or posteriorly for a short distance, the other, longer division, passing upward or anteriorly. Each of these main stems may give off one or more lateral branches, sensory collaterals. A main stem, therefore, which runs upward in the fasciculus cuneatus (6) to terminate in the medulla oblongata may give off collaterals at various levels which terminate in the gray matter of the cord, either around tract cells or around the anterior root cells, forming in the latter case a simple reflex arc. The existence of collaterals upon the root fibers within the cord has been demonstrated in the human embryo, but we have little exact information concerning their numerical value in the adult. The schema given in Fig. 76 must, therefore, be accepted as an entirely diagrammatic representation of the chief possibilities of the mode of ending of the fibers of the posterior root by way of their collaterals as well as by way of the main stems. Ascending (Afferent or Sensory) Paths in the Posterior Funiculi. — The posterior funiculi are composed partly of fibers derived directly from the posterior roots (6 in schema) and arising, therefore, from the cells in the posterior root ganglia, and partly SPINAL CORD AS A PATH OF CONDUCTION. 171 from fibers that arise from tract cells in cord itself. It is convenient to speak of the former group as exogenous fibers, using this term to designate nerve fibers which arise from cells placed outside the cord; and the latter group as endo- genous fibers — that is, fibers that have their cells of origin in the gray matter of the cord. If we omit a consideration of their collaterals the course of the exogenous fibers is easily understood. They come into the cord at every pos- terior root, enter into the fasciculus cuneatus, and pass upward. The fibers of this kind that enter at the lower regions, sacral and lumbar, are, however, gradually pushed toward the median line by the exogenous fibers entering at higher levels, so that in the upper tho- racic or cervical regions the fasciculus gracilis is composed mainly of exogenous fibers that have entered the cord in the lumbar or sacral region. These fibers continue upward to end in two groups of cells that lie on the dorsal side of the medulla oblongata, and are known, respectively, as the nucleus of the fasciculus gracilis (or nucleus of Goll) and the nucleus of the fasciculus cunea- tus (or nucleus of Burdach). Their path forward from the medulla is con- tinued by new neurons arising in these nuclei, and will be described later. The course of these fibers in the cord may be shown beautifully by the method of secondary degeneration. If one or more of the posterior roots of the lumbar spinal nerves are cut or, better still, if the posterior funiculi are severed in this region, the degeneration will affect the exogenous fibers throughout their course to the medulla, and it will be seen that in the cervical region the degen- erated fibers are grouped in the area of the fasciculus gracilis (see Fig. 77). The the gray matter of the 4^ Cervical 7LhDorsal 2^ Lumbar JfrL Fig. 77. — Diagrams to show course of upward de- generation of fibers of poste- rior funiculi after section of a number of posterior roots of the nerves forming the lumbosacral plexus. — (Mott.) It will be noted that in the cervical regions the degener- ated area is confined to the fasciculus gracilis. 172 PHYSIOLOGY OF CENTRAL NERVOUS SYSTEM. endogenous fibers, so far as they are ascending, represent afferent paths in which two or more neurons are concerned. The pos- terior root fibers concerned in these paths end in the gray matter of the cord, and thence the conduction is continued by one or more tract cells. The conduction by this set of fibers may be on the same side of the cord as that on which the root fibers entered, or it may he crossed, or, using a convenient terminology, it may be homolateral or contralateral. The physiological value of the ascending fibers in the posterior funiculi has been investigated by a large number of observers. The physiologists have employed the direct method of cutting the funiculi in the thoracic or lumbar region and observing the effect upon the sensations of the parts below the lesion. The positive results of these experiments have been difficult to discover. Most of the older observers found that there was no detectable change in the sensations of the parts below, but they paid attention only to cutaneous sensations, and, indeed, chiefly to the sense of pain. Later observers* have differed also in their description of the effects of this operation; but most of them state that the animal shows an awkwardness or lack of skill in the movements of the hind limbs, especially in the finer movements, and this effect is interpreted to mean that there is some loss of muscle sense. This conclusion is strength- ened by the results of pathological anatomy. In the disease known as tabes dorsalis the posterior funiculi of the cord in the Lumbar region are affected and the striking symptom of this condition is an interference with the power of co-ordinating properly the movements of the lower limbs, particularly in the act of maintaining body equilibrium in standing and walking, — a condition known as locomotor ataxia. So far as the cutaneous sensations are concerned, — that is, the sensations of touch (pressure), pain, and temperature, — all observers agree that the two latter are not affected by section of the funiculi, while regarding touch, opinions have differed radically. Schiff contended that touch sensations are detectable as long as these funiculi are intact, and are seriously interfered with when they are sectioned; but most of the results, pathological and experimental, indicate that when the continuity of these fibers is destroyed, the sense of touch is still present in the parts supplied by the cord below the lesion. An explanation of the confusion in the reported results may be found perhaps in the fact reported below (see p. 176) that fibers conveying the impulses necessary to tactile discrimination pass upward in these funiculi, while other touch (pressure) impulses cross in the cord and pass upward in the anterior funiculi. To * Borchert, "Anhiv f. Physiologic," 1902, 3 cords Fig. 87. — Location of motor areas in brain of chimpanzee. — (Sherrington and Green- baum.) The extent of the motor areas is indicated by stippling; it lies entirely in front of the fissure of Rolando (sulcus centralis). Much of the motor area is hidden in the sulci. The regions marked eyes indicate the areas whose stimulation gives conjugate movements of the eyeballs. It is doubtful, however, whether these represent motor areas proper. careful stimulation of the region in monkeys was more or less verified upon man, since in operations upon the brain it was often necessary to stimulate the cortex in order to localize a given motor area. By these means charts have been made showing the cortical area for the musculature of each part of the body. It was found that in general the distribution of the areas lies along the central sulcus of Rolando and follows GENERAL PHYSIOLOGY OF THE CEREBRUM. 195 the order of the cranial and spinal nerves. Within each area smaller centers may be located by careful stimulation; thus, the hand and arm area may be subdivided into centers for the wrist, fingers, thumb, etc. More recently, Sherrington and Greenbaum,* making use of electrical stimulation, unipolar method, have explored carefully the motor areas in the monkey. They state that these areas do not extend back of the central sulcus, but lie chiefly along the anterior central convolution, as represented in Figs. 87 and 88 extending for only a small distance on to the mesial surface of the cerebrum. The area thus delimited by physiological experiments is the region from which arises the pyramidal system of fibers, and clin- ical experience has shown that lesions in this part of the cortex are accompanied by a paralysis of the muscles on the other Sulc. Central, Anus, * Vagina, „ . „ \ / Sulc.precentr.morg. Sulccculoso \***7&*v^ s Sulc.parieCo occig. Stdccalcarin C.S.S. te. Fig. 88. — To show extension of motor areas on to the mesial surface, brain of chim- panzee.— (Sherrington and Greenbaum). Mesial surface of left hemisphere: Stippled region marked L E G gives the motor area for lower limb; /, s, and h indicate regions from which movements were obtained occasionally with strong stimuli; /, foot and leg; s, shoulder and chest; h, thumb and fingers. The shaded area marked EYES indicates a region stimulation of which gives conjugate movements of the eyes. side, particularly in the limbs. Pathological or experimental lesions here, moreover, are followed by a degeneration of the pyramidal ' neurons, — a degeneration which extends to the ter- mination of the neurons in the cord. With these data we can con- struct a fairly complete account of the mechanism of voluntary movements. The initial outgoing or efferent impulses arise in the large pyramidal cells of the motor areas and proceed along the axons of their neurons to the motor nuclei of the cranial or spinal nerves. The neurons of the pyramidal tract constitute the motor * "Reports of the Thompson- Yates and Johnson Laboratories," 4, 351, 1902; 5, 55, 1903. 196 PHYSIOLOGY OF CENTRAL NERVOUS SYSTEM. tract for voluntary movements; a lesion anywhere along this tract causes paralysis, more or less complete and on the other side of the body in general, if the lesion is anterior to the decussation. The path of the motor fibers is represented in the schema given in Fig. 89. Arising in the cortex, they take the following route (see also Fig. 82, B) : 1. Corona radiata. 2 Internal capsule. 3. Peduncle of cerebrum. 4. Pons Varolii, in which they are broken into a number of smaller bundles by the fibers of the middle peduncle of the cerebellum (brachium pontis). In this region, also, some of the fibers cross the mid-line, to end in the motor nuclei of the cranial nerves: Third, fourth, fifth, sixth, and seventh. 5. Anterior pyramids. 6. Pyramidal decussation. 7. Anterior and lateral pyramidal fasciculi in the cord. After ending in the motor nuclei of the cranial or spinal nerves the path is continued by a second neuron from these nuclei to the mus- cles. The entire path involves, therefore, two neurons, and injury to either will cause paralysis of the corresponding muscles. Difference in the Paralysis from Injury to the Spinal and the Pyramidal Neuron. — With regard to the musculature of the limbs especially a difference has been observed in the paralysis caused by injury to the spinal and pyramidal (cerebrospinal) neurons, respectively. Lesions of the anterior root cells in the cord or of the axons arising from them cause complete paralysis of the corresponding muscles, since these muscles are then re- moved not only from voluntary control, but also from reflex effects. The muscles are entirely relaxed and in time exhibit a more or less complete atrophy. When the pyramidal neurons are affected, as in the familiar condition of hemiplegia resulting from a unilateral lesion of the motor cortex, there is paralysis as regards voluntary control, but, the spinal neuron being intact, the muscles are still subject to reflex stimulation through the cord, especially to the so-called tonic impulses. Under these conditions, especially if the lesion is in the cord, it is frequently noticed that the paralyzed muscles are thrown into a state of continuous contraction, contracture, in which they exhibit a spastic rigidity. This fact, therefore, may be used in diagnosing the general location of the lesion. A satisfactory explanation of the cause of the contraction has not been furnished. It may be due to uncontrolled reflex excitation of the spinal neurons, or, as suggested by Van Gehuchten, to the action of the indirect motor path by way of the rubrospinal tract (fasciculus intermediolateralis). GENERAL PHYSIOLOGY OF THE CEREBRUM. 197 Is the Pyramidal System the Only Means of Voluntary (Cor- tical) Control of the Muscles? — Much discussion has arisen regarding this question. It is, in fact, one of those questions of nervous mechanism in which experiments upon lower animals must be applied with caution to the conditions in man. As we have seen, the entire cerebral cortex may be removed from the frog, the pigeon, and the dog without causing permanent paralysis, although in the animal last named there is at first a more or less marked loss of voluntary control. But in man and the higher types of the monkey the pyramidal system is more completely devel- oped, and corresponding with this fact it is found that the paralysis from lesion of the motor cortex is more permanent. In fact, observa- tions upon men in whom it has been necessary to remove parts of the motor area by surgical opera- tion indicate that the voluntary control of the muscle is lost or im- paired permanently. It would seem, therefore, that even in an animal as high in the scale as the dog volun- tary control of the muscles can be maintained through fibers other than those belonging to the pyra- midal system. A system such as that found in the rubrospinal tract (p. 181) may be considered as ade- quate to fulfil such a function. In man, however, along with the more complete development of the pyr- amidal system, the efficacy of the phylogenetically older motor sys- tems is correspondingly reduced. The Crossed Control of the Muscles and Bilateral Represen- tation in the Cortex. — It has been known from very ancient times that an injury to the brain on one side is accompanied by a paralysis of voluntary movement on the other side of the body, a condition known as hemiplegia. The facts given above regarding the origin and course of the pyramidal system of fibers explain the crossed character of of the paralysis quite satisfactorily. The schema thus pre- Fig. 89. — Schema representing the course of the fibers of the pyra- midal system: 1, Fibers to the nuclei of the cranial nerve ; 2, uncrossed fibers to the lateral pyramidal fasciculus ; 3, fibers to the anterior pyramidal fasciculus crossing in the cord ; 4 and 5, fibers that cross in the pyramidal decussation to make the lateral pyramidal tract of the opposite side. 198 PHYSIOLOGY OF CENTRAL NERVOUS SYSTEM. sented to us is, however, not entirely without exception. In cases of hemiplegia in which the whole motor area of one side is included it is known that the paralysis on the other side does not involve all the muscles, and, in the second place, it is said that there is some muscular weakness on the same side. The paralysis in hemiplegia affects but little, if at all, those muscles of the trunk which are accustomed to act in unison, — the muscles of inspiration, for instance, the diaphragm, abdominal and intercostal muscles, and the muscles of the larynx. It would appear that these muscles are bilaterally represented in the cortex; so that if one side of the brain is intact the muscles of both sides are still under voluntary control. The mechanism of this bilateral representation is not definitely known; one may conceive several possibilities. The motor area on each side may send down a double set of pyramidal fibers, one of which crosses and the other remains on the same side, or the fibers may bifurcate. Or it is possible that the bilateral control is due to commissural connections between the lower centers in the cord. Some evidence in favor of the former view is found in the undoubted histological fact brought out by Melius and others, that small unilateral lesions in the motor area — the center of the great toe in the monkey, for instance — are followed by degeneration in the lateral pyramidal fasciculus in the cord on both sides, show- ing that some portions of the motor area send fibers to both sides of the body. In cases of hemiplegia it may be added that the muscles of the limbs are not all equally affected. Are the Motor Areas Only Motor in Function? — The great number of nerve cells in the cortex in addition to the large pyramidal cells that give origin to the fibers of the pyramidal system make it possible histologically that other functions may be mediated in the same region. This possibility has been kept in view since the early experiments of Munk, in which he showed that lesions in the Rolandic region are followed by disturbances in what are designated as the body sensations, that is, in muscular and cutaneous sensibility, but especially the former. It was suggested, therefore, at one time that one and the same spot in the cortex might serve as the origin of the motor impulses to a given muscle and as the cortical termination of the sensory impulses coming from the same muscle, the reaction in con- sciousness, the muscular sensations, being mediated perhaps through cells other than those giving rise to the pyramidal fibers. Recent physiological and clinical work has, however, not tended to support this view. The motor areas appear to be confined to the region in front of the central sulcus of Rolando, while the cortical area, which gives rise to that kind of consciousness that GENERAL PHYSIOLOGY OF THE CEREBRUM. 199 we designate in general as body sensibility, extends back of this sulcus in the posterior central convolution. Whether, on the other hand, the sense areas for the body (cutaneous and muscular) extend forward into the cortex of the frontal lobe is not clearly shown by experimental or clinical evidence. Flechsig, from his studies upon the time of myelinization of the afferent fibers in the embryo brain, concludes that this is the case, and that, therefore, the motor and sensory areas overlap for a part at least of their extent (see p. 224 and Fig. 98). On the con- trary, in an interesting report by Cushing* of two cases in which the anterior central convolution was stimulated in conscious patients, it is stated that there was no sensation other than that arising from the change in position of the muscles which were thrown into contraction. In the motor area there are numerous connections by afferent fibers, association tracts, with other parts of the brain. By this means the motor area, without doubt, is brought into relation with many other parts of the cortex, and the* sensations or perceptions aroused elsewhere may react upon the motor paths. A voluntary movement, however simple it may be, is a psychological act of some com- plexity, that is to say, every movement is preceded or accom- panied by certain sensations and perceptions which depend upon sensory stimulations occurring at that time, or upon experiences derived from conditions of excitation that have occurred at some previous period — every action is part of a train of conscious or subconscious processes whose neural mech- anism extends over wide regions of the cortex. The mental processes, the associations, that lead to and originate the motor discharge, the mental image of the movement to be effected, cannot be definitely located in the cortex, and it is possible that the so-called motor area itself participates in these psychical ante- cedents. But what may be said with confidence is that the im- mediate origin of the motor impulse lies in the area along the anterior margin of the central sulcus of Rolando, which contains the foci, so to speak, into which all accessory processes are gathered, so far as they affect our muscular acts, and from which emerge the actual efferent stimuli to the different muscles. * Cushing, "American Journal of Physiology," 1909 ("Proc. Amer. Physiol. Soc"). CHAPTER X. THE SENSE AREAS AND THE ASSOCIATION AREAS OF THE CORTEX. The delimitation of the sensory areas in the cortex is a matter of very considerable difficulty, owing partly to the fact that the determination of the presence or absence of certain states of con- sciousness in the animal or person under observation cannot be made except by indirect means, and partly no doubt to the fact that the organization of the sensory mechanism in the brain is more complex and diffuse than in the case of the motor apparatus. Moreover, the distinction between what we may call simple sensa- tions and the more complex psychical representations and judg- ments of which these sensations form a necessary constituent can- not be made clearly, even by the individual in whom the reactions occur. We recognize in ourselves different stages in the degree of consciousness aroused by sensory reactions. Our visual and auditory sensations are clearly differentiated; but many of the lower senses escape recognition in the individual himself, since the state of consciousness accompanying them is of a lower order. Our muscular sensations, for instance, are so indefinite as to be practically subconscious. They are most important to us in every act of our lives, yet the uninformed person is unconscious of the existence of such a sensation, and if deprived of it would recognize the defect only in the consequent loss of control of the voluntary muscular movements. In the attempts to determine in what part of the brain the various sensations are mediated every possible method of inquiry has been used : the anatomical course of the sensory paths, physiological experiments of stimulation and ablation, and observations upon individuals with pathological or traumatic lesions in the brain. In the long run, the study of neuropatholog- ical cases in man must give us the last word, because in such cases the estimate of the sensory defect can be made wTith most accuracy and because in man the specialization of the psychical functions has reached its highest development. The results that have been obtained are perhaps the most definite in the case of the higher senses, vision and hearing, since defects in these senses are recog- nized most clearly, and the anatomical mechanisms involved have proved to be more accessible to investigation. 200 SENSE AREAS AND ASSOCIATION AREAS. 201 The Body -sense Area. — In his early experiments Munk insisted that lesions of the cortex involving the area around the central sulcus are accompanied by a state of anesthesia on the other side of the body, hemianesthesia, particularly as regards the tactile and muscular sensations. It is not necessary, perhaps, to go into the details of the long controversy that arose in connection with this point. Both the clinical and the experi- mental evidence has been contradictory in the hands of different observers, but the tendency of recent studies has been to show, as stated above, that, whereas the motor areas lie anterior to the central sulcus, the sensory areas concerned with the cutaneous and muscular sensations extend posterior to this sulcus.* Posi- tive cases are recorded in which lesions involving the anterior central convolutions were accompanied by paralysis on the other side, hemiplegia, without any detectable disturbance of sensibility, and, on the other hand, lesions have been described in the posterior central and neighboring parietal convolutions in which there was a hemianesthesia more or less distinctly marked without any paralysis. As stated above, Cushing,f in his report upon the stimulation of the cortex in two conscious patients, states that no sensations were aroused by stimuli applied to the anterior central convolution, while stimulation of the posterior convolution aroused distinct sensations of numbness and of touch. Such cases tend to support the view that the motor and body sense areas, although contiguous, do not overlap. Regarding the sensory defects associated with lesions of the parietal lobe posterior to the central sulcus (pos- terior central convolution, supramarginal, superior, and possibly inferior parietal convolutions), it seems probable that they involve chiefly the muscular sense, pressure and temperature sense, and the judgments or perceptions based upon these sensations, while the sense of pain is affected but little, if at all. Monakow gives the order in which sensory defects manifest themselves after such lesions, as follows : The localizing and muscle senses are chiefly affected, in fact, almost lost on the opposite side; the temperature and pressure sense may be affected, while the pain sense is retained or but slightly affected. The clinicians have observed that the most positive and invariable symptom of lesions in this region is a condition of astereognosis, that is, a diminution in what may be called the stereognostic perceptions. By stereog- nostic perception is meant the power to judge concerning the form and consistency of external objects when handled, and it must be regarded as a perception based upon localized sensations of touch, * Consult Monakow, "Ergebnisse der Physiol.." 1902, vol. i, part i, p. 621. f Cushing, loc. cit. 202 PHYSIOLOGY OF CENTRAL NERVOUS SYSTEM. together perhaps with those of temperature and muscular sen- sibility. On the whole, therefore, we must infer that the cortex in this postcentral area is concerned with the finer and more con- scious interpretations of the sensations of pressure, temperature, and muscular conditions, and especially the higher type of these sensations, which we can project or localize accurately. In this general region there lie, in the first place, the centers in which Cen/ra/ ^u/cus Medial lemniscus (?) Fig. 90. — Schema representing the origin and course of the fibers of the median fillet, — the intercentral paths of the fibers of body sense. terminate the projection fibers contained in the lemniscus, and in which, therefore, the primary sensations of pressure and tempera- ture are mediated, so that lesions here may be associated with a loss or impairment of these sensations in the skin of the opposite side of the body, a condition spoken of in general as hemianesthesia. Secondly, in this region there are mediated also probably some of the syntheses and associations of these sensations, which we designate as perceptions or judgments, and it is possible that in- SENSE AREAS AND ASSOCIATION AREAS. 203 juries or defects here may be followed by an impairment of these higher perceptive reactions, without any definite loss of sensibility in the skin. Such a defect falls under the general head of agnosia, and is illustrated by the condition of astereognosis referred to above, which might be defined as chiefly a tactile agnosia. The definite part of the cortex, if any, concerned in the primary conscious mediation of the sense of pain has not been definitely localized. The Histological Evidence. — Course of the ''Lemniscus." — On the histological side there is very strong corroborative evi- dence for the view that cortical centers for the sensory fibers of the skin and muscles lie in the parietal lobe in the region in- dicated above. This evidence is connected with the path taken Fig. 91. — Cross-section through midbrain (Kolliker) to show the position of the lemniscus (L, L): Nr, The red nucleus; Sn, the substantia nigra; Fp, the peduncle. by the sensory fibers in the cord, especially those of the pos- terior funiculi, after ending in the nucleus of the funiculus gra- cilis and the nucleus of the funiculus cuneatus of the medulla. This path is represented in a schematic way in the accompanying diagram (Fig. 90). The second sensory neurons arise in the nuclei mentioned. For the most part, at least, these new neu- rons run ventrally, as internal arcuate fibers, cross the mid-line, and then pass forward or anteriorly. The crossing occurs mainly just in front of — -that is, cephalad to — the pyramidal decussa- tion, forming thus a sensory decussation (decussation of the lemniscus), which explains the crossed sensory control, as the pyramidal decussation explains the crossed motor control of the cerebrum in relation to the body. After this decussation 204 PHYSIOLOGY OF CENTRAL NERVOUS SYSTEM. the sensory fibers form a longitudinal bundle on each side known as the median fillet or lemniscus, which in the pons lies just dorsal to the pyramidal system of fibers. The lemniscus fibers may be traced forward (see Fig. 91) as far as the superior colliculus of the corpora quadrigemina and the thalamus, the important termination being in the thalamus (ventral or lateral nucleus). Those neurons that end in the thalamus are continued forward by a third set of neurons, which end in the parietal lobe of the cerebrum (see Fig. 82, C). On its way through the medulla and pons the lemniscus is believed to receive accessions of sensory fibers from the sensory nuclei of the cranial nerves of the opposite side. The course of the lem- niscus has been traced by various means, but especially by the method of myelinization during embryonic life and by degenera- tion consequent upon long-standing disuse. As was stated in the section upon *Nerve Degeneration, injury to an axon is followed quickly by degeneration of the peripheral end, and much more slowly by a degeneration of the central end and the nerve cell itself, when the path is not again established. Certain long-standing cystic lesions (porencephaly) in the parietal cor- tex have resulted in an atrophic degeneration of the lemniscus fibers, thus adding materially to the evidence that this sensory tract ends eventually in the region indicated.* Further evidence of the same character is found in the observations made by Campbellf upon cases of tabes dorsalis. The lesion in such cases is in the posterior funiculi of the spinal cord, but eventually the whole upward path is affected and degenerative changes are found in the cells of the posterior central convolution. From the connections of the lemniscus with the tracts of the posterior funiculi of the cord it is evident that it forms one pathway at least for the fibers of muscle sense. Whether or not the fibers of pressure, pain, and temperature take the same route is not known, but it seems probable, at least, from the known connections of the lemniscus with the sensory nuclei of the cranial nerves and with the sensory tracts of the lateral as well as the posterior funiculi of the cord. The lemniscus ends chiefly in the thalamus, before passing on to the cortex, and here, as in other similar cases, we have the possibility that the lower centers, in addition to the reflex connections which they make, may mediate also some form of conscious reaction. While the general tendency has been to confine the conscious quality of the central reactions to the cortex, there is no proof that the lower centers are entirely lacking in this property. * Hosel, "Archiv f. Psychiatric " 24, 452, 1892. t Campbell. ' Histological Studies on Localisation of Cerebral Functions, " Cambridge, 1905. SENSE AREAS AND ASSOCIATION AREAS. 205 In Goltz's dog without cerebral cortex, for instance, the animal responded to various sensory stimuli, and when hungry gave evidence, so far as his actions were concerned, of experiencing the sensations of hunger; but whether or not these actions were associated with conscious sensations is hidden from us, and we can hope to arrive at positive conclusions upon this point only by obser- vations upon man himself. The Center for Vision. — The location in the cortex of the general area for vision has been established by anatomical, physio- logical, and clinical evidence. The physiologists have experimented chiefly by the method of ablation. Munk, Ferrier, and later ob- servers have found that removal of both occipital lobes is followed by defects in vision. According to Munk, removal of both occip- ital lobes is followed by complete loss of visual sensations, or, as he expresses it, by cortical blindness. Goltz, however, contends that in the dog at least removal of the entire cerebral cortex leaves the animal with some degree of vision, since he will close his eyes if a strong light is thrown upon them. All the experiments upon the higher mammals (monkeys) and clinical experience upon man tend, however, to support the view of Munk. Complete removal of the occipital lobes is followed by apparently total blindness. If any degree of vision remains it is not sufficient for recogni- tion of familiar objects or for directing the movements. In an animal in this condition the pupil is constricted when light is thrown upon the eye; but this reaction we may regard as a reflex through the midbrain, and there is no reason to believe that it is accompanied by a visual sensation. When the injury to the occip- ital cortex is unilateral the blindness affects symmetrical halves of the two eyes, a condition known as hemiopia. Destruction of the right occipital lobe causes blindness in the two right halves of the eyes, or, in accordance with the law of projection of retinal stimuli, in the two left halves of the normal visual field when the eyes are fixed upon any object. Destruction of the left occipital lobe is followed by blindness in the two left halves of the retinas or the right halves of the visual field. This result of physiological ex- periments is borne out by clinical experience. Any unilateral injury to the occipital lobes is followed by a condition of hemiopia more or less complete according to the extent of the lesion. Obser- vation, however, has shown that this general symmetrical relation has one interesting and peculiar exception. The most important part of the retina in vision is the region of the fovea centralis, whose projection into the visual field constitutes the field of direct or central vision. It is said that the hemiopia caused by unilateral lesions of the cortex does not involve this part of the retina. The Histological Evidence. — The histological results supple- 206 PHYSIOLOGY OF CENTRAL NERVOUS SYSTEM. ment in a very satisfactory way the findings from physiology and pathology. The retina itself, considered from an embryological standpoint, is an outgrowth from the brain vesicles, and is there- fore an outlying portion of the central nervous system. The optic fibers, in terms of the neuron doctrine, must be considered as axons of the nerve cells in the retina. If, therefore, an eye is enu- cleated or an optic nerve is cut the fibers connected with the brain undergo secondary degeneration and their course can be traced microscopically to the brain. By this means it has been shown that in man and the mammalia there is a partial decus- sation of the optic fibers in the chiasma. The fibers from the inner side of each retina cross at this point to the opposite optic tract; those from the outer side of the retina do not decussate, Occipital lobe. Occipito-thalamic radiation. Superior colliculus. Lateral geniculate. Thalamus. Optic tract. Optic chiasm. Optic nerve. r- Retina. Fig. 92. — Diagram to indicate the general course of the fibers of the optic nerves and the bilateral connection between cortex and retina. but pass into the optic tract of the same side. The fibers of the optic tract end mainly in the gray matter of the lateral genicu- late body, but some pass also to the thalamus (pulvinar) and some to the superior colliculus of the corpora quadrigemina. SENSE AREAS AND ASSOCIATION AREAS. 207 These locations, therefore, particularly the lateral geniculates, must be considered as the primary optic centers. From these points the path is continued toward the cortex by new neurons whose axons constitute a special bundle, the occipitothalamic radiation, lying in the occipital part of the internal capsule (see Fig. 82, D). A schema representing this course of the optic fibers is given in the accompanying diagram (Fig. 92). According to this schema, the general relations of each occipital lobe to the retinas of the two eyes is such that the right occip- ital cortex represents the cortical center for the two right halves of the retinas, while the left occipital lobe is the center for the two left halves of each retina, — a relation that agrees completely with the results of experimental physiology and clinical studies. In addition to the fibers described, which may be regarded as the visual fibers proper, there are other fibers in the optic tracts and optic nerves whose physiological value is not entirely clear. The fibers of this kind that have been described are: (1) Inferior or Gudden's commissure. Fibers that pass from one optic tract to the other along the posterior border of the chiasma. These fibers form a commissural band connecting the two internal (or median) geniculate bodies, and possibly also the inferior colliculi. It seems probable that they belong to the central auditory path rather than to the visual system. (2) Fibers passing from the chiasma into the floor of the third ventricle. The further course of these fibers is not clearly known, but it is possible that they make connections with the nuclei of the third nerve. They will be referred to in the section on Vision in con- nection with the light reflex of the iris. (3) A superior com- missure. Several observers have claimed that there is a com- missural band along the anterior margin of the chiasma which connects one optic nerve or retina with the other. There are many points in connection with the course of the optic fibers and the physiology of the different parts of the occip- ital cortex which are unknown and require further investigation. Some of these points may be referred to briefly. The Amount of Decussation in the Chiasma. — According to the schema given above, half of the fibers in each optic nerve decussate in the chiasma. There is, however, no positive proof that the division of the fibers is so symmetrically made. In the lower vertebrates, — fishes, amphibia, reptiles, and most birds — the crossing is said to be complete, while in the mammalia a certain proportion of the fibers remain in the optic tract of the same side. In a general way, it would appear that the higher the animal is in the scale of development the larger is the number of fibers that do not cross in the chiasma. At least it is true that a larger num- ber remain uncrossed in man than in any of the mammalia, and it is 208 PHYSIOLOGY OF CENTRAL NERVOUS SYSTEM. also possible or probable that the extent of decussation in man shows individual differences. There seems to be no acceptable suggestion regarding the physiological value of this partial decus- sation other than that of a probable relation to binocular vision. It has been used to explain the physiological fact that simultaneous stimulation of symmetrical points in the two retinas gives us a single visual sensation. The Projection or Localization of the Retina on the Occipital Cortex. — It would seem most probable that the paths from each spot in the retina terminate in a definite region of the occipital cortex, and attempts have been made by various methods to determine this relation. According to Henschen.* the Fig. 93. — Perimeter fields in quadrant hemianopia. The outline of the visual fields is given by the dotted lines. Blindness in the left upper quadrants; cortical lesion in and below the calcarine fissure (taken from Beevor and Collier;. visual paths in man end around the calcarine fissure on the mesial surface of the brain, and this portion of the occipital lobe should be regarded as the true cortical center for vision, the remainder of the occipital cortex being perhaps the seat of visual memories or associations. There seems to be much evidence, indeed, that the immediate ending of the optic paths lies in this region. Thus, Donaldsonf found, upon examination of the brain of Laura Bridgman, the blind deaf-mute, that the cuneus especially showed marked atrophy, and Flechsig,t by means of the myeliniza- tion method, arrived at the conclusion that the optic fibers end chiefly along the margin of the calcarine fissure. Clinical cases are frequently quoted in which lesions of the region of the calcarine fissure were followed by a more or less complete hemianopia. When, as seems to be the most common occurrence, such lesions occur above the fissure, in the cuneus, or below the fissure, in the gyrus lingualis, the resulting hemiopia is confined to corresponding * Henschen, " Brain," 1893, 170. t Donaldson, " American Journal of Psychology," 1892, 4, | Flechsig, "Localisation der geistigen Vorgange," Leipzig, IS!)'). SENSE AREAS AND ASSOCIATION AREAS. 209 quadrants of the retina, and is designated frequently as quadrant hemianopia (see Fig. 93) . It has been assumed that the fibers from the fovea end perhaps in the fissure itself — according to some authors (Henschen), along the anterior third of the fissure, according to others (Schmid and Laqueur*) along the posterior portion of the fissure. Moreover, since unilateral lesions in this region, however extensive, do not cause complete blindness in the fovea, it has been supposed that this important part of the retina is bilaterally represented in the cortex, so that complete foveal blindness — that is, blindness of the centers of the visual fields — can only occur when both occipital lobes are injured in the region of the calcarine fissure. While the general opinion seems to be that this last-named region is the main cortical ending of the retinal fibers, especially of those arising from the foveal area, other observers contend that the entire occipital cortex, lateral as well as mesial surfaces, must be regarded as the cortical termination of the visual paths, and that even the foveal portion of the retina is con- nected with a wide area in this lobe. Those who hold this view explain the known fact that lesions in the region of the calcarine fissure give the most permanent condition of hemiopia, on the view that these lesions involve the underlying fibers of the occipitothalamic radiation. Monakow,f for instance, points out that while extensive lesions of the occipital cortex on both sides leave, with a few exceptions, some degree of central vision, no cases are reported of cortical lesions involving only or mainly the vision in the macular region. He, therefore, argues that while the paths from the retina to the lower visual centers (lateral geniculate) may be isolated, the further connections with the cortex must be widespread. The cortical center for distinct vision according to this view is not limited to a narrow area, but must involve a large region in the occipital cortex. It is difficult to reconcile this view with the ideas of isolated conduction and specific function of each part of the cortex. Some additional facts of interest have been obtained from experiments involving the stimulation of the occipital cortex. Stimulation of this kind causes movements of the eyes, and the movements vary with the place stimulated, t Stimulation of the upper border of the lobe causes movements of the eyes downward, stimulation of the lower border movements upward, and of intermediate regions movements to the side. Assuming that the direction of the move- ment is toward- that part of the visual field from which a normal visual stimulus would come, it is evident that movements of the * Schmid and Laqueur, "Virchow's Archiv," 158, 1900. t Monakow, loc. cit., also "Ergebnisse d. Physiologie," 1907. t Schafer, "Brain," 11, 1, 1889, and 13, 165, 1890. 14 - 210 PHYSIOLOGY OF CENTRAL NERVOUS SYSTEM. eyes downward would imply stimulation of the upper half of the retina, since objects in the lower part of the visual field form their image on the upper half of the retina. This fact, that stimulation of the occipital cortex causes definite movements of the eyeballs, seems to imply that there are efferent fibers in the occipitothal- amic radiation running from the occipital cortex to the midbrain, where they make connections with the motor nuclei of the third, fourth, and sixth cranial nerves. The Function of the Lower Visual Centers. — The first ending of the optic fibers lies in the lateral geniculate and to a lesser extent in the thalamus and superior colliculus. It is conceiv- able, of course, that some degree of visual sensation may be mediated through these centers. Goltz observed that in dogs with the cerebrum removed the animals showed a constriction of the pupils when a bright light was thrown upon the eyes or even closed the eyes. It is the general belief that reactions of this kind are mechanical reflexes accompanied by no higher psychical reaction than in the case of spinal reflexes. The existence in the midbrain of the motor nuclei of the third nerve, and of the medial longitudinal fasciculus through which con- nections are established with the motor nuclei of other cranial nerves, furnishes us with a possible reflex arc through which the visual impulses brought into the lower optic centers, especially the superior colliculus, may cause co-ordinated movements of the eyes or of the head. Usually it is assumed that conscious visual sensations, and especially visual associations and mem- ories, are aroused only after the impulses reach the occipital cortex. In the fishes the midbrain forms the final ending of the optic fibers, and in these animals, therefore, whatever psychical activity accompanies the visual processes must be mediated through this portion of the brain. In the higher animals, how- ever, the development of a cerebral cortex is followed by the evolution of the occipitothalamic radiation, and as the connec- tions of the occipital cortex increase in importance, those of the midbrain (with the optic fibers) dwindle correspondingly. Here, as in other cases, the psychical activity is concentrated in th£ por- tions of the brain lying most anteriorly, and doubtless the degree of consciousness is greatly intensified in the higher animals in cor- respondence with the development of the cerebral cortex, whose striking characteristic is its capacity to evoke a psychical reaction. The Auditory Center. — The location of the auditory area has been investigated along lines similar to those used for the visual center. The experimental physiological work has yielded varying results in the hands of different observers. Munk and Ferrier placed the cortical center for hearing in the temporal lobe, and SENSE AREAS AXD ASSOCIATION AREAS. 211 in spite of negative results by Schafer and others this localization has been shown to be substantially correct. Entire ablation of both temporal lobes is followed by complete deafness. Ablation on one side, however, is followed only by impairment of hearing, and in the light of the results from histology and from the clinical side it seems probable that the connections of the auditory cortex with the ear follow the general schema of the optical system rather than that of the body senses. That is, it is probable that the Posterior nucleus. Deiters's nucleus. Dorsal nucleus. Ventral nucleus. Cochlear branch. Vestibular branch. Semicircular canals. Scarpa's ganglion. Cochlea. Spiral ganglion. Fig. 94. — The medullary nuclei of the eighth nerve. — (From Poireer and C harpy.) auditory fibers from each ear end partly on the same side and partly or mainly on the opposite side of the cerebrum. The exact portion of the temporal lobe that serves as the immediate organ of auditory sensations cannot be determined with certainty, but it seems probable that it lies mainly in the superior temporal gyrus and the transverse gyri extending from this into the lateral fissure of the cerebrum (fissure of Sylvius). The Histological Evidences. — On the histological side the paths of the auditory fibers have been followed with a large measure of success, although in many details the opinions of the different investigators vary considerably. The eighth cranial nerve 212 PHYSIOLOGY OF CENTRAL NERVOUS SYSTEM. springs from the bulb by two roots: the external and the internal. The former has been shown to supply, mainly at least, the cochlear portion of the internal ear, and is, there- fore, the auditory nerve proper. This division is spoken of as the cochlear branch. The internal root supplies mainly the vestibular branch of the internal ear, and is, therefore, spoken of as the vestibular branch (see Fig. 94). It seems cer- tain that the latter is not an auditory nerve, but is concerned with peculiar sensations from the semicircular canals and vestibule that have an important influence on muscular activity, especially in complex movements. The central course of these two roots is quite as distinct as their peripheral distribution, — a fact that bears out the supposition that they mediate different functions. The- vestibular branch ends in the nucleus of Deiters, the nucleus of Bechterew, and the nucleus fastigii of the cerebellum. Through these nuclei reflex connections are made with the motor centers of the cord and midbrain, and probably also with the cerebellum. The path is not known to be continued forward to the cerebrum. The central course of the cochlear branch is indicated schematically in Figs. 94 and 95. The <£» fibers constituting this branch arise from nerve cells in the modiolus of the cochlea, — the spiral ganglion. These cells, like those in the poste- rior root ganglia, are bi- polar. One axon passes peripherally to end around the sense cells of the cochlea, at which point the sound waves arouse the nerve im- pulses. The other axon passes toward the pons, forming one of the fibers of the cochlear branch. On entering the pons these cochlear branches end in two nuclei, one lying ventral to the res- tiform body and known as the ventral or acces- sory nucleus (V.n., Fig. 95), and one dorsally, known as the dorsal nucleus or the tuber- culum acusticum (D.n.). From these nuclei the path is continued Fig. 95. — Diagram to show central course of auditory fibers (modified from Van Gehuchten): D.n., Dorsal nucleus giving rise to the fibers that form the medullary stria- (a.s.); V.n., the ventral nucleus, giving origin to the fibers of ttie corpus trapezoideum (dr.); s.u., superior olivary nucleus; /./., lateral lemniscus; ».«., nucleus of the lateral lemniscus; t.g.i.,, the inferior colliculus. SENSE AREAS AND ASSOCIATION AREAS. 213 by secondary sensory neurons, and its further course toward the brain is still a matter of much uncertainty in regard to many of the details.* The general course of the fibers, however, is known. Those axons that arise from the accessory nucleus pass mainly to the opposite side by slightly different routes (Fig. 95). Some strike directly across toward the ventral side of the pons, forming a conspicuous band of transverse fibers that has long been known as the corpus trapezoideum; others pass dorsally around the restiform body and then course downward through the tegmental region to enter the corpus trapezoideum. The fibers of this cross band end, according to some observers, in certain nuclei of gray matter on the opposite side of the pons, especially in the superior olivary body and the trapezoidal nucleus, and thence the path forward is continued by a third neuron. Certainly from the level of the superior olivary body the auditory fibers enter a distinct tract long known to the anat- omist and designated as the lateral fillet or lateral lemniscus. Authors differ as to whether the auditory fibers of this tract arise from nerve cells in the superior olivary and neighboring nuclei, or are the fibers from the accessory nucleus which pass by the superior olivary body without ending and then bend to run for- ward in a longitudinal direction. This last view is represented in the schema (Fig. 95). The secondary sensory fibers that arise in the tuberculum acusticum pass dorsally and then transversely, forming a band of fibers that comes so near to the surface of the floor of the fourth ventricle as to form a structure visible to the eye and known as the medullary or auditory striae. The fibers of this system dip inward at the raphe, cross the mid-line, and a part of them at least eventually reach the lateral lemniscus of the other side either with or without ending first around the cells of the superior olivary nucleus. According to the description of some authors, the fibers from the accessory nucleus and tuberculum acusticum do not all cross the mid-line to reach the lateral lemniscus of the other side; some of them pass into the lateral lemniscus of the same side; so that the relations of the fibers of the cochlear nerves to the lateral lemnis- cus »esemble, in the matter of crossing, the relations of the optic fibers to the optic tract. After entering the lateral lemniscus the auditory fibers pass forward toward the midbrain and end in part in the gray matter of the inferior colliculus of the median or internal geniculate, and, according to Van Gehuchten, in a small mass of nerve cells in the midbrain known as the superior * For literature, see Van Gehuchten, "Le Nevraxe, " 4, 253, 1903, and 8, 127, 1906. 214 PHYSIOLOGY OF CENTRAL NERVOUS SYSTEM. nucleus of the lemniscus. From this second or third termination another set of fibers, the auditory radiation, continues forward through the inferior extremity of the internal capsule to end in the superior temporal gyrus (see Fig. 82, E). According to Flechsig,* who has studied the course of these fibers in the embryo by the myelinization method, the main group passes from the median geniculates to the transverse gyri of the tem- poral lobe within the lateral fissure of the cerebrum (fissure of Sylvius). The median geniculates, in man at least, have, therefore, the function of a subordinate auditory center, as the lateral geniculates have the function of a subordinate visual center. The median geniculates are connected with the inferior colliculus, and also, it will be remembered, with each other, by commissural fibers (Gudden's commissure) that pass along the optic tracts and the inferior margin of the chiasma. The auditory path, therefore, involves the following structures: The spiral ganglion, the cochlear nerve, accessory nucleus and tuberculum acusticum, corpus trapezoideum, medullary stris, superior olivary, lateral lemniscus, inferior colliculus, median geniculate, Gudden's commissure, auditory radiation, and temporal cortex. The Motor Responses from the Auditory Cortex. — According to Ferrier, stimulation of the cortex of the temporal lobe (inferior convolution) causes definite movements, such as pricking of the ears and turning of the head and eyes to the opposite side. As in the case of the visual area, therefore, we must suppose that distinct motor paths originate in the auditory region, and it is natural to suppose that these paths give a means for cortical reflex movements following upon auditory stimulation. The Olfactory Center. — The olfactory sense is quite un- equally developed in different mammals. Broca divided them from this standpoint into two classes: the osmatic and the anosmatic group, the latter including the cetacea (whales, porpoise, dolphin). The osmatic group in turn has been divided into the microsmatic and macrosmatic animals, the latter class including those animals in which the sense of smell is highly developed, such as the dog and rabbit, while the former includes those animals, such as man, in which this sense is relatively rudimentary. f The peripheral end- organ of smell consists of the olfactory epithelium in the upper portion of the nasal chambers. The physiology of this organ will be considered in the section on special senses. The epithelial cells of which it consists are comparable to bipolar ganglion cells. The processes or hairs that project into the nasal chamber * Flechsig, " Localisation der geistigen Vorgrange," Leipzig, 1896. t See Barker, " The Nervous System,'' 1899, for references to literature. SENSE AREAS AND ASSOCIATION AREAS 215 are acted upon by the olfactory stimuli, and the impulses thus aroused are conveyed by the basal processes of the cells, the olfac- tory fibers, through the cribriform plate of the ethmoid bone into the olfactory bulb. The Olfactory Bulb and its Connections.— The olfactory bulbs are outgrowths from and portions of the cerebral hemi- spheres. Each bulb is connected with the cerebral hemispheres by its olfactory tract. The connections established by the fibers Fig. 96. — Diagram of the central course of the olfactory fibers: /, Olfactory bulb; II, olfactory tract; ///, cortex of the hippocampal lobe (gyrus uncinatus) ; IV, anterior commissure, olfactory portion; A, olfactory epithelial cells of nose (their fibers, olfactory nerve fibers, terminate in the glomeruli of the bulb) ; B, glomeruli of olfactory bulb where the olfactory fibers come in contact with the dendrites of the mitral cells; C, mitral and brush cells; 1, 2, 3, axons from the mitral cells constituting the fibers of the olfactory tract._ Fibers 3, which enter the commissure, arise, according to some observers, from cells in the olfactory lobe near the base of the tract. of this tract are widespread, complicated, and in part incom- pletely known. All those portions of the brain connected with the sense of smell are sometimes grouped together as the rhinenceph- alon. According to von Kolliker, the parts included under this designation are, in addition to the olfactory bulb and tract, Am- nion's horn, the fascia dentata, the hippocampal lobe, the fornix, the septum pellucidum, and the anterior commissure. The schematic connections of the olfactory fibers are as follows (Fig. 96) : After entering the olfactory lobe the fibers terminate in certain globular bodies, the glomeruli olfactorii (B), whose diameter varies from 0.1 to 0.3 mm. Here connections are made by contact with the dendrites 216 PHYSIOLOGY OF CENTRAL NERVOUS SYSTEM. of nerve cells of the olfactory lobe, the mitral and brush cells (C). The axons of these cells pass toward the brain in the olfactory tract. Three bundles of these fibers are distinguished: (1) The precommis- sural bundle, the fibers of which terminate in part in nerve cells sit- uated in the tract itself, but, for the most part, enter the anterioi commissure and pass to the same or the opposite side, to end in the hippocampal lobes or other gray matter belonging to the rhinen- cephalon. (2) The mesial bundle, the fibers of which terminate in the gray matter adjacent to the base of the olfactory tract, the tuberculum olfactorium, whence the path is probably continued by other neurons to the region of the hippocampal lobe. (3) The lateral tract, whose fibers seem to pass to the hippocampal lobe of the same side. According to Van Gehuchten,* none of the fibers of the anterior commissure arise from the nerve cells in the olfactory bulb. He considers that the fibers in the olfactory portion of this commissure constitute an association system connecting the olfac- tory lobe of one side with the olfactory bulb of the other side. The Cortical Center for Smell. — So far as the histological evidence goes, it tends to show that the chief cortical termination of the olfactory paths is found in the hippocampal convolution, especially its distal portion, the uncus. The experimental evi- dence from the side of physiology points in the same direction. Ferrier states that electrical stimulation in this region is followed by a torsion of the lips and nostrils of the same side, muscular movements that accompany usually strong olfactory sensations. On the other hand, ablations of these regions are followed by de- fects in the sense of smell. The experimental evidence is not very satisfactory, owing to the technical difficulties in operating upon these portions of the brain without at the same time involving neighboring regions. There is some clinical evidence also that lesions in this region involve the sense of smell. Thus Carbonieri records that a tumor in this portion of the temporal lobe occa- sioned epileptic attacks which were accompanied by nauseating odors. The Cortical Center for Taste Sensations. — Practically nothing definite is known concerning the central paths and cortical termination of the taste fibers. The course of these fibers in the peripheral nerves has been much investigated and the facts are mentioned in the section upon "special senses." It is usually assumed, although without much decisive proof, that the cortical center lies also in the jiippocampal convolution posterior to the area of olfaction. Experimental lesions in this region, according to Ferrier, are accompanied by disturbances of the sense of taste. On embryological grounds Flechsig supposes that the cortical * Van Gehuchten, "Le Nevraxe," 6, 191, 1904. SENSE AREAS AND ASSOCIATION AREAS. 217 center may lie in the posterior portion of the gyrus fornicatus (6, Fig. 99). Aphasia. — The term aphasia means literally the loss of the power of speech. It was used originally to indicate the condition of those who from accident or disease affecting the brain had lost in part or entirely the power of expressing themselves in spoken words, but the term as a general expression is now extended to include also those who are unable to understand spoken or written language — - that is, those who are word-blind or word-deaf. It is usual, there- fore, to distinguish sensory aphasia from motor aphasia. By the latter term is meant the condition of those who are unable to speak, although there is no paralysis of the muscles of articulation, and by sensory aphasia, those who are unable to understand the written, printed, or spoken symbols of words, although there is no loss of the sense of vision or of hearing. Motor Aphasia. — A condition of motor aphasia not infrequently results from injuries to the head or from hemorrhage in the region of the middle cerebral artery. The first exact statement of the portion of the brain involved seems to have been made by Bouil- laud (1825), who, as the result of numerous autopsies, attributed the defect to lesions of the frontal lobe. (It is a curious fact that Bouillaud's observations were inspired by the work of Gall. Gall having observed, as he thought, that individuals who are fluent speakers or who have retentive memories are characterized by projecting eyes, concluded that this peculiarity is due to the larger size of the lower part of the frontal lobe, and he therefore located the faculty of speech in this region of the brain. In spite of the vagaries into which he was led by his false methods Gall made many most important contributions to our knowledge of the anatomy of the brain and the cord. The discovery of the location of the center of speech, however, cannot be rightly placed to his credit, since his reasons for its location were, so far as we know, entirely unjustified. It cannot be reckoned as more than a coincidence that in this particular his phrenological localization was afterward in a measure justified by facts.) The essential truth of Bouillaud's observations was established by other observers, and Broca located the part of the brain in- volved in these lesions in the posterior part of the third or inferior frontal convolution. He described conditions of pure motor aphasia, designated by him as aphemia, which he thought were due to lesions in this gyrus. This region is, therefore, frequently known as Broca's convolution or Broca's center. Subsequent ob- servations have tended to confirm this localization, and what is designated as the " speech center - has been placed in the inferior frontal convolution in the gyrus surrounding the anterior or ascending limb of the lateral fissure (fissure of Sylvius, S, Fig. 97). Many authors insist that this localization is too limited, and that defects in the power of speech may result not only from injuries to this region, but also from lesions of contiguous areas, 218 PHYSIOLOGY OF CENTRAL NERVOUS SYSTEM. including the anterior portion of the island and the opercular por- tion of the central convolution. Autopsies have shown that in right-handed persons the speech center is placed or is functional usually in the left cerebral hemisphere, while, on the other hand, it is stated, although hardly demonstrated, that in the case of left- handed individuals aphasia is produced by lesions involving the right side of the brain. This region is not the direct cor- tical motor center for the muscles of speech. It is possible that aphasia may exist without paralysis of these latter muscles. Tt is rather the memory center of the motor innervations necessary to form the appropriate sounds or words with which we have learned to express certain concepts. The child is taught to express certain ideas by definite words, and the memory apparatus through which these associations are transmitted to the motor apparatus may be conceived as located in the speech center. Lesions of any kind affecting this area will, therefore, destroy more or less the ability to use appropriately spoken words, and clinical experience shows that motor aphasia may be exhibited in all degrees of complete- ness and in many curious varieties. The individual may retain the power to use a limited number of words, with which he ex- presses his whole range of ideas, as, for instance, in the case de- scribed by Broca,* in which the individual retained for the ex- pression of numbers only the word " three," and was obliged to make this word do duty for all numerical concepts. Other cases are recorded in which the patient had lost only the power to use names — that is, nouns (" Marie ") — or could remember only the initial letters. Others still, in which words could be used only when associated with musical memories, as in singing; or in which the words were misused or employed in wrong combinations (paraphasia). Motor aphasias have been classified in various ways to suit the different schemata which have been invented to explain the cerebral mechanism of speech, but the whole subject is in reality so complex that most of these classifications must be received with caution. There seems to be no doubt, however, that a condition of what may be called pure motor aphasia may result from localized injuries to the brain. In this condition there is loss of the power of articulate speech, without paralysis of the muscles of articulation, and with the preservation of what has been called internal language, that is, the power to conceive the ideas for which the appropriate verbal expressions are missing. Most authors conclude that this condition is due to an injury or lesion in Broca's convolution, but others contend that the evidence for * Exner, "Hermann's Handbuch der Physiologie," vol. iii, part u, p. 342. Consult for older literature. SENSE AREAS AND ASSOCIATION AREAS. 219 this localization is at present unsatisfactory.* It does not seem to be certain whether or not, in the case of complete lesion of the center on one side, the ability to speak can be again acquired by education of new centers, f Some recorded cases seem to indicate that this re-education is possible in the young, while in the old it is more difficult or impossible. We express our thoughts not only in spoken, but also in written, symbols. As this latter form of expression involves a different set of muscles and a different educational experience, it is natural to assume that the complex associations concerned or, to use a convenient expression, the memory centers, should involve a different part of the cortex. It is, in fact, observed that in some aphasics the loss of the power of writing, a condition designated as agraphia, is the characteristic defect, rather than the loss of the ability to use articulate language. There may be also, as a result of cerebral injury, a loss of the power to make various kinds of purposive movements or combinations of movements other than those used in speaking or writing, and for this general condition the term " apraxia " has been employed. Using this term in its widest sense, pure motor aphasia (aphemia) might be defined as an apraxia limited to the muscles of articula- tion, and agraphia as an apraxia involving the movements of writing. The general evidence seems to show that these conditions of apraxia, other than the aphemia, are associated with lesions in the first and second frontal convolutions anterior to the motor area. Sensory Aphasia.— In sensory aphasia J the individual suffers from an inability to understand spoken or written language. Conditions of this kind have been referred to lesions in the cortex of the temporal or temporo-parietal region (H and V, Fig. 96), and, as in the case of motor aphasia, the lesion is usually on the left side. Since the cortical centers for hearing and seeing are situated in distinct parts of the brain, we should expect that the mechanism for the association, in one case of visual memories of verbal symbols with certain concepts, and in the other case, of auditory memories, should also be located in separate regions. Inability to understand spoken language, or word-deafness, is, in fact, usually attributed to a lesion involving the superior or middle temporal convolution contiguous to the cortical sense of hearing ( H, Fig. 97) , while loss of power to understand written or printed language, word-blindness (alexia) , is traced to lesions involving the * For these opposing views and the work of Marie see Moutier, " L' Aphasia de Broca," Paris, 1908. fSee Mills, "Journal of the Amer. Med. Assoc," 1904, xliii. | Consult Starr, "Aphasia," "Transactions of the Congress of American Physicians and Surgeons," vol. 1, p. 329, 1888; also Monakow, "Gehirn- pathologie," 1906; Collier, "Brain," 1908. 220 PHYSIOLOGY OF CENTRAL NERVOUS SYSTEM. inferior parietal convolution, the gyrus angularis, contiguous to the occipital visual center (V, Fig. 97). These two conditions may occur together, but cases are recorded in which they existed independently. It may be imagined that the individual suffering from word-blindness alone is essentially in the condition of one who attempts to read a foreign language. The power of vision exists, but the verbal symbols have no associations, therefore no meaning. So one who is word-deaf alone may be compared to the normal individual who is spoken to in a foreign tongue. The words are heard, but they have no associations with past experience. Sensory aphasia may be complete or incom- plete. In the com- plete form there is word-deafness as well as word-blindness, and there may be difficul- ties as well in the pow- er of articulate speech. In the incomplete type these symptoms are exhibited in milder and varying form. One may imagine that our ability to recog- nize external objects through the senses might be affected in other ways than a failure to comprehend the visual or auditory symbols, and some writers, therefore, employ the wider term agnosia to indicate any failure in the intellectual recog- nition of external objects. From this point of view word-blindness might be designated as visual agnosia, word-deafness as auditory agnosia, and astereognosis as chiefly a tactile agnosia. The exact localization in the cortex of the areas involved in the auditory and visual associations and perceptions connected with speech has not been established definitely. The question is a complex and difficult one, and those who have had the most experience are perhaps the most cautious in referring word-blindness or word-deafness to the lesion of circumscribed areas of the cortex.* It may be said, however, with some certainty, that the phenomena of sensory aphasia in general are connected with lesions involving the area * For a general review see Monakow, "Ergebnisse der Physiologie," 1907, p. 334. H Fig. 97. — Lateral view of a human hemisphere; cor- tical area V, damage to which produces "mind-blind- ness" (word-blindness); cortical area //, damage to which produces "mind-deafness" (word-deafness); cortical area S, damage to which causes the loss of articulate speech; cortical area W, damage to which abolishes the power of writing. — (Donaldson.) SENSE AREAS AND ASSOCIATION AREAS. 221 along the margins of the posterior portion of the lateral fissure (fissure of Sylvius), and extending into the parietal lobe as far as the angular gyrus, and with the cortex within the fissure including the cortex of the island. The general facts regarding aphasia illustrate excellently the prevalent conception of cerebral localization. The understanding and the use of spoken or written language is, so to speak, a mental whole, both from the standpoint of education and of use. To understand or to express certain conceptions implies the use of definite words, and our visual, auditory, and motor experiences are combined in these symbols. Each phase of this complex may be cultivated more or less separately; in the case of the unlettered man, for instance, the written or printed symbols form no part in the associations connected with his verbal concepts. Corre- sponding to these facts we have, on the anatomical side, a portion of the brain in which the auditory memories are organized, — that is, they are connected in some way with a definite arrangement of nerve cells and their processes, another part in which the visual memories are organized, and other parts in which the motor memories as regards speaking or writing are laid down in some definite form. Each part is a distinct center, but their combined use in intellectual life would imply that they are connected by association fibers, so that, although fun- damentally distinct, they are practically combined in their activity. Corresponding with this conception it is found from clinical experience that sensory aphasics suffer a deterioration, more or less pronounced, of their general intellectual capacity according to the extent of the area involved. We may believe that the varying gifts of individuals, in the matter of the use of language, rest partly on the amount of training received and partly on the inborn character and completeness of the nervous machinery in the different centers. The Association Areas. — According to the views presented above, it will be seen that the motor and sense areas occupy only a small portion of the cortex, forming islands, as has been said, surrounded by much larger areas. Flechsig* has designated these latter areas as association areas, and has advocated the view that they are the portions of the cortex in which the higher and more complex mental activities are mediated, the true organs of thought. His views as to the relations and physiological significance of these areas have been based chiefly on the study of the embryo brain with reference to the time of acquisition of the myelin sheaths. Thus he finds that the fibers to the sense areas acquire their myelin. t Flechsig, "Gehirn und Seele, " Leipzig, 1896; also, "Archives de Neurol- ogie," vol. ii, 1900. 222 PHYSIOLOGY OF CENTRAL NERVOUS SYSTEM. and therefore according to his view become fully functional before those distributed to the association areas. Moreover, in the em- bryo, at least, these latter areas are not supplied with projection fibers, — that is, they are not connected directly with the under- lying parts of the nervous systems. Their connections are with each other and with the various sense centers and motor centers of the cortex. The association areas may be regarded therefore as the regions in which the different sense impressions are synthesized into complex perceptions or concepts. The foundations of all knowledge are to be found in the sensations aroused through the various sense organs; through these avenues alone can our consciousness come into relation with the external or the internal (somatic) world, and the union of these sense impressions into organized knowledge is, according to Flechsig, the general function of the association areas. This function of the association areas is indicated by the anatomical fact that they are connected with the various sense centers by tracts of association fibers, suggesting thus a mechanism by which the sense qualities from these separate sense centers may be combined in consciousness to form a mental image of a complex nature. The sequence of phenomena in the external world is or- derly, and, corresponding to this fact, the reflection of these phenom- ena in the sequence and combinations of sensations is also orderly. In the association areas our memory records of past experiences and their connections are laid down in some, as yet unknown, material change in the network of nerve cells and fibers. Here, as elsewhere in the nervous system, it may be supposed that the efficiency of the nervous machinery is conditioned partly by the completeness and character of training, but largely also by the inborn character of the machinery itself. The very marked differ- ences among intelligent and cultivated persons — for instance, in the matter of musical memory and the power of appreciating and reproducing musical harmonies — cannot be attributed to differences in training alone. The gifted person in this respect is one who is born with a certain portion of his brain more highly organized than that of most of his fellow-men. This general conception that the special capacities of talented individuals rest chiefly upon inborn differences in structure or organization of the brain may be re- garded as one outcome of the modern doctrine of localization of functions in this organ. In the beginning of the nineteenth century- it seems to have been the general view that those who had a high degree of mental capacity might direct their activity with equal success in any direction according to the training received. A man who could walk fifty miles to the north, it was said, could just as easily walk fifty miles to the south, and a man whose training SENSE AREAS AND ASSOCIATION AREAS. 223 made him an eminent mathematician might with different training have made an equally eminent soldier or statesman. In our day, however, with our ideas of the organization of the brain cortex, and our knowledge that different parts of this cortex give different reactions in consciousness, it seems to follow that special talents are due to differences in organization of special parts of the cortex. Subdivision of the Association Areas. — On anatomical grounds Flechsig distinguishes three (or four) association areas : The frontal or anterior 35, Fig. 100), which lies in front of the motor area; the median or insular, — that is, the cortex of the island of Reil; and the posterior, which lies back of the body feeling area, extending to the occipital lobe and also laterally into the temporal lobe. This area Flechsig suggests may be subdivided into a parietal area, 34, Fig. 100, and a temporal area, 36, Fig. 100. The greater rela- tive development of these areas is one of the features distinguishing the human brain from those of the lower mammals. In accordance with the general conception of localization of functions Flechsig suggests that these areas have different functions, — that is, take different parts in the complex of mental activity. Basing his views upon the nature of the association tracts connecting them with the sense centers, he suggests that the posterior area is concerned particularly in the organization of the experiences founded upon visual and auditory sensations, and shows especial development in cases of talents, such as those of the musician, which rest upon these experiences. The anterior area, being in closer connection with the body sense area, may possibly be espe- cially concerned in the organization of experiences based upon the internal sensations (bodily appetites and desires). In this part of the brain possibly arises the conception of individuality, the idea of the self as distinguished from the external world. And in alterations or defective development of this portion of the brain may He possibly the physical explanation of mental and moral degeneracy. This general idea is borne out in a measure by his- tological studies of the brains of those who are mentally deficient (amentia) or mentally deranged (dementia). It is stated* that the brain in such cases shows a distinct thinning of the cortex and that the maximum focus of this change is found in the prefrontal lobes (anterior association area). In the case of the idiotic this area is distinctly undeveloped and in the insane the atrophy is marked in proportion to the degree of dementia. Regarding the peculiar functions of the cortex of the island of Reil there are no facts sufficiently distinct to warrant a positive statement, although, as stated above, the data from pathological anatomy * Bolton, "Brain," 1903, p. 215, and 1910, p. 26. 224 PHYSIOLOGY OF CENTRAL NERVOUS SYSTEM. would seem to indicate that this portion of the cortex may form a part of the speech area both on the motor and the sensory side. The area is much more developed in man than in the lower mam- mals, and its connections with other parts of the cortex by means of association tracts are such as to lead to the supposition that its general functions are of the higher synthetic character attributed to the association areas in general. By way of caution it should be stated that the general ideas developed above in accordance withjFlechsig's views do not meet with universal accept- ance. Some of the most experienced observers are unwilling to admit that such a degree of localization of the psychical activities really exists. They contend that the whole cortex may be concerned in mediating the highest mental processes, and quote post-mortem examinations of carefully studied cases in support of this view. Even in the primary sense centers or motor centers the character of the lamination of the cortex indicates the possibility that the higher synthetic functions may be mediated there in addition to the reception of sensory impulses or the generation of motor impulses. We must recognize, in fact, that the schemata designed to show the distribution of the higher psychical activities in the cortex represent at present only hypotheses which need confirmation before they can be finally accepted. We may feel considerable confidence in the localizations of the motor areas, and of some, at least, of the sensory areas, but in the matter of the more complex mental acts, failure in which expresses itself in the conditions of aphasia, dementia, perversions, etc., our knowledge is incomplete, both as regards analysis of the symptoms and the localities affected in the brain. The Development of the Cortical Area. — Flechsig * has published the results of an extensive study of the time of mye- linization of the fibers in the cerebrum of man from the fourth month of intra-uterine to the fourth month of extra-uterine life. The first areas to develop in the cortex are the primary sense centers (smell, cutaneous and muscle sense, sight, hearing, and touch), and later in connection with these centers systems of motor fibers appear. There are thus formed seven primary zones, sensory and motor, to which he gives the name of projection areas. The location of these areas is shown in part in Figs. 98 and 99, 2 {$, 2°), 5, 6, 7 (7b), s, 15. Two areas connected with the olfactory sense are not shown in these figures; they appear in the anterior per- forate lamina on the base of the brain and in the uncinate gyrus. Later there is developed around these primary zones areas that Flechsig calls marginal or border zones, which have no projection fibers, but which are connected by short association fibers with one or more of the primary projection zones, 14, 16 to 38, in Figs. 100 and 101. These areas all develop after birth; and from a physiological standpoint may be regarded perhaps as the seat of the organized memories connected with the primary sense centers. * Flechsig, "Berichte der mathematisch-physischen Klasse der konigl. Sachs. Gesellschaft der Wissenschaften zu Leipzig," 1904. For a summary of the results of this work see Sabin, "The Johns Hopkins Hospital Bulletin," February, 1905. SENSE AREAS AND ASSOCIATION AREAS. 225 *00* ■■••■ M I M V?**: 9 ih iWr # *::/3m 2§i Fig. 98. — Lateral surface of the brain, showing the primordial areas, both sensory and automatic, in clotted zones. — (Flechsig.) ,#f&ms%T ?'•■ r:-' '"S ^ jtf:sb 'w&iiJmR V ■-- \b y m w S0[ 10 Fig. 99. — Same zones on the mesial surface of the brain. — (Flechsig), 15 226 PHYSIOLOGY OF CENTRAL NERVOUS SYSTEM. 4Xfi *'' '& • *M> sffliWB« i list Fig. 100. — Lateral surfaces of the brain, showing the primordial and marginal zones. — (FlechsigJ) f ?'-"■"■ Fig. 101.— Same areas on the mesial surface. — (Flechsig.) SENSE AREAS AND SENSE ASSOCIATIONS. 227 It is injuries in these centers which may be supposed to produce the various kinds of aphasia described above. Thus, areas 17, 20, and 24 form border areas to the primary area of sight (5); 16 has the same relation to 2, 18 to 2h, and 14, ub with 7. Later still the great association areas — 34, 35, 36, Figs. 100 and 101 — acquire their myelinated fibers. These latter centers, as indicated above, may be considered as association areas with more complex connec- tions, and they serve to mediate, therefore, the higher psychical activities. Flechsig, in his report, designates these areas from an anatomical point of view as terminal or central zones. As the result of his histological work, as far as it has progressed, he distin- guishes thirty-six areas in the cortex in which the myelinization of the fibers occurs separately, and in which, therefore, by inference different physiological activities are mediated. These 36 areas are subdivided as follows: I. Primary areas. la. Primary projection areas (1, 2, 4, 5, 6, 7, 8 (15), seven or eight in number, and provided with projection fibers — sensory and motor. lb. Primary areas without projection fibers (3, 9, 10, 11, 12, 13) and apparently without association fibers. Functions un- certain. II. Association areas. IIa" Intermediate or border areas, 14, 16-33, provided with short association fibers. II&* Terminal or central areas, 34, So, 36, provided with long association fibers. Histological Differentiation in Cortical Structure. — While the general structure of the cortex is everywhere similar, detailed examination has shown differences in the shape of the cells, the thickness and number of the strata or laminae, the calibre of the fibers, etc., which are said to be constant for any given region. By this means it is possible to divide the cerebral cortex into a number of areas whose structures are sufficiently distinct to be recognized with some certainty. Reasoning from analogy, we should infer that a differentiation in structure implies a subdivision of physio- logical activity, and to this extent this recent histological work supports the view of a localized distribution of function in the cortex. Campbell,* in a very thorough investigation of this kind, has succeeded in separating some fifteen or sixteen different areas, and the results obtained by him support in a general way the local- izations described in the preceding pages. Thus the cortex in the postcentral convolution (body-sense area) has a structure dis- tinctly different from that of the precentral convolution (motor area), the latter being characterized among other things by the * Campbell, "Histological Studies on Localisation of Cerebral Functions," Cambridge, 1905; See also Brodmann, "Journal f. Psychol, u. Xeurol.," 1902, 7. 228 PHYSIOLOGY OF CENTRAL NERVOUS SYSTEM. presence of giant pyramidal cells (Betz cells) , and a marked dimi- nution in the width of the granular layer of cells. In the occipital lobes the region round the calcarine fissure (visuosensory) has a structure different from that of the contiguous cortex (visuo- psychic), and a similar difference is claimed for the auditory region. Campbell believes that the extreme end of the i'rontal lobe (prefrontal region) has a comparatively undeveloped struc- ture, but Bolton,* on the contrary, states that it has a typical structure and believes that it plays a part of the greatest impor- tance in the higher or general processes of association. It is the last region of the cortex to be evolved. In mental decadence or dementia it is the first region to undergo dissolution, and in condi- tions of amentia it is undeveloped. Fig. 102. — Diagram to show the composition of the corpus callosum as a system of com- missural fibers, without projection fibers. — (Cajol.) The Corpus Callosum. — The corpus callosum is the most conspicuous of the bands of commissural fibers that connect one cerebral hemisphere with the other. Similar tracts of the same general nature are the anterior commissure and the fornix. The position and great development of the corpus callosum has made it the object of experimental as well as anatomical investigation. When the corpus is divided by a section along the longitudinal fissure (v. Koranyi) no perceptible effect of either a motor or sensory nature is observed in the animal. When it is stimulated electrically (Mott and Schafer) from above, symmetri- cal movements on the two sides of the body may be obtained. If the motor cortex on one side is removed, stimulation in the lon- gitudinal fissure causes movements only on the side controlled by the uninjured cortex. These facts are in harmony with the * Bolton, "Brain," 1910, p. 26. SENSE AREAS AND ASSOCIATION AREAS. 229 results of histological studies, which indicate that the fibers of the corpus callosum do not enter directly into the internal capsules, to be distributed to underlying portions of the brain, but are truly commissural and connect portions of the cortex of one hemisphere with the cortex of the other side. This relation is indicated in the accompanying diagram (Fig. 102). So far as the motor regions are concerned, there is some evidence that the connection thus es- tablished is between symmetrical parts of the cortex (Muratoff), — that is, between parts having similar functions, — and we may regard the corpus as a means by which the functional activities of the two sides of the cerebrum are associated. On the human side, study of cases of lesions of the corpus callosum has yielded an important suggestion in line with the conclusion just stated. Liepmann* has reported cases of this kind in which there were apraxic symptoms (dyspraxia) in the movements of the left side of the body, although the right cortex was uninjured. He draws the conclusion that in movement complexes in general the left hemisphere leads or initiates, as in the case of articulate speech, and that through the commissural fibers of the corpus callosum a stimulus is conveyed to the right cortex when the movement affects the musculature of the left side. The Corpora Striata and Thalami. — The numerous masses of gray matter found in the cerebrum beneath the cortex, in the thalamencephalon, and in the midbrain have each, of course, specific functions, but, in general, it may be said that they are intercalated on the afferent or efferent paths to or from the cortex. Their physiology is included, therefore, in the description of the functions mediated by these paths. For instance, the lateral geniculate bodies form part of the optic path. In addition, however, these masses of cells contain in many cases reflex arcs of a more or less complicated kind, through which afferent impulses are converted into efferent impulses that affect the musculature or the glandular tissues of the body. The large nuclei constituting the corpora striata (nucleus caudatus and n. lenticularis) and the thalami have been frequently studied experimentally to ascertain whether they have specific functions independently of their rela- tions to the cortex. These efforts have given uncertain results. Older experiments (Nothnagel), in which the attempt was made to destroy these nuclei by the localized injection of chromic acid, are probably unreliable, as the destruction involved also the projection fibers passing to the cortex. Lesions of the nucleus caudatus are said to be accompanied always by a rise in body temperature «.nd an increase in heat production, and stimulation of the same nucleus * Liepmann, "Med. Klin.," 1907, 725. 230 PHYSIOLOGY OF CENTRAL NERVOUS SYSTEM. gives a very marked rise in blood-pressure. These facts indicate a possible connection of this nucleus with heat and vasomotor regulation. Other observers have supposed that these nuclei are especially concerned in the co-ordination of the muscles employed in involuntary or unconscious movements. While the nucleus lenticularis is connected with the posterior Rolandic region of the cortex, the n. caudatus seems to be independent in this regard, and to be provided with its own system of projection fibers. With regard to the various nuclei of the thalamus, it is known that they form abundant connections with the sensory areas of the cor- tex cerebri, and from this standpoint they may be regarded as consisting of subcenters, with a probability, however, that reflexes may occur through them (subcortical reflexes) independently of the cortex. Numerous fibers have been traced from the thalamus to the body sense area (Flechsig) . Sachs* states that the thalamus may be considered as being composed of two practically inde- pendent parts : an inner division, which has relation with the nucleus caudatus and the rhinencaphalon, and an outer division, which, on the one hand, serves as a terminus for the fibers of the lem- niscus and of the superior cerebellar peduncle, and, on the other hand, is connected by afferent and efferent paths with the cortex of the Rolandic region. It is evident, from these relations and from the proximity of the internal capsule, that lesions in the thalamus may occasion symptoms of a very diverse character. Among these symptoms, we should expect to find hemianesthesia on the opposite side, owing to the fact that the thalamus serves as a sub- station for the fibers of the lemniscus. ♦Sachs, "Brain," 1, 1909. CHAPTER XI. THE FUNCTIONS OF THE CEREBELLUM, THE PONS, AND THE MEDULLA. The functions of the cerebellum are, in some respects, less satis- factorily knuwn than those of any other part of the central nervous system. Many theories have been held. Most of these views have been attempts to assign to the organ a single function of a definite character, but latterly the insufficiency of the theories proposed has led observers to attribute to the cerebellum general properties the nature of which can not be expressed satisfactorily in a single phrase. Before attempting to give a summary of exist- ing views it will be helpful to recall briefly the important facts re- garding its structure and relations, so far as they are known and can be used to explain its functional value. Anatomical Structure and Relations of the Cerebellum. — The finer histology of the cerebellar cortex is represented in Fig. 103. Three layers may be distinguished. The external molecular layer (A), the middle granular layer (B), and the internal medullary layer consisting of the white matter or medullated nerve fibers, afferent and efferent (C). Between the molecular and granular layers lie the large and characteristic Purkinje cells (a). The dendrites of these cells branch profusely in the molecular layer; their axons pass into the medullary layer. From the standpoint of the neuron doctrine these cells, so far as the cerebellum is con- cerned, are efferent. They form, indeed, the sole efferent system of the cerebellar cortex. The afferent fibers of the cerebellum end in both the granular and the molecular layers. Those that termi- nate in the granular layer — designated by Cajal as moss fibers, have at their terminations and points of branching curious clumps of small processes; they probably connect with the dendrites of the nerve cells in this layer. Those that pass deeper into the molec- ular layer come into connection with the dendrites of the Purkinje cells, around which, indeed, they seem to twine, so that Cajal desig- nated them as climbing fibers. The granular layer (B) contains numerous granules (g) or small nerve cells. These cells are spherical, and have a relatively large nucleus and a small amount of cyto- plasm. Their dendrites are few and short; their axons run into the molecular layer, divide in T, and the two branches then run 231 232 PHYSIOLOGY OF CENTRAL NERVOUS SYSTEM. parallel to the surface and doubtless make connections with the den- drites of the Purkinje cells as well as with the cells of the molecular layer. A few larger nerve cells of Golgi's second type (/) are found also in the granular layer. In the molecular layer are found two types of cells: the larger basket cells (b) whose axons terminate in a group of small branches that inclose the body of the Purkinje cells, and a number of smaller cells (e), situated more superficially, whose axons pass longitudinally in the molecular layer and termi- nate in arborizations or baskets that doubtless make connections with the dendrites of the Purkinje cells. Fig. 103. — Histology of the cerebellum. — (From Obersteiner.) A consideration of this peculiar and intricate structure enables us to comprehend that the cerebellar cortex presents a reflex arc of a very considerable degree of complexity. The incoming im- pulses through the moss and climbing fibers may pass at once to the Purkinje cells and lead to efferent discharges, or they may end in the cells of the granular or molecular layer and thus be distributed to the Purkinje cells in a more indirect way. In addition to the cortex the cerebellum contains several masses of gray matter in its interior: the large dentate nucleus in the center of each hemi- sphere and the group of nuclei lying in or near the middle of the CEREBELLUM, PONS, AND MEDULLA. 233 medullary substance of the vermiform lobe (nucleus fastigii, n. globosi, and the n. emboliformis). The axons of the Purkinje cells of the cortex terminate in these subcortical nuclei, and the efferent path from the cerebellum is then continued by new neurons. Thus, the fibers of the superior peduncles (brachium conjunctivum) of the cerebellum arise chiefly from the dentate nuclei, and only indirectly from the cortex. The anatomical connections, afferent and efferent, between the cerebellum and other parts of the nervous system are very complex and not yet entirely known. Without attempting to recall all of these connections, which will be found described in works upon anat- omy or neurology, emphasis may be laid upon those which are at present helpful in discussing the physiology of the organ. 1. Connections with the Afferent Paths of the Cord. — Through the inferior peduncles (restiform bodies) the cerebellum receives affer- ent fibers from the spinal cord and the medulla. The cerebello- spinal fasciculus undoubtedly terminates in the cerebellum, and according to some observers the fibers of the posterior funiculi after ending in the n. gracilis and n. cuneatus are also continued in part to the cerebellum by nerve fibers passing by way of the inferior peduncles. This latter view has, however, not found confirmation in recent work, most authors believing that the afferent fibers of the posterior funiculi all enter the lemniscus, after decussating, and pass forward to the thalamus. Ascending fibers arising in the reticular formation of the medulla and the olivary nucleus also take this path to the cerebellum, and, on the other hand, probably make connections with the sensory tracts of the cord or the sensory nuclei of the medulla. Another afferent tract of the cord, that of Gowers (fasciculus anterolater- alis superficialis), ends in the cerebellum, in large part at least, forming a part, in fact, of the cerebellospinal system. The nature of the sensory impulses conveyed in this way to the cerebellum is not entirely understood, but it seems certain that some of them, at least, are what we designate as impulses of deep sen- sibility, that is, sensibility of muscle, tendon, and joint, as opposed to cutaneous sensibility, and this fact, as we shall see, throws some light on the specific functional importance of the cerebellum. 2. Connections with the Vestibular Branch of the Eighth Cran- ial Nerve. — This branch, arising in the semicircular canals and utriculus and sacculus, ends in the pons in several nuclei (Deiters', Bechterew's) and also in the n. fastigii of the cerebellum. These nuclei, in turn, are connected with other parts of the central nervous system, but the details are not yet completely known. The connections that have been most clearly established are those made with the motor centers. Through the medial longi- 234 PHYSIOLOGY OF CENTRAL NERVOUS SYSTEM. tudinal fasciculus these nuclei are connected with the motor nuclei of the cranial nerves and with descending paths in the spinal cord (vestibulospinal), which end in the motor centers for the spinal nerves. In how far the vestibular nuclei may make afferent con- nections with the cerebellum is undecided, but it seems probable Fig. 104. — Diagram to indicate a possible descending path from cerebrum to cord in ad- dition to the pyramidal system, namely, the secondary or cerebellar motor path (Van Gehuchten). The path is indirect and comprises the following units: 1. The cortico- ponto-cerebellar path, represented as arising in the motor area of the cerebrum and*passing down with the pyramidal system to end in the pons, thence continued through the middle peduncles to the cerebellar cortex of opposite side. 2. The path from the cerebellar cortex to the dentate nucleus. 3. The path from the dentate nucleus to the red nucleus passing by way of the superior peduncles, brachium conjunctivum. 4. The path from the red nucleus to the motor cells of the spinal cord (rubro-spinal tract). that such tracts exist, in view of the fact that destruction of the semicircular canals and severe lesions of the cerebellum cause motor disturbances that are strikingly similar. 3. Connections with Other Sensory Nuclei.— In addition to the CEREBELLUM, PONS, AND MEDULLA. 235 special sensory connections just described, it is stated by various neurologists that the sensory nuclei of the vagus, the trigeminal and the auditory nerves, send afferent paths into the cerebellum, and that similar paths extend from the primary end stations of the optic fibers.* 4. Connections with the Cortex of the Cerebrum. — The cerebellar cortex is connected with the cerebral cortex by the large system known as the cortico-ponto-cerebellar tract (see Fig. 82, A). The fibers of this tract arise in the motor area of the cerebrum or in the frontal cortex anterior to the motor area, descend in the internal capsule and cerebral peduncle, and end in the gray matter of the pons. Thence new axons continue the path across the mid-line and to the cerebellar cortex by way of the middle peduncle (brachium pontis). The tract would seem to convey efferent impulses from the cerebral cortex (motor region) of one side to the cerebellar cortex of the opposite side. A second possible connection with the cerebrum is made by way of the thalamus. Fibers arising in the dentate nucleus emerge by way of the brachium conjunctivum and connect with the red nucleus in the subthalamic region and perhaps also with the thalamus. The latter fibers may be continued forward to the cortex of the cerebrum and thus constitute an afferent path from cerebellum to cerebrum. Those fibers, on the contrary, which end in the red nucleus are brought into reflex connection with the motor bundle (rubrospinal tract), extending from the red nucleus to the motor centers in the spinal cord. Making use of the connec- tions described above, Van Gehuchten pictures an indirect motor path from the cortex of the cerebrum to the motor nerves by way of the cerebellum (see Fig. 104). The motor impulses descend by way of the cortico-ponto-cerebellar path to the cerebellar cortex, thence to the dentate nucleus, thence to the red nucleus, and then, by way of the rubrospinal tract, to the motor nuclei of the spinal nerves. Theories Concerning the Functions of the Cerebellum.— Modern views concerning the functions of the cerebellum may be classified under three general heads: First, those that consider it a general co-ordinating center or organ for the muscular movements and especially for those concerned in equilibrium and locomotion. This view, first proposed essentially by Flourens (1824), has been adopted by many, perhaps by most, writers since his time. The manner in which the organ serves to co-ordinate these movements has been explained in various ways. According to the older ob- servers, it was supposed so to arrange or group the various motor impulses that they reached the lower motor centers in the cord * See Edinger, "Brain," 29, 483, 1906. 236 PHYSIOLOGY OF CENTRAL NERVOUS SYSTEM. in the necessary combination for co-ordinated contractions. Ac- cording to more recent observers, this synergetic action is exer- cised not directly on the motor side of the reflex but on the sensory side. The numerous sensory paths connected with the organ, especially those of the muscular sense, and those from the vestibular nerve, suggest the view that in the complex cortex of the cerebel- lum these afferent impulses act upon nervous combinations whose discharges in turn are conveyed to the motor centers in a definite and orderly sequence. Either point of view assumes that there are in the cerebellum certain distinct mechanisms — that is, combi- nations of neurons that are essentially reflex centers, and that in all of our more complex bodily movements these mechanisms intervene. The second general set of theories regarding the cere- bellum assumes that this organ is essentially the center or a center for the muscle sense. This view is connected usually with the name of Lussana,* but has been supported since in one sense or another by many observers, f It is, in fact, not essentially different per- haps from the second phase of the first group of theories. Those who have expressed their idea of the physiology of the cerebellum by saying that it is a center of the muscle sense have, in recent times at least, recognized that this sense has a cortical center also in the cerebrum. The view can not assume, therefore, a conscious muscle sense mediated by the cerebellum, but only that fibers of muscular sensibility have a cortical termination therein, and that the cerebellar activity thus aroused is in some way necessary to the orderly adjustment of complex voluntary movements. According to another point of view, the cerebellum is a great augmenting organ for the neuromuscular system. It is added on, as it were, to the cerebrospinal motor system, and serves not to co-ordinate the motor discharges, but to increase their strength or effectiveness. This general view, first proposed by Weir Mitchell (1869), has been supported by Luys, and especially, although with important modi- fications, by Luciani. J Some of the details of the work of the latter observer are given below. Experimental Work Upon the Cerebellum. — Rolando, and par- ticularly Flourens, gave the direction to modern experimentation in this subject. The latter observer made numerous observations, especially on pigeons, in regard to the effect of removing all or a part of the cerebellum. He describes in detail the striking results of such an operation. When all or a large part of the organ is re- * Lussana. See "Journal 't f '6 Fig. IIS. — Curve to indicate the Weber-Fechner law of a logarithm ical relation be- tween excitation and sensation. — (From Waller.) The excitations are indicated along the abscissas, the sensations along the ordinates. The increase in sensation is represented as tak- ing place in equal steps, "the minimal perceptible difference," while the corresponding excitations require an increasing increment of i at each step, namely 1, 1.33, 1.77, 2.37, etc. That is, for equal increments of sensation increasing increments of stimulation are necessary. tion, then, with a weight of 60 gms. upon the finger the addition of another gram would not be perceived ; it would require again an increment of -^ — that is, 2 gms. — to make a just perceptible dif- ference in sensation. This relationship is known as Weber's law. While its exactness has often been disputed, it seems to be generally admitted that for a median range of stimulation the law expresses the approximate relation between the two variables considered. Fechner attempted to give this law a more quantitative and ex- tensive application by assuming that just perceptible differences 272 THE SPECIAL SENSES. in sensation represent actually equal amounts of sensation. Ac- cepting this assumption, we can express the relationship between stimulus and sensation as determined by Weber's experiments by saying that for the sensation to increase by equal amounts, — that is, by arithmetical progression, — the stimulus must vary according to a certain factor, — that is, by geometrical progression. The sensation may be regarded as a geometrical function of the stimulus. If the relation between stimulus and sensation is repre- sented as a curve in which the ordinates express the sensation in- creasing by equal amounts, and the abscissas the corresponding stimuli increasing at each interval by -J, a result is obtained such as is represented in the accompanying figure (Fig. 118). A curve of this kind is a logarithmical curve, and Fechner expressed the rela- tionship between stimulus and sensation in what has been called the psychophysical law, — namely, that the sensation varies as the logarithm of the stimulus. From the physiological standpoint it is important to bear in mind, as has been emphasized by Waller,* that several steps intervene between the action of the external stimulus and the production of the conscious sensation. The external stim- ulus acts first on the end-organ, this in turn upon the sensory nerve fiber, producing a nerve impulse which finally in the brain gives the conscious reaction. It is a question, therefore, whether the logarith- mical relation of the stimulus holds between it and the reaction of the end-organ or between the internal stimulus — that is, the sensory- nerve impulse — and the psychical reaction. This author has given some facts obtained by recording the action current in the optic nerve, the retina being stimulated by known intensities of light, which indicate that the relation observed is between the external stimulus and the internal stimulus, — that is, the sensory nerve impulse. * Waller, "Brain," 201, 1895. CHAPTER XV. CUTANEOUS AND INTERNAL SENSATIONS. General Classification. — According to the older views, the sensory nerves of the skin give sensations of touch. Modern physiology has shown, however, that these nerves mediate at least four different qualities of sensation — namely, pressure, warmth, cold, and pain. Our so-called touch sensations are usually compound, consisting of a pressure and a temperature component and also very frequently an element of muscle sense when muscular efforts are involved, as, for instance, in measuring weights or resistances. The four sensory qualities enumerated constitute the cutaneous senses, and they are present, or, to speak more accurately, the nerves through which these senses are mediated are present not only over the general cutaneous surface but also in those membranes — such as the mucous membrane of the mouth and the rectum (stomodeum and proctodeum) — which embryologically are formed from the epiblast. The surfaces in the interior of the body, on the contrary — such as the membranes of the alimentary canal, muscles, fasciae, etc. — have only nerves of pain, but no sense of touch or temperature. Of these cutaneous senses, three — pressure, warmth, and coid — may be grouped with the exterior senses, the sensations being projected to the exterior of the body, into the substance causing the stimulation; although, as was mentioned above, the temperature sensations under con- ditions— fever, vascular dilatation, etc. — may be projected to parts of the skin itself and be felt as changes in ourselves. The temperature sensations are, in fact, projected to the exterior whenever they are combined with pressure sensations, the latter serving, as it were, as the dominant sense. The pain sense, on the other hand, belongs to the group of interior senses, the sensations being always projected into our own body and being felt as changes in ourselves. Protopathic, Epicritic, and Deep Sensibility. — In the matter of the classification of the cutaneous senses and, indeed, the body senses in general, a new point of view has been suggested by Head and Rivers.* These authors made a careful study of the loss of sensa- tions after division of the cutaneous nerves, and of the subsequent gradual and separate return of these sensations following upon suture of the divided ends. They find that in skin areas made completely * Head and Rivers, " Brain," 1905, 99, and 1908, 323. 18 273 274 THE SPECIAL SENSES. anesthetic there is present a deep or subcutaneous sensibility to pressure and movements, a sensibility which must be mediated through sensory fibers contained in the nerves to the muscles In the skin itself there are present two systems of sensory fibers which regenerate at different times in a nerve that has been severed, and may be studied separately by this means. One system conveys sensations of pain and of extreme changes in tempera- ture, but the sensations are imperfectly localized and the sensi- bilitv is low. or. to express the same idea in another way, the threshold is high. This kind of sensation is found in the viscera also, and it may be considered from the functional standpoint as a defensive agency toward pathological changes in the tissues; it is designated as protopathic sensibility. It is stated that the glans penis possesses only this kind of sensibility. Protopathic sensibility comprises three qualities of sensation and presum- ably three sets of nerve-fibers, namely — for pain, for heat (not stimulated below 37° C), and for cold (not stimulated above 26° C). The second system of fibers responds to stimulations by light pressures and small differences in temperature between 26° and 37° C, the range of temperature to which the tem- perature nerves of the protopathic system are insensitive. These fibers regenerate after lesions much more slowly than the pro- topathic variety, and since the sensations mediated by them are localized very exactly, they furnish us the means for making fine discriminations of touch and temperature. For this reason they are described as an epicritic system, and the corresponding sensations are designated as epicritic sensibility. This system of fibers is not found in the other organs, and it constitutes,, therefore, the special characteristic of the skin area. In this system there are included separate fibers for heat, for cold, for light pressures, and for tactile discrimination. It is through the sensations mediated by these fibers that we recognize the shape and size of objects According to this classification we may assume that the posterior roots of the spinal nerves carry into the spinal cord the following varieties of afferent fibers: ! Heat (small differences;. ( PV,irritir ' Cold (small differences), epicritic -, Touch (li?ht preSSUres)- Cutaneous sensory fibers \ I Tactile discrimination. ( Heat (extremes). ( Protopathic - Cold (extremes;. i Pain. | Pressure. Subcutaneous or deep sensory fibers - Pain. I Muscular (position). ~ - « ,ck ' From muscles, joints, etc. Non-sensory afferent fibers j (Ending in cer'PJbeilum). The paths taken by these fibers after entering the cord are de- scribed on p. 177. CUTANEOUS AND INTERNAL SENSATIONS. 275 The Punctiform Distribution of the Cutaneous Senses. — A most interesting fact in regard to the cutaneous senses is that they are not distributed uniformly over the whole skin, but are present in discrete points or spots. This fact was first clearly established by Blix,* although it was discovered independently by Goldscheider and in this country by Donaldson. These ob- servers paid attention chiefly to the warm and cold spots. The existence of these spots may be demonstrated easily by anyone upon himself by moving a metallic point gently over the skin. If the point has a temperature below that of the skin it will be noticed that at certain spots it arouses simply a feeling of contact or pressure, while at other spots it gives a distinct sensation of coldness. If, on the other hand, the point is warmer than the skin it will at certain spots give a sensation of warmth. On mark- ing the cold and warm spots thus obtained it is found that they * « « . .'. r' Fig. 119. — -Representation of the distribution of cold and warm spots on the volar surface of forearm in a space 2 cms. by 4 cms. The red dots represent the cold spots as tested at a temperature of 10° C. The black dots represent the warm spots as tested at a temperature of 41° to 48° C. occupy different positions on the skin. Elaborate charts have been made of the warm and cold spots on different regions of the skin, the apparatus usually employed being a metal tube through which water of any desired temperature may be circulated. The temperature of the skin, whatever it may be, *Blix, "Zeitschrift f. Biologie," 20, 141, 1884; Donaldson, "Mind," 39, 1, 1885. See also Goldscheider, "Archiv f. Physiologie," 1885, suppl. volume. 276 THE SPECIAL SENSES. forms the zero line; any object of a higher temperature stimulates only the warm spots, while one of a lower temperature acts upon the cold spots. The pressure or tactile sense and the pain sense are also distributed in a punctiform manner; they have been studied most carefully by von Frey.* To determine the loca- tion of the pressure points he used fine hairs of different diam- eters fastened to a wooden handle. The cross-areas of these hairs are determined by measurements under the micro- scope, and the pressure exerted by each is measured by pressing it upon the scale pan of a balance. The quotient of the pressure exerted divided by the cross-area of the hair in square millimeters, |^, reduces the pressure to a uniform unit of area. For the pain points fine needles may be employed or stiff hairs similar to those used for the pressure points. From the experiments made there seems to be no doubt that each of the four cutaneous senses has its own spots of distribution in the skin, those for pain being most numerous and those for warmth the least numerous. There is some reason for believing also that the nerve endings mediating the pain sense lie most superficially in the skin and those for the warm sense the deepest. Specific Nerve Energies of the Cutaneous Nerves. — Many attempts have been made to determine whether the doctrine of specific nerve energies applies to these cutaneous senses; that is, whether each sense has its own nerve fibers capable of giving only its own quality of sensation. The evidence, on the whole, is favorable to this view. According to some observers, electrical or mechanical stimulation of the different points calls forth for each its character- istic reaction. Donaldson has found that cocain applied to the eye or throat destroys the senses of pain and pressure, but leaves those of heat and cold, which again supports the view of separate fibers for each sense. In addition there are a number of interesting pathological cases which point in the same direction. In some lesions of the cord — syringomyelia, for instance — the senses in the skin of the parts below are dissociated, — that is, there may be loss of pain and temperature in a certain area with a retention of the pressure sense, — a fact which indicates that these senses have separate paths and therefore separate nerve-fibers, f Still more interesting cases of dissociation are reported as the result of the compression of peripheral nerve trunks. Thus, BarkerJ describes his own case, in which, as the result of the pressure of a cervical rib upon some of the cords of the brachial plexus, there was a region in the arm lacking in the pressure and temperature senses, but retain- * Von Frey, "Konigl. Sachsischen Gosellschaft dor Wissenschaften, Math.- phys. Klasse," 1894-95-96. t For many interesting cases of dissociation due to spinal lesions see Head, "Brain," 1906, 537. J Barker, "Journal of Experimental Medicine," 1, 348, 1896. CUTANEOUS AND INTERNAL SENSATIONS. 277 ing the sense of pain. He quotes other cases in which the reverse dissociation occurred, pressure sense alone remaining. The simplest explanation of these facts is the view that each pressure, pain, warm, and cold spot is supplied by its own nerve fiber, and that each, when stimulated, reacts, if it reacts at all, only with its own peculiar quality of sensation. According to this view, artificial stimulation, if properly controlled, of the trunks of the nerves supplying the skin should be capable of bringing out these different sense qualities. Experiments made with this point in view have not, however, been very successful. Mechanical or electrical stimu- lation of the ulnar nerve, for instance, gives usually only pain sensa- tions, although if the stimulus is feeble contact sensations are aroused. The method, however, is probably at fault. In the case of amputated fingers or limbs a more decisive result is obtained. As is well known, individuals after such operations may for many years have sensations of their lost fingers or limbs. In such cases the pressure in the stump of the wound acting upon the central ends of the sensory fibers arouses sensations which are projected in the usual way, and give the feeling that would be experienced if the lost parts were still there and were stimulated in the normal manner. The Temperature Senses. — The main facts regarding the distribution of heat and cold spots have been determined, but in most of the experiments on record no distinction was made between protopathic temperature sensations and those mediated by the epicritic temperature nerves. It is difficult to adapt the older descriptions to this newer terminology, but when not otherwise specifically stated it may be assumed that the epicritic system is referred to. In general, the cold spots are more numerous than the warm spots, and react more promptly to their adequate stimulus. The threshold stimulus varies in different parts of the skin, the tip of the tongue requiring the smallest stimulus to arouse a sensation, and the eyelids, fore- head, cheeks, lips, limbs, and trunk following in the order named. According to Goldscheider, the spots on most portions of the skin form chains that have a somewhat radiate arrange- ment with reference to the hair follicles. The temperature points possess each its adequate stimulus, that for the cold spot being temperatures lower than the skin or of the terminal organ of the cold nerves, that for the heat spots temperatures higher than their own. From the standpoint of specific nerve ener- gies it is most interesting to find that these points, particularly the cold spots, may be stimulated by other than their adequate stimuli. Mechanical and electrical stimulation has, in the hands of several observers, been efficient in causing a sensation of cold upon a cold spot and of heat upon a warm spot. Some chemical stimuli are also effective. Menthol applied to the skin gives a cold sensa- 278 THE SPECIAL SENSES. tion, while, on the other hand, if the arm be plunged into a jar of carbon-dioxid gas a distinct warm sensation will be experienced. A curious effect of this kind is what is known as the paradoxical cold reaction. It is produced by applying a very warm object, with a temperature of 40° to 60° C, to a cold spot. According to Head and Rivers this reaction is rather characteristic of the protopathic temperature fibers. It can be obtained, for example, from the glans penis, which possesses only protopathic sensibility, or during the course of regeneration of a severed cutaneous nerve. In this latter condition hot objects applied to a cold spot give a vivid sensation of cold. The same result may be felt sometimes at the instant of entering a hot bath. Many efforts have been made to determine whether there is a specific kind of end-organ for each of these senses. Numerous observers have cut out the skin from cold or hot spots and examined the removed part carefully by histological methods. The general result has been that no distinctive end-organs have been found. Von Frey, however, believes that, although the heat spots are supplied simply by a terminal end plexus, the cold spots in some places at least have as a special end-organ the end-bulbs of Krause. This conclusion is based upon the fact that these end-bulbs are found in places, such as the glans penis and con- junctiva, where the cold sense is especially prominent or exclu- sively present. The (Epicritic) Sense of Pressure or Touch. — The cutaneous pressure points are smaller and more numerous than the cold or warm spots. Von Frey has shown that in those portions of the body that are supplied with hairs the pressure points lie over the hair follicles. The pressure nerve-fibers, in fact, terminate in a ring surrounding the hair follicle, this form of termination serving as an end-organ. " On account of their position they are stimulated by any pressure exerted upon the hair. The hair, indeed, acts like a lever and transmits any pres- sure applied to it with increased intensity, acting, therefore, as re- gards the pressure organ somewhat like the ear-bones in the case of the endings of the auditory nerve. In parts of the body not furnished with hairs the tactile or Meissner corpuscles are found and these structures doubtless function as pressure end-organs. They are particularly abundant in the parts of the hand and feet in which a delicate sense of pressure is present in spite of a much thick- ened epidermis. It has been estimated that for the entire surface of the body, excluding the head region, there are about 500,000 of these pressure points. These points are close together on those parts, such as the tongue and fingers, which have a delicate tactile sense and more widely scattered where the sense is less developed. The Threshold Stimulus and the Localizing Power. — The CUTANEOUS AND INTERNAL SENSATIONS. 279 delicacy of the sense of pressure may be measured by determining the minimal pressure necessary to arouse a sensation, — that is, the threshold stimulus, — or it may be estimated in terms of the power of discriminating two contiguous stimuli, — that is, the mini- mal distance that two points must be apart in order for the sensa- tions to be recognized as distinct. The two methods of measure- ment do not coincide. As determined by the threshold stimulus, the greatest delicacy is exhibited by the skin of the face, the fore- head, and temples. According to the older methods of measure- ment, the forehead will perceive a pressure of 2 mgs., while the skin of the tips of the fingers needs a pressure of from 5 to 15 mgs. to arouse a perceptible sensation. The back of the hand or the arm is more sensitive from this standpoint than the tips of the fingers. When measured by the power of discriminating two points — that is, the localizing sense — the tips of the fingers are far more sensitive than the skin of the face or of the arm. This latter prop- erty, in fact, stands in relation to the closeness of the pressure points to one another. The localizing sense may be determined by Weber's method of using a pair of compasses with blunt points. For any given area of the skin the power of discrimination or local- ization is expressed in terms of the number of millimeters between the two points at which they are just distinguished as two separate sensations when applied simultaneously to the skin. Instruments made for this purpose are designated as esthesiometers. They carry two points the distance of which apart can be readily adjusted and read off on a scale. The most satisfactory form of esthesiom- eter is that devised by von Frey. The two points in this case are made by long, rather stiff hairs whose pressure can be made quite uniform. According to the older measurements, the discriminat- ing sense of different parts of the skin varies greatly, as is shown by the accompanying table: Tip of the tongue 1.1 nuns. Tip of finger, palmar surface 2.3 Second phalanx finger, palmar surface 4.5 First phalanx finger, palmar surface 5.5 Third phalanx finger, dorsal surface 6.8 Middle of palm 8 to 9 Second phalanx finger, dorsal surface 11.3 Forehead 22.6 Back of the hand 31.6 Forearm 40.6 Sternum 45 Along the spine 54 Middle of neck or back 67.7 The tips of the tongue and the fingers are, therefore, the most delicate surfaces, and that the tongue surpasses the fingers in this respect is easily within the experience of everyone who will recall the ease with which small objects between the teeth are detected by 280 THE SPECIAL SENSES. the tongue as compared with the fingers. From the above data it is evident also that the whole skin may be imagined as composed of a mosaic of areas of different sizes, the sensory circles of Weber, in each of which two or more simultaneous stimulations of the pres- sure nerves give only one pressure sensation. The size of these areas, particularly where they are large, may be reduced by practice, as is shown by the increased tactile sensibility of the blind. The fact that we can recognize two simultaneous pressure stimuli of the skin as two distinct sensations implies that the two sensations have some recognizable difference in consciousness. This difference is spoken of as the local sign. We may believe that every sensitive point upon the skin has its own distinctive local sign or quality, and that by experience we have learned to project each local sign more or less accurately to its proper place on the skin surface. Two points on this surface that are a great distance apart are easily recognized as different ; but as we bring the points closer together the difference becomes less marked and finally disappears when the distance corresponds to the area of the sensory circle for the part of the skin investigated, for instance, 1 mm. for the tongue, 22 mms. for the forehead, etc. The ultimate limit of the power of discrimination was assumed by Weber to depend upon the area of distribution of a single nerve fiber. Assuming that each nerve fiber at its termi- nation spreads over a certain skin area, it was suggested that the size of this area forms a limit to the power of discrimination, since two stimuli within it would affect a single fiber and therefore would give a single sensation. This view, however, has not been supposed to accord with the facts even when the additional supposition was made that the local signs of two adjacent fibers may not be distinct enough for us to recognize them as separate and that practically there must be a number of intervening unstimulated areas, the number varying according to the sensitiveness of the area. Von Frey has, however, given a new method of testing the localizing sense of the skin, the results of which seem to accord with this anatomical explanation. If instead of applying the two points simultaneously they are applied in succession, at an interval of one second, the individual can distinguish the difference when two neighboring pressure points are stimulated. Each pressure point in the skin, therefore, has a local sign, which enables us to distinguish it from all others, and by this method the ultimate sensory circles on the skin become much smaller than when measured by the usual method of Weber. The center of each is a pressure point and the area is determined by the distance from this center at which an isolated stimulation of this point can be obtained. It seems probable, moreover, that each of these pressure points is connected to the brain by a separate nerve path, possibly a single fiber, and that this anatomical arrangement CUTANEOUS AND INTERNAL SENSATIONS. 281 determines the limitation of the localizing sense for different regions of the skin. In the newer work of Head and Rivers, which has been referred to several times, it will be recalled that they distinguish first of all between cutaneous sensibility to pressure and a deep sense of pressure. When the cutaneous fibers of a given area are all destroyed by degeneration, the area is still sen- sitive to pressure applied so as to deform the skin inward. The spot so stimulated can be localized accurately. This deep sense of pressure is mediated by the deep nerve fibers which supply the muscles. According to these authors the cutaneous pressure sensibility is mediated by two sets of fibers, those which give us the power of tactile discrimination when the compass points are applied simultaneously to the skin, and those which give us the power of recognizing simply light pressures. In lesions of the spinal cord one of these sensibilities may be lost and the other retained over a given skin area (Head and Thompson, "Brain," 1906). In fact, the fibers of tactile discrimi- nation are stated to pass up the cord (uncrossed) in the posterior funiculi, while those of light pressures ascend in the lateral or anterolateral funiculi and cross before reaching the medulla. The Pain Sense. — Pain is probably the sense that is most widely- distributed in the body. It is present throughout the skin, and under certain conditions may be aroused by stimulation of sensory nerves in the various visceral organs, and indeed in all of the mem- branes of the body. Our knowledge of the physiological properties of the end-organs and nerves mediating this sense is chiefly limited to the skin, and for cutaneous pain at least the evidence, as stated above, is very strongly in favor of the view that there exists a special set of fibers which have a specific energy for pain. All recent ob- servers agree that the pain sense has a punctiform distribution in the skin, the pain points being even more numerous than the pres- sure points. The threshold stimulus of these points in various regions may be determined by von Frey's stimulating hairs, and experiments of this kind show, as we should expect, that it varies greatly. The cornea, for instance, gives sensations of pain with much weaker stimuli than in the case of the finger tips. In general, however, the threshold stimulus is much higher for the pain than for the pressure points. Histological examination of the pain points indicates that there is no special end-organ, the stimulus taking effect upon the free endings of the nerve fibers. Any of the usual forms of artificial nerve stimuli may affect these endings if of suf- ficient intensity, and, as is well known, stimuli applied to sensor}7 nerve trunks affect these fibers with especial ease. A temperature of 50° to 70° C. applied to an afferent nerve will cause violent pain sensations, but has no effect upon the motor nerve fibers in the same trunk. Mechanical stimulation gives usually only pain sensations, and the results of inflammatory changes, as in neuritis or neuralgia, are equally marked. Localization or Projection of Pain Sensations. — Under normal conditions. cutaneous pains are projected with accuracy to the point stimulated, and it is possible that this result is due in part at least to the training acquired in connection with concomitant (epicritic) 282 THE SPECIAL SENSES. pressure sensations, the latter acting as a guide or aid in the pro- jection. Thus in the cases referred to above, in which a portion of the skin had lost the sense of pressure and temperature, but retained that of pain, it was found that the localization was very incomplete. Pain arising in the internal organs, on the contrary, is located very inaccurately. The pain from a severe toothache, for example, may be projected quite diffusely to the side of the face. A very interesting fact in this connection is that such pains are often referred to points on the skin and may be accompanied by skin areas of tenderness. Pains of this kind that are misreferred to the surface of the body are designated as reflected pains. It has been shown by Head * and others that the different visceral organs have, in this respect, a more or less definite relation to certain areas of the skin. Pains arising from stimuli acting upon the intestines are located in the skin of the back, loins, and abdomen in the area supplied by the ninth, tenth, and eleventh dorsal spinal nerves; pains from irritations in the stomach are located in the skin over the ensiform cartilage; those from the heart in the scapular region, and so on. The explanation offered for this misreference is that the pain is referred to the skin region that is supplied from the spinal segment from which the organ in question receives its sensory fibers, the misreference being due to a diffusion in the nerve centers. As Head expresses it, "when a painful stimulus is applied to a part of low sensibility in close central connection with a part of much greater sensibility the pain pro- duced is felt in the part of higher sensibility rather than in the part of lower sensibility to which the stimulus was actually applied." It is interesting that affections of the serous cavities — e. g., the peritoneum — do not cause reflected pains or cutaneous tenderness as in the case of the viscera. Another notable fact in this connec- tion is the occurrence of the condition known as allochiria. When from any cause one or other of the cutaneous senses is depressed in a given area stimulation in this region may give sensations which are referred to the symmetrical area on the other side of the body, or, if this also is involved, it may be referred to the area next above or below in the spinal order. The above law, according to which projection is made to the area of high sensi- bility most closely connected with the area of low sensibility, seems to hold in this case also. Muscular or Deep Sensibility. — The existence of a special set of sensory nerve-fibers distributed to the muscles was clearly recognized by some of the older physiologists. Charles Bell,f for example, says : " Between the brain and the muscles * Head, "Brain," 16, 1, 1893, and 24, 345, 1901. t Bell, "The Nervous System of the Human Body," third edition, Lon- don, 1844, p. 200. CUTANEOUS AND INTERNAL SENSATION. 283 there is a circle of nerves; one nerve conveys the influence from the brain to the muscle; another gives the sense of the condition of the muscle to the brain." The conclusive proof of the existence of such fibers, however, has only been fur- nished within recent years. It has been demonstrated that there are special sensory endings in the muscles, the so-called muscle spindles, and in the attached tendons, the tendon spindles or tendon organs of Golgi. The muscle spindles are found most frequently in the neighborhood of the tendons, at tendinous inter- sections or under aponeuroses. Sherrington* has shown that the nerve fibers in them do not degenerate after section of the anterior roots of the corresponding spinal nerves and are therefore derived from the posterior roots. In the muscles of the limbs he estimates that from one-half to one-third of the fibers in the muscular nerve branches are sensory, and that most of these sensory fibers end in the muscle spindles. On the physiological and clinical side facts of various kinds have accumulated that make clear the existence of this group of sensory fibers and emphasize their essential importance in the co-ordination of our muscular movements. It has been shown that stimulation of the nerves distributed to the muscles or mechani- cal stimulation of the muscles themselves causes a depressor effect upon blood-pressure, thus demonstrating the presence of afferent fibers in the muscles. As described in the section upon the central nervous system, the numerous experiments upon the effect of section of the posterior and lateral funiculi of the cord, and observations upon the results of pathological lesions of the posterior funiculi (tabes dorsalis) give results which are interpreted to mean that fibers of muscular sensibility form the most important group in the posterior funiculi and constitute, as well, perhaps, the long, ascending fibers in the cerebellospinal fasciculus in the lateral funiculi. It is believed, therefore, that our so-called voluntary muscles are richly supplied with afferent fibers and that the im- pulses carried by these fibers to the brain are necessary for the proper contraction of the muscles, and particularly for the ade- quate combination of the contractions of groups of muscles in the co-ordinated movements of equilibrium. Indeed, section of the posterior^ roots of the spinal nerves supplying a given region is followed by a loss of control of the muscles in this region hardly less complete than the paralysis produced by direct section of the anterior roots; the muscles not only lose their tonicity in consequence of the dropping out of the reflex sensory stimuli from the skin and muscles of the region, but they are apparently withdrawn from voluntary control in spite of the maintenance of their normal motor connections. Within the central nervous system the fibers of muscle sense end in part in * Sherrington, "Journal of Physiology," 17, 237, 1894. 284 THE SPECIAL SENSES. the cerebellum and in part pass forward, by way of the median fillet, to end in the cerebrum. In the cerebrum they end in the cortex of the parietal lobe in the region of the posterior central convolution. There is reason to believe that this cortical sense area of the muscle sense is connected by association fibers with the motor areas lying anterior to the central fissure of Rolando, and we have thus a reflex arc — or, as Bell expressed it, a circle of nerves between the muscles and the brain. It is probable that a similar arc or circle is formed by the connections through the cerebellum, and still a third one of a lower order by the connections in the spinal cord. In the higher animals the impulses received in the cerebellum through the fibers of muscle sense, in connection with those received from the semicircular canals and vestibular sacs of the ear, furnish the sensory basis for the cerebellar control of muscular movements, particularly of the synergetic combinations necessary in locomotion. Through the circle or arc in the cortex of the cerebrum it may be supposed that our characteristic voluntary movements are affected, and it may be doubted whether a so-called voluntary contraction can be made when this circle is broken on the sensory side. Whether or not this latter suggestion is true, it seems to be beyond doubt that adequately controlled voluntary movements depend for their adaptation upon the inflow of sensory impulses along the fibers of muscle sense. We have a certain conscious- ness of the condition of our muscles at all times, and if we were deprived of this knowledge we should be unable to control them properly, perhaps unable to use them voluntarily. The Quality of the Muscular Sensibility. — Under the term muscular sensibility in its wide sense we must understand the sensibility mediated by the afferent fibers from the muscles, the tendons, ligaments, and joints. The quality of these deep sensations is of several kinds — we have first of all the deep pressure sensibility (see p. 281), which gives a definite conscious reaction that is well localized. It is usually projected to the exterior and is not consciously separated from the tactile or pressure sensations of the skin. We probably make much use of this sensibility in judging the weight and resistance of bodies. Muscular sensibility proper is that ill-defined consciousness which we possess of the condition and position of our muscles or of the joints or limbs moved by them. It includes also the sense of passive position, and the sense of effort and of the spatial relations of the limbs in motion or at rest. When the afferent fibers from the muscles and joints are traced into the central nervous system, some of them, it will be remembered, enter the tracts of Flechsig and Gower and end in the cerebellum, while others pass up the cord in the posterior funiculi, enter the lemniscus, CUTANEOUS AND INTERNAL SENSATIONS. 285 and terminate eventually in the cerebral cortex in the post- Rolandic region. Our conscious muscular sensations are mediated presumably by this latter group. The untrained person scarcely recognizes the existence of these sensations, but they are evi- dent enough upon analysis, and it is most certain that they take a fundamental part in regulating our movements. In all our estimations of the extent of the muscular contractions they form the chief sensory basis, and in this way they may indi- rectly furnish us with data for perceptions and judgments of various kinds. Thus, in the judgments of distance based upon visual impressions it is believed that for close objects, partic- ularly, the muscle sense connected with the extrinsic and in- trinsic musculature of the eyeballs plays a fundamental part. Doubtless also this sense takes an essential part in the primitive formation of our conceptions of space, since it may be assumed that the continual movements of the extremities in connection with our visual and tactile impressions furnish essential data upon which we build our perceptions of distance and size, our judgments of spatial relations. As is explained in the chapter on the Physiology of the Ear, the sensations from the semi- circular canals and vestibular sacs co-operate in giving data for these fundamental conceptions, and it is not possible for us to disentangle the parts taken by these senses separately in building up our knowledge of the external world. In excessive muscular effort the quality of the muscle sensation undergoes a change and becomes strong enough to make a distinct and peculiar impression upon our consciousness. We designate this feeling as fatigue, but there is no question apparently that this sensation is mediated through the same nerve-fibers that ordinarily give us our muscular sensibility. Sensations of Hunger and Thirst. — Hunger and thirst are typical interior (or common) sensations. We feel them as changes in ourselves. Neither sense has been the direct object of much experimental investigation, and what knowledge we possess is there- fore derived largely from accidental or pathological sources. Hunger in its mild form is designated as appetite. It occurs normally at a certain interval after meals, and is referred or projected more or less accurately to the stomach. It is not known whether this sense is mediated by a special set of sensory fibers distributed to the mucous membrane of the stomach, or whether, perhaps, it may be a quality of the sensory impressions from the muscular coat. The former view seems more probable, especially when it is remembered that loss of appetite or anorexia is so frequently an accompaniment of pathological changes in the membrane of the stomach. The nervous mechanism through which this sense is me- diated is of most essential importance and deserves more careful 2S6 THE SPECIAL SENSES. study at the hands of physiologists and pathologists. Under ordi- nary conditions of life all of the regulation of the amount and quality of the food necessarj' to the proper nutrition of the body and the maintenance of body equilibrium is effected through this sense. Its striking influence upon the body at large is well illustrated in the case of animals (pigeons, dogs) deprived of their cerebrum. During the period of fasting these animals show all the external signs of hunger and keep in continual, restless movement that seems to imply a con- stantly acting sensory stimulus. We may assume that appetite has its sensory origin, its peripheral nerve endings in the stomach, and that these endings are excited in some unknown way when the stomach is empty. This gastric hunger, as it might be called, disappears, or the appetite is appeased when the stomach is filled. This fact in itself would indicate that the stimulus has a local origin in the stomach, and is not dependent upon any general change in the nutritive condition of the body. The appetite is satisfied by filling the stomach with food long before this food is actually absorbed and distributed to the tissues. The inges- tion of totally indigestible material would probably have temporarily a similar result. The exact nature of the conditions that lead to or cause a stimulation of the sensory nerves of appetite in the stomach remains unexplained. The well-known fact that muscular exercise and low temperatures and particularly a combination of the two cause a marked augmentation of the appetite would suggest that the sensory stimulus is influenced by the extent or character of the oxidations in the muscular tissues, and that, therefore, some substance may be formed as the result of these oxidatiorjs which affects the sensory nerves of the stomach. The same general sug- gestion is contained in the fact that diabetics exhibit an abnormal appetite in spite of abundant feeding. In these individuals the carbohydrate food escapes oxidation more or less completely, and the metabolism, particularly in the muscles, involves, therefore, to a greater extent, the oxidation of protein material, — a fact which may stand in some relation to the abnormal appetite that is observed. The complexity of the nervous apparatus that controls the appetite is shown also by many facts from the experiences of life and from the results of laboratory investigations. For example, it is found that large amounts of gelatin in the diet, although at first accepted willingly, soon provoke a feeling of dislike and aversion to this particular foodstuff such as cannot be overcome. An animal will starve rather than use the gelatin, although all of our direct physio- logical evidence would indicate that this substance is an efficient food, playing much the same part as the fats or carbohydrates. A fact of this kind indicates that the sensory apparatus of the appe- tite is influenced in some specific way by the metabolism of this particular material. So also the feeling of satiety and aversion for CUTANEOUS AND INTERNAL SENSATIONS. 287 food that follows overfeeding indicates something more than a sim- ple removal of the sensations of appetite; it implies an active state, due possibly to the excitation of sensory fibers of a different char- acter. With regard to the effects of prolonged starvation, the pangs of hunger that are felt at first do not seem to increase in in- tensity to such an extent as to cause actual suffering. The testi- mony of the "professional f asters," at least, seems to show that, if water is provided, prolonged deprivation of food is not accompanied by the intense discomfort or suffering popularly associated with the idea of complete starvation. The Sense of Thirst. — Our sensations of thirst are projected more or less accurately to the pharynx, and the facts that we know would seem to indicate that the sensory nerves of this region have the important function of mediating this sense. The water con- tents of the body are subject to great changes. Through the lungs, the skin, and the kidneys water is lost continually in amounts that vary with the conditions of life. This loss affects the blood directly, but is doubtless made good, so far as this tissue is concerned, by a call upon the great mass of water contained in the storehouse of the tissues. To restore the body tissues to their normal equilibrium in water we ingest large quantities, and the control of this regula- tion is effected through the sense of thirst. We know little or nothing about the nervous apparatus involved; but it may be assumed that when the water content falls below a certain amount the nerve fibers in the pharyngeal membrane (fibers of the glosso- pharyngeal nerve) are stimulated and give us the sensation of thirst. That we have in this membrane a special end-organ of thirst is indicated, moreover, by the fact that local drying in this region, from dry or salty food, or dry and dusty air, produces a sensation of thirst that may be appeased by moistening the mem- brane with a small amount of water not in itself sufficient to relieve a genuine water need of the body. Our normal thirst sensations might be designated, therefore, as pharyngeal thirst, to indicate the probable origin of the sensor}' stimuli. Prolonged deprivation of water, however, must affect the water content of all the tissues, and under these conditions sensations are experienced whose quality is not that of simple thirst alone, but of pain or suffering. All ac- counts agree that complete deprivation of water for long periods induces intense discomfort, anguish, and possibly mental troubles, and we may suppose that under these conditions sensory nerves are stimulated in many tissues, and that the metabolism in the ner- vous system in addition is directly affected by the loss of water. It is interesting to note that while in diseases due to a general infection, loss of appetite, anorexia is a frequent symptom, there is no corre- sponding loss of the sense of thirst. Even in hydrophobia the patient experiences the sensations of thirst, although unable to drink water. CHAPTER XVI. SENSATIONS OF TASTE AND SMELL. The sense of taste is mediated by nerve fibers distributed to parts of the buccal cavity and particularly to parts of the tongue. The most sensitive regions are the tip, the borders, and the posterior portion of the dorsum of the tongue in the region of the circum- vallate papillae. Taste buds and a sense of taste are described also for the soft palate, the epiglottis, and even for the larynx. The sense is not present uniformly over the entire dorsum of the tongue. On the contrary, it has an irregular, punctiform distribution over most of this region with the exception of the parts mentioned above. The Nerves of Taste. — The anterior two-thirds of the tongue are supplied with sensory fibers from the lingual nerve, a branch of the inferior maxillary division of the fifth nerve, and the posterior third from the glossopharyngeal. The taste fibers for these regions, therefore, are supplied immediately through these nerves. It has been shown, moreover, that the taste fibers carried in the lingual are brought to it through the chorda tympani nerve, which arises from the seventh cranial nerve and joins the lingual soon after emerging from the tympanic cavity of the ear. There has been much discussion as to the origin of these taste fibers from the brain. At first sight it would seem that the fibers for the posterior third of the tongue must have their origin from the brain in the glosso- pharyngeal and those for the anterior two-thirds in the sensory portion of the facial. Many surgeons have reported, however, that complete extirpation of the semilunar ganglion of the fifth nerve is followed by complete loss of taste in the corresponding side of the tongue, and others have described a loss of taste for the anterior two-thirds following a similar operation. Some authors have asserted, therefore, that all the taste fibers originate or rather end in the sensory nucleus of the fifth, while others believe that the fibers running in the chorda tympani, at least, take their origin in the fifth nerve. It is supposed by these authors that the fibers reach the semilunar ganglion by a cir- cuitous route, as is indicated in the diagram given in Fig. 120. Those that run in the lingual and chorda tympani nerves are assumed to pass to the ganglion by way of the great superficial petrosal and Vidian nerves and the sphenopalatine ganglion, while those that are contained in the glossopharyngeal reach 288 SENSATIONS OF TASTE AND SMELL. 289 the same ganglion through the tympanic nerve, the small super- ficial petrosal, and the otic ganglion. A report by Cushing* of the results of removal of the Gasserian ganglion in thirteen cases throws much doubt upon these views. This author made careful examinations of the sense of taste, not only immediately after the operation, but for a long period subsequently. He states that in no case was there any effect upon the sense of taste in the posterior third of the tongue. We may believe, therefore, that the taste fibers of this part arise immediately from the ganglion- cells in the petrosal ganglion and enter the brain with the roots of the nerve to terminate in its sensory nucleus in the medulla. I-^«tfos.SUfCT^VCltV(X\OT (vlpetrosum. KJ • Fig. 120. — Schema to show the course of the taste fibers from tongue to brain. — (Cushing.') The dotted lines represent the course as indicated by Cushing's observations. The full black lines indicate the paths by which some authors have supposed that these fibers enter the brain in the trigeminal nerve. Regarding the anterior two-thirds of the tongue, the lingual region, it was found that in some cases there was at first a loss of acuity of taste or even an entire disappearance of the sense, but subsequently it returned. It would seem, therefore, that the loss of taste de- scribed after removal of the Gasserian ganglion is an incidental result the cause of which is not entirely clear. Cushing attributes it to a postoperative degeneration and swelling in the fibers of the lingual nerve, which affect the conductivity of the intermingled fibers of the chorda tympani. Since, however, there is no perma- * Cushing, " Bulletin of the Johns Hopkins Hospital," 14, 71, 1903. Gives also the surgical literature. 19 290 THE SPECIAL SENSES. nent loss of taste in this region, it follows that the taste fibers do not pass through the Gasserian ganglion. We may assume, therefore, that they originate directly in the nerve cells of the geniculate ganglion and enter the brain with the fibers of the intermediate nerve (n. intermedins Wrisbergii). The End-organ of the Taste Fibers. — In the circumvallate papillae, in some of the fungiform papillae, and in certain portions of the fauces, palate, epiglottis, or even the vocal cords there are found the organs known as taste buds which are believed to act as peripheral organs of taste. These curious structures are repre- sented in Fig. 121. They are oval bodies with an external layer of tegmental or cortical cells, and they contain in the interior a number of elongated cells each of which ends in a hair- like process which projects through the central taste pore of the organ. These latter cells may be consid- ered as the true sense cells; the hair-like process con- stitutes probably the part that is stimulated directly by sapid substances. The impulse thus aroused is communicated through the body of the cell to the endings of the taste fibers which terminate around these cells by terminal arborizations of the same general type as in the case of the hair cells in the cochlea. Sensations.— Our taste sensations Fig. 121. — Section through one of the taste buds of the papilla foliata of the rabbit (from Quain, after Ranvier), highly magnified: p. Gus- tatory pore: 8, gustatory cell; r, sustentacular cell; ra, leucocyte containing granules; e, super- ficial epithelial cells; n, nerve fibers. Classification of Taste are very numerous, but it has been shown that there are four primary or fundamental sensations, — namely, sweet, bitter, acid, and salty, and that all other tastes are combinations of these primary sensations, or combinations of one or more of them with sensations of odor or with sensations derived from stimulation of the so-called nerves of common sensibility in the tongue. Thus, the taste of pepper may be resolved into a slight odor sensation and a sensation due to stimulation of the fibers of general sensi- bility,— that is, it gives no taste sensation proper. The taste of alum may be considered as a combination of a salty taste with common sensibility. Combinations of sweet and acid tastes, sweet SENSATIONS OF TASTE AND SMELL. 291 and bitter tastes, etc., form a part of our daily experience, and in the fused or compound sensation that results from such com- binations one may usually recognize without difficulty the con- stituent parts. The seemingly great variety of our taste sensations is largely due to the fact that we confuse them or combine them with simultaneous odor sensations. Thus, the flavors in fruits and the bouquet of wines are due to odor sensations which we designate ordinarily as tastes, since they are experienced at the time these objects are ingested. If care is taken to shut off the nasal cavities during the act of ingestion even imperfectly, as by holding the nose, the so-called taste disappears in large measure. Aery dis- agreeable tastes are usually, as a matter of fact, due to unpleasant odor sensations. On the other hand, some volatile substances which enter the mouth through the nostrils and stimulate the taste organs are interpreted by us as odors. The odor of chloro- form, for instance, is largely due to stimulation of the sweet taste in the tongue. Distribution and Specific Energy of the Fundamental Taste Sensations. — Regarding the distribution of the funda- mental taste sensations over the tongue and palate there seem to be many individual differences. In general, however, it may be said that the bitter taste is more developed at the back of the tongue and the adjacent or posterior regions; at the tip of the tongue the bitter sense is less marked or in cases may be absent altogether. On the contrary, in this latter region the sweet taste is well developed. On this account it may happen that substances which when first taken into the mouth give a not unpleasant sweet taste subsequently when swallowed cause disagreeably bitter sen- sations, like the little book of the evangelist, which in the mouth was "sweet as honey, and as soon as I had eaten it. my belly was bitter." Oehrwall * has made an interesting series of experiments in which he stimulated separately a number of fungiform papillae on the surface of the tongue. Each papilla was stimulated sepa- rately for its fundamental taste senses of sweet, bitter, and acid, by using drops of solutions of sugar, quinin, and tartaric acid. Of the 125 papillae thus examined, 27 gave no reaction at all, although sensitive to pressure and temperature. In the 98 papillae that reacted to the sapid stimulation it was found that 60 gave taste sensations of all three qualities, 4 gave only sweet and bitter, 7 only bitter and acid, 12 only sweet and acid, 12 only acid, and 3 only sweet. None was found to give only a bitter sensation. These facts bear directly upon the question of the specific energy of the taste fibers. It is possible that the four fundamental taste qualities may be mediated by four different end-organs and four separate * Oehrwall, "Skandinavisches Archiv f. Physiologie," 2, 1, 1S90. 292 THE SPECIAL SENSES. sets of nerve fibers, each giving, when stimulated, only its own quality of sensation. On the other hand, it is possible that one and the same nerve fiber might give different qualities of sensation according to the nature and mode of action of the sapid substances. The fact, as shown by Oehrwall's experiments, that there are sensory spots upon the tongue which will not react to some kinds of sapid substance, but do react to others, and perhaps only to one particular kind, speaks strongly in favor of the view that there are different end-organs and nerve fibers for each fundamental taste. This view is still further supported by the fact that certain chemically pure sub- stance; give different tastes according to the part of the tongue upon which they are placed. Thus, sodium sulphate (Guyot) may taste salty upon the tip of the tongue and bitter when placed upon the posterior part. A better instance still is given by solutions of a bromin substitution product of saccharin, the chemical name for which is parabrom-benzoic sulphinid: C6H3Br < rr ^NH. C oil,' When this substance is placed upon the tip of the tongue it gives a sweet sensation, while upon the posterior region it gives only a bitter taste together with a sensation of astringency (Howell and Kastle). Extracts of the leaves of a tropical plant, Gymnema silvestre, applied to the tongue, destroy the sense of taste for sweet and bitter sub- stances (Shore), and this fact may be explained most satisfactorily by assuming that this substance exercises a selective action upon taste terminals in the tongue, paralyzing those for the bitter and the sweet substances. Finally, the fact that electrical, me- chanical, or chemical stimulation of the chorda tympani, where it passes through the tympanic cavity, may arouse taste sensations is proof that the taste sensation in general is not due to a peculiar kind of impulse that can be aroused only by the action of sapid bodies upon the terminals in the tongue, but, on the contrary, that it is a specific energy of these fibers, and depends for its quality, there- fore, upon the specific reaction of the terminations in the brain. Method of Sapid Stimulation. — In order that sapid substances may react upon the taste terminals it is necessary, in the first place, that they shall be in solution. It is impossible to taste with a dry tongue. We may assume, therefore, that the stimulation consists essentially in a chemical reaction between the sapid substance and the terminal of the taste fiber, — for instance, the hair process of the sense cells in the taste buds,— and the question naturally arises whether the distinctive reactions corresponding to the separate taste qualities can be referred to a definite chemical structure in the sapid bodies. Are there certain chemical groups which possess the property of reacting specifically with the end-organs? Experience shows that substances of very different chemical constitution may SENSATIONS OF TASTE AND SMELL. 293 excite the same taste. Thus, sugar, saccharin, and sugar of lead (lead acetate) all give a sweet taste, while, on the other hand, starch (soluble starch), which stands so close in structure to the sugars, has no effect upon the taste terminals. It is interesting to remember that the taste nerves may be stimulated by sapid sub- stances dissolved in the blood as well as when applied to the ex- terior of the tongue. A sweet taste may be experienced in diabetes from the sugar in the blood, or a bitter taste in jaundice from the bile. The Threshold Stimulus. — The determination of the threshold stimulus for different sapid substances is made by ascertaining the minimal concentration of the solution which is capable of arousing a taste sensation. The delicacy of the sense of taste is influenced, however, by certain accessory conditions which must be taken into account. Thus, the temperature of the solution is an important condition. Very cold or very hot solutions do not react, — that is, the extremes of temperature seem to cUminish or destroy the sensi- tiveness of the end-organ. A temperature between 10° and 30° C. gives the optimum reaction. So also the delicacy of the sense of taste is increased by rubbing the sapid solution against the tongue. Doubtless this mechanical action facilitates the penetration of the sapid body into the mucous membrane, but it seems also to in- crease the irritability of the end-organ. It is our habit in tasting bodies with the tongue to rub this organ against the hard palate. With regard to the threshold stimulus such results as the following are reported: Salty (sodium chloric!) . 0.25 gm. in 100 c.c. H20 — detectible on tip of tongue. Sweet (sugar) 0.50 " " " " detectible on tip of tongue. Acid (HC1) 0.007 " " " " detectible on border of tongue. Bitter (quinin) 0.00005 " " " " detectible on root of tongue. The very great sensitiveness of the tongue to bitter substances is evident from this table. The Olfactory Organ. — The end-organ for the olfactory sense lies in the upper part of the nose, and consists of elongated, epithe- lial-like cells, each of which bears on its free end a tuft of six to eight hair-like processes, while at its basal end it is continued into a nerve fiber that passes through the cribriform plate of the ethmoid bone and ends in the olfactory bulb. These olfactory sense cells lie among supporting epithelial cells of a columnar shape (Fig. 122). At the free edge of the cells there is a limiting membrane through which the olfactory hairs project. The olfactory sense 294 THE SPECIAL SENSES. cells are essentially nerve cells, and in this respect resemble the sense cells in the retina, the rods and cones, rather than those of the ear or of the organs of taste. The distribution of the olfactory cells, according to v. Brunn, is confined to the nasal septum and a portion of the upper turbinate bone. The area covered in each nos- tril corresponds to about 250 square millimeters. The epithelium of the lower and middle turbinates and the floor of the nostrils is composed of the usual ciliated cells found in the respiratory passages, while the so-called vestibular region of the nose, the part roofed in by the cartilage, is covered by a stratified pavement epithelium corresponding in structure with that of the skin. These latter portions of the nose are supplied with sensory fibers derived from the fifth or trigeminal nerve. We must consider the 500 sq. mm. of olfac- tory epithelium as the olfactory sense organ com- parable physiologically and perhaps anatomically to the rod and cone layer of the retina. The connections of these cells with the central nervous system have al- ready been described (p. 214). It will be remem- bered that the fine, non- medullated fibers springing from the basal end of the sense cells enter the olfac- tory bulb and end in ter- minal arborizations in the olfactory glomeruli, where they make con- nections by contact with the dendrites of the mitral cells of the bulb. Through the axons of these mitral cells the impulses are con- ducted along the olfactory tract to their various terminations in the olfactory lobe itself, either of the same or of the opposite side, and eventually also in the cortical region, the uncinate gyrus of the hippocampal lobe. As regards the olfactory sense cells, the nerve cells in the olfactory bulb might be compared with the nerve gan- glion layer of the retina, and the nerve fibers of the olfactory tract with the fibers of the optic nerve. The Mechanism of Smelling. — Odoriferous substances to Fig. 122. — Cells of the olfactory region (after v. Brunn): a, a, Olfactory cells; b, b, epithelial cells; n, n, central process prolonged as an olfac- tory nerve fibril; I, I, nucleus; c, knob-like clear termination of peripheral process; h, h, bunch of olfactory hairs. SENSATIONS OF TASTE AND SMELL. 295 affect the olfactory cells must, of course, penetrate into the upper part of the nasal chamber. This end is attained during inspiration, either by simple diffusion or by currents produced by the act of sniffing. It may also happen by way of the posterior nares. In fact, the flavors of many foods, fruits, wine, etc., are olfactory rather than gustatory sensations. When such food is swallowed the poste- rior nares are shut off from the pharynx by the soft palate, but in the expiration succeeding the swallow the odor of the food is con- veyed to the olfactory end-organ. Flavors are perceived, therefore, not during the act of swallowing, but subsequently, and if the nostrils are blocked, as in coryza, foods lose much of their flavor. Simply holding the nose will destroy much of the so-called taste of fruits or the bouquet of wines.* Nature of the Olfactory Stimulus. — The fact that smells are transmitted through space like light and sound has suggested the possibility that they may depend upon a vibratory movement of some medium. This view, although occasionally defended in modern times, is apparently entirely incompatible with the facts. The usual view is that odoriferous bodies emit particles which, as a rule at least, are in gaseous form. These particles are con- veyed to the olfactory epithelium by currents in the air or by simple gaseous diffusion, and after solution in the moisture of the membrane act chemically upon the sensitive hairs of the sense cells. All vapors or gases are, however, not capable of acting as stimuli to these cells; so that evidently the odoriferous character depends upon some peculiarity of structure. It is assumed that there are certain groups, "odoriphore groups," which are character- istic of all odoriferous substances and by virtue of which these substances react with the special form of protoplasm found in the hair cells. Haycraftf has formulated certain fundamental conceptions bearing upon the relation between chemical structure and odoriferous stimulation. He has shown that the power to cause smell, like other physical properties, is a periodic function of the atomic weight — that in the periodic system, according to Men- dele jeff, the elements in certain groups are characterized by their odoriferous properties ; for instance, the second, fourth, and sixth members— sulphur, selenium, and tellurium — of the sixth group. Moreover, in organic compounds belonging to an homologous series the smell gradually changes and, indeed, increases in the higher members of the series, — that is, in those having a more complex molecular structure. The Qualities of the Olfactory Sensations. — While we dis- * For many interesting facts concerning smelling and the literature to 1895 see Zwaardemaker, "Die Physiologie des Geruchs," Leipzig, 1895. tHaycraft, "Brain," 1888, p. 166. 296 THE SPECIAL SENSES. tinguish a great many different kinds of odors, it has been found difficult, indeed impossible, to classify them very satisfactorily into groups. That is, it is not possible to pick out what might be called the fundamental odor sensations. This sense was doubtless used by primitive man chiefly in detecting and testing food, in protect- ing himself from noxious surroundings, and perhaps also in controll- ing his social relations. The olfactory sensations, in accordance with this use made of them, give either pleasant or unpleasant sensa- tions in a more marked and universal way than in the case of vision or hearing, approaching, in this respect, rather the purely sensual characteristics of the lower senses, the bodily appetites. Mankind has been content to classify odors as agreeable and disagreeable, and to designate the many different qualities of odors by the names of the substances which in his individual experience usually give rise to them. A number of observers have proposed classifications more or less complete in character. One of the latest and perhaps the best is that suggested by Zwaardemaker on the basis of the nomenclatures introduced by previous observers. Adopting first the general grouping into pure odors, odors mixed with sensa- tions of common sensibility from the mucous membrane of the nose, and odors mixed or confused with tastes, he separates the pure odors or odors proper into nine classes, as follows : I. Odores setherei or ethereal odors, such as are given by the fruits, which depend u}x>n the presence of ethereal substances or esters. II. Odores aromatici or aromatic odors, which are typified by camphor and citron, bitter almond and the resinous bodies. This class is divided into five subgroups. III. Odores fragrantes, the fragrant or balsamic odors, comprising the vari- ous flower odors or perfumes. The class falls into three subgroups. IV. Odores ambrosiaci, the ambrosial odors, typified by amber and musk. This odor is present in the flesh, blood, or excrement of some ani- mals, being referable in the last instance to the bile. V. Odores alliacei or garlic odors, such as are found in the onion, garlic, sulphur, selenium and tellurium compounds. They fall into three subgroups. VI. Odores empyreumatici or the burning odors, the odors given by roasted coffee, baked bread, tobacco smoke, etc. The odors of benzol, phenol, and the products of dry distillation of wood come into this class. VII. Odores hircini or goat odors. The odor of this animal arises from the caproic and caprylic acid contained in the sweat; cheese, sweat, spermatic and vaginal secretions give odors of a similar quality. VIII. Odores tetri or repulsive odors, such as are given by many of the nar- cotic plants and acanthus. IX. Odores nauseosi or nauseating or fetid odors, such as are given by feces and certain plants and the products of putrefaction. While the classification serves to emphasize a number of marked resemblances or relations that exist among the odors, it does not rest wholly upon a subjective kinship, — that is, the different odors brought together in one class do not in all cases arouse in us sensa- SENSATIONS OF TASTE AND SMELL. 297 tions that seem to be of related quality. It is not impossible, how- ever, that further analysis may succeed in showing that there are certain fundamental qualities in our numerous odor sensations. Our position regarding the odors is similar to that which formerly prevailed in the case of the taste sensations. It was thought to be impossible to classify these latter satisfactorily on the basis of a few fundamental sensations, but it is now universally accepted that all of our true gustatory sensations show one or more of four primary taste qualities. As was said above, our odor sensations are classi- fied in ordinary life as agreeable or disagreeable, and, indeed, Haller, the great physiologist of the eighteenth century, divided odors along this line into three classes: (1) the agreeable or am- brosial, (2) the disagreeable or fetid, and (3) the mixed odors. In many cases, no doubt, the agreeableness or disagreeableness of an odor depends solely upon the associations connected with it. If the associative memories aroused are unpleasant the odor is dis- agreeable. Thus, the odor of musk, so pleasant to most persons, produces most disagreeable sensations in others, on account of past associations. It is possible, however, that there is some funda- mental difference in physiological reaction between such odors as those of putrefaction and of a violet which may be considered as the cause of the difference in psychical effect. It has been suggested, for instance, that they may affect the circulation in the brain in opposite ways, one producing an increased, the other a decreased flow. This improbable supposition has been shown to be devoid of foun- dation by the observations of Shields.* In his experiments the vascu- lar suppfy to the skin of the arm was determined by plethysmo- graphic methods, and it was found that both pleasant (heliotrope perfume) and unpleasant (putrefactive) odors give a similar vascu- lar reaction. Each class, if it acts at all, causes, as a rule, a con- striction of the skin vessels, such as is obtained normally from in- creased mental activity, — a reaction usually interpreted to mean a greater flow of blood to the brain. Fatigue of the Olfactory Apparatus. — It is a matter of common observation that many odors, such as the perfumes of flowers, quickly cease to give a noticeable sensation when the stimu- lation is continued. This result is usually attributed to fatigue of the sense cells in the end-organ and it is noticeable chiefly with faint odors. One who sits in an ill-ventilated room occupied by many persons may be quite unconscious of the unpleasant odor from the vitiated air, while to a newcomer it is most distinct. Threshold Stimulus — Delicacy of the Olfactory Sense.— The extraordinary delicacy of the sense of smell in some of the lower animals is -seemingly beyond the power of objective measurement or * Shields, "Journal of Experimental Medicine," 1. 1896. 298 THE SPECIAL SENSES. expression. The ability of a dog, for instance, to follow the trail of a given person depends undoubtedly upon the recognition of the individual odor, and the actual amount of olfactory material left upon the ground which serves as the stimulus must be infinitesi- mally small. Even in ourselves the actual amount of olfactory material which suffices to give a distinct sensation is often beyond our means of determination except by the aid of calculation. It is recognized in chemical work, for instance, that traces of known substances too small to give the ordinary chemical reactions may be detected easily by the sense of smell. By taking known amounts Fig. 123. — Zwaardemaker's olfactometer. of odoriferous substances and diluting them to known extents it is possible to express in weights the minimal amount of each substance that can cause a sensation. By this method such figures as the following are obtained: Camphor is perceived in a dilution of 1 part to 400,000; musk, 1 part to 8,000,000; vanillin, 1 part to 10,000,000; while, according to the experiments of Eischer and Penzoldt, mercaptan may be detected in a dilution of ^r 'ouV ¥o"cr °f a mmi- gram in 1 liter of air or TBTTTOTTo o °f a milligram in 50 c.c. of air. Various methods have been proposed to determine the relative delicacy of the olfactory sense in different persons, and these methods have some application in the clinical diagnosis of certain cases. Zwaardemaker has devised a simple apparatus, the olfactometer, the principle of which is illustrated in Fig. 123. It consists of an outside cylinder — the olfactory cylinder, whose inner surface is of porous material which can be filled with a known strength of olfac- tory solution — and an inside tube, smelling tube. This latter is applied ro the nose and where it runs inside the cylinder it is gradu- SENSATIONS OF TASTE AND SMELL. 299 ated in centimeters. It is evident that the further out the inner tube is pulled the greater will be the amount of olfactory substance which will be exposed to the incoming air of an inspiration. Conflict of Olfactory Sensations. — When different odors are inhaled simultaneously through the two nostrils they may give rise to the phenomenon of a conflict of the olfactory fields similar to that described for the visual fields. That is, we perceive first one then the other without obtaining a fused or compound sensation. The result depends largely on the odors selected. In some cases one odor may predominate in consciousness to the entire suppression of the other, — a phenomenon which also has an analogy in binocular sensations. It is well known, also, that certain odors antagonize or neutralize others. It is said, for instance, that the odor of iodoform, usually so persistent and so disagreeable, may be neutralized by the addition of Peru balsam, and that the odor of carbolic acid may destroy that of putrefactive processes. Whether the neutralization is of a chemical nature or is physiological does not seem to have been definitely ascertained. Olfactory Associations. — Personal experience shows clearly that olfactory sensations arouse numerous associations — our olfactory memories are good. On the anatomical side the cortical center in the hippocampal lobe is known to be widely connected with other parts of the cerebrum, and we have in this fact a basis for the extensive associations connected with odors. In animals like the dog, with highly developed olfactory organs, it is evident that this sense must play a correspondingly large part in the psychical life. In such animals as well as among the invertebrates it is in- timately connected with the sexual reflexes, and some remnant of this relationship is obvious among human beings. Among the so- called special senses that of smell is perhaps the one most closely connected with the bodily appetites, and overgratification or over- indulgence of this sense, according to historical evidence, has at least been associated with periods of marked decadence of virtue among civilized nations. PHYSIOLOGY OF THE EYE. The eye is the peripheral organ of vision. By means of its peculiar physical structure rays of light from external objects are focused upon the retina and there set up nerve impulses that are transmitted by the fibers of the optic nerve and optic tract to the visual center in the cortex of the brain. In this last organ is aroused that reaction in consciousness which we designate as a visual sensation. In studying the physiology of vision we may consider the eye, first, as an optical instrument physically adapted to form an image on the retina and provided with certain physi- ological mechanisms for its regulation; secondly, we may study the properties of the retina in relation to its reactions to light, and lastly, the visual sensations themselves, or the physiology of the visual center in the brain. CHAPTER XVII. THE EYE AS AN OPTICAL INSTRUMENT— DIOPTRICS OF THE EYE. Formation of an Image by a Biconvex Lens. — That the re- fractive surfaces of the eye form an image of external objects upon the retinal surface is a necessary conclusion from its physical struc- ture. The fact may be demonstrated directly, however, by ob- servation upon the excised eye of an albino rabbit. The thin coats of such an eye are semitransparent, and if the eye is placed in a tube of blackened paper and held in front of one's own eyes it can be seen readily that a small, inverted image of external objects is formed upon the retinal surface, just as an inverted image of the exterior is formed upon the ground glass plate of a photographic camera. This image is formed in the eye by virtue of the refractive surfaces of the cornea and the lens. The curved surfaces of these transparent bodies act substantially like a convex glass Ions, and the physics of the formation of an image by such a lens may be used to explain the refractive processes in the eye. To understand the formation of an image by a biconvex lens the following physical facts must be 300 DIOPTRICS OF THE EYE. 301 borne in mind. Parallel rays of light falling upon one surface of the lens are brought to a point or focus (F) behind the other surface (Fig. 124). This focus for parallel rays is the principal focus and the distance of this point from the lens is the principal focal dis- tance. This distance depends upon the curvature of the lens and its refractive power, as measured by the refractive index of the material of which it is composed. Parallel rays are given theo- retically by a source of light at an infinite distance in front of the lens, but practically objects not nearer than about twenty feet give rays so little divergent that they may be considered as par- Fig. 124. — Diagrams to illustrate the refraction of light by a convex lens : a., Refrac- tion of parallel rays ; b., refraction of divergent rays ; c, refraction of divergent rays from a luminous point nearer than the principal focal distance. allel. On the other hand, if a luminous object is placed at F the rays from it that strike upon the lens will emerge from the other surface as parallel rays of light. If a luminous point (/, Fig. 124) is placed in front of such a lens at a distance greater than the principal focal distance, but not so far as to give practically parallel rays, the cone of diverging rays from it that impinges upon the surface of the lens will be brought to a focus (/') further away than the principal focus. Conversely the rays from a luminous point at f will be brought to a focus at /. These points, / and /', are therefore spoken of as conjugate foci. All luminous 302 THE SPECIAL SENSES. points within the limits specified will have their corresponding conjugate foci, at which their images will be formed by the lens. Lastly, if a luminous point is placed at v, Fig. 124, nearer to the lens than the principal focal distance, the cone of strongly di- vergent rays that falls upon the lens, although refracted, is still divergent after leaving the lens on the other side and consequently is not focused and forms no real image of the point. For every lens there is a point known as the optical center, and for biconvex lenses this point lies within the lens, o. The line joining this center and the principal focus is the principal axis of the lens {p-F, Fig. 124). All other straight lines passing through the optical center are known as secondary axes. Rays of light that are coincident with any of these secondary axes suffer no angular deviation in passing through the lens; they emerge parallel to their line of entrance and practically unchanged in direction. Moreover, any luminous point not on the Fig. 125. — Diagrams to illustrate the formation of an image by a biconvex lens: a, For- mation of the image of a point ; b, formation of the images of a series of points. principal axis will have its image (conjugate focus) formed some- where upon the secondary axis drawn from this point through the optical center. The exact position of the image of such a point can be determined by the following construction (Fig. 125) : Let A represent the luminous point in question. It will throw a cone of rays upon the lens, the limiting rays of which may be represented by A-b and A-c. One of these rays, A-p, will be parallel to the prin- cipal axis, and will therefore pass through the principal focus, F. If this distance is determined and is indicated properly in the construction, the line A-p may be drawn, as indicated, so as to pass through F after leaving the lens. The point at which the DIOPTRICS OF THE EYE. 303 prolongation of this line cuts the secondary axis, A-o, marks the conjugate focus of A and gives the position at which all of the rays will be focused to form the image, a. In calculating the position of the image of any object in front of the lens the same method may be followed, the construction being drawn to de- termine the images for two or more limiting points, as shown in Fig. 124. Let A-B be an arrow in front of the lens. The image of A will be formed at a on the secondary axis A-o, and the image of B at b along the secondary axis B-o. The images of the intervening points will, of course, lie between a and b; so that the image of the entire object will be that of an inverted arrow. This image may be caught on a screen at the distance indicated by the construction if the latter is drawn to scale. The principal focus of a convex lens may be determined experimentally or it may be calculated from the formula — + \ = j, in which / represents the principal focal dis- tance and p and p1, the conjugate foci for an object farther away than the principal focal distance. That is, if the distance of the object from the lens, p, is known, and the distance of its image, p1, is determined experimentally, the principal focal distance of the lens, /, may be determined by the formula, or if any two of the fac- tors, p, p1, and /, are known the third may be reckoned from the formula. Formation of an Image by the Eye. — As stated above, the re- fractive surfaces of the eye act essentially like a convex lens. As a matter of fact, these refractive surfaces are more complex than in the case of the biconvex lens. In the latter the rays of light suffer refraction at two points only. Where they enter the lens they pass from a rarer to a denser medium and where they leave the lens they pass from a denser to a rarer medium. At these two points, therefore, they are refracted. In the eye there is a larger series of refractive surfaces. The light is refracted at the anterior surface of the cornea, where it passes from the air into the denser medium of the cornea ; at the anterior surface of the lens, where it again enters a denser medium ; and at the posterior surface of the lens, where it enters the less dense vitreous humor. The relative refractive powers of these different media have been determined and are expressed in terms of their refractive indices, that of air being taken as unity.* * The term index of refraction expresses the constant ratio between the angles of incidence and of refraction, or specifically between the sine of the angle of incidence and the sine of the angle of refraction: = index of ° sine r refraction. 304 THE SPECIAL SENSES. Index of refraction for air = 1 Index of refraction for cornea and aqueous hu- mor = 1.3365 Index of refraction for crystalline lens = 1.4371 Index of refraction for vitreous humor = 1.3365 The three points at which the light is refracted are indicated in the accompanying schema (Fig. 126). The refractive surfaces of the eye may be considered as being composed of a concavo-convex lens, the cornea and aqueous humor, and a biconvex lens, the crystalline lens. In a system of this kind, composed of several refractive media, it has been shown that to construct geometrically the path of the rays it is necessary to know six points ; these are the six car- dinal points or optical con- stants of Gauss, — namely, the anterior and the poste- rior focal distance, the two nodal points, and the two principal points. So far Fit'. 126.— Diagram to illustrate the surfaces as the eve is Concerned, it in the eye at which the rays of light are chiefly , , , , , , refracted. has been shown that the path of the rays of light may be represented with sufficient accuracy by employing what is known as the reduced schematic eye of Listing, in which the refraction is supposed to take place at a single convex surface separating two media, the air on one side and the media of the eye on the other, the latter having a refractive index of 1.33 (see Fig. 127). In this reduced eye the position of the ideal refracting surface c' lies in the aqueous humor, at a distance of 2.1 mms. from the anterior surface of the cornea, and the position of the nodal point or optical center — that is, the center of curvature of the ideal ' refracting surface lies in the crystalline lens at n, a J? distance of 7.3 mms. from the anterior surface of the *,. ,OT ~. fig. 127. — Diagram to illustrate the reduced COl'nea. The principal fo- or schematic eye with a single refracting surface ... , .%• c separating two media of different densities: c\ Cal distance IOr thlS retract- the ideal refracting surface situated 2.1 mms. . •• , j. behind the anterior surface of real cornea; n, ing SUIT aCe lies at a CllS- the nodal point, or center of curvature of the tant.n r>f 9H 7 mm« ™>W.V> surface c', and 15.5 mms. in front of retina, tame 01 ZU./ mms., WlllCn The eyeball is supposed to be filled with a uni- TirrmLl Kr> omii vnlonl + r\ form substance having a refractive index of 1 .33, WOU1U De equi\dieni tO equal tQ tha(. of the ^^^^ humor. 22.8 mms. (20.7 + 2.1) from the actual surface of the cornea and 15.5 mms. (22.8 — 7.3) from the nodal point. In the eye at rest this principal focal DIOPTRICS OF THE EYE. 305 distance coincides with the retina, since the refracting surfaces in the normal resting eye are so formed that parallel rays (rays from distant objects) are brought to a focus on the retina. To show the formation of the image of an external object on the retina it suffices, therefore, to use a construction such as is represented in Fig. 128. Secondary axes are drawn from the limiting points of the object— A and B — through the nodal point. Where these axes cut the retina the retinal image of the object will be formed. That is, all the rays of light proceeding from A that penetrate the eye will be focused at a, and all proceeding from B at b. The image on the retina will therefore be inverted and will be smaller than the object. The angle formed at the nodal point by the lines A-n and B-n is known as the visual angle; it varies inverse!}* with the dis- tance of the object from the eye. The Inversion of the Image on the Retina. — Although the images of external objects on the retina are inverted, we see them erect. This fact is easily understood when we remember that our actual visual sensations take place in the brain and that the pro- jection of these sensations to the exterior is a secondary act that has been learned from experience. Experience has taught us to project the visual sensation arising from the stimulation of any given point on the retina to that part of the external world from which the stimulus arises — that is, to the luminous point giving origin to the light rays. According to the physi- cal principles described above, the image of such a point mUSt be formed FiS- 12S— Diagram to illustrate the eonstruc- L . tion necessary to determine the location and size 01 on the retina where the the retinal image. secondary axis from that point through the nodal point touches the retina. In projecting this retinal stimulus outward to its source, therefore, we have learned to project it back, as it were, along the line of its secondary axis. In Fig. 128 the retinal stimulus at a is projected outward along the line a-n- A, and to such a distance as, from other sources, we estimate the object .4. to be. This law of projection is fixed by experience, but it implies, as will be noted, that we are conscious of the differences in sensation aroused by stimulation of different parts of the retina. Considering the retina as a sensory surface, — like the skin, for instance, — each point, speaking in general terms, may be assumed to be connected with a definite portion of the cortex, and the sensation aroused by the stimulation of these dif- ferent points must differ to some extent in consciousness, each has 20 306 THE SPECIAL SENSES. its local sign. The sensations arising from each of these points we have learned to project outward into the external world along the line from it to the nodal point of the eye, because under the normal conditions of life this point is stimulated only by external objects situated on this line. This law of projection is so firmly fixed that if a given point in the retina is stimulated in some unusual way we still project the resulting sensation outward according to the law, and thus make a false projection and interpretation. For instance, if the little finger is inserted into the inner and lower angle of the eye and is pressed upon the eyeball the edge of the retina is stimulated mechanically. One experiences, in consequence, a visual sensation, known as a phosphene, consisting of a dark-blue spot surrounded by a light halo. This sensation, however, is projected out toward the upper and outer angle of the eye, accord- ing to the law of projection, since normally this part of the retina is only stimulated by light coming from such a direction. A similar error in projection is obtained by holding objects so close to the eye that a physical inverted image cannot be formed, but only an erect shadow image. This experiment may be performed as follows: Hold the head of a pin close to the eye, and, in order that a sharp shadow may be thrown, allow the light to fall on this pin through a pinhole in a card held somewhat farther from the eye. By this means an erect shadow of the pin, lying in the circle of light from the hole, will be thrown on the eye. This shadow image will be projected outward according to the usual law, and consequently will appear inverted. The Size of the Retinal Image. — The size of the image of an object on the retina may be reckoned easily, provided the size of the object and its distance from the eye is known. As will be seen from the construction given in Fig. 128, the triangles A-n-B and a-n-b are symmetrical ; consequently we have the ratio : A-B : a-b : : A A-B A that is a-b a-n Size of object Distance of object from nodal point. Size of image " " Distance of image from nodal point. As was stated above, the distance of the image from the nodal point — that is, the distance of the retina from the nodal point — may be placed at 15.5 or 15 mms. Consequently, three of the factors in the above equation being known, it is easily solved for the un- known factor — namely, the size of the image on the retina. To take a concrete example; suppose it is desired to know the size on the retina of the image made by an object 120 feet high at a distance of one mile (5280 feet). If we designate the size of the image as x DIOPTRICS OF THE EYE. 307 and substitute the known values for the other terms of the equation, we have — • = -35-, orx = 0.341 mm., which is about the diam- eter of the fovea centralis. The retinal image of the object in this case would be, in round numbers, about tfoVto of the actual height of the object. Accommodation of the Eye for Objects at Different Dis- tances.— The normal or, as it is sometimes named, the emmetropic eye, is arranged to focus parallel rays more or less accurately upon the retina. That is, the refractive media have such curvatures and densities that parallel, or substantially parallel rays are brought to a focus upon the retinal surface. When objects are brought closer to the eye, however, the rays proceeding from them become more and more divergent. If the eye remains unchanged the refracted rays cut the retina before coming to a focus — so that each luminous point in the object, instead of forming a point upon the Fig. 129. — Diagram explaining the change in the position of the image reflected from th? anterior surface of the crystalline lens. — (.Williams, after Danders.) retina, forms a circle, known as a diffusion circle. As this is true for each point of the object, the retinal image as a whole is blurred. We know, however, that up to a certain point at least this blurring does not occur when the object is brought closer to the eyes. The eye, in fact, accommodates itself to the nearer object so as to obtain a clear focus. In a photographic camera this accommodation or focusing is effected by moving the ground glass plate farther away as the object is brought closer to the 308 THE SPECIAL SENSES. lens. In the eye the same result is obtained by increasing the curva- ture and therefore the refractive power of the lens. That a change in the lens is the essential factor in accommodation for near objects is demonstrated by a simple and conclusive experiment devised by Helmholtz with the aid of what are known as the images of Pur- kinje. The principle of this experiment is represented by the dia- gram given in Fig. 129. The eye to be observed is relaxed; that is, gazes into the distance. A lighted candle is held to one side as represented, and the observer places his eye so as to catch the light of the candle when reflected from the observed eye. With a little practice and under the right conditions of illumina- tion the observer will be able to see three images of the candle re- A B Fig. 130. — Reflected images of a candle flame as seen in the pupil of an eye at rest and accommodated for near objects. — (Williams.) fleeted from the observed eye as from a mirror: one, the brightest, is reflected from the convex surface of the cornea (a, Fig. 130, A) ; one much dimmer and of larger size is reflected from the convex surface of the lens (b, Fig. 130, A). This image is larger and fainter because the reflecting surface is less curved. The third image (c, Fig. 130, A) is inverted and is smaller and brighter than the second. This image is reflected from the posterior surface of the lens, which acts, in this instance, like a concave minor. If now the observed eye gazes at a near object, it will be noted (Fig. 130, B) that the first image does not change at all, the third ima^e also remains practically the same, but the middle image (6) becomes smaller and approaches nearer to the first (a). This result can only mean that in the act of accom- modation the anterior surface of the lens becomes more convex. In this way its refractive power is increased and the more diver- gent rays from the near object are focused on the retina. Helm- holtz has shown that the curvature of the posterior surface of the lens is also increased slightly; but the change is so slight that the increased refractive power is referred chiefly to the change in the anterior surface. The means by which the change is effected DIOPTRICS OF THE EYE. 309 was first explained satisfactorily by Helmholtz.* He attributed it to the contraction of the ciliary muscle. This small muscle, composed of plain muscle fibers, is found within the eyeball, lying between the choroid and the sclerotic coat at the point at which the sclerotic passes into the cornea and the choroid falls into the ciliary processes. Some of its fibers take a more or less circular direction around the eyeball, resembling thus a sphincter muscle, while others take a radial direction in the planes of the meridians of the eye and have their insertion in the choroid coat (Fig. 131). When this muscle contracts the radial fibers especially will pull forward the choroid coat. The effect of this change in the choroid is to loosen the pull of the suspensory ligament (zonula Zinnii) on the lens and this organ then bulges forward by its own elasticity. The theory assumes that in a condition of rest the suspensory ligament, which runs from the ciliary processes to the capsule of the lens, exerts a Ciliary Border process, of iris. Ciliary muscle. Pigment epithelium, Ora serrata. Fig. 131. — Meridional section of eyeball after removal of sclerotic coat, cornea, and iris, to show the position of the ciliary muscle. — (Schultze.) tension upon the lens which keeps it flattened, particularly along its anterior surface, since the ligament is attached more to this side. When this tension is relieved indirectly by the contraction of the ciliary muscle the elasticity of the lens, or rather of the capsule of the lens, causes it to assume a more spherical shape along its anterior surface, and the amount of this change is proportional to the extent of contraction of the muscle. Other theories have been proposed to explain the way in which the contraction of the ciliary * Helmholtz, "Handbuch der phvsiologischen Optik," second edition. 1896. 310 THE SPECIAL SENSES. muscle effects a change in the curvature of the lens,* but none is so simple and, on the whole, so satisfactory as the one suggested bv Helmholtz. It is interesting to note that in fishes accommodation is effected in a different way, namely, by movements of the lens forward and backward. In these animals the eye when at rest is accommodated for near vision, and to see objects at a distance the refractive power of the eye is diminished by the contraction of a special muscle, retractor lentis, which pulls the lens toward theretina.f Limit of the Power of Accommodation — Near Point of Distinct Vision.- — When an object is brought closer and closer to the eye a point will be reached at which it is impossible by the strongest contraction of the ciliary muscle to obtain a clear image of the object. The rays from it are so divergent that the refractive surfaces are unable to bring them to a focus on the retina. Each luminous point makes a diffusion circle on the retina, and the whole image is indistinct. The distance at which the eye is just able to accommodate and within which distinct vision is impos- sible is called the near point. Observation shows that this near point varies steadily with age and becomes rapidly greater in dis- tance between the fortieth and the fiftieth year. In the case of the normal eye the recession of the near point varies so regularly with age that its determination may be used to estimate the age of the individual. Figures of this kind are given : Age. 10 20 30 40 50 60 Near Point. 7 cm. or 2.76 in 10 " " 3.94 " 14 " " 5.61 " 22 " " 8.66 " 40 " " 15.75 " 100 " " 39.37 " This gradual lengthening of the near point is explained usually by the supposition that the lens loses its elasticity, so that con- traction of the ciliary muscle has less and less effect in causing an increase in its curvature. The process starts very early in life, and is one of the many facts which show that senescence begins practically with birth. The change in near point in early life is so slight as to escape notice, but after it reaches a distance of about 25 cm. (about 10 inches) the fact obtrudes itself upon us in the use of our eyes for near objects, — reading, for example. The condition is then designated as old-sightedness or presbyopia. Most normal eyes become so distinctly presbyopic between the fortieth and the fiftieth year as to recjuire the use of glasses in reading. If no other defect exists in the eye, this deficiency of the lens is readily over- * See Tscherning, "Optique physiologique," Paris, 1898; and Schoen, " Archiv f. die gesammte Physiologic," 59, 427, 1895. f See Beer, "Wiener klinische Wochenschrift, " 1898, No. 12. DIOPTRICS OF THE EYE. 311 come by using suitable convex glasses to aid the eye in focusing the rays. It is obvious that in such cases the glasses need not be used except for near work. Far Point of Distinct Vision. — The normal eye is so adjusted that parallel rays are brought to a focus on the retina. The far point is therefore theoretically at infinity. Objects at a great distance are seen distinctly, as far as their size permits, without accommodation, — that is, with the eye at rest. Practically it is found that objects at a distance of 6 to 10 meters (20 to 30 feet) send rays that are sufficiently parallel to focus on the retina without muscular effort on the part of the eyes, and this distance, therefore, measures the practical far point, punctum remotum, of the normal eye. The rays at this distance are, in reality, somewhat divergent, and that they produce a distinct image without an act of accom- modation may be due to the fact that the rods and cones, the really sensitive part of the retina, do not form a mathematical plane, but have a certain thickness or depth. In the fovea centralis, for in- stance, the cones have a length estimated (Greeff) at 85 jj. (0.085 mm.), and since the displacement of the focus of an object moved from an infinite distance (parallel rays) to 6 or 10 meters from the eye is less than this amount, the focused image would continue to fall on some part of the cones without the aid of the mechanism of accommodation. The Refractive Power of the Eye and the Range of Accom- modation.— -The refractive power of lenses is expressed usually in terms of their principal focal distance. A lens with a distance of one meter is taken as the unit and is designated as having a refractive power of one diopter, 1 D. Compared with this unit, the refractive power of lenses is expressed in terms of the recipro- cal of their principal focal distance measured in meters; thus, a lens with a principal focal distance of ^ meter is a lens of 10 diopters, 10 D., and one with a focal distance of 10 meters is ^ diopter (0.1 D.). The anterior principal focal distance of the combination of refractive surfaces in the eye is 15.5 mms. or i^o meters. The reciprocal of this length of focus. ^ or 64.5 D., expresses the refractive power of the eye under the normal con- ditions in which the rays are refracted into the dense vitreous humor. The anterior focal length of the cornea alone is given as 23.3 mm., which would correspond to a power of 42.9 D., while the anterior focal length of the lens alone is equal to 50.6 mm. or about 20 D. In the combined system, therefore, the action of the cornea is more important than that of the lens. Removal of the lens, as in cataract operations, does not lessen the refractive power of the 312 THE SPECIAL SENSES. eye so much as when the action of the cornea is destroyed, as happens for the most part when the head is immersed in water. The total refractive power of the eye is increased by the act of accommodation, on account of the greater curvature of the lens. As stated in a preceding paragraph the extent of accommodation varies with age. At 10 years the range is from infinity, when the eye is at rest, to 7 ctm. when the maximum accommodation is used. In this case, therefore, the refractive power is increased from 64.5 D. to 78.5 D., since a distance of 7 ctm., y^- meter, is equivalent to -j2 or 14 + D. The decreasing range of accom- modation as age increases is expressed conveniently in the number of diopters which may be added to the refractive power of the eye by the action of the ciliary muscle. The following table illustrates the usual range of accom- modation for different ages : Range of accommodation Years. in diopters. 10 14 15 12 20 10 25 8.5 30 7 35 5.5 40 4.5 45 3.5 50 2.5 55 1.75 60 1 65 0.75 70 0.25 Optical Defects of the Normal Eye. — The refractive surfaces of the eye exhibit some of the optical defects commonly noticed in lenses, particularly those defects known as chromatic and spherical aberration. White light is composed of ether waves of different lengths and different rapidities of vibration, the shortest waves being those at the violet end of the spec t mm and the longest those at the red end. In passing through a prism or lens these waves are re- fracted unequally and are therefore more or less dispersed accord- ing to the character of the refracting medium. The short, rapid waves at the violet end are refracted the most and are brought to a focus before the longer, red waves, so that the image shows fringes of color instead of being pure white. This phenomenon is known as chromatic aberration. Lenses used for scientific purposes are corrected for this defect or made achromatic by a combination of lenses of crown and flint glass so placed that the dispersive power of one neutralizes that of the other. The eye exhibits this defect, but not to such an extent as to be noticeable in ordinary vision. If, however, an object is in focus when viewed DIOPTRICS OF THE EYE. 313 by red light it can be shown that the focus must be changed if the same object is illuminated by violet light. Helmholtz estimates that if the media of the eye possess the same dispersive power as water the rays of violet light must be brought to a focus at about 0.434 mm. in front of that of the red rays. Spherical aberration depends upon the fact that the rays near the circumference of a lens are refracted more and therefore are brought to a focus sooner than those entering nearest the center. This defect may be noticed in an uncorrected lens by the fact that when the center of the image is in exact focus its margins are slightly out of focus and vice versa. The defect is usually cor- rected, as in photography, by use of a diaphragm to cut off the rays from the periphery of the lens. In the eye both spher- ical and chromatic aberrations are remedied to a large extent by a similar device. The iris constitutes an adjustable diaphragm, which reflex! y narrows as the light increases in intensity and thus cuts off the rays that would go through the periphery of the lens. The interesting physiological control of the movements of the iris is described below. In the eye the defect of spherical aberration is counteracted also by the peculiar structure of the crystalline lens. This organ is composed of concentric layers whose density increases toward £he center. The result of this arrangement is that the center of the lens is more refractive than the periphery, and the tendency of the latter portion to refract more strongly is more or less neutralized. A third optical defect of the eye consists in the fact that its refractive surfaces are not absolutely centered, — that is, the centers of curvature of the cornea and of the anterior and the posterior surfaces of the lens do not lie in the same straight line. Moreover, the optical axis of the system does not coincide exactly with the line of sight. By the latter term we mean the line from the point looked at to the fovea centralis or the part of the fovea on which the image of the point falls. This line of sight or visual axis makes an angle of about five degrees with the optical axis. The system would be more perfect as an optical apparatus if the two axes coincided. Abnormalities in the Refraction of the Eye — Ametropia. — The eye that is normal and in which parallel rays focus on the retina when the eye is at rest is designated as emmetropic. Any abnormality in the refractive surfaces or the shape of the eyeball prevents this exact focusing of parallel rays and makes the eye ametropic. The most common refractive troubles of the eye are due to short-sightedness or myopia, far-sightedness or hyper- metropia, astigmatism, and old-sightedness or presbyopia. Some description of these conditions is useful to emphasize by contrast 314 THE SPECIAL SENSES. the mode of action of the dioptric mechanism in the normal eye, but for a full description of the extent and complexity of these defects reference must be made to special treatises upon the errors of refraction in the eye. In myopia or near-sightedness parallel rays of light are brought to a focus before reaching the retina. Consequently when the rays fall upon the retina each point forms a diffusion circle and the image is indistinct. This 'defect may be due to an abnormally great cur- vature of the refractive surfaces, the cornea or the lens, or to an ab- normal length of the eyeball in its anteroposterior diameter. The latter cause is the more common. The defect may be congenital, but usually it is acquired, and in the latter case its cause is generally attributed to a weakness in the coats of the eyeball. The interior of the eye is under some pressure, intra-ocular tension, which is estimated to be equal to the pressure of a column of mercury 25 to 30 mms. in height. This tension is increased by strong convergence of the eyeballs in looking at near objects. If the coats of the eye are weak or become so from disease or malnutrition they may yield somewhat to this pressure and the eyeball become lengthened in the anteroposterior diameter. The condition as regards refraction of parallel rays is represented then by the diagram B, in Fig. 132. The retina is farther away than the principal focal distance of the refractive surfaces, and if the defect is excessive even diverging rays may not be focused. The obvious remedy for such a condition is to use concave lenses before the eyes for distant vision. By this means, if the lenses are properly chosen, the rays will be given such an amount of divergence that the focus will be thrown back to the retina. As compared with the normal or emmetropic eye, the myopic eye has its far point of distinct vision — that is, the farthest point that can be seen distinctly without an effort of accommo- tion — less than twenty feet from the eye, the exact distance depend- ing upon the extent of the myopia. On the contrary, the near point of distinct vision — that is, the nearest point at which distinct vision can be obtained with the aid of the muscles of accommodation — is closer than in the normal eye. Much of the prevalent myopia in the young is attributed by oculists to bad methods in reading, such as insufficient lighting, small print, and a faulty position of the book. Such conditions lead to an excessive muscular effort and thus aggravate any tendency that exists toward the development of a near-sighted condition. In hypermetropic, the conditions are the opposite of those in myopia. Parallel rays of light after refraction in the eye cut the retina before they come to a focus. The principal focal distance, in other words, is behind the retina. In this case, also, each point DIOPTRICS OF THE EYE. 315 of a distant object will make upon the retina, when the eye is not accommodated, a diffusion circle, and the image consequently is blurred. This defect may be caused by a lessened curvature or refractive power in the cornea or lens, but in the majority of cases it is referable to a diminution in the anteroposterior diameter of the eyeball. This condi- tion is usually congenital: the eyeball from birth is smaller than the normal. The path of the parallel rays in this case is repre- sented in the diagram C, Fig. 132. When such an eye looks at a distant ob- ject a clear image may be obtained only by using the ciliary muscle, and to pre- vent this constant strain upon the muscle of accom- modation convex glasses must be worn. Glasses of this kind converge the rays and if properly chosen will bring parallel rays to a focus without the con- stant aid of accommoda- tion. It is obvious that in the hypermetropic eye there is no far point of distinct vision when the eye is at rest, since some accommodation must be used to bring even parallel rays to a focus. The near point of distinct vision will be farther away than in the normal eye. since accommodation begins when the rays are parallel and its limits are reached with a less degree of divergence; hence the name of far-sightedness. Presbyopia or old-sightedness has been referred to above. It is due to a gradual failure in the effectiveness of accommodation with increasing age, and is attributed usually to a progressive in- crease of rigidity in the lens. The near point of distinct vision recedes farther and farther from the eye. and consequently in close work convex glasses must be worn to aid the accommodation. It is obvious that this effect of old age will be less noticeable in the Fig. 132. — Diagram showing the difference be- tween normal (.4), myopic (B), and hypermetropic (C) eyes. In B and C the dotted lines represent the path of the rays after correction by glasses. — {Bow- ditch.) 316 THE SPECIAL SENSES. mvopic than in the emmetropic eye. since in the former the greater length of the eyeball requires less accommodation in near vision and the failure of the lens to refract is therefore not felt so soon What is known as second-sight in the old may be brought about by the late development of a myopic condition.- — that is. by a change in the length of the eyeball or by a swelling of the crystalline len-=. — and in such a case convex glasses for near work may be dispensed with. Astigmatism. — In a perfectly normal or ideal eye the refractive surfaces, cornea, anterior and posterior surfaces of the lens, are sections of true spheres, and, aU the meridians being of equal curvature, the refraction along these different meridians is equal. Such an eye will bring the cone of rays proceeding from a luminous point to a focal point on the retina, barring the disturbing influence of chromatic and spherical aberration. If, however, one or all of the refractive surfaces have unequal curvatures along different merid- ians, then it is obvious that the rays from a luminous point can not be brought to a focal point, since the rays along the meridian of greater curvature will be brought to a focus first and begin to diverge before the rays along the lesser curvature are focused. Such a condition is designated as astigmatism (from a, not, and ariytta, point). The effect may be illustrated by the diagram in Fig. 133, which represents the refraction of the rays from a luminous point by a planoconvex lens whose curvature along the vertical meridian is greater than along the horizontal meridian. The rays along the vertical meridian are brought to a focus first at G,but those from the horizontal meridian are still converging ; so that a screen placed at this point will give the image of a horizontal line {a-a'). The rays along the horizontal meridian are brought to a focus at B, but those from focus G have by this time spread out in a vertical plane, so that a screen placed at this point will give the image of a vertical line ih-c). In between the images will be elliptical or circular, as represented in the diagram. In the eye astigmatism may be due to an inequality in curvature of either the cornea or the lens, and may be either regular or irregular. By regular astigmatism is meant that condition in which while the curvature along each individual meridian is equal throughout its course, the curvatures of the different meridians vary and in such a way that the meridians of greatest and least curvature are at right angles to each other or approximately so. Ordinary astig- matism is of the regular variety, and is usually attributed to a defect in the curvature of the cornea. If the astigmatism is such that the vertical meridian has the greatest curvature it is termed "with the rule."' since usuallv this meridian is slightly more DIOPTRICS OF THE EYE. 317 curved than the horizontal one. If, on the contrary, the cur- vature along the horizontal meridian is greater, the astigmatism is "against the rule." The meridians of greatest and least curva- ture may not lie in the vertical and horizontal planes, but in some of the oblique planes; but so long as they are at right angles the astigmatism is regular. It is evident that such a condition may be corrected by the use of cylindrical lenses, so chosen as to in- crease the refraction along the meridian in which the cornea has the least curvature, in which case a convex or plus cylinder is used, or, on the other hand, to diminish appropriately the refraction along the meridian of greatest curvature, in which case a concave or minus cylinder is used. An eye that suffers from a marked Fig. 133. — Schema to illustrate the paths of the rays of light in a cornea showing regular astigmatism. — (McKendrick.) The lower line of figures represents the section of the cone of light, or the images obtained at different distances. The image varies from a horizontal to a vertical line, but at no place can a point be obtained at which rays along all meridians are focused. degree of astigmatism cannot focus distinctly at the same time lines that are at right angles to each other; hence the use of a series of lines whose images are formed along the different meridians of the eye, as shown in Fig. 134, will reveal this defect if it exists. If the eye is directed to the center of intersection of the lines some of the lines appear distinct while those at right angles to them are blurred. A normal eye can be thrown into an astigmatic con- dition by approximating the eyelids closely. In this position the tears make a concave cylindrical lens, which alters the curvature along the vertical meridian. What is known as irregular astig- matism is due to the fact that the meridians of greatest and least curvature are not at approximately right angles, or, as is more 318 THE SPECIAL SENSES. commonly the case, it is due to an irregularity in the curvature along some one meridian, such as may be produced by a scar upon the cornea. This condition may be produced from a variety of causes affecting either the cornea or the lens, and practically it can not be corrected by the use of lenses. As Helmholtz has shown, a small degree of irregular astigmatism is present nor- mally, owing to a certain asymmetry in the curvature of the lens. This defect is made apparent in the visual sensations caused by a point of light, such as is furnished, for instance, by a fixed star. The retinal image in these cases, instead of being a sym- metrical point, is a radiate figure the exact form of which may vary in different eyes. For this reason the fixed stars give us the well- known star-shaped image instead of a clearly defined point. Innervation and Physiological Control of the Ciliary Muscle and the Muscles of the Iris. — From an optical point of view the iris plays the part of a diaphragm. It is, moreover, an adjustable diaphragm the aperture of which — that is, the size of the pupil — is varied reflexly according to the conditions of illumination. Its adjustments are made possible by the fact that it contains within its substance two bands of muscular tissue, one, the sphincter muscle, forming a circular ring whose contraction diminishes the aperture of the pupil, and the other a dilator muscle whose contrac- tion widens the pupil. Each of these muscles possesses its own nerve fibers that arise ultimately from the brain, and through these fibers reflex movements of great delicacy are effected. The sphinc- ter pupillse is a well-defined band of plain muscle whose width varies, according to the state of contraction, from 0.6 to 1.2 mms.; it forms a ring lying just on the margin of the pupil, and it is im- bedded in the stroma of the iris. The histological differentiation of the dilator pupillae is much less distinct. For a long time its existence was the subject of controversy, but it is now conceded that such a muscle is present in the form of a layer of elongated spindle-like cells which lie close to the pigment layer of the iris and Fig. 134. — Astigmatic chart. DIOPTRICS OF THE EYE. 319 form radial bundles stretching from the ciliary border of the iris toward the pupillary orifice.* Both of these muscles are supplied by autonomic nerve fibers — that is, the motor nerve path comprises a preganglionic fiber, arising from the central nervous system, and a postganglionic fiber, arising from a sympathetic ganglion. Anatomically it can be shown that the sphincter muscle is supplied by the short ciliary nerves arising from the ciliary ganglion, which supply also the muscle of accommoda- tion, the ciliary muscle; while the dilator muscle is supplied by the long ciliary nerves that arise from the ophthalmic branch of the fifth cra- nial nerve, as represented in Fig. 135. The entire course of the motor paths, preganglionic and postganglionic fibers, is represented diagrammat- ically in Fig. 136. The motor fibers to the ciliary muscle and sphincter pupillse arise in the mid- brain in the nucleus of origin of the third cranial nerve, and indeed in a special part of this nu- cleus lying most ante- riorly. They leave the third nerve in the orbit and end within the sub- stance Of the Ciliarv San- Fis- 135— Diagrammatic representation of the , nerves governing the pupil fatter Foster): II, Optic gllOn, whence the path nerve; e.g, ciliary ganglion; r.b, its short root from . . . Ill, motor oculi nerve; sym., its sympathetic root ; rl, IS COntUlUed by SVmpa- its long root from V, ophthalmonasal branch of oph- ,i ,- / , f- ■ \ thalmic division of fifth nerve; s.c, short ciliary thetlC ( postganglionic ) nerves; l.c, long ciliary nerves. fibers emerging from the ganglion in the short ciliary nerves. The fibers to the dilator muscle have a very different path. They arise also in the brain, most probably in the midbrain, although their exact origin has not been determined satisfactorily, and pass down the spinal * For a physiological proof and the literature of the controversy see Langley and Anderson, "Journal of Physiology," 13, 554, 1S92. For the histological proof, Grunert, "Archives of Ophthalmology," 30, 377, 1901. Course of constrictor nerve fibers, Course of dilator nerve fibers,- - 320 THE SPECIAL SENSES. cord to terminate in the lower cervical region. From this point the path is continued by spinal neurons which leave the cord in the eighth cervical and the first and second thoracic spinal nerves and pass by way of the corresponding rami communicantes into the sympathetic chain at the level of the first thoracic ganglion. From this point the fibers pass upward in the cervical sympathetic with- out terminating until they reach the superior cervical ganglion near the base of the skull. From this ganglion the path is continued by sympathetic (postganglionic) fibers which pass to the Gasserian ganglion and unite with its ophthalmic branch. Subsequently they leave the ophthalmic nerve in the long ciliary branches. These fibers under normal conditions are in constant (tonic) activity, so that if the path is interrupted at any point— by section of the cervi- Gasserian *> — . Ophthalmic branch of 7SU, Lorn c diary nerves. Gallon-. Y > \ ^Dilator huftillae. Superior Cervical/ 6anqlion/'~7\ wfrinal Cord / SdCranial / Tie rue 'ifihin.eter joupillae. Cituuy Ganj lioiu ^ i'si:»"--- 1 610 CM KU 60S 590 SYS S5S ASS StO SOS M0 MB BCD E £ 4SO C Fig. 146. — Diagram showing the distribution of the intensity of the spectrum as de- pendent upon the degree of illumination. The spectrum is represented along the abscissa, the numerals giving the wave lengths from red, 670, to violet, 430. The ordinates give the luminosity of the different colors._ Eight curves are given to show the changes in distribution of relative brightness with changes in degree of illumination. _ With the greatest illumination the maximum brightness is in the yellow (605-625); with weaker illumination it shifts to the green (535). — (Konig.) of the different spectral colors is found to vary with the amount of illumination, as shown in the curves given in Fig. 146. With a brilliant spectrum the maximum brightness is in the yellow, but with a feeble illumination it shifts to the green. This fact accords PROPERTIES OF THE RETINA. 343 with what is known as the " Purkinje phenomenon," — namely, the changing luminosity and color value of colors in dim lights. As the light becomes more feeble the colors toward the red end of the spectrum lose their quality, the blue colors being perceived last of all, just as in late twilight it may be noticed that the sky remains distinctly blue after the colors of the landscape become indistin- guishable. It should be added that the " Purkinje phenomenon" is true only for the parts of the retina lying outside the fovea, that is, for the peripheral field. As the light grows dimmer the perception of blue is lost first in the fovea, so that with a certain feebleness of illumination the central field becomes blue-blind. With a very feeble illumination the dark-adapted eye becomes practically totally color blind. • Qualities of Visual Sensations. — The different qualities of our color sensations may be arranged in two series: an achromatic series, consisting of white and black and the intermediate grays, and a chromatic series, comprising the various spectral colors, together with the purples made by combination of the two ends of the spectrum, red and blue, and the colors obtained by fusion of the spectral colors with white or with black, such, for instance, as the olives and browns. The Achromatic Series. — Our standard white sensation is that caused by sunlight. Objects reflecting to our eye all the visible rays of the sunlight give us a white sensation. This sensation, therefore, is due primarily to the combined action of all the visible rays of the spectrum, each of which, taken separately, would give us a color sensation. White or gray may be produced also by the combined action of certain pairs of colors, — complementary colors, — as is described below. Black, on the contrary, is the sensation caused by withdrawal of light. It must be emphasized that in order to see black a retina must be present. It is probable that a person with both eyes enucleated has no sensation of darkness. That black is a sensation referable to a condition of the retina is made probable also by the interesting observations recorded by Gotch,* — namely, that when an eye that has been exposed to light is suddenly cut off from the light there is an electrical change in the retina, a dark response, similar to that caused by throwing light on a retina previously kept in the dark. Blackness, therefore, is a sensation produced by withdrawing light from the retina, and a black object is one that reflects no light to the eye. Black may be combined with white to produce the series of grays, and when com- bined with the spectral colors it gives a series of modified color tones, thus the olives of different shades may be considered as combina- tions of green and black in varying proportions. * Gotch, " Journal of Physiology," 29, 388, 1903. 344 THE SPECIAL SENSES. The chromatic series consists of those qualities to which we give the name of colors, and, as stated above, they comprse the spectral colors, and the extraspectral color, purple, together with the light- weak and light-strong hues obtained by combining the colors with white or black. In the spectrum many different colors may be detected, — some observers record as many as one hundred and sixty, — but in general we give specific names only to those that stand sufficiently far apart to represent quite distinct sensations, — namely, the red, orange, yellow, green, blue, and violet. When light is taken from a definite limited portion of the spectrum we have a monochromatic light that gives us a distinct color sensation varying with the wave length of the portion chosen. Color Saturation and Color Fusion. — The term saturation as applied to colors is meant to define their freedom from accompany- ing white sensation. A perfectly saturated color would be one entirely free from mixture with white. On the objective side it is easy to select a monochromatic bundle of rays from the spectrum without admixture of white light, but on the physiological side it is not probable that the color sensation thus produced is entirely free from white sensation, since the monochromatic rays may initiate in the retina not only the specific processes underlying the pro- duction of its special color, but at the same time give rise in some degree to the processes causing white sensations. Even the spectral colors are therefore not entirely saturated, but they come as near to giving us this condition as we can get without changing the state of the retina itself by previous stimulation. Color Fusion. — By color fusion we mean the combination of two or more color processes in the retina, this end being obtained by superposing upon the same portion of the retina the rays giving rise to these color processes. It must be borne in mind that color fusion upon the retina is quite a different thing from color mixture as practised by the artist. A blue pigment, such as Prussian blue, for instance, owes its blue color to the fact that when sunlight falls upon it the red-yellow rays are absorbed and only the blue, with some of the green, rays are reflected to the eye. So a yellow pig- ment, chrome yellow, absorbs the blue, violet, and red rays and reflects to the eye only the yellow with some of the green rays. A mixture of the two upon the palette will absorb all the rays except the green and will therefore appear green to the eye. If, however, by means of a suitable device, we throw simultaneously upon the retina a blue and a yellow light, the result of the retinal fusion is a sensation of white. Many different methods have been employed to throw colors simultaneously upon the retina, the most perfect being a system of lenses or mirrors by which different portions of PROPERTIES OF THE RETIXA. 345 a spectrum can be superposed. The usual device employed in laboratory" experiments is that of rotation of discs of colored paper. Each disc has a slit in it from center to periphery so that two discs can be fitted together to expose more or less of each color. If a combination of this kind is attached to a small electrical motor it can be rotated so rapidly that the impressions of the two colors upon the retina follow at such a short interval of time as to be prac- tically simultaneous. The Fundamental Colors. — By the methods of color fusion it can be shown that three colors may be selected from the spec- trum whose combinations in different proportions will give white, •or any of the intermediate color shades, or purple Considered purely objectively, a set of three such colors may be designated as the fundamental colors, and red, yellow, and blue, or red, green, and violet have been the three colors selected. On the physiological side, however, it has been assumed that there are certain more or less independent color processes — photochemical processes — in the retina which give us our fundamental color sen- sations, and that all other color sensations are combinations of these processes in varying proportions with each other or with the proc- esses causing white and black. Referring only to the colors proper, the fundamental color sensations according to some views are red, green, and blue or violet; according to others, they are red, yellow, green, and blue. (See paragraph on Theories of Color Vision.) Helmholtz calls attention to the fact that the names used for these funda- mental color sensations are obviously of ancient origin, thus indicating that the difference in quality of the sensations has been long recognized. Red is from the Sanskrit rudhira, blood; blue from the same root as blow, and re- fers to the color of the air ; green from the same root as grow, referring to the color of vegetation. Yellow seems to be derived from the same root as gold, which typified the color. The other less distinct qualities have names of Tecent application, such as orange, violet, indigo blue, etc. Complementary Colors. — It has been found by the methods of color fusion that certain pairs of colors when combined give a white (gray) sensation. It may be said, in fact, that for any given color there exists a complement such that the fusion of the two in suitable proportions gives white. If we confine ourselves to the spectral colors we recognize such complementary pairs as the following: Red and greenish blue. Orange and cyan blue. Yellow and indigo blue. Greenish yellow and violet. The complementary color for green is the extraspectral purple. Colors that are closer together in the spectral series than the 346 THE SPECIAL SENSES. complementaries give on fusion some intermediate color which is more saturated — that is, less mixed with white sensation — the nearer the colors are together. Thus, red and yellow, when fused, give orange. Colors farther apart than the distance of the comple- mentaries give some shade of purple. On the physical side, there- fore, we can produce a sensation of white in two ways : Either by the combined action of all the visible rays of the spectrum (sunlight) or by the combined action of pairs of colors whose wave lengths vary by a certain interval. It is probable that in the retina the processes induced by these two methods are qualitatively the same, the wave-lengths represented by the complementary colors setting up by their combined action the same photochemical processes that normally are induced by the sunlight. After-images. — As the name implies, this term refers to images that remain in consciousness after the objective stimulus has ceased to act upon the retina. They are due doubtless to the fact that the changes set up in the retina by the visual stimulus continue, with or without modification, after the stimulus is withdrawn. After- images are of two kinds: positive and negative. In the positive after-images the visual sensation retains its normal colors. If one looks at an incandescent electric light for a few seconds and then closes his eyes he continues to see the luminous object for a con- siderable time in its normal colors. Objects of much less inten- sity of illumination may give positive after-images, especialy when the eyes have been kept closed for some time, as, for instance, upon waking in the morning. In negative after- images the colors are all reversed — that is, they take on the complementary qualities (see Fig. 147). White becomes black, red, a bluish green, and vice versa. Negative after-images are produced very easily by fixing the eyes steadily upon a given object for an interval of twenty seconds or more and then closing them. In the case of colored objects the after- image is shown better, perhaps, by turning the eyes upon a white surface after the period of fixation is over. After-images produced in this way often appear and disappear a number of times before ceasing entirely, and, although the color at first is the complementary of that of the object looked at, it may change before its final disappearance. Anyone who has gazed for even a brief interval at the setting sun will remember the number of colored and changing after-images seen for a time when the eye is turned to another portion of the sky. That several different after-images are seen in this case is due to the fact that the eyes are not kept fixed under the dazzling light of the sun, and a number of different images are formed, therefore, upon the retina. -M ?lo ^ 3 TO I 2 £.*» c '""3.P o o ,3P"cd ioi«22Mo o a M._«j s g „. E*co _- CT t^ B" K m 2,3 5-tt> £.3, Si P » TO „, g 3 O -! 2 ffl 3*» a -1- a- p |^|| S p a G. S'.'o to 2 »&"!» ^a,M sfS 5'p ^to'i 2. ». '< CD C 1 2,0 0 -% g to ? 2, £TO P § rt-2,^'2 s'ffi g a" , red, and green compared with white (gray). Right eye: The outlines of the color fields are repre- sented as smooth since the chart is an average from many determinations. As a matter of fact, in each individual the outline is highly irregular. Normally green (bright green) is the smallest field, green objects outside the limit appearing yellow and farther out colorless (gray). the different fields usually show many irregularities, and in some cases it will be found that bright green is perceived over a larger area than the red. The fields are not identical in the two eyes, and in each eye it is, as a rule, more extensive upon the nasal than upon the temporal side of the retina. In the red-green blind the peripheral fields of color vision, judged by the individual's own standards, may be markedly constricted as compared with the nor- mal retina (see Fig. 151). Functions of the Rods and Cones. — Many facts unite in mak- ing it probable that the rods and cones are different in function. They differ in structure and especially in their connections. As is shown in the diagram given in Fig. 152, the cones terminate in the external nuclear layer in arborizations which connect with the bi- polar ganglion cells, and in the fovea at least this connection is such •It is interesting to find (Haycraft) that around the blind spot there is a small zone which, like the periphery of the retina, is completely color-blind. that is, perceives only gray, and external to this the color sense is developed in zones whose order is similar to that on the periphery of the retina, PROPERTIES OF THE RETINA. 353 that each cone connects with a single nerve cell and eventually per- haps with a single optic nerve fiber. The rods, on the contrary, end in a single knob-like swelling, and a number of them make con- nections with the same nerve cell. Histologically, therefore, the Fig. 151. — Perimeter chart showing the highly restricted color fields in the left eye of a typical case of so-called red-green color blindness. The ability to distinguish red and green, by whatever characteristics of intensity or color they possessed extended for a very short distance outside the fovea. It is interesting that the ability to distinguish blue was in this case limited as compared with a normal eye. conduction paths for the cones seem to be more direct than in the case of the rods. These latter elements, moreover, possess the visual purple, which is lacking in the cones. Lastly, in the eye of the totally color blind, in the dark-adapted eye in dim lights, in the color-blind peripheral area of the normal eye, and in the eyes of most distinctly night-seeing animals, such as the mole and the owl, vision seems to be effected solely by the rods. These facts find their simplest explanation perhaps in the view advocated by Pari- naud, Franklin, von Kries,* and others, according to which the perception of color is a function of the cones alone, while the rods are sensitive only to light and darkness, and by virtue of their power of adaptation in the dark through the regeneration of their visual purple, they form also the special apparatus for vision in dim * Von Krie«, " Zeitschrift f . Psyehologie u. Physiol, d. Sinnesorgane," 9, 81, 1895. 23 354 THE SPECIAL SENSES. lights (night vision). Color blindness, therefore, whether total or partial, may be regarded as an affection or lack of normal develop- ment of the cones. On the other hand, those interesting cases in Fig. 152. — Schema of the structure of the human retina (Greeff): I, Pigment layer; //, rod and cone layer; ///, outer nuclear layer; IV, external plexiform layer; V, layer of horizontal cells; VI, layer of bipolar cells (inner nuclear) ; VII, layer of amacrinal cells (without axons); VIII, inner plexiform layer; IX, ganglion cell layer; X, nerve fiber layer; 6, fiber of Muller. which the vision, while good in daylight, is faulty or lacking in dim lights (night blindness, hemeralopia) may be referred to a defective functional activity of the rods, probably from lack of formation of visual purple. Theories of Color Vision. — A number of theories have been proposed to explain the facts of color vision. None of them has been entirely successful in the sense that the explanations it affords PROPERTIES OF THE RETINA. 355 have been submitted to satisfactory experimental verification. The immediate stimuli that give rise to the visual impulses are assumed to be of a chemical nature, and it seems probable that in this case as in that of many other problems of physiology, we must await the development of a more complete knowledge of the chemical processes involved. The theories proposed at present, while all tested by experimental inquiries, are in a large measure hypotheses constructed to fit more or less completely the facts that are known. Three of these theories may be described briefly as examples of the modes of reasoning employed: /. The Young-Helmholtz Theory. — This theory, proposed essen- tially by Thomas Young (1807) and afterward modified and ex- panded by Helmholtz,* rests upon the assumption that there are three fundamental color sensations, — red, green, and violet — and corresponding with these there are three photochemical substances in the retina. By the decomposition of each of these substances cor- responding nerve fibers are stimulated and impulses are conducted to a special system of nerve cells in the visual center of the cerebrum. The theory, therefore, assumes special nerve fibers and nerve centers corresponding respectively to the red, green, and violet photo- chemical substances, and the peculiar quality of the resulting sensa- tions are referred, in the original theory, to the different reactions in consciousness in the three corresponding centers in the brain. When these three substances are equally excited a sensation of white results, of greater or less intensity according to the extent of the excitation. White, therefore, on this theory, is a compound sensation produced by the combination or fusion in consciousness of the three equal fundamental color sensations. The sensation of black, on the other hand, results from the absence of stimulation, from the condition of rest in the retina and in the corresponding nerve fibers and nerve centers. All other color sensations — yellow, for instance — are compound sensations produced by the combined stimulation of the three photochemical substances in different propor- tions. It is assumed, furthermore, that each of the photochemical substances is acted upon more or less by all of the visible rays of the spectrum, but that the rays of long wave lengths at the red end of the spectrum affect chiefly the red substance, those corresponding to the green of the spectrum chiefly the green substance, and the rays of shortest wave length chiefly the violet substance. These rela- tionships are expressed in the diagram given in Fig. 153) The figure also indicates that it is impossible to stimulate any one of these sub- stances entirely alone, — that is, we cannot obtain a perfectly satu- rated color sensation. Even the extreme red or the extreme violet * Helmholtz, "Handbuch der physiologisehen Optik," second edition, 1896, I, 344. 356 THE SPECIAL SENSES. rays act more or less on all of the substances, and the resulting red or violet sensation, is, therefore, mixed to some extent with white, — that is, is not entirely saturated. The theory, as stated by Helm- holtz, held strictly to the doctrine of specific nerve energy, in assuming that each photochemical substance serves simply as a means for the excitation of a nerve fiber, and that the quality of the sensation aroused depends on the ending of this fiber in the brain. The phe- nomenon of negative after-images finds a simple explanation in terms of this theory. If we look fixedly at a green object, for example, the corresponding photochemical substance is chiefly acted upon, and if subsequently the same part of the retina is exposed to white light, the red and violet substances, having been previously less acted upon, now respond in greater proportions to the white light, and Fig. 153. — Schema to illustrate the Young-Helmholtz theory of color vision. — (Helm- holtz.) The spectral colors are arranged in their natural order, — red to violet. The curves represent the intensity of stimulation of the three color substances: 1, The red perceiving substance; 2, the green perceiving; 3, the violet perceiving. Verticals drawn at an*' point of the spectrum indicate the relative amount of stimulation of the three substances for that wave length of the spectrum. the after-image takes a red- violet — that is, purple — color. Many objections have been raised to the Young-Helmholtz theory. It has been urged, for instance, that we are not conscious that white or yellow sensations are blends or compounded color sensations; we perceive in them none of the supposed component elements as we do in such undoubted mixtures as the blue-greens or the purples. The theory explains poorly or not at all the fact that on the periphery of the retina we are color blind and yet can perceive white or gray, and it breaks down also in the face of the facts of partial and com- plete color blindness. The explanation given for black is also unsatisfactory in that it assumes an active state of consciousness associated with a condition of rest in the visual mechanism. 77. Hering's Theory of Color Vision. — This theory also assumes the existence in the retina of three photochemical substances, but of such a nature as to give us six different qualities of sensation. There is a white-black substance which when acted upon by the PROPERTIES OF THE RETINA. 357 visible rays of light undergoes disassimilation and sets up nerve impulses that arouse in the brain the sensation of white. On the other hand, when not acted upon by light this same substance under- goes assimilatory processes that in turn set up nerve impulses which in the brain give us a sensation of black. There are in the retina also a red-green and a yellow-blue substance. The former when acted upon by the longer rays undergoes disassimilation and gives a sensation of red, while the shorter waves cause assimilation and produce a sensation of green. A similar assumption is made for the yellow-blue substance. The essence of the theory may be stated, therefore, in tabular form, as follows *: Photochemical Substance. ■p, j ( Disassimi Red-green \ Assimilat Yellow-blue Retinal Process. Sensation. Disassimilation = red ion = green / Disassimilation = yellow l Assimilation = blue Tm--.i. iii / Disassimilation = white White-black ( Assimilation = black It will be observed that the theory gives an independent ob- jective cause for the sensations of white, black, and yellow, and in Fig. 154. — Schema to illustrate the Hering theory of color vision. — (Foster.) The curves indicate the relative intensities of stimulation of the three color substances by dif- ferent parts of the spectrum. Ordinates above the axis, X-X, indicate catabolic changes (disassimilation), those below anabolic changes (assimilation). Curve a represents the conditions for the black-white substance. It is stimulated by all the rays of the visible spectrum with maximum intensity in the yellow. Curve c represents the red-green sub- stance, the longer wave lengths causing disassimilation (red) , the shorter ones assimilation (green). Curve b gives the conditions for the yellow-blue substance. this respect satisfies the objections made on this score to the Young- Helmholtz theory. It fits better, also, the facts of partial and total color blindness. In the latter condition one may assume, in terms of * For discussion of color theories see Calkins, "Archiv f. Physiologie," 1902, suppl. volume, p. 244; also Greenwood in Hill's " Further Advances in Physiology," p. 378, 1909. 358 THE SPECIAL SENSES. this theory, that only the white-black substance is present, while red and green blindness — both of them, it will be recalled, really forms of red-green blindness — are explained on the view that in such persons the red-green substance is deficient or lacking. On this theory, complementary colors — red and blue-green, yellow and blue — are, in reality, antagonistic colors. When thrown on the retina simultaneously their effects neutralize each other, and there remains over only the disassimilatory effect on the white substance which is exerted by all the visible rays. The effect of the vari- ous visible rays of the spec- trum on the three photo- chemical substances is illus- trated by the chart given in Fig. 154. Ordinates above the abscissa representing dis- assimilatory effects; those below, assimilatory. HI. The Franklin Theory of Color Vision {Molecular Dissociation Theory) .—This theory, proposed by Mrs. C. L. Franklin,* takes into ac- count the fact of a gradual evolution of the color sense of the retina from a primitive condition of colorless vision such as still exists in the periphery of the retina and in the eyes of the totally color blind. It assumes that the colorless sensations — white, gray, black — are occa- sioned by the reactions of a photochemical material which for convenience may be designated as the gray substance. This substance in the normal eye exists in both rods and cones; in the latter, however, in a differentiated condition capable of giving color sensations. When the molecules of this substance are completely dissociated by the action of light, gray * Franklin, " Zeitschrift f. Psychologie und Phys. d. Sinnesorgane," 1892, iv; also "Mind," 2, 473, 1893, and " Psychological Review," 1894, 1896, 1899. Fig. 155. — Schema to illustrate the Frank- lin theory of color vision (Franklin) : W, The molecule of the primitive visual (gray-perceiv- ing) substance; Y and B, the first step in the differentiation into a yellow- and a blue-per- ceiving substance, whose combined dissociation gives the same effect as that of the original sub- stance, W ; G and R, the second step in the differentiation of the yellow-perceiving sub- stance, the combined dissociation of the two giving the same effect as that of the yellow-per- ceiving substance alone. The complete devel- opment of color vision as it exists in the central part of the retina consists in the existence of three substances, which, taken separately, give red, green, and blue color sensations. PROPERTIES OF THE RETINA. 359 sensations result, and as this is the only reaction possible in the rods these elements can furnish us only sensations of this quality. The molecules of gray substance in the cones, on the other hand, have undergone a development such that certain portions only of the molecule may become dissociated by the action of light of certain periods of vibration. This development may be sup- posed to have taken place in two stages: first, the formation of two groupings within the molecule, one of which is dissociated by the slower waves and gives a sensation of yellow, and one of which is dissociated by the more rapid waves and gives the sensation of blue. This stage remains still on portions of the periphery of the retina, and is the condition present in the fovea also in the eyes of the red-green blind. The second stage consists in the division of the yellow component into two additional groupings in one of which the internal movements are of such a period as to be affected by the longest visible waves, the red of the spectrum, while the other is dissociated by rays corresponding to the green of the spectrum and gives rise to the sensation of green. If the red and green groupings are dissociated together the resulting effect is the same as follows from the dissociation of the entire yellow component, while the complete dissociation of the red, green, and blue groupings gives the stimulus obtained originally from the disso- ciation of the whole molecule, and causes gray sensations. The idea of this subdivision or differentiation in structure of the original gray substance is indicated diagrammatically in Fig. 155. The theory accounts admirably for many phenomena in vision, and is perhaps especially adapted to explain the facts of color blindness and the variations in quality of our visual sensations in the peripheral areas of the retina. An extension and modification of this theory has been published by Schenck.* He assumes that each of the three-color perceiving substances is composed of two parts. One part which acts as a receiver for the stimulus, a sort of an optical resonator, in fact, and a second part which is set into activity by the receiver and gives rise to the corresponding color sensation. The theory is very elastic in its adaptability to the various kinds of color blindness. The two latter theories seem to imply that a number of different kinds of impulses may be transmitted along the optic fibers. Hering's theory re- quires apparently the possibility of six qualitatively different impulses, — ■ namely, white, black, red, green, yellow, and blue, — while the Franklin theory assumes impulses corresponding to white (gray), red, green, yellow, and blue. Black is not specifically accounted for except as a part of the gray series. At present in physiology there is no proof that nerve impulses can differ quali- tatively from each other, although it may be urged, perhaps with equal force, that there is no proof that they can not so differ. The doctrine of specific nerve energy assumes that nerve impulses are, as regards quality, always * Schenck, "Archiv f. d. gesammte Physiologie, " 118, 129, 1907. 360 THE SPECIAL SENSES. the same, and differ from one another only in intensity, the qualitative differ- ences that exist among sensations being referred to a difference in reaction in the end-organ in the brain. Entoptic Phenomena. — Under the term entoptic phenomena is included a number of visual sensations due to the shadows of various objects within the eyeball itself. Ordinarily these shadows are imperceptible, owing to the diffuse illumination of the interior of the eye through the relatively wide opening of the pupil. By means of various devices the illumination of the eye may be so controlled as to make these shadows more distinct and thus bring the retinal images into consciousness. Some of these entopic ap- pearances are described briefly, but for a detailed description the reader is referred to the classical work of Helmholtz.* The Blood-corpuscles. — The entoptic images that are most easily recognized perhaps are those of the moving corpuscles in the capil- laries of the retina. If one looks off into the blue sky he will have no difficulty in recognizing a number of minute clear and dark specks that move in front of the eye in definite paths. The character of the movement leaves no doubt that these sensations are due to the shadows of the blood-corpuscles. In fact, the shadows often show a rhythmic acceleration in velocity synchronous with the heart- beats, a pulse movement. By projecting the moving images upon a screen at a known distance from the eye the velocity of the capil- lary circulation has been estimated in man. The Retinal Blood-vessels. — The blood-vessels of the retina lie in front of the rods and cones and must necessarily throw their shadows upon these sensitive end-organs. The shadows may be made more distinct and a visual picture of the vessels obtained by a number of methods. For instance, if a card with a pin hole through it is moved slowly in front of the eye the images of the blood-vessels stand out in the field of vision with more or less distinctness. The card should be given a circular movement. If it is kept in one position the images quickly disappear, since the retina apparently fatigues very quickly for such faint impressions. A more impressive picture may be obtained by the method of Purkinje. In a dark room one holds a candle toward the side of the head in such a position as to give the sensation of a glare in the corresponding eye. If the eye is directed toward the opposite side of the room and the candle is kept in continual circular movement the blood-vessels appear in the field of vision magni- fied in proportion to the distance of projection; the picture makes the impression of a thicket of interlacing branches. In this ex- periment the light from the candle strikes the nasal side of the * Helmholtz, "Handbuch der physiologischen Optik," second edition, I, 184. PROPERTIES OF THE RETINA. 361 retina at an oblique angle and is reflected toward the other side of the globe. The blood-vessels are in this way illuminated from an unusual direction and their shadows are thrown upon a por- tion of the retina not usually affected and for that reason perhaps more sensitive to the impression. Imperfections in the Vitreous Humor and the Lens. — Small frag- ments of the cells from which the vitreous humor was constructed in the embryo and simi- lar relatively opaque ob- jects in the lens may throw shadows on the retinal bottom. These shadows take different forms, but usually are de- scribed as small spheres or beads, single or in groups, that move with the eyes and are desig- nated, therefore, as the muscae volitantes (flitting flies or floating flies). To bring out these shadows it is convenient to make the source of illu- mination small and to bring it at or nearer than the anterior focal distance of the eye (15 to 16 mms.). The method employed for this purpose by Helmholtz is illustrated in Fig. 156. In this figure b is a candle flame, and a a lens of short focus which makes an image of the flame at the small opening shown in the dark screen, c. The eye is placed just behind this opening and is illuminated by the rays from the small, bright image of the flame at that spot. The shadows are seen projected upon the illuminated surface of the glass lens. Fig. 156. — Helmholtz's method of showing en- toptic phenomena due to imperfections in the lena and vitreous {Helmholtz): c, a screen with pinhole; a, lens with short focus. CHAPTER XIX. BINOCULAR VISION. Vision with two eyes differs from monocular vision chiefly in the varied combinations of movements of the two eyeballs and the aid thereby afforded in the determination of distance and size, in the enlarged field of vision, and, above all, in the more exact per- ception of solidity or perspective, especially for near objects. The Movements of the Eyeballs. — Each eyeball is moved by six extrinsic muscles which are innervated through three cranial nerves. The third or oculomotor nerve controls the internal rectus, the superior rectus, the inferior rectus, and the inferior oblique; the fourth cranial nerve (n. patheticus) innervates the superior oblique alone; and the sixth cranial (n. abducens) the external rectus alone. By means of these muscles the eyeballs may be given various movements, all of which may be considered as rotations of the ball around various axes. The common point of intersection of these axes is designated as the rotation point or center of rotation of the eyeball; it lies about 13.5 mms. back of the cornea in the emmetropic eye. The various axes of rotation all pass through this point, and we may classify them under four heads: (1) The horizontal or sagittal axis, which is the line passing through the rotation point and the object looked at, — the fixation point. This axis corresponds practically with the line of sight, — that is, the line drawn from the object looked at to the middle of the fovea, and it may therefore, without serious error, be spoken of as the visual axis. Rotations around this axis give a wheel movement or torsion to the eyeballs. (2) The transverse axis, the line passing through the rotation points of the two eyes and perpendicular to 1. Rotations around this axis move the eyeballs straight up or down. (3) The vertical axis, the vertical line passing through the rotation point and perpendicular at this point to the horizontal and transverse axes. Rotations around this axis move the eyeball to the right or the left. (4) The oblique axes, under which are in- cluded all the axes of rotation passing through the rotation point at oblique angles to the horizontal axis. These axes all lie in the equatorial plane of the eye, and rotations around any of them move the eyeball obliquely upward or downward. These definitions all have reference to what is known as the primary position of the 362 BINOCULAR VISION. 363 eyes, — that is, that position taken by the eyes when we look straight before us toward the horizon, — a position, therefore, in which the plane of the horizontal axes is parallel to the ground; all other positions of the eyes are spoken of as secondary. With regard to the movements of the eyes about its axes of rotation the following general statements are made: Starting from the primary position, rotations of the eyes about the vertical axis — that is, movements directly to right or left — may be made by the contraction of the internal or the external rectus as the case may be. Rotations around the transverse axis — that is, movements directly up or down — require in each case the co-operation of two muscles. In movements upward the superior rectus, acting alone, would in Fig. 157.— Diagram showing for the left eye the paths of the line of sight caused by the action of the different eye-muscles (Hering). The horizontal line indicates movements out or in to various degrees as caused by the contraction of the internal or external rectus. The curved lines show the amount of torsion given the eyeball by the superior and inferior rectus and the superior and inferior oblique when contracting separately. Tne short heavier line at the end of the paths indicates the position of the horizontal meridian at the end of the movement." R. e., the external rectus; R, i., the internal rectus; R. S., the superior rectus; R. inf., the inferior rectus; O. i., the inferior oblique; O. S., the superior rotating the eyeball upward also give it a slight torsion so as to turn the upper part of the vertical meridian inward. To obtain a movement directly upward (rotation around the transverse axis) the superior rectus and inferior oblique must act together. For a similar reason rotation directly downward requires the com- bined action of the inferior rectus and superior oblique. These facts are expressed clearly in Hering' s diagram, reproduced in Fig. 157, which indicates the paths traversed by the line of sight when the eyeball is moved by the different muscles acting sepa- rately. Rotation of the eyeballs around oblique axes require the co-operation of three of the muscles : movements upward and outward — the superior rectus, inferior oblique, and external rectus; movements upward and inward — superior rectus, inferior 364 THE SPECIAL SENSES. oblique, and internal rectus; movements downward and outward — inferior rectus, superior oblique, and external rectus; movements downward and inward — inferior rectus, superior oblique, and internal rectus. Most of the movements of the eyes are of the latter kind, — namely, rotations around an oblique axis, — and the position of the axis for each definite movement of this character may be determined by Listing's law, which may be stated as follows : When the eye passes from a primary to a secondary position it may be considered as having rotated around an axis perpendicular to the lines of sight in the two positions. It will be noted readily from observations upon the movements of one's own eyes that they ordinarily make only such movements as will keep the lines of sight of the two eyes parallel or will converge them upon a common point. In movements of convergence the internal recti of the two eyes are associated, while in symmetrical lateral movements the internal rectus of one eye acts with the external rectus of the other. Under normal conditions it is impossible for us to diverge the visual axes,— that is, to associate the action of the external recti. A movement of this kind would produce useless double vision (diplopia), and it is, therefore, a kind of movement which all of our experience has trained us to avoid. The Co-ordination of the Eye Muscles — Muscular Insuf- ficiency— Strabismus. — In order that the eyeballs may move with the minute accuracy necessary in binocular vision, a beautifully balanced or co-ordinated action of the opposing muscles is neces- sary. The object of these movements is to bring the point looked at in the fovea of each eye and thus prevent double vision, diplopia (see following paragraphs). This object is attained when the eye- balls are so moved that the lines of sight unite upon the object or point looked at. In viewing an object or in reading we keep readjusting the eyes continually to bring point after point at the junction of the lines of sight. When we look before us at a distant object the muscles in each eye should be so adjusted that without any contraction the antagonistic muscles will just balance each other — that is, when the eye muscles are entirely relaxed, except for their normal tone, the visual axes should be parallel. If this balance does not exist, we have a condition designated as heterophoria. In this condition a constant contraction of one or more muscles is required, even in far vision, to prevent diplopia. When the eye at rest shows a tendency to drift toward the temporal side, owing to the fact that the pull of the external rectus overbalances that of the internal rectus, the condition is known as exophoria. If, for the opposite reason, there is a tendency to drift to the nasal side, the condition is described as esophoria. A tendency to drift up or down is called hyperphoria, and this is further specified as right BINOCULAE VISION. 365 or left hyperphoria according to the eye whose axis deviates upward. A lack of resting balance of this kind will make itself felt also in near work, particularly in reading, sewing, etc., since it will require a constantly greater innervation of the muscle whose antagonist overbalances it. Under some conditions the resulting muscular strain causes much uneasiness or distress. The heterophorias are easily detected and measured by the use of prisms, but they do not show the same constancy as the refractive errors of the eye, owing probably to the fact that they involve the variable factor of muscular tonus. The defect may be remedied by surgical operations upon the muscles or by the use of proper prisms with their bases so adjusted as to help the weaker muscle. In exophoria, for example, the greater pull of the external rectus rotates the front of the eye outward, while the back of the eye with the fovea is moved inward toward the nose. A prism of the proper strength placed before the eye with its base in toward the nose will throw the image of an external object on the fovea where it is, without necessitating a contraction of the internal rectus to bring the fovea back into its normal position. When the lack of balance between the opposing muscles is so great that the visual axes cannot by muscular effort be brought to bear upon the same points, we have the condition of squint or strabismus. Such a condition may result from a deficiency in strength or in actual paralysis of one or more of the muscles, or from an overaction in some of the muscles as contrasted with their antagonists. The Binocular Field of Vision. — When the two eyes are fixed upon a given point, placed, let us say, in front of us in the median plane, each eye has its own visual field that may be charted by means of the perimeter. But the two fields overlap for a portion of their extent, and this overlapping area constitutes the field of binocular vision (see Fig. 158). Every point in the bin- ocular field forms an image upon the two retinas. The most interesting fact about the binocular field is that some of the objects contained in it are seen single in spite of the fact that there are two retinal images, while others are seen or may be seen double when one's attention is directed to the fact. Whether any given object is seen single or double depends upon whether its image does or does not fall upon corresponding points in the two retinas. Corresponding or Identical Points. — By definition corre- sponding or identical points in the two retinas are those which when simultaneously stimulated by the same luminous object give us a single sensation, while non-corresponding points are those which when so stimulated give us two visual sensations. It is evident, from our experience, that the foveae form corresponding points or areas. When we look at any object we so move our eyes that the 366 THE SPECIAL SENSES. images of the point observed shall fall upon symmetrical parts of the two fovese; the lines of sight of the two eyes converge upon and meet in the point looked at. If, while observing an object, we press gently upon one eyeball with the end of the finger, two images are seen at once, and they diverge farther and farther from each other as the pressure upon the eyeball is increased. Experiment shows, also, that, in a general way, portions of the retina symmetrically placed to the right side of the fovese in the two eyes are cor- responding, and the same is true for the two left halves and the two upper and lower halves. The right half of the retina in one eye is non-corresponding to the left half of the other retina, and vice * 061 081 OUV Fig. 158. — Perimeter chart to show the extent of the binocular visual field (shaded area) when the eyes are fixed upon a median point in the horizontal plane. versa; and the same relation is true of the upper and lower halves, respectively. If we imagine one retina to be lifted without turning and laid over the other so that the fovea? and vertical and horizontal meridians coincide, then the corresponding points will be superposed throughout those portions of the retina that represent the binocular field. This statement, however, is theoretical only; an exact point to point correspondence has not been determined experimentally. Experiments have shown, however, that the corresponding points in the upper halves of the retinas along the vertical mid-line do not cover each other, that is, they do not lie in the actual anatom- ical vertical meridian, but form two meridians which diverge BINOCULAR VISION. 367 symmetrically from the mid-line so as to make an angle of about 2 degrees (physiological incongruence of the retinas). Within the limits of our powers of observation for ordinary objects we may adopt Tscherning's rule, — namely, that when the images of an object on the two retinas are projected to the same side of the point of fixation they are seen single, their retinal images in this case falling on the retina to the same side of the lines of sight; when, however, the retinal images fall on opposite sides of the lines of sight and are projected to opposite sides of the point of fixation, they are seen double. The doubling of objects that do not fall on corresponding points (physiological diplopia) is most readily demonstrated for objects that lie between the lines of sight, either closer or farther away than the object looked at. If, for instance, one holds the two forefingers in front of the face, in the median plane, one hand being at about the near point of distinct vision and the other as far away as possible, it will be noticed that when the eyes are fixed on the far finger the near one is seen double and vice versa. In this, as in other experiments in which the eyes are accommodated for One object while the attention is directed to another, some difficulty may be experienced at first in disso- ciating these two acts which normally go together, but a little practice will soon enable one to distinguish clearly the doubling of the point upon which the lines of sight are not converged. If a long stick is held horizontally in front of the eyes the end near the face will be doubled when the eyes are directed to the far end and vice versa. Moreover, by a simple experiment it may be shown that objects nearer the eyes than the point looked at are doubled heteronymously, — that is, the right-hand image be- longs to the left eye and the left-hand one to the right eye. This is easily demonstrated by closing the eyes alternately and noting which of the images disappears. The reason for the cross-projec- tion of the images is made apparent by the construction in Fig. 159, J, bearing in mind the essential fact that in projecting our retinal images we always project to the plane of the object upon which the eyes are focused. In the figure the eyes are converged on A ; the images of point B fall to opposite sides of the line of sight and are seen double and are projected to the plane of A, the image on the right eye being projected to b' on the left of A and that on the left eye to b on the right of A. In a similar way it may be shown that ob- jects farther away from the eye than the point looked at are doubled homonymously, — that is, the right-hand image belongs to the right eye, and the left-hand one to the left eye. The fact is explained by the construction in Fig. 159, II, in which A is the point converged upon and B the more distant object. In all binocular vision, there- fore, the series of objects between the eye and the point looked at are 368 THE SPECIAL SENSES. doubled heteronymously, and those extending beyond the point in the same line are doubled homonymously. Normally we take no conscious notice of this fact, our attention being absorbed by the object upon which the lines of sight are directed. Some physi- ologists, however, have assumed that the knowledge plays an im- portant part subconsciously in giving us an idea of depth or per- spective,— an immediate perception, as it were, of the distinction between foreground and background. It is usually assumed that the explanation of corresponding points is to be found in the anatomical arrangement of the optic nerve fibers. Those from the right halves of the two retinas, which are corresponding halves, unite in the Fig. 159. — Diagrams to show homonymous and heteronymous diplopia: In / the eyes are focused on A; the images of B fall on non-corresponding points, — that is, to_ different sides of the fovea;, — and are seen double, being projected to the plane of A, giving heter- onymous diplopia. In // the eyes are focused on the nearer point, A, and the farther point, B, forms images on non-corresponding points and is seen double, — homonymous diplopia, — the images being projected to the focal plane A. right optic tract and are distributed to the right side of the brain, while the fibers from the left halves go to the left side of the brain. The basis of the single sensation from two visual images is to be found probably in the fact that the cerebral terminations through which the final psychical act is mediated lie close together or possibly unite. The Horopter. — In every fixed position of the eyes there are a certain number of points in the binocular field which fall upon corresponding points in the two retinas and are therefore seen single. The sum of these points is designated as the horopter for that position of the eyes. It may be a straight or curved line, or a plane or curved surface. Helmholtz calls attention to the fact that, when standing with our eyes in the primary position, — that is, directed toward the horizon, — the horopter is a plane coinciding with the ground, and this fact may possibly be of service to us in walking. Suppression of Visual Images. — It happens not infrequently that when an image of an object falls upon non-corresponding BINOCULAR VISION. 369 points in the two retinas the mind ignores or suppresses one of the images. This peculiarity is exhibited especially in the case of per- sons suffering from "squint" (strabismus). In this condition the individual, for one reason or another, is unable to adjust the contrac- tions of his eye muscles so as to unite his lines of sight upon the object looked at. The image of the object falls upon non-corre- sponding points and should give double vision, diplopia. This would undoubtedly be the case if the condition came on suddenly ; just as double vision results when we dislocate one eyeball by pressing slightly upon it. But in cases of long standing one of the images, that from the abnormal eye, is usually suppressed. The act of suppression seems to be a case of a stronger stimulus prevail- ing over a weaker one in consciousness, just as a painful sensation from stimulation of one part of the skin may be suppressed by a stronger pain from some other region. Struggle of the Visual Fields. — When the images of two dis- similar objects are thrown, one on each retina, the mind is presented, so to speak, simultaneously with two different sensations. Under such circumstances what is known as the struggle of the visual fields ensues. If the image on one eye consists of vertical lines and on the other of horizontal lines we see only one field at a time, first one then the other, or the field is broken, vertical fines in part and horizontal lines in part; there is no genuine fusion into a con- tinuous, constant picture. The struggle of the two fields is better illustrated when different colors are thrown on the two retinas. When red and yellow are superposed on one retina we obtain a com- pound sensation of orange; if they are thrown one on one retina, one on the other, no such fusion takes place. We see the field alternately red or yellow or a mixture of part red and part yellow, or at times one color, as it were, through the other. If, however, one field is white and the other black a peculiar sensation of glitter is obtained, quite unlike the uniform gray that would result if the two fields were superposed on one retina. Judgments of Solidity. — Our vision gives us knowledge not only of the surface area of objects, but also of their depth or solidity, — that is, from our visual sensations we obtain conceptions of the three dimensions of space. The visual sensations upon which this conception is built are of several different kinds, partby monocular,— that is, such as are perceived by one eye alone, — partly binocular. If we close one eye and look at a bit of landscape or a solid object we are conscious of the perspective, of the right relations of fore- ground and background, and those individuals who have the misfortune to lose one eye are still capable, under most circum- stances, of. correct visual judgments concerning three dimen- sional space. Nevertheless it is true that with binocular vision 370 THE SPECIAL SENSES. our judgments of perspective are more perfect, and that under certain circumstances data are obtained from vision with two eyes which give us an idea of solidity far more real than can be obtained with one eye alone. This difference is shown especially in the combination of stereoscopic pictures, and in ordinary vision when the light is dim, as in twilight, or in exact judgments of perspective in the case of objects close at hand. If, for example, we close one eye and attempt to thread a needle, light a pipe, or make any similar co-ordinated movement that depends upon an exact judgment of the distance of the object away from us, it will be found that the resulting movement is far less perfectly performed than when two eyes are used. The sensation elements upon which our judgments of depth or perspective are founded may be classified as follows :* The Monocular Elements.- — That is, those that are experienced in vision with one eye. (a) Aerial 'perspective. The air is not en- tirely transparent, and, therefore, in viewing landscapes the more distant objects are less distinctly seen, as is illustrated, for instance, by the haze covering distant mountains. This experience leads us sometimes to make erroneous judgments when the conditions are unusual. An object seen suddenly in a fog looms large, as the expression goes, since the feeling that hazy objects are at a great distance leads us to give a proportional overvaluation to the rela- tively large visual image made by the near object. (b) Mathematical perspective. The outlines of objects before us are projected upon the surface of the eye in two dimensions only, just as they are represented in a drawing. The lines that indicate depth are therefore foreshortened, and lines really parallel tend to converge more and more to a vanishing point in proportion to their distance away from us. When one stands between the tracks of a railway, for instance; this convergence of the parallel lines is dis- tinctly apparent. We have learned to interpret this mathematical perspective correctly and with great accuracy. The use of this perspective in drawings is, in fact, one of the chief means employed by the artist to produce an impression of depth or solidity. For distant objects at least this factor is probably the most potent of those that can be appreciated by monocular vision. The importance of the mathematical perspective for our visual judgments may be illustrated very strikingly by a simple experiment. If one takes a biconvex lens of short focus and standing at a window that looks out upon a long street holds the lens in front of the eyes at arm's length he will be able to see, by focusing on the inverted image formed by the lens, that not only are objects inverted as regards their surface features, but, for most persons at least, the perspective is also inverted. Objects actually in the foreground will appear in the background, and one may have the curious sensations of watching persons who. as they walk, seem to recede farther and farther into * See Lie Conte, " Sight," vol. 31 of "The International Scientific Series," 1881. BINOCULAR VISION. 371 the distance in spite of the fact that they continue to increase in size. The inverted or pseudoscopic vision thus produced is due undoubtedly to the in- version of the lines of perspective. Parallel lines which, without the lens, would have on the retina a projection of this kind /\ are with the lens projected inverted V, and our visual judgments are controlled by this factor in spite of the opposing evidence from the size of the retinal images. In order for the experiment to succeed it is necessary that the objects viewed shall be far enough away so that a flat picture may be given by the lens, — that is, a pic- ture in which the foci for the near points shall not differ practically from those of more distant points, otherwise the muscular movements of accommodation interfere with the delusion. The relative importance of this last factor (see succeeding paragraph) is well illustrated by varying the experiment in this way: Place two objects upon a well-lighted table, one at the near end and one at the far end. Then standing close to the table view these objects through the lens as before. They will be seen in their right relations to each other. If, however, one backs away from the table while watching the images there will come a distance at which the near object will be seen to shift around to the rear of the far object. (c) The Muscle Sense {Focal Adjustment). — For objects near enough to require accommodation it is obvious that the nearer object will need a stronger contraction of the ciliary muscle, and also of the internal rectus in order to bring the line of sight to bear correctly. By means of the fibers of muscle sense we have a verv exact conception of the degree of contraction of these muscles, and this sensation is perhaps the most important factor used in making our monocular judgments of depth for objects at a short distance. In binocular vision the same factor is doubtless of increased effi- ciency by reason of the sensations obtained from the two eyes. (d) The disposition of lights and sJuides and the size of familiar objects. It may be assumed that in distant vision of complex fields the varying lights and shades exhibited by objects according as they stand in front of or behind each other also aid our judg- ment. The actual size also of the retinal images of familiar objects — such as animals, trees, etc. — gives us an accessory fact which con- tributes to the impression derived from the sources mentioned above. These factors are employed with effect by the artist in strengthening the general impression which he wishes to give of the difference between the foreground and the background. The Binocular Perspective. — In binocular vision there is an additional element which contributes greatly to our judgment of depth. This element consists in the fact that the retinal images of external objects, particularly near objects, are different in the two eyes. Inasmuch as the eyes are separated by some distance the projection of any solid object upon one retina is different from the projection on the other. If a truncated pyramid is held in front of the eyes, the right eye sees more of the right side, the left more of the left side. The projection of the same object upon the two retinas may, in fact, be represented by the drawings given in Fig. 160. Whenever this condition prevails, whenever what we 372 THE .SPECIAL SENSES. N / \ \ / / L R Fig. 161). — Right- and left-eyed images of truncated pyramid. May be combined to produce solid image by relaxing the accommodation, — that is, gazing to a dis- tance through the book. may call a right -eyed image of an object is thrown on the right eye and simultaneously a left-eyed image on the left eye, whether in nature or by an artifice, we at once perceive depth or solidity in the object. This fact is made use of in all devices employed to produce stereoscopic vision. Stereoscopic Vision. — Stereoscopic pictures may be obtained by photographing the same object or collec- tion of objects from slightly different points so as to get a right-eyed and a left- eyed picture ; or for simple outline pic- tures, such as geo- metrical figures, they may be made by draw- ings of the object as seen by the two eyes, respectively (see Figs. 160 and 162). Any optical device that will enable us to throw the right-eyed picture on the right eye and the left-eyed picture on the left eye constitutes a stereoscope. Many different forms of stereoscope have been devised; the one that is most frequently A i used is the Brewster stereoscope :\ \ / represented in principle in Fig. 161. Each eye views its corre- sponding picture through a curved prism. The sight of the left-eyed picture is cut off from the right eye, and vice versa, by a partition extending for some distance in the median plane. The prisms are placed with their bases outward and the rays of light from the pictures are re- fracted, as shown in the diagram, so as to aid the eyes in converg- ing their lines of sight upon the same object. The prisms also magnify the pictures somewhat. Stereoscopic pictures are mounted usually for this instrument so that the distance between the same object in the two pictures is about 80 nims. — greater, therefore, than the interocular distance. A simple form of stereoscope that is very )>'B Fig. 161.- Diagram to illustrate the principle of the Brewster stereoscope (Landois) : P and P', the prisms, a, b, and a, 0, the left- and ri^ht-eyed pictures, respectively, b, /3, being a point in the foreground and a, a, a point in the back- ground. The eyes are converged and focused separately for each point as in viewing naturally an object of three di- mensions. BINOCULAR VISION. 373 effective and interesting is sold under the name of the anaglyph. The two pictures in this case are approximately superposed, but the outlines of one are in blue and the other in red. When looked at, therefore, the picture gives an ordinary flat view with confused red-blue outlines. If, however, one holds a piece of red glass in front of the left eye and apiece of blue glass in front of the right eye, or more conveniently uses the pair of spectacles provided which have blue glass on one side, red on the other, then the picture stands out at once in solid relief with surprising distinctness — and as a black and white object only. The red and blue glasses in this case simply serve to throw the right-eyed image -on the right eye and the left-eyed image on the left eye. Assuming that the right-eyed image is outlined in red, then the blue glass should be in front of the right eye. This glass will absorb the red rays completely so that the red outlines in the picture will seem black and a distinct right- eyed picture is thrown on the right eye, distinct enough to make us overlook the much fainter image in blue, which is also trans- mitted through the blue glass. The red glass before the left eye cuts out, in the same way, the right-eyed image and presents in dark outline the left-eyed image. By simply reversing the spectacles the right-eyed image may be thrown upon the left eye and vice versa. Under these conditions the picture for most per- sons may be seen in inverted relief (pseudoscopic vision), objects in the foreground re- ceding into the background. This inversion of the relief when the projection upon the retinas is reversed is a strik- ing indication of the potency of the normal projection as a fnn+^r. ™ ^,,„ ;,,J„™ 4- t rig. ±oz.— stereoscopic picture ot an octahe- 1 actor m Our judgments Ot dral crystal. May be combined stereoscopicaliy solid nhifptc: Tt will V>o nU by relaxing the accommodation by the method bOllQ O DjeCT.S. It Will De 00- of heteronymous diplopia. Hold the object at a served, moreover, that those dlstance of a foot or more and eaze beyond, pictures that show least mathematical perspective are the most readily inverted, and that the ability to invert the picture varies in different individuals; in some, what we have called the binocular perspective, founded upon the dissimilar images, prevails over the mathematical perspective more readily than in others. Stereoscopic pictures may also be combined very successfully without the use of a stereoscope by virtue of the phenomenon of physiological diplopia. If, for instance, two stereoscopic drawings, such as are represented in Fig. 162, are held before the eyes and one relaxes his accommodation so as to look through the pictures, as it 374 THE SPECIAL SENSES. were, to a point beyond, then, in accordance with what was stated on p. 367, each picture gives a double image, since it falls on non-corresponding parts of the two retinas. Four pictures, there- fore will be seen, all out of focus. With a little practice one can so converge his eyes as to make the two middle images come together, and since one of these is an image of the right-eyed picture and is falling on the right eye, and the other is a left-eyed picture falling on the left eye, the combination of the two fulfills the necessary conditions for binocular perspective. The figure stands out in bold relief. Explanation of Binocular Perspective. — Our perception of solidity or relief is a secondary psychical act, and, so far as the binoc- ular element is concerned, it is based upon the fact that the images are slightly different on the two retinas ; but why this dissimilarity should produce an inference of this kind is not entirely understood. Certain facts have been pointed out as having a probable bearing upon the mental process. In the first place, in stereoscopic pictures, as in nature, we do not see the whole field at once. To see the ob- jects in the foreground the eyeballs must be converged by the eye muscles so that the lines of sight may meet in the object regarded. When attention is paid to objects in the background less convergence is necessary (see Fig. 159). The point of fixation for the lines of sight is kept continually moving to and fro, and the sensation of this muscular movement undoubtedly plays an important part in giving us the idea of depth or solidity. For persons not practised in the matter of observing stereoscopic pictures the full idea of relief comes out only after this muscular activity has been called upon. But for the practised eye this play of the muscles is not absolutely necessary. The stereoscopic picture stands out in relief even when illuminated momentarily by the light of an electric spark. The per- ception of solidity in this case is instantaneous, and it has been sug- gested that this result may depend upon the immediate recognition of jDhysiological diplopia, — that is, the fact that objects nearer than the point of fixation are doubled heteronymously, while those farther away are doubled homonymously (see p. 367). Such an effect can only be produced distinctly by objects having depth and possibly in the case of the trained eye it alone is sufficient to give the immediate inference of solidity or relief, while the un- trained eye requires the accessory sensations aroused by focal adjustment, mathematical perspective, etc. Judgments of Distance and Size. — Judgments of distance and size are closely related. Our judgments regarding size are based primarily upon the size of the retinal image, the amount of the visual angle. This datum, however, is sufficient in itself only for objects at the same distance from us. If they are at different BINOCULAR VISION. 375 distances or we suppose that such is the case, our judgment of the distance controls our judgment of size. This fact is beautifully shown in the case of after-images (see p. 346). When an after- image of any object is obtained on the retina our judgment of its size depends altogether on the distance to which we project it. If we look at a surface near at hand, it seems small ; if we gaze at a wall many feet away it is at once greatly enlarged. The familiar instance of the variation in the size of the full moon according as it is seen at the horizon or at the zenith depends upon the same fact. The distance to the horizon as viewed along the surface of the earth seems greater than to the zenith; we picture the heavens above us as an arched dome flattened at the top, and hence the same size of retinal image is interpreted as larger when we suppose that we see it at a greater distance. Our judgments of distance, on the other hand, depend primarily upon the data already enumerated in speaking of the perception of solidity or depth in the visual field. For objects within the limit of accommodation we depend chiefly on the muscle sense aroused by the act of focusing the eyes, — that is, the contractions of the ciliary and of the extrinsic muscles. For objects outside the limit of accommodation we are influenced by binocular perspective, mathematical perspective, aerial perspective, - J. ^ B Fig. 163. — Mtiller-Lyer figures to show illusion in space perception. The lines A and B are of the same length. etc. But here again our judgment of distance is greatly influenced in the case of familiar objects by the size of the retinal image. A striking instance of the latter fact is obtained by the use of field glasses or opera glasses. When we look through them properly the size of the retinal image is enlarged, and the objects, therefore, seem to be nearer to us. If we reverse the glasses and look through the large end the size of the retinal image is reduced and the objects, therefore, seem to be much farther away, since under normal condi- tions such small images of familiar objects are formed only when they are at a great distance from us. Optical Deceptions.— Wrong judgments as regards distance and size are frequently made and the fact may be illustrated in a number of interesting ways. Thus, in Fig. 163 the lines A and B are of the same length, but B seems to be distinctly the longer. So in Fig. 164 the vertical lines, although exactly parallel, seem, on the contrary, to run obliquely with reference to one another. Both of these deceptions depend apparently upon our inability to estimate angles exactly; we undervalue the acute angles and overvalue those 376 THE SPECIAL SENSES. that are obtuse. A very remarkable delusion is given by Fig. 165. If the book is held flat at the level of the chin and six or eight ',. It is not destroyed by mod- erate heating. The immune body is enabled to act upon the corpuscles by the co-operation of certain substances which are normally present in the serum and are therefore not produced by the process of immunization. These substances are known usually as complements, and it is they that are destroyed by heating to 55° C. If the immune serum of a guinea pig is heated to boz C. its hemolytic action upon rabbits' corpuscles is destroyed. The action may be restored, however, by adding a little of the rabbit's own serum, since in terms of the above hypothesis the complements are present in normal serum. That is to say. an experiment of the following kind may be performed. Washed blood corpuscles of a rabbit plus immune serum from a guinea pig show hemolysis. Washed blood corpuscles of a rabbit plus immune serum which has been made inactive by heating show no hemolysis. Addition of normal rabbits' serum to this latter mixture again activates the immune serum and causes hemolysis. The rabbits' serum in this case supplies the needed complement. These facts, it should be stated, are interpreted somewhat differently by Bordet.* The immune substance he designates as a "substance sensibila- trice" and the complement as alexin. The latter forms the protective sub- tance of the blood, but is unable to act upon the foreign cells until these latter have been changed in some way, that is, sensitized by the specific immune substance developed during the process of immunizing. In the case of some of the natural hemolysins referred to above it has also been shown that the solution of the corpuscles depends upon the combined action of two substances. This point has been made clear particularly in regard to the snake- poisons, such as cobra venom. In these venoms there is present a substance analogous to the immune body or amboceptor, but in order for it to affect the red corpuscles it must hie activated by a complement of some sort, present in the plasma or the red corpuscle itself. Kyesf has given some interesting facts to prove that lecithin is an effective complement for these venoms, and that probably it is this definite substance which is furnished by the blood in activating the venom toxin. Speaking in general terms, the serum of any animal is more or less hemolytic in relation to the blood-corpuscles of an animal of another species; but great differences are shown in this respect. The blood-serum of the horse shows but little hemolytic action * Bordet, "Studies in Immunitv,'' translated bv Gay, New York, 1909. tKyes, "Berl. klin. Wochenschrift," 1902 and 1903. 27 418 BLOOD AND LYMPH. upon the red corpuscles of the rabbit when compared with the effect of the serum of the dog or cat. Eels' serum has a re- markably strong hemolytic action upon the red corpuscles of most mammals; a very minute quantity of this serum (0.04 c.c.) injected into the veins of a rabbit will cause hemolysis of the corpuscles and, as a consequence, the appear- ance of bloody urine (hemoglobinuria). It should be added that this curious toxic or lytic effect of foreign serums is not confined to the red corpuscles. They contain cytotoxins that affect also other tissue elements, especially those of the central nervous system, and may therefore cause death. As little as 0.04 c.c. of eels' serum injected into a small rabbit will cause the death of the animal, the fatal effect being due apparently to an action on the vasomotor and respiratory centers in the medulla. The hemolytic and generally toxic effect of foreign sera has been known for a long time. It was discovered practically in the numerous attempts made in former years to transfuse the blood of one animal into the veins of another. It has been found that this process of transfusion as a means of combatting severe hemorrhage is dangerous unless the blood is taken from an animal of the same or a nearly related species. Nature and Amount of Hemoglobin. — Hemoglobin is a very complex substance belonging to the group of conjugated proteins. Under the influence of heat, acids, alkalies, etc., it may be broken up, with the formation of a simple protein, globin, belonging to the group of histons (see appendix) and a pigment, hematin. The globin forms, according to different estimates, from 86 to 94 per cent, of the molecule, and the hematin about 4 per cent. Other sub- stances of an undetermined character result from the decomposition.* When the decomposition takes place in the absence of oxygen, the products formed are globin and hemochromogen, instead of globin and hematin. Hemochromogen in the presence of oxygen quickly undergoes oxidation to the more stable hematin. Hoppe-Seyler has shown that hemochromogen possesses the chemical grouping which gives to hemoglobin its power of combining readily with oxy- gen and its distinctive absorption spectrum. On the basis of facts such as these, hemoglobin may be defined as a compound of a protein body with hematin. It seems, then, that, although the hemochro- mogen or hematin portion is the essential constituent, giving to the molecule of hemoglobin its valuable physiological properties as a respiratory pigment, yet in the blood corpuscles this substance is incorporated into the much larger and more unstable molecule of hemoglobin, whose behavior toward oxygen is different from that of the hematin itself, the difference lying mainly in the fact that the hemoglobin as it exists in the corpuscles forms with oxygen a * Schulz, 'Zeitschrift f. physiologische Chemie, " 24; also Lauraw, ibid., 26. GENERAL PROPERTIES: THE CORPUSCLES. 419 comparatively feeble combination that may be broken up readily with liberation of the gas. Hemoglobin is widely distributed throughout the animal king- dom, being found in the blood corpuscles of mammalia, birds, reptiles, amphibia, and fishes, and in the blood or blood corpuscles of many of the invertebrates. The composition of its molecule is found to vary somewhat in different animals; so that, strictly speaking, there are probably a number of different forms of hemo- globin— all, however, closely related in chemical and physiological properties. Elementary analysis of dogs' hemoglobin shows the following percentage composition (Jaquet): C, 53.91; H, 6.62; N, 15.98; S, 0.542; Fe, 0.333; 0, 22.62. Its molecular formula is given as C758H1203N195S3FeO218, which would make the molec- ular weight 16,669. Other estimates are given of the molecular formula, but they agree at least in showing that the molecule is of enormous size. The hematin that is split off from the hemoglobin is a pigment whose constitution is relatively simple, as is indicated by its percentage formula, C34H34N4Fe05 (Kiister). It contains all of the iron of the original hemoglobin molecule. Gamgee has called attention to two facts which seem to indicate that the globin and hematin do not exist as such in the hemoglobin molecule. Thus, hematin is magnetic, — that is, is attracted by a magnet, — while hemoglobin, on the contrary, is diamagnetic. Globin alone rotates the plane of polarized light to the left, levorotatory, while hemo- globin solutions are dextrorotatory. The exact amount of hemo- globin in human blood varies naturally with the individual and with different conditions of life. According to Preyer,* the average amount for the adult male is 14 grams of hemoglobin to each 100 grams of blood. It is estimated that in the blood of a man weighing 68 kilograms there are contained about 500 to 700 grams of hem- oglobin, which is distributed among some 25,000,000,000,000 of corpuscles, giving a total superficial area of about 3200 square meters. Practically all of this large surface of hemoglobin is available for the absorption of oxygen from the air in the lungs, for, owing to the great number and the minute size of the capil- laries, the blood, in passing through a capillary area, becomes subdivided to such an extent that the red corpuscles stream through the capillaries, one may say, in single file. In circu- lating through the lungs, therefore, each corpuscle becomes exposed more or less completely to the action of the air, and the utilization of the entire quantity of hemoglobin must be nearly perfect. Instruments known as hemometers or hemoglobinometers have been devised for clinical use in determining the amount of hemoglobin in the blood of patients. A number of different forms of this instrument are in * "Die Blutkrystalle," Jena, 1871. 420 BLOOD AND LYMPH. use. In all of them, however, the determination is made with a drop or two of blood, such as can be obtained without difficulty by pricking the skin. The amount of hemoglobin in the withdrawn blood is determined usually by a colorimetric method, — that is, its color, which is due to the hemoglobin, is compared with a series of standard solutions containing known amounts of hemoglobin, or with a wedge of colored glass whose color value in terms of hemo- globin has been determined beforehand. For details of the structure of the several instruments employed and the precautions to be ob- served in their use reference must be made to the laboratory guides.* Compounds with Oxygen and Other Gases. — Hemoglobin has the property of uniting with oxygen gas in certain definite propor- tions, forming a true chemical compound. This compound is known as oxyhemoglobin ; it is formed whenever blood or hemoglobin solu- tions are exposed to air or are otherwise brought into contact with oxygen. According to a determination by Hiifner, | one gram of hemoglobin combines with 1.36 c.c. of oxygen. These figures would indicate the probability that each molecule of hemoglobin unites with a molecule of oxygen, since 1.36 c.c. of oxygen weighs approximately 0.0019 4- gram, and the ratio of 1 gram of hemoglobin to 0.0019 gram of oxygen is that of the molecular weight of hemo- globin to the molecular weight of oxygen, that is, 16669:32 : : 1: 0.0019. It should be stated that some observers t find that the maximum oxygen capacity of the blood may show individual varia- tions within narrow limits, and that, therefore, what we designate as hemoglobin may not be a single chemical substance, but a mixture of closely related compounds. Oxyhemoglobin is not a very firm compound. If placed in an atmosphere containing no oxygen it is dissociated, giving off free oxygen and leaving behind hemo- globin or, as it is often called by way of distinction, "reduced hemoglobin.'7 This power of combining with oxygen to form a loose chemical compound, which in turn can be dissociated easily when the oxygen pressure is lowered, makes possible the function of hemoglobin in the blood as the carrier of oxygen from the lungs to the tissues. The details of this process are described in the section on Respiration. Hemoglobin forms with carbon monoxid gas (CO) a compound, similar to oxyhemoglobin, which is known as carbon monoxid hemoglobin. In this compound also the union takes place in the proportion of one molecule of hemoglobin to one molecule of the gas. The compound formed differs, however, from oxyhemoglobin in being much more stable, and it is for this reason that the breathing of carbon monoxid gas is liable to prove fatal. The CO unites with the hemoglobin, forming a firm com- *See Simon, "A Manual of Clinical Diagnosis," Philadelphia. t "Archiv. f. Physiologie," 1894, p. 130. X See Bohr, in Nagel's "Handbuch der Physiologie," vol. i, pt. 1., 1905. GENERAL PROPERTIES: THE CORPUSCLES. 421 pound; the tissues of the body are thereby prevented from obtain- ing their necessary oxygen, and death results from suffocation or asphyxia. Carbon monoxid forms one of the constituents of coal-gas. The well-known fatal effect of breathing coal-gas for some time, as in the case of individuals sleeping in a room in which gas is escaping, is traceable directly to the carbon monoxid. Nitric oxid (NO) forms also with hemoglobin a definite compound that is even more stable than the CO hemoglobin; if, therefore, this gas were brought into contact with the blood, it would cause death in the same way as the CO. Oxyhemoglobin, carbon monoxid hemoglobin, and nitric oxid hemoglobin are similar compounds. Each is formed, apparently, by a definite combination of the gas with the hematin portion of the hemoglobin molecule, and a given weight of hemoglobin unites presumably with an equal volume of each gas. In marked contrast to these facts, Bohr* has shown that hemoglobin forms a compound with carbon dioxid gas, carbohemoglobin, in which the quantitative relationship of the gas to the hemoglobin differs from that shown by oxygen. In a mixture of O and C02 the latter gas is absorbed by hemoglobin solutions independently of the oxygen, so that a solu- tion of hemoglobin nearly saturated with oxygen will take up C02 as though it held no oxygen in combination. Bohr suggests, there- fore, that the 0 and the C02 must unite with different portions of the hemoglobin — the oxygen with the pigment portion and the C02 possi- bly with the protein portion. Although the amount of C02 taken up by the hemoglobin is not influenced by the amount of 0 alreadv in combination, the reverse relationship does not hold in all cases. It is found that the presence of the C02 loosens, as it were, the combina- tion between the hemoglobin and the oxygen so that the oxyhemo- globin dissociates more readily than would otherwise be the case. This is observed at least when the oxygen is under a low pressure, °uch as occurs, for instance, in the capillaries of the tissues. The importance of this fact in regard to the oxygen supply to the tissues is referred to more explicitly in the section on Respiration. Presence of Iron in the Molecule.— It is probable that iron is quite generally present in the animal tissues in connection with nuclein compounds, but its existence in hemoglobin is noteworthy because it has long been known, and because the important property of combining with oxygen seems to be connected with the presence of this element. According to recent analyses, the proportion of iron in hemoglobin is constant, lying between 0.33 and 0.34 per cent.f The amount of hemoglobin in blood may be determined, therefore, by making a quantitative determination of the iron. The amount of oxygen with which hemoglobin will combine may * "Skandinavisehes Archiv f. Physiologie," 3, 47, 1892, and 16, 402, 1904. t Butterfield, Zeit. f. ph}\siol. Chemie, 62, 173, 1909. 422 LYMPH AND BLOOD. be expressed by saying that one molecule of oxygen will be fixed for each atom of iron in the hemoglobin molecule In the decomposi- tion of hemoglobin into globin and hematin, which has been spoken of above, the iron is retained in the hematin. Crystals. — Hemoglobin may be obtained readily in the form of crystals (Fig. 181). As usually prepared, these crystals are really oxyhemoglobin, but it has been shown that reduced hemoglobin also crystallizes, although with more diffi- culty. Hemoglobin from the blood of different ani- mals varies to a marked degree in respect to the power of crystallization. From the blood of the rat, dog, cat, guinea pig, and horse, crystals are readily obtained, while hemoglobin from the blood of man and of most of the vertebrates crystallizes much less easily. Methods for preparing and purifying these crystals will be found in works on phys- iological chemistry. To ob- tain specimens quickly for examination under the mi- croscope, one of the most certain methods is to take some blood from one of the animals whose hemoglobin crystallizes easily, place it in a test-tube, add to it a few drops of ether, shake the tube thoroughly until the blood be- comes laky, — that is, until the hemoglobin is discharged into the plasma, — and then place the tube on ice until the crystals are deposited. Small portions of the crystalline sediment may then be removed to a glass slide for examination. According to Reichert, the deposition of the crystals is hastened by adding ammonium oxalate to the blood in quantities sufficient to make from 1 to 5 per cent, of the mixture. Hemoglobin from different animals varies not only as to the ease with which it crystallizes, but in some cases also as to the form that the crystals take. In man and in most of the mammalia hemoglobin is deposited in the form of rhombic prisms; in the guinea pig it crystallizes in tetrahedra (d, Fig. 181), Fig. 181. — Crystallized hemoglobin (after Fret/) : a, b, Crystals from venous blood of man ; c, from the blood of a cat; d, from the blood of a guinea pig; e, from the blood of a hamster; /, from the blood of a squirrel. GENERAL PROPERTIES: THE CORPUSCLES 423 and in the squirrel in hexagonal plates. In an elaborate and care- ful study of the crystallographic characters of hemoglobin from a large number of animals Reichert and Brown* have shown that differences exist between the crystals of various species of such a character that they may be used to determine whether or not animals belong to the same genus. This difference in crystal- line form implies some difference in molecular structure, and taken together with other known variations in property shown by hemo- globin from different animals leads us to believe that the huge mole- cule has a labile structure, and that it may differ somewhat in its molecular composition or atomic arrangement without losing its physiological property of an oxygen-carrier. In this connection it is interesting to state that the hemoglobin of horses' blood, which crystallizes ordinarily in large rhombic prisms, may be made to give hexagonal crystals by allowing it to undergo putrefaction, and that the form of the crystals may then be changed from hexagons to rhombs by varying the temperature of the solutions. f The crystals are readily soluble in water, and by repeated crystallization the hemoglobin may be obtained perfectly pure. As in the case of other soluble protein-like bodies, solutions of hemoglobin are precipitated by alcohol, by mineral acids, by salts of the heavy metals, by boiling, etc. Notwithstanding the fact that hemoglobin crystallizes so readily, it is not easily dialyzable, behaving in this respect like non-crystallizable colloidal bodies. The compounds which hemoglobin forms with carbon monoxid (CO) and nitric oxid (NO) are also crystallizable, the crystals being isomorphous with those of oxyhemoglobin. Absorption Spectra. — Solutions of hemoglobin and its deriv- ative compounds, when examined with a spectroscope, give distinctive absorption bands. Light, when made to pass through a glass prism, is broken up into its constituent rays, giving the play of rainbow colors known as the spectrum. A spectroscope is an apparatus for producing and observing a spectrum. A simple form, which illustrates sufficiently well the construction of the appara- tus, is shown in Fig. 182, P being the glass prism giving the spectrum. Light falls upon this prism through the tube (A) to the left, known as the "colli- mator tube." A slit at the end of this tube (S) admits a narrow slice of light — lamplight or sunlight — which then, by means of a convex lens at the other end of the tube, is made to fall upon the prism (P) with its rays parallel. In passing through the prism the rays are dispersed by unequal refraction, giving a spectrum. The spectrum thus produced is examined by the observer with the aid of the telescope (B) . When the telescope is properly focused for the rays entering it from the prism (P), a clear picture of the spectrum is seen. The length of the spectrum will depend upon the nature and the number of the prisms through which the light is made to pass. For ordinary purposes a short spectrum is preferable for hemoglobin bands, and a spectroscope with one prism is generally used. If the source of light is a lamp flame of some kind, * Reichert and Brown, " The Crystallography of Hemoglobins," Carnegie Institution of Washington, No. 116, 1909. t Uhlik, "Archiv f. d. gesammte Physiologie," 104, 64, 1904. 424 BLOOD AND LYMPH. the spectrum is continuous, the colors gradually merging one into another from red to violet. If sunlight is used, the spectrum will be crossed by a number of narrow dark lines known as the " Fraunhofer lines." The position of these lines in the solar spectrum is fixed, and the more distinct ones are designated by letters of the alphabet, A, B, C, D, E, etc., as shown in the charts below. If while using solar light or an artificial light a solution of any sub- stance which gives absorption bands is so placed in front of the slit that the light is obliged to traverse it, the spectrum as observed through the telescope will show one or more narrow or broad black bands that are characteristic of the substance used and constitute its absorption spectrum. The positions of these bands may be designated by describing their relations to the Fraun- hofer lines, or more directly by stating the wave lengths of the portions of the spectrum between which absorption takes place. Some spectroscopes are provided with a scale of wave lengths superposed on the spectrum, and when properly adjusted this scale enables one to read off directly the wave lengths of ?ny part of the spectrum. When very dilute solutions of oxyhemoglobin are examined with the spectroscope, two absorption bands appear, both occurring in Fig 182.— Spectroscope : P, The glass prism ; A , the collimator tube, showing the slit, S, through which the light is admitted; B, the telescope for observing the spectrum. the portion of the spectrum included between the Fraunhofer lines D and E. The band nearer the red end of the spectrum is known as the "«-band"; it is narrower, darker, and more clearly defined than the other, the ",*-band" (Fig. 183). The width and distinct- ness of the bands vary naturally with the concentration of the solution used (see Fig. 184) or, if the concentration remains the same, with the width of the stratum of liquid through which the light passes. With a certain minimal percentage of oxyhemoglobin (less than 0.01 per cent.) the /3-band is lost and the a-band is very faint in layers 1 centimeter thick. With stronger solutions the GENERAL PROPERTIES: THE CORPUSCLES. 425 bands become darker and wider and finally fuse, while some of the extreme red end and a great deal of the violet end of the spectrum are also absorbed. The variations in the absorption spectrum, with differences in concentration, are clearly shown in the accom- panying illustration from Rollett * (Fig. 184) ; the thickness of the layer of liquid is supposed to be one centimeter. The numbers on the right indicate the percentage strength of the oxyhemoglobin solutions. It will be noticed that the absorption which takes 6£fl| 650 6M 630 620 610 600 5S0 580 570 560 550 546 536 „L„.LML,.ilMji.iiliiiliili.Jii.iliiJni1linlllnilMlllllllllM.lriilllllllllllluilllllllllillii1llHllli|i' Fig. 183. — Table of absorption spectra (Ziemke and . M tiller) ; 1, Absorption spectrum of oxyhemoglobin, dilute solution; 2, absorption spectrum of reduced hemoglobin; 3, ab- sorption spectrum of methemoglobin, neutral solution; 4, absorption spectrum of met- hemoglobin, alkaline solution ; 5, absorption spectrum of hematin, acid solution; 6, ab- sorption spectrum of hematin, alkaline solution. place as the concentration of the solution increases affects the red-orange end of the spectrum last of all. Solutions of reduced hemoglobin examined with the spectroscope show only one absorption band, known sometimes as the "f-band." This band lies also in the portion of the spectrum included between the lines D and E; its relations to these lines and the bands of * Hermann's " Handbuch der Physiologie," vol. iv., 1880 426 BLOOD AND LYMPH. oxyhemoglobin are shown in Fig. 183. The f-band is much more diffuse than the oxyhemoglobin bands, and its limits, therefore, especially in weak solutions, are not well defined. The width and distinctness of this band vary also with the concentration of the solution. This variation is sufficiently well shown in the accom- panying illustration (Fig. 185), which is a companion figure to the one given for oxyhemoglobin (Fig. 184). It will be noticed that the last light to be ab- sorbed in this case is partly in the red end and partly in the blue, thus explaining the pur- plish color of hemoglo- bin solutions and of venous blood. Oxy- hemoglobin soluti o n s can be converted to hem oglobin solutions, with a corresponding change in the spectrum bands, by placing the former in a vacuum or, more conveniently, by adding reducing solu- tions. The solutions most commonly used for this purpose are am- monium sulphid and Stokes's reagent.* If a solution of reduced hemoglobin is shaken with air, it quickly changes to oxyhemo- globin and gives two bands instead of one when examined by the spectroscope. Any given solution may be changed in this way from oxyhemoglobin to hemoglobin, and the reverse, a great number of times, thus demonstrating the facility with which hemoglobin takes up and surrenders oxygen. Solutions of carbon monoxid hemoglobin also give a spec- * Stokes's reagent is an ammoniacal solution of a ferrous salt. It is made by dissolving 2 parts (by weight) of ferrous sulphate, adding 3 parts of tar- taric acid, and llien ammonia to distinct alkaline reaction. A permanent precipitate should not be obtained. aBC Eb Fig. 184.- — Diagram to show the variations in the absorption spectrum of oxyhemoglobin with varying concentrations of the solution. — (After Rolleit.) The numbers to the right give the strength of the oxy- hemoglobin solution in percentages; the letters give the positions of the Fraunhofer lines. To ascertain the amount of absorption for any given concentration up to 1 per cent., draw a horizontal line across the diagram at the level corresponding to the concentra- tion. Where this line passes through the shaded part of the diagram absorption takes place, and the width of the absorption bands is seen at once. The diagram shows clearly that the amount of absorption increases as the solutions become more concentrated, especially the absorption of the blue end of the spectrum. It will be noticed that with concentrations between 0.6 and 0.7 per cent, the two bands between D and E fuse into one. GENERAL PROPERTIES: THE CORPUSCLES. 427 aBC Eb trum with two absorption bands closely resembling in posi- tion and appearance those of oxyhemoglobin. They are dis- tinguished from the oxyhemoglobin bands by being slightly nearer the blue end of the spectrum, as may be demonstrated by observing the wave lengths or, more con- veniently, by super- posing the two spectra. Moreover, solutions of carbon monoxid hem- oglobin are not re- duced to hemoglobin by adding Stokes's liquid, two bands be- ing still seen after such treatment. A solu- tion of carbon mon- oxid hemoglobin suit- able for spectroscopic examination may be prepared easily by passing ordinary coal- gas through a dilute oxyhemoglobin solution for a few minutes and then filtering. Derivative Compounds of Hemoglobin. — There are a number of pigmentary bodies which are formed directly from hemoglobin by decompositions or chemical reactions of various kinds. Some of these derivative substances occur normally in the body. The best known are as follows * : Methemoglobin. — When blood or a solution of oxyhemoglobin is allowed to stand for a long time exposed to the air it undergoes a change in color, taking on a brownish tint. This change is due to the formation of methemoglobin, and it is said that to some extent the transition occurs very soon after the blood is exposed to the air, and that, therefore, determinations of the quantity of hemoglobin by the ordinary colorimetric methods should be made promptly to avoid a deterioration in color value. Methemoglobin may be obtained rapidly by the action of various reagents on the blood, * For more detailed information concerning the chemistry and literature of these compounds, see Hammarsten, "Physiological Chemistry, " translated by Mandel, fourth edition, 1904; Abderhalden, " Physiologische Chemie," 1906. Fig. 185. — Diagram to show the variations in the ab- sorption spectrum of reduced hemoglobin with vary- ing concentrations of the solution (after Rollett). The numbers to the right give the strength of the hemo- globin solution in percentages; the letters give the posi- tions of the Fraunhofer lines. For further directions as to the use of the diagram, see the description of Fig. 184. 428 BLOOD AND LYMPH. some of them oxidizing substances, such as permanganate of potash or ferricyanid of potash, some of them reducing substances. In- deed, it is known that the change may occur within the blood-vessels by the action of such bodies as the nitrites, antifebrin, acetanilid, etc. According to most observers, methemoglobin contains the same amount of oxygen as hemoglobin ; it is combined differently, however, forming a more stable compound, which can not be dis- sociated by the action of a vacuum. On this account, therefore,, methemoglobin is not capable of acting as a respiratory pigment, and to the extent that it is formed in the blood this tissue suffers a loss of its functional value as a carrier of oxygen. By the stronger action of reducing solutions— such as ammonium sulphid — the oxygen may be removed from the methemoglobin and reduced hemoglobin be obtained. Methemoglobin crystallizes in needles,. and its solutions give an absorption spectrum which varies ac- cording as the solution is neutral or has an alkaline reaction. In neutral solutions the characteristic band is one in the orange, as indicated in Fig. 183. In alkaline solution the absorption spectrum has three bands, two of which are nearly identical with those of oxyhemoglobin. Hematin (C34H34N4Fe05) is obtained when hemoglobin is de- composed by the action of acids or alkalies in the presence or oxygen. It may occur in the feces if the diet contains hemoglobin or hematin, or in case of hemorrhage in the stomach or small intestine, since both the pancreatic and the gastric secretion break up hemoglobin, with the formation of hematin. It is an amorphous substance, of a dark-brown color, easily soluble in alkalies or in acid alcoholic solu- tions. These solutions give a characteristic absorption spectrum which is represented in Fig. 183. Hemin (C34H3304N4FeCl) is regarded as the hydrochloric acid ester of hematin and is obtained by the action of HG1 upon blood previously treated with alcohol. The compound is obtained in the form of crystals, which under the microscope appear usually as small, rhombic plates of a dark-brown color. These crystals may be obtained from small quantities of blood stains, etc., no matter how old, and they have been relied upon, therefore, as a sure and easy test for the existence of blood, — that is, hemoglobin. The test is one that has been much used in medicolegal cases, and may be carried out as follows: A bit of dried blood is powdered with a few crystals of NaCl. Some of the powder is placed upon a glass slide and covered with a cover-slip. By means of a pipette a drop or two of glacial acetic acid is run under the slip, and then by draw- ing the slide repeatedly through a flame the acid is evaporated to dryness, taking care not to heat the acid so high as to cause it to boil. After the evaporation of the acid water is run under the slip and the specimen is ready for examination with the microscope. GENERAL PROPERTIES: THE CORPUSCLES. 429 Hernochromogen (C34H36N4Fe05 ?) is obtained when hemoglobin is decomposed by acids or alkalies in the absence of free oxygen. By oxidation it is converted to hematin. Hernochromogen is crystal- line, and gives a characteristic absorption spectrum. Hernatoporphyrin (C34H38N406) differs from the preceding deriv- atives of hemoglobin in that it contains no iron. It may be ob- tained from hematin by the action of strong acids, and is of much physiological interest because of its relationship to the bile pigments, which, like it, are iron-free derivatives of the hemoglobin. In old blood-clots or extravasations it has long been known that a colored crystalline product may be formed. This product was designated as hematoidin by Virchow and later was stated, on the one hand, to be identical with the bile pigment, bilirubin, and, on the other hand, to be isomeric with hernatoporphyrin. Later observers have prepared from hernatoporphyrin by careful reduction a substance designated as mesoporphyrin. It contains one less oxygen atom than the hernatoporphyrin, and is claimed to be identical with hematoidin. Another fact of great general interest is that from plant chlorophyl there may be prepared a compound, phylloporphy- rin, very similar to the mesoporphyrin. It would appear from this relationship that the red coloring matter of the blood and the green coloring matter of plants are compounds that have some similarity in chemical structure. Histohematins. — This name is a general term that has been given to the coloring matter found in the tissues, so far as it has the property of taking up oxygen. The red coloring matter in some muscles is an example of such a compound and has been designated specifically as myohematin. According to most observers, myo- hematin is identical with hemoglobin, — that is, the muscle substance contains some hemoglobin, — and we may suppose that its presence in the tissue furnishes a further means for the transportation of oxygen to the muscle protoplasm. Bile Pigments and Urinary Pigments. — These pigments are referred to in the description of the composition of bile and urine. In this connection the fact may be emphasized that each of them is supposed to be derived from hemoglobin, and each constitutes, so to speak, a form of excretion of hemoglobin. Origin and Fate of the Red Corpuscles. — The mammalian red corpuscle is a cell that has lost its nucleus. It is not probable, there- fore, that any given corpuscle lives for a great while in the circulation. This is made more certain by the fact that hemoglobin is the mother substance from which the bile pigments are made, and, as these pigments are being excreted continually, it is fair to suppose that red corpuscles are as steadily undergoing disintegration in the blood- stream. 430 BLOOD AND LYMPH. The number of red corpuscles destroyed daily in the body has never been determined with any accuracy, but it may be quite large, as would appear from the following approximate calculation based upon our incomplete knowledge of the amount of bile-pigment secreted daily. From observations made upon cases of biliary fistulas in man it is estimated that the daily flow of bile amounts to about 15 gms. per kilogram of body weight. If we assume in accordance with the figures given by some authors that the bile contains as much as 0.2 per cent, of pigment, then 1.95 gins, of pigment will be secreted per day (65 X 15 X. 002). This pigment is formed from approximately the same weight of hematin and for its formation would require the destruction of 48 gms. of hemoglobin, since hematin forms 4 per cent, of the molecule of hemoglobin (1.95 -*-. 04 = 48). The total amount of blood in a man weighing 65 kilograms, according to modern estimates, is about 3510 grams (65,000 X .054), and this gives us about 480 gms. of hemoglobin (3510X0.14). Accord- ing to this estimate, therefore, one-tenth of the total hemoglobin may be broken down daily, and the total duration of life of a red corpuscle in the circulation could not exceed ten days. A calculation of this kind is, however, only suggestive; it cannot be accepted as a basis for further estimates, owing to the uncertainty that prevails as to the amount of bile pigment formed and excreted daily. Just when and how the corpuscles go to pieces is not defi- nitely known. It has been suggested that their destruction takes place in the spleen and lymph-glands, but the observations advanced in support of this hypothesis are not very numerous or conclusive. Among the reasons given for assuming that the spleen is especially concerned in the destruction of red corpuscles, the most weighty is the histological fact that one can sometimes find in teased preparations of spleen-tissue or of lymph-glands certain large cells (macrophags) which contain red corpuscles in their cell-substance in various stages of disintegration. It has been supposed that the large cells actually ingest the red corpuscles, selecting those, presumably, that are in a state of physiological decline. Against this idea a number of objections may be raised. Large leucocytes with red cor- puscles in their interior are not found so frequently nor so constantly in the spleen as we should expect would be the case if the act of ingestion were constantly going on. There is some reason for believing, indeed, that the whole act of ingestion may be a postmortem phenomenon; that is, after the cessation of the blood-stream the ameboid movements of the large leucocytes continue, while the red corpuscles lie at rest, — conditions that are favorable to the act of ingestion. It may be added also that the blood of the splenic vein contains no hemoglobin in solu- tion, indicating that no considerable dissolution of red corpuscles is taking place in the spleen. Moreover, complete extirpation of the spleen does not seem to lessen materially the normal destruction of red corpuscles, if we may measure the extent of that normal destruction by the quantity of bile pigment formed in the liver, remembering that hemoglobin is the mother-substance from which the bile pigments are derived. It is more probable that there is no GENERAL PROPERTIES: THE CORPUSCLES. 431 special organ or tissue charged with the function of destroying red corpuscles, but that they undergo disintegration and dissolution while in the blood-stream and in any part of the circulation, the liberated hemoglobin being carried to the liver and excreted in part as bile pigment. The continual destruction of red corpuscles implies, of course, a continual formation of new ones. It has been shown satisfactorily that in the adult the organ for the reproduction of red corpuscles is the red marrow of bones. In this tissue hema- topoiesis, as the process of formation of red corpuscles is termed, goe? on continually, the process being much increased after hemorrhages and in certain pathological conditions. The details of the histo- logical changes will be found in the text-books of histology. It is sufficient here to state simply that groups of nucleated, colorless cells, erythroblasts, are found in the red marrow. These cells multiply by karyokinesis and the daughter-cells eventually produce hemoglobin in their cytoplasm, thus forming nucleated red cor- puscles. The nuclei are subsequently lost, either by disintegration or by extrusion, and the newly formed non-nucleated red corpuscles (erythrocytes) are forced into the blood-stream, owing to a gradual change in their position during development caused by the growing hematopoietic tissue. When the process is greatly accelerated, as after severe hemorrhages or in certain pathological conditions, red corpuscles still retaining their nuclei (normoblasts) may be found in the circulating blood, having been forced out prematurely. Such corpuscles may subsequently lose their nuclei while in the blood-stream. In the embryo, hematopoietic tissue is found in parts of the body other than the marrow, notably in the liver and spleen, which at that time serve as organs for the production of new red corpuscles. In the blood of the young embryo nucleated red corpuscles are at first abundant, but they become less numerous as the fetus grows older.* It is interesting to note that in the adult after severe anemias — e. g., pernicious anemia — and in rabbits after the injection of saponin the spleen may again take on its hematopoietic function. The venous sinuses become crowded with cells of the marrow type.f Variations in the Number of Red Corpuscles. — The average number of red corpuscles for the adult male, as has been stated already, is usually given as 5,000,000 per c.mm. The number is found to vary greatly, however. Outside pathological con- ditions, in which the diminution in number may be extreme, dif- ferences have been observed in human beings under such conditions as the following: The number is less in females (4,500,000) ; it varies * Howell, "Life History of the Blood Corpuscles," etc., "Journal of Morphology." 1890, vol. iv.; Bunting, "Univ. of Pennsylvania Medical Bulletin," 1903, xvi., 200. t See Bunting, "The Journal of Experimental Medicine," 1906, viii., 625. 432 BLOOD AND LYMPH. in individuals with the constitution, nutrition, and manner of life; it varies with age, being greatest in the fetus and in the new-born child: it varies with the time of the day, showing a distinct diminu- tion after meals: in the female it varies somewhat in menstruation and in pregnancy, being slightly increased in the former and di- minished in the latter condition. Variation with Altitude. — Perhaps the most interesting of the conditions that may influence the number of the blood corpuscles is a change in altitude. Attention was first directed to this point by Bert,* who believed that the diminished supply of oxygen in high altitudes may be compensated by an increased amount of hemoglobin, and subsequently Viaultf demonstrated that living for a short time at very high altitudes (4000 meters) causes a marked in- crease in the number of red corpuscles, — an increase, for instance, from 5.000,000 per c.mm. to 7.000.000 or even 8.000.000. This fact has since been investigated with great care by a large number of observers and under a great variety of conditions. The observation has been abundantly confirmed, and indeed it would seem that the reaction takes place very quickly. Within twenty-four hours, according to some observers, and in less time, according to others who have experimented during balloon ascensions (Gaule, Hallion, and Tissot), the increase in the number of corpuscles may be de- tected, although the maximum increase comes on more gradually. According to Kemp, J the number of blood plates is also greatly increased by high altitudes, while the leucocytes are not affected. There has, however, been much difference of opinion as to whether this increase in number of the red corpuscles is relative or absolute, — that is, wdiether the total number of red corpuscles in the blood, and therefore probably the total amount of hemoglobin, is increased, or whether it is simply an apparent increase due, for instance, to a diminution in the water of the blood and a consequent concentration as regards the number of corpuscles, or to a variation in the distri- bution of the corpuscles between the vessels of the skin and those of the internal organs. The results published upon these questions have been conflicting. One may. however, believe that the in- creased number or concentration of red corpuscles is an adaptation by means of which the oxygen-carrying capacity of the blood is raised to compensate for the diminished amount of oxygen in the air. According to one set of observers, this adaptation is brought about by an absolute increase in the total number of red corpuscles, and therefore in the total amount of hemoglobin. There seems to be little doubt that such a change occurs in cases of long residence * Bert, "La pre.ssion barometrique, " 1878, p. 1108. t Viault, "Comptee rendus de I'academie des sciences." 1890 and 1891. % Kemp, "American Journal of Physiology," 10. 34, 1904. GENERAL PROPERTIES: THE CORPUSCLES. 433 in high altitudes, and we may assume that the diminished amount of oxygen in the air or some other condition peculiar to these altitudes acts as a stimulus to the blood-forming tissues (red mar- row) and augments the output of corpuscles and hemoglobin. Zuntz and his co-workers have shown in experiments upon dogs that there is a visible increase in the red marrow of the bones as a result of living for some months at a high altitude. According to another set of observers, the adaptation is brought about by a concentration of the blood. The blood-plasma is reduced in quantity, perhaps by transudation of water into the tissues, and therefore the number of red corpuscles and the amount of hemo- globin become greater for each cubic millimeter. If we assume that this smaller bulk of blood, more concentrated in corpuscles and hemoglobin, circulates more rapidly, then also the oxygen- carrying capacity of the blood is increased. In favor of this view, Abderhalden, for instance, has claimed that, if animals of the same species and same litter are bled to death and the total quan- tity of hemoglobin is estimated, the average figures obtained for the animals at low levels are the same as for those at the high altitudes. Zuntz has, however, called attention to the fact that when Abderhalden's figures are estimated per kilogram of weight they show an increase in total hemoglobin in the high altitudes, and he and other observers have obtained similar results. It seems certain, therefore, that high altitudes cause eventually a marked increase in the production of red corpuscles, but that the very sudden changes of this kind reported by some authors as happening within a few hours must be considered as apparent rather than real, and are to be explained by some change in the water contents or in the distribution of the blood.* Physiology of the Blood Leucocytes. — The function of the blood leucocytes has been the subject of numerous investigations, particularly in connection with the pathology of blood diseases. Although many hypotheses have been made as the result of this work, it cannot be said that we possess much positive information as to the normal function of these cells in the body. It must be borne in mind, in the first place, that the blood leucocytes are not all the same histologically, and it may be that their functions are as diverse as their morphology. Various classifications have been made, based upon one or another difference in microscopical structure and reaction, but at present the system most used is that adopted by Ehrlich.f According to this nomenclature, the white cor- * For the extensive literature see Van Voornveld. ' ' Das Blut im Hoch- gebirge, " " Pfliiger's Archiv," 92, 1, 1902; Zuntz et al., "Hohenklima und Bergwanderungen in ihrer Wirkung auf den Menschen, " 1906. t Ehrlich, "Die Anaemie, " 1898; see also Seemann, "Ergebnisse der Physiologic, " 3, part I., 1904. 28 434 BLOOD AND LYMPH. puscles fall into two main groups, — the lymphocytes and the leucocytes, — and each of these into two or more subgroups. Thus: I. Lymphocytes. No granules in the cell substance, and, though capable of ameboid changes of form, this property is not characteristic and prob- ably not sufficient to cause locomotion. (a) Small lymphocytes are about the size of the red corpuscles; the nu- cleus is large, symmetrically placed, stains homogeneously, and the cytoplasm is reduced to a very small amount. They form from 20 to 25 per cent, of all the white corpuscles. (jb) Large lymphocytes. Two to three times as large a9 the preceding. Nucleus somewhat eccentric; the cytoplasm is relatively more abundant than in a, but non-granular. These forms exist only in small numbers, forming 1 per cent, or less of the white corpuscles. II. Leucocytes. Granules of different sorts found in the cytoplasm. Cells characteristically ameboid. (a) Transition forms (uninuclear leucocytes). Single large nucleus, more or less lobulated; cytoplasm abundant and faintly granulated. The granules stain with neutral dyes and are therefore designated as neutrophile granules. The name, transition form, implies that these leucocytes represent an intermediate stage between the large lympho- cytes and the following variety, but this belief is vigorously denied by many competent hematologists. This form exists in small numbers — 2 to 10 per cent, of the total number of white corpuscles. (6) Polynuclear or polymorphonuclear leucocytes. The nucleus is seg- mented into lobes connected by narrow strands. The cytoplasm is especially ameboid and is granular. The granules in most cases are neutrophilic and small in size. The typical cells of this kind form the bulk of the white corpuscles of the blood, — 60 to 75 per cent. Eosinophilic leucocytes form a subgroup of this variety. They have a similar segmented nucleus, but the cytoplasm contains nu- merous coarse granules that stain in acid dyes, such as eosin, whence the name. (c) Mast cells. These peculiar cells exist in very small numbers under normal conditions, — less than 1 per cent, of the total number of white corpuscles. They have a polymorphic nucleus like the pre- ceding group, but differ in the fact that the granules in the cyto- plasm are strongly basophilic, — that is, will stain only with basic dyes, such as thionin. Opinions differ greatly as to whether these different varieties of leukocytes have a common origin or represent really different types distinct in origin and in functional activity. According to some authors the small lymphocytes are cells that have an origin and function different from those of the granular leucocytes. While the latter are supposed to originate from cells (leucoblasts, myeloblasts) in the bone-marrow, the lymphocytes are produced in the nodules of the lymph glands and lymphoid tissue, and enter the blood through the lymph circulation. Others, however, lay stress on the fact that lymphocytes occur in the bone- marrow and hold that it is possible or probable that the lympho- cytes of the blood may be derived from the marrow tissue as well as from the lymphoid tissue. Moreover, it is stated by competent observers that transitional forms between the lymphocytes and leucocytes can be observed even in the circulating blood. The GENERAL PROPERTIES: THE CORPUSCLES. 435 subject is one that at present is discussed chiefly in connection with the pathology of blood diseases.* Variations in Number. — Under normal conditions the total number of leucocytes may show considerable variation; the aver- age number in health varies usually between 5000 and 7000 per cubic millimeter. A distinct increase in number is designated as a condition of leucocytosis, a marked diminution as a condition of leucopenia. Leucocytosis occurs under various normal conditions, such as digestion, exercise or cold baths, pregnancy, etc. The variations, relative or absolute, under pathological conditions, have been studied with exhaustive care as an aid to diagnosis and classi- fication. Functions of the Leucocytes. — Perhaps the most striking property of the leucocytes as a class is their power of making ameboid movements, — a characteristic which has gained for them the sobriquet of "wandering" cells. By virtue of this property some of them are able to migrate through the walls of blood capil- laries into the surrounding tissues. This process of migration takes place normally, but is vastly accelerated under pathological con- ditions. As to the function or functions fulfilled by the leucocytes, numerous suggestions have been made, some of which may be stated in brief form as follows: (1) They protect the body from pathogenic bacteria and other foreign cells or organisms. In explanation of this action it has been suggested that they may either ingest bacteria, and thus destroy them directly, or they may form certain substances, bacteriolysins, that destroy the bacteria. The wonderful protective adaptation of the body des- ignated by the term "biological reaction" has already been referred to (p. 416). The formation of immune substances in the blood is attributed, in part at least, to the leucocytes. Leucocytes that act by ingesting the bacteria are spoken of as " phagocytes " ( / \\ / / 100 Erythrocytes Fig. 186. — To show the effect of hemorrhage upon the number of red and white cor- puscles and the amount of hemoglobin. — (Dawson.) The ordinates express the numbers of corpuscles and also the percentages of hemoglobin as stated in the figures to the left. The abscissas give the days after hemorrhage. The experiment was made upon a dog of 8.1 kgms. The hemorrhage, which lasted 2.3 minutes, was equal to 4.3 per cent, of the body-weight. An equal amount of physiological saline (NaCl, 0.8 per cent.) was injected immediately. show more or less individual variation, it may be said that in dogs a hemorrhage of from 2 to 3 per cent, of the body-weight* is re- covered from easily, while a loss of 4.5 per cent., more than half the entire blood, will probably prove fatal. In cats a hemorrhage of from 2 to 3 per cent, of the body-weight is not usually followed by a fatal result. Just what percentage of loss may be borne by the human being has not been determined, but it is probable that a healthy individual may recover without serious difficulty from the loss of a quantity of blood amounting to as much as 3 per cent, of * Frederic, "Travaux du Laboratoire" (Universite de Liege), 1, 189, 1885. 460 BLOOD AND LYMPH. the body-weight. It is known that if liquids that are isotonic to the blood, such as physiological saline (NaCI, 0.7 to 0.9 per cent.) or Ringer's solution, are injected into the veins immediately after a severe hemorrhage, recovery is more certain; in fact, it is possible by this means to restore persons after a hemorrhage that would otherwise have been fatal. By an infusion of this kind, particularly if at or somewhat above the body temperature, the heart beat is increased, the volume of the circulating liquid is brought to an amount sufficient to maintain approximately normal conditions of pressure and velocity, and the red corpuscles that still remain are kept in more rapid circulation and are thus utilized more completely as oxygen carriers. If a hemorrhage has not been fatal, experiments on lower animals show that the plasma of the blood is regenerated with some rapidity, the blood regaining its normal vol- ume within a few hours in slight hemorrhages, and in from twenty- four to forty-eight hours if the loss of blood has been severe; but the number of red corpuscles and the hemoglobin are restored more slowly, getting back to normal only after a number of days or after several weeks. The accompanying curves illustrate the results of a severe hemorrhage (4.3 per cent, of the body-weight) followed by transfusion of an equal volume of physiological saline. So far as the red corpuscles and the amount of hemoglobin are concerned, it will be noticed that the large sudden fall from the hemorrhage, first day, is followed by a slower drop in both factors during the second and third days. This latter phenomenon constitutes what is known as the posthemorrhagic fall.* Blood-transfusion. — Shortly after the discovery of the circu- lation of the blood (Harvey, 1628), the operation was introduced of transfusing blood from one individual to another or from some of the lower animals to man. Extravagant hopes were held as to the value of such transfusion not only as a means of replacing the blood lost by hemorrhage, but also as a cure for various infirmities and diseases. Then and subsequently fatal as well as successful results followed the operation. So far as the use of the blood of another animal is concerned, it is now known to be a dangerous undertaking, mainly for two reasons: first, the strange blood, whether transfused directly or after defibrination, is liable to con- tain a quantity of thrombin sufficient, perhaps, to cause intravas- cular clotting; second, the serum of one animal may be toxic to another or cause a destruction of its blood corpuscles. Owing to this hemolytic and toxic action, which has previously been referred to (p. 415), the injection of foreign blood is likely to be directly injurious instead of beneficial. In human surgery modern technic (Carrel) has overcome some of the difficulties formerly * Dawson, "American Journal of Physiology," 4, 1, 1900. BLOOD-TRANSFUSION. 461 encountered in the transfusion of blood from one human being to another. Anastomoses may be made between the blood-vessels of the " donor " and the " recipient," so that the blood passes from one to the other without coming into contact with a foreign sur- face and, therefore, without danger of coagulation or the formation of thrombin. In cases of loss of blood from severe hemorrhage it is far simpler and usually quite sufficient to inject a neutral liquid, such as the so-called " physiological salt solution " — a solution of sodium chlorid of such a strength (0.7 to 0.9) as will suffice to prevent hemolysis of the red corpuscles. CHAPTER XXIV. COMPOSITION AND FORMATION OF LYMPH. Lymph is a colorless liquid found in the lymph- vessels as well as in the extravascular spaces of the body. All the tissue elements, in fact, may be regarded as being bathed in lymph. To understand its occurrence in the body one has only to bear in mind its method of origin from the blood. Throughout the entire body there is a rich supply of blood-vessels penetrating every tissue with the ex- ception of the epidermis and some epidermal structures, as the nails and the hair. The plasma of the blood, by the action of physical or chemical processes, the details of which are not yet entirely under- stood, makes its way through the thin walls of the capillaries, and is thus brought into immediate contact with the tissues, to which it brings the nourishment and oxygen of the blood and from which it removes the waste products of metabolism. This extravascular lymph is collected into small capillary spaces which in turn open into definite lymphatic vessels. It is still a question among the his- tologists whether the lymph- vessels form a closed system or are in direct anatomical connection with the tissue spaces. Modern work* supports the view that the lymph capillaries are closed vessels similar in structure to the blood capillaries. They end in the tissues generally, but are not in open communication with the spaces between the cellular elements or with the larger serous cavities between the folds of the peritoneum, pleura, etc., or with the spaces between the meningeal membranes surrounding the central nervous system. From the physiological standpoint, however, the liquid in these latter cavities, the cerebrospinal liquid and the liquid bathing the tissue elements, must be regarded as a part of the general supply of lymph and as being in communication with the liquid contained in the lymph- vessels. That is to say, the water and the dissolved substances contained in the tissue spaces interchange more or less freely with the lymph proper found in the formed lymph-vessels. The lymph-vessels unite to form larger and larger trunks, making eventually one main trunk, the thoracic or left lymphatic duct, * See Sabin, "American Journal of Anatomy," 1, 367, 1902, and 3, 183, 1904; also "General and Special Anatomy of the Lymphatics," from Poirier and Charpy, translated by Leaf, 1904. 462 COMPOSITION AND FORMATION OF LYMPH. 463 and a second smaller right lymphatic duct, which open into the blood-vessels, each on its own side, at the junction of the sub- clavian and internal jugular veins. While the supply of lymph in the lymph-vessels may be considered as being derived ulti- mately entirely from the blood-plasma, it is well to bear in mind that at any given moment this supply may be altered by direct interchange with the plasma on one side and the extravascular lymph permeating the tissue elements on the other. The intravascular lymph may be augmented, for example, by a flow of water from the blood-plasma into the lymph-spaces, and thence into the lymph-vessels, or by a flow from the tissue elements into the lymph-spaces that surround them. The lymph movement is from the tissues to the veins, and the flow is main- tained chiefly by the difference in pressure between the lymph at its origin in the tissues and in the large lymphatic vessels. The continual formation of lymph in the tissues leads to the development of a relatively high pressure in the lymph capil- laries, and as a result of this the lymph is forced toward the point of lowest pressure — namely, the points of junction of the large lymph-ducts with the venous system. A brief discussion of the factors concerned in the movement of lymph will be found in the section on Circulation. As would be inferred from its origin, the composition of the intravascular lymph is essentially the same as that of blood-plasma. It contains the three blood proteins, the extractives (urea, fat, lecithin, cholesterin, sugar), and inorganic salts. The salts are found in the same proportions as in the plasma; the proteins are less in amount, especially the fibrinogen. Lymph coagulates, but does so more slowly and less firmly than the blood. Histologically, lymph consists of a colorless liquid containing a number of leucocytes, and after meals a number of minute fat droplets; red blood corpuscles occur only accidentally, and blood-plates, according to most accounts, are likewise normally absent. The composition of the exudative liquids of the body, such as the pericardial liquid, the synovial liquid, the aqueous humor, the cerebrospinal liquid, etc., which are sometimes classed under the general term lymph, may vary greatly; thus, the cerebrospinal liquid possesses no morphological elements, contains no fibrinogen, and, therefore, does not clot, and, indeed, has only minute traces of protein of any kind. Formation of Lymph. — -The careful researches of Ludwig and his pupils were formerly believed to prove that the lymph is derived directly from the plasma of the blood mainly by filtration through the capillary walls. Emphasis was laid on the undoubted fact that the blood within the capillaries is under a pressure higher than that 464 BLOOD AND LYMPH. prevailing in the tissues outside, and it was supposed that this excess of pressure is sufficient to squeeze the plasma of the blood through the very thin capillary walls. Various conditions that alter the pressure of the blood were shown to influence the amount of lymph formed in accordance with the demands of a theory of filtration. Moreover, the composition of lymph as usually given seems to sup- port such a theory, inasmuch as the inorganic salts contained in it are in the same concentration, approximately, as in blood-plasma, while the proteins are in less concentration, following the well- known law that in the filtration of colloids through animal mem- branes the filtrate is more dilute than the original solution. This simple and apparently satisfactory theory has been subjected to critical examination within recent years, and it has been shown that filtration alone does not suffice to explain the composition of the lymph under all circumstances. At present two divergent views are held upon the subject. According to some physiologists, all the facts known with regard to the composition of lymph may be satisfactorily explained if we suppose that this liquid is formed from blood-plasma by the combined action of the physical processes of filtration, diffusion, and osmosis. According to others, it is believed that, in addition to filtration and diffusion, it is necessary to assume an active secretory process on the part of the endothe- lial cells composing the capillary walls. The actual condition of our knowledge of the subject can be presented most easily by briefly stating some of the objections that have been raised by Heidenhain* to a pure filtration-and-diffusion theory, and indicating how these objections have been met. 1. Heidenhain showed by simple calculations that an impossible formation of lymph would be required, upon the filtration theory, to supply the chemical needs of the organs in various organic and in- organic constituents. Thus, to take an illustration that has been much discussed, one kilogram of cows' milk contains 1.7 gms. CaO and the entire milk of twenty-four hours would contain, in round numbers, 42.5 gms. CaO. Since the lymph contains normally about 0.18 part of CaO per thousand, it would require 236 liters of lymph per day to supply the necessary CaO to the mammary glands. Heidenhain himself suggests that the difficulty in this case may be met by assuming active diffusion processes in connection with filtration. If, for instance, in the case cited, we suppose that the calcium of the lymph is quickly combined by the tissues of the mam- mary gland, then the diffusion tension of calcium salts in the tissue will be kept at zero, and an active diffusion of calcium into the lymph will occur so long as the gland is secreting. In other words, the gland will receive its calcium by much the same process as it ♦"Archiv f. die gesammte Physiologie," 49, 209, 1891. COMPOSITION AND FORMATION OF LYMPH. 465 reoeives its oxygen, and will get its daily supply from a compara- tively small bulk of lymph. Strictly speaking, therefore, the difficulty we are dealing with here shows only the insufficiency of a pure filtration theory. It seems possible that nitration and diffusion together would suffice to supply the organs, so far at least as the diffusible substances are concerned. 2. Heidenhain found that occlusion of the inferior vena cava causes not only an increase in the flow of lymph — as might be ex- pected, on the filtration theory, from the consequent rise of pressure in the capillary regions — but also an increased concentration in the percentage of protein in the lymph. This latter fact has been satisfactorily explained by the experiments of Starling * Accord- ing to this observer, the lymph formed in the liver is normally more concentrated than that of the rest of the body. The occlusion of the vena cava causes a marked rise in the capillary pressure in the liver, and most of the increased lymph-flow under these circum- stances comes from the liver; hence the greater concentration. The results of this experiment, therefore, do not antagonize the filtration-and-diffusion theory. 3. Heidenhain discovered that extracts of various substances, which he designated as " lymphagogues of the first class," cause a marked increase in the flow of lymph from the thoracic duct, the lymph being more concentrated than normal, and the increased flow continuing for a long period. Nevertheless, these substances cause little, if any, increase in general arterial pressure; in fact, if injected in sufficient quantity they produce usually a fall of arterial pressure. The substances belonging to this class comprise such things as pep- tone, egg-albumin, extracts of liver and intestine, and especially extracts of the muscles of crabs, crayfish, mussels, and leeches. Heidenhain supposed that these extracts contain an organic substance which acts as a specific stimulus to the endothelial cells of the capillaries and increases their secretory action. The results of the action of these substances has been differently explained by those who are unwilling to believe in the secretion theory. Starling f finds experimentally that the increased flow of lymph in this case, as after obstruction of the vena cava, comes mainly from the liver. There is at the same time in the portal area an increased pressure that may account in part for the greater flow of lymph; but, since this effect upon the portal pressure lasts but a short time, while the greater flow of lymph may continue for one or two hours, it is obvious that this factor alone does not suffice to explain the result of the injections. Starling suggests, therefore, that these extracts act pathologically upon the blood capillaries, particularly those of * "Journal of Physiology," 16, 234, 1894. t Ibid., 17, 30, 1894. 30 466 BLOOD AND LYMPH. the liver, and render them more permeable, so that a greater quantity of concentrated lymph flows through them. Starling's explanation is supported by the experiments of Popoff.* According to this observer, if the lymph is collected simultaneously from the lower portion of the thoracic duct, which conveys the lymph from the abdominal organs, and from the upper part, which contains the lymph from the head, neck, etc., it is found that injection of peptone increases the flow only from the abdominal organs. Popoff finds also that the peptone causes a dilatation in the intestinal circulation and a marked rise in the portal pressure. At the same time there is some evidence of injury to the walls of the blood- vessels from the occurrence of extravasations in the intestine. As far, therefore, as the action of the lymphagogues of the first class is concerned, it may be said that the advocates of the filtration-and- diffusion theory have suggested a plausible explanation in accord with their theory. The facts emphasized by Heidenhain with regard to this class of substances do not compel us to assume a secretory function for the endothelial cells. 4. Injection of certain crystalline substances — such as sugar, sodium chlorid and other neutral salts — causes a marked increase in the flow of lymph from the thoracic duct. The lymph in these cases is more dilute than normal, and the blood- plasma also becomes more watery, thus indicating that the increase in water comes from the tissues themselves. Heidenhain designated these bodies as "lymphagogues of the second class." His explanation of their action is that the crystalloid materials introduced into the blood are eliminated by the secretory activity of the endothelial cells, and that they then attract water from the tissue liquid, thus augmenting the flow of lymph. These substances cause but little change in arterial blood-pressure ; hence Heidenhain thought that the greater flow of lymph can not be explained by an increased filtration. Starling f has shown, however, that, although these bodies may not seriously alter general arterial pressure, they may greatly augment intracapillary pressure, particularly in the abdominal organs. His explanation of the greater flow of lymph in these cases is as follows : " On their injection into the blood the osmotic pressure of the circu- lating fluid is largely increased. In consequence of this increase water is attracted from lymph and tissues into the blood by a process of osmosis, until the osmotic pressure of the circulating fluid is restored to normal. A condition of hydremic plethora is thereby produced, attended with a rise of pressure in the capillaries generally, especially in those of the abdominal viscera. This rise of pressure will be proportional to the increase in the volume of the blood, and * "Centralblatt f. Physiologie, " 9, No. 2, 1895. t hoc. cit. COMPOSITION AND FORMATION OF LYMPH. 467 therefore to the osmotic pressure of the solutions injected. The rise of capillary pressure causes great increase in the transudation of fluid from the capillaries, and therefore in the lymph-flow from the thoracic duct." This explanation is well supported by experi- ments, and seems to obviate the necessity of assuming a secretory action on the part of the capillary walls. 5. Numerous other experiments have been devised by Heidenhain and his followers to show that the physical laws of filtration, diffu- sion, and osmosis do not suffice to explain the production of lymph; but in all these cases possible explanations have been suggested in terms of the physical laws, so that it may be said that the facts do not compel us to assume a secretory activity on the part of the endothelial cells of the capillaries. Asher* and his co-workers have brought forward many facts to show that the lymph is controlled as to its amount by the activity of the tissue elements and may be considered as a product of the activity of the tissues, as a secretion, in fact, of the working cells. When the salivary glands, the liver, etc., are in greater functional activity the flow of lymph from them is increased beyond doubt, so that the activity of the organs does influence most markedly the production of lymph. Most physiologists, however, prefer to explain this relationship on the view suggested by Koranyi, Starling, and others, — namely, that in the metabolic changes of functional activity the large molecules of protein, fat, etc., are broken down to a number of simpler ones, the number of particles in solution is increased and therefore the osmotic pressure is increased. According to most observers the molecular concentration of the lymph in the thoracic duct, and, therefore, the osmotic pressure, is greater than that of the blood. Thus Botazzi,f in one experiment, reports that the lowering of the freezing-point of the blood-serum was A =0.595° C, while that of the lymph from the thoracic duct of the same animal was A =0.615° C. Back in the tissues, where phys- iological oxidations are going on, this difference is probably greater, and greater in proportion to the activity of the tissues. We can understand that in this way functional activity of an organ may result in attracting more water from the blood-capil- laries into the tissue spaces and may thus cause an augmented flow of lymph. The liquid of the tissues may be drained off not only through the lymph-vessels but also through the blood- vessels. That liquids injected directly into the tissues or special substances dissolved in such liquids may be absorbed directly by the blood has long been known. Magendie, for example, * "Zeitschrift f. Biologie," vols, xxxvi-xl. 1897 to 1900. t Quoted from Magnus, "Handbuch der Biochemie," 1908, vol. ii.2 (Formation of Lymph) . 468 BLOOD AND LYMPH. proved that when a poison was injected into an organ which was connected with the rest of the body only by its blood-vessels, the animal quickly showed the symptoms of a corresponding intoxication. Ordinary hypodermic injections are absorbed much more quickhr into the general circulation than would be the case if they were obliged to traverse the lymph-vessels and enter the blood through the thoracic duct. Meltzer has shown that this absorption by the blood from the tissue spaces takes place with especial promptness if the injection is made into a mass of muscular tissue. The liquid in the extravascular tissue spaces is, in fact, sub- ject to a play of influences from several sides, and it is the bal- ance among these competing influences which determines at any time the amount and composition of this tissue lymph. Thus, the supply of this liquid is furnished, on the one hand, by water and dissolved substances coming to it from the blood in the capillaries, on the other hand, by water and dissolved substances derived from the great reservoir contained in the tissue cells. The amount of the tissue lymph is continually depleted on the other side by water and dissolved substances passing back into the capillaries, or into the tissue elements, or, finally, into the lymph capillaries. The amount that passes by this latter route varies greatly in the different tissues, and in the same tissue may be influenced greatly by pathological as well as normal changes in conditions. Summary of the Factors Controlling the Flow of Lymph. — We may adopt, provisionally at least, the so-called mechanical theory of the origin of lymph. Upon this theory the forces in activity are, first, the intracapillary pressure tending to filter the plasma through the endothelial cells composing the walls of the capillaries; second, the force of diffusion depending upon the inequality in chemical composition of the blood-plasma and the liquid outside the capillaries, or, on the other side, between this latter liquid and the contents of the tissue elements; third, the force of osmotic pressure, which varies with the molecular concentration. These three forces acting everywhere control primarily the amount and composition of the lymph; but still another factor must be considered; for when we come to examine the flow of lymph in different parts of the body striking differ- ences are found. It has been shown, for instance, that in the limbs, under normal conditions, the flow is extremely scanty, while from the liver and the intestinal area it is relatively abundant. In fact, the lymph of the thoracic duct may be considered as being derived almost entirely from the latter two regions. Moreover, the lymph from the liver is characterized by COMPOSITION AND FORMATION OF LYMPH. 469 a greater percentage of proteins. To account for these differences Starling suggests the plausible explanation of a variation in permea- bility in the capillar}7 walls. The capillaries seem to have a similar structure all over the body so far as this is revealed to us by the microscope, but the fact that the lymph-flow varies so much in quantity and composition indicates that the similarity is only superficial, and that in different organs the capillar}- walls may have different internal structures, and therefore different permea- bilities. This factor is evidently one of great importance. The idea that the permeability of the capillaries may vary under dif- ferent conditions has long been used in pathology to explain the production of that excess of lymph which gives rise to the condition of dropsy or edema. The theories and experiments made in con- nection with this pathological condition have, in fact, a direct bearing upon the theories of lymph formation.* Under normal conditions the lymph is drained off as it is formed, while under pathological conditions it may accumulate in the tissues owing either to an excessive formation of lymph or to some interruption in its circu- lation. The scanty flow of lymph from the limbs has been referred by Magnusf to another possible cause, namely, to the great capacity of the muscular tissue to imbibe water (and salts). According to this author the tissues, particularly the muscular tissues, constitute great reservoirs in which excess of water and salts may be stored. If, for example, a hypotonic solution of sodium chloride is injected into the circulation, most of the water added will be removed from the circulation by imbibition into the muscular tissues. In the limbs, with their large supply of muscular tissue, it may be that lymph is formed as elsewhere from the blood plasma, but it is held back from the lymph-vessels by absorption into the muscular mass. From the foregoing considerations it is evident that changes in capillary pressure, however produced, may alter the flow of lymph from the blood-vessels to the tissues, by increasing or decreasing, as the case may be, the amount of filtration; changes in the composition of the blood, such as follow periods of digestion, will cause diffusion and osmotic streams tending to equalize the composition of blood and lymph; and changes in the tissues them- selves following upon physiological or pathological activity will also disturb the equilibrium of composition, and, therefore, set up diffusion and osmotic currents. In this way a continual interchange is taking place by means of which the nutrition of the tissues is * Consult Meltzer, "Edema" ("Harrington Lectures"), "American Medicine," 8, Xos. 1, 2, 4- and 5, 1904. t Magnus, Loc tit. 470 BLOOD AND LYMPH. effected, each according to its needs. The details of this interchange must of necessity be very complex when we consider the possibilities of local effects in different parts of the body. The total effects of general changes, such as may be produced experimentally, are simpler, and, as we have seen, are explained satisfactorily by the physical and chemical factors enumerated. SECTION V. PHYSIOLOGY OF THE ORGANS OF CIRCULA- TION OF THE BLOOD AND LYMPH. The heart and the blood-vessels form a closed vascular system containing a certain amount of blood. This blood is kept in endless circulation mainly by the force of the muscular contractions of the heart. But the bed through which it flows varies greatly in width at different parts of the circuit, and the resistance offered to the moving blood is very much greater in the capillaries than in the large vessels. It follows from the irregularities in size of the chan- nels through which it flows that the blood-stream is not uniform in character throughout the entire circuit; indeed, just the opposite is true. From point to point in the branching system of vessels the blood varies in regard to its velocity, its head of pressure, etc. These variations are connected in part with the fixed structure of the system and in part are dependent upon the changing properties of the living matter of which the system is composed. It is con- venient to consider the subject under three general heads: (1) The purely physical factors of the circulation, — that is, the me- chanics and hydrodynamics of the flow of a definite quantity of blood through a set of fixed tubes of varying caliber under certain fixed conditions. (2) The general physiology of the heart and the blood-vessels, — that is, mainly the special properties of the heart muscle and the plain muscle of the blood-vessels. (3) The innerva- tion of the heart and the blood-vessels, — that is, the variations in the circulation produced by the action of the nervous system. CHAPTER XXV. THE VELOCITY AND PRESSURE OF THE BLOOD-FLOW, The Circulation as Seen Under the Microscope. — It is a comparatively easy matter to arrange a thin membrane in a living animal so that the flowing blood may be observed with the aid of a microscope. For such a purpose one generally employs the web between the toes of a frog, or better still the mesentery, lungs, or 471 472 CIRCULATION OF BLOOD AND LYMPH. bladder of the same animal. With a good preparation many important peculiarities in the blood-flow may be observed directly. If the field is properly chosen one may see at the same time the flow in arteries, capillaries, and veins. It will be noticed that in the arteries the flow is very rapid and somewhat intermittent, — that is, there is a slight acceleration of velocity, a pulse, with each heart beat. In the capillaries, on the contrary, the flow is relatively very slow; the change from the rushing arterial stream to the deliber- ate current in the capillaries takes place, indeed, with some suddenness. The capillary flow, as a rule, shows no pulses corre- sponding with the heart beats, but it may be more or less irregular, ■ — that is, the flow may nearly cease at times in some capillaries, while again it maintains a constant flow. In the veins the flow increases markedly in rapidity, and indeed it may be observed that, the larger the vein, the more rapid is the flow. There is not, however, as a rule, any indication of an intermittence or pulse in this flow, — the velocity is entirely uniform. In both arteries and veins it will be noticed that the red corpuscles form a solid column or core in the middle of the vessel, and that between them and the inner wall there is a layer of plasma containing only, under normal conditions, an occasional leucocyte. The accumulation of cor- puscles in the middle of the stream makes what is known as the axial stream, while the clear layer of plasma is designated as the inert layer. The phenomenon is readily explained by physical causes. As the blood flows rapidly through the small vessels the layers nearer the wall are slowed by adhesion, so that the greatest velocity is attained in the middle or axis of the vessel. The cor- puscles, being heavier than the plasma, are drawn into this rapid part of the current. It has been shown by physical experiments that, when particles of different specific graAdties are present in a liquid flowing rapidly through tubes, the heavier particles will be found in the axis and the lighter ones toward the periphery. In accordance with this fact, leucocytes, which are lighter than the red corpuscles, may be found in the inert layer. When the con- ditions become slightly abnormal (incipient inflammation) the leucocytes increase in number in the inert layer sometimes to a very great extent, owing apparently to some alteration in the endothelial walls whereby the leucocytes are rendered more ad- hesive. The agglutination of the leucocytes and their migration through the walls into the surrounding tissues are described in works on Pathology. The Velocity of the Blood-flow. — The microscopical observa- tions described above show that the velocity of the blood-current varies widely, being rapid in the arteries and veins and slow in the capillaries. To ascertain the actual velocity in the larger vessels and the variations in vessels of different sizes experimental de- VELOCITY AND PRESSURE OF BLOOD-FLOW. 473 terminations are necessary. While the general principle involved in these determinations is simple, their actual execution in an experiment is attended with some difficulties, and various devices have been adopted. The most direct method per- haps is that used in the in- strument devised by Ludwig, — ■ namely, the stromuhr. The prin- ciple used is to cut an artery or vein of a known size and de- termine how much blood flows out in a given time. We may define the velocity of the blood at any point as the length of the column of blood flowing by that point in a second. If we cut the artery there a cylindri- cal column of blood of a defi- nite length and with a cross-area equal to that of the lumen of the artery will flow out in a second. The volume of the outflow can be determined di- rectly by catching the blood. Knowing this volume and the cross-area of the artery, we can determine the length of the column — that is, the velocity of the flow — since in a cylinder the volume, V, is equal to the product of the length into the cross-area. V = length X cross-area, or V length = cross-area Fig. 187. — Ludwig's stromuhr: a and b, The glass bulbs; a is filled with oil to the mark (5 c.c), while b and the neck are filled with salt solution or defibrinated blood; p, the movable plate by means of which the bulbs may be turned through 180 degrees, c, c, for the cannulas inserted into the artery; s. the thumb screw for turning the bulbs; h, the holder. When in place the clamps on the arteries are removed, blood flows through c into a, driving out the oil and forcing the salt solution in b into the head end of the artery through c'. When the blood entering a reaches the mark, the bulb' are turned through 180 degrees so that b lies over c. The blood flows into b and drives the oil back into a. When it just fills this bulb, they are again rotated through 180 degrees, and so on. The oil is driven out of and into a a given number of times, each movement being equal to an outflow of 5 c.c. of blood. When the instrument has been turned, say, ten times, 50 c.c. of blood have flowed out. Knowing the time and the caliber of the artery, the calculation is made as described in the text. Several modifi- cations of the form of this instrument have been devised. We cannot, of course, make the experiment in this simple way upon a living animal; the loss of so much blood would at once change the physical and physiological conditions of the circula- tion, and would give us a set of conditions at the end of the experi- *A modification by Tigerstedt is described in the " Skandinavisches Archiv f. Physiol./' 3, 152, 1891. One by Burton-Opitz in the "Arch. f. d. ges. Physiologie," 121, 151, 1908. 474 CIRCULATION OF BLOOD AND LYMPH. ment different from those at the beginning. By means of the stromuhr, however, this experiment can be made, with this important variation, that the blood that flows from the central end of the cut artery is returned to the peripheral end of the same artery, so that the circulation is not blocked nor deprived of its normal volume of liquid. The instrument, as is explained in the legend of Fig. 187, measures the volume of blood that flows out of the cut end of an artery in a definite time. The calculation for velocity is made as follows: Suppose that the capacity of the bulb is 5 c.c, and that in the experiment it has been filled 10 times in 50 seconds, — i. e., the bulbs have been reversed 10 times; then obviously 10 X 5 or 50 c.c. have flowed out of the artery in this time, or 1 c.c. in 1 second. The diameter of the vessel can be meas- ured, and if found equal, say, to 2 mms., then its cross-area is rr2 = 3.15 X 1 = 3.15. Since 1 c.c. equals 1000 c.mm., the length of our cyl- inder of blood would be given by the quotient of ^- = 317 mms. So that the blood in this case was moving with the velocity of 317 mms. per second. Another instru- ment that has been employed for the same purpose is the dromograph or hemodromograph of Chauveau. This instrument is represented in the accompanying figure (Fig. 188). A rigid tube (p-c) is placed in the course of the artery to be examined. This tube is provided with an offset (a) the opening of which is closed with rubber dam (m). The rubber dam is pierced by a needle the lower end of which terminates in a small plate lying in the tube (pi). When the instrument is in place and the blood is allowed to stream through the tube, it deflects the needle, which turns on its insertion through the rubber as a ful- crum. The angle of deflection of the free end of the needle may be measured directly upon a scale or it may be transmitted through tambours and recorded upon a kymographion. The in- strument must, of course, be graduated by passing through it cur- pl Fig. 188. — Chauveau's hemodromo- graph (after Langendorff) . The tube, p-c, is placed in the course of an ar- tery, the blood after removal of clamps flowing in the direction shown by the arrow. The current strikes the plate, pi, and forces it to an angle varying with the velocity. The movement of pi is transmitted through the stem, n, which moves in a rubber membrane as a fulcrum, m. The angular move- ment of the projecting end of n may be measured directly or may be made to act upon a tambour, as shown in the figure, and thus be transmitted to a recording drum. VELOCITY AND PRESSURE OF BLOOD-FLOW. 475 rents of known velocity, so that the angle of deflection may be expressed in terms of absolute velocities. It possesses the great advantage over the stromuhr that it gives not simply the average velocity during a given time, but also the variations in velocity coincident with the heart beat or other changes that may occur during the period of observation. Efforts have been made to devise a method for the determination of the velocity of the blood-flow in the arteries of man. The method used, however, depends upon certain assumptions that are not entirely certain and the re- sults obtained, therefore, can not be used with confidence. The principle of the method consists * in determining the volume of the arm by placing it in a plethysmograph. Assuming that the outflow from the veins is constant in the part of the arm inclosed, then the variations in volume of the arm may be referred to the greater inflow of blood into this part through the arteries. The curve showing the variations in volume may, therefore, under proper conditions, be interpreted in terms of velocity changes. Mean Velocity of the Blood-flow in the Arteries, Veins, and Capillaries. — Actual determinations of the average velocity in the large arteries and veins give such results as the following: Carotid of horse (Volkmann), 300 mms. per second; (Chauveau) 297 mms. Carotid of the dog (Vierordt), 260 mms. The flow in the carotid, as in the other large arteries, is not, however, uniform; there is a marked acceleration or pulse at each systole of the heart during which the velocity is greatly augmented. Thus, in the carotid of the horse it has been shown by the hemo- dromograph that during the systole the velocity may reach 520 mms. and may fall to 150 mms. during the diastole. It is found, also, that this difference between the systolic velocity and the diastolic velocity tends to disappear as the arteries become smaller, and, as was said above, disappears altogether in the capillaries, in which the pulse caused by the heart beat is lacking. The smaller the artery, therefore, the more uniform is the movement of the blood. The flow in the large veins is uniform or approximately uniform and increases as one approaches the heart, although the velocity in the large veins near the heart is somewhat slower than in the large arteries of the same region, owing to the fact that the total area of the venous bed is larger than that of the arterial bed. Burton-Opitzf gives the following average figures obtained from experiments upon anesthetized dogs. Jugular, 147 mms.; femoral, 61.6 mms.; renal, 63 mms.; mesenteric vein, 84.9 mms. In the capillaries, however, the velocity is relatively very small. From direct observations made by means of the microscope and from indirect observations in the case of man, the capillary velocity is estimated as lying between 0.5 mm. and 0.9 mm. per sec. * Von Kries, " Archiv f. Physiologie, " 1887, 279; also Abeles, ibid., 1892, 22. t Burton-Opitz, "Am. Journal of Physiology," vols. 7 and 9, and "Pfliiger's Archiv," vols. 123 and 124, 1908. 476 CIRCULATION OF BLOOD AND LYMPH. Vierordt reports some interesting calculations upon the velocity of the blood, in the capillaries of his own eye. Under suitable conditions,* the movements of the corpuscles in the retina may be perceived in consequence of the shadows that they throw upon the rods and cones. The visual images thus produced may be projected upon a surface at a known distance from the eye and the space traversed in a given time may be observed. The distance actually covered upon the retina may then be calculated by the following con- struction, in which A-B = the distance traveled by the projected image; A-n, the distance of the surface from the eye; and a-n, the distance of the retina from the nodal point of the eye. We have then the proportion ab : an :: AB:An, or ab = AB * an- An According to this method, Vierordt calculated that the velocity of the blood in the human capillaries is equal to about 0.6 to 0.9 mm. per second. In the arteries, more- ^it^- :<. «™„„ v. u i Fig. 189. — Diagram of the eye to show the con- Over, It may De Observed struction used to determine the size of the retinal tbnt tbp QvproTO -irolr.r.if-ir image when the size of the external object is known: inat Ilie average Velocity n> The nodal point of the eye. See text. diminishes the farther one goes from the heart, — that is, the smaller the artery,— and reaches its minimum when the arteries pass into the capillaries. Thus, Volkmann reports for the horse the following figures: Ca- rotid, 300 mms. ; maxillary, 232; metatarsal, 56 mms. In the veins also the same fact holds. The smaller the vein — that is, the nearer it is to the capillary region — the smaller is its velocity, the maxi- Fig. 190. — Schematic representation of the relative velocities of the blood-current in different parts of the vascular system: a, The arterial side, indicating the changes with each heart beat and the fall of mean velocity as the arterial bed widens; c, the capillary region — the great diminution in velocity corresponds with the great widening of the bed; v, the venous side, showing the gradual increase toward the heart, and represented as entirely uniform, although, as a matter of fact, the velocity in the large veins is affected by the respirations and to a small extent by the heart beat, owing to the phenomenon known as the venous pulse (p. 520). mum velocity being found in the vena cava. The general rela- tions of the velocity of the blood in the arteries, capillaries, and veins may be expressed, therefore, by a curve such as is shown in Fig. 190. * "Archiv f. physiologische Heilkunde," 15, 255, 1856. VELOCITY AND PRESSURE OF BLOOD-FLOW. 477 Explanation of the Variations in Velocity. — The general rela- tionship between the velocities in the different parts of the vascular system is explained by the difference in the width of the bed in which the blood flows. In the systemic circulation the main stem, the aorta, branches into arteries which, taken individually, are smaller and smaller as we approach the capillaries. But each time that an artery branches the sum of the areas of the two branches is greater than that of the main stem. The arterial system may be compared, in fact, to a tree, the sum of the cross-areas of all the twigs is greater than that of the main trunk. It follows, there- fore, that the blood as it passes to the capillaries flows in a bed or is distributed in a bed which becomes wider and wider, and as it returns to the heart in the veins it is collected into a bed that be- comes smaller as we approach the heart. Vierordt estimates that the combined calibers of all the capillaries in the systemic circula- tion would make a tube with a cross-area about 800 times as large as the aorta. If the circulation is proceeding uniformly it follows that for any given unit of time the same volume of blood must pass through any given cross-section of the system, — that is, at a given point in the aorta or vena cava as much blood must flow by in a second as passes through the capillary region — and that consequently where the cross-section or bed is widest the velocity is correspondingly diminished. If the capillary bed is 800 times that of the aorta, then the velocity in the capillaries is •g-^-g- of that in the aorta, — say, -g-g-g- of 320 mms. or 0.4 mm. Just as a stream of water flowing under a constant head reaches its greatest velocity where its bed is narrowest and flows more slowly where the bed widens to the dimensions of a pool or lake. Variations in Velocity with Changes in the Heart-beat or the Size of the Vessels. — While the above statement holds true as an explanation of the general relationship between the velocities in the arteries, veins, and capillaries at any given moment, the absolute velocities in the different parts of the system will, of course, vary whenever any of the conditions acting upon the blood-flow vary. In the large arteries, as has been said, there are extreme fluctua- tions in velocity at each heart beat; but if we consider only the average velocities it may be said that these will vary throughout the system with the force and rate of the heart beat, or with the variations in size of the small arteries and the resulting changes in blood-pressure in the arteries. Marey* gives the two following laws: (1) Whatever increases or diminishes the force with which the blood is driven from the heart toward the periphery will cause the velocity of the blood and the pressure in the arteries to vary in the same sense. (2) Whatever increases or diminishes the resis- tance offered to the blood in passing from the arteries (to the veins) * "La Circulation du Sang," Paris, 1881, p. 321. 478 CIRCULATION OF BLOOD AND LYMPH. will cause the velocity and the arterial pressure to vary in an inverse sense as regards each other. That is, an increased re- sistance diminishes the velocity in the arteries while increasing the pressure, and vice versa. The Time Necessary for a Complete Circulation of the Blood. — It is a matter of interest in connection with many physio- logical questions to have an approximate idea of the time necessary for the blood to make a complete circuit of the vascular system, — that is, starting from any one point to determine how long it will take for a particle of blood to arrive again at the same spot. In considering such a question it must be borne in mind that many different paths are open to the blood, and that the time for a complete circulation will vary somewhat with the circuit actually followed. For example, blood leaving the left ventricle may pass through the coronary system to the right heart and thence through the pulmonary system to the left heart again, or it may pass to the extremities of the toes before getting to the right heart, or it may pass through the intestines, in which case it will have to traverse three capillary areas before completing the circuit. It is obvious, there- fore, that any figures obtained can only be regarded as averages more or less exact. The experiments that have been made, however, are valuable in indicating how very rapidly any substance that enters the blood may be distributed over the body. The method first employed by Hering (1829) was to inject into the jugular vein of one side a solution of potassium ferrocyanid, and then from time to time specimens of blood were taken from the jugular vein of the opposite side. The first specimen in which the ferrocyanid could be detected by its reaction with iron salts gave the least time necessary for a complete circuit. The method was subsequently improved in its technical details by Vierordt, and such results as the following were obtained : Dog, 16.32 seconds; horse, 28.8 seconds; rabbit, 7.46 seconds ; man (calculated), 23 seconds. The time required is less in the small than in the large animals, and Hering and Vierordt con- cluded that in general it requires from 26 to 28 beats of the heart to effect a complete circulation. Stewart has devised a simpler and better method,* based upon the electrical conductivity of the blood. If a solution of a neutral salt, such as sodium chlorid, more concen- trated than the blood, is injected into the circulation, the con- ductivity of the blood is increased. If the injection is made at a given moment and a portion of the vessel to be examined is properly connected with a galvanometer so as to measure the electrical conductivity through it, then the instant that the solution of salt reaches this latter vessel the fact will be indicated by a deflection of the galvanometer. Using this method, Stewart was able to show that in the lesser circulation (the pulmonary circuit) the velocity * "Journal of Physiology," 15, 1, 1894. VELOCITY AND PRESSURE OF BLOOD-FLOW. 479 is very great compared with that of the systemic circulation — only about one-fifth of the time required for a complete circuit is spent in the lesser circulation. Attention may also be called to the fact that the important part of the circulation, as regards the nutritive activity of the blood, is the capillary path. It is while flowing through the capillaries that the chief exchange of gases and food material takes place. The average length of a capillary is estimated at 0.5 mm.; so that with a velocity of 0.5 mm. per second the average duration of the flow of any particle of blood through the capillary area is only about 1 sec. The Pressure Relations in the Vascular System. — That the blood is under different pressures in the several parts of the vascu- lar system has long been known and is easily demonstrated. When an artery is cut the blood flows out in a forcible stream and with spurts corresponding to the heart beats. When a large vein is wounded, on the contrary, although the blood flows out rapidly, the stream has little force. Exact measurements of the hydrostatic pressure under which the blood exists in the large arteries and veins were first published by Rev. Dr. Stephen Hales, an English clergy- man, in his famous book entitled "Statical Essays, containing Haemostaticks," 1733.* This observer measured the static pressure of the blood in the arteries and veins by the simplest direct method possible. After tying the femoral artery in a horse he connected it to a glass tube 9 feet in length. On opening the vessel the blood mounted in the tube to a height of 8 feet 3 inches, showing that normally in the closed artery the blood is under a tension or pressure sufficient to support the weight of a column of blood of this height. A similar experiment made upon the vein showed a rise of only 12 inches. Methods of Recording Blood-pressure. — Since Hales's work the chief improvements in method which have marked and caused the development of this part of the subject have been the application of the mercury manometer by Poiseuillef (1828), the invention of the recording manometer and kymographion by LudwigJ (1847), and the later numerous improvements by many physiologists, and latterly the development of methods for measuring blood-pressures directly in man. The Hales method of measuring arterial pressure directly in terms of a column of blood is inconvenient on account of the great height, large fluctuations, and rapid clotting. The two former disadvantages are overcome by using a column of mer- cury. Since this metal is 13.5 times as heavy as blood, the column which will be supported by the blood will be correspondingly shorter * For an account of the life and works of this physiologist see Dawson, "The Johns Hopkins Hospital Bulletin," vol. xv, Nos. 159 to 161, 1904. f Poiseuille, "Recherches sur la force du cceur aortique." Paris, 1828. j Ludwig, "Midler's Archiv f. Anatomie, Physiologie, etc.," 1847, p. 242 480 CIRCULATION OF BLOOD AND LYMPH. and all the fluctuations will be similarly reduced. Poiseuille placed the mercury in a U tube of the general form shown in Fig. l9l, M. One leg was connected with the interior of an artery by appropriate tubing filled with liquid and when the clamp was removed from the vessel its pressure displaced the mercury in the limbs by a certain amount. The difference in height between the levels of the mercury in the two limbs in each experiment gives the blood pressure, which is therefore usually expressed as being equal to so many millimeters of mercury. By this expression it is meant that the pressure within the artery is able to support a column Fig. 191. — A, Schema to show the recording mercury manometer and its connection with the artery: M, The manometer with the position of the mercury represented in black (the pressure is given by the distance in millimeters between the levels 1 and 2 ; one-half of this distance is recorded on the kymographion by the pen, P) ; F, the float resting upon the surface of the mercury ; G, the cap through which the stem carrying the pen moves; E, offset for driving air out of the manometer and for filling or washing out the tube to the artery; R, the receptacle containing the so.'ation of sodium carbonate; c. the cannula for insertion into the artery; w, the washout arrangement shown in detail in B. B, The washout cannula: c, the glass cannula inserted into the artery; r, the stem connected with the reservoir of carbonate solution ; o, the stem connected with the manom- eter. The arrows show the current of carbonate solution during the process of washing out, the artery at that time being closed by a clamp. of mercuryr that many millimeters in height, and by multiplying this value by 13.5 the pressure can be obtained, when desirable, in terms of a column of blood or water. For continuous obser- vations and permanent records the height of the column of mercury and its variations during an experiment are recorded by the device represented in Fig. 191. VELOCITY AND PRESSURE OP BLOOD-FLOW. 481 The distal limb of the U tube in which the mercury rises carries a float of hard rubber, aluminum, or some other substance lighter than the mercury. The float in turn bears an upright steel wire which at the end of the glass tube plays through a small opening in a metal or glass cap. At its free end it bears a pen to trace the record. If smoked paper is used the pen is simply a smooth- pointed glass or metal arm, while if white paper is employed the wire carries a small glass pen with a capillary tube, which writes the record in ink. The tube connecting the proximal end of the manometer to the artery of the ani- mal must be filled with a solution that retards the coagulation of blood. For this purpose one employs ordinarily a saturated solution of sodium carbonate and bicarbonate or a 5 per cent, solution of sodium citrate. This tube is connected also by a T piece to a reservoir containing the carbonate solu- tion, and by varying the height of this latter the pressure in the tube and the manometer may be adjusted beforehand to the pressure that is sup- posed or known to exist in the artery under experiment. By this means the blood, when connections are made with the manometer, does not pen- etrate far into the tube, and clotting is thereby delayed. In long obser- vations it is most convenient to use what is known as a washout cannula, the structure of which is represented in Fig. 191, B. When this instru- ment is attached to the cannula inserted into the blood-vessel one can, after first clamping off the artery, wash out the connections between the artery and the manometer with fresh carbonate solution as often as desired. By such means continuous records of arterial pressure may be obtained during many hours. Determinations of the pressure in the veins may be made with a similar apparatus, but owing to the low values that prevail on this side of the circulation it is more convenient to use some form of water manometer and thus record the venous pressures in terms of the height of the water column supported. It should be added also that when it is necessary to know the pressure in any special artery or vein the connections of the manometer are made usually to a side branch opening more or less at right angles into the vessel under investigation, or if this is not possible then a X tube is inserted and the manometer is connected with the side branch. The reason for this procedure is that if the artery itself is ligated and the manometer is con- nected with its central stump, the flow in it and its dependent system of capil- laries and veins is cut off; the stump of the artery constitutes simply a con- tinuation of the tube from the manometer and serves as a side connection to the intact artery from which it arises. Thus, when a manometer is inserted into the carotid artery the pressure that is measured is the side-pressure in the innominate or aorta from which it arises, while a cannula in the central stump of a femoral artery measures the pressure in the iliac. A specimen of what is known as a blood-pressure recoid is shown in Fig. 192. The exact pressure at any instant, in millimeters of mercury, is obtained by measuring the distance between the base fine and the record and multiplying by 2. The base line represents the position of the recording pen when it is at its zero position for the conditions of the experiment. It is necessary to multiply the distance between the base line and the record by 2, because, as is seen in Fig. 191, the recording apparatus measures only the rise of the mercury in one limb of the manometer; there is, of course, an equal fall in the other limb. The blood-pressure record (Fig. 192) shows usually large rhyth- mical variations corresponding to the respiratory movements and in addition smaller waves caused by the heart beat. The causes of the respiratory waves of pressure are discussed in the section on respi- ration. Regarding the heart waves or pulse waves the usual record obtained by means of a mercury manometer gives an entirely false picture of the extent of the variations in pressure caused by the heart beat. The mass of mercury possesses considerable weight and iner- tia, which unfits it for following accurately very rapid changes in pressure. When the pressure changes are slow, as in the case of 31 482 CIRCULATION OF BLOOD AND LYMPH. the long respiratory waves seen in the record, the manometer un- doubtedly indicates their extent with entire accuracy. But when these changes are very rapid, as in the beat of a dog's or rabbit's heart, the mercury does not register either extreme in the variation, but tends to record the mean or average pressure. The full extent of the variations in arterial pressure caused by the heart beat can be Fig. 192. — Typical blood pressure record with mercury manometer: Bp, The record showing the heart beats and the larger curves due to the respirations (respiratory waves of blood-pressure) and still longer waves due to vasomotor changes; T, the time line, giving the time in seconds. The actual arterial pressure at any moment is the distance from the base line — that is, the line of zero pressure — to the blood-pressure line, multiplied by two. These values are indicated in the vertical line drawn to the right, which shows that the average pressure at the time of the experiment was 100 mms. Hg. The small size of the variations in pressure due to each heart beat is altogether a false picture due to the inertia of the mercury, its Inability to follow completely the quick change. Each heart beat, instead of being lower, should be higher than the respiratory waves. determined by other means (see below), and, if the knowledge thus obtained is applied to the correction of the record of the mercury manometer, the tracing given in Fig. 192 should have, so far as the heart beats are concerned, somewhat the appearance shown in Fig. 193. This latter figure gives a more accurate mental picture of the actual conditions of pressure in the large arteries, as influenced by VELOCITY AND PRESSURE Gi ELOOD-FLOW. 483 the heart beat. These arteries are, in fact, subject to very rapid and very extensive changes in pressure at each beat of the heart, and these changes are naturally more pronounced when the force of the heart beat is increased, — for instance, 1 y muscular exercise. Systolic, Diastolic, and Mean Arterial Pressure. — As stated in the last paragraph, the arterial pressure in the larger arteries undergoes extensive variations with each heart beat. The maxi- mum pressure caused by the systole of the heart, the apex of the pulse wave, is spoken of as systolic pressure; the minimum pressure in the artery— that is, the pressure at the end of the diastole of the heart, or the bottom of the pulse-wave, is known as the diastolic pressure. In a dog under ordinary conditions of experimentation the systolic (lateral) pressure in the aorta may be as much as 168 mms., while the diastolic pressure is only 100 nuns. In man the <3i/istance (narrowing the tube by means of a stopcock) between the artery and the manometer. The latter * See Dawson, " British Medical Journal." 1906. 996. VELOCITY AND PRESSURE OF BLOOD-FLOW 485 « Fig. 195. — Diagram showing construction of Hurthle's manometer. — (After Curtis.) The interior of the heart or the artery is connected by rigid tubing to a very small tambour, T. The tubing and the tambour are filled with liquid. The movements of the rubber dam covering the tambour are greatly magnified by a compound lever, 5. _ The tendency of this lever to "fling" may be prevented by an arrangement not shown in the diagram. The essential principles of the recorder are, first, liquid conduction from heart to tambour; second, a very small tambour and membrane so that a minimal volume of liquid escapes from the heart into the tambour. will then record mean pressure and show no variations with the heart -beat. A general idea of the variations in systolic, diastolic, and mean pressures, throughout the arterial system, may be obtained from the schema given in Fig. 194. Method of Measuring Systolic and Diastolic Pres- sure in Animals. — In animals a manometer may be con- nected directly with the artery and systolic and diastolic pressures may be obtained in one of two general ways: (1) By using some form of pressure recorder or manom- eter sufficiently mobile to follow very quick changes of mum. . To the artejy- 7TkfUmuf?2' Fig._196. — Schema to illustrate the use of valves in determining maximum (systolic) and minimum (diastolic) blood-pressure. When stopcock a is open the heart beats are transmitted through the maximum valve and the mercury in the manometer is prevented from falling between beats. The manometer will record the highest pressure reached during the period of observation. The reverse occurs when valve b alone is open. 486 CIRCULATION OF BLOOD AND LYMPH. pressure. (2) By using a mercury manometer provided with maximum and minimum valves. Of the manometers that have been devised to register accurately the quick changes in pressure due to the heart beat, the one that has been most successful is the membrane manometer of Hurt hie.* The principle made use of in the Hiirthle manometer is illustrated by the diagram in Fig. 195. The instrument consists essentially of a small box or tambour of very limited capacity; the top of the tambour is covered with thin rubber dam and the cavity is filled with liquid and connected by rigid tubing, also filled with liquid, with the interior of the artery or heart. Variations in pressure in the artery are transmitted through the column of liquid to the rubber membrane of fhe tambour, and the movements of this latter are greatly magnified by a sensitive lever attached to it. The liquid conduction and the small size of the tambour, which prevents any notice- able outflow of liquid, combine to give a sensitive and very prompt record of pressure changes. It is necessary to calibrate this instrument whenever used in order to give absolute values to the records obtained. A specimen of a blood-pressure record obtained with this instrument is shown in Fig. 197. It will be noticed that the size of the heart-beat, relative to the distance from the base line, is much greater than in the record obtained with the mercury manometer, Fig. 192. Fig. 197. — Blood-pressure record from a dog with a Hiirthle manometer. The size of the heart beats is relatively much greater than with a mercury manometer. In this case the systolic pressure is about 150 mms. Hg; the diastolic, 100 mms. ; and the heart beat or pulse pressure, 50 mms. The method that depends upon the use of maximum and minimum valves may be understood by reference to Fig. 196. On the path between the artery and the manometer one may place a maximum and a minimum valve so ar- ranged that the blood-pressure and heart beat may be transmitted through either valve. As is shown by the figure, if the connection is maintained through the maximum valve for a certain time the highest pressure reached during that period will be recorded, while, when the minimum valve is used the lowest pressure reached will be indicated. Such valves, of course, act slowly and can not be used to determine the maximum and minimum pressure in the artery during a single heart beat; they record the highest and lowest point reached during a certain given interval. Actual Data as to the Mean Pressure in Arteries, Veins, and Capillaries. — The mean value of the pressure in the aorta has been determined for many mammals. It is found that the actual * Archiv. f. d. gesammte Physiologie," 49, 45, 1891. VELOCITY AXD PRESSURE OF BLOOD-FLOW. 5b C-M R F P 487 ifc M 4a JU 'I 1 \ \ \ \ -s" V< '•toll e ""^"^■-i - — — -'/ vf '■on _,_ 7 ^^^^ ^^.="^ ,' ^ L u M e , Fig. 198. — Curve showing the results of actual measurement of systolic, diastolic, and mean pressure (lateral pressures) along the aorta and femoral of the dog. The branches through which the lateral pressures were obtained are indicated as follows: 56, Left sub- clavian ; C-M, celiac and superior mesenteric ; R, left renal ; F, left femoral (Ellenberger and Baum), external iliac; P, profunda branch of femoral: 5, saphena. The pressure in millimeters is given along the ordinates to the left. It will be noted that the mean and the diastolic pressures remain practically the same throughout the descending aorta and into the femoral. The systolic pressure shows a marked increase at the lower end of the aorta and then falls off rapidly. The pulse pressure at the inferior end of the descend- ing aorta is much larger than at the arch. — (Dawson.) figures vary with the conditions under which the results have been obtained. Such values as the following may be quoted:* Horse 321 mms. to 150 mms. Hg. Dog 172 Sheep 206 Cat 150 Rabbit 108 Man (probable, Tigerstedt) .... 150 104 156 90 *See Volkmann, "Die Haemodynamik," 1850. 488 CIRCULATION OF BLOOD AND LYMPH. It appears from these figures that there is no proportion between the size of an animal and the amount of mean arterial pressure. It is probable that there may be a general relationship between the size of the animal — that is, the size of the heart — and the amount of pulse pressure or the oscillation of pressure with each heart beat, but sufficient data are not at hand to determine this point. As we pass from the aorta to the smaller arteries the mean pressure decreases somewhat, although not very rapidly, while the pulse pressure decreases also and to a more noticeable extent. This fact is illustrated in Fig. 198, which gives a graphic representation of a number of experimental determinations* of systolic and diastolic pressures in the large arteries of the dog. If we turn to the other end of the vascular system, the veins, we find that the lowest pressure is in the venae cava? and that it increases gradually as we go toward the capillary area. Accord- ing to one observer, f the fall in pressure from periphery toward the heart is at the rate of 1 mm. Hg for every 35 mms. of distance. We have such figures as the following: Dog (Opitz). Sheep. Superior vena cava (near Jugular vein 0.2 mm. Hg. auricle) = —2.96 mms. Hg. Facial vein 3.0 mms. " Superior vena cava more Branch of brachial ... 9.0 " " distal = — 1.38 " " Crural 11.4 " " External jugular (left) . . = 0.52 mm. " Right brachial = 3.90 mms. " Left facial = 5.12 " Left femoral = 5.39 " " Left saphenous = 7.42 " " Fig. 199. — Schematic representation of the general relations of blood-pressure (side pressure) m different parts of the vascular system: a, The arteries; c, the capillaries; v, the veins. The mean and diastolic pressures remain nearly constant in the arterial system, as far as they can be measured accurately. The pressures in the veins are represented as uniform at any one point. In the large veins near the heart there are variations of pressure with each respiration and with each heart beat (Venous Pulse, p. 520). At the heart, therefore, the pressure of the blood upon the walls of the veins is nearly nil, and, indeed, owing to the circumstance that the large veins lie in the thoracic cavity, in which the pres- sure is below that of the atmosphere, the tension of the blood in * Dawson, ".American Journal of Physiology, " 15, 244, 1906. t Burton-Opitz, "American Journal of Physiology," 9, 198, 1903. VELOCITY AND PRESSURE OF BLOOD-FLOW. 489 them may also be below atmospheric pressure, although doubt- less at this point (vena cava) the pressure within the vein is greater, certainly not less than the pressure on its exterior (intrathoracic pressure). To complete the general conception of the pressure relations in the vascular system it is necessary to know the pressure of the blood in the smallest arteries and veins and in the capillaries. It is not possible — in the cases of the capillaries, for instance — to connect a manometer directly with the vessels, and recourse has been had to a less direct and certain method. The pressure in the capillaries in dif- ferent regions of the skin has been estimated by determining the pressure necessary to obliterate them — that is, to blanch the skin. A glass plate is laid upon the skin or mucous membrane and weights are added until a distinct change in the color of the skin is noted.* Knowing the necessary weight to produce this effect and the area submitted to compression, the pressure may be expressed in terms of millimeters of mercury or blood. The following example may be used to illustrate this method: Suppose that the glass plate has an area of 4 sq.mms., and that to blanch the skin under it a weight of 1 gm. is necessary; 1 gm. of water = 1 c.c. or 1000 c mms. Therefore to blanch this area would require a column of water contain- ing 1000 c.mms. with a cross-area of 4 sq.mms. The height of this column would therefore be equal to i-0/— or 250 mms. of water, — that is, 18.5 mms. Hg. The results obtained by this method are not very constant and can only be considered as approximate. It would appear, how- ever, that the pressure lies somewhere between 20 and 40 mms. of mercury. Thus, upon the gums of a rabbit von Kries found a capillary pressure of 33 mms. Hg. By means of a more adjustable instrument von Reckling- hausen! estimates that in man the pressure within the capil- laries of the finger-tips or, to be more accurate, within the small arteries supplying these capiUaries, is equal to 55 mms. Hg. (See p. 497.) The general relations of the pressures in arteries, veins, and capillaries may be expressed in a curve such as is shown in Fig. 199. It should be added that in this curve and in all the figures so far quoted in regard to the actual pressure within the different arteries and veins, it is assumed that the animal is in a recumbent posture. In an animal standing upon his feet, especially in * V. Kries, "Berichte d. Sachs. Gesellschaft d. Wiss. Math.-phys. Classe," 1875, p. 148. f Von Recklinghausen, "Archiv f. exp. Path. u. Pharnak.," 55, 375, 1907. 490 CIRCULATION OF BLOOD AND LYMPH. an upright animal like man, it is obvious that the effect of gravity will modify greatly the actual figures of pressure. Upon the arteries and veins of the feet, for example, there will be exerted a hydrostatic pressure equal to the height of the column of liquid between the feet and the heart, which adds itself to the pressure resulting from the circulation as caused by the heart. When the animal is in a recumbent position the hydrostatic fac- tor practically disappears. (See p. 506.) d Fig. 200. — Figure of the Riva-Rocci apparatus (Sahli) : a. The leather collar with inside rubber bag to go on the arm ; c, the bulb for blowing up the rubber bag and thus compressing the artery; d, the manometer dipping into the reservoir of mercury, b, to meaa- sure the amount of pressure. The Method of Determining Blood-pressure in the Large Arteries of Man. — It is a matter of interest and practical impor- tance to ascertain even approximately the arterial pressure in man and its variations in health and disease. The first practical method for determining this point upon man was suggested by von Basch (1887), who devised an instrument for this purpose, the sphygmo- manometer. Since that time a number of different instruments have been described, but attention may be called to two only, which are among the most recent and convenient. In the first place, it must be clearly recognized that the arterial pressure in the large arteries of man shows marked variations with the heart beat; the pressure during the beat of the heart rises suddenly to a much higher level than during the diastole. The relation of the systolic (or maximum) and diastolic (or minimum) pressures is indicated by the diagram in Fig. 194. The instruments that have been invented for determining human blood-pressure are in reality adapted, more or less accurately, to determine one or the other or both of these pies- VELOCITY AND PRESSURE OF BLOOD-FLOW. 491 sures. No instrument has been devised for determining the mean pressure, and as a matter of fact such a thing as mean pressure does not exist in the large arteries, it is simply an abstraction. What really occurs in these arteries is a rapid swing of pressure with each heart-beat from the diastolic to the systolic level, and to interpret fully our records it is important to determine each of these values. The principle of determining the systolic pressure alone is very simple : it consists in determining the amount of pres- sure necessary to completely obliterate the artery, — that is, to pre- vent a pulse from passing through the region under compression. This principle was used originally by von Basch, but its application has been made perhaps most successfully in the simple apparatus suggested by Riva-Rocci, which is adapted especially for measure- ments of pressure in the brachial artery. One form of this instru- ment is represented in Fig. 200. The leather or canvas band, a, is buckled snugly around the arm. On the inner surface of this band there is a rubber bag which communicates with the mercury manometer, d, and the pressure bulb, c. When the band is in place rhythmical compressions of c will force air into the rubber bag surround- ing the arm. This bag is blown up and exerts pressure upon the arm and through the arm tissue upon the brachial artery. The amount of pressure that is being exerted upon the arm is indicated at any moment by the mer- d e==o) Fig. 201. — Schema to illustrate the fact that when the pressure upon the outside of the artery is equal to the diastolic pressure the pulse wave wili cause a maximal expansion of the artery: a represents the normal artery distended by diastolic blood-pressure; the dotted lines indicate the additional expansion caused by the pulse wave; b represents the artery when compressed by an outside pressure equal to the diastolic pressure within ; the artery then takes the size of an empty artery kept patent by the rigidity of its walls. Thepulse wave, on reaching this section, finds a relaxed wall and causes, therefore, a maximum extension. cury manometer. The moment of obliteration of the artery is determined by feeling (or recording) the pulse in the radial artery. The moment that this pulse disappears, as the pressure upon the brachial is raised, indicates the maximum or systolic pressure in the brachial artery. As the pressure is low- ered again the pulse reappears. Among other sources of error involved in this method it is to be remembered that the tactile sensibility is not sufficiently delicate to detect a minimal pulse in the artery. Other methods of determin- ing the systolic pressure (see below) indicate, as a matter of fact, that the pulse continues some time after an individual of average tactile sensibility is unable to detect it. . To determine the diastolic pressure is more difficult and requires somewhat more apparatus. The principle employed was first suggested by Marey and first practically applied by Mosso.* The method consists in recording by some means the pulsations of the artery under different pressures and determining under * "Archives italiennes de biologie," 23, 177, 1895. 492 CIRCULATION OF BLOOD AND LYMPH. what pressure the maximal pulsations are given. This pressure should be equal to the diastolic pressure within the artery. The principle involved mav be illustrated by the accompanying figure (Fig. 201). Fig. 202. — Record (Erlanger) to show the maximum size of the recorded pulse wave when the outside or extravascular pressure is equal to the internal diastolic pressure. The artery is compressed first with a pressure above systolic, sufficient to obliterate the lumen. As this pressure is lowered in steps of 5 mms. the recorded pulse wave increases in size to a maximum and then again becomes smaller. The outside pressure with which the maximum pulse is obtained measures the amount of the internal diastolic pressure (Marey's principle). Let a represent a longitudinal section of an artery distended by normal diastolic arterial pressure. At each heart beat the force of the pulse will dis- tend the artery still more, as represented by the dotted lines, and this in- crease in size may be measured by proper transmitting apparatus. If now Fig. 203.— Schema showing the construction of the Erlanger apparatus: a. Rubber bag of the arm piece; c, bulb for blowing up this bag and putting pressure on the arm; 6, the manometer for measuring the pressure; i, two-way stopcock (when turned so as to communicate with the capillary opening, k, it allows the pressure in a to fall slowly); e, a rubber bag in a glass chamber, /,• e communicates with a when stopcock d is open and the pulse waves from a are transmitted to e; the pulsations of e in turn are transmitted to the delicate tambour, h, and are thus recorded. pressure is brought to bear upon the outside of the artery its lumen will be diminished as the outside pressure is increased, and when this pres- sure is equal to the diastolic blood-pressure within the artery one will neu- tralize the other, and the diameter of the artery will be equal to that assumed VELOCITY AXD PRESSURE OF BLOOD-FLOW. 493 when the vessel contains blood under no pressure and is kept patent only by the stiffness of its walls (&). Under this condition the pulse wave when it traverses this portion of the vessel finds its walls completely relaxed, as it were, and the force of the heart wave will consequently cause a greater dis- tention of the arterial walls and a larger pulse wave in the recording appa- ratus. If the outside pressure is increased beyond the amount of diastolic pressure it will not only neutralize this latter, but will tend to overcome the stiffness of the arterial wall. When the pulse wave passes through this stretch it will be forced not only to distend the walls, but also to overcome the excess Fig. 204. — Erianger apparatus. The collar for the arm is not shown. The parts may be understood by reference to the schema given in Fig. 203. of pressure on the outside. The movement of the walls with the pulse wave will be less extensive in proportion to the excess of pressure on the outside. If, therefore, one starts with an outside pressure sufficient to obliterate the artery completely the recorded pulse wave will be small. As this pressure is diminished, the pulse waves become larger up to a certain point and then decrease again in size (see Fig. 202). The outside pressure at which this maximum pulse is obtained measures, according to the principle stated above, the diastolic pressure within the artery. That the principle is correct has been shown by direct experiments upon the exposed artery of a dog, in which the pressure was measured by the method outlined above and also directly 494 CIRCULATION OF BLOOD AND LYMPH. by a manometer connected with the interior of the artery.* In such experi- ments upon man, however, one condition is present which detracts from the absolute value of the results obtained, although, since it is substantially a constant factor, it does not seriously interfere with relative results, that is, with observations upon the variations of pressure under different condi- tions. This source of error lies in the fact that in the living person the out- side pressure can not be applied directly to the arteries, but only indirectly through the intervening tissues. These tissues interpose a certain resistance to the pressure exerted from without, and some of this pressure must be spent in overcoming this resistance. The amount of the resistance offered by the tissues has been estimated differently by various authors, but probably lies between 6 and 10 mms. of mercury, — that is, the pressure as measured exceeds the real diastolic pressure by this amount. Several instruments have been devised, according to this principle, to measure diastolic pressures, but the sphygmomanometer described by Erlangerf is probably the most complete Fig. 205. — To show the method of detecting the systolic pressure upon the tracing given by the Erlanger sphygmomanometer. The pressure upon the arm is raised above systolic pressure and is then dropped 5 mm. at a time, a short record being taken after ;each drop. Records are shown for 130, 125, 120, 115, and 110 mm. At 115 mm. it will be seen that the limbs of the pulse-wave show the separation or spreading which indicates the first pulse- wave to get through the occluded artery, and therefore the systolic pressure. and the most convenient for actual use. This instrument is illustrated in Figs. 203 and 204. It may be used to determine both systolic and diastolic pressure. The way in which the apparatus is used may be understood from the sche- matic Fig. 203. a is the rubber bag which is buckled upon the arm by a leather strap. This bag communicates with the mercury manometer, b, with a pres- sure bag, c, through the two-way stopcock, i, and through the stopcock d with a rubber bag, e, contained in a glass chamber, /. This glass chamber com- municates above with a sensitive tambour, h, and by means of the stopcock g can be placed in communication with the outside air. The systolic pressure may be determined in two ways: By one method only the mercury manom- eter is necessary, the instrument corresponding with the Riva-Rocci appa- ratus described above. By means of the pressure bag, c, the bag, a, upon the arm is blown up until the pressure is above the systolic pressure and the radial pulse below disappears. By turning stopcock % properly the system is allowed to communicate with the air through a capillary opening, k. Consequently the pressure upon the artery in the arm falls slowly, and by palpating the * Howell and Brush, " Proceedings of the Massachusetts Medical Society " 1901. f" American Journal of Physiology," "Proceedings of the American Physiological Society," 6, xxii., 1902; and " Johns Hopkins Hospital Reports," 12, 53, 1904. VELOCITY AND PRESSURE OF BLOOD-FLOW. 495 radial artery one can determine the pressure, as measured by the mercury manometer, at which the pulse just gets through. This pressure will measure approximately the systolic pressure. The second method (method of v. Recklinghausen) gives higher and doubtless more accurate results. In this method the pressure is at first raised above systolic pressure with stopcocks d and g open, a, e, and b are under the same pressure. If stopcock g is now turned off, the pulsations in a are transmitted to e and through it to the tambour, h, and the lever of the tambour writes these pulsations on a kymo- graphion. It should be explained that pulsations are obtained even when the pressure on the arm is much more than sufficient to completely obliterate the brachial artery. The reason for this is that the pulsations of the central stump of the closed artery will be communicated to bag a. When the pressure is suprasystolic these pulsations are small. If now the pressure in the system is diminished slowly by turning stopcock i so as to communicate with the capillary opening, k, it will be found that at a certain point the pulsations suddenly increase in height (Fig. 205) . This point marks the moment when the pulse wave is first able to break through the brachial artery, and it gives, therefore, the systolic pressure. In many cases this method of determining the point of systolic pressure is not satisfactory, since the pulse waves increase gradually in amplitude without a sudden break, or perhaps there is more than one place at which a sudden increase occurs. A more reliable method according to Erlanger is to note the point at which the ascending and descend- ing limbs of the pulse wave show a noticeable separation (Fig. 205). "At the moment the pressure on the artery falls below systolic, blood succeeds in making its way beneath the cuff. This must be squeezed out before the lever can return to the base line, whereas at higher pressures the lever is raised only through the hydraulic-ram action of the pulse wave upon the upper edge of the cuff." After finding the systolic pressure the diastolic pressure is obtained by allowing the pressure to drop still further. The pulsations increase in height to a maximum size and then decrease. The pressure at which the maximum pulse wave is obtained marks the diastolic pressure. It is better perhaps in dropping the pressure for this last purpose to manipu- late stopcock i so as to drop the pressure 5 mms. at a time, recording the pulse wave at each pressure. In this way a record is obtained such as is given in Fig. 202. It should be added, also, that in order to keep the lever of the tambour horizontal while the pressure in the system is being lowered there is a minute pinhole in the metal bottom of the tambour. Through this pinhole the pressure in the tambour and chamber, /, is kept atmospheric throughout, except during the quick changes caused by the pulse waves. By means of this instrument one can determine within a minute or so the amount of the systolic and diastolic pressure in the brachial artery, and also, of course, the difference between the two, the pulse pressure, which may be taken as an indication of the force of the heart-beat. Auscultation Method. — Korotkoff has suggested a simple and apparently satisfactory method of detecting the systolic and the diastolic pressure. He uses a stethoscope, which is placed over the brachial artery just below the cuff. The pressure in the cuff is raised above that necessary to obliterate the artery completely, and is then allowed to fall slowly. At the moment that the first pulse-wave breaks through the artery a sound is heard through the stethoscope and a reading of the manometer at this point gives systolic pressure. As the pressure falls the sound is heard synchronous with each heart-beat, but becoming fainter and fainter — the pressure at which the sound is last heard is the diastolic pressure. It would seem probable that the origin of the sound is to be traced to the vibration of the vessel-walls and surrounding tissues caused by the sudden separation of the endothelial surfaces as the pulse-wave breaks through. The Normal Arterial Pressure in Man and its Variations. — By means of one or other of the instruments devised for the purpose, numerous results have been obtained regarding the blood-pressure in man at different ages and under varying 496 CIRCULATION OF BLOOD AND LYMPH. normal and abnormal conditions. Unfortunately the methods used have not always been complete. Some authors give only systolic pressures, for example. In such experiments also a troublesome factor is always the psychical element. The mental interest that the individual experimented upon takes in the procedure almost always causes a rise of pressure and perhaps a changed heart rate. Results, as a rule, upon any individual show lower values after the novelty of the procedure has worn off and the patient submits to the process as an uninteresting routine. It should be remembered also that in measuring arterial pressures in man the measurements must always be made at the level of the heart, as is usually done, the brachial artery being selected, or if other arteries are employed, an allow- ance must be made for differences in level. (See paragraph on the Hydrostatic Effect, p. 506.) Under normal conditions Potain* estimated the systolic pressure in the radial of the adult at about 170 mms. of mercury and the variations for different ages he expressed in the following figures: Age 6-10 15 20 25 30 40 50 60 80 Pressure (systolic). 89 135 150 170 180 190 200 210 220 Without the other side of the picture — that is, the diastolic pres- sure and the force of the heart beat (pulse pressure)— it is difficult to interpret these figures. The rapid increase up to maturity probably represents chiefly the larger output of blood from the heart; the slower and more regular increase from maturity to old age is due possibly to the gradual hardening of the arteries, since the less elastic the arteries become, the greater will be the systolic rise with each heart beat. With his more complete apparatus Erlanger reports that in the adult (20 to 25), when the psychical factor is excluded, the average pressure in the brachial is 110 mms., systolic, and 65 mms., diastolic, — figures much lower than those given by Potain. Von Recklinghausen's figures for the same artery are, systolic pressure 116 mms. Hg, diastolic pressure 73 mms. Hg. Erlanger and Hooker report observations upon the effect of meals, of baths, of posture, the diurnal rhythm, etc.f The effect of meals is particularly instructive in that it illustrates admirably the play of the compensatory mechanisms of the circu- lation by means of which the heart and the blood-vessels are ad- justed to each other's activity. During a meal there is a dilatation of the blood-vessels in the abdominal area, or, as it is frequently called in physiology, the splanchnic area, since it receives its vasomotor fibers through the splanchnic nerve. The natural * " La pression arterielle de l'homme," Paris, 1902. t Erlanger and Hooker, " The Johns Hopkins Hospital Report," vol. xii., 1904. VELOCITY AND PRESSURE OP BLOOD-FLOW. 497 effect of this dilatation, if the other factors of the circulation remained constant, would be a fall of pressure in the aorta and a diminution in blood-flow to other organs, such as the skin and the brain. This tendency seems to be compensated, however, by an increased output of blood from the heart. Observations with the sphygmomanometer show that after full meals there is a marked increase in the pulse pressure, indicating a more forcible beat of the heart. So far as the effect on the heart is concerned, the result of a meal is similar to that of muscular exercise, and this reaction may account for the fact, not infrequently observed, that in elderly people whose arteries are rigid an apoplectic stroke may follow a heavy meal. The Method of Determining Venous Pressures and Capillary Pressures in Man. — A number of methods have been proposed for determining venous pressures in man, the simplest being that described by Gaertner.* It consists simply in raising slowly the arm of the patient until the veins on the back of the hand just disappear. The height above the heart at which this occurs gives the venous pressure in the right auricle, since the vein may be considered as a manometer tube ending in the auricle. In this and in other methods of measuring venous Fig. 206. — To illustrate the method of measuring venous pressure: H, The back of the hand in which a single vein is represented; B, the circular rubber bag with central opening, and with a tube, T, which leads to the pump and the manometer; G, glass plate held over the rubber bag. The bag, B, is blown up by pressure through the tube T until the vein is collapsed. The pressure at which this occurs, or the pressure at which the vein reappears as the bag is allowed to empty, gives the pressure within the vein. — (von Recklinghausen.) pressures, and the same is true, of course, of arterial and capillarv pressures, there must be some agreement as to what constitutes the heart-level, since the highest and lowest points of the heart when the individual is standing or sitting may differ by as much as 15 centimeters, von Recklinghausen proposes the level made by a dorsoventral line drawn from the bottom of the sternum (costal angle) to the spinal column. This authorf has devised a simple apparatus for determining venous and capillary pressures, the principle of which is shown by the schema repre- sented in Fig. 206. * " Muench. mediz. Wochenschrift," 1903, 1904. fVon Recklinghausen, "Archiv f. exper. Pathol, u. Pharmakol," 55, 470, 1906. 32 498 CIRCUATION OF BLOOD AND LYMPH. A circular bag of thin rubber with a diameter of about 5§ cm. is provided with a central opening of 2 cm. The bag is connected with a pump so that it can be blown up, and the degree of pressure exerted is measured by an attached manometer. This bag, moistened with glycerine, is laid upon a vein, as represented in the diagram. It is covered by a glass plate held firmly Fig. 207. — Apparatus for determining venous blood-pressure in man: B, The box ■with glass top for putting pressure on the vein; the details are shown in the small figure (Fig. 2), in which 1 show- the alumimum box; 2, the brass collar which fits over 1 and holds in place the perforated sheet of rubber dam; 3, which forms the bottom of the box and is forced down on the vein. E, pressure bulb for increasing pressure in the box until the vein is obliterated. G, water manometer to measure the pressure. (Eyster and Hooker.) in position and the bag is then blown up until the vein disappears; the pressure at which this happens is shown by the manometer and marks the pressure within the vein. A convenient modification of this apparatus which has been described by Eyster and Hooker* is shown in Fig. 207. The box, B, used for compressing the vein is connected by rubber tubing with a rubber manometer, G, and a pressure-bulb, E. The structure of the pressure box is shown in the smaller figure. It consists of an aluminum frame or box, the top and one side of which are made of glass. One of the sides is perforated by a tube which connects with the manometer, as shown in the larger figure. The frame is cut away on two sides, so that when it is tied upon the arm the * Eyster and Hooker, " The Johns Hopkins Hospital Bulletin," 274, 1908. VELOCITY AND PRESSURE OF BLOOD-FLOW. 499 vein will not be compressed. Over the bottom of this frame is laid a thin sheet of rubber dam, 3, with a hole cut in the center, and the aluminum frame with its rubber bottom is then set into a close-fitting brass frame, 2, which serves to keep the rubber membrane in place. When placed in position upon the arm the rubber dam lies upon the vein and presses upon it as the pressure is raised in the box. The vein is observed through the glass top and the hole in the rubber, and the pressure at which it is just obliterated is read from the manometer. With instruments of this kind the degree of pressure neces- sary to obliterate a given vein in the arm, hand, or foot can be determined readily in terms of a column of water, but it is obvious that for any given vein this pressure will vary with the position of the vein. When the hand hangs pendent at the side the pressure within its veins will be greater than when the hand is raised to the heart-level. The pressure actually measured for any given position of the hand or foot must, therefore, be corrected for the heart-level by determining the vertical distance between the vein and the heart (costal angle), and subtracting this distance, expressed in centimeters, from the pressure, also expressed in centimeters, which was found necessary to obliterate the vein. Measurements made by this method and corrected for the heart-level show that in the normal person the pressure within the small veins of the hand or arm may vary between 3 and 10 centimeters of water. Unusual or pathological conditions which cause a congestion in the venous side of the heart will raise the venous pressure correspondingly to 20 centimeters or more.* When the venous pressure is measured in the small veins of the feet in a person while standing we should suppose that after a reduction to the heart level it would be about the same as that noted for the veins of the hands, since the vessels are of about the same order with reference to their distance from the capillary bed. In a series of observations of this kind, reported by von Recklinghausen, it was found, on the contrary, that after subtracting the distance between the foot and the heart, the pressure within the veins was negative by as much as 40 cm. The author explains this unexpected result by supposing that the flow through the foot got up only enough pressure in the veins to lift the blood to the level of the pelvis, and that the complete closure of the venous valves at this level protected the veins from the full pressure of the column of blood. Eventually, no doubt, the pressure in the veins would have risen sufficiently to lift the blood to the heart-level, but it seems probable that under the ordinary conditions of life this result is effected by the cooperation of the muscles of the legs and the respiratory movements of the thorax (see p. 508). The contractions of these muscles, aided by the venous valves, squeeze the blood upward to the heart. The fact that in standing quietly the flow through the feet may be suspended or impeded, for a time at least, throws some light, as von Recklinghausen suggests, upon the fact that it is so difficult to stand for any length of time without moving. The apparatus described above may be used for determining capillary as well as venous pressures, according to the principle * For a description of some pathological cases, see Eyster and Hooker, loc. cit. 500 CIRCULATION OF BLOOD AND LYMPH. described on p. 489. For this purpose the pressure box is laid upon a given skin area and the pressure is raised until the skin beneath is blanched. The pressure is then lowered slowly until the skin again reddens, showing the reestablishment of the capil- lary flow. The pressure thus obtained is corrected as described for the level of the heart.* * For some tehnical details, see von Recklinghausen, loc. cit. CHAPTER XXVI. THE PHYSICAL FACTORS CONCERNED IN THE PRO- DUCTION OF BLOOD-PRESSURE AND BLOOD- VELOCITY. In the preceding pages some of the essential facts have been stated regarding the pressure and the velocity of the blood in the different parts of the vascular system. We may now consider the physical factors that are responsible for the production and mainte- nance of these peculiarities. The problem as it actually exists in the circulation, with its elastic vessels varying in size from the aorta, with an internal diameter of nearly 20 mms., to the capil- laries, with a diameter of 0.009 mm., is extremely complex, but the general static and dynamic principles involved are simple and easily understood. Side Pressure and Velocity Pressure. — When water flows through a tube under, let us say, a constant head of pressure it encounters a resistance due to the friction between the walls of the vessel and the particles of water. This resistance will be greater, the narrower the tube. A part of the head of pressure used to drive the liquid along the tube will be used in overcoming this resistance to its movement, and the volume of the outflow will be correspond- ingly diminished. If we use an apparatus such as is represented in Fig. 208, consisting of a reservoir, H, and a long outflow tube, 1, 2, 3, 4, 5, the outflow from the end and the pressure along the tube may be measured directly. We must suppose that the head of pressure — that is, the height of the water in H — is kept constant by some means. The resistance or tension due to the friction in the tube may be measured at any point by inserting a side-tube or gauge (piezometer) at that point. The liquid will rise in this tube to a level corresponding to the pressure or resistance offered to the movement of the liquid at that point — that is, the weight of the column of liquid will measure the pressure at that point upon a surface corresponding to the cross-area of the tube. The pressure or tension at any point may be spoken of as the side pressure or lateral pressure, and it expresses the amount of resistance offered to the flow of the liquid because of the friction exerted upon the water by the walls of the tube between that point and the exit. This side pressure increases in a straight line from the point of exit 501 502 CIRCULATION OF BLOOD AND LYMPH. to the reservoir, and this in general is the picture presented by the circulation. The reservoir, the head of pressure, is represented by the aorta, the exit for the outflow by the opening of the venae cavae into the right auricle, and the side pressure or internal tension of the blood due to friction against the walls of the vessels increases from the vense cavse back to the aorta. If from aorta to vena cava the vessels were of the same diameter the increase would be in a straight line, as in the case of the model. In this model it will be noticed that the straight line showing the side pressure does not strike the top of the column of liquid in the reservoir, but corre- sponds to a certain height, h! . This expresses the fact that, of the total head of pressure in the reservoir, which we may designate as H, a certain portion only, but a large portion, h' , is used in over- Fig. 208. — Schema to illustrate the side pressure due to resistance, and the velocity pres- sure (Tigerstedt) : H, A reservoir containing water; 1, 2, 3, 4, 5, the outflow tube with gauges set at right angles to measure the side pressure ; h', the portion of the total pressure used in overcoming the resistance to the flow; h, the portion of the total pressure used in moving the column of liquid — the velocity pressure. coming the resistance along the tube. What is left — that is, H-h', represents the force that is employed in driving the liquid through the tube with a certain velocity ; this portion of the pressure we may speak of as the velocity pressure, h. If in measuring the side pressure at any point the gauge were prolonged into the tube and bent so as to face the stream, this velocity pressure would add itself to the side pressure at that point and the water would rise to a higher level in this particular tube. There are two important differences between the circulation as it exists in the body and that repre- sented by the model. In the body, in the first place, we have the area of capillaries, small arteries, and veins, intercalated be- tween the large arteries on one side and the veins on the other; and, in the second place, the vessels, especially the arteries, are extensible and elastic. The effect caused by the first of these BLOOD-PRESSURE AND BLOOD-VELOCITY. 503 factors — namely, a great resistance placed in the middle of the course — may be illustrated by the model shown in Fig. 209, which differs from that in Fig. 208 in having a stopcock in the outflow tube, which, when partly turned off, makes a narrow opening and a relatively great resistance. When the stopcock is open the pressure falls equally throughout the tube, provided the bore of the stopcock is equal to that of the tube. If, however, it is partially turned the side pressure is much increased between it and the reservoir on what we may term the arterial side of the schema, and it is correspond- ingly diminished between the stopcock and the exit, on the venous side of the schema." Substantially this condition prevails in the body. The capillary region, including the smallest arterioles and veins, offers a great resistance to the flow of blood, and this resistance is spoken of in physiology as the peripheral resistance. Its effect is to i -— -— ;: \ \ \ \ \ -^ Fig. 209. — Schema like the preceding except that a stopcock is inserted at the middle of the outflow to imitate the peripheral resistance of the capillary area. The relations of the internal pressure on the arterial and venous sides of this special resistance is shown by the height of the water in the gauges. raise the pressure on the arterial side and lower it on the venous side. When other conditions in the circulation remain constant it is found that an increase in peripheral resistance, caused usually by a con- striction of the arterioles, is followed by a rise of arterial pressures and a fall of venous pressures. On the contrary, a dilatation of the arterioles in any organ is followed by a fall of pressure in its artery or arteries and a rise of pressure in its veins. The effect of the elastic- ity of the arteries is of importance in connection with the fact that in reality the circulation is charged with blood not from a constant reservoir as in the models, Figs. 208 and 209, but by the rhythmical beats of the heart. If the vascular system were perfectly rigid each rhythmical charge into the aorta would be followed by an equal dis- charge from the venae cavae, the pressure throughout the system would rise to a high point during systole and fall to zero during the 504 CIRCULATION OF BLOOD AND LYMPH. diastole. The elasticity of the arteries, in connection with the peripheral resistance, makes an important difference. As the heart discharges into the aorta the pressure rises, but the walls of the arterial system are distended by the increased pressure, and during the following diastole the recoil of these distended walls maintains a flow of blood through the capillaries into the veins. With a certain rapidity of heart beat the distension of the arterial walls is increased to such a point that the outflow through the capillaries into the veins is as great during diastole as during systole; the rhythmical flow in the arteries becomes converted by the elastic tension of the overfilled arterial system into a continuous flow in the capillaries and veins. This effect may be illustrated by a simple schema such as is represented in Fig. 210. A syringe bulb (a), rep- resenting the heart, is connected by a short piece of rubber tubing to a glass tube (6), and also by a jjiece of distensible band tubing (e) with Fig. 210. — Simple schema to illustrate the factors producing a constant head of pres- sure in the arterial system: a, A syringe bulb with valves, representing the heart; b, glass tube with fine point representing a path with resistance alone, but no extensibility (the out- flow is in spurts synchronous with the strokes of the pump) ; c, outflow with resistance and also extensible and elastic walls represented by the large rubber bag, e ; the outflow is a steady stream due to the elastic recoil of the distended bag, e. a similar glass tube drawn to a fine point (c). In the latter case the distensible, elastic tubing represents the arterial system, and the fine pointed glass tube the peripheral resistance of the capillary area. If the syringe bulb is put into rhythmical play and the flow is directed through tube b the discharges are in rhythmical spurts, but if directed through tube c the discharge is a continuous stream, since the force of the separate beats becomes stored as elastic tension in the walls of the band tubing, and it is this constant force which drives a steady stream through the capillary point. In a general way, this schema gives us a true picture of the conditions in the cir- culation. The rhythmical force of the heart beat is stored as elastic tension in the walls of the arteries, and it is the squeeze of these distended walls which gives the continuous driving force that is responsible for the constant flow in the capillaries and veins. Enumeration of the Factors Concerned in Producing Nor- mal Pressure and Velocity. — In the normal circulation we ma}' BLOOD-PRESSURE AXD BLOOD-VELOCITY. 505 say that four chief factors co-operate in producing the conditions of pressure and velocity as we find them. These factors are: (1) The heart beat. (2) The resistance to the flow of blood through the vessels, and especially the peripheral resistance in the region of the small arteries, capillaries, and small veins. (3) The elasticity of the arteries. (4) The quantity of blood in the system. The way in which these factors act va&y be pictured as follows : Suppose the system at rest with the definite quantity of blood distributed equally throughout the vascular system. The internal or side pressure throughout the system will be everywhere the same, — probably zero (atmospheric) pressure, since the capacity of the vascular system is sufficient to hold the entire quantity of blood without distension of its walls. If, now, the heart begins to beat with a definite rhythm and discharges a definite quantity of blood at each beat the whole mass will be set into motion. The arteries receive the blood more rapidly than it can escape through the capil- laries into the veins, and consequently it accumulates upon the arterial side until an equilibrium is reached, — that is, a point at which the elastic recoil of the whole arterial tree suffices to force through the capillaries in a unit of time as much blood as is received from the heart during the same time. In this condition of equilib- rium the flow in capillaries and veins is constant, and the side pressure in the veins increases from the right auricle back to the capillaries. In the arteries there is a large side pressure throughout, owing to the resistance between them and the veins and especially to the great resistance offered by the narrow capillaries. This pressure rises and falls with each discharge from the heart, and the pulse waves, both as regards pressure and velocity, are most marked in the aorta and diminish farther out in the arterial tree, failing completely in the last small arterioles, since if taken together these arterioles constitute a large and distensible tube of much greater capacity than the aorta. General Conditions Influencing Blood-pressure and Blood- velocity. — Alterations in any of the four chief factors mentioned above must, of course, cause a change in pressure and velocity. I. An increase in the rate or force of the heart beat will increase the velocity of the flow throughout the system, although, of course, that general difference in velocity in the arteries, capillaries, and veins which depends upon the variations in width of bed will remain. Such a change will also cause a rise of pressures throughout the system. The energy exhibited in the vascular system as side pres- sure, velocity pressure, etc., comes, in the long run, mainly from the force of contraction of the heart muscle. This force is what is represented in the model, Fig. 208, as the total head of pressure ( H). An increase in rate or force of heart-beat is equivalent, therefore, 506 CIRCULATION OF BLOOD AND LYMPH. to an increase in this head of pressure, and along with the increase in velocity thus caused there is an increased friction or resistance. II. An increase or decrease in the width of the vessels will influence both the resistance to the flow and the velocity. Under normal conditions it is the small arteries that are constricted or dilated (vasoconstriction and vasodilatation). A constriction of these arteries causes an increase in arterial pressures and a decrease in venous pressure. The velocity of the blood-flow is decreased. A dilatation has the opposite effects. Numerous instances of this relation will be referred to in describing the physiology of the vaso- motor nerves. III. A diminution in elasticity of the arteries will tend to interfere with the constancy of the flow from the arteries into the capillaries, and in the arteries themselves the swings of pressure from systolic to diastolic during the heart beat will be more extensive. This latter fact can be shown upon elderly individuals whose arteries are becoming rigid, but whether a change of this character is ever so advanced in human beings as to seriously modify the capillary circulation does not appear to have been investigated. IV. A loss of blood, other conditions remaining the same, will also cause a fall in blood-pressures and velocity. As a matter of fact, however, a considerable amount of blood may be lost with- out any marked permanent change in arterial blood-pressure. The reason for this result is found in the adjustability or adaptability of the vascular system. It is in such respects that the system differs greatly from a rigid schema such as we use for our models. When blood is withdrawn from the vessels the loss may be offset by an increased action of the heart and by a contraction of the arterioles, the two effects combining to give a normal or approximately normal arterial pressure. To carry out the analogy with the model (Fig. 208) if by chance some of the store of water was lost we might sub- stitute a narrower reservoir, so that with a diminished supply we could still maintain the same level of pressure. In the body, moreover, a loss of blood by hemorrhage may be compensated in part, so far as the bulk of the liquid is concerned, by a flow of liquid from the tissues into the blood-vessels. The Hydrostatic Effect. — In the living animal, especially in those, like ourselves, that walk upright, the actual pressure in the arteries of the various tissues must vary much also with the position. For instance, in standing erect the small arteries in the hands or feet are, in addition to other conditions noted above, exposed to the weight of the column of arterial blood standing over them. In the pendent arm the skin of the fingers is congested; if, however, the arm is raised above the head the skin may become blanched because now the column of blood from fingers to shoulder exercises BLOOD-PRESSURE AND BLOOD-VELOCITY. 507 a hydrostatic pressure in the opposite direction. In determinations of blood-pressure in the brachial artery of man care should be taken to keep the arm in the same position in a series of observations in order to equalize the effect of the hydrostatic factor. The impor- tance of this gravity effect is most evident in the case of the ab- dominal (splanchnic) circulation. When an animal accustomed to go on all fours is held in a vertical position the great vascular area of the abdomen is placed under an increased pressure clue to gravity, and, unless there is a compensatory contraction of the arterioles or of the abdominal wall, so much blood may accumulate in this portion of the system that the arterial pressure in the aorta will fall markedly or the circulation may stop entirely.* In most cases the compensation takes place and no serious change in the circulation results. In rabbits, however, which have lax abdominal walls, it is said that the animal may be killed by simply holding it in the erect position for some time. For the same reason an erect posture in man may be dangerous when the compensatory nervous reflexes controlling the arteries and the tone of the abdominal wall are thrown out of action, as, for instance, in a faint or in a condition of anesthesia. In such conditions the recumbent position favors the maintenance of the normal circulation. Indeed, under ordinary conditions some individuals are quite sensitive to the effects of a vertical position, especially if unaccompanied by muscular or mental activity, and may suffer from giddiness and a sense of faintness in consequence of a fall in general blood-pressure. It seems prob- able that in these cases the gravity effect has drafted off an undue amount of blood into the splanchnic area. Individuals who have been kept in bed for long periods by sickness, accident, or other causes suffer from giddiness and unsteadiness when they first attempt to stand or walk. It seems quite possible that in such cases the effect is caused by a fall in arterial pressure brought about by the dilatation in the splanchnic area. The added weight of blood thrown on these vessels by the effect of gravity is not compensated by a vasoconstriction of the arterioles or an increased tone in the abdominal walls. While certain general deductions of the kind given above may be made from our knowledge of the hydrodynamics and hydrostatics of the cir- culation, it is evident that in particular cases, whether affecting special organs or the organism as a whole, it is necessary to obtain directly, if possible, the facts, not only for the arterial pressure and velocity but also for the venous pressure and velocity, in order to draw safe conclusions as to the changes in the circulation. In all observations made upon man it is especially important to standardize the results by reducing * Hill and Barnard, "Journal of Physiology," 21, 321, 1897. 508 CIRCULATION OF BLOOD AND LYMPH. them to a common level. The arterial or venous pressure in the foot or hand of a man standing erect is increased by the hydrostatic effect of the vertical column of blood between the point measured and the heart. This hydrostatic effect varies, of course, for the different parts of the body, and to compare the pressures in the different arteries or veins with one another the vertical distance from the heart should be measured and this pressure in terms of a column of water or mercury should be subtracted or added, as the case may be, to the pressure actually observed. The exact level for which these measurements should be adjusted has varied somewhat in practice; to simply say the heart-level is too indefinite, since in the upright position there is a considerable distance between the level of the base and of the apex of the heart, von Recklinghausen recommends the middle of the clorsoventral axis drawn from the lower end of the sternum to the spinal column. Accessory Factors Aiding the Circulation. — The force of the heart beat is the main factor concerned in the movement of the blood, but certain other muscular movements aid more or less in maintaining the circulation as it actually exists in the living animal, particularly in their effect upon the flow of blood in the veins. The most important of these accessory factors are the respiratory movements and the contractions of the muscles of the limbs and viscera. At each inspiratory movement the pressure relations are altered in the thorax and abdomen, and reverse changes occur dur- ing expiration. These effects influence the flow of blood to the heart, and alter the velocity and pressure of the blood in a way that is described in the section on Respiration under the title of The Respiratory Waves of Blood-pressure. In brief, it may be said that the main effect of the respiratory movements is to force or to suck blood from the large veins of the abdomen and neck into the large thoracic veins, and, therefore, into the right side of the heart. Keith* has called attention to the fact that the system of large veins in the thorax and abdomen, namely, the superior and in- ferior venge cavae, the innominate, iliac, hepatic, and renal veins constitute what he calls a venous cistern, whose capacity may be reckoned as about 400 to 500 c.c. This cistern is shut off below from the veins of the lower extremity by the valves in the femoral veins at their entrance into the pelvis; it is shut off from the veins of the upper extremity by valves in the subclavian veins, and from the veins of the neck and head by the jugular valves. When an inspiration is made, the lowered pressure in the thoracic cavity aspirates blood from the veins in the neck and upper extremities into the superior cava, and on the return to the expiratory position * Keith, "Journal of Anatomy and Physiology," 42, 1, 1908. BLOOD-PRESSURE AND BLOOD-VELOCITY. 509 blood cannot be forced back owing to the jugular and subclavian valves. In the same way the lessened intrathoracic pressure during inspiration must tend to aspirate blood from the abdominal portion of the inferior vena cava into the thoracic portion, and this move- ment of blood into the thorax is probably aided by the rise in pressure in the abdomen caused by the descent of the diaphragm, since an increase of pressure in the abdomen would be prevented from driving blood toward the legs by the presence of the femoral valves. The play of the respiratory movements must, therefore, constitute a constant factor tending to empty the venous cistern into the right heart, and in this way promoting the circulation on the venous side. Contractions of the skeletal muscles must also influence the blood-flow. The thickening of the fibers in con- traction squeezes upon the capillaries and small vessels and tends to empty them. On account of the valves in the veins the blood is forced mainly toward the venous side of the heart, so that rhythmical contractions of the muscles may accelerate the cir- culation. This pumping effect of our muscular movements is probably quite an important factor in returning the blood from the lower extremities. In this portion of the body the venous flow to the heart has to overcome the hydrostatic pressure of the column of blood, and it has been shown that when one is standing quite still, the venous pressure alone may be insufficient to overcome this resistance, so that the blood-flow from the feet may be much retarded. Under these circumstances movements of the legs, as in walking, aided by the valves in the veins, probably help to " milk " the blood into the pelvic veins. The contractions of the smooth muscles, especially in the stomach and intestines, during digestion have a similar effect. The musculature of the spleen also is supposed to aid the circulation through that organ by its rhythmical contractions. The Conditions of Pressure and Velocity in the Pulmonary Circulation. — The general plan of the smaller circulation from right ventricle to left auricle is the same as in the major or systemic circulation, and the same general principles hold. The right ventricle pumps its blood into the pulmonary artery, and. on ac- count of the peripheral resistance in the lung capillaries, the side pressure in the artery is higher than in the capillaries, and higher in these than in the pulmonary veins. The velocity of movement is least, on the other hand, in the extensive capillar}' area and greatest in the pulmonary artery and veins, on account of the variations in width of the bed. So also in the pulmonary artery the pressure and velocity must fluctuate between a systolic and diastolic leA*el at each heart beat, while in the pulmonary veins they are more or less uni- form. An interesting; difference between the two circulations 510 CIRCULATION OF BLOOD AND LYMPH. consists in the fact that the peripheral resistance is evidently much less in the pulmonary circuit, and consequently the pressure in the pulmonary arteries is much less than in the aortic system. The velocity of the flow, as already stated (p. 478), is also greater in the lung capillaries than in the systemic capillaries. Exact deter- minations of the pressure in the pulmonary artery are made with difficulty on account of the position of the vessel.* The results obtained by various observers give such values as the following: Mean Pressure. Extreme Variations. Mms. Hg. Mms. Hg. Dog 20 10 to 33 Cat 18 7.5 " 24.7 Rabbit 12 6 "35 It will be seen, therefore, that the mean pressure is not more than one-seventh to one-eighth of that prevailing in the aorta. The thinner walls and smaller muscular power of the right ventricle as compared with the left are an indication of the fact that less force is necessary to keep up the circulation through the pulmonary circuit. The Variations in Pressure in the Pulmonary Circuit. — Experimental results indicate that the pressures in the pulmonary circuit do not undergo as marked changes as in the systemic circu- lation; the flow is characterized by a greater steadiness. With a systemic pressure, as taken in the carotid, varying from 144 to 222 mms., that in the pulmonary artery changes correspondingly only from 20 to 26 mms., and extreme variations of pressure in the pulmonary artery probably do not exceed, as a rule, 15 to 20 mms. The regulations of the pressure and flow of blood in the small circulation do not seem to be so direct or complex as in the aortic system. The part taken by the vasomotor nerves is referred to in the chapter upon the innervation of the blood-vessels, and attention may be called here only to the mechanical factors, which, indeed, for this circulation are probably the most important. The output from the right ventricle, and therefore the amount of flow and the pressure in the pulmonary artery, depends mainly on the amount of blood received through the vena? cavse by the right auricle. If one of the venae cavse is closed the pulmonary pressure sinks; pressure upon the abdomen, on the other hand, by squeezing more blood toward the right heart may raise the pressure in the pulmonary artery. By such means, therefore, the variations in blood-flow in the systemic circulation indirectly influence and control the pressure relations in the pulmonary circuit. But the changes in the systemic * For a discussion of the special physiology of the pulmonary circulation and for references to literature, see Tigerstedt, "Krgebnis.se der Physiologie," vol. ii., part ii., p. 528, 1903. BLOOD-PRESSURE AND BLOOD- VELOCITY. 511 circulation may affect the blood-flow through the lungs in still another way, — namely, by a back effect through the left auricle. When for any reason the blood-pressure in the aorta is driven much above the normal level the left ventricle may not be able to empty itself sufficiently., and if this happens the pressure in the left auricle will rise and the flow through the lungs from right ventricle to left auricle will be more or less impeded. On the whole, it would seem that the pulmonary circulation is subject to less changes than in the case of the organs supplied by the aorta. The mechanical conditions, especially in the capillary region, are such that the blood is sent through the lungs with a relatively high velocity, although under small actual pressure. The special effects of the respiratory movements and of variations in intrathoracic pressure upon the pulmonary circulation are referred to in con- nection with respiration. CHAPTER XXVII. THE PULSE. General Statement. — When the ventricular systole discharges a new quantity of blood into the arteries the pressure within these vessels is increased temporarily. If the arteries, capillaries, and veins were perfectly rigid tubes it is evident that this pressure would be transmitted practically instantaneously throughout the system, and that a quantity of blood would be displaced from the vense cava? into the auricles equal to the quantity forced into the aorta by the ventricle. The flow of blood throughout the vascular system would take place in a series of spurts or pulses, the pressure rising suddenly during systole and falling rapidly during diastole. Since the blood is incompressible and the walls of the vessels if rigid would be inextensible, the rise of pressure, the pulse, would be simultaneous in all parts of the system. The fact, however, that the walls of the vessels are extensible and elastic modifies the trans- mission of the pulse wave in several important particulars: It explains why it is that the pulse dies out in or at the beginning of the capillaries and why it occurs at different times in different arteries — that is, why the wave of pressure takes a perceptible time to travel over the arteries. The result that follows from the elasticity of the arteries may be pictured as follows: Under the normal conditions of the circulation when the heart contracts and forces a new quantity of blood into the aorta room must be made for this blood either by moving the whole mass of the blood forward ■ — that is, by discharging an equal amount at the other end into the auricle — or by the enlargement of the arteries. This latter alter- native is what really happens, as it takes less pressure to distend the aorta than to move forward the entire mass of blood under the conditions that exist in the body. So soon, therefore, as the semi- lunar valves open and the new column of blood begins to enter the aorta, the walls of that vessel begin to expand and during the time that the blood is flowing out of the heart — that is, in round numbers, about 0.3 sec. — the extension of the walls passes from point to point along the arterial system. At the end of the outflow from the heart all the arteries are beginning to enlarge, the maximum extension being in the aorta, and room is thus made for the new quantity of blood. The new blood that is actually discharged from the heart 512 THE PULSE. 513 lies somewhere in the aorta, but the pressure that has been trans- mitted along the system and has caused it to expand has made room for the blood forced out of the aorta by the new blood. With the cessation of the heart beat and the closure of the semilunar valves, the sharp recoil of the distended aorta drives forward the column of blood, and as the aorta sinks back to its normal diastolic diameter the more distal portions of the arterial system are at first distended to a certain point and then return to their diastolic size as the excess of blood streams through the capillaries into the veins. At the time that the aorta has reached its diastolic size the walls of the most distant arterioles have passed their maximum extension and are beginning to collapse. The distension caused by the pulse, therefore, spreads through the arterial system in the form of a wave. At any given point the distension of the walls increases to a maxi- mum and then declines, and when this change in size is recorded in the large arteries, by methods described below, it is found that the expansion of the artery is much more sudden than the subse- quent collapse. This difference is understood when we remember that the heart throws its load of blood into the arteries with sud- denness and force, causing a sharp rise of pressure, while the collapse of the arteries is due to their own elasticity. The disappearance of the pulse before reaching the capillary area is readily compre- hended when one remembers that the arterial tree constantly in- creases in size as one passes out from the aortic trunk. Many facts, such as those of pressure and velocity already described, indicate that the increase in capacity of the arterial system is somewhat gradual until the region of the smallest arterioles and capillaries is reached and that at this point there is a sudden widening out or increase in capacity of the whole system, although the individual vessels diminish in diameter. It is in this region that the pulse, under ordinary conditions, becomes imperceptible.* When the arterioles in any organ are dilated the pulse may spread through the capillary regions and be visible in the veins. Velocity of the Pulse Wave. — From the above considerations it is evident that in a system such as is presented by our blood- vessels the velocity of the pulse wave must vary with the rigidity of the tubes. If perfectly rigid the pressure would be transmitted practically instantaneously; if the walls were very extensible the propagation would be relatively slow. For our blood-vessels as they exist at any given moment the velocity of the pulse wave may be estimated by a simple method : Two arteries may be selected at different distances from the heart and the pulse wave as it passes by * For a satisfactory discussion of the pulse and for literature consult von Frey, "Die Untersuchung des Pulses." Berlin, 1892. For a description of the variations in disease consult Mackenzie, " The Study of the Pulse, etc." New York. 1902. 33 514 CIRCULATION OF BLOOD AND LYMPH. a given point in each artery may be recorded by some convenient apparatus, such as can be devised in any laboratory. If the waves are recorded on a rapidly revolving kymographion whose rate of movement can be determined, then the difference in time in the arrival of the pulse wave at the two points is easily ascertained. That there is a perceptible difference in time one can easily demon- strate to himself by feeling simultaneously the pulse of the radial and the carotid arteries. If this difference in time is determined for two arteries — for instance, the femoral and the tibialis anterior — and the distance between the two points is recorded, we have evidently the necessary data for obtaining the velocity of the pulse wave in the arteries of that region. A record of this kind is shown in Fig. 211. Fig. 211. — To illustrate the method of determining the velocity of the pulse wave in man. Shows record of the pulse at two points on the leg at a known distance apart. The difference in time is given by the verticals dropped from the beginning of these waves to the time curve. This last is made by the vibrations of a tuning fork giving 50 vibra- tions per second. The difference in this case was equal to 0.07 sec. The results obtained by various authors indicate that the velocity varies somewhere between 6 and 9 meters per second for adults. The figures published by recent observers show also that the velocity is somewhat greater in the upper extremities (7.5 m. for carotid- radial estimation) than in the descending aorta (6.5 m. for carotid- femoral estimation).* The average of thirty determinations made in the author's laboratory upon medical students shows that the velocity in the leg (femoral-anterior tibial) is 6.1 m. when the records are made upon the same leg, and 7.4 m. when the record for the femoral is taken from one leg and that for the anterior tibial * Edgren, "Skandinavisches Archiv f. Physiol.," 1, 96, 1889. THE PULSE. 515 from the other. The latter condition would seem to be more nor- mal, since the blood-flow and normal tension of the walls are probably less disturbed. An increase in rigidity of the arteries causes the velocity to rise; in elderly people, therefore, the velocity is distinctly greater. In arterial sclerosis with hypertrophy of the heart the velocity may increase to as much as 11 or 13 m. Any marked dilatation of the arteries — such as occurs, for instance, in aneurysms, — retards the pulse wave markedly; so that the existence of an aneurysm may be detected in some cases by this fact. If we know the velocity of the wave and the time that it takes to pass any given point the length of the wave is given by the formula 1= vt. In an adult the duration of the wave (t) at the radial may be taken as 0.5 to 0.7 sec; so that if the velocity of the wave were uniform throughout the arteries the length of the wave would be from 3.25 to 4.5 m. We can conclude, therefore, that before Fig. 212. — The Dudgeon sphygmograph in position. the wave has disappeared at the root of the aorta it has reached the most distant arteries. The Form of the Pulse Wave — Sphygmography. — The pulse wave may be felt upon any superficial artery in consequence of the distension of the vessel. By the tactile sense alone the experienced physician may distinguish some of the characters of the wave, its frequency, its force, etc. The details of the form of the wave, however, were made evident only when the variations in size of the artery were recorded graphically by placing a lever upon it. Any instrument suitable for this purpose is designated as a sphygmo- graph, and very numerous forms have been devised. The move- ment of the artery is very small and to obtain a distinct record it is necessary to magnify this movement greatly by a properly con- structed lever. The form of lever that is perhaps most frequently employed is shown in the accompanying figures. The instrument is strapped upon the arm so that the 516 CIRCULATION OF BLOOD AND LYMPH. button of the metallic spring rests over the radial artery. The movements of the artery are transmitted to this spring and this latter in turn acts upon the bent lever, and the magnified movement is recorded by the writing point, upon a strip of blackened paper which is moved under the point by clockwork contained in the case. To obtain a satisfactory record or sphyg- mogram, two details are of special importance: First, the button of the lever must be pressed upon the artery with the proper force. Theo- retically this pressure should be about equal to the diastolic pressure within the artery. All sphygmographs are provided with means to regulate the pressure, and practically one must learn so to place the button and to arrange the pressure as to obtain the largest tracing. A second detail of importance is that the weight of the lever when set suddenly into motion causes a movement, due to the inertia of the mass, which may alter the true form of the wave. To overcome this defect the lever should be as light as possible, or the spring upon which the artery plays should have considerable resis- tance. In those sphygmographs in which the inertia factor is practically eliminated the diffi- culty of obtaining a tracing, especially from a weak pulse, is correspondingly increased, and in the sphygmographs most commonly employed, such as the Dudgeon, facility in application is obtained at the expense of incomplete correction of the error of inertia. The pulse wave obtained from the radial artery is represented in Fig. 214. It will be seen from this figure that the artery dilates rapidly and then falls more slowly, but it must be borne in mind that the very pointed apex of the wave recorded by this form of sphygmograph is due to the instrumental error referred to above, namely, the "fling" of the lever caused by the sudden expansion Fig. 213.— The lever of the Dudgeon sphygmograph: P, The button of the spring F, to be placed upon the artery. The movement is transmitted to the lever, Fi, and thence to the bent lever, Fi, whose movement is effected through the weight, g. The writing point S, of this lever makes the record on the smoked sur" face, A. Fig. 214. — Sphygmogram from the radial artery, Dudgeon sphygmograph: D, The dicrotic wave ; P, the predicrotic wave. of the artery. The ascending portion of the wave is spoken of as the anacrotic limb, the descending, as the catacrotic limb. Under usual conditions the anacrotic limb is smooth, — that is, shows no secondary waves, — while the catacrotic limb shows one or more secondary waves, which are spoken of in general as the catacrotic waves. The most constant of these latter waves occurs usually THE PULSE. 517 approximately at the middle of the descent (D) and is designated as the dicrotic wave. A less conspicuous wave between it and the apex of the pulse wave is known usually as the predicrotie wave, P, while the wave or waves following the dicrotic are designated as postdicrotic. These catacrotic waves are too small, under normal conditions, to be felt by the finger. Under certain abnormal conditions, however, which cause a low blood-pressure without marked diminution in the heart beat, the dicrotic wave is empha- sized and may be detected by the finger. A pulse of this kind is known as a dicrotic pulse. In each pulse wave we may distinguish a systolic and a diastolic phase; the former, making due allowance for transmission, corresponds with the time during which the aortic valves are open, and blood is streaming from the heart to the aorta, the latter represents the period during which the aortic valves are closed and the arteries are shut off from the heart. In Fig. 214 the systolic phase extends from s to d, the diastolic from d to s'. Explanation of the Catacrotic Waves. — It has been found difficult to give an entirely satisfactory explanation of the catacrotic waves or, to speak more accurately, it is difficult to decide between the different explanations that have been proposed. Concerning the dicrotic wave, it may be said that tracings from different ar- teries show that, like the main pulse wave, it has a centrifugal course, — that is, it starts in the aorta and runs peripherally with the same velocity as the main wave upon which it is superposed. More- over, simultaneous tracings of the pressure changes in the heart and in the aorta show that the closure of the semilunar valves is synchro- nous with the small depression or negative wave (d, Fig. 214) which immediately precedes the dicrotic wave. The general belief, there- fore, is that the dicrotic wave results from the closure of the semi- lunar valves. When the distended aorta begins to contract by virtue of the elasticity of its walls, it drives the column of blood in both directions. Owing to the position of the semilunar valves the flow to the ventricle is prevented; but the interposition of this sudden block causes a reflected wave which passes centrifugally over the arterial system. The dicrotic wave is preceded by a small negative wave or notch in the curve which marks the time of closure or just follows the closure of the semilunar valves. The sequence of events as pictured by Mackenzie* is as follows: "As soon as the aortic pressure rises above the ventricular the valves close. At the moment this happens the valves are supported by the hard, contracted ventricular walls. The withdrawal of the support by the sudden relaxation of these walls will tend to produce a negative pressure wave in the arterial system. But this negative * Mackenzie, "The Study of the Pulse and the Movements of the Heart. " 1902. 518 CIRCULATION OF BLOOD AND LYMPH. wave is stopped by the sudden stretching of the aortic valves, which, on losing their firm support, have now themselves to bear the resistance of the arterial pressure. This sudden checking of the negative wave starts a second positive wave, which is prop- agated through the arterial system as the dicrotic wave." The smaller waves, such as the predicrotic, have been explained simply as reflected waves, or as instrumental errors, due to fling of the lever. According to some authors,* an important — perhaps the chief — factor in the production of the secondary waves is the reflection that occurs from the periphery. Where each arterial stem breaks up into its smaller vessels the main pulse wave suffers a reflection, a wave running backward toward the heart. It is probable that such reflected waves from different areas — for instance, from the coronary system, the subclavian system, the mesenteric system, etc. — meet in the aorta and may in part summate to larger waves, which again pass peripher- ally. The catacrotic waves, according to this view, probably differ in character in the different arteries, and tracings indicate that this is the case. The radial pulse differs, for instance, from the carotid pulse in the character of its waves. Between these Fig. 215. — Anacrotic pulse from a case of aortic stenosis (Mackenzie): b. The anacrotic wave. opposite views it is not possible to decide, but it is perhaps permissible to believe that while the dicrotic wave is due pri- marily to the impulse following upon the closure of the semilunar valves, nevertheless the actual form of this and the other second- ary waves is variously modified in different parts of the system by the reflected waves from different peripheral regions. f Anacrotic Waves. — As was said above, the anacrotic limb under normal conditions shows no secondary waves. Under pathological conditions, however, a secondary wave more or less clearly marked may appear, as is shown, for instance, in the tracing given in Fig. 215. Such waves are recorded in cases of stiff arteries or stenosis of the semilunar valves. In the normal individual an anacrotic pulse in the radial may be obtained, according to von Kries,| by raising the arm. He believes that in this position the reflection of the pulse wave from the periph- * See von Frey, loc. cit. t For a general discussion, see Tigerstedt, "Ergebnisse d. Physiologie, " vol. viii., 1909. X Von Kries, "Studien zur Pulslehre," 1892. THE PULSE. 519 ery is favored, and that the anacrotic wave is simply a quickly reflected wave. An opposite interpretation, however, is given by von Recklinghausen, who states that conditions which lead to a diminution in vascular tone and a dilation of the arteries produce "weak reflection" and an anacrotic pulse. Constric- tion of the small arteries in any system favors quick reflection in the artery supplying the system and produces a pulse with a sharp-pointed apex. Characteristics of the Pulse in Health and in Disease. — By mere palpation the physician obtains from the pulse valuable indications concerning the heart and the circulation. The fre- quency of the heart beat is at once made evident, so far at least as the ventricle is concerned. One may determine readily whether the frequency is above or below the normal, whether the rhythm is regular or irregular. By the same means one can determine Fig. 216. — Sphygmograms illustrating the effect of variations in blood-pressure, partic- ularly upon the position of the dicrotic wave and notch : n. The dicrotic notch ; d, the dicrotic wave. A, Sphygmogram while blood-pressure was relatively low. B, Sphygmo- gram with higher blood-pressure. (Mackenzie.) whether the pulse is large (pulsus magnus) or small (pulsus parvus), whether the wave rises and falls rapidly (pulsus celer) as happens in the case of insufficiency of the aortic valves, or whether in one phase or the other it is more prolonged than normal (pulsus tardus). It seems obvious, however, that a more satisfactory conclusion may be reached in all such cases by obtaining a sphygmographic record. In the works devoted to clinical methods numerous such sphygmo- grams are described. By mere pressure upon the artery one can determine also approximately whether the blood-pressure is high 520 CIRCULATION OF BLOOD AND LYMPH. or low by estimating the force with which the wave presses upon the fingers, or the pressure necessary to occlude the artery. A similar inference may be drawn from the character of the sphyg- mogram, and especially from the relative size and position of the dicrotic wave. When this latter wave falls at or near the base line of the curve it indicates a low arterial pressure, since under these circumstances the artery collapses readily after its first systolic expansion (see Fig. 216). Since the introduction of the sphyg- momanometer (p. 492), however, it seems evident that this instru- ment must be appealed to whenever the determination of blood- pressure is a matter of importance. Venous Pulse. — Under usual conditions the pulse wave is lost before entering the capillary regions, but as a result of dilatation in the arteries of an organ the pulse may carry through and appear in the veins, in which it may be shown, for instance, by the rhythmical flow of blood from an opened vein. The term venous pulse, how- ever, as generally used applies to an entirely different phenomenon, — namely, to a pulse observed especially in the large veins (jugular) near the heart. The pulse in this case is not due to a pressure wave transmitted through the capillaries, but to pressure changes of both a positive and negative character occurring in the heart and transmitted backward into the veins. The venous pulse that has this origin may usually be seen and recorded in the external (or internal) jugular. Under pathological conditions, especially when the flow through the right heart is more or less impeded, it may be plainly apparent at a further distance from the heart and may cause a noticeable pulsation of the liver, which is designated as a liver pulse. The venous pulse curve has been much studied in recent yea/s.* It is somewhat complicated and an explanation of some of its details has not been agreed upon, but there can be no doubt that when properly interpreted it will throw much light upon the pressure changes in the heart, and will afford a valuable means of diagnosis in cases of valvular lesions and other pathological conditions of the heart. It is evident also that the venous pulse gives a ready means of determining the rate of beat of the auricles, just as the arterial pulse enables us to count the beats of the ven- tricles, and in this way records of the venous pulse are important in the interpretation of irregularities in the beat of the heart (arrhythmia). As usually recorded the venous pulse shows three positive waves, designated commonly as the a, c, and v waves, and three negative waves. Of the three positive waves, the a wave marks, *See Mackenzie, " The Study of the Pulse," 1902; also Lewis, in Hill's " Further Advances in Physiology," New York, 1909. THE PULSE. 521 undoubtedly, the contraction of the auricle, but in order to locate this wave or, indeed, to interpret at all the complicated venous pulse, it is necessary to have a simultaneous tracing of the arterial pulse, preferably the carotid, or of the apex beat of the heart. Either of these latter tracings enables one to mark upon the venous pulse the point at which the ventricular systole begins, and the wave immediately preceding this point must be due to the auricular contraction, the a wave (Figs. 217 and 218). Following the rise of the a wave there is a fall, the first negative wave, which is clue to the auricular relaxation. The interpretation of the other two positive and negative waves has been the subject of much discussion. Mackenzie, one of whose tracings is reproduced in Fig. 218, believed that the Fig. 217. — Simultaneous tracings of the carotid and venous pulses. In the venous tracing (internal jugular) a indicates the auricular wave due to the contraction of the auri- cle; c is the carotid wave due (Mackenzie) to an impulse from the neighboring carotid artery; v is the ventricular wave due to the checking or stagnation of the flow into the auricle as this chamber fills during the period of closure of the auriculoventricular valves; x, dilatation due to auricular relaxation; y, the period of ventricular diastole. (Mackenzie.) c wave is due simply to the pulse in the neighboring carotid artery, and that, therefore, it has no significance in regard to changes within the heart itself. Careful records made by other observers show, however, that this explanation is insufficient. The c wave begins in the jugular before the arterial pulse wave reaches the carotid, hence this wave cannot be due wholly to the carotid pulse. As is shown in the tracing given in Fig. 218, the c wave begins, in fact, at the very moment of ventricular systole. The explanation of it which meets with most accept- ance is that it is due to a sharp protrusion of the auriculo- ventricular valves into the cavity of the auricle. At the begin- ning of the ventricular systole these latter valves are in position for closure, while the semilunar valves at the opening to the pulmonary artery are tightly closed. For a short period the ven- tricular muscle contracts upon a closed cavity, and the pressure upon the contents rises rapidly. It is at the beginning of this brief period that the auriculoventricular valves are protruded 522 CIRCULATION OF BLOOD AND LYMPH. somewhat into the auricle and thus cause a positive wave in the venous blood which is propagated back into the large veins. Immediately upon the opening of the semilunar valves blood streams out of the ventricle into the pulmonary artery, and the ventricle diminishes rapidly in size — especially in the diameter from base to apex. This sudden descent of the base of the ventricle pulls downward the floor of the auricle and causes a sudden enlargement of the auricular cavity, which in turn produces a temporary negative pressure in the auricle and Fig. 218. — Simultaneous tracings of the jugular pulse, the carotid pulse, and the apex beat, ( Bachmann.) At the bottom of the tracing the time is given in fiftieths of a second. The vertical line- 0, 1, 2, 3, etc., mark synchronous points on the curves. A, The auricular wave; s, the so-called c wave caused by the systole of the ventricle; v, the stagnation wave caused by the filling of the auricle. It will be noticed that the c wave (marked s in the tracing) occurs at the beginning of the ventricular systole as marked on the apex beat, and shortly before the puise in the carotid artery. The height of the r wave is reached just after the occurrence of the dicrotic notch on the carotid wave, and coin- cide- with the opening of the auriculoventricular valves; Af, the negative wave caused by the effect of the ventricular systole; Vf, the negative wave following the opening of the auriculoventricular valves. attached veins. The second negative wave is, therefore, due to a forcible dilation of the auricle caused by the systole of the ventricle. This negative wave is converted into a positive wave by the steady inflow of venous blood, which continues to pour into the auricle during the whole period of the systole of the ventricle and of the closure of the auriculoventricular valves. In this way the wave v is produced. It is frequently of irregular or toothed form and rises somewhat gradually to its maximum. The end or maximum of the wave falls in with the beginning of the muscular relaxation of the ventricle, and the return, THE PULSE. 523 therefore, of the base of the ventricle to its diastolic position. Immediately afterward the auriculoventricuiar valves open, and the blood accumulated in the auricles is discharged into the ventricle, causing again a sudden fall of pressure in the auricles and veins, the third negative wave. The true relations of these different venous waves to the sequence of events in the ventricle and aorta are clearly shown Fig. 219. — Schema of the variations of pressure in the ventricle, auricle, aorta, and superior vena cava during a cardiac cycle in the dog : a, b, Systole of the auricle; b, c, d, e, systole of the ventricle ; b', opening of the semilunar valves ; e, closure of the semilunar valves ; 6, 6', closure of the auriculoventricuiar valves ; f , opening of the auriculoventricuiar valves. On the curve for the auricle and vein the wave from a to b represents the auricular contraction, the a wave; that beginning at b is the wave due to ventricular systole, the c wave, and the rise of pressure extending from d to e and ending with the opening of the auriculoventricuiar valves constitutes the v wave. The time relations are given along the abscissa in tenths of a second, the pressure relations in nuns, of mercury for the ventricle and aorta are given along the ordinates to the left. (After Fredericq.) in the diagram given by Fredericq, which is reproduced in Fig. 219. Following this author,* the series of positive and negative waves which ma}r usually be shown in the auricles and great veins during a single heart beat may be enumerated as follows: 1. The auricular wave (a wave), auricular systole. 2. The first negative wave, auricular diastole. 3. First systolic wave (positive), c wave. Beginning of ventricular systole. Due to sudden closure and protrusion of the auriculoventricuiar valves. * Fredericq, " Centralblatt f. Physiol.," 22, No. 10, 1908. 524 CIRCULATION OF BLOOD AND LYMPH. 4. Second negative wave. At the time of opening of the semi- lunar valves. Due to descent of the base of the ventricle, causing dilatation of auricle. 5. Second systolic wave (positive), v wave. Latter part of systole. Due to gradual filling of auricle and at the end to the return of the base of the ventricle to its diastolic position. 6. Postsystolic (third) negative wave begins at moment of opening of the a-v valves. Due to emptying of auricular blood into ventricle. Other waves have been described, especially one in the post- systolic or early diastolic phase of the ventricular beat, which is known as the h wave (Hirschf elder) or b wave (Gibson). This wave occurs between the v and the a wave, it is seen only occasionally in the tracings, and has been referred to the tri- cuspid valves, which at this time are thrown suddenly into position as the ventricle is distended by the inflow of venous blood in early diastole. For the variations in the form of the venous pulse under pathological conditions of the heart, reference must be made to clinical literature.* * See Hewlett, "Journal of Medical Research," 17, 1907; "Journal of the Amer. Med. Assoc," 51, 1908, and Hirschfelder, " Diseases of the Heart and Aorta," Philadelphia, 1910 CHAPTER XXVIII. THE HEART BEAT. General Statement. — We divide the heart into four chambers, — the two auricles and the two ventricles. What we designate as a heart beat begins with the simultaneous contraction of the two auricles, immediately followed by the simultaneous contraction of the two ventricles; then there is a pause, during which the whole heart is at rest and is filling with blood. As a matter of fact, the heart-beat is initiated not by the auricles proper, but by an area of specialized tissue in the right auricle lying between the open- ings of the two cavse. This portion of the auricular wall corre- sponds physiologically to a definite chamber, the venous sinus, BBBIIBBMBBBBBBfilieaflBBBBflBBaSBBBB niiHamf ~ PIHHflB r^liJilBBIHB IBBBtifflBBBBBBfll BB9BBBBBBB SBftiS IB9BB! SBBSSi !SSB Mill It'll IBfllBBBBj JBHI BBBI 1HBBBUB! SS5BBBBHI ._nnnn s^bi JBUBBHI IBIBI 1BB1 IBIIBBBI BRiBI 1B1BI SSBI IBBB! BMBI1BBBB KBBBrsaBBHBBI iBirasB : IBBRBSEIBI BUBBBT BBBIIBBBIIBBBBBBBBBBBBBBBBBBBBBBBB ER&IMIimil """JLJBMI IBBBBI IBI!SBI 19»ilBBI5iBI iBBBI MV5! ■liBI BRIBBBBNB SSBBI IBUB ■BBBBB Fig. 220. — To show the time relations of the auricular systole and diastole, and ven- tricular systole and diastole (Marey) : Or. D, Tracing from right auricle ; Vent. D, tracing from right ventricle ; Vent. G, tracing from left ventricle. Obtained from the heart of the horse by means of tubes communicating with the cavities. in the heart of the lower vertebrates (see Fig. 224) . The contrac- tion of any part of the heart is designated as its systole, its relaxa- tion and period of rest as its diastole. In the heart-beat we have, therefore, the auricular systole, the ventricular systole, and the heart pause, during which both chambers are in diastole. The general relations of systole, diastole, and pause are represented graphically in the accompanying figure (Fig. 220). It will be noted that the auricular systole is shorter and its diastole longer than the similar conditions in the ventricles. The Musculature of the Auricles and Ventricles. — Embryo- 525 526 CIRCULATION OF BLOOD AND LYMPH. logically the four-chambered heart is developed from a simple tube, and this origin is indicated in the adult by the fact that the musculature of the two auricles is in large part common to both chambers, — that is, surrounds them as though they were a single chamber, — and the same is true of the ventricles. In the auricles there is a superficial layer of fibers which runs transversely and en- circles both auricles. The simultaneous contraction of the two chambers would seem "to be insured by this arrangement alone. In addition, each auricle possesses a more or less independent system of fibers, whose course is at right angles to that of the Fig. 221. — Schema to show the course of the superficial and deep fibers of the bulbo- spiral and sinospiral systems. The heart is viewed from the dorsal side. BS, superficial bulbo- spiral system; BS', deep bulbospiral system; SS, superficial sinospiral system; SS', deep sino- spiral system; C, circular fibers round the conus; C", circular fibers round the base of the aorta and the left ostium; LRV, longitudinal bundle of right ventricle, from membranous septum to right ventricle; IV, interventricular or interpapillary layer (Mall). preceding layer. These fibers may be considered as loops arising and ending in the auriculo-ventricular ring. The course of the fibers in the ventricles has been difficult to make out, and several more or less different accounts have been published. The fibers on the surface of the heart arise from the tendinous rings and mem- branes at the base and take a spiral course to the apex, where they form a vortex and pass into the interior of the left ventricle to enter the septum and make connections with the papillary muscles. In this way they return upon themselves toward the base of the heart and form spiral loops whose contractions serve to approxi- THE HEART BEAT. 527 mate base and apex and at the same time to give a rotation to the apex from left to right. Mall* divides these superficial fibers into two groups. First, the superficial bulbo-spiral fibers (B S) which arise from the conus, the left side of the aorta, and the left side of the left ostium venosum, take a spiral course to the apex, where they form the posterior horn of the vortex, and penetrate to the interior of the left ventricle to end in the septum and along the posterior side of the ventricle, making connections also with the posterior papillary muscle. Some of the deeper fibers of this layer encircle the lower part of the ventricle and then pass upward to end at the base of the heart. The bulbospiral fibers belong chiefly to the left ventricle. Second, the superficial sinospiral Fig. 222. — Anterior surface of the heart, to show the arrangement of the superficial fibers over the right ventricle: SS, Sinospiral band; BS, bulbospiral band; B, C, fibers of the bulbo- spiral svstem as thev enter the vortex; D, E, fibers of the sinospiral band as thev enter the vortex (Mall). fibers (S S), which arise mostly on the posterior aspect of the heart from the right ostium venosum, the sinus end of the embryonic heart, take a spiral course to the apex over the anterior surface of the right ventricle, running more transversely than the bulbo- spiral group. At the vortex this system forms the anterior horn of the vortex and penetrates into the interior of the left ventricle, to end along the anterior side and in the papillary muscles, par- ticularly the anterior papillary. Beneath these superficial layers lie corresponding deep layers of the bulbospiral and sinospiral systems, which have a more transverse or circular course. The deep bulbospiral fibers {B Sf) encircle the left ventricle and end * Mall, "The American Journal of Anatomy," 2, 211, 1911. 528 CIRCULATION OF BLOOD AND LYMPH. by way of the septum on the dorsal side of the aorta. These fibers in the developed heart make a strong circular system whose contraction tends to diminish the lumen of the left ventricle. Below the superficial sinospiral system lies the deep sinospiral sheet (*S S'), which arises from the posterior side of the left ostium and passes transversely to enter the interior of the right ventricle and then turn upward toward the base. At the base of the heart some of the fibers of the bulbospiral system pass circularly round the base of the aorta and the left ostium, and in the right ventricle some of the sinospiral system form circular loops round the coniis at the base of the pulmonary artery. As will be described below, there is physiological evidence that this latter group of circular Fig. 223. — Posterior view of heart, somewhat to left, after the superficial sinospiral band has been removed to the posterior longitudinal sulcus: BS', deep bulbospiral band; BS, super- ficial bulbospiral band, A, B, and C are fibers belonging to this system and forming the posterior horn of the vortex; S8, superficial sinospiral band, D and E are fibers belonging to this system and forming the anterior horn of the vortex; CLV, the circular band (bulbospiral system) round the left venous ostium (Mall). fibers around the base of the pulmonary artery and aorta are the last to enter into contraction in the systole of the ventricle, as might be expected from their homology with the musculature of the bulbus arteriosus in the hearts of the lower vertebrates. The Auriculoventricular Bundle. — A matter of very great physiological interest in connection with the invariable sequence of the heart-beat has been the question of the existence of a direct muscular connection between the auricles and ventricles. In the lower vertebrates there is muscular continuity throughout the heart from the venous end to the arterial end. In hearts of this type (see Fig. 224) we may distinguish four different chambers — the sinus venosus, into which the great veins open, the auricle THE HEART BEAT. 529 (right and left), the ventricle (single), and the bulbus arteriosus or bulbus cordis. The musculature of each chamber connects with that of the succeeding one, and the contraction wave, which begins in the sinus, spreads in order to the following divisions of the heart. There is, however, a pause or interruption in the pas- sage of this wave at the sino-auricular junction, at the auriculo- ventricular junction, and at the bulboventricular junction, so that the contraction of each chamber is marked off as a separate oc- currence. In the human heart and the mammalian heart in general we are accustomed to distinguish only the auricles and ventricles, but physiological and anatomical studies combined have shown that in such hearts a remnant of the sinus venosus is Fig. 224. — A generalized type of vertebrate heart, combining features found in the eel, dogfish and frog {Keith) : a, Sinu3 venosus and veins; b, auricular canal; c, auricle; d, ventricle; e, bulbus cordis; /, aorta; 1-1, sino-auricular junction and venous valves; 2-2, canalo-auricular junction; 3-3, annular part of auricle; 4-4, invaginated part of auricle; 5, bulboventricular junction. found in the right auricle, particularly in the area lying between the openings of the venae cavae and round the coronary sinus. A special collection of this tissue which lies " in the sulcus terminalis just below the fork formed between the junction of the upper sur- face of the auricular appendix with the superior vena cava" has been described by Keith and Flack, and is designated as the sino- auricular node. The beat of the heart begins in this tissue, as in the case of the hearts of the lower vertebrates, and spreads directly to the auricular muscle, with, perhaps, a pause at a sino-auricular junction, although this is uncertain. At the other end the bulbus cordis remains in the human heart as the conus arteriosus of the right ventricle, and, as we shall see, there is some evidence that this portion of the ventricle contracts somewhat independently. 34 530 CIRCULATION OF BLOOD AND LYMPH. The matter of greatest interest in connection with the different chambers has been the nature of the auriculoventricular junction. In the mammalian heart tendinous tissue develops in this region, and for a long time it was supposed that there was no muscular connection between auricles and ventricles. In recent years, how- ever, it has been shown most satisfactorily that there is a peculiar band of cardiac muscle or modified muscle, known usually as the auriculoventricular bundle, which connects auricle and ventricle.* The bundle as a definite structure begins at the base of the inter- auricular septum, at the posterior margin, and on the right side in Fig. 225. — To show the position of the auriculoventricular bundle in the heart of the calf: 2, The auriculoventricular bundle. As it runs along the top of the ventricular septum, it is seen to divide into two branches, one entering the right, the other the left, ventricle; 3, the begin- ning of the bundle in the auricular septum known as the A-V node; 4, the branch of the bundle entering the right ventricle in the septal wall; 1, central cartilage (Jrom Keith). a collection of small cells or fibers known as the node, or the auriculoventricular node (A-V node), it runs as a bundle along the top of the interventricular septum (see Fig. 225), and near the union of the posterior and median flaps of the aortic valve it divides into two main branches, one of which enters the right ventricle, the other the left, each lying beneath the endocardium. Passing down the septal wall, these branches divide, f as repre- sented in Fig. 226, to form a system of strands that can be traced * See Retzer, " Archiv f. Anatomie," 1904, p. 1, and "Anatomical Record," 2, 149, 1908; Braeunig, "Archiv f. Physiologie," 1904, suppl. volume, p. 1; Tawara, "Das Reizleitungssystem des Saugethierherzens," Jena, 1906. t DeWitt, "Anatomical Record," 3, 475, 1909. THE HEART BEAT. 531 over the inner surface of the ventricles, constituting what were formerly designated as Purkinje fibers. The auriculo ventricular node in the interauricular septum is connected with the muscula- ture of the auricles, and through muscle bundles in the septum with the remnant of sinus tissue (sino-auricular node) at the mouth of the superior vena cava. The main bundle and the larger branches of this system are surrounded by fibrous tissue, and it is uncertain whether or not it actually contracts during the beat of the heart, but there is little doubt that it constitutes a conducting system of modified muscular tissue through which the excitation is conveyed Fig. 226. — The auriculoventricular bundle and its terminal ramifications in the interior of the ventricles (from model constructed by Miss De Witt on basis of dissections). The divi- sion of the bundle into right and left branches is shown, and the ramifications of each of these branches in the interior of the right and left ventricles. The branching system in the left ven- tricle is incomplete in the model, as the outer wall of this ventricle had been removed in the dissection. from right auricle to the ventricles, and perhaps from the sinus region first to the auricles and then to the ventricles. The A-V node and the main bundle in the human heart are small in size — about 18 mm. long, and from 1.5 to 2.5 mm. wide, and they and their dependent system of fibers or strands in the interior of the ventricles constitute, according to Keith and Flack,* a remnant of the original invagination of muscular tissue from the auricular ring (Fig. 224), through which auricle and ventricle are connected in the lower vertebrates. The Contraction Wave in the Heart. — It seems to be demon- strated that normally the contraction of the heart begins in the sinus tissue of the right auricle — the so-called sino-auricular node * Keith and Flack, "Journal of Anat. and Physiology," 41. 172, 1906, and 43, p. 1. 532 CIRCULATION OF BLOOD AND LYMPH. described in the preceding paragraph — and thence it spreads first to the auricles and subsequently to the ventricles. In the mammalian heart, when exposed to view, it is evident that the auricular systole is not sufficient to empty its cavity, so far at least as the atrium is concerned. The contraction of the auricular appendages is more forcible. The contraction may be regarded as a rapid peristalsis, which sweeps a portion of the blood before it into the ventricle. The force of the contraction has been determined in a number of cases. For the auricle of the dog's heart the pressure caused by the contraction has been estimated to be equal to 9 to 20 mm. Hg. The systole of the ventricle is to the eye a simultaneous contraction of the whole musculature. Various observers, however, have shown that the wave of contrac- tion travels over the heart with a certain velocity, which for the human heart has been estimated at 5 m. per second (Waller) , and for the rabbit's heart (Gotch) at 3 m. per second. It is probable that this wave starts at the base of the ventricle and travels along the course of the fibers — that is, first toward the apex and then into the interior of the heart. In regard to this point there have been great differences of opinion among different investigators. While the older view assumed as a matter of course that the con- traction begins at the base and passes toward the apex, the newer knowledge in regard to the conduction system between auricles and ventricles seems to indicate from the anatomical side that the auriculoventricular bundle spreads out upon the papillary muscles in the interior of the ventricle, and that, therefore, the contraction of the ventricles may begin with the papillary musculature and thence spread to the oblique and circular fibers of the ventricles.* This anatomical indication has been confirmed experimentally by some investigators and contradicted by others. Observations upon the papillary muscles seem to show that they are not the last portion of the musculature to enter into contraction, but whether the ventricular systole begins in them is not so clear. The course of the contraction wave has been studied chiefly by means of the accompanying electrical variation, and the results obtained from this method are stated briefly in the succeeding paragraph. Between the auricular and ventricular contractions there is a perceptible interval, which, for the human heart, can be estimated from a study of the records of the jugular pulse. The in- terval between the a and the c waves, the a-c interval, as it is called, marks the time intervening between the contraction of the auricles and of the ventricles. This interval may be valued at 0.2 sec. or less (0.12 to 0.2 sec), and is due chiefly to the time necessary for * Consult Nicolai in "Nagel's Handbuch d. Physiologie," vol. i, p. 824. THE HEART BEAT. 533 the excitation wave to pass over the conducting system between auricles and ventricles. In all probability the conduction in this system is slower than in the musculature of the auricles or ven- tricles. In the dog, for example, the interval between auricular and ventricular contraction is about 0.1 sec. Since the connecting auriculoventricular bundle has a length of 10 to 15 mm., the velocity of the conduction through this bundle must be about 10 to 15 cm. per second. The Electrical Variation. — The contraction of the heart muscle, like that of skeletal muscle, is accompanied by an electrical change. That is, where the muscle substance is in contraction its electrical potential is different from that of the resting muscle. The advancing wave of contraction causes a corresponding electrical change. If two points of the heart are connected with an electrom- eter an electrical current will be shown, since the electrical change will affect the electrodes at different times. This electrical varia- tion of the contracting heart muscle may be shown easily by means of the rheoscopic muscle-nerve preparation (see p. 106). If the heart is exposed and the nerve of the preparation is laid over its surface each ventricular systole is accompanied by a kick of the muscle, since the nerve by connecting separated points acts as a conducting wire for the current generated, and is stimulated, there- fore, at each systole. Since the muscle-nerve preparation gives only a simple contraction for each ventricular systole, we may assume that this latter contraction is itself simple, — that is, due to a single stimulus. The electrical variation may be obtained also by means of the capillary electrometer or the string-galvanometer (p. 100), and since the movement of the mercury or of the string in these instruments may be photographed, the results can be studied in detail. Owing to the sensitiveness of the instrument, the beat of the human heart may be registered in this way (Waller) when the right hand, giving the potential changes of the base of the heart, is connected with one electrode, and the left hand (apex of heart) is connected with the other. The electro- cardiograms thus obtained photographically show that, in the ventricle at least, the electrical variation exhibits several phases, and the character of these phases, that is, whether the base or the apex first shows a negative potential, has been used in discussions upon the direction of the wave of contraction. In Fig. 227 is given an illustration of a human electro-cardiogram obtained by connecting the right and left hands with the electrodes of a string galvanometer. With such an arrangement or " lead " the elec- trode in the right hand may be regarded as leading off from the auricular end of the heart, while that in the left hand leads off 534 CIRCULATION OF BLOOD AND LYMPH. from the apex of the ventricle.* As the galvanometer is arranged, a negativity (indicative of contraction) toward the auricular end is shown by a movement above the horizontal base line, while a negativity toward the apex is shown by a movement in the opposite direction. The cardiogram shows that the heart- beat begins with a sudden development of negativity at the auricular end, wave P; this is interpreted satisfactorily as being due to the contraction of the auricles. The following ventricular contraction begins with a wave Q below the line, which would indicate a contraction toward the apex of the heart. The inter- pretation of Q has not been made satisfactorily, but in accordance ... :::|IJE:!| ===== J|l==5===== ppipiii::! ii!| |i :::3Elfc±:" — ill "llll "t" — = ±::::: ±:::::_ :t:::::::::±t:±::_::::±::±::::: 5 i St '( Fig. 227. — Electrocardiogram obtained by photographing the movements of the thread of a .string-galvanometer. The upper figure shows the photographed curve, while the lower one is a diagram constructed from the photograph to make clearer the electrical changes in a single cardiac cycle. To obtain this record the electrodes were connected with the right and left hands. Waves with the apex upward indicate that the base of the heart (or the right ventricle) is negative to the apex (or left ventricle). Waves with the apex downward have the opposite significance. Wave P is due to the contraction of the auricle. Waves (J, R, S, and T occur during the systole of the ventricle. (Einthoven) . with the anatomical arrangement of the auriculoventricular bundle referred to in the last paragraph we may suppose provisionally that it indicates that the initial contraction in the ventricle starts in the fibers of the papillary musculature. Q is immediately followed by the large wave It, which indicates a contraction at the base of the ventricles, followed by a rapid transition to the opposite phase S, as this contraction passes to the apex of the ventricle. The wave T, occurring at the end of the ventricular systole, indicates that some portion of the base of the ventricles again passes into a condition of contraction. This wave has been explained satisfactorily by * For a description of the electrocardiogram and the literature consult James and Williams, "American Journal of the Medical Sciences," Nov., 1910. THE HEART BEAT. 535 Gotch* in experiments upon the exposed heart. He shows that it is due to a contraction of the ventricular musculature near the root of the aorta and pulmonary artery, the region which corre- sponds to the bulbus arteriosus in the lower animals. This portion of the ventricle is the last to enter into contraction, as would be expected when we remember that the ventricle develops originally from a tube having a venous and arterial end, and that this tube becomes bent upon itself so that these two ends, the ostium venosum and the bulbus arteriosus, lie together at the base of the heart. As expressed by Keith, the base of the ventricle consists in reality of two parts — an auricular base and an aortic base, the beginning and the end of the ventricular tube, and the electric cardiogram traces satisfactorily the wave of contraction from one to the other, R to T, by way of the apex. Change in Form of the Ventricle During Systole. — Much attention has been paid to the external change of form of the ventricle during systole. Does it diminish in size in all diameters or only in certain diameters? The question is one that cannot be answered definitely for all normal conditions, owing to the fact that the form of the heart during diastole varies with the posture of the body. During diastole the heart muscle is quite soft and relaxed, and consequently its shape is influenced by gravity. The exact change of form that it undergoes in passing from diastole to systole will vary with its shape, what- ever that may happen to be, in diastole. During systole the musculature, on the contrary, is hard and resisting and the form of the heart in this phase is probably constant. The change from the variable diastolic to the constant systolic form will natu- rally be different in different positions. With an excised frog's heart one can show that the ventricle is elongated in passing from diastole to systole or one can show the reverse. If the heart is laid upon its side it flattens in diastole so as to increase in length, and systole causes a shortening. If the heart is held or placed with its apex pointing upward it flattens during diastole so as to shorten the diameter from base to apex and during systole this diameter is lengthened. In ourselves the exact change of shape is probably different in the erect from what it is in the recumbent posture. Speaking generally, the accounts agree in stating that the long diameter of the heart is decreased, base and apex are brought closer together, and the diameter from right to left is also decreased, while the anteroposterior or ventrodorsal diameter is increased. That is, the outline of the base of the heart during diastole is an ellipse with its short diameter in the ventro- dorsal direction. During systole this outline approaches that of a * Gotch, "Heart," vol. i, p. 235, 1910. 536 CIRCULATION OF BLOOD AND LYMPH. circle.* A more interesting change is described for the apex of the ventricle. Owing to the whorl made by the superficial fibers at this point as they turn to pass into the interior (see Fig. 223), the systole causes a rotation of the apex, which is thereby forced more firmly against the chest wall. This rotation and erection of the apex during systole may be seen upon the exposed heart of the lower mammals and has been described also for man in cases in which the heart is covered only by the skin, owing to malformation in the chest wall (ectopia cordis) or to surgical operations. The exact position and size of the heart in man and its variations in these respects under various normal and patho- logical conditions may be studied quite successfully by means of the z-rays. When the x-rays are passed through the chest, the heart forms a shadow which may be seen with the aid of the fluor- escent screen and which may also be photographed. The appa- ratus used for this purpose may be so arranged that the rays pass through the chest in parallel lines and give a shadow of the exact size of the heart. The arrangement of apparatus for this purpose is designated usually as an orthodiagraph, and the photographic record obtained is spoken of as an orthodiagram. It may be shown by this means, for example, that during muscular exercise there is a diminution in the size of the heart accompanying the increase in heart-rate. The Apex Beat. — The apex of the heart rests against the chest wall at the fourth or fifth intercostal space, and here the systole may be seen and felt in consequence of a slight protrusion of the wall. Much discussion has ensued as to why this protrusion occurs during systole, since the apex is drawn toward the base and the volume of the heart is diminished by the output of blood. The fact seems to be explained satisfactorily by two con- siderations: The heart during diastole rests against the chest wall at its apex and a portion of its anterior surface, but causes no pro- trusion of the wall because the tenseness of this latter is sufficient to flatten or deform the softer heart muscle. During systole the hardened heart muscle, on the contrary, overcomes the now rela- tively less resistant integument. , The rotation of the apex tends also to maintain the contact; so that, although the heart is short- ened in its long diameter, the extent of the movement is not sufficient to draw it away from the chest wall. In the second place, the discharge of the heart contents into the curved aorta by tending to straighten this tube causes a movement of the whole heart downward which counteracts the effect of the shortening in the long diameter. The apex beat is proof that the apex remains * See Haycraft and Kde.s, "Journal of Physiology," 12, 426. THE HEART BEAT. 537 against the chest wall during systole and in mammals corroborative experiments have been made by running needles through the chest wall into the base and the apex of the heart. Such needles act as levers with a fulcrum in the skin, and from the movement of the projecting portion it has been shown that, while the basal portion of the heart moves downward during systole, the apex remains more or less stationary except for the lateral movements due to the rotation. The Cardiogram. — The apex beat may be recorded easily by means of appropriate tambours. Several instruments have been especially devised for this purpose and are designated as cardio- graphs. The cardiograph described by Marey is shown in Fig. 228. It consists essentially of a tambour inclosed in a metal box. The rubber membrane of the tambour carries a button which can be brought to bear, under a suitable pressure, upon the apex of the heart. The movements of this button cause pressure changes in Fig. 228. — Marey's cardiograph. The button on the tambour is pressed upon the chest over the apex. The movements are transmitted through the tube to the right to a recording tambour. the air of the tambour which are transmitted through tubing to a recording tambour and recorded on a kymographion. A simple and effective cardiograph may be made by pressing a funnel against the skin over the apex and connecting the stem of the funnel by tubing to a suitable recording tambour. The car- diograms obtained by such methods have been the subject of much discussion. The form of the curve varies somewhat with the instrument used, the way in which it is applied, the position of the heart apex with reference to the chest wall, and with the con- ditions of the circulation, and it is often difficult to give it a correct interpretation. An uncomplicated form of the cardiogram is 538 CIRCULATION OF BLOOD AND LYMPH. represented in Fig. 229, 7, and a curve more difficult to interpret in Fig. 229, 8. It should be borne in mind that the cardiograph curve is partly a pressure curve and partly a volume curve, — that is, the changes in volume as well as the changes in pressure of the heart during systole will affect the instrument. The Intraventricular Pressure During Systole. — The best analyses of the details of the systole of the ventricle have been made by a study of the changes in pressure within the ventricle. For this purpose a tube filled with liquid is introduced into the cavity of the ventricle. A tube used for such a purpose is designated as a heart-sound. For the right ventricle it is introduced through an opening in the jugular vein and pushed down until it lies in the ventricle. For the left ventricle it is introduced by way of the carotid or subclavian artery and in this case is forced through the opening guarded by the semilunar valves. The sound is then connected to a suitable recording apparatus by rigid tubing filled with liquid. The changes in pressure in the ventricle are extensive Fig. 229. -Two cardiograms from the same individual to show characteristic records: Beginning of systole; b-c, systolic plateau. — (After Marey.) and very rapid. To register them accurately the recording instru- ment must respond with great promptness and at the same time must be free from inertia movements. A mercury manometer, for instance, would be entirely useless for such a purpose, since the heavy mass of mercury could not follow accurately the quick changes in pressure. The recording manometer devised by Hiirthle (p. 485) seems to have met the requirements more satisfactorily than any other of the numerous instruments described. A typical curve obtained by means of the Hiirthle manometer is given in Fig. 230, V, (Consult also the classical curve obtained by Chauveau and Marey from the heart of the horse [Fig. 220].) It will be seen that the pressure in the heart rises suddenly with the beginning of the ven- tricular contraction and a certain time elapses before this pressure THE HEART BEAT. 539 is strong enough to open the semilunar valves. The moment that this occurs (1, on the ventricular curve in Fig. 230) is determined by simultaneous measurement of the pressure in the aorta, it being evident that the pressure will begin to rise in this latter vessel the moment that the valves open. It is interesting to find that the yielding of the valves to the rising pressure in the ventricle is not indicated on the curve itself by any variation, — a fact which indicates that the valves open smoothly, and are not thrown back with a sudden shock. A very characteristic feature of the ventric- ular curve is its flat top, or plateau as it is called. In some cases the plateau slopes more or less upward, in other cases downward, depending, doubtless, on the respective values of the force of the Fig. 230. — Synchronous record of the intraventricular pressure (V), and the aortic pressure (A) : S, The time record, — each vibration = ifor sec. ; 0-5, corresponding ordi- nates in the two curves; 1 marks the opening ot the semilunar valves; 3 (or shortly after) marks the closure of these valves and the beginning of diastole. — (Hurthle.) heart contraction and the aortic tension, for during the whole time of the plateau the semilunar valves are open and the ven- tricle is discharging a column of blood into the aorta. The different features of the ventricular systole as gathered from these pressure curves are expressed by Hurthle * as follows : I. Systole, phase of contraction of the muscle fibers (0 to 3 in Fig. 230, V) . (a) Period of tension (0 to 1) , during which the auriculo-ventricular and semilunar valves are both closed and the heart muscle is squeezing upon the contained blood. This period ends at the opening of the semilunar valves. (&) Period of emptying (1 to 3). During this time the heart is empty- ing itself into the aorta and the intraventricular pressure remains above aortic pressure. It ends with the cessation of the contrac- tion of the muscle and the beginning of the rapid relaxation. II. Diastole, phase of relaxation and rest of the muscle fibers. (a) Period of relaxation from 3 until the curve reaches a horizontal. At the beginning of the relaxation the semilunar valves are closed, and from comparison with the aortic curve the instant of the occur- rence of this closure is placed shortly after 3. * Hurthle, "Archiv f. d. gesammte Physiologie, " 49, 84, 1891. 540 CIRCULATION OF BLOOD AND LYMPH. (b) Period of filling. This period begins as soon as the auriculo-ventric- ular valves open and the stream of blood, which had been flowing into the auricle throughout the ventricular systole, is permitted to enter the ventricle. During this period of filling the ventricular pressure rises slightly as the heart becomes turgid with blood. This increase of pressure is indicated in most cardiograms by a gradual rise of the curve during this period. It is shown in the curve of Chauveau and Mary, given in Fig. 220. The Volume Curve and the Ventricular Output. — In the lower animals the thorax may be opened with suitable pre- cautions as regards anesthesia and artificial respiration, and the heart may be placed within a plethysmograph (see p. 596) to measure its changes in volume during systole and diastole. If the whole heart is treated in this way the curve of volume changes is complicated by the fact that one chamber, the auricle, is filling, while the other, the ventricle, is emptying. Fig. 231. — Diagram to show the arrangement of the Henderson cardiometer. The recording tambour is inverted, so that the systole will give an up-stroke on the curve. (After Hirschf elder.) A more useful disposition of the apparatus is to enclose only the ventricles. Several different forms of plethysmograph have been devised for this purpose, and they are usually spoken of as cardiometer s. The form described by Henderson* is simple and easily applied to the heart. Its structure and the connections of the recording apparatus are indicated in the diagram given in Fig. 231. The apparatus consists of a rubber ball or glass cham- ber with a circular opening at one point. Over this opening is placed a membrane of rubber dam with a central opening through which the heart is introduced, as shown in the diagram. The rubber membrane lies snugly in the auriculo ventricular groove, making an air-tight joint. The interior of the ball is connected by stiff tubing with a recording tambour. By an arrangement of this kind the ventricles are kept within an air-chamber closed everywhere except at the outlet to the recording tambour. Every change in volume of the ventricles will be recorded accu- * Henderson, "American Journal of Physiology," 16, 325, 1906, and 23, 345, 1909, contain also the literature. THE HEART BEAT. 541 rately provided there is no leak. Moreover, these volume changes may be given absolute values in cubic centimeters if the appa- ratus is calibrated beforehand. The cardiometer furnishes a convenient method of estimating directly the amount of blood entering and leaving the ventricles under varying conditions, as well as the changes in heart-volume that may result from variations in tonicity. When the heart is beating slowly the volume curve has the form shown in Fig. 232. During systole the ventricles shrink in size as the blood is discharged into the aorta and pulmonary artery — the up-stroke of the curve. At the end of the systole, after the closure of the semilunar and the opening of the auriculoventricular valves, the ventricles are I Fig. 232. — Diagram of the normal volume curve (plethysmogram) of the dog's heart when beating at a slow rate (after Hirschf elder). The up-stroke represents the systole, the down-stroke the diastole; 4 to 5 the period of diastasis (Henderson). At 5 the auricular contraction causes a slight additional dilatation of the ventricle. 1,2, and 3 represent the time of occurrence of the first, second, and third heart-sounds respectively. dilated rapidly by the inflow of venous blood. Henderson has emphasized the fact that the filling takes place nearly as rapidly as the emptying, owing doubtless to the fact that at the end of ventricular systole the auricles are dilated under some pressure, so that their contents escape at once into the ventricles as soon as the intervening valves are opened. The diastolic curve comes back nearly to the base line and then forms a shoulder (4) from which it runs parallel to or approaches gradually to the base line up to the moment of auricular contraction (5). The period of rest of the filled or nearly filled ventricles, which on the curve is shown from 4 to 5, is called the period of diastasis by Henderson. The heart cycle, so far as the ventricles are concerned, falls, therefore, into three periods: 1, Systole; 2, diastole; 3, diastasis. Variations in heart rate affect chiefly the last period; this becomes shorter and shorter the more rapid the rate. When the heart rate is so rapid that the period of diastasis drops out altogether and the systole begins as soon 542 CIRCULATION OF BLOOD AND LYMPH. as the diastole is complete, then we should have the maximum output of blood per minute. An increase of rate beyond this point would lead to a curtailment of the period of diastole and eventually to a diminished output of blood per minute. Accord- ing to the account just given, the filling of the ventricle is practically completed before the auricles contract. Henderson believes that the contraction of the auricles adds very little or nothing to the change of blood in the ventricles, but other authors, using the same methods, differ from him in this conclusion. It is at least certain that the ventricles are for the most part filled before the auricular contraction comes on — this latter act may add a greater or less amount to this charge, according to the conditions prevailing, and in all cases its contraction, besides initiating the ventricular systole, doubtless serves, by raising the tension in the ventricular chamber, to bring the auriculoventricular valves more completely into the position of closure. When these valves are deficient, as in mitral stenosis, the contraction of the auricles plays a larger part in completing the filling of the ventricles (Hirschfelder). For the cases in which it can be applied, the volume curve enables us to estimate the ventricular discharge at each beat and the outflow per minute. The curve as registered gives the outflow for the two ventricles, one-half of its indicated volume will give the outflow from the left ventricle, and this figure, multiplied by the pulse rate, will give the output per minute. It was formerly assumed that at each systole the ventricles emptied themselves com- pletely, but work of the kind described in this paragraph in which the volume curves were obtained have shown, on the contrary, that at the end of systole a considerable proportion of the blood may be left in the cavity of the ventricle. The amount thus left behind will vary with the rate and other conditions. According to Henderson's figures for the dog, about one-third or somewhat less of the ventricular charge is left in the heart after systole, when the heart is beating at the normal rate (90), and the quantity of blood discharged from the left ventricle at each systole is approximately .002 of the body weight. It is evident that when the aortic pressure rises to an abnormal level the discharge of blood from the left ventricle will be or may be diminished, with the result that the blood backs up in the left auricle, thus raising the venous pressure in the lungs and retard- ing the pulmonary circulation. On the other hand, as Hender- son has especially emphasized, the outflow from the ventricle must be influenced very directly by the inflow into the auricle from the veins. Variations in the size of the blood-vessels, such as dilatation of the small arteries or possibly loss of tone in the THE HEART BEAT. 543 veins, may bring about a condition of venous stasis and cut down the supply of blood to the heart on the venous side. Con- siderations of this kind are helpful or necessary in explaining the changes in circulation which occur under pathological conditions. The Heart Sounds. — An interesting and important feature of the heart beat is the occurrence of the heart sounds. Two sounds are usually described, one at the beginning, the other at the end, of the ventricular systole. The first sound has a deeper pitch and is longer than the second, and their relative pitch and duration are represented frequently by the syllables lubb-dup. According to Haycraft,f both tones, from a musical standpoint, fall in the bass clef, and are separated by a musi- cal interval of a minor third. The sounds are readily heard by applying the ear to the thorax over the heart, but for diagnostic purposes the stethoscope is usually employed, and this method of investigation by hearing is designated as auscultation. The importance of these heart sounds in diagnosis was first em- phasized by Laennec (1819), and since his time a great number of theories have been proposed to explain their causation. Indeed, the subject is not yet closed, although certain general views regard- ing their cause and the time of their occurrence are generally accepted. The second sound is found to follow immediately upon the closure of the semilunar valves. The usual view, therefore, is that the sound is due ultimately to the vibrations set up in these valves by their sudden closure. These vibrations are transmitted to the column of blood in the aorta (or pulmonary artery) and then to the intervening tissue of the chest wall. This view is made probable by a number of experimental results, some of the most important of which were brought out by Williams in a report (1836) of a committee appointed by the British Association for the special purpose of investigating the subject. It has been shown: (1) That the second sound disappears before the first sound when the animal is bled to death, and indeed as soon as the heart ceases to throw out a supply of blood sufficient to maintain aortic tension. It disappears also when cuts are made in the ventricles so that the blood may escape otherwise than through the arteries. (2) When the valves of the pulmonary artery and aorta are hooked back in the living animal the second sound is replaced by a murmur due to the rushing back of the blood into the ventricle, and if the valves are dropped back into place the normal second sound is again heard. (3) Similar sounds may be produced if the root of the aorta with its valves in place is excised and attached to a glass tube carrying a column of water. With such an arrangement, if the valves are held * "Journal of Physiology," 11, 486, 1890. 544 CIRCULATION OF BLOOD AND LYMPH. open for a moment and then closed sharply by the pressure of the column of water a sound similar to that of the second heart sound is heard. The physician uses this view of the cause of the second sound in auscultation, and it is evident that the nature of the sound or its replacement by murmurs will give useful testimony regarding the condition of the semilunar valves. The first heart sound has of- fered more difficulty. It occurs at or shortly before the closure of the auriculo-ventricular valves, and it would seem natural, therefore, to attribute it to the vibration of these valves when suddenly put under tension by the ventricular systole. Most authors, indeed, believe that this factor is at least partially responsible for the sound, — that is, that the sound contains a valvular element. But that this is not the sole cause is shown by the fact that the bloodless beating heart still gives a sound at the time of the ventricular systole. Indeed, if the apex of the rabbit's heart is cut off, it continues to beat for a few minutes and during this time gives a first heart hJ I _ J ^ Fig. 233. — To show the time relation of the heart sounds to the ventricular beat (Marey) : V.D., Tracing of the ventricular pressure in the right ventricle of the horse. Be- low the two marks show, respectively, the time of the first and second sounds. The first occurs immediately after the beginning of systole, the seoond immediately after the begin- ning of diastole. Bound. It is usually said, therefore, that the first heart sound is caused by the combination of at least two factors, — a valvular element due to the vibration of the auriculo-ventricular valves, and a muscular element due to the vibration of the contracting muscular mass. Accepting this view, there is a further difficulty in explain- ing the origin of the muscular element. According to some, it is due to the fact that the contraction of the muscle fibers is not simultaneous throughout the ventricle and the friction of the inter- lacing fibers sets up vibration in the muscular mass; according to others, the so-called muscular element is mainly a resonance tone of the ear membrane of the auscultator, — the shock of the contracting heart sets the tympanic membrane to vibrating. It seems useless to attempt a detailed discussion of these conflicting views, since no convincing statements can be made. Practically, the time at which the heart sounds occur is of great importance. A number of observers have recorded the time upon a cardiographic tracing of THE HEART BEAT, 545 the heart beat with results such as are shown in Fig. 233. The figure shows clearly the general fact that the first sound is heard very shortly after the beginning of systole and the second one immediately after the end of systole. The first sound is therefore systolic, and the second sound diastolic. A more exact and de- tailed study of the time relations of the heart sounds has been made by Einthoven and Geluk.* These authors obtained graphic records of the heart sounds. The sounds received first by a microphone were transmitted to a capillary electrometer and the movements of the latter were photographed. As one result of their work they give the schema shown in Fig. 234. It will be seen from this figure that the first sound begins about 0.01 sec. before the cardiogram shows the commencement of systole, and that for the first 0.06 sec. the sound is heard only over the apex of the heart (a-b). Over the ojsee. Fig. 234. — Schematic representation of the relation of the heart sounds to the ventric- ular beat: C, The cardiogram; 1, to show the duration of the first heart sound; 2, the duration of the second heart sound; S, the time record, each division corresponding to 0.02 sec. In 1, a-a' marks the instant that the first heart sound is heard over the apex, and b-b' the moment that it is heard at the second intercostal space. — (Einthoven and Geluk.) base of the heart (second intercostal space) the first sound is heard (b to c-d) just at the time when the semilunar valves are opened (&'), — that is, at the beginning of the period of emptying according to the classification given on p. 539. The first sound ceases long before the ventricular contraction itself is over, — a fact which would seem to indicate that the muscular element in the first sound is not a muscular sound, such as is given out by a contracting skeletal muscle. The beginning of the second sound seems to mark exactly the time of closure of the semilunar valves. The character and the time relations of the murmurs that accompany or replace the heart sounds form the interesting practical continuation of this theme; but the subject is so large that the student must be referred for this information to the works upon clinical methods. The Third Heart Sound. — Several observers* have called attention to the fact that in certain individuals a third heart * Einthoven and Geluk, "Archiv f. d. gesammte Physiologie," 57, 617, 1894. Einthoven, ibid., 1907, vol. 117. t Thayer, "Boston Med. and Surg. Journal," 158, 713, 190S; Einthoven, "Archiv f. d. ges. Physiol.," 120, 31, 1907; Gibson, "Lancet," 1907, II., 1380. 35 546 CIRCULATION OF BLOOD AND LYMPH. sound may be heard very shortly (0.13 sec.) after the beginning of the second sound. Thayer describes this sound as being "softer and of lower pitch" than the second sound, and in some cases as resembling rather a dull thud or hum. In those persons in whom it can be detected it is heard most distinctly over the apex of the heart. Einthoven has shown the existence of this sound by objective methods. By means of a microphone attachment the heart sounds can be transmitted to the string- galvanometer, in which they cause deflections of the string that can be photographed. In this way he has obtained records of the third sound upon individuals in whom the stethoscope failed to reveal its existence. The cause of this sound has been explained differently by the several authors who have inves- tigated. It occurs early in the diastole, and Einthoven suggests that it is due to an after-vibration of the semilunar valves. Thayer and Gibson suggest the more probable explanation that it is due to a vibration of the auriculoventricular valves which is set up by the sudden inrush of blood from the auricles at the beginning of diastole. This inflow of venous blood distends the ventricle sharply and throws the valves into a position of closure with some suddenness. The sound occurs at about the time of the shoulder on the diastolic limb of the volume curve, as is indicated in the diagram in Fig. 232. The Events that Occur During a Single Cardiac Cycle. — By a complete cardiac cycle is meant the time from any given feature of the heart beat until that feature is again produced. It may be helpful to summarize the events in such a cycle, both as regards the heart and as regards the blood contained in it. We may begin with the closure of the semilunar valves. At that moment the second heart sound is heard and at that moment the ventricle is quickly relaxing from its previous contraction. Since the auriculoventricular valves are still closed (see diagram, Fig. 219), the ventricles for a brief interval are shut off on both sides. The blood is flowing steadily into the auricles and dilating them. As soon as the ventricles relax the pressure of blood in the auricles opens the auriculoven- tricular valves, and from that moment until the beginning of the auricular systole the blood from the large veins is filling both ventricles and auricles. As stated on p. 541, the venous blood which has been accumulating in the auricles during the ventricular systole flows into the ventricles with some sudden- ness on the opening of the auriculoventricular valves. The ventricles, therefore, dilate rapidly and the auriculoventricular valves are floated into a position ready for closure. This event occurs at about the time that the third heart sound is heard. THE HEAET BEAT. 547 In a slowly beating heart there may be quite an interval (period of diastasis) between this point and the auricular contraction. The auricular systole sends a sudden wave of blood into the ventricles, dilating them still further and momentarily blocking or retarding the flow from the large veins, and causing one of the waves seen in the normal venous pulse as recorded in the jugular veins. The ventricular systole follows at once upon the auricular systole, the exact relations in this case depend- ing somewhat upon the pulse rate. As the ventricle enters into contraction the auriculo-ventricular valves are tightly closed, the first sound is heard, and for a short interval the ventricular cavity is again shut off on both sides. Soon the rising pressure in the interior forces open the semilunar valves, and then a column of blood is discharged into the aorta and pulmonary artery as long as the contraction lasts. During this interval the flow at the venous end of the heart continues, the blood being received into the yielding auricles. Indeed, this capacity for receiving the venous inflow during the comparatively long-lasting ventricular systole may be considered as one valuable mechanical function fulfilled by the auricles. The venous flow is never completely blocked and at the most suffers only a slight retardation during the very brief auricular systole. At the end of the ventricular sys- tole the excess of pressure in the aorta and the pulmonary artery closes the semilunar valves and completes the cycle. Time Relations of Systole and Diastole. — The duration of the separate phases of the heart beat depends naturally on the rate of beat. Assuming a low pulse rate of 70 per minute, the average duration of the different phases may be estimated as follows: Ventricular systole = 0.379 sec. Ventricular diastole and pause = 0.483 " Auricular systole =0.1 to 0.17 " Auricular diastole and pause = 0.762 to 0.692 " Einthoven and Geluk, in the investigation referred to above, measured the time intervals of systole and diastole during fifteen heart periods of a healthy man, and found that the time for the ventricular systole varied between 0.312 and 0.346 sec, while that for the diastole varied from 0.385 to 0.518 sec. Experiments by a number of observers indicate that in the great changes of rate which the heart may undergo under normal conditions the diastolic phase (period of diastasis) is affected relatively much more than the systolic, as we should expect. The Normal Capacity of the Ventricles and the Work Done by the Heart. — Various efforts have been made to measure the normal capacity of the ventricles in man, but the deter- mination has encountered many difficulties. Experiments and 548 CIRCULATION OF BLOOD AND LYMPH. observations made upon the excised heart are of little value, since the distensible walls of the ventricles yield readily to pressure, and it is difficult or impossible to imitate exactly the conditions of pressure that prevail during life. Nor is it certain whether normally the ventricles empty themselves completely during systole; in fact, the evidence from experiments on the lower animals indicates that, contrary to the opinion which for- merly prevailed, the ventricles throw out only a portion of their blood at each beat. The older observers (Volkmann, Vierordt) attempted to arrive at a determination of the normal output of the ventricles by calculations based upon the velocity of the blood in the carotid and the width of the stream bed. from observations on many animals they arrived at the general- ization that at each systole the amount of blood ejected from the ventricles is equal to about ^7 of the body weight. For a man weighing, say, 72 kilograms (158 lbs.) this ratio would give an output for each systole of 180 gms. (6 ozs.). More recent observers, however, have found this estimate too high. Howell and Donaldson* measured the output directly for the heart of the dog, making use of a heart isolated from the body and kept beating by an artificial circulation. The ratio of the output varied with the rate of beat; for a rate of 180 beats per minute it was equal to 0.00117 (st?) of the body weight; for a rate of 120 beats per minute it was equal to 0.0014 (ttit)- This ratio is therefore about one-half of that proposed by Volkmann. Tigerstedt, from observations upon rabbits, obtained a lower ratio still (0.00042); but from his own results and those obtained by other workers he concludes f that an average valuation for the volume of blood discharged by each ventricle of the human heart is from 50 to 100 c.c. On this basis one may make an approximate estimate of the work done at each beat. Using Tigerstedt's figures, such results as the follow- ing are obtained: On the left side the heart empties its 100 c.c. against a pressure of 150 mms. Hg. (0.150 meter) and on the right side against a pressure of, say, 60 mms. Hg. (0.06 meter). The work done is calculated from the formula w = pr, in which p repre- sents the weight of the mass thrown out and r the resistance or mean aortic pressure. This latter factor must be multiplied by 13.6, the density of mercury, to reduce to a column of blood. Lett ventricle, 100 gms. X (0.150 X 13.6) = 204.0 grammeters. Right " 100 " X (0.06 X 13.6) = 81.6 285.6 grammeters. * Howell and Donaldson, " Philosophical Transactions," Royal Soc, Lon- don, 1884. t Tigerstedt, " Lehrbuch der Physiologie des Kreislaufe.s," p. 152, 1893. THE HEART BEAT. 549 To this must be added the energy represented by the velocity of the mass ejected into the aorta. Placing this velocity at 500 mms. (0.5 meter) for both aorta and pulmonary artery, the energy represented in mechanical work is estimated from the formula — in which p represents the weight of the mass moved, v the velocity of its movement, and g the accelerating force of gravity. Applying this formula we have for each ventricle 2 x 9 8 = 1 .28 grammeters, or for both ventricles 2.56 grammeters, making a total of over 288 grammeters of work. That is, the mechanical work done at each contraction of the heart is equal to that necessary to raise 288 gms. a meter in height. The calculations made by different authors as to the amount of blood discharged from each ventricle during systole may be tabulated as follows: Thomas Young 45 gms. Volkmann 188 " for weight of 72 kgms. Vierordt 180 " " " " " " Fick 50-73 " Howell and Donaldson 75-90 " " " "65 " Hoorweg 47 " Zuntz 60 " Tigerstedt 50-100 " Plumier 70 " Loewy and v. Schrotter .... 55 " " " 60-65 kgms. The Coronary Circulation during the Heart Beat. — The condition of the blood-flow in the coronary vessels during the phases of the heart beat has been the subject of much speculation and experiment, since it has entered as a factor in the discussion of several mechanical and nutritive problems that are connected with the physiology of the heart. According to a view usually attributed to Thebesius (1708), the flaps of the semilunar valves are thrown back during systole and shut off the coronary circulation, and therefore the coronary vessels, unlike those of other organs, are filled during diastole. In modern times this view has been revived by Briicke, who made it a part of his theory of the " self -regulation " of the heart beat. According to this view, the coronaries are shut off from the aorta during systole by the flaps of the semilunar valves, so that the contraction of the ventricle is not opposed by the distended arteries, while, on the other hand, the reinjection of these vessels from the aorta during diastole aids in the dilatation of the ventricular cavities. Experimental work has shown decisively that the part of this theory relating to the closure of the coronary arteries by the semilunar valves is incorrect.* Records of pressure changes in the coronary arteries during the heart beat made by Martin and Sedgwick and by Porter show that they are substantially identical * See Porter, "American Journal of Physiology," 1, 145, 1898, for dis- cussion and literature. 550 CIRCULATION OF BLOOD AND LYMPH. with those in the carotid or aorta, and records of the velocity of the blood-flow made by Rebatel show that at the beginning of systole the flow in the coronaries suffers a sudden systolic acceleration as in the case of other arteries. During systole, therefore, the mouths of the coronary arteries are in free communication with the aorta. But the coronary system — arteries, capillaries, and veins — is in part imbedded in the musculature of the ventricles, and we should suppose that the great pressure exerted by the contracting muscu- lature would at the height of systole clamp off this system and stop the coronary circulation. That this result really happens is indi- dicated by Rebatel's curves of the velocity of the flow in the coro- nary arteries. As shown in Fig. 235, the great acceleration (a) in velocity at the beginning of systole is quickly followed by a drop to zero (b) or even a negative value, — that is, a flow in the other direc- tion, toward the aorta. At the end of the first (relaxation) phase of diastole there is again a sudden increase in velocity (c), corre- sponding with the injection of the arteries from the aorta, followed again by a decrease at the end of the diastole at the time when the ventricular cavity is filled with venous blood under some pressure. Porter, moreover, has shown in an interesting series of experiments that when a piece of the ventricle is kept beating, by supplying it with blood through its nutrient artery from a reservoir at con- stant pressure, each systole causes a jet of blood from the sev- Fig. 235. — Simultaneous record of the blood-pressure (A) and the blood-velocity (B) in the coronary arteries (Chauveau and Rebatel) : a, Marks the beginning of the systole (there is a rise in pressure and in velocity); 6, marks a second rise of pressure (A) due to the closure of the coronary capillaries by the contracting ventricle (at this moment in B the velocity falls off rapidly) ; c, curve (B) shows an increase in velocity due to the open- ing of the small coronary vessels at the beginning of diastole. ered vessels at the margin of the piece. In fact, the rhythmical squeeze of its own vessels during systole accelerates effectively the coronary circulation. The volume of blood flowing through the heart vessels increases with the frequency or the force of the beat, since each systole empties the coronary system more or less com- pletely toward the venous side and at each diastole the distended aorta quickly fills the empty vessels. THE HEART BEAT. 551 The Suction-pump Action of the Heart. — So far in con- sidering the mechanics of the circulation attention has been directed only to the force-pump action of the heart. All of the energy of the circulation, the velocity of the flow and the internal pressure, has been referred to the force of contraction of the ventricles as the main cause, and to certain accessory factors, such as the respiratory movements and the contractions of the skeletal muscles, as subsid- iary causes. It is possible, however, that the heart may also act as a suction-pump, sucking in blood from the venous side in conse- quence of an active dilatation. According to this view, the heart works after the manner of a syringe bulb, which when squeezed forces out liquid from one end and when relaxed sucks it in from the other in consequence of its elastic dilatation. While this view has long been entertained, modern interest in it was aroused chiefly perhaps by the experiments of Goltz and Gaule, which showed that at some point in the heart beat there is or may be a strong negative pressure in the interior of the ventricles.* Their method consisted in connecting a manometer with the interior of the ventricle and interposing between the two a valve that opened only toward the heart. The manometer was thus converted into a minimum manometer, which registered the lowest pressure reached during the period of observation. By this method they and others have shown that in an animal (dog) with an opened thorax the pressure in the interior of the ventricles may be negative to an extent equal to 20, 30, or even 50 mms. of mercury. Moreover, by the use of some form of elastic manometer, such as the Hurthle instrument (p. 485), it has been shown that this negative pressure occurs at the end of the period of relaxation, at the time, therefore, at which it might be supposed to exert a marked influence upon the inflow of venous blood. It should be added, however, that a negative pressure can not be shown for every heart beat. It may be absent altogether or slight in amount, varying, no doubt, with the force of contraction and the condition of the heart. Physiologists have attempted to determine the cause of this negative pressure and the extent of its influence on the blood-flow. With regard to the first question, so many answers have been proposed that it is difficult to arrive at a satisfactory opinion. According to some, the heart tends to dilate at the end of its systole by virtue of its own elasticity, — that is, the elasticity of its own musculature or of the connective tissue contained in its substance, for example, beneath the en- docardium, in the walls of the arteries, etc. This view, however, finds little or no support from direct experiments made upon the * For a complete discussion of this subject and the literature see the ar- ticle by Ebstein, " Die Diastole des Herzens," in the " Ergebnisse der Physi- ologie," vol. iii, part n, 1904. 552 CIRCULATION OF BLOOD AND LYMPH. fresh, living heart. If such a heart in a bloodless condition is squeezed by hand there is no evidence of an elastic recoil as in the case of a syringe bulb. Others have explained the negative pressure as due not to a simple elastic expansion, but to what may be called a physiological expansion, — that is, an expansion due to physiological processes, such as anabolic changes. Such a view, however, is at present more or less speculative and can not be con- clusively demonstrated. Still others have traced the expansion of the ventricle and the resulting negative pressure to the sudden in- jection of the coronary system from the aorta at the beginning of diastole. The heart in contracting exerts a force greater than that of the blood in the coronary vessels, and probably, therefore, these vessels are emptied and their cavities obliterated in part. At the beginning of diastole they are reinjected with blood under a pressure of perhaps 100 mms. of mercury, and this fact seems to offer a probable explanation for a partial dilatation of the ventricular cavity and a production of negative pressure in the brief interval before the opening of the auriculo-ventricular valves. No view, however, has met with general acceptance, and the cause or causes that produce the negative intraventricular pressure are still a subject for investiga- tion. Regarding the second question proposed above, — namely, the extent of the influence of this negative pressure on the flow of venous blood to the ventricles, — much diversity of opinion also exists. Direct experiments made by Martin and Donaldson* indicate that this factor has little or no actual influence upon the venous flow. These authors used an isolated dog's heart kept beating by an artificial supply of blood. At a given moment the stream of blood into the vena cava was shut off and the auricle of the heart was brought into communication with a U tube filled with blood. It was found that the auricle took blood from this tube only so long as the pressure in it was positive. Although the heart continued to beat vigorously, whatever negative pressure was present in the ventricle was unable to suck any blood into the auricle from the U tube. Porter f also has shown that at the time of a strong negative pressure in the ventricle the auricle may give little or no evidence of a similar fall in pressure. It would seem most probable, therefore, that the negative pressure observed under certain conditions in the ventricles is a fleeting phenomenon, and disappears with the entrance of the first portion of the blood from the auricles. While it may be of value in accelerating the opening of the auriculo-ventricular valves, its influence does not extend to an * Martin and Donaldson, "Studies from the Biological Laboratory, Johns Hopkins University," 4, 37, 1887; also Martin's "Physiological Papers," Baltimore, 1895. See also, for confirmatory results, von den Velden, " Zeit- schrift f. exp. Pathol, u. Therapie, 190G, hi., 432. t "Journal of Physiology," 13, 513, 1892. THE HEART BEAT. 553 actual suction of the blood from the veins toward the heart. Other authors, however, on theoretical grounds attribute more actual importance to the negative pressure as a factor in moving the blood. In one respect it would seem that the contractions of the ventricle must exert a direct influence in accelerating the in- flow of venous blood into the heart. In the paragraph upon the venous pulse (p. 520) it will be recalled that the steep fall of pressure in the auricles immediately after the c wave is attributed mainly to the fact that the contracting ventricles pull the flow of the auricles downward toward the apex as the blood is discharging from the ventricular cavities into the aorta and pulmonary artery. This action for a brief period must exert a suction effect in drawing blood from the veins into the auricles. Occlusion of the Coronary Vessels. — The coronary vessels supply the tissues of the heart with nutrition, including oxygen, so that if the circ ulation is interrupted the normal contractions soon cease. The branches of the large coronaries form what are known as terminal arteries, — that is, each supplies a separate region of the musculature, and although anastomoses may exist they appear to be too incomplete to allow a collateral circulation to be estab- lished when one of the main arteries is occluded. The portion of the heart supplied by it dies, or to use the pathological term, under- goes necrosis. On account of the pathological interests involved — the known serious results that may follow occlusion of an}7- of the coro- nary vessels or even any interference with the normal structure of the vessels — a number of investigations have been made upon animals to determine the effect of occluding one or more of the coronary vessels.* It would seem from Porter's experiments that the results of such an operation vary according to the size of the area deprived of its blood. When the arteria septi alone was occluded the heart was not affected, when the arteria coronaria dextra was occluded the ventricular contractions were arrested in 18 per cent, of the cases observed. Occlusion of the ramus descendens of the left coronary artery caused arrest of the ventricles in 50 per cent, of the cases, while occlusion of the circumflex branch of the same artery caused arrest in 80 per cent, of the cases. Ligation of three of the arteries caused stoppage of the heart in all cases. Fibrillar Contractions. — The arrest of the ventricles in the experiments just described followed immediately or witrun a short period, and the ventricles went into fibrillar contractions. In this curious condition the various fibers of the ventricular muscle, in- stead of contracting together in a co-ordinated fashion, contract * For a description of results and the literature see Porter, "Journal of Physiology," 15, 121, 1893; also "Journal of Experimental Medicine," 1, 1, 1896. 554 CIRCULATION OF BLOOD AND LYMPH. separately and irregularly; so that the surface of the ventricle has the appearance of a vibrating, twitching mass. Such a condition in the ventricle is usually fatal — that is, the musculature is not able to recover its co-ordinated movement. This condition may come on with great suddenness as the result of occlusion of the arteries, of injury to certain parts of the heart, or from strong electrical stimulation. Fibrillation of the auricles also occurs frequently under experimental conditions, and, indeed, in the human heart ap- parently under pathological conditions, but the musculature in this part of the heart seems to be able to return to its normal co-ordin- ated contractions with much less difficulty. The cause of the sudden change from co-ordinated to fibrillar contractions has never been satisfactorily explained. In this connection it is interesting to recall also that when any injury is done to either ventricle suf- ficient to stop the contractions or to cause fibrillation, both ven- tricles stop together. This result is doubtless due to the fact that their musculature is, after all, one set of fibers common to both chambers. CHAPTER XXIX. THE CAUSE AND THE SEQUENCE OF THE HEART BEAT— PROPERTIES OF THE HEART MUSCLE. General Statement. — The cause of the heart beat has naturally constituted one of the fundamental objects of physiological inquiry. The various views that have been proposed in different centuries reflect more or less accurately the advancement of the science. With each new discovery of general significance a new point of view is obtained and the theories of the heart beat, like those of the other great problems of physiology, shift their standpoint from generation to generation. The general modern conception of this problem is referred usually to Haller (1757), who first taught that the activity of the heart is not dependent on its connections with the central nervous system. As we shall see, the heart beat is controlled and influenced constantly by the central nervous system, but never- theless the important point has been established beyond question that the heart continues to beat when all these nervous connections are severed. The central nervous system regulates the activity of the heart, but has nothing to do with the cause of its rhythmical contractions. The heart, in other words, is an automatic organ. When in 1848 Remak discovered that nerve cells are contained in the frog's heart it was natural that the causation of the beat should be attributed to this tissue. Subsequent histological work has demonstrated the existence of numerous nerve cells in the substance of the heart tissue of all vertebrates, and the view that the au- tomaticity of the heart is due in reality to the properties of the contained nerve cells was the prevalent view throughout the middle and latter part of the nineteenth century. In the latter part of the century an opposite view arose, — namely, that the muscular tissue of the heart itself possesses the property of automatic rhythmical contractility. Both these points of view persist to day. The theory that refers the automaticity of the heart beat to the contained nerve cells is designated as the neurogenic theory of the heart beat; the one that refers this property to the muscle tissue itself is known as the myogenic theory. Beyond this question lies the still deeper problem of the explanation of the automaticity itself, the cause or causes of the rhythmical excitation, whether occurring primarily in the muscle cells or in the nerve cells. 555 556 CIRCULATION OF BLOOD AND LYMPH. The dividing line between the ancient and the modern views of the heart beat is found in the work of William Harvey (1628). Before his time physi- cians thought along the lines laid down by the ancient masters, Hippocrates, Aristotle, and Galen, in that they believed that the diastole of the heart is the active part of the beat. They believed that the heart dilated at the mo- ment of the apex beat, the dilatation being due to the implanted heat, the vital spirits, a special pulsatile force, etc. The arteries dilated at the same time for a similar reason. For a period of over two thousand years men's minds were so chained to this belief that they apparently could take no other view. Harvey, however, had the boldness and originality to look at the matter differently. He saw and proved that the active movement of the heart is a contraction during systole, which drives blood out of the ventricles into the arteries, and consequently that the pulse of the arteries is not due to their active dilatation, but to a distension by the blood forced into them. Harvey may be considered also as the founder of the myogenic theory of the heart beat. For although he did not speculate concerning the cause of the beat, he taught that the systole is an active contraction of the heart's own muscu- lature not dependent upon any external influence. In the same century the first neurogenic hypothesis was formulated. Willis conceived that the cere- bellum controls the activity of the involuntary organs, including the heart. The animal spirits engendered in the cerebellum were conveyed to the heart by the vagus nerve and caused its beat. Borelli formulated a somewhat different view. According to him the nerve juice, succus spirituosus, elabo- rated in the central nervous system was transmitted to the heart through the cardiac nerves and, distilling slowly into the musculature, set up an ebullition which caused an active expansion of the fibers. This expansion constituted the systole and drove the blood out of the heart. Both of these views were disproved or rendered improbable largely by the work of HaUer, who in 1757 published the second myogenic theory in a form which, somewhat modified, prevails to-day. Haller believed that the contraction of the heart is due to the inherent irritability of its musculature, and that the venous blood as it enters the heart stimulates it to contraction. Haller's views were generally accepted for some years, but some physiologists continued to believe that the heart beat is controlled directly by the central nervous system. This theory found its most definite expression in the work of Legallois, 1812, who advanced what may be called the second neurogenic hypothesis. From experiments made upon animals he concluded that the principle or force that causes the heart beat is formed in the spinal cord, in all of its parts, and reaches the heart through the branches of the sympathetic nerve supplying this organ. Legallois's conclusions were soon shown to be erroneous, but the general view advocated by him was entertained by some as late as the middle of the 19th century, in fact until experimental physiology had demonstrated the true functions of the vagus and accelerator nerves with reference to the heart. Toward the middle of the 19th century a third form of neurogenic hypothesis arose, which in the beginning seems to have been due to the work or the system of Bichat. According to this author the ganglionic or sympathetic system supplies the tissues of the organic life, meaning thereby the visceral organs which are not under the direct influence of the will. In 1844 Remak discovered that the heart possesses intrinsic nerve ganglia, and this fact seems to have induced most physiologists to believe that these ganglia constitute a motor center for the heart, initiating and co-ordinating its beat. For a period of forty years this form of the neurogenic hypothesis enjoyed almost universal acceptance. In 1881-83 Gaskell published experiments upon the heart of the frog ami tortoise in which he gave strong reasons for believing that the beat is myogenic in origin, and that the intrinsic ganglia are simply a part of the inhibitory ap- paratus of the heart. Since that time many physiologists have adopted the myogenic view, and the current arguments tending to support this rather than the neurogenic hypothesis are presented in the text. The most significant addition to our knowledge of the cause of the heart beat made during the last quarter of a century is the discovery that the inorganic salts of the blood and lymph play a special and essential role. The facts bearing upon this interesting discovery are sufficiently described in the text. PROPERTIES OF THE HEART MUSCLE. 557 The Neurogenic Theory of the Heart Beat. — The literature upon this topic is very large.* The neurogenic theory has suffered some changes in its details since first proposed by Volkmann, particularly in the specific functions assigned to the different ganglia that exist in the heart. In general, however, the theory assumes that the excitation to each beat arises within the nerve cells, and since the cardiac cycle begins with a contraction at what may be called the venous end of the heart, — that is, at the junction of the veins with the auricles, — it is assumed that the excitation or inner stimulus arises in the nerve cells situated in this region. These cells constitute, therefore, what may be called the automatic motor center of the heart. The stimuli generated within it are transmitted through its axons first to the musculature of the venous end of the heart. The subsequent orderly march of this contraction, to auricles and then to ventricles, is also upon this theory usually attributed to the intrinsic nerve cells and fibers. Through a definite mechanism the impulses generated in the motor center are trans- mitted to subordinate nerve centers through which the auricles are excited, and then to other nerve cells lying in or near the auriculo- ventricular groove through which the ventricles are excited. In this form the theory assumes for the heart an intrinsic central nervous system, as it were, with a principal motor center in which the property of automaticity is chiefly developed and subordinate centers whose activity usually depends upon the principal center, but which may show automatic properties of a lower order if the connections between them and the main center are interrupted. This intrinsic nervous system is responsible not only for the spon- taneous origination and normal sequence of the beat, but also for its co-ordination. The many muscular fibers of the ventricle contract normally in a definite manner and sequence, so that their effect is summated. Under abnormal conditions the fibers may contract irregularly, giving the so-called fibrillar contractions of the heart, which are inco-ordinated. It may be said that this con- ception of the connections of the intrinsic nervous system rests mainly upon deductions from physiological experiments. The histological details regarding the connections of the nerve cells in the heart are not yet sufficiently known, but it can not be said at present that they give any positive support to such a view. In regard to the neurogenic theory the following general statements may be made : 1. Most of the very numerous facts known regarding the heart * For recent general presentations from different standpoints see Gaskell, article on "The Contraction of Cardiac Muscle," in Schafer's "Text-book of Physiology," vol. ii, 1900; Langendorff, "Herzmuskel und intrakardiale In- nervation" in "Ergebnisse der Physiologie," vol. i, part n, 1902; and Cyon, " L'innervation du cceur," Richet's " Dictionnaire du Physiologie," vol. iv, 1900; Flack, in Hill's "Further Advances in Physiology," 1909, 53. 558 CIRCULATION OF BLOOD AND LYMPH. beat and its variations under experimental conditions may be explained in terms of the theory, or at least do not contradict it. The same statement, however, may be made regarding the myogenic theory. Both theories may be applied successfully from a logical standpoint to the explanation of known facts. 2. No single fact is known which can be cited as positive proof that the nerves participate in the production of the normal beat of the vertebrate heart. The experiment by Kronecker and Schmey is sometimes given this significance. These observers have shown that, when a needle is thrust into a certain spot in the dog's ventricle, the regularly contracting heart falls suddenly into fibrillar contractions so far as the ventricles are concerned. The ex- periment is certainly a striking and interesting one. The needle may be thrust many times into certain portions of the muscu- lar mass without affecting the powerful co-ordinated contractions, but in the region specified by Kronecker a single puncture, if it reaches the right spot, causes the ventricle to fall into ir- regular fibrillar twitches from which it does not recover. The spot as described by Kronecker is along the line of the septum at the lower border of its upper third. The experiment frequently fails; and it would seem that there must be a definite and quite circum- scribed structure whose lesion produces the effect described. We have no evidence as yet what this structure is, and are therefore in no condition to make positive inferences with regard to the bearing of the experiment upon the origin of the heart beat. Carlson * has described experiments upon the heart of the horseshoe crab (Limulus) which seem to show conclusively that in this animal the rhythmical contractions are dependent upon the intrinsic nerve cells. These latter are placed superficially, forming a cord that runs the length of the tubular heart. When this cord is removed the heart ceases to beat. There are reasons, however, which at present make it doubtful whether we can apply the results of this experiment to the vertebrate heart. The crustacean heart differs from the vertebrate heart in its fundamental properties; unlike the latter, it has no refractory period (see p. 564), can be tetanized, and gives submaximal contractions. f It is a tissue, therefore, that resembles in its properties ordinary skeletal muscle in the verte- brate, and, like this muscle, it seems to be lacking in automaticity. Carlson's experiments give, however, another instance of automatic rhythmicity in nerve tissue, and to that extent support the neuro- genic theory. The Myogenic Theory of the Heart Beat. — The myogenic ♦Carlson, "American Journal of Physiology," 12, 67, and 471, 1905. t Hunt, Bookman, and Tierney, " Central blatt f. Physiologie," 11, 275, 1897. PROPERTIES OF THE HEART MUSCLE. 559 theory has been developed chiefly by Gaskell and by Engelmann. It assumes that the heart muscle itself possesses the property of automatic rhythmicity and that this property is most highly de- veloped at the venous end. This portion of the heart, therefore, contracts first and the wave of contraction spreads directly to the musculature of the auricle and thence to that of the ventricle. The quickly beating venous end sets the pace, as it were, for the entire heart. The nerve cells and nerve fibers that are present in the heart are upon this theory supposed to be connected with the extrinsic nerves through which the rate and force of the heart beat are regu- lated, but they are not concerned in the production of the beat. Many experimental facts have been accumulated which give probability to this view, and it has been adopted by many, perhaps most, of the recent workers in this field. Some of the facts that favor this theory are as follows: 1. The anatomical arrangement of the musculature of the heart is not opposed to such a theory. It was formerly stated quite positively that there is no muscular connection between the auricles and ventricles in the mammalian heart, but we now know that these two parts of the heart are connected through a peculiar system of muscular tissue, the auriculoventricular bundle and its ramifications. It may be accepted also that the wave of excitation from the sinus end of the heart passes along this system. All the detectable nerve trunks crossing the auriculoventricular groove may be cut without altering the sequence of the heart beat, but section or compression of the A-V bundle brings on at once the condition of dissociated heart-rhythm known as heart block. According to some observers, however, the auriculoventricular bundle contains nerve-fibers as well as muscle-fibers, and the advo- cates of the neurogenic hypothesis make, therefore, the somewhat improbable claim that these particular nerve-fibers of all those that pass between auricle and ventricle are the only ones concerned in the conduction of the normal stimulus from auricle to ventricle. 2. The fact that a contraction started at one part of the heart may travel to other portions through the intervening musculature may be said to be demonstrated. Thus, Engelmann has shown that if the ventricle in the frog's heart is cut in a zigzag fashion, so that strips are obtained which are connected only by narrow bridges, a stimulation applied at one end starts a wave of con- traction which propagates itself over all of the pieces. This and similar experiments scarcely permit of explanation on the supposi- tion that conduction from piece to piece is effected by a definite nervous mechanism. So too it has been shown that under certain conditions the normal auriculo-ventricular rhythm can be changed at will to a ventriculo-auricular rhythm. If, for instance, a ligature be tied around the frog's heart between the sinus venosus and the 560 CIRCULATION* OF BLOOD AND LYMPH. auricle (first ligature of Stannius) the auricle and ventricle cease to beat. In this quiescent condition a slight mechanical stimulus to the ventricle causes it to beat and its contraction is immediately- followed by that of the auricle. A similar reversed rhythm may be obtained from the mammalian heart under suitable conditions. Such an experiment makes it most probable that the contraction is propagated from one .chamber to the other directly through the muscular connections. It is not possible at present to conceive that a definite mechanism of neurons should work thus in either direction. 3. There is much probable proof that the heart muscle tissue possesses the property of automatic rhythmical contractions. Ex- periments, initiated by Gaskell and since extended by numerous observers, show that in the cold-blooded animals strips of heart muscle taken from various parts of the heart will under proper conditions develop rhythmical contractions. It is very improbable that each of these strips, no matter how made, contains its own resident nerve cells or nerve tissue which act as a motor center. These results seem to demonstrate an inherent property of rhythm- icity in cardiac muscle, whether or not this rhythmicity is directly responsible for the normal beat. 4. It has been shown that in the embryo chick the heart pul- sates normally before the nerve cells have grown into it, and it is stated that in the hearts of a number of invertebrates no nerve cells can be found. It is evident from this brief and imperfect presentation that it is not possible to claim that either the neuro- genic or the myogenic theory is demonstrated, but most physiol- ogists perhaps at present believe that the latter view is more in accord with the facts.* Automaticity of the Heart. — As was said above, the ques- tion of the cause or causes of the automatic rhythmical con- tractions must be sought for whether the phenomenon turns out to be a property of the muscular tissue or of the nervous tissue of the heart. When we say that a given tissue is automatic we mean that the stimuli which excite it to activity arise within the tissue itself, and are not brought to it through extrinsic nerves. In the heart, therefore, we assume that a stimulus is continually being produced, and we speak of it as the inner stimulus. Experiment and speculation have been directed toward unraveling the nature of this inner stimulus. Most of the physiologists who have expressed an opinion upon the subject have sought an explanation in the composition of the blood or lymph bathing the heart tissue, or in the products of metabolism of the tissue itself. Regarding this latter * For a compromise view, partly myogenic and partly neurogenic, see Fredericq, "Archives internationales de Physiologic," 1906, i\\, 57. PROPERTIES OF THE HEART MUSCLE. 561 view there is nothing of the nature of direct experimental evidence in its favor. No product of the metabolism of the heart tissue capable of exerting this stimulating effect has been isolated. In regard to the former view, that the inner stimulus is connected with a definite composition of the blood or lymph, there has been considerable experimental work which is of fundamental signifi- cance. While the older physiologists paid attention mainly to the organic substances in the blood, it has been shown in recent years that the inorganic salts are the elements whose influence upon the heart beat is most striking. These salts are in solution in the liquid of the tissue, and are therefore probably more or less com- pletely dissociated. Attention has been directed mainly to the influence of the cations, of which three are especially important, — namely, the sodium, the calcium, and the potassium. The Action of the Calcium, Potassium, and Sodium Ions in the Blood and Lymph. — It has long been known that the heart of a frog or terrapin may be kept beating normally for hours after removal from the body, provided it is supplied with an artificial circulation of blood or lymph, so arranged that this liquid enters the heart through the veins from a reservoir of some sort and is pumped out through the arteries leading from the ventricle. It was first shown by Merunowicz, working under Ludwig's direction, that an aqueous extract of the ash of the blood possesses a similar action. Ringer afterwards proved that the frog's heart can be kept beating for long periods upon a mixture of sodium chlorid, potassium chlorid, and calcium phosphate or chlorid, and he laid especial stress upon the importance of the calcium. This work was after- wards confirmed and extended by Howell, Loeb, and others, who attempted to analyze the part played by the several ions.* If a frog's or terrapin's heart is fed with a solution of physiological saline (NaCl, 0.7 per cent.) it beats well for a while, but the beats soon weaken and gradually fade out. If in this condition the heart is fed with a proper mixture of sodium, potassium, and calcium chlorids it beats vigorously and well for very many hours. A solution containing these three salts in proper propor- tions is known usually as Ringer's mixture. The exact com- position has been varied by different workers, but for the heart of the frog or terrapin the following composition is most effective: NaCl = 0.7 per cent. KC1 = 0.03 " " CaCl = 0.025 " " * For literature and discussion see Howell, "American Journal of Phys- iology," 2, 47, 1898, and 6, 181, 1901, and "Journal of the American Medical Association," 1906. 36 562 CIRCULATION OF BLOOD AND LYMPH. The addition of a trace of alkali, HNaC03, 0.003 per cent., often increases the effectiveness of the solution, but it cannot be considered an essential constituent in the same sense as sodium, potassium, and calcium. It has been shown, moreover, that even the mammalian heart can be kept beating for long periods when fed with a Ringer solution if provision is made for a larger supply of oxygen than can be obtained by simple exposure to the air. For the irrigation of the isolated mammalian heart different forms of Ringer's solution have been employed, but the mixture most frequently used is that recommended by Locke, consisting of NaCl, 0.9 per cent.; CaCl2, 0.024 per cent.; KC1, 0.042 per cent.; NaHC03, 0.01 to 0.03 per cent.; and dextrose, 0.1 per cent. The solution is fed to the heart under an atmosphere of oxygen, and with this solution Locke and others have kept the mammalian heart beating for many hours. The dextrose, while not essential to the action of the irrigating liquid, is said to increase its effi- ciency, and Locke* has shown that the sugar is apparently utilized by the heart, since a considerable amount disappears from the solution when the heart is beating strongly. The general fact that comes out of these experiments is that the heart can beat for very long periods upon what has been called an inorganic diet. Moreover, the salts that are used cannot be chosen at random; it is necessary to have salts of the three metals named, and substitution is possible only to a very limited ex- tent. Thus, strontium salts may replace those of calcium more or less perfectly. It is evident that these salts play some very important part in the production of the rhythmical beat of the heart; and analysis has shown that the sodium, calcium, and potassium has each its special role. We may say that the presence of these salts in normal proportions is an absolute necessity for heart activity. A striking experiment which shows the importance of the calcium is to irrigate a terrapin's heart with blood-serum from which the calcium has been removed by precipitation with sodium oxalate. In spite of the fact that all other constituents of the blood are present the heart ceases to beat, and normal contractions can be started again promptly by adding calcium chlorid in right amounts to the oxalated blood. Regarding the specific part taken by each of the cations in the production of the alternate contractions and relaxations, much diversity of opinion exists, owing to our ignorance of the chemical changes going on in the heart during systole and diastole and to the difficulty of controlling experimental conditions. Thus, while it is an easy matter to control accurately the com- position of the liquids supplied to the heart, a variable and uncon- trollable factor is introduced by the fact that within the tissue * Locke and Rosenheim, "Journal of Physiology," 36, 205, 1907. PROPERTIES OF THE HEART MUSCLE. 563 elements themselves there is a store of combined calcium, potas- sium, and sodium which may serve to supply these elements to a greater or less extent to the tissue liquids. The controversial details upon this question cannot be presented in an elementary book, but the following brief statements may be made regarding one view of the specific effects of the separate cations: (1) The sodium salts in the blood and lymph take the chief part in the maintenance of normal osmotic pressure. The sodium chlorid exists in blood-plasma to the extent of 0.5 to 0.6 per cent., and the normal osmotic pressure of the blood is mainly dependent upon it. A solution of sodium chlorid of 0.7 to 0.9 per cent, forms what is known as physiological saline, and although not adequate to maintain the normal composition and properties of the tissues it fulfills this purpose more perfectly than the solution of any other single substance. The sodium ions have in addition a specific influence upon the state of the heart tissue. Contractility and irritability disappear when they are absent; when present alone, in physiological concentration, in the medium bathing the heart mus- cles they produce relaxation of the muscle tissue. (2) The calcium ions are present in relatively very small quantities in the blood, but they also are absolutely necessary to contractility and irritability. When present in quantities above normal or when in a propor- tional excess over the sodium or potassium ions they cause a con- dition of tonic contraction that has been designated as calcium rigor. (3) The potassium ions are present also in very small quan- tities, and, unlike the calcium and sodium ions, their presence in the circulating liquid does not seem to be absolutely necessary to rhythmical activity. Under proper conditions a terrapin's heart beats well for a time upon a solution containing only sodium and calcium salts. The potassium seems to promote relaxation of the muscle and in physiological doses it exercises through this effect a regulating influence upon the rate of beat. When the proportion of potassium ions is increased the heart rate is proportionally slowed, and finally the contractions cease altogether, the heart coming to rest in a state of extreme relaxation, known sometimes as potassium inhibition. (4) It appears from these statements that there is a well-marked antagonism between the effects of the calcium, on the one hand, and the potassium and sodium, on the other. The calcium promotes a state of contraction, the sodium and the potassium a state of relaxation. It is conceivable, there- fore, that the alternate states of contraction and relaxation which characterize the rhythmical action of heart muscle are connected in some way with an interaction of an alternating kind between these ions and the living contractile substance of the heart. It is impossible' to say positively whether or not the inorganic salts are directly connected with the cause of the beat, — that is, with 564 CIRCULATION OF BLOOD AND LYMPH. the origination of the inner stimulus. According to one point of view, they are necessary only to the irritability and contractility of the heart tissue. The inner stimulus is produced otherwise by some unknown reaction, but it is not able to cause a contraction of the heart muscle in the absence of the proper inorganic salts. According to another view, the reaction of these ions with the living substance constitutes or leads to the development of the inner stimulus. Physiological Properties of Cardiac Muscle. — Cardiac muscle exhibits certain properties which distinguish it sharply from skeletal muscular tissue and which have a direct bearing upon the rhyth- micity of the contractions and the sequence shown by the different chambers. The most characteristic of these properties are the following: 1. The contractions of heart muscle are always maximal. In skeletal muscle and in plain muscle the extent of contraction is related to the strength of the stimulus, and we recognize the exis- tence of a series of submaximal contractions of varying heights. This is not true of heart muscle. As was first shown by Bow- ditch, a piece of ventricular muscle when stimulated responds, if it responds at all, with a maximal contraction. The apex of a frog's heart does not beat spontaneously, but contracts upon electrical stimulation. If such an apex is connected with a lever to register its contractions, and the electrical stimulus applied to it is gradually increased, the first contraction to appear is maxi- mal, and it is not further increased by augmenting the stimulus. This property is sometimes described by saying (Ranvier) that the contraction of the heart muscle is all or none. This fact must not, however, be interpreted to mean that the force of contraction of heart muscle is invariable under all conditions. Such is not the case. The heart muscle under favorable nutritive conditions may give a much larger and more forcible contraction than is possible under conditions of poor nutrition; but the point is, that, whatever may be the condition of the muscle at any given moment, its contraction in response to artificial stimulation is maximal for that condition, — that is, does not vary with the strength of the stimulus. As was said above, this property is not exhibited by the crustacean (lobster) heart, but has been shown to be true for the mammalian heart muscle.* 2. The refractory 'period of the beat. It was shown by Marey f that the heart muscle is irritable to artificial (electrical) stimuli only during the period of diastole. During the period of systole an elec- trical stimulus has no effect ; during the period of diastole such a * For experiments on mammalian heart and literature, see Woodworth, "American Journal of Physiology," 8, 213, 1903. t Marey, "Travaux du laboratoire," 1876, p. 73. PROPERTIES OF THE HEART MUSCLE. 565 stimulus calls forth an extra contraction and the latent period preceding the extra contraction is shorter the later the stimulus is ir, tv^ fL J C~ 1° s, £w s eS?ct of a short electrical stimulus applied at different times Simnl,!^ h? "F^fc? Th! re-Cord ls taken from the fr°S's heart. In 1, 2, and 3 the stimulus (e) falls into the heart during systole (refractory period) and has no effect. In Z'„a ■ i'u a u stlmulus falls lnt° the heart toward the end of systole or during diastole, itwT i7 a.n ex*ra ,sTst?le, and corresponding compensatory pause. It will be "S 7? i latf^* Penod (shaded area) between the stimulus and the extra systole is Sorter the longer the diastole has preceded before the stimulus is applied 566 CIRCULATION OF BLOOD AND LYMPH. applied in the diastolic phase. This relationship is well shown by Marey's curves reproduced in Fig. 236. The period of inexcitabil- ity is designated as the refractory period of the heart beat. Marey defined this refractory period as falling within the first part of the systole, and stated that its duration varies with the actual strength of the stimulus. Later experiments by other investigators make it probable that the refractor}^ period lasts during practically the entire systole.* According to this point of view, therefore, the heart muscle during its period of actual contraction is entirely unirritable, and in this respect it offers a striking difference to skeletal and plain muscle. The existence of this refractory period explains why the heart muscle cannot be thrown into complete tetanic contractions by rapidly repeated stimuli. Since each contraction is accompanied by a condition of loss of irritability, it is obvious that those stimuli that fall into the heart during this period must prove ineffective. The refractory period and the gradual increase in irritability during the diastole may throw some light also on the rhythmical character of the beat. The occurrence of the refractory period and the subsequent gradual return of irritability are connected no doubt with the metabolic changes taking place in the heart muscle. It is in the character of this metabolism that we must seek for the final explanation of these two phenomena and the cause of the rhythmicity of the contractions. As was stated above, it has been shown that the crustacean (lobster) heart muscle does not obey the all-or-none law, shows no refractory period, and is capable of giving tetanic contractions when rapidly stimulated. In all these respects it differs from the typical heart muscle of the vertebrate, but the difference is perhaps sufficiently explained by the discovery (p. 558) that the crustacean heart, in one form at least, is not an automatically rhythmical tissue. Its rhythmical contractions, like those of the diaphragmatic muscle in the higher vertebrates, depend upon rhythmical impulses received from nerve centers. The Compensatory Pause. — It has been observed that when an extra systole is produced by stimulating a ventricle it is followed by a pause longer than usual; the pause, in fact, is of such a length as to compensate exactly for the extra beat ; so that the total rate of beat remains the same. The pro- longed pause under these conditions is therefore frequently designated as the compensatory pause. It has been shown, t however, that the exact compen- sation in this case is not referable to a property of heart muscle, but is due to the dependence of the ventricular upon the auricular beat. When the auricle or ventricle is isolated and stimulated the phenomenon of exact compensation is not observed. In an entire heart, on the contrary, the beat originates at the venous end of the auricle and is propagated to the ventricle. If the latter chamber is st Lmulated so as to give an extra beat out of sequence it will remain in diastole until the next auricular beat stimulates it, and will thus pick up the regular sequence of the heart beat. * See paper by Woodworth, loc. cit. Also Schultz, "American Journal of Physiology," 16, 483, 1900, and 22, 133, 1908. f Cushny and Matthews, "Journal of Physiology," 21, 227, 1897. PROPERTIES OF THE HEART MUSCLE. 567 The Normal Sequence of the Heart Beat.— The normal rhythm of the heart beat is first a contraction of the auricles, then one of the ventricles. Many efforts have been made to determine the precise spot in which the contraction of the heart normally starts. Formerly it was supposed that the contraction began in the great veins just before they pass into the auricle, and it was implied that this initiation of the beat might occur in the pulmonary veins as well as in the vense cavse. More recent experiments* which have been made largely upon the isolated heart while perfused with a Ringer-Locke solution have shown pretty conclusively that the most rhythmic part of the heart and the part from which the beat, in all probability, normally starts is an area of the wall of the right auricle lying between the openings of the vense cavse, or, according to the most recent views, in that remnant of the sinus tissue known as the sino-auricular node which lies in this region, and which is connected with the auricular muscle and with the auriculoventricular bundle (p. 528). When this portion of the heart is warmed or cooled the rate of beat of the whole heart is correspondingly increased or decreased, while, on the contrary, warming or cooling of the ven- tricles themselves, the auricular appendages, the left auricle, etc., has no effect upon the heart-rate. From the point of confluence of the vense cavse the wave of contraction spreads over the auricles and through the auriculoventricular bundle to the ventricles. This sequence from venous to arterial end is beautifully shown in the frog's heart, in which the contraction begins in the sinus venosus, spreads to the auricles, thence to the ventricle, and finally to the bulbus arteriosus. Under normal conditions this sequence is never reversed, and an explanation of the natural order forms obviously an important part of any complete theory of the heart beat. Those who hold to the neurogenic theory naturally explain the sequence of the beat by reference to the intrinsic nervous apparatus. If the motor ganglia lie toward the venous end of the heart one can imagine that their discharges may affect the different chambers in sequence, the pause between auricular and ventricular contraction being due, let us say, to the fact that the motor impulses to the ventricle have to act through subordinate nerve cells in the auriculo-ventricular region, and the time necessary for this action brings the ventricular contraction a certain interval later than that of the auricle. There is no immediate proof or disproof of such a view. The numerous exper- iments made upon the rapidity of conduction of the wave of * Consult especially Adam, "Archiv f. d. ges. Physiol.," Ill, 607, 1906; Erlanger and Blackman, "American Journal of Physiology," 19, 125, 1907, and Flack, "Journal of Physiology," 41, 64, 1910. 568 CIRCULATION OF BLOOD AND LYMPH. contraction over the heart are not conclusive either for or against the view. The fact, however, that in the quiescent but still irritable heart the rhythm may be reversed by artificially stimulating the ventricle first seems to the author to speak strongly against the dependence of the sequence upon any definite arrangement of neuron complexes. On the myogenic theory the sequence of the heart beat is accounted for readily by relatively simple assumptions. Ga^kell and Engelmann have each laid emphasis upon the facts in this connection, and the application of the myogenic theory to the explanation of the normal sequence of contractions forms one of its most attractive features. Gaskell assumes* that the rhythmical power of the muscle at the venous end is greater than that at the ventricular end, that is, if pieces from the two ends are examined separately it will be found that the spontaneous rhythm of the tissue from the venous end is more rapid. This portion of the heart, therefore, beating more rapidly, sets the rhythm for the whole organ, since a contraction started at the venous end will propagate itself from chamber to chamber. That each chamber of the heart has a rhythm of its own and that the rhythm of the ven- ous end is the more rapid and constitutes the rhythm of the intact heart has been shown in various ways upon the hearts of different animals. Thus, Tigerstedt has devised an instrument, the atrio- tome,f by means of which the connections between auricle and ventricle may be crushed without hemorrhage. Under such condi- tions the ventricle continues to beat, but with a much slower rhythm and with a rhythm entirely independent of that of the auricles. The same result has been obtained recently in a very striking way by Erlanger. This observer arranged a clamp by means of which he could compress the small bundle of fibers connecting auricle and ventricle. When the compression is made the ventricle, after an in- terval, exhibits a slower rhythm and one entirely independent of that of the auricles. When the compression is removed the ventricle falls in again with auricular rhythm. By variations in the pressure upon the bundle intermediate conditions may be obtained in which the "block" between auricle and ventricle is only partial, and in which, therefore, the ventricular systole follows regularly every second or third auricular contraction. When the "block" is com- plete the ventricular rhythm ceases to have any definite relation- ship to that of the auricle, it beats entirely independently and its rate is slower tnan that of the auricle. It is interesting to remember that cases of complete or partial heart block occur in man. In the condition known as the Stokes-Adams syndrome the striking ♦Gaskell, "Journal of Physiology," 4, 61, 1883; also vol. ii, p. 180, of Schafer'e "Text-hook of Physiology," 1900. t See "Lehrhufh der Physiologic des Kreislaufes," 1893. PROPERTIES OF THE HEART MUSCLE. 569 feature in addition to attacks of syncope is a permanently slowed pulse, the heart bea c falling to 30 or 20 beats per minute or lower. Erlanger has shown that in such cases there may be complete or partial heart block. In the former condition the rhythm of the ventricle is entirely independent of that of the auricle and of course much slower. The ventricles may be beating at 27 per minute and the auricles at 90. In partial block the ratio between the ventric- ular and auricular rate is definite, every second or third auricular beat being followed by a ventricular systole (see Fig. 237). In a number of these cases it has been shown at autopsy that there was a distinct lesion involving the auriculoventricular bundle, but in other cases lesions of this kind were not discoverable.* Fig. 237. — Cardiogram from a case of Stokes-Adams disease, showing two auricular beats (1, 2) to each ventricular beat. — (Erlanger.) The time-record marks fifths of a second. In the hearts of the cold-blooded animals the same general results are readily obtained when the tissue between the different chambers is compressed or destroyed. In the frog's heart, for instance, if one ties a ligature (first ligature of Stannius) between the sinus venosus and the auricle, the auricle and ventricle cease beating while the sinus continues pulsating with its normal rhythm. Later the auricle and ventricle may commence beating again, but if this happens their rhythm is slower than that of the sinus and independent of it. So in the terrapin's heart, in which the sequence of beat is so beautifully exhibited, if one ties a ligature between auricle and ventricle, or cuts off the ventricle entirely, the sinus venosus and auricle continue beating at their normal rhythm, while the ventricle remains usually entirely quiescent so long as normal blood flows through it. It would seem from these facts that in the mammalian heart the ventricle when disconnected from the auricle is capable of maintaining a fairly rapid rhythm of its own. At the other extreme, the terrapin's ventricle when similarly treated shows no spontaneous beats at all. These and many other facts that might be quoted support well the general view proposed by Gaskell, that the venous end of the heart possesses the greater rhythmical * See Erlanger, "Journal of Experimental Medicine," 1905, vii., 1906, viii., and "American Journal of Physiology," 1906, xv. and xvi. For the literature upon autopsies in cases of Stokes-Adams' disease consult Krumbhaar, "Bulletin of the Ayer Clinical Laboratory," Philadelphia, No. 6, 1910. 570 CIRCULATION OF BLOOD AND LYMPH. power and starts the heart beat, and that the wave of contraction is propagated from chamber to chamber through the intervening muscular substance. There remains a deeper question as to what occasions this greater rhyth- micity at the venous end, — a question that is, of course, bound up with the problem of the ultimate causes or conditions of automatic rhythmicity. In connection with this latter problem the absolute necessity of the presence of certain inorganic salts in certain proportions has been emphasized. In this same general line the author has called attention to the fact that in the ter- rapin the amount of potassium salts present in the blood explains in itself why the sinus sets the heart rate. In blood, or in Ringer's solution con- taining potassium salts in the same amounts as blood, the ventricular muscle is not automatically contractile; the sinus end of the heart, on the contrary, beats well in such media, while an increase in the potassium contents will bring it to rest also. In this animal, therefore, the amount of potassium in the blood is so adapted that it holds the ventricular end entirely quiescent. In the mammalian heart it may be assumed that the amount of potassium is sufficient to keep the spontaneous rhythm of the ventricle slower than that of the auricles or veins, and therefore subordinates the rhythm of the whole heart to that of the venous end. In the terrapin's heart, at least, the re- moval or reduction of the potassium or the increase of the calcium may lead to an independent ventricular rhythm — the beat of the heart becomes arhyth- mical. The Tonicity of the Heart Muscle. — In describing the phys- iology of skeletal and plain muscle attention was called to their property of tonicity, — that property by means of which they remain in a more or less permanent although variable condition of con- traction. So far as the skeletal muscles are concerned, this con- dition is dependent upon their connections with the nervous system. Cut the motor nerve, or destroy the motor center, and the muscle loses its tone,— becomes completely relaxed. Tonicity or tonic activity is therefore characteristic of the motor nerve centers, and is due, no doubt, to a more or less continuous inflow of sensory impulses into those centers. The tonus of the nerve centers is a reflex tonus. In the plain muscle the condition of tonus is also marked. The blood-vessels, the bladder, the various viscera are rarely, if ever, entirely relaxed for any length of time. This tonus is also dependent, in many cases, upon a constant innervation through the motor nerves, but after these latter have been destroyed the plain muscle still shows this property of tonicity. So in the heart muscle the power to maintain a certain degree of contraction, a certain state of muscle tension quite independently of the sharp systolic contractions, is very characteristic. At the end of a normal diastole, for example, the ventricle is not entirely relaxed, it retains a certain amount of tonicity as compared with its condition when inhibited through the vagus nerve or when dead. The degree of this tonicity determines, of course, the size of the ventricular cavity and the extent of the charge it will take from the auricles. PROPERTIES OF THE HEART MUSCLE. 571 As will be described in the next chapter the tone of the heart muscle is dependent in part upon its extrinsic nerves, but it is more dependent probably upon the composition of the blood. Like the property of rhythmicity, that of tonicity is most developed at the venous end of the heart. At least this is the case with the heart of the cold-blooded animals, upon which this property has been studied most carefully. The ventricle of the terrapin, or strips excised from the ventricle and susT pended so that their movements can be recorded, often vary greatly in length with differences in condition. These varia- tions are clue to changes in tone. Not infrequently these changes take on a rhythmical character; so that if the ven- tricle is beating one sees upon the record regular tone waves, an alternate slow shortening and slow relaxation quite inde- pendent of the rhythmical beats. The tissue of the auricle and especially of the sinus venosus exhibits this property to a much more marked extent (see Fig. 238). The tone — that is, the length of the piece — if in strips, or the capacity of the chamber, if used entire, is continually changing and oftentimes in a rhythmical _ Fig. 238. — To show tone waves in heart muscle. The record shows contractions of a strip of the sinus venosus (terrapin's heart) suspended in a bath of blood-serum. In addi- tion to the sharp contractions marked by the lines there are longer, wave-like shortenings and relaxations, irregular in character, which are due to variations in tone. way. Fano* has made a special study of this property and has suggested that the tone changes or contractions may be due to the activity of a substance in the heart different from that which mediates the ordinary contractions. Botazzif suggests that, while the usual sharp systolic contraction is due to the cross-striated (anisotropous) substance, the slower tone changes may be due * Fano, "Beitrage zur Physiologie." C. Ludwig, zu s. 70 Geburtstage gewid. Leipzig, 1887. t "Journal of Physiology," 21, 1, 1897. 572 CIRCULATION OF BLOOD AND LYMPH. to tke undifferentiated sarcoplasm. However this may be, the property of tonicity is an important one in the physiology of the heart and of the other visceral organs. Through it a certain tension of the musculature is maintained, and the size of the cavities is controlled. The property may be of special regulative value in the large veins where they open into the auricles, but at present we have little positive knowledge of the conditions that control the tonicity, of the extent of its regulating action normally, or of the extent of its derangement under pathological conditions. CHAPTER XXX. THE CARDIAC NERVES AND THEIR PHYSIOLOGICAL ACTION. The heart receives two sets of efferent nerve fibers from the central nervous system. One set reaches the heart through the vagus nerves, and, since their activity slows or stops the heart beat, they are spoken of as the inhibitory nerve fibers. The other set passes to the heart by way of the sympathetic chain, and since their activity accelerates or augments the heart beat they are designated usually as the accelerator nerve fibers. In addition the heart is provided with a set of afferent nerve fibers. Regarding the functional activity of these latter fibers, our experimental knowledge is limited to the fact that some of them, at least, are stimulated at each beat of the heart (p. 606) and that possibly some of them help to form the so-called depressor nerve (p. 606). Under pathological conditions these afferent fibers may produce painful sensations. The Course of the Cardiac Fibers. — The vagus nerve gives off several branches that supply the heart. The superior car- diac branches arise from the vagus in the neck somewhere between the origins of the superior and the inferior laryngeal nerves. The inferior cardiac branches arise from the thoracic portion of the vagus near the origin of the inferior laryngeal {N. recurrens) and, indeed, some of these branches may spring directly from the latter nerve. The inhibitory fibers probably arise in these inferior branches chiefly. Both superior and inferior cardiac branches pass toward the heart and unite with the cardiac branches from the sympathetic chain to form the cardiac plexus. This plexus lies on the arch and ascending portion of the aorta, and from it the heart receives directly both its inhibitory and accelerator fibers. The inhibitory fibers of the heart form a part of the outflow of autonomic fibers (p. 251) through the vagus nerve. The preganglionic fibers probably end around ganglion cells in the heart, which in turn send their axons as postganglionic fibers to the heart muscle. The Action of the Inhibitory Fibers. — If the vagus nerve in the neck of an animal is cut and its peripheral end is stimulated the heart is slowed or stopped altogether according to the strength of the stimulus. This effect is illustrated in Figs. 239 and 240. 573 574 CIRCULATION OF BLOOD AND LYMPH. This inhibitory influence upon the heart beat was first described in 1845 by the two brothers, Edward Weber and E. H. Weber. It was a physiological discovery of the first importance, not only as regards the physiology of the heart, but from the standpoint of general physiology, since it gave the first clear instance of the possibility of inhibitory action through nerve fibers. If the heart is examined during its complete inhibition it will be seen that it stops in diastole, and indeed the diastole is more complete than normal, — the heart dilates to a very large extent, and becomes swollen with blood. This latter fact is taken usually as proof that the action of the inhibitory fibers not only prevents the usual systole, but also removes the to- nicity of the musculature. Some observers believe that the unusual dilatation is due simply to the effect of the increased venous pressure (Roy and Adami). Examination of the heart shows also that the inhi- bition affects the whole heart, — both auricles and ventricles are slowed or stopped, as the case may be. That the vagus nerve in man also con- tains inhibitory fibers to the heart is made highly probable by every- thing known concerning the condi- tions under which the heart is slowed or stopped temporarily, and has, moreover, been demonstrated directly in several instances upon living men.* These inhibitory fi- bers have been shown to exist in all classes of vertebrates and in a num- ber of the invertebrates, — a fact which in itself would indicate the great importance of their influence upon the effective activity of the heart. In the mammals gener- ally employed in laboratory experiments the inhibitory fibers occur in both vagi; in some of the lower vertebrates, however, * See especially Thanhoffer, " Centralblatt f. d. med. Wiss.," 1875, who gives an account of an experiment in which the vagi were compressed in the neck, with a resulting stoppage of the heart and loss of consciousness. Fig. 239. — To show the inhibition of the terrapin's heart due to stimula- tion of the vagus nerve. The upper tracing (/) records the contractions of the left auricle; the lower (//) the con- tractions of the ventricle. The vagus was stimulated three times, each chamber coming to a complete stop. On removing the stimulus it will be noted that the auricular contractions increase gradually to their normal, while the ventricular contractions start off at full strength. THE CARDIAC NERVES. 575 especially in the terrapin, the inhibitory fibers may be found exclusively or mainly in the right vagus. Analysis of the Action of the Inhibitory Fibers. — The prom- inent effect of the action of the inhibitory fibers is the slowing Fig. 240. — To show the inhibition of the heart from stimulation of the vagus in the dog. Record B is the blood-pressure tracing. The vagus was stimulated twice. The marks x, x, indicate the beginning and end of the stimulus. The first stimulation was weak ; it will be noted that the heart escaped and began beating before the stimulus was withdrawn. The second stimulus was stronger ; the inhibition lasted some time after re- moval of the stimulus. The upper curve (K) is a plethysmography (oncometer) tracing of the volume of the kidney. It will be noted that when the heart stops and blood-pressure falls the kidney, like the other organs, diminishes in volume. (Dawson.) of the rate of the heart beat. Numerous observers have called attention to the fact that the vagus fibers may also cause a weaken- ing in the force of the beat as well as a slowing in the rate, or, indeed, the two effects may be obtained separately. This fact has been shown especially for the auricles.* In the heart of the terrapin one may, by using weak stimuli, obtain only a weakening of the auricular beats without any interference with the rate (Fig. 241), while by increasing the stimulus the slowing in rate becomes evident * Bayliss and Starling, "Journal of Physiology," 13, 410, 1892. 576 CIRCULATION OF BLOOD AND LYMPH. combined with a diminution in force or extent. Although the force of the beat may be influenced without altering the rate, the reverse does not hold. Usually, for the auricle, at least, any stimulus that slows the beat also weakens the individual beat. Whether the vagus fibers exercise a similar double influence directly upon the ventricle is not so clear. Some observers find that when the ventricle is inhibited the beats, although slower, are stronger, while others obtain an opposite result. It seems probable, as stated by Johansson and Tigerstedt, that the result obtained depends largely on the strength of stimulus used. These observers found* that with relatively weak stimuli the contractions of the ventricle, though slower, are stronger, while with stronger stimuli the contractions are diminished in strength as well as rate. The question is complicated by the difficulty of separating the direct effect of the vagus on the ventricle from the indirect effect brought about by the changes in the auricular beat. The inhibitory in- fluence makes itself felt also upon the conductivity of the heart. This fact has been noted by several ob- servers. A striking example is seen in the case of partial heart block. When as the result of some injury or pressure in the auriculo-ventricu- lar region or from some other less evident cause there is a partial block, so that the ventricle con- tracts once to two or three beats of the auricle, vagus stimulation may be followed at once, as an after-effect, by a return to the normal beat, a re-establishment of a one-to-one rhythm. Under other circumstances the contrary effect of vagus stimulation has been described. From the results cited it seems evident that the vagus nerve may affect the rate and the force of the con- tractions, and also the conductivity or the propagation of the wave of contraction. These separate influences have been referred by some authors to the existence of different kinds of nerve fibers, each exerting its own influence, but it seems preferable to assume, on the contrary, that only one kind of fiber is present, and that its influence on the metabolic changes in the heart muscle expresses itself differently upon the several different properties of the tissue according to the extent of its action. * See Tigerstedt, " Lehibuch der Physiologic des Kreislaufes," 1893, p. 247. Fig. 241.— To show the effect of vagus stimulation on the force only of the auricular beat in the terrapin's heart: .4, Record of the auricular beats; V, record of the ventricular beats. The vagus was stimulated be- tween x and x. It will be noted that the ventricular beats are not affected, and that the auricular beats diminish in extent without any change in rate. THE CARDIAC NERVES. 577 Engelmann has made the most complete attempt to analyze the influence exerted by the cardiac nerves (inhibitory and accelerator). He designates these influences under four different heads with the further supposition that they are mediated by different fibers: (1) The chronotropic influence, affecting the rate of contraction, positive chronotropic actions causing an acceleration and negative chronotropic actions a slowing of the rate. (2) The bathmo- tropic influence, affecting the irritability of the muscular tissue ; this also may be positive or negative. (3) The dromotropic influence, positive or negative, affecting the conductivity of the tissue. (4) The inotropic influence, posi- tive or negative, affecting the force or energy of the contractions.* Does the Vagus Affect Both Auricle and Ventricle? — The inhibitory action of the vagus is most marked upon the venous end of the heart, and the question has arisen as to whether it affects the ventricle directly or not. Gaskell gave evidence to indicate that in the terrapin the auricle only is inhibited, the ventricle stop- ping because it fails to receive its normal impulse from the auricle. When this heart is inhibited the contractions of the auricle after cessation of inhibition gradually increase in amplitude until the normal size is reached; in the ventricle, on the contrary, the first contraction after inhibition is of normal size or greater than normal (see Fig. 239). When a block is produced in the mammalian heart between auricle and ventricle — by clamping the connecting muscular bundle, for instance — stimulation of the vagus stops the auricle only f, and the result would seem to indicate that the vagus affects only the auricle, unless it is assumed that the clamp has interrupted the inhibitory paths to the ventricle. On the other hand, in favor of the view that the vagus fibers reach the ventricle and influence its beats directly, we have the fact, emphasized by Tigerstedt, namely, that when the connection between auricle and ventricle is severed suddenly the ventricle frequently continues to beat at its own rhythm without any obvious pause. It would seem from this fact that when the whole heart is inhibited by stimulation of the vagus the ventricle does not stop simply because the auricle fails to send on its usual contraction wave, since, if that were so, cutting off the auricle or clamping the connection between it and the ventricle should also bring on a ventricular pause, as happens in the case of the terrapin's heart. It seems, however, to be the general belief of those who have experi- mented with the subject that the action of the vagus is exerted mainly upon the auricles, and, indeed, there is some evidence! that its effect is felt mainly upon that small portion of the auricle (the sin o-auricular node) in which the normal heart-beat takes its origin. Escape from Inhibition. — Strong stimulation of the vagus may stop the entire heart, but the length of time during which the *Englemann, "Archiv f. Physiologie," 1900, p. 313, and 1902, suppl. volume, p. 1. f Erlanger, "Archiv f. d. ges. Phvsiologie," 127, 77, 1909. j Flack, "Journal of Physiology," 41, 64, 1910. 37 578 CIRCULATION OF BLOOD AND LYMPH. heart may be maintained in this condition varies in different species and indeed to some extent in different individuals.* In some ani- mals— cats, for example — the strongest stimulation of the nerve serves frequently only to slow the heart instead of causing complete standstill. In dogs the heart is stopped by relatively weak stimu- lation, although if the stimulation is maintained the heart, as a rule, escapes from the inhibition. In some dogs the heart may be held inhibited long enough to cause the death of the animal unless artificial respiration is maintained, but usually the heart beat soon breaks through the complete inhibition. The "inner stimulus" in such cases increases in strength sufficiently to overcome the opposing inhibitory influence, and this circumstance may be regarded as an argument against those views that trace the origin of the " inner stimulus " to some of the products formed during the ca- tabolism of contraction. Moderate stimulation of the vagus, suffi- cient simply to slow the rate of beat, can be maintained without dimi- nution in effect for very long periods; indeed, as is explained in the next paragraph, the heart beat is kept partially inhibited more or less continuously through life by a constant activity of the vagus. In the cold-blooded animals, especially the terrapin, the heart may be kept completely inhibited for hours by stimu- lation of the vagus. Mills reports that he has kept the heart of the terrapin in this condition for more than four hours. f Most observers state that complete inhibition can be maintained for a longer time when the stimulus is applied alternately to the two vagi, but it is possible that this result is due to the fact that continuous stimulation applied to a nerve usually results in some local loss of irritability. Reflex Inhibition of the Heart Beat — Cardio-inhibitory Center. — The inhibitory fibers may be stimulated reflexly by action upon various sensory nerves or surfaces. One of the first experi- mental proofs of this fact was furnished by Goltz's often-quoted "Klopfversuch."J In this experiment, made upon frogs, the ob- server obtained standstill of the heart by light, rapid taps on the abdomen, and the effect upon the heart failed to appear when the vagi were cut. In the mammals every laboratory worker has had numerous opportunities to observe that stimulation of the central stumps of sensory nerves may cause a reflex slowing of the heart beat. The effect is usually very marked when the central stump of one vagus is stimulated, the other vagus being intact. The vagus carries afferent fibers from the thoracic and abdominal viscera, and most observers state that the heart may be reflexly inhibited most readily by simulation of the sensory surfaces of *See Hough, "Journal of Physiology," 18, 101, 1895. f " Journal of Physiology, " 6, 246. JGoltz, " Virchow's Archiv f. pathol. Anatomie, etc.," 26, 11, 1863. THE CARDIAC NERVES. 579 the abdominal viscera, by a blow upon the viscera, for example, or by sudden distension of the stomach. In man similar results are noticed very frequently. Acute dyspepsia, inflammation of the peritoneum, painful stimulation of sensory surfaces,— the testes, for instance, or the middle ear, — may cause a marked slowing of the heart, — a condition designated as bradycardia. What takes place in all such cases is that the afferent impulses carried into the central nervous system reflexly stimulate the nerve cells in the medulla which give origin to the inhibitory fibers. These cells form a part of the great motor nucleus (N. ambiguus) from which arise the motor fibers of the vagus and the glossopharyngeus. The particular group of cells from which the inhibitory fibers to the heart originate has not been delimited anatomically. Efforts have been made to locate them by vivisection experiments, but this method has shown no more perhaps than that they are found in the region of origin of the vagus nerve. Physiologically, however, this group of cells forms a center which is of the greatest importance in controlling the activity of the heart. It is designated, therefore, as the cardio-inhibitory center. We may define the cardio-inhibitory center as a bilateral group of cells lying in the medulla at the level of the nucleus of the vagus and giving rise to the inhibitory fibers of the heart. The two sides are probably connected by commis- sural cells or else each nucleus sends fibers to the vagus of each side. Through this center all reflexes that affect the heart by way of the inhibitory fibers must take place. These reflexes may be occa- sioned by incoming sensory impulses through the spinal or cranial nerves, or by impulses coming down from the higher portions of the brain. The center may also be stimulated directly, either by pressure upon the medulla, which may give rise to slow heart beats or, as they are sometimes called, vagal beats, or by changes in the composition of the blood. With regard to the reflex stimulation of this center it is important to bear in mind the general physiological rule that afferent impulses may either excite or inhibit the activity of nerve centers. In the former case the heart rate would be slowed, in the latter case it would be quickened if the center were previously in a state of activity. The Tonic Activity of the Cardio-inhibitory Center.— The cells of the cardio-inhibitory center are in constant activity to a greater or less extent. As a consequence, the heart beat is kept con- tinually at a slower rate than it would normally assume if the inhibitory apparatus did not exist. This tonic activity of the vagus is beautifully exhibited by simple section of the two vagi, or by inter- rupting, in some other way — cooling, for example — the connection between the center and the heart. When the two vagi are cut the heart rate increases greatly and the blood-pressure rises on account of the greater output of blood in a unit of time (Fig. 242) . Section 580 CIRCULATION OF BLOOD AND LYMPH. of one vagus gives usually a partial effect, — that is, the heart -rate is increased somewhat, — but it is still further increased by section of the second vagus. The exact result obtained when the nerves are Fig 242 — To show the effect of section of the two vagi in the dog upon the rate of heart beat and the blood-pressure: 1 marks the section of the vagus on the right side; 2 section of the second vagus. The numerals on the vertical mark the blood-pressures ; the numerals on the blood-pressure record give the rate of heart beats. (Dawson.) severed separately varies undoubtedly with the conditions.— for instance, with the intensity of the tonic activity of the center. Throughout life, speaking in general terms, the cardio-inhibitory center keeps the "brakes" on the heart rate, and the extent of its action varies under different conditions. When its tonic action is increased the rate becomes slower; when it is decreased the rate becomes faster. In all probability, this tonic action of the center, like that of the motor centers generally, is in reality a reflex tonus. That is, it is not due to automatic processes generated within the nerve cells by their own metabolism or by changes in their liquid environment, but to stimulations received through sensory nerves. The continuous though varying inflow of impulses into the central nervous system through different nerve paths keeps the center in that state of permanent gentle activity which we THE CARDIAC NERVES. 581 designate as "tone." It is possible, of course, that certain afferent paths may be in specially close functional relationship to the center, and the fact that at each heart beat its own sensory fibers are stimulated (p. 606, Fig. 280) would suggest that these fibers may have this function. The Action of Drugs on the Inhibitory Apparatus.— The existence of the inhibitory fibers to the heart furnishes a means of explaining the cardiac action of a number of drugs, — atropin, muscarin or pilocarpin, nicotin, curare, digitalis, etc., — for the details of which reference must be made to works on pharmacology.* The action of the first three named illustrates especially well the application that has been made of physiology in modern pharma- cology. Atropin administered to those animals, such as the dog or man, in which the inhibitory fibers of the vagus are in constant activity, causes a quickening of the heart rate. Indeed, the heart beats as rapidly as if both vagi were cut. After the use of atropin, moreover, stimulation of the vagus nerve fails to produce inhibition. The action of atropin is satisfactorily explained by assuming that it paralyzes the endings of the (postganglionic) inhibitor}' fibers in the heart muscle, just as curare paralyzes the terminations of the motor fibers in skeletal muscle. Atropin exercises a similar effect upon the nerve terminations in the intrinsic muscles of the eyeball and in many of the glands. On the contrary, when mus- carin or pilocarpin is administered it causes a slowing and finally a cessation of the heart beat. Since this effect may be removed by the subsequent use of atropin it is assumed that the two former drugs excite or stimulate the endings of the inhibitory fibers in the heart and thus bring the organ to rest in diastole, as happens after electrical stimulation of the vagus nerve. Some authors, however, believe that these drugs do not act upon the terminals of the vagus fibers, but upon the muscular tissue itself or upon a specialized " receptive substance " (Langley) contained in the muscle. A final statement cannot be made upon this point, but the current belief is that the atropin paralyzes while the muscarin or pilocarpin stimulates the endings of the inhibitory fibers in the substance of the heart. The Nature of Inhibition. — Since the discovery of the inhibi- tory nerves of the heart furnished the first conclusive proof of the existence in the body of definite nerve fibers with apparently the sole function of inhibition, it seems appropriate in this connection to refer to the views regarding the nature of this process. Several general views of the nature of inhibition have been proposed, but the one that is most definite and has met with most favor is that * Consult Cushney, "Text-book of Pharmacology and Therapeutics," Philadelphia. 5*2 CIRCULATION OF BLOOD AND LYMPH. suggested by Gaskell.* This author has shown that the after-effects of stimulation of the inhibitory' fibers are beneficial rather than in- jurious to the heart; that is, under certain circumstances an improve- ment may be noticed in the rate or force of the beat or in the con- ductivity. He has also shown, by an interesting experiment, that during the state of inhibition the heart tissue is made increasingly electropositive in comparison with a dead portion of the tissue. To show this fact the tip of the auricle was killed by heat and this spot (a) and a point at the base of the auricle (6) were connected with a galvanometer. Under such conditions a strong demarcation cur- rent was obtained flowing through the galvanometer from b to a. If the auricle contracted a negative variation resulted, since during activity b became less positive as regards a. If, on the contrary, the auricle was inhibited by stimulation of the inhibitory fibers a positive variation was obtained; b became more positive toward a. On the basis of such results Gaskell concludes that inhibition in the heart is due to a set of metabolic changes of an opposite character to those occurring during contraction. In the latter condition the metabolism is catabolic, and consists in the breaking down of complex substances into simpler ones with the liberation of energy as heat and work. During inhibition, on the contrary, the processes are anabolic or synthetic and result in the formation of increased contractile material whereby the condition of the heart is improved. He would regard the inhibitory fibers, therefore, as the anabolic nerve of the heart and their constant action throughout life as an aid to the nutrition of the heart. The same general view may be extended to all cases of inhibition, and Gaskell believes that all muscular tissues are supplied with anabolic (inhibitory) and catabolic (motor) fibers. f A more specific theory applicable to the case of the heart has been proposed by the author. J In experiments made upon the isolated heart of the dog it has been shown that during stimulation of the vagus potassium in diffusible form is given off from the heart muscle (auricles). It is known that potassium salts in a certain concentration in the circulating liquid will bring the heart to a stand-still, and the state of potassium inhibition thus produced resembles very closely the state of vagus inhibition. Since the vagus when stimulated liberates potassium in a diffusible form, it is suggested that its action in stopping the heart is effected through the agency of this substance. The potassium exists in large percentage in the heart-muscle, but in a combined form, and the theory assumes that the vagus impulses initiate a dissociation or cleavage of some sort which sets free some potassium in soluble form. If it is assumed that this liberation takes place in the part of the heart in which ♦Gaskell, "Philosophical Transactions of the Royal Society," London; Croonian Lecture, part m , 1882; also "Beitriige zur Physiologie, " dedicated to C. Ludwig, 1887; and "Journal of Physiology," 7, 46. t For a general discussion of this idea and of the importance of inhibitory actions, see Meltzer, "Inhibition," "New York Medical Journal," May 13, 20, 27, 1899. X Howell and Duke, "American Journal of Physiology," 21, 51, 1908. THE CARDIAC NERVES. 583 the beat originates, the theory offers a simple explanation of the stoppage^ of the beat, of the quick recovery after stimulation ceases, and of the retention of irritability to direct stimula- tion shown by the heart during vagus inhibition. A heart that has been stopped by an excess of potassium chloride added to the circulating liquid beats very promptly as soon as the excess of the potassium is removed, and as m the case of vagus inhibition it seems often to show a notice- able improvement in condition. That the inhibitory ef- fect of the vagus im- pulses upon the heart is not due to any peculiarity in properties of these fibers or of the impulses themselves, but is depend- ent rather upon the place or manner of ending in the heart, has been demon- strated by direct experi- ment. Erlanger* has shown that when an ordinary spinal nerve (fifth cervical) is sutured to the peripheral end of the cut vagus, it will, after time for regeneration has been allowed, cause, when stimulated, the usual stoppage of the heart. The Course of the Ac- celerator Fibers. — The heart receives efferent or motor nerve fibers from the sympathetic system in addition to those reaching it by way of the vagus nerve. Atten- tion was first called to these sympathetic fibers by Legallois (1812), but our recent knowledge dates from the experiments made by von Bezold (1862), which were afterward completed by the Cyon brothers— M. and E. Cyonf— 1866. These fibers when stimulated cause an increased rate of beat and are, there- fore, designated as the accelerator nerve of the heart. Their * Erlanger, "American Journal of Physiology," 13, 372, 1905. | For the history and literature of the accelerator nerves, see Cyon, article "Cceur," p, 103, in Richet's "Dictionnaire de Physiologie," 1900; or Tiger- stedt, "Lehrbuch der Physiologie des Kreislaufes," 260, 1893, Fig. 243. — Schematic representation of the eourse of the accelerator fibers to the dog's heart — right side. — (Modified from Pawlow.) the sym- pathetic nerve is represented in solid black. The course of the accelerator fibers is indicated by ar- rows. /, Cervical sympathetic combined in neck with, 10, the vagus; //, ///, IV, rami communi- cantes from the second, third, and fourth thoracic spinal nerves, carrying most of the accelerator fi- bers to the sympathetic chain ; 7, annulus of Vieus- sens; 8, inferior cervical ganglion; 2, 3, 4, 5, branches from vagus and vago-sympathetic trunk going to cardiac plexus (some of these — 3, 5, — carry accelerator fibers; 9, the inferior laryngeal nerve. 584 CIRCULATION OF BLOOD AND LYMPH. course has been worked out physiologically in a number of animals. Among the mammalia and, indeed, among different animals of the same species there is some variation, but a general conception of their origin and course may be obtained from Figs. 243 and 244, which represent in a schematic way the anatomical path taken by these fibers. They emerge from the spinal cord in the anterior roots of the second, third, and fourth thoracic spinal nerves. Accord- ing to some authors they may be found also in the fifth tho- racic, the first thoracic, or even the lower cervical spinal nerves. They pass then bj* way of the white rami to the stellate or first thoracic ganglion (6), and thence by way of the annulus of Vieussens (ansa subclavia) (7) to the inferior cervical ganglion. A number of branches leave the sympathetic system and the vagus in this region to pass to the cardiac plexus and thence to the heart. The accelerator fibers are found in some of these branches, mixed in some cases with inhibitory fibers from the vagus. In the cat Boehm has described a special branch (ner- vus accelerans) which runs from the stellate ganglion directly to the cardiac plexus (Fig. 244). The preganglionic portion of some of the accelerator fibers ends around the ganglion cells in the first thoracic ganglion, while others apparently make their first termination in the inferior cervical ganglion. The accelerator fibers may be stimulated in the spinal roots in which they emerge (II, III, IV), in the annulus, or in some of the branches that arise from the annulus, or from the inferior cervical ganglion (5, 3, 2). It will be borne in mind that no accelerator fibers are found in the cervical sympathetic above the inferior cervical ganglion. At various times investigators have asserted that accelerator fibers are contained also in the vagus nerve. Thus, it has been shown that, after the paralysis of the inhibitory fibers in the heart by atropin, stimulation of the vagus causes an acceleration of the heart. Little attention has been paid to the physiology of these fibers, since ii seems evident that the great outflow of accelerators is made via the sympathetic system. Fig. 244.- — Sketch to show the accel- erator 'and augmentor) branches from the stellate ganglion (in the cat. left side): 1, the ventral branch of the annulus (ansa subclavia); 2, small branch not constantly present; 3, Boehm's accelerator nerve (X. cardiacus e ganglio stellato). THE CARDIAC NERVES. 5S5 The Action of the Accelerator Fibers. — In experimental work the accelerators are usually stimulated in one or more of the branches represented schematically as 5, 3, 6, in Fig. 243, or 3, in Fig. 244, The effect is an increase in the rate of beat of the heart, which may be very evident, amounting to as much as 70 per cent, or more of the original rate, or may be very slight. When accelera- tion is obtained the latent period is considerable and the heart does not return at once to its normal rate upon cessation of the stimulus (see Figs. 245 and 246). In some cases the effect upon the heart is an acceleration pure and simple, — that is, the rate of beat is Fig. 245. — To show the acceleration of the heart-rate in dog upon stimulation of the accelerator fibers. The uppermost line gives the heart-rate as recorded by a Hiirthle manometer inserted into the carotid; the middle line indicates the beginning and duration of the stimulus (tetanizing induction shocks) ; the bottom line marks seconds. The pulse-rate was increased from 105 to 135 per minute. The heart did not recover its normal rate until thirty seconds after the stimulation. increased without any evidence of an increase in the force of the beats. The larger number of beats is offset by the smaller amplitude of each beat; so that the blood-pressure in the arteries is unchanged. In other cases the effect upon the heart may be an increase not only in rate but also in the force or amplitude of the beats, or the rate may remain unaffected and only the amplitude of the heart beats be increased. For these reasons most authors favor the view that the accelerator nerves, so called, contain in reality two sets of fibers, one, the accelerators proper, whose function is simply to accelerate the rate, and one. the augmentors, that cause a more forcible beat. The augmenting action is obtained especially from the nerves of the left side. Tonicity of the Accelerators and Reflex Acceleration.— The results of the most careful work show, without doubt, that the accelerators to the heart are normally in a state of tonic activity.* * For a discussion of this and other points in the physiology of the ac- celerators see Hunt, "American Journal of Physiology," 2, 395, 1899, and "Journal of Experimental Medicine," 2, 151, 1897. 586 CIRCULATION OF BLOOD AND LYMPH. When these nerves are cut upon both sides the heart rate is decreased. We must believe, therefore, that under normal conditions the heart muscle is under the constant control of two antagonistic influ- ences, one through the inhibitory fibers tending to slow the rate, one through the accelerator fibers tending to quicken the rate. The actual rate at any moment is the resultant of these two influences. While such an arrangement seems at first sight to be unnecessary from a mechanical standpoint, it is doubtless true that it possesses some distinct advantage. Possibly it makes the heart more promptly responsive to reflex regulation. Balanced mechanisms of this kind are found in other parts of the body where smooth and prompt reactions to stimulation seem to be especially necessary, — for example, the constrictor and dilator fibers of the iris, the ex- tensor and flexor muscles of the joints, etc. Physiologists have studied experimentally the effect upon the heart of stimulating simultaneously the inhibitory and the accelerator nerves. The work done upon this subject by Hunt seems to make it very certain that in all such cases the result, so far as the rate is concerned, is the algebraic sum of the effects of the separate stimulations of the nerve. The inhibitory and the accelerator fibers must be considered, therefore, as true antagonists, acting in opposite ways upon the heart. The existence of the accel- erator nerves makes possible, of course, their reflex stimulation. Experimentally it is found that stimulation of various sensory nerves — those of the limbs or trunk, for instance — may cause reflexly either an increase or decrease in the heart rate, and as a matter of experience we know that our heart rate may be increased by various changes, particularly by emotional states. The natural explanation of such accelerations is that they are Fig. 246. — To show the acceleration and augmentation produced by a strong stimulus. Isolated cat's heart, stimulation on left side. The upper curve gives the ventricular contractions, the lower one the auricular contractions. The lowermost line gives the time in seconds and the line above indicates the duration of the stimulation of the accej- eratrr nerve. due to reflex stimulation of the nerve cells in the central nervous system which give rise to the accelerator fibers. But another point of view is possible. An increase in heart rate may be brought about either by a reflex stimulation of the accelerator THE CARDIAC NERVES. 587 fibers or by a reflex inhibition of the cardio-inhibitory center. Hunt especially has presented many experimental facts which indicate that an increase in heart rate from reflex action may be produced by an inhibition of the tonic activity of the cardio- inhibitory center. He finds, for instance, that when the two vagi are cut stimulation of various sensory nerves fails to give any increase in the already rapid heart rate, while, on the con- trary, when the two accelerator paths are cut a reflex increase in heart rate may be obtained readily. The negative result after previous section of the vagi may well be due, however, to the fact that the heart is then beating at a very rapid rate, too rapid for the production of an additional acceleration through the ordinary physiological mechanism. Acting on this view, Hooker* has shown that if the heart is kept slowed by artificial stimulation of the peripheral end of the vagi, then various sensory stimuli will provoke a reflex acceleration which can only occur through the accelerator center. In addition, Hering f has given experimental evidence to show that the acceleration of the heart following upon muscular exercise does not occur when the accelerator nerves are cut, a fact which also seems to show that these nerves may be reflexly stimulated. We may conclude, therefore, that the accelerator and the inhibitory fibers are working constantly on the heart, and that its rate is the resultant or algebraic sum of their effects, and that sudden changes in this rate, such as follow from sensory or psychical disturbances of any kind, may be referred to a reflex effect upon either the cardio-inhibitory or the accelerator center. While physiology has demonstrated the general properties of the regulating nerves of the heart, the inhibitory, on the one hand, and the accelerator and augmentor on the other, it is necessary for much more work to be done in order to explain satisfactorily how these nerves participate in the various normal and pathological changes of rate and force of beat. The Accelerator Center. — The accelerator fibers arise primarily in the central nervous system. Since stimulation of the upper cervical region of the cord causes acceleration, it seems evident that the path must begin somewhere in the brain. It has been assumed that, like the inhibitory fibers, the path starts in the medulla, and that, therefore, the cells in that organ which give rise to the accelerator fibers constitute the accelerator center through which reflex effects, if any, take place. As a matter of fact, the location of these cells of origin has not been made out satisfactorily. The matter offers unusual difficulty on the experimental side, owing to the existence of the cardio-inhibitory center in the medulla and the absence of any entirely satisfactory method of distinguishing certainly between reflex acceleration through this center and through the accelerator center. * Hooker, "American Journal of Physiology," 19, 417, 1907. t Hering, " Centralblatt f. Physiol.," 1894, viii., 75. CHAPTER XXXI. THE RATE OF THE HEART BEAT AND ITS VARIA- TIONS UNDER NORMAL CONDITIONS. The rate of heart beat changes quickly in response to variations in either the internal or external conditions. Therein lies, in fact, the great value of the regulatory (inhibitory and accelerator) nerves. Through their agency, in large part, the pump of the circulation is reflexly adjusted to suit the changing needs of the organism and adapted more or less successfully to alterations in the external environment. The variations in the rate of beat may be considered under three general heads: (I) Fixed adjustments to the different mechanical conditions of the circulation. (II) Variations caused by reflex effects upon the inhibitory or accelerator nerves. (Ill) Variations caused by changes in the physical or chemical conditions of the blood. The Fixed Adjustments of Rate.— When we speak of the normal pulse rate we mean the rate in an adult when in a condition of mental and bodily repose. Examination shows that under these circumstances there are great individual variations. The average normal rate for man may be estimated at 70 beats per minute; for woman, 78 to 80 beats; but the normal rate for some individuals may be much lower (50) or much higher (90). Among the condi- tions for which the heart rate shows a certain constant fixed adapta- tion the following may be mentioned : Variations ivith Sex. — The average pulse rate in women is, as a rule, higher than that in men, and this difference seems to hold for all periods of life. Variations with Size. — Tall individuals have a slower pulse rate than short persons of the same age. Several observers have thought that they could detect a constant relationship between size and pulse rate. Thus, Volkmann believed that the pulse rate varies inversely as the five-ninth power of the height. In the same direction it is found that small animals, as a rule, have a higher pulse rate than larger ones. Thus, elephant, 25-28; horse and ox, 36-50; sheep, 60-80; dog, 100-120; rabbit, 150; mice, 700. The smaller the animal, speaking generally, the more rapid is the consumption of oxygen in its tissues, and the increased demand for oxygen is met by an acceleration of the flow, due to the quicker beat of the heart. According to Buchanan* the heart of the canary beats at the extraordinary rate of 1000 per minute. * Buchanan, "Science Progress," July, 1910. 588 THE RATE OF THE HEART BEAT 589 Variations with Age. — In line with the last condition it is found in man that the pulse rate is highest in infancy, sinks quite rapidly at first and then more slowly up to adult life, and rises again slightly in very old age at the time that the body undergoes a perceptible shrinkage. The most extensive data upon this point are found in the works of the older observers.* According to Guy, a condensed summary of the average results obtained at different periods of life, both sexes included, may be given as follows: At birth 140 Infancy 120 Childhood 100 Youth 90 Adult age 75 Old age 70 Extreme age 75-80 The Variations in Pulse Rate Effected through the In- hibitory and Accelerator Nerves. — Most of the sudden adaptive •changes of the heart rate come under this head. In the laboratory we find that stimulation of all sensory nerve trunks may affect the heart rate, in some cases increasing it, in others the reverse. In life we find that the pulse rate is very responsive to our changing sensations and especially to mental conditions that indicate deep interest or emotional excitement. In a previous paragraph (p. 585) the physiological cause of this effect has been discussed briefly. It may arise either from a reflex excitation of the accelerator nerves or a reflex inhibition of the tonic activity of the inhibitory nerves. The facts at present seem to indicate that both mechanisms are used. In addition to these reflexes associated with conscious states the heart is susceptible to reflex influences of a totally unconscious char- acter connected with the states of activity of the visceral organs. For example, after meals the heart-beat increases usually in rate and especially in force of beat, thereby counteracting the effect on blood-pressure of the large vascular dilatation in the intestinal area. Variations in Heart Rate with the Condition of Blood-pressure. — It has long been known that when the blood-pressure in the arteries falls the pulse rate increases and when it rises the pulse rate de- creases. Thus, the low< blood-pressure that is characteristic of the condition of surgical shock is associated with a very rapid rate of heart beat. There is a certain inverse relationship between pressure and rate which has the characteristics of a purposeful adaptation. The quicker pulse rate following upon the low pressure tends to increase the output of blood and raise the pressure. There was formerly much discussion as to whether this relationship is brought about by reflexes through the extrinsic nerves of the heart or whether it is due to some direct, perhaps mechanical, * See Volkmann, "Die Hamodynamik," p. 427, 1850; also Guy, article ■"Pulse" in Todd's "Cyclopaedia of Anatomy and Physiology," 1847-49. 590 CIRCULATION OF BLOOD AND LYMPH. effect upon the heart. The experiments of Newell Martin upon the isolated heart seem to have settled the matter satisfactorily.* By a method devised by him he kept dogs' hearts beating for many hours when isolated from all connections with the body except the lungs. Under these conditions it was found that even extreme variations in blood-pressure did not affect the heart rate. Consequently, the variation that does take place under normal conditions must be due to a stimulation of the cardiac nerves. A rise of pressure in the arteries may affect directly the cardio-inhibitorv center or it may affect afferent fibers in the heart or arteries, and thus reflexly stimulate the cardio-inhibitory center. This point has been the subject of a number of investigations, but Eyster and Hookerf appear to have demonstrated that both methods of stimulation occur. High arterial pressure affects the medullary center directly and thus slows the rate, but it affects also certain sensory fibers in the aorta at or beyond the arch, and through them causes a reflex slowing. Variations with Muscular Exercise. — It is a matter of everyday experience that the heart rate increases with muscular exercise. A simple change in posture, in fact, suffices to affect the heart rate. The rate is higher when standing (80) than when sitting (70) and higher in this latter condition than when lying down (66). Unusual exertion, as in running, causes a very marked and long-lasting increase in the pulse rate. The beneficial character of this adaptation is very evident. Increase in muscular activity calls for a more rapid circulation to supply the oxygen and other elements of nutrition, but the physiological mechanism by which this adaptation is obtained is not explained satisfactorily. Johans- son, J who has studied the matter carefully, concludes that the effect is due mainly to two causes: First, to the effect of the chem- ical products of metabolism in the active muscle, which are given off to the circulation and are then carried to the nerve centers where they affect the cardiac nerves, or possibly to an effect of these metabolic products on the heart directly. He considers this factor as of relatively subordinate importance. Second, the chief factor is found in an associated activity of the accelerator nerves. That is, the discharge of impulses along the voluntary motor paths (pyramidal) sets into activity at the same time and proportionally the center of the accelerator nerve fibers. Hering§ supports the latter part of this explanation to the extent of showing that the increase in heart rate after muscular exercise is dependent * Martin, "Studies from the Biological Laboratory, Johns Hopkins Uni- versity," 2, 213, 1882; also "Collected Physiological Papers," p. 25, 1895. t Eyster and Hooker, "American Journal of Physiology," 21, 373, 1908- % Johannson, "Skandinavisches Archiv f. Physiologic," 5, 20, 1895. % "Centralblatt f. Physiologie, " 8, 75, 1894. THE RATE OF THE HEART BEAT. 591 upon the integrity of the accelerator nerves. On the other hand, after prolonged or excessive muscular exertion the heart rate remains accelerated for a considerable period after cessation of the work — in the untrained individual at least — a fact which would indicate some long-lasting influence, such as is implied in the first factor given above, namely, the effect of the products of muscular metabolism. Variations with the Gaseous Conditions of the Blood. — In con- ditions of asphyxia the altered gaseous contents of the blood, increase in C02 and decrease in 02, act upon the medullary centers of the cardiac nerves, causing, first, an increase and then a decrease in heart rate. The Variations in Pulse Rate Due to Changes in the Composi- tion or Properties of the Blood. — - The condition under this head that has the most marked influence upon the heart rate is the temperature of the blood. Speaking generally, the rate of beat increases regularly with the temperature of the blood or other circulating liquid up to a cer- tain optimum temperature. On the heart of the cold-blooded animal this relationship is easily demonstrated by supplying the heart with an arti- ficial circulation of Ringer's solu- tion, which can be heated or cooled at pleasure. The rate and force of the beat increase to a maximum, which is reached at about 30° C. (see Fig. 247). Beyond this opti- mum temperature the beats decrease in force and also in rate, becoming irregular or fibrillar before the heart finally comes to rest. Newell Mar- tin* has shown the same relation- ship in a very conclusive way upon the isolated heart of the dog. Within physiological limits the rate of beat rises and falls substantially parallel to the variations in temperature as is shown by the chart reproduced in Fig. 248. The accelerated heart rate in fevers is therefore due probably to the * Martin, "Croonian Lecture, Philosophical Transactions, Royal Society," London, 174, 663, 1883; also "Collected Physiological Papers," p. 40, 1895. Fig. 247. — To show the effect of temperature on the rate and force of the heart beat. Contractions of the terrapin's ventricle at different tem- peratures. Kymograph moving at the same speed. At 30° the rate is still increasing, but the extent of con- traction has passed its optimum. 592 CIRCULATION OF BLOOD AND LYMPH. direct influence of the high temperature upon the heart itself. The same observer determined experimentally the upper and lower lethal limits of temperature for the mammalian heart. The experi- ments were made upon cats' hearts kept alive by artificial circu- lation through the coronary arteries.* It was found that the high- est temperature at which the heart will beat is about 44° to 45° C, fl 1 | 1 ■* — fS! V Ss- \ \ { \ ' \ \ \ / / , / / / f '* 1 lii i 1 *** \ \ j( 41 31 i ; ■t * . < ' 1 I 1 J 5 1 i 1 j i 1 \\ ■ 111 ? ^ t o « > * »» i » : i - to i* sir «■ /* it Lt cc le ti iz sz (7 I? 6/ it 1/ et ii 60 U> so £t> toil 19 If IS CI IS to U '• o B & c3 - O -^ £? £ M ° & ~rt2M_ c a> u.s e « 3 O. c gc goo ^'SiS &=> "3 C 0J ti c3 2 b! 8 I •£ 2 * £3 -> - « «1 O . o S 3 c) -is. a t) oa ja c3-a a a » ;*^w although a slightly higher temperature may be withstood under special conditions. At the other extreme the mammalian heart ceases to beat when the temperature falls as low as 17° to 18° C. The rate of the heart beat may be influenced also by many sub- stances added to the blood. The influence of atropin and muscarin * Martin and Applegarth, "Studies from the Biological Laboratory, Johns Hopkins University," 4, 275, 1890; also "Collected Physiological Papers," p. 97, 1895. THE RATE OF THE HEART BEAT. 593 has already been alluded to, but changes also in the normal con- stituents of the blood may have similar effects. Thus, an increase in the sodium carbonate of the blood affects the heart beat, particu- larly in regard to the amplitude or force of the contraction, while variations in the other inorganic constitutents may have a marked influence on the rate. The most significant and strik- ing fact in this connection is the relation of the potassium salts. As the amount of diffusible potassium is increased the pulse rate becomes slower and slower, until the heart stops in a con- dition of potassium inhibition. 38 CHAPTER XXXII. THE VASOMOTOR NERVES AND THEIR PHYSIO- LOGICAL ACTIVITY. During the first half of the nineteenth century the physical or mechanical conditions of the circulation were carefully studied and great emphasis was laid upon such properties as the elasticity of the coats of the vessels. The physical adaptability thereby con- ferred upon the vascular tubes was thought to be sufficient for the purposes of the circulation. We now know that many of the blood- vessels are supplied with motor and inhibitory nerve fibers through whose activity the size of the vascular bed and the distribution of blood to the various organs are regulated. We know, also, that without this nervous control the vascular system fails entirely to meet what seems to be the most important condition of a normal circulation, — namely, the maintenance of a high arterial pressure. Although a number of physiologists had assumed the existence of nerve fibers capable of acting upon the muscular coats of the blood- vessels, the experimental proof of the existence of such nerves, and the beginning of the modern development of the theory of vasomotor regulation were a part of the brilliant contributions to physiology made by Claude Bernard.* In 1851 Bernard discovered that when the sympathetic nerve is cut in the neck of a rabbit the blood-vessels in the ear on the same side become very much dilated. He and other observers afterward showed that if the peripheral (head) end of the severed nerve is stimulated electrically the ear becomes blanched, owing to a constriction of the blood-vessels. Thus the existence of vasoconstrictor nerve fibers to the blood-vessels was demonstrated. A vast amount of experimental work has been done since to ascertain the exact distribution of these fibers to the various organs and the reflex conditions under which they function normally. Few subjects in physiology are of more practical im- portance to the physician than that of vasomotor regulation; it plays such a large and constant part in the normal activity of the various organs. Bernard was doubly fortunate in being the first to demonstrate the existence of a second class of nerve fibers, which, when stimulated, cause a dilatation of the blood-vessels and which * See "Life of Claude Bernard," by Sir Michael Foster, 1899, in the series, "Masters of Medicine." 594 THE VASOMOTOR NERVES. 595 are therefore designated as vasodilator nerve fibers. This discovery was made in connection with the chorda tympani nerve, a branch of the facial, which sends secretory fibers to the submaxillary gland. When this nerve is cut and the peripheral end is stimulated a secre- tion of saliva results and at the same time, as Bernard showed, the blood-vessels of the gland dilate; the flow of blood is greatly in- creased in the efferent vein and may even show a pulse. In the nervous regulation of the blood-vessels we have to eon- sider, therefore, the existence and physiological activities of two antagonistic sets of nerve fibers: First, the vasoconstrictor fibers, whose action causes a contraction of the muscular coats of the ar- teries and therefore a diminution in the size of the vessels. Second, the vasodilator nerve fibers, whose action causes an increase in size of the blood-vessels, due probably to a relaxation (inhibition) of the muscular coats of the arteries. Before attempting to describe the present state of our knowledge upon these points it will be help- ful to refer to some of the methods by means of which the existence of vasomotor fibers has been demonstrated. Methods Used to Determine Vasomotor Action. — The simplest and most direct proof is obtained from mere inspection, when this is possible. If stimulation of the nerve to an organ causes it to blanch, the presence of vasoconstrictor fibers is dem- onstrated unless the organ is muscular and the blanching may be regarded as a mechanical result. On the other hand, if stimulation of the nerve to an organ causes it to become congested or flushed with blood the presence of vasodilator fibers may be accepted. It is obvious, however, that this method is applicable in only a few instances and that in no case does it lend itself to quantitative study. 2. Vasomotor effects may be determined by measur- ing the outflow of blood from the veins. If stimulation of the nerve to an organ causes a decrease in the flow of blood from the veins of that organ, this fact implies the existence of vasoconstrictor fibers, while an opposite result indicates vasodilator fibers. 3. By variations in arterial and venous pressures. When vaso- constrictor fibers are stimulated there is a rise of pressure in the artery supplying the organ and a fall of pressure in the veins emerging from the organ. This result is what we should expect if the constriction takes place in the region of the arterioles. The diminution in size of these vessels by increasing peripheral resistance augments the internal pressure on the arterial side of the resistance, and causes a fall of side pressure on the venous side (see p. 503). If the area involved is large enough the increased resistance will make a perceptible difference in pressure, not only in the organ supplied, but also in the aorta ; there will be a rise of general (dias- tolic) blood-pressure. On the other hand, a vasodilator action in 596 CIRCULATION OF BLOOD AND LYMPH. any organ is accompanied by the reverse changes. Peripheral resistance being diminished there will be a fall of pressure on the arterial side and a rise of pressure on the venous side. When, therefore, the stimulation of any nerve brings about a rise of arterial pressure that can not be referred to a change in the heart beat the inference made is that the result is due to a vasocon- striction. When the method is applied to a definite organ — the brain, for instance — it becomes conclusive only when simultaneous observations are made upon the pressure in the artery and the vein of the organ, and proof is obtained that the pressures at these points vary in opposite directions. 4. By observations upon the volume of the organ. It is obvious that, other conditions remaining un- changed, a vasoconstriction in an organ will be accompanied by a diminution in volume, and a vasodilatation by an increase in volume. This method of studying the blood-supply of an organ is designated as 'plethysmography, and any instrument designed to record the changes in volume of an organ is a -plethysmography* Plethysmographs have been designed for special organs, and in such cases they have sometimes been given special names. Thus, the plethysmograph used upon the kidney and spleen has been desig- nated as an oncometer, that for the heart, as a cardiometer. The precise form and structure of a plethysmograph varies, of course, with the organ studied, but the principle used is the same in all cases. The organ is inclosed in a box with rigid walls that have an opening at some one point only, and this opening is placed in connection with a recorde? of some kind by tubing with rigid walls. The connections between recorder and plethysmograph and the space in the interior of the latter not occupied by the organ may be filled with air or, as is more usually the case, with water. The idea of a plethysmograph may be illustrated by the skull. This structure forms a natural pelthysmograph for the brain. If a hole is bored through the skull at any point and a connection is then made with a recorder of some kind, such as a tambour, the volume changes of the brain may be registered successfully. The plethysmograph generally employed in laboratories, particularly for in- vestigations on man, is some modification of the form devised by Mosso (see Fig. 249). The hand and more or less of the arm is placed in a glass cylinder which is swung freely from a support. The opening around the arm is shut off by a cuff of rubber dam that must be chosen of such a size as to fit the arm snugly without compression of the superficial veins. The forward end of the plethysmograph is connected by tubing with a re- corder. Through appropriate openings the cylinder and connecting tubes are filled with warm water and then all openings are closed except the one leading to the recorder. Any increase in volume of the arm will drive water from the plethysmograph to the recorder, and any decrease, on * For a description of the development of this method, see Francois-Franck- Marey's "Travaux du Laboratoire, " 1876, p. 1. THE VASOMOTOR NERVES. 597 the contrary, will suck water from the recorder into the plethysmography In the author's laboratory a modification that has been found most conve- nient is represented in Fig. 250. To avoid escape of water at the upper end of the tube and at the same time to prevent compression of the veins of the arm a very thin rubber glove with long gauntlet is used. The gauntlet is strengthened by cuffs of dam tubing, as shown in the illustration, and all are reflected over the end of the plethysmograph. The outer cuff (3) may be omitted. The hand is inserted into the cylinder and is held in place by flexing the fingers through the rings. The plethysmograph being suspended freely from the ceiling, any movement of the arm will move the instrument as a whole without disturbing the position of the arm in the instrument. By means of rings of hard rubber (D,E), one fitting around the rim of the plethys- mograph and the other adapted more or less closely to the size of the forearm, the reflected portion of the gauntlet and cuff is held in place and prevented from giving way readily to any rise of pressure in the plethysmograph. The Fig. 249. — A schematic diagram of Mosso's plethysmograph for the arms: a, the glass cylinder for the arm, with rubber sleeve and two tubulatures for filling with warm water; s, the spiral spring swinging the test tube, t. The spring is so calibrated that the level of the liquid in the test tube above the arm remains unchanged as the tube is filled and emptied. The movements of the tube are recorded on a drum by the writing point, p. interior of the latter is connected, as shown in Fig. 249, to a test tube swung by a spiral spring (Bowditch's recorder) . The spring is so adjusted by trial that it sinks and rises exactly in proportion to the inflow or outflow of water. By this means the level of the water in the tube is kept constant, and since the posi- tion of this level determines the pressure upon the outside of the arm in the plethysmograph this pressure is also kept constant independently of the changes in volume of the arm. The level should be set in the beginning so as to make a slight positive pressure on the arm sufficient to flatten the thin glove to the skin and thus drive out the air between the two. When the apparatus is conveniently arranged, with slings to support the elbow, observations may be made upon the changes in volume of the arm during long periods. The results so obtained are referred to under several headings. With the form of recorder described the plethysmograph gives usually only the slow changes in volume of the arm, due to a greater or less amount of blood. By using a more sensitive recorder and making the con- 598 CIRCULATION OF BLOOD AND LYMPH Elections entirely rigid the .smaller, quicker changes in volume caused by the heart beat are also recorded. A volume pulse is obtained resembling in its general form the pressure pulse given by the sphygmograph. When used for this purpose the instrument is described as a hydrosphygmngraph. Records taken of the volume of the hand, foot, brain, or any- other organ show that in addition to the changes caused by the heart beat and by the respiratory movements, there are other more irregular variations that are continually occurring, the cause of which is to be found in the variations in the amount of blood in the organ. Day and night these changes in volume take place, and they are referable to the activity of the vasomotor system. Vasoconstriction or vasodilatation in the organ itself cause what may be called Fig. 250. — Detailed drawing of the class plethysmograph with the arrangement of rub- ber glove to prevent leaking without compressing the veins. 2, The glove with its gauntlet reflected over the end of the glass cylinder; 1 and 3, supporting pieces of stout rubber tub- ing: D and E, sections of outer and inner rings of hard rubber to fasten the reflected rubber tubing and reduce the opening for the arm. an active change in volume. But vasoconstriction or vasodilata- tion in other organs may cause a perceptible change, of a passive kind, in the volume of the organ under observation. For, since the amount of blood remains the same, a change in any one organ must affect more or less the volume — that is, the blood contents — of all other organs. General Distribution and Course of the Vasoconstrictor Nerve Fibers. — These fibers belong to the autonomic system, and consist, therefore, of a preganglionic fiber arising in the central nervous system and a postganglionic fiber arising from the cell of some sympathetic ganglion. The general arrangement of the auto- nomic system (p. 248) should be reviewed in this connection. It has been shown by experiments of the kind described under the last heading that vasoconstrictor fibers are present in numerous nerve THE VASOMOTOR NERVES. 599 trunks, but especially in those distributed to the skin and to the abdominal and pelvic organs. If, for instance, the sciatic or the splanchnic nerve be cut, to avoid reflex effects, and the peripheral end be stimulated, there will be a strong constriction of the vessels, which may be detected by ocular inspection, blanching; by the increase in arterial pressure ; or by the diminution in volume of the organs. The vasoconstrictor fibers supplying these two great regions arise immediately (postganglionic fibers) from one or other of the ganglia constituting the sympathetic chain, or from the large prevertebral ganglia (celiac ganglion, for instance) directly con- nected with it. Ultimately, of course, they arise in the central nervous system (preganglionic fiber), and it has been shown that, for the regions under consideration, the}' all, with a few compara- tively unimportant exceptions, leave the spinal cord in the great Fig. 251. — Schema to show the path of the preganglionic and postganglionic portions of a vasoconstrictor nerve fiber: a. Anterior root, showing the course of the preganglionic fiber as a dotted line ; d, v, dorsal and ventral branches of the spinal nerve ; r, the ramus communicans ; g, the sympathetic ganglion. The postganglionic fibers in each ramus come from the sympathetic ganglion with which it is connected. The preganglionic fibers enter- ing at any ganglion may pass up or down to end in the cells of some other ganglion. outflow that takes place in the thoracic region from the second thoracic to the second lumbar nerves (p. 250). In this outflow they are mixed with other autonomic fibers, such as the sweat fibers, pilomotor fibers, accelerator fibers to heart, pupilodilator fibers, visceromotor fibers, etc. Emerging in the anterior roots, they pass to the sympathetic chain by way of the corresponding ramus communicans. Having reached the chain, they end in one or other of the ganglia, not necessarily in the ganglion with which the ramus connects anatomically. The preganglionic fibers for the blood- vessels of the submaxillary gland, for instance, enter the first thoracic ganglion of the sympathetic chain, but do not actually terminate until they reach the superior cervical ganglion high in the neck. The postganglionic fibers arise in the ganglion in which the 600 CIRCULATION OF BLOOD AND LYMPH. preganglionic fibers terminate. Those destined to supply the skin of the trunk and extremities pass from the ganglion to the cor- responding spinal nerve by way of the ramus communicans (gray ramus) and after reaching the spinal nerve they are distributed with it to its corresponding region (Fig. 251). In the general region Fig. 252. — Vasomotor effect of stimulation of the splanchnic nerve — peripheral end— in the dog (Dawson): 1. The line of zero pressure ; 2, the line of the stimulating pen; on and off mark the beginning and end of the stimulation; 3, the time record in seconds; 4, the blood-pressure record (stimulation causes a marked ri.se of blood-pressure due to stimu- lation of vasoconstrictor fibers); 5, plethysmography tracing of the volume of the kidney (oncometer); stimulation of the splanchnic causes a diminution in volume of the kidney owing to the constriction of its arterioles. under consideration (lower cervical to upper lumbar) each ramus communicans between a spinal nerve and a sympathetic ganglion consists, therefore, of two parts, one (white ramus) of preganglionic fibers passing from the spinal nerve to the ganglion, the other (gray ramus) of postganglionic fibers coming from the ganglion to THE VASOMOTOR NERVES. 601 the spinal nerve for distribution to the peripheral tissues. It should be borne in mind that the fibers in the white ramus do not return to the spinal nerve by the gray portion of the same ramus, but passing upward or downward in the sympathetic chain return to some other spinal nerve as postganglionic fibers. In this way, therefore, it happens that the various intercostal nerves and the nerves of the brachial and sciatic plexus contain vasoconstrictor fibers as postganglionic or sympathetic fibers. On the other hand, the vasoconstrictor fibers destined for the great vascular region of the intestines and other abdominal viscera, after reaching the sym- pathetic chain by way of the white rami as preganglionic fibers, do not return to the spinal nerves by the gray rami. They leave the sympathetic chain, still as preganglionic fibers, in the branches of the splanchnic nerves and through them pass to the celiac ganglion, where they mainly end, and their path is continued by the post- ganglionic or sympathetic fibers arising from this ganglion. More specific information concerning the origin of the vasomotor fibers to the different organs is given in condensed form farther on. It is quite important in the beginning, however, to obtain a clear general conception of the paths taken by the constrictor fibers from their origin in the spinal cord to their termination, on the one hand, in the vessels of the skin, or, on the other, in the vessels of the abdominal and pelvic viscera. The Tonic Activity of the Vasoconstrictor Fibers. — A very important fact regarding the vasoconstrictor nerve fibers is that they are constantly in action to a greater or less extent. This fact is demonstrated by the simple experiment of cutting them. If the sympathetic nerve in the neck is cut in the rabbit the blood- vessels of the ear become dilated. If the splanchnic nerves on the two sides are cut the intestinal region becomes congested, and the effect in this case is so great that the general arterial pressure falls to a very low point. From these and numerous similar ex- periments we may conclude that normally the arteries — that is, the arterioles — are kept in a condition of tone by impulses received through the vasoconstrictor fibers. Cut these nerves and the arte- ries lose their tone and dilate, with the result that, the peripheral resistance being diminished, the lateral pressure falls on the arterial side and rises on the venous side. The relatively enormous effect upon aortic pressure caused by paralysis of the tone of the arteries in the splanchnic area shows that under normal conditions the peripheral resistance in this great area plays a predominant part in the maintenance of normal arterial pressure, and by the same reasoning variations in tone in the arteries of this region must play a very large part in the regulation of arterial pressure. The Vasoconstrictor Center. — As stated in the last two para- 602 CIRCULATION OF BLOOD AND LYMPH. graphs, the vasoconstrictor fibers emerge from the cord over a definite region, and they exhibit constant tonic activity. It has been shown, moreover, that if the cord be cut anywhere in the cervical region all of the constrictor fibers lose their tone; a great vascular dilatation results in both the splanchnic and skin areas. We may infer from this fact that the vasoconstrictor paths originate from nerve cells in the brain and that their tonic activity is to be traced to these cells. Such a group of cells exists in the medulla oblongata, and forms the vaso- constrictor center. The axons given off from these cells de- scend in the cervical cord and terminate at various levels in the anterior horn of gray mat- ter in the region from the upper thoracic to the upper lumbar spinal nerves. A spinal neuron continues the path as the pre- ganglionic vasoconstrictor fiber which terminates, as already described, in some sympathetic ganglion, whence the path is further continued by the post- ganglionic fiber. This arrange- ment of the constrictor paths is indicated schematically in Fig. 253. The exact location of the group of cells that plays the im- portant role of a vasoconstrictor center has not been determined histologically. The region has. however, been delimited roughly by physiological experiments. If the brain is cut through at the level of the midbrain there is no marked loss of vascular tone in the body at large. If, however, similar sections are made farther and farther back a point is reached at which vascular paralysis begins to be apparent and a point farther down at which this paralysis is as complete as it would be if the cervical cord were cut. Between these two points the vasoconstrictor center must lie. The careful experiments of this kind made by Dittmar* are now somewhat old. According *"Berichte d. Sachs. Akademie, Math.-phys. Klasse," 1873, p. 449. Fig. 2.5:5. — Schema to show the path of tlu> vasoconstrictor fibers from the vaso- constrictor center to the blood-vessels and the mechanism for the reflex stimulation of these fibers : v. c. The vasoconstrictor center; 1, the central neuron of the vaso- constrictor path; 2, the spinal neuron (preganglionic fiber); 3, the sympathetic neuron (postganglionic fiber); a, the arte- riole; 4, the sensory fibers of the posterior root making connections by collaterals with the vasoconstrictor .enter; 5, an in- tercentral fiber (efferent) acting upon the vasoconstrictor center. THE VASOMOTOR NERVES. 603 to his description, the center is bilateral, — that is, consists of a group of cells on each side, — and lies about the middle of the fourth ventricle in the tegmental region, in the neighborhood of the nucleus of the facial and of the superior olivary. In the rabbit it has a length of 3 mms., a breadth of 1 to 1.5 nuns., and lies about 2 to 2.5 mms. lateral to the mid-line. Assuming the existence of this group of cells, we must attribute to them functions of the first importance. Like other motor cells, they are capable of being stimulated refiexly and by this means the regulation of the blood- flow is largely controlled. Moreover, they are in constant activity, — due doubtless also to a constant reflex stimulus from the inflow of afferent impulses. The complete loss of this tonic influence would result in a complete vascular paralysis, the small arteries would be dilated, peripheral resistance would be greatly diminished, and the arterial pressure in the aorta would fall from a level of 100-150 mms. Hg to about 20 or 30 mms. Hg, — a pressure insuffi- cient to maintain the life of the organism. There seems to be no question now that in the condition known as surgical shock the loss of control by the vasomotor center, and the consequent vascular paralysis and fall of blood-pressure, are the chief symptoms of a serious character. We must conceive, also, that in this vasocon- strictor center the different cells are connected by definite paths with the vasoconstrictor fibers to the different regions of the body ; that some of the cells, for instance, control the activity of the fibers distributed to the intestinal area, and others govern the vessels of the skin. Under physiological conditions the different parts of the center may, of course, be acted upon separately. Vasoconstrictor Reflexes — Pressor and Depressor Nerve Fibers. — It is obvious that such a mechanism as that described above is susceptible of reflex stimulation through sensory nerves, and according to our general knowledge we should suppose that a, tonic center of this kind may have its tonicity increased (excita- tion) or decreased (inhibition). Numerous experiments in phys- iology warrant the view that both kinds of effects take place normally. Those afferent nerve fibers which when stimulated cause refiexly an excitation of the vasoconstrictor center, and therefore a peripheral vasoconstriction and rise of arterial pressure, are frequently designated as pressor fibers, or their effect upon the circulation is designated as a pressor effect. Those afferent fibers, on the contrary, which when stimulated cause a diminution in the tone of the vasoconstrictor center and therefore a periph- eral vasodilatation and fall of arterial pressure, are designated as dep?%essor nerve fibers, or their effect upon the circulation is a de- pressor effect. Pressor effects may be obtained by stimulation of almost any of the large nerves containing afferent fibers, but espe- 604 CIRCULATION OF BLOOD AND LYMPH. cially perhaps of the cutaneous nerves. And there is abundance of evidence to show that similar results can be obtained in man. The pressor effect manifests itself by a rise in general arterial pres- sure, if a sufficiently large region is involved, and by a diminution in size of the organ involved. On the other hand, depressor effects may also be obtained from stimulation of many of the large nerve trunks. If one stimulates the central end of the sciatic nerve, for example, one obtains a pressor effect on the circulation in most cases, but under certain conditions a marked depressor effect fol- lows the stimulation.* The simplest explanation of such a result is that the nerve trunks contain afferent fibers of both kinds. When we apply our electrodes to a nerve we stimulate every fiber in it and the actual result will depend upon which group of fibers exerts the stronger action, and this may vary with the condition Fig. 254. — Plethysmography curve of forearm. The volume of the arm was recorded by means of a counter-weighted tambour and the record shows the pulse wave^. A problem in mental arithmetic — the product of 24 by 43 —caused a marked constriction of the arm. of the nerve, the condition of the center, the anesthetic used, etc. Under normal conditions no such gross stimulation occurs. The pressor fibers are stimulated under some circumstances, the de- pressor fibers under others. For instance, when the skin is exposed i;o cold it is blanched not by a direct, but by a reflex, effect. The low temperature stimulates the sensory (cold) fibers in the skin, and the nerve impulses thus aroused reflexly stimulate the vaso- constrictor center, or a part of it, and cause blanching of the skin. Exposure to high temperatures, on the contrary, flushes the skin., and in this case we may suppose that the sensory impulses carried by the heat nerves inhibit the tone of the vasoconstrictor center and cause dilatation or flushing of the skin. So far as man is concerned, experiments made with the plethysmograph show very *See Hunt. "Journal of Physiology," 18,381, 1895. THE VASOMOTOR NERVES. 605 clearly that the vasoconstrictor center is easily affected in a pressor or depressor manner by psychical states or activities. Mental work, especially mental interest, however aroused, is followed by a constriction of the blood-vessels of the skin, — a pressor effect (see Fig. 254) ; and we may find an explanation of the value of the reflex in the supposition that the rise of arterial pressure thus produced A/VWy, J?^^ gC C*i Stirr... of Car olio- oppressor (far&Itc 13 ct Fig. 255. — Effect of stimulating the central end of the depressor nerve of the heart in a rabbit. The time record marks seconds. Ov and off mark the beginning and end of the stimulation. The blood-pressure rises slowly after the removal of the stimulus and eventually reaches the normal level. This complete recovery is not shown in the portion of the record reproduced. (Dawson.) forces more blood through the brain (p. 623). On the other hand, feelings of embarrassment or shame may be associated with a de- pressor effect, a dilatation in the vessels of the skin manifested, for example, in the act of blushing. In both cases we must assume intracentral nerve paths between the cortex and the center in the medulla, the impulses along one path exciting the center, while those along the other inhibit its tone, or, as explained below, excite 606 CIRCULATION* OF BLOOD AND LYMPH. a vasodilator center. Among the many depressor effects that have been observed on stimulation of afferent nerve fibers one has aroused especial interest — namely, that caused by certain afferent fibers from the heart or from the aorta. So far as the effect in question is concerned the physiological evidence indi- cates that the fibers arise from the descending aorta and it might be more appropriate to speak of them as the depressor nerve of the aorta.* These fibers in some animals — the dog, for instance — run in the vagus nerve, but in other animals, the rabbit, they form a separate nerve, the so-called depressor nerve of the heart — discovered by Ludwig and Cyon (1866). In the rabbit this nerve forms a branch of the vagus, arising high in the neck by two roots, one from the trunk of the vagus and one from the superior laryngeal branch. It runs toward the heart in the sheath with the vagus and the cervical sympa- thetic. The nerve is entirely afferent. If it is cut and the peripheral end is stimulated no result follows. If, however, the central end is stimulated a fall of blood-pressure occurs and also perhaps a slowing of the heart beat (see Fig. 255). The latter effect is due to a reflex stimulation of the cardio-inhibitory center and may be eliminated by previous section of the vagus. The fall of blood-pressure is explained by supposing that the nerve, when stimulated, inhibits, to a greater or less extent, the tonic activ- ity of the vasoconstrictor center, f Physiological experiments indicate that the nerve plays an important regulatory role. % When, for instance, blood-pressure rises above normal limits, it may be supposed that the endings of this nerve in the aorta or heart are stimulated by the mechanical effect, and the blood- pressure is thereby lowered by an inhibition of the tone of the con- strictor center. Moreover, it has been shown by Einthoven that every heart beat sends up this nerve a series of nerve impulses, that is, when the nerve is cut and the ends are connected with a string-galvanometer, electrical variations occur synchronous with the heart beat (Fig. 280). To explain this result we can only assume that each heart beat stimulates sensory endings in the heart itself or in the aorta, and that the nerve impulses thus transmitted to the medulla probably play a role in main- taining the tonic activity of some of its centers, perhaps, as Einthoven suggests, the tonic activity especially of the cardio- inhibitory center. * See Eyster and Hooker, ''American Journal of Physiology," 21, 373, 1908; also Koster and Tschermak, "Archiv f. die gesammte Physiologie, " 93, 24, 1902. t See Porter and Beyer, "American Journal of Physiology," 4, 283, 1900; also Bayliss, "Journal of Physiology," 14, 303, 1893. % Sewall and Steiner, "Journal of Physiology," 6, 162, 1885. THE VASOMOTOR NERVES. 607 A most suggestive example of the regulating action of the depressor nerve is given by Sewall. When the carotids in a rabbit are clamped a variable and not very large rise of arterial pressure is observed. If, however, the depressor nerves are first cut, clamping the carotids causes an extraordinary rise of arterial pressure. When the carotids are closed we may suppose that the resulting anemia of the medulla stimulates the vasoconstrictor center and thus tends to raise arterial pressure, but this effect is neutralized because as the pressure rises the depressor fibers of the heart are stimulated. It seems evident that during life the depressor fibers must exert a very important regulating effect upon the circulation. A similar nerve has been described anatomically in man, while in animals like the dog, in which it is not present as a separate anatomical structure, it probably exists within the trunk of the vagus. If this latter nerve is cut in the dog and the central end is stimulated a depressor effect is usually obtained. Vasoconstrictor Centers in the Spinal Cord. — From the description of the vasoconstrictor mechanism given above the probable inference may be made that throughout the thoracic region the cells of origin of the preganglionic fibers may, under special conditions; act as subordinate vasoconstrictor center- capable of giving reflexes and of exhibiting some tonic activity. Numerous experiments tend to support this inference When the spinal cord is cut_ in the lower thoracic region there is a paralysis of vascular tone in the posterior extremities. If, however, the animal is kept alive the vessels gradually re- cover their tone, although not connected with the medullary center. The re- sumption of tone in this case may be attributed to the nerve cells in the lower thoracic and upper lumbar region, since vascular paralysis is again produced when this portion of the cord is destroyed. Finally, CJoltz has shown that when the entire cord is destroyed, except the cervical region (p. 155), vascular tone may be restored finally in the blood-vessels affected. In this case the re- sumption of tonicity must be refened either to the properties of the muscular coats of the arteries themselves reacting to the stimulus of the internal pres- sure, or to the activity of the sympathetic nerve cells that give rise to the postganglionic fibers. Under normal conditions it seems quite clear that the great vasoconstrictor center in the medulla is the important seat of tonic and of reflex activity. If the connections of this center with the blood-vessels are destroyed suddenly — for example, by cutting the cervical cord — blood-pressure falls at once to such a low level, 20 "to 30 mms. Hg., that death usually results unless artificial means are employed to sustain the animal. Rhythmical Activity of the Vasoconstrictor Center. — Throughout life the vasoconstrictor center is in tone the intensity of which varies with the intensity and character of the reflex im- pulses playing upon it. Under certain unusual conditions the center may exhibit rhythmical variations in tonicity which make themselves visible as rhythmical rises and falls in the general arterial pressure (Fig. 256), the waves being much longer than those due to the respiratory movements. These waves of blood- pressure are observed often in experiments upon animals, ' but their ultimate cause is not understood. They are usually desig- nated as Traube-Hering waves, although this term, strictly speak- ing, belongs to waves, synchronous with the respiratory move- ments, that were observed by Traube upon animals in which the diaphragm was paralyzed and the thorax was opened. These latter waves are also due to a rhvthmical action of the 608 CIRCULATION OF BLOOD AND LYMPH. vasomotor center. During sleep, certain much longer, wave-like variations in the blood-pressure also occur that are again due doubt- less to a rhythmical change of tone in the vasoconstrictor center. Fig. 256. — Rhythmical vasomotor waves of blood-pressure in a dog (Traube-Hering waves). The upper tracing (1) is the blood-pressure record as taken with the mercury manometer; the lower tracing (2) is taken with a Hiirthle manometer. Seven distinct respiratory waves of blood-pressure may be recognized on each large wave. (Dawson.) General Course and Distribution of the Vasodilator Fibers. — By definition a vasodilator fiber is an efferent fiber which when stimulated causes a dilatation of the arteries in the region supplied. In searching for the existence of such fibers in the various nerve trunks physiologists have used all the methods referred to above, — namely, the flushing of the organ as seen by the eye, the increased blood-flow, the increase in volume, or the fall in blood-pressure on the arterial side associated with a rise on the venous side. By these methods vasodilator fibers have been demonstrated in the following regions : 1. In the facial nerve. The dilator fibers are found in the chorda tym- pani branch and are distributed to the salivary glands (submaxil- lary and sublingual) and to the anterior two-thirds of the tongue. 2. In the glossopharyngeal nerve. Supplies dilator fibers to the posterior third of tongue, tonsils, pharynx, parotid gland (tympanic nerve). 3. In the sympathetic chain. In the cervical portion of the sympathetic dilator fibers are carried which are distributed to the mucous mem- brane of the mouth (lips, gums, and palate), nostrils, and the skin of the cheeks. These fibers pass up the neck to the superior cervi- cal ganglion and thence by communicating branches reach the Gas- serian ganglion and are distributed to the bucco-facial region in the branches of the fifth cranial nerve.* From the thoracic portion of the sympathetic vasodilator fibers pass to the abdominal viscera by way of the splanchnic nerves and to the limbs by way of the branches of the brachial and lumbar plexuses, but the data regarding the dilator fibers for these regions are not as yet entirely satisfactory. Goltz and others have shown that dilator fibers are found in the nerves of the limbs, but the origin of these fibers from the sympa- thetic chain has not been demonstrated. * See "Kecherches experimentales sur le systeme nerveux vasomoteur, " Dastre and Morat, 1884. THE VASOMOTOR NERVES. 609 4. In the nervi ergentes. Eckhard first gave conclusive proof that tha erection of the penis is essentially a vasodilator phenomenon. The fibers arise from the first, second, and third sacral spinal nerves, pass to the hypogastric plexus as the nervi erigentes, and thence are dis- tributed to the erectile tissues of the penis. The General Properties of the Vasodilator Nerve Fibers. — Unlike the vasoconstrictors, the vasodilators are not in tonic activity; at least, no experimental proof has been given that they are. In the case of the erectile tissue of the penis and the dilators of the glands it would seem that the fibers are in activity only during the functional use of the organ, at which time they are excited refiexly. There has been much discussion in physiology as to the nature of the action of the dilator fibers. The muscular coat of the small arteries runs transversely to the length of the vessel, and it is easy to see that when stimulated to greater con- traction through the constrictor fibers it must cause a narrowing of the artery. It is not so evident how the nerve impulses carried by the dilator fibers bring about a widening of the artery. At one time peripheral sympathetic ganglia in the neighborhood of the arteries were used to aid in the explanation, but, since histo- logical evidence of the existence of such ganglia is lacking, the view that seems to meet with most favor at present is as follows: The dilator fibers end presumably in the muscle of the walls of the arteries, and when stimulated their impulses inhibit the tonic contraction of this musculature and thus indirectly bring about a relaxation. Dilatation caused by a vasodilator nerve fiber always presupposes therefore a previous condition of tonic contraction in the walls of the artery, this tonic condition being produced either by the action of vasoconstrictor fibers or possibly by the intrinsic properties of the muscle itself. In the nerves of the limbs, as stated above, both vasoconstrictor and vasodilator effects may be detected by stimulation. It has been shown that the separate fibers may be differentiated by certain differences in properties. Thus, if the peripheral end of the cut sciatic nerve is stimulated by rapidly repeated induction shocks a vasoconstrictor effect is obtained as shown plethysmographically by a diminution in volume of the limb. If, however, the same nerve is stimulated by slowly repeated induction shocks the dilator effect will predominate,* indicating a greater degree of irritability on the part of these latter fibers. After section of the sciatic nerve the vasodilators degen- erate more slowly than the vasoconstrictors, and they retain their irritability when heated or cooled for a longer time than the constrictors.! Vasodilator Center and Vasodilator Reflexes. — Since the * Bowditch and Warren, "Journal of Physiology," 7, 439, 1886. t Howell, Budgett, and Leonard. "Journal of Physiology," 16, 298, 1894. 39 610 CIRCULATION OF BLOOD AND LYMPH. vasodilator fibers form a system similar to that of the vasocon- strictors, it might be supposed that, like the latter, their activity is controlled from a general center, forming a vasodilator center in the brain similar to the vasoconstrictor center. What evidence we have, however, is against this view. In the dog with his spinal cord severed in the lower thoracic region the penis may show normal erection when the glans is stimulated, — a fact that indicates a reflex center for these dilator fibers in the lumbar cord. For the other clear cases of vasodilator fibers we have no reason at present to believe that they are all normally connected with a single group of nerve cells located in a definite part of the nervous system. The dilator fibers in the facial, glossopharyngeal, and cervical sympa- thetic (distributed through the trigeminal) all arise probably in the medulla, but not, so far as is known, from a common nucleus. Intimately connected with the question of the existence of a general vasodilator center is the possibility of definite reflex stimulation of the vasodilator fibers. As stated above, reflex dilatation of the blood-vessels may be produced by stimulating various nerve trunks containing afferent fibers. The depressor nerve fibers of the (heart give only this effect, and the sensory fibers from certain other regions, notably the middle ear and the testis, cause mainly, if not exclusively, a fall of arterial pressure due presumably to vascular dilatation. The sensoiy nerves of the trunk and limbs, when stimulated by the gross methods of the laboratory, give either reflex vasoconstriction or reflex vasodilatation, and, as was stated above, there is reason to believe that these trunks contain two kinds of afferent fibers, — the pressor and the depressor. The action of the former predominates usually, but in deep anesthesia, and particu- larly in those conditions of exposure and exhaustion that precede the appearance of " shock, " the depressor effect is more marked or, indeed, may be the only one obtained. To explain such depressor effects we have two possible theories. They may be due to reflex excitation of the centers giving origin to the vasodilator fibers or to reflex inhibition of the tonic activity of the vasoconstrictor centers. The latter explanation is the one usually given, especially for the typical and perhaps special effect of the depressor nerve of. the heart. This explanation seems justified by the general consideration that in the two great vascular areas through whose variations in capacity the blood-flow is chiefly regulated, — namely, the abdominal viscera and the skin, — the vasoconstrictor fibers are chiefly in evidence and are, moreover, in constant tonic activity. On the other hand, the fact that vasodilator fibers exist is presumptive evidence that they are stimulated reflexly, since it is by this means only that they can normally affect the blood-vessels. Some of the many depressor effects occurring in the body must be due, therefore, to reflex THE VASOMOTOR NERVES. 611 stimulation of the dilators and others to reflex inhibition of the constrictors. It would be convenient to retain the name depressor for the sensory fibers causing the latter effect, and to designate those of the former class by a different name, such as reflex vaso- dilator fibers.* Only experimental work can determine positively to which effect any given reflex dilatation is due, but provisionally at least it would seem justifiable to assume that dilatation by reflex stimulation of the vasodilator fibers occurs in those parts of the body in which vasodilator fibers are known to exist. Thus, the erection of the penis from stimulation of the glans may be explained in this way, also the congestion of the salivary glands during activity, the blushing of the face from emotions, and possibly the dilatation in the skeletal muscles during contraction. Gaskell and others have given reasons for believing that the vessels in the muscles are supplied with vasodilator nerve fibers, and Kleen f has shown that mechanical stimulation of the muscles — kneading, massage, etc. — causes a fall of arterial pressure. Vasodilatation Due to Antidromic Impulses. — The existence of definite effer- ent vasodilator fibers in the nerve trunks to the limbs has been made doubt- ful by the work of Bayliss. This author has discovered certain facts which at present tend to make the question of vasodilatation more obscure, but which, when fully understood, will doubtless give us a much deeper insight into the subject. Briefly stated, he has shownf that stimulation of the posterior roots of the nerves supplying the lumbo-sacral and the brachial plexus causes vas- cular dilatation in the corresponding limbs. He has given reasons for believing that the fibers involved are afferent fibers from the limbs and that, therefore, when stimulated they must conduct the impulses in a direction opposite to the normal — antidromic. It is most difficult to understand how such impulses, conveyed to the terminations of the sensory fibers, can affect the muscular tissue of the blood-vessels. It is most difficult to understand also how such anatomically afferent fibers can be stimulated reflexly in the cen- tral nervous system. Bayliss gives reasons for believing that the limbs receive no vasodilator fibers via the sympathetic system, and that either the blood-vessels in this region are lacking altogether in such fibers or else the afferent fibers function in the way described (see also p. 83). General Schema. — The main facts regarding the vasomotor apparatus may be summarized briefly in tabular form as follows: I. Vasoconstrictor fibers — distributed mainly to the skin and the abdominal viscera (splanch- nic area), all connected with a general center Efferent vasomotor ) f *he m.edulla oblongata, and in constant nerve fibers \ Ttonic activity. II. Vasodilator fibers — distributed especially to the erectile tissue, glands, bucco-facial region, and muscles; not connected with a general center and not in tonic activity. * See Hunt, "Journal of Physiology," 18, 381, 1895. t Kleen, " Skandinavisches Archiv f. Physiologic" 247, 1887. % Bayliss, "Journal of Physiology," 26, 173, 1900, and 28, 276, 1902. 612 CIRCULATION OF BLOOD AND LYMPH. I. Pressor fibers. Cause vascular constriction and rise of arterial pressure from reflex stimula- tion of the vasoconstrictor center — e. g., sensory nerves of skin. II. Depressor fibers. Cause vascular dilatation and Afferent fibers e-ivin? i ^a^ °^ ai"terial pressure from reflex inhibition v^m^r rpflpv*, of the tonic activity of the vasoconstrictor center, — e. g., depressor nerve of heart. III. Depressor (or reflex vasodilator) fibers. Cause vascular dilatation and fall of arterial pres- sure from stimulation of the vasodilator center, — e.g., erectile tissue, congestion of glands in functional activity. It may be supposed that under normal conditions the activity of this mechanism is adjusted so as to control the blood-flow through the different organs in proportion to their needs. When the blood- vessels of a given organ are constricted the flow through that organ is diminished, while that through the rest of the body is increased to a greater or less extent corresponding to the size of the area in- volved in the constriction. When the blood-vessels of a given organ are dilated the blood-flow through that organ is increased and that through the rest of the body diminished more or less. The adaptability of the vascular system is wonderfully complete, and is worked out mainly through the reflex activity of the nervous system exerted partly through the vasomotor fibers and partly through the regulatory nerves of the heart. Regulation of the Blood-supply by Chemical and Mechan- ical Stimuli. — From time to time attention has been called to the fact that the calibre of the blood-vessels may be influenced otherwise than through the agency of vasoconstrictor and vaso- dilator nerve fibers. Gaskell, for example, has shown that acids in slight concentration cause a vascular dilatation. Bayliss * has recently generalized the facts of this kind, and has suggested that in addition to the nervous regulation described in the preceding pages there may be formed chemical substances of a definite char- acter which exert a similar useful regulating action. As examples of this influence, we have the lactic acid produced in muscles during activity and probably also the carbon dioxid produced in this as in other tissues. These substances may act to produce a local dilatation during functional activity and thus provide the organ with more blood at the time that it is needed. On the other hand, the internal secretion of the adrenal glands (epinephrin) and possi- bly also of the infundibular portion of the pituitary gland have the reverse effect, causing a vasoconstriction and thus tending to maintain normal vascular tone. In a similar way it is probable that the distention of the arteries by internal pressure acts as a mechan- ical stimulus which leads to increased tone and thus aids in main- * Bayliss in "Ergebnisse der Physiologie," 1906, v., 319. THE VASOMOTOR NERVES. 613 taining a normal arterial tension. Therapeutically, various sub- stances may be introduced into the circulation which by chemical action cause a constriction or a dilatation of the peripheral arteries and thus raise or lower general blood pressure. In the former class of vasoconstricting reagents we have such substances as epinephrin, digitalis, etc., while in the latter class the nitrites, especially amyl nitrite (Brunton), have been much used, particularly in such condi- tions as angina pectoris, in which a quick relief from a state of vascular hypertension is desirable. CHAPTER XXXIII. THE VASOMOTOR SUPPLY OF THE DIFFERENT ORGANS. There are three important organs of the body — namely, the heart, the lungs, and the brain — in which the existence of a vaso- motor supply is still a matter of uncertainty. A very great deal of investigation has been attempted with reference to these organs, but the technical difficulties in each case are so great that no entirely satisfactory conclusion has been reached. A brief review of some of the experimental work on record will suffice to make evident the present condition of our knowledge. Vasomotors of the Heart. — The coronary vessels lie in or on the musculature of the heart. Any variation in the force of con- traction or tonicity of the heart muscle itself will therefore affect possibly the caliber of the arterioles and the rate of blood-flow in the coronary system. At each contraction of the ventricles the coro- nary circulation is probably interrupted by a compression of the smaller arteries and veins, and the size of these -vessels during dias- tole will naturally vary with the extent of relaxation of the cardiac muscle. Since stimulation of either of the efferent nerves supplying the heart, vagus and sympathetic, affects the condition of the mus- culature, it is evident at once how difficult it is to distinguish a simultaneous effect upon the coronary arteries, if any such exists. Newell Martin* found that stimulation of the vagus causes dilata- tion of the small arteries on the surface of the heart as seen through a hand lens. Moreover, when the heart is exposed and artificial respiration is stopped the arteries may be seen to dilate before the asphyxia causes any general rise of arterial pressure. Martin interpreted these observations to mean that the coronary arteries receive vasodilator fibers through the vagus. Porterf measured the outflow through the coronary veins in an isolated cat's heart kept alive by feeding it with blood through the coronary arteries. He found that this outflow is diminished when the vagus nerve is stimulated, and hence concluded that the vagus carries vasocon- strictor fibers to the heart. Maas % reports similar results also obtained from cats' hearts kept alive by an artificial circulation through the coronary arteries. Stimulation of the vagus slowed * Martin, " Transactions Medical and Chirurgical Faculty of Maryland," 1891. t Porter, " Boston Medical and Surgical Journal, " January 9, 1896. % Maas, " Archiv f. die gesammte Physiologie, " 74, 281, 1899. 614 VASOMOTOR SUPPLY OF THE ORGANS. 615 the stream (vasoconstrictor fibers), while stimulation of the sympathetic path quickened the flow (vasodilator fibers). Neither Maas nor Porter gives conclusive proof that the heart musculature was not affected by the stimulation. Wiggers reports* that the effect of adrenalin upon a heart perfused through the coronary arteries, but not beating, is to decrease the flow, while upon the beating heart this effect is reversed, owing to the action of the adrenalin upon the heart contractions. Schaefer,f on the contrary, gets entirely opposite results. When an artificial circulation was maintained through the coronary system and the amount of outflow was determined, he found that this quantity was not definitely influenced by stimulation of either the sympathetic or the vagus branches. Moreover, injection of adrenalin into the coronary circulation had no influence upon the outflow, and since this substance causes an extreme constriction in the vessels of organs provided with vasoconstrictor fibers, the author concludes that the coronary arteries have no vasomotor nerve fibers. It is evident from a consideration of these results that the existence of vasomotor fibers to the heart vessels is still a matter open to investigation. Vasomotors of the Pulmonary Arteries. — The pulmonary circulation is complete in itself and, as was stated on p. 510, it differs from the systemic circulation chiefly in that the peripheral resistance in the capillary area is much smaller. Consequently the arterial pressure in the pulmonary artery is small, while the velocity of the blood-flow is greater than in the systemic circuit, — that is, a larger portion of the energy of the contraction of the right ventricle is used in moving the blood. From the mechanical conditions present it is obvious that the pressure in the pulmonary artery might be increased by a vasoconstriction of the smaller lung arteries, or, on the other hand, by an increase in the blood- flow to the right ventricle through the venae cava?, or, last, bj back pressure from the left auricle when the left ventricle is not emptying itself as well as usual on account of high aortic pressure. While it is comparatively easy, therefore, to measure the pressure in the pulmonary artery, it is difficult, in the interpretation of the changes that occur, to exclude the possibility of the effects being due indirectly to the systemic circulation. Bradford and Dean, J by comparing carefully the simultaneous records of the pressures in the aorta and a branch of the pulmonary artery, came to the conclusion that the latter may be affected independently by stimu- lation of the third, fourth, and fifth thoracic spinal nerves, and hence concluded that these nerves contain vasoconstrictor fibers * Wiggers, "American Journal of Physiology," 1909. Proceedings of the American Physiological Society. t "Archives des sciences biologiques, " 11, suppl. volume, 251, 1905. j Bradford and Dean, " Journal of Physiology, " 16, 34, 1894. 616 CIRCULATION OF BLOOD AND LYMPH. to the pulmonary vessels, the course of the fibers being, in general, that taken by the accelerator fibers to the heart, namely, to the first thoracic sympathetic ganglion by the rami communicantes and thence to the pulmonary plexus. They give evidence to show that these fibers are stimulated during asphyxia. The authors state, however, that the effects obtained upon the pressure in the pulmonary artery are relatively and absolutely small as compared with the vasomotor effects in the aortic system. Similar results have been obtained by other observers (Francois-Franck). Using another and more direct method, Brodie and Dixon* have come to an opposite conclusion. These authors maintained an artificial circulation through the lungs and measured the rate of outflow when the nerves supplying the lungs were stimulated. Under these conditions stimulation of the vagus or the sympathetic caused no definite change in the rate of flow, — a result which would indicate that neither nerve conveys vasomotor fibers to the lung vessels. This conclusion was strengthened by the fact that in similar per- fusions made upon other organs (intestines) vasomotor effects were easily demonstrated. Moreover, adrenalin, pilocarpin, and mus- carin cause marked vasoconstriction when irrigated through the intestine, but have no such effect upon the vessels in the lungs. These authors conclude that the lung vessels have no vasomotor nerves at all, and their experimental evidence might be accepted as satisfactory except for the fact that a similar method in the hands of another observer has given opposite results. Plumierf finds that the outflow through a perfused lung is diminished in some cases by stimulation of the sympathetic branches to the lungs, and also by the use of adrenalin. Under such conditions it is necessary to defer a decision until more experiments are reported. Regarding the vasomotors of the lungs, one can only say, as in the case of the heart, that their existence has not been demonstrated. The Circulation in the Brain and Its Regulation. — The question of the existence of vasomotor nerves to the brain brings up necessarily the larger question of the special characteristics of the cranial circulation. The brain is contained in a rigid box so that its free expansion or contraction with variations in the amount of blood can not take place as in other organs and we have to con- sider in how far this fact modifies its circulation. The Arterial Supply of the Brain. — The brain is supplied through the two internal carotids and the two vertebfals, which together form the circle of Willis. It will be remembered also that the vertebral arteries give off the posterior and the anterior spinal arteries, which supply the spinal cord, and that the last-named artery makes anastomoses along the cord with the intercostal arteries * Brodie and Dixon, "Journal of Physiology," 30, 476, 1904. t Plunder, "Journal de physiologie et de pathologie g£ne>ale," 6, 665, 1904; see also "Archives internationales de physiologie," 1, 189, 1904. VASOMOTOR SUPPLY OF THE ORGANS. 617 and other branches from the descending aorta. From the ana- tomical arrangement alone it is evident that the circulation in the brain is very well protected from the possibility of being inter- rupted by the accidental closure of one or more of its arteries. In some animals, the dog, one can ligate both internal carotids and both vertebrals without causing unconsciousness or the death of the animal. In an animal under these conditions a collateral circula- tion must be brought into play through the anastomoses of the spinal arteries. In man, on the contrary, it is stated that ligation of both carotids is dangerous or fatal. The Venous Supply. — The venous system of the brain is peculiar, especially in the matter of the venous sinuses. These large spaces are contained between folds of the dura mater or, on the base of the skull, between the dura mater and the bone. The channel hollowed out in the bone is covered with a roof of tough, inex- tensible dura mater, and indeed in some animals the basal sinuses SjCulL. uusaTHatkr. PuLlliatZr. CerehrutrL. Fig. 257. — Diagram to represent the relations of the meningeal membranes of the cere- brum, the position of the subarachnoidal space and of the venous sinuses. may in part be entirely incased in bone. The larger cerebral veins open into these sinuses; the openings have no valves, but, on the contrary, are kept patent and protected from closure by the struc- ture of the dura mater around the orifice. The sinuses receive blood also from the veins of the pia mater, dura mater, and from the bones of the skull through the diploic veins. The venous blood emerges from the skull in man mainly through the opening of the lateral sinuses into the internal jugular vein, although there is also a communication in the orbit between the cavernous sinus and the ophthalmic veins through which the cranial blood may pass into the system of facial veins or vice versa, another communication with the venous plexuses of the cord, and a number of small emis- sary veins. In some of the lower animals — the dog, for instance — the main outflow is into the external jugular through what is known as the superior cerebral vein. A point of physiological interest is that the venous sinuses and their points of emergence from the skull are by their structure well protected from closure by compression. 618 CIRCULATION OF BLOOD AND LYMPH. The Meningeal Spaces. — The general arrangement of the menin- geal membranes, and particularly of the meningeal spaces, is im- portant in connection with the mechanics of the brain circulation. In the skull the dura mater adheres to the bone, the pia mater invests closely the surface of the brain, while between lies the arachnoid (Fig. 257). The capillary space between the arachnoid and the dura, the so-called subdural space, may be neglected. Between the arachnoid and the pip, mater, however, lies the sub- arachnoidal space more or less intersected by septa of connective tissue, but in free communication throughout the brain and cord. This subarachnoidal space is filled with a liquid, the cerebro- spinal liquid, which forms a pad inclosing the brain and cord on all sides. The liquid surrounding the cord is in free communication with that in the brain, as is indi- cated in the accompanying schematic figure (Fig. 258). Within the brain itself there are certain points at the an- gles and hollows of the differ- ent parts of the brain at which the subarachnoidal space is much enlarged, forming the so-called cisternse, which are in communication one with another by means of the less conspicuous canals (see Fig. 259). The whole system is also in direct communica- tion with the ventricles of the brain on the one hand, through the foramen of Magendie, the foramina of Luschka, and perhaps at other places, and on the other hand, along the cranial and spinal nerves it is continued outward in the tissue spaces of the sheaths of these nerves. The Pacchionian bodies constitute also a peculiar feature of the sub- arachnoidal space. These bodies occur in numbers that vary with the individual and with age, and are found along the sinuses, especially the superior longitudinal sinus. Each body is a minute, Mull. Bratru. Cerebrv-Jjbutal iSfnnal Column,, Dura ftlater. Ce retro Spinal liaucd. jJhinal Cord. Fig. 258. — Diagram to show the connec- tion of the subarachnoidal space in the brain and the cord. VASOMOTOR SUPPLY OF THE ORGANS. 619 pear-shaped protrusion of the arachnoidal membrane into the inte- rior of a sinus, as represented schematically in Fig. 260. Through these bodies the cerebrospinal liquid is brought into close •contact with the venous blood, the two being sepa- rated only by a thin layer -of dura and the very thin arachnoid. The number of the Pacchionian bodies is hardly sufficient to lead us to suppose that they have a special physiological impor- tance. The cerebrospinal liq- uid, found in the subarach- noidal space and the ventri- cles of the brain is a very thin, watery liquid having a specific gravity of only 1.007 to 1.008. It contains only traces of proteins and other ■organic substances, which may vary under pathological condi- tions. It is thinner and more watery than the lymph, resembling rather the aqueous humor of the eye. The amount of this fluid Fig. 259. — Diagram to show the location of the cisternse and canals of the subarach- noidal space. — (Poirier and Charpy.) Fig. 260. — Schema to show the relations of the Pacchionian bodies to the sinuses: d, d, Folds of the dura mater, inclosing a sinus between them J v.b., the blood in the sinus; n > \\ M M M V'v. f> . .. v ' 16fl.se Li-ne. .< Fig. 271. — Respiratory waves of blood-pressure. Typical blood-pressure record as taken with a mercury manometer: Bp the blood-pressure record, shows the separate heart beats and the larger respiratory waves, each of which comprises six to seven heart beats. nation of the occurrence of the respiratory waves of blood-pressure : (1) During inspiration there is an increased flow of blood into the right auricle (aspiratory action of inspiration). (2) During inspira- * For discussion and literature see de Jager, '' Archiv f. die gesammte Physiologie," 20, 426, 1879, and 27, 152, 1882; also "Journal of Physiology," 7, 130. „ 656 PHYSIOLOGY OF RESPIRATION. tion the capacity of the blood-vessels in the lungs is increased and also the velocity of the flow; consequently there is an increased volume of blood flowing through the lungs during inspiration. The increased capacity of the lung capillaries during the expansion of the lungs was shown experimentally by Heger and Spehl. They opened the anterior mediastinum without wounding the pleura and proved that if the lungs are tied off at the end of inspiration they con- tain more blood than when tied off at the end of expiration. The in- creased velocity of the blood-flow through the lungs during inspira- tion is explained by the fact that the greater negative pressure affects the thin-walled pulmonary veins more than the pulmonary artery; consequently the head of pressure driving the blood through the lungs,— that is, the difference in pressure between the blood in the pulmonary artery and veins — is increased. These data explain satisfactorily the general fact regarding the respiratory waves, — ■ namely, that during inspiration there is a rise of aortic pressure due to a greater output of blood from the heart, and during expiration Fig. 272. — Diagram to represent the time relation between the respiratory waves of blood-pressure and the respiratory movements (dog): A represents the blood-pressure record, showing the heart-beats and the larger respiratory waves. B represents a simul- taneous record of the respiratory movements. At the beginning of inspiration there is a fall of blood-pressure, but the final and main effect is a rise. At the beginning of expi- ration there is a rise of pressure, but the final and main effect is a fall. the reverse. To account for the subsidiary fact that at the begin- ning of inspiration the pressure falls and at the beginning of expira- tion it rises for a time two explanations are offered. De Jager refers these temporary effects to the changes in capacity of the blood- bed in the lungs. At the end of inspiration there is a certain ca- pacity of the l)ed; when expiration comes on, the lungs shrink, the capacity of the blood-vessels is thereby diminished, and consequently some blood is squeezed out of the lungs in the direction of least resistance, — that is, toward the left auricle. This accounts for the initial rise of pressure during expiration. At the beginning of inspi- ration, on the other hand, the sudden increase in capillary capacity in the lungs retards for a moment the flow of blood to the left auricle, and thus accounts for the temporary fall of pressure. Tigerstedt,* * See Tigerstedt, " Ergebnisse rter Physiologie," vol. ii, part II, 560, 1903. PRESSURE CONDITIONS IN LUNGS AND THORAX. 657 on the other hand, finds that shutting off the entire circulation of one lung may have little or no influence upon the pressure in the systemic circulation, and therefore doubts whether small changes in the capacity of the lung vessels can have any distinct effect on the inflow into the left auricle. He thinks that the main factor is the increased flow of blood to the right auricle during inspiration, and that this increased amount is then passed on to the left auricle and ventricle, but that this takes some little time, so that the true effect of inspiration is not felt in the aorta at the very beginning of the act. This delay may vary in different animals and may account for the fact that in some animals there is an apparent inversion of the relations to respiration, the aortic pressure falling throughout inspiration and rising during expiration. The increased rate of heart beat during inspiration varies as to its degree in different individuals. It has been shown by Fredericq that this change occurs when the chest is widely opened and the respiratory movements can have no mechanical effect upon the heart. He suggests, therefore, that the accelerated pulse during inspiration is due to an associated activity in the nerve centers of the medulla. When the inspiratory center discharges its efferent impulses into the phrenic nerves it also sends impulses by a sort of overflow into the neighboring cardio-inhibitory center. This latter cen- ter is, thereby, partially inhibited, its tonic effect on the heart is diminished, and the rate of the heart is increased. In artificial respiration carried out by means of a bellows — that is, by expanding the lungs with positive pressure — all the conditions of pressure in inspiration and expiration are reversed. During such an inspiration the flow of blood to the right heart, and through the lungs to the left heart, is decreased. Respirator}' waves of pressure are present under such conditions, but the rela- tions of rise and fall to the phases of respiration are reversed. 42 CHAPTER XXXVI. THE CHEMICAL AND PHYSICAL CHANGES IN THE AIR AND THE BLOOD CAUSED BY RESPIRATION. The Inspired and the Expired Air. — The inspired air, atmos- pheric air, varies in composition in different places. The essential constituents from a physiological standpoint are the oxygen, nitrogen, and carbon dioxid. The new elements — argon, krypton, etc. — have not been shown to have any physiological significance, and are included with the nitrogen. The accidental constituents of the air vary with the locality. In average figures, the composi- tion of this air is, in volume per cent.: nitrogen, 79; oxygen, 20.96; carbon dioxid, 0.04. The expired air varies in composition with the depth of the expiration and, of course, with the composition of the air inspired. Under normal conditions the expired air contains, in volume per cent. : nitrogen, 79; oxygen, 16.02; carbon dioxid, 4.38. In passing once into the lungs the air, therefore, gains 4.34 volumes of carbon dioxid to each hundred, and loses 4.94 volumes of oxygen. n. o. co2. Inspired 79 20.96 0.04 Expired 79 16.02 4.38 4.94 4.34 This table expresses the main fact of external respiration: the respired air loses oxygen and gains carbon dioxid and consequently the blood absorbs oxygen and eliminates carbon dioxid. It will be noted, also, that the volume of oxygen absorbed is greater than the vo'ume of carbon dioxid given off. This discrepancy is explained by the general fact that the oxygen absorbed is used in the long run to oxidize the carbon and also the hydrogen of the food; conse- quently, while most of it is eliminated in the expired air as carbon dioxid, some of it is excreted as water. For the sake of complete- ness it may be stated that traces of hydrogen and methane are also found in the expired air. They probably originate in the intestines from fermentation processes and are carried off in solution in the blood. Physical Changes in the Expired Air.— The expired air is warmed nearly or quite to the body temperature and is nearly saturated with water vapor. Since, as a rule, the air that we inspire is much cooler than the body and is far from being saturated with water vapor, it is evident that the act of respiration entails upon the body a loss of heat and of water. Breathing is, in fact, 658 CHANGES IN AIR AND BLOOD IN RESPIRATION. 659 one of the means by which the body temperature is regulated, although in man it is a subsidiary means. In other animals — the dog, for instance — panting is a very important aid in controlling the body heat. Heat is lost in respiration not simply in wanning the air in the air passages, but also by the evaporation of water in the alveoli, the conversion of water from the liquid to the gaseous form being attended by an absorption of heat. Breathing is also one of the means by which the water contents of the body are regulated. The water that we ingest or that is formed within the body is kept within certain limits, and this regulation is effected by the secretions of urine and sweat mainly, but in part also by the constant loss of water from the blood as it passes through the lungs. The Injurious Effect of Breathing Expired Air —Ventila- tion.— It is generally recognized that in badly ventilated rooms the air acquires a disagreeable odor, perceptible especially immediately on entering, and that persons remaining under such conditions for any length of time suffer from headache, depression, and a general feeling of uncomfortableness. It has been assumed, although without sufficient proof, that these effects are due to the vitiation of the atmosphere by the expired air. When the ventilation is very imperfect and the room greatly crowded death may result, as, for instance, in the historical case of the Black Hole of Calcutta. In extreme cases of this latter kind it is most probable that several causes combine to produce a fatal result. The conditions are such as to lead to a very large increase in carbon dioxid and dhninution of oxygen ia the respired air — a result which carried to a certain point will itself cause death; and in addition the air becomes heated to a high temperature and saturated with water vapor, both of these latter conditions preventing loss of heat from the body and producing a fever temperature. Under the or- dinary conditions of life poor ventilation produces its ob- viously evil results in rooms temporarily occupied — schools, churches, lecture rooms, theaters, etc., — and it is important to know what is the cause, and how it may be avoided. On the basis of older work it has been assumed that there is present in the expired air a volatile organic substance which when breathed again, possibly after having undergone some further change, exerts a toxic influence. The evil effects of badly ventilated rooms have been attributed mainly to this supposed substance. Unfortunately the investigations that have been made upon this substance are not altogether conclusive.* It seems to beclear that, when the expired air is condensed bypass- ing it into a cooled chamber, the water thus obtained, about 100 c.c. for 2500 liters of air, is clear, odorless, and has only a minute * See Haldane and Smith, "Journal of Pathology and Bacteriology, '*• 1, 168 and 318, 1893; Merkel, "Archiv f. Hygiene," 15, 1, 1892; Formanek, "Archiv f. Hygiene," 38, 1, 1900; Weichardt, ibid., 65, 252, 1908. 660 PHYSIOLOGY OF RESPIRATION. trace of organic matter. If this liquid with or without conden- sation is injected under the skin or into the blood-vessels no evil result follows, according to the testimony of the majority of observers. But it remains possible, of course, that the substance if present may be destroyed by this method or may escape precipi- tation in the condensed water. The experiment that gives the most positive indication of the existence of an organic (basic) poison in the expired air is the following, first performed by Brown- SSquard: A series of — say, five — bottles, each of a capacity of a liter or more, are connected together in train so that air can be drawn through them by an aspirator. A live mouse is placed in each bottle, and between bottles 4 and 5 an absorption tube is ar- ranged containing sulphuric acid. Under these conditions only the mouse in bottle 1 gets fresh air, those in the successive bottles get more and more impure air, while in bottle 5 this air is purified to the extent of removing the organic matter by passing it through sul- phuric acid. The result of such an experiment as described by some observers is that the mouse in bottle 4 dies after a certain num- ber of hours, the one in bottle 3 later, while those in the first and last bottles show no injurious effects. The obvious conclusion is that death in such cases is due to some organic toxic substance, and not to a mere increase of carbon dioxid, chemical analysis showing that this latter substance does not accumulate sufficiently under these conditions to cause a fatal result. Some other observers have failed to get this effect, but even assuming it to be correct it will be noted that the experiment gives no proof that the organic substance in question is excreted in the expired air. Indeed, the seemingly very careful experiments of Formanek make it probable that in these experiments the toxic substance is ammonia or an ammonia compound, which is not given off from the lungs, but from the decom- position of the urine and feces in the cage. When this latter source of contamination is removed the expired air is practically free from ammonia and without injurious effect. The expired air therefore, according to work of this character, contains no organic poison which can be regarded as a product of respiration. Some observers (Hermann, Haldane, and Smith) have made careful experiments upon men which also seem to throw much doubt upon the existence of a toxic substance in expired air. In- dividuals kept in a confined space for a number of hours show no evil effects except when the accumulation of the carbon dioxid has reached a concentration of over 4 per cent. At this concentration rapid breathing is apparent, and if it rises to 10 per cent, great distress is felt and the face becomes congested and blue. These authors conclude that expired air is injurious in itself only from the carbon dioxid it contains, and not because of any special poison. As opposed to these negative results, Weichardt reports CHANGES IN AIR AND BLOOD IN RESPIRATION. 661 a series of experiments upon mice in which the expired air of a number of animals was passed through acidulated water, and the latter was then condensed in a vacuum to a small volume and neutralized. When injected into a fresh animal this material brought on a soporific condition, fall of body tempera- ture, and diminution in output of carbon dioxid. The author ex- plains these results on the assumption that some of the so-called fatigue-toxin (kenotoxin) is excreted by way of the lungs, and he believes that the known depressing effects of poor ventilation are an expression of the action of this substance. This latter work needs confirmation and, at present, the definitely known evil results of breathing the air of crowded, poorly ventilated rooms must be referred to other possible causes, such as the increase in temper- ature and moisture. These two conditions cause depression and malaise even when an adequate supply of air is provided. It is possible, also, that the material given off from the skin in the per- spiration, sebaceous secretions, etc., may account sufficiently for the odor and, possibly, also for some of the general evil effects. If the ventilation is so poor that the carbon dioxid accumulates to the extent of 3 to 4 per cent., then this factor begins to exercise a direct effect upon the respiratory movements and the general condition, — an effect which increases as the percentage of carbon dioxid rises. Ventilation. — It is obvious from the foregoing statements that our knowledge is not yet sufficiently complete to enable us to say positively at what point air in a room becomes injurious to breathe, whether from products of expiration, or exhalation, or changes in temperature and moisture. The statement is frequently made in the books that, when the air contains as much as 1 per cent, of carbon dioxid (Smith) that has been produced by breathing, evil results, as judged by one's feelings, are sure to occur, but the ex- periments of Haldane and Smith seem to disprove this statement entirely. The practical rule in ventilation is to keep the air in chambers as nearly as possible of the composition of the atmosphere outside. Since carbon dioxid is the constituent of the air that is most easily determined the relative purity of room air is judged conveniently by quantitative estimations of this constituent. Or- dinary atmospheric air contains, on the average, 0.04 per cent, of carbon dioxid — that is, 4 parts to 10,000. The hygienists main- tain that the ventilation should be sufficiently ample to keep the carbon dioxid down to 6 parts per 10,000, thus leaving 2 parts per 10,000, 0.02 vol. per cent., as the permissible limit of vitia- tion by breathing. To determine on this basis the amount of air necessary for each person the following formula is used: d = ^j in which d represents in liters the delivery of fresh air per hour; e, the amount of C02 expired per hour in liters; and r the ratio of permissible vitiation of the air by C02. Assuming this (j(32 PHYSIOLOGY OF RESPIRATION. latter factor, in accordance with the above statement, to be equal to 0.02 per cent, and e to be equal to 20 liters per hour (500 X 0.04 X 17 X 60), the value of d is equal to 100,000 liters of air per hour for each person. The rapidity of renewal of air will depend naturally upon the cubic space allotted to each individual. The smaller this space, the more ample must be the ventilation. The following figures* give an idea of the values adopted for dif- ferent conditions. Amount of Ventilation Cubic Space per per Hour per Person Person in Cubic in Cubic Meters. Meters. Hospitals 60-100 30-50 Prisons 50 25 Factories 60-100 30-50 Barracks 30-50 15-25 Theaters 40-50 20-25 Halls and assembly rooms 30-60 1.5-30 Schools 15-20 7.5-10 Classrooms for adults 25-30 12-15 Systems of ventilation which have held in view simply this object of maintaining the air at an approximately normal com- position as regards the oxygen and the carbon dioxid have not proved entirely satisfactory in practical use, and probably for the reason that they have neglected to take into account the conditions as regards temperature and moisture. Laboratory experiments tend to show that individuals in a confined space may rebreathe air until its composition is noticeably altered in regard to the carbon dioxid and oxygen, and yet no distress be felt if provision is made for avoiding a rise in temperature and humidity, and, on the other hand, rooms may seem to be poorly ventilated, as judged by the sensations, when the renewal of air is sufficient to prevent an obvious change in its gaseous composition. The Gases of the Blood. — The gases that are contained in the blood are oxygen, carbon dioxid, and nitrogen. These gases may be extracted completely and in a condition for quantitative analysis, by means of some form of gas-pump. The principle of most of the gas-pumps used in the physiological laboratories is the same. The apparatus is arranged so that the blood to be examined is brought into a vacuum while kept at the temperature of the bod}'. Under these conditions all of the oxygen and nitrogen and part of the car- bon dioxid are given off and may be collected by suitable means. A portion of the carbon dioxid present in the blood is in such stable combination that to remove it it may be necessary to add some dilute acid, such as phosphoric acid. This portion of the carbon dioxid is designated in this connection as the fixed carbon dioxid. The principle of the gas pump may be explained most easily by describing the simple form devised by Grehant. The essential parts of this pump are * Taken from Bergey, "The Principles of Hygiene," 1904. CHANGES IN AIR AND BLOOD IN RESPIRATION. 663 represented in Fig. 273. The mercury pump consists of two bulbs, one mov- able (M), the other fixed (F). M may be raised and lowered by the windlass (P). Above F, there is a three-way stopcock (to) by means of which the chamber F may be put into communication with the outside air by way of C, or with the bulb B, which is to contain the blood, or may be shut off com- pletely. If M is raised so as to fill F entirely, and the stopcock to is shut off, then on lowering M the mercury will flow into it, leaving a perfect vacuum in F, since the distance between F and M is greater than the barometric height. If the stopcock to is turned so as to throw F into communication Fig. 273. — Gas pump for extracting the gases of blood (Grehant): M and F, The mercury receivers; P, the windlass for raising and lowering M; m, a three-way stopcock protected by a seal of mercury or water; C, a cup with mercury over which the receiving eudiometer is placed to collect the gases; B, the bulb in which, after a vacuum is made, the blood is introduced by the graduated syringe, S. By means of the stopcock m the vacuum in F, caused by the fall of the mercury, can be placed in communi- cation with B. After the gases have diffused over into F, M is raised, and when the stop- cock m is properly turned these gases are driven out through C into the receiving tube. The operation is repeated until no more gas is given off from B. with B, the chamber of this latter is brought under the influence of the vac- uum and any gases that it may contain will be distributed between B and F. If stopcock to is again turned off and M is raised, the gases in F will be condensed at its upper end, and by turning the stopcock to properly these gases may be forced to the outside by way of C or may be collected, if de- 664 PHYSIOLOGY OF RESPIRATION. sired, in a burette filled with mercury and inverted over the opening from F contained in the bottom of C. In performing an experiment the flask B, which is to contain the blood, is connected with F, as shownin the figure, all joints being protected from leakage by a seal of water outside, as shown at h, which represents a piece of wide rubber tubing filled with water so as to protect a joint between two pieces of glass tubing. B is next exhausted completely by raising and lowering M a number of times in the way described above until on throwing B into communication with a vacuum in F no further gas is given off. The last particles of air may be driven out from B by boil- ing a little water in it. After a complete vacuum has been established in B a measured amount of blood is introduced from a graduated syringe, S, as represented in the figure. This blood must be taken directly from the vessels of the animal and be introduced into B at once. B is kept immersed in water at the temperature of the body, and the bulb M is now raised and lowered a number of times so that the gases given off from the blood are drawn over into F and then by proper manipulation of the stop-cock are driven into a burette fastened over the opening of the tube in C. To drive off all of the carbon dioxid a little dilute phosphoric acid must be added to the blood in B by means of the syringe, S. The gases thus collected into the burette are first measured and are then analyzed for the three important constituents by some of the accepted gasometric methods. The principle involved is to absorb first from the mixture all of the C02 by introducing a solution of sodium or potassium hydrate. The reading of the volume left after this absorption is completed compared with the first reading gives the volume of C02. Next, a freshly made alkaline solution of pyrogallic acid is introduced into the tube. This solution absorbs all of the oxygen, whose volume is thus easily determined. The gas that is left unabsorbed after the action of these two solutions is nitro- gen. The volumes of gases are reduced, as is the custom, to unit pressure and temperature, — that is, to zero degree centigrade and 760 mms. barometric pressure. A correction must also be made for the tension or pressure exerted by the aqueous vapor hi the gases. These corrections are made by means of the following formula : V(B-T) 760 X (1 + 0.003665 1) in which I"1 represents the corrected volume, V the volume actually observed, B the barometric height at the time and place of the observation, T the aqueous tension at the temperature of the reading, and t the temperature in degrees centigrade. By means of such methods the gases in the blood have been de- termined. The quantities vary somewhat, of course, with the con- ditions of the animal and with the species of animal. In a quick analysis of dogs' arterial blood made by Pfluger the following figures were obtained reckoned in volumes per cent.: O, 22.6; C02, 34.3; N, 1.8. In this case each 100 c.c. of arterial blood contained 22.6 c.c. of O and 34.3 c.c. of C02 measured at O0 C. and 760 mms. Hg. An analysis of human blood (Setschenow) gave closely similar figures; O, 21.6 per cent.; C02J 40.3 per cent.; and N, 1.6 per cent. When the arterial and the venous bloods are compared it is found that the venous blood has more carbon dioxid and less oxygen. Average figures showing the difference in composition are as follows: o. co8. N. Arterial blood 20 38 1.7 Venous blood 12 45 1.7 Difference ."" 8 ~7 ~~0 CHANGES IN AIR AND BLOOD IN RESPIRATION. 665 The actual amounts of oxygen and carbon dioxid in the venous blood vary with the nutritive activity of the tissues, and differ therefore in the various organs according to the state of activity of each organ in relation to the volume of its blood supply. This point is well illustrated by some analyses made by Hill and Na- barro* of the gases in the venous blood from the brain and the muscles, respectively. Their average results when both tissues were at rest were as follows: Oxygen. Caebon Dioxid. Venous blood from limbs (femoral) .... 6.34 per cent. 45.75 per cent. " " " brain (torcular) . . . 13.49 " " 41.65 " " It will be seen that under similar conditions there is much less oxygen used and carbon dioxid formed in the brain than in the limbs (muscles). In the former organ the physiological oxidations must either be small compared with those of the muscles, or the brain tissues receive a relatively ample supply of blood, so that the tissue metabolism has less effect upon the blood composition. The venous blood as it comes to the lungs is a mixture of bloods from different organs, and its composition in gases will be constant only when the conditions of the body are kept uniform. Much work has been done in physiology to determine the condition in which these various gases are held in the blood. The results obtained show that they are held partly in solution and partly in chemical combination. To understand the part played by each factor and the conditions that control the exchange of gases in the lungs and tissues it is necessary to recall some facts regarding the physical and chemical properties of gases. The Pressure of Gases and the Terms Expressing these Pressures. — The air around us exists under a pressure of one atmosphere and this pressure is expressed usually in terms of the height of a column of mercury that it will support, — namely, a column of 760 mms. Hg, which is known as the normal barometric pressure at sea-level. Air is a mixture of gases, and according to the mechanical theory of gas-pressure each constituent exerts a pressure corresponding to the proportion of that gas present. In atmospheric air, therefore, the oxygen, being present to the extent of 20 per cent., exerts a pressure of A of an atmosphere or -^ X 760 = 152 mms. Hg. When we speak of one atmosphere of gas pressure, therefore, we mean a pressure equivalent to 760 mms. Hg, and in any given mixture the pressure exerted by any constituent may be expressed in percentages or fractions of an atmosphere, or in the equivalent height of the mercury column which it will support. Absorption of Gases in Liquids. — When a gas is brought into contact with a liquid with which it does not react chemically a certain number of the moving gaseous molecules penetrate the * Hill and Nabarro, "Journal of Physiology/' 18, 218, 1895. 666 PHYSIOLOGY OF RESPIRATION. liquid and become dissolved. Some of these dissolved molecules escape from the water from time to time, again becoming gaseous. It is evident, however, that if a liquid, water, is brought into contact with a gas under definite pressure, — that is, containing a definite number of molecules to a unit volume, — an equilibrium will be established. As many molecules will penetrate the liquid in a given time as escape from it, and the liquid will hold a definite number of the gas molecules in solution: it will be saturated for that pressure of gas. If the pressure of the gas is increased, how- ever, an equilibrium will be established at a higher level and more molecules of gas will be dissolved in the liquid. Experiments have shown, in accordance with this mechanical conception, that the amount of a given gas dissolved by a given liquid varies, the temper- ature remaining the same, directly with the pressure, — that is, it in- creases and decreases proportionally with the rise and fall of the gas pressure. This is the law of Henry. On the other hand, the amount of gas dissolved by a liquid varies inversely with the temperature. It follows, also, from the same mechanical views that in a mixture of gases each gas is dissolved in proportion to the pressure that it exerts, and not in proportion to the pressure of the mixture. Air consists, in round numbers, of 4 parts of N and 1 part of 0. Consequently, when a volume of water is exposed to the air the oxygen is dissolved according to its "partial pressure," — that is, under a pressure of -5- of an atmosphere (152 mms. Hg). The water will contain only A- as much oxygen as it would if exposed to a full atmosphere of oxygen — that is, to pure oxygen. And, on the other hand, if water has been saturated with oxygen at one atmosphere (760 mms.) of pressure and is then exposed to air, four-fifths of the dissolved oxygen will be given off, since the pressure of the surrounding oxygen has been diminished that much. Ab- sorption coefficient. By this term is meant the number that ex- presses the proportion of gas dissolved in a unit volume of the liquid under one atmosphere of pressure. The absorption coefficient will van-, of course, with the temperature. The gases that interest us in this connection are oxygen, nitrogen, and carbon dioxid. The absorption coefficients of these gases for the blood at the tempera- ture of the body are as follows: 0. 0.0262: X. 0.0130: CO,. 0.5283.* That is, 1 c.c. of blood at body temperature dissolves 0.0262 of 1 c.c. of oxygen if exposed to an atmosphere of pure oxygen, and so on. The solubility of the C02 is therefore twenty times as great as that of oxygen. Accepting these figures, we may calculate how much of these three gases can be held in the arterial blood in physical solution, provided we know the pressure of the gases in the alveoli of the lungs. The composition of the alveolar air will be discussed * As given by Bohr, the absorption coefficients of these three gases at 40° C. are as follows: Oxygen, 0.0231; nitrogen, 0.0118; carbon dioxid, 0.530. CHANGES IX AIR AND BLOOD EN RESPIRATION. 667 farther on, but we may assume at present that it contains 80 per cent, of nitrogen, 15 per cent, of oxygen, and 5 per cent, of carbon dioxid. In 100 c.c. of blood, therefore, the following amounts of these gases should be held in solution: Nitrogen 100 X 0.013 X 0.80 = 1.04 c.c. Oxvgen 100 X 0.0262 X 0.15 = 0.393 " Carbon dioxid 100 X 0.5283 X 0.05 = 2.64 " As will be seen from the analyses given above of the actual amounts of these gases obtained from the blood, the nitrogen alone is present in quantities corresponding to what would be expected if it is held in simple physical solution. The Tension or Pressure of Gases in Solution or Combi- nation.— When a gas is held in solution the equilibrium is de- stroyed if the pressure of this gas in the surroimding medium or atmosphere is changed. If this pressure is increased the liquid takes up more of the gas, and an equilibrium is established at a higher level. If the pressure is decreased the liquid gives off some of the gas. That pressure of the gas in the surrounding atmosphere at which equilibrium is established measures the tension of the gas in the liquid at that time. Thus, when a bowl of water is exposed to the air the tension of the oxygen in solution is 152 nuns. Hg; that of the nitrogen is 608 mms. Hg. If the same water is exposed to pure oxygen the tension of the oxygen in solution is equal to 760 mms. Hg, while that of the nitrogen sinks to zero if the gas that is given off from the water is removed. With compounds such as oxyhemoglobin the tension under which the oxygen is held is measured by the pressure of the gas in the sur- rounding atmosphere at which the compound neither takes up nor gives off oxygen. If, therefore, it is necessary to determine the tension of any gas held in solution or in dissociable combination it is sufficient to determine the percentage of that gas in the surrounding atmosphere and thus ascertain the partial pressure that it exerts. If the atmosphere contains 5 per cent, of a given gas the partial pressure exerted by it is equal to 38 mms. Hg (760 X 0.05). and this figure expresses the tension under which the gas is held in solution or combination in a liquid exposed to such an atmosphere. As regards the tension of the gases in arterial and venous blood, this procedure is, of course, not possible, since the blood is sur- rounded, not by an atmosphere whose composition can be analyzed, but by the liquids of the body, the lymph and cell juices. To determine the tension of the gases in the blood it is necessary to remove the blood from the vessels and bring it into contact with an atmosphere containing a known quantity of O. C02, or X. according to the gas to be measured. By trial an atmosphere can be obtained 668 PHYSIOLOGY OF RESPIRATION. in which this gas is contained in amounts such that there is no marked increase or decrease in quantity after standing in diffusion relations with the blood. The percentage of the gas in the atmo- sphere chosen will measure the tension of that gas in the blood. An instrument which has been much used for such determinations is represented diagrammatically in Fig. 274. It is known as an aerotonometer (Pfliiger). It con- sists of a tube (A) which can be connected through b directly with the blood-vessels. This tube A is surrounded by a jacket (C) con- taining warm water, so that the blood may be kept at the body temperature during the experi- ment. A is first completely filled with mercury from the bulb M to drive out the air. An atmosphere of known composition is then sucked into A by dropping the bulb. Blood is allowed to flow into A through the stopcock b and to trickle down the sides of the tube. Diffusion relations are set up between the blood and the known atmosphere, and after equi- librium has been established the gas is driven out through a into a convenient receiver and analyzed. If two aerotonometers are used, one containing the gas at some- what higher pressure than that expected, and the other at a some- what lower pressure, an average result is obtained which expresses with sufficient accuracy the pres- sure of the given gas in the blood. It is important not to confuse the tension at which a gas is held in a liquid with the volume of the gas. Thus, blood exposed to the air contains its oxygen under a tension of 152 mms. Hg, but the amount of oxygen is equal to 20 volumes per cent. Water exposed to the air contains its oxygen under the same tension, but the amount of gas in solution is less than 1 volume per cent. Tensions of gases in liquids are ex- pressed either in percentages of an atmosphere or in millimeters Fig. 274. — Diagram to show the principle of the aerotonometer: .4, The tube containing a known mixture of gases, O, CO2, N; C, the outside jacket for maintaining a constant body tem- perature. When stopcock b is open the blood trickles down the sides of A and enters into diffusion relations with the contained gases. After equilibrium is reached the stopcock u is closed and a is opened. By means of the mer- cury bulb the gases can then be forced out of A into a suitable receiver for analysis. CHANGES IN AIR AND BLOOD IN RESPIRATION. 669 of mercury. Thus, the tension of oxygen in arterial blood is found to be equal to about 13 per cent, of an atmosphere or 100 mms. Hg. (760X0.13). The Condition and Significance of the Nitrogen. — We may accept the view that the nitrogen of the blood is held in physical solution. The amount present corresponds with this view, and, moreover, it is found that the quantity varies directly with the pressure in accordance with the law given above. If an animal is permitted to breathe an atmosphere of oxygen and hydrogen the nitrogen disappears from the blood, and when ordinary air is breathed the nitrogen contents of the arterial and venous bloods exhibit no constant difference in quantity. It seems certain, there- fore, that the nitrogen plays no direct role in the physiological pro- cesses. It is absorbed by the blood in proportion to its partial pressure in the alveoli of the lungs and circulates in the blood in small amounts without exerting any immediate influence upon the tissues. Condition of Oxygen in the Blood. — That the oxygen is not held in the blood merely in solution is indicated, in the first place, by the large quantity present and, in the second place, by the fact that this quantity does not vary directly with the pressure in the surrounding medium. It is definitely known that by far the largest portion of the oxygen is held in chemical combination with the hemoglobin of the red corpuscles, while a much smaller portion, varying with the pressure, is held in solution in the plasma. The compound oxyhemoglobin possesses the important property that when the pressure of oxygen in the surrounding medium falls suffi- ciently it begins to dissociate and free oxygen is given off. The proc- ess of dissociation is facilitated also by increase of temperature, provided, of course, that it does not rise to the point of coagulating the hemoglobin. The amount of dissociation that takes place under different pressures of oxygen in the surrounding medium has been studied both for solutions of pure hemoglobin * and for defibrinated blood. t It would seem from recent work that the compound between oxygen and hemoglobin is more easily dissociated when the hemoglobin is in its natural condition in the corpuscles than when it has been crystallized out and obtained in pure solutions. The re- sults that have been obtained from experiments upon defibrinated blood probably represent, therefore, more nearly the conditions of dissociation in the body. The results obtained by Bohr are indicated in the curve of dissociation shown in Fig. 275, obtained from experiments on dog's blood. At a pressure of oxygen of 152 mms.— that is, when exposed to ordinary air — the hemoglobin * Hlifner, " Archiv f. Physiologie," suppl. volume, 1901, p. 213. f Loewy, "Archiv f. Physiologie," 1904, p. 245. 670 PHYSIOLOGY OF RESPIRATION. is nearly or completely saturated with oxygen. If the oxygen pressure is increased, — if, for instance, the blood is exposed to pure oxygen (pressure, 760 mms.),— no more oxygen is combined chemically by the hemoglobin. Additional oxygen will be taken up by the blood, but only in so far as it can pass into solution in the blood-plasma. Oxygen thus dissolved in the blood-plasma obeys the physical law of solution, and will be at once given off when the oxygen pressure of the surrounding medium is lowered. If the pressure of oxygen falls below that of the air (152 mms.) the chemi- cally combined oxyhemoglobin begins to dissociate slowly at first, but as the pressure falls below 70 mms, the dissociation becomes 100 90 1 J-d=5S^S JS5fc^===,*"J~ ■ RO i^ *r L*^"^ i ^^-"T 70 /[ 60 1 / / / / JO 40 / j 1 / In / / 111/ / 30 lli// 20 //// ' 10 III/ / 0 10 iO 30 40 50 60 70 80 90 100 110 1£0 130 140 150 160 Fig. 275. — Curves of dissociation of the oxyhemoglobin at different pressures of oxygen. Five curves are shown to indicate that the dissociation of the oxyhemoglobin is greatly influenced by the presence of COa. The figures along the ordinates (10 to 100) indicate percentages of saturation of the hemoglobin with oxygen, while the figures along the abscissa (0 to 160) indicate different pressures of oxygen.* The curve marked 5 mm. COa shows the amount of combination of oxygen and hemoglobin when the COo is absent or present only in traces. In this curve at a pressure of 30 mms. of oxygen it will be seen that the hemoglobin is 80 per cent, saturated with oxygen, while with a pressure of 40 mms. of CO2, which approximates that in the body, the hemoglobin at the same pressure of oxygen is only 50 per cent, saturated. (After Bohr.) much more rapid, and the oxygen thus liberated from chemical combination is from a quantitative standpoint much more impor- tant than that freed from solution in the plasma. This, in fact, is the process that takes place as the blood circulates through the tissues. The arterial blood enters the capillaries with its hemo- globin nearly saturated with oxygen, — about 19 c.c. to each 100 c.c. of blood. After it leaves the capillaries the venous blood contains only about 12 volumes of oxygen to each 100 c.c. of blood. In the passage of the capillaries, which takes only about one second, the blood loses, therefore, about 35 per cent, or more of its oxygen. The physical theory of respiration furnishes data to show that this loss is due to a dissociation of the oxyhemoglobin, owing to the fact CHANGES IN AIR AND BLOOD IN RESPIRATION. 671 that in passing through the capillaries the blood is brought into exchange with a surrounding medium — lymph, cell liquid — in which the oxygen pressure is very low. A fact of subsidiary importance in this connection is shown in the curves reproduced in Fig. 275. It will be noted in this figure that the dissociation of the oxyhemoglobin is facilitated by an increase in the pressure of the carbon dioxid. In the tissues where the oxyhemoglobin is broken up there is always a certain tension of carbon dioxid, a pressure which lies somewhere between 40 and 80 mms. of mercury, and the presence of this gas in this proportion probably helps the dissociation of the oxyhemoglobin to the extent shown by the curves in this figure. Condition of the Carbon Dioxid in the Blood. — The condition in which the carbon dioxid is held in the blood is not entirely understood. It has long been recognized that a certain small percentage is held in simple physical solution in the plasma and in the corpuscles, and that a certain additional amount, much larger than the preceding, is chemically combined with the alkali cf the blood as a carbonate, most probably as a bicarbonate (HNaC03). It has been suggested, in fact, that the carbon dioxid of the venous blood is carried chiefly as a bicarbonate and that in passing through the lungs this compound gives off some of its carbon dioxid and is converted into a carbonate, according to the equation 2HNaC03 = Na2C03-f C02 + H20. It is known, however, that an aqueous solution of bicarbonate of soda does not give off carbon dioxid when exposed to low pressures of the gas with anything like the facility shown by blood. Con- sequently it was further assumed that the proteins of blood, acting like weak acids, tend to combine with the alkali and that this additional factor suffices to explain the relative ease with which the bicarbonate as it exists in blood breaks up into carbon dioxid and carbonate. This theory has not proved to be com- pletely satisfactory. Other facts tend to show that the available alkali of the blood exists as bicarbonate in the arterial as well as in the venous blood, and, indeed, the total amount of the alkali in the blood in combination as carbonate or phosphate is not sufficient to account' for the quantity of carbon dioxid normally present. In recent years an additional possibility has been suggested by the discovery (Bohr) that carbon dioxid forms a dissociable compound with hemoglobin (p. 421), and the probability that a similar compound may be formed with the proteins of the plasma. Accepting this suggestion it would seem that the carbon dioxid exists in the blood in three forms. The amounts present in each form is estimated by Loewy* * Loewy, " Handbuch d. Biochemie," 1908, IV. 672 PHYSIOLOGY OF RESPIRATION. as follows: In each 100 c.c. of arterial blood, containing normally 40 volume per cent, of carbon dioxid, there is Physically absorbed in plasma and corpuscles 1.9 per cent. Held as sodium bicarbonate { P ^^^ [ [ £% \ ■ • 18.8 " " TT ,, • • i • .. (in corpuscles . . 7.51 in 0 « « Held in organic combination ^ jn p]g^mai X1 8 | - • 19-3 When serum or plasma is exposed to a vacuum at body tem- perature only a portion of the carbon dioxid is given off; to obtain the balance it is necessary to add acid to the liquid. This latter portion, liberated only by a stronger acid, is spoken of as the "fixed carbon dioxid." If instead of exposing serum or plasma to a vacuum one uses full blood, that is, plasma or serum plus corpuscles, all the carbon dioxid may be obtained without the necessity of adding acid. This fact has been explained on the supposition that the hemoglobin under these conditions plays the part of an acid in breaking up the compound in which the carbon dioxid is firmly held. Presumably this fixed carbon dioxid is the portion which in the above classification is repre- sented as bicarbonate. Since the portion that is held in organic combination is apparently more easily dissociated, it seems likely that it furnishes the main compound which is physio- logically useful in providing a means for the transportation of carbon dioxid from the tissues, where it is formed, to the lungs, where it is eliminated. The Physical Theory of Respiration. — The physical theory of respiration assumes that the gaseous exchange in the lungs and in the tissues takes place in accordance with the physical laws of diffusion of gases. If a permeable membrane separates two vol- umes of any gas, or two solutions of any gas at different pressures, the molecules of the gas will pass through the membrane in both directions until the pressure is equal on both sides. As the excess of movement is from the point of higher pressure to the point of lower pressure, attention is paid only to this side of the process, and we say that the gas diffuses from a point of high tension to one of lower tension. After equilibrium is established and the pressure is the same on both sides we must imagine that the diffusion is equal in both directions, and the condition is the same as though there were no further diffusion. In order for this theory to hold for the exchange in the body it must be shown that the physical conditions are such as it demands. Numerous experi- ments have been made, therefore, to determine the actual pressure of the oxygen and carbon dioxid in the venous blood as com- pared with the pressures of the same gases in the alveolar air, and the pressures in the arterial blood as compared with those in the CHANGES IN AIR AND BLOOD IN RESPIRATION. • 673 tissues. Although the actual figures obtained have varied some- what with the method used, the species or condition of the ani- mal, yet, on the whole, the results tend to support the physical theory. The Gaseous Exchange in the Lungs. — It is difficult to deter- mine the exact composition of the alveolar air. The expired air can, of course, be collected and analyzed, but obviously this is a mixture of the air in the bronchi and the alveoli, and consequently has more oxygen and less carbon dioxid than the air in the alveoli. The probable composition of the alveolar air has been calculated by Zuntz and Loewy for normal quiet breathing in the following way : The capacity of the bronchial tree is 140 c.c, and this air may be considered as similar in composition to atmospheric air, that is, the inspired air. A normal expiration contains 500 c.c; hence the alveolar air constitutes only 360 c.c. or |f of the entire amount. If the expired air contains 4.38 per cent, of CO,, then the alveolar air must contain 4.36 + If, or 6 per cent, of carbon dioxid. Or, to put the mode of calculation in a more general form, the amount of oxygen in the expired air is equal to the amount of oxygen in the true alveolar portion of the expired air plus the amount of oxygen in the "dead space," namely, the trachea and bronchi. Let A equal the volume of expired air, e the percentage of oxygen in the expired air, a the volume of air in the dead space, and i the percentage of oxygen in this air or what is the same thing in the inspired air. According to the above statement we have the fol- lowing equation, Ae = ai -f- (A — a) x, in which x represents the unknown percentage of oxygen in the alveolar air. We have: therefore, x = -*. In ordinary breathing these values are as follows: A — 500 c.c, a = 140 c.c, e = 16.02 per cent., and i — 20.96 per cent. Substituting these values, x will be found equal to 14.1 per cent. Reckoned in millimeters of mercury this would be equal to (760 X 0.141) 107.2 mm. In order, however, to ascertain the true pressure exerted by the oxygen allowance must be made for the baro- metric pressure and for the tension of the aqueous vapor. In the depths of the lungs the air is saturated with water vapor and the tension of this vapor at the body temperature may be valued at 46.6 mms. Hg. If we suppose further that the observation was made at a barometric pressure of 750 mms., then the pressure of the oxygen in the alveoli would be (750 — 46.6X0.141) 99+ mms. Hg. Actual observations made by these authors upon human beings in whom the expired air was analyzed indicate that the composition of the alveolar air may vary between the following limits: Oxygen between 11 and 17 per cent, of an atmosphere; carbon dioxid be- tween 3.7 and 5.5 per cent, of an atmosphere. Haldane and Priestley have devised a simple method by means of which the last portions of the air breathed out in an expiration may be col- lected. The sample thus collected represents practically the alveolar air, and its average composition may be given as oxygen, 14.5 per cent.; carbon dioxid, 5.5 per cent.; and nitrogen, 80 per cent. Loewy and von Schrotter have determined also the average ten- 43 674 PHYSIOLOGY OF RESPIRATION. sion of these gases in the blood of man. Their method* consisted in blocking off one lung or one lobe of a lung by a metal catheter inserted through the trachea. After the lapse of half an hour or so the gases in this occluded portion had reached an equilibrium by interchange with the venous blood which represented the tension actually existing in the circulating venous blood. A portion of this air was then withdrawn by means of a suitable device and was analyzed. Their average result was that in the venous blood the oxygen exists under a tension of 5.3 per cent, of an atmosphere ^710 X .053 = 37.6 mms. Hg), and the CO, under a tension of 6 per cent. (42.6 mms. Hg). The physical relations of pressure between the alveolar air and the gases in the venous blood may be represented as follows : Oxygen. Carbon Dioxid. Alveolar air 100 mms. 35 to 40 mms. Membrane \ ~ t ' Venous blood . . . 37,6 mms. 42.6 mms. Diffusion must take place, therefore, in the direction indicated by the arrows. As the oxygen passes through into the blood it is combined with the hemoglobin and it is estimated that the arterial blood as it flows away from the lungs is nearly saturated with oxygen, iacking perhaps only 1 volume per cent, of being completely saturated (Pfiuger). That is, if the normal arterial blood contains 19 c.c. of oxygen for each 100 c.c. of blood, it is probable that one more cubic centimeter might be combined by the hemoglobin if exposed fully to the air or oxygen. The difference in tension between the carbon dioxid on the two sides of the membrane is not so great as in the case of the oxygen, but owing to the more rapid diffusion of this gas it is probable that this difference suffices to explain the exchange. In this matter one must bear in mind also the very large expanse of surface offered by the lungs and the very complete subdivision of the mass of blood in the capillaries. Thus, following a calculation made by Zuntz, the surface of the human lungs may be estimated at 90 sq.ms. or 900,000 sq.cms. If we assume that 300 c.c. of carbon dioxid (500 X 0.04 X 15) are given off from the blood in a minute this would indicate a diffusion through each square centimeter of only 0.0003 c.c. (t^AVu)- This same idea is expanded by Loewy as follows: The surface of the lungs exposed to the air may be reckoned at 90 square meters, and the thick- ness of membrane intervening between this air and the blood in the capillaries may be estimated at 0.004 of a millimeter. Under these conditions as much as 6083 c.c. of oxygen might diffuse into the blood in a minute. As a matter of fact only about 250 to 300 c.c. of oxygen are really absorbed per minute in quiet breathing, and not more than ten times this amount in the violent * Loewy and von Schrotter, "Zeitschrift fiir experimentelle Pathologie und Therapie, " 1, 197, 1905. See also Loewy, " Handbuch der Biochemie," IV, 1908. CHANGES IN AIR AND BLOOD IN RESPIRATION. 675 respiration following excessive muscular exercise. It would seem, therefore, that diffusion should suffice to supply the oxygen actually needed. This reasoning applies a fortiori to the carbon dioxid, since the velocity of diffusion of this gas through a moist membrane is much (25 times) greater. If the tension of the C02 in the blood were only 0.03 mm. higher than that in the alveoli, the known exchange might be explained by diffusion. Exchange of Gases in the Tissues. — The arterial blood passes to the tissues nearly saturated with oxygen so far as the hemo- globin is concerned, and this oxygen is held under a tension equivalent probably to at least 100 mms. Hg. The carbon dioxid is less in quantity than on entering the lungs and exists under a smaller pressure, which may be assumed to be the same as that of the carbon dioxid in the alveoli of the lungs— namely, 5 per cent, of an atmosphere (35 mms.). In the systemic capil- laries the blood comes into diffusion relations with the tissues, and direct examination of the latter shows that the oxygen in them exists under a very small pressure, practically zero pres- sure, while the C02 is present under a tension (Strassburg) of 7 to 9 per cent. The high tension of the C02 is explained by the fact that it is being formed in the tissues constantly as a result of their metabolism, while the low tension of the oxygen is due to the fact that on entering the tissue this substance is combined in some way in a chemical compound too firm to dissociate. The physical conditions are, therefore, such as would cause a stream of C02 from tissue to blood and a stream of oxygen in the reverse direction. Oxygen. Carbon Dioxid. Arterial blood 100 mms. 35 mms. Wall of capillary I . ^ f Tissues 0 mm. 50 to 70 mms. It is to be remembered that in this exchange the blood and the lymph act as intermediaries. The C02 diffuses from lymph to plasma and from tissues to lymph. The oxygen diffuses from lymph to tissues, from plasma to lymph, and from oxyhemo- globin to plasma. Bohr* has found experimentally that in blood, when the oxygen tension is low, an increase in the C02 pressure tends to dissociate the oxyhemoglobin (Fig. 275). Since these conditions prevail in the capillaries of the body, it is probable that the mere presence of the C02 in increased amounts facilitates the liberation of the oxygen. Suggested Secretory Activity in the Respiratory Exchange.— The view that the exchange of gases in the lungs and tissues is entirely explained by the diffusion of the gases from points of high tension to points of low ten- * Skandinavisches Archiv f. Physiologie," 16, 402, 1896. 676 PHYSIOLOGY OF RESPIRATION. sion, and, that the membranes interposed are entirely passive in the process has not passed unchallenged. Certain observers (Bohr, Haldane and Smith)* claim that the tension of the oxygen in the arterial blood may be higher than the pressure of oxygen in the alveolar air. Bohr, moreover, in a series of experiments made upon dogs f determined by calculation the tension of oxygen within the surface layer of the lungs. This tension was found to vary lrom 35 to 105 mms. The tension of the arterial blood, determined at the same time, varied from 101 to 144 mms., being in every case distinctly higher than the tension of the oxygen in the surface layer of the lungs. If these facts were fully demonstrated they would show that the physical theory outlined above is insufficient, and would indicate that the membranes concerned take an active part in the passage of the gases, exerting possibly a secretory activity. That the cells of these membranes might secrete the gases is not at all impos- sible, but at present it seems to be unnecessary to make such a supposition. The results obtained by the observers mentioned in this paragraph have not been corroborated by the numerous other observers who have worked in the same field, and it seems possible that they may be due to experimental errors. A well-known set of experiments that strengthen this conclusion has been reported by Wolffberg and by NussbaumJ and has since been repeated upon man. In these experiments one bronchus in a dog was completely blocked by a specially designed lung catheter, so arranged as to occlude the bronchus and yet allow the observer to draw off a specimen of the air at any time. In such an occluded lung the captured air is in diffusion relations with the venous blood of the pulmonary artery, and if these relations are maintained for a sufficient time an equilibrium should be established on the physical theory, the tension of the gases in the occluded lungs becoming the tame as in the venous blood. Such was found to be the case. When at the end of the experiment air was drawn off and analyzed it was found to contain 3.6 per cent, of C02, while the tension of the CO., in specimens of the venous blood taken from the Yight heart was practically identical. If there is an active secretion of C02 from the lungs one should have expected to obtain a higher tension in the carbon dioxid of the alveolar air than in the venous blood. * See Haldane and Smith, " Journal of Physiology," 20, 497, 1896. t Bohr, in Nagel's " Handbuch der Physiologie des Menschen," 1897, vol. i, part 1, p. 146. t "Archiv f. die gesammte Physiologie," 4, 465, 1871, and 7, 296, 1873. CHAPTER XXXVII. INNERVATION OF THE RESPIRATORY MOVEMENTS. The nervous supply to the respiratory muscles is received from a number of nerves, the nervous machinery being widely dis- tributed in the brain and cord. The most important of the motor nerves of respiration is the phrenic, which supplies the diaphragm and originates from the fourth and fifth cervical spinal nerves. The N. accessorius and branches of the cervical and brachial plexus innervate the muscles of the neck and shoulder which are concerned in inspiration; the intercostals innervate the muscles of the thorax and abdomen, while branches of the lumbar plexus send fibers to the muscles of the groin. Moreover, the facial sends motor branches to the muscles of the nose and the vagus supplies the muscles of the larynx. All of these muscles belong to the skeletal group and are under voluntary control. Under normal conditions, however, this entire respiratory apparatus works rhythmically without voluntary control, in alternate inspirations and expirations, all the inspiratory muscles contracting together, and all the expiratory muscles together in their turn when the expirations are active. The co-ordinated activity of such an ex- tensive mechanism is explained by the existence of a respiratory center in the medulla oblongata. The Respiratory Center. — The discovery of the location of the respiratory center was due mainly to the experiments of two French physiologists, Legallois and Flourens. The latter placed the center in the medulla at the level of the calamus scriptorius, and described it as a very small area or spot, which he designated at first as the vital knot (nceud vital) under the mistaken impression that it formed, as it were, a central or focal point of the motor system. It has since been shown that this center, like the vasomotor center, is bilateral. If the medulla is cut through in the mid- line the respirations may proceed in a normal manner. The center consists of two parts, each connected primarily with the muscula- ture of its own side. Each half occupies an area that lies some distance lateral to the mid-line and beneath the floor of the medulla at the general level of the calamus. According to Gierke,* the area extends in rabbits from a point 3 or 4 mms. in front of, to a point 2 or 3 mms. posterior to the calamus. No especial group of cells can be found in this region sufficiently separated anatomically to make it probable that they constitute the center in question. The * Gierke, " Archiv f. die gesammte Physiologie," 7, 583, 1873; and "Cen- tralblatt f. d. med. Wissenschaften," No. 34, 1885. 677 678 PHYSIOLOGY OF RESPIRATION. region has been delimited by vivisection experiments only, and. according to Gierke, corresponds in location to the position of the solitary bundle (tractus solitarius). According to Mislawsky * it lies near the mid-line in the formatio reticularis, while Gadf gives it a relatively large area in the lateral portion of the formatio reticularis, the continuation into the medulla of the lateral horn of the gray matter of the cord. Destruction of these areas or section of the cord anywhere between this region and the origin of the phrenic nerve cuts off the respiratory movements, except those of the nose and larynx, and causes death. The rapid death from injuries to the cord or medulla in this region — from hanging, for instance — is explained by the effect upon the respirator}- center or its connections. There is no doubt that the respiratory center in man occupies the same general position as in the other mammals. There is on record a casej in which sect ions were made of the medulla in a new-born infant . On delivery it was necessary to puncture the cranium and remove the brain. The child still lived and the medulla was cut across with scissors. A section at the posterior end of the calamus stopped the respirations immediately, while one somewhat anterior had failed to have this effect. The general idea of the connections of this center with the respir- atory muscles may be described as follows: The respiratory fibers arising in the center pass down the cord, probably in the antero- lateral columns, and end in the gray matter of the cord at the different levels at which the motor nuclei of the respiratory nerves are situated. It is probable that these descending fibers decus- sate in part, so that each half of the respiratory center is con- nected with the musculature of both sides of the chest and the diaphragm. A connection of this kind is indicated by the fact that section of one-half of the medulla at the lower end of the fourth ventricle is followed not by a paralysis, but only by a weakening of the action of the respiratory muscles on that side. Whether the connection between the respiratory center and the spinal motor nuclei is made by one or by a series of neurons is not known, but we may assert that the nerve path from the respiratory center to the respiratory muscles must be composed of at least two neurons. According to this conception, the impulses of inspiration and expiration for the entire respira- tory mechanism originate in the medullary center and are thence distributed in a co-ordinated way to the lower motor centers in the cord, or, in the case of the nose and larynx, to the motor centers of the vagus and facial. Spinal Respiratory Centers. — At different times various authors (Brown-Sequard, Langendorff, et al.) have insisted that there exist one or * Mislawsky, ('entralblatt f. die med. "Wissenschaften," No. 27, 1885. t Gad, "Archiv f. Physiologie," 1893, p. 75. X See Kehrer, " Monatshefte f. prakt. Dermatol.," 28, 450, 1892. INNERVATION OF THE RESPIRATORY MOVEMENTS. 679 more spinal respiratory centers, and that the medullary center has not the commanding importance indicated in the above description. The fact that, when the medulla or cervical cord below the medulla is cut, the animal at once ceases to breathe is explained by these authors on the assumption that the operation causes a prolonged inhibition of the underlying spinal centers. They state that young animals, especially if made hyperirritable by the in- jection of strychnin, may continue to breathe after section of the cord below the medulla. This point of view, however, has not prevailed in physiology. Other operations on the cord or brain are not attended by such profound inhibition, and indeed Porter and Miihlberg have shown* that, if half of the cord alone is cut, the movements of the diaphragm on that side are permanently paralyzed. It is entirely conceivable that under exceptional conditions the lower neurons, the direct motor centers of the respiratory muscles, might be made to act rhythmically, since during life they have been rhythmically stim- ulated from the medullary center ; but the evidence at present is altogether against any distinct physiological independence on the part of those neurons. The Automatic Activity of the Respiratory Center. — The constant activity of the respiratory center throughout life suggests the question as to its automaticity. Is it automatic like the heart? That is, are the stimuli discharged from it produced within its own cells as a result of its own metabolism under the normal conditions of circulation? Or, on the other hand, is it, like most of the motor nuclei of the central nervous system, only a reflex center, its motor discharges being dependent upon impulses received from other neurons by way of the sensory paths? Obviously the only way to answer such a question directly is to isolate the center from all afferent paths and leave it connected with the respiratory muscles only by motor nerves. If under such conditions the respiratory rhythm continues the center may be regarded as essentially auto- matic, however susceptible it may be to reflex influences. A close approximation at least has been made to such an experiment. Rosenthal finds that rhythmical respiratory movements continue after the following operations: first, section of the brain at the cor- pora quadrigemina to cut off influences from the cerebrum, thala- mus, and midbrain; second, section of the vagi, to shut off afferent impulses from the viscera, especially from the lungs; third, section of the cord at the seventh cervical vertebra to exclude sensory influences through all the underlying posterior roots; and, fourth, section of the posterior roots of the cervical spinal nerves. The medulla with its respiratory center was thus isolated from all afferent impulses except such as might enter through the fifth, seventh, eighth, and ninth cranial nerves. Since under these con- ditions the center continued to act rhythmically we may draw the probable conclusion that it is essentially automatic, and that it probably possesses an intrinsic rhythmical activity resembling that of the heart. Reflex Stimulation of the Center. — According to the results of numerous observers, stimulation of any of the sensory nerves of the body may affect the rate or the amplitude of the respiratory * " American Journal of Physiology, " 4, 334, 1900. 6S0 PHYSIOLOGY OF RESPIRATION. movements. This experimental result is confirmed by our own experience, since every one must have noticed that the respiratory movements are readily affected by strong stimulation of the cutane- ous nerves — a dash of cold water, for example — as well as through the nerves of sight and hearing. In addition, emotional states are apt to be accompanied by notice- able changes in the respirations, and corresponding to this fact experiment shows that stimula- tion of certain portions of the cor- tex and midbrain gives distinct effects upon the respiratory cen- ter. We must assume, therefore, that this center is in connection with the sensory fibers of per- haps all of the cranial and spinal nerves, and is influenced also by intracentral paths passing from cerebrum to medulla, paths which are efferent as regards the cere- brum, but afferent as regards the medulla. As stated above, the effect of these sensory nerves upon the activity of the respiratory center is varied ; the rate ma> Fig. 276. — To show the augmenta- tion of the respiratory movements caused by stimulation of the sciatic nerve. Ex« periment upon a rabbit. Fig. 277. — To show the inhibition of the respiratory movements in a rabbit due to stimulation of the central end of the vagus. The respiratory movements in this ca-«. before and after stimulation, were forced, owing to the fact that both vagi were cut. be changed together with an increased or decreased amplitude, the inspirations and expirations may each be increased, or one phase INNERVATION OF THE RESPIRATORY MOVEMENTS. 681 may be affected more markedly than the other. In general, how- ever, experimental stimulation of a sensory nerve trunk which con- tains cutaneous fibers gives one of two effects: either a stimulating action, manifested by quicker, stronger inspirations and active ex- pirations, or an inhibitory effect, in which the respirations cease altogether or become slower and more feeble (Figs. 276 and 277). If in this, as in other similar cases, we assume that the two oppo- site effects are produced by different nerve fibers we may speak of sensory fibers which have a stimulating or augmenting effect, and of those that have an inhibiting influence on the center, or following the terminology used in the case of the vasomotor center, we may speak of respiratory pressor and respiratory depressor fibers. It is quite probable that these fibers have other functions, — that is, they are not distributed exclusively to the respiratory center. A cuta- neous fiber, which through its central chain of neurons eventually ends in the cortex cerebri and gives us a sensation of pain, may by collateral connections affect also the medullary center and pro- duce effects upon the heart, blood-vessels, and respirations. The Special Relations of the Afferent Fibers of the Vagus to the Center. — Although the sensory nerves in general exert a reflex effect upon the respiratory center, experimental work has shown that the sensory fibers distributed along the respiratory passages from the anterior nares to the alveoli have a specially important relation to this center. This fact is most clearly shown in the case of the sensory fibers of the vagus, which are distributed to the lungs themselves. If the two vagi are cut in the neck the respiratory movements are at once altered in character; they show a much slower rhythm and greater amplitude (Fig. 278). The inspirations especially are deeper and longer, with something of a pause at the end. When only one vagus is cut an intermediate effect may be obtained, the respiratory movements may be slowed somewhat and slightly deepened; but the striking effect is observed only after section of both nerves. This result is not a temporary one due to the stimulation of cutting, but is permanent, and there- fore leads to the conclusion that some influence has been cut off which normally keeps the respiratory movements at a more rapid rate. Experiment has shown that this influence consists in the tonic action of sensory fibers contained in the vagus and distributed to the lungs. It is the constant effect of these fibers on the respira- tory center which maintains the normal rhythm; when they are severed the center drops into a slower, unregulated rhythm. Ex- periment has shown, also, that when the central stump of the divided vagus is stimulated artificially the respiratory center is affected, as indicated by the respiratory movements, in a variety of ways which depend upon the strength of the stimulus and the 6.82 PHYSIOLOGY OF RESPIRATION. condition of the center. The two results which are most constantly obtained and which may therefore be especially emphasized are as follows: first, with weak stimuli the inspiratory movements are in- hibited partially or completely, giving either smaller movements or, in a condition of narcosis, complete cessation of respirations, with Fig. 2(8. — To show the effect of section of the vagi on the respiratory movements (rabbit). The right vagus was cut at .r and caused a slight augmentation and slowing of the movements. The left vagus was cut at xx and caused first a short inhibition (due to mechanical stimulation) which was then followed by the typical slow and deep respi- rations seen under these conditions. — (Dawson.) the thorax in the stage of passive expiration (Fig. 277), or, second, the rate of the inspiratory movements may be increased and this may end finally in an inspiratory standstill, — that is, the respiratory movements cease with the chest in an inspiratory position (Fig. 279), Fig. 279.— To illustrate the inspiratory effect from stimulation of the central end of the vagus. The downstroke represents inspiration; the upstroke, expiration. During the period of stimulation the respirations are increased in frequency and the chest remains in a condition of inspiration. — (Lewandowsky.) the inspiratory muscles being in a condition of tetanic contraction. When both the inspiratory and expiratory muscles are considered, the variety of effects that may be obtained from stimulation of the afferent fibers of the vagus is perplexing, especially with strong INNERVATION OF THE RESPIRATORY MOVEMENTS. 683 stimuli, and has led to much difference of opinion among investi- gators.* The two main effects described above are usually inter- preted to mean that the vagus contains two kinds of sensory fibers which are distributed to the lungs and act normally on the respira- tory center. These are: (I) The inspiratory fibers, whose effect is to increase the rate of inspiratory discharge from the respiratory center; therefore to quicken the rate. (II) The expiratory (or inspiratory inhibiting) fibers, whose effect is to inhibit the inspira- tory discharges, partially or completely. Some authors find it simpler to assume only one kind of sensory fiber and to explain the different results by a difference in the nature of the stimulus or in the condition of the center: but it seems advisable at present. in accordance with the doctrine of specific nerve energies, to hold to the view of two varieties. Influence of the Inspiratory and the Inhibitory Fibers of the Vagus on the Normal Respirations. — It is assumed that these two sets of fibers are in constant activity and keep the re- spiratory rate more rapid than it would be otherwise. Hence the slowing and deepening of the respirations when the vagi are cut. The way in which these sensory fibers are stimulated normally was referred by Hering and Breuer to the alternate expansion and collapse of the lungs. Each inspiration stimulates the inhibitory fibers in consequence of the expansion of the lungs, and thus cuts short the inspiration, prematurely, as it were. So at each expira- tion the collapse of the lungs stimulates the inspirator,- fibers and brings on an inspiration sooner than would otherwise occur. In this way the respiratory rate is kept automatically at an accel- erated rhythm. This hypothesis has been much discussed and many efforts have been made to prove or disprove it by means of experiments. The result of this work on the whole tends to show that the hypothesis is essentially correct. Two kinds of afferent fibers exist in the vagus, one of which is stimu- lated by expansion of the lungs, the other by collapse. This fact is shown most clearly by Einthoven'sf experiments with his string-galvanometer. When the vagus nerve is cut high in the neck and is then connected in the usual way with the string- galvanometer, the latter shows a marked action current through- out each inspiration, indicating, therefore, the passage of a series of nerve impulses during inspiration (Fig. 280). When by suction the lungs were collapsed, another electrical variation of a different * For discussion and literature, see Meltzer, "Archiv f. Physiologie," 1892, p. 340; also "New York Medical Journal," January- 18, 1890. Lewan- dowsky, "Archiv f. Physiologie," 1896, pp. 195 and 483. fEinthoven, "Quarterly Journal of Exp. Physiology," 1908, 1, 243; also "Researches of the Physiological Laboratory of the University of Leyden, VII., 1908. 684 PHYSIOLOGY OF RESPIRATION. character was produced, indicating the existence of a separate set of fibers brought into action by the diminution in volume of the lungs. In quiet respirations the expiration consists in merely a passive return to what may be called the neutral or normal volume of the lungs, and in this movement it is probable that the inspiratory fibers are not affected, being stimulated only by an active expiration. We may assume, therefore, with Gad that the normal rate of respirations is maintained Fig. 280. — To show the electrical changes in the different fibers of the vagus nerve caused by the respirations and the heart beats: V, The electrovagogram, the large waves are electrical oscillations synchronous with the respiratory movements. The smaller ones are electrical changes synchronous with the heart beats; P, Mechanical record of the respiratory movements, ascent of curve, inspiration; C, Mechanical record of pulse beats. (From Einthoven.) by the action of the inhibitory fibers alone. Each inspiration is cut short by the mechanical stimulation of these fibers, but on the collapse of the lungs the new inspiration is due to a normal discharge from the inspiratory center. Loewy* has shown by an ingenious experiment that the expansion of the lungs is the factor that actually stimulates the sensory fibers and quickens the respiratory rate, as follows : An animal was made to breathe pure oxygen for a while to displace the nitrogen in the alveoli. The chest on one side- say, the right side— was then opened with the result that the lung collapsed, and, owing to the rapid absorption of the oxygen, soon became practically solid. The respirations (rabbit N showed their normal rate — 66. The vagus nerve on the left side was then cut and immediately the respirations took on the character usually shown when both vagi are severed, — respirations =-3u' NeXt the coUaPsed riSht lunS was expanded by artificial respiration, .with the result that the respiratory rate at once returned to normal. Respiratory Reflexes from the Larynx, Pharynx, and Nose. — The mucous membrane of the larynx receives its sensory fibers from the superior laryngeal nerve. When this nerve is stimulated artificially the respirations are always inhibited; the chest comes to rest in the position of passive expiration. The same effect may be * "Archiv f. die gesammte Physiologic," 42, 27-J INNERVATION OF THE RESPIRATORY MOVEMENTS. 685 obtained from the sensory fibers of the glossopharyngeal supplying the pharynx, and indeed a temporary inhibition of respirations occurs through this nerve during every act of swallowing. The sensory fibers of the nasal mucous membrane (trigeminal) cause a similar reflex inhibition when stimulated by injurious or so called irrespirable gases, such as HC1, CI, NH3, S02, etc. We may regard this inhibitor}' influence exerted by the sensory fibers distributed along the air passages as a protective reflex which guards the lungs automatically from injurious gases. This protective action is made more evident by the fact that, together with the cessation of respirations, the glottis is reflexly closed by contraction of the ad- ductor muscles and, if the stimulation is strong, even the bronchial musculature may be contracted, so that in every way the passage to the alveoli is made more difficult. The reflex is, of course, more or less temporary, but it possesses the great advantage of being automatic, and may enable the animal or individual to escape unharmed from a dangerous locality before the increasing irritabil- ity of the respiratory center breaks through the inhibition. In special cases the inhibition may last for an unusually long time. Thus, Fredericq states that in aquatic birds water allowed to flow over the beak so as to penetrate slightly into the nostrils brings about an inhibition of respirations for many minutes. There would seem in this case to be a special adaptation of the reflex to the needs of diving. We know also that irritating gases or foreign bodies of any sort that enter the larynx may lead to a coughing reflex, — that is, to a series of expiratory blasts which have a pur- poseful end in the expulsion of the stimulating object. In this case there is not simply an inhibition of the inspiratory movements, but a reflex excitation of a peculiar type of expiratory movements. The Voluntary Control of the Respiratory Movements.— We can control the respiratory movements within wide limits, make forced or feeble inspirations or expirations, accelerate the rhythm, or completely inhibit the respirations in any phase. If, however, the "breath is held," — that is, if the respiratory movements are inhibited and the glottis is closed, the increasing irritability of the respiratory center eventually breaks through the voluntary inhibition. How far this voluntary control is based upon direct connections between the cerebrum and the respiratory center and how far it depends upon voluntary paths to the separate spinal nuclei of the muscles involved cannot be discussed profitably. The Nature of the Respiratory Center. — The respiratory center located in the medulla oblongata might with more propriety be designated as the inspiratory center. Our normal respirations throughout life consist of an active inspiration and a passive expiration. It is the co-ordinated activity of the inspiratory 686 PHYSIOLOGY OF RESPIRATION. muscles that is characteristic of the respiratory movements. The expiratory muscles come into action only occasionally and under special conditions. It is, in reality, incorrect to speak of the normal respirations as consisting of alternate inspiratory and expiratory movements; as a matter of fact, they consist of rhythmical in- spiratory movements alone. So also when we describe the respira- tory center as essentially automatic we refer only to the action on the inspiratory muscles, since a series of active inspirator}' move- ments is the essential feature of respiration. Under certain con- ditions, however, we do have rhythmical expiratory movements, active expirations. Such movements may occur independently of the respirations proper, as in coughing and laughing, or in the straining movements of defecation, micturition, and parturition; or they may occur as an integral part of the respirations, as in the forced movements of dyspnea. Under the conditions of partial suffocation, for instance, as the blood becomes more and more venous the respirations increase in force and active expirations appear. It becomes a question, therefore, as to the existence of what might be called an expiratory center, a group of nerve cells controlling the co-ordinated activity of the expiratory muscles. The mere fact that in dyspnea we have a rhythmical and co-ordi- nated activity of these muscles seems to imply the existence of such a center, but there is no definite experimental knowledge as to its location. Assuming that there is such a center, it may be believed that it exists in the medulla, since after section below the medulla there is no evidence of the occurrence of rhythmical expiratory movements even in extreme conditions of venosity of the blood. The expiratory center may or may not be located in the same region as the inspiratory center, but the following general char- acteristics may be assigned to it : In the first place, it is not auto- matic ; at least not under normal conditions. In the second place, its activity must be dependent in some way upon that of the in- spiratory center. Even our most violent respiratory movements show an orderly sequence of inspiration and expiration, — and we may believe that the action of the expiratory center is conditioned by the previous discharge of the inspiratory center, just as in the heart the beat of the ventricle depends upon the previous systole of the auricle. That an active expiration is not caused reflexly by the mechanical expansion of the lungs seems to be demonstrated by the fact that the most forcible voluntary inspiration is followed by a passive, not an active expiration. Until our knowledge is extended by further experimental work we may consider the ex- piratory center as a group of cells connected by definite paths with the expiratory muscles and capable of being stimulated in one of at least four general ways: (1) In special reflexes, such as coughing. INNERVATION OF THE RESPIRATORY MOVEMENTS. 6S7 (2) By voluntary control from the cerebrum, as in straining. (3) By stimulation through afferent fibers from the skin, especially the pain fibers. (4) By the action of an increased venosity of the blood. Under the latter two conditions it is possible that the irritability of the center is so increased that it becomes responsive to the in- fluence of the inspiratory center. The relations of the inspiratory and expiratory centers under the various conditions of artificial stimulation are very complex, and although it is possible to rep- resent these relations more or less completely by schemata of some sort it does not seem advisable at present to seriously consider such hypotheses. The Accessory Respiratory Centers of the Midbrain. — Several observers have called attention to the existence of a possible accessory respiratory center in the midbrain at the level of the posterior colliculus. Martin and Booker found that stimulations in this region caused a marked increase in the rate of inspiratory movements and finally a standstill in inspiration, — that is, a complete tetanic contraction of the inspiratory muscles lasting during the stimulation.* Lewandowskyf has shown that section of the brain stem at or below the inferior colliculi causes an alteration in the respiratory rhythm similar to that following section of both vagi. After cutting through the inferior colliculi further sections more posteriorly do not add to the effect. He considers that there is an automatic inhibitory center in the midbrain which influences continually the automatic activity of the medullary center. The Nature of the Automatic Stimulus to the Respiratory Center. — We have accepted the view that the respiratory (inspira- tory) center is essentially automatic, although very sensitive to reflex stimulation. The further question arises as to the nature of the automatic stimulus. Inasmuch as the activity of the center controls the gaseous exchanges of the blood, it was natural perhaps for physiologists to look to the gases of the blood for the origin of the internal stimulus. Experiments show beyond question that the condition of the gases in the blood has a direct and marked influence upon the activity of the center. If for any reason the blood supplying the center becomes more venous, the respirations are increased in force or rate or both, and indeed the activity of the center is in a general way increased in proportion to the venosity of the blood. On the other hand, if the blood supplying the center is more arterialized than normal, by active ventilation of the lungs, for instance, the center acts more feebly or may fail to act altogether, giving the condition known as apnea. These facts may be accepted as completely demonstrated, but they do not go far enough. When we speak of the arterial blood being more venous than normal we mean that it contains less oxygen and more carbon dioxid than normal arterial blood. Which of these conditions serves to stimulate * Martin and Booker, "Journal of Physiology," 1, 370, 1878. t "Archiv f . Physiologie, " 1896, 489. 688 PHYSIOLOGY OF RESPIRATION. the center, and which may be regarded as the constant stimulus throughout life ? The three possible views have been defended: (1) That the normal stimulus is a lack of sufficient oxygen (Rosen- thal). When sufficient O is supplied the center ceases to act, becomes apneic. (2) That the normal stimulus is the presence of an. excess of C02 (Traube). When this excretion is quickly re- moved the center ceases to act, — becomes apneic. (3) It is possible that the two factors may co-operate. The blood that flows through the center may stimulate the cells by virtue of the fact that it does not remove the C02 fast enough and does not supply sufficient oxygen. Much evidence has been collected to show that the action of the respiratory center is increased when the tension of the C02 in the blood is raised without altering that of the oxygen and that a similar result is obtained if the tension of oxygen is greatly diminished without any change in that of the carbon dioxid, so that it must be admitted that a change in either factor, if suffi- ciently great, acts as a stimulus. Experiments, however, have indicated that the accumulation of the C02 is the more efficient stimulus of the two.* Zuntz reports the following interesting experiments, in which the extent of the respiratory movements was measured by the amount of air breathed in a minute. In one series the amount of oxygen in the air breathed was reduced. This change did not affect the quantity of carbon dioxid in the blood. The following results were obtained: Normal air volume breathed per minute = 7,325 to 9,000 c.c. Air with 10 to 11.5 per cent, oxygen " " " " = 8,166 to 9,428 " Air with 8 to 10 per cent, oxygen " " " " = 9,093 to 12,810 " A reduction of one-half of the oxygen in the air breathed had little effect upon the respirations. From our present standpoint, how- ever, the important thing w not the amount of oxygen in the air, but the amount in the blood. Paul Bert's experiments! upon living animals indicate that when the oxygen of the air is reduced by a half the amount of oxygen in the blood is diminished by about one-third. Assuming this to be correct, it is evident that a very considerable reduction may be made in the oxygen of the blood without noticeably affecting the respirations. A similar conclusion may be drawn from Haldane's experiments J with carbon monoxid. He found upon breathing mixtures of this gas that no distinct effects were observable until the blood was about one-third saturated with the gas, — that is, had lost one-third of its oxygen. Zuntz's ex- * See Zuntz, " Archiv f. Physiologie," 1897, 379. See also Friedlander and Herter, " Zeit. f. physiol. Chemie," 2, 99, and 3, 19. t Bert, " La pression barometrique," 1878, 691. % Haldane, "Journal of Physiology," 18, 442, 1895. INNERVATION OF THE RESPIRATORY MOVEMENTS. 689 periments, in which the C02 in the air breathed was increased, while the oxygen remained normal, gave quite different results, as follows : Normal air volume breathed per minute, 7,433 c.c. Air of 20.2 per cent. O, 0.95 per cent. C02 " " " " 9.060 " Air of 18.06 per cent. O, 2.97 per cent. C02 " " " " 11,326 " Air of 18.42 per cent. O, 11.5 per cent. C02 " " " " 32,464 " These and similar results* show that small differences in the amount of the carbon dioxid in the blood have a distinct effect upon the activity of the respirator}^ center. Under normal con- ditions the respiratory center receives blood containing 19 to 20 volumes per cent, of oxygen, while the venous blood flowing away from the center still holds 10 to 12 per cent. Considering the small effect of lowering this oxygen supply by one-third, it is difficult to believe that normally the amount of oxygen is so deficient for the normal metabolism as to set up a constant stimulus. The trend of recent work favors rather the view that the normal stimulus to the respiratory center is the carbon dioxid. When this substance is present above a certain amount or tension it acts as a stimulus and gives rise to the moderate movements of normal inspiration. If the tension of the carbon dioxid is increased its stimulating action becomes stronger and leads to the production of a condition of hyperpnea and dyspnea. On the other hand, if for any reason, such as active ventilation of the lungs, the tension of the carbon dioxid in the blood falls below a certain value, estimated by Zuntz as lying between 19 and 24 mms., no stimu- lation occurs, the center is in a condition of apnea and respiratory movements cease. Accepting the view that carbon dioxid in the blood circulating in the medulla constitutes the normal stimulus to the respiratory center, one naturally inquires why a deficient supply of oxygen should also stimulate the center. It is true, as stated above, that the supply of oxygen may be diminished considerably before any augmented action of the center is observed, but there seems to be no question that dyspneic movements result when the oxygen tension falls below a certain point. One explanation has been suggested which may be accepted provisionally at least. We may believe that in the metabolism of the nerve cells constituting the center, as in the metabolism of the muscle, certain organic acids, such as lactic acid, are formed which in the presence of a normal supply of oxygen are further oxidized. When, however, the oxygen supply is insufficient these acids may accumulate and serve as a stimulus, either directly, or indirectly by making the cells * See Haldane and Priestley, "Journal of Physiology," 32, 225,1905. 44 690 PHYSIOLOGY OF RESPIRATION. more irritable to the effect of the carbon dioxid.* This point of view enables us to understand also some interesting results of the effect of breathing oxygen. When one holds his breath the carbon dioxid tension in the blood increases, and eventually the stimulus becomes so strong that respirations ensue in spite of the strongest effort to inhibit them. This " breaking point " is reached f in 23 to 77 seconds when the carbon dioxid in the alveoli of the lungs has a concentration of 6.2 to 7.5 per cent., and the oxygen is reduced to 9 to 11 per cent. If before holding the breath the lungs are filled with oxygen by taking several breaths of the pure gas, the breaking point may be prolonged to as much as 160 seconds, and one observer (Vernon) reports that if the lungs are first thoroughly aerated by forced breathing, so as to wash out the car- bon dioxid in the alveoli, and at the end pure oxygen is breathed in, the breaking point may be deferred as long as eight minutes. Evidently, therefore, an accumulation of carbon dioxid in the blood, as indicated by the composition of the alveolar air, is less efficient as a stimulus to the center when an adequate supply of oxy- gen is provided, and this fact may be explained on the hypothesis that the oxygen prevents the accumulation of the acid products of metabolism. The Cause of the First Respiratory Movement. — The mam- malian fetus under normal conditions makes no respiratory move- ments while in utero. After birth and the interruption of the pla- cental circulation the first breath is taken. The cause of this sudden awakening to activity on the part of the respiratory center must be closely connected, if not identical with, the cause of the automatic activity of the center throughout life. Two or perhaps three views have been held regarding its immediate cause: (1) That it is due to the increased venosity of the blood brought about by the interruption of the placental circulation; (2) that it is due to stimulation of the skin by handling, drying, etc.; (3) that it is due to a combination of these causes. Preyer has shown that stimula- tion of the skin of the fetus while in utero and with the placental circulation intact sufncies to cause respiratory movements. Cohn- stein and ZuntzJ have shown that interruption of the placental circulation while the fetus is kept bathed in the amniotic liquid also brings about respirations. Since both of these events occur normally at birth, we may believe that each aids in causing the first respira- tion, and indeed it may be necessary at times deliberately to in- crease the stimulation of the skin in order to bring on respiratory movements. If the two causes, stimulation through the nerves and stimulation through the blood, normally co-operate, it may, how- *Haldane and Poulton, "Journal of Physiology," 37, 390, 1908. t Hill and Flack, "Journal of Physiology," 37, 77, 1908. JCohnstein and Zuntz, "Arch. f. die gesammte Physiol.," 42, 342, 1888. INNERVATION OF THE RESPIRATORY MOVEMENTS. 691 ever, be said that the essential cause, according to the theory adopted in the preceding paragraphs, lies in the greater venosity of the blood, that is. the increased tension of the carbon dioxid follow- ing interruption of the placental circulation. During the intra- uterine period it is evident that the fetal blood is aerated so well by exchange with the maternal blood that it does not act as a stimulus to the fetal respiratory center. The fetus is, physiolog- ically speaking, in a condition of apnea. Since the maternal blood acts upon the respiratory center of the mother, while the fetal blood which exchanges gases with it does not act on its own respira- tory center, it follows that the fetal respiratory center possesses a lower degree of irritability than that of the mother. Dyspnea, Hyperpnea, Apnea. — By the term dyspnea in its widest sense we mean any noticeable increase in the force or rate of the respiratory movements. As said above, such a condition may be caused either by stimulation of sensory nerves, particularly the pain nerves or the sensory fibers of the vagus distributed to the lungs themselves, or by an increased venosity of the blood — that is, by an increase in the C02 or by a marked decrease in the oxygen. Changes of other kinds in the com- position of the blood, some of which are considered in the next chapter, may also stimulate the respiratory center and cause dyspnea. The dyspneic movements naturally show many degrees of intensity corresponding with the strength of the stimulus, and sometimes the initial stages are designated as hyperpnea, while the term dyspnea is reserved for the more labored breathing in which the expirations are active and forced. When dyspnea is produced by withholding air (suffocation) the respiratory movements become more and more violent until the}* take on a convulsive character. This stage is succeeded by one of apparent calm, indicative of exhaustion of the centers. Deep, long-drawn inspirations follow at intervals and finally cease. The animal lies quietly, with feeble heart beat and dilated pupils, in a condition designated as asphyxia or complete asphyxia. The term apnea means literally a condition of no breathing, and since this condition may occur from several causes some confusion in nomenclature has resulted. In medical literature the term is some- times employed as a synonym for asphyxia or suffocation. In physiological literature it is restricted to a very interesting con- dition which is of great importance with reference to the theories of respiration. This condition is one of cessation of breathing movements due to lack of stimulation of the respiratory center. It is brought about by rapid and prolonged ventilation of the lungs. If, for instance, in a rabbit or other animal, a tracheal cannula is inserted and connected with a bellows or respiration 692 PHYSIOLOGY OF RESPIRATION. apparatus, the lungs may be inflated artificially at a rapid rate for any given period of time. If such an experiment is per- formed it will be found that when the blasts are stopped the animal makes no breathing movements at all, sometimes for a con- siderable interval. When the respirations start again they begin with feeble movements, which gradually increase to the normal am- plitude (Fig. 281). One may produce a similar condition upon him- self, approximately at least, by a series of rapid, forced inspirations. The question of importance is: Why does the respiratory center cease to act? The numerous researches made upon this condition seem to show very clearly that in the ordinary method used to pro- duce it two factors co-operate, namely, a change in the condition of the gases of the blood and a stimulation of sensory fibers in the wJ it ■"it 1 % ill If I ill 11 Sttl Pi hi if 'Ml is; I 111 m if;' Fig. 281. — To show the recovery from apnea. The animal (rabbit) had been venti- lated with a bellows and thrown into a condition of apnea shown at the beginning of the record. The respirations returned first as feeble movements which gradually in- creased to the normal. — (Dawson.) lungs. Since either one of these factors alone may cause a cessation of breathing, some authors have distinguished two kinds of apnea, apnea vera or chemical apnea, and apnea vagi or inhibitory apnea. Whether or not it is proper to speak of this latter condition as apnea depends altogether upon the definition one gives to the term. If we adhere to the definition suggested above, namely, that apnea is a cessation of breathing, due to lack of stimulation of the respiratory center, then the inhibition of respirations produced by stimulation of the vagi, the so-called apnea vagi, ought not to be included under the term. It is generally stated* that after section of the vagi it is more difficult than in the normal animal to produce apnea *See Head, "Journal of Physiology," 10, 1, and 279, 1889. INNERVATION OF THE RESPIRATORY MOVEMENTS. 693 by vigorous artificial respiration, so doubtless in this last proce- dure, as usually carried out with a bellows, the rapid stimulation of the inhibitory fibers of the vagus by the expansion of the lungs facilitates the production of a true or chemical apnea de- pendent upon a change in the gases of the blood. That chemical apnea may exist is shown by the fact that after section of both vagi apnea may still be produced by artificial respiration, and, indeed, several observers* find that after section of both vagi and of the medulla above the respiratory center the animal may still be made apneic. In such cases it is difficult to see any other cause for the apnea than a change in the gases of the blood. Rosenthal assumed that the apnea is due to an overoxygenation of the blood, but since the vigorous respirations lower especially the contents of the blood in C02 it is probable, as insisted upon by Traube, that this latter factor is the more important. In the preceding paragraphs evidence has been given to show that the normal stimulus to the center is due to the presence of C02, and it fol- lows logically that the more complete removal of this gas by venti- lation of the lungs should be considered as the chief cause of true apnea. Experimentally, this view is well borne out by an old obser- vation of Berns, according to which a conditioD of apnea in a rabbit may be cut short instantly at any moment by a blast of C02 sent into the lungs, a blast of air having no such effect. This observa- tion is further supported by recent experiments by Mossof upon men, in which he shows that apnea cannot be produced by inflation with carbon dioxid. This author designates the condition of diminished C02 in the blood as acapnia. According to this terminology, true apnea is due to a condition of acapnia. Much other work has tended to strengthen the general view that a certain tension or pressure of C02 in the blood is neces- sary to stimulate the respiratory center, and that if the CO, is washed out to a certain point by unusual ventilation of the lungs (condition of acapnia), then the respiratory center ceases to give off its rhythmic discharges. There is no desire to breathe and the animal lies quiet in a condition of apnea. Voluntary forced respirations in man maintained for some minutes will produce a similar condition. According to the interesting- account given by Haldane and PoultonJ an apnea may be produced in this way which will last for 100 to 150 seconds, and before the individual begins to breathe again he may become very blue in the face, owing to the loss of oxygen from the blood. Henderson! has given experimental evidence to show * Loewy, "Archiv f. die gesammte Physiologie," 42, 245, 1888; and Langendorff, "Archiv f. Physiologie," 1888, p. 286. t Mosso, "Archives itaiiennes de biologie," 40, 1, 1903. j Haldane and Poulton, " Journal of Physiology," 37, 390, 1908. \ Henderson, "American Journal of Physiology," 21, 128, 1908. 694 PHYSIOLOGY OF RESPIRATION. that a marked diminution in the pressure of the C02 in the blood, brought about by forced respiration, may cause not only a condition of apnea but also a feeble rapid heart-beat, with fall of blood-pressure and the symptoms of surgical shock. It is known that a cessation of respirations maybe brought about in still a third way, namely, by a condition of more or less complete anemia produced by shutting off the blood-supply to the respira- tory center. The lack of activity in this case is probably not a true apnea in the sense of the term given above, since we may suppose that under these conditions the tension of the carbon dioxid increases rather than decreases. In other words, there is no removal of stimulus, but the cells have lost their irritability, and hence fail to respond to stimulation. Innervation of the Bronchial Musculature. — Numerous investigators, using different methods, have demonstrated that the bronchial musculature is supplied through the vagus with motor and inhibitory fibers, bronchoconstrictor and bronchodilator fibers, as they are usually called.* Stimulation of the constrictors causes a narrowing of the bronchi, and therefore increases the resistance to the inflow and outflow of air. Some observers state that these fibers are nor- mally in a condition of tonic activity (Roy and Brown), but others find little evidence for this belief. An artificial tonus — that is, a condition of maintained activity of the constrictor fibers — may be set up by the action of a number of drugs, such as muscarin, pilocarpin, and physostigmin, which in this case, as in so many other instances of autonomic fibers, are supposed to stimulate the endings of the fibers in the lungs. Their effect is removed by the action of atropin. These fibers are stimulated also during the ex- citatory stages of asphyxia. Reflex stimulation of the constrictors is obtained most readily (Dixon and Brodie) by irritation of the nasal mucous membrane, and it seems probable that in bronchial or spasmodic asthma these fibers are also stimulated reflexly. The normal conditions under which the constrictors and dilators are brought into play can scarcely be stated. Irritating vapors or even C02 lead to a bronchoconstriction and this reflex, as stated on p. 685, may be regarded as protective. When a constriction of the bronchial musculature exists it may be abolished by the paralyzing action of atropin, or temporarily by injections of extracts of lobelia or by the anesthetic effect of inhalations of chloroform or ether. Nicotin also causes a dilatation. *For references to literature, see Dixon and Brodie, "Journal of Physi- ology, " 29, 97, 1903. CHAPTER XXXVIII. THE INFLUENCE OF VARIOUS CONDITIONS UPON THE RESPIRATIONS. The Effect of Muscular Work upon the Respiratory Move- ments.— It is a matter of common experience that muscular ex- ercise increases the rate and amplitude of the respiratory move- ments. Roughly speaking, the increase is proportional to the amount of muscular work, and the relationship is evidently a bene- ficial adaptation. The greater the amount of work done, the larger will be the amount of C02 produced and the greater will be the need of oxygen. The adaptation was formerly explained in what seemed to be an entirely satisfactory way by assuming that the increased consumption of O and the greater production of C02 in the muscles resulted in rendering the blood more venous, and consequently the respiratory center was stimulated more strongly, and indeed proportionally to the muscular effort. Geppert and Zuntz,* however, have shown by gas analyses that whatever may be the condition of the venous blood during muscular exercise the arterial blood sent out from the left heart shows no constant change in the quantity or tension of the contained gases. They proved, also, that the effect on the center is not simply a reflex from the nerves in the muscles, since when the hind limbs were made to contract by stimulation the respiratory center was affected in the usual way although all the nerve connections were destroyed. They conclude, therefore, that the respiratory effect of muscular work must be due to certain substances produced in the muscle and given off to the blood. Other experiments (Lehmann) make it probable that these substances are the acid products, lactic acid and acid phosphates, known to be formed in muscle during contraction, and, indeed, it can be shown that the lactic acid in the blood is increased during muscular exercise, t The adaptive reaction, by means of which the need of the contracting muscles for more oxygen is met, may be explained, therefore, as follows: Owing to the greatly increased metabolism in the contracting muscle the resting supply of oxygen is inadequate to oxidize the acid intermediary products of metabolism, these latter escape into the blood-stream, * Geppert and Zuntz, " Archiv f. die gesammte Physiologie," 42, 189, 1888. t Ryffei; "Journal of Physiology," 39, 1909. 695 696 PHYSIOLOGY OF RESPIRATION. and by stimulating the respiratory center (and accelerating the heart-rate) they occasion a more abundant supply of oxygen to the muscle. The Effect of Variations in the Composition of the Air Breathed. — Variations in the amount of nitrogen in the inspired air have no distinct physiological effect. The important elements to consider are the oxygen and the carbon dioxid. Increased Percentages of Oxygen. — The normal pressure of oxygen in the air is 20 per cent, or 152 mms. We may increase this pres- sure either by changing the volume per cent, of the gas or by raising the barometric pressure by compression. The somewhat natural supposition that breathing pure oxygen — that is, oxygen at a pres- sure of 760 mm. — should have a beneficial effect on the oxidations of the body has found no support in physiological experiments. Atmospheric air supplies us with an excess of oxygen over the needs of the body; a still further increase of this excess has no positive advantage. This is true at least for ordinary conditions of rest or moderate activity. In excessive and prolonged muscular exertion the supply may be inadequate, and under these or similar condi- tions an increase in the percentage of oxygen in the respired air would naturally be advantageous. Paul Bert, in his interesting- work on barometric pressures,* has called attention to the fact that at a certain pressure oxygen is not only not beneficial, but, on the contrary, is markedly toxic. From experiments made upon a great variety of animals and plants he concluded that all living things are killed when the oxygen pressure is sufficiently high, — say, 300 to 400 per cent. Warm-blooded animals die with convulsions when sub- mitted to 3 atmospheres of pure oxygen or 15 atmospheres of air. At these high pressures the blood contains about 28 volumes of oxy- gen to each 100 c.c. of blood instead of the usual 20 volumes. The additional 8 volumes are contained in solution. Fish also are killed when the oxygen pressure is increased to such a point that the water contains 10 volumes of dissolved oxygen to each 100 c.c. In more recent experiments by Smith, f made upon mice, it was found that oxygen at pressures of 100 per cent, to 130 per cent, proves fatal in a few days, the animals showing inflammatory changes in the lungs. Oxygen at 180 per cent, kills mice and birds within twenty- four hours. Pressures of two atmospheres of air (40 per cent. O) have no injurious effect. No adequate chemical explanation can be offered at present for this toxic action of oxygen at high tensions. The matter is one of practical importance in connection with caisson and submarine work and the therapeutical use of oxygen. Decreased Percentages of Oxygen. — Numerous observers (Bert, * " La pression barometrique, " p. 764, Paris, 1878. t "Journal of Physiology," 24, 19, 1899. INFLUENCE OF VARIOUS CONDITIONS ON RESPIRATION. 697 Zuntz, et al.) have shown that a fall in oxygen pressure has no perceptibly injurious result until it reaches about 10 per cent. At or somewhat below this pressure the hemoglobin is unable to take up its full amount of oxygen, and the body consequently suffers from a real deficiency in its oxygen supply, a condition designated as anoxemia. According to Bert's experimental results, death with convulsions quickly follows a fall of atmospheric pressure to 250 mms. (oxygen pressure, 50 mms. or 6 to 7 per cent.). Animals supplied with an atmosphere containing a deficient amount of oxygen show dyspneic respirations, which increase in violence and finally become convulsive. The ordinary symptoms described for death from asphyxia are due, therefore, to the anoxemia — that is, lack of oxygen — not to the accumulation of C02. Increased Percentages of Carbon Dioxid. — It was pointed out clearly by the researches of Friedlander and Herter* that death from increased percentages of C02 is accompanied by symptoms quite different from those due to lack of oxygen. As the C02 is increased a noticeable hyperpnea may be observed (Zuntz) at a concentration of about 3 per cent. When the concentration of C02 reaches 8 per cent, to 10 or 15 per cent, there is distinct dyspnea; but beyond this point further concentration, instead of augmenting the respirations, decreases them, and the animal dies, at concen- trations of 40 to 50 per cent., without convulsions, but with the appearance, rather, of a fatal narcosis. High and Low Barometric Pressures, Mountain Sickness, Caisson Disease, etc. — High barometric pressures are used in submarine work, diving, caisson work, etc. As stated above, it follows from the work of Bert and Smith that when the pressure reaches 5 to 6 atmospheres long continuance in it may be followed by injurious or fatal results due to the toxic action of the oxygen. If the pressure is increased to 15 atmospheres the toxic influence of the oxygen brings on death with convulsions. Practically, however, such pressures are not encountered in submarine work. A caisson is a wooden or steel chamber arranged so that it may be sunk under water. The water is driven out by air under pres- sure.^ Since the pressure increases 1 atmosphere for each 10 meters (33 feet), it will be seen that very high pressures of air are not usually required. Caisson workers are at times attacked by serious or even fatal symptoms, not while in the compressed air, but during or after the " decompression" that is necessary in the return to normal conditions. The symptoms consist of pains in the muscles and joints, paralysis, dyspnea, congestion. Those * Friedlander and Herter, "Zeitschrift f. physiol. Chemie," 2, 99, 1878, and 3, 19, 1879. 698 PHYSIOLOGY OF RESPIRATION. who have investigated the subject* state that the injurious results are due to a too rapid decompression. When this occurs the gases in the blood, particularly the nitrogen, are suddenly liberated as bubbles, which block the capillaries and thus produce anemia in different organs. If the decompression is effected gradually no evil results follow. The effect of low barometric pressures is chiefly of interest in connection with residence in high altitudes, balloon ascensions, etc. At certain altitudes, from 3000 to 4000 meters, disagreeable symptoms are experienced by many persons, especially after muscular effort, which are designated usually under the term mountain sickness. The individual so affected suffers from head- ache, nausea, vertigo, great weakness, etc. Much investigation, especially of recent years, has been devoted to this subject, -j- Paul Bert concluded, from his numerous experiments, that a fall in baro- metric pressure acts upon the organism only in so far as there is a diminution of the partial pressure of the oxygen in the air respired. This Adew has been generally accepted in physiology, and mountain sickness and similar disturbances in balloon ascents have been explained, therefore, as due mainly to the lack of oxygen, — that is, to the condition of anoxemia. Mosso, on the contrary, has insisted upon the part played by the carbon dioxid. He gives experi- ments to show that there is a diminution in the carbon dioxid contents of the blood (a condition of acapnia), and it is to this, rather than to the anoxemia, that he would attribute the physio- logical results of low barometric pressures. Other authors lay stress upon the mechanical disturbances of the lung circulation, while still others assume that certain vaguely understood cosmical influences — such as the electrical condition of the air, its ioniza- tion, or radiations of some kind — may affect the metabolisms of the body and thus produce the symptoms in question. It would seem that the whole matter is more complex than was at first supposed. At a height of 4000 meters, at which mountain sick- ness is apt to occur, the barometric pressure is 460 mms., so that there is an oxygen pressure of 92 rams., — a pressure high enough, one would suppose, not to endanger the oxygen supply. Mosso states, also, from experiments upon monkeys, that lowering the barometric pressure sufficiently (to about 250 nuns.) causes un- consciousness (sleep) even when the partial pressure of the oxygen is kept normal. The historical incident of the death of Sivel and * See Bert, loc. cit., p. 939; also Hill and MacLeod, "Journal of Physi- ology, " 29, 382, and "Journal of Hygiene, " 3, 407. t See "Zuntz et al. Hohenklima u. Bergwanderungen in ihrer Wirkung auf d. Menschen," Berlin, 1906. Mosso and Morro, "Archives italiennes de biologie," 39, 387, also vols. 40 and 41. Cohnheim, article on " Alpinismus," " Ergebnisse der Physiologie," vol. ii., part 1, 1903. INFLUENCE OF VARIOUS CONDITIONS ON RESPIRATION. 699 Croce-Spinelli at an altitude of 8600 meters (barometric pressure, 262 mms. ; oxygen pressure, 52.4 mms.) seems to indicate also that something more than mere diminution in oxygen pressure is respon- sible for the effects of extremely high altitudes. The incidents connected with the ascent in the balloon Zenith of Sivel, Croce-Spinelli, and Tissandier, April 15, 1875, are described in detail by the last named in "La Nature," 1875, p. 337, also in Bert's "La pression baro- metrique, " p. 1061. Only Tissandier survived. The balloonists were pro- vided with bags containing oxygen (72 per cent.), but they were unable to make satisfactory use of them since shortly after passing 7500 meters they be- came so weak that the effort to raise the arm to seize the oxygen tube was impossible. Tissandier's graphic description relates that at 8000 meters it was impossible for him to speak, and that shortly afterward he became entirely unconscious. None of the three seems to have shown any signs of the violent dyspnea that usually precedes asphyxia caused by lack of oxygen. It is noteworthy, however, that the heart beats were very rapid, and that they experienced at first great depression of muscular strength without loss of consciousness. The onset of complete unconsciousness was sudden, but was preceded by feelings of sleepiness, which, however, were not associated with any distress. These latter facts recall the conditions of "shock," and would suggest that probably the rapid heart beat was an indication of a great fall in blood-pressure, which may have been directly responsible for the mus- cular weakness and final unconsciousness and death. The Respiratory Quotient and its Variations. — In studying the gaseous exchanges of respiration one may determine the varia- tions in the oxygen absorbed under different conditions or in the carbon dioxid eliminated, or finally in the ratio of one to the other, ^, which is known as the respirator}- quotient. In short-lasting experiments the respiratory quotient is not a very reliable indicator of the extent or character of the physiological oxidations in the body, since any alteration in the depth or rapidity of the respiratory movements may, by changing the ventilation of the, alveoli, make a difference in the output of C02, — a difference, however, which would have no significance in regard to the nutritive changes of the body. In longer experiments and in those during which the respira- tory movements are not altered the determination of this ratio throws light upon the character of the oxidations that are taking- place, as will be apparent from the following considerations : Under ordinary conditions of rest and upon a mixed diet the R. Q. varies between 0.65 and 0.95 (Loewy) or between 0.75 and 0.89 (Magnus Levy). If, however, the material oxidized in the body is entirely carbohydrate the R. Q. should be equal to unity: ^ = 1. All the oxygen used in the combustion might be considered as uniting with the C to form C02, since enough O is present in the sugar to account for that used in oxidizing the H to H20. Or, as expressed in a reaction, C6H1206r+e602 = 6C02 + 6H20. R. Q. = f = 1. 700 PHYSIOLOGY OF RESPIRATION. The number of molecules of C02 formed in the oxidation is equal to the number of molecules of 02 used. If fats alone are oxidized in the body the R. Q. should be low (0.7), since these substances are poor in oxygen compared with the amount of C and H present in the molecule. The combustion of palmitin may be represented as follows : Palmitin, C3H5(C16H3102)3 = CB1HM06. 2(CfilH9806) + 14502 = 102CO2 + 98H20. R- Q- = iff = 0.703. In estimating the respiratory quotient for proteins one must bear in mind the fact that these substances vary somewhat in composition and, moreover, that they are not completely oxidized in the body. Calculations based upon the amount of unoxidized carbon and hydrogen escaping in the urine and feces give the average figure of 0.801 for the R. Q. of proteins. It is evident from these statements that an increase in the proportion of carbohydrate food will cause the R. Q. to approach unity, while an increase in protein and especially in fat will lower its value. In this way we can understand the actual variation observed in the average respiratory quotient of different classes of animals, as shown in the following brief table (Loewy) : Horse, herbivorous — R.Q. =0.960 Sheep, " " =0.900 Man, omnivorous " =0.800 Dog, carnivorous " =0.750. In starvation, when the body is living only on its own protein and fat, the R. Q. is much lower than under a normal diet with its large proportion of carbohydrate. By a determination of the respiratory quotient before and after varying certain con- ditions one may ascertain whether the given condition causes a change in the character of the body metabolism. For example, this method has been used to ascertain whether muscular work effects any change in the nature of the material consumed in the body. Experiments made upon this point indicate that the R. Q. is not changed by muscular work when it is not excessive or prolonged. Consequently we may infer that the same kind of material, sugar, for example, is oxidized by the contracting muscle as by the muscle at rest. In prolonged or fatiguing muscular work the R. Q. may be lowered, due probably to the body using more of its fat ; or in some conditions it may be raised, owing to some insufficiency in the respiratory and circulatory apparatus in furnishing an adequate supply of oxygen. Under certain special conditions the respiratory quotient may exceed unity or fall distinctly below 0.7. A rise INFLUENCE OF VARIOUS CONDITIONS ON RESPIRATION. 701 to a value over unitymay occur temporarily because of increased ventilation of the alveoli. Deeper and more rapid breathing will drive out some of the C02 in the air of the lungs and thus increase greatly the R. Q. As previously stated, this increase Fig. 282. — Record showing typical Cheyne-Stokes respiration (from a case of aortic and mitral insufficiency with arteriosclerosis). The time record gives seconds. has in itself no nutritional significance, but it is a factor that must be allowed for in such experiments. A more suggestive increase of the R. Q. is observed during convalescence. In this period, as is well known, an individual may increase in weight rapidly, chiefly from the laying on of fat. This fat is made in large part probably from the carbohydrate of the food. An oxygen-rich food, therefore, is converted to an oxygen-poor one, so that some of the oxygen must be split off partly as carbon dioxid, and there is a larger output of this substance in the expired air. Modified Respiratory Movements. — Laughing, coughing, yawn- ing, sneezing, sobbing, and even vomiting may be considered as modified respiratory movements, since the same group of muscles comes into play. These are all movements, with the exception of yawning, which may be regarded as reflexes that have nothing to do directly with the processes of respiration. A most interesting variation of the normal type of respiration is known as the Cheyne- Stokes respiration. It occurs in certain pathological conditions, such as arteriosclerosis, uremic states, fatty degeneration of the heart, and especially under conditions of increased intracranial pressure. It is characterized by the fact that the respiratory movements occur in groups (10 to 30) separated by apneic pauses, which may last for a number (30 to 40) of seconds. After each pause the respirations begin with a small movement, gradually increase to a maximum, and then fall off gradually to the point of complete cessation (see Fig. 282). Great variations, however, are shown in 702 PHYSIOLOGY OF RESPIRATION. the character and number of the respirations during the so-called dyspneic phase. From observations made by means of the sphygmomanometer Eyster* has shown that in this condition there are also rhythmic waves of blood-pressure (Traube-Hering waves), and according to the relation of these pressure waves to the groups of respirations the Cheyne-Stokes cases fall into two groups. In one group the dyspneic phase coincides with a fall of blood-pressure and a slowing of the pulse-rate. In the other group the reverse relations hold, the blood-pressure and pulse-rate both rising during the dyspneic phase and falling during the apnea. This latter group consists of cases in which there is evidence of increased intracranial tension. Under experimental conditions the author was able to show on dogs that an artificial increase in intracranial tension calls forth Cheyne-Stokes respirations, whenever it happens that rhythmic changes in blood-pressure are produced of such a character that the blood-pressure rises and falls alternately above and below the line of intracranial pressure. It is probable, therefore, that in the clinical cases associated with a rise of intra- cranial pressure the blood-pressure likewise rises and falls above and below intracranial tension, and that the alternating periods of apnea and dyspnea are due to this fact in this class of cases. When the blood-pressure falls below intracranial pressure there is a condition of deep anemia of the medulla sufficient to suspend the activity of the respiratory center. The following rise of blood- pressure by forcing more blood through the medulla calls forth a group of respiratory movements. By examination of the expired air Pembrey f has shown that during the dyspneic phase the percentage of C02 in the alveolar air is markedly diminished (2 per cent.), and he believes, therefore, that the following phase of apnea is due entirely to this washing out of the C02, that is, to the removal of the normal stimulus to the respiratory center. Practically he finds that the apneic phase can be removed by the administration of either pure oxygen or carbon dioxid (2.2 to 11.2 per cent.). Pembrey does not give the clinical histories of his patients, but apparently he has studied cases belonging chiefly to Eyster's first group. None of the suggestions made at present seem to account adequately for the very labored breathing at the acme of the dyspneic phase, and the phenomenon evidently requires further experimental study. More or less rhythmical variations in the strength of the breathing movements have been described also in normal sleep, hibernation, chloral narcosis, etc., but nothing so definite and characteristic as in these very interesting Cheyne-Stokes cases. * Eyster, "Journal of Experimental Medicine," 1906. t Pembrey, "Journal of Pathology and Bacteriology," 12, 258, 1908 SECTION VII. PHYSIOLOGY OF DIGESTION AND SECRETION. CHAPTER XXXIX. MOVEMENTS OF THE ALIMENTARY CANAL. Mastication. — Mastication is an entirely voluntary act. The articulation of the mandibles with the skull permits a variety of movements; the jaw may be raised and lowered, may be projected and retracted, or may be moved from side to side, or various com- binations of these different directions of movement may be effected. The muscles concerned in these movements and their innervation are described as follows: The masseter, temporal, and internal pterygoids raise the jaw; these muscles are innervated through the inferior maxillary division of the trigeminal. The jaw is depressed mainly by the action of the digastric muscle, assisted in some cases by the mylohyoid and the geniohyoid. The two former receive motor fibers from the inferior maxillary division of the fifth cranial, the last from a branch of the hypoglossal. The lateral movements of the jaws are produced by the external pterygoids, when acting separately. Simultaneous contraction of these muscles on both sides causes projection of the lower jaw. In this latter case forcible retraction of the jaw is produced by the contraction of a part of the temporal muscle. The external pterygoids also receive their motor fibers from the fifth cranial nerve, through its inferior maxillary division. The grinding movements commonly used in masticating the food between the molar teeth are produced by a combination of the action of the external pteryogids, the elevators, and perhaps the depressors. At the same time the movements of the tongue and of the muscles of the cheeks and lips serve to keep the food properly placed for the action of the teeth, and to gather it into position for the act of swallowing. Deglutition. — The act of swallowing is a complicated reflex movement which may be initiated voluntarily, but is, for the most part, completed quite independently of the will. The classical description of the act given by Magendie divides it into three stages, 703 704 PHYSIOLOGY OF DIGESTION AND SECRETION. corresponding to the three anatomical regions — mouth, pharynx, and esophagus — through which the swallowed morsel passes on its way to the stomach. The first stage consists in the passage of the bolus of food through the isthmus of the fauces, — that is, the opening lying between the ridges formed by the palatoglossi muscles, the so-called anterior pillars of the fauces. This part of the act is usually ascribed to the movements of the tongue itself. The bolus of food lying upon its upper surface is forced backward by the ele- vation of the tongue against the soft palate from the tip toward the base. This portion of the movement may be regarded as vol- untary, to the extent at least of manipulating the food into its proper position on the dorsum of the tongue, although it is open to doubt whether the entire movement is usually effected by a voluntary act. Under normal conditions the presence of moist food upon the tongue seems essential to the complete execution of the act ; and an attempt to make the movement with very dry material upon the tongue is either not successful or is performed with difficulty. The second act comprises the passage of the bolus from the isthmus of the fauces to the esophagus, — that is, its transit through the pharynx. The pharynx being a common passage for the air and the food, it is important that this part of the act should be consummated quickly. According to the older description, the motor power driving the bolus downward through the pharynx is derived from the contrac- tion of the pharyngeal muscles, particularly the constrictors, which contract from above downward and drive the food into the esopha- gus. Kronecker and Meltzer,* however, have shown that the con- traction of the mylohyoid muscle in the floor of the mouth is the most important factor in this act of shooting the food suddenly through the pharynx into the esophagus. The contraction of this muscle marks the beginning of the purely involuntary part of the act of swallowing. The bolus of food lies upon the dorsum of the tongue and by the pressure of the front of the tongue against the hard palate it is shut off from the front part of the mouth cavity. When the mylohyoids contract sharply the bolus is put under pres- sure and is shot into and through the pharynx. This effect is aided by the contraction of the hyoglossi muscles, which by moving the tongue backward and downward tend to increase the pressure put upon the food. Simultaneously, a number of other muscles are brought into action, the general effect of which is to shut off the nasal and laryngeal openings and thus prevent the entrance of * Kronecker and Meltzer, " Arehiv f. Physiologie, " 1883, suppl. volume, p. 328; also "Journal of Experimental Medicine," 2, 453, 1897. For later work, consult Cannon and Moser, "American Journal of Physiology, " 1, 435, 1898; Schreiber, "Arehiv f. exper. Pathol, u. Pharmakologie^ " 46, 414, 1901 ; and Evkman, " Arehiv f. die gesammte Phvsiologie, " 99, 513. 1903. MOVEMENTS OF THE ALIMENTARY CANAL. 705 food into the corresponding cavities. The whole reflex is there- fore an excellent example of a finely co-ordinated movement. The following events are described: The mouth cavity is shut off by the position of the tongue against the palate and by the con- traction of the muscles of the anterior pillars of the fauces. The opening into the nasal cavity is closed by the elevation of the soft palate (action of the levator palati and tensor palati muscles) and the contraction of the posterior pillars of the fauces (palatopharyn- geal muscles) and the elevation of the uvula (azygos uvula? muscle;. The soft palate, uvula, and posterior pillars thus form a sloping surface shutting off the nasal chamber and facilitating the passage of the food backward through the pharynx. The respiratory opening into the larynx is closed by the adduction of the vocal cords (lateral crico-arytenoids and constrictors of the glottis) and by the strong elevation of the entire larynx and a depression of the epiglottis over the larynx (action of the thyrohyoids, digastrics, geniohyoids, and mylohyoids and the muscles in the aryteno-epiglottidean folds). If the elevation of the larynx be prevented by fixation of the thy- roid the act of swallowing becomes impossible. There is also at this time, apparently as a regular part of the swallowing reflex, a slight inspiratonr movement of the diaphragm, the so-called swallowing respiration. The movements of the epiglottis during this stage of swallowing have been much discussed. The usual view is that it is pressed down upon the laryngeal orifice like the lid of a box and thus effectually protects the respiratory passage. It has been shown, however, that removal of the epiglottis does not prevent normal swallowing, and Stuart and McCormick* have reported the case of a man in whom part of the pharynx had been permanently removed by surgical operation and in whom the epiglottis could be seen during the act of swallowing. In this individual, according to their observations, the epiglottis was not folded back during swallowing, but remained erect. Kanthack and Anderson f state that in normal individuals the movement of the epiglottis backward during swallowing may be felt by simply passing the finger back into the pharynx until it comes into contact with the epiglottis. According to most observers, it is not necessary for the protection of the larynx that the epiglottis shall be actually folded down over it by the contraction of its own muscles. The forcible lifting of the larynx, together with the descent of the base of the tongue, effects the same result by mechanically crowding the parts together, and the larynx is still further guarded by the ap- proximation of the false and true vocal cords, thus closing the glottis. The whole act is very rapid as well as complex, so that not more * "Journal of Anatomv and Phvsiologv, " 1S92. t "Journal of Physiology, " 14, 154, 1893. 45 706 PHYSIOLOGY OF DIGESTION AND SECRETION. than a second elapses between the beginning of the contraction of the mylohyoids and the entrance of the food into the upper end of the esophagus. The passage of the food through the esophagus differs apparently with its consistency. When the food is liquid or very soft Kronecker and Meltzer have shown that it is shot through the whole length of the esophagus by the force of the initial act of swallowing. It arrives at the lower end of the esophagus in about 0.1 sec, and may pass immediately into the stomach or may lie some moments in the esophagus according to the conditions of the sphincter guarding the cardiac orifice. When, however, the food is solid or semi- solid, as was shown by Cannon and Moser, it is forced down the esophagus by a peristaltic movement of the musculature. The circular muscles are constricted from above downward by an ad- vancing muscular wave, while the longitudinal muscles contract probably somewhat in advance of this wave so as to dilate the tube and facilitate the passage of the bolus. The upper portion of the esophagus contains cross-striated fibers indicating rapid contraction; the lower end consists of plain muscle only, while the intermediate portion is a mixture of the two varieties. Kronecker and Meltzer believe that each of these segments contracts as a whole and in orderly succession, but other observers, on the evidence furnished by Roentgen-ray photographs, agree that there is no perceptible pause in the downward movement of the wave of contraction. These same movements occur in the swallowing of liquid or soft food, but in such cases the peristaltic wave follows the actual descent of the food. According to the observation of Kronecker and Meltzer, it takes about 6 sec. for the peristaltic wave to reach the stomach, and the passage of the food through the cardia takes place with sufficient energy to give rise to a murmur that may be heard by auscultating over this region. In the case of the more liquid food that is shot at once to the lower end of the stomach within 0.1 sec, it may apparently pass at once into the stomach or it may lie in the lower end of the esophagus until the wave of contraction reaches it (6 sec) and forces it through the opening. According to the observations made by Hertz,* liquids or liquid food are held up at the end of the esophagus and pass slowly into the stomach through the sphincter. He estimates that an interval of from 4.6 to 8.6 sec elapses before the swallowed bolus disappears into the stomach, about one-half of this time being occupied by the passage to the bottom of the esophagus and one-half in the transit through the cardiac orifice of the stomach. At the cardia or cardiac orifice the circular layer of muscles acts as a sphincter which is normally in a condition of tone, particularly * Hertz, "Guy's Hospital Reports," 61, 389, 1907. MOVEMENTS OF THE ALIMENTARY CANAL. 707 when the stomach contains food. The advancing wave of con- traction in the esophagus either forces the food through the resistance offered by this sphincter, or probably the sphincter suffers an inhibition at this moment as a part of the general reflex action. Indeed, experiments have shown (von Mikulicz) that the tonus of the cardiac sphincter is largely controlled through the extrinsic nerves. Small pressures in the bottom of the esophagus cause a dilatation of the cardia by inhibition. Anatomically the cardiac sphincter receives-nerve fibers not only from the vagus but also from the sympathetic by way of the celiac ganglion. The precise control exerted through these nerves has not yet been worked out. Kronecker and Meltzer have noted the interesting fact that if a second swallow is made within an interval of six seconds after the first, the peristaltic wave occasioned by the latter is inhibited at whatever portion of its path it may have reached. The food carried down by the first swallow waits in this case for the arrival of the succeeding wave before entering the stomach. Nervous Control of Deglutition. — The entire act of swallowing, as has been said, is essentially a reflex act. Even the comparatively simple wave of contraction that sweeps over the esophagus is due to a reflex nervous stimulation, and is not a simple conduction of contraction from one portion of the tube to another. This fact was demonstrated by the experiments of Mosso,* who found that after removal of an entire segment from the esophagus the peristaltic wave passed in due time to the portion of the esophagus left on the stomach side, in spite of the anatomical break. The same experi- ment was performed successfully on rabbits by Kronecker and Meltzer. Observation of the stomach end of the esophagus in this animal showed that it went into contraction two seconds after the beginning of a swallowing act whether the esophagus was intact or ligated or completely divided by a transverse incision. A still more striking proof of the same fact is the interesting case cited by v. Mikulicz of a man in whom a portion of the esophagus had been resected on account of a carcinoma. The lower end of the esophagus was given a fistulous opening in the neck and and it was found that food introduced into this opening was not moved toward the stomach until the patient made a swallow- ing movement. f The afferent nerves concerned in this reflex are the sensory fibers to the mucous membrane of the pharynx and esophagus, including branches of the glossopharyngeal, trigeminal, vagus, and superior laryngeal division of the vagus. Artificial stimulation of this last nerve in the lower animals * Moleschott's " ' Untersuchungen, " 1876, volume xi. t Quoted from Cohnheim in Xagel's "Handbuch d. Physiologie." 708 PHYSIOLOGY OF DIGESTION AND SECRETION. is known to produce swallowing movements. Several observers have attempted to determine the precise area or areas in the pharyngeal membrane from which the sensory impulses lib- erating the reflex normally start. According to Kahn,* the most effective areas from whose stimulation the reflex may be produced vary in location in different animals. In the rabbit the reflex is originated most easily by stimulation at the entrance to the pharynx — the soft palate — along the line extending from the posterior edge of the hard palate to the tonsils (superior maxil- lary branch of trigeminal); in the dog irritation of the posterior pharyngeal wall is most effective (glossopharyngeal nerve); in monkeys the area is approximately as in rabbits, — that is, in the region of the tonsils. The motor fibers concerned in the reflex comprise the hypoglossal, the trigeminal, the glossopharyngeal, the vagus, and the spinal accessory. For an act of such complexity and such perfect co-ordination it has been assumed that there is a special nerve center, the swallowing or deglutition center, which has been located in the medulla at the level of the origin of the vagi. There is little positive knowledge, however, concerning the existence of this center as a definite group of intermediary nerve cells, after the type of the vasoconstrictor or respiratory center, which send their axons to the motor nuclei of the several efferent nerves con- cerned. As in the case of other complicated reflex acts, we can only say that the deglutition reflex is controlled by a definite nervous mechanism the final motor cells of which are scattered in the several motor nuclei of the efferent nerves mentioned above. The Anatomy of the Stomach. — The stomach in man belongs to the simple type as distinguished from the compound stomachs of some of the other mammalia, — the ruminating animals, for example. Physiological and histological investigations have shown, however, that the so-called simple stomachs are divided into parts that have different properties and functions. The names and bound- aries of these parts can not be stated precisely, since they vary in different animals, and, moreover, there is some want of agree- ment among different authors regarding the nomenclature of the parts of the stomach, f For the purposes of a physiological description we may use the names indicated in the accompany- ing schematic figure. The main interest lies in the separation of the pyloric part of the stomach or antrum pylori from the main cavity of the stomach. The line of separation is marked by a fissure on the small curvature, incisura angularis (I. A.), and on the large curvature by an abrupt change of direction. The pyloric part * Kahn, "Archiv f. Physiologie," 1903, suppl. volume, 3S6. t See His, "Archiv f. Anatomie," 1903, p. 345; also Cunningham, "Trans- actions of the Royal Society of Edinburgh," 45, 9, 1905-06. MOVEMENTS OF THE ALIMENTARY CANAL. 709 makes an angle, therefore, with the body of the stomach, and differs from the latter in its musculature, the macroscopical and microscop- ical characteristics of its mucous membrane, and in its functional importance. Some writers divide the antrum further into a pyloric vestibule, forming the larger part of the antrum, and a pyloric canal, consisting of the narrower tube-like portion which connects with the duodenum. The pyloric canal is short, about 3 cm., and is more marked as a separate structure in the stomach of young children. The rest of the stomach falls into two sub- divisions, the fundus and the corpus or body. The fundus is the blind, rounded end of the stomach to the left of the cardia, or, in a vertical position of the stomach, the portion that lies above a horizontal plane passing through the cardia; the portion between the fundus and the pylorus is the body of the stomach or the Duodenum Pylorus Pyloric part 'of- 'stomad or antrum pylori Position of transverse 6an> ntermediate or prepyloric region. Fig. 283. — Schematic figure to show the different parts of the stomach. — (After Retzivx.) intermediate or prepyloric region. This latter region shows in many animals a characteristic structure in its secreting glands, and it is in this portion that the hydrochloric acid of the gastric- juice is mainly secreted. The Musculature of the Stomach. — The musculature of the stomach is usually divided into three layers, — a longitudinal, an oblique, and a circular coat. The longitudinal coat is continuous at the cardia with the longitudinal fibers of the esophagus; it spreads out from this point along the length of the stomach, forming a layer of varying thickness; along the curvatures the layer is stronger than on the front and posterior surfaces, while at the pyloric end it increases considerably in thickness, and passes over the pylorus to be continued directly into the longitudinal coat of the duodenum. The layer of oblique fibers is quite incomplete; it seems to be continuous with the circular fibers of the esophagus, and spreads out from the cardia for a certain distance over the front and posterior surfaces of the fundus of the stomach, but toward the pyloric end 710 PHYSIOLOGY OF DIGESTION AND SECRETION. disappears, seeming to pass into the circular fibers. The circular coat, which is placed between the two preceding layers, is the thick- est and most important part of the musculature of the stomach. At the fundus the circular bands are thin and somewhat loosely placed, but toward the pyloric end they increase much in thickness, forming a strong, muscular mass, which, as we shall see, plays the most important part in the movements of the stomach. At the pylorus itself a special development of this layer functions as a sphincter pylori, which with the aid of a circular fold of the mucous membrane makes it possible to shut off the duodenum completely from the cavity of the stomach. The line of separation between the antrum pylori and the body of the stomach is made by a special thickening of the circular fibers which forms a structure known as the "transverse band" by the older writers,* and de- scribed more recentlyf as the "sphincter antri pylorici." Under certain conditions, such as vomiting, stimulation of the vagus, etc., this sphincter may be contracted with such force as to sep- arate the antrum entirely from the fundic end of the stomach. The Movements of the Stomach. — The solid food remains in the stomach for several hours, and during this time the musculature contracts in such a way that the thinner portions as thev are formed by digestion are ejected from time to time through the pylorus into the intestine. Except at the definite intervals when the pyloric sphincter relaxes the food is entirely shut off from the rest of the alimentary canal by the tonic closure of the sphincters at the cardia and the pylorus. There is a certain orderliness in the movements of the stomach, and especially in the separation and ejection of the more liquid from the solid parts, which shows the existence of a specially adapted mechanism. These movements have been studied by many investigators, making use of various experimental meth- ods. The first noteworthy contributions to this subject were those made in this country by Beaumont in his famous observations upon Alexis St. Martin, the Canadian voyageur, who had a per- manent fistulous opening in his stomach as the result of a gunshot wound. | in recent years the subject has been studied with great success by means of the x-rays, § on the excised stomach, || and by means of tambours or sounds introduced into the stomach to meas- ure the pressure changes. 1 These researches all unite in em- * See Beaumont, "Physiology of Digestion," second edition, 1847, p. 104 f Hofmeister und Schiitz, "Archiv f. exper. Pathologie und Pharmakol- ogie, " 1886, vol. xx. % See Osier, "Journal of the American Medical Association," Nov. 15, 1902, for life of Beaumont and account of his work. § See Cannon, "American Journal of Physiology," 1, 359, 1898; and Etoux and Balthazard, "Archives de Physiologic, " 10, 85, 1898. || Hofmeister and Schiitz, loc. tit. % Moritz, "Zeitschrift f. Biologie," 32, 359, 1895. MOVEMENTS OP THE ALIMENTARY CANAL. 711 phasizing one fundamental point — namely, that the fundic end of the stomach is not actively concerned in these movements, but serves rather as a reservoir for retaining the bulk of the food, while the muscular pyloric region is the apparatus which triturates and macerates the food and forces it out from time to time into the duodenum. According to the observations made with the x-ray apparatus, movements begin a few minutes after the entrance of food into the stomach. Small contractions start in the middle region of the stomach and run toward the pylorus. These moving waves of contraction appear at regular intervals. The pyloric portion becomes lengthened and it may be noticed that in this region the peristaltic waves become more and more forcible as digestion progresses. These running waves or rings of contraction serve to press the stomach contents against the pylorus. According to Cannon, they occur in the cat at intervals of 10 seconds and each wave requires about 20 seconds to reach the pylorus. While in human beings, to judge from the sounds which may be heard upon ausculation when food mixed with air is given, they occur at intervals of about 20 seconds. The obvious result of these movements is to mix the food thoroughly, in the intermediate and pyloric portions of the stomach, with the acid gastric juice and to reduce it to a thin, liquid mass, — the chyme. At certain intervals the pyloric sphincter relaxes and the contraction wave squeezes some of the fluid con- tents into the duodenum with considerable force. The mechanism controlling the relaxation of this sphincter is obscure. It does not occur with the approach of each contraction wave, but at irregular intervals. Cannon connects it in part with the consistency of the food, but mainly with the effect of the hydrochloric acid in the gastric secretion. Solid objects forced against the pylorus prevent relaxation and retard the passage of the chyme into the intestine. When liquid food alone is taken into the stomach numerous ob- servations, made by means of intestinal fistulas, prove that the material may be forced into the duodenum within a few minutes. Hydrochloric acid in the stomach seems to favor or produce a relaxation of the pyloric sphincter, while in the duodenum, on the contrary, it causes a contraction of the sphincter. In this way it may be imagined that after each ejection of acid chyme the sphinc- ter is kept closed until the acid material in the duodenum is neutral- ized, and so, automatically, a mechanism is provided by means of which the duodenum is charged at intervals and at such times as it is prepared to receive and neutralize a new quantity of the chyme. According to this description, the portion of the food toward the pyloric end of the stomach is the first to be thoroughly mixed with the gastric juice, and to be broken down partly by digestion and partly by the mechanical action of the contractions. This portion, 712 PHYSIOLOGY OF DIGESTION AND SECRETION. as it is liquefied, is expelled, and its place is taken by new material forced forward from the fundic end. It would seem that this latter portion of the stomach is in a condition of tone, and the pressure thus put upon the contents is sufficient to force them slowly toward the pyloric end as this becomes emptied. The older view was that the contents of the stomach are kept in a general rotary movement so as to become more or less uniformly mixed; but Cannon's obser- vations, and also those of Grutzner,* indicate that the material at the fundic end may remain undisturbed for a long time and thus escape mixture with the acid gastric juice, so far at least as the interior of the mass is concerned. This fact is of importance in con- nection with the salivary digestion of the starchy foods. Obviously, salivary digestion may proceed for a time in the fundic end without being affected by the acid of the stomach. Grutzner fed rats with food of different colors and found that the successive portions were arranged in definite strata. The food first taken lay next to the walls of the stomach, while the succeeding portions were arranged regularly in the interior in a con- centric fashion, as shown in the figure. Such an arrangement of the food is more readily understood when one recalls that the stomach has never any empty space within; its cavity is only as large as its contents, so that the first portion of food eaten entirely fills it and successive por- tions find the wall layer occupied and are therefore received into the interior. The ingestion of much liquid must interfere somewhat with this stratification. Cannon f has reported some interesting experiments upon the relative duration of gastric digestion for carbohydrates, proteins, and fats when fed separately and combined. The foods were mixed with subnitrate of bismuth and their position in the stomach and passage into the intestine were watched by means of the Roentgen rays. It was found that carbohydrate food begins to pass out from the stomach soon after ingestion, and requires only about one-half as much time as the pro- teins for complete gastric digestion. Fats remain long in the stomach when taken alone, and when combined with the other * Grutzner, "Archiv f. die gesammte Physiologic," 106, 463, 1905. t Cannon, "American Journal of Physiology," 12, 387, 1904. For a general review of Cannon's work, see "American Journal of the Medical Sciences," April, 1906. Fig;. 284. — Section of frozen stomach of rat during digestion to show the stratification of food given at different times. — (Grutzner.) The food was given in three portions and colored differently: first, black; sec- ond, white (indicated by vertical marking) ; third, red (indicated by transverse marking). MOVEMENTS OF THE ALIMENTARY CANAL. 713 foodstuffs markedly delay their exit through the pylorus. This distinct difference in the main foodstuffs can hardly be referred to mere mechanical consistency, since the fats are liquefied by the heat of the body. Cannon has shown that this regulation is not effected through the agency of the extrinsic nerves. After section of the splanchnics and vagi the difference in time between the ejection of carbohydrate and protein material still exists, so that the con- trol in this matter must be exerted through some local mechanism in the stomach itself. If, in a given diet, the carbohydrate is fed before the protein, the former, having the position of advantage toward the pyloric end, will be ejected promptly into the intestine, while the protein is retained for gastric digestion. If the order is reversed and the protein is fed first, the passage of the carbohydrate out of the stomach will be retarded. This author has also reported numerous interesting experiments, of medical and surgical interest, which indicate that the motor activity of both stomach and intes- tines may be greatly depressed by certain conditions, especially by mechanical handling or by conditions of general asthenia. Regarding the general mechanism of the stomach, it may be pointed out that it forms an admirably adapted apparatus for receiving at once, or within a short period, a large amount of food which it reduces to a liquid or semiliquid condition, partly by digestion, partly mechanically, and that it charges the intestine at intervals with small amounts of this chyme in such a condition as to admit of rapid digestion. It seems obvious that without the stomach our mode of eating would have to be changed, as it would not be possible to load the intestine rapidly with a large supply of food such as is consumed at an ordinary meal. The Relation of the Nerves to the Movements of the Stomach. — The stomach receives nerve fibers from two sources, — - the vagi and the splanchnics, — but its orderly movements are merely regulated through these extrinsic fibers; it is essentially an auto- matic organ. Thus, it has been shown that the excised stomach (Hofmeister and Schutz), when kept warm, continues to execute regular movements which, if not identical with those observed under normal conditions, have at least an orderly sequence. So also it would appear from the results of several observers * that gastric digestion may proceed normally both as regards secretion and movements after section of the extrinsic nerves. We may regard the stomach, considered as a motor mechanism, as an automatic organ like the heart. Its stimuli to movement arise within itself, but these movements are regulated by the action of the extrinsic nerve fibers so as to adapt them to varying conditions. Whether * See Heidenhain in Hermann's "Handbuch der Physiologie, " vol. v., p. 118. Also Cannon, "American Journal of Physiology, " 1906. 714 PHYSIOLOGY OF DIGESTION AND SECRETION the automaticity is a property of the plain muscle tissue itself, or depends upon the rich supply of intrinsic nerve ganglia (plexuses of Meissner and Auerbach), is a question that cannot be answered definitely at present. The extrinsic nerves not only supply the stomach with efferent fibers, motor and secretory, but also carry afferent fibers from the stomach to the central nervous system. Regarding the purely efferent action of the extrinsic nerves, the results of numerous experiments seem to show quite conclusively that in general the fibers received along the vagus path are motor, artificial stimulation of them causing more or less well-marked con- tractions of part or all of the musculature of the stomach. It has been shown that the sphincter pylori as well as the rest of the muscu- lature is supplied by motor fibers from these nerves. The fibers coming through the splanchnics, on the contrary, are mainly inhib- itory. When stimulated they cause a dilatation of the contracted stomach and a relaxation of the sphincter pylori. Some observers have reported experiments which seem to show that this anatomical separation of the motor and inhibitory fibers is not complete; that some inhibitoiy fibers may be found in the vagi and some motor fibers in the splanchnics. The anatomical courses of these fibers are insufficiently known, but there seems to be no question as to the existence of the two physiological varieties. Through their activity, without doubt, the movements of the stomach may be influenced, favorably or unfavorably, by conditions directly or indirectly affect- ing the central nervous system. Wertheimer* has shown experi- mentally that stimulation of the central end of the sciatic or the vagus nerve may cause reflex inhibition of the tonus of the stomach, and Doj-on f has confirmed this result in cases in which the move- ments and tonicity of the stomach were first increased by the action of pilocarpin and strychnin. Cannon, in his observations upon cats, found that all movements of the stomach ceased as soon as the animal showed signs of anxiety, rage, or distress. Movements of the Intestines. — The muscles of the small and the large intestine are arranged in two layers, — an outer longitudinal and an inner circular coat, — while between these coats and in the submucous coat there are present the nerve-plexuses of Auerbach and Meissner. The general arrangement of muscles and nerves is similar, therefore, to that prevailing in the stomach, and in accor- dance with this we find that the physiological activities exhibited are of much the same character, only, perhaps, not quite so complex. Two main forms of intestinal movement have been distinguished, — the peristaltic and the pendular or rhythmic. Peristalsis. — The peristaltic movement consists in a constriction * "Archiv de physiologie normale et pathologique," 1892, p. 379. t Ibid., 1895, p. 374. MOVEMENTS OF THE ALIMENTARY CANAL. 715 of the walls of the intestine, which, beginning at a certain point, passes downward away from the stomach, from segment to segment, while the parts behind the advancing zone of constriction gradually relax. The wave of constriction may be recorded by the use of suitable apparatus. When thus recorded it is found that the ad- vancing area of constriction is preceded by an area of inhibition or relaxation, so that the peristaltic movement consists of two parts, following in a definite sequence, which seem to combine to facili- tate the movement onward of the intestinal contents; for it is obvious that the wave of constriction will be more effective in forcing the contents forward if just in front of it the intestine is relaxed by inhibition of the tonicity of the muscular coat (Fig. 285). Fig. 285. — Peristaltic contraction of the small intestine (dog). The horizontal line gives the time in seconds. The curve was obtained by recording the diameter of the intestine at a given point during the passage of a peristaltic wave. It will be seen that there was first a dilatation (wave of inhibition), followed by a strong contraction. The smaller waves on the intestinal curve are due to the effect of the respiratory movements on the recording mechanism. Bayliss and Starling,* to whom we owe the discovery of this two- fold character of the movement, regard it as a reflex which is con- trolled within the intestinal wall itself through its intrinsic ganglia and their afferent and efferent connections. When a bolus is inserted into the intestine at any point its effect upon the sensory fibers is such as to cause a reflex contraction of the muscle above the bolus, that is, toward the stomach, and a reflex inhibition or dilatation below. They speak of this definite relationship as the "aw of the intestine. It is obvious that the circular layer of muscles is chiefly involved in peristalsis, since constriction can only be pro- duced by contraction of this layer. To what extent the longitudi- nal muscles enter into the movement is not definitely determined. The term " antiperistalsis " is used to describe the same form of movement running in the opposite direction — that is, toward the stomach. Antiperistalsis is said not fco occur under normal condi- * Bayliss and Starling, "Journal of Physiology," 24, 99, 1899. 716 PHYSIOLOGY OF DIGESTION AND SECRETION. tions ; it has been observed in isolated pieces of intestine or in the ex- posed intestine of living animals when stimulated artificially or after complete intestinal obstruction (Cannon), and Grutzner* reports a number of curious experiments which seem to show that substances such as hairs, animal charcoal, etc., introduced into the rectum may travel upward to the stomach under certain conditions. The peris- taltic wave normally passes downward, and that this direction of movement is dependent upon some definite arrangement in the in- testinal walls is shown by the experiments of Mallf upon reversal of the intestines. In these experiments a portion of the small intestine was resected, turned around, and sutured in place again, so that in this piece what was the lower end became the upper end. In those animals that made a good recovery the nutritive condition gradually became very serious, and when the animals were killed and ex- amined it was found that there was an accumulation of food at the stomach end of the reversed piece of intestine, and that this region showed marked dilatation. The peristaltic movements of the intestines may be observed upon living animals when the abdomen is opened. If the operation is made in the air and the intestines are exposed to its influence, or if the conditions of temperature and circulation are otherwise disturbed, the movements observed are often violent and irregular. The peristalsis runs rapidly along the intestines and may pass over the whole length in about a minute; at the same time the con- traction of the longitudinal muscles gives the bowels a peculiar writhing movement. Movements of this kind are evidently abnormal, and only occur in the body under the strong stimulation of pathological conditions. Normal peristalsis, the object of which is to move the food slowly along the alimentary tract, is quite a different affair. Observers all agree that the wave of contraction is gentle and progresses slowly, although at different rates perhaps in different parts of the intestine. The force of the contraction as measured by Cash J in the dog's intestine is very small. A weight of five to eight grams was sufficient to check the onward movement of the substance in the intestine and to set up violent, colicky contractions which caused the animal evident uneasiness. The time required for the passage of food through the small in- testine must vary with its amount and character. From obser- vations made upon man with the x-ray, Hertz estimates that on the average it requires about 4f hours. After a meal, therefore, we may imagine that at about the time the stomach has finished discharging its contents into the duodenum the first portions *" Deutsche medicinische Wochenschrift," No. 48, 1S94. t "Johns Hopkins Hospital Reports," 1, 93, 1896. j " Proceedings of the Royal Society," London, 41, 1887. MOVEMEMTS OF THE ALIMENTARY CANAL. 717 have reached the ileocecal valve. That is to say, a column of food, broken into separate segments, stretches at one time practi- cally along the whole length of the small intestine. Mechanism of the Peristaltic Movement. — The means by which the peristaltic movement makes its orderly forward progression have not been determined bej^ond question. The simplest explana- tion would be to assume that an impulse is conveyed directly from cell to cell in the circular muscular coat, so that a contraction started at any point would spread by direct conduction of the contraction change. This theory, however, does not explain satisfactorily the normal conduction of the wave of contraction always in one direc- tion, nor the fact that the wave of contraction is preceded by a wave of inhibition. Moreover, Bayliss and Starling state that, although the peristaltic movements continue after section of the extrinsic nerves, — indeed, become more marked under these con- ditions,— the application of cocain or nicotin prevents their oc- currence. Since these substances may be supposed to act on the intrinsic nerves, it is probable that the co-ordination of the move- ment is effected through the local nerve ganglia, but our knowledge of the mechanism and physiology of these peripheral nerve-plexuses is as yet quite incomplete. Rhythmical Movements. — In addition to the peristaltic wave a second kind of movement may be observed in the small intestines. It consists essentially in a series of local constrictions of the intes- tinal wall, the constrictions occurring rhythmically at those points at which masses of food lie. Cannon * has studied1 these movements most successfully by means of the Roentgen rays. He finds that as a result of these contractions the masses or strings of food lying in the intestine are suddenly segmented, repeatedly and in a definite manner, into a number of small pieces, which move to and fro as the pieces combine and are again separated (see Fig. 286). These segmentations may proceed at the rate of thirty per minute for a certain time, and the apparent result is that the material is well mixed with the digestive secretions and is brought thoroughly into contact with the absorp- tive walls. During these rhythmical contractions there is no steady progression of the food; it remains in the same region, although subjected to repeated divisions. From time to time the separated pieces are caught by an advancing peristaltic wave, moved forward a certain distance, and gathered again into a new mass. In this new location the rhythmical contractions again segment and churn the mass before a new peristaltic wave moves it on. According to this description, the rhythmical movements are local contractions (mainly of the circular muscles) which seem * Cannon, "American Journal of Physiology," 6, 251, 1902. 718 PHYSIOLOGY OF DIGESTION AND SECRETION. to be due to the local distention caused by the food. They occur rhythmically for a certain period and then cease until a new series is started, and it is obvious that they must play a very important- part in promoting both the digestion and absorption of the food. Mall* has suggested that these rhythmical contractions of the q56 t ^booooo Fig. 286. — Diagram to show the effect of the rhythmical constricting movements of the small intestine upon the contained food. A string of food (1) is divided suddenly into a series of segments (2) ; each of the latter is again divided and the process is repeated a number of times (3 and 4). Eventually a peristaltic wave sweeps these segments forward a certain distance and gathers them again into a long string, as in (1). The process of segmentation is then repeated as described above. (Cannon.) circular coats may also act as a pumping mechanism upon the venous plexuses in the walls and thus aid in driving the blood into the portal system. Similar movements have been observed in the human being. f The curious observation is reportedj that during the period of fasting (dog) the whole gastro-intestinal canal, although empty, shows at intervals rhythmical con- tractions of its musculature which may last for twenty to thirty minutes (see p. 778). The Nervous Control of the Intestinal Movements. — There is some evidence to show that the rhythmical contractions of the intestines are muscular in origin (myogenic), while the more co- ordinated peristaltic movements depend upon the intrinsic nervous mechanism. The intestine is, however, not dependent for either movement upon its connections with the central nervous system. Like the stomach, it is an automatic organ whose activity is simply regulated through its extrinsic nerves. The small intestine and the greater part of the large intestine receive visceromotor nerve fibers from the vagi and the sympathetic chain. The former, according to most observers, when artifically stimulated cause movements of the intestine, and are therefore regarded as the motor fibers. It seems probable, however, that the vagi carry or may carry in some animals inhibitory fibers as well, and that the motor effects usually obtained upon stimulation are *Mall, "Johns Hopkins Hospital Reports," 1896, i., 37. t Hertz, loc. cit. % BoldirefT, "Archives des sciences biologiques, " 11, 1, 1905. MOVEMENTS OF THE ALIMENTARY CANAL. 719 due to the fact that in these nerves the motor fibers predominate. The fibers received from the sympathetic chain, on the other hand, give mainly an inhibitory effect when stimulated, although some motor fibers apparently may take this path. Bechterew anti Mislawski * state that the sympathetic fibers for the small intestine emerge from the spinal cord as medullated fibers in the sixth dorsal to the first lumbar spinal nerves, (or lower — Bunch) and pass to the sympathetic chain in the splanchnic nerves and thence to the semilunar plexus. The paths of these fibers through the central nervous system are not known, but there are evidently connections extending to the higher brain centers, since psychical states are known to influence the movements of the intestine, and according to some observers stimulation of portions of the cerebral cortex may produce movements or relaxation of the walls of the small and large intestines. Effect of Various Conditions upon the Intestinal Move- ments.— Experiments have shown that the movements of the in- testines may be evoked in many ways in addition to direct stimu- lation of the extrinsic nerves. Chemical stimuli may be applied directly to the intestinal wall. Mechanical stimulation — pinching, for example, or the introduction of a bolus into the intestinal cavity — may start peristaltic movements. Violent movements may be produced also by shutting off the blood-supply, and again temporarily when the supply is re-established. A condition of dyspnea may also start movements in the intestines or in some cases inhibit movements which are already in progress, the stimu- lus in this case seeming to act upon the central nervous system and to stimulate both the motor and the inhibitory fibers. Oxygen gas within the bowels tends to suspend the movements of the intes- tine, while C02, CH4, and H2S act as stimuli, increasing the move- ments. Organic acids, such as acetic, propionic, formic, and caprylic, which may be formed normally within the intestine as the result of bacterial action, act also as strong stimulants. Movements of the Large Intestine. — The opening from the small intestine into the large is controlled both by the ileocecal valve and by a sphincter, the ileocecal or ileocolic sphincter. It is stated that this sphincter is normally in tonus and that its condition of tonus is regulated through the splanchnic nerve (Magnus). The musculature in the large intestine has the same general arrangement as in the small, and the usual view has been that the movements are similar, although more infre- quent, so that the material received from the small intestine is slowly moved along while becoming more and more solid * "Archiv f. Physiologie," 1889, suppl. volume. 720 PHYSIOLOGY OF DIGESTION AND SECRETION. from the absorption of water, until in the form of feces it reaches the sigmoid flexure and rectum. Bayliss and Starling state that their law of intestinal peristalsis holds in this portion of the intestine, — that is, local excitation causes a constriction above and a dilatation below the point stimulated. Cannon,* however, from his studies of the normal movements in cats, as seen by the Roentgen rays, comes to the conclusion that the movements in the large intestine show a marked peculiarity previously overlooked. He divides the large intestine into two parts; in the second, cor- responding roughly to the descending colon the food is moved toward the rectum by peristaltic waves. A number of constrictions may be seen simultaneously within a length of some inches. In the ascending and transverse colon and cecum, on the contrary, the most frequent movement is that of antiperistalsis. The food in this portion of the canal is more or less liquid and its presence sets up running waves of constriction, which, beginning somewhere in the colon, pass toward the ileocecal valve. These waves occur in groups separated by periods of rest. The presence of the ileocecal valve prevents the material from being forced back into the small in- testine. The value of this peculiar reversal of the normal move- ment of the bowels at this particular point would seem to lie in the fact that it delays the passage of the material toward the rectum and by thoroughly mixing it gives increased opportunities for the completion of the processes of digestion and absorption. Hertz estimates that in man the food requires about 2 hours to pass from the ileocecal valve to the hepatic flexure and about 4\ hours to reach the splenic flexure. As the colon becomes filled some of the material penetrates into the descending part, where the normal peristalsis carries it very slowly toward the rectum. The large intestine — particularly the descending colon and rectum — receives its nerve supply from two sources (Fig. 287) : (1) Fibers which leave the spinal cord in the lumbar nerves (second to fifth in cat), pass to the sympathetic chain, and thence to the inferior mesenteric ganglia, which probably form the termination of the preganglionic fibers. From this point the path is continued by fibers running in the hypogastric nerves and plexus. Stimulation of these fibers has given different results in the hands of various observers, but the most recent workf indicates that they are inhibitory. (2) Fibers that leave the cord in the sacral nerves (second to fourth), form part of the nervi erigentes and enter into the hypogastric plexus. When * Cannon, loc. cit. t Langley and Anderson, "Journal of Physiology," 18, 67, 1895. Bay- lias and Starling, ibid., 20, 107, 1900. Also Wischnewsky, in Hermann's " Jahresbericht der Physiologie," vol. xii., 1895. MOVEMENTS OF THE ALIMENTARY CANAL. 721 stimulated these fibers cause contractions of the muscular coats; they may be regarded, therefore, as motor fibers. As in the ease of the small intestine and stomach, we may assume that jjjrripofhfAc Trunk Komi. Ifferetttes GonqLioH rtiesenlericum tnftr/us Branches ta Cofo, l.L umhar I. Lumbar QonqlUn n r. II. L. ganal. m.L. ML ganal. 1V.L IV.L qanq V.L V.Lganal. VI. L VI.Jj.aano/. vn.L. Valiganol- 1. Sacral U.S. MS. rlkrus ffy/xyos/r/cus Fig. 287. — Schema to show the innervation of the rectum and internal sphincter of the anus, and the formation of the hypogastric plexus. (After Frankl-Hochwart and Frohlich.) •these motor and inhibitory fibers serve for the reflex regulation and adaptation of the movements. Defecation. — The undigested and indigestible parts of the food, together with some of the debris and secretions from the alimentary tract eventually reach the sigmoid flexure and rectum. Authorities differ as to whether the rectum normally contains fecal material or not. According to the observations of Hertz,* made upon man by means of x-ra}rs, fecal material is normally absent, from the rectum except just before defeca- tion. It seems probable that a distinct desire to defecate is felt only when the feces have actually entered the rec- tum and produced some distension. The fecal material is retained within the rectum by the action of the two sphincter muscles which close the anal opening. One of these muscles, the internal sphincter, is a strong band of the circular layer of involuntary muscle which forms one of the coats of the rectum. 46 Hertz, "Guy's Hospital Reports," 61, 389, 1907. 722 PHYSIOLOGY OF DIGESTION AND SECRETION. When the rectum contains fecal material this muscle is thrown into a condition of tonic contraction until the act of defecation begins, when it is relaxed. The external sphincter ani is com- posed of striated muscle tissue and is under the control of the will to a certain extent. It is supplied by a motor nerve, the Xn. hemorrhoidales inferiores, arising from the N. pudendus and eventually from the sacral spinal nerves. This muscle, therefore, like striated muscle in general, is innervated directly from the spinal cord, but it possesses properties which are to some extent intermediate between those of plain and of striated muscle. For example, it differs from the latter and resembles the former in the fact that it does not atrophy after section of its motor nerve; it is much less sensitive to the paralyzing action of curare than the typical striated muscle, and it is stated that its curve of contraction, when it is stimulated through its nerve, exhibits a long latent period and a slow contraction and relaxa- tion. Both the internal and the external sphincter are normally in tonus and unite in protecting the anal opening. The force of the tonic contraction of the internal is somewhat less (30 to 60 per cent.) than that of the external sphincter. f The innerva- tion and control of the internal sphincter is better understood than that of the external. Like the rest of the rectum, it receives motor fibers from the hypogastric plexus by way of the nervus erigens, and inhibitory fibers from the same plexus by way of the hypogastric nerve. It has been possible to show experimentally that each of these sets of fibers may be acted upon reflexly, for example, by stimulation of the sensory nerves in the sciatic. The reflex takes place in this case through the lower portion of the cord. Both the hypogastric nerve and the N. erigens con- tain also afferent fibers. Stimulation of the central end of the severed N. erigens gives a reflex inhibition through the hypo- gastric nerve, and stimulation of the central stump of the cut hypogastric causes a reflex contraction through the N. erigens. It is even stated that these latter reflexes may be obtained when the lumbosacral cord is destroyed, a fact which if correct would indicate a reflex effected through an outlying ganglion (inf. mesenteric ganglion). The act of defecation as it occurs normally is partly a voluntary and partly an involuntary act. The involuntary act consists in peristaltic contractions of the rectum or, indeed, of the whole colon, together with an inhibi- tion of the sphincters. Whether the inhibition of the sphincters is normally entirely an involuntary reflex cannot be stated * Consult Frankl-Hochwart and Frohlkh, "Archiv f. d. ges. Physiologic," 81, 420. MOVEMENTS OF THE ALIMENTARY CANAL. 723 definitely. No doubt the sensory stimuli arising from the accu- mulation of fecal material would eventually cause in this way a relaxation of the sphincters, but the act of defecation usually takes place before such a strong necessity arises. It is initiated usually by a voluntary act and it is possible that in such cases the relaxation of both sphincters may be effected by voluntary inhibition acting upon the spinal centers. The voluntary factor in defecation consists mainly in the contraction of the abdominal muscles. When these latter muscles are contracted and at the same time the diaphragm is prevented from moving upward by the closure of the glottis, the increased abdominal pressure is brought to bear upon the abdominal and pelvic viscera, and aids strongly in pressing the contents of the descending colon and sigmoid flexure into the rectum. The pressure in the abdominal cavity is still further increased if a deep inspiration is first made and then maintained during the contraction of the abdominal muscles. Hertz, on the basis of his skiagraphic observations, insists that simul- taneously with the contraction of the abdominal muscles and the closure of the glottis the diaphragm is also contracted and thus aids in bringing pressure to bear upon the pelvic organs. Although the act of defecation is normally initiated by voluntary effort, it may also be carried out as a purely involuntary reflex when the sensory stimulus is sufficiently strong. Goltz* has shown that in dogs in which the spinal cord had been severed in the lower thoracic region defecation was performed normally. In later experiments, in which the entire spinal cord was removed except in the cervical and upper part of the thoracic region, it was found that the animal, after it had recovered from the operation, had normal movement once or twice a day, indicating that the rectum and lower bowels acted by virtue of their intrinsic mechanism. An interesting result of these experi- ments was the fact that the external sphincter suffered no atrophy, although its motor nerve was destroyed, and that it eventually regained its tonic activity. It would seem that the whole act of defecation is, at bottom, an involuntary reflex. The physiological center for the move- ment probably lies in the lumbar cord, and it has sensory and motor connections with the rectum and the muscles of defecation. As stated above, the inhibitory fibers to the internal sphincter pass by way of the hypogastric nerve, the motor fibers through the nervus erigens, and both of these nerves contain afferent fibers which may reflexly excite inhibition or contraction. But * "Archiv f . die gesammte Physiologie," 8, 160, 1874; 63, 362, 1896. 724 PHYSIOLOGY OF DIGESTION AND SECRETION. this center is probably provided also with intraspinal con- nections with the centers of the cerebrum, through which the act may be controlled by voluntary impulses and by various psychical states; the effect of emotions upon defecation being a matter of common knowledge. In infants the essentially in- voluntary character of the act is well known. Vomiting. — The act of vomiting causes an ejection of the con- tents of the stomach through the esophagus and mouth to the exterior. It was long debated whether the force producing this ejection comes from a strong contraction of the walls of the stom- ach itself or whether it is due mainly to the action of the walls of the abdomen. A forcible spasmodic contraction of the abdominal muscles takes place, as may easily be observed by any one upon himself, and it is now believed that the contraction of these muscles is the principal factor in vomiting. Magendie found that if the stomach was extirpated and a bladder containing water was sub- stituted in its place and connected with the esophagus, injection of an emetic caused a typical vomiting movement with ejection of the contents of the bladder. Gianuzzi showed, on the other hand, that upon a curarized animal vomiting could not be produced by an emetic — because, apparently, the muscles of the abdomen were paralyzed by the curare. There are on record a number of ob- servations which tend to show that the stomach is not passive during the act. On the contrary, it may exhibit contractions, more or less violent in character. According to Openchowski,* the pylorus is closed and the pyloric end of the stomach firmly con- tracted so as to drive the contents toward the dilated cardiac por- tion. Cannon states that in cats the normal peristaltic waves pass over the pyloric portion in the period preceding the vomiting and that finally a strong contraction at the "transverse band" com- pletely shuts off the pyloric portion from the body of the stomach, which at this time is quite relaxed. The act of vomiting is, in fact, a complex reflex movement into which many muscles enter. The following events are described : The vomiting is usually preceded by a sensation of nausea and a reflex flow of saliva into the mouth. These phenomena are succeeded or accompanied by retching move- ments, which consist essentially in deep, spasmodic inspirations with a closed glottis. The effect of these movements is to compress the stomach by the descent of the diaphragm, and at the same time to increase decidedly the negative pressure in the thorax, and therefore in the thoracic portion of the esophagus. During one of these retching movements the act of vomiting is effected by a convulsive contraction of the abdominal wall that exerts a sudden additional "Archiv f. Physiologic/' 1889, p. 552. MOVEMENTS OF THE ALIMENTARY CANAL. 725 strong pressure upon the stomach. At the same time the cardiac orifice of the stomaCh is dilated, probably by an inhibition of the sphincter caused by the rise of pressure in the stomach, and according to the above description the fundic end of the stomach is also dilated, while the pyloric end is in strong contraction. The stomach contents are, therefore, forced violently out of the stomach through the esophagus, the negative pressure in the latter probably assisting in the act. The passage through the esophagus is effected mainly by the force of the contraction of the abdominal muscles; there is no evidence of antiperistaltic move- ments on the part of the esophagus itself. During the ejection of the contents of the stomach the glottis is kept closed by the adductor muscles, and usually the nasal chamber is likewise shut off from the pharynx by the contraction of the posterior pillars of the fauces on the palate and uvula. In violent vomit- ing, however, the vomited material may break through this latter barrier and be ejected partially through the nose. Nervous Mechanism of Vomiting. — That vomiting is a reflex act is abundantly shown by the frequency with which it is produced in consequence of the stimulation of sensory nerves or as the result of injuries to various parts of the central nervous system. After lesions or injuries of the brain vomiting often results. Disagreeable emotions and disturbances of the sense of equilibrium may produce the same result. Irritation of the mucous membrane of various parts of the alimentary canal (as, for example, tickling the back of the pharynx with the finger); disturbances of the urogenital apparatus, the liver, and other visceral organs; artificial stimula- tion of the trunk of the vagus and of other sensory nerves, may all cause vomiting. Under ordinary conditions, however, irritation of the sensory nerves of the gastric mucous membrane is the most common cause of vomiting. This effect may result from the prod- ucts of fermentation in the stomach in cases of indigestion, or may be produced intentionally by local emetics, such as mustard, taken into the stomach. The afferent path in this case is through the sensory fibers of the vagus. The efferent paths of the reflex are found in the motor nerves innervating the muscles concerned in the vomiting, — namely, the vagus, the phrenics, and the spinal nerves supplying the abdominal muscles. Whether or not there is a defi- nite vomiting center in which the afferent impulses are received and through which a co-ordinated series of efferent impulses is sent out to the various muscles has not been satisfactorily deter- mined. It has been shown that the portion of the nervous system through which the reflex is effected lies in the medulla, and it may be observed that the muscles concerned in the act, outside those 726 PHYSIOLOGY OP DIGESTION AND SECRETION. of the stomach, are respiratory muscles. Vomiting, in fact, consists essentially in a simultaneous spasmodic contraction of expiratory (abdominal) muscles and inspiratory muscles (diaphragm). It has therefore been suggested that the reflex involves the stimulation of the respiratory center or some part of it. Thumas claims to have located a vomiting center in the medulla in the immediate neighbor- hood of the calamus scriptorius. Further evidence, however, is required upon this point. The act of vomiting may be produced not only as a reflex from various sensory nerves, but may also be caused by direct action upon the medullary centers. The action of apomorphin is most easily explained by supposing that it acts directly on the nerve centers. CHAPTER XL. GENERAL CONSIDERATIONS UPON THE COMPOSITION OF THE FOOD AND THE ACTION OF ENZYMES. Foods and Foodstuffs. — The term food when used in a popular sense includes everything that we eat for the purpose of nourishing the body. From this point of view the food of mankind is of a most varied character, comprising a great variety of products of the animal and vegetable kingdoms. Chemical analysis of the animal and vegetable foods shows, however, that they all contain one or more of five or six different classes of substances which are usually designated as the foodstuffs (older names, alimentary or proximate principles) on the belief that they form the useful constituent of our foods. The classification of foodstuffs usually given is as follows: f Water. _ I Inorganic salts. | Proteins. Foodstuff J Albuminoids, a group of bodies belonging to the general group of proteins, but having in some respects a different nutri- tive value. | Carbohydrates. I Fats. From the scientific point of view, a foodstuff or food may be defined as a substance absolutely necessary to the normal composition of the body, as in the case of water and salts, or as a substance which can be acted upon by the tissues of the body in such a way as to yield energy (heat, for example) or to furnish material for the pro- duction of living tissue. Moreover, to be a food in the physiological sense the substance must not directly or indirectly affect injuriously the normal nutritive processes of the tissues. The five or six substances named above are all foods in this sense. The water and certain salts of sodium, potassium, calcium, magnesium, iron, and perhaps other elements are absolutely necessary to maintain the normal composition of the tissue. Complete withdrawal of any one of these constituents would cause the death of the organism. Proteins, fats, and carbohydrates, on the other hand, are substances whose molecules have a more or less complex structure. When eaten and digested they enter the body liquids and are employed either in the synthesis of the more complex living matter, or they undergo various chemical changes, spoken of in general as metab- olism, which result finally in the breaking up of their complex 727 728 PHYSIOLOGY OF DIGESTION AND SECRETION. molecules into simpler compounds. The chemical changes of metab- olism or nutrition are, in the long run, mainly exothermic, — that is, they are attended by the production of heat. Some of the chem- ical or internal energy that held the complex molecules together assumes the form of heat, or perhaps muscular work, after these molecules are broken down by oxidative changes to simpler, more stable structures, such as water, carbon dioxid, and urea. Proteins, fats, and carbohydrates form materials that the tissue cells are adjusted to act upon after they have undergone certain changes during digestion. Other complex organic compounds containing chemical energy are either injurious to the tissues, or they have a structure such that the tissues cannot act upon them. Such substances cannot be considered as foods in the scientific sense. When, therefore, we desire to know the food value of any animal or vegetable product, we analyze it to determine its composition as regards water, salts, proteins, fats, and carbohydrates. The following table compiled by Munk from the analyses given by Konig * may be taken as an indication of the average composition of the most commonly used foods: COMPOSITION OF FOODS. In 100 Parts. Water. Protein. Fat. 76.7 20.8 1.5 73.7 12.6 12.1 36-60 25-33 7-30 87.7 3.4 3.2 89.7 2.0 3.1 13.3 10.2 0.9 35.6 7.1 0.2 13.7 11.5 2.1 42.3 6.1 0.4 13.1 7.0 0.9 13.1 9.9 4.6 10.1 9.0 0.3 12-15 23-26 1^-2 75.5 2.0 0.2 87.1 1.0 0.2 90 2-3 0.5 73-91 4-8 0.5 84 0.5 Carbohydrate Meat Eggs Cheese Cows' milk Human milk Wheat flour Wheat bread Rye flour Rye bread Rice Com Macaroni Peas, beans, lentils Potatoes Carrots Cabbages Mushrooms Fruit An examination of this table shows that the animal foods, par- ticularly the meats, are characterized by their small percentage in carbohydrate and by a relatively large amount of protein or of protein and fat. With regard to the last two foodstuffs, meats differ *See Konig, "Die menschlichen Nahrungs und Genussmittel "; and Atwater and Bryant, "The Chemical Composition of American P'ood Mate- rials," Bulletin 28, United States Department of Agriculture, 1899. COMPOSITION OF FOOD AND ACTION OF ENZYMES. 729 very much among themselves. Some idea of the limits of variation may be obtained from the following table, taken chiefly from Konig's analyses: Water. Protein. Fat. 73.03 20.96 5.41 72.31 18.88 7.41 75.99 17.11 5.77 72.57 20.05 6.81 62.58 22.32 8.68 10.00 3.00 80.50 71.6 18.8 8.2 Carbohydrate. Ash. Beef, moderately fat . . Veal, fat Mutton, moderately fat Pork, lean Ham, salted Pork (bacon), very fat* Mackerel * 0.46 0.07 1.14 1.33 1.33 1.10 6.42 6.5 1.4 The vegetable foods are distinguished, as a rule, by their large percentage in carbohydrates and the relatively small amounts of proteins and fats, as seen, for example, in the composition of rice, corn, wheat, and potatoes. Nevertheless, it will be noticed that the proportion of protein in some of the vegetables is not at all insignifi- cant. They are characterized by their excess in carbohydrates rather than by a deficiency in proteins. The composition of peas and other leguminous foods is remarkable for the large percentage of protein, which exceeds that found in meats. Analyses such as are given here are indispensable in determining the true nutritive value of foods. Nevertheless, it must be borne in mind that the chemical composition of a food is not alone sufficient to determine its precise value in nutrition. It is obviously true that it is not what we eat, but what we digest and absorb, that is nutritious to the body; so that, in addition to determining the proportion of food- stuffs in any given food, it is necessary to determine to what extent the several constituents are digested. This factor can be obtained only by actual experiments. It may be said here, however, that in general the proteins of animal foods are more completely digested than are those of vegetables, owing chiefly to the fact that the latter may contain a'considerable amount of indigestible cellulose, which tends to protect the protein from the action of the diges- tive secretions. In the animal foods, therefore, chemical analysis comes nearer to expressing directly the nutritive value. Accessory Articles of Diet. — In addition to the foodstuffs proper, our foods contain numerous other substances which in one way or another are useful in nutrition, although not abso- lutely necessary. These substances, differing in nature and importance, may be classified under the three heads of: Flavors: the various oils or esters that give odor and taste to foods. Condiments: pepper, salt, mustard, etc. Stimulants: alcohol, tea, coffee, cocoa, etc. * Atwater: "The Chemistry of Foods and Nutrition," 1887. 730 PHYSIOLOGY OF DIGESTION AND SECRETION. The specific influence of these substances in digestion and nutri- tion is considered in the section on Nutrition. The Chemical Changes of the Foodstuffs during Digestion. — The physiology of digestion consists chiefly in the study of the chemical changes that the food undergoes during its passage through the alimentary canal. It happens that these chemical changes are of a peculiar character. The peculiarity is due to the fact that the changes of digestion are effected through the agency of a group of bodies known as enzymes, or unorganized ferments, whose chemical action is more obscure than that of the ordinary reagents with which we have to deal. It will save repetition to give here certain general facts that are known with reference to these bodies, reserving for later treatment the details of the action of the specific enzymes found in the different digestive secretions. ENZYMES AND THELR ACTION. Historical. — The term fermentation and the idea that it is meant to convey has varied greatly during the course of years. The word at first was applied to certain obvious and apparently spon- taneous changes in organic materials which are accompanied by the liberation of bubbles of gas: such, for instance, as the alcoholic fermentations, in which alcohol is formed from sugar; the acid fer- mentations, as in the souring of milk; and the putrefactive fer- mentations, by means of which animal substances are disintegrated, with the production of offensive odors. These mysterious phenom- ena excited naturally the interest of investigators, and with the development of chemical knowledge numerous other processes were discovered which resemble the typical fermentations in that they seem to be due to specific agents whose mode of action differs from the usual chemical reactions, especially in the fact that the causa- tive agent itself, or the ferment as it is called, is not destro}red or used up in the reaction. Thus it was discovered that germinating barley grains contain a something which can be extracted by water and which can convert starch into sugar (Kirchhoff, 1814). Later this substance was separated by precipitation with alcohol and was given the name of diastase (Payen and Persoz, 1833). Schwann in 1836 demonstrated the existence of a ferment (pepsin) in gastric juice capable of acting upon albuminous substances, and a number of similar bodies were soon discovered: trypsin in the pancreatic juice, amygdalin, invertin, ptyalin, etc. These substances were all designated as ferments, and their action was compared to that of the alcoholic fermentation in yeast, the process of putrefaction, etc. Naturally very many theories have been proposed regarding the cause of the processes of fermentation. For the historical develop- COMPOSITION OF FOOD AND ACTION OF ENZYMES. 731 ment and interrelation of these theories references must be made to special works.* It is sufficient here to say that the brilliant work of Pasteur established the fact that the fermentations in the old sense — alcoholic, acid, and putrefactive — are due to the presence and activity of living organisms. He showed, moreover, that many diseases are likewise due to the activity of minute living organisms, and thus justified the view held by some of the older physicians that there is a close similarity in the processes of fer- mentation and disease. The clear demonstration of the importance of living organisms in some fermentations and the equally clear proof of the existence of another group of ferment actions in which living material is not directly concerned led to a classification which is used even at the present day. This classification divided fer- ments into two great groups : the living or organized ferments, such as the yeast cell, bacteria, etc.; and the non-living or unorganized ferments, such as pepsin, trypsin, etc., which later were generally designated as enzymes (Kuhne). The separation appeared to be entirely satisfactory until Buchner (1897) showed that an unor- ganized ferment, an enzyme (zymase) capable of producing alcohol from sugar, may be extracted from yeast cells. Later the same observer (1903) succeeded in extracting enzymes from the lactic- acid-producing bacteria and the acetic-acid-producing bacteria which are capable of giving the same reactions as the living bacteria. These discoveries indicate clearly that there is no essential difference between the activity of living and non-living ferments. The so- called organized ferments probably produce their effects not by virtue of their specific life-metabolism, but by the manufacture within their substance of specific enzymes. If we can accept this conclusion, then the general explanation of fermentation is to be sought in the nature of the enzymatic processes. Within recent years the study of the enzymes has attracted especial attention. The general point of view regarding their mode of action that is most frequently met with to-day is that advocated especially by Ostwald. He assumes, reviving an older view (Berzelius), that the ferment actions are similar to those of catalysis. By catalysis chemists designated a species of reaction which is brought about by the mere contact or presence of certain substances, the catalyzers. Thus, hydrogen and oxj^gen at ordinary temperatures do not combine to form water, but if spongy platinum is present the two gases unite readily. The platinum does not enter into the reaction, at least it undergoes no change, and it is said, therefore, * Consult Green, "The Soluble Ferments and Fermentations," 1899 Effront, "Enzymes and their Applications" (translation by Prescott), 1902 Oppenheimer, "Die Fermente und ihre Wirkungen," second edition, 1903 Moore, in "Recent Advances in Physiology and Biochemistry, London and New York," 1906; Vernon, "Intracellular Enzymes," London, 1908. 732 PHYSIOLOGY OF DIGESTION AND SECRETION. to act by catalysis. Many similar catalytic reactions are known, and the chemists have reached the important generalization that in such reactions the catalyzer, platinum in the above instance, simply hastens a process which would occur without it, but much more slowly. A catalyzer is a substance, therefore, that alters the velocity of a reaction, but does not initiate it. This idea is illustrated very clearly by the catalysis of hydrogen peroxid. This substance decomposes spontaneously into water and oxygen accord- ing to the reaction H202 = H20 + 0, but the decomposition is greatly hastened by the presence of a catalyzer. Thus, Bredig has shown that platinum in very fine suspension, so-called colloidal solution, exerts a marked accelerating influence upon this reaction; one part of the colloidal platinum to 350 million parts of water may still exercise a perceptible effect. The blood and aqueous ex- tracts of various tissues also catalyze the hydrogen peroxid readily, and this effect has been attributed to the action of an enzyme (cata- lase). The view has been proposed, therefore, that the enzymes of the body act like the catalyzers of inorganic origin: they influence the velocity of certain special reactions. Such a general conception as this unifies the whole subject of fermentation and holds out the hope that the more precise investigations that are possible in the case of the inorganic catalyzers will eventually lead to a better under- standing of the underlying physical causes of fermentation. It should be borne in mind, however, that some of the best known of the ferment actions of the body, such as the peptic or tryptic digestion of protein, fit into this view only theoretically and by analogy. As a matter of fact, albumins at ordinary temperatures do not split up spontaneously into the products formed by the action of pepsin; if we consider that the pepsin simply accelerates a reaction already taking place, it must be stated that this reaction at ordinary temperatures is infinitely slow, — that is, practically does not occur. At higher temperatures, however, similar decompositions of al- bumin may be obtained without the presence of an enzyme. Reversible Reactions. — It has been shown that under proper conditions many chemical reactions are reversible, — that is, may take place in opposite directions. For instance, acetic acid and ethyl-alcohol brought together react with the production of ethyl- acetate and water: CH3COOH + C2H5OH = CH3COOC2Hs + H20. Acetic acid. Alcohol. Ethyl-acetate. Water. On the other hand, when ethyl-acetate and water are brought together they react with the formation of some acetic acid and ethyl-alcohol, so that the reaction indicated in the above equation COMPOSITION OF FOOD AND ACTION OF ENZYMES. 733 takes place in opposite directions, figuratively speaking, — a fact which may be indicated by a symbol of this kind: CH3COOH + C2H5OH q± CH3COOC2H5 + H20. It is evident that in a reversible reaction of this sort the opposite changes will eventually strike an equilibrium, the solution or mix- ture will contain some of all four substances, and this equilib- rium will remain constant as long as the conditions are unchanged. If the conditions are altered, however, — if, for example, some of the substances formed are removed or the mixture is altered as to its concentration, — then the reaction will proceed unequally in the two directions until a new equilibrium is established. The importance, in the present connection, of this conception of reversibility of reac- tions is found in the fact that a number of the catalytic reactions are also reversible. The catalyzer may not only accelerate a reac- tion between two substances, but may also accelerate the recom- position of the products into the original substances. An excellent instance of this double effect has been obtained by Kastle and Loevenhart in experiments upon one of the enzymes of the animal body, lipase. Lipase is the enzyme which in the body acts upon the neutral fats, converting them into fatty acids and glycerin, — a process that takes place as a usual if not necessary step in the diges- tion and absorption of fats. The authors above named* made use of a simple ester analogous to the fats, ethyl-butyrate, and showed that lipase causes not only an hydrolysis of this substance into ethyl- alcohol and butyric acid, but also a synthesis of the two last-named substances into ethyl-butyrate and water. The reaction effected by the lipase is therefore reversible and may be expressed as: C3H7COOC2H5 + H20 ^± C3H7COOH + C2H6OH. Ethyl-butyrate. Water. Butyric acid. Ethyl-alcohol. Lipase is capable of exerting probably a similar reversible reaction on the fats in the body. Assuming the existence of such an action in the body, it is possible to explain not only the digestion of fats, but also their formation in the tissues and their absorption from the tissues during starvation. That is, according to the conditions of concentration, etc., one and the same enzyme may cause a splitting up of the neutral fat into fatty acids and glycerin or a storing up of neutral fat by the synthesis of fatty acid and glycerin. In the subcutaneous tissues, therefore, fat may be stored, to a certain point, or, if the conditions are altered, the fat that is there may be changed over to the fatty acids and glycerin and be oxidized in the body as food. A similar reversibility has been shown for some of the other * Kastle and Loevenhart, "American Chemical Journal," 24, 491, 1900. See also Loevenhart, "American Physiological Journal," 6, 331, 1902. 734 PHYSIOLOGY OF DIGESTION AND SECRETION. enzymes of the body (maltase by Hill, 1898), but whether or not all of them will be shown to possess this power under the conditions of temperature, etc., that prevail in the body can only be determined by actual experiments. The Specificity of Enzymes. — A most interesting feature of the activity of enzymes is that it is specific. The enzymes that act upon the carbohydrates are not capable of affecting the pro- teins or fats, and vice versa. So in the fermentation of closely related bodies such as the double sugars, the enzyme that acts upon the maltose is not capable of affecting the lactose; each re- quires seemingly its own specific enzyme. In fact, there is no clear proof that any single enzyme can produce more than one kind of ferment action. If in any extract or secretion two or more kinds of ferment action can be demonstrated, the tendency at present is to attribute these different activities to the existence of separate and specific enzymes. The pancreatic juice, for example, splits proteins, starches, and fats and curdles milk, and there are assumed to be four different enzymes present, — namely, trypsin, diastase, lipase, and rennin. So if an extract containing diastase is also capable of decomposing hydrogen peroxid it is believed that this latter effect is due to the existence of a special enzyme, catalase. It seems quite probable that this specificity of the different enzymes may be related, as Fischer* has suggested, to the geometrical struc- ture of the substance acted upon. Each ferment is adapted to act upon or become attached to a molecule with a certain definite structure, — fitted to it, in fact, as a key to its lock. In this respect the action of the so-called hydrolytic enzymes differs markedly from the dilute acids or alkalies which hydrolyze many different substances without indication of any specificity. Attention has been called to the fact that this adaptibility of enzymes to certain specific struc- tures in the molecules acted upon resembles closely the specific activity of the toxins, and many useful and suggestive com- parisons may be drawn between the mode of action of enzymes and toxins. It has become customary to speak of the substance upon which an enzyme acts as its substrate, and it has been assumed that the action of the enzyme, like that of the toxins, takes place in two stages; first, the combination of the enzyme and the substrate; second, the breaking down of this compound to give the final products of the reaction. There is some reason for believing that these two stages may be separated, and that enzymes which on account of certain conditions, such as heating, have lost their power of decomposing the substrate, may still have the power of combining with it. Toxins showing a similar property are designated as toxoids, and for the enzyme in this condition the term zymoid has been suggested (Bayliss) * Fisher, " Zeitschrift f. physiolog. Chemie," 26, 71, 1898. COMPOSITION OF FOOD AND ACTION OF ENZYMES. 735 Definition and Classification of Enzymes (Ferments). — On the basis of the considerations presented in the preceding paragraphs Oppenheimer suggests the following definition: An enzyme is a substance, produced by living cells, which acts by catalysis. The enzyme itself remains unchanged in this process, and it acts specifi- cally,— that is, each enzyme exerts its activity only upon substances whose molecules have a certain definite structural and stereochemi- cal arrangement. The enzymes of the body are organic substances of a colloid structure whose chemical composition is unknown. A distinction is made frequently between endo-enzymes and exo- enzymes. Under the latter group are included those enzymes which are eliminated from the cells in which they are formed, and which are found, therefore, in solution in the secretions, for example, the ptyalin of the saliva or the pepsin of the gastric juice. By endo-enzymes is meant a group of intracellular enzymes which are not secreted, but are held within the cells in some form of com- bination. To obtain them in solution or suspension it is necessary to destroy this cell, usually by mechanical means, such as grinding the tissue with sand and, in some cases, by submitting the ground mass to a great pressure in a hydraulic press. The liquid obtained by this latter method is known as the " press juice " of the tissue. In life the endo-enzymes play their part within the bounds of the cells in which they are contained, and probably constitute the chief means through which are effected the metabolic processes that characterize living matter. With regard to the names and classification of the different enzymes, much difficulty is experienced. There is no consensus among workers as to the system to be followed. Duclaux has sug- gested that an enzyme be designated by the name of the body on which its action is exerted, and that all of them be given the termin- ation -ase. The enzyme acting on fat on this system would be named lipase; that on starch, amylase; that on maltose, maltase, etc. The suggestion has been followed in part only, the older en- zymes which were first discovered being referred to most frequently under their original names. Having in mind only the needs of animal physiology, the following classification will be used in the treatment of the subjects of digestion and nutrition: 1. The proteolytic or protein-splitting enzymes. Examples: pepsin of gastric juice, trypsin of pancreatic juice. They cause a hydro- lytic cleavage of the protein molecule. 2. The amylolytic or starch-splitting enzymes. Examples: ptyalin or salivary diastase, amylase, or pancreatic diastase. Their action is closely similar to that of the classical enzyme of this group — dias- tase— found in germinating barley grains. They cause a hydrolytic cleavage of the starch molecule. 3. The lipolytic or fat-splitting enzymes. Example : the_ lipase found in the pancreatic secretion, in the liver, connective tissues, blood, etc. They cause a hydrolytic cleavage of the fat molecule. 736 PHYSIOLOGY OF DIGESTION AND .SECRETION. 4. The sugar-splitting enzymes. These again fall into two subgroups: (a) The inverting enzymes, which convert the double sugars or di- saccharids into the monosaccharids. Examples: maltase, which splits maltose to dextrose; invertase, which splits cane-sugar to dextrose and levulose ; and lactase, which splits milk-sugar (lactose) to dextrose and galactose, (b) The enzymes which split the mono- saccharids. There is evidence of the presence in the tissues of an enzyme capable of splitting the sugar of the blood and tissues (dextrose) into lactic acid. 5. The coagulating enzymes, which convert soluble to insoluble pro- teins. Example: The coagulation of the casein of milk by rennin. 6. The oxidizing enzymes or oxidases. A group of enzymes which set up oxidation processes. Some of the details of the activity of these enzymes are considered in the discussion of physiological oxidations (p. 938). 7. The deamidizing enzymes, such as adenase and guanase, which by hydrolytic cleavage split off an NH2 group as ammonia. The enzymes contained in the first, second, third, and fourth (a) of these groups are the ones that play the chief roles in the digestive processes, and it will be noticed that they all act by hydrolysis, — ■ that is, they cause the molecules of the substance to undergo de- composition or cleavage by a reaction with water. Thus, in the conversion of maltose to dextrose by the action of maltase the re- action may be expressed so : C^O,, + H20 = C6H1206 + C6H1206. Maltose. Dextrose. Dextrose. And the hydrolysis of the neutral fats by lipase may be expressed so: C3H5(C18H3502)3 + 3H20 = OH5(OH)3 + 3(C18H3ti02). Tristearin. Glycerin. Stearic acid. General Properties of Enzymes. — The specific reactions of the various enzymes of the body are referred to under separate heads. The following general characteristics may be noted briefly : Solubility. — Most of the enzymes are soluble in water or salt solutions, or in glycerin. By these means they may be extracted conveniently from the various tissues. In some cases, however, such simple methods do not suffice, particularly for the endo-enzymes ; the enzyme is either insoluble or is destroyed in the process of ex- traction, and to prove its presence pieces of the tissue or the juice pressed from the tissue must be employed. Temperature. — The body enzymes are characterized by the fact that they are destroyed by high temperatures (60° C. to 80° C.) and that their effect is retarded in part or entirely by low temperatures. Most of them show an optimum activity at temperatures approxi- mating that of the body. Precipitation. — The enzymes are precipitated from their solutions in part at least by excess of alcohol. This precipitation is frequently used in obtaining purified specimens of enzymes. The enzymes, moreover, show an interesting tendency to be carried down mechani- cally by flocculent precipitates produced in their solutions. If COMPOSITION OF FOOD AND ACTION OF ENZYMES. 737 protein present in the solution is precipitated, for instance, the enzymes may be carried down with it in part. Incompleteness of their Action. — -In any given mixture of a sub- stance and its enzyme the action of the latter is usually not com- plete,— that is, all of the substance does not disappear. An explana- tion for this fact has been found in the reversibility of the action of the enzyme. If the reaction proceeds in both directions, then evidently under fixed conditions a final equilibrium will be reached in which no further apparent change takes place, although in reality the condition is not one of rest, but of balance between opposing processes proceeding at a definite rate. Within the body itself, on the contrary, the action of an enzyme may be complete, since the products are removed by absorption and the possibility of a re- versed reaction is removed. Active and Inactive Form. — In many cases it can be shown that the enzyme exists within the cell producing it in an inactive form or even when secreted it may still be inactive. This antecedent or inactive stage is usually designated as zymogen or 'proferment. The zymogen may be stored in the cell in the form of granules which are converted into active enzyme at the moment of secretion, or it may be secreted in inactive form and require the co-operation of some other substance before it is capable of effecting its normal reaction. In such cases the second substance is said to activate the enzyme. In connection with the process of activation various terms have been employed to designate the substance responsible for the activation. Accord- ing to a recent classification* it has been suggested that inorganic substances causing activation shall be designated simply as acti- vators, while organic substances playing a similar role shall be named kinases. An example of the latter is found in the case of the entero- kinase which activates the trypsin of the pancreatic secretion. Coenzymes or Coferments. — In addition to the process of ac- tivation it would seem that in some cases the action of an enzyme is facilitated by, or perhaps is even dependent upon the presence of some other substance. Perhaps the best example of this com- bined activity is furnished by the influence of bile salts upon lipase (p. 786). These cases of coactivity are to be distinguished from activation by the fact that the combination may be easily made or unmade, that is to say, it constitutes a reversible reac- tion. In a mixture of bile salts and lipase, for example, the bile salts may be removed by dialysis. Inactivation, on the contrary, we have an irreversible reaction — the active trypsin cannot be changed to the inactive trypsinogen.f * Samuely in "Handbuch der Biochemie," i., 190S. t Consult Bayliss, "The Nature of Enzyme Action" (series of monographs on Biochemistry), London, 1908. 47 738 PHYSIOLOGY OF DIGESTION AND SECRETION. PARTIAL LIST OF THE ENZYMES CONCERNED IN THE PROC- ESSES OF DIGESTION AND NUTRITION. -3 ■3 >> a a Enzyme. f Ptyalin (sali- vary diastase. Amylase (pancreatic diastase). Liver diastase. Muscle diastase. Invertase. Maltase. Lactase. Glycolytic? Lipase (steap- sin). ' Pepsin. Trypsin. Erepsin. Group of auto- lytic enzymes. Nuclease. Guanase. Adenase. Oxidases. Catalase. Arginase Where Chiefly Found. Salivary secretion. Pancreatic secre- tion. Liver. Muscles. Small intestine. Small intestine, salivary and pancreatic se- cretion. Small intestine. Muscles? Pancreatic secre- tion, fat tissues, blood, etc. Gastric juice. Pancreatic juice. Small intestine. Tissues generally. Pancreas, spleen, thymus, etc. Thymus, adrenals, pancreas. Spleen, pancreas, liver. Lungs, liver, mus- cle, etc. Many tissues. Liver, spleen. Action. Converts starch to sugai I maltose). Converts starch to sugar (maltose). Converts glycogen to dex- trose. Converts glycogen to dex- trose. Converts cane-sugar to dextrose and levulose. Converts maltose to dex- trose. Converts lactose to dex- trose and galactose. Splits and oxidizes dex- trose. Splits neutral fats to fatty acids and glycerin. Converts proteins to pep- tones and proteoses. Splits proteins into sim- pler crystalline prod- ucts. Splits peptones into sim- pler products. Splits proteins into nitrog- enous bases and amino- bodies. Splits nucleic acid with for- mation of purin bases, etc. Converts guanin to xan- thin by splitting off an NH, group as ammonia (NH3). Converts adenin to hypo- xanthin by splitting off an NH, group as am- monia (NH3). Cause oxidation of organ- ic substances, as in the conversion of hypoxan- thin to xanthin and of xanthin to uric acid. Decomposes hydrogen peroxid. Splits arginin with pro- duction of urea and ornithin (diamino-val- erianic acid). COMPOSITION OF FOOD AND ACTION OF ENZYMES. 739 Chemical Composition of the Enzymes. — It was formerly believed that the enzymes belong to the group of proteins. They are formed from living matter, and their solutions as usually prepared give protein reactions. Increased study, however, has made this belief uncertain. The enzymes cling to the proteins when precipitated, and it seems possible that the protein reac- tions of their solutions may be due, therefore, to an incomplete purification. In fact, it is stated that solutions of some of the enzymes may be prepared which show ferment activity, but give no protein reactions. In this group may be included the lipase, diastase, invertase, pepsin, oxidase, and catalase. Appar- ently, however, all enzymes contain nitrogen and most of them also sulphur. They probably also contain some ash, especially calcium. Much of the older work upon the composition of supposedly purified preparations of enzymes is not accepted to-day, on the ground that the evidence for the purity of the preparations is insufficient. In spite, however, of the very great amount of attention that has been paid to these substances in recent years, there is at present no agreement as to their chemical structure. The statement made above that they are organic substances, derived from proteins and of a colloidal nature, is perhaps as much as can be said positively in regard to their chemical structure. As a rule, they are destroyed by moderately high temperatures (80° C. or below), they are not easily diffusible through parchment membranes, and, like the proteins, are " salted out " by certain concentrations of neutral salts. CHAPTER XLI. THE SALIVARY GLANDS AND THEIR DIGESTIVE ACTION. The first of the secretions with which the food comes into contact is the saliva. This is a mixed secretion from the large salivary glands and the small unnamed mucous and serous glands that open into the mouth cavity. The Salivary Glands. — The salivary glands in man are three in number on each side — the parotid, the submaxillary, and the sublingual. The parotid gland communicates with the mouth by a large duct (Stenson's duct) which opens upon the inner surface of the cheek opposite the second molar tooth of the upper jaw. The submaxillary gland lies below the lower jaw, and its duct (Wharton's duct) opens into the mouth cavity at the side of the frenum of the tongue. The sublingual gland lies in the floor of the mouth to the side of the frenum and opens into the mouth cavity by a number (eight to twenty) of small ducts, known as the ducts of Rivinus. One larger duct that runs parallel with the duct of Whar- ton and opens separately into the mouth cavity is sometimes present in man. It is known as the duct of Bartholin and occurs normally in the dog. The course of the nerve fibers supplying the large salivary glands is interesting in view of the physiological results of their stimulation. The description here given applies especially to their arrangement in the dog. These glands receive their nerve supply from two general sources, — namely, the bulbar autonomics (or cerebral fibers) and the sympathetic autonomics. The parotid gland receives its bulbar autonomic fibers from the glossopharyngeal or ninth cranial nerve; they pass into a branch of this nerve known as the tympanic branch or nerve of Jacobson, thence to the small superficial pe- trosal nerve, through which they reach the otic ganglion. From this ganglion they pass (postganglionic fibers) by way of the auricu- lotemporal branch of the inferior maxillary division of the fifth cranial nerve to the parotid gland (Fig. 288). The sympathetic autonomics pass to the superior cervical ganglion by way of the cervical sympathetic (Fig. 112) and thence as postganglionic fibers in branches which accompany the arteries distributed to the gland. The bulbar autonomic supply for the submaxillary and sublingual 740 THE SALIVARY GLANDS. 741 glands arises from the brain in the facial nerve and passes out in the chorda tympani branch (Fig. 289) . This latter nerve, after emerging from the tympanic cavity through the Glaserian fissure, joins the Tetrous Ganglion- Fig. 288. — Schematic representation of the course of the cerebral fibers to the parotid gland. lingual nerve. After running with this nerve for a short distance, the secretory (and vasodilator) nerve fibers destined for the sub- maxillary and sublingual glands branch off and pass to the glands, TTtferiofltlaxiUari/ iBmnehofjtt-! Jiranehes to^ Sub- 7HaxiU°-rif- ana Sui>litty(taU. branches ^^ to Sanolion- Fig. 289. — Schematic representation of the course of the chorda tympani nerve to the submaxillary gland. following the course of the ducts. Where the chorda tympani fibers leave the lingual there is a small ganglion which has received the name of submaxillary ganglion. The nerve fibers to the glands 742 PHYSIOLOGY OF DIGESTION AND SECRETION". pass close to this ganglion, but Langley has shown that only those destined for the sublingual gland really connect with the nerve cells of the ganglion, and he suggests, therefore, that it should be called the sublingual instead of the submaxillary ganglion. The nerve fibers for the submaxillary gland make connections with nerve cells lying mainly within the hilus of the gland itself. The supply of sympathetic autonomics has the same general course as those for the parotid, — namely, through the cervical sympathetic to the superior cervical ganglion and thence to the glands. Histological Structure. — The salivary glands belong to the type of compound tubular glands. That is, the secreting portions are tubular in shape, although in cross-sections these tubes may pre- sent various outlines according as the plane of the section passes through them. The parotid is described usually as a typical serous or albuminous gland. Its secreting epithelium is composed of cells which in the fresh condition as well as in preserved specimens contain numerous fine granules and its secretion contains some albumin. The submaxillary gland differs in histology in different animals. In some, as the dog or cat, the secretory tubes are composed chiefly or exclusively of epithelial cells of the mucous type. In man the gland is of a mixed type, the secretory tubes containing both mucous and albuminous cells. The sublingual gland in man also contains both varieties of cells, although the mucous cells predominate. In accordance with these histological characteristics it is found that the secretion from the submaxillary and sublingual glands is thick and mucilaginous as compared with that from the parotid. In the mucous glands another variety of cell, the so-called demilunes or crescent cells, is frequently met with, and the physiological significance of these cells has been the subject of much discussion. The demilunes are crescent-shaped, granular cells lying between the mucous celLs and the base- ment membrane, and not in contact, therefore, with the central lumen of the tube. According to Heidenhain, these demilunes are for the purpose of replacing the mucous cells. In consequence of long-continued activity the mucous cells may disintegrate and disappear, and the demilunes then develop into new mucous cells. Another view is that the demilunes represent distinct secretory cells of the albuminous type, while others assert that they are a specific type of cell with probably specific functions.* The salivary glands possess definite secretory nerves which when stimulated cause the formation of a secretion. This fact indicates that there must be a direct contact of some kind between the gland cells and the terminations of the secretory fibers. The ending of the nerve fibers in the submaxillary and sublingual glands has been de- scribed by a number of observers.! The accounts differ somewhat as to details of the finer anatomy, but it seems to be clearly established that the secretory fibers from the chorda tympani end first around the * See Noll, " Archiv f. Physiologie, " 1902, suppl. volume, 166. t See Huber, "Journal of Experimental Medicine," 1, 281, 1896. THE SALIVARY GLANDS. 743 intrinsic nerve ganglion cells of the glands (preganglionic fibers), and from these latter cells axons (postganglionic fibers) are distributed to the secreting cells, passing to these cells along the ducts. The nerve fibers terminate in a plexus upon the membrana propria of the alveoli, and from this plexus fine fibrils pass inward to end on and between the secreting cells. It would seem from these observations that the nerve fibrils do not penetrate or fuse with the gland cells, as was formerly supposed, but form a terminal network in contact with the cells, following thus the general schema for the connection between nerve fibers and peripheral tissues. Composition of the Secretion. — The saliva as it is found in the mouth is a colorless or opalescent, turbid, and viscid liquid of weakly alkaline reaction to litmus paper, and a specific gravity of about 1.003. It may contain numerous flat cells derived from the epithelium of the mouth, and the peculiar spherical cells known as salivary corpuscles, which seem to be altered leucocytes. The important constituents of the secretion are mucin, a diastatic en- zyme known as ptyalin, maltase, traces of protein and of potassium sulphocyanid, and inorganic salts, such as potassium and sodium chlorid, potassium sulphate, sodium carbonate, and calcium car- bonate and phosphate. The carbonates are particularly abundant in the saliva, and the secretion in addition contains much carbon dioxid in solution. Thus, Pfliiger found that 65 volumes per cent, of CO, might be obtained from the saliva, of which 42.5 per cent, was in the form of carbonates. The amount of C02 in solution and combined is an indication of the active chemical changes in the gland. Of the organic constituents of the saliva the protein exists in small and variable quantities, and its exact nature is not determined. The mucin gives to the saliva its ropy, mucilaginous character. This substance belongs to the group of combined proteins, glyco- proteins (see Appendix), consisting of a protein combined with a carbohydrate group. The most interesting constituent of the mixed saliva is the ptyalin or salivary diastase. This body belongs to the group of enzymes or unorganized ferments, whose general properties have been described. In some animals (dog) ptyalin seems to be normally absent from the fresh saliva. The secretions of the parotid and the submaxillary glands can be obtained separately by inserting a cannula into the openings of the ducts in the mouth, or, according to the method of Pawlow, by trans- ferring the end of the duct so that it opens upon the skin instead of in the mouth, making thus a salivary fistula. The secretion of the sublingual can only be obtained in sufficient quantities for analysis from the lower animals. Examination of the separate secretions shows that the main difference lies in the fact that the parotid saliva 744 PHYSIOLOGY OF DIGESTION AND SECRETION. contains no mucin, while that of the submaxillary and especially of the sublingual gland is rich in mucin. The parotid saliva of man seems to be particularly rich in ptyalin as compared with that of the submaxillary. The Secretory Nerves. — The existence of secretory nerves to the salivary glands was discovered by Ludwig in 1851. The discover}' is particularly interesting in that it marks the beginning of our knowl- edge of this kind of nerve fiber. Ludwig found that stimulation of the chorda tympani nerve causes a flow of saliva from the submaxil- lary gland. He established also several important facts with regard to the pressure and composition of the secretion which will be referred to presently. It was afterward shown that the salivary glands receive a double nerve supply, — in part by way of the cervical sympathetic and in part through cerebral nerves. It was discovered also that not only are secretory fibers carried to the glands by these paths, but that vasomotor fibers are contained in the same nerves, and the arrangement of these latter fibers is such that the cerebral nerves contain vasodilator fibers that cause a dilatation of the small arteries in the glands and an accelerated blood-flow, while the sym- pathetic carries vasoconstrictor fibers whose stimulation causes a constriction of the small arteries and a diminished blood-flow. The effect of stimulating these two sets of fibers is found to vary somewhat in different animals. For purposes of description we may confine ourselves to the effects observed on dogs, since much of our funda- mental knowledge upon the subject is derived from Heidenhain's * experiments upon this animal. If the chorda tympani nerve is stimulated by weak induction shocks, the gland begins to secrete promptly, and the secretion, by proper regulation of the stimulation, may be kept up for hours. The secretion thus obtained is thin and watery, flows freely, is abundant in amount, and contains not more than 1 or 2 per cent, of total solids. At the same time there is an increased flow of blood through the gland. The whole gland takes on a redder hue, the veins are distended, and if cut the blood that flows from them is of a redder color than in the resting gland, and may show a distinct pulse — all of which points to a dilatation of the small arteries. If now the sympathetic fibers are stimulated, quite different results are obtained. The secretion is relatively small in amount, flows slowly, is thick and turbid, and may contain as much as 6 per cent, of total solids. At the same time the gland becomes pale, and if the veins be cut the flow from them is slower than in the resting gland, thus indicating that a vasoconstriction has occurred. The increased vascular supply to the gland accompanying the * " Pfluger's Archiv fur die gesammte Physiologie," 17, 1, 1878; also in Hermann's "Handbuch der Physiologie," 1883, vol. v, part i. THE SALIVARY GLAXDS. 745 abundant flow of "chorda saliva" and the diminished flow of blood during the scanty secretion of " sympathetic saliva " suggest naturally the idea that the whole process of secretion may be, at bottom, a vasomotor phenomenon, the amount of secretion depending only on the quantity and pressure of the blood flowing through the gland. It has been shown conclusively that this idea is erroneous and that definite secretory fibers exist. The following facts may be quoted in support of this statement: (1) Ludwig showed that if a mercury manometer is connected with the duct of the submaxillary gland and the chorda is then stimulated for a certain time, the pressure in the duct may become greater than the blood-pressure in the gland. This fact shows that the secretion is not derived entirely by processes of filtration from the blood. (2) If the blood-flow be shut off completely from the gland, stimulation of the chorda still gives a secretion for a short time. (3) If atropin is injected into the gland, stimulation of the chorda causes vascular dilatation, but no secretion. This may be explained by supposing that the atropin paralyzes the secretory, but not the dilator fibers. (4) Hydro- chlorate of quinin injected into the gland causes vascular dilatation, but no secretion. In this case the secretory fibers are still irritable, since stimulation of the chorda gives the usual secretion. A still more marked difference between the effect of stimulation of the cerebral and the sympathetic fibers may be observed in the case of the parotid gland in the dog. Stimulation of the cerebral fibers, in any part of their course, gives an abundant, thin, and watery saliva, poor in solid constituents. Stimulation of the sym- pathetic fibers alone (provided the cerebral fibers have not been stimulated shortly before and the tympanic nerve has been cut to prevent a reflex effect) gives usually no perceptible secretion at all. But in this last stimulation a marked effect is produced upon the gland, in spite of the absence of a visible secretion. This is shown by the fact that subsequent or simultaneous stimulation of the cerebral fibers causes a secretion very unlike that given by the cerebral fibers alone, in that it is very rich indeed in organic constituents. The amount of organic matter in the secretion may be tenfold that of the saliva obtained by stimulation of the cerebral fibers alone. Relation of the Composition of the Secretion to the Strength of Stimu- lation.— If the stimulus to the chorda is gradually increased in strength, care being taken not to fatigue the gland, the chemical composition of the secretion is found to change with regard to the relative amounts of the water, the salts, and the organic material. The water and the salts increase in amount with the increased strength of stimulus up to a certain maximal limit, which for the salts is about 0.77 per cent. It is important to observe that this effect may be obtained from a perfectly fresh gland as well as from a gland which had previously been secreting actively. With regard 746 PHYSIOLOGY OF DIGESTION AND SECRETION. to the organic constituents the precise result obtained depends on the condition of the gland. If previous to the stimulation the gland was in a resting condition and unfatigued, then increased strength of stimulation is followed at first by a rise in the percentage of organic constituents, and this rise in the beginning is more marked than in the case of the salts. But with continued stimulation the increase in organic material soon ceases, and finally the amount begins actually to diminish, and may fall to a low point in spite of the stronger stimulation. On the other hand, if the gland at the beginning of the experiment had been previously worked to a considerable extent, then an increase in the stimulating current, while it augments the amount of water and salts, either may have no effect at all upon the organic constituents or may cause only a temporary increase, quickly followed by a fall. Similar results may be obtained from stimulation of the cerebral nerves of the parotid gland. The above facts led Heidenhain to believe that the conditions determining the secretion of the organic material are different from those controlling the water and salts, and he gave a rational explanation of the differences observed, in his theory of trophic and secretory fibers. Theory of Trophic and Secretory Nerve Fibers. — This theory supposes that two physiological varieties of nerve fibers are distrib- uted to the salivary glands. One of these varieties controls the secretion of the water and inorganic salts and its fibers may be called secretory fibers proper, while the other, to which the name trophic is given, causes the formation of the organic constituents of the secre- tion, probably by a direct influence on the metabolism of the cells. Were the trophic fibers to act alone, the organic products would be formed within the cell, but there would be no visible secretion, and this is the hypothesis which Heidenhain uses to explain the results of the experiment described above upon stimulation of the sympathetic fibers to the parotid of the dog. In this animal, apparently, the sympathetic branches to the parotid contain exclusively or almost exclusively trophic fibers, while in the cerebral branches both trophic and secretory fibers proper are present. The results of stimulation of the cerebral and sympathetic branches to the submaxillary gland of the same animal may be explained in terms of this theory by supposing that in the latter nerve trophic fibers preponderate, and in the former the secretory fibers proper. It is obvious that this anatomical separation of the two sets of fibers along the cerebral and sympathetic paths may be open to individual variations, and that dogs may be found in which the sym- pathetic branches to the parotid glands contain secretory fibers proper, and therefore give some flow of secretion on stimulation. These variations might also be expected to be more marked when animals of different groups are compared. Thus, Langley* finds * "Journal of Physiology," 1, 96, 1878. THE SALIVARY GLAXDS. 747 that in cats the sympathetic saliva from the submaxillary gland is less viscid than the chorda saliva, — just the reverse of what occurs in the dog. To apply Heidenhain's theory to this case it is necessary to assume that in the cat the trophic fibers run chiefly in the chorda. The way in which the trophic fibers act has been briefly indicated. They may be supposed to set up metabolic changes in the proto- plasm of the cells, leading to the formation of certain definite prod- ucts, such as mucin or ptyalin. That such changes do occur is abundantly shown by microscopical examination of the resting and the active gland, the details of which will be given presently. In general, these changes may be supposed to be catabolic in nature; that is, they consist in a disassociation or breaking down of the complex living material, with the formation of the simpler and more stable organic constituents of the secretion. That these changes involve processes of oxidation is shown by the fact that during activity the gland takes up more oxygen and gives off more carbon dioxid. There is evidence to show that these gland cells during activity form fresh material from the nourishment supplied by the blood; that is, that anabolic or building-up processes occur along with the catabolic changes. The latter are the more obvious, and are the changes which are usually associated with the action of the trophic nerve fibers. It is possible, also, that the anabolic or growth changes may be under the control of separate fibers, for which the name anabolic fibers would be appropriate. Satis- factory proof of the existence of a separate set of anabolic fibers has not yet been furnished. The method of action of the secretory fibers proper is difficult to understand. At present the theories suggested are entirely specula- tive. Experiments have shown that the amount of water given off from the blood during secretion is somewhat greater than the amount contained in the saliva,* and there is reason to believe that the difference between the two is accounted for by an increase in the flow of lymph from the gland during activity. A satisfactory explanation of the causes leading to and controlling the flow of water cannot yet be given. In a general way it has been assumed that the effect of the nerve impulses is to cause the production of substances within the cells whereby their osmotic pressure is increased, and a stream of water is set up from the blood in the capillaries toward the gland cells, but it cannot be said that this assumption has been supported by the experiments so far made.f We must limit ourselves to the more general statement that the activity of the cells themselves initiates and controls the flow of water. *Barcroft, "Journal of Physiology," 1900, 25, 479. t Carlson, Greer, and Beeht, "American Journal of Physiology, " 19, 360, 1907. 748 PHYSIOLOGY OF DIGESTION AND SECRETION. Histological Changes During Activity— The cells of both the albuminous and mucous glands undergo distinct histological changes in consequence of prolonged activity, and these changes may be recognized both in preparations from the fresh gland and in preserved specimens. In the parotid gland Heidenhain studied the changes in stained sections after hardening in alcohol. In the resting gland the cells are compactly filled with granules that stain readily and are imbedded in a clear ground substance that does not stain. The nucleus is small and more or less irregular in outline. After stimulation of the tympanic nerve the cells show but little alteration, but stimula- tion of the sympathetic produces a marked change. The cells become smaller, the nuclei more rounded, and the granules more closely packed. This last appearance seems, however, to be Mm D Fig. 290. — Parotid gland of the rabbit in a fresh state, showing portions of the secret* ing tubules: A, In a resting condition; B, after secretion caused by pilocarpin; C, after stronger_ secretion, pilocarpin and stimulation of sympathetic ; D, after long-continued stimulation of sympathetic— (After Langley.) due to the hardening reagents used. A truer picture of what occurs may be obtained from a study of sections of the fresh gland. Lang- ley,* who first used this method, describes his results as follows: When the animal is in a fasting condition the cells have a granular appearance throughout their substance, the outlines of the different cells being faintly marked by light lines (Fig. 290, A). When the gland is made to secrete by giving the animal food, by injecting pilocarpin, or by stimulating the sympathetic nerves, the granules begin to disappear from the outer borders of the cells (Fig. 290, B), * "Journal of Physiology," 2, 260, 1879. THE SALIVARY GLANDS. 749 so that each cell now shows an outer, clear border and an inner granular one. If the stimulation is continued the granules become fewer in number and are collected near the lumen and the margins of the cells, the clear zone increases in extent, and the cells become smaller (Fig. 290, C, D). Evidently the granular material is used in some way to make the organic material of the secretion. Since the ptyalin is a conspicuous organic constituent of the secretion, it is assumed that the granules in the resting gland contain the ptyalin, or rather the preliminary material from which the ptyalin is con- structed during the act of secretion. On this latter assumption the granules are frequently spoken of as zymogen granules. During the act of secretion two distinct processes seem to be going on in the cell, leaving out of consideration, for the moment, the secretion of the water and the salts. In the first place, the zymogen granules undergo a change such that they are forced or dissolved out of the cell, and, second, a constructive metabolism or anabolism is set up, leading to the formation of new pro- toplasmic material from the substances contained in the blood and lymph. The new material thus formed is the clear, non- granular substance, which appears first toward the basal sides of the cells. We may sup- pose that the clear sub- stance during the resting periods undergoes meta- bolic changes, whether of a catabolic or anabolic character can not be safely asserted, leading to the formation of new granules, and the cells are again ready to form a secretion of normal composition. It should be borne in mind that in these experiments the glands were stimulated beyond normal limits. Under ordinary conditions the cells are probably never depleted of their granular material to the extent represented in the figures. In the cells of the mucous glands changes equally marked may be observed after prolonged activity. In stained sections of the resting gland the cells are large and clear (Fig. 291), with flattened nuclei placed well toward the base of the cell. When the gland is made to secrete the nuclei- become more spherical and lie more toward the middle of the cell, and the cells themselves become distinctly smaller. After prolonged secretion the changes become more marked (Fig. 292) and. according to Heidenhain, some of the Fig. 291. — Mucous gland: submaxillary of dog; rest* ing stage. 750 PHYSIOLOGY OF DIGESTION AND SECRETION*. Fig. 292. — Mucous gland: submaxillary of dog after eight hours' stimulation of the chorda tympani. mucous cells may break down completely. According to most of the later observers, however, the mucous cells do not actually dis- integrate, but form again new material during the period of rest, as in the case of the goblet cells of the intestine. In the mucous as in the albuminous cells observations upon pieces of the fresh gland seem to give more reliable results than those upon preserved specimens. Langley* has shown that in the fresh mucous cells of the submax- illar}' gland numerous large granules may be discovered, about 125 to 250 to a cell. These granules are comparable to those found in the goblet cells, and may be inter- preted as consisting of mu- cin or some preparatory material from which mucin is formed. The granules are sensitive to reagents; addition of water causes them to swell up and dis- appear. It may be as- sumed that this happens during secretion, the gran- ules becoming converted to a mucin mass which is extruded from the cell. Action of Atropin, Pilocarpin, and Nicotin upon the Secre- tory Nerves. — The action of drugs upon the salivary glands and their secretions belongs properly to pharmacology, but the effects of the three drugs mentioned are so decided that they have a peculiar physiological interest. Atropin in small doses injected either into the blood or into the gland duct prevents the action of the cerebral autonomic fibers (tympanic nerve or chorda tympani) upon the glands. This effect may be explained by assuming that the atropin paralyzes the endings of the cerebral fibers in the glands. That it does not act directly upon the gland cells themselves seems to be assured by the interesting fact that, with doses sufficient to throw out entirely the secreting action of the cerebral fibers, the sympathetic fibers are still effective when stimulated. Pilocarpin has directly the opposite effect to atropin. In minimal doses it sets up a continuous secretion of saliva, which may be explained upon the supposition that it stimulates the endings of the secretory fibers in the gland. Within certain limits these drugs antagonize each other, — that is, the effect of pilocarpin may be removed by the sub- sequent application of atropin, and vice versa. Nicotin, according to the experiments of Langley, f prevents the action of the secretory * "Journal of Physiology," 10, 433, 1889. t "Proceedings of the Royal Society," London, 46, 423, 1889. THE SALIVARY GLANDS. 751 nerves, not by affecting the gland cells or the endings of the nerve fibers around them, but by paralyzing the connections between the nerve fibers and the ganglion cells through which the fibers pass on their way to the gland, — that is, the connection between the pre- ganglionic and postganglionic fibers. If, for example, the superior cervical ganglion is painted with a solution of nicotin, stimulation of the cervical sympathetic below the gland gives no secretion; stim- ulation, however, of the fibers in the ganglion or between the ganglion and gland gives the usual effect. By the use of this drug Langley is led to believe that the cells of the so-called submaxillary ganglion are really intercalated in the course of the fibers to the sublingual gland, while the nerve cells with which the submaxillary fibers make connection are found chiefly in the hilus of the gland itself. Paralytic Secretion. — A remarkable phenomenon in connection with the salivary glands is the so-called paralytic secretion. It has been known for a long time that if the chorda tympani is cut the submaxillary gland after a certain time, one to three days, begins to secrete slowly, and the secretion continues uninterruptedly for a long period — as long, perhaps, as several weeks — and eventually the gland itself undergoes atrophy. Langley states that section of the chorda on one side is followed by a continuous secretion from the glands on both sides; the secretion from the gland of the opposite side he designates as the antiparalytic or antilytic secretion. After section of the chorda the nerve fibers peripheral to the section degenerate, the process being completed within a few days. These fibers, how- ever, do not run directly to the gland cell; they terminate in end arborizations around sympathetic nerve cells placed somewhere along their course, — in the sublingual ganglion, for instance, or within the gland substance itself. It is the axons from these second nerve units that end around the secreting cells. Langley has accumulated some facts to show that within the period of continuance of the paralytic secretion (five to six weeks) the fibers of the sympathetic cells are still irritable to stimulation. He is inclined to believe, therefore, that the continuous secretion is due to a continuous excitation, from some cause, of the local nervous mechanism in the gland. A natural extension of this view which has been suggested (Parlow) is that normally the activity of the sympathetic cells or of the secreting cells is kept in check by inhibitory fibers. After section of the chorda the action of these fibers falls out and the secre- tion continues until the glandular tissue undergoes atrophy. On the histological side it is stated* that after section of the chorda the resulting degenerative changes affect only the cytoplasm, while after the section of the sympathetic the nuclei of the cells are affected, and, indeed, to some extent on the sound as well as on the injured side. * Gerhardt, "Archiv f. die gesammte Physiologie, " 97, 317, 1903. 752 PHYSIOLOGY OF DIGESTION* AND SECRETION. Normal Mechanism of Salivary Secretion. — Under normal con- ditions the flow of saliva from the salivary glands is the result of a reflex stimulation of the secretory nerves. The sensory fibers concerned in this reflex must be chiefly fibers of the glossopharyn- geal and lingual nerves supplying the mouth and tongue. Sapid bodies and various other chemical or mechanical stimuli applied to the tongue or mucous membrane of the mouth produce a flow of saliva. The normal flow during mastication must be effected by a reflex of this kind, the sensory im- pulse being carried to a center and thence transmitted through the efferent nerves to the glands. It is found that section of the chorda prevents the reflex, in spite of the fact that the sympathetic fibers are still intact. No satisfactory explanation of the normal functions of the secretory fibers in the sympathetic has yet been given. Various authors have suggested that possibly the three large salivary glands respond normally to different stimuli. This view has been supported by Pawlow. who reports that in the dog at least the parotid and the submaxillary may react quite differently. When fistulas were made of the ducts of these glands it was found that the submaxillary responded readily to a great num- ber of stimuli, such as the sight of food, chewing of meats, acids, etc. The parotid, on the contrary, seemed to react only when dry food, dry powdered meat, or bread was placed in the mouth. Dryness in this case appeared to be the efficient stimulus. Pawlow lays great stress upon the adaptability of the secretion of saliva to the character of the material chewed. Dry, solid food stimulates a large flow of saliva, such as is necessary in order to chew it properly and to form it into a bolus for swallowing. Foods containing much water, on the contrary, excite but little flow of saliva. If one places a handful of clean stones in the mouth of a dog he will move them around with his tongue for a while and then drop them from his mouth; but little or no saliva is secreted. If the same material is given in the form of fine sand a rich flow of saliva is produced, and the necessity for the reflex is evident in this case, since otherwise the material could not be conveniently removed from the mouth. Such adaptations must be regarded from the physiological point of view as special reflexes depending upon some difference in the nervous mechanism set into play.* Since the flow of saliva is normally a definite reflex, we should expect a distinct salivary secretion center. This center has been located by physiological means in the medulla oblongata; its exact position is not clearly defined, but possibly it is represented by the nuclei of origin of the secretory fibers which leave the medulla by way of the facial and glossopharyngeal nerves. Owing to the wide connections of nerve cells in the central nervous system, we should expect this center to be affected by stimuli from various sources. *See Pawlow, "The Work of the Digestive Glands.'' translation by Thompson, London, 1902; also " Ergebnisse der Physiologie," vol in., part i, 1904, and " Archives Internationales de physiologie, " 1, 119, 1904. THE SALIVARY GLANDS. 753 As a matter of fact, it is known that the center and through it the glands may be called into activity by stimulation of the sensory fibers of the sciatic, splanchnic, and particularly the vagus nerves. So, too, various psychical acts, such as the thought of savory food and the feeling of nausea preceding vomiting, may be accompanied by a flow of saliva, the effect in this case being due probably to stimula- tion of the secretion center by nervous impulses descending from the higher nerve centers. Lastly, the medullar}' center may be inhibited as well as stimulated. The well-known effect of fear, embarrassment, or anxiety in producing a parched throat may be explained in this way as due to the inhibitory action of nerve impulses arising in the cerebral centers. Electrical Changes in the Gland during Activity. — It has been shown that the salivary as well as other glands suffer certain changes in electrical potential during activity which are comparable in a gen- eral way to the "action currents" observed in muscles and nerves.* The Digestive Action of Saliva — Ptyalin. — The digestive action proper of the saliva is limited to the starchy food. In human beings and most mammals the saliva contains an active enzyme belonging to the group of diastases and designated usually as ptyalin or salivary diastase. It may be prepared in purified form from saliva by precipitation with alcohol, but its chemical nature, like that of the other enzymes, is still an unsolved problem. Saliva or preparations of ptyalin act readily upon boiled starch, converting it into sugar and dextrin. This action may be demonstrated very readily by holding a little starch paste or starchy food, such as boiled potatoes, in the mouth for a few moments. If the solution is then examined the presence of sugar is readily shown by its reducing action on solutions of copper sulphate (Fehling's solution). There is no doubt that the action of ptyalin upon the starch is hydrolytic. Under the influence of the enzyme the starch molecules take up water and undergo cleavage into simpler molecules. The steps in the process and the final products have been investigated b}r a very large number of workers, but much yet remains in doubt. The following points seem to be determined: The end-result of the reaction is the formation of maltose, a disaccharid, having the general formula Ci2H22Ou, and some form of dextrin, a non-crystallizable poly- saccharid. When the digestion is effected in a vessel some dextrose (C6H1206) may be found among the products, but this is explained on the assumption that there is present in the saliva some maltase, an enzyme capable of splitting maltose into dextrose. So far as the ptyalin itself is concerned, its specific action is to convert starch to maltose and dextrin. It seems very certain, however, that a number *See Biedermann, "Electro-physiology," translation by Welby, London, 48 754 PHYSIOLOGY OF DIGESTION AND SECRETION. of intermediate products are formed consisting of a variety of dex- trins, so that the hydrolysis probably takes place in successive stages. There is little agreement as to the exact nature of the in- termediate dextrins. The following facts, however, may be easily demonstrated in a salivary digestion carried on in a vessel and ex- amined from time to time. The starch at first gives its deep-blue reaction with iodin ; later, instead of a blue, a red reaction is obtained with iodin, and this has been attributed to a special form of dextrin, erythrodextrin, so named on account of its red reaction. Still later this reaction fails and chemical examination shows the presence of maltose and a form of dextrin which gives no color reaction with iodin and is therefore named achroodextrin. While the number of intermediate products may be large, the main result of the action of the ptyalin is expressed by the following simple schema : Starch<^al*?se- , , . ^Maltose. ^Erythrodextrmt poss< s its lull acidity in the beginning owing to the facl tin) tii m the first periods of digestion, * Si lical Diagnosis." DIGESTION AND ABSORPTION IN THE STOMACH. 761 while the secretion is still scanty in amount, a portion of its acid is neutralized by the swallowed saliva, the alkaline mucus, and the alkaline secretion of the pyloric end of the stomach. It is probable that the juice as secreted has a more or less constant acidity, but after it is poured out in the stomach this acidity is not only dimin- ished by the neutralizing action of any alkalies that may be present, but, what is far more important, the free acid may be combined with the protein of the food. If the stomach contents of an animal fed on meat be examined from time to time, it may not be possible to prove the existence of free HC1 for an hour or more after the digestion has been going on, owing to the fact that it has com- bined with the protein material. In speaking of the acidity of the stomach contents, therefore, it is necessary to distinguish between the combined acid and the free acid, the two together constituting the total acidity. The acidity of the human gastric juice is usually estimated at 0.3 per cent., but during digestion it may reach (Hornborg) 0.4 to 0.5 per cent., and these figures express probably its strength as secreted. The acidity of the dog's gastric juice, according to Pawlow, lies between 0.46 and 0.56 per cent. The Origin of the HC1. — The gastric juice is the only secretion of the body that contains a free acid. The fact that the acid is a mineral acid and is present in considerable strength makes the cir- cumstance more remarkable. Attempts have been made to ascer- tain the histological elements concerned in its secretion and the nature of the chemical reaction or reactions by which it is produced. With regard to the first point it is generally believed that the border cells of the gastric tubules constitute the acid-secreting cells. This belief is founded upon the general fact that in the regions in which these cells are chiefly present — that is, the middle region of the stomach — the secretion is distinctly acid, and where they are absent or scanty in number the secretion is alkaline or less acid. In the pyloric region, for instance, these cells are lacking entirely and the secretion is alkaline. So also in the fundus the secretion does not seem to be acid, and this fact corresponds with a marked diminution or absence of the border cells. With regard to the origin of the acid it is evident that it is formed in the secreting cells, since none exists in the blood or lymph. It seems also perfectly evident that the HC1 must be formed from the chlorids of the blood. The chief chlorid is NaCl and by some means this compound is broken up: the chlorin is combined with hydrogen, and is then secreted upon the free surface of the stomach as HC1. In support of this general statement it has been shown that if the chlorids in the blood are reduced by removing them from the food for a sufficient time the secretion of gastric juice no longer- contains acid. On the other hand, addition of NaBr or 762 PHYSIOLOGY OF DIGESTION AND SECRETION. KI to the food may cause the formation of some HBr and HI, together with HC1 in the gastric juice. Maly has suggested that acid phosphates may be produced in the first instance, and then by reacting with the sodium chlorid may give hydrochloric acid, accord- ing to the formula NaH2P04 + NaCl = Na2HP04 + HC1. Other theories have been proposed, but, as a matter of fact, no explanation of the details of this reaction is satisfactory. We must be content to say that in the acid-forming cells the neutral chlorids (NaCl) are broken up with the formation of free HC1, and in all probability this reaction involves a specific metabolism on the part of these cells. The Secretory Nerves of the Gastric Glands. — Although several facts indicated to the older observers that the secretion of gastric juice is under the control of nerve fibers, we owye the actual experi- mental demonstration of this fact to Pawiow.* He demonstrated that the secretion is under the control of the nervous system and that the secretory fibers are contained in the vagus. Direct stimulation of the peripheral end of the cut vagus causes a secretion of gastric juice after a long latent period of several minutes. This long latency may be due possibly to the presence in the vagus of inhibitory fibers to the gland, which, being stimulated simultaneously with the secretory fibers, delay the action of the latter. Very striking proof of the general fact that the secretion is due to the action of vagus fibers is furnished by such experiments as these : Pawiow divided the esophagus in the neck and brought the two ends to the skin so as to make separate fistulous openings to the exterior. Under these con- ditions, when the animal ate and swallowed food it was discharged to the exterior instead of entering the stomach. The animal thus had the enjoyment of eating without actually filling the stomach. Eating in this style forms what the author called a fictitious or sham meal (Scheinfiitterung) . It wras found that it causes an abundant flow of gastric juice as long as the vagi are intact, but has no effect on the secretion when these nerves are cut. Evidently, therefore, the sensations of taste, odor, etc., developed during the mastication and swallowing of food, set up reflexly a stimulation of secretory fibers in the vagus. Pawiow desig- nates a secretion produced in this way as a psychical secretion, — a term which implies that the reflex must be attended by conscious sensations. In favorable cases the fictitious feeding has been continued for five or six hours and a large amount of gastric juice (700 c.c.) has been collected from a fistula, although no food actually entered the stomach. It is important to note, also, that a psychical secretion, once started, may continue for a long time after * See Pawiow, "The Work of the Digestive Glands," translated by Thomp- son, 1902. DIGESTION AND ABSORPTION IN THE STOMACH. 763 the stimulus (the eating) has ceased. Experiments have been made upon human beings under similar conditions. Thus, Hornborg* reports the case of a boy with a stricture t>f the esophagus and a fistula in the stomach. Food when chewed and swallowed did not reach the stomach, but was regurgitated; it caused, nevertheless, an active psychical secretion in the empty stomach. Normal Mechanism of the Secretion of the Gastric Juice. — During a meal the gastric juice is secreted, under normal conditions, as long as the food remains in the stomach. The modern explana- tion of the origin, maintenance, and regulation of this flowT of secre- tion is due chiefly to Pawlow. Contrary to a former general belief, he showed that mechanical stimulation of the gastric mucous mem- brane has no effect on the secretion of the tubules. This factor may therefore be ehminated. In an ordinary meal the secretion first started is due to the sensations of eating — that is, it is a psychical secretion. The afferent stimuli originate in the mouth and nostrils; the efferent path, the secretory fibers, is through the vagus nerve. This reflex insures the beginning at least of gastric digestion, but its effect is supplemented by a further action arising in the stomach itself. It seems that some foods contain substances designated as secretogogues, that are able to cause a secretion of gastric juice when taken into the stomach. In other foods these ready-formed secretogogues are lacking. Thus, meat extracts, meat juices, soups, etc, are particularly effective in this respect; milk and water cause less secretion. Certain common articles of food, such as bread and white of eggs, have no effect of this kind at all. If introduced into the stomach of a dog through a fistula so as not to arouse a psychical secretion, — for instance, while the dog's attention is diverted or while he is sleeping, — they cause no flow of gastric juice and are not digested. If such articles of food are eaten, however, they cause a psychical secretion, and when this has acted upon the foods some products of their digestion in turn become capable of arousing a further flow of gastric juice. The steps in the mechanism of secretion are, therefore, three: (1) The psychical secretion; (2) the secretion from secretogogues contained in the food; (3) the secretion from secretogogues contained in the prod- ucts of digestion. The manner in which the secretogogues act cannot be stated positively. Since the gastric glands possess secretory nerve fibers the first explanation to suggest itself is that the secretogogues by acting on sensory fibers in the gastric mucous membrane renexly stimulate the secretory fibers. This explanation, however, is rendered untenable by the fact that the effect of these substances is obtained after complete severance * Hornborg, " Skandinavisches Archiv f. Physiologie," 15, 209, 1904; see also Bickel, "Verhandl. Kongr. f. innere Medizin," 23, 491. 764 PHYSIOLOGY OF DIGESTION AND SECRETION. of the nervous connections of the stomach. If, therefore, this so-called chemical secretion is produced by a nervous reflex the nerve centers concerned must lie in the stomach itself, the reflex must take place through the peripheral ganglion cells. Another more probable explanation has been offered. Edkins * has shown that decoctions of the pyloric mucous membrane, made by boiling in water acid or peptone solutions, when injected into the blood cause a marked secretion of gastric juice. These substances when in- jected alone into the blood cause no such effect, and decoc- tions of the mucous membrane of the fundic end of the stomach are with- out action on the gastric secretion. This author sug- gests, therefore, that the secretogogues, whether preformed in the food or formed during digestion, act upon the pyloric mu- cous membrane and form a substance which he designates as gastrin or gastric secretin, and this sub- stance after absorp- tion into the blood is carried to the gas- tric glands and stimulates them to secretion. The effect is, therefore, not a usual nervous reflex, but an instance of the stimulation of one organ by chemical products formed in another. Starling f has emphasized the fact that this mode of control is frequently employed in the body, as will be described in the following pages in connection with the pancreatic secretion and * Edkins, "Journal of Physiology," 1906, xxxiv., p. 133. t Starling, " Recent Advances in the Physiology of Digestion," 1906. § o S .s a >J Sh b :2s c.i, . - - i) ■£ t- © Mi Milk, Meat, Bread, 600 c.c. 100 gms. 100 gms. R a^ 0.576 0.528 0.480 0.432 0.384 0.336 0.288 18 16 14 12 \ s : i i \ i \ i i \ 1 10 > 8 \ 0.144 0.096 6 4 2 0 g \ 4 \ 2 0.048 0 ^ K .■ ' \ 0 1 Hours /P.IAJi/ilr/iV M1f19 Quantity of secretion. i Acidity. ^___^^_ Digestive power. Fig. 295; — Diagram showing the variation in quantity of gastric secretion in the dog after a mixed meal; also the variations in acidity and in digestive power. — (After Khigine.) DIGESTION AND ABSORPTION IN THE STOMACH. 765 the internal secretions. He proposes to designate such sub- stances by the general term of hormones (from bpixaco, arouse or excite). Leaving aside for the moment the way in which the secretogogues excite the secretion it is important to empha- size the fact that in the normal secretion of gastric juice, that is to say, in the secretion which takes place during an ordinary meal, we must distinguish between a nervous secretion due to the action of the secretory fibers in the vagus, and a chemical secretion due to the chemical stimulation of the secretogogues or of the hormones produced by them. The researches of Pawlow and his co-workers seem also to in- dicate that the quantity and properties of the secretion vary with the character of the food. The quantity of the secretion varies, also, other conditions being the same, with the amount of food to be digested. The apparatus is adjusted in this respect to work economically. Different kinds of food produce secretions varying not only as regards quantity but also in their acidity and diges- tive action. The secretion produced by bread, though less in quantity than that caused by meat, possesses a greater digestive action. On a given diet the secretion assumes certain characteris- tics, and Pawlow is convinced that further work will disclose the fact that the secretion of the stomach is not caused normally by general stimuli all affecting it alike, but by specific stimuli contained in the food or produced during digestion, whose action is of such a kind as to arouse reflexly the secretion best adapted to the food ingested. One of the curves, showing the effect of a mixed diet (milk, 600 c.c; meat, 100 gms.; bread, 100 gms.) upon the gastric secretion, as determined by Pawlow's method, is reproduced in Fig. 295. It will be noticed that the secretion began shortly after the ingestion of the food (seven minutes), and increased rapidly to a maximum that was reached in two hours. After the second hour the flow decreased rapidly and nearly uniformly to about the tenth hour. The acidity rose slightly between the first and second hours, and then fell gradu- ally. The digestive power showed an increase between the second and third hours. Nature and Properties of Pepsin. — Pepsin is a typical proteo- lytic enzyme that exhibits the striking peculiarity of acting only in acid media; hence peptic digestion in the stomach is the result of the combined action of pepsin and hydrochloric acid. Pepsin is influenced in its action by temperature, as is the case with the other enzymes; low temperatures retard, and may even suspend its activity, while high temperatures increase it. The optimum tem- perature is stated to be from 37° to 40° C, while exposure for some time to 80° C. results, when the pepsin is in a moist condition, in the total destruction of the enzyme. Pepsin may be extracted from the 766 PHYSIOLOGY OF DIGESTION AND SECRETION. gastric mucous membrane by a variety of methods and in different degrees of purity and strength. The commercial preparations of pepsin consist usually of some form of extract of the gastric mucous membrane to which starch or sugar of milk has been added. Labora- tory preparations are made conveniently by mincing thoroughly the mucous membrane and then extracting for a long time with glycerin. Glycerin extracts, if not too much diluted with water or blood, keep for an indefinite time. Purer preparations of pepsin have been made by what is known as "Briicke's method," in which the mucous membrane is minced and is then self-digested with a 5 per cent, solution of phosphoric acid. The phosphoric acid is pre- cipitated by the addition of lime-water, and the pepsin is carried down in the flocculent precipitate. This precipitate, after being washed, is carried into solution by dilute hydrochloric acid, and a solution of cholesterin in alcohol and ether is added. The cholesterin is precipitated, and, as before, carries down with it the pepsin. This precipitate is collected, carefully washed, and then treated repeatedly with ether, which dissolves and removes the cholesterin, leaving the pepsin in aqueous solution. This method is interesting not only because it gives a pure form of pepsin, but also in that it illustrates one of the properties of enzymes — namely, the readiness with which they adhere to precipitates occurring in their solutions. In spite of much work, the chemical nature of pepsin is undeter- mined. Pekelharing* has prepared pepsin from gastric juice by dialysis, the substance precipitating as the acid is dialyzed off. The precipitate may be purified by repeated resolutions in acid followed by dialysis. As prepared by this method pepsin is a substance of a protein nature which contains sulphur and also some chlorin, but no phosphorus. It does not belong, therefore, to the group of nucleoproteins. Other authors, on the contrary, assert that active preparations of pepsin may be obtained which give no protein reactions, although they contain nitrogen. Pepsin is supposed to be formed in the chief cells of the gastric tubules, but as in other cases it is present in the cells as a zymogen or propepsin, which is not changed to the active pepsin until after secretion. The propepsin may be extracted readily from the mucous membrane, and, since it is known that the zymogen is converted quickly to active pepsin by the action of acids, it is evident that in the normal gastric juice the existence of the hydrochloric acid insures that all of the pepsin shall be present in active form. There has been much discussion as to the nature of the secretion of the pyloric glands. Heidenhain isolated this portion of the stomach and collected its secretion. He found that it was alkaline and contained pepsin. Later observers, however, still continue to doubt the secre- * Pekelharing, "Zeitschrift f. physiol. Cheraie," 35, 8, 1902. DIGESTION AND ABSORPTION IN THE STOMACH. 767 tion of a true pepsin in this portion of the stomach. Glaessner* states that propepsin can not be obtained from extracts of the pyloric glands, and that the proteolytic enzyme that can be shown in this portion of the stomach by self-digestion in acid or alkaline media is not a true gastric pepsin. The possibility that a special secretin (hormone) is formed in the pyloric mucous membrane has been referred to above (p. 764). From the description of the events in the stomach (p. 710) it would seem that the food material which is churned and stirred by the contractions of the pyloric musculature has already been charged with pepsin and hydrochloric acid by the glands of the middle and fundic regions before reaching the antrum pylori. Artificial Gastric Juice. — In studying peptic digestion it is not necessary for all purposes to establish a gastric fistula. The active agents of the normal juice are pepsin and an acid of a proper strength ; and, as the pepsin can be extracted and preserved in various ways and the hydrochloric acid can easily be made of the proper strength, an artificial juice can be obtained at any time and may be used in place of the normal secretion for many purposes. In laboratory ex- periments it is customary to employ a glycerin or commercial prep- aration of the gastric mucous membrane, and to add a small portion of this preparation to a large bulk of 0.2 per cent, hydrochloric acid. The artificial juice thus made, when kept at a temperature of from 37° to 40° C, will digest proteins rapidly if the preparation of pepsin is a good one. While the strength of the acid employed is generally from 0.2 to 0.3 per cent., digestion will take place in solutions of greater or less acidity. Too great or too small an acidity, however, will retard the process; that is, there is for the action of the pepsin an optimum acidity which lies somewhere between 0.2 and 0.5 per cent. Other acids may be used in place of the hydrochloric acid — for example, nitric, phosphoric, or lactic — but they are not so effective, and the optimum concentration is different for each ; for phosphoric acid it is given as 2 per cent. , The Pepsin-hydrochloric Digestion of Proteins. — It has long been known that solid proteins, when exposed to the action of a normal or an artificial gastric juice, swell up and eventually pass into solution. The soluble protein thus formed was known not to be coagulated by heat and was remarkable also for being more diffusible than other forms of soluble proteins. This end-product of digestion was formerlv conceived as a soluble protein with properties fitting it for rapid absorption, and the name of peptone was given to it. It was quickly found, however, that the process is complicated — that in the conversion to so-called "peptone" the protein under digestion passes through a number of intermediate stages. The intermediate * Glaessner, "Beitrage zur chem. Physiol, u. Pathol.," 1, 24, 1901. 768 PHYSIOLOGY OF DIGESTION AND SECRETION. products were partially isolated and were given specific names, such as acid-albumin, parapeptone, and propetone. The present concep- tion of the process we owe chiefly to Kuhne. This author believed that the protein passes through three general stages before reaching the final condition of peptone. This view is indicated briefly by the following schema : Native protein. Acid albumin (syntonin) . Primary proteoses (protalbumoses). Secondary proteoses (deutero-albumoses). Peptone. The first step is the conversion of the protein to an acid albumin. This change may be considered as being chiefly an effect of the hy- drochloric acid, although in some way the combined action of the pepsin-hydrochloric acid compound is more effective than a solution of the acid alone of the same strength. Like the acid albumins (metaproteins) in general (see Appendix), the syntonin is readily precipitated on neutralization. In the beginning of peptic diges- tion, therefore, if the solution is neutralized with dilute alkali, an abundant precipitate of syntonin occurs. Later on in the digestion, neutralization gives no such effect — the syntonin has all passed to a further stage of digestion. Under the in- fluence of the pepsin the syntonin undergoes hydrolysis, with the production of a number of bodies which, as a group, are designated as primary proteoses or protalbumoses.* Although several members of this group have been isolated and given separate names, so much doubt prevails as to the chemical individ- uality of these substances that it is best perhaps to regard them as a group of compounds which under the continued influence of the pepsin undergo still further hydrolysis with the formation of secon- dary proteoses or deutero-albumoses. As compared with the primary proteoses, the secondary ones are distinguished by a greater solu- bility ; they require a stronger saturation with neutral salts to precipi- tate them. (See Appendix.) The secondary proteoses undergo still further hydrolysis, with the production of peptone, or perhaps it would be better to say peptones. The peptones show still greater solubility, and, in fact, peptone, in Kiihne's sense, is that compound or group of compounds formed in peptic digestion which, while still showing protein reactions (biuret reaction), is not coagulated by heat nor precipitated when its solutions are completely saturated with ammonium sulphate. According to the schema and descrip- tion given above, the several stages in peptic digestion are repre- * The products intermediate between the original protein and the pep- tone are described in general as albumoses or as proteoses, according as one takes the term protein or albumin as the generic name for the original sub- stance. The term protein is generally used in English ; hence, the intermedi- ate products are more appropriately designated as proteoses. DIGESTION AND ABSORPTION IN THE STOMACH. 769 sented as following in sequence. It should be stated, however, that many authors consider that even in the beginning of the digestion the protein molecule may be split into several complexes, and that some of the end-products may be formed in the very beginning of the action. All that Ave can state very positively is that the protein molecules undergo a series of hydrolytic cleav- ages, the end-result of which is that in place of the originally very large molecule with a weight of 5000 to 7000 there is obtained a number of much smaller and much more soluble molecules whose molecular weights are perhaps only 250 to 400 or less. It was formerly believed that pepsin was not able to split the complex protein molecule into compounds of a simpler structure than the peptone. But a number of recent authors have stated that if time enough is given the breaking up of the protein molecule may be as complete as after the action, of trypsin, or after hydrolysis by acids (see Proteins in appendix). That is, along with the peptone or in place of it are found certain simpler bodies which no longer give the biuret reaction, but are precipitable by phospho- tungstic acid and for which Hofmeister proposes the general name of pep- toids. They would correspond, also, apparently, to the group of compounds designated by Fischer as peptids or polypeptids. In addition, many of the amino-acicls and nitrogenous bases which constitute the final end-products of the breaking up of the protein molecule may be found.* In judging the digestive action of any given specimen of natural or artificial gastric juice it is customary to measure the rapidity with which an insoluble protein is converted into a soluble form. The method most commonly employed is that devised in Pawlow's laboratory by Mett. The Mett test is made by sucking white of egg into a thin-walled glass tube having an internal diameter of 1 to 2 mms. The egg-albumin is coagulated in the tube by immersing it for five minutes in water at 95° C. After some time the tube is cut into ' lengths of 10 to 15 mms. and these are used to test the digestive action or amount of pepsin. One or more of the tubes are placed in the solution to be measured and kept for ten hours at body temperature. The digestive power is measured in terms of the length in millimeters of the column of egg-albumin that is dissolved. The relative amounts of pepsin in solutions compared in this way are determined by the law of Schiitz, according to which the digestive power is proportional to the square root of the amount of pepsin. If in two specimens of gastric juice the number of millimeters of egg albumin digested was in one case two and in the other three, the pepsin in the two solutions would be as the squares of the numbers, as 4 to 9. The Rennin Enzyme (Rennet, Chymosin). — The property possessed by the mucous membrane of the calf's stomach of curdling milk has been known from remote times, and has been utilized in the manufacture of cheese and curds. This action takes place with remarkable rapidity under favorable conditions, a large mass of milk * See Hofmeister, " Ergebnisse der Physiologie," vol. i., part i., 796, 1902. 49 770 PHYSIOLOGY OF DIGESTION AND SECRETION. setting to a firm coagulum within a very brief time. It has been shown that this effect is due to an enzyme — rennin or rennet. The rennin. like the pepsin, is supposed to be formed in the chief cells of the gastric tubules and to be present in the glands in a zymogen form, the prorennin or prochymosin, which after secretion is con- verted to the active enzyme. This conversion takes place very readily under the influence of acid. Rennin (or its zymogen) may be obtained easily from the mucous membrane of the stomach (with the exception of the pyloric end) by extracting with glycerin or water or by digesting with dilute acid. Good extracts of rennin cause the milk to clot with great rapidity at a temperature of 40° C; the milk (cows' milk), if undisturbed, sets at first into a solid clot, which afterward shrinks and presses out a clear, yellowish liquid — the whey. With human milk the curd is much less firm, and takes the form of loose flocculi. The whole process resembles much the clotting of blood. The rapidity of clotting is said to vary inversely as the amount of rennin, or, in other words, the product of the amount of rennin and the time necessary for clotting is a constant. The curdling of the milk involves two apparently independent proc- esses : First, the rennin acts upon the casein of the milk and converts it into a substance known as paracasein. The paracasein then reacts with the calcium phosphate of the milk, forming an insoluble calcium salt, which constitutes the curd or coagulum. According to this view, the enzyme does not cause clotting directly.* What takes place when the casein is changed to paracasein is not under- stood. Hammarsten originally regarded the change as a cleavage process, but this view has not been supported. Others have sup- posed that a transformation or rearrangement of molecular struc- ture occurs. Indeed, the differences in properties between casein and paracasein are not great, the most marked difference being that the calcium salts of the latter are insoluble. If soluble calcium salts are removed from milk by the addition of oxalate solutions, it does not curdle upon the addition of rennin. Addition of lime salts re- stores this property. It should be added that casein is also pre- cipitated from milk by the addition of an excess of acid. The curdling of sour milk in the formation of bonnyclabber is a well- known illustration of this fact. When milk stands for some time the action of bacteria upon the milk-sugar leads to the formation of lactic acid, and when this acid reaches a certain concentration, it causes the precipitation of the casein. So far as our positive knowledge goes, the action of rennin is confined to milk. Casein is the chief protein constituent of milk, and has, therefore, an important nutritive value. It is interesting to find that before its peptic digestion begins the casein is acted upon by an altogether different enzyme. The value of the curdling * See Bang, " Skandinavisches Archiv. f. Physiologie," 25, 105, 1911. DIGESTION AND ABSORPTION IN THE STOMACH. 771 action is not at once apparent, but we may suppose that casein is more easily digested under the conditions that exist in the body after it has been brought into a solid form. This has, however, been doubted, and it has even been suggested that the process is a hin- drance rather than an aid to the digestion of the casein. Until the contrary is definitely demonstrated it is preferable to assume that the process is of importance in the digestion of milk. The action of rennin goes no further than the curdling; the digestion of the curd is carried on by the pepsin, and later, in the intestines, by the trypsin, with the formation of proteoses and peptones as in the case of other proteins.* Rennin is found elsewhere than in the gastric mucosa. It has been described in the pancreatic juice, in the testis, and in many other organs as well as in the tissues of many plants. In fact, wherever proteolytic enzymes are found there also some evidence of a curdling action on milk may be ob- tained. For this reason some observers t have taken the view that the milk coag- ulation is not due to a specific ferment, but is an action of the pepsin itself. That is, the proteolytic enzyme is capable of causing the change from casein to paracasein as well as the hydrolysis of the protein. This view is opposed to the prevalent opinion regarding the specificity of enzyme actions. Another interesting fact concerning rennin is that an animal may be im- munized against it (see p. 416). If rennin be injected subcutaneously in an animal an antirennin will be formed in its blood. This antirennin added to milk prevents its curdling by rennin, giving a result, therefore, similar to the reaction between toxins and antitoxins. The Digestive Changes Undergone by the Food in the Stomach. — In addition to the pepsin and rennin various observers have described other enzymes in the gastric juice or gastric mem- brane, but the evidence at hand is uncertain regarding these latter, except in the case of what is known as gastric lipase (Volhard). As was said above, it is probable that the ptyalin swallowed with the food continues to exert its action upon the starchy material in the fundus for a long time, so that in this way the starch digestion in the stomach may be important. Regarding the fats, it is usually believed that they undergo no truly digestive change in the stomach. They are set free from their intimate mixture with other food stuffs by the dissolving action of the gas- tric juice upon proteins, they are liquefied by the heat of the body, and they are disseminated through the chyme in a coarse emulsion by the movements of the stomach. In this way they are mechan- ically prepared so that the subsequent action of the pancreatic juice is much favored. When, however, fats are ingested in emulsified form, as in milk, for instance, the lipase of the stomach, according to Volhard, may cause a marked hydrolysis. It is * For references to the very abundant literature, consult Oppenheimer. loc. cit. t See Pawlow and Parastschuk, "Zeitschrift f. physiol. Chemie," 42, 415. 772 PHYSIOLOGY OF DIGESTION AND SECRETION. supposed that this action may be important in the digestion of the milk-fat by infants. Regarding the proteins, the practical point of interest is as to how far they are digested during their stay in the stomach. It seems probable that this question does not admit of a categorical answer — that is, the extent of the digestion varies under different circumstances; with the consistency of the food, the duration of its stay in the stomach, etc. In some experiments reported by Tobler it is stated that 48 per cent, of a given amount of protein passed through the pylorus as peptones or proteoses, about 20 per cent, entered the intestine undigested, and 20 to 30 per cent, was absorbed from the stomach. In the liquid material (chyme) forced through the pylorus into the duodenum one may find unchanged proteins, primary or secondary proteoses, peptones, or even the final split products of proteolytic action. The true value of peptic digestion is not so much in its own action as in its combined action with the trypsin of the pancreatic juice. The digestion of the proteins of the food is accomplished by both enzymes, and normally we are justified in considering them together as effecting a peptic-tryptic digestion. The preliminary digestion in the stomach is important as regards the protein foods from several standpoints: First, in the matter of mechanical preparation of the food and its discharge in convenient quantities easily handled by the duodenum. Second, in the more or less complete hydrolysis to peptones and proteoses whereby the action of the pancreatic juice must be greatly acceler- ated. Indeed, in some cases, this preliminary action of the pepsin- hydrochloric acid may be absolutely necessary. Native proteins, such as serum-albumin, are not acted upon by trypsin, but if sub- mitted first to pepsin-hydrochloric acid they are quickly digested by this enzyme. Third, for some as yet unknown reason proteins sub- mitted to peptic digestion are split by the trypsin in a way different from its action on proteins without this preliminary treatment. These and other facts seem to indicate that the peptic digestion is not so much an end in itself as a preparation for subsequent intestinal digestion. The stomach, therefore, may be removed without a fatal result. Several cases are on record in which the stomach was practically removed by surgical operation, the esophagus being stitched to the duodenum.* The animals did well and seemed perfectly normal, although special precautions were necessary in the matter of feeding. Absorption in the Stomach. — In the stomach it is possible that there may be absorption of the following substances : Water ; salts ; sugars and dextrins that may have been formed in salivary digestion *Ludwig and Ogata, "Archiv f. Physiologie," 1883, p. 89; Carvallo and Pachon, "Archives de physiologie norm, et path.," 1894, p. 106. DIGESTION AND ABSORPTION IN THE STOMACH. 773 from starch, or that may have been eaten as such; the proteoses and peptones formed in the peptic digestion of proteins or albuminoids. In addition, absorption of soluble or liquid substances — drugs, alcohol, etc., that have been swallowed — may occur. It was formerly assumed, without definite proof, that the stomach absorbs easily such things as water, salts, sugars, and peptones. Actual experi- ments, however, made, under conditions as nearly normal as possible, show, upon the whole, that absorption does not take place readily in the stomach — certainly nothing like so easily as in the intestine. The methods made use of in these experiments have varied, but the most interesting results have been obtained by establishing a fistula of the duodenum just beyond the pylorus.* After establishing this fistula food may be given to the animal and the contents of the stomach as they pass out through the pyloric opening may be caught and examined. Water. — Experiments of the character just described show that water when taken alone is practically not absorbed at all in the stomach. Von Mering's experiments especially show that as soon as water is introduced into the stomach it begins to pass into the intestine, being forced out in a series of spurts by the contractions of the stomach. Within a comparatively short time practically all the water can be recovered in this way, none or very little having been absorbed in the stomach. For example, in a large dog with a fistula in the duodenum, 500 c.c. of water were given through the mouth. Within twenty-five minutes 495 c.c. had been forced out of the stomach through the duodenal fistula. This result is not true for all liquids ; alcohol, for example, is absorbed readily. Salts. — The absorption of salts from the stomach has not been investigated thoroughly. According to Brandl, sodium iodid is absorbed very slowly or not at all in dilute solutions. Not until its solutions reach a concentration of 3 per cent, or more does its absorp- tion become important. This result, if applicable to all the soluble inorganic salts, would indicate that under ordinary conditions they are practically not absorbed in the stomach, since it can not be sup- posed that they are normally swallowed in solutions so concentrated as 3 per cent. In the same direction Meltzer reports that solutions of strychnin are absorbed with difficulty from the stomach as com- pared with the intestines, rectum, or even the pharynx. It is said that the absorption of sodium iodid is very much facilitated by the use of condiments, such as mustard and pepper, or alcohol, which act either by causing a greater congestion of the mucous membrane or perhaps by directly stimulating the epithelial cells. * Compare von Mering, " Verhandl. des Congresses f. innere Med.," 12, 471, 1893; Edkins, "Journal of Physiology," 13, 445, 1892; Brandl, " Zeit- schrift f. Biologie," 29, 277, 1892. 774 PHYSIOLOGY OF DIGESTION AND SECRETION. Sugars and Peptones. — Experiments by the newer methods leave no doubt that sugars and peptones can be absorbed from the stomach. In von Mering's work different forms of sugar — dextrose, lactose, saccharose (cane-sugar), maltose, and also dextrin — were tested. They were all absorbed, but it was found that absorption was more marked the more concentrated were the solutions. Branch reports that sugar (dextrose) and peptone are not sensibly absorbed until the concentration has reached 5 per cent. With these substances also the ingestion of condiments or of alcohol increases distinctly the absorptive processes in the stomach. Examination of the mucous membrane of a stomach in full digestion shows that it contains albumoses (Glaessner), — a fact that indicates some absorption. Direct examination of the stomach contents* indicates that the products of peptic action beyond the albumose stage — namely, the peptones, peptids, and amino-bodies — are absorbed. On the whole, however, it would seem that sugars and peptones are ab- sorbed with some difficulty from the stomach. Fats. — As we have seen, fats probably undergo no digestive changes in the stomach, except when eaten in emulsified form. The processes of saponification and emulsification are supposed to be preliminary steps to absorption, and these processes take place usually after the fats have reached the small intestine. The fat that is not acted upon at all in the stomach is, of course, not absorbed, and even those fats in emulsified form which are partially saponified in the stomach escape absorption until they reach the small intestine. * Zunz, 'Beitrage zur chem. Physiol, u. Pathol.," 3, 339, 1903. CHAPTER XLni. DIGESTION AND ABSORPTION IN THE INTESTINES, The food undergoes its most profound digestive changes in the intestines, and here also the products of digestion are mainly ab- sorbed. The intestinal digestion begins in the duodenum, and is largely completed by the time that the food arrives at the ileocecal valve. It is effected through the combined action of three secretions, — the pancreatic juice, the secretion from the intestinal glands (succus entericus), and the bile. These secretions are mixed with the food from the duodenum on, so that their action proceeds simultaneously. For purposes of description it is necessary to speak of each more or less separately. The Pancreas. — The pancreas forms a long, narrow gland reach- ing from the spleen to the curvature of the duodenum. Its main duct in man (duct of Wirsung) opens into the duodenum, together with the common bile-duct, about 8 to 10 cms. beyond the pylorus. The points at which the duct or ducts of the pancreas enter the intestine vary somewhat in different mammals. In the dog there are two chief ducts, one opening, together with the bile-duct, about 3 to 5 cm. below the pylorus, while a second enters the duodenum some 3 to 5 cms. farther down. In rabbits the principal pancreatic duct opens separately into the duodenum about 35 cms. below the opening of the bile-duct. The pancreas is a compound tubular gland like the salivary glands. The cells lining the secreting portion of the tubules, the alveoli, belong to the serous or albuminous type. They are characterized by the fact that the outer portion of each cell is composed of a clear, non-granular material which stains readily, while the inner portion, the portion facing the lumen, contains numerous granules. Histological study of the gland after active secretion, as compared with the resting state, has shown very con- " clusively that these granules represent a preparatory material for secretion. As the secretion proceeds the granules are dissolved and discharged into the lumen, while during the periods of rest new granules are formed by metabolic processes at the expense, appar- ently, of the non-granular material in the basal portion of the cell. (Heidenhain, Kiihne, Lea). The histological picture of secretion is in general the same in this as in the salivary and gastric glands, only somewhat more distinctly shown. On the supposition that the granules constitute an antecedent material from which the enzymes 775 776 PHYSIOLOGY OF DIGESTION AND SECRETION. of the secretion are formed they are frequently designated as zymo- gen granules. The pancreas contains also certain peculiar groups of cells, the islands (or bodies) of Langerhans. These cells probably have nothing to do with the digestive activity of the pancreas. Their supposed function is referred to in the sections on Internal Secretions and Nutrition. Composition of the Secretion. — The pancreatic secretion is an alkaline liquid which in some animals is thin and limpid, in others thick and glairy. The secretion in man belongs to the former type ; it is described as water-clear and as ha -ring a specific gravity of 1.0075. The secretion may be collected by opening the abdomen and inserting a cannula directly into the duct, or a permanent fistula may be made by the method of Pawlow. This method, applicable to the dog, consists in cutting out a small portion of the duodenum where the pancreatic duct opens and then suturing this piece, the mucous membrane outward, into the abdominal wall. The secretion in this case pours out upon the exterior and may be collected. The animal, however, suffers nutritive disturbances from the loss of the secretion, and requires careful dieting and atten- tion. The secretion of the human pancreas has been collected in a single case* in which for a few days it was necessary to drain off the pancreatic juice to the exterior. From the observations made in this case it appears that the secretion in man is quite abundant, amount- ing to 500 to 800 c.c. per day. In the cow (Delezenne) from 1^ to 2 liters may be collected in the course of a day. The secretion possesses a strong alkaline reaction, due to the presence of sodium carbonate; it contains also a small amount of coagulable protein and a number of organic substances in traces. The important constituents, how- ever, are three enzymes or their zymogens, — namely, trypsin, a proteolytic enzyme; pancreatic diastase (amylopsin), an amylolytic enzyme; and lipase (steapsin), a lipolytic enzyme. Some authors state, also, that the secretion contains a rennin enzyme. Glaessner reports that he got no eridence of this last enzyme in human pan- creatic juice. Secretory Nerve Fibers to the Pancreas. — The pancreas receives its nerve supply immediately from the celiac plexus, but stimulation of the nerves going to this plexus — namely, the splaneh- nics and the vagi — have given negative results in the hands of most observers so far as the pancreatic secretion is concerned. Pawlow f and his coworkers claim to have been more successful. Mechanical stimulation or electrical stimulation of the vagus or splanchnic gave * See Glaessner, " Zeitschrift f. physiol. Chemie, " 40, 465, 1903. t For recent work upon the pancreas and the literature see Pawlow. "The Work of the Digestive Glands," translation by Thompson, 1902; Bay- liss and Starling, "Journal of Physiology," 30, 61, 1904; Walter, "Archives des sciences biologiques, " 7, 1. ?899. DIGESTION AND ABSORPTION IN THE INTESTINES. 777 them a marked flow of pancreatic juice, but when the latter form of stimulus was used upon the splanchnic, it was necessary to cut the nerve some days previously in order that the vasoconstrictor fibers might degenerate. The secretion provoked by stimulation of the vagus is more easily obtained when the stimulus is applied to the nerve in the thorax below the origin of the branches to the Heart. The secretion obtained upon stimulation of the nerves is characterized, as in the case of the gastric glands, by a long latent period of some minutes, — a fact that is explained, although not satisfactorily, on the assumption that the nerve trunks stimu- 1. X. 3. U. 5. 6. 7. 8. Ai / \ MO / / / \ \ / \ \ SI \ / / \ \ ! 1 ! i > U ■ i i i \ \ i i ; 1 l i \ \ lb 1 i / \ \ 1 / \ "n^ i ■1 i \ V \ Xv .'/ N — ' ^ i. 0 1 / ■~^^_ .311 Ok. .QxeaA. .3Keat. Fig. 296. — Four curves of the secretion of the pancreatic juice, the three in black, from Walter, showing the secretion in dogs on different diets: (1) on 600 c.c. of milk; (2) on 250 gms. bread; (3) on 100 gms. of meat. The curve in red, from Glaessner, shows the secretion in man on a mixed diet, soup, meat, and bread. The figures, 1, 2, 3 etc., along the abscissa indicate hours after the beginning of the meal. The figures along the ordinates indicate the quantity of the secretion in cubic centimeters. lated contain both secretory and inhibitory fibers and that the antagonistic action of the latter delays the appearance of the secretion. These observations have been taken as proof of the existence of secretory nerve fibers to the pancreas, the fibers running chiefly in the vagus nerve. The Curve of Secretion. — The rate of flow of the pancreatic juice with reference to the period of digestion has been determined by a number of observers. In the careful experiments reported by Walter it is shown that the quantity of secretion is dependent to a considerable extent upon the character of the food. Thus, the flow is more abundant and reaches its maximum sooner after a 778 PHYSIOLOGY OF DIGESTION AND SECRETION. meal of bread alone than after a meal of meat alone. It seems possible that the latter point, the time at which the maximum flow is reached, may depend upon the difference in rate at which these foods are ejected from the stomach. Cannon (p. 712) has shown that the carbohydrate foods leave the stomach sooner than the proteins or fats. It is stated, however, that the composition of the secretion varies also with the character of the food, and indeed shows an adaptation to the character of the food. The secretion caused by protein food is especially rich in trypsin, that caused by fatty food in lipase, etc. The mechanism by which this adaptation is secured is not understood. Glaessner* has measured the rate of flow in man, and his curve for a mixed diet is represented also (in red) in Fig. 296. These curves indicate in general that the secretion of pancreatic juice begins very soon after food enters the stomach, and increases rapidly to a maximum, which is reached somewhere between the second and fourth hour. According to Glaessner's case, there is a continuous small secretion of the juice during fast- ing. The observations on dogs, on the contrary, indicate an entire cessation of the flow when the stomach is empty. Boldirefft has reported a very curious activity of the digestive organs during fasting. It seems that (in dogs) when the stomach or even the small intestine is empty the entire gastro-intestinal canal exhibits periodical out- breaks of activity, which occur at intervals of two hours and last for twenty to thirty minutes. During this stage the stomach and intestines exhibit movements, and there is an abundant secretion of pancreatic juice, bile, and intestinal juice, which is subsequently absorbed. Acids introduced into the stomach or intestines prevent the occurrence of these periods, and they are absent, therefore, as long as the stomach contains gastric juice. The author's suggestion that the secretions thus formed furnish active enzymes which are absorbed into the blood and utilized by the tissues in destroying the newly absorbed food does not commend itself as probable. Normal Mechanism of the Pancreatic Secretion — Secretin. — Much light was thrown upon the mechanism of pancreatic secretion by the discovery (Dolinsky, 1895) that acids brought into contact with the mucous membrane of the duodenum set up promptly a secretion of pancreatic juice. Since this discovery it has been be- lieved that the acid gastric juice is the means that serves to inaugurate the flow from the pancreas. As soon as any of the acid contents of the stomach pass through the pylorus this action begins. Just as the chewing and swallowing of the food initiate the gastric secretion, so the acid of the latter starts the pancreatic secretion. Assuming that the pancreatic gland possesses secretory fibers it was thought at first that the acid acts reflexly through these fibers — that is, the acid in the duodenum acting upon sensory endings causes a reflex stimu- lation of the efferent secretory fibers. It has been shown, however, that the same effect takes place after section of the vagus and * Claessner, loc.cit. t Boldireff, "Archives des sciences biologiques, " 11, 1, 1905. DIGESTION AND ABSORPTION IN THE INTESTINES. 779 splanchnic nerves (Popielski), and Bayliss and Starling * have called attention to another more probable explanation. These authors find that if the mucous membrane of the duodenum (or jejunum) is scraped off and treated with acid (0.4 per cent. HC1) the extract thus made when injected into the blood sets up an active secretion of pancreatic juice. They have shown that this effect is due to a special substance, secretin, which is formed by the action of the acid upon some substance (prosecretin) present in the mucous membrane. Secretin is not an enzyme, since its activity is not destroyed by boil- ing nor by the action of alcohol. The experimental evidence at present favors the view that the normal sequence of events is as follows: The acid of the gastric juice upon reaching the duodenum produces secretin; this in turn is absorbed by the blood, carried to the pancreas, and stimulates this organ to activity. The pan- creatic secretion furnishes, therefore, a second example of the group of substances designated by Starling as hormones (p. 765) . Accord- ing to the evidence at present in our possession we must believe that the pancreatic secretion, like the gastric secretion, consists of two parts: 1, A nervous secretion caused by the secretory fibers in the vagus and splanchnic; 2, a chemical secretion due to the action of the secretin. These two secretions are said to present quite different characters. f The former is, thick, opales- cent, rich in ferments and proteins, but poor in alkalies. The trypsin contained in it may be secreted in active form, and the secretion is suspended by the action of atropin. Administration of pilocarpin, on the contrary, excites this secretion. The chemical secretion, on the contrary, is thin and watery, contains relatively little ferment or proteins, and is rich in alkali. The trpysin in it is secreted in inactive form (see next paragraph), and the secretion is not affected by the administration of atropin. The normal relation of these two forms of secretion in an ordinary meal is not so apparent as in the case of the gastric secretion, but will doubtless be made clear by subsequent work. Activation of the Trypsin — Enterokinase. — It was discovered in Pawlow's laboratory (Chepowalnikow) that the pancreatic juice obtained from a fistula may have little or no digestive action on proteins, but if brought into contact with the duodenal membrane or an extract of this membrane it shows at once powerful pro- teolytic properties. This discovery has been confirmed repeatedly. Evidently the proteolytic enzyme of the juice is secreted in a zymogen or pro-enzyme form (trypsinogen) , which is activated or converted to trypsin by something contained in the mucous mem- * Bayliss and Starling, "Journal of Physiology," 28, 235, 1902. fSawitsch, " Zentralblatt f. d. ges. Physiol, u. Pathol, d. Stoffwechsels,' 10, 1, 1909. 780 PHYSIOLOGY OF DIGESTION AND SECRETION. brane of the small intestine (duodenum, jejunum). This something Pawlow supposed is an enzyme, and since its action is on another enzyme, "a ferment of ferments," he designated it as a kinase or enterokinase. The action of the enterokinase is very prompt and decided and was supposed to be specific, but later observers (Delezenne-Zunz) state that an inactive pancreatic secretion may be activated by a number of salts, especially those of calcium and magnesium. The physiological value of this very interesting relation is not clear, but it seems possible that it may serve to protect the living tissues from the powerful digestive action of the trypsin. The other enzymes of the pancreatic juice, the diastase and the lipase, are secreted in part, at least, in active form. The Digestive Action of Pancreatic Juice. — The digestive action of the secretion depends upon the three enzymes, trypsin, diastase (amylase), and lipase. The specific effects of each may be considered separately. Action of Trypsin. — The activated trypsinogen causes hydrolytic cleavage of the protein molecule in a manner analogous to that described for pepsin. Its action differs from that of pepsin, however, in several respects. It attacks the protein in neutral as well as in slightly acid or markedly alkaline solutions. Its effect upon the protein is more rapid and powerful than that of pepsin and the protein molecule is broken up more completely. As was said in describing the action of pepsin, it and the trypsin really act to- gether— the change begun by the pepsin is completed by the tryp- sin. The preliminary action of the pepsin not only hastens that of the trypsin, but to some extent alters it; a protein submitted first to pepsin and then to trypsin is more completely broken up than if the trypsin acted alone. The steps in the hydrolysis of the protein molecule by trypsin have been the subject of a very great amount of study, and views as to the details have changed somewhat from time to time. It would seem that the trypsin, like the pepsin, hj'drolyzes the simple proteins first to a proteose, and then to a pep- tone stage, but the latter product may be split still further into a variety of simpler bodies, the number and character of which de- pend on the amount of trypsin and the time that it acts. After a prolonged pancreatic digestion no peptone or peptone-like body can be found; in fact, no substance which gives a biuret reac- tion. Under such conditions the protein molecule is broken up very completely into a great number of smaller molecules, many of which have been identified, while some have as yet escaped de- tection so far as their chemical structure is concerned. The actual products formed depend on the length of time the trypsin is allowed DIGESTION AND ABSORPTION IN THE INTESTINES. 781 to act and the conditions, favorable or unfavorable, under which it acts. The end-products usually obtained most easily are tyrosin, leucin, aspartic acid, glutaminic acid, tryptophan, lysin, arginin, histidin. The first two of these substances have been known for a long time and may be obtained easily in crystalline form from pancreatic digestions. If the trypsin is allowed to exert its complete action upon the protein the end-products are closely similar to those obtained by boiling protein with acids. The hydrolysis caused by the acids and by the trypsin seems to be nearly identical, although that caused by the acids is probably more complete, and perhaps is attended by secondary reactions, since the split products of a complete acid hydrolysis when fed to an animal give a different result from those obtained from a complete trypsin-hydrolysis (see p. 877). The numerous products obtained by this complete hydrolysis consist chiefly of amino-acids — that is, organic acids containing one or more amino-groups (NH2) in direct union with carbon. The nitrogen of the protein molecule appears in the split products in this form and also partly as ammonia compounds. Some of the amino bodies are monamino-acids— that is, contain one XH2 group, such as leucin, tyrosin, glycin — and include sub- stances belonging to the fatty acid series (aliphatic series), the benzene or carbocyclic series, and the heterocyclic series. Others are the so-called diamino-acids which exhibit marked basic prop- erties and, therefore, are frequently described as nitrogenous bases, and sometimes as the hexon bases, since they contain six carbon atoms. This group consists of leucin, arginin, and hys- tidin. The chemical formulas for some of these bodies are as follows. For their properties and chemical relationships reference must be made to the text- books on physiological chemistry (see also Appendix, Chemistry of Proteins, for a more complete list) : I. MONAMINO-BODIES. FATTY ACID SERIES. Glycin or amino-acetic acid: CH2NH2COOH. This product is obtained in especially large quantities by hydrolysis of gelatin. According to Abderhalden,* it is split off with difficulty by trypsin. Alanin or a-aminopropionic acid: CH3CHXH,COOH. C'Tf Valin or amino valerianic acid: ,-,tt3>CHCHXH2COOH. Leucin or aminocaproic acid: £g3^CHCH2CHNH2COOH. As stated above, this compound was one of the first end-products of protein hydrolysis that was recognized. It may be obtained readily in crystalline form. * Abderhalden, "Zeitschrift f. physiol. Chemie," 44, 17, 1905. Consult for general description of the digestion of proteins. 782 PHYSIOLOGY OF DIGESTION AND SECRETION. CHNH,COOH tnic acid: • r<-tnvTTT r Glutaminic acid: CH, Aspartic or amine-succinic acid: CH COOH. CHNH2COOH CH,COOH. BENZENE OR AROMATIC SERIES. Tyrosin (para-oxyphenylaminopropionic acid) : C9H4OH . CH2 . CHNH2- COOH. This substance was also among the first recognized prod- ucts of protein hydrolysis It occurs early in the process of pan- creatic digestion, and is easily obtained in crystalline form from the digested mixture. It is especially interesting because of the presence of a benzene nucleus, thus giving proof that the benzene grouping occurs normally in the protein molecule. Phenylalanin (phenvlaminopropionic acid) : C6H5CH2CHNH2COOH. This benzene derivative is, according to Abderhalden, split off from the protein with difficulty by the action of trypsin, although readily produced by acid hydrolysis. PYRROL AND INDOL SERIES. CH— CH2 Prolin or a-pyrrolidin carboxylic acid: CH2 CHCOOH. This substance, NH discovered first by Fischer among the products of acid hydrolysis of proteins, has since been shown to occur in tryptic digestion. Like the glycin and phenylalanin, it is produced with difficulty by trypsin acting alone, but more readily if the tryptic action follows upon previous peptic digestion, as is the case in the body. Tryptophan (indolaminopropionic acid) : This substance has long been recog- nized among the products of tryptic digestion by the reddish-violet color (Tiedemann and Gmelin, 1826) observed upon the addition of chlorin or bromin. Its chemical structure was determined by Hopkins and Cole (1901). According to Ellinger,* tryptophan is an indol- amino-propionic acid of the formula C.CHCOOHCH2NH2. c6h/Vh NH When fed to dogs it causes the appearance of kynurenic acid (C,0H7NO3) in the urine. It is interesting as showing the existence of an indol grouping in the protein molecule. II. The Diamino-bodies (Hexon Bases). Lysin (a-£-diaminocaproic acid) : C8HMN302 or CH2NH2(CH2)3CHNH2- COOH. Arginin (guanidin a-aminovalerianic acid) : C6HHN402 or NHCNH2NH- CH2(CH2)2CHXH2COOH. Histidin: QjHg^Oj (imidazolaminopropionic acid). .NH— CH CH/ || ^N — C— CH2CHNH,COOH. The Significance of Tryptic Digestion. — It was formerly- supposed that the object of peptic and tryptic digestion is to con- vert the insoluble and non-dialyzable proteins into the simpler, more soluble, and more diffusible peptones and proteoses. In this * Ellinger. " Zeitschrift f. physiol. Chemie," 43, 325, 1904. DIGESTION AXD ABSORPTION IN THE INTESTINES. 783 way absorption of protein material was explained. This view, however, is not sufficient. On the one hand, it has not been possible to prove conclusively that peptones or proteoses are found in the blood; on the other hand, a better - knowledge of the processes of tryptic or of peptic-tryptic digestion has shown that the hydrolysis does not stop at the peptone stage; the protein molecule is split into a number of simpler crystalline substances, the various amino- bodies. At present different views exist as to the extent of this latter process. Some believe that the protein molecule is entirely broken down into its so-called end-products, and that in order to serve its nutritive function these products or some of them must be synthetically combined again during or after absorption. This view is supported, moreover, by the discovery of the existence of the enzyme erepsin (see below) in the intestinal mucosa. The action of this latter enzyme is exerted especially upon the albumoses and pep- tones, breaking them down into the amino-acids, so that apparently whatever peptone or albumose may escape the final action of the trypsin before absorption is likely to be acted upon by the erepsin before reaching the blood.* Another interesting view is that sug- gested by Abderhalden. | According to this author, the hydrolysis of the protein by pepsin and trypsin (and perhaps by erepsin) is not complete. Many amino-bodies, such as tyrosin, leucin, arginin, etc., are split off from the protein molecule, but there remains behind what one may call a nucleus of the original molecule, which serves as the starting point for a synthesis. This nucleus is a substance or a number of substances intermediate between the peptone and the simpler end-products, and is spoken of as a peptid or polypeptid (see Appendix). Abderhalden has shown that in tryptic digestion such substances are formed — that is, substances which are not peptones, since they no longer give the biuret reaction, but which have a certain complexity of structure, since upon hydrolysis with acids they split into a number of monamino- and diamino- bodies. A schema of peptic-tryptic digestion from this standpoint may be given as follows: Native protein. Peptone. Polypeptid. Tyrosin, leucin, glutaminic acid, aspartic acid. a-pyrrolidin carboxylic acid, tryptophan, etc. Arginin, lysin, histidin. * Vernon ("Journal of Physiology," 30, 330, 1904) believes "that the pancreatic secretion contains two proteolytic enzymes — trypsin proper, which converts the proteins to peptones, and pancreatic erepsin, which breaks up the peptones into the simpler end-products, the amino-bodies. t Abderhalden, loc. tit. 784 PHYSIOLOGY OF DIGESTION AND SECRETION. From either of the points of view presented it may be suggested that the value of this more or less complete splitting of the protein of the food lies in the possibility that thereby the body is able to construct its own peculiar type of protein. Many different kinds of proteins are taken as food and many of them if introduced directly into the blood act as foreign material incapable of nourishing the tissues. If these proteins are broken down more or less completely during digestion the tissue cells may reconstruct from the pieces a form of protein adaptable to their needs, and more or less characteristic for that particular organism. This general point of view is gaining ground in recent years and has obtained much support from the fact that an animal may be nourished properly on a diet in which the protein of the food is entirely replaced by the split products of a complete pancreatic digestion (see p. 877). Action of the Diastatic Enzyme (Amylase) of the Pan- creatic Secretion. — This enzyme is found in the secretion of the pancreas or it may be extracted from the gland. Its action upon starchy foods is closely similar to or identical with that of ptyalin. It causes an hydrolysis of the starch with the production finally of maltose and achroodextrin. Before absorption these substances are further acted upon by the maltase of the intestinal secretion and converted to dextrose. The starchy food that escapes digestion in the mouth and stomach becomes mixed with tins enzyme in the duodenum, and from that time until it reaches the end of the large intestine conditions are favorable for its conversion to maltose and dextrin. Most of this digestion is probably completed, under normal conditions, before the contents of the intestinal canal reach the ileo- cecal valve. Action of the Lipolytic Enzyme (Lipase, Steapsin). — The importance of the pancreatic secretion in the digestion of fats was first clearly stated by Bernard (1849). We know now that this secre- tion contains an active enzyme capable of hydrolyzing or saponifying the neutral fats. These latter bodies are chemically esters of the trihydric alcohol glycerin. When hydrolyzed they break up into glycerin and the constituent fatty acid. The action of lipase may be represented, therefore, by the following reaction, in the case of palmitin : C3H6(C15H31COO)3 + 3H20 = C3H5(OH)3 + 3(C15H3ICOOH) Palmitin. Glycerin. Palmitic acid. When lipase from any source is added to neutral oils its splitting action is readily recognized by the development of an acid reaction due to the formation of the fatty acid. If a bit of fresh pancreas is added to butter, for example, and the mixture is kept at the bod}' temperature the hydrolysis of the fats is soon made evident by the DIGESTION AND ABSORPTION IN THE INTESTINES. 785 rancid odor due to the butyric acid produced. When pancreatic juice is mixed with oils or liquid fats two phenomena may be noticed: first, the splitting of the fat already referred to, and, second, the emulsification of the fat. The latter process is very striking. An oil is emulsified when it is broken up into minute globules that do not coalesce. Artificial emulsions may be made by vigorous and prolonged shaking of the oil in a viscous solution of soap, mucilage, etc. Milk may be regarded as a natural emulsion that separates slowly on standing, as the fat rises to the top to form the cream. When a little pancreatic juice is added to oil at the body temperature the mixture, after standing for some time, will emulsify readily with very little shaking or even spontaneously. It is now known* that the emulsification is due to the formation of soaps. The lipase splits some of the fats, and the fatty acid liberated combines with the alkaline salts present to form soaps. The emulsification produced under these conditions is very fine and quite permanent, and it was formerly believed that the formation of this emulsion is the main function of the pancreatic juice so far as fats are concerned. It was thought that in the form of fine droplets the fat may be taken up directly by the epithelial cells of the villi, and this view was supported by the histological fact that during the digestion of fats the epithelial cells may be shown to contain fine oil drops in their interior. The tendency of recent work, however, has been to indicate that the fats are completely split into fatty acids and glycerin before absorption, and that the emulsification may be regarded, from a physiological standpoint, as a mechanical preparation for the action of the lipase rather than as a direct preparation for the act of absorption. The two products of the action of the lipase, the glycerin and the fatty acid, are absorbed by the epithelium and again combined to form neutral fat. It is very probable, moreover, that during this synthesis the fatty acids are combined with the glycerine in such proportions as to make for the most part the fat characteristic of the animal, fat of a high melting-point in the case of the sheep,' for example, and of a lower melting-point for the dog. In connection with this fact of a synthesis of the split products to form neutral fat, the discovery by Kastle and Loevenhart (see p. 733) that the action of lipase is reversible assumes much significance. It seems quite possible that the same enzyme may cause both the splitting of the fat and the synthesis of the split products, not only in the intestine during absorption, but in the various tissues during the metabolism or the storage of fat. Lipase is found in the blood and in many tissues, — muscle, liver, mammary gland, f etc. — and during its nutritive history in the body the fat may * See Ratchford, "Journal of Physiology," 12, 27, 1891. f See' Loevenhart, "Amer. Journal of Physiology," 6, 331, 190^ 50 786 PHYSIOLOGY OF DIGESTION AND SECRETION. be split and synthesized a number of times. In this connection it is interesting to note that the process of splitting does not involve much work. Very little heat is liberated in the process, and a corre- spondingly small amount of energy is needed for the synthesis.* The lipase as formed in the pancreas is easily destroyed, especially by acids. For this reason probably it is not found usually in simple extracts of the gland made by laboratory methods. It should be added, also, that the action of this enzyme is aided very materially by the presence of bile. This latter secretion contains no lipase itself, but mixtures of bile and pancreatic juice split the neutral fats much more rapidly than the pancreatic juice alone. This effect is now explained on the hypothesis that the bile-acids or the bile-acids and the lecithin either activate a portion of the lipase which is in the state of a proferment or play the part of a coferment (page 737). The Intestinal Secretion (Succus Entericus). — The small intestine is lined with tubular glands, the crypts of Lieberkuhn, which in parts of the intestine at least give rise to a liquid secretion, the so-called intestinal juice. To obtain this secretion recourse has been had to the operation known as the Thiry-Vella fistula. In this operation a given portion of the intestine is separated from the remainder without injuring its blood-vessels or nerves and the two ends are sutured into the abdominal wall. In the loop thus isolated the secretions may be collected and experiments may be made upon the digestion and absorption of various substances. The secretion from these loops is usually said to be small in quantity, especially in the jejunum. Pregl estimates that as much as three liters may be formed in the whole of the small intestine in the course of a day, but this estimate does not rest upon very satisfactory data. The liquid gives an alkaline reaction, owing to the presence of sodium carbon- ate. Experiments have shown that this liquid has little or no digestive action except upon the starches, and it may perhaps be doubted whether it is a true secretion. Extracts of the walls of the small intestine or the juice squeezed from these walls have been found, on the contrary, to contain four or five different enzymes and to exert a most important influence upon intestinal digestion. These enzymes belong probably to the group of endo-enzymes, and are not actually secreted into the lumen of the intestines. While they are not, strictly speaking, constituents of the intestinal juice, never- theless it is their action on the food which forms the characteristic contribution to the process of digestion made by the glands of the intestinal wall. These enzymes and their actions are as follows: 1. Enterokinase ("see p. 779), an enzyme which in some way activates the proteolytic enzyme of the pancreatic juice, by converting the tryp- sinogen to trypsin. * Consult Herzog, "Zeitschrift f. physiol. Chemie," 37, 383, 1903. DIGESTION AND ABSORPTION IN THE INTESTINES. 787 2. Erepsin. This enzyme, discovered by Cohnheim,* acts especially upon the deutero-albumoses and peptones, causing further hydrolysis. Whether its splitting action upon the peptones is complete is not as yet known, but, as was said above (p. 783), the natural suggestion regarding this enzyme is that it supplements the work begun by the trypsin. 3. Inverting enzymes capable of converting the disaccharids into the monosaccharids. These enzymes are three in number: maltase, which acts upon maltose (and dextrin) ; invertase or invertin, which acts upon cane-sugar; and lactase, which acts upon lactose. The maltase acts upon the products formed in the digestion of starches, the maltose and dextrin, converting them to dextrose according to the general formula: C12H22Ou + H20 = C6H1206 + C6H1206 Maltose. Dextrose. Dextrose. In the same way invertase converts cane-sugar to dextrose and levu- lose, and lactase changes milk-sugar to dextrose and galactose. This inverting action is necessary to prepare the carbohydrate food for nutritive purposes. Double sugars can not be used by the tissues and would escape in the urine, but in the form of dextrose or dextrose and levulose they are readily used by the tissues in their normal metabolic processes. 4. Nuclease. There is some evidence that this enzyme which acts upon the nucleic acids is found normally in the small intestine and that it may play a part in the digestion of the nucleins of our food. 5. Lastly, the substance secretin, which, as explained above, plays such an important role in the control of the secretion of the pan- creas, is formed in the walls of the small intestine. It is not an enzyme, but a more stable and definite chemical substance which is secreted or formed in the intestinal mucosa in a preliminary form, prosecretin, and under the influence of acids is changed to secretin. In this latter form it is absorbed, carried to the pancreas, and causes a flow of pancreatic secretion. Absorption in the Small Intestine. — Absorption takes place very readily in the small intestine. The general correctness of this statement may be shown by the use of isolated loops of the intestine. Salt solutions of varying strengths or even blood-serum nearly identical in composition with the animals' own blood may be ab- sorbed completely from these loops. Examination of the contents of the intestine in the duodenum and at the ileocecal valve shows that the products formed in digestion have largely disappeared in traversing this distance. All the information that we possess in- dicates, in fact, that the mucous membrane of the small intestine absorbs readily, and it is one of the problems of this part of physiology to explain the means by which this absorption is effected. Anatomi- cally two paths are open to the products absorbed. They may enter the blood directly by passing into the capillaries of the villi, or they may enter the lacteals of the villi, pass into the lymph circulation, and through the thoracic duct of the lymphatic system eventually reach the blood vascular system. The older physiologists assumed * Cohnheim, " Zeitschrift f. physiol. Chemie," 33, 451, 1901 ; also 35, 134 et seq. 788 PHYSIOLOGY OF DIGESTION AND SECRETION. that absorption takes place exclusively through the central lacteals of the villi, and hence these vessels were described as the absorbents. We now know that the digested and resynthesized fats are absorbed by way of the lacteals, but that the other products of digestion are absorbed mainly through the blood-vessels and therefore enter the portal system and pass through the liver before reaching the general circulation. According to observations made upon a patient with a fistula at the end of the small intestine,* food begins to pass into the large intestine in from two to five and a quarter hours after eating, and it requires from nine to twenty-three hours before the last of a meal has passed the ileocecal valve; this estimate includes, of course, the time in the stomach. During this passage absorption of the digested products takes place nearly completely. In the fistula case referred to above it was found that 85 per cent, of the protein had disappeared, and similar facts are known regarding the other food- stuffs. The problems that have excited the greatest interest have been, first, the exact form in which the digested products are ab- sorbed, and, second, the means by which this absorption is effected. With regard to the last question, much work has been done to ascertain whether the known physical laws of diffusion, osmosis, and imbibition are sufficient to account for the movements of the absorbed substances or whether it is necessary to refer them in part to some unknown activities of the living epithelial cells. It would seem that diffusion and osmosis occur „in the intestines. Concentrated solutions of neutral salts, — sodium chlorid, for instance, — if introduced into a Thiry-Vella loop, cause a flow of water into the lumen in accordance with their high osmotic pressure, and, on the other hand, some of the sodium chlorid diffuses into the blood in accordance with the laws of diffusion. It seems equally clear, however, that absorption as it actually takes place is not governed simply by known physical laws. Thus, the animal's own serum,f possessing presumably the same concentration and osmotic pres- sure as the animal's blood, is absorbed completely from an isolated intestinal loop. So also it has been shown that in the absorption of salts from the intestine J the rapidity of absorption stands in no direct relation to the diffusion velocity. The energy that effects the absorption is furnished, therefore, by the wall of the intestine, presumably by the epithelial cells. It constitutes a special form of imbibition which is not yet understood. That this particular form of energy is connected with the living structure is shown by the fact that when the walls are injured by the action of sodium * Macfadyen, Nencki, and Sieber, "Archiv f. experiment. Pathol, u. Pharmakol.," 28, 311, 1891. f Heidenhain, " Archiv f. die gesammte Physiologie," 56, 579, 1894. % Wallace and Cushny, " Archiv f. die gesammte Physiologie," 77, 202, 1899. DIGESTION AND ABSORPTION IN THE INTESTINES. 789 fluorid, potassium arsenate, etc., their absorptive power is dimin- ished and absorption then follows the laws of diffusion and osmosis.* Absorption of the Carbohydrates. — Our carbohydrate food is absorbed, for the most part, as simple sugars, — monosaccharids. As has been said, there is reason to believe that but little sugar is absorbed in the stomach. Cane-sugar and milk-sugar are inverted in the small intestine by invertase and lactase, the first being con- verted to dextrose and levulose, the second to dextrose and galactose. If, however, these substances are fed in excess they are absorbed in part without conversion to simple sugar, and in that case may be eliminated in the urine. The bulk of our carbohydrate food is taken, however^ in the form of starch, and the conditions for absorption in this case are more favorable. The time required for the digestion of the starch to maltose and dextrin, and the subsequent inversion of these substances to dextrose, iDsures a slower and more complete absorption. Five hundred grams or more of starch may be digested and absorbed in the course of the day and it all reaches the blood in the form of dextrose. This dextrose enters the portal vein and is distributed first to the liver. In this organ the excess of sugar is withdrawn from the blood and stored as glycogen, so that the amount of sugar in the general circulation is thereby kept quite constant, — about 0.15 per cent. When a large amount of carbohydrate food is eaten, however, it is possible that the liver may not be able to remove the excess completely. In that case the amount of sugar in the gen- eral circulation may be increased above normal, giving a condition of hyperglycemia, and the excess may be excreted in the urine, thus bringing about the condition known as " alimentary glyco- suria." The amount of any carbohydrate that can be eaten without producing alimentary glycosuria is designated by Hof- meisterf as the assimilation limit of that carbohydrate. If taken beyond this limit there is a physiological excess, and some sugar is lost in the urine. The assimilation limit varies with a great many conditions; but, so far as the different forms of carbo- hydrates are concerned, it is lowest for the milk-sugar and high- est for starch. That starch may be eaten in larger amounts than sugar without raising the percentage of sugar in the sys- temic blood above the normal level is in accord with what we know of the digestion of the two forms of carbohydrates. Dex- trose requires no digestion, it is absorbed as such, while cane- sugar needs only to be inverted. Starch, on the contrary, requires the action of ptyalin or amylase and subsequent inversion by * Cohnheim, "Zeitschrift f. Biologie," 37, 443, 1899. t Hofmeister, "Archiv f. exper. Pathol, u. Pharmakol.," 25, 240, 1889, and 26, 355, 1890. 790 PHYSIOLOGY OF DIGESTION AND SECRETION. maltase. Its absorption will, therefore, be much slower than that «f the sugars. In fact, it probably goes on for the period of four or five hours, during which an ordinary meal is making its progress from pylorus to ileocecal valve. During this period the entire quantity of blood in the body is passed through the mesenteric arteries over and over again, and it is probable that even in the portal vein the quantity of sugar at any one moment rises but little above the normal level, and this small excess is held back by the liver cells, so that the systemic circulation is protected from becoming hyperglycemic. So far as the carbohydrates escape absorption as sugar they are liable to undergo acid fermentation from the bacteria always present in the intestine. As the result of this fermentation there may be produced acetic acid, lactic acid, butyric acid, succinic acid, carbon dioxid, alcohol, hydrogen, etc. This fermentation probably occurs to some extent in the small intestines under normal conditions. Macfadyen,* in the case already referred to, found that the contents of the intestine at the ileocecal valve contained acid equivalent to that of a 0.1 per cent, solution of acetic acid. Under less normal conditions, such as excess of sugars in the diet or deficient absorp- tion, the large production of acids may lead to irritation of the intes- tines,— diarrhea, etc. Absorption of Fats. — Numerous theories have been held in regard to the mode of absorption of fats. It has been supposed that the emulsified (neutral) fat is ingested directly by the epithelial cells, that the fat droplets enter between the epithelial cells in the so-called cement substance, that the fat droplets are ingested by leucocytes that lie between the epithelial cells, or lastly that the fat is first split into fatty acid and glycerin and is absorbed by the epithelial cells in these forms. The tendency of recent work is to favor this last view. During digestion the epithelial cells contain fat droplets without doubt, but it seems probable that these droplets are formed in situ by a synthesis of the absorbed glycerin and fatty acids. The border of the cell is said to be free from fat globules, — a fact which would indicate that the neutral fat is not mechanically ingested as oil drops. But, granting that the fat is absorbed in solution, as fatty acids and glycerin, the mechanism of absorption remains unexplained. It is known that the bile as well as the pancreatic juice plays an important part in the process. The pancreatic juice furnishes the lipase, the bile furnishes the bile salts (glycocholate and taurocholate of sodium) which aid the lipase in splitting the neutral fat, and moreover aid greatly the absorption of the split fats. This latter function is due probably to the fact that the bile (bile salts) dissolves the fatty acids * Macfadyen, Nencki, and Sieber, loc. cit. DIGESTION AND ABSORPTION IX THE INTESTINES. 791 readily* and thus brings them into contact, in soluble form, with the epithelial cells. When the bile is drained off from the intestine by a fistula of the gall-bladder or duct, a large proportion of the fatty foods escapes absorption and appears in the feces. Direct observation shows that the fat after passing the epithelial lin- ing and entering the stroma of the villus is taken up by the lymphatic vessels, the so-called lacteals. This fact is beautifully demonstrated by the mere appearance of the lymphatics of the mesentery after a meal containing fats. These vessels are injected with milky chyle during the period of absorption so that their entire course is revealed. The chyle on microscopical exami- nation is found to contain fat in the form of an extremely fine emulsion. In this form it is carried to the thoracic duct and thence to the venous circulation. For hours after a meal the blood contains this chyle fat. If a specimen of blood is taken during this time and centrifugalized in the usual way, the chyle fat may be collected at the top in the form of a cream. It is an easy matter to insert a cannula into the thoracic duct at the point at which it opens into the subclavian and jugular veins and thus collect the entire amount of fat absorbed from the intestines by way of the lacteals. Experiments of this kind show that, after deducting the amount of fat that escapes absorption and is lost in the feces, the amount that may be recovered from the thoracic duct is less than that taken in the food. It seems probable, therefore, that some of the fat is absorbed directly by the blood-vessels of the villi. The portion thus absorbed enters the portal vein and passes through the liver before reaching the general circulation. The liver holds back more or less of the fat taking this route, as it is found that during absorption the liver cells show an accumulation of fat droplets in their interior, f The amount of fat that may be absorbed from the intestines varies with the nature of the fat. Experiments show that the more fluid fats, such as olive oil, are absorbed more completely, that is, less is lost in the feces than in the case of the more solid fats. Compara- tive experiments have given such results as the following: Olive oil — absorption, 97.7 per cent.; goose and pork fat, 97.5 per cent.; mutton fat, 90 to 92.5 per cent.; spermaceti, 15 per cent. The amount of fat that may be lost in the feces varies also with other conditions. If, for instance, an excess is taken with the food, or if the bile flow is diminished or suppressed, the percentage in the feces is increased. The usual amount of fat allowed as a maximum in dietaries is from 100 to 120 gm. daily. Absorption of Proteins. — Most of the experimental work on record shows that the digested proteins are absorbed by the blood- *See Moore and Rockwood, "Journal of Physiology," 21, 58, 1897; also Moore and Parker, "Proceedings, Royal Society," London, 58, 64, 1901. f See Frank, "Archiv f. Physiologie," 1892, 497, and 1894, 297. 792 PHYSIOLOGY OF DIGESTION AND SECRETION. vessels of the villi, although after excessive feeding of protein a portion may be taken up also in the lymphatics.* This accepted belief rests upon two facts: First (Schmidt-Mulheim), if the thoracic duct (and right lymphatic duct) is ligated, so as to shut off the lym- phatic circulation, an animal will absorb and metabolize the usual amount of protein as is indicated by the urea excreted during the pe- riod. Second (Munk), if a fistula of the thoracic duct is established and the total lymph flow from the intestines is collected during the period of absorption after a diet of protein, it is found that there is no increase in the quantity of the lymph or in its protein contents. The form in which protein is absorbed and circulates in the blood is not satisfactorily determined. Under normal conditions the protein food is digested by the successive actions of pepsin, trypsin, and probably erepsin. Daring this digestion peptones and proteoses are formed and may be absorbed as such, or they may be further broken down by tiypsin and erepsin to the amino-bodies, leucin, tyrosin, arginin, etc., and the intermediate compounds, the poly- peptids (see p. 781), and be absorbed in the form of these split products. Some observers claim to have found peptones or proteoses as a normal constituent of the blood, but this claim has not been satisfactorily established. Others have shown the presence of traces of the amino-acids,f but much uncertainty exists as to the precise form in which the protein nourishment for the body exists normally in the blood. Several possibilities have been sug- gested. It is conceivable that the peptones or the more simple split products may be synthesized in the wall of the intestine or in the liver to the proteins of the blood, the serum-albumin or globulin ; it is possible that many of the end-products of the digestive splitting may be further oxidized and converted to urea in the liver and only a fractional part be really synthesized into the proteins of the body, or it is possible that the absorbed protein exists in the blood in some special form not as yet recognized. Perhaps the most important fact to be emphasized in this connection is the dis- covery that animals may be nourished when fed only with the split products of protein, that is to say, with the products of a complete pancreatic digestion (p. 877). It is evident that in such cases the body must take some of these split products and build them up again to the protein form. The prevailing hypoth- esis is that this synthesis takes place in the walls of the intestine and that the body protein thus reconstructed constitutes a part of the proteins of the blood. It must be borne in mind, however, that this hypothesis is far from having been demonstrated. Atten- * See Mendel, "American Journal of Physiology," 2, 137, 1899. t For references, see Howell, "American Journal of Physiology," 1906, 17, 273. DIGESTION AND ABSORPTION IN THE INTESTINES. 793 tion should also be directed to the fact that many forms of protein may be absorbed apparently without previous digestion. This fact has been demonstrated for isolated loops of the small intestine and also for parts of the large intestine. It is, moreover, borne out by the medical practice of giving enemata into the rectum when the conditions are such that the patient can not be fed in the normal way. That absorption and utilization of the protein take place under such conditions is shown not only by the improved nutritive condition of the individual, but also by the increased output of nitrogen in the urine. This phenomenon occurs in parts of the intestinal canal in which normally no proteolytic enzymes occur, so that the whole process must be referred to an activity of the cells composing the walls of the intestine. There seems at present little grounds for a satisfactory explanation of the absorption of proteins, with or without digestion, by a direct application of the known laws of osmosis, diffusion, and imbibition. Examination of the contents of the small intestine at its junction with the large shows that under normal conditions most of the protein has been ab- sorbed before reaching this point. The process is continued in the large intestine, modified somewhat by bacterial action, and the amount that finally escapes absorption and appears in the feces varies, in perfectly normal individuals, with the character of the protein eaten. According to Munk,* the easily digestible animal foods — such as milk, eggs, and meat — are absorbed to the extent of 97 to 99 per cent., while with vegetable foods the utilization is less complete. This difference is not due, however, to any peculiarity of the vegetable proteins; it is probably an incidental result of the presence of the indigestible cellulose found in our vegetable foods. It is stated that from 17 to 30 per cent, of the protein may be lost in the feces if the vegetable food is in such form as not to be attacked readily by the digestive secretions. Digestion and Absorption in the Large Intestine. — Observa- tions upon the secretions of the large intestine have been made upon human beings in cases of anus praeternaturalis, in which the lower portion of the intestine was practically isolated, and also upon lower animals, in which an artificial anus was established at the end of the small intestine. These observations all indicate that the secretion of the large intestine, while it contains much mucus and shows an alkaline reaction, is not characterized by the presence of distinctive enzymes. When the contents of the small intestine pass the valve they still contain a certain amount of unabsorbed food material. As was stated in the chapter on the movements of the intestine, this material remains a long time in the large intestine, and since it contains the digestive enzymes received in the duodenum the *See Munk, "Ergebnisse der Physiologie," vol. i., part i., 1902, article, "Resorption," for literature and discussion. 794 PHYSIOLOGY OF DIGESTION AND SECRETION. digestive and absorptive processes no doubt continue as in the small intestine. This general fact is well illustrated in experiments made upon dogs, most of whose small intestine (70 to 83 per cent.) had been removed.* These animals could digest and absorb well, and form normal feces, provided care was taken of the diet. An excess of fat or indigestible material caused diarrhea and serious loss of food material in the feces. An interesting feature in the large intestine is the marked absorption of water. In the small intestine no doubt water is absorbed in large quantities, but its loss is evidently made good by osmosis or secretion of water into the intestine, since the contents at the ileocecal valve are quite as fluid as at the pylorus. In the large intestine the absorption of water is not compensated by a secretion; the material becomes more and more solid as it ap- proaches the rectum, and is thus formed into the feces. The alkaline reaction of the contents of the large intestine makes a favorable environment for the growth of bacteria, particularly the putrefactive bacteria that attack protein material. Putrefaction is a normal occurrence in the large intestine, and much interest has been shown in its extent and its possible physiological significance. Bacterial Action in the Small Intestine. — Bacteria are con- stantly present in both the large and the small intestine. Under normal conditions, however, it would seem that in the small intestine only those bacteria capable of fermenting carbohydrate food show any distinct activity. Putrefactive fermentation of protein material is limited or absent in this part of the intestine as long as the products of protein digestion are promptly absorbed. Conditions that pre- vent or retard this absorption favor the occurrence of protein putrefaction. Opinions among investigators differ as to the means by which the protein contents are protected from the action of the bacteria. It has been shown that the presence of carbohydrate material has a restraining effect upon protein putrefaction. The simplest explanation of this relation is that the fermentation of the carbohydrates gives rise to a number of organic acids — lactic, acetic, etc. — and these acids inhibit the action of the protein bac- teria. To make this explanation satisfactory, however, it is neces- sary to show that the contents of the small intestine possess an acid reaction. Concerning this point opinions also differ. The secretions of the small intestine are all alkaline and we should expect their contents to have this reaction. Examination shows that the con- tents of the small intestine are acid or not according to the indicator used. With phenolphthalein they may give an acid reaction, while with litmus, lakmoid, etc., no such reaction is obtained, f Such a result as this indicates that no strong organic acids, such as acetic * Erlanger and Hewlett, "American Journal of Physiology," 6, 1, 1902. t Consult Macfadyen, Nencki, and Sieber, loc. cit.; Moore and Bergin, "American Journal of Physiology," 3, 316, 1900; Munk, "Centralblatt f. Physiologie," 16, 33, and 146, 1902. DIGESTION AND ABSOEPTION IN THE INTESTINES. 795 and lactic, are present, the phenolphthalein being affected possibly by the C03. As Munk has stated it seems that the contents of the small intestine throughout the duodenum and jejunum are at least never alkaline, and when carbohydrates are used the reaction may not only be acid to phenolphthalein but also to the stronger indica- tors. On the whole, therefore, it would seem probable that the small amount or total lack of protein putrefaction in the small intes- tine is due in part to the rapid absorption of the digested protein and in part to an unfavorable reaction. Some observers contend that there is a struggle for existence or antagonism between the bacteria acting upon carbohydrates and those living upon proteins. When the former have conditions favorable for growth, their increase in some way affects injuriously the protein bacteria.* Bacterial Action in the Large Intestine. — In the large intestine protein putrefaction is a constant and normal occurrence. The reaction here is stated to be alkaline, and whatever protein may have escaped digestion and absorption is in turn acted upon by the bac- teria and undergoes so-called putrefactive fermentation. The split- ting up of the protein molecule by this process is very complete, and differs in some of its products from the results of hydrolytic cleavage as caused by acids or by trypsin. The list of end-products of putre- faction is a long one. Besides peptones, proteoses, ammonia, and the various amino-acids, there may be produced such substances as indol, skatol, phenol, phenylpropionic and phenylacetic acids, fatty acids, carbon dioxid, hydrogen, marsh gas, hydrogen sulphid, etc. Many of these products are given off in the feces, while others are absorbed in part and excreted subsequently in the urine. In this latter connection especial interest attaches to the phenol, indol, and skatol. Phenol or carbolic acid, C6H5OH, after absorption is com- bined with sulphuric acid, to form an ethereal sulphate (conjugated sulphate) or phenolsulphonic acid, C6H5OS02OH, and in this form is found in the urine. So also with cresol. The indol, C8H7N, and skatol (methyl-indol), CgII9N, are also absorbed, undergo oxidation to indoxyl and skatoxyl, and are then combined or conjugated with sulphuric acid, like the phenol, and in this form are found in the urine — C8H6NOS02OH, or indoxyl-sulphuric acid, and C9H8NOS02OH, skatoxyl-sulphuric acid. These bodies have long been known to occur in the urine, and the proof that they arise primarily from putre- faction of protein material in the large intestine is so conclusive as not to admit of any doubt. The amount to which they occur in the urine is, therefore, an indication of the extent of the putrefaction in the large intestine. Is the Putrefactive Process of Physiological Importance? — Recognizing that fermentation by means of bacteria is a normal occurrence in the gastro-intestinal canal, the question has arisen * See Bienstock, " Archiv f. Hygiene," 39, 390, 1901. 796 PHYSIOLOGY OF DIGESTION* AND SECRETION. whether this process is in any way necessary to normal digestion and nutrition. It is -.veil known that excessive bacterial action may lead to intestinal troubles, such as diarrhea, or to more serious interference with general nutrition owing to the formation of toxins. It is, however, possible that some amount of bacterial action may be necessary for completely normal digestion. As a special case it has been pointed out that the gastro-intestinal tract is not provided with enzymes capable of acting upon cellulose, a material that forms such an important constituent of vegetable foods. Bacteria, on the other hand, may hydrolyze the cellulose and render it useful in nutrition. Leaving aside this special case, the question as to the necessity of bacterial action has been investigated directly by attempting to rear young animals under perfectly sterile conditions. Nuttall and Thierf elder * report some very interesting experiments upon guinea pigs in which the young animals from birth were kept sterile and fed with perfectly sterile food. The}* found that the animals lived and increased in weight, and concluded therefore that the intestinal bacteria are not necessary to normal nutrition. This conclusion is supported by the observations of Levin, f who finds that animals in the Arctic regions in many cases have no bacteria in their intestines. Schottelius"j: reports contrary results upon chickens. When kept sterile they lost steadily in weight and showed normal growth only when supplied with food containing bacteria. The idea that the relations between the bacteria and the animal that harbors them constitutes a kind of symbiosis in which each derives a benefit from the other has certainly not been demonstrated. The con- trary view, that bacterial putrefaction is the occasion for constant danger to the human organism, has been stated in extreme form, perhaps, by Metchnikoff. According to this author the constant production and absorption of bacterial toxins from the intestine is one of the important causes of a loss of resistance on the part of the body to the changes which bring on senescence and death. At present it seems wise to take the conservative view that while the presence of the bacteria confers no positive benefit, the organ- ism has adapted itself under usual conditions to neutralize their injurious action. Composition of the Feces. — The feces differ widely in amount and in composition with the character of the food. Upon a diet composed exclusively of meats, they are small in amount and dark in color; with an ordinary mixed diet the amount is increased; and it is largest with an exclusively vegetable diet, especially with vege- tables containing a large amount of cellulose. The average * Nuttall and Thierfelder, "Zeitsehrift f. physiol. Chemie," 21, 109, 189.5; 22, 62, 1896; 23, 231, 1897. t " Skandinavisches Arehiv f. Physiologie, " 16, 249, 1904. t "Arehiv f. Hygiene," 42, 48, 1902. DIGESTION AND ABSORPTION IN THE INTESTINES. 797 weight of the feces in twenty-four hours upon a mixed diet is given as 170 gms., while with a vegetable diet it may amount to as much as 400 or 500 gms. The quantitative composition, therefore, varies greatly with the diet. Qualitatively, we find in the feces the following things: (1) Indigestible material, such as ligaments of meat or cellulose from vegetables. (2) Undigested material, such as fragments of meat, starch, or fats which have in some way escaped digestion. Naturally, the quantity of this material present is slight under normal conditions. Some fats, however, are almost always found in feces, either as neutral fats or as fatty acids, and to a small extent as calcium or magnesium soaps. The quantity of fat found is increased by an increase of the fats in the food or by a deficient secretion of bile. (3) Products of the intestinal secretions. Evi- dence has accumulated in recent years* to show that the feces in man on an average diet are composed in part of the unabsorbed material of the intestinal secretion. The nitrogen of the feces, for- merly supposed to represent only undigested food, seems rather to have its origin largely in these secretions, together with the cellular debris thrown off from the walls of the intestines. (4) Products of bacterial decomposition. The most characteristic of these products are indol and skatol. They are crystalline bodies possessing a dis- agreeable, fecal odor; this is especially true of skatol, to which the odor of the feces is mainly due. (5) Cholesterin, or a deriva- tive, which is found always in small amounts, and is probably derived from the bile. (6) Some of the purin bases, especially guanin and adenin. (7) Mucus and epithelial cells thrown off from the intestinal wall. (8) Pigment. In addition to the color due to the undigested food or to the metallic compounds contained in it, there is normally present in the feces a pigment, urobilin or stercobilin, derived from the pigments (bilirubin) of the bile. Urobilin is formed from the bilirubin by reduction in the large intestine. (9) Inorganic salts — salts of sodium, potassium, calcium, magnesium, and iron, but chiefly the last three together with phosphoric acid. The significance of the calcium and iron salts will be referred to in a subsequent chapter, when speaking of their nutritive importance. (10) Micro-organisms. Great quantities of bacteria of different kinds are found in the feces. In addition to the feces, there is found often in the large intestine a quantity of gas that may also be eliminated through the rectum. This gas varies in composition. The following substances have been found at one time or another: CH4, C02, H, N, H2S. They arise mainly from the bacterial fermentation of the proteins, although some of the N may be derived from air swallowed with the food. * Prausnitz, 'Zeitschrift f. Biologie," 35, 335, 1897; and Tsuboi, ibid., p. 68. CHAPTER XLIV. PHYSIOLOGY OF THE LIVER AND THE SPLEEN. The liver plays an important part in the general nutrition of the body. Its functions are manifold, but in the long run they depend upon the properties of the liver cell, which constitutes the anatomical and physiological unit of the organ. These cells are seemingly uniform in structure throughout the whole substance of the liver, but to understand clearly the different functions they fulfill one must have f, clear idea of their anatomical relations to one another and to the blood-vessels, the lymphatics, and the bile-ducts. The histol- ogy of the liver lobule, and the relationship of the portal vein, the hepatic artery, and the bile-duct to the lobule, must be obtained from the text-books upon histology and anatomy. It is sufficient here to recall the fact that each lobule is supplied with blood coming in part from the portal vein and in part from the hepatic artery. The blood from the former source contains the soluble products absorbed from the alimentary canal, such as sugar and protein, and these absorbed products are submitted to the metabolic activity of the liver cells before reaching the general circulation. The hepatic artery brings to the liver cells the arterialized blood sent out to the systemic circu- lation from the left ventricle. In addition, each lobule gives origin to the bile capillaries which arise between the separate cells and which carry off the bile formed within the cells. In accordance with these facts, the physiology of the liver cell falls naturally into two parts, — one treating of the formation, composition, and physiological signifi- cance of bile, and the other dealing with the metabolic changes pro- duced in the mixed blood of the portal vein and the hepatic artery as it flows through the lobules. In this latter division the main phenomena to be studied are the formation of urea and the forma- tion and significance of glycogen, but it cannot be doubted that the liver possesses other important metabolic functions which at present are only guessed at or imperfectly understood. Such, for example, as its relations to the production of fibrinogen and of antithrombin, which have been referred to in the section on Blood. Bile. — From a physiological standpoint, bile is partly an excre- tion carrying off certain waste products, and partly a digestive secre- tion playing an important role in the absorption of fats, and possibly in other ways. Bile is a continuous secretion, but in animals possess- ing a gall-bladder its ejection into the duodenum is intermittent. Bile is easily obtained from living animals by establishing a fistula of the bile-duct or, as seems preferable, of the gall-bladder. The 798 PHYSIOLOGY OF THE LIVER AND SPLEEN. 799 latter operation has been performed a number of times on human beings. In some cases the entire supply of bile has been diverted in this way to the exterior, and it is an interesting physiological fact that such patients may continue to enjoy fair health, showing that, whatever part the bile takes normally in digestion and absorption, its passage into the intestine is not absolutely necessary to the nu- trition of the body. The quantity of bile secreted during the day has been estimated for human beings of average weight (43 to 73 kgms.) as varying between 500 and 800 c.c. This estimate is based upon observations on cases of biliary fistula.* Chemical analyses of the bile show that, in addition to the water and salts, it contains bile pigments, bile acids, cholesterin, lecithin, neutral fats and soaps, sometimes a trace of urea, and a mucilaginous nucleo-albumin for- merly designated improperly as mucin. The last-mentioned sub- stance is not formed in the liver cells, but is added to the bile by the mucous membrane of the bile-ducts and gall-bladder. The quantity of these substances present in the bile varies in different animals and under different conditions. As an illustration of their relative importance in human bile and of the limits of variation, the two following analyses by Hammarstenf may be quoted: i. ii. Solids 2.520 2.840 Water 97.480 97.160 Mucin and pigment 0.529 0.910 Bile salts 0.931 0.814 Taurocholate 0.3034 0.053 Glycocholate 0.6276 0.761 Fatty acids from soap 0.1230 0.024 Cholesterin 0.0630 0.096 Fatlthm } 0.0220 0.1286 Soluble salts 0.8070 0.8051 Insoluble salts 0.0250 0.0411 The color of bile varies in different animals according to the pre- ponderance of one or the other of the main bile pigments, bilirubin and biliverdin. The bile of carnivorous animals has usually a golden color, owing to the presence of bilirubin, while that of the her- bivora is a bright green from the biliverdin. The color of human bile seems to vary : according to some authorities, it is yellow or golden yellow, and this seems especially true of the bile as found in the gall- bladder of the cadaver; according to others, it is of a dark-olive color with the greenish tint predominating. Its reaction is feebly alkaline, and its specific gravity varies in human bile from 1.050 or 1.040 to 1.010. Human bile does not give a distinctive absorption spectrum, * Copeman and Winston, "Journal of Physiology," 10, 213, 1889; Rob- son, "Proceedings of the Royal Society," London, 47, 499, 1890; Pfaff and Balch, "Journal of Experimental Medicine," 2, 49, 1897. t Reported in " Centralblatt f. Physiologie," 1894, No. 8. 800 PHYSIOLOGY OF DIGESTION AXD SECRETION. but the bile of some herbivora, after exposure to the air at least, gives a characteristic spectrum. Bile Pigments. — Bile, according to the animal from which it is obtained, contains one or the other, or a mixture, of the two pigments, bilirubin and biliverdin. Indeed, it is probable that in some animals at least still other pigments, such as urobilin, may be present in the bile, together with the bilirubin or biliverdin. Biliverdin is supposed to stand to bilirubin in the relation of an oxidation product. Bilirubin is given the formula C16H18N203, and biliverdin, C16H18N204, the latter being prepared readily from the former by oxidation. These pigments give a characteristic reaction, known as "Gmelin's reaction," with nitric acid con- taining some nitrous acid (nitric acid with a yellow color). If a drop of bile and a drop of nitric acid are brought into con- tact, the former undergoes a succession of color changes, the order being green, blue, violet, red, and reddish yellow. The play of colors is due to successive oxidations of the bile pigments; starting with bilirubin, the first stage (green) is due to the formation of bili- verdin. The pigments formed in some of the other stages have been isolated and named. The reaction is very delicate, and it is often used to detect the presence of bile pigments in other liquids — urine, for example. The bile pigments originate from hemoglobin. This origin was first indicated by the fact that in old blood clots or in extravasations there was found a crystalline product, the so-called "hematoidin," which was undoubtedly derived from hemoglobin, and which upon more careful examination was proved to be identical with bilirubin. This origin, which has since been made probable by other reactions, is now universally accepted. It is supposed that when the blood-corpuscles disintegrate the hemoglobin is brought to the liver, and there, under the influence of the liver cells, is converted to an iron-free compound, bilirubin or biliverdin. The bilirubin is formed from the hematin of the hemoglobin by a process which involves the splitting off of its iron. It is very significant that the iron separated by this means from the hematin is, for the most part, retained in the liver, a small portion only being secreted in the bile. It seems probable that the iron held back in the liver is again used in some way to make new hemoglobin in the hema- topoietic organs. Since the hematin constitutes only 4 per cent, of the hemoglobin molecule, it is evident that in the production of the bilirubin a considerable amount of globin must be formed also, but nothing is known of the fate of this portion of the hemo- globin molecule. Quantitative data, in fact, are conspicuously lacking in regard to the amount of bile pigment secreted daily. Owing to the lack of a satisfactory method of estimating this substance, its percentage in the bile, as given by different authors, varies greatly, from .04 per cent, to 0.25 per cent. The bile PHYSIOLOGY OF THE LIVER AND SPLEEN. 801 pigments are carried in the bile to the duodenum and are mixed with the food in its long passage through the intestine. Under normal conditions neither bilirubin nor biliverdin occurs in the feces, but in their place is found a reduction product, urobilin or stercobilin, formed in the large intestine. Moreover, it is believed that some of the bile pigment is reabsorbed as it passes along the intestine, is carried to the liver in the portal blood, and is again eliminated. That this action occurs, or may occur, has been made probable by experiments of Wertheimer* on dogs. It happens that sheep's bile contains a pigment (cholohematin) that gives a characteristic spectrum. If some of this pigment is injected into the mesenteric veins of a dog it is eliminated while passing through the liver, and can be recognized unchanged in the bile. The value of this "circulation of the bile," so far as the pigments are concerned, is not apparent. Bile Acids. — "Bile acids" is the name given to two organic acids, glycocholic and taurocholic, which are always present in bile, and, indeed, form very important constituents of that secretion; they occur in the form of their respective sodium salts. In human bile both acids are usually found, but the proportion of taurocholate is variable, and in some cases it may be absent altogether. Among herbivora the glycocholate predominates, as a rule, although there are some exceptions ; among the carnivora, on the other hand, taurocholate occurs usually in greater quantities, and in the dog's bile it is present alone. Glycocholic acid has the formula C26H43N06, and taurocholic acid the formula C26H45NS07. Each of them can be obtained in the form of crystals. When boiled with acids or alka- lies these acids take up water and undergo hydrolytic cleavage, the reaction being represented by the following equations: C26H43N06 + H20 = C^H^A + CH2(NH2)COOH. Glycocholic acid. Cholic acid. Glyeocoll (amino-acetic-acid). C^H^NSO, + H20 = C24H40O5 + C^NH^OH Taurocholic acid. Cholic acid. Taurin (amino-ethyl- sulphonic acid). These reactions are interesting not only in that they throw light on the structure of the acids, but also because similar reactions doubtless take place in the intestine, cholic acid having been detected in the intestinal contents. As the formulas show, cholic acid is formed in the decomposition of each acid, and we may regard the bile acids as compounds produced by the synthetic union of cholic acid with glycin in the one case and with taurin in the other. Cholic acid or its compounds, the bile-acids, are usually detected in suspected liquids by the well-known Pettenkofer reaction. As usually per- formed, the test is made by adding to the liquid a few drops of a 10 * "Archives de physiologie normale et pathologique," 1892, p. 577. 51 802 PHYSIOLOGY OF DIGESTION AND SECRETION. per cent, solution of cane-sugar and then strong sulphuric acid. The latter must be added carefully and the temperature be kept below 70° C. If bile acids are present, the liquid assumes a red-violet color. It is now known that the reaction consists in the formation of a substance (furfurol) by the action of the acid on sugar, which then reacts with the bile acids. The bile acids are formed directly in the liver cells. This fact, which was for a long time the subject of discussion, has been demonstrated in recent years by an important series of researches made upon birds. It has been shown that if the bile-duct is ligated in these animals, the bile formed is reabsorbed and bile acids and pigments may be detected in the urine and the blood. If, however, the liver is completely extirpated, then no trace of either bile acids or bile pigments can be found in the blood or the urine, showing that these substances are not formed elsewhere in the body than in the liver. It is more difficult to ascertain from what sub- stances they are formed. The fact that glycocoll and taurin con- tain nitrogen, and that the latter contains sulphur, indicates that some protein constituent is broken down during their production. From the standpoint of nutrition the taurocholate is interesting as giving one of the forms in which the sulphur of protein material is eliminated. Some light has been thrown upon the origin of taurin by the discovery (Friedmann*) that it may be formed from cystin. This latter body, C6Hj.2N.2S204, or its reduction product cystein, is known to occur as one of the end-products in the acid hydrolysis of proteins, and it is possible that it occurs also in the tryptic- erepsin hydrolysis in the small intestine, representing the end-product in which the sulphur of the protein molecule is found. Cystin may be oxidized to cysteinic acid (COOHC2H3NH2S02OH) and from this taurin (C2H4NH2S02OH) may be obtained. It is probable, therefore, that the taurin is formed nor- mally from cystin in the body and that the latter represents one of the split products of protein. f Some of the sulphur of the cystin appears also in the urine in oxidized form as sulphate. Under certain pathological conditions the cystin itself appears in the urine, giving the phenomenon of cystinuria. A circumstance of considerable physiological significance is that these acids or their decomposition products are absorbed in part from the intestine and are again secreted by the liver; as in the case of the pigments, there is an intestinal-hepatic circulation. The value of this reabsorption may lie in the fact that the bile acids constitute a very efficient stimulus to the bile-secreting activity of the cells, being one of the best of cholagogues, or it may be that it economizes material. From what we know of the history of the bile acids it is evident that they are not to be considered solely as excreta: they have some important function to fulfill. The following suggestions as to their value have been made : In the first place, they serve as a menstruum for dissolving the cholesterin which is constantly present in the bile and which is an excretion to be removed; secondly, they facilitate greatly the splitting and the absorption of fats in the intestine. It ♦Friedmann, " Hofmeister's Beitrage," 3, 1, 1902. t See Simon, "Johns Hopkins Hospital Bulletin," 15, 365, 1904. PHYSIOLOGY OF THE LIVER AND SPLEEN. 803 is an Undoubted fact that when bile is shut off from the intestine the absorption of fats is very much diminished, and it has been shown that this action of the bile in fat absorption is due chiefly to the presence of the bile-acids, and in the same way the known acti- vating influence of bile upon the activity of pancreatic lipase has been traced to the bile-acids. The bile-acids, the taurocholate, at least, possess the property of precipitating proteins in acid solu- tions. This property probably explains the fact that the acid chyme as it passes into the duodenum is precipitated by coming into contact with the bile, a fact which has long been known, although its physiological significance is not clear. Cholesterin or Cholesterol. — Cholesterin is a non-nitrogenous substance of the formula C27H460. (See p. 79.) It is a constant constituent of the bile, although it occurs in variable quantities. Cholesterin is very widely distributed in the body, being found especially in the white matter (medullary substance) of nerve- fibers. It- seems, moreover, to be a constant constituent of all animal and plant cells. It is assumed that cholesterin is not formed in the liver, but that it is eliminated by the liver cells from the blood, which collects it from the various tissues of the body. This is at least a possible explanation of its occur- rence in the bile, for it seems certain that the cholesterin is a constant constituent of the blood, either as such or in the form of an ester. Some authors suggest, however, that in the disso- lution of red corpuscles that takes place in the liver the cho- lesterin liberated from the stroma of the corpuscles forms the source of the cholesterin found in the bile. That it is an excretion is indicated by the fact that it is eliminated in the feces, but here again the opposite view has been suggested that the cholesterin is in part at least reabsorbed and used again in the formation of new tissue.* Cholesterin is insoluble in water or in dilute saline liquids, and is held in solution in the bile by means of the bile-acids. We must regard it as a waste product of cell life, formed probably in minute quantities, and excreted mainly through the liver. It is partly eliminated through the skin, in the sebaceous and sweat secretions, and in the milk. Lecithin, Fats, and Nucleo-albumin. — Lecithin, C44H90- NP09, is a compound of glycerophosphoric acid with fatty acid radicals (stearic, oleic, or palmitic) and a nitrogenous base, cholin (see p. 79). When hydrolyzed by boiling with alkali it splits up into these three substances. It is found generally as such, or in combination, in all cells, and evidently plays some as yet unknown part in cell metabolism. It occurs in largest quantity in the white matter of the nervous system. In the liver it occurs to a considerable extent both as lecithin and in a more complex * See Gardner and co-workers, " Proc. Roy. Soc," B, vols. 81 and 82. 1910. S04 PHYSIOLOGY OF DIGESTION AND SECRETION combination with a carbohydrate residue, a compound designated as jecorin. So far as it is found in the bile, it represents possibly a waste product derived from the liver or from the body at large. Little is known of its precise physiological significance. According to Hewlett and others it may serve to activate the lipase of the pancreatic secretion. The special importance, if any, of the small proportion of fats and fatty acids in the bile is unknown. The ropy, mucilaginous character of bile is due to the presence of a body formed in the bile- ducts and gall-bladder. This substance was formerly designated as mucin, but it is now known that in ox bile at least it is not a true mucin, but a nucleo-albumin (see appendix). Hammarsten reports that in human bile some true mucin is found. Outside the fact that it makes the bile viscous, this constituent is not known to possess any especial physiological significance. The Secretion of the Bile. — Numerous experiments have been made to ascertain whether or not the secretion of bile is controlled by a special set of secretory fibers. The secretion itself is continuous, but varies in amount under different conditions. These conditions may be controlled experimentally in part. It has been shown, for example, that stimulation of the spinal cord or splanchnic nerve diminishes the flow of bile, while section of the splanchnic branches may cause an increased flow. These and similar actions are ex- plained, however, by their effect on the blood-flow through the liver. The splanchnics carry vasomotor nerves to the liver, and section or stimulation of these nerves will therefore alter the circulation in the organ. Since the secretion increases when the blood-flow is increased and vice versa, it is believed that in this case no special secretory nerve fibers exist. The metabolic processes in the liver cells which produce the secretion probably go on at all times, but they are increased when the blood-flow is increased. We may believe, there- fore, that the quantity of the bile secretion varies with the quantity and composition of the blood flowing through the liver, and that the blood contains normally chemical substances of the nature of hormones, which stimulate the liver cells to secrete bile. On the physiological and pharmacological side efforts have been made to discover the nature of the substances which stimulate the formation of bile. Such substances are1 designated as cholagogues. The thera- peutical agents capable of giving this action are still a subject of con- troversy. On the physiological side the following facts arc accepted : Any agent that causes an hemolysis of red corpuscles increases the flow of bile, or the same effect is produced if a solution of hemoglobin is injected directly into the blood. This result is in harmony with the views already stated regarding the significance of the bile pig- ments as an excretory product of hemoglobin. The cholagogue whose action is most distinct and prolonged is bile itself. When fed PHYSIOLOGY OF THE LIVER AND SPLEEN. S05 or injected directly into the circulation, bile causes an undoubted in- crease in the secretion. This effect is due both to tne bile acids and bile pigments. Since the bile acids have a hemolytic effect on red corpuscles, it might at first be assumed that their action as chola- gogues is due indirectly to this circumstance. The action of the bile acids is, however, much more pronounced than that of other hemolytic agents, and it seems certain, therefore, that they exert a specific effect on the liver cells. So also it is stated (Weinberg) that peptones and proteoses have a marked stimulating effect, and since these substances may be brought to the liver in the portal blood, it is possible that they act as stimuli under normal conditions. Lastly, there is evidence that the secretin, whose ac- tion upon the pancreatic secretion has been described, exerts a sim- ilar effect upon the secretion of bile. Statements differ somewhat in regard to the extent of this action, but it seems to be certain that, when acids (0.5 per cent. HC1) are injected into the duodenum or upper part of the jejunum, the secretion of bile is increased; and, since this effect takes place when the nervous connections are severed, the effect, as in the case of the pancreatic secretion, is explained by as- suming that the acid converts prosecretin to secretin, and this latter after absorption into the blood acts upon the liver cells.* A similar effect may be obtained by injecting secretin directly into the blood. Since during a meal the stomach normally ejects acid chyme into the duodenum, the importance of this secretin reaction in adapting the secretion of bile to the period of digestion is evident. The Ejection of Bile into the Duodenum — Function of the Gall-bladder. — Although the bile is formed more or less continu- ously, it enters the duodenum periodically during the time of digestion. The secretion during the intervening periods is prevented from enter- ing the duodenum apparently by the fact that the opening of the common bile-duct is closed by a sphincter. The secretion, therefore, backs up into the gall-bladder. According to Bruns,f no bile appears in the duodenum as long as the stomach is empty. When, how- ever, a meal is taken, the ejection of the chyme into the duodenum is followed by an ejection of bile. J It would seem, therefore, that each gush of chyme into the duodenum excites, probably by reflex action, a contraction of the gall-bladder, and an inhibition of the sphincter closing the opening into the intestine. An interesting application of this fact has been made in surgical practice. After operations upon the gall-bladder trouble is experienced at times owing to the failure of the fistulous opening to heal, so that there is constant oozing of gall. It is found that frequent feeding of the patient facilitates the per- manent closure of the fistula, because apparently the sphincter is kept inhibited and the pressure in the gall-bladder is lowered. * See Falloise, quoted in Maly's "Jahres-bericht der Thier-chemie," 33, 611, 1904. t "Archives des sciences biologiques," 7, 87, 1899. X See also Klodnizki, quoted from Maly's "Jahres-bericht der Thier- chemie," 33, 617, 1904. 806 PHYSIOLOGY OP DIGESTION AND SECRETION. The substances in the chyme that are responsible for the stim- ulation have been investigated by Bruns. He finds that acids, alkalies, and starches are ineffective, and concludes that the reflex is due to the proteins and fats or some of the products of their digestion. The gall-bladder has a muscular coat of plain muscle, and records made of its contractions show that the force exerted is quite small. According to Freese,* the maximal contraction does not exceed that necessary to overcome the hydrostatic pressure of a column of water 220 mms. in height, — a force, therefore, which is about equivalent to the secretion pressure of bile as determined by Heidenhain. The innervation of the gall-bladder and gall-ducts has been studied especially by Doyon. f It would seem, from the experiments made by this author together with later experiments reported by others, J that the bladder receives both motor and in- ID 8 h 4 X. 30' JO' 30' JO' JO' JO'- JO' JO' 30' JO1 JO' 30' 30' JO' JO' , s. 1 \ / j \ 8 (, z 1 "— — "\ ,' ,," ^ "•».. 1 "—"■ \ a 6 z / v / / \ ■' ' \ /. \ y vn / f ~] \ -_. Fig. 297. — Curves showing the velocity of secretion of bile into the duodenum on (1) a diet of milk, uppermost curve; (2) a diet of meat, middle curve; (3) a diet of bread, lowest curve. The divisions on the abscissa represent intervals of thirty minutes; tha figures on the ordinates represent the volume of secretion in cubic centimeters. — (Bruns.) hibitory fibers by way of the splanchnic nerves. These fibers emerge from the spinal cord in the roots of the sixth thoracic to the first lumbar spinal nerve, and pass to the celiac plexus by way of the * "Johns Hopkins Hospital Bulletin," June, 1905. t Doyon, "Archives de physiologie," 1894, p. 19. j Bainbridge and Dale, "Journal of Physiology," 1905, xxxiii., 138. PHYSIOLOGY OP THE LIVER AND SPLEEN. 807 splanchnic nerves. Motor fibers may occur also in the vagi . Sensory fibers capable of causing a reflex constriction or dilatation of the bladder are found in both the vagus and splanchnic nerves. Stim- ulation of the central end of the cut splanchnic causes a dilatation of the bladder (reflex stimulation of the inhibitory fibers), while stimulation of the central end of the vagus causes a contraction of the bladder and a dilatation (inhibition) of the sphincter muscle at the opening of the common duct into the intestine. These latter movements are the ones that occur during normal digestion. When bile is emptied periodically into the duodenum by a contrac- tion of the gall-bladder, we may suppose, therefore, that the afferent fibers concerned in the reflex run in the vagus nerve. Effect of Complete Occlusion of the Bile-duct. — When the flow of bile is prevented by ligation of the bile-duct, or when this duct is occluded by pathological changes the bile eventually gets into the blood, producing a condition of jaundice (icterus). There has been much discussion as to whether the bile is absorbed directly into the blood from the liver cells or the liver lymph-spaces, or whether it is carried to the blood by way of the lymph-vessels and thoracic duct.* Experimental evidence points to both possibili- ties. The increased pressure in the bile system leads possibly to a rupture of the delicate bile capillaries, and the bile thus escapes into the lymph-spaces. From these spaces it may be absorbed directly by the blood-vessels of the liver, or it may be carried off in the lymph-stream toward the thoracic duct. General Physiological Importance of Bile. — The physiological value of bile has been referred to in speaking of its several constitu- ents. Bile is of importance as an excretion in that it removes from the body waste products of metabolism, such as cholesterin, lecithin, and bile pigments. With reference to the pigments, there is evidence to show that a part at least may be reabsorbed while passing through the intestine, and be used again in some way in the body. The bile acids represent end-products of metabolism involving the proteins of the liver cells, but they are undoubtedly reabsorbed in part, and can not be regarded merely as excreta. As a digestive secretion, the most important function attributed to the bile is the part it takes in the digestion and absorption of fats. It accelerates greatly the action of the lipase of pancreatic juice in splitting the fats to fatty acids and glycerin, and it aids materially in the absorption of the products of this hydrolysis. A number of observers have shown that when a permanent biliary fistula is made, and the bile is thus prevented from reaching the intestinal canal, a large proportion of the fat of the food escapes absorption and is found in the feces. This action of the bile may be referred directly to the fact that the bile acids serve as a * See Mendel and TJnderhill for literature, " American Journal of Phys- iology," 1905, xiv., 252. 808 PHYSIOLOGY OF DIGESTION AND SECRETION. solvent for the fats and fatty acids. It was formerly believed that bile is also of great importance in restraining the processes of putre- faction in the intestine. It was asserted that bile is an efficient antiseptic, and that this property comes into use normally in prevent- ing excessive putrefaction. Bacteriological experiments made by a number of observers have shown, however, that bile itself has very feeble antiseptic properties, as is indicated by the fact that it putrefies readily. The free bile acids and cholalic acid do have a direct retard- ing effect upon putrefactions outside the body; but this action is not very pronounced, and has not been demonstrated satisfactorily for bile itself. It seems to be generally true that in cases of biliary fistula the feces have a very fetid odor when meat and fat are taken in the food. But the increased putrefaction in these cases may possibly be an indirect result of the withdrawal of bile. It has been suggested, for instance, that the deficient absorption of fat that follows upon the removal of the bile results in the protein and carbohydrate material becoming coated with an insoluble layer of fat, so that the penetration of the digestive enzymes is retarded and greater opportunity is given for the action of bacteria. We may conclude, therefore, that, while there does not seem to be sufficient warrant at present for believing that the bile exerts a direct antiseptic action upon the intestinal contents, nevertheless its presence limits in some way the extent of putrefaction. Glycogen. — One of the most important functions of the liver is the formation of glycogen. This substance was found in the liver in 1857 by Claude Bernard, and is one of several brilliant discoveries made by him. Glycogen has the formula (C6H10O5)n, which is also the general formula given to vegetable starch ; glycogen is therefore frequently spoken of as "animal starch." It gives, however, a port- wine-red color with iodin solutions, instead of the familiar deep blue of vegetable starch, and this reaction serves to detect glycogen not only in its solutions, but also in the liver cells. Glycogen is readily soluble in water, and the solutions have a characteristic opalescent appearance. Like starch, glycogen is acted upon by ptyalin and other diastatic enzymes, and the end-products are apparently the same — namely, maltose, or maltose and some dextrin, or else dex- trose, depending upon the enzyme used. Under the influence of acids it may be hydrolyzed at once to dextrose.* Occurrence of Glycogen in the Liver. — Glycogen can be detected in the liver cells microscopically. If the liver of a dog is removed twelve or fourteen hours after a hearty meal, hardened in alcohol, and sectioned, the liver cells are found to contain clumps of clear material which give the iodin reaction for glycogen. Even * The extensive literature of glycogen is collected and reviewed by Cre- naer in the " Krgebnisse der Physiologie, " vol. i, part i, 1902; and by Pfhiger, "Archiv f. die gesammte Physiologie," 90, 1, 1903. PHYSIOLOGY OF THE LIVER AND SPLEEN. 809 when distinct aggregations of the glycogen cannot be made out, its presence in the cells is shown by the red reaction with iodin. By this simple method one can demonstrate the important fact that the amount of glycogen in the liver increases after meals and decreases again during the fasting hours, and if the fast is sufficiently prolonged it may disappear altogether. This fact is, however, shown more satisfactorily by quantitative determinations, by chemical means, of the total glycogen present. The amount of glycogen in the liver is quite variable, being influenced by such conditions as the character and amount of the food, muscular exercise, body tem- perature, drugs, etc. From determinations made upon various animals it may be said that the average amount lies between 1.5 and 4 per cent, of the weight of the liver. But this amount may be in- creased greatly by feeding upon a diet largely made up of carbohy- drates. It is said that in the dog the total amount of liver glycogen may be raised to 17 per cent., and in the rabbit to 27 per cent., by this means, while it is estimated for man (Xeumeister) that the quan- tity may be increased to at least 10 per cent. It is usually believed that glycogen exists as such in the liver cells, being deposited in the substance of the cytoplasm. Reasons have been brought forward to show that this is not strictly true, and that the glycogen is prob- ably held in some sort of weak chemical combination. It has been shown, for instance, that although glycogen is easily soluble in cold water, it can not be extracted readily from the liver cells by this agent. One must use hot water, salts of the heavy metals, and other similar agents that may be supposed to break up the combination in which the glycogen exists. For practical purposes, however, we may speak of the glycogen as lying free in the liver-cells, just as we speak of hemoglobin existing as such in the red corpuscles, although it is probably held in some sort of combination. Origin of Glycogen. — To understand clearly the views held as to the origin of fiver glycogen, it is necessary to describe briefly the effect of the different foodstuffs upon its formation. Effect of Carbohydrates on the Amount of Glycogen. — The amount of glycogen in the liver is affected very quickly by the quantity of car- bohydrates in the food. If the carbohydrates are given in excess, the supply of glycogen may be increased largely beyond the average amount present, as has been stated above. Investigation of the differ- ent sugars has shown that dextrose, levulose, saccharose (cane-sugar), and maltose are unquestionably direct glycogen-formers, — that is, glycogen is formed directly from them or from the products into which they are converted during digestion. The bulk of our car- bohydrate food reaches the liver as dextrose, or as dextrose and levu- lose, and these forms of sugar may be converted into glycogen in the liver cells by a simple process of dehydration, such as may be repre- sented in substance by the formula C6H1206 — H20 = C6H10O5. 810 PHYSIOLOGY OF DIGESTION AND SECRETION. There is no doubt that both dextrose and levulose increase markedly the amount of glycerin in the liver; and, since cane-sugar is inverted in the intestine before absorption, it also must be a true glycogen- former, — a fact that has been abundantly demonstrated by direct experiment. Lusk* has shown, however, that, if cane-sugar is in- jected under the skin, it has a very feeble effect in the way of increas- ing the amount of glycogen in the liver, since under these conditions it is probably absorbed into the blood without undergoing inversion. Experiments with subcutaneous injection of lactose gave similar results, and it is generally believed that the liver cells can not convert the double sugars to glycogen, at least not readily; hence the value of the hydrolysis of these sugars in the alimentary canal before absorption. We may assume, therefore, that dextrose, levulose, and galactose are the true glycogen-formers that occur normally in the blood, and that the clisaccharids (cane-sugar, milk-sugar, etc.) and the polysaccharids (starches) are true glycogen-formers to the ex- tent that they are converted into dextrose, levulose, or galactose. Effect of Protein on Glycogen Formation. — In his first studies upon glycogen Bernard asserted that it may be formed from protein material. Since that time there have been much discussion and experimentation upon this point. The usual view is that protein must be counted among the true glycogen-formers in the sense that some of the material of the protein molecule is directly converted to glycogen. The protein in digestion undergoes, it will be remem- bered, a splitting process, the limits of which are not definitely settled. It is assumed, however, that the nitrogenous split products are acted upon in the liver, the nitrogen being converted first to an ammonia compound and then to urea, while the non-nitrogenous residue is converted to sugar by a synthetic process. Positive results have been obtained showing that some, at least, of the amino acids, such as glycin, alanin, and aspartic acid, may be converted to sugar in the body. Experimentally observers find for the warm-blooded animals, at least, that feeding with proteins, even in the case of those proteins, such as casein, that contain no carbohydrate grouping, causes an increased production of glycogen, f The conclusion to be drawn from these experiments is strengthened by clinical experience upon human beings suffer- ing from diabetes. In severe forms of this disease the carbo- hydrate material of the food escapes oxidation in the body and is secreted unchanged in the urine. If under these conditions the individual is given an exclusively protein diet, sugar still continues to appear in the urine, and it would seem that this sugar can only arise from the protein food. In the similar condition of severe glycosuria that may be pro- * Voit, "Zeitschrift f. Biologie," 28, 285, 1891. t See Stookey, "American Journal of Physiology," 9, 138, 1903. PHYSIOLOGY OF THE LIVER AND SPLEEN. 811 duced by the use of phloridzin it has been shown that the animal continues to excrete sugar even when fed on protein alone or when starved. Under such conditions the amount of dextrose in the urine bears a definite ratio to the amount of nitrogen excreted D:N: :3.65 : 1 (Lusk), which would indicate that both arise from the breaking down of the protein molecule. On this supposition a maximum of 58.4 per cent, of the protein may be converted to sugar. So also the fact that during prolonged starvation, lasting for forty or even ninety days, the blood retains a practically constant com- position in sugar indicates that this material is being formed from either the protein or fat supply of the body. Other considerations tend to exclude the fat, and we are, therefore, led to the belief that the protein can give rise to sugar in the body. If this change is part of the normal metabolism of the body it would make protein a gly- cogen-former, since the sugar formed from the protein may, of course, be converted to glycogen. Whether or not all proteins yield gly- cogen or sugar in the body is not entirely determined. Some authors have thought that only those proteins that contain a carbohydrate residue have this property; but, as stated above, casein and other proteins that do not possess this grouping seem also to increase the glycogen supply when fed alone. Effect of Fats upon Glycogen Formation. — A large number of substances have been found by some observers to increase the store of glycogen in the liver. In some of these cases at least it is evident that the substance is not a direct glycogen-former in the sense that the material is itself converted to glycogen. It may increase the supply of liver glycogen in some indirect way, — for example, by diminishing the consumption of glycogen in the body. The most important substance in this connection from a practical standpoint is fat. Whether or not the body can convert fats into sugar or glycogen is a question about which at present there is much difference of opinion, and much evidence might be cited on each side. Cremer, however, has furnished apparent proof that glycerin acts as a direct glycogen or sugar-former. When fed, especially in the diabetic condition, it causes an increase in the sugar which can not be explained as a result of protein metabolism. Since in the body neutral fats are normally split into glycerin and fatty acid, the fact that glycerin can be converted to sugar seems to carry with it the admission that fats may contribute directly to sugar production. Whether the synthesis of sugar (or glycogen) from glycerin is, so to speak, a normal process or occurs only under especial condi- tions, cannot be decided at present. Since, however, the glycerin radicle constitutes but a small fraction of the fat molecule, the quantitative importance of a change of this kind cannot be very great under' any circumstances. The Function of Glycogen — Glycogenic Theory. — The 812 PHYSIOLOGY OF DIGESTION AND SECRTTION. meaning of the formation of glycogen in the liver has been, and still is, the subject of discussion. The view advanced first by Bernard is perhaps most generally accepted. According to Bernard, glycogen forms a temporary reserve supply of carbo- hydrate material that is laid up in the liver during digestion and is gradually made use of in the intervals between meals. During digestion the carbohydrate food is absorbed into the blood of the portal system as dextrose or as dextrose, levulose, and galactose. If these sugars passed through the liver unchanged, the contents of the systemic blood in sugar would be increased perceptibly. It is now known that when the percentage of sugar in the blood rises above a certain low limit a condition of hyperglycemia prevails, and the excess is excreted through the kidney and is lost. But as the blood from the digestive organs passes through the liver the excess of sugar is abstracted by the liver cells, is dehydrated to make glycogen, and is retained in the cells in this form for a short period. An objection has been made to this part of the glycogenic hypothesis by Paw on the ground that if all the carbohydrates of a meal were absorbed into the blood as free sugar, a condition of hyperglycemia and glycosuria must evidently result. We know that glycosuria does occur when the carbohydrates are eaten in excess (alimentary glycosuria) for this very reason. But within what we may call the normal limits of a carbohydrate diet it seems most probable that the contents of the portal vein never rise much above the usual level, since the carbohydrate is absorbed slowly during a period of four to five hours, and during this period a very large amount of blood must flow through the intestines, as much perhaps in five hours as 180 to 190 liters, if one may apply to man the results of Burton- Opitz, obtained for the dog, namely, a flow of 31 cc. per minute for each 100 gms. of intestine. From time to time the glycogen of the liver is reconverted into sugar (dextrose) and is given off to the blood. By this means the percentage of sugar in the systemic blood is kept nearly constant (0.1 to 0.2 per cent.) and within limits best adapted to the use of the tissues. The great importance of the formation of glycogen and the consequent conservation of the sugar supply of the tissues is evident when we consider the nutritive value of carbohydrate food. Carbohydrates form the bulk of our usual diet, and the proper regulation of the supply to the tissues is, there- fore, of vital importance in the maintenance of a normal, healthy condition. The second part of this theory, which holds that the glycogen is reconverted to dextrose, is supported by observations upon livers removed from the body. It has been found that shortly after the removal of the liver the supply of glycogen begins to dis- appear and a corresponding increase in dextrose occurs. Within a comparatively short time all the glycogen is gone and only dextrose PHYSIOLOGY OF THE LIVER AND SPLEEN. 813 is found. It is for this reason that in the estimation of glycogen in the liver it is necessary to mince the organ and to throw it into boiling water as quickly as possible, since by this means the liver cells are killed and the conversion of the glycogen is stopped. How the gly- cogen is changed to dextrose by the liver is a matter not fully ex- plained. According to most authors, the conversion is due to an enzyme produced in the liver. Extracts of liver, as of some other tissues, yield a diastatic enzyme that changes glycogen to dextrose.* It is probable, therefore, that the normal conversion of glycogen to dextrose is effected by a special enzyme produced in the liver cells. In this description of the origin and meaning of the liver glycogen reference has been made only to the glycogen derived directly from digested carbohydrates. The glycogen derived from protein foods, once it is formed in the liver, has, of course, the same functions to fulfil. It is converted into sugar, and eventually is oxidized in the tissues. For the sake of completeness it may be well to add that some of the sugar of the blood formed from the glycogen, when an excess is eaten beyond the energy needs of the tissues, ma}' be converted into fat in the adipose tissues instead of being burnt, and in this way it may be retained in the body as a reserve supply of food of a more stable character. Glycogen in the Muscles and other Tissues. — The history of glycogen is not complete without some reference to its occurrence in the muscles. Glycogen is, in fact, found in various places in the bod}', and is widely distributed throughout the animal kingdom. It occurs, for example, in leucocytes, in the placenta, in the rapidly growing tissues of the embryo, and in considerable abimdance in the oyster and other molluscs. But in our bodies and in those of the mammals generally the most significant occurrence of glycogen, outside the liver, is in the voluntary muscles, of which glycogen forms a normal constituent. It has been estimated that the percentage of glycogen in resting muscle varies from 0.5 to 0.9 per cent., and that in the musculature of the whole body there may be contained an amount of glycogen equal to that in the liver itself. Muscular tissue, as well as liver tissue, has a glycogenetic function — that is, it is cap- able of laying up a supply of glycogen from the sugar brought to it by the blood. The glycogenetic function of muscle has been demonstrated directly by Kulz,t who has shown that an isolated muscle irrigated with an artificial supply of blood to which dextrose is added is capable of changing the dextrose to glycogen, as shown by the increase in the latter substance in the muscle after irriga- tion. Muscle glycogen is to be looked upon as a temporary and local reserve supply of material; so that, while we have in the liver a large general depot for the temporary storage of glycogen for * Tebb, -Journal of Physiology," 22, 423, 1897-98. t "Zeitschrift f. Biologie," 72, 237, 1890. 814 PHYSIOLOGY OF DIGESTION AND SECRETION. the use of the body at large, the muscular tissue, which, considering its bulk, is the most active tissue of the body from the standpoint of energy production, is also capable of laying up in the form of gly- cogen any excess of sugar brought to it. The fact that glycogen occurs so widely in the rapidly growing cells of embryos indicates that this glycogenetic function majr at times be exercised by any tissue. Conditions Affecting the Supply of Glycogen in Muscle and Liver. — In accordance with the view given above of the general value of glycogen — namely, that it is a temporary reserve supply of carbohydrate material that may be rapidly converted to sugar and oxidized with the liberation of energy — it is found that the supply of glycogen is greatly affected by conditions calling for increased metabolism in the body. Muscular exercise quickly exhausts the supply of muscle and liver glycogen, provided it is not renewed by new food. Observations on isolated muscles have shown definitely that the local supply of glycogen is diminished when the muscle is made to contract (see p. 66). In a starving animal glycogen finally disappears, except perhaps in traces, but this disappearance occurs much sooner if the animal is made to use its muscles at the same time. It has been shown also by Morat and Dufourt that if a muscle has been made to contract vigorously it takes up much more sugar from an artificial supply of blood sent through it than a similar muscle which has been resting ; on the other hand, it has been found that if the nerve of one leg is cut so as to paralyze the muscles of that side of the body, the amount of glycogen is greater in these muscles than in those of the other leg that have been contracting meantime and using up their gly- cogen. The further history of glycogen is considered in the section on Nutrition. Formation of Urea in the Liver. — The nitrogen contained in the protein material of our food is finally eliminated, mainly in the form of urea. It has been definitely proved that the urea is not formed in the kidneys, the organs that eliminate it. It has long been considered a matter of the greatest importance to ascertain in what organ or tissues urea is formed. Investigations have gone so far as to demonstrate that it arises in part at least in the liver; hence the property of forming urea must be added to the other important func- tions of the liver cell. Schroder * performed a number of experi- ments in which the liver was taken from a freshly killed dog and irrigated through its blood-vessels with a supply of blood obtained from another dog. If the supply of blood was taken from a fasting animal, then circulat ing it through the isolated liver was not followed by any increase in the amount of urea contained in it. If, on the contrary, the blood was obtained from a well-fed dog, the amount * Archiv f. cxperimentelle Pathologic und Pharmakologie," 15, 364, 1882, and 19, 373, 1885. PHYSIOLOGY OF THE LIVER AND SPLEEN. 815 of urea contained in it was distinctly increased by passing it through the liver, thus indicating that the blood of an animal after digestion contains something that the liver can convert to urea. It is to be noted, moreover, that this power is not possessed by all the organs, since blood from well-fed animals showed no increase in urea after being circulated through an isolated kidney or muscle. As further proof of the urea-forming power of the liver Schroder found that if ammonium carbonate was added to the blood circulating through the liver — to that from the fasting as well as from the well-nourished animal — a very decided increase in the urea was always obtained. It follows from the last experiment that the liver cells are able to convert carbonate of ammonium into urea. The reaction may be expressed by the equation (NH4)2C03— 2H20 = CON2H4. Schon- dorff * in some later work showed that if the blood of a fasting dog is irrigated through the hind legs of a well-nourished animal, no increase in urea in the blood can be detected; but if the blood, after irrigation through the hind legs, is subsequently passed through the liver, a marked increase in urea results. Obviously, the blood in this experiment derives something from the tissues of the leg which the tissues themselves cannot convert to urea, but which the liver cells can. Finally, in some remarkable experiments upon dogs made by four investigators (Hahn, Massen, Nencki, and Pawlow), which are described more fully in the next chapter, it was shown that when the liver is practically destroyed there is a distinct diminution in the urea of the urine. In birds uric acid takes the place of urea as the main nitrogenous excretion of the body, and Minkowski has shown that in them removal of the liver is followed by an important diminution in the amount of uric acid excreted. From experiments such as these it is safe to conclude that urea is formed in the liver and is then given to the blood and excreted by the kidney. In treating of the physiological history of urea an account will be given of the views proposed with regard to the antecedent substance or substances from which the liver produces urea. Physiology of the Spleen. — Much has been said and written about the spleen, but we are yet in the dark as to the distinctive function or functions of this organ. The few facts that are known may be stated briefly without going into the details of theories that have been offered at one time or another. The older experimenters demonstrated that this organ may be removed from the body without serious injury to the animal. An increase in the size of the lymph- glands and of the bone-marrow has been stated to occur after ex- tirpation; but this is denied by others, and, whether true or not, it gives but little clue to the normal functions of the spleen. Some observers f find that the removal of the spleen causes a marked * Pfluger's "Archiv f. die gesammte Physiologie, " 54, 420, 1893. t Laudenbach, " Centralblatt fur Physiologie," 9, 1, 1895. 816 PHYSIOLOGY OF DIGESTION AND SECRETION". diminution in the number of red corpuscles and the quantity of hemoglobin. They infer, therefore, that the spleen is normally concerned in some way in the formation of red corpuscles. Others, however, report with equal positiveness that removal of the spleen has no effect upon the number of red corpuscles or upon the power of the animal to regenerate its corpuscles after hemorrhage* The most definite facts known about the spleen are in connection with its movements. It has been shown that there is a slow expansion and contraction of the organ synchronous with the digestion periods. After a meal the spleen begins to increase in size, reaching a maximum at about the fifth hour, and then slowly returns to its previous size. This movement, the meaning of which is not known, is probably due to a slow vasodilatation, together, perhaps, with a relaxation of the tonic contraction of the musculature of the trabecular In addition to this slow movement. Royf has shown that there is a rhythmical contraction and relaxation of the organ, occurring in cats and dogs at intervals of about one minute. Roy supposes that these con- tractions are effected through the intrinsic musculature of the organ, — that is, the plain muscle tissue present in the capsule and trabecular, — and he believes that the contractions serve to keep up a circulation through the spleen and to make its vascular supply more or less independent of variations in general arterial pressure. The fact that there is a special local arrangement for maintaining its cir- culation makes the spleen unique among the organs of the body, but no light is thrown upon the nature of the function fulfilled. The spleen is supplied richly with motor nerve fibers which when stimu- lated either directly or reflexly cause the organ to diminish in volume. According to Schaefer,J these fibers are contained in the splanchnic nerves, which carry also inhibitory fibers whose stimu- lation produces a dilatation of the spleen. The chemical composition of the spleen is complicated, but sug- gestive. Its mineral constituents are characterized by a large percentage of iron, which seems to be present as an organic compound of some kind. Analysis shows also the presence of a number of fatty acids, fats, cholesterin, and, what is perhaps more noteworthy, a number of nitrogenous extractives belonging to the group of purin bases, such as xanthin, hypoxanthin, adenin, guanin, and uric acid. The presence of these bodies seems to indicate that active metabolic changes of some kind occur in the spleen. As to the theories of the splenic functions, the following may be mentioned: (1) The spleen has been supposed to give rise to new red corpuscles. This it un- doubtedly does during fetal life and shortly after birth, and in some animals throughout life, but there is no reliable evidence that the * Paton, Gulland, and Fowler, "Journal of Physiology," 28, 83, 1902. t •■Journal of Physiology," 3, 203, 1881. J Ibid., 20, 1, 1896. PHYSIOLOGY OF THE LIVER AXD SPLEEN. 817 function is retained in adult life in man or in most of the mammals. The presence of a large amount of iron in organic combination suggests, however, that the spleen may play a part in the prepara- tion of new hemoglobin, or in the perservation of the iron set free by the death of the red corpuscles. This suggestion is strengthened by the fact that after extirpation of the spleen there is a distinct increase in the daily loss of iron from the body, in dogs an increase from 11- to 18 or 29 mgm.* (2) It has been supposed to be an organ for the destruction of red corpuscles. This view is founded chiefly on microscopical evidence, according to which certain large ameboid cells in the spleen ingest and destroy the old red corpuscles, and partly upon the fact that the spleen tissue seems to be rich in an iron-containing compound. This theory cannot be considered at present as satisfactorily demon- started. (3) It has been suggested that the spleen is concerned in the production of uric acid. This substance is found in the spleen, as stated above, and it was shown by Horbaczewsky that the spleen contains substances from which uric acid or xanthin may readily be formed by the action of the spleen-tissue itself. More recent investigations f have shown that the spleen, like the liver and some other organs, contains special enzymes (adenase, guanase, and xanthin oxydase), by whose action the split products of the nucleins may be converted to uric acid, and it is probable, therefore, that this latter substance is constantly formed in the spleen. (4) Lastly, a theory has been supported by Schiff and Herzen, according to which the spleen produces something (an enzyme) which, when carried in the blood to the pancreas, acts upon the trypsinogen con- tained in this gland, converting it into trypsin. This view has been corroborated by a number of observers, but it is difficult at present to decide whether such an action occurs normally during digestion. As already stated, the general testimony at present indicates that the pancreatic juice when secreted contains its trypsin in inactive form. It is activated only after reaching the duodenum under the influence of the enterokinase. * Grossenbacher and Asher, "Zentralblatt f. Physiol," No. 12, 1908. t Consult Jones and Austrian, " Zeitschrift f. physiol. Chem.," 1906, xlviii., 110. 52 CHAPTER XLV. THE KIDNEY AND SKIN AS EXCRETORY ORGANS. Structure of the Kidney. — The kidney is a compound tubular gland. The uriniferous tubules composing it may be roughly separated into a secreting part comprising the capsule, convoluted tubes, and loop of Henle, and a collecting part, the so-called straight or collecting tube, the epithelium of which is assumed not to have any secretory function. Within the secreting part the epithe- lium differs greatly in character in different regions ; its peculiarities may be referred to briefly here so far as they seem to have a physio- Fig. 298. — Portions of the various divisions of the uriniferous tubules drawn from sections of human kidney: A, Malpighian body; x, squamous epithelium lining the cap- sule and reflected over the glomerulus; y, z, afferent and efferent vessels of the tuft; e. nuclei of capillaries; n, constricted neck marking passage of capsule into convoluted tu- bule; B, proximal convoluted tubule; C, irregular tubule; D and F, spiral tubules; E, ascending limb of Henle's loop; G, straight collecting tubule.— (PtersoZ.) logical bearing, although for a complete description reference must be made to works on histology. The arrangement of the glandular epithelium in the capsule with reference to the blood-vessels of the glomerulus is worthy of special attention. It will be remembered that each Malpighian corpuscle con- sists of two principal parts, a tuft of blood-vessels, the glomerulus, and an enveloping expansion of the uriniferous tubule, the capsule. The glomerulus is an interesting structure (see Fig. 298, A). It consists of a small afferent artery which after entering the glomerulus, breaks up into a number of capillaries. These capillaries, although twisted 818 KIDNEY AND SKIN AS EXCRETORY ORGANS, 819 together, do not anastomose, and they unite to form a single efferent vein of a smaller diameter than the afferent artery. The whole structure, therefore, is not an ordinary capillary area, but a rete mirabile, and the physical factors are such that within the capil- laries of the rete there must be a greatly diminished velocity of the blood-stream, owing to the great increase in the width of the stream bed, and a higher blood-pressure than in ordinary capillaries, owing to the narrow afferent vessel and the capillaries of the tubule which form a resistance beyond the rete. Surrounding this glomerulus is the double-walled capsule. One wall of the cap- sule is closely adherent to the capillaries of the glomerulus; it not only covers the structure closely, but dips into the interior between the small lobules into which the glomerulus is divided. This layer of the capsule is composed of flattened, endothelial- like cells, the glomerular epithelium, to which great importance is attached in the formation of the secretion. It will be no- ticed that between the interior of the blood-vessels of the glomerulus and the cavity of the capsule, which is the beginning of the urin- iferous tubule, there are interposed only two very thin layers, — namely, the epithelium of the capillar}* wall and the glomerular epithelium. The apparatus would seem to afford most favorable conditions for filtration of the liquid parts of the blood. The epi- thelium clothing the convoluted portions of the tubule, including under this designation the so-called irregular and spiral portions and the loop of Henle, is of a character quite different from that of the glomerular epithelium (Fig. 298, B, C, D, E, F, G). The cells, speaking generally, are cuboidal or cylindrical, protoplasmic, and granular in appearance; on the side toward the basement mem- brane they often show a peculiar striation, while on the lumen side the extreme periphery presents a compact border which in some cases shows a cilia-like striation. These cells have the general appearance of an active secretory epithelium, and one theory of urinary secretion attributes this function to them. The Secretion of Urine. — The kidneys receive a rich supply of nerve fibers, but most histologists have been unable to trace any connection between these fibers and the epithelial cells of the kidney tubules. The majority of purely physiological experiments upon direct stimulation of the nerves going to the kidney are adverse to the theory of secretory fibers, the marked effects obtained in these ex- periments being all explicable by the changes produced in the blood- flow through the organ. Two general theories of urinary secretion have been proposed. Ludwig held originally that the urine is formed by the simple physical processes of filtration and diffusion. In the glomeruli the conditions are most favorable to filtration, and he supposed that in these structures water filtered through from the 820 PHYSIOLOGY OF DIGESTION AND SECRETION. blood, carrying with it not only the inorganic salts, but also the specific elements (urea, etc.) of the secretion. There was thus formed at the beginning of the uriniferous tubules a complete but diluted urine, and in the subsequent passage of this liquid along the convoluted tubes it became concentrated by diffusion with the more concentrated lymph surrounding the outside of the tubules. Bowman's theory of urinary secretion, which has since been vigorously supported and extended by Heidenhain, was based orig- inally mainly on histological grounds. It assumes that in the glomeruli water and inorganic salts are produced, wrhile the urea and related bodies are eliminated through the activity of the epi- thelial cells in the convoluted tubes. The first of these theories (Ludwig) is sometimes spoken of as the mechanical theory, since as originally proposed it attempted to explain the formation and composition of the urine by reference only to the physical forces of filtration and diffusion.* Adherents of this view in recent years have modified it, however, to the extent that the absorption supposed to take place in the convoluted tub- ules is designated as a selective absorption, or selective diffusion, the characteristics of which depend upon unknown peculiarities of struc- ture in the epithelial cell, so that it is no longer a purely mechanical theory. The difference between the mechanical and the secretory theories may be stated briefly in this way. The former assumes that in the glomerulus all of the constituents of the urine are produced from the blood, probably by filtration, and that the function of the epithelium lining the convoluted tubules is absorptive, like the epithelium of the intestines, and not secretory. The Bowman view as formulated by Heidenhain teaches that the glomerular epithe- lium forms the water and salts of the urine by an act of secretion, the ultimate chemistry or physics of which is not known. The theory asserts that the epithelial cells participate actively in the process of secretion and do not serve simply as a passive membrane. The cells of the convoluted tubules are also secretory, their special activity being limited mainly to the organic constituents, urea, etc., although, in this respect, — namely, in the precise distinction be- tween the secretory products of the glomerular epithelium and those of the convoluted tubules, — the theory is not very explicit. Much interest and a large literature have been stimulated by controver- sies based on these theories, and to-day the facts accumulated are not such as to demonstrate conclusively one view or the other, although, on the whole, perhaps, it may be said that the majority of * Sir Lauder Brunton calls my attention to the fact that Ludwig, in some of his earlier investigations (Ustimowitsch, Ludwig's "Arbeiten," 1870), recognized the fact that the flow of urine through the glomeruli is influenced by factors other than the mechanical pressure. He called attention especially to the influence of the diuretic substances present in the blood, such as urea and sodium chlorid. KIDNEY AND SKIN AS EXCRETORY ORGANS. 821 physiologists adhere to the more conservative view of Bowman- Heidenhain to the extent at least of recognizing that the physical laws of filtration, diffusion, and imbibition, so far as they are known, do not suffice for a satisfactory explanation of the facts.* As in other similar cases, our knowledge of the physical structure and chemical properties of the walls of the living cells is still very de- ficient, and it seems necessary to designate these activities by the indefinite term secretion. Function of the Glomerulus. — As stated above, the structure of the glomerulus is peculiar and suggestive of a special adaptation. The mechanical theory looks upon it as a filter, the pressure of the blood in the glomerular capillaries driving the water and salts through the endothelium of the capillaries and the glomerular epi- thelium into the cavity of the urinary tubule. If we consider only the water and assume that the membranes traversed are freely permeable to its molecules, then it is evident that, upon this theory, the quantity of urine formed will depend upon the filtration pres- sure, and that this filtration pressure can be expressed by the formula F=P — p, in which P represents the blood-pressure in the glom- erular capillaries and p the pressure of the urine in the capsular end of the uriniferous tubules. Some of the interesting facts de- veloped by experiment may be presented in connection with this formula. According to the mechanical theory, the amount of urine formed should vary directly with P and inversely with p. The factor P may be increased in two general ways: First, by those changes which raise general arterial pressure and therefore the pressure in the renal arteries, — such changes, for instance, as are brought about by an increased force of heart beat or a large vaso- constriction. Second, by obstructing or occluding the renal veins. Experiments have been made along these lines. With regard to the first possibility it has been found in general, although not invar- iably, that raising arterial pressure increases the quantity of urine if the means used are such as may be assumed to raise the pressure in the glomerular capillaries. The reverse experiment, however, of raising P by blocking the venous outflow fails entirely to support the theory. When the renal veins are compressed the capillary pressure in the glomeruli must be increased, and, if the veins are blocked entirely, we may suppose that the capillary pressure is raised to the level of that of the renal arteries. In such experiments, however, the flow of urine is di- minished instead of being increased, and indeed may be stopped altogether when the veins are completely blocked. The adherents of the mechanical theory have attempted to explain this unfavorable result by assuming that the swollen interlobular veins press upon * For discussion and literature see Magnus, "Miinchener med. Wochen- schrift," 1906, Nos. 28 and 29. 822 PHYSIOLOGY OF DIGESTION AND SECRETION. and block the uriniferous tubules. According to the antagonistic theory of Heidenhain, blocking the veins suppresses the secretory activity of the glomerular epithelium by depriving it of oxygen and the chance for removal of C02, — that is, by producing local as- phyxia. The latter explanation seems the simpler of the two, and it is very strongly supported by the opposite experiment of clamping the renal artery. When this is done the blood-flow through the kidney ceases and the secretion of urine also stops, as would be expected. But when after a few minutes' closure the artery is un- damped, the secretion is not restored with the return of the cir- culation. On the contrary, a long time (as much as an hour or more) may elapse before the secretion begins. This fact is quite in harmony with the Heidenhain theory, since complete removal of their blood supply might well result in a long-continued injury to the delicate epithelial cells. On the mechanical theory, however, we should expect a contrary result. Injury to the cells should be followed by greater permeability and an increased filtration, as is found to be the case with the production of lymph. These two experiments, blocking the renal artery and the renal vein, seem at present to dis- credit the filtration theory and to support the secretion theory. If we accept this latter theory it may be asked how it agrees with the experiments mentioned above upon the variations in capillary pressure brought about otherwise than by obstructing the venous outflow. Heidenhain has emphasized the fact that all of these ex- periments involve not only a variation in capillary pressure, but also in the blood-flow, and that it is open to us to suppose that the effect upon the secretion of urine is dependent upon the rate of flow rather than upon the capillary pressure. If we adopt this expla- nation we are led again to the secretion hypothesis. Mere rate of flow should not influence filtration, but might affect secretion, since it would alter the volume of blood which passed by the cells in a given time and thereby would vary the quantity of oxygen sup- plied and of carbon dioxid removed, and also the quantity of chem- ical substances in the blood which may act as chemical stimuli to the cells. An important fact, which seems at first sight to show a direct influence of pressure, is that when general arterial pressure falls below a certain point, about 40 mm. of mercury, the secretion of urine ceases altogether. Such a condition may be brought about by surgical shock, by hemorrhage, or by section of the spinal cord in the cervical or thoracic region. But here again the great vascular dilation causing this fall of pressure is associated with a feeble cir- culation, and the effect upon the kidney secretion may well be due to this latter factor. In addition to varying the factor P in the formula given above, it is possible also to increase the factor p. Normally, the pressure of the urine in the capsule must be very low, owing to the fact that KIDNEY AND SKIN AS EXCRETORY ORGANS. 823 the secretion drains away as rapidly as it is formed. If the ureter is occluded, however, the pressure of the urine will increase, and the filtration pressure P — p will diminish. When this experiment is performed and the pressure in the ureter is measured by a manom- eter, it is found to rise to 50 or 60 mms. of mercury and then to i-emain stationary. This fact might be explained b}^ supposing that when p = P the secretion stops on account of the failure of the filtration pressure. Little weight, however, can be given to this argument, since it is quite possible that under these condi- tions the urine may still continue to form, but be reabsorbed under the high tension reached. The experiment simply serves to show the secretion pressure of the urine, and the fact that this pressure rises as high as 50 to 60 mms. mercury, while the capillary pressure is probably somewhat lower, would rather serve as an argument against the filtration theory. Moreover, experiments show * that when a certain moderate resistance is established in the ureters {p = 10 cms. H20) the flow of urine is actually increased instead of falling off, a fact entirely opposed to the mechanical theory, but explicable on the secretion theory on the assumption that the resistance acts as a stimulus. Function of the Convoluted Tubule. — By the term convoluted tubule is meant here the entire stretch from the glomerulus to the straight tubules. Its epithelium varies in character; its cells are distinguished in general, as contrasted with the glomerular epithe- lium, by a relatively large amount of granular protoplasm. The question of interest at present in regard to this epithelium is whether it is secretory or absorptive. The original view of Ludwig that diffusion takes place in these tubules between the urine and the blood (lymph) in accordance with simple physical laws and that by this action alone the dilute urine is brought to its normal concen- tration must be abandoned. The mere fact that the urine may be more concentrated in certain constituents than the blood is suffi- cient evidence that other factors must co-operate. Those who be- lieve that the main function of the tubules is absorptive are obliged to regard this process as physiological, as a selective absorption depending upon the living structure and properties of the epithelial cells. The kind of evidence upon which this view is based is some- what indirect; a single example may suffice. Cushny statesf that if certain diuretics — for example, sodium chlorid and sodium sul- phate— are injected simultaneously into the blood and in such amounts that an equal number of the anions (CI and SO J are pres- ent, the quantities that are excreted in the urine during the next hour or two follow different curves and vary independently of their concentration in the plasma. While this independence might be * Bro'die and Cullis, "Journal of Physiology," 1906, xxxiv., 224. t "Journal of Physiology," 27, 429, 1902. 824 PHYSIOLOGY OF DIGESTION AND SECRETION. referred to a specific secretory action, the author finds a simpler explanation in variations in absorption, the epithelium of the con- voluted tubule, like that of the intestine, absorbing the sulphate with more difficulty. On the other side, the facts that have been urged in favor of the secretory hypothesis are more numerous and varied, but none is entirely convincing. Some of these facts are as follows: (1) It is stated that if the ureters are ligated in birds the urates will be found deposited in the uriniferous tubules, but never at the capsular end. (2) Heidenhain has given proof that the convoluted tubules are capable of excreting indigo-carmin after this substance is injected into the blood. His experiment consisted essentially in injecting the material into the blood, after dividing the cord so as to reduce the rapidity of secretion. After a certain interval the kidney was removed and irrigated with alcohol to pre- cipitate the indigo-carmin in situ in the organ. Microscopical ex- amination showed that after this treatment the granules of the indigo-carmin are found in the convoluted tubules, but not in the capsules around the glomeruli. (3) Microchemical reactions indicate that the iron secreted from the kidney as well as the uric acid is given off through the epithelium of the convoluted tubules. (4) Several observers (Van der Stricht, Disse, Trambasti, Gur- witsch*) have described microscopical appearances in the cells lining the tubules indicative of an active secretion. They picture the formation of vesicles in the cells and appearances which indi- cate the discharge of these vesicles into the cavity of the tubules. (5) Xussbaum made use of the fact that in the frog the glomeruli are supplied by branches of the renal artery, while the rest of the tubes are supplied by the renal portal vein. He stated that if the renal artery is ligated the glomeruli are deprived completely of blood, and that as a result the flow of urine ceases. If under these conditions urea is injected into the circulation, it is excreted together with some water, thus proving the secretory activity of the tubules with regard to urea. These results, although denied at one time, have later been confirmed and extended.! (6) Dreser has shown that the acidity of the urine is due to an action of the epithelium of the tubules. If an acid indicator, such us acid fuchsin, is injected into the dorsal lymph-sac of a frog, and an hour or so later the kidneys are examined, it will be found that the convoluted tubules are colored red, while the capsular end is colorless, indicating that the secretion at the latter point has an alkaline reaction. The experiment shows that the acid substances in the urine are produced in the convoluted tubules. The sim- plest explanation is that they are formed by a secretory activity * See Gurwitsch, " Archiv f. die gesammte Physiologie," 91, 71, 1902. t Bainbridge and Beddard, "Journal of Physiology," 1906, xxxiv. (Proc. Physiol. Soc); also Cullis, ibid., p. 250. KIDNEY AND SKIN AS EXCRETORY ORGANS. 825 of the epithelial cells. (7) Studies of the gaseous exchanges in the kidney during diuresis* and during the glycosuria caused by phlorhizinf tend to support the secretion hypothesis to the extent that they prove an increased metabolism during func- tional activity. (8) The action of diuretics (see below). On the whole, it must be admitted that the weight of evidence is in favor of the Bowman-Heidenhain theory of secretion, and it remains for future investigations to explain more definitely what is meant by the obscure term " secretory activity." Under pathological conditions it has been shown satisfactorily that the albumin and sugar which may be present in the urine are secreted or eliminated at the glomerular end of the tubule. Action of Diuretics. — An important side of the theories of secretion of urine is their application to the action of diuretics. Water; various soluble substances, such as salts, urea, and dextrose; and certain special drugs, such as caffein or digitalis, exert a diuretic action on the kidneys. Much experimental work has been done to ascertain whether the action of these substances can be explained mechanically by their influence on the blood-flow or the blood- pressure in the kidney capillaries, or whether it is necessary to fall back upon a specific stimulating effect exerted by them upon the epithelial cells of the tubules. Adherents of the original Ludwig theory are forced to explain their action by the effect they pro- duce upon the pressure in the kidney capillaries, and, indeed, it has been shown with reference to the saline diuretics that their effect upon the secretion is in proportion to the osmotic pressure they exert. It has been suggested, therefore, that the action of these diuretics lies in the fact that they attract water from the tis- tues into the blood and thus cause a condition of hydremic plethora. But whether the elimination of this excess of water is due to filtra- tion or to an active secretion by the glomerular epithelium is a question that revives the discussion that has been presented briefly above. Most observers find that the vascular changes in the kid- ney, particularly after the administration of caffein and digitalis, do not explain satisfactorily the phenomenon of diuresis, and al- though it is necessary to admit that the diuretics, or some of them, act in part by the changes which they cause in the circulation in the kidney, it is not possible to demonstrate that all the phenomena under this head can be thus explained. The bulk of the work published indicates that some at least of the known diuretics act as stimulants to the secreting cells. In the case of the inorganic salts it may be said (Magnus) that there is for each salt a " secretion thresh- old." An increase in concentration above this level leads to the elimination of the excess of salt and an increased secretion of water. * Barcroft and Brodie, "Journal of Physiology," 1906, xxxiii., 52. t Pavy, Brodie, and Siam, ibid., 1903, xxix., 467. 826 PHYSIOLOGY OF DIGESTION AND SECRETION. The Blood-flow through the Kidneys. — It will be inferred from the discussion above that, other conditions remaining the same, the secretion of the kidney varies with the quantity of blood flowing through it. It is, therefore, important to refer briefly to the nature and especially the regulation of the blood-flow through this organ, although the same subject is referred to in connection with the general description of vasomotor regulation (see Circulation). It has been shown by Landergren* and Tigerstedt that the kidney is a very vascular organ, at least when it is in strong functional activ- ity such as may be produced by the action of diuretics. They esti- mate that in a minute's time, under the action of diuretics, an amount of blood flows through the kidney equal to the weight of the organ; this is an amount from four to nineteen times as great as occurs in the average supply of the other organs in the systemic circulation. Taking both kidneys into account, their figures show that (in strong diuresis) 5.6 per cent, of the total quantity of blood sent out of the left heart in a minute may pass through the kidneys, although the combined weight of these organs makes only 0.56 per cent, of that of the body (see table p. 458). The nature of the supply of vasomotor nerves to the kidney and the conditions which bring them into activity are fairly well known, owing to the useful invention of the oncometer by Roy. This in- strument is, in principle, a plethysmograph especially modified for use upon the kidney of the living animal. It is a kidney-shaped box of thin brass made in two parts, hinged at the back, and with a clasp in front to hold them together. In the interior of the box thin peritoneal membrane is so fastened to each half that a layer of olive oil may be placed between it and the brass walls. There is thus formed in each half a soft pad of oil upon which the kidney rests. When the kidney, freed as far as possible from fat and sur- rounding connective tissue, but with the blood-vessels and nerves entering at the hilus entirely uninjured, is laid in one-half of the on- cometer, and the other half is shut down upon it and tightly fas- tened, the organ is surrounded by oil in a box which is liquid-tight at every point except one, from which a tube is led off to some suitable recorder such as a tambour. Under these conditions every increase in the volume of the kidney causes a proportional outflow of oil from the oncometer, which is measured by the recorder, and every diminution in volume is accompanied by a reverse change. At the same time the flow of urine during these changes can be determined by inserting a cannula into the ureter and measuring directly the outflow of urine. By this and other means it has been shown that the kidney receives a rich supply of vasoconstrictor nerve fibers that reach it between and around the entering blood- vessels. These fibers emerge from the spinal cord chiefly in the * " Skandinavisches Archiv f. Physiologie, " 4, 241, 1892. KIDNEY AND SKIN AS EXCRETORY ORGANS. 827 lower thoracic spinal nerves (tenth to thirteenth in the dog) , pass through the sympathetic system, and reach the organ as postgan- glionic fibers. Stimulation of these nerves causes a contraction of the small arteries of the kidney, a shrinkage in volume of the whole organ as measured by the oncometer (see Fig. 240) , and a dimin- ished secretion of urine. When, on the other hand, these con- strictor fibers are cut as they enter the hilus of the kidney, the ar- teries are dilated on account of the removal of the tonic action of the constrictor fibers, the organ enlarges, and a greater quantity of blood passes through it, since the resistance to the blood-flow is diminished while the general arterial pressure in the aorta remains practically the same. Along with this greater flow of blood there is a marked increase in the secretion of urine. Under normal conditions we must suppose that these fibers are brought into play to a greater or less extent by reflex stimulation, .and thus serve to control the blood-flow through the kidney and thereby influence its functional activity. It has been shown, too, that the kidney receives vasodilator nerve-fibers, — that is, fibers which when stimulated directly or reflexly cause a dilatation of the arteries, and therefore a greater flow of blood through the or- gan. According to Bradford, these fibers emerge from the spinal ■cord mainly in the anterior roots of the eleventh, twelfth, and thir- teenth thoracic spinal nerves. Under normal conditions these fibers -are probably thrown into action by reflex stimulation and lead to an increased functional activity. It will be seen, therefore, that the kidneys possess a local nervous mechanism through which their secretory activity may be increased or diminished by correspond- ing alterations in the blood-supply. So far as is known, this is the only way in which the secretion in the kidneys can be directly af- fected by the central nervous system. It should be borne in mind, also, that the blood-flow through the kidneys, and therefore their secretory activity, may be affected by conditions influencing general arterial pressure. Conditions such as asphyxia, strychnin poison- ing, or painful stimulation of sensory nerves, which cause a general vasoconstriction, influence the kidney in the same way, and tend, therefore, to diminish the flow of blood through it ; while conditions which lower general arterial pressure, such as general vascular dila- tation of the skin vessels, may also depress the secretory action of the kidney by diminishing the amount of blood flowing through it. In what way any given change in the vascular conditions of the body will influence the secretion of the kidney depends upon a num- ber of factors and their relations to one another, but any change which will increase the difference in pressure between the blood in the renal artery and the renal vein will tend to augment the flow of blood unless it is antagonized by a simultaneous constriction in the small arteries of the kidney itself. On the contrary, any vas- 828 PHYSIOLOGY OP DIGESTION AND SECRETION. cular dilatation of the vessels in the kidney will tend to increase the blood-flow through it unless there is at the same time such a general fall of blood-pressure as is sufficient to lower the pressure in the renal artery and reduce the driving force of the blood to an extent that more than counteracts the favorable influence of dimin- ished resistance in its small arteries. Although the kidney does not possess specific secretory nerve fibers, it is possible that there may be formed in the body specific chemical excitants or diuretics belonging to the general group of hormones (p. 765). Schafer* has shown that such a substance occurs normally in the nervous lobe of the pituitary gland, and it is possible that the internal secretion of this lobe may play toward kidney activity a role similar to that of the adrenalin toward muscular metabolism. The Composition of Urine. — The urine of man is a yellowish liquid that varies greatly in depth of color. It has an average specific gravity of 1.020 and usually an acid reaction. This acid reaction is attributed generally to the presence of acid phosphates, particularly acid sodium phosphate (NaH2P04); but, according to Folin,f the acidity is due partially and indeed in larger part to or- ganic acids. When tested by the usual indicators (litmus) human urine may show an alkaline reaction, and, in fact, observations indicate that the reaction may vary in accordance with the character of the food. Among carnivora the urine is uniformly acid, and among herbivora it is alkaline so long as they use a veg- etable diet. During starvation, however, or when living upon the mothers' milk, — that is, whenever they are existing upon a purely animal diet — the urine becomes acid. The general explanation of this effect of food that has been suggested (Drechsel) is that upon an animal diet more acids are formed (from the oxidation of the sulphur and phosphorus of the proteins) than in the case of the vegetable foods in which the alkaline salts of the vegetable acids give rise on oxidation in the body to alkaline carbonates. The kidney separates from the neutral blood and lymph the excess of acid salts and thus maintains a normal balance between the acid and basic equivalents in the blood, but the fact that on an ordinary mixed diet the urine has an acid reaction indicates that the acids formed in the body during metabolism must exceed the bases. The composition of the urine is very complex. In addition to the water and inorganic salts the following elements are important, namely, urea, the purin bodies (uric acid, xanthin, hypoxanthin), creatinin, hippuric acid, oxalic acid (calcium oxalate), several conjugated sulphates and conjugated glycuronates, several aromatic oxyacids and nitrogenous acids, fatty acids, dissolved gases ( N and C02), and the urinary pigments urochrome and urobilin. This list * Schafer and Herring, "Phil. Trans." 1906, B. excix., 1. t "American Journal of Physiology," 9, 26.5, 1903. KIDNEY AND SKIN AS EXCRETORY ORGANS. 829 is not complete; a number of additional substances have been de- scribed as occurring constantly or occasionally in traces within the limits of health, and some substances are secreted whose composi- tion is unknown. Under pathological conditions the composition may be still further modified. The complexity of the composition may be understood when it is recalled that through this organ are eliminated some of all the end-products formed in the various tis- sues, together with products arising from bacterial fermentation in the gastro-intestinal canal and various more or less foreign sub- stances taken with the food. It is not possible to describe all the numerous constituents that have been observed. Attention may be directed to those that quantitatively or otherwise are of chief physiological interest. The Nitrogen Elimination in the Urine. — Nearly all of the ex- cretion of nitrogen occurs in the urine. In the metabolism of the usual foodstuffs — carbohydrates, fats, and proteins — the end-prod- ucts of their destruction or physiological oxidation in the body are water, carbon dioxid, and nitrogenous waste products (and sulphates and phosphates from the sulphur and phosphorus in the proteins). The water is eliminated in the urine, the sweat, saliva, etc., and the expired air. The C02 is eliminated in the expired air. and in smaller part in dissolved form in the secretions (sweat, urine). The nitrog- enous excretion, representing the breaking down of protein material, is found in minute part in the sweat, to a larger extent in the feces. but in by far the main amount in the urine. In all problems con- cerning protein metabolism in the body, both as regards its char- acter and extent, the quantitative study of this excretion is of par- amount importance. In order to determine the total amount of protein metabolism it is customary to determine the total nitrogen eliminated in the urine, without regard to its specific form. This determination is made usually by the method of Kjeldahl. The total weight of nitrogen multiplied by 6.25 gives the amount of pro- tein broken down, since nitrogen forms, on the average, 16 per cent, of the weight of the protein molecule. In an average-sized man the total nitrogen eliminated in a day varies, let us say, between 14 and 18 gms., which would correspond to 88 and 117 gms. of pro- tein. It being often necessary to distinguish between the forms in which this nitrogen is eliminated, the following distinctions are made: (1) The urea nitrogen, — that is, the nitrogen eliminated as urea. According to analyses made by Folin,* the urea nitrogen in man averages 87.5 per cent, of the total nitrogen. (2) The am- monia nitrogen — that is, the nitrogen found in the form of am- monia salts which liberate free ammonia on the addition of a fixed alkali. The proportion of this ammonia nitrogen often varies, especially under pathological conditions affecting the liver. Its * American Physiological Journal," 13, 45, 1905. 830 PHYSIOLOGY OF DIGESTION AND SECRETION. quantitative determination is a matter of importance. The aver- age amount in health may be stated (Folin) as 4.3 per cent, of the total nitrogen. (3) The creatinin nitrogen — that is, the amount excreted as creatinin and indicative of a special (muscular) metab- olism (3.6 per cent, of total nitrogen). (4) The purin nitrogen (uric acid, xanthin, hypoxanthin), also indicative of a special metabolism. (5) The unknown nitrogen. A considerable portion of the nitrogen is eliminated in compounds whose composition as yet has not been determined satisfactorily. According to some analyses this portion of the nitrogen may amount to more than 5 per cent, of the total nitrogen. The so-called oxyproteic acid constitutes a part of this unknown residue. This nitrogenous substance is said to yield leucin and other amino acids on hydroly- sis,* a fact which would suggest that it belongs to the protein group or is derived from a protein; possibly it is a polypeptid. Origin and Significance of Urea. — Urea has the formula, CO- N2H4. It may be considered as an amid of carbonic acid, and has, therefore, the structural formula of CO<^H2. It occurs in the urine in relatively large quantities (2 per cent.). As the total quan- tity of urine secreted in twenty-four hours by an adult male may be placed at from 1500 to 1700 c.c, it follows that from 30 to 34 gms. of urea are eliminated from the body during this period. It is the most important of the nitrogenous excreta of the body, the chief end-product, so far as the nitrogen is concerned, of the phys- iological metabolism of the proteins and the- albuminoids of the foods and the tissues. If we know how much urea is secreted in a given period, we know approximately how much protein has been broken down in the body in the same time. In round numbers, 1 gm. of protein will yield £ gm. of urea, as may be calculated easily from the amount of nitrogen contained in each. Since, however, some of the nitrogen of protein is eliminated in other forms — uric acid, creatinin, etc. — even an exact determination of all the urea is not sufficient to determine with accuracy the total amount of protein of all kinds that has been metabolized. This fact is arrived at more perfectly, as stated above, by a determination of the total nitrogen of the urine and other excretions. In addition to the urine, urea is found in slight quantities in other secretions — in milk (in traces) and in sweat. In the latter liquid the quantity of urea in twenty-four hours may be quite appreciable — as much, for instance, as 0.8 gm. — although such a large amount is found only after active exercise. It has been ascertained definitely that urea is not formed by the kidneys; it is brought to the kidneys by the blood for elimi- nation. That urea is not made in the kidneys is demonstrated ♦Consult Ginsberg, Hofmeister's "Beitr&ge," 10, 411, 1907. KIDNEY AND SKIN AS EXCRETORY ORGANS. 831 by such facts as these: If blood, on the one hand, is irrigated through an isolated kidney, no urea is formed, even though substances (such as ammomium carbonate) from which urea is readily produced are added to the blood; on the other hand, urea is constantly present in the blood (0.0348 to 0.1529 per cent.), and if the two kidneys are removed, it continues to accumulate steadily in the blood as long as the animal survives. It has been ascertained that the urea is produced in part in the liver. The most important questions to be decided are: Through what steps is the protein molecule metabolized to the form of urea? and What is the antecedent substance brought to the liver, from which it makes urea? It is impossible to answer these questions perfectly, but recent investi- gations have thrown a great deal of light on the whole process, and they give hope that before long the entire history of the deriva- tion of urea from proteins will be known. The results of this work may be stated briefly as follows: 1. Urea arises from ammonia salts which in the liver are converted to urea by a process equivalent to dehydration. It has long been known that when ammonium carbonate is added to blood perfused through a liver it is converted to urea.* The reaction may be represented as follows: co<8™j-2H.° = co<™; Ammonium carbonate. Urea. Moreover, the experiments made by Hahn, Pawlow, Massen, and Nencki f show that in dogs removal of the liver is followed by a decrease in the amount of urea in the urine and an increase in the ammonia contents. In these remarkable experiments a fistula (Eck fistula) was made between the portal vein and the inferior vena cava, the result of which was that the whole portal circulation of the liver was abolished, the organ receiving blood only by way of the hepatic artery. If now the latter artery was liga.ted and the liver was cut away as far as possible, the result was practically a complete extirpation of the organ. Later investigations $ showed that in normal animals the ammonia contents of the blood of the portal vein may be three to four times as great as in arterial blood, but that after removal of the liver the ammonia in the general circulation increases to a point equal to that observed for the portal blood and produces symptoms of poisoning which may result fatally. It would seem, therefore, that the liver protects the body from the poisonous action of the ammonia compounds by converting them to urea. Now in the normal digestive hydrolysis *Schroeder, "Archiv f. exp. Pathol, u. Pharmakol.," vols. xv. and xix., 1882, 1885. f See "Archiv f. exp. Pathol, u. Pharmakol.," 1893, xxxii., 161. j See Nencki and Pawlow, "Archives des sciences biologiques, ,T v. , 213. 832 PHYSIOLOGY OF DIGESTION AND SECRETION. of proteins brought about by the successive action of pepsin, tryp- sin, and erepsin the evidence at present indicates that the protein material is split largely or entirely into its constituent elements and its nitrogen appears mainly in three forms — as ammonia, as monamino-acids, and as diamino-bodies. The ammonia produced is probably carried to the liver and there converted to urea. In what form the ammonia exists in the blood is not positively known: it may be present as a carbonate or possibly, as some observers have thought, as a carbamate. Ammonium carbamate might be changed to urea according to the following reaction : co<0nh:-^° = co N — C — W hydrogen compound of this nucleus would be designated as purin, * Folin, "American Journal of Physiology," 13, 117, 1905. 53 834 PHYSIOLOGY OF DIGESTION AND SECRETION. N = CH and would have the formula: HC C— NH , C5H4N4. Addi- II ii v„ N — C — N^CH tion of an atom of oxygen gives hypoxanthin, C5H4N40: HN — CO HC C — NH ]l II N^>CH. Addition of two atoms of oxygen gives xan- HN — CO thin, C5H4N402: CO C — NH jj'j^ k N^CH. And addition of three atoms HN — CO of oxvgen gives uric acid, G.H.N.CL: CO C — NH , which HN — C — NH from this standpoint might be named trioxypurin. If one of the H atoms in the purin is substituted by an amino-group, NH2, the com- pound, adenin (C5H5N5), is obtained, and the substitution of an NH2 group in hypoxanthin gives the compound guanin (C5H5N50). Moreover, caffein, the active principle of coffee and tea, and theo- bromin, the active principle of cocoa, are respectively trimethyl and dimethyl compounds of xanthin. We have to distinguish, therefore, three classes of purin compounds, namely, the oxypurins, comprising monoxypurin or hypoxanthin, dioxypurin or xanthin, and trioxypurin or uric acid; the aminopurins, comprising adenin or aminopurin and guanin or aminohypoxanthin, and the methi/I- purins, comprising caffein or trimethyl xanthin (CgH10N4O2 orC.H- (CH3)3N402) and theobromin or dimethyl xanthin (C.HsN402 or C.H2(CH3)2N402). Uric acid, xanthin, and hypoxanthin are found constantly in the urine and in the feces small amounts of xanthin, hypoxanthin, adenin, and guanin may also occur. It has been pointed out * that these substances come partly from purin bodies taken as food. If materials containing the purin bodies, such as meat, are fed, these bodies are excreted in part in the urine. It is proposed to designate the uric acid, etc., that has this origin as the exogenous purin material. A portion of the amount daily secreted comes, however, from a metabolism of the protein material of the body, and this portion may be distinguished as the endogenous purin bodies. This latter amount is found to be practically constant. 0.15 to 0.20 gm. per day for any one individual, and the amount is not affected by changes in the quantity or character of the food, but varies within certain limits with the manner of life. Evidently * See Burian and Schur, "Archiv f. die gesammte Physiologie, " 94, 273, 1903. KIDNEY AXD SKIX AS EXCRETORY ORGAXS. 835 the endogenous purin nitrogen represents a special metabolism, propably of the living tissues, that goes on independently, in great measure, of the mere oxidation of food. According to Siven, the production during sleep is much less than during the waking hours. Since the purin bodies may be obtained readily by hydrolytic cleavage of the nuclein or nucleic acid constituent of the nucleoproteins, and since nucleoprotein material or nucleins when fed to animals cause an increase in the amount of purin nitrogen eliminated in the urine, it is most probable that in the body these purin bases represent the end-products of the metabolism of nuclein material. The intermediate processes in this metabolism, whether it affects the nuclein taken as food or the nuclein contained within the tissues of the body, are supposed to take place according to the following general schema: The nucleins that are split off from the nucleoprotein are acted upon first by an enzyme belonging to the group of nucleases, which have been demonstrated to exist in various tissues, e. g., in the spleen, liver, lungs, and kidneys. By the action of this enzyme the nuclein is split, with the formation of adenin and guanin. The adenin and guanin are then deamidized and converted respectively to hypoxanthin and xanthin. Jones * has given reasons to believe that two specific deamidizing enzymes of this character may exist in the body, namely, adenase and guanase. Their action may be represented by the following equations : CsHsXs - H20 = C5H4X40 + NH3 Adenin. Hypoxanthin. CsHjNsO - H20 = C5H4X402 - XH, Guanin. Xanthin. The hypoxanthin and xanthin thus formed f are in turn oxidized to uric acid by the action of an oxidase to which the specific name of xanthinoxidase has been given. Its action upon the hypoxanthin or xanthin is represented by the series: C5H4X40 - O = C5HtX402 Hypoxanthin. Xanthin. C5H4X402 - O = C5H4X403 Xanthin. Uric acid. Finally, as stated above, it can be shown that a portion of the uric acid may be further metabolized by the action of a specific urico- lytic enzyme and give rise to urea. The portion of the uric acid under- going this last change varies in different animals, as may be clemon- * Jones and Austrian, "Zeitschrift f. physiol. Chem.," 1906, xlviii., 110; see also Jones, "Journal of Biological Chemistry," 9, 169, 1911. t The same author has shown that xanthin and hypoxanthin may be produced from the nucleic acid by a somewhat different process. Phosphoric acid is first split off from the nucleic acid, leaving guanosine or adenosine, which are then diamidized, each by a specific enzyme (guanosinase, adeno- sinase), with the production of xanthosin or inosin. These latter are then hydrolyzed to xanthin and hypoxanthin. 836 PHYSIOLOGY OF DIGESTION AND SECRETION. strated by giving definite amounts of uric acid in the food. Ex- periments of this kind have shown that in man about one-half of the uric acid formed gives rise to urea, while in dogs and cats only about 07 suffers this change. In rabbits the proportion is £. According to a former view (Horbaczewsky) it was supposed that the endogenous purin nitrogen represents an end-product of the metabolism of the nuclein found in the nuclei of cells, especially in the nuclei of the leucocytes. But Burian has shown, on the contrary, that most of this nitrogen in the excreta arises from a metabolism in the muscular tissues* Increased muscular activity is followed within an hour or two by an increased output of uric acid, and when an isolated muscle is perfused with a mixture of defibrinated blood and Ringer's solution, uric acid is given off to the circulating liquid. When the muscle under these last-mentioned conditions is made to work a distinct increase in the hypoxanthin and uric acid can be determined. It would seem, therefore, that under normal conditions the uric acid and other purin bases are derived mainly from a metabolism of the muscular substance whereby hypoxanthin is produced. This substance is then oxidized to uric acid and a part of the uric acid is further changed to urea, f Origin and Significance of the Creatinin and Creatin. — Creatinin (C4H7N30) occurs in the urine, and it has been assumed that it is derived from the creatin (C4H9N30,) found in muscle. Its /NH — CO structural formula is given as NHC/ and its chemical re- XN(CH3)CH2 lations are indicated by the fact that it may be prepared synthetically from methvl-glvcocoll and cyanamid, — that is, the union of these two substances gives creatin, from which in turn creatinin may be obtained. NEC-NH, + NH(CH3)CH2COOH = NHC^^^^^ Cyanamid. Methyl-glycocoll. Creatin. Creatinin occurs in the urine constantly and in amounts equal to 1 to 2 gms. per day, or, according to Shaffer, J there is an excretion of from 7 to 11 mg. of creatinin nitrogen per kilogram of body- weight. Next to the urea and the ammonia compounds it forms the most important of the known nitrogenous constituent of the urine. Its physiological history is imperfectly known. Under constant conditions of life the amount of creatinin formed in the body is independent of the quantity of protein eaten, and this fact indicates (Folin) that it represents an end-product of the * Burian, "Zeitschrift f. physiol. ('hemic," xliii., p. .532. t For a review of the extensive literature, see Block, "Biochemisches Centralblatt," 1906, v., Nos. 12-14. X Consult Shaffer, "American Journal of Physiology," 33, 1, 1908. KIDNEY AND SKIN AS EXCRETORY ORGANS. 837 metabolism of living or organized protein tissue rather than one of the results of the metabolism of the food protein. This con- clusion is strengthened by the fact that in fevers and other patho- logical conditions in which there is an increased breaking down of tissues the creatinin excretion is increased.* As stated above, the usual view has been that the creatinin of the urine is derived from the creatin of the muscles, but the effort to demonstrate that this relationship actually exists has met with many difficulties. The older observers pointed out what seems to be an objection to this view, namely, the lack of relationship between the amount of creatin in the musculature of the body (about 90 gms.) and the small amount of creatinin (1 to 2 gms.) excreted daily. If the creatin is a nitrogenous waste constantly formed at this rate and excreted as creatinin, there ought to be a larger amount of the latter substance. To meet this difficulty it was suggested that some of the creatin may be converted to urea, but as a matter of fact the possibility of such a conversion in the body has not been demonstrated. Moreover, the conversion by the body of creatin into creatinin is not so simple a matter as was supposed. When creatinin is added to the diet it is excreted as creatinin. When creatin, on the contrary, is fed, there is no apparent increase in the creatinin of the urine. In fact, in the experiments reported the creatin nitrogen was not recovered in any form in the urine. The newer analyses seem also to show that normal muscular work causes no increase in the excretion of creatinin in the urine. Experimental work, in fact, upon the relationship, if any, and significance of the creatin and creatinin has got only so far as to show that the story is more complex and difficult than was formerly supposed. Normally, creatin exists in the muscular tissue of the vertebrate animals — not in that of the invertebrates. Creatinin, on the contrary, does not occur in detectable amounts in the blood or tissues of the body, but is a constant constituent of the urine. Creatin is not present normally in the urine, but under conditions which involve a destruction of the organized body-proteins, for example, in fevers, starvation, in women after delivery, during the period of involution of the uterus, etc., it may be secreted by the kidney in distinct amounts. Several investigators have assumed that the liver is concerned in the history of these two substances, but the part played by this organ is interpreted differently by those working at the subject; and it seems abso- lutely necessary at present to suspend judgment in regard to the connection and significance of these two substances until inves- tigations have reached more satisfactory results, f * Hoogenhuyze and Verploegh, "Zeitschrift f. physiol. Chemie," 57, 161, 1908. f For a recent review and the literature, consult Mendel, " Science," April 9, 1909. 838 PHYSIOLOGY OF DIGESTION AND SECRETION. Hippuric Acid. — This substance has the formula (^HoNO;,. Its molecular structure is known, since upon decomposition it yields benzoic acid and glycocoll, and, moreover, it may be produced syn- thetically by the union of these two substances. Hippuric acid may be described, therefore, as a benzoyl-amino-acetic acid (CH2- NH[C6H5CO]COOH). It is found in considerable quantities in the urine of herbivorous animals (1.5 to 2.5 per cent.), and in much smaller amounts in the urine of man and of the carnivora. In human urine, on an average diet, about 0.7 gm. are excreted in twenty-four hours. If the diet is largely vegetable, this amount may be much increased. This last fact is readily explained, for it has been found that if benzoic acid or substances containing this grouping are fed to animals they appear in the urine as hippuric acid. Evi- dently a synthesis occurs in the body, and Bunge and Schmie- deberg proved conclusively that in dogs the union of benzoic acid and glycocoll to form hippuric acid takes place in the kidney itself. Later it was discovered* that the same synthesis may be effected by ground-up kidney tissue, mixed with blood and kept under oxygen pressure. It seems possible, therefore, that the synthesis is due to some specific constituent of the kidney cells, possibly an enzyme. Vegetable foods contain benzoic acid com- pounds, and we can understand, therefore, why when fed they in- crease the hippuric acid output of the urine. Since, however, in starving animals or animals fed upon meat hippuric acid is still present in the urine, although reduced in amount, it is evident that it arises in part as a result of the body metabolism. It should be added finally that some of the hippuric acid may be derived from the process of protein putrefaction that occurs in the large intestine. The Conjugated Sulphates and the Sulphur Excretion. — The sulphur excretion of the urine possesses an importance similar to that of nitrogen. Sulphur constitutes an element in most of the proteins, and in some form, therefore, it will be represented in the end-products of protein metabolism. The sulphur elimination in the urine, like the nitrogen elimination, has been taken as a measure of the amount of protein destruction. In the urine the sulphur occurs in three forms: (1) In an oxidized form as inorganic sul- phates. Some of the sulphates are undoubtedly derived or may be derived from the mineral sulphates ingested with the food, but the larger part arises from the oxidation of the sulphur of the proteins. (2) The so-called conjugated or ethereal sulphates are combinations between sulphuric acid and indoxyl, skatoxyl, phenol, and cresol, giving us phenolsulphuric acid (CHH-OSO,OH), cresolsulphuric acid (C.H7OSO,OH), indoxylsulphuric acid or indican (C8H6NOS02OH), and skatoxylsulphuric acid (C9H8NOS02OH). The indol, skatol, phenol, and cresol are formed in the large intestine as a result of bac- * Bashford and Cramer, " Zeitschrift f. physiol. Chemie," 35, 324, 1902. KIDNEY AND SKIN AS EXCRETORY ORGANS. 839 terial putrefaction. They are eliminated in part in the feces, but in part are absorbed into the blood, and after oxidation are conjugated with sulphuric acid and eliminated in the urine. The process of conjugation is valuable from a physiological standpoint, as it converts substances having an injurious action into harmless compounds. It should be added, also, that to a small extent the phenol, indoxyl, and skatoxyl may be secreted in the urine as con- jugated glucuronates, — that is, in combination with glycuronic acid (G6H10O7), a reducing substance closely connected with dextrose. From a nutritional standpoint the amount of these substances pres- ent furnishes a measure of the extent of protein putrefaction in the intestine, by virtue of the indol and phenol constituents. All con- ditions that increase the putrefactive processes in the intestine are accompanied by a parallel increase in the ethereal sulphates. By virtue of the sulphuric acid component these bodies represent also one of the forms in which sulpnur is excreted from the body. (3) Some of the sulphur in the mine may occur in unoxid- ized form as sulphocyanid or as ethyl-sulphide (Abel) ([C2H5]2S). Under certain pathological conditions (cystinuria) some sulphur may be excreted in the form of cystin, but this is not a normal con- stituent of the urine. For other most interesting and significant changes in the composition of the urine under pathological condi- tions reference must be made to special works upon the urine or upon pathological chemistry. Water and Inorganic Salts. — Water is lost from the body through three main channels, — namely, the lungs, the skin, and the kidney, the last of these being the most important. The quan- tity of water lost through the lungs probably varies within small limits only. The quantity lost through the sweat varies, of course, with the temperature, with exercise, etc., and it may be said that the amoimts of water secreted through kidney and skin stand in something of an inverse proportion to each other; that is, the greater the quantity lost through the skin, the less will be secreted by the kidneys. Through these three organs, but mainly through the kidneys, the blood is being continually depleted of water, and the loss must be made up by the ingestion of new water. When water is swallowed in excess the superfluous amount is rapidly eliminated through the kidneys. The amount of water secreted may be in- creased by the action of diuretics, such as potassium nitrate and caffein. The inorganic salts of urine consist chiefly of the chlorids, phos- phates, and sulphates of the alkalies and the alkaline earths. It may be said, in general, that they arise partly from the salts ingested with the food, and are eliminated from the blood by the kidney in the water secretion ; and in part they are formed in the destruc- tive metabolism that takes place in the body, particularly that 840 PHYSIOLOGY OF DIGESTION AND SECRETION. involving the proteins and related bodies. Sodium chlorid occurs in the largest quantities, averaging about 15 gms. per day, of which the larger part, doubtless, is derived directly from the salt taken in the food. The phosphates occur in combination with cal- cium and magnesium, but chiefly as the acid phosphates of sodium or potassium. The acid reaction of the urine is usually attributed to these latter substances. The phosphates result in part from the destruction of phosphorus-containing tissues in the body, but chiefly from the phosphates of the food. The sulphates of urine are found partly in an oxidized form as simple sulphates or con- jugated with organic compounds, as described above. Micturition. — The urine is secreted continuously by the kid- neys, is carried to the bladder through the ureters, and is then at intervals finally ejected from the bladder through the urethra by the act of micturition. Movements of the Ureters. — The ureters possess a muscular coat consisting of an internal longitudinal and external circular layer. The contractions of this muscular coat form the means by which the urine is driven from the pelvis of the kidney into the bladder. The movements of the ureter have been carefully studied by Engel- mann* According to his description, the musculature of the ureter contracts spontaneously at intervals of ten to twenty seconds (rab- bit), the contraction beginning at the kidney and progressing toward the bladder in the form of a peristaltic wave and with a velocity of about 20 to 30 mms. per second. The result of this movement should be the forcing of the urine into the bladder in a series of gentle, rhythmical spurts, and this method of filling the bladder has been observed in the human being. Suter and Mayerf report some observations upon a boy in whom there was ectopia of the bladder, with exposure of the orifices of the ureters. The flow into the bladder was intermittent and was about equal upon the two sides for the time the child was under observation (three and a half days). The causation of the contractions of the ureter musculature is not easily explained. Engelmann finds that artificial stimulation of the ureter or of a piece of the ureter may start peristaltic con- tractions which move in both directions from the point stimulated. He was not able to find ganglion cells in the upper two-thirds of the ureter and was led to believe, therefore, that the contraction orig- inates in the muscular tissue independently of extrinsic or intrinsic nerves, and that the contraction wave propagates itself directly from muscle cell to muscle cell, the entire musculature behaving * "Pfliiger's Archiv f. die gesammte Physiologie, " 2, 243, 1869, and 4, 33; see also Lucas, "American Journal of Physiology," 17, 392, 1906. f " Archiv f. exper. Pathologie und Pharmakologie," 32, 241, 1893. KIDNEY AND SKIX AS EXCRETORY ORGANS. 841 as though it were a single, colossal, hollow muscle fiber. The liber- ation of the stimulus which inaugurates the normal peristalsis of the ureter seems to be connected with the accumulation of urine in its upper or kidney portion. It may be supposed that the urine that collects at this point as it flows from the kidney stimulates the muscular tissue to contraction, either by its pressure or in some other way, and thus leads to an orderly sequence of contraction waves. It is possible, however, that the muscle of the ureter, like that of the heart, is spontaneously contractile under normal conditions, and does not depend upon the stimulation of the urine. Thus, according to Engelmann, section of the ureter near the kidney does not materially affect the nature of the contractions of the stump attached to the kidney, although in this case the pressure of the urine could scarcely act as a stimulus. Moreover, in the case of the rat, in which the ureter is highly contractile, the tube may be cut into several pieces and each piece will continue to exhibit period- ical peristaltic contractions. It does not seem possible at present to decide between these two views as to the cause of the contrac- tions. The nature of the contractions, their mode of progression, and the way in which they force the urine through the ureter seem, however, to be clearly established. Efforts to show a regulator}' action upon these movements through the central nervous system have so far given negative results. Movements of the Bladder. — The bladder contains a muscular coat of plain muscle tissue, which, according to the usual description, is arranged so as to make an external longitudinal coat and an internal circular or oblique coat. A thin, longitudinal layer of muscle tissue lying to the interior of the circular coat is also de- scribed. The separation between the longitudinal and circular layers is not so definite as in the case of the intestine; they seem, in fact, to form a continuous layer, one passing gradually into the other by a change in the direction of the fibers. At the cervix the circular layer is strengthened, and has been supposed to act as a sphincter with regard to the urethral orifice — the so-called sphinc- ter vesicae internus. Around the urethra just outside the blad- der is a circular layer of striated muscle that is frequent ly desig- nated as the external sphincter or sphincter urethras. The urine brought into the bladder accumulates within its cavity to a certain limit. It is prevented from escaping through the urethra at first by the mere elasticity of the parts at the urethral orifice, aided per- haps by tonic contraction of the internal sphincter, although this function of the circular layer is disputed by some observers. When the accumulation becomes greater the external sphincter is brought into action. If the desire to urinate is strong the external sphincter seems undoubtedly to be controlled by voluntary effort, but whether 842 PHYSIOLOGY OF DIGESTION AND SECRETION. or not, in moderate rilling of the bladder, it is brought into play by an involuntary reflex is not definitely determined. Backflow of urine from the bladder into the ureters is effectually prevented by the oblique course of the ureters through the wall of the blad- der. Owing to this circumstance, pressure within the bladder serves to close the mouths of the ureters, and, indeed, the more completely, the higher the pressure. At some point in the filling of the bladder the pressure is sufficient to arouse a conscious sen- sation of fullness and a desire to micturate. Under normal condi- tions the act of micturition follows. It consists essentially in a strong contraction of the bladder, with a simultaneous relaxation of the external sphincter, if this muscle is in action, the effect of which is to obliterate more or less completely the cavity of the blad- der and drive the urine out through the urethra. The force of this contraction is considerable, as is evidenced by the height to which the urine may spurt from the end of the urethra. According to Mosso, the contraction may support, in the dog, a column of liquid two meters high. The contractions of the blad- der may be and usually are assisted by contractions of the walls of the abdomen, especially toward the end of the act. As in defeca- tion and vomiting, the contraction of the abdominal muscles, when the glottis is closed so as to keep the diaphragm fixed, serves to in- crease the pressure in the abdominal and pelvic cavities, and thus assists in or completes the emptying of the bladder. It is, however, not an essential part of the act of micturition. The last portions of the urine escaping into the urethra are ejected, in the male, in spurts produced by the rhythmical contractions of the bulbocavernosus muscle. Considerable uncertainty and difference of opinion exists as to the physiological mechanism by which this series of muscular con- tractions, and especially the contractions of the bladder itself, are produced. According to the frequently quoted description given by Goltz,* the series of events is as follows: The distention of the bladder by the urine causes finally a stimulation of the sensory fibers of the organ and produces a reflex contraction of the blad- der musculature which squeezes some urine into the urethra. The first drops, however, that enter the urethra stimulate the sensory nerves there and give rise to a conscious desire to urinate. If no obstacle is presented the bladder then empties itself, assisted per- haps by the contractions of the abdominal muscles. The emptying of the bladder may, however, be prevented, if desirable, by a volun- tary contraction of the sphincter urethra?, which opposes the effect of the contraction of the bladder. If the bladder is not too full and the sphincter is kept in action for some time, the contractions * "Archiv f. die gesammte Physiologie, " 8, 478, 1874. KIDNEY AND SKIN AS EXCRETORY ORGANS. 843 of the bladder may cease and the desire to micturate pass off. Ac- cording to this view, the voluntary control of the process is limited to the action of the external sphincter and the abdominal muscles; the contraction of the bladder itself is purely an unconscious reflex taking place through a lumbar center. The experiments of Goltz and others, upon dogs in which the spinal cord was severed at the junction of the lumbar and the tho- racic regions, indicate that micturition is essentially a reflex act, with its center in the lumbar cord, although the same observer has shown that in dogs whose spinal cord has been entirely destroyed, except in the cervical and upper thoracic region, the bladder emp- ties itself normally without the aid of external stimulation. Mosso and Pellacani* have made experiments upon women in which a catheter was introduced into the bladder and connected with a record- ing apparatus to measure the volume of the bladder. Their ex- periments indicate that the sensation of fullness and desire to micturate come from sensory stimulation, in the bladder itself, caused by the pressure of the urine. They point out that the bladder is very sensitive to reflex stimulation; that every psychical act and every sensory stimulus is apt to cause a contraction or in- creased tone of the bladder. The bladder is therefore subject to continual changes in size from reflex stimulation, and the pressure within it will depend not simply on the quantity of urine, but on the condition of tone of its muscles. At a certain pressure the sensory nerves are stimulated and under normal conditions mictu- rition ensues. We may understand, from this point of view, how it happens that we have sometimes a strong desire to micturate when the bladder contains but little urine, — for example, under emotional excitement. In such cases if the micturition is prevented, probably by the action of the external sphincter, the bladder may sub- sequently relax and the sensation of fullness and desire to micturate pass away until the urine accumulates in sufficient quantity, or the pressure is again raised by some circumstance which causes a reflex contraction of the bladder. Nervous Mechanism. — According to Langley and Anderson, f the bladder in cats, dogs, and rabbits receives motor fibers from two sources: (1) From the lumbar nerves, the fibers passing out in the second to the fifth lumbar nerves and reaching the bladder through the sympathetic chain and the inferior mesenteric ganglion and the hypogastric nerves and plexus (Fig. 287). Stimulation of these nerves causes a comparatively feeble contraction of the blad- der. (2) From the sacral spinal nerves, the fibers originating in the second and third sacral spinal nerves, or in the rabbit in * "Archives italiennes de biologie," 1, 1882. t " Journal of Physiology, " 19, 71, 1895. 844 PHYSIOLOGY OF DIGESTION AND SECRETION. the third and fourth, and taking their course through the so-called nervi erigentes and the hypogastric plexus. Stimulation of these nerves, or some of them, causes strong contractions of the blad- der, sufficient to empty its contents. Little evidence was obtained of the presence of vasomotor fibers. According to Nawrocki and Skabitschewsky,* the spinal sensory fibers to the bladder are found in part in the posterior roots of the first, second, third, and fourth sacral spinal nerves, particularly the second and third. When these fibers are stimulated they excite reflexly the motor fibers to the bladder found in the anterior roots of the second and third sacral spinal nerves. Some sensory fibers to the bladder may pass by way of the hypogastric nerves. When the central stump of one hypogastric nerve is stimulated it produces, according to these authors, a reflex effect upon the motor fibers in the other hypo- gastric nerve, causing a contraction of the bladder, the reflex oc- curring through the inferior mesenteric ganglion. This observa- tion has been confirmed by several authorities, but has been ex- plained by Langley and Anderson as a pseudoreflex or axon reflex (see p. 152). According to Elliott the innervation of the bladder varies in the different mammals. Speaking generally, the fibers passing by way of the nervi erigentes when stimulated cause contraction of the bladder (and inhibition of the sphincter). These fibers, therefore, are mainly concerned in the act of micturi- tion. The fibers supplied through the hypogastric nerve, on the contrary, cause mainly relaxation of the bladder musculature, and their stimulation, by inhibiting the tonus of the musculature, would seem to provide a means for holding the urine. The immediate spinal center through which the contractions of the bladder may be reflexly stimulated or inhibited lies, accord- ing to the experiments of Goltz, in the lumbar portion of the cord, probably between the second and fifth lumbar spinal nerves. In dogs in which this portion of the cord was isolated by a cross- section at the junction of the thoracic and lumbar regions, mic- turition still ensued when the bladder was sufficiently full, and it could be called forth reflexly by sensory stimuli, especially by slight irritation of the anal region. This localization has been confirmed by others J but Elliot states that the sacral portion of the cord, which gives rise to the fibers of the nervi erigentes, may also serve as a reflex center for the bladder. Excretory Functions of the Skin. — The physiological activi- ties of the skin are varied. It forms, in the first place, a sensory surface covering the body, and interposed, as it were, between the * "Archiv f. die gesammte Physiologie, " 49, 141, 1891. t Klliot, "Journal of Physiology," 35, 367, 1907. % See Stewart, "American Journal of Physiology," 2, 182, 1899. KIDXEY AND SKIX AS EXCRETORY ORGANS. 845 external world and the inner mechanism. Xerve fibers of pressure, temperature, and pain are distributed over its surface, and by means of these fibers reflexes of various kinds are effected which keep the body adapted to changes in its environment. The physiology of the skin from this standpoint is discussed in the section on special senses. Again, the skin plays a part of immense value to the body in regulating the body temperature. This regulation, which is effected by variations in the blood supply or the sweat secretion, is described at appropriate places in the sections on Nutrition and Circulation. In the female, during the period of lactation, the mam- mary glands, which must be reckoned among the organs of the skin, form an important secretion, the milk; the physiology of this gland is referred to in the section on Reproduction. In this section we are concerned with the physiology- of the skin from a different standpoint, — namely, as an excretory organ. The excretions of the skin are formed in the sweat-glands and the sebaceous glands. Sweat. — The sweat or perspiration is a secretion of the sweat glands. These latter structures are found over the entire cutaneous surface except in the deeper portions of the external auditory meatus, the prepuce, and the glans penis. They are particularly abundant upon the palms of the hands and the soles of the feet. Krause estimates that their total number for the whole cutaneous surface is about two millions. In man they are formed on the type of simple tubular glands; the terminal portion contains the secretory cells, and at this part the tube is usually coiled to make a more or less compact knot, thus increasing the extent of the secreting sur- face. The larger ducts have a thin, muscular coat of involuntary tissue that may possibly be concerned in the ejection of the secre- tion. The secretory cells in the terminal portion are columnar in shape, possess a granular cytoplasm, and are arranged in a single layer. The amount of secretion formed by these glands varies greatly, being influenced by the condition of the atmosphere as re- gards temperature and moisture, as well as by various physical and psychical states, such as exercise and emotions. The average quan- tity for twenty-four hours is said to vary between 700 and 900 gms., although this amount may be doubled under certain conditions. According to an interesting paper by Schierbeck,* the average quantity of sweat in twenty-four hours may amount to 2 to 3 liters in a person clothed, and therefore with an average temperature of 32° C. surrounding the skin. This author states that the amount of sweat given off from the skin in the form of insensible perspira- tion increases proportionately with the temperature until a certain critical point is reached (about 33° C. in the person investigated), * "Archiv f. Physiologie, " 1893, 116; see also Willebrand, "Skandi- navisches Archiv f. Physiologie," 13, 337, 1902. 846 PHYSIOLOGY OF DIGESTION AND SECRETION. when there is a marked increase in the water eliminated, the in- crease being simultaneous with the formation of visible sweat. At the same time there is a sudden increase in the C02 eliminated from the skin. It is possible that the sudden increase in C02 is an in- dication of greater metabolism in the sweat glands in connection with the formation of visible sweat. Composition of the Secretion. — The precise chemical composition of sweat is difficult to determine, owing to the fact that as usually obtained it is liable to be mixed with the sebaceous secretion. Nor- mally it is a very thin secretion of low specific gravity (1.004) and an alkaline reaction, although when first secreted the reaction may be acid owing to admixture with the sebaceous material. The larger part of the inorganic salts consists of sodium chlorid. Small quantities of the alkaline sulphates and phosphates are also pres- ent. The organic constituents, though present in mere traces, are quite varied in number. Urea, uric acid, creatinin, aromatic oxy- acids, ethereal sulphates of phenol and skatol, serin (oxyaminopro- pionic acid), and albumin, are said to occur when the sweating is profuse. Argutinsky has shown that after the action of vapor baths, and as the result of muscular work, the amount of urea eliminated in this secretion may be considerable. Under patho- logical conditions involving a diminished elimination of urea through the kidneys it has been observed that the amount found in the sweat is markedly increased, so that crystals of it may be deposited upon the skin. Under perfectly normal conditions, however, it is obvious that the organic constituents are of minor importance. The main fact to be considered in the secretion of sweat is the form- ation of water. Secretory Fibers to the Sweat Glands. — Definite experimental proof of the existence of sweat nerves was first obtained by Goltz * in some experiments upon stimulation of the sciatic nerve in cats. In the cat and dog, in which sweat glands occur on the balls of the feet, the presence of sweat nerves may be demonstrated with great ease. Electrical stimulation of the peripheral end of the divided sciatic nerve, if sufficiently strong, will cause visible drops of sweat to form on the hairless skin of the balls of the feet. When the electrodes are kept at the same spot on the nerve and the stimula- tion is maintained the secretion soon ceases; but this effect seems to be due to a temporary injury of some kind to the nerve fibers at the point of stimulation, and not to a genuine fatigue of the sweat glands or the sweat fibers, since moving the electrodes to a new point on the nerve farther toward the periphery calls forth a new secretion. The secretion so formed is thin and limpid, and has a marked alkaline reaction. The anatomical course of these fibers * "Archiv f. die gesammte Physiologic*," 11, 71, 1875. KIDNEY AND SKIN AS EXCRETORY ORGANS. 847 has been worked out in the cat with great care by Langley.* He finds that for the hind feet they leave the spinal cord chiefly in the first and second lumbar nerves, enter the sympathetic chain, and emerge from this as postganglionic fibers in the gray rami which pass from the sixth lumbar to the second sacral ganglion, but chiefly in the seventh lumbar and first sacral, and then join the nerves of the sciatic plexus. For the forefeet the fibers leave the spinal cord in the fourth to the tenth thoracic nerves, enter the sympathetic chain, pass upward to the first thoracic ganglion, whence they are continued as postganglionic fibers that pass out of this ganglion by the gray rami communicating with the nerves forming the brachial plexus. The action of the nerve fibers upon the sweat glands can not be explained as an indirect effect, — for instance, as a result of a variation in the blood-flow. Experiments have repeatedly shown that, in the cat, stimulation of the sciatic still calls forth a secre- tion after the blood has been shut off from the leg by ligation of the aorta, or indeed after the leg has been amputated for as long as twenty minutes. So in human beings it is known that profuse sweating may often accompany a pallid skin, as in terror or nausea, while, on the other hand, the flushed skin of fever is char- acterized by the absence of perspiration. There seems to be no doubt that the sweat nerves are genuine secretory fibers, causing a secretion in consequence of a direct action on the cells of the sweat glands. In accordance with this physiological fact histological work has demonstrated that special nerve fibers are supplied to the glandular epithelium. According to Arnstein, the terminal fibers form a small, branching, varicose ending in contact with the epithelial cells. The sweat gland may be made to secrete in many ways other than by direct artificial excitation of the sweat fibers, — for example, by external heat, dj^spnea, muscular exercise, strong emotions, and by the action of various drugs, such as pilocarpin, muscarin, strychnin, nicotin, picrotoxin, and physostigmin. In all such cases the effect is supposed to result from an action on the sweat fibers, either directly on their terminations or indirectly upon their cells of origin in the central nervous system. In ordinary life the usual cause of profuse sweating is a high external temper- ature or muscular exercise. With regard to the former it is known that the high temperature does not excite the sweat glands im- mediately, but through the intervention of the central nervous system. If the nerves going to a limb be cut, exposure of that limb to a high temperature does not cause a secretion, showing that the temperature change alone is not sufficient to excite the gland or its terminal nerve fibers. We must suppose, therefore, that the high temperature acts upon the sensory cutaneous nerves, * "Journal of Physiology," 12, 347, 1891. 848 PHYSIOLOGY OF DIGESTION AND SECRETION. possibly the heat fibers, and reflexly stimulates the sweat fibers. Although external temperature does not directly excite the glands, it should be stated that it affects their irritability either by direct action on the gland cells or upon the terminal nerve fibers. At a sufficiently low temperature the cat's paw does not secrete at all, and the irritability of the glands is increased by a rise of temper- ature up to about 45° C. Dyspnea, muscular exercise, emotions, and many drugs affect the secretion, probably by action on the nerve centers. Pilocarpin, on the contrary, is supposed to stimulate the endings of the nerve- fibers in the glands, while atropin has the opposite effect, com- pletely paralyzing the secretory fibers. Sweat Centers in the Central Nervous System. — The fact that secretion of sweat may be occasioned by stimulation of afferent nerves or by direct action upon the central nervous system, as in the case of dyspnea, implies the existence of physiological centers controlling the secretory fibers. The precise location of the sweat center or centers has not, however, been satisfactorily determined. Histologically and anatomically the arrangement of the sweat fibers resembles that of the vasoconstrictor fibers, and, reasoning from analogy, one might suppose the existence of a general sweat center in the medulla comparable to the vasoconstrictor center, but positive evidence of the existence of such an arrangement is lacking. It has been shown that when the medulla is separated from the cord by a section in the cervical or thoracic region the action of dyspnea, or of various sudorific drugs supposed to act on the central nervous system, may still cause a secretion. On the evidence of results of this character it is assumed that there are spinal sweat centers; but whether these are few in number or represent simply the various nuclei of origin of the fibers to different regions is not definitely known. It is possible that in addition to these spinal centers there is a general regulating center in the medulla. Sebaceous Secretion. — The sebaceous glands are simple or compound alveolar glands found over the cutaneous surface, usually in association with the hairs, although in some cases they occur separately, as, for instance, on the prepuce and glans penis, and on the lips. When they occur with the hairs the short duct opens into the hair follicle, so that the secretion is passed out upon the hair near the point at which it projects from the skin. The alveoli are filled with cuboidal or polygonal epithelial cells, which are arranged in several layers. Those nearest the lumen of the gland are filled with fatty material. These cells are supposed to be cast off bodily, their detritus going to form the secretion. New cells are formed from the layer nearest the basement membrane, and thus the glands cont inue to produce a slow but continuous secretion. The sebaceous KIDNEY AND SKIN AS EXCRETORY ORGANS. 849 secretion, or sebum, is an oily, semiliquid material that sets, upon exposure to the air, to a cheesy mass, as is seen in the comedones or pimples which so frequently occur upon the skin from occlusion of the opening of the ducts. The exact composition of the secretion is not known. It contains fats and soaps, some cholesterin, albu- minous material (part of which is a nucleo-albumin often described as a casein), remnants of epithelial cells, and inorganic salts. The cholesterin occurs in combination with a fatty acid, and is found in especially large quantities in sheep's wool, from which it is extracted and used commercially under the name of lanolin. The sebaceous secretion from different places, or in different animals, is probably somewhat variable in composition as well as in quantity. The secretion of the prepuce is known as the smegma prceputii; that of the external auditory meatus, mixed with the secretion of the neigh- boring sweat glands or ceruminous glands, forms the well-known earwax or cerumen. The secretion in this place contains a reddish pigment of a bitterish-sweet taste, the composition of which has not been investigated. Upon the skin of the newly born the se- baceous material is accumulated to form the vernix caseosa. The well-known uropygal gland of birds is homologous with the mam- malian sebaceous glands, and its secretion has been obtained in sufficient quantities for chemical analysis. Physiologically it is believed that the sebaceous secretion affords a protection to the skin and hairs. Its oily character doubtless serves to protect the hairs from becoming too brittle, or, on the other hand, from being too easily saturated with external moisture. In this way it prob- ably aids in making the hairy coat a more perfect protection against the effect of external changes of temperature. Upon the surface of the skin, also, it forms a thin, protective layer that tends to prevent undue loss of heat from evaporation of the sweat and possibly is important in other ways in maintaining the physiological integrity of the external surface. Excretion of C02. — In some of the lower animals — the frog, for example — the skin takes an important part in the respirator}' exchanges, eliminating C02 and absorbing 0. In man, and pre- sumably in the mammalia generally, it has been ascertained that changes of this kind are very slight. Estimates of the amount of CO 2 given off from the skin of man during twenty-four hours vary greatly, but the amount is small, about 7 to 8 gms. in twenty-four hours, unless there is marked sweating, in which case the amount is noticeably increased. 54 CHAPTER XLVI. SECRETION OF THE DUCTLESS GLANDS-INTERNAL SECRETION. The term "internal secretion" is used to designate those secre- tions of glandular tissues which, instead of being carried off to the exterior by a duct, are eliminated in the blood or lymph. The idea that secretory products may be given off in this way has long been held in reference to the ductless glands, such as the thyroid, pitui- tary body, etc., the absence of a duct suggesting naturally such a possibility. The term, however, seems to have been employed first by Claude Bernard, who emphasized the distinction between the ordinary secretions, or external secretions, and this group of internal secretions. Modern interest in the latter is due largely to work done by Brown-Sequard (1889) upon testicular extracts, work which itself was of doubtful value. This author was led to amplify the conception of an internal secretion by the assumption that all tissues give off a something to the blood which is characteristic, and is of importance in general nutrition. This idea led in turn to a revival of some old notions regarding the treatment of diseases of the different organs by extracts of the corresponding tissue, a therapeutical method usually designated as opotherapy. Brown- Sequard's extension of the idea of internal secretion has not been justified by subsequent work, and to-day we must limit the term to tissues that have a glandular structure. Experience has shown, however, that not only the ductless glands, but some at least of the typical glands provided with ducts may give rise to internal secre- tions, the pancreas, for example. In some of the ductless glands, on the contrary, the existence or non-existence of an internal secre- tion is still an open question. The work done since 1889 has, how- ever, demonstrated fully that some of the ductless glands play a role of the very greatest importance in general nutrition, and this knowledge has proved useful in widening our conception of the nutritional relations in the organism and besides has found a valuable application in practical medicine. The conception that certain glandular organs may give rise to chemical products which on entering the circulation influence the activity of one or more other organs has recently found a fruitful application in the study of the digestive secretions. The gastric and pancreatic secretins may 850 SECRETION OF THE DUCTLESS GLANDS. 851 be regarded as examples of internal secretions. Chemical products of this kind which stimulate the activity of special organs Starling designates as hormones* From this point of view the active substances formed in the thyroids, adrenal glands, etc., may all be classified as specific hormones. Starling suggests that this means of coordinating the activities of the various parts of a complex organism may be regarded as the most primitive, while the better-known coordination through the medium of a nervous system is of later development. In the mammalian body both methods, as we have seen, are employed. Liver. — We do not usually regard the liver as furnishing an internal secretion. As a matter of fact, it does form two products within its cells — glycogen (sugar) and urea — which are subsequently given off to the blood for purposes of general nutrition or for elim- ination. The processes in this case fall under the general defini- tion of internal secretion, and, in fact, may be used to illustrate specifically the meaning of this term. The history of glycogen and urea has been considered. Internal Secretion of the Thyroid Tissues. — The most im- portant and definite outcome of the work on internal secretions has been obtained with the thyroids. Recent experimental work on this organ makes it necessary for us now to distinguish between the thyroid and the parathyroid tissues. The thyroids proper form two oval bodies lying on the sides of the trachea at its junction with the larynx. They have no ducts, and are composed of vesicles of different sizes, which are lined by a single layer of cuboidal epithe- lium and contain in their interior a material known as colloid. A number of histologists have traced the formation of this colloid to the lining epithelial cells, and have stated, moreover, that the vesicles finally rupture and discharge the colloid into the surrounding lym- phatic spaces. Accessory thyroids varying in size and number rna}^ be found along the trachea as far down as the heart. They possess a vesicular structure and no doubt have a function similar to that of the thyroid body. The 'parathyroids are, according to most authors, quite different structures. Four of these bodies are usually described, two on each side, and their positions vary somewhat in different animals or, indeed, in different individuals. | In man the superior (or internal) parathyroids are found upon the posterior surface of the thyroid, at the level of the junction of its upper with its middle third. They may be imbedded in the thyroid tissue. The inferior (or external) parathyroids lie near the lower margin of the thyroid on its poster- * For general discussion, consult Starling, "Recent Advances in the Physiology of Digestion," Chicago, 1906. f Thompson, "Philosophical Transactions, Roy. Soc," London, B. 201, 91, 1910. 852 PHYSIOLOGY OF DIGESTION AND SECRETION. ior surface and in some cases lower down on the sides of the trachea. The tissue has a structure quite different from that of the thy- roids, being composed of solid masses or columns of epithelial cells which are not arranged in vesicles and contain no colloid. Extirpation of the Thyroids and Parathyroids.— In 1856 Schiff showed that extirpation of the thyroids (complete thyroi- dectomy) in dogs is followed usually by the death of the animal in one to four weeks. The animal exhibits certain characteristic symp- toms, such as muscular tremors, which may pass into convulsions, cachexia, emaciation, and a condition of apathy. This result was confirmed by subsequent observers, but many exceptions were noted. Great interest was shown in these results, because on the surgical side reports were made showing that after complete removal of the thyroids in cases of goiter evil consequences might ensue, either acute convulsive attacks or chronic malnutrition. On the other hand, it became known that atrophy of the thyroids in the young is responsible for the condition of arrested growth and deficient mental development designated as cretinism, and in the adult the same cause gives rise to the peculiar disease of myxedema, character- ized by distressing mental deterioration, an edematous condition of the skin, loss of hair, etc. Schiff and others found that the evil results of complete thyroidectomy in dogs might be obviated by grafting pieces of the thyroid in the body, and this knowledge was quickly applied to human beings in cases of myxedema and cretinism with astonishingly successful results. Instead of grafting thyroid tissue it was found, in fact, that injection of extracts under the skin or better still simple feeding of thyroid material gave similar favorable results: the individuals recovered their normal appear- ance and mental powers.* It is stated that in cases of myxedema the patient maybe kept in perfect health by the administration of as little as 60 to 130 mgm. every three or four days. Later Baumann succeeding in isolating from the glands a substance designated as iodothyrin, which shows in large measure the beneficial influence exerted by thyroid extracts in cases of myxedema and parenchy- matous goiter. This substance is characterized by containing a large amount of iodin (9.3 per cent, of the dry weight). It is contained in the gland in combination with protein bodies, from which it may be separated by digestion with gastric juice or by boiling with acids. The Function of the Parathyroids. — Most of the results des- * For a general account of the development of the subject and the liter- ature see "Transactions of the Congress of American Physicians and Sur- geons" (Howell, Chittenden, Adami, Putnam, Kinnicutt, Osier), 1X97; Jean- delize, " Insnffisance thyroidienne et parathyroidienne," Nancy, 1902; Vincent, "Internal Secretions," etc., Lancet, Aug. 11 and IS, 1906. Biedl, " Innere Sekretion," Berlin, 1910. | " Zeitschrift f physiolog. Chemie," 21, 319, and 4S1, 1896. SECRETION OF THE DUCTLESS GLANDS. 853 cribed above were obtained before the existence of the parathy- roids was recognized. Early in the history of the subject it was recognized that complete removal of the thyroids proper in herbiv- orous animals (rats, rabbits) is not attended by a fatal result. Gley and others, however, proved that if the parathyroids also are removed these animals die with the symptoms described in the case of dogs, cats, and other carnivorous animals. This result attracted attention to the parathyroids. Numerous experiments by Moussu, Gley, Vassale and Generale, and others have seemed to show a marked difference between the results of thyroi- dectomy and parathyroidectomy. When the parathyroids alone are removed the animal dies quickly with acute symptoms, muscular convulsions (tetany), etc.; when the thyroids alone are removed the animal may survive for a long period, but develops a condition of chronic malnutrition, — a slowly increasing cachexia which may exhibit itself in a condition resembling myxedema in man. This distinction has been generally accepted, and it throws much light upon the discrepancy in the results obtained by some of the earlier observers. Complete thyroidectomy with the acutely fatal results usually described includes those cases in which both thyroids and parathyroids were removed, *while probably many of the apparently negative results obtained after excision of the thyroids are expli- cable on the supposition that one or more of the parathyroids were left in the animal. It should be stated, however, that two recent observers, Vincent and Jolly, as the result of numerous experi- ments made upon different varieties of animals, throw some doubt upon these conclusions. They contend that in herbivorous animals fully half of those operated upon survive complete removal of all thyroid tissue, showing no evil symptoms except perhaps a di- minished resistance to infection. Carnivorous animals, on the con- trary, usually die after such an operation.* In spite of such con- tradictory results in the hands of some observers the general opinion prevails that complete removal of the parathyroids is followed by acutely toxic results which develop rapidly, and the most common symptom of which is muscular tetany. This tetany exhibits itself as fibrillar contractions of the muscles, a general muscular tremor, tonic and clonic spasms of the muscles or " intention spasms," that is, spasmodic or uncoordinated contractions follow- ing upon an effort to make a voluntary movement.! As is well known, similar symptoms are often observed under other condi- tions, infantile tetany, gastro-intestinal tetany, etc., and it has been suggested that in all such cases the initial difficulty may consist in the insufficiency of active parathyroid tissue. Several * See also Halpenny in "Surgery, Gynecology, and Obstetrics," May, 1910. t For literature and Summary, see Bing, "Zentralblatt f. d. Physiol, u. Pathol, d. Stoffwechsels," 1908, Xos. 1 and 2; also Biedl, loc. cit. 854 PHYSIOLOGY OF DIGESTION AND SECRETION'. observers have reported that injections of extract of the parathy- roids cause the tetany to disappear without, however, protecting the animal from a fatal outcome, but the most striking results have been obtained by Macallum and Voegtlin. * These observers find that injection or ingestion of solutions of calcium salts removes completely the symptoms of tetany and restores the animal to an apparently normal condition. They have obtained similar results upon human beings suffering from tetany as a result of unintentional removal of the parathyroids. The experimental evidence in the case of the parathyroids tends to support the view that their function consists in neutralizing in some way toxic substances formed elsewhere in the body, and that, therefore, after removal of these glands death occurs from the accumulation of such toxic bodies in the blood and tissues. Thus Macallum states that in animals in which tetany has developed as a conse- quence of extirpation of the parathyroids, bleeding and infusion of salt solution causes the tetany to disappear. The results quoted above in regard to the therapeutic value of calcium salts would seem, moreover, to connect the parathyroid function with the calcium metabolism and to relate the development of toxic substances with an insufficiency of calcium, but at present no precise statement can be made in regard to the way in which these bodies perform their very important function. The view that the parathyroids are simply immature thyroid tissue is still supported by some observers, being based chiefly on the his- tological assertion that after removal of the thyroids the para- thyroids may hypertrophy and show thyroid cysts containing colloidal material. Most observers, however, take the view outlined above, that the parathyroids have a functional signifi- cance essentially different from that of the thyroids, and that the parathyroids as they exist in the body are not simply undeveloped or immature thyroid tissue. At the same time it is becoming generally recognized that different as the functions of these two tissues may be, they are in some way correlated, and that the removal of one of them influences the activity of the other. The Function of the Thyroid. — According to the opinion of most writers on the subject, removal of the thyroid alone, leaving, at least, the external parathyroids uninjured, is followed by the development of a state of chronic malnutrition which expresses itself finally in a condition of cachexia. Following a terminology sometimes used in medical literature, this cachectic condition may be designated as "cachexia thyreopriva," whereas the convulsive phenomena or tetany, formerly also described as •Macallum and Voegtlin, "Johns Hopkins Hospital Bulletin," March. 1008. SECRETION OF THE DUCTLESS GLANDS. 855 a symptom of loss of the thyroid, may be characterized as "tetania parathyreopriva." No adequate explanation has been furnished of the influence exercised by the thyroid on the nutrition of the body. It is usually assumed that the thyroid cells form an inter- nal secretion which is contained possibly in the colloid material found in the vesicles. This view assumes that the thyroid forms a specific hormone which acts as a chemical stimulus to other tissues, particularly those of the central nervous system. Some justification for this view is found in the effect of feeding thyroid tissue to normal individuals. There may be produced under these circumstances a condition which may be designated as hyperthyroidism, that is to say, the metabolism of the tissues is augmented as is shown by an increase in the excretion of nitrogen, carbon dioxid, and phosphoric acid, and by an increased con- sumption of oxygen, the heart-rate is also accelerated, and other evidences are given of an excitation of the nervous system. Simi- lar symptoms are observed in the pathological condition known as exophthalmic goiter, which is now usually explained as being due to a Iryperthyroidism resulting from an hypertrophy of the thyroid tissue. As was stated above, Baumann isolated from the thyroid a peculiar substance, iodothyrin, which is characterized chemically by its large percentage of iodin, and physiologically by the fact that when used upon patients suffering from a defi- ciency in functional activity of the thyroid (myxedema, goiter) it gives the same beneficial results as thyroid tissue itself. In the gland this iodothyrin is combined with protein to form a thyreo- globulin or thyreoprotein. There has been much discussion regarding the iodin constituent of the thyroid tissue. Extensive observations have shown that in some entirely healthy animals iodin is absent or is present only in traces, and in animals in which it is present the amount may vary greatly with the character of the food. Hunt gives the following table: Per cent, of iodin. Children's thyroid none. Maltese kid thyroid none. Guinea-pig thyroid 0.05 Dog thyroid 0.061 Cat thyroid 0.08 Sheep thyroid 0.176 Beef thyroid 0.25 Hog thyroid 0.33 Human (Wells) 0.236 Human (goitre) 0.04 Opinions in regard to the significance of the iodin have varied from the view, on the one hand, that it is an essential constituent of the physiologically active substance secreted by the gland, to the opposite extreme that it is an injurious substance which is 856 PHYSIOLOGY OF DIGESTION AND SECRETION. bound and made innocuous by the thyroid cells. The balance of evidence seems to favor the first point of view,* and at present we may conclude that the iodin in some way intensifies the activity of the internal secretion of the thyroid. That it is abso- lutely necessary to this activity is rendered improbable by the fact that iodin-free thyroids appear still to exercise their normal influence upon metabolism, but administration of iodin in the food not only raises the iodin percentage in the gland but also increases proportionately the physiological activity of extracts of the tissue. Experiments show also that the known effects of thyroid extracts are greater in the iodin-rich than in the iodin- poor glands. Cyon's View of the Function of the Thyroid. — Cyon, in numerous publications, has advocated a different view of the function of the thyroids. These bodies have a very large vascular supply, and this avthor assumes that this area serves as a vascular shunt or flood-gate to protect mechanically the circulation in the brain. The dilatation of the thyroid area under con- ditions that threaten congestion of the brain is effected reflexly by means of the hypophysis cerebri and the vagi. For details of this mechanism and also of the supposed effect of the thyroid secretion on the irritability of the centers innervating the heart and blood-vessels see " Archives de physiologie, " 1898, p. 618. Thymus. — The physiology of the thymus gland is very obscure, indeed, practically nothing is known about its functions. Its prox- imity to the thyroids and parathyroids and its general similarity in origin would indicate that like them it may have some impor- tant specific influence upon metabolism, but physiological experi- ments so far have failed to discover what this influence is. Ac- cording to Verdun the thymus arises from the endothelial pouches belonging to the branchial clefts, chiefly from that of the third cleft. Formerly it was supposed to reach its maximal develop- ment at birth and subsequently to atrophy, being replaced by a growth of lymphoid and fatty tissues. More recently doubt has been thrown upon this belief. Several observers have stated that it continues to increase in size after birth until the appearance of puberty, and that true thymus tissue may persist throughout life. Stohr, in fact, insists that what has usually been taken as lymphoid tissue in the adult thymus is, in reality, epithelial or endothelial tissue which presumably has some specific function. The organ, in fact, seems to be an unusually labile structure. Deficient nutrition leads to a rapid decline in weight. According to Jonson, chronic underfeeding in rabbits for a period of four weeks will reduce the weight to ^j of its normal, and from this con- * For discussion and literature, consult Hunt, "Studies on Thyroid," "Hygienic Laboratory Bulletin," 1909, No. 47, Washington, D. C; and Hunt and Seidell, "Journal of Pharmacology and Experimental Therapeutics," 2, 15, 1910. SECRETION OF THE DUCTLESS GLANDS. 857 dition it recovers rapidly upon the restoration of a normal diet. On the physiological side, Abelous and Billard have stated that extirpation of these glands in the frog is followed by the death of the animal, but later observers have failed to con- firm this result either upon frogs or mammals except in the case of very young animals. Removal of the gland in young dogs (Basch) is said to cause a retarded growth of the bony tissues and to induce a condition resembling rickets. At the same time the peripheral nervous system shows an increased excitability as determined by the response of the nerves to galvanic stimulation. Somewhat similar but more extensive experiments have been reported by Klose and Vogt. When thymectomy is performed on quite young dogs (10 days), very serious consequences result, ending perhaps in a condition of coma and death. These results develop slowly: there is first a stage of increased fat formation and later one of malnutrition or cachexia which manifests itself strikingly in an atrophic and undeveloped condition of the bones, although there is besides a general asthenic or adynamic condition which manifests itself also in a mental deterioration. These results indicate decisively that in very early life the thymus exercises important, indeed, essential functions, which later, after the period of involu- tion of the gland begins, are gradually suspended or transferred. Injections of extract of the gland (Svehla) cause a fall of blood- pressure and some quickening of the heart-beat, but these effects are not specific. Unlike the thyroid and parathyroid glands, the thymus contains no iodin (Mendel) . One suggestion made regard- ing its influence is that there is some sort of reciprocal relationship between it and the reproductive glands. Castration (Henderson) causes a persistent growth and retarded atrophy of the thymus, while removal of the thymus (Paton) hastens the development of the testes.* Another hypothesis is the one advocated by Klose and Vogt in the work referred to above, namely, that the thymus prevents the excessive accumulation of acid in the body, particu- larly phosphoric acid or its compounds, and that it exerts this action probably by synthesizing these acids into nucleic acid or nuclein compounds. Adrenal Bodies. — The adrenal bodies — or, as they are frequently called in human anatomy, the suprarenal capsules — belong to the group of ductless glands. It was shown first by Brown-Sequard (1856) that removal of these bodies is followed rapidly by death. * References: Friedleben, "Die Physiologie der Thymusdruse," 1858; Verdun, " Derives branchiaux chez les vertebres," 1898; Henderson, "Journal of Physiology," 1904, xxxi., 222; Stohr, "Beit. z. Anat. u. Entwick. Anatom.," Hefte, 1906, xxxi., 409; Jonson, "Archiv f. mik. Anat.," 73, 390, 1909: Basch, "Jahrbuchi. Kinderheilkunde," 64, 1906, and 68, 1908; Klose and Vogt, "Klinik u. Biologie d. Thymusdruse," Tubingen, 1910. 858 PHYSIOLOGY OF DIGESTION AND SECRETION. This result has been confirmed by many experimenters, and so far as the observations go the effect of complete removal is the same in all animals. The fatal effect is more rapid than in the case of removal of the thyroids, death following the operation usually in two to three days, or, according to some accounts, within a few hours. The symptoms preceding death are great prostration, mus- cular weakness, and marked diminution in vascular tone. These symptoms resemble those occurring in Addison's disease in man, — a disease which clinical evidence has shown to be associated with pathological lesions in the suprarenal capsules. It has been ex- pected, therefore, that the results obtained from thyroid treatment of myxedema might be paralleled in cases of Addison's disease by the use of adrenal extracts, but so far these expectations have not been completely realized. Oliver* and Schaefer, and, about the same time, Cybulski and Szymonowicz,f discovered that this organ forms a peculiar substance that has a very definite physiological action, especially upon the circulatory system. They found that aqueous extracts of the medulla of the gland when injected into the blood of a living animal have a remarkable influence upon the heart and blood-vessels. If the vagi are intact, the adrenal extracts cause a very marked slowing of the heart beat together with a rise of blood- pressure. When the inhibitory fibers of the vagus are thrown out of action by section or by the use of atropin the heart rate is ac- celerated, while the blood-pressure is increased sometimes to an extraordinary extent. These results are obtained with very small doses of the extracts, and only from extracts which include the medullary substance of the gland. The medullary cells contain a chromogen substance (chromaphil or chromaffin) which gives a yellow reaction with chromates. The physiological activity of the gland, so far as the effects on the circulatory system are concerned, seems to be proportional to the amount of chromaffin material in the medullary cells. Schaefer states that as little as 5| mgms. of the dried gland may produce a maximal effect upon a dog weigh- ing 10 kgms. The effects produced by such extracts are quite temporary in character. In the course of a few minutes the blood- pressure returns to normal, as also the heart-beat, showing that the substance has been destroyed in some way in the body, al- though where or how this destruction occurs is not known. Ac- cording to Schaefer, the kidneys and the adrenals themselves are not responsible for this prompt elimination or destruction of the active substance. Several observers have shown satisfactorily that the material producing this marked effect on the heart and blood-pressure is present in perceptible quantities in the blood * "Journal of Physiology," 18, 230, 1895. t "Archiv f. die gesammte Physiologic," f>4, 07, 1896. SECRETION OF THE DUCTLESS GLANDS. 859 of the adrenal vein, so that there can be but little doubt that it is a distinct internal secretion of the adrenal. Dreyer* has shown, moreover, that the amount of this substance in the adrenal blood is increased, judging from the physiological effects of its injection, by stimulation of the splanchnic nerve. Since this result was obtained independently of the amount of blood-flow through the gland, Dreyer makes the justifiable assumption that the adrenals possess secretory nerve fibers. More recently it has been claimed by Schur and Wiesel that adrenalin is present in detectable amounts in the general circulation after partial or complete nephrectomy, in cases of chronic nephritis and after prolonged muscular exercise. In such cases of excessive secretion the chromaffin substance in the gland is apparently used up, since the reaction with chromates can no longer be obtained. The Chromaphil Tissues. — Cells possessing the same histo- logical characteristics as the medullary cells of the adrenals and giving the same yellow or brown reaction with chromates have been discovered in other locations, for example, within the ganglia of the sympathetic and in the form of separate clumps or strings along the course of the abdominal aorta below the level of the adrenal glands, f Physiological experiments indicate that extracts of these outlying chromaphil bodies have an effect on blood- pressure similar to that given by the medullary cells of the adrenals. It has been suggested, therefore, that this material, wherever it occurs, has the property of producing epinephrin or some similar substance, and constitutes a tissue with a common function, although apparently the portion of it which is enclosed within the adrenal bodies has a more highly developed activity. The Active Principle. — The substance formed by the medullary cells has been isolated by different observers in varying degrees of purity and has been given different names, such as epinephrin, adrenalin, suprarenin, etc. J The credit for the important initial work in this series of investigations belongs to Abel, while the final isolation of the substance in crystalline form was accomplished by Takamine and independently by Aldrich. The latter observer de- termined also its empirical formula as C9H13N03, and subsequently other workers (Stolz-Dakin) succeeded in demonstrating its structure as a methyl amino-ethanol derivative of dioxyphenol, C6H3(OH)2CHOHCH2NHCH3. This substance has been con- structed synthetically with physiological properties as active as those exhibited by the material isolated directly from the gland. Unfortunately, there is no agreement at present in regard to the * "American Journal of Physiology," 2, 203, 1899. t Consult Vincent, " Proceedings "Royal Society," B, 82, 502, 1910. t For further details see Biedl, "Innere Sekretion," also an interesting, account in "Journal of the American Medical Association," 45, 910, 1911. 860 PHYSIOLOGY OF DIGESTION AND SECRETION. name to be given to this active principle. In this country epi- nephrin and adrenalin have both been used. The substance itself is a basic, insoluble body, and for therapeutic use is prepared as a salt, with hydrochloric acid, for example. Its chief value medicin- ally lies in its property of causing a constriction of the blood-vessels, and on this account it is used very frequently as a hemostatic to check hemorrhage in minor surgical operations. As has been stated above, extracts of the medulla of the gland or preparations of the active principle when injected intravenously cause an enormous although short-lasting rise of blood-pressure, particu- larly if the inhibitory action of the vagus or the heart is first re- moved by section of the nerves or the administration of atropin. It would seem that in the intact animal this effect is due in part to a peripheral effect on the blood-vessel and in part to a stimulating action on the vasoconstrictor center in the medulla. As regards this last effect it may well be that it is a secondary result due to the fact that the blood-vessels in the medulla are constricted and a condition of anemia is produced. There is no question in regard to the fact that epinephrin causes a contraction of the muscles in the walls of the vessels. This fact can, indeed, be demonstrated upon isolated strips of muscle taken from the arteries. Under proper conditions such strips show contraction when immersed in solutions containing epinephrin even in excessively dilute solutions. When, however, the blood-vessels of different regions of the body are ex- amined in this respect it has been found that in some areas the blood-vessels are much less affected by the epinephrin than in others. The blood-vessels of the brain and lungs, for example, although made to constrict by such solutions, are obviously much less affected than those of the intestines or skin, while the coronary vessels are said to be relaxed instead of being constricted. Light was thrown upon this apparent selective action of epinephrin by a suggestion first made by Langley that the epinephrin stimulates only that plain muscle, whether in the blood-vessels or in the other visceral organs, which is innervated by sympathetic autonomic nerve-fibers, and that its stimulating effect is exerted not on the mus- cle substance itself, nor possibly on the terminations of the nerve- fibers, but rather on a receptive substance in the muscle at the junction of nerve-fiber and muscle. This view has been adopted quite generally and has been made use of, as is explained elsewhere, in ascertaining whether or not any given region, the brain, for example, is provided with vasomotor nerve-fibers. Where the normal effect of the sympathetic fibers is to cause an inhibition or dilatation instead of a contraction, as is the case, for example, with the musculature of the stomach and intestines, there injections of epinephrin likewise cause a dilatation, a result which tends to SECRETION OF THE DUCTLESS GLANDS. 861 confirm the view that this substance has a selective action upon the terminals of the sympathetic fibers. The rise of blood-pressure caused by intravenous injections of adrenal extracts is usually quite temporary, although a re- newed effect may be obtained by repetition of the injection. It is evident, therefore, that the epinephrin thus introduced artificially into the circulation is rendered inactive in some way, but it has not been possible as yet to explain the rapidity with which its effect disappears — that it is not due to a destructive oxidation seems to be shown by the fact that the blood of the injected animal still shows the presence of the epinephrin after the blood-pressure has returned to normal. It is stated that when a very dilute solution of epinephrin is used and it is injected slowly but continuously into the vein, a continuous rise of pressure may be maintained. It will be noted that this method of inject- ing the material is an imitation of what may be considered the normal mode by which the adrenal gland delivers its secretion to the blood. The Physiological Role of the Adrenals. — There :seems to be no question that the medullary substance forms epinephrin or some related compound which has a marked stimulating effect upon the tone of the blood-vessels and upon the heart, and that this material passes into the blood. The general view, there- fore, has been that one at least of the functions of the adrenals is the internal secretion of this material. It is assumed at present that this internal secretion is essential to the full activity of the sympathetic autonomic nervous system and that its failure or diminution will be followed by impairment of the functional activ- ity of the tissues thus innervated. The tissues whose dependence on the secretion seems to be demonstrated most clearly by experi- mental work are the heart and blood-vessels, and it is probable that the normal and essential tonicity of these organs is controlled in some way by the presence of this internal secretion in the blood. Removal of the adrenal bodies in mammals by surgical operation is followed usually by an asthenic condition of the heart and blood- vessels which may be regarded as the immediate cause of death. It is very evident, however, that the physiological significance of the adrenal glands is not limited to the action of epinephrin on the musculature of the circulatory organs. Epinephrin is a secre- tion of the medullary portion of the adrenal gland, a tissue which, as we have seen, is found in other parts of the body, but there can be no doubt that the large cortical portion of the gland which has nothing to do directly with the formation of epinephrin has also some important function. These two portions of the gland, the cortical and the medullary, occur separately in the fishes, and it is 862 PHYSIOLOGY OF DIGESTION AND SECRETION. possible that even in the mammal, where they are so closely united anatomically, they may have separate functions. The cells form- ing the cortical tissue have distinct histological characteristics, and may occur in structures distinct from the adrenal bodies, so that it has been proposed to call this tissue in general the " inter- renal tissue " or the " interrenal system," while the medullary substance is designated as the adrenal system or, on account of its color reaction with the chromates, as the " chromaffin " or " chromaphil " system. The latter tissue produces epinephrin and its physiology is connected chiefly with the properties of this hormone. Whether or not the " interrenal tissue " produces a similar internal secretion is not known definitely, but much evi- dence has accumulated to show that it also is in some way import- ant or essential to the body. Several hypotheses have been pro- posed to explain its specific activity, for example, that it neutral- izes certain toxins produced in the body; that it manufactures the lipoid element which seems to be essential in the structure of all cells; that its secretion is connected with the processes of growth and particularly with the metabolism of the sexual organs, and so on. It is certain that the physiology of this organ or of the two kinds of tissue represented in it presents a difficult and intricate problem which will be understood only as the result of much investigation. One other relationship of the adrenal body may be mentioned as a further illustration of the complex character of its influence. It has been shown that, in addition to the circulatory results of the injection of epinephrin, there may occur also a distinct disturbance in the carbohydrate metabolism of the body, which is indicated by the fact that a condition of glycosuria results. This influence of the adrenals seems to be a part of the functional activity of its medullary or chromaphil tissue, and inasmuch as the pancreas (islands of Langerhans), the thyroids, and the hypophysis are also connected in one way or another with the intermediary metabolism of the carbohydrates in the body it has been assumed that there is an interrelation of some kind between the secretions of these several glands and their influence upon metabolism, so that it becomes necessary to study the functions of these glands not only separately, but with refer- ence to one another. In the pathological condition known as Addison's disease it has long been known that the adrenal glands are affected, usually from a tubercular lesion. In this disease there are among other symptoms great prostration and an asthenic condition of the musculature and of the organs of circulation. This latter condition has been attributed directly to the deficient formation of epinephrin, and attempts have been made to treat the disease with injections SECRETION OF THE DUCTLESS GLANDS. 863 of adrenal extracts. This treatment has not been successful, owing possibly to the fact, stated above, that the effects of such injections, so far as blood-pressure is concerned, are only of brief duration. It has been hoped that more successful results may be obtained by the methods of grafting. As carried out on lower animals, it has been shown that the organ may be grafted success- fully and that the grafts exert a normal physiological activity, since they enable the animal to survive the otherwise fatal opera- tion of excision of the adrenal bodies.* Pituitary Body (Hypophysis). — This body is usually described as consisting of two parts — a large anterior lobe of distinct glandular structure and a much smaller posterior lobe of nervous origin and composed chiefly of neuroglia cells and fibers. Embryologically the two lobes are entirely distinct. The anterior lobe arises from an invagination (Rathke's pouch) of the buccal ectoderm. A portion of this epithelium soon develops into a glandular structure belonging to the type of glands which have no excretory duct and which probably, therefore, form an internal secretion. The posterior lobe arises as an outgrowth from the floor of the third ventricle of the brain, the infunclibulum, which comes into contact with the epithelial pouch forming the anterior lobe. The epithelial cells of the latter soon show a differentiation into two parts, one of which gives rise to the anterior lobe, while the other invests the body and neck of the posterior or nervous lobe. To this latter the special name of the pars intermedia has been given. When fully formed the posterior lobe consists of two parts, the pars nervosa, composed of neuroglia cells and fibers and ependymal cells, and an investing layer of epithelial cells, derived from the buccal ectoderm and known as the pars intermedia^ (see Fig. 299). The cells of the pars intermedia may also penetrate more or less into the sub- stance of the pars nervosa. Howell { and others have shown that extracts of the anterior lobe when injected intravenously have little or no physiological effect, while extracts of the posterior lobe, on the contrary, cause a marked rise of blood-pressure and slowing of the heart-beat. These effects resemble in general those obtained from adrenal extracts, but differ in some details. It was subsequently shown by Schafer and Herring§ that extracts * For details and references to literature on this and other points in internal secretion consult the excellent work by Biedl, "Innere Sekretion," Berlin, 1910. | See Herring, "Quarterly Journal of Experimental Physiology," 1, 121, 161, 1908. X "Journal of Experimental Medicine," 3, 245, 1898; also Schafer and Vincent, "Journal of Physiology," 25, 87, 1899; and Herring, "Quarterly Journal of Experimental Physiology," 1, 261, 1908. § Schafer and Herring, "Philosophical Transactions, Royal Society," London, 1906, B. cxcix., 1. 864 PHYSIOLOGY OF DIGESTION AND SECRETION. made from the posterior lobe when injected into the blood cause a dilatation of the renal vessels and an internal secretion of urine. Evidence was thus obtained that the posterior lobe fur- nishes an internal secretion which has a specific effect upon the organs of circulation and upon the kidneys. In addition, it has been shown that these extracts cause dilatation of the pupils and stimulate the musculature of the bladder, uterus, and intestines. Further work by Herring* has made it very probable that this internal secretion is furnished by the epithelial cells of the pars intermedia. These cells apparently invade the pars nervosa, Fig. 299. — Mesial sagittal section through developing pituitary body of a human fetus (fifth month;. Drawing from a photograph. — (Herring.) a, Optic chiasma ; b, tongue- like process of epithelium ; c, third ventricle ; d, anterior lobe ; e, neck of posterior lobe; /, epithelium surrounding neck ; g, epithelial cleft ; li, posterior lobe. undergo a hyaline transformation, and are finally discharged into the third ventricle of the brain. The active material (pituitin) is formed or activated during the process of transformation in the nervous lobe and it has been possible to prove its presence in the cerebrospinal liquid, f There is some evidence also from histo- logical appearances that this secretion is augmented after complete thyroidectomy, a fact which has Led to the view that there is a functional relationship between this lobe of the pituitary body and the thyroid tissue. Physiological experiments upon the large glandular anterior lobe have given quite different results. In- * Herring, loc. cit., and 1, 281, 190s. t Cushing and Goetsch, "American Journal of Physiology," 27, 60, 1910. SECRETION OF THE DUCTLESS GLANDS. 865 • jections of extracts of the anterior lobe have given negative results so far as an immediate effect on the animal is concerned; but a study of its relations under pathological conditions and the effects of its excision by surgical methods indicate that it also plays a most important part in the metabolism of the body. On the pathological side, tumors or hypertrophies of the pituitary have been associated with the conditions known as acromegaly and gigantism. The former term applies to cases of disturbed nutri- tion in which there is abnormal growth, shown especially in the enlargement of the bones of the face and the extremities, while gigantism includes less distinctly pathological cases of overgrowth, particularly of the skeleton. That this abnormal nutrition is connected with a disturbance (hypertrophy) of the pituitary seems most probable. It is assumed in these cases that it is the anterior lobe which is involved, and that, therefore, normally it controls in some way skeletal growth. A number of observers have at- rempted to remove all or a portion of the pituitary body, and in this way to arrive at a conception of its physiological importance. Paulesco* has obtained decisive results by this method. Complete removal of the gland was followed by death in a short time, twenty- four hours on the average. As between the anterior and the pos- terior lobes his experiments indicate that the quickly fatal result is due to the loss of the former. Ablation of the nervous lobe caused no immediate evil effect. In this country the work of Paulesco has been confirmed by Cushing and his co-workers, f so far, at least, as the fatal result of a total hypophysectomy is concerned. Their animals soon after the operation exhibited a condition of lethargy which passed rapidly into a coma that ended in death, but the fatal result did not develop so quickly as in the experiments of Paulesco. Like Paulesco, these observers find that the quickly fatal result follows only after complete loss of the anterior lobe. With regard to the posterior lobe (pars nervosa and pars inter- media) numerous experiments by Cushing + and his co-workers indicate that partial or complete ablation of this portion- of the gland is followed by distinctive effects upon the animal's metab- olism. The most striking effect is a marked increase in the tol- erance shown by the animal toward carbohydrate foods — that is to say, a much larger amount of carbohydrate food may be in- gested without the development of a condition of " alimentary glycosuria." On the other hand, intravenous or subcutaneous injections of extracts of the posterior lobe lower the tolerance * Paulesco, "Journal de Physiologie et de Path, generale," p. 441, 1907. f Reford and Cushing, "Johns Hopkins Hospital Bulletin," April, 1909; and Crowe, Cushing, and Homans, ibid., May, 1910. % Goetsch,' Cushing, and Jacobson, " Bulletin of the Johns Hopkins Hos- pital," June 1, 1911. 55 866 PHYSIOLOGY OF DIGESTION AND SECRETION. toward carbohydrate food, and may even cause a distinct glyco- suria. They attribute this action upon the carbohydrate metab- olism to the secretion of the posterior lobe (pars intermedia). This secretion, as is stated above, normally enters the cerebro- spinal liquid, and thence finds its way to the circulation. Hyper- secretion, or a condition of functional hyperplasia, leads to a dimin- ished tolerance for carbohydrate food and possibly to a condition of glycosuria. On the other hand, a hyposecretion or a condition of functional hypoplasia leads to a greater tolerance for carbohy- drate foods and apparently stimulates the processes in the body by which the sugar is converted to fat, since one of the results of such a condition is a general state of adiposity. There would seem to be no doubt from these observations that both the anterior and the posterior lobes of the hypophysis exert an important influence upon general body-metabolism. The secretion of the anterior lobe is connected, for one thing, with the processes of growth, particularly of the skeleton; but, since its complete suppression is attended by a quickly fatal result, it is evident that this statement does not express fully its entire physiological value. The secretion of the posterior lobe, in addition to its effect on the circulation and on the secretion of urine, is connected in some way with carbohy- drate metabolism, but a complete explanation of its role in this lat- ter particular is a difficult matter, which will have to be considered in connection with the effects of the internal secretions of other glands, such as the pancreas, the adrenals, and the thyroids. The Pineal Body (Epiphysis Cerebri). — This small body projects from the roof of the third ventricle and embryologically develops as an outgrowth from this vesicle of the brain. In early life it has a glandular structure which seems to reach its greatest development at about the seventh year. After this period and particularly after puberty it undergoes a process of involution during which the glandular structure gradually disappears and its place is taken by fibrous tissue. The gland is noteworthy also for the appearance of calcareous concretions, the so-called brain sand, which may appear even in early life. Intravenous injections of ex- tracts of this gland seem to cause a distinct fall in blood-pressure, indicating the presence of a depressor substance. On the patho- logical side it is stated that in young children invasion of the gland by pathological growths results in distinctive effects. Under such conditions there is presumably a diminished activity of the gland, and the results observed are an accelerated development of the reproductive organs, with an attending mental precocity and an increased growth of the skeleton. The inference made, therefore, from these observations is that in the young child the gland fur- nishes a secretion which inhibits growth and particularly restains the development of the reproductive glands. SECRETION OF THE DUCTLESS GLANDS. 867 Organs of Reproduction. — Some of the earliest work upon the effect of the internal secretions of the glands was done upon the reproductive glands, especially the testis, by Brown-Sequard.* Ac- cording to this observer, extracts of the fresh testis when injected under the skin or into the blood may have a remarkable influence upon the nervous system. Mental and physical vigor, and the activity of the spinal centers, are greatly improved, not only in cases of general prostration and neurasthenia, but also in the case of the aged. Brown-Sequard maintained that this general dynamogenic effect is due to some unknown substance formed in the testis and subsequently passed into the blood, although he admitted that some of the same substance may be found in the ex- ternal secretion of the testis — i. e., the spermatic liquid. Poehlf asserts that he has prepared a substance, spermin, to which he gives the formula C5H14X2, which has a very beneficial effect upon the metabolism of the body. He believes that this spermin is the sub- stance that gives to the testicular extracts prepared by Brown-Se- quard their stimulating effect. He claims for this substance an extraordinary action as a physiological tonic. Zothf and also Pregel§ seem to have obtained exact objective proof, by means of ergographic records, of the stimulating action of the testicular extracts upon the neuromuscular apparatus in man. They find that injections of the testicular extracts cause not only a climinu- tion in the muscular and nervous fatigue resulting from muscular work, but also lessen the subjective fatigue sensations. The fact that the internal secretion of the testis, if it exists at all, is not ab- solutely essential to the life of the body as a whole, as in the case of the thyroids, adrenals, and pancreas, naturally makes the satis- factory determination of its existence and action a more difficult task. Similar ideas in general prevail as to the possibility of the ova- ries furnishing an internal secretion that plays an important part either in general nutrition or in the specific nutrition of the other reproductive organs. In gynecological practice it has been observed that complete ovariotomy with its resulting premature menopause is often followed by distressing symptoms, mental and physical. In such cases many observers have reported that these symptoms may be alleviated by the use of ovarian extracts. Morris || reports a number of cases in which, after complete removal of the ovaries, a piece of ovary from the same or a different person was grafted * "Archives de physiologie normale et pathologique," 1889-92. t "Zeitschrift f. klinische Medicin," 26, 133, 1894. % "Pfliiger's Archiv f. die gesammte Phvsiologie," 62, 335, 1S96; also 69, 386, 1897. I Ibid., p. 378. || Morris, "Medical Record," 1901, p. 83. 868 PHYSIOLOGY OF DIGESTION AND SECRETION. into the fundus of the uterus or into the broad ligament. In all cases menstruation persisted, showing, therefore, that the presence of the ovaries is necessary for this function. A similar operation in cases of amenorrhea or dysmenorrhea brought on free and easy menstruation and an improvement in general nutrition and well- being. Glass* also reports a case in which the entire ovary from one woman was transplanted into another patient upon whom com- plete ovariotomy had been performed two years before. The result of the operation was a return of menstruation and sexual desire, and a marked alleviation of the disagreeable symptoms following the artificial menopause. Similar results have been reported upon the lower animals. After complete ovariotomy a condition of "heat" may be reproduced by grafting ovarian tissue, f and several observers agree in stating that removal of the ovaries in young animals prevents the normal development of the uterus, while in adult animals it causes the organ to undergo a fibrous degeneration (see section on Reproduction). In the natural menopause, as well as in the premature menopause following operations, it is a frequent, though not invariable, result for the individual to gain noticeably in weight. An effect of the ovaries on general nutrition is indicated also by the interesting fact that in cases of osteomalacia, a disease characterized by softening of the bones, removal of the ovaries may exert a favor- able influence upon the course of the disease. These indi- cations have found some experimental verification in a research by Loewy and RichterJ made upon dogs. These observers found that complete removal of the ovaries, although at first apparently without effect, resulted in the course of two to three months in a marked diminution in the consumption of oxygen by the animal, measured per kilogram of body-weight. If now the animal in this condition was given ovarian extracts (oophorin tablets), the amount of oxygen consumed was not only brought to its former amount, but considerably increased beyond it. A similar result was obtained when the extracts were used upon castrated males. The authors believe that their experiments show that the ovaries form a specific substance which is capable of increasing the oxidations of the body. In addition to the internal secretion of the ovaries which is respon- sible for the phenomenon of menstruation, other similar secretions have been assumed to account for changes occurring during the time of pregnancy. Thus the implantation of the fertilized ovum in the uterine mucous membrane and the development of the placenta have been supposed to be effected through the agency * Glass, "Medical News," 1899, p. 523. t Marshall and Jolly, " Philosoph. Transact ions," B. cxcvii., 99, 1905. X Loewy and Riehter, "Archiv f. Physiologic," 1889, suppl. volume, p. 174. SECRETION OF THE DUCTLESS GLANDS. 869 of some chemical stimulus arising in the cells of the corpus luteum. So also the development of the mammary glands during pregnancy- is attributed to the action of a hormone formed in the tissues of the fetus itself (see section on Reproduction). Pancreas. — The importance of the external secretion, the pan- creatic juice, of the pancreas has long been recognized, but it was not until 1889 that von Mering and Minkowski * proved that it fur- nishes also an equally important internal secretion. These observers succeeded in extirpating the entire pancreas without causing the immediate death of the animal, and found that in all cases this operation was followed by the appearance of sugar in the urine in considerable quantities. Further observations of their own and of other experimenters have corroborated this result and added a num- ber of interesting facts to our knowledge of this side of the activity of the pancreas. It has been shown that when the pancreas is com- pletely removed a condition of glycosuria inevitably follows, even if carbohydrate food is excluded from the diet. Moreover, as in the similar pathological condition of glycosuria or diabetes mel- litus in man, there is an increase in the quantity of urine (polyuria) and of urea, and an abnormal thirst and hunger. Acetone also is present in the urine. These symptoms in cases of complete extir- pation of the pancreas are followed by emaciation and muscular weakness, which finally end in death in two to four weeks. If the pancreas is incompletely removed, the glycosuria may be serious, or slight and transient, or absent altogether, depending upon the amount of pancreatic tissue left. According to the experiments of von Mering and Minkowski on dogs, a residue of one-fourth to one-fifth of the gland is sufficient to prevent the appearance of sugar in the urine, although a^maller fragment may suffice apparently if its physiological condition is favorable. The portion of pancreas left in the body may suffice to prevent glycosuria, partly or com- pletely, even though its connection with the duodenum is entirety interrupted, thus indicating that the suppression of the pancreatic juice is not responsible for the glycosuria. The same fact is shown more conclusively by the following experiments: Glycosuria after complete removal of the pancreas from its normal connections may be prevented partially or completely by grafting a portion of the pancreas elsewhere in the abdominal cavity or even under the skin. So also the ducts of the gland may be completely occluded by liga- ture or by injection of paraffin without causing a condition of per- manent glycosuria. On the basis of these and similar results it is believed that the pancreas forms an internal secretion which passes into the blood ♦Minkowski, " Arciiiv f. exper. Pathologie u. Pharmakologie," 31, 85, 1893. 870 PHYSIOLOGY OF DIGESTION AND SECRETION. and plays an important, indeed, an essential part in the metabolism of sugar in the body. Moreover, considerable evidence has been accumulated to show that the tissue concerned in this important function is not the pancreatic tissue proper, but that composing the so-called islands of Langerhans. In man these islands are scattered through the pancreas, forming spherical or oval bodies that may reach a diameter of as much as one millimeter. The cells in these bodies are polygonal; their cytoplasm is pale, finely granular, and small in amount. The nuclei possess a thick chromatin network which stains deeply. Each island possesses a rich capillary network that resembles somewhat the glomerulus of the kidney. According to Ssbolew,* ligation of the pancreatic duct is followed by a complete atrophy of the pancreatic cells proper, while those of the islands of Langerhans are not affected. Since under these conditions no glycosuria occurs, while removal of the whole organ including the islands is followed by pancreatic diabetes, the obvious conclusion is that the diabetes is due to the loss of the islands. This conclusion is strengthened by reports from the pathological side. A number of recent observers (Opie, Ssbolew, Herzog, et al.) find that in diabetes mellitus in man the islands may be markedly affected, f They show signs of hyaline degeneration or atrophy or in severe cases may be absent altogether. It should be added that this connection of the islands of Langerhans with the internal secretion of the pancreas is not accepted by all writers. Sev- eral observers J contend that the islands represent a stage in the development of the ordinary secreting alveoli of the pancreas. When the pancreas is subjected to prolonged and excessive activity, by the injection of secretin, for example, the number of islands is greatly increased, and the same result follows periods of prolonged inactivity, as in fasting. Several theories have been advanced to explain the action of the internal secretion of the pancreas. It has been suggested that the secretion contains an enzyme which is necessary for the hydrol- ysis or oxidation of the sugar of the body and in the absence of this enzyme the sugar accumulates in the blood and is drained off through the kidney. Cohnheim§ states that, while the juices ex- pressed from muscle and from pancreas have little effect upon sugar when taken separately, yet when combined they cause a marked disappearance (glycolysis) of sugar added to the mixture. The inference from this result is that the pancreas furnishes a substance which activates the glycolytic enzyme or enzymes of the muscle * "Virchow's Archiv," 168, 91, 1902. t Heiberg, '*Centralbl. f . ges. Physiol, u. Pathol, d. Stoffwechsel," No. 16, 1910. J Dale, "Philosophical Transactions," B. cxcvii., 1904; also Vincent and Thompson, "Journal of Physiology," 1906, xxvii., xxxiv. §Cohnheim, "Zeitschrift f. physiolog. Chemie," 39, 336, 1903; also 1904. SECRETION OF THE DUCTLESS GLANDS. 871 and thus makes possible the physiological consumption of sugars in the body. Since the pancreas extracts do not lose this property upon boiling it is evident that the activating substance is not an enzyme, but a body of a more stable character (hormone) . Other investigators adopt an entirely different view of the relation of the pancreas to carbohydrate metabolism. They believe that the internal secretion of the pancreas regulates in some way the output of sugar from the liver (and other sugar-producing organs). In the absence of this secretion the liver gives off its glycogen as sugar too rapidly, the sugar contents of the blood are thereby increased (hyperglycemia) above normal, and the excess passes out in the urine. Kidney. — Tigerstedt and Bergman* state that a substance may be extracted from the kidneys of rabbits which when injected into the body of a living animal causes a rise of blood-pressure. They get the same effect from the blood of the renal vein. They conclude, therefore, that a substance, for which they suggest the name "rennin," is normally secreted by the kidney into the renal blood, and that this substance causes a vasoconstriction. Other observers claim that the kidneys furnish an important internal secretion that affects the metabolism. The absence of this secretion after complete nephrectomy leads to the production of uremia, f * " Skandinavisches Archiv f. Physiologie," 8, 223, 1898; see also Brad- ford, "Proceedings of the Royal Society," 1892. f Suner, " Zentralblatt f. d. ges. Physiol, u. Path, des Stofferechsel," 1907, ii., 3. SECTION VIII. NUTRITION AND HEAT PRODUCTION AND REGULATION. CHAPTER XLVII. GENERAL METHODS-HISTORY OF THE PROTEIN FOOD. Under the head of nutrition or general metabolism we include usually all those changes that occur in our foodstuffs from the time that they are absorbed from the alimentary canal until they are eliminated in the excretions. In many of these processes the oxygen absorbed from the lungs takes a most important part, and the changes directly due to this element, the physiological oxidations of the body, can not be separated from the general metabolic phe- nomena of the tissues. As was said in another place, the respiratory history of oxygen ceases after this element has reached the tissues; its subsequent participation in the chemical changes of the organ- ism forms an integral part of the nutritional processes. These latter processes are varied and complex and only partially understood. For the sake of simplicity in presentation it is convenient to con- sider separately each of the so-called foodstuffs, — the proteins, carbohydrates, fats, water, and inorganic salts, — and attempts to trace its nutritive history from the time it is absorbed into the blood until it is eliminated from the body in the form of excretory products. Before undertaking this description it is desirable to call attention to certain general methods and conceptions that have been developed in connection with this part of physiology. Nitrogen Equilibrium. — Among our main foodstuffs the pro- teins are characterized by containing nitrogen. After this ma- terial is metabolized in the body the nitrogen is eliminated in various forms, chiefly in the urine, but to a smaller extent in the feces and sweat. In the feces, moreover, there may be pres- ent some undigested protein which, although taken with the food, has never really entered the body. It is evident that the urine, feces (and sweat) may be collected during a given period and analyzed to determine their contents in nitrogen. The sweat is 872 GENERAL METHODS HISTORY OF PROTEIN FOOD. 873 usually neglected except in observations upon conditions in which muscular activity has been a prominent feature. As a rule, the amount of nitrogen is determined by some modification of the Kjel- dahl method. In principle this method consists in heating the material to be analyzed with strong sulphuric acid. The nitrogen is thereby converted to ammonia, which is distilled off and caught in a standardized solution of sulphuric acid. By titration the amount of ammonia can be determined, and from this the amount of nitrogen is estimated. Nitrogen forms a definite percentage of the protein molecule (about 16 per cent.); so that if the weight of nitro- gen is multiplied by 6.25 the weight of protein from which it is de- rived is obtained. If. on the other hand, the nitrogen is determined in the food eaten during the period of the experiment it is evident that a balance may be struck which will determine whether the body is receiving or losing nitrogen. If the balance is even the body is in nitrogen equilibrium— that is. it is receiving in the food as much protein nitrogen as it is metabolizing and eliminating in the excreta. If there is a plus balance in favor of the food it is evident that the body is laying on or storing protein, while if the balance is minus, the body must be losing protein. During the period of growth, in convalescence, etc., the body does store protein, and under these conditions the balance is in favor of the food nitrogen. But throughout adult life under normal conditions our diet is so regulated by the appetite that a nitrogen equilibrium is maintained through long periods. Under experimental condi- tions, involving, for instance, a special diet, it often becomes neces- sary to make the analyses for nitrogen in order to determine whether or not the individual is losing or gaining protein or is in equilibrium. It is important also to bear in mind that nitrogen or protein equilibrium may be established at different levels. If, for instance, a man is in nitrogen equilibrium on a diet containing 10 gms. of nitrogen, what will happen if the protein in this diet is doubled ? Our experience teaches us that the extra 10 gms. of nitrogen or 62.5 gms. of protein is not stored in the body indefinitely. As a matter of fact, the extra protein is metabolized in the body and nitrogen equilibrium becomes established at a higher level. Where- as under the first condition 62.5 gms. of protein were eaten and 62.5 gms. of protein were lost from the body, either in the form of nitrog- enous excreta or in the feces as undigested protein, under the second condition 125 gms. of protein are eaten and 125 gms. of pro- tein are lost. The total mass of protein tissue in the body may remain the same, or if any increase takes place at the beginning of the change in diet it soon ceases. Experimentally it is found that there is a certain low limit of protein which just suffices to maintain nitrogen equilibrium, and between this level and the capacity of 874 NUTRITION AND HEAT REGULATION. the body to digest and absorb protein food, nitrogen equilibrium may be maintained upon any given amount of protein. Carbon Equilibrium and Body Equilibrium. — The term car- bon equilibrium is sometimes used to describe the condition in which the total carbon of the excreta (in the carbon dioxid, urea, etc.) is balanced by the carbon of the food. It is possible that an individual may be in nitrogen equilibrium and yet be losing or gaining in weight, since, although the consumption of proteins may just be covered by the proteins of the food, the consumption of non-protein material, particularly the fats of the body, may be greater than the supply furnished by or manufactured from the food. An animal may lose or gain in carbon when his nitrogen supply is in equilib- rium. In the same way under special circumstances we may speak of a water equilibrium or a salts equilibrium, although these terms are not generally used. An adult under normal conditions lives so as to maintain a general body equilibrium; his ingesta of all kinds are balanced by the corresponding excretions, and the individual maintains a practically constant body-weight. Complete Balance Experiments — Respiration Chamber. — According to the statements made in the last paragraph, it is obvious that if the analytical work is properly done, an exact balance may be drawn between the proteins, fats, and carbohydrates eaten as food and the proteins, fats, and carbohydrates destroyed in the body as represented by the nitrogen and carbon contained in the excreta. Complete experiments of this kind were attempted first by Voit * and Pettenkofer, to whose work much of our fundamental knowledge is due. In the experiments of these authors, made upon men as well as animals, the total nitrogen of the urine and feces was determined and the total quantity of C02 given off from the lungs was estimated. This last determination was made possible by placing the individual in a specially constructed chamber or respi- ration apparatus. Air was drawn through this room by means of a pump. The total quantity of air passing through the room was measured by a gasometer and definite fractions were drawn off from time to time, which were analyzed for C02. From the figures thus obtained it was possible to estimate the entire C02 given off during the period of observation. Knowing the total nitrogen and carbon eliminated, it was possible to estimate the amount of protein and fat or carbohydrate destroyed in the body. From the nitrogen the quantity of protein metabolized was obtained by multipving by 6.25, as explained above. If then the carbon belonging to the amount of protein metabolized was deducted from the total carbon excreta, what was left represented either fat or carbohydrate burnt in the body, and, knowing the * See Hermann's " Handbuch der Physiologie, " vol. vi., 1881. GENERAL METHODS — HISTORY OF PROTEIN FOOD. 875 amount of these materials taken in the diet, it was possible to ascertain whether the corresponding amount of carbon had all been excreted. By experiments of this kind a nearly perfect balance may be struck between the income and the outgo of the body. Absolute accuracy is not sought for, since the materials eaten vary somewhat in composition and some little of the carbon or nitrogen excreted is found in the secretions from the skin, the saliva, etc., which are not usually examined. More recent experiments made in this country under the direc- tion of Atwater* have attempted to balance not only the material income and outgo of the body during a given period, but also the income and outgo of energy. For this purpose the individuals ex- perimented upon were placed in a very carefully constructed respi- ration chamber so that their expired air could be analyzed as well as the urine and feces. The chamber, however, was also arranged to act as a calorimeter (see p. 927) by means of which the heat given off by the person could be measured. The heat value of the diet being known, it is possible in this way to ascertain whether or not this theoretical amount of heat is actually given off from the body. Atwater's respiration chamber is described as a respiration calorim- eter; some of the results obtained from its use are referred to later on. The Effect of Non-protein Food on Nitrogen Equilibrium. — By use of the methods referred to above the general influence of the non-protein foods (fats, carbohydrates) upon the protein consumption of the body has been made evident. An animal may be brought into nitrogen equilibrium on protein food alone, the amount of protein required being relatively large. If now non-protein foodstuffs are added to the diet it is found that the amount of protein necessary to maintain nitrogen equilibrium may be reduced correspondingly. With reference to the consumption of protein in the body the non-protein foods are all protein-sparers, and herein lies one great peculiarity of their nutritional value. On a mixed diet of protein and non-protein food the proportion of the latter may be increased and that of the former decreased to a marked extent without breaking down nitrogen equilibrium — that is, without causing a loss of protein tissue from the body. This fact is explained by the consideration that in our body the food fulfils two great functions. First, it furnishes the material for the formation of new living matter or the replacement of the loss of this matter that is continually going on; second, it furnishes a supply of energy for the work done by the various cells, the contraction of the muscle, the secretion of the gland, the discharges of the nerve cells, etc. This second function, the energy requirement, is met by any of the three energy-yielding food-stuffs, carbohydrates, fats, or proteins, especially, as we shall * Atwater, Bulletins 45, 63, 69, United States Department of Agriculture. 876 NUTRITION AND HEAT REGULATION. find, by the carbohydrates. For the first, function protein (or its split-products) is absolutely needed, and perhaps is alone needed. In any event, if the supply of non-protein is sufficiently large, then the amount of protein can be lowered to a certain irreducible minimum which is required for purposes of genuine assimilation, that is, the construction of living material. The Nutritive History of the Protein Food. — The digestive changes undergone by protein and its subsequent absorption have been described in the section on Digestion. It will be remembered that the products of protein digestion are absorbed mainly into the blood-vessels of the intestine, and therefore must pass through the liver before reaching the general circulation. It will also be remem- bered that we are as yet ignorant of the precise form in which these products enter the portal blood. This deficiency in our knowledge constitutes a serious obstacle to a satisfactory explanation of the nutritional history of the protein. Two general views may be mentioned concerning the ultimate fate of the absorbed material. One of these theories (Voit) assumes that the digested material is all synthesized into a new protein, during or after absorption, being converted into what we might call a body protein charac- teristic of the animal. Although it is not specifically stated the assumption seems to be that this body protein is serum-albumin or, at least, one of the blood-proteins. The theory assumes, moreover, that some of the absorbed material is assimilated to form living protoplasm, so far as this is necessary to replace the wastes of the tissue or to provide new material for growth. The portion of the absorbed protein that subserves this function is designated as tissue protein. It is obvious that this function cannot be replaced by the non-protein — that is, the non-nitrogenous — foodstuffs when taken without accompanying nitrogenous material. The larger portion of the absorbed material, however, after distribution to the tissues is destroyed, with liberation of heat, under the influence of the ac- tivity of the living cells, but without actually becoming trans- formed into living matter. The cells act toward this material as the yeast cells do toward the sugar that they decompose into alcohol and carbon dioxid. The portion of the protein that under- goes this fate is designated as the circulating protein, on the hy- pothesis that it enters the circulating liquids of the body, the blood, and lymph. The second general point of view represents perhaps the trend of modern investigation. It starts from the belief now generally accepted that the digestive processes do not stop at the peptone stage, but result in splitting the protein molecule more or less completely into its constituent amino bodies, or into a mixture of GENERAL METHODS — HISTORY OF PROTEIN FOOD. 877 such amino bodies and polypeptids. From this group of split products, none of which is of sufficient complexity to be desig- nated as a protein, some protein is reconstructed by processes of synthesis taking place in the wall of the intestine or in the liver. That this is a possibility, that, in other words, the body may build its own protein out of the split products of a complete pancreatic hydrolysis, has been demonstrated by the work of Loewi and others.* Dogs fed on the split products of a pancreatic digestion, together with sufficient carbohydrates and fats, may be kept in nitrogenous equilibrium or may even store up protein in the body. It is interesting to know that the split products of pro- tein obtained by complete hydrolysis with boiling acids cannot be utilized in this way by the body. The end products of pancreatic and acid hydrolysis of protein are very similar, but evidently the latter process either goes too far or results in the production of sec- ondary reactions which unfit the split products for synthesis by the tissues of the body. It is possible, as was suggested first by Abderhalden, that in the normal digestion of protein in the body some polypeptids remain which serve as a sort of nucleus for the reconstruction of the body protein. Any way, the view that we are now describing assumes that the protein material of the food is first broken down quite completely in digestion and then a new body protein is reconstructed from some of this material. In other words, out of the various pieces into which the food-protein is split by the processes of digestion a certain number are united by synthetic processes to form the special body-protein of the animal. The balance of the amino bodies not thus used is of value to the body only as a source of energy, but not for tissue building. The nitrogen ra-them is useless to the body and con- sequently it is promptly split off, probably in the liver, as ammonia, which is then converted to urea and excreted. The organic acid group left behind is important as a source of energy. It can be oxidized with the production of heat, or if the food is in excess of the energy requirements of the body, it may be converted to glyco- gen or fat and stored as a reserve. So much of the food protein as is not resynthesized into tissue protein for the construction of tissue, is used or destroyed for purposes of energy without again passing into the protein form. Folinf has called attention to the fact that the proportions of the different nitrogen compounds in the urine vary with the amount of protein food. Upon an average diet containing 16 to 17 gms. of nitrogen (100 to 106 gms. of usable protein) the urea forms 87 to 88 per cent, of the total nitrogen of the urine, while * For discussion and literature, consult Liithje in " Ergebnisse der Physi- ologie," vii., 1908. fFolin, "American Journal of Physiology," xiii., 45, 66, and 117, 1905. 878 NUTRITION AND HEAT REGULATION. when the protein intake is reduced to 3 or 4 gms. of nitrogen the urea forms onjy 61 to 62 per cent, of the total nitrogen of the urine. On the other hand, the creatinin and the purin bodies (uric acid, xanthin, etc.) are not diminished in amount with a decrease in the protein food. He suggests, therefore, that the latter bodies, creatinin and purin bases, arise from the breaking down of the living tissues, the catabolism or wear and tear of the living machinery, and may be taken as an index of the extent of this metabolism. The urea, on the other hand, represents in part that portion of the protein food which, from the present point of view, is not used for construction of living matter, but which acts simply as an energy food. The amount of urea, there- fore, while a reliable index of the weight of protein destroyed in the body, is not an index, as was formerly supposed of the amount of living tissue protein broken down, since a portion of it may arise from the food-protein as described above. The Amount of Protein Necessary for Normal Nutrition. — As was stated above, nitrogen equilibrium may be maintained on different amounts of protein food. It is important, from a scientific and from an economic standpoint, to determine the low limit for this equilibrium and to ascertain whether, for the purpose of the best as well as the most economical nutrition, this low limit is as good as or preferable to a higher amount of protein in the diet. Examination of the dietaries of civilized races shows that, on the average, 100 to 120 gms. of protein are used daily by an adult man. Voit gives 118 gms. of protein as the average daily consumption. A variable portion of this amount passes into the feces in undigested form, but we may assume that about 100 to 105 gms. are absorbed and actually metabolized in the body. If we take into account the weight of the body, this amount of protein may be estimated as equivalent in round numbers to 1.5 gms. of protein (or 0.23 gm. nitrogen) per kilogram of body- weight. In recent years serious attempts have been made to ascertain how Low this daily quota of protein may be reduced without destroying nitrogen equilibrium or injuring the effective- ness of the body for muscular or mental work. Siven was able for short periods to reduce his daily diet of protein to as little as 0.5 gm. (0.08 gm. N.) per kilo of body weight, but probably the most important experiments of this kind were those carried out by Chittenden.* In this work the experiments were continued over long periods of time, and were made upon three different groups of men, five university teachers, a detail of thirteen men from the Hospital Corps of the Army, and eight university students * Consult Chittenden, "Physiological Economy in Nutrition," New York, 1905, for discussion and literature. GENERAL METHODS HISTORY OF PROTEIN FOOD. 879 classed as athletes. The general result of the investigation showed that the body can be maintained in protein equilibrium and in a normal state of efficiency upon a diet containing only 30 to 50 gms. of protein per day, according to the weight of the individual — or, expressed in more general terms, the daily quota of protein per kilo of weight may be reduced from 1.5 gms. (0.23 gm. N.) to about one-half, that is, 0.75 gm. of protein or 0.12 gm. of nitrogen per kilo. This general result has been confirmed on a large scale by the studies made by McCabe * of the metabolism of the Bengalis of India. He finds that the average Bengali metabolizes in his body, so far as may be judged from the nitrogen excreted in the urine, only about 37.5 gms. of protein daily, corresponding to a consumption per kilo of 0.7 gm. of protein or 0.113 gm. of nitrogen. A corresponding average amount of protein was, of course, eaten daily, and on this low protein diet they exist in apparent health. Rubner f also empha- sizes the fact that milk, which forms the sole diet of the infant, is a protein poor food. The usual daily diet of the adult has a heat value of from 2400 to 3000 calories (see p. 920). Of this total heat value the protein food in the diets usually recommended forms about 15 to 20 per cent. In milk, however, according to Rubner's estimates, the protein constitutes only about 10 per cent, of the total heat value. As the result of these and similar investigations, the practical question presents itself as to what constitutes the optimum daily quota of protein. If the body can be kept in good condition upon 0.75 gm. per kilo per day, will an ingestion of more than this, say twice as much, prove injurious or beneficial or indifferent to the body? Outside its hygienic aspect the question is important from an economical standpoint, since the proteins are the most expensive foods, and in the feeding of large masses of individuals — armies, schools, asylums, etc. — it is not desirable to waste money on protein food if it is not needed. The full and satisfactory answer to this question must be deferred until more experience is obtained. The report upon the Bengalis, noted above, would seem at first to constitute a satisfactory demonstration of the practicability of a low protein diet, but McCabe states the Bengali is inferior physically to the average European, and is particularly deficient in capacity for muscular work, and he is inclined to attribute this inferiority to the diet. Moreover, the Bengali is quite susceptible to kidney troubles, a fact which seems to destroy one prediction often made by those who advocate a low protein diet, namely, that the * McCabe, " The Metabolism of the Bengalis, Calcutta," 1908. (Scientific Memoirs, Medical Department Government of India, No. 34.) Also later report upon Jail Dietaries, ibid., No. 37, 1910. t Rubner, "Das Problem des Lebensdauer," 1908; Cohnheim, '"Die Physiologie der Verdauung u. Ernahrung," 1908. 880 NUTRITION AND HEAT REGULATION. smaller amount of work thus thrown on the kidneys would result in a diminution of diseases of the kidney. The newer conceptions in regard to the digestion and nutritive history of the protein foods certainly seem to favor the adoption of a low protein diet. If protein is eaten in excess of the real assimilation needs of the tissues, all the excess, so far as we can see, might just as well be substituted by carbohydrate or by carbohydrate and fat. The excess nitrogen thus eaten appears to be so much useless ballast which the body very promptly gets rid of. The uncertain point, however, is what constitutes the assimilation need of the tissues. The experiments given above would place this need very low, according to the lowest estimate, at about 5 per cent, of the total energy value of the food. That is to say, if the daily diet contains heat energy equivalent to 2400 calories, only 5 per cent, of this, 120 calories, needs to be in the form of protein, an estimate which would bring the protein to about 30 gms. daily. Against this line of reasoning it may be urged, in the first place, that our positive knowledge of the history of protein in the body is too incomplete to justify its application in a wholesale way to such an important matter as the daily diet. Serious blunders have been made in the past, notably in the nutritive employment of gelatin, by a premature application of incomplete knowledge. Secondly, it must be remembered that mankind, left to the guidance of the natural appetites and the eliminating influence of natural selec- tion, has always, when possible, adopted the high protein level of 90 to 100 gms. per day. Indeed, the uniformity with which this level has been unconsciously maintained is a striking fact. Among the rich as well as the poor, and in races very differently placed as regards quantity of available food, substantially the same amount of protein (80 to 100 gms.) is consumed daily by each individual. The element of the diet which varies most widely, as Cohnheim points out in an interesting discussion of this ques- tion, is, on the contrary, the non-protein, particularly the carbo- hydrate material. Those who are obliged to do much muscular work to earn a living or for the sake of pleasure (sports, athletics) add to their daily quota of protein an excess of carbohydrate food to furnish the requisite energy. On the contrary, those whose daily life requires but little muscular exertion, cut clown the carbo- hydrates and fats, and make their diet relatively but not abso- lutely richer in proteiii. That mankind has made a mistake in adopting the higher protein level can hardly be claimed on the basis of our present knowledge. We must be content to await until the matter is tested more completely on a larger scale or until our knowledge of the details of protein metabolism is more satisf actor v. GENERAL METHODS — HISTORY OF PROTEIN FOOD. 881 The Intermediate Stages in Protein Metabolism. — The urea found in the urine and in lesser amounts in the sweat and other secretions may arise in two general ways: 1. As an end-product of the digestive hydrolysis of the protein food. As was explained above, the protein material is split by the successive actions of the pepsin, trypsin, and erepsin into products which no longer give the biuret reaction for protein. As a result of this process much of the nitrogen appears in the form of ammonia, monamino-acids, and the so-called diamino-bodies, such as arginin, and we may suppose that in these forms some of it is carried to the liver. In this organ the ammonia, as ammonia salts, is transformed into urea. The monamino-acids, some of them, at least, are deamidized, that is, their NH2 group is split off as ammonia which then is like- wise converted to urea. The organic acid radicles left after removal of the NH2 group may subsequently be oxidized through various stages to carbon dioxid and water, or they may be synthesized to form a carbohydrate body or possibly a fat, and thus be kept temporarily as storage, although their eventual fate is to suffer oxidation to carbon dioxid and water. It is a very significant indi- cation of the complexity of the processes that may take place in the liver to find that not only can it deamidize the amino-acids and get rid of the (NH2) group as urea, but it can also effect the opposite process, that is, convert oxyacids to amino-acids; lactic acid, for example, to amino-propionic acid (alanin).* Regarding the diamino-compounds like arginin it is known that when this substance is injected subcutaneously its nitrogen is excreted for the most part if not entirely as urea. Since Kossel and Dakin have shown that the liver contains a hydrolytic enzyme, arginase, which is capable of splitting off the guanidin residue of arginin to form urea, we may assume that the arginin formed during protein digestion actually undergoes this fate. The process is represented by the following equation : NHC:„rrA f Alcohol-free days. . 212.58 gms. carbon. Cjerre I Alcohol days 220.84 " + 8.26 " Clonatt -f Alcohol-free days. .214.83 gms. carbon. p \ Alcohol days 220.87 " " + 6T04 " These results indicate that the alcohol is used by the body in place of the other carbon-containing foodstuffs. Geppert and Zuntz have also found that on alcohol days there is no material increase in the carbon dioxid eliminated or the oxygen absorbed. Theoretically if the alcohol takes the place of the other material the amount of carbon dioxid excreted should be diminished. One gram of alcohol when oxidized furnishes as much heat as 1.7 gms. of sugar or 0.75 gm. of fat. But 1 gm. of alcohol when burnt yields only 1.91 gms. of CO,, while 1.7 gms. of sugar yield 2.77 gms. CO,, and 0.75 gm. of fat, 2.13 gms. of CO,. If fat were replaced by the alcohol the amount of COj should be reduced about 10 per cent., while if the sugar were replaced the reduction should amount to 31 per cent. That such a reduction is not actually observed is explained by the fact that the alcohol leads to more muscular activity and a greater loss of heat from the congested skin, thus indirectly augmenting the oxidations of the body. To determine whether the combustion of the alcohol protects the protein material from metabolism to the same extent as is done by carbohydrates and fats, experiments have been made in which the individual was brought into nitrogen equilibrium on a mixed diet. * Sec Atwater and Benedict, Bulletin 69, United States Department of Agriculture, 1889. INORGANIC SALTS, STIMULANTS, AND CONDIMENTS. 909 Then for a given period a portion of the carbohydrate was omitted and alcohol in isodynamic amounts was substituted. The result was an increase in the nitrogen excretion, showing that the alcohol did not protect fully the protein tissue. In a third period the first diet was resumed, and after nitrogen equilibrium had again been established the same proportion of carbohydrate was omitted from the diet, but this time alcohol was not substituted. If the diet was poor in protein it was found that less protein was lost from the body when the alcohol was omitted than when it was used. Hence alcohol not only did not take the place of the carbohydrate in protecting the protein, but it actually caused an increased pro- tein consumption.* Other observers (Neumann, Rosemann f) have found that, although the effect just described may occur in the first few days, yet if the alcohol diet is maintained the injurious effect exercised by it disappears, the body ceases to lose its protein tissue, and may even lay on protein. These results, taken with those given above, indicate, therefore, that the alcohol may actually take the place physiologically of fat or carbohydrates as a source of energy and as a protector of protein metabolism. J Under these circumstances, therefore, it acts as a true foodstuff. It is perhaps scarcely necessary to emphasize the fact that this scientific con- clusion does not mean that alcohol can be regarded as a prac- tical food. Its expensiveness, its dangers when the dose is too large, etc., prevent us from regarding it in this light. As Rosemann says, however, it is possible that on account of its ready absorption and palatableness it may form a useful substitute for the solid, non-nitrogenous foodstuffs in sickness. This suggestion seems to be supported by many reports of cases in which alcohol has served as the sole or main nutriment during the critical periods of fevers and in other conditions, but it needs to be tested more carefully by direct experiments before it can be accepted generally for prac- tical purposes. In line with this suggestion there are some results upon diabetic patients (Benedict and Torok) which indi- cate that in this condition alcohol used as a food diminishes the production of acetone bodies and protects the protein. * See Miura, "Zeitschrift fur klin. Medicin," 20, 1892. t See Rosemann, "Archiv f. die gesammte Physiologie, " 86, 307, 1901, and 100, 348, 1903, for discussion and literature. % See also At water and Benedict, "Memoirs of National Academy of Sciences," 1902; and Atwater, "The Nutritive Value of Alcohol," in "Physi- ological Aspects of the Liquor Problem," vol. ii., 1903. CHAPTER L. EFFECT OF MUSCULAR WORK AND TEMPERATURE ON BODY METABOLISM— HEAT ENERGY OF FOODS— DIETETICS. The Effect of Muscular Work. — It is a matter of common knowledge that muscular exercise increases the food consumed, and scientific experiments have shown that it greatly augments the consumption of material in the body. Physiologists have attempted to determine which of our energy-yielding foodstuffs is directly affected by muscular activity. A brief statement of the development of our knowledge upon this point will make clear our present theories. According to Liebig, our foods fulfill two general purposes in the bod}' : they are burnt to supply heat, respira- tory foods — fats, and carbohydrates, or they are used to construct tissue, plastic foods — proteins. It seemed to follow, from this generalization, that muscular tissue in activity should use protein material, and it was believed at that time that the metabolism of protein furnished the source of muscular energy. That it is not the sole source was demonstrated by the interesting experiments of Fick and Wislicenus. These physiologists ascended the Faul- horn to a height of 1956 meters. Knowing the weight of his body, each could estimate how much work was done in ascending such a height. Fick's weight, for example, was 66 kilograms; therefore in climbing the mountain he performed 66X1956=129,096 kilo- grammeters of work. In addition, the work of the heart and the respirator}- muscles, which could not be determined accurately, was estimated at 30,000 kilogrammeters. There was, moreover, a certain amount of muscular work performed in the move- ments of the arms and in walking upon level ground that was omitted entirely from their calculations. For seventeen hours before the ascent, during the climb of eight hours, and for six hours afterward their food was entirely non-nitrogenous, so that the urea eliminated came entirely from the protein of the body. Nevertheless, when the urine was collected and the urea estimated, it was found that the energy contained in the protein destroyed, reckoned as heat energy, was entirely insufficient to account for the work done. Although later estimates would modify somewhat the actual figures of their calculation, the margin was so great that 910 EFFECT OF MUSCULAR WORK AND TEMPERATURE. 911 the experiment has been accepted as showing conclusively that the total energy of muscular work does not come necessarily from the oxidation of protein. Later experiments made by Voit upon a dog working in a tread-wheel and upon a man performing work while in the respiratory chamber gave the surprising result that not only may the energy of muscular work be far greater than the heat energy of the protein simultaneously oxidized, but that the performance of muscular work within certain limits does not affect at all the amount of protein metabolized in the body, since the output of urea is the same on working days as during days of rest. Careful experiments by an English physiologist, Parkes, made upon soldiers, while resting and after performing long marches, showed also that there is no distinct increase in the secretion of urea after muscular exercise. It followed from these latter experiments that Liebig's theory as to the source of the energy of muscular work is incorrect, and that the increase in the oxidations in the body, which undoubtedly occurs during muscular activity , must affect only the non-protein material — that is, the fats and carbohydrates. Subsequently the question was reopened by experiments made under Pfluger by Argutinsky.* In these experiments the total nitrogen excreted was determined with especial care in the sweat as well as in the urine and the feces. The muscular work done consisted in long walks and mountain climbs. Argutinsky found that work caused a marked increase in the elimination of nitrogen, the increase extending over a period of three days, and he estimated that the additional protein metabolized in consequence of the work was sufficient to account for most of the energy expended in per- forming the walks and climbs. A number of objections have been made to Argutinsky 's work. It has been asserted that during his experiment he kept himself upon a diet deficient in non-protein material, and that if the supply of this material had been sufficient there would not have been an increase in protein metabolism. These experiments were repeated in various forms by many ob- servers (Zuntz, Speck, et at.), and the general result has been the abandonment of both the former views — the Liebig theory, that the energy comes only from the consumption of protein, and the Voit theory, that it comes only from the oxidation of non-pro- tein material. It has been found that in muscular work carried to the ordinary extent protein material, in excess of that destroyed in conditions of rest, may or may not be used according to the amount of fats and carbohydrates contained in the diet. If these latter elements are in sufficient quantity they furnish the energy required, and the protein metabolism is not increased by work. If, however. * Argutinsky, "Pfluger's Archiv f. die gesammte Physiologie, " 46. 552. 1890. 912 NUTRITION AND HEAT REGULATION. the non-proteins are not sufficient in quantity some of the energy- is obtained at the expense of the protein of the body, and there is an increase in the nitrogen excretion. We may believe, in fact, that the energy necessary for muscular work may be obtained from any of the heat-yielding foodstuffs — carbohydrates, fat, or proteins. It seems probable that the sugar (glycogen) of the muscle is, so to speak, the easiest source; but, when the carbohydrates are deficient or absent altogether in the diet, muscular exercise is accompanied by an increase in the consumption of fats or proteins or both. According to the view adopted in the preceding pages, it will be re- membered that when protein-food is used as a source of energy it is used not as protein, but after the nitrogen has been split off in the liver by the process of deamidization of the amino-acids. According to this view, therefore, the working muscle cells obtain their energy always by oxidation of non-nitrogenous material, although a portion of this material may have been derived ulti- mately from the protein of the food. The Voit theory is correct to the extent that on an abundant non-protein diet much muscular work may be done without any increase in the consumption of protein tissue. The muscle is a protein machine for the accom- plishment of work, but in the performance of moderate work there is apparently no greater wear and tear of the machinery, no greater tissue waste, than under resting conditions. If, however, the muscular work is excessive, the tissue waste may be increased. Argutinsky found an increased nitrogen elimination lasting two or three days after the cessation of the work. It is probable that this result indicates a greater waste of the protein apparatus itself, and this idea is borne out by the fact that under similar conditions other observers have detected an increase in the creatinin and uric acid excretion, nitrogenous wastes that are derived from muscle. The effect of muscular work on the carbon excretion, car- bon dioxid, is, of course, marked and invariable. Some extra ma- terial must be oxidized to furnish the energy, and since this material is usually sugar, or sugar and fat, or the non-nitrogenous portion of the protein of the diet, the effect, so far as the excretions are con- cerned, will be most manifest in the amount of carbon dioxid given off. Pettenkofer and Voit found that the carbon dioxid eliminated by a man during a day of work was nearly double that excreted during a day of rest. Along with this rise in the carbon dioxid excretion there is a corresponding increase in the absorption of oxygen. These results are well illustrated in the following table, which shows the effect of posture and of severe muscular work upon the hourly excretion of carbon dioxid and absorption of oxygen (Benedict and Carpenter).* * Carnegie Institution of Washington, No. 126, 1910. EFFECT OF MUSCULAR WORK AND TEMPERATURE. 913 . co2 eliminated. o2 absorbed. Heat produced. Man at rest, sleeping Man at rest, sitting Man at rest, standing Man during severe work Grams. 23 33 37 248 Grams. 21 27 31 213 Calories. 71 97 114 653 Metabolism During Sleep. — It has been shown that during sleep there is no marked change in the total nitrogen excreted, and therefore no distinct decrease in the protein metabolism. According to Siven, there is a distinct diminution in the secretion of the endogenous purin nitrogen. On the contrary, the carbon dioxid eliminated and the oxygen absorbed are unquestionably diminished. This latter fact finds its simplest explanation in the supposition that the muscles are less active during sleep. The muscles do less work in the way of contractions, and, in addition, probably suffer a diminution in tonicity, which also affects their total metabolism. Effect of Variations in Temperature. — In warm-blooded animals variations of outside temperature within ordinary limits do not affect the body temperature. An account of the means by which this regulation is effected will be found in the chapter upon Animal Heat. So long as the temperature of the body remains con- stant, it has been found that a fall of outside temperature may increase the oxidation of non-protein material in the body, the in- crease being in a general way proportional to the fall in tempera- ture. That the increased oxidation affects the non-protein con- stituents is shown by the fact that the urea remains unchanged in quantity, other conditions being the same, while the oxygen con- sumption and the carbon dioxid elimination are increased. This effect of temperature upon the body metabolism is due mainly to a reflex stimulation of the motor nerves to the muscles. The tem- perature nerves of the skin are affected by a fall in outside tempera- ture, and bring about reflexly an increased innervation of the muscles of the body. Indeed, it is stated * that unless the lowering of the temperature is sufficient to cause shivering or muscular tension no increase in the excretion of C02 results. This fact suf- fices to explain, therefore, the physiological value of shivering and muscular restlessness when the outside temperature is low. The fact that variations in outside temperature affect only the con- sumption of non-protein material falls in, therefore, with the concep- tion of the nature of the metabolism of muscle in activity, given above. When the means of regulating the body temperature * Johannson, " Skandinavisches Archiv f. Physiologie," 7, 123, 1897. 58 914 NUTRITION AND HEAT REGULATION. break down from too long an exposure to excessively low or ex- cessively high temperatures, the total body metabolism, protein as well as non-protein, increases with a rise in body temperature and decreases with a fall in temperature. In fevers arising from pathological causes it has been shown that there is an increased excretion of nitrogen as well as of carbon dioxid. Effect of Starvation. — A starving animal must live upon the material present in its body. This material consists of the fat stored up, the circulating and tissue protein, and the glycogen. The latter, which is present in comparatively small quantities, is quickly used, disappearing more or less rapidly according to the extent of muscular movements made. Thereafter the animal lives on its own protein and fat, and if the starvation is continued to a fatal termination the body becomes correspondingly emaciated. Examination of the several tissues in animals starved to death has brought out some interesting facts. Voit took two cats of nearly equal weight, fed them equally for ten days, and then killed one to serve as a standard for comparison and starved the other for thirteen days; the latter animal lost 1017 gms. in weight, and the loss was divided as follows among the different organs : Loss TO Supposed Weight Actual Loss Each 100 Gms. of Organs Before of Organs of Fresh Organ Starvation. in Gms. (Percentage Loss) Bone 393.4 54.7 13.9 Muscle 1408.4 429.4 30.5 Liver 91.9 49.4 53.7 Kidney 25.1 6.5 25.9 Spleen 8.7 5.8 66.7 Pancreas 6.5 1.1 17.0 Testes 2.5 1.0 40.0 Lungs 15.8 2.8 17.7 Heart 11.5 0.3 2.6 Intestines 118.0 20.9 18.0 Brain and cord 40.7 1.3 3.2 Skin and hair 432.8 89.3 20.6 Fat 275.4 267.2 97.0 Blood 138.5 37.3 27.0 Remainder 136.0 50.0 36.8 According to these results, the greatest absolute loss was in the muscles (429 gms.), while the greatest percentage loss was in the fat (97 per cent.), which had practically disappeared from the body. It is very significant that the central nervous system and the heart, organs which we may suppose were in continual activity, suffered practically no loss of weight : they had lived at the expense of the other tissues. We must suppose that in a starving animal the fat and the protein materials, particularly in the voluntary muscles, pass into solution in the blood, and are then used to nourish the tissues generally and to supply the heat necessary to maintain the body temperature. Examination of the excreta in starving ani- POTENTIAL ENERGY OF FOOD. 915 mals has shown that a greater quantity of protein is destroyed dur- ing the first day or two than in the subsequent days. This fact is explained on the supposition that the body is at first supplied with a certain excess of protein material derived from its previous food, and that after this is metabolized the animal lives entirely, so far as protein consumption is concerned, upon its "tissue protein." If the animal remains quiet during starvation, the amount of nitrogen excreted daily soOn reaches a nearly constant minimum, showing that a practically constant amount of protein (together with fat) is consumed daily to furnish body heat, and material for the energy needs and tissue waste in the active organs, such as the heart. Shortly before death from starvation the daily amount of protein consumed may increase, as shown by the larger amount of nitrogen eliminated. This fact is explained by assuming that the body fat is then exhausted and the animal's metabolism is confined to the tissue proteins alone. The general fact that the loss of protein is greatest during the first one or two days of starvation has been confirmed upon men in a number of interesting experiments made upon professional f asters. For the numerous details as to loss of weight, variations of temperature, etc., carefully recorded in these latter experiments, reference must be made to original sources.* It may be added, in conclusion, that the fatter the body is, to begin with, the longer will starvation be endured, and if water is consumed freely the evil effects of starvation, as well as the disagreeable sensations of hunger, are very much reduced. The Potential Energy of Food. — The food material during digestion and after absorption undergoes numerous chemical changes in the body. Some of these changes are not attended by the liberation of heat to any marked extent. Such is the case, for instance, with the hydrolytic cleavages of the molecule which have been described especially in connection with the digestive processes. As an example of this fact one may take the inversion of the double sugars — one molecule of maltose yields two molecules of dextrose. The heat value of a gram molecule of maltose is 1350.7 calories. The heat value of the dextrose resulting from its inversion is 1347.4 cal., so that the process of hydrolysis liberates only 3.3 cal. or about 0.2 per cent, of the total available energy in the maltose, f Similar hydrolytic cleavages occur doubtless within the tissues, and other changes connected with muscular, nervous, and glandular activity, and the building up and breaking down *"Virchow's Archiv," vol. 131, supplement, 1893; and Luciani, "Das Hungern," 1890. See also Weber, "Ergebnisse der Physiologie, " vol. L, part i., 1902. fSee Herzog, "Zeit. f. physiol. chem.," 37,383, 1903, and Tangl, "Pfluger's Archiv," 115, 1, 1906. 916 NUTRITION AND HEAT REGULATION. of the living substance take place constantly as a part of general nutritional metabolism. On the other hand, many of the chemical processes occurring in the body are especially valuable on account of the heat liberated. These reactions, for the most part, at least, are oxidations; they are effected under the influence of oxidizing enzymes or by some other means of activating the oxygen. The various stages in the process are not explained, but we know that oxygen is necessary and that the carbon and the hydrogen contained in the substances acted upon appear eventually in the form of oxidation products — namely, carbon dioxid and water — Liebig designated the fats and carbohydrates as respiratory foods on the hypothesis that their fate in the body is to be oxidized and furnish heat. While this view is, in the main, correct, it is evident now that a portion at least of the protein molecule, after the splitting off of the nitrogen, may also undergo oxidation and furnish heat. In Liebig's sense, therefore, the proteins play the part of respiratory or heat-pro- ducing foods as well as acting as tissue formers. On the other hand, fats and carbohydrate material may enter to some extent, together with the protein, into the synthesis of cell material, and thus play the role of a plastic or tissue-forming as well as of a respiratory food. We cannot divide the foodstuffs, therefore, strictly into two such classes, but we may perhaps consider the chemical processes in the body under the two heads mentioned above — namely, the oxidation or energy-producing changes and those due to hydrolytic cleavages, synthesis, etc., which are attended by a small liberation of energy, or, indeed, may be accom- panied by an absorption of energy (synthesis). The great supply of heat energy needed by the body to maintain its temperature comes from the oxidation processes. This classification is employed by some physiologists, and is helpful in emphasizing the fact that many chemical changes occur in the body that are of no importance from the standpoint of heat production, and that the changes that do give rise mainly to heat form, as it were, a special group, which is not connected with the building up or breaking down of the living matter, but furnishes the energy by means of which these latter changes and perhaps other functions, such as muscular work, are made possible. The heat produced in and given off from the body is estimated in terms of calories. The small calorie (c) or gram-calorie is the quantity of heat neces- sary to raise one gram of water one degree Centigrade in tempera- ture, while the large calorie (C) or kilogram-caloric is the quantity of heat necessary to raise the temperature of one thousand grams of water one degree. In round numbers an adult man produces in his body and gives off to the surrounding air about 2,400,000 calories POTENTIAL ENERGY OP FOOD. 917 (2400 C.) of heat per day. This great supply of heat is derived from the physiological oxidation of the carbohydrate, fat, and protein material of the food. These same materials may be oxi- dized outside the body by burning them at a high temperature or under a high pressure of oxygen, and the heat that they give off in the process can be measured directly. So far as the fats and carbo- hydrates are concerned, the end-products of the oxidation in the body are the same as in their combustion out of the body, and we may believe, therefore, that the amount of heat produced is the same in both cases. Consequently the heat value of a gram of fat or carbohydrate burnt outside the body is spoken of as its combus- tion equivalent, and it measures the amount of potential energy of these foodstuffs which is available for the production of heat or for the supply of energy in other forms to the working cells. With regard to the protein, the case is somewhat different. Its end-products in the body are carbon dioxid, water, and urea or some other of the nitrogenous waste products. These nitrog- enous wastes are capable of further oxidation with liberation of heat, so that, as far as they are eliminated, the body loses a possible supply of heat energy, which must be subtracted from the total heat energy that the protein gives upon oxida- tion outside the body, in order to determine the available heat energy yielded within the body. The figures obtained for the heat equivalents of the foodstuffs by burning them outside the body in some form of calorimeter are as follows : 1 gm. of fat yields an aver- age of 9300 calories, or 9.3 large calories (C), 1 gm. of carbohydrate yields an average of 4100 calories (4.1 C). These figures may be taken, therefore, to express the quantity of heat given to the body by the oxidation within its tissues of these elements of our food. A gram of protein when burnt outside of the body yields on the aver- age 5778 calories. The heat value of the urea is estimated as 1 gm. = 2523 calories. If we assume that all the nitrogen of the pro- tein appears as urea and that 1 gm. of protein yields J gm. of urea, then the available heat energy of a gram of protein should be equal to 5778—841 (or £ of 2523) = 4937 calories. Later workers, however, have given reasons for believing that this last figure is too high. All of the nitrogen is not eliminated as urea, and, moreover, all of the nitrogenous waste is not excreted in the urine; a distinct pro- portion is given off in the feces. Rubner has calculated the avail- able heat energy of proteins by direct experiments upon animals. In these experiments the heat value of the protein fed was directly determined by burning a sample in a calorimeter. Then after feed- ing a known amount of the protein the urine and feces were col- lected and their heat value was determined in the same way. The difference between the total heat value of the protein fed and the heat value lost in its excreted products in the feces and urine gave 918 NUTRITION AND HEAT REGULATION. the actual heat energy obtained from the protein by the animal body. Results obtained by this method give an average value for 1 gm. protein of 4100 calories (4.1 C), or, since protein contains an average of 16 per cent, of nitrogen, we may say that 1 gm. of ni- trogen ingested as protein has a heat value of 4.1 X 6.25 = 25.6 C. The figures that are used, therefore, in estimating the heat value of our foodstuffs are: 1 gm. protein = 4100 calories (4.1 C). 1 gm. carbohydrate = 4100 calories (4.1 C). 1 gm. fat = 9305 calories (9.3 C). Making use of these values, it is obvious that we can calculate the total heat value of any given diet. If we analyze the food for its composition in the three principal foodstuffs we may determine how many calories will be furnished to the body. In many of the tables published to show the composition of the different foods figures are given also to express their heat value or potential energy, on the belief that, for the most part, our food is used as fuel to supply energy to the body. These values for some of our ordinary foods are as follows : * Protein. Beefsteak, porterhouse 19.1 Beefsteak, round (lean) 20.2 Corned beef (canned) 26.3 Veal, leg (lean) 19.4 Veal liver 19.0 Mutton, leg (lean) 16.5 Pork, ham (fresh, lean) 24.8 Pork chops, medium fat 13.4 Chicken (fowl) 13.7 Shad 9.4 Shad roe 20.9 Eggs 11.7 Milk 3.3 Oatmeal 16.1 Rice 8.0 Wheat flour (entire wheat) 13.8 Green peas 7.0 Potatoes (raw) 2.2 Spinach 2.1 Tomatoes 0.9 Apples 0.4 Bananas 1.3 It must be borne in mind, however, that the entire nutritional value of a food is not expressed in its heat value. Some of our food material — the green foods and fruits, for example — are useful and in a measure essential because of their salts and organic acids, and it seems quite possible that the different proteins or even the different carbohydrates or fats may be found to have each a specific * Selected from Atwater and Bryant, Bulletin 28 (revised edition), United States Department of Agriculture, 1889. Fat. Carbohy- ^ Heat Value in Calories DRATE. Per Pound. 17.9 0.8 1110 2.4 1.2 475 18.7 4.0 1280 3.7 1.1 520 5.3 1.3 575 10.3 0.9 740 14.2 1.3 1060 24.2 0.8 1270 12.3 0.7 775 4.8 0.7 380 3.8 2.6 1.5 600 10.7 0.7 680 4.0 5.C 0.7 325 7.2 < S7.5 1.9 1860 0.3 ■o.c 0.4 1630 1.9 U.9 1.0 1675 0.5 6.1 1.0 465 0.1 ] x.-l 1.0 385 0.3 3.2 2.1 110 0.4 3.9 0.5 105 0.5 ] 1.2 0.3 290 o.6 : 52.1 0.8 460 DIETETICS. . 919 influence upon metabolism. Thus it' is stated that the disease known as beri-beri, which formerly in the Japanese navy showed the high incidence of 325 cases out of 1000, has been entirely eradicated by substituting for an exclusive diet of rice one of equal quantities of barley and rice. Just what this change in diet signi- fies has not been determined, but the result suggests strongly the idea of a qualitative difference in the metabolic influence of the foodstuffs. In this respect the science of dietetics has a wide field for investigation. In a general way, however, the heat energy of a food expresses its value as a means for supplying the energy needs of the living cells. In the work that these cells perform, whether it is contraction, secretion, or nervous activity, energy is needed, and this energy is carried into the body in the potential chemical energy of the proteins, fats, and carbohydrates, whatever may be the source from which these foodstuffs are obtained. Dietetics. — The subject of the proper nourishment of individ- uals or collection of individuals in health and in sickness is treated usually in works upon hygiene or dietetics. The practical details of the preparation and composition of diets must be obtained from such sources.! The general principles upon which practical dieting depends have been obtained, however, from experimental work upon the nutrition of man and the lower animals, some account of which has been given in the foregoing pages. In a healthy adult the main objects of a diet are to furnish sufficient nitrogenous and non-nitrogenous foodstuffs, salts, and water to maintain the body in an equilibrium of material and of energy — that is, the diet must furnish the material for the regeneration of tissue and the material for the heat produced and the muscular work and other work done. Nutritional experiments prove that this object may be accomplished by protein food alone, together with salts and water. It is doubtful, however, whether, in the case of man, such a diet could be continued for long periods without causing some nutritional disturbance, -directly or indirectly. It will be remembered that a pure meat diet is not entirely protein, since all flesh contains some fats and carbohydrates (glycogen). The functions of a diet are accomplished more easily and more economically when it is composed of proteins and fats, or proteins and carbohydrates, or, as is almost universally the case, of proteins, fats, and carbohydrates. The experience of mankind shows that such a mixed diet is most beneficial to the body and most satisfying to that valuable regulating mechanism of nutrition, the appetite. Expressed in its most general form the cells of our body need food for two purposes: first, to supply the energy needs; second, to furnish the material for the construction of their *For practical directions, see Gautier, " L'alimentation et les regimes," 1904; Blyth, "Foods: their Composition and Analysis." 920 NUTRITION AND HEAT REGULATION. own living substance, that is, for assimilation. The first of these purposes is fulfilled by any of the three energy-yielding foodstuffs, carbohydrates, fats or proteins, but as a matter of fact we use chiefly the carbohydrates on account of their economy and the ease with which they are utilized by the body. For the second purpose, the construction of protoplasm or living matter proteins (or their cleavage products) are absolutely necessary. Whether fats or carbohydrates participate at all in this process is perhaps an open question. In accordance with this specific and necessary function of the protein we find that the amount used in the daily diet is fairly constant, about 100 grams, while the proportions of fat and carbohydrate show wide variations. Since from the energy standpoint the fats and carbohydrates have a common function, serving as fuel for the energy needs of the body, we ought to be able to exchange them in the diet in the ratio of their heat values. This ratio, or as it is frequently called, the isodynamic equiva- lent, is as 9.3 to 4.1 or 2.3 to 1, and within the limits permitted by the appetite we should be able to substitute 1 part of fat for 2.3 parts of sugar or starch. Experiments upon animals, as well as the experience of mankind, show that this substitution can be made in a general way, although it is not advisable to eliminate either of these foodstuffs entirely from the diet. The fact that within certain limits fats and carbohydrates may be substituted for each other is illustrated in a general way by the different diets recommended by various physiologists, since it will be noticed that in those in which the proportion of fat is large the amount of carbohydrate is reduced. AVERAGE DIETS AND THEIR HEAT VALUES. MOLESCHOTT. RANKE. VoiT. Calories. Calories. Calories. Protein 130 gms. . . . 533 100 gms. . . . 410 118 gms. ... 483 Fats 40 " ... 372 100 " ... 930 56 " ... 520 Carbohydrates. . . 550 " . . ■ 2275 240 " . ■ .984 500 " . . . 2050 2980 2324 3053 FORSTER. ATWATER. Calories. Calories. Protein 131 gms. ... 567 125 gms 512 Fats 68 " ... 632 125 " .... 1172 Carbohydrates . . 494 " ... 1825 400 " .... 1640 2024 3324 The average heat value of these diets is equal to 2742 calories, of which about 18 per cent, is furnished by the protein. Generally speaking, it will be found that in the dietaries selected voluntarily by mankind the protein furnishes from 15 to 20 per cent, of the total heat value of the diet. According to some physiologists this proportion is unnecessarily large and it might be reduced to as little as 5 or 10 per cent. Whether or not such a change is DIETETICS. 921 justified has already been discussed to some extent (p. 878). Leaving aside this point, it is usually estimated in round numbers that the diet should furnish daily 2400 Calories for an individual weighing 60 kgms., or about 40 Calories per kgm. of body weight. It will be noticed that in all cases the greatest portion of this energy is obtained from the carbohydrate food, which, on account of its economy, its abundance, and its ease of digestion and oxidation in the body, constitutes the bulk of our diet. In cases of excessive muscular work the food eaten may supply more than twice the average heat value given above. Thus, Atwater and Sherman estimate that in a six-day bicycle race by professionals the heat value of the food for the different participants varied from 4770 to 6095 calories. Chittenden, in the work previously re- ferred to,* has raised the question whether the heat value of the diet ordinarily employed is unnecessarily high. In his own case he found that the body could be well nourished on a diet con- taining a total heat value of only 1600 calories or 28 calories per kgm. of body weight instead of 40 calories. The diet in this case, it will be remembered, contained only 36 to 40 gms. of protein in place of the 100 to 130 gms. recommended in the diets mentioned above. The question thus raised is one that must be decided by actual experience, but from the numerous statistical and experi- mental results now available! it would appear, as has been stated above, that the total energy necessary in a diet, estimated in terms of its heat value, varies chiefly with the amount of muscular work to be done. Persons who lead a very muscular life require a correspondingly large amount of energy in the diet, and this demand is met usually by augmenting the proportion of carbo- hydrate and fat, especially the carbohydrate. Since the amount of protein is not varied greatly in such cases the diet is relatively poor in this foodstuff. On the contrary, those who lead a sedentary life, including, broadly speaking, all the well-to-do class, require less energy in their diet, and they can afford to reduce the pro- portion of carbohydrate and fat. The diet in such cases may be relatively rich in protein, although the amount per kilogram of body weight is not increased, in fact, is usually diminished some- what. These facts are illustrated in Atwater's estimate of the diet necessary for men performing different amounts of muscular work. Protein. Carbohydrate and Fat. Man doing hard muscular work 600 cal. 3550 cal. Man doing moderate muscular work 500 ' 2900 Man doing no muscular work 360 " 2040 ' * Chittenden, "Physiological Economy in Nutrition," 1905. t See especially the numerous Bulletins of the U. S. Department of Agriculture, Nos. 28, 116, 129, 149, etc. 922 NUTRITION AND HEAT REGULATION. On comparing these diets it will be observed that in per- forming hard muscular work the diet contained 1700 calories of energy beyond that used when no work was done. About six- sevenths of this increase was provided for by the carbohydrates and fats. It will be seen also that in this case the proportion of the total energy obtained from protein remained practically identical. Mankind is guided and has been guided in all times by the control of the appetite, using this term in a general sense to designate the conscious desire for food, and also the desire, more or less clearly recognized, for special kinds of food. If scientific experiments indicate that this regulatory apparatus leads us to ingest more food than is actually required for the assimilation needs and the energy needs of the body, it remains for observa- tion and experiment to determine whether this excess is beneficial or useless or, perhaps, even harmful. Munk gives an interesting table showing how much of certain familiar articles of food would be necessary, if taken alone, to supply the requisite daily amount of protein or non-protein material; his estimates are based upon the percentage composition of the foods and upon experimental data showing the extent of absorption of the foodstuffs in each food. In this table he supposes that the daily diet should contain 110 gms. of protein = 17.5 gms. of N, and non- proteins sufficient to contain 270 gms. of C: Fok 110 Gms. Protein v 97n r r (17.5 Gms. N). * or 270 (jMS- U Milk 2900 gms. 3800 gms. Meat (lean) 540 " 2000 " Hen's eggs 18 eggs. 37 eggs. Wheat flour 800 gms. 670 gms. Wheat bread 1650 " 1000 " Rve bread 1900 " 1100 " Rice 1870 " 750 " Corn 990 " 660 « Peas 520 " 750 " Potatoes 4500 " 2550 " As Munk points out, this table shows that any single food, if taken in quantities sufficient to supply the nitrogen, would give too much or too little carbon and the reverse; those animal foods which, in certain amounts, supply the nitrogen needed furnish only from one- fourth to two-thirds of the necessary amount of carbon and, vice versa, the vegetable foods if taken in sufficient quantity to supply the carbon would not give sufficient nitrogen, or if used alone to furnish the requisite nitrogen would give an excess of carbon. This same fact is illustrated in another way in a table compiled by Cohnheim.* To furnish the body with its necessary daily * Cohnheim, " Die Physiologie der Verdauung und Ernahrung," 1908. DIETETICS. 923 quota of 100 grams of protein the following amounts of different foods, expressed in their heat values, would be required: Meat 495 Coarse bread 4552 Eggs 1133 Fine bread 4720 Cheese 1704 Potatoes 5000 Milk 2070 Rice 5600 Corn 4104 It is evident from this table that a person leading a sedentary life who used a vegetable diet alone would be required, in order to obtain his necessary protein, to consume much more carbohy- drate than from an energy standpoint was needed by the body. As Cohnheim points out, the animal foods are for this reason espe- cially suited to supply the protein needs of those who lead a com- paratively inactive life. In practical dieting we are accustomed to get our supply of proteins, fats, and carbohydrates from both vegetable and animal foods. To illustrate this fact by an actual case, in which the food was carefully analyzed, an experimenter weighing 67 kgms. records that he kept himself in nitrogen equilib- rium upon a diet in which the protein was distributed as follows: 300 gms. meat 666.3 c.c. milk 100 gms. rice 100 " bread 500 c.c. wine For a person in health and leading an active, normal life, appetite and experience seem to be safe and sufficient guides by which to control the diet; they may be relied upon, at least, to protect the body from undernutrition. The opposite danger of overeating is a real one, particularly among those who do not lead an active life. It is, however, a hygienic offence that is usually committed knowingly and may consequently be controlled by those who have sufficient wisdom. Physiological knowledge emphasizes clearly enough the great fact that the mechanisms of nutrition and digestion, like the other mechanisms of the body, should not be subjected to unnecessary strain. For those who are in health, the important rule to follow in the matter of diet is to avoid an excess in eating. In conditions of disease, in regulating the diet of children or of collections of individuals, as in the army, navy, etc., it is necessary for purposes of hygiene or for purposes of economy to arrange the diet in accordance with the knowledge obtained from experience and from scientific investigations. In this direction much has already been accomplished, but more remains to be clone, particularly perhaps in the relation of diet to pathological conditions. 63.08 gms. protein = 9.78 gms. X. 18.74 = 2.905 " " 7.74 it u =: 1.2 " " 11.32 a it := 1.755 " " 1.17 a It 0.182 gm. " 102.05 15.868 gms. " CHAPTER LI. THE PRODUCTION OF HEAT IN THE BODY— ITS MEAS- UREMENT AND REGULATION— BODY TEMPERA- TURE—CALORIMETRY— PHYSIOLOGICAL OXIDATIONS. It is customary to date our modern ideas of the origin of animal heat from the time of Lavoisier (1774-77). To the older physiologists it was a most difficult problem. The animal's body produces heat continually and maintains a temperature higher, as a rule, than that of the surrounding air. Since oxygen and the nature of ordinary combustions were unknown, they naturally explained this heat formation by reference to causes which the science of the day had shown to be capable of producing warmth, such as friction and fermentation. Haller (1757), for instance, taught that the body heat arises mainly from the friction of the circulating blood and the movements of the heart and blood-vessels, and this view found currency in text-books well into the nine- teenth century. Lavoisier first gave to the physiologist the con- ception that the heat produced in the body is due to a combustion or oxidation, and that therein lies the significance of our respiration of oxygen. He believed himself that this oxidation takes place in the lungs, — that is, the blood brings to the lungs a hydrocarbon- ous material which is attacked by the oxygen and burnt with the formation of water and carbon dioxid and the liberation of heat. Later experimenters demonstrated that the heat production does not occur in the lungs, at least not exclusively, but over the whole of the body. After a long and interesting controversy it was also shown satisfactorily that the oxidations of the body do not occur in the blood, but in the tissues themselves. The oxygen is transported to the cells and there does its work of effecting oxi- dations and giving rise to heat. This heat is equalized more or less over the whole body, chiefly by the circulation of the blood, which absorbs heat from the warmer organs and distributes it to the cooler ones. The body temperature is maintained at a nearly constant level by an intricate adjustment of physiological reflexes which together constitute the heat-regulating mechanism. Such in brief is the general theory of our time regarding heat production in the body. Many of the problems that interested the older phys- 924 BODY TEMPERATURE. 925 iologists have been solved satisfactorily, but there remain, of course, many more to interest this and succeeding generations. Investi- gations in this field at present are directed mainly to an effort to understand the details of the heat-regulating apparatus, on the one hand, and, on the other, to comprehend more satisfactorily the nature of the process of oxidation. This latter problem is one of common interest at present in chemistry and in physiology. The Body Temperature. — We divide animals into the two great classes of warm blooded and cold blooded, according as their temperature is or is not above that of the surrounding air. In this sense, birds and mammals are warm blooded and reptiles, amphibia, and fishes are cold blooded. The names, however, are badly chosen. The difference of deepest significance between the mammals and birds, on the one hand, and the fishes, amphibia, and reptiles, on the other, is that in the former the body temperature is, within wide limits, independent of the outside temperature; it remains practically constant during winter and summer, whether the surrounding air is hotter or cooler than the body. They are, therefore, constant-temperature animals (homoiothermous). The reptiles, amphibia, and fishes, on the contrary, have a body tem- perature that changes with the environment. On winter days their temperature is low, approximately that of the surrounding air or water, and in summer their body temperature rises to cor- respond with that of the outside. Strictly speaking, they are cold blooded only in cold surroundings. This group may be designated as the changeable-temperature animals (poikilothermous). The warm-blooded animals maintain a constant high body temperature on account of their relatively active oxidations and the existence of a heat-regulating mechanism. In the cold-blooded animals the oxidations are not so intense and a heat-regulating mechanism is absent or poorly developed. The hibernating animals form a group intermediate in many ways between these two classes. They possess a heat-regulating apparatus that maintains a constant body tem- perature under most conditions, but breaks down in very cold weather; so that during the period of winter sleep their tem- perature is but little above that of the surrounding air. In some of the cold-blooded animals the production of heat is more rapid during warm weather than its loss; so that they exhibit a body temperature slightly higher than the surrounding me- dium. A hive of bees in activity may raise the temperature within the hive through a number of degrees, and snakes and many reptiles show a temperature of 2° to 8° C. above that of the air. So also some reptiles possess a rudimentary means of protecting, their bodies from too great a rise of temperature, — for instance, by accelerated breathing whereby more water is evap- 926 NUTRITION AND HEAT REGULATION. orated from the lungs and thus more heat is lost.* The distinc- tion between the two great groups of animals is not entirely abso- lute, but it is sufficiently marked to constitute a striking physio- logical characteristic. The temperature of the human body is measured usually by thermometers placed in the mouth, in the axilla, or in the rectum. Measurements made in this way show that in general the tempera- ture in the interior of the body (rectal) is slightly higher than on the surface of the skin. The average temperature in the rectum is 37.2° C. (98.96° F.); in the axilla, 36.9° C. (98.45° F.); in the mouth, 36.87° C. (98.36° F.). We may speak of the body temperature, therefore, in the places in which it can be conveniently measured, as varying between 36.87° C. and 37.2° C. Some of the internal or- gans have a higher temperature, particularly during their period of greatest activity. The temperature of man, measured in the places mentioned, shows also a distinct variation during the day, a diurnal rhythm. This daily variation has been measured by many ob- servers, and shows individual peculiarities that depend largely upon the manner of living, time of meals, etc. In general it may be said that the lowest temperature is shown early in the morning, — 6 to 7 a.m. ; that it rises slowly during the day to reach its maximum in the evening, 5 to 7 p.m. ; and falls again during the night. The difference between early morning and late afternoon or evening may amount to a degree or more centigrade, and this fact must be borne in mind by physicians when observing the temperature of patients. Muscular activity and food appear to be the factors that are mainly responsible for the rise in temperature during the day. Most observers state that when the habits of life are reversed for some time — that is, when work is performed and meals are eaten during the night, and the day is given up to sleep and rest — the daily variation of temperature is inverted to correspond, — that is, the highest temperature is observed in the early morning and the lowest in the late afternoon. Age also has a slight influence. Newly born infants and young children have a somewhat higher temperature than adults. The difference may amount to half a degree or a degree centigrade, — 37.6° C. in infants as compared with 36.6° C. or 37. 1° C. in the adult. It is known, also, that the heat- regulating mechanism in infants and young children is not so efficient as in adults, and that therefore febrile disturbances are more easily excited in the former than in the latter. In the matter of body temperature, as in so many other characteristics, aged people show a tendency to revert to infantile conditions. Their temperature, according to most observers, is slightly higher than in middle life. ♦See Langlois, "Journal de physiologie et de pathol. generate, " 1902, 249. CALORIMETRY. 927 Among physiological conditions that influence the body tempera- ture, muscular work and meals, as stated above, have the most posi- tive effect. Marked muscular activity implies a great increase in the production of heat in the body and most observers find that the initial result at least is a small rise in body temperature, — a fact which indicates that the heat regulation is not perfect; the excess of heat produced is not dissipated promptly. In the period of rest following upon work, on the contrary, the body temperature may fall, owing probably to the fact that more heat is lost through the flushed skin than is produced within the body. In this matter of the effect of muscular work individual variations are to be expected, since the perfection of the heat-regulating mechanisms may vary somewhat in different persons. Meals also cause a slight rise in body temperature, which reaches its maximum about an hour and a half after the ingestion of the food. The explanation in this case also is to be found doubtless in a greater production of heat, due to the increased metabolism in the secreting glands, the liver, and the musculature of the gastro-intestinal canal. The excessive production of heat is not compensated completely by a corresponding increase in the heat dissipated.* It is sufficiently obvious, perhaps, from these facts that the temperature as measured by the thermometer is a balance between the amount of heat produced and the amount of heat lost or dissipated. The thermometer alone gives us no cer- tain indication of the quantity of heat produced in the body. A temperature higher than normal, fever temperature, may be due either to an excessive production of heat or to a deficient dissipa- tion. To understand and control the processes by which the body temperature is kept normal it is necessary to discover a means for ascertaining at any time the actual quantities of heat produced and dissipated, and the effect upon each factor of different normal and pathological conditions. The method used for determining the quantity of heat is designated as calorimetry. It is necessary, therefore, to describe the principle and construction of calorimeters and the methods of calorimetry before attempting to explain the mechanism of heat regulation. Calorimetry. — A calorimeter is an instrument for measuring the quantity of heat given off from a body. The unit employed in these determinations is the calorie, — that is, the amount of heat necessary to raise 1 gm. of water 1° C, or more accurately the amount of heat required to raise 1 gm. of water from 15° to 16° C. This unit is sometimes designated as a small calorie to distinguish it from the large calorie (C), — that is, the quantity of heat necessary to raise 1 kgm. of water 1° C. The large calorie is equal to 1000 * For further details see Puchet, "La chaleur animale, " 1889; and Pem- brey, " Animal Heat, " Schaefer's " Text-book of Physiology, " vol. i, 1898. 928 NUTRITION AND HEAT REGULATION. small calories. In physiology calorimeters have been used for two main purposes : to determine the heat equivalent of foods, — that is, the amount of heat given off when the various foodstuffs are burned, — and, secondly, to determine the heat produced and the heat dissi- pated by living animals during a given period. For the first pur- pose the apparatus that is most frequently employed at present is the bomb calorimeter devised by Berthelot. The bomb consists of a strong steel cylinder in which the food to be burned is placed Fig. 300. — Reichert's water calorimeter. and which is filled with oxygen. The combustion of the foodstuff is initiated by means of a spiral of platinum wire heated by an electrical current. The bomb is immersed in water and the heat given off raises the water to a measured extent of temperature. The weight of water being known, the amount of heat is easily expressed in calories. For the purpose of measuring the heat given off by living animals two principal forms of calorimeter are used, each form having a number of modifications. These two forms are the water calorimeter and the air calorimeter. The water calorimeter was the form used in the first experiments on rec- ord (Crawford, 1779). In principle it consists of a double-walled box with a known weight of water between the walls. The animal is placed in the inner box and the heat given off is absorbed by the CALORIMETRY. 929 water. Knowing the weight of the water and how much its tem- perature is raised, the data are at hand for determining the number of calories given off during the experiment. One form of this variety of calorimeter, used in this country by Reichert, is shown in Fig. 300. It consists of two concentric boxes of metal with a space between them of about 1^ inches. The animal is placed in the inner box (A). The two boxes are inclosed in a large wooden box, the space between the metal and wooden boxes being filled with shavings (SH). The object of this outer box is to prevent radiation of heat from the metal boxes. The tubes EN and EX, which lead into the interior chamber containing the animal, are for the entrance and exit of the ventilating air. A thermometer is placed in each to determine the heat carried off by the air. The thermometer, CT, measures the temperature of the water, and S is a stirrer to keep the water well mixed and thus insure a uniform temperature. When the animal is placed in the apparatus the heat given off warms not only the water, but also the metal; so that to determine the total heat the weight of metal must be re- duced to an equivalent amount of water by multiplying its weight by its specific heat, or, a more simple method, the calorimetric equiv- alent of the apparatus is determined, — that is, the actual amount of heat necessary to raise the temperature of the apparatus, water and metal, one degree. This value is obtained by burning in the appa- ratus a known weight of some substance (alcohol, hydrogen) whose heat of combustion is known. Knowing how much heat is given off by this combustion and how much the temperature of the apparatus is raised, the calorimetric equivalent is easily calcu- lated and may be used subsequently in estimating the results ob- tained from animals. In the use of the apparatus many precau- tions must be observed. These practical details need not be des- cribed here except to say that account must be taken of the warm- ing of the air used to ventilate the apparatus and of any changes in the amount of its moisture. The calorimeter used in this way measures directly the amount of heat given off from the animal during the period of observation. The amount of heat produced in the animal's body during this time may be the same, or may be more or less. To arrive at a knowledge of this factor observations must be made upon the animal's body temperature by means of a thermometer in the rectum. If this body temperature is the same at the end as at the beginning of the experiment then it is obvious that the heat produced must have been equal to the heat lost. If the animal's body temperature has fallen, then it is evident that less heat has been produced than was lost. To ascertain how much less, the weight of the animal is multiplied by its specific heat (0 . 8) to reduce it to so much water, and this product is multiplied by the 59 930 NUTRITION AND HEAT REGULATION. difference in body temperature at the beginning and the end of the experiment. The product is obtained in calories and is subtracted from the amount of heat lost, as determined by the calorimeter, to obtain the amount of heat produced. If, on the contrary, the ani- mal's temperature has risen during the experiment the body has produced more heat than it has dissipated. The increase may be determined as above by multiplying the weight of the animal, the specific heat of the body, and the difference in temperature. This amount added to the heat lost gives the heat produced. Many investigators have used some form of air calorimeter. An air calorimeter consists essentially of a double-walled chamber or box with air between the walls. The animal is placed in the inner box and the heat given off is measured by the expansion of the air between the walls. Many different forms are used, prefer- Fig. 301. — D'Arsonval's differential calorimeter. ence being given to some modification of the differential air calo- rimeter. In this last-named instrument two exactly similar chambers are constructed ; one contains the animal while the other serves as a dummy. These two chambers are balanced against each other, the air space in the dummy being heated by immersion in a bath or by burning hydrogen in the interior. As these sources of heat are known and can be controlled, it is evident that if the dummy is made to balance exactly the chamber containing the animal the amount of heat given off in each is the same. The principle of the differential calorimeter is represented in Fig. 301, which gives a schema of the form originally employed by d' Arson val; 8 and 8' represent the two calorimeters, in one of which the animal is placed while the other acts as dummy. Each is double walled and the air spaces are connected by tubes, 10 and 10', to small gasometers, 4, 4', suspended in water and hung on opposite sides of a balance. The movements of these gasometers antagonize each other, and the resultant may be recorded upon smoked paper, as indicated in the figure.* * For detailed accounts of special forms of air calorimeters see Rubner, "Calorimetrische Methodik," 1891; and Rosenthal, ''Archiv f. Physiol ogie," 1897, p. 170. CALOEIMETRY. 931 The Respiration Calorimeter. — When a calorimeter is so arranged that the composition of the air drawn through the apparatus for ventilation can be determined as well as the amount of heat pro- duced, the apparatus becomes a respiration calorimeter. In such an apparatus, if proper provision is made for analyzing the urine, the feces, and the food, the total carbon and nitrogen excretion may be obtained simultaneously with the heat loss. Since we may calculate from the carbon and nitrogen excretion how much pro- tein, fat, and carbohydrate have been burnt in the body, and since the heat values of these constituents are known, it is evident that we may reckon indirectly how much heat ought to be produced from the combustion of so much material. This method of arriv- ing at the heat production is designated indirect calorimetry . With an adequate respiration calorimeter it is possible to ascertain whether the results calculated by the method of indirect calorim- etry really correspond with the heat obtained by direct measure- ment. In the hands of good observers the correspondence is very close, and gives substantial proof of the scientific belief that in the living body the energy liberated as heat or as heat and work is all contained in potential form in the foodstuffs eaten. By means of the respiration calorimeter we can obtain a balance between the energy income and outgo of the body as well as between the material income and outgo, — that is, the carbon and nitrogen equilibrium. The most complete and elaborate form of respiration calorimeter used is that devised by Atwater and Rosa for experiments upon man.* Considered as a calorimeter the appara- tus used by these investigators belongs to the type of water cal- orimeters. Instead, however, of having a stationary stratum of water to be warmed by the heat given off from the body, the appara- tus is arranged so that a stream of water may be circulated between the walls, and this stream is so regulated, as to quantity and temperature, as to keep the temperature of the calorimeter as a constant point. In other words, the heat given off from the body is carried away by the circulating water, and the quantity of the heat may be calculated when the temperature and amount of the water are known. By means of this apparatus many interesting and important experiments have been made upon the nutrition of man under different physiological and pathological conditions, and it seems probable that it will supplant entirely the earlier forms of calorimeter described in the preceding pages. As an indication of its sensitiveness the following result may be quoted of observations made upon a man who, while in the apparatus, did much muscular work on a bicycle ergometer : * See Atwater and Rosa, Bulletin 63, United States Department of Agri- culture, 1899; and for recent improvements, Atwater and Benedict, "A Respi- ration Calorimeter," Carnegie Institution, Washington, 1905. 932 • NUTRITION AND HEAT REGULATION. Income: Potential energy of material metabolized in body — 5459 CaL n . f Energy given off from the body as heat. . . . 4833 Cal. uuigo j Heat equivaieut of muscuiar WOrk 602 Cal. 5435 Cal. 5435 Cal. Experimental error 24 Cal. Results of Calorimetric Measurements. — The actual results obtained from direct calorimetric measurements corroborate those deduced from the study of the energy given off in the oxidation of the foodstuffs of the daily diet. They show that man gives off heat from his body to the amount of 40 to 50 Calories per kgm. of weight during 24 hours under conditions of ordinary life, — a total, therefore, of 2400 to 3000 Calories per day for an individual weighing 60 kgms. This amount is increased greatly under conditions demanding much muscular work. This loss of heat is, of course, made good by the production of an equal amount within the body by the oxidation of the food material. Actual experiments upon different animals* show that small animals produce more heat in proportion to their weight than larger animals of the same species, owing to their relatively larger surface and, therefore, greater loss of heat. This fact has been expressed by Rubner in what he calls his "surface area law." According to this law the metabolism is proportional to the surface area, or for the same amount of surface area there will be the same pro- duction of heat. He estimates that in man there is produced in 24 hours for each square meter of surface 1042 cal. The figures for other mammals are nearly the same. In small animals of a given species in which the surface area is greater relatively to the mass than in the larger animals, the metabolism per kilogram of weight will be larger — for example, in the human infant com- pared with the adult. HEAT REGULATION. From a general standpoint the most important problem that the physiologist has to study is the means by which the heat production and heat loss are so regulated as to maintain a practically constant body temperature. Experiments show that the mechanism of heat regulation is very complex and is two-sided, — that is, the body possesses means of controlling the loss of heat as well as the produc- tion of heat, and under the conditions of normal life both means are used. Regulation of the Heat Loss. — Heat is regularly lost from our bodies in a number of different ways, which may be classified as follows : •See Rubner, " Zeitschrift f. Biologic," 19, 535, 1883; and " Osetze des Energieverbrauchs," 1902. REGULATION OF HEAT LOSS. 933 1 . Through the excreta, urine, feces, saliva, which are at the temperature of the body when voided. 2. Through the expired air. This air is warmer than the inspired air, and, moreover, is nearly saturated with water-vapor. The vaporiza- tion of water requires heat, which is, of course, taken from the body supply. Each gram of water requires for its vaporization about 0.5 cal. 3. By evaporation of the sweat from the skin. The amount lost in this way increases naturally with the amount of sweat secreted. 4. By conduction and especially by radiation of heat from the skin. The relative values of these different means of heat loss are estimated as follows by Vierordt: 1. By urine and feces 1.8 per cent, or 48 calories. 2. By expired air: Warming of air 3.5 " " 84 " Vaporization of water from lungs 7.2 " " 182 " 3. By evaporation from skin 14.5 " " 364 " 4. By radiation and conduction from skin. . . .73.0 " " 1792 " Total daily loss =2470 It is obvious that the relative importance of these factors will vary with conditions. Thus, high external temperatures will tend to diminish the loss from radiation while increasing that from evapora- tion, owing to the greater production of sweat. The variation in this respect is well illustrated by the following table, compiled by Rubner, from experiments made upon a starving dog:* Temperature. Calories lost by radia- Calories lost by Total calories of tion and conduction. evaporation. metabolism. 7° C. 78.5 7.9 86.4 15° 55.3 7.7 63.0 20° 45.3 10.6 55.9 25° 41.0 13.2 54.2 30° 33.2 23.0 56.2 It will be noted that between 25° and 30° C. there was a marked increase in the loss of heat through evaporation. In man loss of heat is regulated chiefly by controlling the impor- tant factors of evaporation and radiation. We accomplish this end in part deliberately or voluntarily by the use of appropriate clothing. Clothing of any kind captures a layer of warm and moist air between it and the skin and thus diminishes greatly the loss by evaporation and by radiation. In cold weather the amount and character of the clothing is changed in order to diminish the heat loss. The ideal clothing for this purpose is made of material, such as wool, which, while porous enough to permit adequate ventilation of the air next to the skin, is at the same time a poor conductor of heat and thus diminishes the main factor of loss by radiation. The most impor- tant means of controlling the heat loss, however, is by automatic ♦Taken, from Lusk, "Elements of the Science of Nutrition," Philadel- phia, 1906. 934 NUTRITION AND HEAT REGULATION. reflex control through the sweat nerves and the vasomotor nerves. By these means the amount of perspiration evaporated from the skin and the amount of warm blood sent through the skin are controlled. Rubner speaks of this side of the heat regulation as the physical regulation. By its means the body may be safe- guarded from an abnormal rise of temperature. In warm weather the secretion of sweat is greatly increased by reflex stimulation of the sweat nerves. The greater amount of water requires a greater amount of heat to vaporize it, and thus the heat loss is increased. The value of this control is illustrated by a case recorded by Zuntz* of a man who possessed no sweat glands. In summer this individual was incapacitated for work, since even a small degree of muscular activity would cause an increase in his body temperature to 40° or 41° C. The control through the vasomotor nerves is doubtless even more important. The blood-vessels bring the warm blood to the skin, where it loses its heat by conduction and especially by radia- tion to the cooler air. When the surrounding air is much below the temperature of the body the vasoconstrictor center is stimulated, the blood-vessels in the skin are constricted, the supply of warm blood to the skin is diminished, and therefore the amount of heat lost is less. The reflex in this case may be attributed primarily to the action of the cool air on the cold nerves of the skin. The impulses carried by these fibers to the nerve centers stimulate the vasocon- strictor center or that part of it controlling the vasomotor fibers to the skin. On warm days, on the contrary, the blood-vessels in the skin are dilated sometimes to an extreme extent, the supply of warm blood is therefore increased, and more heat is lost if the air is lower in temperature than the blood. The reflex in this case may be regarded possibly as an inhibition of the vasoconstrictor center through the warm nerves of the skin. Sub- stances, such as alcohol, which cause a dilatation of the skin ves- sels also increase the loss of body heat, in some cases to a sufficient extent to lower the body temperature. To a smaller extent our heat loss is controlled through an acceleration of the breathing movements. The greatly increased respirations in muscular ac- tivity must aid somewhat in eliminating the excess of heat produced, although this factor must be much less important than the sweating and the flushing of the skin which are produced reflexly during muscular work. In some of the lower animals — the dog, for in- stance— in which the sweat nerves are absent over most of the body and in which the coat of hair interferes with the free loss by radiation, it is found that the loss through the respiratory channel is * Zuntz, "Deutsche medizinal-Zeitung," 1903, No. 25. REGULATION OF HEAT PRODUCTION. 935 relatively more important. The panting of the dog is a familiar phenomenon. Richet has studied this reflex upon dogs and has designated the greatly accelerated breathing in warm weather or after muscular exercise as thermic polypnea (according to Gad, tachypnea). He assumes a special center for the reflex situated in the medulla and acting through the respiratory center. It is a curious fact, as shown by Langlois, that some reptiles exhibit a similar reflex; when their body temperature is raised to 39° C. they show a condition of marked polypnea (rapid breathing) the ap- parent object of which is to augment the loss of heat from the body. Regulation of Heat Production. — Heat production is varied in the body by increasing or decreasing the physiological oxida- tions. This end is effected in part voluntarily by muscular exercise or by taking more food. Muscular contractions are attended by a marked liberation of heat and it is a part of everyone's experience that by work or muscular activity the effect of outside cold may be counteracted. In the case of food the body burns promptly most of the material of a daily diet. By increasing the diet in cold weather provision is made for replacing the greater amount of heat lost from the body without calling upon the tissues of the body itself. In normal individuals this regulation is not, strictly speaking, voluntary. Outside cold is most effective in stimulating the appetite and thus leading us to increase the diet. In this, as in other respects, the appetite serves to control the amount of food in proportion to the needs of the body. The purely involuntary con- trol of heat production consists of an involuntary reflex upon mus- cular metabolism and possibly in the existence of a special set of heat centers and heat nerves. With regard to the first effect we have the striking experiments quoted by Pfluger,* according to which a rabbit paralyzed by large doses of curare is no longer able to maintain its body temperature when the outside temperature is changed. The rabbit behaves, in fact, like a cold-blooded animal. In the calorimeter it shows a marked loss of heat production, and its temperature may be made to go up and down with the outside temperature. The same result may be obtained by section of all the motor nerves, — that is, section of the spinal cord in the upper cervical region. Rubner has shown by calorimetric experiments upon animals that although the body temperature, as we know, may remain constant when the outside temperature is changed, the heat production is increased as the outside temperature is lowered. This fact is well shown by the following table, compiled by Rubner, from experiments made upon a fasting guinea-pig :f * Pfluger " Archiv f. die gesammte Physiologie, " 18, 255, 1878. t Taken from Lusk, loc. cit. 936 NUTRITION AND HEAT REGULATION. Temperature Temperature Grams of CO> eliminated per hour of air. of animal. and per kilogram of animal. 0.0° c. 37.0° C. 2.905 11.1 37.2 2.151 20.8 37.4 1.766 25.7 37.0 1.540 30.3 37.7 1.317 34.9 38.2 1.273 40.0 39.5 1.454 From 0° to about 35° C. the animal's body temperature remained practically constant, but the oxidations at the lower temperature were over twice the amount of those at the higher temperature. At about 33° C. the metabolism of the mammal, according to Rubner, is at its minimum. From 35° to 40° C. the heat regula- ting mechanism in the experiments quoted broke down, in that heat loss was prevented to such an extent by the outside high temperature that the body temperature rose in spite of the diminution in heat production. The increased production of heat in the body in consequence of a fall in external temperature is a characteristic property of warm-blooded animals. Rubner designates this side of the regulating mechanism as the chemical regulation, and he calls attention, moreover, to the fact that in mankind, owing to our custom of protecting the surface of the body by clothing and by artificial heat, chemical regulation plays less of a role than in the lower animals. Man, in fact, keeps most of his skin surrounded by a warm layer of air at about the temperature (33° C.) at which the metabolism, as affected by temperature, is minimal. Cold baths, cold winds, and various climatic conditions, such as high altitudes and sea- side conditions, may cause a marked increase in body metabolism. Johannson* has shown that the increased oxidations that occur under the influence of outside cold, as measured by the C02 out- put, occur only when muscular tension is increased or shivering is noticed. We may believe, therefore, that the increased oxida- tions caused by cold are due to motor reflexes upon the skeletal muscles. These reflexes take place doubtless through the motor fibers, and lead to an augmented muscular tone or to small con- tractions (shivering), according to their intensity. This fact accords with one's personal sensations regarding the condition of his muscles in cold weather. The Existence of Heat Centers and Heat Nerves. — Physi- ologists have long supposed that there may be in the body a special set of heat nerves and heat centers, separate in their action from the motor, secretory, and other efferent nerves that influence the rae- * Johannson, " Skandinavisches Archiv. f. Physiologie, " 7, 123, 1897. EXISTENCE OF HEAT CENTERS AND HEAT NERVES. 937 tabolism of the peripheral organs. It is supposed that these fibers, if they exist, when in activity augment or inhibit the physiological oxidations in the tissues, and that this effect has for its specific object an increase or decrease in heat production, outside of any functional activity of the tissues. Bernard thought at first that he had demonstrated the existence of calorific fibers in the cervical sympathetic, but it was afterward recognized that the fibers in question are vasoconstrictors. Since that time very numerous experiments have been made with this object in view, but it must be admitted that no conclusive proof has yet been obtained of the existence of such a system. The evidence that has been most re- lied upon is the effect of lesions, experimental or pathological, of definite portions of the brain or cord. The following facts are significant: A number of observers* have found that section or puncture of the brain at the junction of medulla and pons causes an increase in heat production and a rise of temperature. Section of the cord in the cervical region is, on the other hand, attended usually by a fall in body temperature. These experiments might be interpreted to mean that there exists in the brain anterior to the medulla a general heat center of an inhibitor}- character. Under normal conditions this center may hold the lower heat-producing centers in check. When cut off by section this inhibitory influence is removed and increase in heat production and body temperature results. A second important fact, brought out by Ott,f is that in- jury to the corpus striatum causes a rise in heat production and body temperature. This result has been confirmed by many other investigators, making use especially of what is known as the " heat puncture." In this experiment, made upon rabbits, a probe or style is inserted into the brain so as to puncture the corpus stria- tum. The result in the majority of cases is a rise of temperature which may last for a long time, although the animal shows no par- alysis and apparently no other effect from the operation. Accord- ing to some observers, J the increased production of heat takes place mainly in the liver, and is due to the oxidation of the glycogen. According to others (Aronsohn), the increased production of heat occurs mainly in the muscles. The fever produced by the " heat puncture " seems to be due essentially to an irritation of the nerv- ous system, and is an experimental demonstration of the possi- bility of fever arising from lesions of the nerve centers. White and others have described similar disturbances of heat production from lesions of the optic thalamus. Heat centers have been located * See Wood, "Fever," " Smithsonian Contributions to Knowledge," Washington," 1880. t Ott, "Journal of Nervous and Mental Diseases," 1884, 1887, 1888; also "Brain," 1889. J Roily, '" Deutches Archiv f. klinische Medicin," 78, 250, 1903. 938 NUTRITION* AND HEAT REGULATION. also in the septum lucidum, in the cortex, the midbrain, pons, and medulla. The great amount of experimental work done along these lines has been inspired doubtless by the hope of discovering a special heat-regulating nervous apparatus which if demonstrated would enable us to explain the causation of fevers. In its most elaborate form this hypothesis assumes the existence of primary heat-producing (thermogenic) centers in the cord and brain from which the calorific or heat nerves arise. These centers in turn are controlled by regulating (thermotaxic) centers of an augmenting and inhibitory character in the higher portions of the brain. By reflex influences upon these latter centers the activity of the thermo- genic centers may be increased or diminished and the production of heat in the body controlled. While such an apparatus may exist, it is nevertheless true that the evidence in favor of it so far produced has failed to convince the majority of physiologists. The existence of a special set of heat nerves, in fact, is still unproved. Most physiologists, perhaps, believe that variations in heat pro- duction occur, as stated above, by alterations in the intensity of the oxidations in the muscles brought about by reflex excitation through the motor nerve fibers, and that a special set of heat fibers does not exist. We may at present adopt the conservative view that heat production and heat dissipation in the body are controlled not by a special heat-regulating apparatus composed of heat centers and heat nerves, but by the co-ordinated activity of a number of different centers in addition to the voluntary means already specified. The unconscious regulation of the body temperature is effected chiefly through the following centers : C 1. The sweat centers and sweat nerves. TT . ,. . ,. j 2. The vasoconstrictor center and the vasoconstrictor Heat dissipation < nerye fiberg tQ the gkin_ V- 3. The respiratory center. ( 1. The motor nerve centers and the motor nerve fibers tt , ,. ) to the skeletal muscles. Meat production s 2 The quantity and character of the food as deter- v. mined by the appetite. Theories of Physiological Oxidations. — Lavoisier compared the oxidations in the body to the oxidation of organic substances in combustions at high temperatures. He supposed that the mo- lecular oxygen unites directly with the substances oxidized in one case as in the other. It soon became evident, however, that this direct analogy is not applicable. The material that is oxidized in the body — fats, carbohydrates, proteins — is consumed with a certain rapidity, — in the case of muscular contractions with great rapidity, — and we know that these same materials out of the body at a temperature of 39° C. are oxidized with extreme slowness. It became customary, therefore, to speak of the oxidations in the body PHYSIOLOGICAL OXIDATIONS. 939 as indirect, meaning thereby that the material is not acted upon directly by the molecular oxygen. Within recent years it has been shown that the oxidation in ordinary combustions — the burning of gaseous hydrogen, for instance — is not explained by assuming that the oxygen unites directly with the hydrogen. It is stated, for instance, that this combustion does not take place if both gases are entirely free from water vapor; the presence of water is necessary for the oxidation. Chemists are not agreed as to the exact nature of simple combustion, and it is therefore increasingly difficult to compare these processes with the oxidations in the body. Leaving aside the details of the process, it may still be believed that- tho metabolism of material in the body by means of which its heat energy is produced is at bottom comparable to ordinary combus- tions. Oxygen is absolutely necessary to the process in each case; the same end-products are formed and the same amount of heat is liberated in the one case as in the other. The fundamental point that the physiologist is attempting to solve is the means by which the body accomplishes these oxidations at such a low temperature. The theories suggested to explain this fact have changed naturally with the advance of chemical knowledge. After the discovery of ozone (Schonbein, 1840) and its great power of oxidation as com- pared with oxygen it was suggested that in some way the oxygen in the body is ozonized and is thus able to burn the food material. Gorup-Besanez showed that some of the oxidations that take place in the body can be successfully accomplished outside the body with the aid of ozone, especially in the presence of alkalies or alka- line carbonates. Others suggested that the oxygen in the body be- comes converted to atomic oxygen and is thus enabled to attack the tissue materials. Hoppe-Seyler formulated a theory according to which the living molecule is first split into smaller molecules by the hydrolytic action of ferments. In this process, as in fermentation, to which he compared it, hydrogen is liberated in the nascent or atomic state, and this hydrogen acting upon the oxygen forms water with the liberation of some atomic oxygen, which in turn oxidizes the split products of the fermentation. Others still (Traube) laid stress upon the possibility of the formation of hydrogen peroxid or similar organic peroxids which are then capable of effecting the oxidation of the body material. This latter theory, in modified form still prevails.* The great amount of experimental and theoretical work upon the nature and cause of physiological oxidations has established pretty clearly two general beliefs which it is important to keep in mind. It has been shown, in the first place, that the amount of *See Ehgler and Weissberg, "Kritische Studien iiber die Vorgange der Autoxydation," 1904. 940 NUTRITION AND HEAT REGULATION. the oxidation is governed by the tissue itself and not by the quantity of oxygen present. The view that by increasing the amount of oxygen offered to the tissue the intensity of the oxidations can likewise be increased was formerly held and is still met with. It is often supposed, for example, that by breathing pure oxygen the oxidations of the body may be augmented. On the contrary, the facts indicate that when a sufficient supply of oxygen is provided any further increase has no immediate effect in aiding or hastening the oxidations. The intensity of the process is conditioned by the tissue itself. The initial stimulus or substance that sets going the whole reaction arises within the tissues. The second generalization that seems to be accepted more and more of recent years is that the oxidations of the body, those reactions that give rise to much heat, do not affect the living tissue itself. They take place under the influence of the living matter, or by the aid of substances (enzymes) formed by the living matter, but the material actually burnt is not organized living substance. As the living yeast cells break down sugar in the liquid surrounding them, so the living tissue cells metab- olize and oxidize the dead food material contained in the lymph and tissue liquid in which they are bathed. The opposite point of view was ably advocated by Pfliiger. This observer, in fact, ex- plained the mystery of physiological oxidations by assuming that the oxygen together with the food material is synthesized into the highly complex and unstable living molecules. The active intra- molecular movement within these molecules leads constantly to a breaking down, a splitting off of simpler molecules which consti- tute the products of physiological oxidation. The instability of the molecule is due to its size and the activity of the intramolecular movements, or, as Pfliiger expressed it, "The intramolecular heat of the cell is its life." This point of view, however, has not found acceptance of late years. It is implied or stated by most recent authors that the food material is attacked and oxidized outside the living molecule, in the form of fat, sugar, protein, etc. The ten- dency for many years has been to show that these processes in the body are chemical changes that do not differ fundamentally from similar processes outside the body. The point of view actually adopted by most workers is that the living matter effects its won- derful changes in the food material with the aid of intracellular ferments or enzymes (endo-enzymes).* That such enzymes are formed, one may say generally in the tissues of the body, has been brought out in the preceding chapters upon Digestion and Nutri- tion. It is necessary only to recall the facts that lipase, the fat- splitting enzyme, has been isolated from many tissues, and that in the liver and muscles and probably other tissues there exist * For literature, see Vernon, " Intracellular Enzymes," London, 1908. PHYSIOLOGICAL OXIDATIONS. 941 enzymes capable of converting glycogen to sugar or the reverse, and of destroying the sugar completely by the serial action of • several intracellular enzymes. Finally, with regard to the protein material, it is now recognized that proteolytic enzymes are formed within many, if not all, of the living tissues. This point is demon- strated by the fact of autolysis, — that is, if living tissue is taken from the body, with precautions against contamination by bacteria, and while under perfect aseptic conditions is kept warm and moist, it will digest itself. The protein is split up into the same simple hydrolytic products as are obtained by boiling it with acids. It has been shown that this digestion is due to enzymes — autolytic enzymes — formed within the living tissue. There is no doubt, therefore, of the existence of intracellular enzymes, and that these substances play a conspicuous part in the metabolism of food material. The lipase, the diastase, and the autolytic enzymes (proteases) just referred to all belong to the group that cause hydrolytic cleavages — that is, they induce splitting or decompo- sition of the material by a reaction with water. The supposition has naturally been made that probably the oxidations of the body are effected also by enzymes which in some way activate the oxygen. Enzymes of this character have been found; they are designated in general as oxidases or as oxidases and peroxidases, the former term referring to those enzymes that effect oxidations in the presence of oxygen, while the latter is applied to certain enzymes supposed to act only in the presence of peroxids. Bach and Chodat have simplified this conception by the hypothesis that all the oxidizing enzymes of the tissues are peroxidases, that is to say, substances which have the power of liberating active oxygen from hydrogen peroxide or similarly constituted organic peroxides. They assume that there are present in the tissues certain organic substances, designated as oxygenases, which have the property of combining with the oxygen furnished by the blood to form organic peroxides, and that these peroxides, under the influence of per- oxidase, give up their oxygen in atomic or active form, which then effects the characteristic physiological oxidations. This view can be presented schematically by the following equations, in which A represents the oxygenase, P the peroxidase, and B the tissue material which undergoes oxidation: A + 02 = AO, (organic peroxide) A02 + P + B = BO" + AO + P. Oxidases or peroxidases have been discovered in the blood, milk, and in various of the tissues of the body, such as the lymphocytes, sperm cells, etc.* They can be tested for by a number of reac- * For discussion and literature consult Kastle, "The Oxidases," Bulletin No. 59, 1910, Hygienic Laboratory, Washington, D. C. 942 NUTRITION AND HEAT REGULATION. tions, chiefly color reactions, such as the bluing of a tincture of guaiacum in the presence of a peroxide or the conversion of a colorless or leucobase to a colored oxidation product. Some of these oxidases or peroxidases have been given specific names in accordance with the particular compounds whose oxidation they effect. For example, xanthinoxidase, which effects the oxidation of hypoxanthin and xanthin to uric acid; the glycolytic oxidase or oxidases which effect the oxidation of the sugars in the tissues; tyrosinase, which effects the oxidation of tyrosin, and in this way is supposed by many observers to give rise to various animal pig- ments, such as melanin; the aldehy doses, which effect the oxidation of aldehydes to their corresponding acids — salicylic aldehyd, for instance, to salicylic acids. This list might be greatly extended, particularly if those that occur in the plants were also considered, but as it is, it suffices perhaps to illustrate the general belief regard- ing the wide-spread occurrence and the specific properties of these important substances. Whereas formerly the general belief among physiologists was that physiological or vital oxidations were effected as part of the metabolism of the living substance, the tendency at present is to assume that these oxidations are not effected directly by changes in the living substance, but indirectly, in that the latter forms these oxidases or peroxidases, which have the property of liberating oxygen in an active form. The oxida- tions effected by this means are the principal source of the develop- ment of heat in the body — they are especially exothermic reactions. Many other of the chemical changes of metabolism, such as the hydrolytic cleavages, liberate but little heat, and others still, such as the syntheses of one kind or another in which there is a union of compounds to form more complex substances, may even be attended by an absorption of heat, that is, a conversion of heat energy to the energy of chemical affinity. The oxidizing reactions constitute, therefore, a large and very characteristic feature of the metabolism of the warm-blooded animals. The heat thus pro- duced by the oxidation of our food material serves to maintain the body temperature at its normal high level. In addition many physiologists believe that a portion of this heat is used in the work of the body, the muscular contractions, for example, or the growth of new living tissue, that is to say, they regard the body as a sort of thermodynamical engine in which the energy of the food is obtained first as heat, and the heat is then utilized in part for the other energy needs of the body. Others, however, are unwilling to accept this view of the body mechanism, and prefer to believe that the chemical energy of the food can be utilized directly for the various energy needs of the body without passing through the form of heat. SECTION IX. THE PHYSIOLOGY OF REPRODUCTION. With the exception of the phenomenon of consciousness, no fact of life excites more interest and seems to offer greater diffi- culties to an adequate explanation than the function of reproduc- tion. The male cell (spermatozoon) and the female cell (ovum) unite to form a new cell which thereupon begins to grow rapidly and produces an organism that in all of its manifold peculiarities of structure and function is essentially a replica of its parents. The fundamental problems presented in this act of reproduction are those of fertilization and heredity. In the former we must ascertain why the union of the two cells is necessary or advanta- geous, and the secret of the stimulating influence upon growth that arises from this union. Under the term heredity we express the obvi- ous, yet mysterious fact that the fertilized ovum of each species de- velops into a structure like that of its parents. Both of these im- portant problems are essentially of a physiological character, — that is, they deal with properties of the living material composing the reproductive cells; but, at present, biological investigation along these lines is largely in the morphological stage. The part of the sub- ject that can be studied with most success is the structural changes that are associated with fertilization and reproduction. Great, indeed wonderful, progress has been made during the last century, but it is needless perhaps to say that much remains unexplained, and that in this, as in so many other problems of nature, the greater our knowledge the clearer becomes our vision of the difficulties and complexities of a final scientific explanation. Outside these funda- mental problems there are other accessory functions connected, for instance, with the external genital organs which in a measure are of more immediate practical interest. In one way or another these functions are necessary or helpful to the final union of the repro- ductive cells. They form a part of the reproductive life which comes more immediately under our observation and control, and consti- tute, therefore, a subject which has been more accessible to in- vestigation. In the brief treatment given in the following chap- ters more emphasis is laid upon this side, the accessory phenomena of reproduction, than upon the deeper, more fundamental prob- 943 944 THE PHYSIOLOGY OF REPRODUCTION. lems, in view of the fact that the accessory phenomena are the ones which have at present the greater practical interest. The function of reproduction is often omitted from physiolog- ical courses, and the reason perhaps is partly that the structural features and the development of the embryo have been assigned to the department of anatomy, and partly because it is a function not essential to the maintenance of the existence and reactions of the organism. The reproductive organs might be eliminated en- tirely and the power of the body as an organism to maintain its individual existence not be seriously interfered with. The physio- logical importance of the reproductive organs lies not in their co-operation in the communal life of the various parts of the body, but in their adaptation to produce another similar being. We may explain, therefore, the co-ordinating mechanisms of the body without reference to the reproductive tissues, except so far as their supposed internal secretions affect general or specific metabolism. CHAPTER LII. PHYSIOLOGY OF THE FEMALE REPRODUCTIVE ORGANS. The Graafian Follicle and the Corpus Luteum. — The functional value of the ovary is connected with the formation and rupture of the Graafian follicles, whereby an ovum is liberated. The pri- mordial follicles consist of an ovum surrounded by a layer of fol- licular epithelium. Beginning at a certain time after birth and continuing throughout the period of active sexual life, some of these primordial follicles develop into mature Graafian follicles and mi- grate to the surface of the ovary. The change consists in a pro- liferation of the follicular epithelium and the formation of a serous liquid, the liquor folliculi, between the layers of this epithelium. In the matured follicle there is a connective tissue covering, the theca folliculi, formed from the stroma of the ovary and consisting of two coats or tunics — the external and the internal. The cells in the internal tunic develop a yellowish pigment as the follicle grows, and are sometimes designated as lutein cells. Within the capsule formed by the internal tunic there is a layer of follicular cells known as the membrana granulosa and attached to one side is a mass of the same cells, the discus proligerus — within which the ovum is imbedded. The follicular liquid lies between. This liquid increases in amount, and when the follicle has reached the THE FEMALE REPRODUCTIVE ORGANS. 945 surface it forms a vesicle projecting to the exterior. This projecting portion is nearly bloodless and thinner than the rest of the wall of the follicle. It is designated as the stigma. When fully mature the follicle ruptures at the stigma and the egg, together with the sur- rounding follicular cells of the discus proligerus and a portion of the membrana granulosa, is extruded, the egg being received into the open end of the Fallopian tube. According to Clark,* the rupture of the follicle is brought about by an increasing vascular congestion of the ovary. The tension within the ovary is thereby increased, the follicle is forced to the surface, and the circulation at the most projecting portion is interfered with to such an extent as to cause necrotic changes at the stigma, at which rupture finally occurs. After the bursting of the follicle its walls collapse, and the central cavity receives also some blood from the ruptured vessels of the theca. Later on the vesicle becomes filled with cells containing a yellow pigment. These cells increase rapidly and form a festooned border of increasing thickness around the central blood clot. The vesicle at this stage, on account of the yellow color of the new cells, is known as a corpus luteum. The structure thus formed increases in size for a period and then undergoes retrogressive changes and is finally completely absorbed. The duration of the period of growth and retrogression varies according as the egg liberated becomes fertilized or not. If fertilization does not occur, as is the case in the usual monthly periods, the corpus luteum reaches its maximum size within two to three weeks and then begins to be absorbed. It is frequently designated under these circumstances as the false corpus luteum (corpus luteum spurium) or corpus luteum of men- struation. In case the egg is fertilized and the woman becomes pregnant the life history of the corpus luteum is much prolonged. Instead of undergoing absorption after the third week it continues to increase in size by multiplication of the lutein cells during the first few months of pregnancy, and does not show retrogressive changes until the sixth month or later. The total size of the corpus in such cases is much larger than in menstruation, and it was des- ignated, therefore, by the older writers as the true corpus luteum (corpus luteum verum) or corpus luteum of pregnancy. Later observers agree that there is no essential difference in structure between the true and the false corpus luteum, although the former has a longer history and attains a greater size. The point of greatest structural interest in the corpus luteum is the origin of the yellow (lutein) cells. Histologists have been and still are divided upon this point ; some believe that they arise from the cells of the membrana granulosa, others that they come from the connective tissue cells in the internal capsule (theca interna) of the follicle. * Clark, "Johns Hopkins Hospital Reports," 7, 181, 1898. 60 946 THE PHYSIOLOGY OF REPRODUCTION. The majority of writers seem to favor the latter view.* Regarding the physiological importance of the corpus opinions also differ. Some regard it as simply a protective mechanism by means of which the empty space in the follicle is filled up by a tissue which is afterward easily absorbed, instead of by scar tissue. Others, how- ever, attribute to the lutein cells secretory functions of the most important character in connection with the subsequent develop- ment of the egg and the activities of the uterus. Some reference will be made to these views farther on. Menstruation. — The attainment of sexual maturity or puberty is marked by a number of visible changes in the body, but in the female the characteristic change is the appearance of the men- strual flow from the uterus. The age at which this phenomenon occurs shows many individual variations, but the average for temperate climates is given usually at 14 to 15 years. In the warmer countries the age is earlier, — 8 to 10 years, — and in the cold regions somewhat later, — 16 years. The racial characteristic in this respect is said to be maintained, however, after generations of residence in countries of a different climate, as is illustrated by the relatively early appearance of menstruation among Jews even in the colder countries. After the phenomenon appears it occurs at regular intervals of 28 days, more or less, and hence is known as the monthly period, menses, menstruation, or catamenia. The interval is not absolutely regular, and shows many individual variations within limits which may be placed at 20 to 35 days. Absence of the menstrual flow is designated as a condition of amen- orrhea. Certain premonitory symptoms usually precede the appearance of the menses, such as pains in the back or head or a general feeling of discomfort, although in some cases these symp- toms are absent. When these premonitory symptoms are unusually painful or serious and the flow is difficult or irregular the condition is designated as dysmenorrhea. The flow begins with a discharge of mucus, which later becomes mixed with blood. The quantity of blood lost is subject to individual variations, but it may amount to as much as 100 to 200 gms. The flow continues for 3 or 4 days and then subsides. Under normal conditions this phenomenon occurs regularly throughout sexual life, — that is, during the period in which conception is possible. If fertilization occurs the flow ceases normally during pregnancy and the period of lactation. At the forty-fifth to the fiftieth year the flow disappears permanently, and this change marks what is known as the natural menopause, climacteric, or change of life. The change is sometimes abrupt, sometimes very gradual, being preceded by irregularities in * For discussion and literature see Marshall, "The Physiology of Repro- duction," London, 1910; and Loeb, "Journal of the American Medical Associa- tion," 1906, xlvi., 416. THE FEMALE REPRODUCTIVE ORGANS. 947 menstruation, and it is not infrequently associated with psychical and physical disturbances of a serious character. If at any time during sexual life the ovaries are completely removed by surgical operation menstruation is brought to a close, this condition being designated as artificial menopause. Structural Changes in the Uterus During Menstruation. — Men- struation is a phenomenon of the uterus. The lining mucous mem- brane, the endometrium, in the period of four or five days preceding the flow, becomes rapidly thicker and its superficial layers are con- gested with blood, and indeed in places small collections of blood may be noticed. Opinions differ very much as to the change under- gone by this thickened membrane during the flow. According to some authors, most of the membrane is thrown off and the blood escapes from the denuded surface mixed with pieces of the mem- brane. According to others, no material destruction of the mem- brane occurs, the blood that escapes being due to small capillary extravasations or perhaps mainly to a process of diapedesis. It would seem that the amount of destruction of the endometrium must be subject to individual variations. After the cessation of the flow the mucous membrane is rapidly repaired by regenerative changes in the tissues; the surface epithelium, if denuded, is re- placed by proliferation of the cells lining the uterine glands and the thickened, edematous condition of the membrane rapidly sub- sides during a period of six or seven days. While the escape of blood takes place only from the surface of the uterus, the other reproductive organs — the ovary, the Fallopian tubes, and even the external genital organs — share to some extent in the vascular con- gestion exhibited by the uterus during the period preceding the menstrual flow. The mucous membrane of the uterus may be said to exhibit a constantly recurring menstrual cycle which falls into four periods: (1) Period of growth in the few (5) days preceding menstruation, characterized by a rapid increase in the stroma, blood-vessels, epithelium, etc., of the membrane. (2) The men- struation or period of degeneration (4 days), during which the capillary hemorrhage takes place and the epithelium suffers de- generative changes and is cast off more or less. (3) The period of regeneration (7 days), during which the mucous membrane returns to its normal size. (4) The period of rest (12 days), during which the endometrium remains in a quiescent condition. The Phenomenon of Heat (CEstrus) in Lower Mammals. — The phenomenon known as heat in lower mammals resembles, in many essential respects, menstruation in human beings, and they may be regarded as homologous functions. Heat is a period of sexual excitement which occurs one or more times during the year and during which the female will take the male. The condition 948 THE PHYSIOLOGY OK REPRODUCTION. lasts, as a rule, for several days, and in the female is accompanied by changes which resemble those of menstruation. The external genital organs become swollen and in many animals there is a discharge of mucus or mucus and blood from the uterus. His- tologically the mucous membrane of the uterus undergoes changes similar to those of menstruation — that is, the membrane increases in size and becomes congested with blood — and it exhibits a phase of degeneration during which some of the epithelial lining may be cast off and some hemorrhage occur. As in the case of the men- strual period, the heat period or oestrous cycle may be divided into four subperiods (Marshall and Jolly) : the procestrum, during which the genital organs are congested and bleeding occurs, corresponds with menstruation; the oestrus, the period of sexual desire; the metcestrum, the period of repair and return to normal conditions, and the anoestrum, the period of rest. If sexual union is prevented during this period heat passes away in a few days, but recurs again at intervals which vary in the different mammals: 4 weeks in the monkey, mare, etc.; 3 to 4 weeks in the cow; 2h to 4 weeks in the sheep; 9 to 18 days in the sow; 12 to 16 weeks in the bitch, etc. The recurrence of the period under these circumstances suggests at once the essential resemblance to the monthly periods of women. According to Heape's most interesting observations upon monkeys (Semnopithecus),* some of these animals show a regular monthly flow lasting for 4 days, except when conception takes place. The changes during heat must be considered as physiologically ho- mologous to those of menstruation. The sexual excitement that attends the condition in the lower animals is not distinctly repre- sented in man, although it is commonly said that in the period following menstruation the sexual desire is stronger than at other times, but in the changes undergone by the uterus and the fact that these changes are connected, as a rule, with the liberation of an egg from the ovary (ovulation), the two phenomena are physiologically similar. Relation of the Ovaries to Menstruation. — It appears to be clearly demonstrated that the phenomenon of menstruation is de- pendent upon a periodical activity in the ovaries. When the ovaries are completely removed menstruation ceases (artificial menopause) and the uterus undergoes atrophy. When the ovaries are congenitally lacking or rudimentary, a condition of amenorrhea also exists. These facts and the connection of the ovaries with menstruation are further corroborated in a striking way by experi- ments upon transplantation or grafting of the ovary. This experi- ment has been performed upon lower animals (apes) as well as upon *Heape, "Philosophical Transactions. Royal Society," 185 (B), 1894, and 188 (B), 1897. THE FEMALE REPRODUCTIVE ORGANS. 949 human beings. Removal of both ovaries in apes is followed by a ces- sation of menstruation. Transplantation of an ovary under the skin serves to maintain menstruation, but if subsequently removed this function disappears.* In the human being Morris and Glass ob- tained similar results, f An ovary or a piece of an ovary trans- planted into the uterus itself or the broad ligament caused a re- turn of the menstrual periods which had ceased after surgical re- moval of the glands, or brought on free menstruation in conditions of amenorrhea or dysmenorrhea. Many views have been proposed to explain this relationship between ovary and uterus. In most cases it has been assumed that the menstruation in the uterus is connected with the act of ovulation, — that is, the ripening and discharge of a Graafian follicle. Gynecologists, it is true, have accumulated facts to show that ovu- lation may occur independently of menstruation, but, as a rule, the two acts occur together, not simultaneously, but in a definite sequence, and the significance' of menstruation is to be found in its physiological connection with the fate of the ovum. It was believed at first that the processes in the ovary influence the uterus by a nervous reflex. This view finds its most complete expression in the theory formulated by Pfluger. According to this physiologist, the congestion of the uterus which leads to menstrua- tion and the congestion of the ovary which leads to ovulation are both reflex vasodilator effects due to the mechanical stimulation of the sensory nerves of the ovary by the growth in size of the fol- licle. As this structure develops the mechanical stimulus increases in intensity, the congestion in both organs becomes more pro- nounced and leads finally to the bursting of the follicle and the hemorrhage in the uterus. This very attractive theory does not, however, accord with the facts. Goltz and Rein! have shown by experiments upon dogs that when the nerves going to the uterus are completely severed from their central connections the animals can be fertilized, become pregnant, and give birth to a litter of young. Moreover, the experiments upon transplantation referred to above seem to show quite conclusively that a nervous connection is not essential to the influence that the ovary exerts upon the uterus. The present view, therefore, is that this influence is exerted through the blood, — the other great system connecting the organs with one another. The usual assumption is that the ovaries form an internal secretion which is given to the blood or lymph and upon reaching the uterine tissues serves to stimulate the mucous mem- brane to a more active growth. This theory has been elaborated *Halban, "Deutsche Gesellschaft f . Gymikol. ." 9, 1901. t Glass,' "Medical News," 523, 1899; Morris, "Medical Record," 83, 1901. % Rein " Archiv f. die gesammte Physiologie," vol. xxiii. 950 THE PHYSIOLOGY OF REPRODUCTION. most fully perhaps by Fraenkel,* who believes that this internal secretion is furnished by the yellow cells of the corpus luteum. This observer, from the results of operations upon women, believes that the ovum is normally discharged two weeks before menstrua- tion, and the resulting increased activity of the cells of the corpus luteum is responsible for the secretion which stimulates the uterus to the augmented growth that takes place in the premenstrual period. Whether or not the monthly change in the endometrium is directly dependent upon an internal secretion from the ovary or is an independent cyclic process peculiar to this tissue, there seems to be no doubt that the physiological integrity of the uterus as a whole is dependent upon the ovaries. Removal of the ovaries in the young prevents the normal development of the uterus, while removal in the adult causes a degeneration of the uterus, which, however, can be averted by a successful transplantation of ovarian tissue. f In the lower animals Marshall and Jolly X have been able to show that extracts of the ovaries, taken from an animal in or just before heat (procestrous or cestrous period), when injected into an animal during the ancestrum bring on a transient condition of heat. These authors do not believe, how- ever, that the chemical stimulus (hormone) formed in the ovary is developed by the cells of the corpus luteum, since according to their observation on cats and dogs ovulation does not occur until after heat has begun (procestrum). The Physiological Significance of Menstruation. — Naturally many views have been proposed to explain the significance of men- struation. According to the Mosaic law, it is a process of purifica- tion; others have seen in it a mechanism to remove an excess of nutriment in the body; but since the period in which our knowl- edge of the structure of the organs concerned and of the histo- logical changes during the act became more definite, theories of the meaning of menstruation have usually assumed that it is a prepara- tion for the reception of the fertilized ovum. These views have taken two divergent forms according as the act of ovulation was believed to precede or to happen simultaneously with or subse- quently to the act of menstruation. According to one view, the swelling and congestion of the membrane constitute a prepara- tion for the reception of the fertilized ovum. If the ovum fails of fertilization, then degenerative changes ensue, and the membrane * Fraenkel, "Archiv f. Gynakologie, " 68,2, 1903. See also Ihm, "Monatsschrift f. Geburtshtilfe u. Gynakol.," 21, 515, 1905, for discussion and extensive literature. fCarmichael and Jolly, "Proc. Roy. Soc.," B, 79, 1907, and Marshall and Jolly, "Roy. Soc. Edinb.," 45, 589, 1907. J Marshall and Jolly, "Philosophical Transactions, Royal Society," London, 1905, B. cxcviii., 99. THE FEMALE REPRODUCTIVE ORGANS. 951 or a portion of it is cast off in the menstral flow, while the re- mainder is absorbed. According to this view, menstruation is an indication that fertilization has not taken place.* This view falls in with the belief that ovulation normally precedes menstrua- tion by a considerable interval. A modification or extension of this general hypothesis is proposed by Bryce and Teacher. f They believe that the process of menstruation is a cyclic one, which has for its object the preparation of the endometrium for the reception of the ovum. The monthly regeneration keeps this membrane in that condition of youthful irritability which enables it to respond promptly to the stimulus of the ovum by the formation of a decidua. The other point of view was advo- cated especially by Pfliiger in connection with his theory of a common cause of ovulation and menstruation. He assumed that menstruation occurs before the ovum reaches the uterus and that its physiological value lies in the fact that a raw surface is thus made upon which the ovum is grafted. Menstruation, according to him, is an operation of nature for the grafting of the fertilized ovum upon the maternal organism. This view finds considerable support in the fact that in some of the lower animals (dogs) the flow of blood (prooestrum) precedes fertilization. The Effect of the Menstrual Cycle on Other Functions. — It is natural to suppose that such marked changes as occur in the ovary and uterus during the menstrual cycle should have an in- fluence upon other parts of the body. As a matter of fact, it is known that in general the sense of well-being varies with the phases of the cycle. At the time of or in the period just preceding the menstrual flow there is usually a more or less marked sense of ill- being or despondency, and a diminution in general efficiency. Among the various observations made by objective methods upon the functions of the different organs during these periods the most significant, probably, are those upon blood-pressure. According to Mosher,J the blood-pressure falls at the time of the menstrual periods. The curves obtained in these experiments are not entirely regular, but at or near the menstruation the blood-pressure falls slowly, the maximum fall being coincident with the appearance of the flow. It would seem probable that the fall of general blood- pressure is due directly to the vascular dilatation in the genital or- gans and in turn is responsible for some of the secondary phenomena observed in the organism as a whole. Similarly, Zuntz records that during the menstrual period there is a fall in pulse-rate and * This view finds expression in the aphorisms: "Women menstruate because they do not conceive," Powers, and "The menstrual crisis is the physiological homologue of parturition," Jacobi. t Bryce- and Teacher, "Early Development and Imbedding of the Human Ovum," 1908. JMosher, "The Johns Hopkins Hospital Bulletin," 1901. 952 THE PHYSIOLOGY OF REPRODUCTION. in body temperature, so that, so far as the female is concerned, there is evidence of a periodic oscillation in pressure, rate, and tempera- ture synchronous with the menses, and it is probable that other functions and even the psychical states may be affected by this rhythm. Some observers claim to have obtained similar periodical falls in blood-pressure in men, suggesting the idea that has fre- quently been expressed, that in man as well as woman there is a rhythmical activity of the genital organs, a reproductive cycle that in man may be referred to the development and extrusion of the spermatozoa in the testis, as in woman it is connected with the growth and expulsion of the ova in the follicles of the ovary. This suggestion at present has very little precise evidence in its favor. The Passage of the Ovum into the Uterus. — The means by which the ovum gains entrance to the Fallopian tubes has given rise to much speculation and some interesting experiments. It was formerly believed (Haller) that at the time of ovulation the fimbriated end of the Fallopian tube is brought against the ovary, the movement being due to a congestion or a sort of erection of the fimbriae. This movement has not been observed, and, as experi- ments show that small objects introduced into the pelvic cavity are taken up by the tubes, it is believed that the cilia upon the fimbria1 and in the tubes may suffice to set up a current that is sufficient to direct the movements of the ovum. Attention has been called to the fact that in animals with a bicornate uterus the ova may be liberated from the ovary on one side, as shown by the presence of the corpora lutea, while the embryos are developed in the horn of the other side. As further evidence for the same possibility of migration it has been shown that the ovary may be excised on one side and the horn of the uterus on the other and yet the animal may become pregnant after sexual union. It would seem probable, therefore, that the ovum is discharged into the pelvic cavity and may be caught up by the ciliary movements at the end of the tube on the same side, or may traverse the pelvic cavity in the narrow spaces between the viscera and be received by the tube on the other side. Such a view explains the possible occurrence of true abdominal pregnancies, and suggests also the possibility that ova may at times fail to reach the uterus at all and may undergo de- struction and absorption in the abdominal cavity. In some of the lower animals — the dog, for example — provision is made for the more certain entrance of the ova into the tubes by the fact that the latter end in connection with a membranous sac of peri- toneum which envelopes the ovary. The sexual fertilization of the ovum is supposed to take place shortly after its entrance into the Fallopian tube, since spermatozoa have been found in this THE FEMALE REPRDOUCTIVE ORGANS. 953 region, and the fertilized ovum, before reaching the seat of its im- plantation in the body of the uterus, has begun its development. By the act of coitus the spermatozoa are deposited at the mouth of the uterus, whence they make their way toward the tubes, being guided in their movements very probably by the opposing force of the ciliary contractions in the uterus. It is known that the cilia of the tubes and uterus contract so as to drive inert objects toward the vagina and the}7 carry the egg in this direction, but the spermatozoa, being moved by the contractions of their own cilia or tails, are stimulated to advance against this ciliary current. The act of fertilization of the ovum is preceded by certain preparatory changes in the ovum itself which are described under the term maturation. Maturation of the Ovum. — The process of maturation occurs before or just after the spermatozoon enters the ovum. At the time the latter is extruded from the follicle it is a single cell sur- rounded by a layer of fol- licular epithelium forming the corona radiata, which ^===^====^ is subsequently lost. The ;- "^ egg proper consists of cyto- plasm and a nucleus or germinal vesicle containing a nucleolus or germinal spot. Within the cyto- \ '_ .;'.;■ :;_ Hts^ plasm is a definite collec- V . tion of food material or /' yolk which is sometimes "^-^ ^^ designated as deutoplasm. The whole structure is sur- rounded by a membrane Fig. 302.— Human ovum (Lee, modified from 1 ,i ]• , Nagel): n. Nucleus (germinal vesicle) containing Known as the ZOna racliata tfie ameboid nucleolus (germinal spot); d, deu- (Fig. 302). Before or after Zfi&fZS&CgZ** ™*'' " ""* the egg reaches the Fal- lopian tube its nucleus undergoes the changes preparatory to a mitotic division. The changes that occur in an ordinary cell division are represented schematically in Fig. 303. The nucleus at first presents the ordinary chromatin network, and in the cytoplasm lies the minute structure known as the centrosome. This latter divides into two daughter-centrosomes (b) which move to opposite sides of the nucleus and become surrounded by rays, each centrosome with its radiating system forming an astro- sphere. The chromatin material in the nucleus meanwhile has collected .into larger threads known as chromosomes (c), and the nuclear membrane disappears (d). The number of chromo- — d 954 THE PHYSIOLOGY OF REPRODUCTION. somes is definite for each species of animal. The chromosomes arrange themselves equatorially between the astrospheres and then each divides longitudinally into two parts (/) . These parts migrate or are drawn toward their respective centrosomes (g, h, i) , and this division is followed by a separation of the cytoplasm into two parts. Thus, two daughter-cells are formed, each containing the same number of chromosomes as the parent cell, but only half the amount of chromatin material. The cell division results in a quantitative reduction of the chromatin material. In ordinary cell division the chromosomes again form a resting reticulum and a nuclear membrane and the chromatin substance increases in quantity. In the ovum during maturation two successive cell- divisions occur which resemble the typical cell-division just described, except that the daughter-cells are of very unequal size and that they contain each only half the normal number of chromosomes. In the first division, known sometimes as the heterotypical division, the process is preceded by a fusion of the chromosomes in pairs. In the division that ensues the pairs of chromosomes are split, one part going to each cell, with the result that each of the latter now contains half the number of chromo- somes— and each chromosome is an entire one from the parent cell, instead of half a one, as in the usual cell division. The two resulting cells are of very unequal size, the larger one is designated still as the ovum, the smaller one as the first polar body. The ovum now divides again (homotypical division), throwing off a second polar body. In this division the chromosomes, according to some observers, divide transversely, according to others, they divide longitudinally as in typical cell division.* In the formation and extrusion of the two polar bodies the matured ovum has suf- fered a quantitative and perhaps a qualitative reduction in chroma- tin material, and is left with only half its number of chromosomes. Since the first polar body after its separation may again divide into two cells, the process of maturation results in the formation of four cells, three of which are polar bodies and may be regarded as abor- tive ova. The fourth, the matured ovum, retains practically all of the original cytoplasm, but has lost a part of its chromatin material and, according to Boveri, also its centrosome. The production of these four cells may be represented, therefore, by a schema of the kind shown in Fig. 304. The details of this process of forma- tion of the polar bodies and of reduction in chromatin material differ somewhat in different animals, f The process has not been followed in the human ovum, but since it occurs in the eggs of all * For further details see Bryce in Embryology, "Quain's Anatomy," 1908. t For details see Wilson, "The Cell in Development and Inheritance," New York. Fig. 303. — Schematic representation of the processes occurring during cell division. CBoveri.) THE FEMALE PRODUCTIVE ORGANS. 955 animals with sexual reproduction, so far as they have been studied, it is justifiable to assume that a similar change takes place in man. From a biological standpoint the reduction of chromosomes throws much light upon the significance of fertilization by the male cell. The spermatozoon before it is ripe undergoes a process of maturation essentially similar to that described for the ovum. Two cell divisions take place with the formation of four spermatozoa, each of which, however, is a functional spermatozoon. In the pro- cess of division the number of chromosomes in each cell is reduced ——Ovarian egg — ——First polar Doay Mature egg VVj-J • • • ■ Abortive ova resulting from division of first polar body. Second polar body (abortive ovum). Fig. 304. — Schema to indicate the process of maturation of the ovum. — (Boveri.) by half. When the matured ovum and the matured spermatozoon fuse, therefore, each brings half the normal number of chromosomes, and the resulting fertilized ovum is a cell with its chromosomes restored to their usual number. The chromatin material has been regarded as the essential part of the reproductive element. Accord- ing to some authors it is the substance which has the power of development and which conveys the hereditary structure specific to the animal. The process which causes each element to lose a part of this material before its union with the cell of the opposite sex is, from this standpoint, a provision by means of which the fertilized egg, from which the offspring develops, shall inherit the characteristics of each parent, without increase in the typical number of the chromosomes.* Fertilization of the Ovum.— The spermatozoon comes into contact with the ovum probably at the beginning of the Fallopian tubes. The meeting of the two cells is possibly not simply a matter of accidental contact, although the number of spermatozoa dis- charged by the male at coitus is so great that there would seem to be little chance for the ovum to fail to meet some of them. Ex- periments upon the reproductive elements of plants indicate, how- ever, that the egg may contain substances which serve to attract the spermatozoon, within a certain radius, by that force which * For a popular presentation see Boveri, "Das Problem der Befruchtung," Jena, 1902. 056 THE PHYSIOLOGY OF REPRODUCTION. is described under the name of chemotaxis. However this may be, the egg unites with a spermatozoon and under normal conditions with only one. A number of the spermatozoa may penetrate the zona radiata, but so soon as one has come into contact with the cytoplasm of the egg a reaction ensues in the surface layer which makes it impervious to other spermatozoa. The spermato- zoon consists of three essential parts, — the head, the middle piece, and the tail. The last named is the organ of locomotion, and after the spermatozoon enters the egg this portion atrophies and disappears, probably by absorption. The head of the spermato- zoon represents the nucleus, and contains the valuable chromatin material. On entering the egg it moves toward the nucleus of the latter, meanwhile enlarging and taking on the character of a nu- cleus. The egg now contains two nuclei, — one belonging to it origi- nally, the female pronucleus; one brought into it by the sperma- tozoon, the male pronucleus. The two come together and fuse, — superficially at least, — forming the nucleus of the fertilized egg, or the segmentation nucleus. The middle piece of the spermatozoon also enters the egg, but its exact function and fate is still a matter of uncertainty. Boveri believes that it brings into the egg a centrosome or material which induces the formation of a centro- some in the ovum, and is, therefore, of the greatest importance in initiating the actual process of cell division which begins promptly after the fusion of the nuclei. In the segmentation nucleus the nor- mal number of chromosomes is restored, and it is believed that in the subsequent divisions of the cell to form the embryo the chromo- somes are so divided that each cell gets some maternal and some paternal chromosomes, and thus shares the hereditary characteris- tics of each parent. This view is represented in a schematic way by Fig. 305, taken from Boveri, the maternal and paternal chromo- somes being indicated by different colors. According to this descrip- tion, both egg and spermatozoon are incomplete cells before fusion. The egg contains a nucleus and a large cell body, cytoplasm, rich in nutritive material, but it lacks a centrosome or the conditions neces- sary for the formation of an astrosphere, so that it cannot mul- tiply. The spermatozoon has also chromatin for a nucleus, and a centrosome or the material which may give rise to a centrosome, but it lacks cytoplasm — that is, food material for growth. It would seem that if the spermatozoon could be given a quantity of cytoplasm it would proceed to develop an embryo without the aid of an ovum. This experiment has, in fact, been made by Boveri. Eggs of the sea-urchin were shaken violently so as to break them into fragments. If now a spermatozoon entered one of these fragments, which consisted only of cytoplasm, cell multiplica- tion began and proceeded to the formation of a larva. On the other Fig. 305. — Schematic representation of the processes occurring during the fertiliza- tion and subsequent segmentation of the ovum. — (Boveri.) The chromatin (chromo- somes) of the ovum is represented in blue, that of the spermatozoon in red. THE FEMALE REPRODUCTIVE ORGANS. 957 ■ hand, it would seem to be equally evident that if a centrosome was present in the egg or some influence could be brought to bear upon it to initiate the process of cell division, it would develop with- out a spermatozoon. In some animals eggs do normally de- velop at times without fertilization by a spermatozoon (par- thenogenesis), the eggs that have this property probably pre- serving their centrosomes. Loeb* has shown, however, in some most interesting experiments that certain eggs, especially those of the sea-urchin (Strongylocentrotus purpuratus), which normally develop by fertilization with spermatozoa, may be made to de- velop by physicochemical means. His latest method is to treat the egg for a minute or two with. an acid (acetic, formic, etc.), which causes the formation of a membrane. They are then placed for a certain interval in a hypertonic sea water, made by adding sodium chlorid to ordinary sea water. They are then transferred to normal sea water and after an hour or so they begin to multiply and eventually develop into normal larvae. Similar although less complete results were obtained previously by Morgan. Experi- ments of this character would indicate that the spermatozoon brings into the ovum definite substances, which, by chemical or psychochemical means, initiate and control the process of .segmen- tation. Suggestions as to the nature of these substances are at present very hypothetical. Implantation of the Ovum. — After fertilization in the tube the ovum begins to segment and multiply, and meanwhile is carried toward the uterus, probabby by the action of the cilia lining the tube. Upon reaching the cavity of the uterus it becomes attached to the mucous membrane, usually in the neighborhood of the fundus. The membrane of the uterus has become much thickened mean- while, and in this condition is known usually as the decidua. The portion to which the egg becomes attached is the decidua serotina, and it eventually develops into the placenta, the organ through which the maternal nutriment is supplied to the fetus. The ovum has made considerable progress in its development before reaching the uterus, having formed amnion and chorion, with chorionic villi. Some of the ectodermal cells in the chorion become specialized to form a group of trophoblastic cells which have a digestive action, and it is suggested that the activity of these cells enables the ovum to become attached to the decidual membrane and to hollow out spaces in which the chorionic papilla become inserted. t The further development of the egg into a fetus, the formation of the decidua graviditatis, and the placenta are anatomical features that need not be described here. Detail,? of these structures will be found * Loeb, " University of California Publications," 2, pp. 83, 80, and 113, 1905. See also Wilson, "Archiv f. entwick. Mechanik," 12, 1901. t See Minot, "Transactions of the American Gynecological Society," 1904. 958 THE PHYSIOLOGY OF REPRODUCTION. « in works on anatomy, embryology, or obstetrics. On the phys- iological side it has been found that removal of the ovaries, or even destruction of the corpora lutea, shortly after pregnancy has begun brings the process to an end, while a similar operation later in pregnancy has no effect upon the developing fetus or the subsequent act of parturition. It seems, therefore, that the process of implan- tation of the ovum in the uterine mucous membrane and the devel- opment of a placenta are dependent in some way upon the ovaries. The apparent explanation of the connection is given in the hypothe- sis that the corpora lutea, during their rapid development at the beginning of pregnancy, give off an internal secretion which controls or influences in some essential way the processes connected with the fixing of the fertilized ovum.* The Nutrition of the Embryo — Physiology of the Placenta. ■ — At the time of fertilization the ovum contains a small amount of nutriment in its cytoplasm. The amount, however, in the mam- malian ovum is small and suffices probably only for the initial stages of growth. When the ovum becomes implanted in the decidual membrane of the uterus the new material for growth must be ab- sorbed directly from the maternal blood of the uterus. Within a short time, however, the chorionic villi begin to burrow into the uterine membrane at the point of attachment, the decidua serotina, and the placenta gradually forms as a definite organ for the control of fetal nutrition. The details of histological structure of this organ must be obtained from anatomical sources. For the purposes of understanding its general functions it is sufficient to recall that the placenta consists essentially of vascular chorionic papilla? from the fetus bathed in large blood-spaces in the decidual membrane of the mother. The fetal and the maternal blood do not come into actual contact ; they are separated from each other by the walls of the fetal blood-vessels and the epithelial layers of the chorionic villi, but an active diffusion relation is set up between them. Nutritive material, protein, fat, and carbohydrate, and oxygen pass from the maternal to the fetal blood, and the waste products of fetal metabolism — carbon dioxid, nitrogenous wastes, etc., pass from the fetal to the maternal blood. The nutrition of the fetal tissues is maintained, in fact, in much the same way as though it were an actual part of the maternal organism. That material passes from the maternal to the fetal blood is a necessary inference from the growth of the fetus. The fact has also been demonstrated repeat- edly by direct experiment. Madder added to the food of the mother colors the bones of the embryo. Salts of various kinds, sugar, drugs,' etc., injected into the maternal circulation may afterward be de- tected in the fetal blood. But we are far from having data that * Marshall and Jolly and Fraenkel, loc. cit. THE FEMALE REPRODUCTIVE ORGANS. 959 would justify us in supposing that the exchange between the two bloods is effected by the known physical processes of os- mosis, diffusion, and filtration. The difficulties in understanding the exchange in this case are the same as in the absorption of nour- ishment by the tissues generally. It is perhaps generally assumed that the chorionic villi play an active part in the process, func- tioning, in fact, in much the same way as the intestinal villi. This assumption implies that the epithelial cells of the villi take an active part in the absorption of material by virtue of processes which can- not be wholly explained, but which without doubt are due to the chemical and physical properties of the substance of which they are composed. This assumption does not mean that the simpler and better understood physical properties of diffusion and osmosis are not also important. The respiratory exchange of gases, the diffusion of water, salts, and sugar, may be largely controlled in this way. There are no facts at least which contradict such an assump- tion. The passage of fats and proteins, however, would seem to require some special activity in the chorionic tissue, which may be connected with the presence of special enzymes. Glycogen occurs in the placenta itself and in all the tissues of the embryo during the period of most active growth. In the later period of embryonic life, as the liver assumes its functions, the glycogen becomes more localized to this organ and disappears, except for traces, in the skin, lungs, and other tissues in which it was present at first in considerable quantities. It would appear, therefore, that glycogen (sugar) represents one of the important materials for the growth of the embryo, and that in the beginning at least the tissues generally have a glycogenetic power. The sugar brought to the placenta in the maternal blood passes over into the fetal blood and the excess beyond that immediately consumed is deposited in the tissues as glycogen. The body fat of the fetus is at first slight in amount, but after the sixth month begins to increase with some rapidity. The fat-forming tissues are in full activity, therefore, before birth, and function doubtless in the same way as in the adult. Before birth also the various organs begin to take on their normal activity. The kidney may form urine long before birth, as is shown by the presence of this secretion in the bladder, and, shortly before birth at least, it has the power of producing hippuric acid, as may be shown by injecting benzoates into the blood of the mother. The kidney functions of the embryo, how- ever, are doubtless performed chiefly by the placenta and the kidney of the mother up to the time of birth. That the liver also begins to assume its functions early is shown by the fact that from the fifth to the sixth month one may find bile in the gall-bladder. In the intestine, colon, there is found also a collection of excrement, 960 THE PHYSIOLOGY OF REPRODUCTION. the meconium, which shows that the motor and secretory functions of the intestinal canal may be present in the last months of fetal life. From the pancreas a proteolytic enzyme may be extracted at the time of birth or before, but the amylolytic enzyme is not formed apparently until some time later. It is stated, at least, that it is not present at birth. In general, it is evident that for a long period the maternal organism digests and prepares the food for the embryo, excretes the wastes, regulates the conditions of temperature, etc., as it does for a portion of its own substance, but as the fetus ap- proaches term its tissues and organs begin to assume more of an independent activity, as indeed must be the case in preparation for the sudden change at birth. In this respect, as in all parts of the reproductive process, we meet with regulations whose mechanism is but dimly understood. Changes in the Maternal Organism during Pregnancy. — The two most distinct effects upon the mother that result from pregnancy are the growth of the uterus and of the mammary gland. The virgin uterus is small and firm, weighing from 30 to 40 gms., while at the end of pregnancy it may weigh as much as 1000 gms. This great increase in material is due partly to the growth of new muscular tissue and partly to an hypertrophy of the muscle already present. In the uterus at term the muscle cells are much longer and larger than in the organ before fertilization. The stimulus that initiates and controls this new growth is seemingly the fertil- ized ovum itself, but the physiological means employed are not comprehended. We know from experiments upon lower animals (Rein) that when all connections with the central nervous system are severed the fetus develops normally and the uterus increases correspondingly in size and weight. The influence of the ovum on the uterus must be exerted, therefore, either through some local nerve centers in the uterus, or, as seems much more probable, through some chemical stimulus which it gives to the organ. The effect of the presence and growth of the fetus on the mammary gland is treated in a separate paragraph below. In addition to these two visible effects it is evident that the growth of the fetus has an important influence on general metabolism and therefore upon the whole maternal organism. This fact is indicated by the marked changes often exhibited in the physical and mental con- dition of the mother. It is shown more precisely by a study of the nutritional changes. Numerous investigations have been made upon this subject, especially as regards the nitrogen equilibrium. During the latter part of pregnancy, especially, the nitrogen balance is positive — that is, nitrogen is stored as protein— due doubtless both to the growth of th \ embryo and the increase in material in t he uterus and mammary gland. The proportion of ammonia in THE FEMALE REPRODUCTIVE ORGANS. 961 the urine increases during pregnancy and especially during labor (Slemmons*). Parturition. — The fetus " comes to term " usually in the tenth menstrual period after conception — that is, about 280 days after the last menstruation. The actual time of delivery, however, shows considerable variation. Delivery occurs in consequence of contractions, more or less periodical, of the musculature of the uterus, and reflex as well as voluntary contractions of the abdom- inal muscles. It has been shown that delivery may occur when the nerves connecting the uterus with the central nervous system are severed, so that the act is essentially an independent function of the uterus, although under normal conditions the contractions of this organ are doubtless influenced by reflex effects through its extrinsic nerves. It has been shown that contractions of the gravid uterus may be caused by stimulation of various sensory nerves, and in women it is known that delivery may be precipitated prematurely by various mental or physical disturbances. The interesting prob- lem physiologically is to determine the normal factor or factors that bring on uterine contractions at term. Various more or less unsatis- factory theories have been proposed. Some authors attribute the act to a change in the maternal organism, such as mechani- cal distension of the uterus, a venous condition of the blood, a degenerative change in the placenta, etc., while others suppose that the initial stimulus comes from the fetus. In the latter case it is suggested that the increasing metabolism of the fetus is insuffi- ciently provided for by the placental exchange, and that therefore certain products are formed which serve to stimulate the uterus to contraction. The duration of the labor pains is variable, but usually they are longer in primiparse, ten to twenty hours or more, than in multip- aras. After the fetus is delivered the contractions of the uterus continue until the placenta also is expelled as the "after-birth." During these latter contractions the fetal blood in the placenta is, for the most part, squeezed into the circulation of the new-born child. The hemorrhage from the walls of the uterus due to the rup- ture of the placenta may be profuse at first, but under normal con- ditions is soon controlled by the firm contraction of the uterine walls. The Mammary Glands. — At the time of puberty the mam- mary glands increase in size, but this growth is confined mainly to the connective tissue; the true glandular tissue remains rudi- mentary and functionless. At the time of conception the gland- ular tissue is in some way stimulated to growth. Secreting alveoli are formed, and during the latter part of pregnancy they produce an incomplete secretion, scanty in amount, known as colostrum. * Slemmons, "The Johns Hopkins Hospital Reports," 12. Ill, 1904. 61 962 THE PHYSIOLOGY OF REPRODUCTION. After delivery the gland evidently is again brought under the influence of special stimuli. It becomes rapidly enlarged and a more abundant secretion is formed. For the first day or two this secretion still has the characteristics of colostrum, but on the third or fourth day the true milk is formed and thereafter is produced abundantly, during the period of lactation, under the in- fluence of the act of milking. If during this period a new con- ception occurs the milk secretion is altered in composition and finally ceases. On the other hand, if the act of nursing is aban- doned permanently the glands after a preliminary stage of turgid- ity undergo retrogressive changes that result in the cessation of secretory activity. The colostrum secretion that occurs during pregnancy and for a day or two after birth differs from milk in its composition and histological structure. It is a thin, yellowish liquid containing a larger percentage of albumin and globulin and a smaller percentage of milk-sugar and fat than normal milk. Under the microscope it shows, in addition to some fat droplets, certain large elements, — the colostrum corpuscles. These con- sist of spherical cells filled with fat droplets, and are most probably leucocytes filled with fat which they have ingested. Colostrum corpuscles may occur in milk whenever the secretion of the gland is interfered with, and their presence may be taken as an indi- cation of an incomplete secretion. The Connection Between the Uterus and the Mammary Gland. — The physiological connection between the uterus and the mammary gland is shown by the facts mentioned in the pre- ceding paragraph. That the ovary also shares in this influence either directly or through its effect on the uterus is shown by the fact that after complete ovariotomy the mammary gland under- goes atrophy. This undoubted influence of one organ upon the other might be exerted either through the central nervous system or by way of the circulation. There are indications that the secretion of the mammary glands is under the control, to some extent at least, of the central nervous system. For instance, in women during the period of lactation cases have been recorded in which the secretion was altered or perhaps entirely suppressed by strong emotions, by an epileptic attack, etc. This indication has not received satisfactory confirmation from the side of ex- perimental physiology. Eckhard found that section of the main nerve-trunk supplying the gland in goats, the external spermatic, caused no difference in the quantity or quality of the secretion. Rohrig obtained more positive results, inasmuch as he found that some of the branches of the external spermatic supply vasomotor fibers to the blood-vessels of the gland and influence the secretion of milk by controlling the local blood-flow in the gland. Section THE FEMALE REPRODUCTIVE ORGANS. 963 of the inferior branch of this nerve, for example, gave increased secretion, while stimulation caused diminished secretion, as in the case of the vasoconstrictor fibers to the kidney. These results have not been confirmed by others — in fact, they have been sub- jected to adverse criticism — and they cannot, therefore, be ac- cepted unhesitatingly. After apparently complete separation of the gland from all its extrinsic nerves, not only does the secretion, if it was previously present, continue to form, although less in quantity, but in opera- tions of this kind upon pregnant animals the glands increase in size during pregnancy and become functional after the act of parturi- tion.* This result confirms the older experiments of Goltz, Rein, and others, according to which section of all the nerves going to the uterus does not prevent the normal effect on lactation after delivery. Regarding the question of the existence of secretory nerves, Baschf reports that extirpation of the celiac ganglion or section of the spermatic nerve does not prevent the secretion, but causes the appearance of colostrum corpuscles. Experiments, therefore, as far as they have been carried in- dicate that the gland is under the regulating control of the cen- tral nervous system, either through secretory or more probably through vasomotor fibers. The bond of connection between the mammary gland and the uterus is, however, established mainly through the blood rather than through the nervous system. Some direct evidence for this point of view is furnished by the interesting experiments of Starling and Lane-Claypon.J These authors found that extracts made from the body of the fetus, or rather from the bodies of many fetuses, when injected repeatedly into a virgin rabbit caused a genuine development of the mammary glands closely simulating the growth that normally occurs during pregnancy. Since similar extracts made from ovaries, placental and uterine tissues had no effect, they conclude that a specific chemical sub- stance (a hormone) is produced in the fetus itself and, after absorp- tion into the maternal blood, acts upon the mammary gland, stim- ulating it to growth. Since the birth of the fetus is followed by active secretion in the mammary glands they adopt further the view that this substance, while promoting the growth of the gland tissue, inhibits the catabolic processes which lead to the formation of the secretion. With the birth of the fetus this substance is withdrawn and secretion begins, and, on the contrary, the secretion is suspended when a new pregnancy is well advanced. *Mironow, "Archives des sciences biologiques, " St. Petersburg, 3, 353, 1894. fBasch, "Ergebnisse der Physiologie, " vol. u., part i, 1903. X Lane-Ciaypon and Starling, "Proceedings of the Royal Society," 1906, B. lxxvii.; see also Starling in "Lancet," 1905. 964 THE PHYSIOLOGY OF REPRODUCTION. As was said in speaking of the histology of the gland, the se- creting alveoli are not fully formed until the first pregnancy. Dur- ing the period of gestation the epithelial cells multiply, the alveoli are formed, and after parturition secretion begins. As the liquid is formed it accumulates in the enlarged galactophorous ducts, and after the tension has reached a certain point further secretion is apparently inhibited. If the ducts are emptied, by the infant or otherwise, a new secretion begins. The emptying of the ducts, in fact, seems to constitute the normal physiological stimulus to the gland-cells, but how this act affects the secreting cells, whether reflexly or directly, is not known. Composition of the Milk. — The composition of milk is com- plex and variable.* The important constituents are the fats, held in emulsion as minute oil droplets, and consisting chiefly of olein and palmitin; casein, a nucleo-albumin which clots under the in- fluence of rennin; milk-albumin or lactalbumin, a proteid resem- bling serum-albumin; lactoglobulin ; lactose or milk-sugar; lecithin, cholesterin, phosphocarnic acid, urea, creatin, citric acid, enzymes, and mineral salts. It is well known also that many foreign sub- stances— drugs, flavors, etc. — introduced with the food are secreted in the milk. An average composition is: proteins, 2 to 3 per cent.; fats, 3 to 4 per cent.; sugar, 6 to 7 per cent.; salts, 0.2 to 0.3 per cent. The fact that casein and milk-sugar do not exist preformed in the blood is an argument in favor of the view that they are formed by the secretory metabolism of the gland cells. The special com- position of the milk-fat and the histological appearance of the gland cells during secretion lead to the view that the fat is also constructed within the gland itself. Bunge has called attention to the fact that the inorganic salts of milk differ quantitatively from those in the blood-plasma and resemble closely the propor- tions found in the body of the young animal, thus indicating an adaptive secretion. This fact is illustrated in the following table giving the mineral constituents in 100 parts of ash: Young Pup. Dogs' Milk. Dogs' Serum. ICO 8.5 10.7 2.4 Na20 8.2 6.1 52.1 CaO 35.8 34.4 2.1 MgO 1.6 1.5 0.5 Fe203 0.34 0.14 0.12 PX>6 39.8 37.5 5.9 CI 7.3 12.4 47.6 On account of the use of cows' milk in place of human milk in the nourishment of infants much attention has been given to * For data as to composition and hygienic relations, see Bulletin 41, "Hygienic Laboratory," Public Health and Marine Hospital Service, U. S., Washington, 1908. THE FEMALE REPRODUCTIVE ORGANS. 965 the relative composition and properties of the two secretions. The chief difference between the two lies apparently in the casein. The casein of human milk is smaller in amount, curdles in looser flocks than that of cows' milk, and seems to dissolve more easily and completely in gastric juice. The former also contains rela- tively more lecithin and less ash, particularly the lime salts'. On the other hand, cows' milk contains less sugar and fat. In using it, therefore, for the nutrition of infants it is customary to add water and sugar. The composition of cows' milk is so well known that it is easy to modify it for special cases according to the in- dications. The rules for this procedure will be found in works upon pediatrics. CHAPTER LIII. PHYSIOLOGY OF THE MALE REPRODUCTIVE ORGANS. The sexual life of the male is longer than that of the female. Puberty or sexual maturity begins somewhat later, — in tem- perate climates at about the fifteenth year; but there is no dis- tinct limitation of the reproductive powers in old age correspond- ing to the menopause of the female. At the time of puberty and for a short preceding period the boy grows more rapidly in stature and weight, and the assumption of its complete functions by the testis exerts a general influence upon the organism as a whole. One of the superficial changes at this period which is very evident is the alteration in pitch of the voice. Owing to the rapid growth of the larynx and the vocal cords the voice becomes markedly deeper, and the change is in some cases sufficiently sudden to cause the well-known phenomenon of the breaking of the voice. The neuromuscular control of the vocal cords becomes for a time un- certain. The completion of puberty can not be determined in the boy with the same exactness as in the girl, in whom menstruation furnishes a visible sign of sexual maturity. Much of the sexual mechanism may be functional long before the time of puberty, as is shown b}r the presence of sexual desire and the possibility of erection; but fully developed spermatozoa are not produced until this period, and indeed the presence of ripe and functional spermatozoa in the testis is the only certain sign that sexual ma* turity has been attained. Puberty consists in the maturation of the testis in the male, and of the ovary in the female. The Properties of the Spermatozoa. — The development and maturation of the spermatozoa in the testis has been followed successfully by histological means. The mother-cells of the sper- matozoa, the spermatocytes, give rise to four daughter-cells, sper- matids, each of which develops into a functional spermatozoon. The process in this case is something more than mere cell division, since in the spermatozoa eventually produced the number of chromosomes present in the nucleus — that is, the head of the sper- matozoon— are reduced by one-half. The process of production of the spermatozoa is therefore quite analogous to the maturation of the ovum during the formation of the polar bodies. The forma- tion and maturation of the spermatozoa may be represented by 966 THE MALE REPRODUCTIVE ORGANS. 967 a schema similar to that used in the case of the ova, as follows (Fig. 306) : In the case of the ovum four ova are produced, but only one is functional, and this one, the ripe egg, is characterized by its large amount of cytoplasm, its inability to undergo further cell division until fertilized, and the reduction of its chromosomes to half the num- ber characteristic of the body cells of the species. In the case of the spermatozoa, the four cells produced are all functional,* and are characterized by the practical loss of cytoplasm, reduc- tion of chromosomes by one-half, and inability to multiply until cell material is furnished. The two cells supplement each other, therefore. Their union restores the normal number of chromo- somes, part of which are now maternal and part paternal; the egg supplies the cytoplasm and the spermatozoon nuclear material and the definite stimulus that leads to multiplication. The spermatozoa are produced in enormous numbers. It is calculated that at ejaculation each cubic centimeter of the liquid contains from sixty to seventy millions of these cells. The » Primary adult ripe spermatozoon is /\ spermatocyte, characterized as an independ- / V_ _ Secondary ent cell by its great motility, A A" spermatocytes. due to the cilia-like contrac- / \ / \ tions of its tail. Its power of f f 7 Spermatids. movement or its vitality is I retained under favorable con- • • • • Spermatozoa. CUtionS for VerV long periods. Fig- 306.— Schema to 'indicate the proc- \ . „ ess of maturation of the spermatozoa. — The most striking instance of (.Bover€>. this fact is found in the case of bats. In these animals copulation takes place in the fall and the uterus of the female retains the spermatozoa in activity until the period of ovulation in the following spring. Even in the human being it is believed that the spermatozoa may exist for many days in the uterus and Fallopian tubes of the female. In the semen that is ejaculated during coitus the spermatozoa are mixed with the secretions of the accessory reproductive glands, such as the seminal vesicles, the prostate gland, and Cowper's gland. The specific in- fluence of each of these secretions is not entirely understood, but experiments show that in some way they are essential to or aid greatly in maintaining the motility of the spermatozoa. Steinachf has found, for example, that removal of the prostate gland and * It is an interesting fact that in some cases (bees) two kinds of spermatids are formed by an unequal division of the spermatocyte, and the smaller of the two is abortive, as in the case of the polar bodies of the egg. t See Steinach, " Archiv f . d. gesammte Phvsiologie," 56, 1894, and Walker, "Archiv f.,Anatomie u. Physiologie," 1899, p. 313. 968 THE PHYSIOLOGY OF REPRODUCTION. seminal vesicles in white rats prevents successful fertilization of the female, although the ability and desire to copulate are not inter- fered with. This result has been corroborated by Walker.* Accord- ing to this author, removal of both the prostate and seminal vesicles in the rat leaves the testes in apparently normal condition, but the animals are not able to fertilize the female. Removal of the testes, on the other hand, prevents the development of the prostate in the young animal and causes atrophy of the gland in the adult. Evi- dently, therefore, the testis controls, in some way, probably by a hormone, the metabolic processes in the prostate. Walker believes that the prostatic secretion aids in rendering the spermatozoon properly motile. The secretion of the seminal vesicles, he finds, exhibits a curious property of clotting upon mixture with the secretion of a small gland at its base — the coagulating gland. If the secretion of the vesicles follows the ejaculation of the semen, it is possible that the coagulation of the former serves to occlude the vagina in the female and thus prevent the loss of the fertilizing liquid. The union of spermatozoon and ovum is believed to take place usually in the Fallopian tube, and under normal con- ditions only one spermatozoon penetrates into the egg. The remainder of the great number that may be present eventually perish. The changes that take place during the process of fer- tilization have already been described (p. 955). Chemistry of the Spermatozoa. — Much chemical work has been done upon the composition of spermatozoa, particularly in the fishes. The results have been most interesting from a chem- ical standpoint, and biologically they are suggestive in that the analytical work has been done upon the heads of the spermatozoa. These heads consist entirely of nuclear material, and contain the substance or substances which convey the hereditary characteristics of the father, or, to speak more accurately, of the race to which the father belongs. Whatever progress may be made in the understand- ing of the chemistry of this material is a step toward the solution of the most difficult and mysterious side of reproduction, the power of hereditary transmission. Miescher, in investigations upon the spermatozoa of salmon, discovered that the heads are composed essentially of an organic combination of phosphoric acid, since designated as nucleic acid, united with a basic albuminous body, protamin. This view has been confirmed and extended by later observers, especially by Kossel and his pupils, f The head of the spermatozoon, the male pronucleus in fertilization, may be de- * Walker, "Johns Hopkins Hospital Reports," 16, 1911, and " Johns Hop- kins Bulletin," 21, 1910. t For literature and details of the chemistry of spermatozoa see Burian, in " Ergebnisse der Physiologie," vol. iii., part i, 1904, and 1900, v., 832. THE MALE REPRODUCTIVE ORGANS. 969 fined, in the case of the fishes at least, as " a salt of an organic base and an organic acid, a protamin-nucleic acid compound." The term protamin is used now to designate a group of closely related substances obtained from the spermatozoa of different animals. The special protamin of each species is designated ac- cording to the zoological name of that species; thus the protamin of salmon is salmin, of hering (Clupea harengus) clupein, and so on. The protamins are all strong bases; their aqueous solutions give an intense alkaline reaction, and they unite readily with various acids to form well-defined salts. They are protein bodies, giv- ing the biuret reaction readily even without the addition of alkali, and they are precipitated by most of the general precipitants of proteins, such as the neutral salts, the alkaloidal reagents, etc. Their solutions, however, are not coagulated by heat. The molec- ular formula for salmin is given as C30H57N17O6. When decom- posed by the action of acids they yield simpler basic products, the so-called hexon bases or diamino-bodies, and particularly the base arginin (C6HuN402), which is contained in the protamin of the spermatozoa in greater abundance than in any other protein. The protamins differ from most other protein compounds by their relative simplicity; they contain no cystin grouping, therefore no sulphur; no carbohydrate grouping in most of the compounds examined; and no ty rosin complex. In the spermatozoa of some fishes the protamins are replaced by more complex compounds belonging to the group of histons which show properties somewhat intermediate between those of protamins and ordinary proteins, and in general it may be said that the head of the spermatozoon, like the nuclei of cells in general, consists chiefly of a nucleoprotein compound, that is, a compound of nucleic acid with a protein body of a more or less distinctly basic character.* The nucleic acid com- ponent of the spermatozoon resembles the same substance as obtained from the nuclei of other cells. In the spermatozoa of the salmon this nucleic acid has the formula CwH56NuP40,6. On decomposition by hydrolysis it yields at first some of the purin bases (adenin, guanin), and on deeper cleavage a number of compounds, including the pyTimidin derivatives, thymin, uracil, and cytosin. While the chemical studies upon spermatozoa, thus briefly referred to, have greatly extended our knowledge, it is still impossible to say that they have given any information concerning the peculiar functions of the spermatozoa in fertilization. The Act of Erection.— In the sexual life of the male the act of erection of the penis during coitus offers a most striking physical phenomenon. During this act the penis becomes hard and erect, owing to an engorgement with blood. The structure of the corpora * Burian, loc. cit. 970 THE PHYSIOLOGY OF REPRODUCTION. cavernosa and corpus spongiosum is adapted to this function, being composed of relatively large spaces inclosed in trabecular of connec- tive and plain muscle tissue, — the so-called erectile tissue. Many- theories have been proposed to explain the mechanism of erection, but it is generally agreed that the work of Eckhard * demonstrated the essential facts in the process. This investigator discovered that in the dog stimulation of the nervi erigentes causes erection. These nerves are composed of autonomic fibers arising from the sacral por- tion of the spinal cord (see Figs. Ill and 112). They arise from the sacral spinal nerves, first to third (dog), on each side and help to form the pelvic plexus. They contain vasodilator fibers to the penis, as well as to the rectum and anus, and also visceromotor fibers to the descending colon, rectum, and anus. Eckhard, Loven, and others ] have shown that when these fibers are stimulated there is a large dilatation of the arterioles in the erectile tissue of the penis and a greatly augmented blood-flow to the organ. If the erectile tissue is cut or the dorsal vein is opened the blood-flow under usual con- ditions is a slow stream, but when the nervus erigens is stimulated the outflow is very greatly increased; according to Eckhard's measurements, eight to fifteen times more blood flows out of the organ. The act of erection is therefore due essentially to a vas- cular dilatation of the small arteries whereby the cavernous spaces become filled with blood under considerable pressure. The caver- nous tissues are distended to the limits permitted by their tough, fibrous wall. It seems probable that the turgidity or rigidity of the congested organ is completed by a partial occlusion of the venous outflow, which is effected by a compression of the efferent vein by means of the extrinsic muscles (ischio and bulbocavernosus) and possibly by the intrinsic musculature as well. This compres^ sion does not occlude the blood-flow completely, but serves to in- crease greatly the venous pressure. This explanation of the act of erection, while no doubt correct, so far as it goes, leaves undeter- mined the means by which the dilatation of the small arteries is produced. Vasodilator nerve fibers in general are assumed to pro- duce a dilatation by inhibiting the peripheral tonicity of the arterial walls. If this explanation is applied to the case under consideration it forces us to believe that throughout life, except for the very occasional acts of erection, the arteries in the penis are kept in a constant condition of active tone. Moreover, on this view we should expect that section of the vasoconstrictor fibers to the penis, by abolishing the tone of the arteries, would also cause ♦Eckhard, "Beitrage zur Anatomie und Physiologie," 2, 123, 1863, and 4, 69, 1869. . , . , ,. t See especially Francois-Franck, "Archives de Physiol, norm, et pathol., 1895, 122 and 138. THE MALE REPRODUCTIVE ORGANS. 971 erection. These constrictor fibers arise from the second to fifth lumbar spinal nerves, and reach the organ by way of the hypo- gastric nerve and plexus and the pudic nerve. No such result of their section is reported and it seems that in the matter of erec- tion the actual mechanism of the great dilatation caused by the nervi erigentes still contains some points that need investigation. The Reflex Apparatus of Erection and Ejaculation.— The dilatation of the arteries of the penis during erection is normally a reflex act, effected through a center in the lumbar cord. This center may be acted upon by impulses descending from the brain, as in the case of erotic sensations, or by afferent impulses arising in some part of the genital tract, — from the testes themselves, from the urethra or prostate gland, and especially from the glans penis. Mechanical stimulation of the glans leads to erection, and Eckhard showed in clogs that section of the pudic nerve prevents this reflex from occurring, proving, therefore, that the sensory fibers concerned run in the pudic nerve. Stimulation of these latter fibers leads also to erotic sensations and eventually to the completion of the sexual orgasm. This latter act brings about the forcible ejection of the sperm through the urethra. It is initiated by contractions of the musculature of the vasa deferentia, ejaculatory duct, the seminal vesicles, and the prostate gland, which force the spermatozoa, to- gether with the secretions of the vesicles and prostate gland, into the urethra, whence they are expelled in the culminating stage of the orgasm by the rhythmical contractions of the ischiocavernosus and bulbocavernosus muscles, together with the constrictor urethrae. The immediate center for this complex reflex is assumed to lie in the lumbar cord, since, according to the experiments of Goltz, mechanical stimulation of the glans in dogs causes erection and seminal emission after the lumbar cord is severed from the rest of the central nervous system. Under ordinary conditions the act is accompanied by strong psychical reactions which indicate that the cortical region of the cerebrum is involved. It is interesting in this connection to find that electrical stimulation of a definite re- gion in the cortex* of dogs may cause erection and ejaculation. *Pussep, quoted from Hermann's " Jahresbericht der Physiologie/-' vol. xi, 1903. CHAPTER LIV. HEREDITY— DETERMINATION OF SEX— GROWTH AND SENESCENCE. Heredity. — The development of the fertilized ovum offers two general phenomena for consideration: First, the mere fact of mul- tiplication by which an infinite number of cells are produced by successive cell-divisions; second, the fact that these cells become differentiated in structure in an orderly and determinate way so as to form an organism of definite structure like those which gave origin to the ovum and the spermatozoon. In other words, the fertilized ovum possesses a property which, for want of a better term, we may designate as a form-building power. The ovum develops true to its species, or, indeed, more or less strictly in accord- ance with the peculiarities of structure characteristic of its parents. The object of a complete theory of heredity is to ascertain the me- chanical causes — that is, the physicochemical properties — resi- dent in the fertilized ovum which impel it to follow in each case a definite line of development. The discussions upon this point have centered around two fundamentally different conceptions designated as evolution and epigenesis. Evolution and Epigenesis.— -The earlier embryologists found a superficial explanation of this problem in the view that in the germ cells there exists a miniature animal already preformed, and that its development under the influence of fertilization consists in a process of growth by means of which the minute organism is unfolded, as it were. The process of development is a process of evolution of a pre-existing structure. Inasmuch as countless in- dividuals develop in successive generations, it was assumed also that in the germ cell there are included countless miniature organ- isms,— one incased, as it were, in the other. Some of the embry- ologists of that period conceived that the undeveloped embryos are contained in the ovum, — the ovists, — while others believed that they are present in the spermatozoon, the animalculists. Other embryologists pointed out that the fertilized egg shows no indication of a preformed structure, and therefore concluded that development starts from an essentially structureless cell, and consists in the successive formation and addition of new parts which do not pre- 972 HEREDITY. 973 exist as such in the fertilized egg. This view in contradistinction to the evolution theory was designated as epigenesis. Microscopi- cal investigation has demonstrated beyond all doubt that the fer- tilized ovum is a simple cell devoid of any parts or organs resem- bling those of the adult, and the evolution theory in its crude form has been entirely disproved. Nevertheless the controversy be- tween the evolutionists and epigenesists still exists in modified form. For it is evident that in the fertilized ovum there may exist preformed mechanisms or complexes of molecules which, while in no way resembling anatomically the subsequently developed parts of the organism, nevertheless are the foundation stones, to use a figure of speech, upon which the character of the adult structure depends. Such a view in one form or another is probably held by most bi- ologists, since it avoids the well-nigh inconceivable difficulties of- fered by a completely epigenetic theory. If the fertilized ovum of one animal is in the beginning substantially similar to that of any other animal the epigenesist must ascertain what combination of conditions during the process of development causes the egg, in a dog, for instance, to develop always into a dog, and moreover into a certain species of dog resembling more or less exactly the parent organisms. The infinite difficulties encountered by such a point of view are apparent at once. In this, as in other similar prob- lems, experimental work is gradually accumulating facts which throw some light upon the matter and may eventually lead us to the right explanation. It has been made highly probable that the chro- matin material in the nuclei of the germ cells, the chromosomes, constitute the physical basis of hereditary transmission. In the fertilized egg, it will be remembered, half of the chromosomes come from the mother and half from the father, and there is good reason for believing that the maternal chromosomes are the bearers of the maternal characteristics, and the chromosomes derived from the spermatozoon convey the hereditary traits of the father. Such a view, it will be noticed, implies at once preformed structures in the chromosomes and constitutes one form of an evolutionary hypothesis. This view is further supported by the interesting ex- periments of Wilson.* This author has shown that in certain molluscs (Dentalium or Patella) if a portion of the egg is cut off, the remaining portion upon fertilization develops into a defective animal that is not a whole embryo, but rather a piece or fragment of an embryo. Or if the fertilized egg after its first segmentation is separated artificially into two independent cells each develops an embryo, but neither one is completely formed, — each is lacking in certain structures and * Wilson, " Science," February 24, 1905, for a popular discussion ; also "Journal of Experimental Zoology," 1, 1 and 197, 1904, and 2, 371, 1905. 974 THE PHYSIOLOGY OF REPRODUCTION. the two must be taken together to constitute an entirely normal animal. By experiments of this kind it has been shown that cer- tain definite portions of the egg are responsible for the formation of particular organs in the adult. If these portions of the egg are removed the organs in question are not developed. Facts of this kind lead to the evolutionary view that in the fertilized ovum there is a collection of different materials designated as formative stuffs each of which is specific, — that is, develops into a special structure. Many facts connected with the regeneration of parts, — regeneration of a lost leg in a crab, for example — may be used to support a similar view of the existence of specific formative stuffs in the cells of the body.* Wilson has suggested an attractive theory which seems to account for the facts known at present and forms an acceptable com- promise between the extremes of epigenesis and evolution. Accord- ing to him, the germ (fertilized ovum) contains two elements, one of which undergoes a development that is essentially epigenetic, while the other contains a preformed structure which controls and deter- mines the course of development. The first is represented by the cytoplasm of the egg, the second by the chromatin (chromosomes) of the nucleus. The latter have specific structures, and under their influence the nutritive undifferentiated material of the cytoplasm is modified to form specific formative stuffs differing in character in the developing ova of different animals. Many interesting gen- eral theories of heredity have been proposed by Darwin, Nageli, Weissmann, Mendel, Galton, Brooks, and others. It is impossible to give here an outline of all these theories, but a word may be said regarding the work of de Vries and Mendel, which have given rise recently to so much discussion. For fuller information the reader is referred to special treatises on the subject. f According to the well-known views of Darwin in regard to the action of natural selection it was assumed that new varieties and species are formed by the cumulative action of selection upon small fluctuating variations. By this cumulative selection certain variations are preserved and strengthened until they are suffi- ciently marked to constitute a specific difference, the process requiring naturally a long period of time. In contrast with this view de Vries has suggested what is commonly known as the theory of mutations. According to this view the variability in the germ plasm is such that it may at times give rise not to fluctu- ating variations but to marked and permanent variations, and * For a discussion of these facts and for various hypotheses, see Morgan, "Regeneration," New York, 1901. t Hertwig, "The Biological Problems of To-day"; Delage, "L'heredite et les grands problemes de la biologie generate," 1903; Thomson, "Heredity," 1908; Kellogg, "Darwinism To-day," 1908; Jordan and Kellogg, "Evolution and Animal Life," 1907. HEREDITY. 975 these latter, if advantageous to the animal, are preserved by natural selection. Such permanent variations are known as mutations or "sports," and in consequence of their formation and preservation the process of evolution may proceed much more rapidly than was assumed to be the case in the original form of Darwin's hypothesis. The contribution made to our understanding of heredity by the work of Mendel and those who have used his conceptions is most significant. By the Mendelian law or Mendelian inheritance is meant in the first place the general idea that characteristics handed down by inheritance from parents to offspring may be treated as separate units. In some cases parental characteristics may blend in the children, as for example, in the case of color, the mulatto being in this regard a blend of a white and a black parent. In other cases, however, there is no blending, but an alternation of one or the other of a pair of con- trasting characteristics. As regards such a pair of alternating characteristics Mendel found that one will be dominant, the other recessive, whenever they are brought together. That is to say, if each parent possesses one of such alternating characteristics, brown eyes and blue eyes, for example, the children will all show the dominant characteristic, in this case brown eyes, but the other characteristic will be present in a recessive or concealed form. In the hybrids possessing both characteristics the germ cells are so divided that half of them possess the dominant alone and half the recessive alone. This constitutes the law of the "purity of the germ cells" or of the "segregation of the gametes." If two such hybrids breed together it follows from the law of probabilities that in the offspring three out of four will show the dominant characteristic and one the recessive characteristic. Moreover, of those that show the dominant characteristic two will be hybrids, containing also the recessive, but one will be a pure dominant. This result may be understood from the following formula, in which D and R represent respectively the dominant and the recessive: D— R | | = 1 DD, 2D(R) and 1 RR. D— R If two pure recessives or two pure dominants breed together, only a recessive or a dominant, as the case may be, will be exhibited in the offspring, and in this way pure characteristics may be selected and established. Such a process of selection is simple in the case of the recessive characteristics, but in the case of the dominant it is, of course, more difficult to distinguish between the DD and the D(R). The distinction may be made by breeding 976 THE PHYSIOLOGY OF REPRODUCTION. with an animal showing the recessive. If the dominant is pure, all of the offspring will exhibit the dominant characteristics. If, on the contrary, it is a hybrid, the offspring will be half dominant and half recessive, according to the formula: D— R | I = DR, DR, RR, RR. R— R The many attempts to verify this law in breeding have shown that it expresses probably a great truth, although the application of it to the practical purposes of breeding is beset with many compli- cations. The newer experimental work in heredity has emphasized the importance of breeding experiments made with what are known as " pure lines," that is to say, with those plants or animals which are capable of propagation without cross fertilization.* These experiments have tended to prove that the characteristics of each race or species are inherent in its germ plasm and will breed true if not fertilized or mixed with germ plasm from another individual of different origin. The racial characteristics proper to each individual may be considered as represented in the sexual cells or gametes as units which have been designated as " genes," and the sum total of these genes constitutes the " genotype " for that individual. From this point of view the parents do not transmit their characteristics directly to the offspring, but each passes on some portion of its characteristic genotype, which has been derived from the ancestral stock. In the union of the sexual cells or gam- etes, to form the fertilized ovum or zygote, there will be a mixture of the genotypes of the two lines, and the resultant may be calcu- lated with more or less accuracy on the Mendelian theory. Such a view lays great stress, in the matter of breeding, upon the import- ance of the characteristics of the respective racial strains, and tends to minimize the importance of the transmission of character- istics acquired during the life of the individual parents. So far as the individual is concerned, environment or nurture may exer- cise a great influence in the development of his qualities, but so far as his offspring are concerned, "nature counts for more than nurture," that is to say, it is the character of the stock, the pe- culiar racial genotype, which is of greater moment. It is upon this idea that the modern movement of eugenics hopes to improve the quality of the race by restraining or preventing the breeding of the unfit. Determination of Sex. — The conditions which lead to the determination of the sex of the developing ovum have attracted * For a general presentation see "American Naturalist," February and March, 1911, Jennings and others. DETERMINATION OF SEX. 977 much investigation and speculation. In the absence of precise data very numerous and oftentimes very peculiar theories have been advanced.* Such views as the following have been main- tained: that the sex is determined by the ova alone; that it is determined by the spermatozoa alone; that one side (right ovary or testis) contains male elements, the other female; that the sex is a result of the interaction of the ovum and spermatozoon, the most virile element producing its own sex, or according to another possibility "the superior parent produces the opposite sex"; that the sex depends on the time relation of coitus to menstruation, fertilization before menstruation favoring male births, after men- struation female births; that it depends upon the nutritive con- ditions of the ovum during development or of the maternal parent; that it depends upon the relative ages of the parents; that there are preformed male and female ova and male and female sper- matozoa, etc. What we may call the scientific study of the problem began with the collection of statistics of births. Statistics in Europe of 5,935,000 births indicate that 106 male children are bom to 100 female, and the data from other countries show the same fact of an excess of male children. Owing to the greater death-rate of the male, the proportion of male to female in the adult population of Europe is as 1000 to 1024. Examination of these statistics with reference to determining conditions led to the formulation of the so- called Hof acker-Sadler law or laws, which may be stated as follows : (1) When the man is older than the woman the ratio of male births is increased (113 to 100). (2) When the parents are of equal age the ratio of female births is increased (93.5 males to 100 females). (3) When the woman is older the ratio of female births is still further increased (88.2 to 100). These laws have been corroborated by some statisticians and contradicted or modi- fied by others. Ploss attempted to show that poor nutritive con- ditions affecting the parents, especially the mother, favor the birth of boys. Dusing combined these results in a sort of general compensatory law of nature, according to which a deficiency in either sex leads, by a process of natural selection, to an increase in the births of the opposite sex. Thus, when males are few in number, — as the result, for instance, of wars, — females marry later and more males are produced. When males are in excess early marriages are the rule and this condition favors an excess of female births. However interesting these statistics may be. it is very evident that they do not touch the real problem of the cause of the determination of sex. * For accounts of the various theories and discussion, see Morgan, " Popular Science Monthly," December, 1903, and "Experimental Zoology," 1907; Len- hossek, "Das Problem der geschlechtsbestimmenden Ursachen," 1903. 62 978 THE PHYSIOLOGY OF REPRODUCTION. Modern work has turned largely to observations and direct experiments upon the lower animals, particularly the inverte- brates, with the result that a very large number of facts have been collected of a most interesting kind, but difficult as yet to interpret so as to formulate a general law. The trend of modern work tends to oppose an older view founded largely upon experi- ments on frogs, bees, and wasps, according to which the sex is not determined at or before fertilization, but is controlled or may be controlled by the conditions of nourishment during development, favorable conditions of nutriment leading to the development of female cells from the germinal epithelium of the embryo. In contrast with this latter view an opinion that has been frequently advocated is that the sex of the embryo is determined in the egg before fertilization or at the time of fertilization. This view, as first presented, assumed substantially that there are male and female eggs to begin with, and that the determination of sex resides in the maternal organism alone. Some of the facts that support this view with more or less conclusiveness are as follows: (1) In certain worms (Dinophilus) eggs of two sizes are produced; the large eggs on fertilization develop always into females, the small ones into males. Similar facts are recorded for other animals (Hydatina). (2) Many species of invertebrates exhibit the phenomenon of parthenogenesis — that is, the eggs of the mother develop without fertilization. In some cases this method forms the only means of reproduction, and the individuals of the race are all females. But in other animals reproduction is effected either by parthenogenesis or by fertilization, according to the conditions — change of seasons, etc. Among these latter animals it may be shown, in some cases at least, that the parthenogenetic eggs may give rise either to males or females — a fact which accords with the hypothesis of the existence of male and female eggs in the mother. (3) In man twins may be born and these twins may be of two kinds. First, those that are developed from two different eggs, each of which has its own chorion and develops its own placenta, This kind may be designated as false twins, and in the matter of sex they may be male and female, or both male, or both female. The matter varies as in the statis- tics of births in general. In the other group, however, of true twins or identical twins, the two embryos are developed from a single ovum and are included in a single chorion. In such cases the sexes of the twins are always the same, they are both boys or both girls. This fact favors the view that the sex may be pre- determined in the ovum, which may be either male or female. However, if we grant the fundamental fact, so far as the ova are concerned, that they are either male or female at the time of forma- GROWTH AND SENESCENCE. 979 tion or are made so during the process of growth and maturation, it is still logically possible that there may also be male and female spermatozoa, and that in the union of the two cells the sex of the fertilized ovum may be referable either to the ovum or spermatozoon. It is not justifiable to assert that the paternal organism is without influence upon the sex of the offspring. In fact, in the case of honey bees it is observed that if the egg of the queen bee is unfer- tilized it develops into a male, but, if fertilized, into a female, thus indicating a determining influence upon the part of the male ele- ment. Other instances of a similar kind might be quoted, but perhaps the most significant fact in this connection is the dis- covery made by Wilson* that in some insects the spermatozoa fall into two classes, a portion of them having an unpaired chromosome, the so-called accessory or x-chromosome. The eggs fertilized by the spermatozoa possessing the accessory chromosomes produce females only, while those fertilized by the spermatozoa without the accessory chromosome give rise to males. In still other insects the spermatozoa fall into two groups, one of which shows the x-chromosome, and the other a similar but smaller chromosome, the y-chromosome. Here also fertilization by the sperm carrying the x-chromosome produces a female, while fertilization by the spermatozoa with the y-chromosome gives a male. In still other animals it is the egg rather than the sperm which carries a specific chromosome whose presence determines the sex, and the accumula- tion of these facts seems to prove quite conclusively that sex is not determined by influences from without, that is, by environmental conditions, but rather by some mechanism within which expresses itself visibly in many instances by the presence of accessory chromo- somes. It seems evident also from this work that the determina- tion of sex does not rest exclusively with either egg or spermatozoon. There may be male and female eggs and male and female spermato- zoa, and, in recent years, there has been a tendency to regard sex as a unit quality or gene which shows the contrasting relations of maleness and femaleness. This quality, like other qualities, may be segregated in the germ cells giving rise to male and female eggs or male and female spermatozoa. When the gametes unite to form the fertilized ovum (zygote) the sex will depend on which gametes fuse together or on the relative potency (dominance) of the con- trasting elements, f Growth and Senescence. — The body increases rapidly after birth in size and weight. It is the popular idea that the rate of growth increases up to maturity and then declines as old age ad- vances. As a matter of fact, careful examination of the facts shows * Wilson, "The Journal of Experimental Zoology," 1906, iii., 1. t Consult Morgan, "American Naturalist," 1910, 449. 980 THE PHYSIOLOGY OF REPRODUCTION. that the rate of growth decreases from birth to old age, although not uniformly. At the pubertal period and at other times its downward tendency may be arrested for a time. But, speaking generally, the maximum rate of growth is reached some time during the intra- uterine period, and after birth the curve falls steadily. Senescence has begun to appear at the time we are born.* Thus, according to the statistics of Quetelet, the average male child weighs at birth 6£ pounds. At the end of the first year it weighs 18? pounds, a gain of 12 pounds. At the end of the second year it weighs 23 pounds, a gain of only 4^ pounds, and so on, the rate of increase falling rap- idly with advancing years. Jackson f has published an interesting series of observations upon the relative and absolute growth of the human fetus and its different organs during the intra-uterine period. Relative growth is defined as the "ratio of the gain during a given period to the weight at the beginning of the period." From this standpoint he finds that the maximum rate of growth occurs during the first month of fetal life. As determined by the volume of the fetus the ovum increases more than 10,000 times in size during this period. In the succeeding months of intra-uterine life the relative monthly growth rate may be expressed by the figures 74, 11, 1.75, .82, .67, .50, .47, .45. During this period the absolute weight is, of course, increasing rapidly, and according to Jackson's observations the total weight of the embryo may be (A o*fk ( (\ *i vs^) \ 4 — 07 — ) The actual statistics of growth have been collected and tabulated with great care by a number of observers; for this country especially by Bowditch, Porter, and Beyer.* An interesting feature of the records collected by Bowditch is the proof that the prepubertal acceleration of growth comes earlier in girls than in boys, so that between the ages of twelve and fifteen the average girl is heavier and taller than the boy. Later, the boy's growth is accelerated and his stature and weight increase beyond that of the girl. It appears from the examinations made upon school children by Porter and by Beyer that a high degree of physical development is usually associated with a corresponding ] >re-eminence in mental ability. The signs of old age may be de- tected in other ways than by observations upon the rate of growth. Changes take place in the composition of the tissues; these changes, at first scarcely noticeable, become gradually more obvious as old * See Minot, "Journal of Physiology," 12, 97. t Jackson, "The American Journal of Anatomy," 9, 119, 1909. J See Bowditch, ''Report of State Hoard of Health of Massachusetts," 1877, 1879, and 1891; Porter, "Transactions, Academy of Science," St. Louis, 1893-94; Beyer, "Proceedings, United States Naval Institute," 21, 297, 1895. GROWTH AND SENESCENCE. 981 age advances. The bones become more brittle from an increase in their inorganic salts, the cartilages become more rigid and calca- reous, the crystalline lens gradually loses its elasticity, the muscles lose their vigor, the hairs their pigment, the nuclei of the nerve cells become smaller, and so on. In every way there is increasing evidence, as the years grow, that the metabolism of the living mat- ter of the body becomes less and less perfect ; the power of the protoplasm itself becomes more and more limited, and we may suppose would eventually fail, bringing about what might be called a natural death. As a matter of fact, death of the organism usually results from the failure of some one of its many complex mechanisms, while the majoritj- of the tissues are still able to maintain their exis- tence if supplied with proper conditions of nourishment. The phys- iological evidences of an increasing senescence warrant the view, however, that death is a necessary result of the properties of living matter in all the tissues except possibly the reproductive elements. The course of metabolism is such that it is self-limited, and even if perfect conditions were supplied natural death would eventually result. We do not understand the nature of these limitations, — that is, the ultimate causes of senescence. Many examples of unusual longevity are on record, the most authentic being probably that of Thomas Parr. An account of his life and the results of a postmor- tem examination by Harvey are given in volume hi of the " Philo- sophical Transactions of the Royal Society of London." "He died after he had outlived nine princes, in the tenth year of the tenth of them, at the age of one hundred and fifty-two years and nine months." The immediate cause of his death was attributed to a change of food and air and habits of life, as he was brought from Shrop- shire to London, "where he fed high and drunk plentifully of the best wines."* With reference to the phenomenon of senescense as a neces- sary attribute of living matter, Weissmann has called attention to the fact that inasmuch as the species continues to exist after the in- dividual dies, we must believe that the protoplasm of the repro- ductive elements is not subject to natural death, but has a self- perpetuating metabolism which under proper conditions makes it immortal. Weissmann f designates the protoplasm of the germ cells as germ-plasm, that of the rest of the body as somatoplasm, and inasmuch as the former continues to propagate itself indefinitely under proper conditions, while the latter has a limited existence, he concludes that originally protoplasm possessed the propertjT of potential immortality. That is, barring accidents, disease, etc., it was capable of reproducing itself indefinitely. He assumes, more- * A picture of Parr painted by van Dyck (1635) is exhibited in the Royal Gallery, Dresden, No. 1032. jWeissman, "Essays upon Heredity and Kindred Biological Prob- lems"; also "Germ-plasm" in the "Contemporary Science Series." 982 THE PHYSIOLOGY OF REPRODUCTION. over, that this property is exhibited at present in many of the sim- pler forms of life, such as the ameba. This latter phase of his theory has been the subject of much interesting investigation,* with some contradictory results, but it has been shown (Woodruff) that a specimen of Paramecium, isolated and kept in a varying culture medium during three and a half years, passed through 2000 divisions at an average rate of three in every 48 hours, without the appearance of signs of senility. Such a result would indicate the correctness of Weismann's view. Assuming that the poten- tial immortality exhibited by the reproductive cells was originally a general property of protoplasm, Weissman conceives that the phe- nomenon of senescence and death exhibited by other cells, somato- plasm, is a secondary property, which was acquired as a result of variation and was preserved by natural selection because it is an advantage in the propagation of the species. An actual immor- tality of the entire organism, — that is, the property of indefinite existence except as death might be caused by accidental occur- rences of various kinds — would be a disadvantage in many ways. The vast increase in the number of individuals might exceed the capacity of nature to provide for; the retention of the maimed and imperfect would make many useless mouths to feed, and perhaps the evolution of higher and more perfect forms by the slow action of variation and natural selection would be retarded. From this point of view senility and natural death constitute a beneficial adaptation, acquired because of its utility to the race, on the one hand, and, on the other, because, after the beginning of a differen- tiation in function among the cells, the possession of immortality by all the cells was no longer of any value to the race, and therefore was not brought under the preserving influence of natural selection. Perhaps the most significant and definite contribution to the subject of growth has been made by Rubner* upon the basis of the energy factor. His estimates were made upon data collected for man and the following mammalia, horse, cow, sheep, pig, dog, cat, rabbit, and guinea-pig — and they bring out the sur- prising fact that human growth constitutes a type of its own differing greatly from that shown by the other mammals named. His conclusions are expressed in two general laws which are founded upon calculations made upon these animals in the first period after birth during the time necessary for doubling the weight of the animal: First, the law of constant energi/ consumption. During the first period of growth the total amount of energy necessary * Rubner, "Das Problem der Lebensdaucr," etc., Berlin, 1908 GROWTH AND SENESCENCE. 983 for maintenance (metabolism) and growth, as expressed by the heat value of the food consumed, is the same for all mammals except man. To form one kilogram of animal weight requires in round numbers 4808 Calories in food; while for man about six times this amount is needed. Since the several mammals con- sidered require very different times to double their weight, it follows from this law that the shorter the time necessary for this result the more intense will be the metabolism, or, expressed in another way, the rapidity of growth is proportional to the intensity of the metabolic processes. Second, the law of the constant growth quotient. In all the mammals considered, with the exception of man, the same fractional part of the entire food energy is utilized for growth. This fractional portion is designated as the "growth- quotient," and it averages 34 per cent., that is to say, for every 1000 Calories of food 340 Calories are applied to growth. In man, on the contrary, the growth quotient is only 5 per cent. This growth quotient is a specific property of the cell and a charac- teristic of youthfulness. It has its maximal value at birth, so far as extra-uterine life is concerned, and then sinks slowly, so that at maturity, that is, at the end of the growth period, it becomes zero. Thence forward the energy of the food is utilized only for the maintenance of the cells and for the work they perform, none is applied to growth. Rubner suggests that the power to grow possessed by the cells of the young organism depends upon some special mechanisms of a chemical nature, that is, probably certain special chemical complexes which are responsible for the " growth tendency" (Wachstumstrieb) . In connection with this growth energy or growth tendency it will be remembered that in the chapter on Internal Secretion evidence was given that in early infancy the thymus forms apparently an internal secretion or hormone which controls or stimulates the process of growth, and the anterior lobe of the pituitary gland also forms an internal secretion which has a similar action. It will be noted also that both of these glands affect mainly the growth of the skeleton. The increase in size of an animal is normally estimated largely from the growth of the skeleton, and Aron has shown in a most interesting way that the growth energy resides chiefly in this tissue. According to this author, young growing dogs if given a diet insufficient to maintain their body weight will still continue to grow, since the skeleton increases in size at the expense of the other tissues, particularly of the muscular tissues. The growth tendency in the skeletal tissue is so strong that other tissues are absorbed to furnish the necessary material. This marked growth tendency of the skeleton, as we have just said, is controlled or stimulated by secretions from the thymus and hypophysis and 984 THE PHYSIOLOGY OF REPRODUCTION. possibly from other sources. The fact that a tissue in which the growth tendency is marked will live at the expense of other tissues finds an illustration in other ways, for example, in the development of malignant growths, such as cancer or in the pro- cesses of regeneration in the lower forms of life. Stockhard reports that in the medusa, when unfed, a regenerating tissue may grow rapidly by feeding on the old body tissues. It would seem that this tendency to grow must, as Rubner suggests, depend upon some peculiarity in the chemical structure of the tissue which exhibits it. We may hope that in the course of time investigation will disclose what this structure is, and enable us perhaps to exer- cise some definite control over it. After the period of maturity has been reached the question arises whether the subsequent duration of life can be foretold or formulated in any definite way. The older naturalists conceived that the duration of mature life might represent a definite multiple of the period of youth. According to Buffon this multiple is 6 to 7, according to Flourens it is 5 — that is, the mean duration of life is 5 to 7 times that required for the completion of growth. The data gathered in regard to the average duration of life among different animals has not borne out these suggestions, and Rubner discusses the matter again from the energy standpoint. He estimates the number of calories of food which are required for each kilogram of body weight in the different mammalia from the end of the period of youth to the end of life. For man this period is estimated at sixty years (20 to 80). On this basis he finds that each human kilogram requires 725,770 Calories, while for the other mammalia for which data are accessible an average of only 191,600 Calories is required, and the figures in the latter animals are so close as almost to warrant the belief that the same amount is required by each animal in spite of the great variations in the duration of life. It follows from these figures that the human cell is characterized, as compared with that of the other mammalia, by its much greater total capacity for obtaining energy from the foodstuffs. This capacity, the property of assimilation, implies chemical changes and transformations in the living matter, and the fact that eventually this property languishes and expires, that is, the fact that there is such a thing as natural or physiological death, means that the somatic protoplasm is capable of effecting only a limited number of such transformations. In man a greater number is possible than in the other mammals, and among the latter the number is practically the same, but in the smaller animals, with their more intense metabolism, the series is com- pleted in a shorter time than in the case of the larger animals. Rubner states, moreover, that if a cell, the yeast cell, for example, GROWTH AND SENESCENCE. 985 by artificial means is forced to live without growing and multiply- ing it dies in a very short time. In some wa3^ the processes of growth contain the very source of the maintenance of life. The injurious by-products which accompany simple metabolism in the living matter are in some way obviated or neutralized by the growth changes. On this basis Rubner suggests, somewhat in the line of Darwin's theory of pangenesis and of Weissmann's theory of the cause of death in the somatoplasm, that the body- cells give off certain molecular complexes which are necessary to the growth processes, and these complexes are taken up by the reproductive cells. After the animal has reached the period of puberty, of reproductive power, and provision is thus made for the perpetuation of the species, the individual organism is depleted of the power of growth, and senescence and death become inevitable. APPENDIX. PROTEINS AND THEIR CLASSIFICATION. Definition and General Structure. — Proteins or albumins are complex organic compounds containing nitrogen which, although differing much in their composition, are related in their properties. They are formed by living matter, and occur in the tissues and liquids of plants and animals, of which they form the most characteristic constituent. On ultimate analy- sis they are all found to contain carbon, hydrogen, oxygen, and nitrogen; most of them contain also some sulphur, and some, in addition, phosphorus or iron. As usually obtained, they leave also some ash when incinerated, showing that they hold in combination some inorganic salts. Percentage analyses of the most common proteins of the body show that the above named constituents occur in the following proportions: Carbon 50 to 55 per cent. Hydrogen 6.5 to 7.3 " Nitrogen 15 to 17.6 " " Oxygen 19 to 24 " " Sulphur 0.3 to 2.4 " The clearest insight into the structure of the protein molecule has been obtained by a study of its decomposition products. When submitted to the action of proteolytic enzymes, or putrefaction, or acid at high temperatures, the large molecules split into a number of simpler bodies in consequence of hydrolytic cleavage. These end-products are very numerous, and, while they differ somewhat for the different proteins, yet a number of them are the same or similar for all proteins. The great variety in the end-products is an indication of the complexity of the molecule, while their similarity is proof that the various proteins are all built, so to speak, upon a common plan, by the union of certain groupings which may be more numerous in one protein than in another. This fact becomes evident from a brief consideration of the prod- ucts obtained by hydrolytic cleavage with acids. The groupings represented by the following compounds may be supposed to exist preformed in protein molecules, some possibly containing them all, some only a portion of the list, while the different groups vary in their proportional amounts in the various proteins: Monamino Acids. 1. Glycocoll or glycin (amino-ace-tic acid). 2. Alanin (aminopropionic acid). 3. Valin (amino valerianic acid). 4. Leucin (aminocaproic acid). 5. Isoleucin (aminocaproic acid). 6. Serin (oxyaminopropionic acid). 7. Cystein (aminothiopropionic acid). 8. Phenylalanin (phenylaminopropionic acid). 9. Tyrosin (oxyphenylaminopropionic acid). 10. Tryptophan (indolaminopropionic acid). 11. Aspartic acid (aminosuccinic acid). 12. Glutaminic acid (aminoglutaric acid). 13. Prolin (pyrrolidin-carboxylic acid). 14. Oxyprolin (oxypyrrolidin-carboxylic acid). Diamino or Basic Bodies. 15. Lysin (diaminocaproic acid). 16. Arginin (guanidinaminovnlerianic acid). 17. Histidin (imidazol aminopropionic acid). 18. Diaminotrioxydodecanic acid. 986 PROTEINS AND THEIR CLASSIFICATION. 987 These split products are all amino-aeids, some of them belonging to the fatty acid (aliphatic) series of carbon compounds, some to the aromatic (carbocyehc) series, and some to the heterocyclic (pyrrol, indol) series. In what may be considered the simplest proteins occurring in nature — namely, the protamms found in the spermatozoa — only from four to six of these groups occur, while in some of the more familiar proteins, such as serum-albumin or casein, a much larger number is found. This fact is illustrated by the following table, taken from Abderhalden, which shows the composition of several proteins belonging to different classes. It will be noted that except for the salmm the known products sum up to less than 100 per cent,, showing that there is a large portion of the molecule as yet unknown. Serum Serum Albumin. Globulin Glycin 0 Alanin 97 Valin Leucin 20.0 Prolin 1.0 Phenylalamin 3.1 Glutaminic acid 7.7 Aspartic acid 3.1 Cystin 2.3 Serin 0.6 Tyrosin 2.1 Tryptophan present Diaminotrioxydodecoic acid Oxyprolin Lysin Arginin Histidin 3.5 0 2.2 0.9 present 1.0 18.7 10.5 2.8 3.1 3.8 3.2 8.0 11.0 2.5 1.2 0.7 .065 0.23 2.5 4.5 present 1.5 0.75 0.25 5.80 4.84 2.59 Caseix. Salmin. 4.3 11.0 7.8 87.4 The a-amino-acids of which these end-products consist all contain the H grouping — C — NH2, and Fischer has shown that such bodies possess the COOH property of combining with one another to make complex molecules containing two, three, or more groups of ammo-acids. The combination takes place with the elimination of water formed by the union of the OH of the carboxyl (COOH) group in one acid and the H of the amino (XH2) group in another. Thus, two molecules of amino-acetic acid (glycocoll) may be made to unite to form a compound, glycylglycin, as follows: NH2CH2COOH + NH2CH2COOH — H20 = NH2CH2COXHCH2COOH. Glycocoll. Glycocoll. Glycylglycin. Compounds of this kind are designated by Fischer as peptids. When formed from the union of two amino-acids they are known as dipeptids; from three, as tripeptids, etc. The more complicated compounds of this sort, the poly- peptids, begin to show reactions similar to those of the proteins. Some of them give the biuret reaction, some are acted upon and split by proteolytic enzymes. It seems justifiable, therefore, to consider proteins as essentially polypeptid compounds of greater or less complexity — that is, they are acid- amids formed by the union of a number of a-amino-acid compounds. More than a hundred of these artificial polypeptids have been thus synthesized, one of the most complex, an octa-deca peptid, consisting of eighteen mon- amino acids, fifteen molecules of glycin, and three of leucin, with a total molec- ular weight of 1213. This conception of the structure of the protein molecule explains a number of their general characteristics — for instance: (1) The fact that they are all decomposed and yield similar products under the influence 988 APPENDIX. of proteolytic enzymes or boiling dilute acid. (2) The fact that the proteins are all so alike in their general properties in spite of the great differences in the complexity of their molecular structure. (3) The fact that they show- both basic and acid characters. (4) The fact that they all give the biuret reaction* (see below). In addition to the amino-acids some proteins — egg-albumin, for example — yield a carbohydrate body upon decomposition. The carbohydrate ob- tained is an amino-sugar compound, usually glucosamin, C6HnN05. It is detected by its reducing action and by the formation of an osazone. It seems probable, therefore, that some of the proteins at least contain such a group- ing as part of the molecular complex, but at present it is undetermined how many possess this peculiarity of structure. General Reactions of the Proteins. — It is evident from what has been said in the preceding paragraph that proteins may give different reactions according to the kinds of groupings contained in the molecule. The reac- tions common to all proteins are few in number, the most certain perhaps being the biuret reaction, the hydrolysis by proteolytic enzymes or putre- factive organisms, and the nature of the split products formed by these latter hydrolyses or by the action of boiling dilute acids. A very large number of reactions, however, have been described which hold for some or all of the proteins usually found in the tissues and liquids of the body. These reactions may be described under two heads: (1) Precipitation of the protein when in solution; (2) color reactions. /. Precipitants. — For one or another protein the following reagents cause precipitation : 1. The addition of an excess of alcohol. 2. Boiling (heat coagulation). 3. The addition of mineral acids, — e. g., nitric acid. 4. The salts of the heavy metals, — e. g., acetate of lead, copper sul- phate, etc. 5. Addition of neutral salts of the alkalies to a greater or less degree of concentration, — e. g., sodium chlorid, ammonium sulphate. 6. Ferrocyanid of potassium after previous acidification by acetic acid. 7. Tannic acid after previous acidification by acetic acid. 8. Phosphotungstic or phosphomolybdic acid in the presence of free mineral acids. 9 Iodin in solution in potassium iodid, after previous acidification with a mineral acid. 10. Picric acid in solutions acidified by organic acids. 11. Trichloracetic acid. This list might be extended still further, but it comprises the precipi- tating reagents that are ordinarily used. Some of them, particularly Nos. 7, 8, and 9, give reactions in solutions containing excessively minute traces of protein. 12. Precipitins. In this connection a brief reference may be made to the interesting group of bodies known as precipitins. As stated on p. 416, the animal organism has the power, when foreign cells are injected into it, of forming anti-bodies by a specific biological reaction. It has been discovered that anti-bodies, or as they are called in this case, precipitins, may be produced in the same way if protein solutions or solutions of animal tissue are in- jected into the circulation. Thus, if cows' milk be injected under the skin of a rabbit there will be produced within the rabbit's blood a precipitin which is capable of precipitating the casein of cows' milk, although it may have no action on the milk of other animals. In the same way any given foreign protein, when injected under the skin of an animal, may cause the production of a pre- * For further details, see Cohnhcim, "Chemie der Eiweisskorper," second edition, 1904; or Abderhalden, "Physiological Chemistry." translated by Hall and Defren, New York, 1908, and Rosenheim, in "Science Progress," April and July, 1908. PROTEINS AND THEIR CLASSIFICATION. 989 cipitin capable of precipitating that particular protein from its solutions. The precipitin is not absolutely specific for the protein used to produce it, but nearly so. If a rabbit is immunized with human blood a precipitin is produced in the animal's blood which causes a precipitate when mixed with human blood or with that of some of the higher monkeys, but gives no reaction with the blood of other mammals. The reaction may be used, therefore, in a measure to test the blood-relationship of different animals.* It has been suggested that the reaction may also be of practical importance in medicolegal cases, in determining whether a given blood-stain is or is not human blood. For such a pur- pose a human antiserum is first produced by injecting human serum into a rabbit. The serum of the rabbit is then mixed with an extract of the suspected blood-stain made with salt solution; if a precipitate forms it proves that the blood stain is human blood provided the possibility of its being monkey's blood is excluded. Concerning the nature of the precipitins, little is known. They combine quantitatively with the protein precipitated and they are inactivated (hematosera) by a temperature of 70° C. Their reactions are not sufficiently specific to be "used as a means of de- tecting or distinguishing closely related proteins. II. The Color Reactions of Proteins. 1. The biuret reaction. The protein solution is made strongly alkaline with caustic soda or potash and a few drops of a dilute solution of copper sulphate are added carefully so as to avoid an excess. A purple color is obtained. Some proteins (peptones) give a red purple, others a blue purple. If only a blue color, without any mixture of red, is obtained, no protein is present. At present this reaction gives the best single test for protein. It obtains POTVTT its name from the fact that it is given by biuret HN<^q,,ttt2, a compound that may be formed by heating urea. Two molecules of urea give off a molecule of ammonia and form biuret. 2. The Miilon reaction. The protein solution is boiled with Millon's reagent. The solution or the precipitate, if one is formed, takes on a reddish color, which varies in intensity with different proteins. Millon's reagent consists of a solution of mercuric nitrate in nitric acid containing some mercurous nitrate. This reaction is supposed to be given by the tyrosin (oxy-aromatic) grouping in the protein molecule, and fails, therefore, with those proteins in which tyrosin is not present. 3. The xantnoproteic reaction. Nitric acid is added to strong acid reaction and the solution is then boiled. After cooling ammonia is added. The ammonia causes the development of a deep-yellow color if protein is present. This reaction is supposed to be due to the presence in the molecule of the groupings belonging to the aromatic series. 4. Adamkiewicz's reaction. A mixture is made of one volume of con- centrated sulphuric and two volumes of glacial acetic acid ; if the protein solution is added to this mixture and warmed a reddish- violet color is obtained. According to Hopkins and Cole, the re- action depends upon the presence of glyoxylic acid in the acetic acid. This reaction seems to be due to the tryptophan grouping in the protein molecule. 5 Liebermann's reaction. Dry protein purified with alcohol and ether gives a blue color upon boiling with strong hydrochloric acid. 6. The lead sulphid reaction. The protein solution is boiled with a solution of a lead salt made strongly alkaline with soda or potash. A black precipitate or black or brown coloration results, according to the amount of protein. The color is due to the splitting off of * For many interesting experiments and the literature, see Nuttall, "Blood Immunity and Relationship." Cambridge, 1904. 990 APPENDIX. sulphur and formation of lead sulphid. It is given, therefore, by the sulphur-containing groups in the protein molecule. 7. The Molisch reaction. A few drops of an alcoholic solution of a- naphthol are added to the protein solution and then strong sul- phuric acid. A violet color is obtained. This reaction is given by the carbohydrate grouping in the protein molecule. The strong acid forms furfurol from this group, which then reacts with the naph- thol. The reaction is not given by those proteins that do not con- tain a carbohydrate group. Classification of the Proteins. — No classification of the proteins has been proposed which is entirely satisfactory. Eventually a classification may be obtained based upon the chemical structure of the various proteins, the number and arrangement of the constituent amino bodies, but our know- ledge at present is much too incomplete for this purpose. We must be con- tent with a less satisfactory system based in part upon empirical reactions which have gradually been recognized in the course of physiological inves- tigations. In the following classification the recommendations are followed of the Joint Committee on Protein Nomenclature appointed by the American Physi- ological Society and the American Society of Biological Chemists ("American Journal of Physiology, Proc. Physiol. Soc," vol. xxi., 1908): Simple proteins (protein sub- f Albumins. Globulins. ,only -j Alcohohsoluble proteins (prolamines), a-amino acids or their denv- tli • • . ^ l ,. i j i • \ Albuminoids, atives on hydrolysis). | Ristons [ Protamins. II. Conjugated proteins (sub- f Glycoproteins, stances which contain the pro- j Nucleoproteins. tein molecule united to some -{ Hemoglobins (chromoproteins). other molecule or molecules | Phosphoproteins. otherwise than as a salt). [ Lecithopoteins. Primary protein derivatives ] (formed through hydrolytic | Proteans. changes which cause only }- Metaproteins. slight alterations of the pro- I Coagulated proteins. III. Derived proteins - tein molecule). J Secondary protein deriva- ] Proteoses tives. (Products of further I p tonps ' hydrolytic cleavage of the [ pgL'ids S' protein molecule.) J F The Albumins. — In addition to the albumins found in the cellular tis- sues, the cell albumins, the conspicuous examples of this group are serum- albumin, milk-albumin (lactalbumin), and egg-albumin (ovalbumin). They are characterized as a class by the fact that they are coagulable by heat in solutions with a neutral or acid reaction, and are soluble in water free from salts. In accordance with the latter part of this definition they are not precipitated by dialysis. They are precipitated from their solutions with more difficulty by saturation with neutral salts, ammonium sulphate, than the globulins with which they are usually associated. Empirically, as regards the liquids of the body, it is stated that they require more than half saturation with ammonium sulphate for precipitation (see section on Blood). All three albumins referred to here may be obtained in crystallized form. They are not precipitated by saturation with sodium chlorid or magnesium sul- phate unless the solution is made acid. They are rich in sulphur, containing from 1.6 to 2.2 per cent., and on hydrolysis they yield no glycocoll. The Globulins. — Proteins belonging to this group are found in the cell tissues together with albumins. The forms that have been most studied PROTEINS AND THEIR CLASSIFICATION. 991 are serum-globulin ( paraglobulin) and fibrinogen (blood, lymph, and transu- data), milk-globulin (laetoglobulin), and egg-globulin. As contrasted with the albumins, they are coagulable by heat, but are insoluble in pure water. They are readily soluble in dilute solutions of neutral salts, that is, salts of strong bases with strong acids. In consequence of their insolubility in water they are precipitated by dialysis. This reaction is not distinctive, however, as the precipitation is not complete. Some of the so-called globulin remains in solution after the salts have been removed as completely as possible by dialysis. They are also precipitated partially from their dilute solutions by the addition of weak acids or by a stream of carbon dioxid. Practically they are isolated from accompanying albumins by precipitation with neutral salts. In neutral solutions the globulins are completely precipitated by saturation with magnesium sulphate or half saturation with ammonium sulphate. In the blood several different forms of globulin are distinguished by the degree of saturation with ammonium sulphate necessary for their precipitation (see Blood). The separations made by this method are not, however, satisfac- tory. Nor, indeed, is the separation between globulins and albumins alto- gether satisfactory. It would seem that these proteins are so closely related that distinctive reactions are difficult to obtain on account of the existence of forms intermediate between the extremes that are used as types. The Glutelins. — These proteins occur in abundance in the seeds of cereals. They are insoluble in all neutral solvents, but are readily dissolved by very dilute acids or alkalies. Alcohol-soluble Proteins (Prolamines). — Found in quantity in cereals, but not in other seeds. They are soluble in alcohol (70-80 per cent.), but insoluble in water or in absolute alcohol. Gliadin of wheat and rye and hor- dein of barley are examples. On hydrolysis these proteins give a very large percentage of glutaminic acid (20 to 37 per cent.) and from 20 to 30 per cent, of their nitrogen is given off as ammonia.* Albuminoids. — Simple proteins which are characterized by great in- solubility in all neutral solvents. They form the principle constituent of the skeletal tissues and connective tissues, epidermis, hairs, etc., including such members as elastin, keratin, and collagen. Physiologically it has been found that gelatin, a derivative of collagen, does not suffice for the construction of living protein, and cannot be used in place of the other proteins to main- tain nitrogen equilibrium. This peculiarity seems to be due to the absence of certain necessary amino-acids in its molecule. (See p. 885.) Protamins and Histons. — The histons are defined as being soluble in water and insoluble in very dilute ammonia. They yield precipitates with solutions of other proteins and give a coagulum on heating. Protamins are soluble in water, not coagulated by heating, and, like the histons, have the property of precipitating other proteins in aqueous solutions. They possess strong basic properties and form stable salts. The protamins have been obtained (Miescher-Kossel) from the heads of the spermatozoa in fishes, in which they exist in combination with nucleic acid. They differ considerably in the spermatozoa of different animals, and are, therefore designated according to the zoological name of the fish from which they arise, as salmin, sturin, clu- pein, scombrin, etc. They show a biuret reaction, but in most cases fail to give Millon's reaction. On hydrolysis they give split products, which consist chiefly of the so-called diamino-bodies (arginin, histidin, lysin) rather than the monamino-acids. Some of the latter may occur, however, such as alanin, serin, aminovalerianic or a-pyrrollidin-carboxylic acid. The protamins all give an alkaline reaction, form salts with acids, and are precipitated easily. Their molecular structure is relatively simple. Salmin is given the formula C30H57- C17H6. The molecule contains no sulphur and is characterized also by its large percentage of nitrogen. Protamin must be regarded as the simplest form of protein occurring normally in the animal body, a protein in which many of the groupings, such as cystin, tyrosin, carbohydrates, found in the usual protein molecule are entirely lacking and in which the basic groupings (arginin) predominate. The histons form a series of compounds intermediate * For description of this and other vegetable proteins, see Osborne, "Science," Oct. 2, 1908. 992 APPENDIX. in many ways between the protamins and the usual proteins. The reaction usually considered as characteristic of the class is that they are precipitated by ammonia. They are precipitated also by the alkaloidal reagents — e. g., phosphotungstic acid — in neutral solutions. Ordinary proteins give a pre- cipitate with these reagents only in acid solutions, while the protamins give one even in alkaline solutions. Protamins, histons, and the usual proteins form a series, therefore, in which the basic reaction is less and less marked. The best known of the histons is the globin obtained from hemoglobin ; an- other form has been obtained from the nucleohiston in the white corpuscles, from the spermatozoa of mackerel (scombron), codfish (gadushiston), sea- urchin (arbacin), and frog (lotahiston). They do not occur free in the liquids or tissues of the body, but in combination, as in the case of hemoglobin. They give the biuret reaction, a faint Millon reaction, and also respond to the tests for sulphur. The products obtained by their hydrolytic cleavage are much more numerous than in the case of the protamins — a fact which would indicate that their molecular structure is correspondingly more complex. The Conjugated Proteins. — The chromoproteins or hemoglobins may be defined as consisting of a simple protein in combination with a pigment grouping, such as occurs in the case of hemoglobin. A number of such com- pounds are known — hemoglobin, hemocyanin, hemerythrin, chlorocruorin — all characterized physiologically by the fact that they serve to transport oxygen from the air or water to the tissues. On boiling, heating with alkalies or acids, etc., they readily decompose into their constituent parts (see Blood). Glycoproteins are compounds of a carbohydrate group with a simple protein. Numerous bodies have been put in this class; some of them contain phos- phorus (phosphoglucoproteins). Those free from phosphorus fall into two divisions: one, the mucins, which on decomposition yield the carbohydrate group in the form of an amino-sugar (glucosamin), and one, the chondropro- teins, found in the connective tissues and in the pathological substance known as amyloid, which yield their carbohydrate group in the form of chondroitin- sulphuric acid (ClgH27NSO,7). True mucin is obtained from the secretion of the salivary glaads and the mucous glands of the various mucous mem- branes. The nucleoproteins constitute the most interesting of the group of compound proteins. They are recognized as forming an important con- stituent of the cell nuclei. They may be defined as ?onsisting of a compound of simple protein with a nucleic acid. In the nuclei (head) of spermatozoa the compound, in some cases at least (fishes), contains a nucleic acid and a protamin. In other cases the protein constituent is more complex. On digestion with pepsin-hydrochloric acid the more complex hucleoproteins split, with the formation, first, of a protein substance and a simpler nucleo- protein, richer in phosphorus and designated as a nuclein. On further decomposition this latter yields a nucleic acid. Nucleic acid is, therefore, the characteristic constituent, and a number of different forms have been described, all rich in phosphorus, such as thymonucleic acid, salmonnucleic acid, guanylic acid, etc. Levene and Jacobs have shown that the various nucleic acids are constructed on a generel type which consists of a phosphoric acid group linked to a nitrogenous base by means of a carbohydrate group. This latter group ;s ,/ ribose, one of the pentoses. Compounds of this type they propose to designate as nuclotides. When the phosphoric acid is split off a compound of the carbohydrate and the nitrogenous base is left, and on further hydrolysis the carbohydrate may be split off and various nitrogenous substances be formed, such as purin bases or pyrimidin derivatives. These final decomposition products are characteristic of the true nucleoprotcins as distinguished from the phosphorus-containing proteins, the nucleo-albumins or phosphoproteins, such as casein. The percentage of phosphorus in the nucleoproteins varies, according to the complexity of the molecule, between 0.5 and 1.6 per cent. The lecithoproteins consist of compounds of the protein molecule with lecithin (lecithans, phosphatids), while the phosphoproteins are compounds of the protein molecule with some, as yet undefined, phosphorus-containing substance other than a nucleic acid or lecithin. This group contains such proteins as the vitellin of the yolk and casein of milk, which were formerly designated as nucleo-albumins. PROTEINS AND THEIR CLASSIFICATION. 993 The Derived Proteins. — Under this designation are included products derived from the simple proteins by hydrolysis. When the hydrolytic change involves only a slight change in the protein molecule we have what are known as primary derivatives, of which three groups are made: (1) Proteans, cer- tain insoluble products which result from the incipient action of water, enzymes, or very dilute acids. (2) Metaproteins, products which result from the further action of acids or alkalies, by means of which the protein is con- verted into a form soluble in weak acids or alkalies, but precipitated on neu- tralization. This group includes what was formerly designated as acid or alkali albumin. (3) Coagulated protein — insoluble products formed by the action of heat, alcohol, etc. If the hydrolysis proceeds further, certain cleavage products result which are simpler than these just named, but are more complex than the final products of complete hydrolysis (amino-acids). These intermediate cleavage products are grouped under the term secondary derivatives and include: (1) Proteoses, products which are soluble in water, not coagulated by heat, and are completely precipitated by saturation with ammonium sulphate or zinc sulphate. (2) Peptones, products which are soluble in water, are not coagulated by heat, and are not precipitated by saturation with ammonium sulphate. (3) Peptids, products which consist of two or more amino-acids in which the carboxyl group of one is united with the amino group of an- other, with the elimination of a molecule of water. The peptones probably are simply polypeptids or mixtures of polypeptids. DIFFUSION AND OSMOSIS. In recent years the physical conceptions of the nature of the processes of diffusion and osmosis have changed considerably. As these newer concep- tions have entered largely into current medical literature, it seems advis- able to give a brief description of them for the use of those students of phys- iology who may be unacquainted with the modern nomenclature. The very limited space that can be devoted to the subject forbids anything more than a condensed elementary presentation. For fuller information refer- ence must be made to special treatises.* Diffusion, Dialysis, and Osmosis. — When two gases are brought into contact a homogeneous mixture of the two is soon obtained. This inter- penetration of the gases is spoken of as diffusion, and it is due to the con- tinual movements of the gaseous molecules to and fro within the limits of the confining space. So also when two miscible liquids or solutions are brought into contact a diffusion occurs for the same reason, the movements of the molecules finally effecting a homogeneous mixture. If the two liquids happen to be separated by a membrane diffusion will still occur, provided the membrane is permeable to the liquid molecules, and in time the liquids on the two sides will be mixtures having a uniform composition. Not only water molecules, but the molecules of many substances in solution, such as sugar, may pass to and fro through membranes, so that two liquids sepa- rated from each other by an intervening membrane and originally unlike in composition may finally, by the act of diffusion, come to have the same composition. Diffusion of this kind through a membrane is frequently spoken of as dialysis or osmosis. In the body we deal with aqueous solu- tions of various substances that are separated from each other by living membranes, such as the walls of the blood capillaries or of the alimentarj'- canal, and the laws of diffusion through membranes are of immediate im- portance in explaining the passage of water and dissolved substances through these living septa. In aqueous solutions such as we have in the body we must take into account the movements of the molecules of the solvent, water, as well as of the substances dissolved. These latter may have different de- * Consult Cohen, "Physical Chemistry for Physicians and Biologists," translated by Fischer, 1903. H. C. Jones, "The Theory of Electrolytic Dis- sociation," 1900; "Diffusion Osmosis, and Filtration," by E. W. Reid, in Schafer's "Text-book of Physiology," 1898. 63 994 APPENDIX. grees of diffusibility as compared with one another or with the water mole- cules, and it frequently happens that a membrane that is permeable to water molecules is less penneable or even impermeable to the molecules of the substances in solution. For this reason the diffusion stream of water and of the dissolved substances may be differentiated, as it were, to a greater or less extent. In recent years it has become customary to limit the term osmosis to the stream of water molecules passing through a membrane, while the term dialysis, or diffusion, is applied to the passage of the mole- cules of the substances in solution. The osmotic stream of water under vary- ing conditions is especially important, and in connection with this process it is necessary to define the term osmotic pressure as applied to solutions. Osmotic Pressure. — If we imagine two masses of water separated by a permeable membrane, we can readily understand that as many water mole- cules will pass through from one side as from the other; the two streams, in fact, will neutralize each other, and the volumes of the two masses of water will remain unchanged. The movement of the water molecules in this case is not actually observed, but it is assumed to take place on the theory that the liquid molecules are continually in motion and that the membrane, being permeable, offers no obstacle to their movements. If, now, on one side of the membrane we place a solution of some crystalloid substance, such as common salt, and on the other side pure water, then it will be found that an excess of water will pass from the water side to the side containing the solution. In the older terminology it was said that the salt attracted this water, but in the newer theories the same fact is expressed by saying that the salt in solution exerts a certain osmotic pressure, in conse- quence of which more water flows from the water side to the side of the solution than in the reverse direction. As a matter of experiment it is found that the osmotic pressure varies with the amount of the substance in solu- tion. If in experiments of this kind a semipermeable membrane is chosen — that is, a membrane that is permeable to the water molecules, but not to the molecules of the substance in solution — the stream of water to the side of the crystalloid will continue until the hydrostatic pressure on this side reaches a certain point, and the hydrostatic pressure thus caused may be taken as a measure of the osmotic pressure exerted by the substance in solu- tion. Under these conditions it can be shown that the osmotic pressure is proportional to the concentration of the solution, or, in other words, to the number of molecules (and ions) of the crystalloid in solution. As a matter of fact, most of the membranes that we have to deal with in the body are only approximately semipermeable — that is, while they are readily permeable to water molecules, they are also permeable, although with more or less difficulty, to the substances in solution. In such cases we get an osmotic stream of water to the side of the dissolved crystalloid, but at the same time the molecules of the latter pass to some extent through the mem- brane, by diffusion, to the other side. In course of time, therefore, the dissolved crystalloid will be equally distributed on the two sides of the mem- brane, the osmotic pressure on both sides will become equal, and osmosis of the water will cease to be apparent, since it is equal in the two directions. All substances in true solution are capable of exerting osmotic pressure, and the important discovery has been made that the osmotic pressure, meas- ured in tenns of atmospheres or the pressure of a column of water or mer- cury, is equal to the gas pressure that would be exerted by a number of molecules of gas equal to that of the crystalloid in solution, if confined within the same space and kept at the same temperature.* A perfectly satisfactory * The interesting researches of Morse and Frazer (" The American Chemi- cal Journal," 34, 1, 1905), who have succeeded in making semipermeable membranes in such a form as may be used for determining directly the os- motic pressures of concentrated (normal) solutions, have shown that this law is not accurately stated. The actual pressure is that which would be exerted if the particles in solution were gasified at the same temperature and kept to the volume of the pure solvent used (water), instead of the volume of the entire solution. PROTEINS AND THEIR CLASSIFICATION. 995 explanation of the nature of osmotic pressure has not been furnished. We must be content to use the term to express the fact described. It is a matter of great importance to measure the osmotic pressures of various solutions. As was stated above, this measurement can be made for anv solution pro- vided a realty semipermeable membrane is constructed. As a matter of fact, however, the use of such membranes has not been general. In actual experiments _ other methods have been employed, and a brief statement of a theoretical and a practical method of arriving at the value of osmotic pressures may be of sendee in further illustrating the meaning of the term. Before stating these methods it becomes necessary to define two terms — namely, electrolytes and gram-molecular solutions — that are much used in this connection. Electrolytes. — The molecules of many substances when brought into a state of solution are believed to be dissociated into two or more parts, known as ions. The completeness of the dissociation varies with the sub- stance used, and for any one substance with the degree of dilution. Roughly speaking, the greater the dilution, the more nearly complete is the dissocia- tion. The ions liberated by this act of dissociation carry an electrical charge and when an electrical current is led into the solution it is conducted in a definite direction by the movements or migration of the charged ions. The molecules of pertectiy pure water undergo almost no dissociation, and water, therefore, does not appreciably conduct the electrical current. If some NaCl is dissolved in water, a certain number of its molecules become dis- sociated into a Na ion charged positively with electricity and a CI ion charged negatively, and the solution becomes a conductor of the electrical current. Substances that exhibit this property of dissociation into electrical ly-fharged ions are known as electrolytes, to distinguish them from other soluble sub- stances, such as sugar, that do not dissociate in solution and, therefore, do not conduct the electrical current. Speaking generally, it may be said that all salts, bases, and acids belong to the group of electrolytes. The conception of electrolytes is very important for the reason that the act of dissociation ob- viously increases the number of particles moving in the solution and thereby increases the osmotic pressure, since it has been found experimentally that, so far as osmotic pressures are concerned, an ion plays the same part as a mole- cule. It follows, therefore, that the osmotic pressure of any given electrolyte in solution is increased in proportion to the degree to which it is dissociated. As the liquids of the body contain electrolytes in solution it becomes neces- sary, in estimating their osmotic pressure, to take this fact into consideration. Gram-molecular Solutions. — The concentration of a given substance in solution may be stated by the usual method of percentages, but from the standpoint of osmotic pressure a more convenient method is the use of the unit known as a gram-molecular solution. A gram-molecule of any sub- stance is a quantity in grams of the substance equal to its molecular weight, while a gram-molecular solution is one containing a gram-molecule of the substance to a liter of the solution. Thus, a gram-molecular solution of sodium chlorid is one containing 58.5 gms. (Na, 23; CI, 35.5) of the salt to a liter, while a gram-molecular solution of cane-sugar contains 342 gms. (CjjH^Oj!) to a liter. Similarly a gram-molecule of H is 2 gms. by weight of this gas, and if this weight of H were compressed to the volume of a litei it would be comparable to a gram-molecular solution. Since the weight of a molecule of H is to the weight of a molecule of cane-sugar as 2 is to 342, it follows that a liter containing 2 gms. of H has the same number of molecules of H in it as a liter of solution containing 342 gms. of sugar has of sugar molecules. On the assumption that a molecule in solution exerts an osmotic pressure that is exactly equal to the gas-pressure exerted by a gas molecule moving in the same space and at the same temperature, we are justified in saying that the osmotic pressure of a gram-molecuiar solu- tion of cane-sugar, or of any other substance that is not an electrolyte, is equal to the gas-pressure of 2 gms. of H when compressed to the volume of 1 liter. This fact gives a means of calculating the osmotic pressure of solutions in certain cases according to the following method: Calculation of the Osmotic Pressure of Solutions. — To illustrate this 996 APPENDIX. method we may take a simple problem such as the determination of the osmotic pressure of a 1 per cent, solution of cane-sugar. One gm. of H at atmospheric pressure occupies a volume of 11.16 liters; 2 gms. of H, there- fore, under the same conditions will occupy a volume of 22.32 liters. A gram-molecule of H — that is, 2 gms. of H — when brought to the volume of 1 liter will exert a gas-pressure equal to that of 22.32 liters compressed to 1 liter — that is, a pressure of 22.32 atmospheres. A gram-molecular solu- tion of cane-sugar, since it contains the same number of molecules in a liter, must therefore exert an osmotic pressure equal to 22.32 atmospheres. A 1 per cent, solution of cane-sugar contains, however, only 10 gms. of sugar to a liter; hence the osmotic pressure of the sugar in such a solution will be -1-0- of 22.32 atmospheres, or 0.65 of an atmosphere, which in terms of a column of mercury gives 760 X 0.65 = 494 mms. This figure expresses the osmotic pressure of a 1 per cent, solution of cane-sugar when dialyzed against pure water through a membrane impermeable to the sugar molecules. In such an experiment water would pass to the sugar side until the hydro- static pressure on this side was increased by an amount equal to the pres- sure of a column of mercury 494 mms. high. Certain additional calculations that it is necessary to make for the temperature of the solution need not be specified in this connection. If, however, we wish to apply this method to the calculation of the osmotic pressure of a given solution of an electro- lyte, it is necessary first to ascertain the degree of dissociation of the electro- lyte into its ions, since, as was said above, dissociation increases the num- ber of parts in solution and to the same extent increases osmotic pressure. In the body the liquids that concern us contain a variety of substances in solution, electrolytes as well as non-electrolytes. In order, therefore, to calculate the osmotic pressure of such complex solutions it is necessary to ascertain the amount of each substance present, and, in the case of electro- lytes, the degree of dissociation. Under experimental conditions such a calculation is practically impossible, and recourse must be had to other methods. One of the simplest and most easily applied of these methods is the determination of the freezing point of the solution. Determination of Osmotic Pressure by Means of the Freezing Point. — This method depends upon the fact that the freezing point of water is low- ered by substances in solution, and it has been discovered that the amount of lowering is proportional to the number of parts (molecules and ions) present in the solution. Since the osmotic pressure is also proportional to the number of parts in solution, it is convenient to take the lowering of the freezing point of a solution as an index or measure of its osmotic pressure. In practice a simple apparatus (Beckmann's apparatus) is used, consisting essentially of a very delicate and adjustable differential thermometer. By means of this instrument the freezing point of pure water is first ascertained upon the empirical scale of the thermometer. The freezing point of the solution under examination is then determined, and the number of degrees or fractions of a degree by which its freezing point is lower than that of pure water is noted. The lowering of the freezing point in degrees centigrade is expressed usually by the symbol A- For example, mammalian blood- serum gives A = 0.56° C. A 6.95 per cent, solution of NaCl gives the same A ; hence the two solutions exert the same osmotic pressure, or, to put it in another way, a 0.95 per cent, solution of NaCl is isotonic or isosmotic with mammalian serum. The A OI anY given solution may be expressed in terms of a gram-molecular solution by dividing it by the constant 1.87, since a gram-molecular solution of a non-electrolyte is known to lower the freezing point 1.87° C. Thus, if blood-serum gives A = 0.56° C.,its concentration in terms of a gram-molecular solution will be -j^_, or 0.3. In other words, blood-serum has 0.3 of the osmotic pressure exerted by a gram-molecular solution of a non -electrolyte, — that is, 22.32 X 0.3, or 6.696 atmospheres. Remarks upon the Application of the Foregoing Facts in Physiol- ogy.— In the body water and substances in solution are continually pass- ing through membranes, — for example, in the production of lymph, in the absorption of water and digested foodstuffs from the alimentary canal, in PROTEINS AND THEIR CLASSIFICATION. 997 the nutritive exchanges between the tissue elements and the blood or lymph, in the production of the various secretions, and so on. In these cases it is a matter of the greatest difficulty to give a satisfactory explanation of the forces controlling the flow to and fro of the water and dissolved substances, but there can be little doubt that in all of them the physical forces of fil- tration, diffusion, and osmosis take an important part. "Whatever can be learned, therefore, concerning these processes must in the end have an im- portant bearing upon the explanation of the nutritive exchanges between the blood and tissues. Some additional facts may be mentioned to indicate the applications that are made of these processes in explaining physiological phenomena. Osmotic Pressure of Proteins. — The osmotic pressure exerted by crys- talloids, such as the ordinary soluble salts, is, as we have seen, very con- siderable, but the ready diffusibility of most of these salts through animal membranes limits very materially their influence upon the flow of water in the body. Thus, if we should inject a strong solution of common salt directly into the blood-vessels, the first effect would be the setting up of an osmotic- stream from the tissues to the blood and the production of a condition of hydremic plethora within the blood-vessels. The salt, however, would soon diffuse out into the tissues, and to the degree that this occurred its effect hi diluting the blood would tend to diminish because the part of the salt that got into the extravascular lymph spaces would now exert an osmotic press- ure in the opposite direction, drawing water from the blood. This fact, together with the further fact that an excess of salts in the body is soon re- moved by the excretory organs, gives to such substances a smaller influence in directing the water stream than would at first be supposed when the inten- sity of their osmotic action is considered. In addition to the crystalloids the liquids of our bodies contain also a certain amount of protein, the blood, especially, containing over 6 per cent, of this substance. It has been gen- erally assumed that proteins in solution exert little or no osmotic pressure, but Starling * and others have claimed, on the contrary, that they exert a distinct, although small, osmotic pressure, and it is possible that this fact is of special importance in absorption, because the proteins do not diffuse or diffuse with great difficulty, and their effect remains, therefore, so to speak, as a permanent factor. According to Starling, the osmotic pressure exerted by the proteins of serum is equal to about 30 mms. of mercury. That the osmotic pressure of the serum proteins is so small is not surprising if we remember the very high molecular weight of this substance. In serum the proteins are present in a concentration of about 7 per cent., but owing to their large molecular weight comparatively few protein molecules are present in a solution of this concentration ; and, assuming that the dissolved protein follows the laws discovered for crystalloids, its osmotic pressure would depend upon the number of molecules in solution. By means of this weak but con- stant osmotic pressure of the indiffusible protein it is possible to explain theoretically the fact that an isotonic or even a hypertonic solution of diffusi- ble crystalloid may be completely absorbed by the blood from the peritoneal cavity. Reid t has published experiments which indicate that pure proteins exert no osmotic pressure ; that as they occur in the body liquids they are combined or mixed with certain substances to which the feeble osmotic pres- sure formerly attributed to the proteins really belongs. Since these unknown substances are themselves indiffusible, the arguments just used still hold for the conditions in the body. It seems probable, however, that in the method used by Reid to purify the proteins the nature of these substances was altered, the state of aggregation of the molecules, for example, and that, there- fore, his negative results do not apply to the proteins as they exist in the blood. Isotonic, Hypertonic, and Hypotonic Solutions. — In physiology the osmotic pressures exerted by various solutions are compared usually with that of the blood-serum. In this sense an isotonic or isosmotic solution is one having an osmotic pressure equal to that of serum, a hypertonic or hy- * "Journal of Physiology," 24, 317, 1899. t Reid, "Journal of Physiology," 1905. 998 APPENDIX. perosmotic solution is one whose osmotic pressure exceeds that of serum, and a hypotonic or hyposmotic solution is one whose osmotic pressure ia less than that of serum. Diffusion, or Dialysis, of Soluble Constituents. — If two liquids of unequal concentration in a given constituent are separated by a membrane entirely permeable to the dissolved molecules of the substance, a greater number of these molecules will pass over from the mce concentrated to the less concentrated side, and in time the composition will be the same on the two sides of the membrane. Diffusion of soluble constituents continually takes place, therefore, from the points of greater concentration to those of less, and this may happen quite independently of the direction of the osmotic stream of water. If, for instance, a 0.9 per cent, solution of sodium chlorid is injected into the peritoneal cavity, it will enter into diffusion relations with the blood in the blood-vessels; its concentration in sodium chlorid being greater than that of the blood, the excess will tend to pass into the blood, while sodium carbonate, urea, sugar, and other soluble crystalloidal substances will pass from the blood into the salt solution in the peritoneal cavity. Through the action of this process of diffusion we can understand how certain constituents of the blood may pass to the tissues of various glands in amounts greater than can be explained if we supposed that the lymph of these tissues is derived solely by filtration from the blood-plasma. An- other important conception in this connection is the possibility that the capillary walls may be permeable in different degrees to the various soluble constituents of the blood, and furthermore the possibility that the permea- bility of the capillary walls may vary in different organs. With regard to the first possibility it has been shown that the blood capillaries are more permeable to the urea molecules than to sugar or NaCl. With the aid oi these facts it is possible to explain in large measure the transportation of material from tiie blood to the tissues, and vice versa. For example, to follow a line of reasoning used by Roth, we may suppose that the functional activity of the tissue elements is attended by a consumption of material which in turn is made good by the dissolved molecules in the tissue lymph. The concentration of the latter is thereby lowered, and in consequence a diffu- sion stream of these substances is set up with the more concentrated blood. In this way, by diffusion, a constant supply of dissolved material is kept in motion from the blood to the tissue elements. On the other hand, the functional activity of the tissue elements is accompanied by a breaking down ©f the complex protein molecule, with the formation of simpler, more stable molecules of crystalloid character, such as the sulphates, phosphates, and urea or some precursor of urea. As these bodies pass into the tissue lymph they tend to increase its concentration, and thus by the greater osmotic pressure developed they serve to attract water from the blood to the lymph, forming one efficient factor in the production of lymph. On the other hand, as these substances accumulate in the lymph to a concentration greater than that possessed by the same substances in the blood, they will diffuse toward the blood. By this means the waste products of activity are drawn off to the blood, from which, in turn, they are removed by the action of the excretory organs. Diffusion of Proteins. — This simple explanation on purely physical grounds of the flow of material between the blood and the tissues can only be applied, however, at present to the diffusible crystalloids, such as the salts, urea, and sugar. The proteins of the blood, which are supposed to be so important for the nutrition of the tissues, are practically indiffusible, so far as we know. It is difficult to explain their passage from the blood through the capillary walls into the lymph. Provisionally it may be assumed that this passage is due to filtration. The blood-plasma in the capillaries is under a slightly higher pressure than the lymph of the tissues, and this higher pressure tends to squeeze the blood constituents, including the protein, through the capillary walls. This explanation, however, cannot be said to be satis- factory ; and in this respect the purely physical theory of lymph formation waits upon a clearer knowledge of the nature of the nutritive proteins and their relations to the capillary wall (see Lymph, p. 462) INDEX. Abdominal respiration, 638 type of respiration, 642 Absolute power of muscle, 38 Absorption coefficient, 666 in large intestine, 793 in small intestine, 787 in stomach, 772 of carbohydrates, 789 of fats, 790 of proteins, 791 spectra of hemoglobin, 423 A-c interval (heart), 532 Acapnia, 693, 698 Accelerator center for heart, 587 nerves, effect of, on heart rate, 589 of heart, 583 reflex stimulation of, 585 Accessory thyroids, 851 Accommodation in eye, limits of, 310 mechanism of, 307 reflex, 320 Acetone bodies, 896 Achromatic series of visual sensa- tions, 343 vision, 351 Achroodextrin, 754 Acid albumin in gastric digestion, 768 aceto-acetic, 896 amino-acetic, 781, 986 aminocaproic, 781, 986 aminoglutaric, 986 amino-oxypropionic, 986 aminopropionic, 986 aminosuccinic, 782, 986 aminothiolactic, 986 aminovalerianic, 781, 986 cholic, 801 conjugated sulphuric, 795, 838 diaminocaproic, 986 diaminotrioxydodecoic, 986 glutaminic, 782 glycocholic, 801 glycuronic, 889 guanidinamino valerianic, 986 hippuric, 838 lactic, 63 oxalic, 890 oxybutyric, 896 oxyphenylaminopropionic, 986 oxyproteic, 830 phenylaminopropionic, 986 Acid, phosphocarnic, 63 pyrrolidin-carboxylic, 986 saccharic, 890 taurocholic, 801 Acidosis, 897 Acromegaly, 865 Action current, diphasic, 104 in heart, 533 in muscle, 103 in nerve, 103 in retina, 331 monophasic, 104 relation of, to contraction wave, 107 to nerve impulse, 107 Activation of lipase, 786 of trypsin, 779 Activators, 737 Adamkiewicz's reaction for proteins, 989 Addison's disease, 858 Adenase, 738, 835 Adenin, 64, 834 Adrenal bodies, functions of, 861 Adrenalin, 858, 859 Aerial perspective, 370 Aerotonometer, 668 Afferent fibers in cranial nerves, 84 position of, in posterior roots, 83 nerve fibers, 80 After-images in eye, 346 Agnosia, 203, 220 Agraphia, 219 Air, effect of variations in, on res- pirations, 696 Alanin, 781, 986 Albumin, properties of, 990 (see also Protein) Albuminoids, nutritive value of, 885 Albumon, 445 Alcohol as food, 907 effect of, on gastric absorption, 773 physiological action of, 906 use of, in diabetes, 909 Alexia, 219 Alexins, 417 Alimentary canal, movements of, 703 glycosuria, 789 principles of food, 727 Altitude, effect of, on red corpuscles, 432 999 1000 INDEX. Amboceptors, 417 Ametropia, 315 Amino-acetic acid, 781, 986 Amino-acids as part of protein mole- cule, 781, 986 Aminocaproic acid, 781, 986 Aminoglutaric acid, 986 Amino-oxypropionic acid, 986 Aminopropionic acid, 781, 986 Aminopurins, 834 Aminosuccinic acid, 782, 986 Aminothiolactic acid, 986 Aminovalerianic acid, 781, 986 Ammonia compounds in urine, 829 salts, relation of, to urea, 831 Ammonium carbamate as precursor of urea, 832 carbonate as precursor of urea, 832 Amylase, 784 Amylolytic enzyme, 735 Anacrotic pulse, 518 Anaglyph, 373 Anelectrotonic currents, 108 Anelectrotonus, 88 Anisotropous substance in muscle, 19 Anode as stimulus to muscle, 88 to nerve, 88 physical, 94 physiological, 94 Anomalous trichromatic vision, 348 Anorexia, 285 Anoxemia, 697 Anterior commissure, 187, 215 roots of spinal nerves, 83 Antidromic impulses in vasodilator nerve fibers, 83, 611 Antigen, 416 Antilytic secretion, 751 Antiparalytic secretion, 751 Antithrombin, 453 Antrum pylori of stomach, 709 Anus praeternaturalis, 793 Apex beat of heart, 536 Aphasia, motor, 217 sensory, 219 Aphemia, 217, 219 Apnea, 691 Apraxia, 219 Arginase, 832 Arginin, 782, 832, 969, 991 Argyll-Robertson pupil, 321 Arterial pressure (see Circulation) Artificial muscle of Engelmann, 73 respiration, 647, 657 stimuli of nerve fibers, 85 Ascending paths in spinal cord, 170 Aspartic acid, 782, 986 Asphyxia, 691 effect of, on heart-rate, 591 Aspiratory action of thorax, 653 Association areas in brain, 221, 223 system of fibers in cerebrum, 185 Astereognosis, 201 Astigmatism, 316 Atropin, action of, on heart, 581 on iris, 322 on salivary secretion, 750 on sweat secretion, 848 Auditory center in cortex, 210 nerve, course of, in brain, 211 effect of section of, 401 sensations (see Ear) striae, 213 Auricle (see Heart) Auriculoventricular bundle of heart, 528, 567 effect of compressing, 567 node, 530 Auscultation, 543 in determining blood-pressure, 495 Autolysis, 941 Autolytic enzymes, 738 Automaticity of heart beat, 560 Autonomic fibers from brain, 251 from sacral cord, 253 from spinal cord, 250 nerve fibers, normal stimulation of, 253 nervous system, general relations _ of, 248 Axial stream in arteries and veins, 472 Axon reflexes, 153 Bacterial action in intestines, 794 Balance experiments in nutrition. 874 Balloon ascensions, effect of, 699 Barometric pressures, effect of, 697 Bartholin, duct of, 740 Basilar membrane, function of, 392 Bathmotropic nerve fibers to heart, 577 Bechterew's nucleus, 212, 233 Bell-Magendie law, 83 Bilateral representation in motor areas, 197 Bile, composition of, 799 curve of secretion of, 806 effect of occluding bile-ducts, 807 ejection of, into duodenum, 805 functions of, summary, 807 quantity of, 799 secretion of, 804 Bile-acids, composition of, 801 Bile-duct, sphincter of, 807 Bile-pigments, 429, 800 Bile-salts, importance of, in fat diges- tion, 791, 807 Bilirubin, 800 Biliverdin, 800 Binocular perspective, 371, 374 vision, 362 horopter in, 368 struggle of visual fields in, 369 INDEX. 1001 Binocular vision, value of, in judg- ments of distance, 374 of size, 374 Biological reaction, 416 Births, ratio of male and female, 977 Biuret reaction for proteins, 989 Bladder, urinary, movements of, 841 sphincter of, 841 gall-, movements of, 805 Blind spot in eye, 331 Blood, blood-plates of, phvsiology of, 436 circulation of (see Circulation) coagulation of, 445 condition of carbon dioxid in, 671 of nitrogen in, 669 curve of dissociation of oxyhemo- globin, 670 defibrinated, 409 gases of, 662 general properties of, 408 hemoglobin in, 412 amount, 418 nature, 418 hemolysis of red corpuscles, 413 histological structure of, 408 leukocytes of, 433 nucleoprotein in, 445 osmotic pressure of, 414 proteins of, 439, 441 reaction of, 409 red corpuscles of, 412 fate of, 429 origin of, 429 regeneration of, after hemorrhage, 459 specific gravity of, 411 total quantity of, 458 transfusion of, 460 Blood-plasma, composition of, 439 Blood-plates, properties of, 436 Blood-pressure, 479 diastolic, 483 effect of menstruation upon, 951 in brain, 621, 622 in capillaries, 489 in man, 490, 495 mean, 483 relation of, to heart -rate, 589 respiratory waves of, 654 systolic, 483 Traube-Hering waves of, 608 venous and capillary, 497 Blood-serum, 409, 440 Body equilibrium in nutrition, 874 sense area, 201 temperature in man, 925 Bowman's theorv of urinarv secre- tion, 820 Brachium conjunctivum, 233 pontis,'235 Brain, association areas of, 221 Brain, auditory center in, 210 center for olfaction, 214 for taste, 216 centers affected in aphasia, 217, 221 development of cortical areas, 224 effect of variations in arterial pres- sure upon, 621, 622 histological differentiation of cor- tex of, 227 intracranial pressure in, 620 localization of function in, 191 motor areas of, 194 regulation of circulation in, 616 sensory areas of, 200 vascular supply of, 616 Brightness in visual sensations, 341 Bronchi, capacity of, 647 constrictor and dilator fibers of, 694 Buffy coat of blood, 446 Bulbospiral fibers of heart, 527 Caffeix, 905 Caisson disease, 697 Calcarine fissure, relation of, to vision, 208 Calcium, fimount of, in cataract, 904 rigor, 55 salts, effect of, on heart, 561 in curdling of milk, 770 nutritive value of, 902 secretion of, in milk, 464 Calorie, definition of, 927 Calorimeters, varieties of, 927 Calorimetric equivalent, 929 measurements, 932 Calorimetry, indirect, 931 principles of, 927 Cannula, washout, 481 Capillary blood-pressure, 489 electrometer, construction of, 99 Carbohemoglobin, 421 Carbohydrates, absorption of, 789 as glycogen formers, 809 as source of body fat, 899 fermentation of, in intestine, 794 general functions of, 893 metabolism of, in body, 889 of muscle, 62 regulation of supply of, 890 supply of, in body, 888 Carbon dioxid, action on respiratory center, 689 condition of, in blood, 671 effect of, in inspired air, 689, 697 on dissociation of oxyhemo- globin, 670 on respiratory movements, 689 excretion of, through skin, 849 in balance experiments, S74 in saliva, 743 production of, in muscle, 65 1002 INDEX. Carbon dioxid, tension of, in alveolar air, 673 in arterial blood, 674 in tissues, 675 in venous blood, 674 equilibrium, 874 monoxid hemoglobin, 421 Cardiac cycle, 546 glands of stomach, 756 muscle, properties of, 57, 564 nerves (see Heart) sphincter, 707 Cardiogram, 537 Cardio-inhibitory center, 578 Carnin, 64 Casein, 770, 964 Catalase, 732, 739 Catalysis, 732 Catelectrotonic currents, 108 Catelectrotonus, 88 Cathode as stimulus, 88 physical and physiological, 94 Centers in cerebrum (see Cerebrum) Central field of vision, 335 Centrosome, 953 Cerebellum, ending of spinal tracts in, 173, 234 f experimental work upon, 236 general functions of, 239 localization of function in, 241 paths connecting with other parts of brain, 233 psychical functions of, 241 structure of, 231 Cerebrin, 80 Cerebrogalactosides, 80 Cerebrosides, 80 Cerebrospinal liquid, 618 Cerebrum, association areas of, 221 center for hearing, 210 for olfaction, 214 for vision, 205 centers affected in aphasia, 217 commissural system of fibers in, 187 development of cortical areas in, 224 general physiology of, 183 histological differentiation of cor- tex, 227 histology of cortex, 184 localization of function in, 191 motor areas of, 194 projection system of fibers in, 185 results of ablation of, 189 sensory areas of, 200 system of fibers in, 185 vasomotor supply of, 623 Cerumen, 849 Chemical heat regulations, 936 secretion, gastric, 765 pancreatic, 779 Chemotaxis, 127 Chevne-Stokes respiration, 701 Cholesterin, 79, 797, 803, 849 Cholic acid, 801 Cholin, 79 Chorda tympani nerve, 288, 741, 744 Chromatic aberration in eye, 312 visual sensations, 344 Chromatolysis, 130 Chromophile substance in nerve cells, 135 Chromoproteins, 992 Chromosomes, 953, 973 Chronotropic nerve fibers to heart, 577 Chyle fat, 791 Chymosin, 769 Ciliary muscle, action of, in accom- modation, 309 nerves to, 318 Ciliated epithelium, 57 Circulating proteins, 876 Circulation, accessory factors in, 508 as seen under microscope, 472 curve showing pressures in, 484, 487, 488 data concerning pressures in (man), 495 mean pressures in, 486 diastole and systole of heart, 525 effect of adrenal extracts upon, 858, 859 of heart beat and size of arteries upon, 477 explanation of side-pressure in, 501 of velocity changes in, 477 pressure in, 502 factors of normal pressure and velocity in, 504 form of pulse wave, 515 general curve of velocities in, 476 statement of pressure relations, 479 hydrostatic effects upon, 506 importance of elasticity of arteries, 503 in brain, 616 in kidneys, 826 means of determining blood-pres- sure in, 479, 490 velocities in, 475 pressure in coronary system, 549 in pulmonary system, 509 pulse pressures in, 483 regulation of blood supply, 612 respiratory waves of pressure in, 654 systole and diastole of heart, 525 systolic, diastolic, and mean pres- sures in, 483 velocities in, 475 time required for complete, 478 Traube-Hering waves of pressure in, 608 velocity in capillaries, 475 INDEX. 1003 Circulation velocity in coronary sys- tem, 549 in man, 475 in pulmonary system, 509 of pulse wave, 513 Clarke's column, 165 Claudication, intermittent, 34 Clotting (see Coagulation) Coagulation, blood, 445 intravascular, 454 means of hastening and retarding, 455 theories of, 446 Cocain, action of, on iris, 322 Cochlea, functions of, 391 sensory epithelium of, 385 Coefficient, absorption, 666 temperature, 116 Coferment, 737 Cold spots on skin, 275 Color blindness, 348 contrasts, 347 fusion, 344 saturation, 344 sense of retina, 351 vision, theories of, 354 Combustion equivalents of foods, 917 Comma tract of Schultze, 181 Commissural system of fibers (cere- brum), 187 Common sensations, 267 Compensatory pause in heart beat, 566 Complemental air, 646 Complementary colors, 345 Compound muscular contractions, 41 Condiments, 729, 905 Conduction as physiological propertv, 76 _ direction of, in nerve fibers, 115 Conjugate foci, 301 Conjugated sulphates, 838 Contraction, 17, 33. See also Muscle. Contralateral conduction in cord, 177 Convoluted tubules of kidney, 818, 823 Core-model of nerve, 109 Coronary arteries, effect of occlusion of, 553 vasomotor supply of, 614 Corpora quadrigemina, relation of, to visual apparatus, 206, 209 striata, functions of, 229 Corpus callosum, structure and func- tion, 228 luteum, 945 trapezoideum, 213 Corresponding points of retina, 365 Cortex of cerebrum, general physi- ology of, 187 histology of, .184, 227 Corti, rods of, 385 Costal respiration, 642 Cowper's glands, 967 Cranial nerves, afferent fibers in, 84 efferent fibers of, 84 nuclei of origin of, 243 Cranioscopy, 191 Creatin, 64, 836 Creatinin, 64, 836 Cresol-sulphuric acid, 795, 838 Cretinism, 852 Crystalline lens, calcium of, in catar- act, 904 Curve, contraction, of artificial mus- cle, 74 of arterial pulse, 516, 519 of plain muscle, 56 of skeletal muscle, 26 dissociation of oxyhemoglobin, 670 extensibility and elasticity of mus- cle, 20 gastric secretion, 763 intensity of sleep, 257 pancreatic secretion, 777 pressures in vascular system, 484, 487, 488 relations of heart sounds, 544, 545 respiratory movements, 644 secretion of bile, 806 systolic, diastolic, and mean blood- pressures, 483 velocity of blood-flow, 476 venous pulse, 521 visual acuity of retina, 338 work of muscle, 39 Cycloplegia, 322 Cystin, 802, 986 Cvstinuria, 802 Dead space of lungs, 647 Deamidizing enzymes, 736 Death rigor, chemical changes during, 69 in muscle, 52 theories of, 981 Deep reflexes, 161 sensibility, 273, 282, 284 Defecation, 721 Degeneration in nerve fibers, 126 Deglutition, 703 nervous control of, 707 Deiter's cells in cochlea, 385 nucleus, 212, 233 Demarcation current, muscle, and nerve, 96 Demilunes of salivary glands, 742 Depressor nerve fibers, 603 of heart, 606 Derived proteins, 993 Descending paths, spinal cord, 179, 181 Deuteranopia, 349 1004 INDEX. Deutero-albumoses, 768 De Yries' theory of mutation, 974 Diabetes, 890 mellitus, 891 pancreatic, 891 phloridzin, 892 use of alcohol in, 909 Dialysis, definition of, 998 Diaminotrioxydodecoie acid, 986 Diaphragm, action of, 638 Diaphragmatic respiration, 638 Diastase, 735 discovery of, 730 Diastasis of heart, 541 Diastole, duration of, in heart, 547 Diastolic arterial pressure, 483 method of determining, in animals, 485 method of determining, in man, 491 Dicrotic pulse wave, 517 Diet, accessory articles of, 729, 905 average daily, 919, 920 effect of reduction of salts in, 902 Dietetics, general principles of, 919 Diffusion circles on retina, 307 definition of, 993 Digestion in large intestine, 793 in small intestine, 775 in stomach, 771 Diopter, definition of, 311 Dioptrics of eye, 300 Diplopia, 364, 367 Direct field of vision, eye, 335 Discord, physiological explanation of, 395 Dissociation of oxyhemoglobin, 670 Diuretics, action of, 825 Dominant characteristics in heredity, 975 Dromograph, 474 Dromotropic nerve fibers to heart, 577 Duct of Bartholin, 740 of Rivinus, 740 of Stenson, 740 of Wharton, 740 of Wirsung, 775 Dyspnea, 641, 691 Dyspraxia, 229 Ear, effect of section of auditory nerves, 401 of stimulation of semicircular canals, 400 Eustachian tube of, 384 Flourens' experiments on semi- circular canals, 398 functions in analyzing sound waves, 391 of cochlea, 391 Ear, functions of ear-bones, 380 of sacculus, 405 of utriculus, 405 intrinsic muscles of, 383 limits of hearing, 395 position of bones in, 380 projection of auditory sensations, 384 semicircular canals of, 397 sensations of discord, 395 of harmony, 395 sensory epithelium in cochlea, 385 structure of, 386, 392 bones of, 380 theories of functions of semicircular canals of, 401 tympanic membrane of, 379 Eck fistula, 831 Efferent nerve fibers, 80 occurrence in anterior roots, 82 in cranial nerves, 84 Ejaculation of spermatic liquid, 971 Elasticity and extensibility of muscle, 20 Electrical changes in heart, 533, 684 in muscle and nerve, 96 with respiratory movements, 6S3 Electrocardiograms, 534 Electrodes, non-polarizable, 101 stimulating, 87 Electrolytes, effect of, on osmotic. pressure, 995 Electrotonic currents, 108 Electrotonus, 88 Eleventh cranial nerve, nucleus of, 247 Embryo, nutrition of, 958 Endogenous fibers of spinal cord, 171 Energy of muscular contraction, 36 Enterokinase, 779, 786 Entoptic phenomena, 360 Enzymes, adenase, 738, 835 amylase, 784 arginase, 832 chemistry of, 739 classification of, 735 deamidizing, 736 definition of, 735 endoenzymes, 735 enterokinase, 779, 786 erepsin, 783, 787 exoenzymes, 735 general properties of, 736 glycolytic, 738, 870 guanase, 738, 835 historical account of, 730 intracellular, 941 inverting, 787 lipase, 784 nuclease, 738 of muscle, 64 oxidases, 736, 938 pepsin, 765 INDEX. 1005 Enzymes, peroxidases, 941 ptyalin, 753 rennin, 769 reversible reactions of, 732 specificity of, 734 trypsin, 780 Epicritic sensations, 274 sensibility, 273 Epigenesis, 972 Epinephrin, 859 Erection, physiology of, 969 Erepsin, 787" Ergograph, 47 Erythroblasts, 431 Erythrocytes. See Red blood-cor- puscles. Erythrodextrin, 754 Eserin, action of, on iris, 322 Ethereal sulphates, 838 Eupnea, 641 Eustachian tube, 384 Evolution, hypothesis of, in heredity, 972 Exogenous fibers in spinal cord, 171 Expiration. See also Respiration. definition of, 637 expiratory center, 685 muscles of, 640 Expired air, composition of, 658 injurious effects of, 659 Extensibility of muscle, 20 Extensor thrust reflex, 159 Eye, abnormalities in refraction of, 313 accommodation in, 307 action of drugs upon, 322 acuity of vision in, 337 after-images in, 346 as optical instrument, 300 binocular field of vision, 365 perspective, 371 chromatic aberration in, 312 color blindness of, 348 contrasts in, 347 vision in, 343 complementary colors, 345 corresponding points in, 365 dark adapted, 332, 340 diffusion circles in, 307 diplopia in, 364, 367 direct field of vision in, 335 entoptic phenomena in, 360 far point of distinct vision, 311 function of cones, 352 of rods, 352 fundamental color sensations, 345 horopter, 368 indirect field of vision in, 335 inversion of image in, 305 light adapted, 332, 340 reflex, in, 320 movements of, 362 Eye, muscular insufficiency, 364 nature of visual stimuli, 332 near point of distinct vision, 310 nodal point of, 304 ophthalmoscopic examination of, 325 optical defects of, 312 delusions, 375 physics of formation of image in, 303 qualities of visual sensations, 343 reduced schematic (Listing), 304 refractive power of, 311 size of retinal images, 306 spherical aberration in, 313 stereoscopic vision, 372 struggle of visual fields, 369 suppression of visual images, 368 theories of color vision, 354 threshold stimulus of, 339 visual field of, 334 judgments, 369 purple of, 332 Eye-muscles, action of, 362 Facial nerve, dilator fibers in, 608 nucleus of, 246 Far point of distinct vision, 311 Fat, absorption of, 790 as glycogen former, 811 digestion of, 784 in stomach, 774 excessive formation of, in obesity, 899 in bile, 804 metabolism of, in body, 895 mode of oxidation of, in body, 896 nutritive value of, 894 of chyle, 791 origin of, from carbohydrates, 898 in body, 898 relation of liver to, 896 Fatigue in nerve fibers, 118 muscular, 48 of olfactory organs, 297 theories of, 69 toxin, 70, 661 Feces, composition of, 796 Fermentation in intestine, 794 of carbohvdrates in small intestine, 790 Ferments, historical account of, 730 Fertilization of ovum, 955 Fibrillary contractions of heart, 553 Fibrin ferment, preparation of, 447 relations to blood-clot, 445 Fibrinogen, 443 preparation of, 447 Fictitious meal (Pawlow), 762 Fifth cranial nerve, 246 Fillet, lateral, 213 100(3 INDEX. Fillet, median, 202 Fistula, Eck's, 831 gall-bladder, 798 stomach, 759 Thiry-Vella, 786 Flavors, 729 dietary, importance of, 905 Flechsig's myelinization method, 166 Fluorid solution, effect on clotting, 456 Food, composition of, 729 definition of, 729 potential energy of, 915 Foodstuffs, definition of, 729 Fourth cranial nerve, nucleus of, 245 Fovea, center for, in occipital cortex, 209 of retina, size of, 336 Franklin theory of color vision, 358 Freezing-point, method of determin- ing, 996 Fundic glands of stomach, 756 Fundus of stomach, 709 Gall-bladder, functions of, 805 nerves of, 806 Galvanometer, construction of, 97 d'Arsonval, 98 string, 100 Gases, laws governing absorption of, 665 of blood, 662 pressure of, 665 tension of, in solution, 667 Gas-pump, 663 Gastric glands, 756 histological changes in, during secretion, 757 secretory nerves of, 762 secretion, acid of, 760 chemical, 765 composition of, 758 curve of, 764 means of obtaining, 758 nervous, 765 normal mechanism of, 763 Gelatin, history of, as a food, 886 nutritive value of, 885 Genes, 976 Genital organs, vasomotor supply of, 628 Genotype, 976 Germ plasm, definition of, 981 Glans penis, sensibility of, 274 Globin, 418, 992 Globulicidal action of blood-serum, 415 Globulins, general properties of, 990 Glomerulus of kidney, functions of, 821 Glossopharyngeal nerve, dilator fibers in, 608 Glossopharvngeal nerve, nucleus of, 247 Glucosamin, 988 Glutaminic acid, 782, 986 Glutelins, 991 Glutolin, 442 Glycin, 781, 801, 986 Glycocholic acid, 801 Glycocoll, 986 Glycogen, amount of, in liver, 809 discovery of, SOS glycogenic theory, 811 importance of, in embrvo, 959 in muscle, 62, 813 loss of, during muscular contrac- tions, 66 metabolism of, in body, 894 origin of, 809 supply of, in body, 888 Glycolysis of sugars in body, 889 Glycoproteins, 992 Glycosuria, 890 alimentary, 789 Glycylglycin, 987 Gmelin's reaction for bile-pigments, 800 Golgi's nerve cells, second type, 134 pericellular nerve net, 136 Graafian follicle, structure of, 944 Gram-molecular solution, 995 Growth, 979 Guanase, 738, 835 Guanin, 64, 834 Gudden's commissure, 207, 214 Harmony, physiological cause of, 395 Hearing. See Ear. cortical center of, 210 limits of, 395 Heart, accelerator center for, 587 nerves of, 5S3 action, current of, 533 of inhibitory nerves, 573 analysis of inhibition, 575 apex beat of, 536 auriculoventricular bundle, 52S, 567 automaticity of, 555 capacity of ventricles of, 547 cardiac nerves of, course, 573 cardiogram, 537 cardio-inhibitory center of, 578 causation of beat, 555 change in form of ventricle in sys- tole, 535 compensatory pause of, 566 contraction wave in, 531 coronary circulation in, 549 course of cardiac nerves, 573 'depressor nerve of, 606 diastasis of, 541 diastole and systole of, 525 INDEX. 1007 Heart, diastole and systole of, time relations of, 547 effect of calcium upon, 561 of drugs on, 581 of occlusion of coronaries upon, 553 of potassium upon, 561 of sodium upon, 561 electrical changes in, 533 escape from inhibition, 577 events of a cardiac cycle, 546 fibrillary contractions, 553 historical account of beat of, 556 inhibition of auricle, 577 of ventricle, 577 intraventricular pressure during sys- tole, 538 intrinsic nerves of, 557 maximal contractions of, 564 musculature of, 525 myogenic theory of beat of, 558 negative pressure in, 551 neurogenic theory of beat of, 557 rate of beat as affeeted by age, 588 by blood-pressure, 589 by intrinsic nerves, 589 by muscular exercise, 590 by sex, 588 by size, 588 by temperature, 591 reflex acceleration of beat, 585 refractory period of, 564 sequence of beat of, 567 sounds of, 543 suction-pump action of, 551 systole and diastole of, 525 time relations of, 547 systolic plateau of beat, 539 theories of inhibition of, 581 third sound of, 545 tonic inhibition of, 579 tonicity of muscle of, 570 vasomotors of, 614 ventricle of, in systole, 535 ventricular output of, 540 volume curve of, 540 work done by, 547 Heart-block, 568 Heart-muscle, general properties of, 57, 564 Heat centers, 936 equivalent of foodstuffs, 916 loss of, physiological regulation of, 932 nerves, 936 production in hydrolysis. 915 physiological regulation of, 935 puncture, 937 regulation, chemical, 936 general statement of, 932 physical, 934 rigor of muscle, 53 Heat, sexual, in lower animals, 947 Helmholtz theory of color vision, 355 Helweg's bundle, spinal cord, 182 Hematin, 419, 428 Hematoidin, 429 Hematopoietic tissue, 431 Hematoporphyrin, 429 Hemeralopia (night-blindness), 354 Hemianopia (quadrant), 209 Hemin, 428 Hemiplegia, 196 Hemochromogen, 418, 429 Hemodromograph, 474 Hemoglobin, absorption spectra of, 423 , compounds of, with carbon dioxid, 421 monoxid, 420 nitric oxid, 420 oxygen, 420 condition of, in corpuscles, 412 crystals of, 422 curve of dissociation of oxyhemo- globin, 670 derivative compounds of, 427 iron in, 421 nature and amount of, 418 Hemolysins, natural and acquired, 415 Hemolysis, 413 Hemorrhage, effect of, 459 Heredity, definition and history, 972 Hering theory of color vision, 356 Heterotypical division of ovum, 954 Hexon bases, 969 Hippuric acid, 838 Histidin, 782, 986 Histohematins, 429 Histons, 969, 991 Hofacker-Sadler law, 977 Homoiothermous animals, 925 Homolateral conduction in cord, 177 Homotypical division of ovum, 954 Hormones, 765 Horopter, 368 Hunger, sense of, 285 Hydrocele liquid, 442 Hydrochloric acid, combined, in gas- tric secretion, 761 function of, in peptic digestion. 767 in gastric juice, 760 Hydrolysis, 736 heat energy of, 915 Hydrostatic factor in circulation, 506 Hyperglycemia, 890 Hypermetropia, 314 Hyperpnea, 691 Hypertonic solutions, 997 Hypnotic sleep, 265 Hypoglossal nerve, nucleus of, 247 Hypotonic solutions, 997 Hypoxanthin, 64, 833 1008 INDEX. Identical points of retina, 365 Identity theory of nerve impulse, 124 Immune body, 417 Incongruence of retinas, 367 Indican, 838 > Indirect calorimetry, 931 field of vision, eye, 335 Indol group in protein molecule, 782 Indoxyl sulphuric acid, 795, 838 Induction coil, 24 Inert layer in circulation, 472 Inheritance, Mendelian, 975 Inhibition, escape from, in heart, 577 of heart, 573 of knee-jerk, 157 of reflexes, 149 of respiratory movements, 683 reflex of heart, 578 theories of, 581 Inotropic nerves to heart, 577 Inspiration. See also Respiration definition of, 637 increased heart-rate during, 657 means of producing, 638 muscles of, 640 Inspired air, composition of, 658 Intermediary metabolism of carbohy- drates, 889 of fats, 895 of nucleoproteins, 882 of proteins, 876 products of nniscle metabolism, 67 Intermittent claudication, 34 Internal secretion, adrenals, 857 definition and historical account, 850 kidney, 871 liver, 841 ovary, 867 pancreas, 869 testis, 867 thyroid tissues, 841 sensations, 268 Intestinal movements, effect of various conditions upon, 719 secretion, 786 Intestines, bacterial action in, 794 large, movements of, 719 nervous control of movements of, 718 reaction of contents of, 794 small, movements of, 714 Intracellular enzymes, 941 Intracranial pressure, 620 Intra-ocular pressure, 324 Intrapulmonic pressure, 649 Intrathoracic pressure, 650 origin of, 652 variations of, with forced breath- ing, 651 Intraventricular pressure, 538 Introductory contractions of muscle,34 Invertase, 738, 787 Involuntary muscle, 55 Iodothyrin, 852 Iris, action of drugs upon, 322 antagonistic action of muscles upon, 319 muscles and nerves of, 318 Iron, effect of removal of spleen on, 817 in hemoglobin, 421 salts, source and nutritive impor- tance of, 902 Irritability, definition of, 22 of muscle, 22 of nerve fibers, 85 Isodynamic equivalent of foodstuffs, 920 Isoleucin, 986 Isometric muscular contractions, 27 Isotonic muscular contractions, 27 solutions, definition of, 997 Isotropous substance in muscle, 19 Jacobson, nerve of, 740 Judgments, visual, of distance and size, 374 of perspective or solidity, 369 Kenotoxin, 70, 661 Kidney, action of diuretics on, 825 blood-flow through, 826 composition of secretion of (urine), 828 function of convoluted tubules, 823 of glomerulus, 821 internal secretion of, 871 secretion of urine in, 819 structure of, 818 Kinases, 737 Kjeldahl's method for determination of nitrogen, 829, 873 Knee-jerk, conditions influencing, 160 definition of, 156 explanation of, 158 reinforcement of, 156 use of, as diagnostic sign, 161 Labor, physiology of, 961 Lactic acid in muscle, 63 increase of, during contraction, 67 Laked blood, 413 Langerhans, islands of, 870 Large intestine, digestion and absorp- tion of food in, 793 movements of, 719 Larynx, reflex effects from, on respi- rations, 684 Latent period of muscular contrac- tion, 27 INDEX. 1009 Law of constant energy consumption, 982 growth-quotient, 983 of surface area, 932 Lecithin, 79, 803 as complement, 417 Lecithoproteins, 992 Lemniscus, lateral, 213 median, 202 Leucin, 781, 986 Leucocytes, effect of hemorrhage upon, 460 functions of, 433 structure and classification, 433 variations in number of, 435 Liebermann's reaction for proteins, 989 Liebig's classification of foodstuffs, 910 Light-reflex in eye, 320 Lipase, 735 activation of, 786 gastric, 771 in pancreatic secretion, 784 reversible reaction of, 733 Lipoids, 78 Listing's law, 364 schematic eye, 304 Liver, bile-pigments of, 800 acids of, 801 formation of urea in, 814 glycogen of, 808 glycogenic action of, 812 internal secretion of, 851 pulse, 520 quantity of bile, 799 relation of, to fat metabolism, 896 secretion of bile, 804 Localization of function in cerebellum, 241 in cerebrum, 191 Localizing power of skin, 278 Locke's solution, 562 Locomotor ataxia, 172 Ludwig theory of urinary secretion, 819 Luminosity of visual sensations, 341 Lungs, gaseous exchanges in, 673 total surface of, 637, 674 vasomotors of, 615 Lymph, action of lymphagogues, 465 circulation of, 630 formation of, 463 summary of factors concerned in formation of, 468 Lymphocytes, 433 Lysin, 782, 986, 991 Maltase, 738, 753, 784, 787 Maltose, 754, 784 Mammary glands, effect of uterus upon, 962 64 Mammary glands, structure and func- tions, 961 Manometer, Hiirthle's, 485 maximum and minimum, 485 use of, for determining blood-pres- sure, 479 Mast cells, 434 Mastication, 703 Mathematical perspective, 370 Mean blood-pressure, 484 Medulla oblongata, 242 respiratory center in, 677 Medullary striae, 213 Mendelian law of inheritance, 975 Meningeal spaces, 618 Menstruation, 946 effect of, on other functions, 951 physiological significance of, 950 Mercury manometer, use of, for blood- pressures, 479 Metabolism, definition of, 872 intermediary, of carbohydrates, 889 of fats, 895 of nucleoproteins, 882 of proteins, 876 Metaproteins, 993 Metathrombin, 454 Methemoglobin, 427 Methylpurins, 834 Microphage, 435 Micturition, physiology of, 840 Milk, composition of, 964 Millon's reaction for proteins, 989 Minimal air, 646 Miosis, definition of, 322 Molisch reaction for proteins, 990 Monakow's bundle, 181 Motor aphasia, 2l7 areas of brain, 194 paths in spinal cord, 179 points in man, 93 Mountain sickness, 697 Movements of alimentary canal, defe- cation, 721 deglutition, 703 large intestine, 719 mastication, 703 small intestine, 714 stomach, 710 vomiting, 724 Mucin in saliva, 743 Muscarin, action of, on heart, 581 on iris, 322 on sweat-glands, 848 Muscle, absolute power of, 38 action current of, 103 artificial stimulation of, 24 calcium rigor of, 55 carbohydrates of, 62 cardiac, properties of, 57, 564 chemical changes of, in contrac- tion, 65 1010 INDEX. Muscle, composition of, 60 compound contractions of, 41 contraction of, 25 wave of, 35 contracture of, 32 curve of work of, 39 death rigor, 52 demarcation current of, 90 direct irritability of, 22 disappearance of glycogen in, 66 effect of temperature upon, 29 of veratrin upon, 31 energy liberated in, 36 Engelmann's artificial, 73 enzymes of, 64 ergographic records from, 47 extensibility and elasticity of, 20 , fatigue of, 35, 49, 69 glycogen of, 813 heat rigor of, 52 inorganic salts of, 65 introductory contractions of, 34 isotonic and isometric contractions of, 27 lactic acid of, 63 latent period of contraction of, 27 maximal and submaximal contrac- ^ tions of, 28 myogenic tonus of, 57 neurogenic tonus of, 56 nitrogenous extractives of, 64 number of stimuli necessary for tetanus, 44 pale fibers in, 19, 25 pigments of, 64 plain, 55 ' plasma, 18, 60 proteins of, 60 red fibers in, 19, 26 sarcoplasm, is simple contraction of, 25 smooth, 55 stroma, 62 structure of fiber, 18 by polarized light, 19 summation of contractions of, 43 theories of nature of contraction, 71 tone of, during contraction, 43 tonicity of, 50 vasomotor supply of, 628 voluntary contractions of, 45 water rigor of, 56 white and red fibers of, 19 Muscle-sense, cortical area for, 201 importance of, in visual judgments, 371 paths for, in spinal cord, 173, 175 quality of, 284 Muscular contraction, electrical varia- tion in, 107 intermediary chemical products in, 65 Muscular insufficiency in movements of eye-balls, 364 or deep sensibility, 282 work, effect of, on heart rate, 590 on physiological oxidations, 910 on protein metabolism, 911 on respiratory movements, 695 Musical sounds, classification and properties of, 387 Mutations, theories of, 974 Mydriasis, definition of, 322 Myelin sheath of nerve fibers, func- tion of, 77 Myelinization method of Flechsig, 166, 224 Myofibrillar (of plain muscle), 55 Myogen, 61 fibrin, 61 Myogenic theory of heart beat, 558 tonus, 57 Myohematin, 429 Myopia, 314 Myosin, 61 fibrin, 61 Myxedema, 852 Narcosis, effect of, upon nerve im- pulse, 117 Near point of distinct vision, 310 Negative pressure in thorax, 650, 652 in ventricle, 551 variation in muscle and nerve, 103, 104 Nerve, abducens, nucleus of, 246 auditory, 211 chorda tympani, 288, 741, 744 facial, nucleus of, 246 fourth cranial, nucleus of, 245 glossopharyngeal, nucleus of, 247 hemorrhoidalis inferior, 722 hypoglossal, nucleus of, 247 motor and sensory roots of, 82 olfactory, 214 optic, 206 pudendus, 722 recurrent, sensibility of anterior roots, 83 spinal accessory, nucleus of, 247 third cranial, nucleus of, 243 trigeminal, nucleus of, 246 twelfth cranial, nucleus of, 247 vagus, nucleus of, 247 Xcrve-cell, chromatolysis of, 12V) classification of, in spinal cord, 163 degenerative changes in, 128 general physiology of, 136 internal structure of, 135 metabolism in, 131) neuron doctrine, 130 reaction of, 137 refractory period of, 140 INDEX. 1011 Nerve-cell, summation of stimuli in, 139 varieties of, 132 Nerve-fibers, action current of, 103 afferent and efferent, 80 anodal and cathodal stimulation of, 88 antidromic impulses in, 83 artificial stimuli of, 85 autoregeneration of, 128 chemistry of, 78 classification of, 81 core model of, 109 degeneration and regeneration of, 126 demarcation current of, 96 direction of conduction, 115 du Bois-Reymond's law of stimu- lation, 87 electrical stimulation of, in man, 94 electrotonic currents of, 108 elect rot onus of, 88 impulse in, historical, 111 independent irritability of, 85 metabolism in, during activity, 120 myelin sheath of, 77 nutritive relations to nerve-cells, 124 opening and closing tetanus of, 91 Pfliiger's law of stimulation of, 89 stimulation of, in man, 91 structure of, 76 unipolar method of stimulating, 92 Nerve-impulse, historical, 111 metabolism during, 119 modification of, by various influ- ences, 117 qualitative changes in, 81, 123 relation of, to action current, 107, 115 theories of, 121 velocity of, 112 Nervi erigentes, 253, 609, 628 Nervous secretion, gastric, 765 pancreatic, 779 Neurogenic theory of heart beat, 557 tonus, 56 Neuron doctrine, 130 Neurons, varieties of, 131 Nicotin, action of, on salivary secre- tion, 750 on sweat secretion, 847 use of, in tracing autonomic fibers, 250 Night-blindness, hemeralopia, 354 Ninth cranial nerve, nucleus of, 247 Nissl's granules, 135 Nitric oxid hemoglobin, 421 Nitrogen, condition of, in blood, 669 determination of, 873 Nitrogen equilibrium, 872 effect of non-protein food on, 875 excretion in urine, 829 Nitrogenous extractives of muscle, 64 Nodal point of eye, 306 Non-polarizable electrodes, 101 Normoblasts, 431 Nuclease, 738, 835 Nucleo-albumin in bile, 804 Nucleon, 63 Nucleoproteins, 992 in blood, 445 intermediary metabolism of, 882 Obesity, physiological cause of, 899 Ohm's law of composition of sound waves, 390 Olfaction, end-organ for, 293 mechanism of, 294 Olfactometer, 298 Olfactory associations, 299 bulb, histological structure of, 215 center in cortex, 214 nerve, course df fibers of, in brain, 216 organs, fatigue of, 297 sensations, classification of, 295 conflict of, 299 qualities of, 295 threshold stimulus, 297 sense cells, 294 stimuli, nature of, 295 Oncometer, 826 Ophthalmometer, 328 Ophthalmoscope, 325 Opotherapy, 850 Opsonins, 435 Optic ehiasma, decussation in, 207 nerve, course of fibers of, in brain, 206 radiation, 207 thalamus, functions of, in vision, 210 tracts, structure of, 207 Optical deceptions, 375 Optograms on retina, 333 Orthodiagram, 536 Orthodiagraph, 536 Osmosis, definition of, 993 Osmotic pressure, definition of, 994 determination of, 995 of blood, 414 Oval field of Flechsig, 181 Ovaries, internal secretion of, 867 relation of, to menstruation, 949 Overtones, production of, 390 Ovulation, 945 Ovum, fertilization of, 955 implantation of, in uterus, 957 maturation of, 953 passage of, into uterus, 952 1012 INDEX. Oxalate solutions, effect of, on coagu- lation, 456 Oxidases, 736, 938 Oxidations, theories of, 938 Oxygen, action of, on respiratory center, 688, 696 compound of, with hemoglobin, 420 condition of, in blood, 669 effects of varying pressures of, on respiration, 696 tension of, in alveolar air, 673 in tissues, 675 in venous blood, 673 Oxygenase, 941 Oxyhemoglobin, 420 Oxyprolin, 986 Oxyproteic acid, 830 Oxypurins, 834 Pacchionian bodies of brain, 619 Pain sense, distribution and char- acteristics of, 281 localization of, 281 path for, in cord, 175 Pale fibers of muscle, 19, 25 Pancreas, action of lipase in, 784 anatomy of, 775 curve of secretion of, 777 digestive action of secretion, 780 on carbohydrates, 784 internal secretion of, 869 normal mechanism of secretion, 778 secretory nerves of, 776 Pancreatic secretion, chemical, 779 nervous, 779 Paraglobulin, 442 Paralysis (motor), 196 Paralytic secretion (saliva), 751 Parapeptone, 768 Paraphasia, 218 Parathyroid, structure and function of, 851, 852 Parthenogenesis, 957, 978 Parturition, physiology of, 961 Pendular movements (intestine), 714 sound waves, 388 Pepsin, 765 discovery of, 730 properties of, 765 Pepsin-hydrochloric acid digestion, 767 Peptids, 783, 987 Peptone, 767 absorption of, in stomach, 774 effect on clotting of blood, 457 Peptozym, 457 Pericardial liquid, 442 Perimeter, 335 Peripheral field of vision, 335 resistance in circulation, 505 Peristalsis, 714 Peroxidases, 941 Perspiration. See Sweat. Pettenkofer's reaction, 801 Pfliiger's law of stimulation, 89 tetanus, 91 Phagocytes, 435 Phenolsulphuric acid, 838 Phenylalanin, 782, 986 Phloridzin diabetes, 892 Phosphatids, 79 Phosphocarnic acid, 63 Phosphoproteins, 992 Phrenology, 191 Phrenosin, 80 Physical heat, regulation, 934 Physiological diplopia, 367 oxidations, theories of, 938 Lavoisier's work, 633, 924 point (vision), 338 saline, 415 Physostigmin, action of, on iris, 322 Pilocarpin, action of, on heart, 581 on iris, 322 on salivary glands, 250 on sweat glands, 848 Pineal bodv, 866 Piqure, 890 Pituitary body, structure and func- tions of, 863 Placenta, functions of, 958 Plain muscle, 55 Plasma of blood, composition of, 439 Plethysmography, 596 Pneumogastric nerve. See Vagus. Pneumograph, 643 Pneumothorax, 653 Poikilothermous animals, 925 Polar bodies of ovum, 954 Polypeptid, 783, 987 Positive electrical variation in heart, 582 Posterior funiculi, descending tracts of, 178, 181 tracts of, 170 root, cells of, origin of, 84 ganglia, type of cells in, 133 termination in cord, 169 Postganglionic nerve-fibers, 249 Potassium salts, action of, on heart, 561 Potential energy of food, 915 Precipitins, 988 Predicrotic pulse wave, 517 Preganglionic nerve-fibers, 249 Pregnancy, changes in, 960 Prepyramidal tracts, 181 Presbyopia, 310, 315 Press-juice, 735 Pressor nerve-fibers, 603 Pressure of gases in solution, 667 sense, deep, 274 distribution of, 278 INDEX. 1013 Pressure sense, localizing power, etc., 278 Primary proteoses, 768 Principal axis of lens, 301 focal distance, 301 Projection system of fibers (brain), 185 Prolamines, 991 Prolin, 782, 986 Propeptone, 768 Prostate gland, 967, 971 Protalbumoses, 768 Protamins, 968, 991 Protanopia, 349 Proteases, 735 Proteins, absorption of, in intestine, 791 as glycogen formers, 810 classification of, 990 definition and structure of, 986 diffusion of, 998 excretion of nitrogen of, 829 general reactions of, 988 in blood-plasma, 441 necessary amount of, in diet, 878, 918, 919 normal metabolism in body, 876 of muscle, 60 osmotic pressure of, 997 putrefaction of, in large intestine, 795 specific dynamic action of, 884 synthesis of, in body, 792 Proteolytic enzymes, 735 Proteoses, 993 general properties of, 768 Protopathic sensations, 274 sensibility, 273 Proximate principles of food, 727 Psychophysical law, 270 Ptyalin, 743 action of, in stomach, 712 digestive action of, 753 effect of various conditions upon, 754 Puberty, 946, 966 Pulmonary arteries, vasomotors of, 615 circulation, peculiarities of, 509 variations of pressure in, 510 Pulse, anacrotic waves of, 518 catacrotic waves of, 517 form of wave, 516 general statement, 512 varieties of, in health and disease, 519 velocity of propagation of, 513 venous, 520 Pulse-pressure, 483 Purin bases, 64, 833 Pur kin je,- images of, 308 phenomenon, 343 Putrefaction in intestines, 795 Pyloric glands of stomach, 756 secretion of, 766 Pyramidal tract in brain, 195 in spinal cord, 179 Pyrrol compounds in protein mole- cule, 782 Pyrrolidin-carboxylic acid, 782, 986 Quadrant hemianopia, 209 Quotient, respiratory, 699 Reaction of degeneration, 94 time, 113 Reactions, biological, 416 for proteins, 988 Gmelin's, 800 of blood, 409 of contents of small intestine, 794 of urine, 828 Pettenkofer's, 801 Recessive characteristics in inherit- ance, 975 Reciprocal innervation, 150 Recurrent sensibilitv of anterior roots, 83 Red blood-corpuscles, chemical com- position of, 440 condition of hemoglobin in, 412 effect of hemorrhage upon, 431 hemolysis of, 413 influence of spleen upon, 430 number and size of, 412 origin and fate of, 429 variations in number of, 431 fibers in muscles, 19, 26 Reduced hemoglobin, 420 schematic eye, 304 Reflex actions, axon reflexes, 153 classification of, 144 definition and historical, 142 from parts of brain, 151 influence of condition of cord on, 151 of sensory endings upon, 147 inhibition of, 149 of heart, 578 knee-jerk, 156 of erection and ejaculation, 971 of respiratory center, 679, 684 of vasomotor nerves, 603 preparation of reflex frog, 144 reflex arc, 142 respiratory, from nose, larynx, and pharynx, 6S4 special and deep reflexes of cord, 161 spinal reflexes, 144 theory of, 146 through peripheral ganglia, 152 1014 INDEX. Reflex actions through vasodilator ' nerves, 609 time of, 148 Turck's method of studying, 151 Reflexes, deep, 161 extensor thrust, 159 special spinal, 161 spinal, 144 Refractive power of eye, 311 Refractory period of heart beat, 564 of nerve-cell, 140 /•«*^-*- , // formerly Instructor in Medicine and Lecturer on Hygiene, Cornell University ; and Tutor in Therapeutics, Columbia University, N. Y. i2mo of 456 pages, illustrated. In Saunders'1 Question- Compend Series. Double number, $1.75 net. Todd's Clinical Diagnosis A Manual of Clinical Diagnosis. By James Campbell Todd, M. D., Associate Professor of Pathologv, Denver and Gross College of Medicine. i2mo of 319 pages, with 131 text-illustrations and 10 colored plates. Flexible leather, $2.00 net. Bridge on Tuberculosis Tuberculosis. By Norman Bridge, A. M., M. D., Emeritus Professor of Medicine in Rush Medical College. i2mo of 302 pages, illustrated. Cloth, #1.50 net. Boston's Clinical Diagnosis Second Edition Clinical Diagnosis. By L. 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