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ANNUAL  REPORT 


F^ROGIRAMI  ACTIVITIES 


[^ATIOMAL  IMSTITOTE  OF  MEMTAL  HEALTH 


FISCAL  YEAR  1972 
PARTS  l-ll 


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ANNUAL  REPORT 


OF 
PROGRAM  ACTIVITIES 


(J^  ^  .  NATIONAL  INSTIUJTE  OF  MENTAL  HEALTH ,  /^2r/>/^»/  Mf^'^^ 
Fiscal  Year  1972 


PARTS  I-II 


ANNUAL  REPORT 

MENTAL  HEALTH  INTRAMURAL  RESEARCH  PROGRAM  - 
Division  of  Clinical  and  Behavioral  Research,  and 
Division  of  Biological  and  Biochemical  Research 


NATIONAL  INSTITUTE  OF  MENTAL  HEALTH 
July  1,  1971  -  June  30,  1972 


VOLUME  I 
Summary  Statements 


i 


ANNUAL  REPORT 

MENTAL  HEALTH  INTRAMUR?lL  RESEARCH  PROGRAM  - 

Division  of  Clinical  and  Behavioral  Research,  and 

Division  of  Biological  and  Biochemical  Research 

NATIONAL  INSTITUTE  OF  MENTAL  HEALTH 

July  1,  1971  -  Jime  30,  1972 


TABLE  OF  CONTENTS 

Volume  I  -  Summary  Statements 

Page 

Director ,  Mental  Health  Intramural  Research  Program 1 

Director ,  Division  of  Clinical  and  Behavioral  Research 5 

DIVISION  OF  CLINICAL  AND  BEHAVIORAL  RESEARCH 

Adult  Psychiatry  Branch 9 

Child  Research  Branch 27 

Laboratory  of  Clinical  Psychobiology 35 

Laboratory  of  Clinical  Science 41 

Laboratory  of  Psychology 49 

Laboratory  of  Socio-environmental  Studies 6  3 

DIVISION  OF  BIOLOGICAL  AND  BIOCHEMICAL  RESEARCH 

Laboratory  of  Brain  Evolution  and  Behavior 73 

Laboratory  of  Cerebral  Metabolism 83 

Laboratory  of  General  and  Comparative  Biochemistry 91 

Laboratory  of  Neurobiology 95 

Laboratory  of  Neurochemistry 97 

Laboratory  of  Neurophysiology 101 

Office  of  the  Director  -  Intramural  Research  Program 

Section  on  Technical  Development 109 

I 


ANNUAL  REPORT 
of  the 
DIRECTOR,  MENTAL  HEALTH  INTRAMURAL  RESEARCH  PROGRAM 
NATIONAL  INSTITUTE  OF  MENTAL  HEALTH 
July  1,  1971  -  June  30,  1972 

John  C.  Eberhart,  Ph.D. 


Perhaps  the  year  just  past  can  best  be  epitomized  for  the  NIMH  Intramural 
Research  Program  as  the  year  when  the  total  NIMH  appropriation  went  up  from 
approximately  $400  million  dollars  to  $600  million,  while  the  strength  of 
the  Intramural  Program,  which  has  lost  20  percent  of  its  manpower  during  the 
past  five  years,  was  slightly  decreased.   One  could  explain  this  in  several 
ways,  but  it  is  clear  that  non-targeted  research  (the  Division  of  Extramural 
Research  Programs  did  not  fare  any  better)  was  not  seen  in  1972  as  the 
answer  to  the  problems  of  mental  illness.   (The  only  budget  increases  for 
research  were  for  drug  abuse  and  alcoholism,  which  were  the  focus  of  much 
legislative  and  political  action  in  1972.)   The  pressure  for  widening  the 
availability  of  such  mental  health  services  as  can  be  provided  on  the  basis 
of  present  knowledge  seems  considerably  greater  than  pressure  for  new 
knowledge  to  provide  more  effective  answers.   The  wisdom  of  this  is  yet  to 
be  tested. 

The  pressures  of  a  static  budget  along  with  increasing  costs  of  research 
have  continued  this  year,  and  all  laboratories  have  felt  the  constraints. 
Adding  to  them  have  been  Government-wide  requirements  that  the  number  of 
persons  employed  be  decreased  by  5  percent,  and  that  the  average  grade  of 
full-time  General  Schedule  staff  members  be  reduced  by  .15  grades  in  fiscal 
'72  and  by  another  .15  grades  in  fiscal  '73.   These  requirements  have  been 
difficult  to  meet,  and  have  made  it  necessary  to  treat  the  whole  Intramural 
Program  as  a  unit,  utilizing  vacancies  where  they  meet  the  most  urgent  needs 
of  the  program  and  pooling  "promotion  points"  to  achieve  an  occasional 
crucial  appointment  as  well  as  to  make  a  few  highly  deserved  promotions. 
Another  effect  of  these  constraints  is  an  increase  in  the  burden  of  adminis- 
tration, especially  personnel  and  financial  management,  and  costs  for  this 
have  had  to  come  from  the  IRP  budget,  thus  further  reducing  the  funds  and 
positions  available  for  research. 

A  final  effect  of  this  support  situation  is  the  diversion  of  management 
effort  and  attention  from  the  substantive  aspects  of  science  and  the  larger 
issues  of  management  to  the  minutiae  of  administration.   Though  there  is 
some  question  whether  this  fact  diminishes  the  research  output  in  any 
significant  way,  or  lowers  its  quality,  the  possibility  exists  that  it  does. 
It  is  appropriate  to  point  out  here  how  much  the  program  owes  to  the 
outstanding  work  of  the  IRP  Administrative  Officer,  Mrs.  Hazel  Rea,  who  with 
the  able  help  of  her  staff,  has  very  competently  handled  regular  adminis- 
tration along  with  the  recurring  crises  and  unusual  expedients  that  have 
become  almost  routine.   Her  work  has  been  a  major  contribution  to  the  IRP 
as  a  whole  since  1969,  and  to  the  Clinical  Investigations  portion  since 
1954. 


Despite  the  personnel  and  dollar  stringencies  of  the  past  year,  the 
scientific  work  of  the  15  Laboratories  has  continued  at  a  high  level,  as 
the  Lab  Chiefs'  summaries  to  follow  indicate.   It  is  always  gratifying  to 
report  that  others  also  have  recognized  the  merit  of  many  of  the  projects 
by  the  award  of  prizes  and  medals  to  scientists  on  our  staff.   Among  the 
awards  during  the  past  year  have  been  the  following:   Drs .  William  Bunney, 
Dennis  Murphy,  and  Frederick  Goodwin  were  co-winners  (with  Dr.  Sjoqvist 
of  Sweden)  of  the  Anna-Monika  Foundation  Prize  of  $10,000,  awarded  in 
August  1971,  in  Basel,  Switzerland,  for  their  work  on  the  switch  process 
from  depression  to  mania.   Drs.  Floyd  Bloom,  B.  J.  Hoffer,  and  A.  P.  Oliver 
received  the  $1,000  A.  Cressy  Morrison  Award  from  the  New  York  Academy  of 
Sciences  in  December  1971,  for  their  work  in  "Cyclic  AMP  Mediation  of 
Norepinephrine  Inhibition  in  Rat  Cerebellar  Cortex:   A  Unique  Class  of 
Synaptic  Responses."   Dr.  Paul  D.  MacLean  was  awarded  the  Karl  Spencer 
Lashley  Prize  of  $2,000  by  the  American  Philosophical  Society  in  Philadelphia 
in  April  1972,  for  "sustained  leadership  in  research  on  evolution  of  the 
brain  and  nervous  system,  particularly  the  brain  centers  which  he  identified 
in  1952  as  the  limbic  system."   Dr.  Michael  Goldberg  was  given  the  S.  Weir 
Mitchell  Award  by  the  American  Academy  of  Neurology  in  May  1972,  for  his 
work  on  "The  role  of  ttie  primate  superior  colliculus  in  usually  evoked  eye 
movements."   Dr.  David  Shakow  was  awarded  the  Distinguished  Service  Award 
by  Division  12  at  the  American  Psychological  Association  meeting  in 
Washington,  D.C. ,  in  September  1971.   Drs.  Burr  S.  Eichelman  and  Lorenz  K. 
Ng  shared  the  A.E.  Bennett  Award  of  $750  in  Dallas,  Texas,  April  1972; 
Dr.  Eichelman  for  his  work  on  "The  Aggressive  Monoamines,"  and  Dr.  Ng  for 
his  work  on  "the  effects  of  L-dopa  on  the  disposition  of  certain  chemical 
substances  in  the  brain."   Dr.  Ichiji  Tasaki  was  awarded  an  honorary  Doctor 
of  Medicine  degree  by  the  Medical  Faculty  of  the  University  of  Uppsala  in 
June  1972. 

Before  leaving  the  recognition  of  our  staff  members,  it  is  a  pleasure  to 
report  the  award  by  the  Health  Services  and  Mental  Health  Administration 
of  the  Superior  Service  Award  to  Dr.  Floyd  E.  Bloom,  Dr.  Erminio  Costa, 
and  Dr.  Marian  R.  Yarrow,  and  of  the  Public  Health  Service's  Meritorious 
Service  Medal  to  Dr.  Harvey  Mudd ,  in  May  1972. 

To  all  these  outstanding  members  of  our  staff,  and  to  the  many  others  who 
have  done  distinguished  work,  I  take  great  pleasure  in  extending 
congratulations  and  thanks  for  a  job  superbly  well  done. 

During  the  year,  work  was  begun  on  a  major  effort  to  review  the  research 
programs  of  the  NIMH  and  to  make  recommendations  for  the  future. 
Dr.  Bertram  S.  Brown,  in  September  1971,  appointed  a  Research  Task  Force 
to  be  chaired  by  Mr.  James  Isbister  to  examine  all  intramural  and 
extramural  research  in  order  to  "provide  an  overview  of  the  scope  and 
national  role  of  the  NIMH  research  programs;  an  assessment  by  a  variety 
of  relevant  criteria  of  the  benefits  achieved  and  of  the  strengths  and 
weaknesses  of  the  effort  to  date;  an  analysis  and  projection  of  a  hierarchy 
of  priorities  for  mental  health  research  and  of  administrative  mechanisms 
for  implementing  them;  and  recommendations  for  organizational  changes  that 
may  be  necessary  to  strengthen  the  Institute's  research  arm."   The  remainder 
of  the  year  was  occupied  in  choosing  and  assembling  a  staff  and  in  selecting 


members  of  the  subject-matter  working  committees  in  the  three  areas  of 
(a)  basic  research,  (b)  clinical  research,  and  (c)  research  on  services 
and  methods  of  treatment.   We  are  grateful  to  the  Intramural  staff  members 
who  accepted  Dr.-  Brown's  invitation  to  join  the  staff  or  one  of  the 
working  committees.   The  following  will  be  staff  members:   Drs .  Donald 
Boomer,  Patricia  Goldman,  William  Pollin,  and  Philippe  Cardon.   About  two 
dozen  others  are  members  of  committees .   The  first  meeting  of  the  total 
task  force  was  held  May  24,  1972.   The  report  of  the  group  is  expected  to 
be  completed  by  June  30,  1973. 

A  year  ago  I  reported  the  beginnings  of  an  Equal  Employment  Opportunity 
Program  for  the  Intramural  Program,  and  I  want  now  to  bring  that  account 
up  to  date.   The  Affirmative  Action  Plan  has  continued  to  guide  our  actions, 
and  the  EEO  Council,  as  a  unit  and  through  its  committees,  continues  to 
make  recommendations,  to  raise  questions,  to  inform  and  stimulate  the 
interest  of  staff,  and  to  exert  pressure.   At  the  beginning  of  the  year, 
Mr.  John  Land  replaced  Mr.  Garrett  Bagley  as  Coordinator  of  the  Council, 
and  in  September  1971,  Dr.  Allen  T.  Dittmann  replaced  Dr.  Winfield  Scott 
as  Deputy  EEO  Officer.   Dr.  Scott,  at  his  request,  returned  to  the  research 
which  too  often  had  had  to  take  a  lower  priority.   He  did  a  fine  job  as 
Deputy  EEO  Officer,  for  which  we  are  all  grateful. 

As  during  the  first  year  of  the  program,  an  important  contribution  has  been 
made  by  the  EEO  Counselors.   Serving  in  this  post  this  year  have  been 
Mrs.  Arliene  M.  Aikens  and  Mr.  James  Boone,  for  the  second  year,  and 
Mrs.  Gwendolyn  K.  Bookman.   We  have  continued  to  have  the  valuable  counsel 
of  Dr.  Marian  R.  Yarrow  as  Coordinator  of  the  Federal  Women's  Program.   A 
new  appointee  is  Mrs.  Doris  Droke  as  EEO  Investigator. 

In  October  1971,  a  progress  report  for  the  first  year  of  the  EEO  program 
was  distributed  to  all  hands.   It  revealed  some  gains  and  some  problems. 
My  own  one-line  summary  of  the  report  was  that  it  showed  reasonable  progress 
under  the  rather  difficult  circumstances  of  that  year.   During  the  current 
year  we  have  developed,  at  the  recommendation  of  the  EEO  Council,  a  nev? 
procedure  for  recruiting  minority  candidates  for  vacant  positions.   It  looks 
promising,  but  we  will  examine  its  usefulness  at  the  end  of  the  year. 

While  on  the  subject  of  personnel,  I  would  like  to  note  with  pleasure  the 
establishment  of  a  personnel  office  in  Building  36  to  serve  the  Intramural 
Program.   It  is  actually  a  satellite  of  the  Parklawn  Personnel  Office,  made 
possible  by  authority  and  one  budgeted  position  from  tliat  office,  and  by 
3  additional  positions  contributed  from  the  diminished  store  of  the  NIMH 
Intramural  Research  Program.   I  regret  the  necessity  for  using  almost 
irreplaceable  research  resources  to  staff  the  personnel  office,  but  the 
function  is  so  important  to  our  operation  that  I  saw  no  other  recourse, 
given  the  unfortunate  decision  on  assignments  of  personnel  staff.   We  are 
greatly  indebted  to  Mrs.  Margaret  Braymer,  Personnel  Officer  for  the 
satellite  office,  for  her  strenuous  and  successful  efforts  to  provide  good 
personnel  seirvice  under  difficult  conditions  and  with  woefully  inadequate 
staff  support. 


Two  members  of  our  senior  staff  were  on  foreign  work  assignments  in  Italy 
this  year.   Dr.  Howard  Moss,  Chief  of  the  Section  on  Parent-Infant  Behavior 
of  the  Child  Research  Branch,  was  stationed  in  Florence  at  the  Harvard- 
Florence  longitudinal  development  project,  continuing  his  studies  of 
behavior.   Dr.  Giulio  Cantoni,  Chief  of  the  Laboratory  of  General  and 
Comparative  Biochemistry,  divided  his  time  between  Rome  and  Milan,  carrying 
out  research  on  gene  action  and  differentiation  in  eukaryotic  cells. 

The  Board  of  Scientific  Counselors  met  twice  this  year,  on  October  29-30, 

1971,  and  on  March  24-25,  1972.   The  fall  meeting  was  devoted  to  a  review 
of  the  research  program  of  the  Adult  Psychiatry  Branch,  in  part  because 
the  Branch  had  not  been  reviewed  for  several  years,  and  in  part  because 
Dr.  Lyman  Wynne,  Chief  of  the  Branch,  had  resigned  effective  June  30,  1972. 
In  making  plans  for  the  future  of  the  Branch  we  wanted  the  advice  of  the 
Board,  based  on  a  comprehensive  review  and  evaluation  of  the  current 
program.   Present  for  the  fall  meeting  were  all  members  of  the  Board — 
Drs.  Eugene  Bliss,  Melvin  Calvin,  Walle  Nauta,  Robert  Stubblefield,  and 
Richard  Solomon,  Chairman,  plus  Dr.  Douglas  Bond,  former  Chairman  of  the 
Board,  as  a  specially  invited  guest.   At  the  spring  meeting,  the  two  days 
were  spent  reviewing  three  laboratories  in  the  Division  of  Biological  and 
Biochemical  Research:   the  Laboratories  of  Neurophysiology,  Neurobiology, 
and  Cerebral  Metabolism.   Because  of  competing  obligations,  Drs.  Calvin 
and  Stubblefield  were  unable  to  attend  that  meeting. 

I  would  like  to  express  my  own  thanks  and  appreciation,  and  that  of  the 
rest  of  the  Intramural  staff,  to  Dr.  Bond  and  Dr.  Theodore  Ruch ,  whose  terms 
on  the  Board  expired  June  30,  1971,  and  to  Dr.  Melvin  Calvin,  whose  term 
expired  June  30,  1972.   They  have  been  of  major  help  in  a  sometimes  difficult 
role,  and  we  are  much  indebted  to  them. 

I  have  mentioned  that  Dr.  Wynne  will  soon  be  leaving  for  the  University  of 
Rochester  to  become  Chairman  of  the  Department  of  Psychiatry.   Also  going 
to  Rochester  will  be  Dr.  John  Strauss.   They  will  both  be  very  much  missed. 
Dr.  Wynne's  distinguished  contributions  have  been  commented  on  by  Dr.  Cohen. 
Early  this  year.  Dr.  William  Bunney  was  appointed  Director  of  the  Division 
of  Narcotic  Addiction  and  Drug  Abuse,  and  has  had  to  give  up  most  of  his 
research  in  the  Laboratory  of  Clinical  Science.   It  is  hoped  that  in  due 
course  he  will  rejoin  the  Intramural  Program.   Dr.  Morris  Parloff  has  spent 
the  year  in  the  Division  of  Extramural  Research  Programs  as  Acting  Chief, 
Psychotherapy  and  Behavioral  Intervention  Section,  Clinical  Research  Branch, 
and  will  become  a  permanent  part  of  that  staff  on  July  1,  1972.   Our  loss 
is  clearly  the  extramural  program's  gain  in  this  transfer.   Finally,  we 
were  all  saddened  by  the  untimely  death  of  Dr.  William  Caudill  on  March  24, 

1972.  He  had  been  a  valuable  member  of  the  Laboratory  of  Socio-environmental 
Studies  since  1960,  and  cannot  really  be  replaced. 


Annual  Report  of  the 

Director,  Division  of  Clinical  and  Behavioral  Research 

National  Institute  of  Mental  Health 

July  1,  1971  -  June  30,  1972 
Robert  A.  Cohen,  M.D. ,  Ph.D. 

As  I  write  this  report  it  is  19%  years  since  I  assumed  my  present  duties 
and  began  the  recruitment  of  our  professional  staff,  and  almost  19  years 
since  we  admitted  our  first  patients  to  the  Clinical  Center.   The  date  of 
my  own  retirement  is  approaching;  perhaps  it  is  not  unnatural  to  find  one's 
thoughts  turning  back  to  early  program  decisions  and  reflecting  upon  them 
in  the  light  of  current  developments  and  of  the  problems  we  face  today. 

Of  the  original  group  of  six  laboratory  chiefs  who  finally  assembled  fifteen 
years  ago,  only  one  remains  in  Bethesda--David  Shakow--who,  although  offi- 
cially retired,  continues  as  creative  and  highly  productive  as  ever.   The 
other  five--Drs.  John  Clausen,  Joel  Elkes,  David  Hamburg,  Seymour  Kety  and 
Fritz  Redl--have  greatly  influenced  developments  in  the  behavioral  and  life 
sciences,  and  hold  distinguished  chairs  in  their  respective  fields.   In 
July,  the  first  of  our  second  generation  of  laboratory  chiefs.  Dr.  Lyman 
Wynne,  will  be  leaving  to  become  Professor  and  Chairman  of  the  Department 
of  Psychiatry  at  the  University  of  Rochester.   In  naming  his  successor,  we 
are  faced  with  the  responsibility  of  deciding  whether  to  maintain  current 
studies  essentially  unchanged  or  to  shift  emphases  somewhat  in  accordance 
with  our  best  judgment  as  to  possible  seminal  developments  in  behavioral 
research. 

From  the  standpoint  of  the  Intramural  Research  Program,  the  recent  decision 
of  the  Director  of  the  National  Institute  of  Mental  Health  to  set  up  a  task 
force  to  review  the  Institute's  entire  research  program,  to  evaluate  its 
achievements  to  date,  and  to  make  recommendations  for  the  future  is  both 
timely  and  welcome.   The  present  program  of  this  Division  was  conceived  in 
general  outline  when  the  budget  of  the  entire  Institute  was  12  million  dol- 
lars.  We  have  long  since  gone  far  beyond  the  horizon  which  19  years  ago 
was  dimly  perceived  and  seemed  light  years  away.   There  are  more  psychia- 
trists in  residency  training  today  than  were  members  of  the  American 
Psychiatric  Association  then,  and  each  year  sees  literally  thousands  of 
trained  mental  health  workers  joining  our  ranks.   Although  we  were  aware 
in  those  days  of  many  of  the  problems  which  are  of  vital  concern  to  the 
Institute  today,  there  was  no  expectation  that  we  would  live  long  enough  to 
be  given  the  responsibility  and  some  of  the  resources  required  to  cope  with 
them. 

In  the  early  days  of  the  program,  we  decided  that  intramural  research  funds 
could  be  most  productively  employed  in  the  development  of  a  basic  research 
program  which  would  attempt  to  define  the  nature  and  timing  of  the  exper- 
iences which  shaped  behavior,  and  the  biological  processes  which  mediated 
it.   Such  knowledge  is  obviously  indispensible  for  the  development  of  a 
rational  therapy,  and  hopefully  might  have  implications  as  well  for  pro- 
grams designed  to  promote  the  optimal  growth  and  development  of  the  person. 


Even  though  the  greatest  strength  of  the  Clinical  Center  lay  in  its  re- 
sources for  the  study  of  biological  processes  in  which  each  of  the  seven 
original  institutes  proposed  to  engage,  we  included  in  our  program  a  com- 
mitment to  the  study  of  the  social  and  behavioral  sciences  as  well.   These 
have  obvious  relevance  for  the  study  and  treatment  of  mental  disorders, 
and  even  though  the  groups  concerned  in  such  studies  would  be  relatively 
more  isolated  in  this  hotbed  of  biology,  there  were  still  certain  freedoms 
and  supports  built  into  the  setting  which  afforded  them  a  unique  opportunity 
to  engage  in  studies  which  could  not  be  carried  out  in  the  average 
psychiatric  hospital  or  university  department. 


I 


As  one  looks  back  one  sees  that,  as  was  to  be  expected,  some  of  our  investi- 
gations have  been  outstandingly  successful  in  that  they  have  added  signifi- 
cant new  knowledge  and  have  opened  important  areas  for  further  study;  others 
are  distributed  along  a  scale  at  the  end  of  which  lie  the  negative  results 
which  constitute  the  necessary  and  important  but  nevertheless  frustrating 
and  disappointing  burden  of  everyone  who  undertakes  a  career  in  research. 
Each  of  the  laboratories  and  branches  has  made  contributions  which  have 
brought  it  distinction,  and  have  cast  a  reflected  glow  on  the  Institute  as 
a  whole.   As  measured  by  the  honors  conferred  by  their  scientific  colleagues, 
our  staff  members  can  justifiably  consider  that  they  have  made  good  use  of 
the  resources  placed  at  their  disposal  and  can  take  great  pride  in  their 
achievements.   Even  though  these  honors  and  awards  have  been  distributed 
throughout  the  program,  it  does  seem  to  me  that  the  most  dramatic  progress 
has  been  made  in  the  biological  area.   The  growth  of  knowledge  in  physiology, 
biochemistry,  pharmacology  and  molecular  biology  has  been  literally  spectac- 
ular.  That  degree  of  control  over  human  behavior  which  Huxley  depicted  in 
Brave  New  World  though  still  distant  can  no  longer  be  considered  only  a 
horror  story  created  by  a  brilliant,  imaginative  novelist.   Hopefully  we 
shall  be  able  to  make  more  constructive  use  of  our  increasing  knowledge. 
We  must  seriously  consider  the  advisability  of  rechanneling  our  limited 
resources  to  augment  our  studies  in  those  areas  where  progress  is  so  rapid 
and  the  probable  payoff  appears  relatively  imminent. 

In  a  sense,  the  present  dilemma  was  to  be  expected.   Science  does  not 
advance  equally  rapidly  on  all  fronts,  nor  are  the  problems  facing  each 
discipline  of  equal  complexity.   Biology  in  general  was  far  enough  along 
both  conceptually  and  in  terms  of  sophisticated  methodologies  that  the 
really  impressive  progress  which  has  been  made  might  have  been  predicted. 
Nevertheless  if,  as  we  think,  there  is  merit  to  providing  optimal  condi- 
tions for  research  for  a  critical  mass  of  dedicated  investigators,  then 
we  must  conclude  that  the  Clinical  Center  was  so  organized  as  to  support 
very  strongly  the  biological  studies  while  offering  comparatively  less 
ideal  resources  for  investigating  the  socio-psychological  aspects  of 
behavior.   In  my  opinion,  the  Institute's  research  task  force  should  con- 
sider the  possible  advantages  of  providing  another  research  setting  which 
would  offer  the  social  and  behavioral  sciences  the  remarkable  and  still 
unique  assets  the  Clinical  Center  affords  biology.   Until  we  can  develop 
a  truly  comprehensive  knowledge  of  both  the  psychology  and  physiology  of 
behavior  we  shall  not  achieve  our  goal.   In  another  connection  I  quoted  a 
statement  by  David  Stafford-Clark  which  is  appropriate  here.   In  his  1959 


Mental  Health  Research  Fund  Lecture  he  described  several  exciting  biological 
advances  and  then  went  on  to  say: 

"We  must  never  forget  that  communication  remains  the  ultimate 
key  to  the  treatment  of  schizophrenia. .. .However  skillful 
and  appropriate  our  physical  treatment. . .may  become  as  a 
result  of  refinement  in  our  knowledge  and  understanding  both 
of  the  biochemical  processes  which  may  underlie  it  and  the 
electrophysical  processes  whose  secondary  disturbance  ultim- 
ately brings  about  the  illness,  it  remains  true  that  we  can 
treat  patients  successfully  and  restore  them  to  true  health 
and  happiness  only  if  we  can  gain  contact  with  them  at  a 
human  and  personal  level,  and  give  them  thereby  the  bridge 
over  which  they  may  cross  back  to  normal  harmony  and  under- 
standing with  their  fellows." 


s4^ 


I 


ANNUAL  REPORT  OF  THE  ADULT  PSYCHIATRY  BRANCH 

National  Institute  of  Mental  Health 

July  1,  1971  -  June  30,  1972 

Helm  Stierlin,  M.D.,  Ph.D.,  Acting  Chief 

In  the  preceding  fiscal  year,  Dr.  Lyman  C.  Wynne,  the  long-time  chief  of  the 
Adult  Psychiatry  Branch,  had  decided  to  leave  NIMH  in  order  to  become  Chair- 
man of  the  Department  of  Psychiatry  at  the  University  of  Rochester,  New  York. 
Although  he  planned  to  continue  his  research  work  in  the  Office  of  the  Chief 
until  July  1,  1972  -  the  date  set  for  the  beginning  of  his  work  in  Rochester  - 
he  resigned  as  Branch  Chief.   Dr.  Helm  Stierlin  was  subsequently  appointed 
Acting  Chief  of  the  Branch. 

Dr.  Wynne's  decision  affected  the  Branch  on  many  levels:   The  Branch  lost  the 
leadership  and  stimulation  he  has  given  it  for  many  years  and,  its  bearings 
suddenly  loosened,  veered  toward  an  uncertain  future.   Unfortunately,  this 
happened  at  a  time  when  resources  were  shrinking  and  government  agencies  had 
to  achieve  a  grade  roll-back  and  reduction  in  work  force.   The  existing  un- 
certainties and  concerns  about  the  Branch's  future  were  thus  magnified.   More- 
over, the  impending  departure  of  two  of  the  Branch's  outstanding  researchers, 
Drs.  John  Strauss  and  William  Pollin,  was  recently  announced.   Dr.  Strauss  is 
scheduled  to  follow  Dr.  Wynne  to  Rochester  in  August,  and  Dr.  Pollin  will  move 
to  the  Parklawn  Building  as  newly-appointed  Area  Chief  in  the  NIMH  Task  Force. 
(However,  at  this  point  it  appears  that  Dr.  Pollin  will  keep  his  section  within 
the  Intramural  Research  Programs  and,  hopefully,  will  return  to  the  Adult  Psy- 
chiatry Branch  after  a  period  of  twelve  to  eighteen  months.) 

It  attests  the  vitality  of  the  Branch  that,  despite  these  pending  losses  and 
uncertainties,  a  vigorous  research  program  could  be  continued  and  expanded. 
A  great  variety  of  -  mostly  cooperative  -  research  projects  were  carried  out 
and  substantial  findings  made,  which  have  been  published  or  accepted  for  pub- 
lication in  numerous  journals  and  books. 

Three  major  features  have  characterized  the  research  in  the  Adult  Psychiatry 
Branch  during  the  last  year: 

First,  an  ongoing,  special  effort  to  integrate  clinical  and  experimental  re- 
search on  various  levels.   This  integrated  research  drew  on  the  patient  popula- 
tion of  two  wards,  an  outpatient  service  and  various  community  resources, 
including  normal  volunteers.   Complementing  its  research  efforts,  the  Branch 
offered  several  therapeutic  programs  that  provided  a  needed  community  service 
and  served  as  models  for  therapeutic  efforts  elsewhere. 

Second,  while  wide-ranging  clinical  and  experimental  research  was  carried  out, 
conceptual  frames  of  reference  were  employed  and  developed  that  increasingly 
allowed  to  link  crucial  bio-physiological  to  behavioral  and  sociocultural  view- 
points and  variables.   Psychodynamic  perspectives  continued  to  hold  here  a 
central  place. 


Finally,  the  research  at  the  Branch  attempted  to  reconcile  a  dispassioned 
empxrical  stance  toward  facts  with  a  sensitivity  to  the  truly  relevant  social 
and  mental  health  issues  of  our  times. 

The  organizational  structure  of  the  Branch,  presently  blurred  by  the  above- 
mentioned  changes  and  uncertainties,  reflects  three  major,  overlapping  re- 
search foci: 

First,  studies  in  schizophrenia,  conducted  chiefly  by  Dr.  Wynne,  by  Drs.  Strauss 
and  Carpenter  (Psychiatric  Assessment  Section),  and  by  Dr.  Pollin  (Section  on 
Twin  and  Siblxng  Studies)  and  their  associates. 

Second,  clinical  and  experimental  studies  which  primarily  involve  the  family 
They  are  carried  out  by  Dr.  Stierlin  (Unit  on  Longitudinal  Studies,  Office  of 
the  Chief),  Drs.  Roger  Shapiro  and  John  Zinner  (Section  on  Adolescence  and  the 
Family),  Dr.  David  Reiss  (Section  on  Experimental  Group  and  Family  Studies) 
and  Dr.  Winfield  Scott  (Section  on  Clinical  Psychology),  and  their  associates. 

Third,  cognitive  and  perceptual  studies,  as  carried  out  by  Dr.  Monte  Buchsbaum 
and  hxs  associates  (Section  on  Perceptual  and  Cognitive  Studies) . 

A  brief  description  of  the  major  research  projects  follows. 

OFFICE  OF  THE  CHIEF 

Unit  on  Longitudinal  Studies 

Dr.  Helm  Stierlin 

Dr.  Stierlin's  Longitudinal  Project  on  Separation  in  Adolescence,  carried  out 
in  cooperation  with  Drs.  Robert  Savard,  Kent  Ravenscroft,  Jr.,  and  others,  has 
reached  its  crucial  follow-up  stage.   Increasing  numbers  of  adolescents  and 
their  families  have  participated  in  this  project  over  the  last  five  years.   The 
adolescents  -  high  risks  for  schizophrenia  and  other  serious  psychopathology  - 
were  referred  to  as  "underachievers"  and,  together  with  their  families,  were 
seen  for  a  minimum  of  three  months  in  conjoint  therapy.   During  the  last  two 
years  most  of  these  adolescents  were  hospitalized  on  3-West  while  their  families 
were  seen  in  outpatient  family  and  couple  therapy.   In  addition  to  participat- 
ing m  therapy,  the  family  members  were  individually  interviewed  and  compre- 
hensively tested   Detailed  predictions  were  made  after  the  initial  screening 
session  and  at  the  end  of  the  therapy.   These  predictions  are  to  be  checked  out 
by  tollow-up  interviews  which  have  been  or  are  taking  place. 

Although  many  crucial  observations  and  data  from  this  project  have  not  yet  been 
obtained  or  analyzed,  some  interesting  findings  have  emerged.   Perhaps  most  im-  t 
portantly,  the  project  has  already  yielded  a  conceptual  framework  which  promises  " 
a  much  more  detailed,  as  well  as  more  comprehensive,  understanding  of  the  adoles- 
cent separation  process  than  seemed  possible  before.  Within  this  framework 
parents  and  adolescent  children  are  viewed  as  contributing  to  dynamic  and  complex 
transactions  that  reflect  their  interweaving  developmental  tasks  and  life  crises. 
Depending  on  how  these  tasks  and  crises  shape  up,  are  resolved,  or  remain  aborted, 
certain  typical  separation  patterns  develop  which  have  been  called  centripetal,   ' 
centrifugal,  and  intermediate.  Where  a  centripetal  pattern  prevails,  a  charac-  ( 
teristic  binding  transactional  mode  is  found  to  operate.   Where  a  centrifugal 

10 


pattern  doFxinates,  an  expelling  mode  is  usually  observed.   Intermediate  pat- 
terns tend  to  reflect  a  predominately  delegating  mode.   Here  we  find  parents 
who  -  overtly  or  covertly  -  send  their  children  out  and  simultaneously  hold 
them  back.   (The  Latin  word  "delegare"  contains  these  two  meanings.)   While 
delegating  their  children,  the  parents  expect  them  to  execute  certain  mis- 
sions -  such  as  the  mission  to  vicariously  live  out  the  parents'  own  unlived 
adolescence  or  the  mission  to  launch  protests  against  the  Establishment.   In- 
evitably, such  parents  burden  their  adolescents  with  their  own  unrealized 
expectations  and  their  (the  parents')  disowned  conflicts  and  ambivalences. 

The  various  theoretical  and  clinical  implications  of  this  point  of  view  were 
developed  in  six  papers  which  have  either  been  published  or  accepted  for  pub- 
lication.  The  family  dynamics  of  different  types  of  adolescent  runaways  and 
parental  perceptions  of  separating  children,  among  other  topics,  were  elabo- 
rated.  In  addition,  typical  constellations  of  adolescent  separation  conflicts, 
the  interconnections  between  peer  relations  and  the  above  transactional  modes, 
the  interpersonal  dynamics  of  internalizations  (such  as  incorporation,  intro- 
jection  and  identification),  the  interweaving  life  crises  of  fathers  and  sons, 
and  the  family  dynamics  and  separation  patterns  of  preschizophrenic  adoles- 
cents were  newly  conceptualized  and  clinically  illustrated.   Also,  the  con- 
cepts of  psychological  exploitation  and  liberation,  the  main  themes  of  one  of 
Dr.  Stierlin's  forthcoming  books,  were  further  developed. 

UNIT  ON  ART  THERAPY 


The  Systematic  Study  of  Family  Art  Evaluations  was  conducted  by  Dr.  James  Dent 
and  Mrs.  Hana  Y.  Kwiatkowska.   Utilizing  factor  analyses,  the  investigators 
have  now  defined  the  chief  dimensions  of  the  art  productions  and  their  rela- 
tions to  such  characteristics  of  the  subject  as  his  intelligence  and  his 
artistic  talent. 

Family  Art  Evaluations  were  conducted  with  adolescents  and  their  families  on 
the  3-West  Unit.   Last  year  the  focus  of  the  study  had  shifted  from  schizo- 
phrenic subjects  to  patients  with  nonpsychotic  problems  such  as  delinquency, 
drug  abuse,  and  truancy.   This  year  the  separation  issue  became  the  central 
point  of  observation.   The  adolescents  and  their  parents  revealed  their  ambi- 
valence over  separation  in  the  realistic  and  abstract  family  portraits  they 
were  required  to  draw.   The  adolescents  either  pictured  themselves  outside  of 
the  family  group  but  still  somehow  clinging  to  it,  or  sought  escape  in  fanta- 
sies.  The  opposite  was  observed  in  the  parents:   Their  pictures  showed  a 
tendency  to  keep  the  family  world  encircled  in  a  pretended  happiness,  and  only 
hinted  at  a  scapegoating  of  the  index  patient. 

As  a  result  of  this  Unit's  work,  the  interest  in  family  art  techniques  has 
spread  in  the  United  States  and  abroad  and  a  graduate  course  in  Family  Art 
Techniques,  leading  to  a  Master's  Degree,  is  being  offered  at  the  Graduate 
School  of  Arts  and  Sciences  of  the  George  Washington  University  in  conjunction 
with  the  Washington  School  of  Psychiatry  and  is  taught  by  Mrs.  Kwiatkowska. 
Two  exhibits  of  Family  Art  Therapy  and  Individual  Art  Therapy  were  presented 
by  invitation  at  the  Fifth  World  Congress  of  Psychiatry  in  Mexico  City  in 
December  1971. 


11 


PSYCHIATRIC  ASSESSMENT  SECTION 

The  Psychiatric  Assessment  Section  under  Dr.  John  Strauss,  Chief,  with 
Dr.  William  Carpenter,  Chief,  Clinical  Research  Unit  has  continued  to  develop 
diagnostic  concepts  and  categories  that  will  more  meaningfully  relate  to 
etiology,  course  of  illness,  and  response  to  treatment,  than  diagnostic 
systems  currently  in  use.   It  has  employed  standardized  clinical  assessment 
techniques,  alternative  diagnostic  models,  cross-cultural  comparisons  of 
psychiatric  syndromes,  and  measures  of  course  of  illness.   The  following 
were  major  foci  of  research: 

I.  International  Pilot  Study  of  Schizophrenia; 

The  Section  has  served  as  the  United  States  Field  Center  in  the  International 
Pilot  Study  of  Schizophrenia  (IPSS)  sponsored  by  the  World  Health  Organiza- 
tion to  develop  cross-culturally  applicable  interview  schedules  for  the 
evaluation  of  psychiatric  patients  in  different  countries.   These  schedules 
were  intended  to  facilitate  future  studies  of  the  comparative  epidemiology 
and  the  interplay  of  cultural  and  biological  factors  in  psychiatric  disorders. 
The  schedules  were  written,  pretested,  revised  and  retested  until  they  were 
suitable  for  use  in  all  nine  participating  countries. 

So  far,  1,202  patients  in  the  participating  countries  have  been  interviewed 
and  have  been  followed  up  after  two  years.   The  information  thus  obtained 
will  permit  to  compare  the  course  of  illness  of  patients  with  different  S3nnp- 
toms  and  different  forms  of  treatment  in  culturally  diverse  countries. 

The  data  from  the  initial  evaluations  have  been  incorporated  into  the  final 
draft  of  Volume  I  of  the  report  of  the  IPSS  soon  to  be  published.   Data 
analyses  of  the  follow-up  interviews  has  been  started  and  Volume  II  of  the 
report  is  being  drafted. 

II.  Methodology  for  Analyzing  Data  for  Psychiatric  Diagnosis; 

Together  with  Dr.  John  Bartko  of  the  Theoretical  Statistics  and  Mathematics 
Group,  Drs.  Strauss  and  Carpenter  have  evaluated  and  adapted  clustering 
techniques  for  defining  types  of  psychiatric  patients.   Such  clustering 
techniques  are  only  minimally  subject  to  theoretical  bias,  and  let  the  data 
itself  define  the  "natural  groups"  that  constitute  a  patient  population. 
When  applied  to  the  IPSS  patients  cluster  analytic  techniques  have  revealed 
interesting  groupings.   In  particular  they  suggest  alternative  subgroupings 
of  schizophrenic  patients.   Affective  psychoses  are  readily  identified  by 
cluster  analysis  and  this  approach  supports  therefore  the  diagnostic  concept 
of  a  schizo-affective  schizophrenia  category. 

III.  Comparative  Study  of  Diagnostic  Systems; 

Different  diagnostic  systems  have  been  evaluated  using  past  psychiatric 
history  and  follow-up  status  as  criteria  for  the  validity  of  diagnostic  types. 
At  first,  four  diagnostic  systems  were  investigated;   (1)  clinical  diagnoses 
using  the  APA  Diagnostic  Manual;  (2)  computer  derived  clinical  diagnoses 

12 


developed  by  J.  K.  Wing  in  London;  (3)  Lorr's  Psychotic  Types  based  on  the 
In-patient  Multidimensional  Psychiatric  Scale;  and  (4)  clusters  of  psychiatric 
patients  developed  from  the  cluster  techniques  described  in  the  preceding 
paragraph.   Results  indicated  that  none  of  the  four  diagnostic  systems  were 
able  to  predict  significantly  two-year  follow-up  status  or  to  postdict  earlier 
psychiatric  history.   On  the  other  hand,  multiple  regression  techniques 
demonstrated  that  prognostic  items  correlate  highly  with  follow-up  status. 

To  further  evaluate  other  diagnostic  systems,  the  criteria  of  schizophrenia 
by  Kurt  Schneider  were  used  to  classify  American  IPSS  patients  and  NIMH 
manic-depressive  patients.   This  first  empirical  test  of  Schneider's  diagnos- 
tic system,  which  is  accepted  throughout  most  of  the  world,  refuted  his  claim 
for  pathognomonic  symptoms  in  schizophrenia.   This  finding  has  now  been 
replicated  using  data  from  each  of  the  eight  other  countries  participating 
in  the  IPSS.   Similarly,  the  value  of  Langfeldt's  widely  used  concept  of 
schizophrenia  has  been  challenged  through  the  use  of  IPSS  data. 

These  and  other  findings  suggest  that  new  concepts  of  schizophrenia  must  be 
considered.   A  dimensional  concept  of  schizophrenia  appears  to  be  more  valid 
than  a  typological  notion. 

IV.   Miscellaneous  Studies; 

In  July  1971  the  Psychiatric  Assessment  Section  assumed  administration  of  a 
clinical  ward  for  acute  psychotic  patients.   Standardized  clinical  instruments 
were  developed  to  provide  a  coordinated  system  for  evaluating  patient  symp- 
tomatology and  behavior.   A  shortened  form  of  the  Present  State  Examination 
originally  used  for  the  IPSS,  a  daily  nurses  rating  scale,  and  a  modification 
of  the  Katz  Adjustment  Scale  were  used  to  provide  comparable  data  on  patients 
from  three  different  sources  of  information.   Scales  were  also  developed  to 
evaluate  more  global  aspects  of  psychopathology.   These  scales  collectively 
provided  a  reliable  and  comprehensive  source  of  information  about  clinical 
characteristics  of  patients.   As  part  of  these  evaluations.  Dr.  Michael  Sacks 
compared  the  one-hour  evaluation  interviews  with  the  entire  data  collection 
of  the  first  three  weeks  of  the  admission  period  to  determine  the  strength 
and  weaknesses  of  the  single  research  interview  which  is  now  being  so  widely 
used.   Initial  findings  suggest  that,  while  information  from  both  the  research 
interview  and  the  larger  source  of  data  often  result  in  the  same  diagnosis 
being  given  to  a  patient,  certain  aspects  of  the  evaluation  interview  appear 
to  be  inadequate  for  indepth  clinical  studies.   The  reliability  study  of  the 
nurses  rating  scale,  variability  in  different  nursing  shifts,  and  contrasts 
in  nurses'  and  doctors'  observations  have  been  evaluated  by  Dr.  Bernard  Frankel. 

In  a  continuing  attempt  to  validate  different  snydromes  and  diagnostic  types, 
the  clinical  characteristics  of  the  patients  on  the  research  ward  were  com- 
pared to  several  biological,  psychophysiological,  and  psychological  variables. 
Leukocyte  abnormalities,  claimed  to  discriminate  between  normal,  neurotic  and 
psychotic  patients  by  investigators  from  Prague,  were  evaluated  in  an  attempt 
to  replicate  this  work,  and  to  determine  more  precisely  what  symptom  patterns 
relate  to  leukocyte  abnormalities.   Steroid  assays  were  conducted  by 


13 


Dr.  Laurence  Drell,  to  understand  the  relationship  between  patient  symptoma- 
tology, classification,  steroid  changes,  and  patient  outcome. 

Harriet  Wadeson,  an  art  therapist  in  the  Section, evaluated  the  relationship 
between  art  productions,  symptom  types  and  course  of  illness.   Dr.  Michael 
Sacks  devised  a  creative  method  for  evaluating  a  patient's  course  of  illness 
in  terms  of  his  ability  to  participate  in  research. 

Collaborative  studies  were  carried  out  with  other  investigators  in  the  Intra- 
mural Program.   Relationships  between  clinical  characteristics  and  psycho- 
physiologica].  function  were  studied  in  conjunction  with  Dr.  Buchsbaum  in  the 
Perceptual  and  Cognitive  Section,  Dr.  Zahn  in  the  Laboratory  of  Psychology, 
Dr.  Redford  Williams  of  the  Laboratory  of  Psychobiology ,  and  Dr.  Carmi 
Schooler  in  the  Socio-environmental  Laboratory.   The  relationships  between 
clinical  characteristics  and  psychological  test  data  were  studied  in  conjunc- 
tion with  Dr.  Winfield  Scott  of  the  Section  on  Psychology,  APB.   In  a  collab- 
orative study  with  Dr.  Herbert  Meltzer  of  the  Illinois  State  Psychiatric 
Institute,  the  relationship  between  abnormal  enzyme  levels  and  clinical 
states  was  investigated  by  using  both  the  evaluation  procedure  developed  in 
the  Psychiatric  Assessment  Section,  and  serum  enzyme  levels  to  be  evaluated 
by  Dr.  Meltzer  at  ISPI.   Similarly,  the  PAS  collaborated  with  Dr.  Harold 
Himwich  in  investigating  the  transmethylation  hypothesis  in  carefully  evalu- 
ated clinical  groups. 

SECTION  ON  TWIN  &  SIBLING  STUDIES 


Despite  unprecedented  administrative  and  staff  problems,  which  imposed  con- 
siderable obstacles  on  research  activities,  the  Section's  work  has  proceeded 
in  two  major  areas  of  continuing  study  -  a)  pathogenesis  of  schizophrenia, 
and  b)  personality  development. 

A  stress  model  of  schizophrenia  pathogenesis  has  been  conceptualized,  and 
after  presentation  at  a  number  of  meetings,  is  now  in  press.   Unlike  the 
weak  ego  boundary  construct,  which  has  been  the  most  widely-used  concept  in 
clinical  and  dynamic  schizophrenia  research,  in  recent  decades,  but  was 
found  by  us  to  be  unsupported  by  empiric  findings,  this  new  model  is  consistent 
with  and  able  to  integrate  a  wide  body  of  data  ranging  from  the  genetic, 
through  the  biochem.ical  and  experiential,  to  sociological  levels  of  organiza- 
tion.  For  each  step  in  the  following  sequence,  hypotheses  based  on  empiri- 
cally-obtained data  have  been  defined,  describing  what  change  or  deviation 
predisposes  to  schizophrenia.   The  sequence  encompasses  a)  an  external  event, 
the  potential  stressor;  b)  the  stressor's  psychological  meaning  and  signal 
(which  is  based  on  (1)  previous  experience,  (2)  role  within  the  family  and 
psychological  characteristics  of  the  family  unit,  and  (3)  role  within  the 
social  structure) ;  and  c)  the  resultant  biochemical  and  physiologic  response 
on  the  cellular  and  organ  level,  (their  extent,  and  possible  qualitative 
abnormality  determined  by  (1)  genetically  controlled  levels  of  enzyme 
activity,  and  by  (2)  changes  in  enzyme  levels  induced  by  previous  experience.) 


14 


Planning  for  a  replication  of  previous  work,  using  a  new  co-twin  comparison 
study  design,  is  far  advanced,  and  extensive  nationwide  screening  for 
specialized  subject  groups  has  been  carried  out.   Arrangements  have  been 
made  for  collaboration  with  Dr.  Harold  Himwich  at  Galesburg  to  determine 
the  presence  or  absence  of  psychotomimetic  dimethylated  indolamine  deriva- 
tives; with  Dr.  Richard  Wyatt,  to  determine  the  presence  or  absence,  and 
possible  genetic  control,  of  the  enzjrme  (NN-nonspecif ic  methyl  transferase) 
which  is  capable  of  forming  DMT,  the  most  significant  of  these  psychotomimetic 
amines;  and  with  Dr.  Axelrod  and  a  number  of  his  collaborators,  to  measure 
other  enzymes  involved  in  catecholamine  metalolism. 

An  extensive  review  of  methionine  studies,  beginning  with  the  initial  one 
reported  from  here  ten  years  ago  by  Pollin,  Cardon  and  Kety,  has  been  completed 
by  Drs.  S.  Cohen,  Pollin,  Wyatt  and  Mrs.  A.  Nichols.   The  administration  of 
very  high  doses  of  methionine,  usually  with  MAO  inhibitor,  to  chronic  schizo- 
phrenic patinets,  are  attempts  to  test  the  hypotheses  that  disorders  in 
biogenic  amine  metabolism,  specifically  disturbances  in  methylation,  with  the 
possible  production  of  psychotomimetic  di-methylated  compounds,  are  involved 
in  the  pathogenesis  of  schizophrenia.   The  clinical  phenomenon  of  exacerba- 
tion of  psychosis  in  schizophrenic  patients  on  large  doses  of  methionine  has 
been  confirmed  by  nine  subsequent  investigators  and  as  pointed  out  by 
Matthysse  and  Baldessarini  in  their  just-published  study,  "is  unique  among 
biochemical  findings  in  schizophrenia  in  that  it  has  been  confirmed  by  several 
groups  and  to  date  has  been  disproven  by  none."  Our  review  analyzes  the  var- 
iations in  treatment  and  response  in  the  107  patients  thus  far  reported  on, 
and  evaluates  the  possible  determinants  and  significance  of  these  findings. 
The  repeated  confirmations  of  the  original  observation;  plus  new  findings 
and  techniques,  such  as  Wyatt 's  and  Axelrod 's  enzyme  method  in  platelets,  may 
signal  major  findings  in  this  area  in  the  near  future. 

Mrs.  Mae  Leisinger,  working  on  her  Ph.D.  dissertation  under  my  supervision, 
tested  a  series  of  hypotheses  relating  the  schizophrenic  to  family  interaction 
and  pathology.   The  conceptual  frame  of  reference  was  that  shared  unconscious 
pathology  of  the  family  system  generates  interlocking  tensions  which  are 
reduced  and  projected  onto  a  particular  member.   TAT  and  Leary  techniques, 
and  data  from  the  discordant-for-schizophrenia  twin  series,  supplemented  by 
additional  matched  normal  control  families,  were  used  to  quantitatively  test 
self,  ideal  and  other  perception  at  three  different  levels  of  conscious  aware- 
ness.  It  was  found  that  individuals  in  the  schizophrenic  families  unconscious- 
ly perceive  themselves  as  very  similar,  whereas  normal  family  members,  instead, 
portray  themselves  as  different  one  from  the  other  within  the  families,  with 
the  father  particularly  being  perceived  as  exhibiting  a  well  differentiated 
role  identity  (the  "undifferentiated  ego  mass"  previously  described  by  Bowen.) 
Further,  there  is  substantial  evidence,  consistent  with  Laing's  formulations, 
that  the  parents  perceive  the  schizophrenic  in  terms  that  mis-define  him  to 
himself.   In  particular,  the  parental  message  for  the  schizophrenic  is  that 
he  is  passive  and  instrumentally  unable  to  master  his  environment.   These 
observations  are  consistent  with  our  earlier  clinical  observations,  in  the 
discordant  MZ  pairs,  that  the  index  was  rigidly  imprinted  with  a  role  expecta- 
tion of  incompetence  and  dependence.   A  significant  relationship  between  such 


15 


disconfirmation  of  the  index,  and  repression  in  the  parents,  strongly 
suggests  that  this  disconfirmation  is  not  primarily  a  process  secondary  to 
the  illness.   The  higher  the  degree  of  parental  repression,  the  greater  the 
degree  of  parental  disconfirmation  of  the  index  twin.   This  finding  presents 
an  interesting  parallelism  to  the  formulation  of  defensive  delineations 
previously  proposed  by  Roger  Shapiro's  group,  and  suggests  that  the  discon- 
firmation is  in  part  a  process  that  is  meeting  unconscious  psychological 
needs  of  the  parent. 

Two  major  activities  use  the  twin  intrapair  comparative  technique  to  study 
the  determinants  of  early  personality  development.   Dr.  D.  Cohen,  Mrs.  Eleanor 
Dibble,  and  Mrs.  Anna  Nichols  have  been  the  major  workers  in  this  area.   One 
is  the  longitudinal  study  in  which  10  families,  with  sets  of  twins  ranging 
between  four  and  six  years  of  age,  have  been  followed  since  before  birth  by 
a  series  of  home  visits,  and  neurological,  psychiatric  and  psychological 
evaluations.   It  has  defined  a  set  of  interactions  between  constitution, 
family  perception  and  behavior,  and  how  these  fit  into  a  developmental 
sequence.   The  more  competent  newborn,  physiologically  and  behaviorally,  has 
bean  found  to  develop  into  the  more  articulate  and  socially  competent  pre- 
schooler. A  key  component  to  such  development  is  the  better  endowed  child's 
ability  to  be  both  highly  attentive  to  external  stimulation  and  at  the  same 
time  relatively  calm,  based  both  on  endowment  and  intrafamilial  relationship. 
Based  on  this  intensive  study,  and  on  prior  adult  work,  a  new  epidemiologic 
study  has  been  initiated.   Particular  variables  have  been  operationally 
defined,  which  emerged  from  the  clinical  observations,  and  9  newly  devised 
psychological  questionnaries  developed  for  this  purpose.   The  first  100  of 
an  eventual  N  of  600  twin  families  are  now  receiving  their  questionnaires. 

Though  I  will  be  transferred  from  the  Section  for  the  coming  year,  I  hope 
these  programs  will  be  able  to  continue  under  alternative  supervisory  arrange- 
ments. 


16 


SECTION  ON  ADOLESCENCE  AND  THE  FAMILY 

The  research  activities  of  this  section,  under  the  direction  of  Dr.  Roger 
Shapiro  and  John  Zinner,  evolved  around  five  major  foci:   (1)   The  Influence 
of  Family  Interaction  on  Adolescent  Identity  Formation,  (2)  The  Relationship 
of  Family  Interaction  to  Adolescent  Drug  Abuse,  (3)  The  Longitudinal  Assess- 
ment of  Cognition  and  Identity  Formation  in  Early  and  Late  Adolescents, 

(4)  The  Interrelationship  of  Behavioral  and  Physiological  Events  in  the  Family, 

(5)  The  Follow-up  Study  of  Families  Treated  in  the  Study  of  Adolescent  Identity. 
These  investigations  included  observations  made  on  the  individual  normal  or 
disturbed  adolescent  and  on  his  family,  peer  group,  treatment  milieu  or  class- 
room and  community  of  families  of  which  his  is  a  member. 

Emotionally  disturbed  adolescents  were  admitted  as  in-patients  to  a  residen- 
tial treatment  center  in  the  Clinical  Center  where  they  and  their  families 
participated  in  individual,  marital,  conjoint  family  and  multiple  family 
group  therapy.   Normal  adolescents  and  their  families,  in  the  main,  were 
studied  in  the  Clinical  Center,  at  the  Sidwell  Friends  School  in  Washington, 
D.C.  and  in  their  homes.   A  brief  description  of  these  invetigations  follows. 

1.  The  Influence  of  Family  Interaction  on  Adolescent  Identity  Formation 

Many  of  the  investigations  carried  out  in  this  section  were  based  on  the 
intensive  study  of  emotionally  disturbed  adolescents  admitted  to  a  long  term 
intensive  and  comprehensive  treatment  program  on  the  3-West  Nursing  Unit  in 
the  Clinical  Center.   The  range  of  symptoms  and  problems  experienced  by  these 
teenagers  is  representative  of  the  array  of  difficulties  found  among  adoles- 
cents around  the  country,  such  as  drug  abuse,  truancy,  failure  at  school, 
impulsive  behavior,  running  away  and  depression  with  suicidal  attempts.   This 
year  the  treatment  and  research  program  has  been  augmented  by  the  initiation 
of  a  multiple  family  therapy  meeting  held  each  week.   In  this  meeting, 
therapeutic  work  is  done  at  the  interface  between  the  community  of  families 
and  the  treatment  staff  on  3  West,  and  on  the  boundaries  between  the  families 
themselves.   The  multiple  family  meeting  provides  a  major  source  of  data  for 
a  predictive  study  of  factors  that  influence  the  outcome  of  psychiatric  treat- 
ment.  This  investigation  is  being  carried  out  by  Dr.  David  Reiss,  Chief  of 
the  Section  on  Experimental  Group  and  Family  Studies,  and  is  an  application 
of  his  theory  of  consensual  variety  derived  from  the  problem-solving  behavior 
of  families  in  the  laboratory. 

A  major  aim  of  Drs.  Roger  Shapiro  and  John  Zinner  is  to  understand  the  ways 
in  which  family  interaction  facilitates  or  impairs  the  development  of  a  sound 
adolescent  identity.   They  have  found  that  adolescents  may  be  diverted  from 
their  own  maturational  course  by  a  need  to  protect  their  parents  from 
anxieties  arising  from  unresolved  parental  intra-psychic  conflicts.   Papers 
reporting  on  these  findings  have  been  accepted  for  publication. 

2.  The  relationshiop  of  Family  Interaction  to  Adolescent  Drug  Use 

Dr.  Robert  Winer  has  begun  to  investigate  the  use  of  "mind-altering"  drugs 
by  youth,  employing  intensive  semi-structured  interviewing  of  adolescents 

17 


with  and  without  their  families.   Two-thirds  of  the  in-patients  on  3  West 
have  made  extensive  use  of  "street  drugs"  prior  to  their  admission.   In 
exploring  the  motivations  for  their  drug  use  with  these  patients,  Dr.  Winer 
has  found  that  taking  drugs  represents  the  troubled  adolescents'  attempt  to 
resolve  potent  internal  psychological  conflicts.   This  finding  contradicts 
ones  that  view  heavy  drug  usage  as  primarily  socially  determined,  as  for 
example,  by  the  peer  group. 

In  the  conjoint  family  interviews  Dr.  Winer  has  found  that  conflict  over 
drug  use  becomes  a  focal  point  in  the  playing  out  of  deep  emotional  conflicts 
within  the  family,  such  that  the  substantive  issues  regarding  drugs  become 
subordinated.   Some  families,  in  an  effort  to  avoid  conflict,  which  they  see 
as  a  threat  to  family  integrity,  ignore  the  drug  issue  altogether  and  thereby 
perpetuate  the  problem. 

3.  Longitudinal  Assessment  of  Cognition  and  Identity  Formation  in  Early  and 
Late  Adolescents 

The  overall  thrust  of  the  studies  by  Dr.  Stuart  Hauser  in  the  Section  on 
Personality  Development  was  to  broaden  and  deepen  previously  developed  tools 
for  the  measurements  of  identity  formation  described  in  his  book  Black  and 
White  Identity  Formation. 

To  broaden  the  studies, new  populations  have  been  sampled.   The  previous  work 
concentrated  on  black  and  white  lower  socioeconomic  class  adolescent  boys, 
following  them  in  their  course  through  high  school.   The  current  investiga- 
tion concentrates  on  middle  socioeconomic  class  early  and  late  adolescents 
of  both  sexes  who  are  of  patient  and  nonpatient  status.   Thus  several  con- 
trasts of  interest  are  built  into  the  design:   patients-versus-non-patients; 
early-versus-late  adolescents;  male-versus-female  adolescents;  and  each  of 
the  main  groupings  (Patients  and  non-patients)  can  be  subdivided  in  terms  of 
sex  and  age  for  intra-group  comparisons  as  well.   All  of  these  subjects  will 
be  studied  over  a  two-year  period. 

The  instruments  for  studying  the  subjects  include  a  self-image  interview,  a 
Q-sort,  and  a  battery  of  cognitive  tests.   The  Q-sort  is  a  major  technique 
of  the  study  as  it  focuses  on  self-images.   Modifications  of  the  Q-sort 
Technique  developed  for  this  project  make  it  possible  to  focus  on  dimensions 
of  each  self-image  as  well  as  overall  integration  and  changes  in  self-images 
for  a  subject.   Both  structural  and  content  aspects  of  self-images  are  being 
analyzed  at  single  points  in  time,   and  over  spans  of  time. 

The  cognitive  tests  focus  on  processes  of  categorization,  differentiation, 
conceptualization,  and  problem  solving.   The  cognitive  data  are  being  analyzed 
in  terms  of  sub-sample  differences  at  single  points  in  time  and  change  over 
time. 

4.  The  Interrelating  of  Behavioral  and  Physiological  Events  in  the  Family 

Clinical  studies  of  family  interaction  carried  out  by  this  section  have 
revealed  the  important  role  of  anxiety  as  a  subjective  experience  which 


18 


mobilizes  and  determines  behavior  within  the  family  group.   Customarily  our 
behavioral  observations  are  of  the  moment  to  moment  verbal  and  non-verbal 
transactions  within  the  family.   On  this  time  scale,  anxiety  is  an  elusive 
variable.   Dr.  Zinner,  with  the  assistance  of  Mrs.  Deborah  Runkle,  sought  to 
gain  access  to  this  area  of  private  subjective  experience  by  monitoring  the 
galvanic  skin  responses  (GSR)  of  family  members  during  family  therapy  sessions. 
The  GSR  is  a  peripheral  reflection  of  more  central  states  of  arousal,  and  is 
a  good  measure  of  anxiety  occurring  durr'ng  interactions  among  people.   This 
year  a  quantitative  analysis  has  been  completed  of  verbal  and  physiological 
events  in  a  pilot  study  of  a  group  of  families  monitored  at  different  times 
during  their  treatment.   These  data  are  being  examined  and  meaningful 
physiologic  variables  are  being  selected  for  a  study  of  family  behaviors 
which  govern  the  locus  and  intensity  of  anxiety  within  the  family  group. 

5.   Follow-up  Study  of  Families  Treated  in  the  Study  of  Adolescent  Identity 

Approximately  half  of  the  families  treated  in  the  study  of  adolescent  identity 
have  been  re-interviewed  after  varying  periods  of  time  following  termination. 
Special  attention  has  been  directed  this  year  to  evaluating  and  interpreting 
the  long-term  meaning  of  the  program  for  the  parents  who  were  in  couples 
treatment.   In  reports  prepared  on  this  study  Mrs.  Carmen  Cabrera  and 
Dr.  Sheldon  Roth  demonstrated  that  parents,  precipitated  into  couples  therapy 
by  the  adolescent  turmoil  of  their  children,  have  important  capacities  for 
intrapsychic  and  marital  change.   These  changes  are  realized  through  sequen- 
tial processes  of  regression  and  progression  in  couples  therapy  described  by 
the  investigators  as  1)  loosening  of  ties  to  the  original  family,  2)  renewed 
adolescence  and  early  marriage,  3)  return  to  parenting.   A  correlation 
between  improvement  in  the  emotional  life  of  the  adolescent  and  in  the  marriage 
relationship  of  the  parents  was  observed.  Mrs.  Cabrera,  in  collaboration  with 
Dr.  Carl  Feinstein,  has  been  interviewing  the  remainder  of  the  sample,  to 
continue  and  expand  upon  earlier  findings. 

SECTION  ON  EXPERIMENTAL  GROUP  AND  FAMILY  STUDIES 


This  Section,  headed  by  Dr.  David  Reiss,  focuses  its  work  on  two  interrelated 
objectives.   The  first,  is  the  continued  development  of  methods  and  theory 
for  studying  the  relationship  of  the  family  to  its  larger  social  context. 
The  second  objective  is  theoretical:   the  development  and  extension  of  systema- 
tic principles  for  validating  experimental  studies  of  expressive  and  intimate 
behavior.   These  principles  of  validation  serve  to  clarify  and  extend  the 
empirical  investigations  of  families  and  are  designed  for  more  general  use 
in  experimental  social  psychiatry  and  social  psychology. 

1.   The  Relationship  of  the  Family  to  its  Social  Context 

During  the  past  year,  with  the  assistance  of  a  new  member  of  the  Section 
staff — Dr.  Ronald  Costell — the  work  of  the  Section  has  become  focussed  on 
the  study  of  the  family's  interaction  with  its  larger  social  context.   This 
work  takes  advantage  of  previous  experiments  on  family  problem-solving  con- 
ducted by  this  Section.   These  previous  studies  have  strongly  suggested  that 
the  family's  capacity  to  solve  problems  presented  to  them  depends  on  a 


19 


shared  awareness  and  evaluation  of  its  immediate  social  environment.   If  the 
family  trusts  its  relationship  with  this  environment  and  believes  it  has 
been  given  a  soluble  problem,  it  will  perform  effectively.   If  a  family  feels 
threatened  by  its  environment  and  feels  it  is  being  given  perverse  and 
insoluble  puzzles,  it  will  huddle  together  protectively  and  its  problem- 
solving  will  be  ineffective.   Shared  perceptions  of  this  kind  seem  to  dominate 
the  character  of  a  family's  interaction  with  its  social  environment. 

In  order  to  extend  these  observations  and  determine  their  role  in  psychiatric 
treatment  programs,  Drs.  Reiss  and  Costell  have  spent  the  past  year  complet- 
ing the  first  phase  of  a  study  of  families  of  psychiatric  in-patients.   This 
study  is  being  conducted  at  two  institutions,  the  Psychiatric  Institute  of 
Washington,  D.C.  and  Nursing  Unit  3  West  at  NIMH.   Both  institutions  use 
psychiatric  treatment  of  the  whole  family  as  a  central  part  of  their  program. 
The  study  is  designed  to  determine  the  role  of  the  family's  shared  evaluation 
of  the  ward  social  community — doctors,  nurses  and  patients — in  the  treatment 
process.   First,  the  family's  typical  affective  response  to  a  novel  social 
environment  is  determined  in  the  laboratory.   Then,  these  laboratory  data  are 
used  to  predict  their  adjustment  to  the  early  phases  of  family  treatment. 
Results  of  this  study  should  substantiate  the  generality  of  our  earlier  lab- 
oratory findings  and  provide  new  insight  into  the  detailed  social  mechanisms 
regulating  interaction  between  families  and  their  social  community.   In  this 
sense,  the  psychiatric  ward,  though  unique  in  several  respects,  will  be 
considered  a  model  of  a  large  social  community  in  which  families  operate. 
Since  the  Psychiatric  Institute  and  Unit  3  West  at  NIMH  differ  in  many 
respects,  the  study  will  also  permit  an  assessment  of  how  differences 
between  social  communities  affect  family-community  interaction. 

This  large-scale  project  has  several  subprojects  for  investigating  smaller, 
more  manageable  questions.   For  example.  Dr.  Costell  is  perfecting  a  ward 
value  questionnaire — used  previously  by  this  Section — for  making  precise 
comparisons  between  the  two  institutions.   Dr.  Reiss  is  completing  an  experi- 
mental study  of  psychiatrist-nurse-patient  interaction  to  determine  some  of 
the  effects  of  ward  values  on  interaction  in  small  groups.   Drs.  Reiss  and 
Costell  are  completing  additional  experimental  studies  of  family  problem- 
solving  to  explore  the  detailed  social  mechanisms  by  which  families  evaluate 
their  immediate  social  community. 

2.   Extending  Principles  for  Validating  Experiments 

From  its  inception,  the  Section  has  attempted  to  design  thoroughly  objective 
and  precise  laboratory  measures  for  studying  subtle,  intimate  and  expressive 
behavior  in  families.   This  is  an  unusual  and  difficult  task  for  an  experi- 
mental social  psychology  and  Dr.  Reiss  has  found  that  existing  principles  of   , 
experimental  design  and  validation  are  inadequate.   During  the  past  year  he 
has  nearly  completed  a  monograph,  entitled  Validation  in  a  New  Key,  in  which 
existing  concepts  of  validation  are  critically  reviewed  and  revisions  of 
these  principles  are  presented.   This  project  has  two  parts.   First  several 
recent  developments  in  the  logic  of  studying  expressive  behavior  are  reviewed. 
This  review  focuses  particularly  on  the  work  of  Langer  and  Devereux.   Then 
the  basic  principles  of  content  validity,  convergent  and  discriminant 


20 


validity  are  extended  into  new  principles  termed,  respectively,  portrayal, 
analysis  of  configuration,  and  interpretative  dialogue.   All  three  attempt 
to  show  how  experiments  can  be  designed  and  their  results  interpreted  to 
illuminate  the  expressive  intent  of  experimental  subjects.   The  continuity 
between  clinical  and  experimental  investigations  is  stressed. 

SECTION  ON  CLINICAL  PSYCHOLOGY 

There  were  two  main  foci  of  research  activities  in  the  Section  on  Clinical 
Psychology.   The  first  involved  the  study  of  small  groups,  particularly  the 
family  as  a  small  group.   The  second  involved  individual  psychodiagnosis. 
All  research  activities  were  rooted  in  clinical  involvements  with  individual 
patients  and  families.   In  collaboration  with  investigators  from  other  units, 
data  were  derived  from  various  sources,  ranging  from  laboratory  measures  of 
perceptual  and  cognitive  functions,  through  standard  and  experimental  psycho- 
logical tests,  to  psychotherapeutic  encounters  with  individual  patients  and 
families.   Families  studied  were  those  of  psychiatrically  impaired  adoles- 
cents hospitalized  on  the  Unit  3-West.   Individual  subjects  studied  ranged 
from  normal  volunteers  to  a  large  variety  of  psychiatric  and  neurological 
patients  hospitalized  for  study  by  the  Section  on  Psychiatric  Assessment  and 
by  units  of  the  Laboratory  of  Clinical  Science. 

1.   Family  Studies 

In  the  study  of  the  family  as  a  small  group,  the  major  research  activity 
involved  administration  of  the  Consensus  Rorschach  to  families  of  psychia- 
trically impaired  adolescents,  followed  by  playback  of  video  or  audio 
recordings  of  the  session  to  the  families,  and  subsequently  by  retesting  to 
assess  the  effects  of  the  procedure  on  task  performance  and  self-image. 

The  family  members  are  met  in  series  of  three  sessions.   During  the  first, 
the  "Consensus  Rorschach"  is  administrered.   This  is  a  procedure  in  which 
family  members  are  asked  to  see  how  many  agreements  they  can  reach  about 
what  an  inkblot  looks  like.   The  procedure  is  tape  recorded  and  audio 
recorded.   During  the  second  session,  depending  upon  the  assignment  of  the 
family  to  one  of  several  different  experimental  conditions,  family  members 
view  or  listen  to  themselves  going  through  the  first  session,  studying  the 
relationship  between  interactional  process  and  test  product.   During  the 
third  session,  they  are  retested  both  with  the  Consensus  Rorschach  and  with 
a  paper  and  pencil  psychological  test.   In  some  families  a  serious  internal 
competition  precluded  their  accepting  the  task  of  reaching  agreements,  or  of 
finding  a  way  to  bring  together  their  individual  views  without  its  necessarily 
meaning  a  victory  or  defeat  for  each  of  the  individual  members.   Other 
families  were  unable  to  differentiate  views  sufficiently  to  permit  the  defini- 
tion of  percepts.   Yet  other  families  were  unable  to  organize  around  the  task 
because  of  their  inability  to  develop  task-related  role  relationships  in  the 
test  situation,  or  because  of  preoccupation  with  their  discomfort  in  the 
test  situation.   The  project  thus  provided  the  opportunity  to  study  the 
family  as  a  small  group  and  is  likely  to  result  in  a  technique  useful  to 
apply  as  a  part  of  the  clinical  evaluation  of  families  prior  to  their 
beginning  in  family  therapy. 


21 


II.   Individual  Diagnosis 

In  the  area  of  individual  diagnosis,  research  activities  included  projects 
to  study  the  relationship  between  performances  on  laboratory  measures  of 
perceptual  and  cognitive  variables  and  styles  of  responding  to  the  Rorschach; 
studies  of  patients  who  were  acutely  psychotic,  including  not  only  schizo- 
phrenics but  patients  with  affective  disturbances;  and  studies  comparing 
patterns  of  deficit  in  intellectual  functioning  among  patients  with  a  variety 
of  psychiatric  and  neurological  impairments.   Additional  work  was  carried 
out  on  studies  of  the  relationships  between  contrasting  approaches  to 
Rorschach  responding  and  performances  on  laboratory  measures  of  perceptual 
and  cognitive  variables.   In  the  first  efforts  in  this  study,  two  contrasting 
approaches  to  Rorschach  responses  were  identified.   The  first,  the  "Recogni- 
tory"  approach  is  one  in  which  subjects  tend  to  respond  to  qualities  of  blots 
with  associations  to  things  previously  seen.   In  the  "Interpretive"  approach, 
on  the  other  hand,  subjects  attribute  qualities  to  the  blots  which  are  not 
intrinsic  in  them,  qualities  such  as  movement  and  depth,  and  these  become 
Important  determinants  of  responses.   It  appears  that  the  thinking  and  per- 
ception of  subjects  who  have  high  scores  on  the  "Recognitory"  factor  are 
largely  stimulus-determined,  and  at  times  even  stimulus-bound.   Among  normal 
subjects,  relationships  were  established  between  Interpretive  tendencies 
and  scores  on  such  laboratory  measures  of  cognitive  variables  as  the  Embedded 
Figures  test,  a  size  estimation  test  and  the  Category  Width  test.   It  appears 
that  there  is  a  relationship  between  Interpretive  tendencies  and  field 
independence.   Further  studies  will  be  carried  out  with  data  on  twins  in  an 
effort  to  establish  other  relationships  with  perceptual  and  cognitive  variables. 

Research  continues  on  studies  of  deficits  in  intellectual,  personality  and 
central  nervous  system  functioning  in  contrasting  groups  of  patients,  includ- 
ing some  with  established  central  nervous  system  pathology,  patients  with 
acute  affective  disturbances  and  schizophrenics.   Work  has  been  extended  to 
include  some  studies  of  the  effects  of  a  variety  of  drugs,  including  L-dopa, 
on  patterns  of  deficit  in  intellectual  functioning.   As  a  result  of  work 
carried  on  during  the  past  year,  a  challenge  is  presented  to  prior  claims 
that  intellectual  functioning  is  improved  by  the  administration  of  L-dopa 
to  patients  with  Parkinsonism.   Further  studies  in  this  area  are  being  con- 
tinued. 


SECTION  ON  PERCEPTUAL  AND  COGNITIVE  STUDIES 

Research  in  this  section  focused  on  disturbances  in  perceptual  and  cognitive 
behavior  in  psychiatric  patients.   Its  work  was  closely  coordinated  with  basic 
electrophysiological  and  perceptual  research  in  the  Unit  on  Psychophysiology, 
DCBR,  NIMH.   The  finding  of  perceptual  and  attentional  deficits  in  a  variety 
of  psychiatric  patient  groups  encouraged  the  development  of  theories  of  psychi- 
atric illness  and  personality  structure  based  on  perceptual  style.   Special 
problems  arise,  however,  in  the  study  of  perceptual  behavior  in  those  psychiatric 
patients  whose  perceptual  behavior  may  reflect  poor  motivation,  poor  coopera- 
tion, failure  to  attend  to  instructions,  or  inability  to  communicate  with  the 
examiner  rather  than  a  perceptual  difference.   For  this  reason,  this  section 
has  emphasized  electrophysiological  correlates  of  perceptual  behavior  using 
average  evoked  response  techniques. 

In  addition  to  methodological  problems,  the  question  of  trait  versus  state  has 
become  important:   Do  the  perceptual  differences  observed  in  psychiatric  pa- 
tients reflect  an  underlying  and  relatively  fixed  biological  characteristic, 
or  are  they  related  to  the  attentional,  affective,  or  autonomic  arousal  state 
of  the  individual  at  the  moment  of  the  perceptual  behavior?   At  a  clinical 
level,  the  approach  to  this  problem  has  been  to  compare  two  patient  groups, 
those  with  affective  disorders  and  those  with  schizophrenia.   At  different 
points  in  the  psychiatric  course  comparisons  were  made  between,  on  the  one  hand, 
correlations  between  perceptual  behavior  and  day-to-day  clinical  ratings  and, 
on  the  other  hand,  correlations  between  perceptual  behavior  and  historical,  demo- 
graphic, and  genetic  features.   In  comparisons  of  perceptual  behavior  in  periods 
of  mania  or  depression  in  cyclic  patients  with  periods  of  depression  in  uni- 
polar depressed  patients,  diagnostic  category  as  determined  by  patient  history 
appeared  to  be  more  closely  related  to  the  perceptual  behavior  than  was  current 
patient  mood  as  measured  by  nurse  or  physician  ratings.   Data  on  a  large  (83) 
population  of  patients  with  affective  disorders  are  being  analyzed.   A  group 
of  drug-free  schizophrenic  patients  is  also  being  studied. 

In  order  to  assess  the  relative  importance  of  genetic  and  environmental  factors, 
monozygotic  and  dizygotic  normal  twins  have  been  studied  using  measures  of 
autonomic  and  psychomotor  functioning,  average  evoked  response  procedures,  a 
battery  of  perceptual  tasks,  questionnaires,  and  interviews.   Thus  far,  ap- 
proximately 60  twin  pairs  have  been  tested  and  the  project  is  currently  enter- 
ing the  data-analysis  phase.   Family  groups,  both  noimal  and  psychiatric,  have 
also  been  evaluated. 

The  effects  of  "state"  variables  such  as  attention  and  arousal  have  also  been 
studied  in  normal  populations.   Comparison  of  the  effects  of  muscle  tension, 
painful  stimulation,  and  shifts  in  attention  toward  or  away  from  evoked  re- 
sponse and  stimuli  have  demonstrated  the  importance  of  each  of  these  factors 
but  have  highlighted  the  importance  of  underlying  individual  differences  in 
the  habitual  deployment  of  attention  or  the  channeling  of  arousal. 

Three  major  perceptual  dimensions  have  been  investigated.   The  first,  termed 
"stimulus  intensity  control,"  is  based  on  recent  studies  of  individual  dif- 
ferences in  responsiveness  to  sensory  stimulation.   Two  different  ways  of 

23 


accepting  sensory  input  have  been  hypothesized:   The  "augmenter"  who  tends  to 
increase  the  perceived  intensity  of  stimuli,  and  the  "reducer"  who  tends  to 
decrease  it.   Reducing,  like  habituation,  may  represent  attempts  to  cope  with 
sensory  overload.   Stimulus  intensity  control  is  being  inferred  from  measure- 
ments of  the  average  evoked  response  to  varying  intensities  of  auditory  and 
visual  stimulation.   The  second  perceptual  dimension,  field  articulation, 
describes  the  subject's  ability  to  separate  elements  in  a  perceptual  field. 
The  Rod  and  Frame  test,  optical  illusions,  size  estimation  and  the  Gestalt 
figures  are  used  to  assess  this  dimension  as  well  as  an  average  evoked  response 
measure  of  anchoring  or  contrast  effects.   The  third  perceptual  dimension  is 
that  of  perceptual  variability.   This  is  being  studied  with  mathematical  anal- 
ysis of  average  evoked  response  variability  as  well  as  error  analysis  on  the 
perceptual  procedures. 

Most  previous  clinical  research  in  the  perceptual  area  has  utilized  a  cross 
sectional  approach.   This  section  has  exploited  the  facilities  of  the 
Clinical  Center  in  a  variety  of  longitudinal  studies  where  the  physiological, 
perceptual,  behavioral,  autonomic,  and  biochemical  measures  can  be  followed 
in  the  same  patient  as  the  course  of  his  psychiatric  illness  evolves. 


24 


PROJECTS  OF  DR.  LYMAN  C.  WYNNE  AMD  DR.  MARGARET  T.  SINGER 


The  research  programs  of  Dr.  Lyman  C,  V^nne  and  Dr.  Margaret  Thaler  Singer  on 
schizophrenics  and  their  families  have  been  described  at  length  in  previous 
reports.  In  anticipation  of  Dr.  Wynne's  retirement  from  the  Public  Health 
Service  on  July  1,  1972,  this  year  they  have  analyzed  these  accumulated  data 
and  prepared  material  for  publication.  Although  a  very  substantial  body  of 
new  findings,  and  new  conceptual  formulations  based  on  these  findings,  are 
emerging  from  the  recent  data  analyses,  it  is  not  appropriate,  at  the  point  in 
time  at  which  this  report  is  being  prepared,  to  attempt  a  detailed  simmiary  of 
the  year's  developments.   Instead,  a  brief  outline  of  major  recent  directions 
will  be  presented  here. 

(1)  Dtiring  l*i  years  of  collaborative  research  Drs.  Vtynne  and  Singer  have 
assembled  fifteen  large  loose-leaf  notebooks  of  published  and  unpublished  majiu- 
scripts.  A  primary  goal  this  year  has  been  to  review  this  material,  to  gain 
perspective  about  both  the  data  obtained  and  the  evolving  concepts  used,  and 

to  distill  as  much  of  the  material  as  possible  for  publication. 

(2)  This  process  of  review  has  stiggested  several  ways  in  which  the  data 
should  be  re-examined  which,  fortunately,  can  now  be  done  more  expeditiously 
than  in  the  early  days  of  this  research  because  of  the  advent  of  computerized 
data  processing.  Follow-up  data  on  families  originally  studied  as  long  ago 
as  1958  are  being  incorporated  into  the  computerized  data  pool,  although  a 
shortage  of  research  assistance  has  made  this  follow-up  less  systematic  and 
comprehensive  than  would  have  been  desirable. 

(3)  An  effort  is  being  made  to  review  past  clinical  data  about  both  index 
family  members  (the  original  presenting  patients  and  their  counterparts  in 
normal  control  families )  and  all  of  the  other  family  members  to  see  how  fully 
new  diagnostic  schedules  can  be  applied  to  case  records  which  were  begun  years 
ago  before  current  standardized  diagnostic  assessments  were  possible.   (These 
assessment  schediiles  have  emerged  primarily  from  the  WHO  International  Pilot 
Study  of  Schizophrenia  in  which  Dr.  Vlynne   was  an  original  principal  investi- 
gator and  which  is  described  elsewhere  in  the  work  of  the  Psychiatric  Assess- 
ment Section). 

(U)  Drs.  Wynne  and  Singer,  with  the  able  assistance  of  Mrs.  Margaret  Toohey 
and  the  consultation  of  Dr.  John  Bartko,  have  been  analyzing  and  comparing 
data  on  families  from  several  sources.  In  addition  to  llU  diverse  families 
comprehensively  studied  and  followed-up  in  Bethesda,  59  families  were  tested 
and  less  fully  examined  in  Houston.  Earlier,  these  data  from  psychological 
tests,  especially  the  Rorschachs,  and  a  variety  of  demographic  and  clinical 
data,  were  examined  in  an  over-all  quantitative  fashion,  for  example,  comparing 
the  frequency  of  communication  deviances  in  parental  Rorschachs.  This  year 
progress  has  been  made  in  a  much  more  detailed  qualitative  breakdown  of  these 
data,  applying  factor  analytic  and  multivariate  statistical  techniques  and 
evaluating  a  nimiber  of  specific  hypotheses.  As  Just  one  example,  Drs.  %nne 
and  Singer  have  hypothesized  earlier  that  certain  types  of  communication  de- 
viances would  be  very  frequent  in  the  parents  of  schizophrenics  but  infrequent 


25 


in  the  schizophrenics  themselves,  and  vice  versa.  This  clinically  derived 
hypothesis  has  now  been  confirmed  and  spelled  out.  Similarly,  earlier  hypotheses 
about  the  nature  of  the  attentional  problems  of  parents  of  schizophrenics  have 
been  confirmed. 

(5)  Three  other  sources  of  family  data  have  also  been  studied  in  detail  and 
compared  with  the  earlier  Bethesda  and  Houston  data.  First,  clinical  and 
Rorschach  data  from  fifty  Japanese  families  have  been  evaluated  further  with 
the  assistance  of  Mieko  Caudill  and  the  late  Dr.  William  Caudill.  An  extensive 
paper  on  the  important  general  issue  of  translating  cross-cultural  psychological 
materials  was  an  off shot  of  this  work.  Unfortunately,  because  of  Dr.  Caudill 's 
untimely  deabh,  it  is  not  possible  at  the  present  time  to  assess  how  fully  the 
Japanese  data  can  be  interpreted  without  his  assistance. 

Second,  Rorschachs  from  parents  in  Uo  London  families,  20  having  a  schizophrenic 
offspring  and  20  a  depressed  offspring,  have  been  examined.   Although  Drs. 
Steven  Hirsch  and  Julian  Leff,  the  London  collaborating  investigators,  had 
written  a  paper  last  year  in  which  they  attributed  positive  findings  to  an 
artifact  having  to  do  with  the  word  count  of  the  subjects,  they  now  agree  that 
this  interpretation  was  mistaken.  Unfortunately,  their  work  does  not  represent 
a  replication  of  the  Bethesda  family  studies  because  of  gross,  systematic  errors 
in  the  way  in  which  their  parental  Rorschachs  were  administered.   However, 
certain  useful  information  is  nevertheless  forthcoming  from  this  work,  mainly 
from  a  study  of  the  reliability  of  scoring  with  the  Singer-Wynne  Rorschach 
manual.  This  is  helpful  to  Dr.  Singer  in  preparing  a  revision  of  the  manual. 

Third,  another  source  of  new  data  has  been  the  Rorschach  from  50  parents  (25 
pairs)  made  available  from  the  adopti  -n  studies  by  Wender  and  Rosenthal  at 
NIMH.  Earlier,  Wender  and  Rosenthal  had  found  that  the  mental  health  ratings 
and  certain  other  measures,  such  as  Zahn's  word-association  indices,  failed 
to  differentiate  the  adoptive  parents  of  schizophrenics  from  the  adoptive 
parents  of  normals,  whereas  the  biologic  parents  of  schizophrenics  clearly  and 
more  severe,  enduring  symptomatic  difficulties.   In  striking  contrast,  when 
aberrant  parental  communication  was  evaluated  blindly  in  the  parental  Rorschachs 
by  Dr.  Singer,  she  found  that  the  adoptive  parents  of  schizophrenics  had  the 
most  deviant  communication,  followed  by  the  biologic  parents  of  schizophrenics, 
with  the  adoptive  parents  of  nonnals  showing  a  lower  frequency  of  deviances 
(a  statistically  significant  difference).   Indeed,  Dr.  Singer  was  able  to  pre- 
dict with  100^  accuracy  which  pairs  of  parents  had  a  schizophrenic  offspring 
versus  a  non-schizophrenic  offspring,  regardless  of  whether  or  not  the  off- 
spring was  biologic  or  adoptive.  This  finding  points  to  the  importance  of 
familial  interaction  processes.  Further  analysis  of  the  data  may  help  clarify 
whether  the  deviant  parental  communication  in  the  adoptive  schizophrenic  sample 
is  likelj'  to  have  been  enduring  or  was  secondary  and  associated  with  recent 
distress  about  their  adoptive  offspring's  status. 

Along  with  these  and  other  analyses  of  family  data.  Dr.  Wynne  has  been  colla- 
borating with  Dr.  Buchsbaum  in  a  study  of  psychophysiologic  and  perceptual 
"response  dispositions"  in  normal  twins.   This  work  will  be  described  elsewhere. 


26 


Annual  Report  of  the  Child  Research  Branch 

Division  of  Clinical  and  Behavioral  Research 

National  Institute  of  Mental  Health 

July  1,  1971  -  June  30,  1972 

Richard  Q.  Bell,  Ph.D.,  Chief 

Psychiatrists,  psychologists,  and  social  workers  were  brought  together 
in  this  branch  in  1959  to  carry  out  a  longitudinal  study,  the  purpose  of 
which  was  to  illuminate  the  development  of  social,  emotional,  and  cog- 
nitive behaviors  in  the  early  phases  of  the  life  cycle.   The  period  from 
early  marriage  through  early  childhood  was  selected  so  as  to  make  it 
possible  to  specify  whether  certain  characteristics  of  parents  preceded 
or  were  a  reaction  to  those  shown  by  a  child.   A  separate  identification 
of  parent  and  infant  contributors  to  development  was  to  be  achieved  by 
studying  husband  and  wife  characteristics  prior  to  the  birth  of  the  first 
child,  and  the  child's  characteristics  early  in  life  before  there  could 
be  any  impact  of  the  family  environment. 

Section  chiefs  were  selected  who  had  long  experience  or  special  train- 
ing relevant  to  one  of  these  phases,  and  who  would  agree  to  carry  out 
their  research  as  part  of  a  coordinated  branch  study.  Given  very  general 
objectives  to  achieve,  each  section  chief  was  then  permitted  a  period  in 
which  to  prepare  for  the  longitudinal  study.   They  selected  and  tested 
measures,  and  carried  out  preliminary  studies  required  to  explore  the  be- 
havioral domain.   To  provide  for  independence  of  measurements  between 
periods,  the  failure  of  which  had  been  a  serious  shortcoming  in  previous 
longitudinal  studies,  four  sections  were  organized  with  separate  personnel 
to  study  (a)  the  newlywed  period  and  later  stages  of  marriage,  (b)  pregnancy 
and  parent-infant  interaction  in  the  first  year  of  life,  (c)  the  newborn 
period,  and  (d)  the  early  preschool  and  school  ages. 

After  the  four  teams  were  organized  between  1959  and  1961,  preparatory 
studies  were  carried  out,  and  a  trial  series  of  cases  was  processed  from 
the  period  of  early  marriage  through  the  preschool  years  (Cohort  I).   The 
main  Cohort  of  2162  couples  (Cohort  II)  was  launched  in  1966  by  studies 
of  early  marriage  that  continued  through  195  9.  Between  1967  and  1970  the 
pregnancies,  newborns,  and  three-  and  eleven-month-old  infants  were  studied. 
Studies  of  the  preschool  phase  were  started  in  1970  and  will  continue  until 
1973.   Samples  for  the  phases  after  early  marriage  range  from  100  to  130. 

We  have  mentioned  that  it  was  necessary  for  the  scientists  in  our 
program  to  accept  a  limitation  in  their  freedom  to  pursue  various  lines  of 
investigation.   This  limitation  was  offset  by  the  fact  that  they  were 
selected  on  the  basis  of  their  known  interest  in  pursuing  research  largely 
within  the  domain  to  which  they  were  assigned.   Nevertheless  it  was 
necessary  for  them  to  concentrate  theoretical  and  methodological  efforts 
within  one  area.  Because  of  the  need  tc  maintain  similar  measures  for  an 
entire  cohort  of  cases,  they  had  to  maintain  sustained  data  gathering 

27 


operations  in  which  month -to -month  or  year-to-year  variations  could  not  be 
tolerated.   However,  I  believe  I  can  speak  for  the  entire  staff  in  saying 
that  the  rewards  of  being  part  of  a  larger  research  program,  and  of  being 
concerned  with  common  theoretical  problems,  have  offset  the  disadvantages 
of  not  having  complete  freedom.   It  has  been  exciting  to  be  part  of  an 
enterprise  that  is  unique  in  attempting  to  put  together  a  theory  of  the 
early  phases  of  the  life  cycle.   The  common  conceptual  interest  has  led 
to  a  further  advantage  for  the  investigators,  the  fact  that  there  was 
an  interested  and  critical  group  of  scientists  always  available  to  review 
and  intensely  analyze  scientific  reports  prepared  by  any  one  of  us.   Hie 
longitudinal  program  also  provided  a  ready  sapply  of  cases  for  the  prep- 
aratory studies,  since  teams  studying  earlier  stages  could  readily  pass 
along  their  cases  at  later  stages  for  the  next  team.   Bius  there  have 
been  operational  advantages  that  have  complemented  the  theoretical 
advantages . 

Since  each  section  is  at  a  different  point  in  the  process  of  data- 
gathering,  primary  data  reduction,  secondary  analyses,  and  reporting, 
the  task  of  understanding  the  overall  functioning  of  the  branch  at  a 
given  point  in  time  is  quite  complex.   Furthermore,  many  of  the  sections 
are  still  reporting  results  from  preparatory  studies.   It  will  be  necessary 
to  keep  in  mind  the  distinction  between  preparatory  studies,  and  between 
Cohort  I  and  II.   Some  of  the  preparatory  studies  were  not  a  part  of 
Cohort  I. 

Office  of  the  Chief 

Interest  in  a  1970  biennial  report  on  the  status  of  our  research  was 
so  great  that  it  was  necessary  to  order  an  additional  1000  copies  of  the 
pamphlet  we  had  prepared.   In  addition  to  responding  to  requests,  we  have 
distributed  the  pamphlet  to  major  investigators  in  the  field  of  psychology 
and  psychiatry.   Our  remaining  supplies  will  be  distributed  to  investigators 
in  the  field  of  sociology,  social  work,  marriage  and  family  life,  and 
pediatrics.   This  biennial  report  was  prepared  with  a  scientific  readership 
in  mind,  rather  than  professionals  in  the  service  occupations,  or  for  semi- 
professional,  or  lay  readership.  We  are  now  preparing  the  biennial  report 
for  1972. 

It  was  not  possible  to  undertake  the  second  phase  of  organizing  our 
data  bank  for  Cohort  II.   During  the  previous  year,  we  had  completed  the 
first  step,  consisting  of  a  summary  tabulation  of  tests,  procedures,  and 
interviews  obtained  for  all  subjects  and  all  phases  of  the  study  finished 
to  date.   The  second  projected  step  was  to  organize  a  central  branch  data 
bank,  in  which  would  be  deposited  copies  of  final  summaries  of  longitudinal 
data  gathered  in  each  section,  with  identifying  information  on  case  numbers, 
phases  of  the  study  on  which  data  has  been  gathered,  and  completeness  and 
adequacy  of  the  data.  As  we  complete  our  data  gathering  for  the  second 
cohort,  and  after  each  of  the  sections  has  analyzed  and  reported  findings  in 
which  they  have  primary  interest,  it  is  planned  that  the  branch  will  move 
into  a  period  in  which  it  will  serve  as  a  national  data  resource  for 


28 


visiting  scientists  from  the  United  States,  and  all  over  the  world,  who 
wish  access  to  this  unique  kind  of  longitudinal  data.   Ihe  launching  of 
the  second  step  was  delayed  by  demands  placed  upon  our  administrator 
resulting  from  an  unusually  high  volume  of  errors  in  payroll  data,  and 
from  the  special  problems  of  administering  our  program  during  a  period 
in  which  a  personnel  freeze  and  grade  roll-back  have  made  administration  of 
the  branch  very  difficult.   It  is  hoped  that  we  can  make  some  progress  on 
the  data  bank  in  this  coming  year . 

Scientific  activities  of  the  office  of  the  Chief  consisted  largely 
this  last  year  in  synthesizing  the  results  from  preparatory  studies,  and 
reporting  these  results  at  various  meetings  in  this  country  and  abroad. 
At  an  International  symposium  concerned  with  society,  stress,  and  disease, 
convened  by  the  Karolinska  Institute  at  Stockholm,  I  provided  summary 
reports  of  the  implications  for  stress  contained  in  our  research  on 
(a)  the  process  of  early  marriage,  (b)  the  effects  of  children  on  parents, 
and  (c)  the  relations  of  newborn  and  preschool  behavior,  A  serendipitous 
result  of  attendance  at  this  conference  was  that  I  received  valuable  help 
on  some  other  data  I  have  been  analyzing  from  our  studies  of  newborns  and 
preschoolers.   These  data  seemed  to  indicate  that  preschoolers  whose 
mothers  had  received  high  levels  of  pre-delivery  medication,  for  sedative 
purposes,  were  more  assertive  in  barrier  situations  in  the  preschool  period, 
A  neonatal  cardiologist  at  the  conference,  and  two  investigators  who 
specialize  in  hormonal  effects  of  stimulation  in  early  infancy,  suggested 
that  the  long-term  results  could  have  been  due  to  the  effects  of  anoxia 
on  the  infant,  acting  as  a  stressor  on  the  hypothalamic-pituitary-adrenal 
cortex  axis.  Maternal  sedation  might  have  the  effect  of  permanently 
resetting  the  level  of  the  functioning  of  the  infant's  adrenal  cortex 
system.   If  this  were  the  case,  one  would  expect  the  same  results  that 
have  been  obtained  both  in  studies  of  lower  animals  as  well  as  in  one 
human  study  of  vaccination  in  early  life,  namely  that  early  stimulation 
produces  greater  body  weight  or  height  in  later  life,  in  addition  to 
behavior  differences.  With  this  hypothesis  in  mind,  when  I  returned  from 
the  Stockholm  conference,  I  re-analyzed  our  data  and  found,  as  anticipated, 
that  at  least  in  one  of  our  samples,  the  males,  higher  levels  of  maternal 
sedation  were  associated  with  above-average  height  in  the  preschool  period. 

At  the  Winter  Conference  on  Brain  Research  in  Colorado,  I  discussed 
the  above  findings  in  a  workshop  group  that  had  special  expertise  in  this 
area.   The  discussions  that  developed  from  this  workshop  have  led  to  ten- 
tative plans  for  a  coordinated  program  of  animal  and  human  research 
designed  to  (a)  test  this  hypothesis  more  directly,  (b)  test  the  action 
of  specific  drugs  that  are  commonly  used  in  obstetrical  practice,  and 
(c)  identify  a  variety  of  later  outcomes  in  development  that  might  be 
expected  on  the  basis  of  this  original  finding.   Current  plans  call  for 
a  conference  of  Victor  Dennenberg  from  the  University  of  Connecticut, 
Yvonne  Brackbill  from  Georgetown  University,  Evelyn  Thoman  from  Stanford 
University,  and  myself,  to  lay  plans  for  such  a  research  program.  My  own 
participation  in  the  project  will  be  limited  to  analyses  of  data  available 
in  the  branch  longitudinal  program,  because  our  data  gathering  resources 


29 


are  completely  consumed  in  our  own  longitudinal  study. 

The  plan  for  a  coordinated  and  comprehensive  program  of  animal  and 
human  research  in  this  area  is  an  exciting  one,  and  has  considerable 
potential  for  benefit  to  the  public.   It  has  long  been  known  that  some 
sedatives  given  the  mother  during  labor  are  transmitted  to  the  infant,  and 
tend  to  concentrate  in  the  brain.   However,  it  has  been  thought  that  the 
effects  were  temporary,  and  primarily  affected  the  liveliness  of  the 
infant's  feeding  and  response  to  the  mother.   Now,  Dr.  Brackbill's  work 
in  the  first  few  months,  and  ours,  covering  a  longer  time  span,  indicate 
that  there  are  likely  to  be  long-term  effects  of  maternal  sedation  that 
must  be  reckoned  with. 

From  the  Stockholm  conference  I  went  to  Nijmegan,  Netherlands,  for 
the  first  symposium  of  the  International  Society  for  the  Study  of  Behavioral 
Development.   At  this  symposium  I  reported  the  gist  of  our  findings  on 
behavioral  relations  between  the  newborn  and  preschool  period.   From  the 
Nijmegan  meeting  I  went  to  visit  M.  P.  M.  Richards,  who  is  carrying  out  a 
longitudinal  study  at  Cambridge,  England.   We  had  an  opportunity  to  further 
discuss  the  findings  on  the  long-term  effects  of  drugs.   Dr.  Richards  has 
data  supporting  both  Dr.  Brackbill's  and  our  own  findings,  and  further 
indicating  the  need  for  opening  up  this  new  area  of  research.  At  that 
time  we  discussed  the  possibilities  of  collaboration  in  order  to  utilize 
data  from  one  other  longitudinal  study  carried  out  in  England,  in  which 
there  is  excellent  information  on  maternal  sedation  and  later  development. 

Later  in  the  year  I  attended  the  Third  Symposium  on  Oral  Sensation 
and  Perception  in  Bethesda,  for  which  I  provided  summarizing  and  perspec- 
tive comments  on  the  overall  conference.  At  this  conference,  a  specialist 
on  histological  study  of  the  development  of  the  skin  provided  information 
that  may  contribute  eventually  to  understanding  both  the  decline  over  days 
in  tactile  threshold  that  we  have  noted  in  newborns,  as  well  as  the  rela- 
tionship of  absolute  level  of  the  tactile  threshold  to  later  preschool 
behavior.  Apparently,  free  nerve  endings  grow  very  rapidly  in  response 
to  an  increase  in  oxygenation  that  occurs  after  birth.   The  decrease  in 
threshold  could  be  due  to  this  response  to  oxygenation,  and  those  who  show 
high  thresholds  during  the  newborn  period,  and  assertiveness  in  barrier 
situations  during  the  preschool  period  (just  as  the  infants  whose  mothers 
received  high  levels  of  sedation  during  labor)  may  be  less  adequately 
oxygenated  than  those  whose  thresholds  are  low  and  who  are  unassertive  in 
later  development.   Consistent  with  the  picture  of  low  oxygenation  for  the 
high  threshold  infant  is  the  fact  that  their  respiration  rates  are  usually 
characteristically  low. 

At  the  La  Jolla  conference  on  self-regulation,  sponsored  by  the 
University  of  California,  Berkeley,  I  presented  a  paper  on  biological 
contributors  to  self-regulation.   Ihis  paper  summarized  evidence  from  our 
own  newborn  to  preschool  studies,  as  well  as  findings  from  studies  of 
heritability,  that  there  is  a  substantial  constitutional  contributor  to  the 
dimension  of  extraversion-introversion,  and  that  four  components  of  this 


30 


dimension  can  be  identified  as  early  as  the  second  or  third  year  of  life. 
Exploratory  behavior  is  also  important  in  self -regulation,  and  here  again, 
congenital  contributors  have  been  identified  in  our  research.   Finally, 
hyperactivity  was  pointed  out  as  a  very  salient  defect  involving  self- 
regulation;  a  stronger  congenital  contributor  has  been  identified  in 
this  area  than  in  any  of  the  others,  namely  the  association  of  minor  physical 
anomalies  with  hyperactivity. 

In  March  I  assisted  on  a  site  visit  to  a  project  at  the  University  of 
Rochester  that  is  searching  through  the  neonatal  period  for  differences  in 
behavior  between  infants  born  to  schizophrenic  mothers  versus  mothers  with 
personality  disorders  or  neuroses.  It  was  very  gratifying  to  see  the  ex- 
tent to  which  this  project  had  been  built  upon  findings  from  our  own  studies 
of  newborns  and  of  early  infancy,  and  the  extent  to  which  our  experience  in 
longitudinal  studies  has  assisted  the  development  of  their  research  strategies, 

Section  on  Family  Development 

Since  this  section  launched  the  studies  of  the  second  Cohort,  it  is 
the  first  to  complete  the  process  of  primary  data  reduction,  and  has  essen- 
tially moved  into  a  phase  involving  higher  order  data  analysis  and  report- 
ing.  New  methods  have  been  developed  for  clustering  self-descriptive  terms, 
and  for  identifyi^ng  sequences  in  marital  interaction  data.   Factor  analyses 
of  interaction  data  have  been  carried  out  to  check  results  from  Cohort  I. 
Our  concern  t±iat  this  trial  cohort  would  not  be  representative  of  a  broader 
sample  of  marriages  has  been  allayed  by  the  replication  in  the  Cohort  II  data 
of  the  factors  previously  obtained.   However,  the  increased  size  of  the 
Cohort  II  sample  permitted  the  extraction  of  some  additional  factors . 

Current  reports  from  the  section  indicate  application  to  issues  and 
hypotheses  in  the  larger  field  of  marriage,  as  well  as  to  our  longitudinal 
data.   For  example,  our  marriage  data  have  been  used  to  demonstrate  that 
previously  reported  decreases  in  marriage  satisfaction,  following  having  a 
child,  are  primarily  a  function  of  the  wife's  feeling  that  her  husband  has 
become  less  attentive  to  her.   One  other  paper  attacks  the  generality  of  the 
concept  of  power  in  family  relations,  and  suggests  new  distinctions  between 
kinds  of  power.   One  report  taps  not  only  the  longitudinal  data,  but  other 
samples  the  section  has  been  studying,  in  order  to  describe  unconventional 
marriages.   The  report  indicates  that  our  affluent  society  has  contributed 
to  the  development  of  such  marriages,  that  they  show  some  novel  features, 
such  as  the  handling  of  sexuality  and  tension,  but  that  they  also  show 
some  of  the  attributes  of  conventional  marriages.  All  in  all,  the  section 
shows  great  versatility  in  the  range  of  its  scientific  reports,  from  highly 
empirical  and  sophisticated  methodological  studies  through  to  impressionis- 
tic explorations  into  new  forms  of  relationships . 

Section  on  Parent -Child  Behavior 

The  personnel  of  this  section  were  the  second  team  to  be  in  contact 
with  Cohort  II,  in  the  case  of  the  marriages  that  led  to  pregnancies  in  the 
first  three  years.   Blanche  Jacobs  has  supervised  research  assistants 

31 


engaged  this  past  year  in  coding,  processing,  and  preliminary  analyses  of 
data  from  interviews,  questionnaires,  home  observations  and  laboratory 
studies,  extending  from  pregnancy  to  home  visits  at  eleven  months  postpartum. 
Mrs.  Jacobs  has  made  excellent  progress  with  the  data,  supplying  the  section 
and  project  chiefs,  both  of  whom  are  in  foreign  countries  this  year,  with 
the  results  of  ongoing  analyses.   She  has  constantly  adjusted  the  activities 
of  the  branch  to  changes  in  direction  that  were  supplied.  Much  of  the  data 
has  been  carried  beyond  the  point  of  computer  storage  to  first  level  analysis, 
such  as  the  derivation  of  combination  and  pattern  variables. 

If  this  section  is  able  to  continue  at  its  present  pace,  the  data  will 
largely  have  reached  a  stage  sufficient  for  higher  order  analyses  that  can 
be  carried  out  by  the  section  chief  on  return  in  the  fall.   These  analyses, 
in  turn,  will  make  it  possible  to  begin  interrelating  the  data  from  preg- 
nancy, the  newborn  period,  and  early  infancy. 

Section  on  Infant  Development 

The  section  was  the  third  in  order  to  study  the  Cohort  II  cases  in 
which  pregnancies  had  occurred.   They  concentrated  on  the  newborn  period, 
even  though  it  occurs  between  two  phases  of  development  being  studied  by 
the  previous  section.   The  practical  difficulties  of  carrying  out  studies 
in  hospitals,  and  with  a  subject  whose  viability  is  still  tentative,  re- 
quires specialized  personnel  such  as  nurses,  and  different  approaches  to 
data  gathering.   Ray  Yang  has  directed  the  data  analysis  since  December  of 
1971  and,  with  the  help  of  two  of  the  three  nurses  who  carried  out  the 
newborn  assessments,  has  brought  the  task  of  primary  data  reduction  very 
near  to  completion.   It  is  some  indication  of  the  magnitude  of  this  task, 
and  of  the  morale  problems  engendered  in  maintaining  day-to-day  coding, 
that  it  has  been  necessary  to  translate  over  35,000  feet  of  polj'graph 
tracings  into  forms  that  could  be  analyzed  by  computer. 

In  addition  to  bringing  the  primary  data  analysis  close  to  completion, 
Dr.  Yang  has  prepared  a  report  this  year  on  neonatal  responses  to  tactile 
stimulation.   The  stimulation  was  produced  by  an  apparatus  that  programmed 
increases  in  the  intensity  of  air  jets  delivered  to  the  skin,  and  that 
produced  repeated  stimulations  once  threshold  levels  had  been  reached. 
Most  studies  carried  out  by  other  investigators  have  indicated  the  relative 
absence  of  an  orienting  response  to  stimulation  in  the  neonate,  as  would  be 
shown  by  deceleration  of  heart  rate  above  pre-stimulus  levels.   They  have 
found  an  acceleration,  as  would  be  expected  in  a  defense  reaction.   Our 
data  have  confirmed  this  general  picture,  despite  the  addition  of  a  feature 
that  might  have  altered  the  function.  Most  of  the  prior  investigations  have 
not  used  stimulus  levels  adjusted  to  the  infant's  own  threshold.   No  sex 
or  state  differences  have  been  found  in  the  heart  rate  response  to  tactile 
stimulation,  and  thus  it  will  be  possible  to  use  it  in  the  longitudinal 
study  without  elaborate  adjustments. 

Since  previous  studies  in  this  section  have  indicated  that  factor 
analyses  and  other  higher  order  forms  of  data  analysis  have  little  to  add 
to  the  longitudinal  validity  of  the  neonatal  data.  Dr.  Yang  is  preparing  to 


32 


move  from  the  primary  stage  of  data  analysis  directly  to  the  task  of  relat- 
ing newborn  data  to  variables  from  pregnancy  and  later  infancy.   The  pace 
of  data  analysis  in  this  section,  and  in  the  Section  on  Parent-Child 
Behavior,  seems  to  be  favorable  for  joint  efforts  in  the  coming  year. 

Section  on  Child  Behavior 

The   major  task  of  this  section,  the  last  team  to  study  Cohort  II  cases, 
is  to  maintain  a  consistent  set  of  procedures  and  observations  through  1973, 
at  which  time  all  of  the  children  bom  to  Cohort  II  families  in  the  first 
three  years  following  the  marriage  studies  will  have  passed  through  the 
early  preschool  phase.   The  preschool  follow-up  has  proceeded  far  enough 
that  we  can  estimate  a  final  sample  of  approximately  130  children  from 
Cohort  II.   This  is  a  somewhat  larger  sample  than  has  completed  some  of  the 
other  phases,  such  as  the  newborn  period,  since  the  Section  on  Child  Behavior 
has  undertaken  the  assessment  of  all  cases  studied  in  early  marriage,  whether 
they  have  completed  the  intermediate  studies  or  not.   It  is  not  necessary  for 
cross-stage  analyses  starting  from  different  points  of  time  to  utilize 
exactly  the  same  sample.   In  fact,  the  larger  the  sample  available  for  any 
given  comparison  the  better,  providing  there  is  no  selective  factor  operating 
to  produce  differences  between  cases  that  have  not  missed  a  phase  versus 
those  who  have. 

The  effort  to  accommodate  the  maximum  number  of  cases  studied  in  earlier 
phases  has  resulted  in  overloading  the  schedule  for  processing  groups  through 
the  nursery  school,  and  the  staff  of  this  section  is  to  be  commended  for  the 
sacrifice  of  the  usual  vacation  periods,  as  well  as  interim  periods  between 
groups,  ordinarily  used  to  catch  up  on  data  gathering,  in  order  to  study  as 
many  children  as  possible  at  the  time  they  reach  the  age  range  which  has  been 
set  for  the  study. 

This  section  is  currently  conducting  intra-branch  case  conferences  for 
selected  children  and  families  that  have  completed  the  preschool  phase.   It 
is  quite  a  task  to  collate  the  vast  amount  of  information  available  from 
early  marriage  through  to  the  preschool  period,  even  for  a  single  family. 
Currently,  each  section  prepares  a  written  summary  on  two  children  and 
families  to  be  contrasted  in  the  case  conference.    The  case  conference 
itself  is  largely  devoted  to  discussion  of  these  summaries,  and  their 
integration  by  the  staff  members  who  have  had  a  prior  opportunity  to  study 
all  reports.   The  summary  reports  include  a  final  study  of  the  marriage 
as  such,  based  on  interviews  conducted  by  the  section  on  family  development 
when  the  child  and  family  have  completed  the  preschool  period.   It  is  grati- 
fying to  reach  a  stage  in  our  studies  where  we  can  have  such  case  conferences. 
In  past  preparatory  studies,  these  conferences  have  led  our  staff  to  reorient- 
ations, such  as  toward  the  appreciation  of  the  impact  of  children  on  their 
parents .   The  insights  we  obtain  have  not  only  led  to  important  contributions 
to  the  child  and  family  development  field  at  large,  but  have  helped  us  to 
adjust  our  analysis  of  the  data  to  trends  that  can  be  seen  in  individual 
cases  but  that  might  not  appear  in  surveying  data  from  large  samples. 


I 


33 


Despite  being  involved  in  a  very  difficult  and  demanding  data  gathering 
process,  the  Section  on  Child  Behavior  has  been  able  to  make  some  progress 
in  preparing  reports  from  our  preparatory  studies  on  relations  between 
preschool  and  early  school-age  behavior.   These  results  were  reported  at 
scientific  meetings  in  the  last  year,  and  are  now  being  prepared  for  publi- 
cation with  some  of  the  feedback  in  mind  that  was  received  at  the  national 
meetings . 

Summary 

When  the  study  of  Cohort  II  was  launched  in  1966  it  seemed  to  many 
scientists  in  the  field,  and  even  to  those  of  us  who  have  been  engaged  in 
preparing  for  the  study  since  1959,  that  it  was  an  extremely  ambitious 
undertaking  to  try  to  keep  four  teams  of  investigators  working  together  for 
seven  years  on  phases  of  the  human  life  cycle  differing  as  much  as  early 
marriage  and  child  rearing.   However,  some  basically  new  information  on 
human  lives  can  only  be  gained  by  trying  new  approaches ,  and  at  this  point 
in  the  story  of  our  longitudinal  study  we  are  far  enough  along  that  we  can 
at  least  say  that  the  task  of  data  gathering  and  analysis  will  be  completed. 
The  coming  year  should  bring  the  first  glimpses  into  the  relations  between 
stages.   In  the  meantime,  our  enthusiasm  for  the  task  is  maintained  by  the 
many  exciting  developments  that  have  come  out  of  preparatory  studies  that 
led  to  Cohort  II.   In  past  reports  I  have  mentioned  one  finding  alone  from 
these  studies  that,  in  terms  of  public  benefit,  could  more  than  return  the 
cost  of  our  years  of  study.   I  am  referring  to  the  finding  of  an  association 
between  minor  physical  anomalies,  that  can  be  assessed  as  early  as  the 
newborn  and  third  month  of  life,  with  hyperactivity  in  later  childhood. 
Hyperactivity  is  one  of  the  most  frequent  bases  for  referral  to  treatment 
centers  in  early  childhood. 

In  the  present  report  I  have  mentioned  an  equally  promising  development. 
If  our  findings  on  the  long-term  consequences  of  sedatives  given  mothers 
during  labor  should  lead  to  a  new  series  of  studies  on  drugs  and  infant 
hormonal  response,  there  is  a  prospect  of  revision  in  current  thinking 
about  the  effects  of  this  aspect  of  obstetrical  practice.  Again,  the 
benefits  to  the  general  public  in  understanding  the  later  consequences  of 
obstetrical  procedures  could  be  considerable. 


34 


Annual  Report  of  the  Laboratory  of  Clinical  Psychobiology 
National  Institute  of  Mental  Health 
Frederick  Snyder,  M.D.,  Chief 
July  1,  1971  —  June  30,  1972 

The  metaphor  which  seems  most  apt  to  describe  the  Laboratory  of 
Clinical  Psychobiology  during  the  past  year  is  that  of  an  amoeba  contracting 
and  extending  at  the  same  tirae--sending  out  vigorous  pseudopods  despite 
continuing  diminution  of  its  total  corpus.  Termination  of  the  clinical 
research  and  treatment  unit  which  had  been  the  heart  of  our  earlier  program 
involved  very  significant  reductions  in  our  professional  staff  which  will 
proceed  still  further  at  the  end  of  this  fiscal  year.  Yet  a  new  clinical 
project  has  been  successfully  launched  without  the  use  of  a  nursing  unit, 
one  devoted  to  outpatient  insomniacs,  while  the  small  remaining  staff  has 
given  good  account  of  itself  in  strong  psychobiological  projects  employing 
patients  from  other  organizational  units,  normal  volunteers  and 
experimental  animals. 

The  most  conspicuously  successful  efforts  this  year  have  been 
those  on  the  psychobiology  of  aggression  in  the  rat,  for  which 
Dr.  Burr  S.  Eichelman  was  co-winner  of  the  A.E.  Bennett  Research  Award 
in  Basic  Science  from  the  Society  of  Biological  Psychiatry.  This  is  the 
second  successive  year  in  which  this  Laboratory  has  been  so  honoured, 
since  Dr.  Richard  J.  Wyatt  received  the  same  prize  last  year  for  his  work 
on  the  biochemistry  of  human  sleep  carried  out  here.  Although 
Dr.  Eichelman 's  approaches  to  rodent  aggression  are  wide  ranging,  encompassing 
(a)  genetic  differences,  (b)  experimental  manipulations,  such  as  hunger, 
thirst,  stress,  sleep  deprivation  and  alterations  of  sensory  input,  and 
(c)  brain  lesions,  perhaps  his  most  profitable  directions  have  involved 
various  pharmacological  manipulations  and  biochemical  measures  in 
collaboration  with  members  of  the  Laboratory  of  Clinical  Science.  They 
have  enabled  him  to  generate  a  categorical  division  of  rat  aggressive 
behavior  into  three  types  having  quite  distinct  biochemistry  underlying 
them.  Predatory  behavior  appears  to  be  influenced  by  serotonergic  and 
cholinergic  systems,  spontaneous  intra  species  aggression  seems  related 
to  dopamine,  while  irritable  aggression,  such  as  results  in  the  standard 
shock-induced  response,  is  most  consistently  associated  with  norepinephrine 
and  is  facilitated  by  activation  of  norepinephrine  receptors.  This 
reconceptualization  of  the  biology  of  aggression  has  already  served  to 
make  sense  out  of  a  great  deal  of  evidence  which  had  previously  seemed 
contradictory  and  chaotic,  and  may  well  be  pertinent  to  future  thinking 
about  human  aggression.  To  make  this  still  more  a  "year  of  aggression" 
for  the  Laboratory,  Dr.  Eichelman  organized  a  series  of  seminars  on  the 
study  of  animal  models  of  aggression  during  which  we  were  privileged  to 
hear  from  a  number  of  the  most  outstanding  experimentalists  now 


35 


pursuing  that  topic  in  this  country. 

A  second  yery   profitable  new  area  has  been  Dr.  Redford  B.  Williams' 
pursuit  of  the  cardiovascular  correlates  of  varying  transactional 
behaviors  both  in  human  and  animal  subjects.  Like  Dr.  Eichelman's 
contribution,  these  studies  promise  to  clarify  much  past  confusion  about     , 
the  concept  of  physiological  arousal,  so  crucial  to  psychiatric  thinking. 
In  essence  they  suggest  that  the  somatic  correlates  of  arousal  have 
directional  as  well  as  intensity  properties  depending  upon  whether  it  is 
in  response  to  internal  or  external  stimuli.  Behaviors  associated  with 
attentive  observation  of  the  environment  give  rise  to  a  norepinephrine 
pattern  of  bodily  response  resembling  that  of  peripheral  sympathetic 
nerve  activation,  while  rejection  of  environmental  stimuli  or  attention 
to  internal  stimuli  yield  an  epinephrine  pattern  of  cardiovascular  response, 
like  that  due  to  adrenal  medullary  activation.  If  attentiveness  to         i 
environmental  stimuli  is  an  important  determinant  of  cardiovascular 
response,  then  persons  who  differ  in  terms  of  characteristic  ways  of  attending 
to  stimuli  might  be  expected  to  differ  in  terms  of  their  typical  cardio- 
vascular functioning.  That  possibility  has  been  tied  in  with  the  interest 
of  Dr.  Monte  Buchsbaum  of  the  Laboratory  of  Psychology  in  "augmenters"  and 
"reducers"  of  incoming  external  stimuli,  augmenters  proving  different 
from  reducers  both  in  their  resting  cardiovascular  measures  and  in  their 
responses  to  experimental  arousal . 

Dr.  Williams'  studies  appear  to  have  at  least  one  important 
clinical  implication  for  plotting  the  course  of  somatic  arousal  over  the 
natural  history  of  acute  psychoses.  Serial  studies  of  forearm  blood  flow 
in  a  number  of  acute  schizophrenic  patients  have  now  documented  marked 
increases  in  forearm  blood  flow,  presumably  reflecting  escalation  of 
anxiety  levels,  just  prior  to  major  change  in  clinical  status,  most 
frequently  resolution  of  psychotic  symptoms,  but  in  a  few  instances  prior 
to  thetr  recurrence  also. 

Along  the  same  lines,  collaboration  between  Drs.  Williams  and 
Eichelman  has  resulted  in  some  provocative  findings  regarding  the 
psychobiology  of  blood  pressure  responses  in  the  rat.  Specifically,  rats 
of  certain  genetic  strains  shocked  in  pairs  and  fighting  in  their 
usual  stereotyped  fashion  were  shown  to  have  a  blood  pressure  fall 
immediately  afterwards,  although  the  same  rats  receiving  shocks  alone 
exhibit  only  disorganized  escape  attempts  and  have  a  subsequent  blood 
pressure  increase.  Going  on  to  elucidate  the  physiology  underlying  this     | 
curious  "social"  influence  on  hypertensive  response,  they  demonstrated 
that  hypotension  after  paired  fighting  depends  upon  intact  peripheral 
and  central  sympathetic  nerve  activation,  while  an  intact  adrenal  medulla 
is  equally  necessary  for  the  blood  pressure  rise  found  after  the  escape 
response  to  shock  alone.  Further  evidence  indicates  that  the  strains  of 
rats  with  blood  pressure  increases  after  fighting  have  low  serum  dopamine- 


36 


B-hydroxylase  levels,  while  all  strains  with  blood  pressure  decreases  under 
the  same  conditions  have  higher  levels  of  dopamine-B-hydroxylase. 

The  above  studies  illustrate  how  important  it  is  to  a  unit  as 
small  as  this  one  htat  it  has  such  rich  and  flexible  opportunities  for 
collaboration  with  other  units  of  the  NIMH  Intramural  program,  as  well  as 
with  other  Institutes  at  NIH.  The  value  of  collaboration  in  the  face  of 
depleted  staff  is  also  exemplified  by  our  partnerships  with  two  alumni, 
Drs.  Wyatt  and  Gill  in,  who  continue  to  channel  large  portions  of  their 
efforts  into  project  here  even  while  building  an  independent  sleep  research 
facility  in  the  Laboratory  of  Clinical  Psychopharmacology,  St.  Elizabeths' 
Hospital .  Only  by  virtue  of  their  initiative  have  we  been  able  to  continue 
studies  of  sleep  biochemistry  and  pharmacology  during  the  past  year, 
examining  effects  of  histidine, ^^Tetrahydrocannabinol ,  carbohydrate  active 
steroids  and  various  catecholamine  precursors  on  human  sleep.  Other 
promising  collaborations  begun  during  the  past  year  are  with  Dr.  Robert 
Coursey  of  the  Department  of  Psychology,  University  of  Maryland,  who  has 
joined  our  efforts  to  fathom  the  psychological  make-up  of  insomniacs,  as 
well  as  with  Miss  Evelyn  Elwell  of  Catholic  University,  Department  of 
Nursing,  who  is  undertaking  a  doctoral  project  with  us  on  the  changes  in 
sleep  patterns  prior  to  and  following  open  heart  surgery.  We  are  also 
most  grateful  for  the  help  of  Dr.  Andrew  G.  Morrow,  Chief  of  NHLI  Surgery 
Branch,  for  welcoming  our  studies  of  sleep  in  his  cardiac  patients  at  the 
time  of  surgery.  Not  all  collaboration  work  out,  however,  and  several 
we  had  undertaken  with  the  Walter  Reed  Institute  of  Research  fell  by  the 
wayside  during  the  past  year.  Projected  studies  of  spontaneous  rhythms 
in  waking  psychophysiology  and  of  effects  of  adversive  conditioning  stress 
on  sleep  of  monkeys  were  begun,  but  had  to  be  abandoned  when  Dr.  Tom  Frazier 
left  Walter  Reed  and  Dr.  William  Orr  was  reassigned  to  other  duties.  As 
discussed  in  a  recent  review  of  available  evidence  about  sleep  patterns  in 
psychiatric  illness,  effects  of  chronic  stress  on  sleep  is  a  crucial 
question  still  unanswered.  If  the  anticipatory  stress  of  impending 
open  heart  surgery  is  a  natural  and  human  counterpart  to  the  stress  we  were 
attempting  to  produce  experimentally  in  monkeys,  we  may  soon  be  able  to 
remedy  that  deficiency. 

Another  experimental  approach  to  the  consequences  of  stress  now 
underway  employs  the  widely  used  model  of  immobilization  stress  in 
laboratory  rats.  In  keeping  with  findings  from  the  Laboratory  of  Clinical 
Science  on  central  biochemical  changes  resulting  from  that  procedure, 
our  Laboratory  has  found  concomitant  changes  in  aggressive  responses 
or  blood  pressure,  and  work  still  in  progress  appears  to  demonstrate 
even  more  striking  changes  in  the  nature  of  sleep,  drastic  attrition  of  the 
REM  phase  qualitatively  similar  to  that  we  have  previously  described  in 
acute  schizophrenic  and  manic  psychoses. 


37 


Throughout  our  many  years  of  studying  sleep  in  psychiatric 
patients  there  was  the  nagging  question  of  what  sleep  patterns  might  be 
like  in  less  ill  persons  who  complain  only  of  inability  to  sleep.  Might 
the  sleep  of  the  millions  who  call  themselves  insomniacs  be  even  more 
disturbed  and  abnormal  than  the  anomalies  we  have  found  in  severely  depressed 
or  acutely  schizophrenic  patersons?  The  problem  was  that  insomniacs  could 
not  be  enticed  to  spend  their  nights  in  our  laboratory  while  we  recorded 
their  sleep  patterns.  Dr.  Bernard  Frankel  finally  overcame  that 
difficulty  during  the  past  year  by  offering  a  therapeutic  trial  of 
"transcerebral  electrotherapy"  (the  so-called  electrosleep  widely 
employed  in  the  Soviet  Union  and  eastern  Europe  but  tried  very  little  in 
this  country)  to  insomniacs  in  exchange  for  our  access  to  their  sleep 
patterns.  Although  the  number  of  respondents  has  not  been  over-whelming, 
by  this  means  we  have  been  able  to  initiate  a  more  thorough  study  of 
insomniacs  and  their  sleep  patterns  than  any  now  available  in  the  world 
literature.  The  possible  effects  of  transcerebral  electrotherapy  would 
be  of  interest  in  themselves  if  we  could  demonstrate  them.  Unfortunately, 
results  of  that  treatment  thus  far  have  not  been  encouraging  in  our 
population  of  insomniacs,  except  insofar  as  they  have  given  us  the  chance 
to  take  an  objective  look  at  insomnia.  Contrary  to  some  rather  sketchy 
earlier  reports,  we  do  find  abnormalities  of  sleep  corresponding  to  the 
Insomniacs'  complaints.  Compared  to  age-matched  controls  their  sleep  is 
delayed,  abbreviated  and  fragmented,  yet  the  degree  of  such  impairment  is 
rather  slight  compared  to  the  extent  of  the  patients'  complaints  and 
obsessive  concern.  Nevertheless,  since  sleep  EEG  patterns  alone  may  not 
reveal  everything  unusual  about  insomniacs,  we  shall  continue  our  studies 
of  them  on  a  broad  front,  gathering  every  accessible  information  about 
their  psychology  and  physiology  during  waking  as  well  as  during  sleep. 

Fully  interpreting  the  significance  of  alterations  in  the  internal 
architecture  of  sleep,  whether  the  rather  minor  ones  of  insomniacs  or  the 
much  more  drastic  ones  of  psychotic  depressives,  will  not  be  possible  until 
we  have  achieved  much  addittonal  understanding  of  the  basic  biological 
significance  of  sleep  and  its  component  states.  It  is  to  that  end  that 
our  long-term  program  of  comparative  studies  of  sleep  is  devoted,  looking 
for  clues  in  the  varied  manifestations  of  sleep  to  be  found  in  diverse 
animal  forms,  as  well  as  in  the  effects  of  experimental  variables  similar 
to  those  encountered  in  the  natural  course  of  animal  life.  Devising  the 
technical  means  to  achieve  such  studies  has  been  a  long  and  still 
continuing  struggle.  We  have  arrived  at  satisfactory,  albeit  still  very 
laborious  expedients,  which  do  now  provide  the  necessary  information. 
With  them  we  pursue  our  longstanding  interest  in  the  prototypical 
characteristics  of  mammalian  sleep  as  found  in  a  number  of  expecially 
primitive  forms,  but  have  also  begun  to  examine  sleep  in  some  of  the 
most  highly  evolved  end-products  of  evolution,  such  as  the  ungulates. 


38 


Just  as  the  overall  adaptations  of  these  creatures  are  highly  specialized, 
so  they  also  appear  to  have  sleep  patterns  most  extremely  modified  from 
the  primitive  mammalian  form  and  much  more  sensitive  to  influence  by 
environmental  variables. 

The  charting  of  such  variations  in  the  comparative  biology  of  sleep 
in  relation  to  other  specializations  of  ecological  adaptation  promises 
an  exciting  quest.  Thanks  to  the  opportunity  for  a  long  over-due  foreign 
work  assignment,  the  Chief  of  Laboratory  of  Clinical  Psychobiology  will 
attempt  to  continue  that  quest  during  the  next  year  through  a  field  project 
in  Africa,  collecting  sleep-waking  patterns  from  a  variety  of  that 
continents' very  special  animals  by  long-range  telemetry.  While  he  chases 
giraffes  through  the  thorn  bush,  the  small  remainder  of  the  Laboratory  of 
Clinical  Psychobiology  staff  will,  he  hopes,  continue  their  diligent 
labours  in  Bethesda. 


39 


Annual  Report  of  the  Laboratory  of  Clinical  Science 
National   Institute  of  Mental  Health 

Irwin  J.  Kopin,  M.D.,  Chief 
July  1,  1971  through  June  30,  1972 

Introduction 

The  scope  of  investigations  conducted  in  the  Laboratory  of  Clinical  Science 
includes  fundamental  research  on  the  biochemical,  neurophysiologic  and 
hormonal  processes  which  control  neuronal  function,  inquiries  on  how  drugs, 
humoral  agents  and  environmental  factors  influence  the  development  and 
function  of  the  nervous  system  and  clinical  studies  to  determine  the  altera- 
tions in  the  fundamental  processes  which  attend  neuropsychiatric  illnesses  and 
how  they  may  be  corrected. 

The  LCS  consists  of  the  Office  of  the  Chief  (which  includes  the  Units  on 
Clinical  Biochemistry,  Clinical  Pharmacology,  Analytical  Biochemistry, 
Psychosomatics  and  Histopharmacology)  and  the  Sections  on  Pharmacology, 
Medicine,  Psychiatry  and  Experimental  Therapeutics.     The  diversity  of  talents 
and  individual  approaches  to  research  provide  a  unique  opportunity  for  inter- 
action of  clinical  and  fundamental  investigations.     The  compiling  of  clinical 
problems  which  can  be  attached  at  a  basic  level  and  of  basic  observations 
which  are  rapidly  applied  to  clinical  situations  has  proved  to  be  particularly 
fruitful. 

Section  on  Pharmacology 
Julius  Axel  rod,  Ph.D.,  Chief 

The  interests  of  the  Section  on  Pharmacology  have  continued  along  three  areas 
of  research:     catecholamines,  tryptamine  and  the  pineal  gland. 

Dr.  Richard  M.  Wei nshil bourn,  who  last  year  reported  the  presence  of  dopamine- 
beta-hydroxylase  in  human  serum,  found  that  the  dopamine-beta-hydroxylase  level 
is  markedly  reduced  or  absent  in  children  with  Familial  Dysautonomi a .     He  also 
found  that  the  serum  levels  of  the  enzyme  gradually  increase  from  birth  to 
puberty.     Dr.  G.   Frederick  Wooten  has  found  a  rapid  increase  in  dopamine-beta- 
hydroxylase  release  into  the  blood  during  stress  and  cardiovascular  responses 
to  cold,  tilt,  etc.       In  collaboration  with  Dr.  Nguyen  B.  Thoa  (Section  on 
Medicine),  Dr.  Wooten  has  been  examining  the  process  of  neurotransmitter 
release  from  the  sympathetic  nerve  endings. 

Dr.  Joseph  T.  Coyle  has  continued  his  work  on  the  development  of  the  adrenergic 
system  in  brain.     He  has  devised  a  sensitive  method  for  measurement  of  tyrosine 
hydroxylase  in  brain  and  examined  its  distribution  in  various  areas  of  the  rat 
brain. 

In  the  rat  brain,  the  enzymes  involved  in  the  biosynthesis  of  norepinephrine 
(tyrosine  hydroxylase,  dopa  decarboxylase  and  dopamine-beta-hydroxylase)  appear 
five  days  after  gestation.     At  first  they  are  located  mainly  in  the  cell 
bodies,  but  reach  the  nerve  terminals  18  days  after  gestation.     Two  days  later 
(20  days  after  gestation),  the  brain  norepinephrine  level  appears  to  be 
strikingly  elevated. 


41 


Drs.  Wooten  and  Coyle  have  found  that  both  tyrosine  hydroxylase  and  dopamine- 
beta-hydroxylase  move  down  the  axon  by  a  rapid  transport  process  involving 
microtubular  elements.  Repeated  administration  of  reserpine  caused  an  increase 
in  axonal  tyrosine  hydroxylase  and  dopamine-beta-hydroxylase,  but  caused  no 
change  in  the  transport  of  the  enzymes. 

Dr.  Roland  Ciarnello  induced  phenyl ethanol ami ne-N-methyl  transferase  (the 
adrenaline-forming  enzyme)  in  sympathetic  ganglia  of  newborn  rats  with 
dexamethasone.  Drs.  Juan  Saavedra  and  Axel  rod  have  developed  a  specific 
sensitive  enzymatic  assay  for  tryptamine  and  found  the  amine  to  be  normally 
present  in  brain  and  other  tissues.  The  intracerebral  administration  of 
tryptamine-C^**  resulted  in  the  formation  of  methyl tryptamine  and  dimethyl - 
tryptamine.  An  enzyme  that  forms  methyl tryptami ne  and  dimethyl tryptamine 
from  tryptamine  has  been  found  in  both  the  human  and  rat  brain;  an  inhibitor 
for  the  enzyme  was  also  detected. 

Drs.  Takeo  Deguchi  and  Axel  rod  have  developed  a  sensitive  assay  for  measuring 
N-acetyl serotonin  in  the  rat  pineal  gland.  The  enzyme  can  be  induced  in  the 
pineal  gland  about  20-fold  by  dopa,  noradrenaline,  isoproterenol  and  monoamine 
oxidase  inhibitors.  The  induction  of  the  enzyme  can  be  prevented  by  the  prior 
administration  of  the  beta-adrenergic  blocking  agent,  propanolol.  Sympathetic 
nerve  denervation  of  the  pineal  gland  causes  a  superinduction  of  N-acetyl - 
serotonin  transferase  in  the  pineal  gland  (100-fold)  by  beta-adrenergic  agents. 

Section  on  Experimental  Therapeutics 
Thomas  N.  Chase,  M.D.,  Chief 

The  research  conducted  in  the  Section  on  Experimental  Therapeutics  is  directed 
towards  elucidation  of  the  mechanism  of  action  of  drugs  which  influence  central 
nervous  system  function. 

Preclinical  studies  carried  out  with  Drs.  Larry  K.Y.  Ng,  Robert  W.  Col  burn  and 
Kopin  indicate  that  5-hydroxy tryptophan  enhances  the  release  of  both  dopamine 
and  serotonin  from  brain  tissues.  The  observations  that  the  enhanced  release 
appeared  dependent  on  the  decarboxylation  of  5-hydroxytryptophan  to  serotonin 
and  that  the  enhanced  release  was  substantially  diminished  in  tissues  where 
catechol  ami ne-containing  terminals  had  been  selectively  destroyed  by 
6-hydroxydopamine  suggest  that  dopamine  may  be  released  by  serotonin  derived 
from  the  decarboxylation  of  5-hydroxytryptophan  in  catechol  ami nergic  neurons. 
Exogenously  administered  5-hydroxytryptophan  decarboxylated  to  serotonin  may 
displace  endogenous  catecholamines,  thereby  offering  a  possible  explanation  for 
some  of  the  behavioral  and  neurologic  effects  of  5-hydroxytryptophan  loading  in 
man. 

Attempts  to  study  naturally  occurring  or  drug-  (phenothiazine)  induced 
involuntary  movement  disorders  have  long  been  hampered  by  the  lack  of  a  suitable 
animal  model.  Intraventricular  or  intracerebral  administration  of  6-hydroxy- 
dopamine significantly  increases  the  susceptibility  of  monkeys  to  involuntary 
movements  induced  by  L-dopa  (the  precursor  of  dopamine)  or  apomorphine  (a 
dopamine-receptor  stimulator).  The  findings  support  the  contention  that 
denervation  supersensitivity  of  central  catechol  ami nergic  receptors  may  be 
involved  in  the  production  of  dyskinesias  during  L-dopa  treatment  of  patients 


42 


with  extrapyramidal  disease  and  suggest  that  6-hydroxydopamine-pretreated 
primates  may  provide  a  useful  paradigm  for  future  studies  of  the  relationship 
between  catechol  ami ne-containing  neural  systems  and  human  dyskinesias. 

The  probenecid-induced  accumulation  of  monoamine  metabolites  in  cerebrospinal 
fluid  has  been  used  to  provide  an  index  of  their  rate  of  formation  and  to  the 
central  turnover  of  the  parent  amines.     In  patients  with  idiopathic  Parkinson's 
disease,  the  basal  concentrations  and  probenecid-induced  accumulations  of 
homovanillic  acid  are  considerably  below  those  of  control  subjects.     Although 
steady-state  levels  of  5-hydroxyindoleacetic  acid  did  not  differ  significantly 
from  normal  values,  there  was  a  substantial  dimunition  in  the  response  of  the 
serotonin  metabolite  to  probenecid.     Pretreatment  severity  of  parkinsonian 
rigidity  and  bradykinesia,  but  not  tremor,  correlated  Inversely  with  the 
probenecid-induced  rise  in  both  monoamine  metabolites.     No  association  was 
found,  however,  between  the  therapeutic  response  to  L-dopa  and  either  the 
severity  of  parkinsonian  signs  prior  to  therapy  or    the  magnitude  of  the  defect 
in  monoamine  metabolism.     Our  results  cast  doubt  on  the  prevailing  notion  that 
the  ability  of  L-dopa  to  ameliorate  parkinsonian  signs  is  solely  contingent  on 
its  conversion  to  dopamine  in  surviving  dopaminergic  neurons.     In  contrast  to 
naturally  occurring  Parkinson's  disease,  normal  or  slightly  elevated 
probenecid-induced  accumulations  of  homovanillic  acid  were  observed  in  patients 
who  developed  parkinsonian  signs  while  receiving  psychotropic  phenothiazines 
or  related  neuroleptics.     The  ability  of  L-dopa  to  ameliorate  parkinsonian  signs 
in  schizophrenics  who  had  developed  extrapyramidal  dysfunction  during  chronic 
neuroleptic  therapy  also  continues  to  yield  favorable  results.     Our 
observations  support  the  contention  that  pharmacologic  parkinsonism  may  be  the 
consequence  of  a  drug-induced  blockade  of  dopaminergic  receptors. 

Studies  carried  out  with  Drs.  Hinrich  Cramer  and  Ng  have  shown  that  probenecid 
significantly  elevates  3 ',5 '-adenosine  monophosphate  (cyclic-AMP)  concentrations 
in  the  lumbar  spinal   fluid  of  patients  with  various  neurologic  disorders. 
Because  experiments  in  the  laboratory  animals  indicate  that  probenecid  does  not 
affect  brain  cyclic-AMP  levels,  our  clinical  observations  suggest  that 
probenecid  may  inhibit  the  efflux  of  cyclic-AMP  from  the  spinal  fluid 
compartment.     The  rate  of  cyclic-AMP  rise  during  probenecid  treatment  may  thus 
provide  a  means  for  estimating  the  central  turnover  of  the  nucleotide.     Mrs. 
Edna  K.  Gordon  developed  an  improved  gas-liquid  chromotography  method  for 
measuring  cerebrospinal  fluid  levels  of  3-methoxy-4-hydroxyphenyl glycol   (MHPG), 
a  major  product  of  norepinephrine  metabolism.     In  studies  of  more  than  60 
patients,  we  found  MHPG  concentrations  to  be  similar  in  ventricular  and  lumbar 
spinal   fluid.     About  one-third  of  the  MHPG  from    either  source  occurred  as  the 
sulfate  conjugate.     The  oral  administration  of  alpha-methyl -para-tyrosine  (an 
inhibitor  of  catecholamine  biosyntheses)  substantially  reduced  MHPG  in  all 
patients  tested.     Because  relatively  little  Intravenously  infused,  isotopically 
labelled  MHPG  enters  spinal   fluid,  our  results  suggest  that  MHPG  levels  in 
lumbar  spinal   fluid  may  provide  an  index  to  central  norepinephrine  metabolism 
in  man. 

Current  clinical  studies  in  patients  with  Huntington's  chorea  indicate  a 
characteristic  abnormality  of  dopaminergic,  but  not  serotonergic,  mechanisms. 
Probenecid-induced  accumulations  of  5-hydroxy1ndoleacet1c  acid  were  found  to 
be  normal   in  the  spinal  fluid  of  patients  with  Huntington's  chorea.     In  doses 


43 


sufficient  to  substantially  affect  the  spinal-fluid  content  of  5-hydroxy- 
indoleacetic  acid,  neither  L-tryptophan  (a  precursor  of  serotonin)  nor 
para-chloro-phenylalanine  (a  specific  inhibitor  of  serotonin  biosynthesis) 
altered  motor  or  behavioral  function.     On  the  other  hand,  the  response  of 
homovanillic  acid  to  probenecid  was  significantly  diminished  in  choreatic 
patients,  although  the  degree  of  abnormality  appeared  independent  of  the 
severity  of  clinical  signs.     The  oral  administration  of  L-dopa  consistently 
exacerbated  the  involuntary  movements,  while  alpha-methyl -para-tyros ine  (an 
inhibitor  of  catecholamine  synthesis)  tended  to  ameliorate  hyperkinesis. 
Because  the  nigrostriatal  dopaminergic  system  remains  morphologically  intact 
in  Huntington's  chorea,  we  hypothesize  that  the  reduction  in  dopamine 
metabolism  in  the  disorder  occurs  as  a  secondary  phenomenon,  possibly  owing 
to  an  interneuronal   feedback  mechanism. 

A  long-term  study  of  the  antiparkinsonian  efficacy  and  toxicity  of  L-dopa 
alone  and  in  combination  with  a  peripheral  decarboxylase  inhibitor  (MK-486) 
has  now  entered  its  third  year.     Results  in  stateside  patients  with  idiopathic 
parkinsonism  and  in  Guamanians  with  Parkinsonism-dementia  (in  collaboration 
with  Dr.  Jacob  A.  Brody)  affirm  the  substantially  improved  therapeutic  to  toxic 
ratio  reported  last  year.     In  contrast,  the  administration  of  3-0-methyldopa, 
alone  or  with  MK-486,  failed  to  benefit  patients  with  idiopathic  parkinsonism. 
Because  levels  of  apparent  L-dopa  in  plasma  and  homovanillic  acid  in  lumbar 
spinal  fluid  approximated  levels  found  in  patients  receiving  therapeutically 
effective  doses  of  L-dopa,  our  findings  raise  some  question  about  the  conven- 
tionally assumed  mechanism  of  action  of  L-dopa.     Clinical   studies  of  fusaric 
acid,  a  new  dopamine-beta-hydroxylase  inhibitor,  have  recently  been  conducted 
in  patients  with  various  extrapyramidal  disorders.     Use  of  fusaric  acid  alone 
or  together  with  a  fixed  dose  of  L-dopa  failed  to  alter  parkinsonian  signs. 

Section  on  Medicine 
Irwin  J.  Kopin,  M.D.,  Chief 

The  Section  on  Medicine  has  continued  to  study  the  mechanisms  controlling 
enzyme  levels  and  amine  synthesis  in  adrenal  glands  and  adrenergic  neurons. 

Repeated  stress  is  associated  with  elevation  of  levels  of  enzymes  required  to 
synthesize  catecholamines.     The  mechanism  of  change  in  rate  of  enzyme  synthesis 
involves  release  of  catecholamines  and  stimulation  of  formation  of  cyclic-AMP. 
Enzymes  are  synthesized  in  the  cell  body  and  transported  to  the  nerve  ending 
where  they  are  essential  for  replacement  of  released  neurotransmitters. 
Dopamine-beta-hydroxylase,  the  enzyme  responsible  for  the  final   step  in 
norepinephrine  formation,  is  stored  in  synaptic  vesicles  of  adrenergic  neurons 
and  IS  released  along  with  norepinephrine.     Interference  with  axonal   transport 
by  application  of  drugs  (colchicine  and  vinblastine)  which  disrupt  neurotubules 
in  the  axon  initially  results  in  accumulation  of  dopamine-beta-hydroxylase- 
after  one  or  two  days,  however,  the  synthetic  processes  in  the  cell   body  are 
switched  to  formation  of  proteins  required  for  structure  (membranes 
neurotubules)  rather  than  enzymes  required  for  function.  * 

Iwl!^S^K"'^"'n°!-*-^"""'"fr  '"^^ease,  which  appears  to  involve  exocytosis.  is 
blocked  by  colchicine,  vinblastine  and  cytochalasin  B,  presumably  as  a 
consequence  of  interference  with  neurotubules  and/or  neurofibrils 


44 


Prostaglandins  diminish  and  phenoxybenzamine  enhances  stimulation-induced 
release  of  both  dopamine-beta-hydroxylase  and  norepinephrine  from  the  guinea 
pig  vas  deferens,  presumably  as  a  consequence  of  interaction  with  calcium  ions 
which  are  required  for  transmitter  release. 

Neurotransmitters  can  be  replaced  by  chemically  related,  but  less  effective, 
compounds  which  have  been  called  "false  transmitters."  Replacement  by  dopamine 
of  serotonin  in  serotonergic  neurons  may  occur  when  large  doses  of  L-dopa  are 
administered  and  may  account  for  some  of  the  effects  of  L-dopa  treatment  of 
parkinsonian  patients.  Similarly,  5-hydroxytryptophan  administration  may  result 
in  replacement  of  dopamine  by  serotonin. 

The  development  of  methods  for  sustaining  adrenergic  tissues  in  vitro  has 
permitted  investigation  of  factors  influencing  induction  of  catechol  ami ne- 
synthesizing  enzymes  and  reinnervation  of  sympathetically  denervated  tissues. 
In  organ  culture,  sympathetic  ganglia  cells  develop  axonal  sprouts,  which  have 
the  properties  of  nerve  endings  almost  as  soon  as  they  form.  The  development 
of  axonal  sprouts  and  their  ramification  into  other  tissues  are  influenced  by 
nerve  growth  factor  and  are  blocked  by  drugs  which  interfere  with  neurotubular 
integrity. 

Our  studies  contribute  to  the  understanding  of  neuronal  development  and  function 
and  how  these  processes  may  be  influenced  by  drugs,  hormones  and  environmental 
factors . 

Section  on  Psychiatry 

Irwin  J.  Kopin,  M.D. ,  Acting  Chief 

Frederick  K.  Goodwin,  M.D.,  Chief,  Clinical  Research  Unit  4-West 

Dennis  L.  Murphy,  M.D.,  Chief,  Clinical  Research  Unit  3-East 

The  Section  on  Psychiatry  has  continued  investigations  on  the  psychobiological 
processes  in  affective  disorders  and  the  effects  of  various  psychoactive  drugs 
on  amine  metabolism  as  reflected  by  metabolites  in  the  cerebrospinal  fluid. 
The  studies  using  cerebrospinal  fluid  levels  of  amine  metabolites  and  the  rate 
of  accumulation  of  the  compounds  after  administration  of  probenecid,  a  drug 
which  blocks  transport  of  the  acid  metabolites  from  the  spinal  fluid,  have  been 
shown  to  be  valid  indices  of  turnover  of  amines  in  brain.  Differences  in  amine 
metabolite  formation  have  been  found  after  administration  of  amine  precursors 
or  psychoactive  drugs.  The  levels  and  rates  of  accumulation  are  influenced  by 
physical  activity  and  are  suggested  in  some  patient  groups. 

A  computer-scored  milieu  rating  scale  for  quantification  of  changes  in  manic 
and  depressive  features  of  mental  illness  was  validated  by  cross-ward 
comparisons.  Therapeutic  trials  based  on  hypotheses  of  the  role  of  amines  in 
affective  disorders  have  continued.  Although  administration  of  tryptophan 
results  in  enhanced  indoleamine  formation,  it  has  only  minimal  antidepressant 
effects.  Tetrahydrocannabinol  is  not  an  effective  antidepressant  agent; 
cocaine,  which  potentiates  the  actions  of  catecholamines  in  peripheral  organs, 
is  definitely  psychoactive,  but  not  clearly  an  antidepressant.  Comparison  of 
the  antidepressant  effects  of  lithium  and  imipramine  suggests  that  unipolar- 
and  bipolar-depressed  patients  may  react  differently  to  the  two  drugs.  Marked 


45 


( 


changes  in  verbal -learning  capacity  and  memory  were  observed  in  mania, 
depression  and  after  administration  of  psychoactive  drugs. 

Blood  platelets  have  been  used  to  study  individual  differences  in  the  cellular 
effects  of  anti depressive  and  antimanic  drugs.     Bipolar-depressed  patients 
have  been  found  to  have  platelets  with  reduced  monoamine  oxidase  activity  and 
increased  levels  of  octopamine. 

Followup  studies  of  manic-depressive  patients  have  been  completed  on  60  former 
patients  and  their  spouses  and  indicate  correlations  between  clinical  features 
during  the  manic  episode  and  the  subsequent  outcome. 

Office  of  the  Chief 
Irwin  J.   Kopin,  M.D.,  Chief 

Unit  on  Clinical  Pharmacology    (Julius  Axelrod,   Ph.D.    and  Irwin  J.    Kopin^ 
M.D.,  CoHeads).     The  metabolism  and  effects  of  tetrahydrocannabinol   have  been 
examined  in  nafve  subjects  and  chronic  users  of  marijuana.     It  was  found  that 
chronic  users  metabolize  the  drug  more  rapidly  and  appear  to  be  more  sensitive 
to  the  agent,  possibly  as  a  consequence  of  more  rapid  formation  of  ll-hydroxy- 
delta'-tetrahydrocannabinol.     Blood  levels  reach  a  peak  more  slowly  after  oral 
administration  than  after  inhalation  or  intravenous  infusion,  and  effects 
appear  to  parallel  the  circulatory  drug  levels:     Initially  rapid  and  subse- 
quently slow  excretion  suggests  that  the  drug  metabolites  are  stored  in  tissues. 
The  acute  cardiovascular  effects  are  consistent  with  elevated  levels  of 
catecholamines  excreted  in  the  urine. 

Unit  on  Analytical  Biochemistry    (Robert  W,    Colbum,    Ph.D.,   Head).      The 
Unit  has  continued  to  develop  methods  for  screening  metabolite  excretion 
patterns  in  psychiatric  patients  and  to  study  the  disposition  of  biogenic 
amines  in  the  synaptosomes  obtained  from  rat  brain.     The  metabolic  fate  of 
norepinephrine  is  altered  in  pinched-off  nerve  endings  by  drugs  such  as 
reserpine  and  tyramine  in  the  same  manner  as  the  drugs  alter  metabolism  of 
amines  in  the  peripheral  adrenergic  neurons.     Tyramine  enhances  release  of  the 
unchanged  amine  by  permitting  its  metabolism  by  monoamine  oxidase.     Synapto- 
somes appear  to  accumulate  tetrahydrocannabinol,  and  its  effects  on  amines  is 
now  being  investigated.     The  effects  of  L-dopa  on  disposition  of  cerebral  mono- 
amines in  rat  brain  homoqenates  has  been  studied  in  the  model  system,  and  Dr. 
Lorenz  Ng  was  a  recipient  of  the  A.E.  Bennett  Award  for  the  research  involved. 

Unit  on  Psijahosomatics    (Philippe  V.    Cordon,   M.D.,   Head).      The  Unit  has 
continued  a  variety  of  clinical   projects  in  collaboration  with  other  groups  of 
the  Laboratory.     Therapeutic  doses  of  L-dopa  result  in  decreased  levels  of  red 
cell  catechol -0-methyl   transferase.     Studies  of  the  effects  of  L-dopa  alone  . 

and  of  L-dopa  plus  MK-486  on  plasma  renin  and  aldosterone  will   soon  be  t 

completed  in  ten  patients.     Effects  of  L-dopa  on  gonadotrophic  hormones,  TSH 
and  HGH  have  been  studied  in  eight  patients.     Circulatory  parameters  previously 
found  to  be  affected  by  L-dopa  have  been  studied  in  five  patients  treated  with 
the  principal  metabolite  of  L-dopa,  0-methyl dopa.     Serum  dopamine-beta- 
hydroxylase  (DBH)  as  an  index  of  sympathetic  nerve  function  was  studied  in 
normal  volunteers.     Increases  in  DBH  activity  were  observed  during  exercise, 
cold  stress  and  as  part  of  the  psychic  response  to  initial  studies.     During         i 

46 


hemorrhage,  DBH  activity  increases  in  parallel  with  increased  sympathetic  nerve 
activity  in  cats.  Study  of  the  effects  of  ethano'i  on  DBH  has  begun.  Fusaric 
acid,  known  to  inhibit  DBH  activity  in  animals,  was  found  to  inhibit  serum  DBH 
activity  in  man. 

Unit  on  Clinical  Biochemistry    (Edna  K.    Gordon^   Head).      The  Unit  has 
continued  to  develop  and  improve  methods  for  assay  of  metabolites  of  amines  in 
various  body  fluids  and  to  provide  the  biochemical  technology  required  for  the 
investigations  conducted  in  the  Section  on  Psychiatry  and  some  o1^  the  studies 
of  the  Section  on  Experimental  Therapeutics. 

Unit  on  Histopharmaaology    (David  M.   Jacobowitz,  Ph.D.^  Head).      Using 
histofluorimetric  techniques,  the  localization  of  biogenic  amines  in  brain, 
ganglia  and  peripheral  tissues  has  been  examined  in  a  variety  of  situations. 
After  6-hydroxydopa  treatment  the  disappearance  of  adrenergic  neurons  in  brain 
has  been  related  to  changes  in  appetitive,  water-consumption  and  fighting 
behaviors.  Reinnervation  in  organ  culture  of  peripheral  tissues  (iris,  pineal 
gland)  by  axon  growth  from  sympathetic  ganglia  has  been  demonstrated  even  when 
species  are  crossed  (e.g.  mouse  ganglion  and  rat  iris).  Tryptamine  formed  from 
tryptophan  after  administration  of  monoamine  oxidase  inhibitors  was  found  to  be 
present  in  the  capillary  walls  of  the  brain. 

The  marked  increase  in  phenyl ethanol ami ne-N-methyl  transferase  (PNMT)  in  the 
ganglia  of  newborn  rats  treated  with  dexamethasone  was  shown  to  be  a  conse- 
quence of  proliferation  of  chromaffin  tissue.  The  chromaffin  cells  persist 
beyond  the  time  of  PNMT  elevation  but  gradually  lose  their  ability  to 
synthesize  and  store  catecholamines.  Using  6-hydroxydopamine  implants  to 
destroy  adrenergic  neurons  in  brain,  movement  disorders  in  monkeys  have  been 
produced.  The  rate  and  extent  of  destruction  can  be  assessed  by  histological 
techniques.  Similar  studies  of  the  autotranspl anted  hearts  of  dogs  reveal 
sympathetic  reinnervation  mainly  localized  to  the  left  atrium  and  left 
ventricle. 


47 


Annual  Report  of  the  Laboratory  of  Psychology 

National  Institute  of  Mental  Health 

David  Rosenthal,  Ph.D.,  Chief 

July  1,  1971  -  June  30,  1972 

FY  1972  has  essentially  been  a  business -as -usual  year  for  the  Lab- 
oratory of  Psychology.   However,  during  the  year  two  investigators  left  the 
Laboratory  to  work  elsewhere,  and  although  we  might  have  used  their  positions 
to  generate  new  research  programs  in  the  Laboratory,  for  various  reasons  this 
has  not  as  yet  been  possible. 

The  research  problems  concerning  the  Laboratory  continue  to  include 
brain  and  behavior,  schizophrenia,  other  psychopathology  -  especially  minimal 
brain  dysfunction  in  children,  behavioral  development,  communication  proc- 
esses, thought  processes,  perception  and  creativity.   The  creativity  research, 
however,  will  be  phased  out  in  another  year.   The  new  laboratory  for  infant 
studies  is  almost  completed  and  should  be  ready  for  occupancy  soon.   The 
major  accomplishments  of  the  Laboratory  in  FY  1972  were  as  follows: 

Brain  Function  and  Behavior  in  Primates: 


Cortical  Mechanisms  in  Vision. 


In  one  study,  lesions  were  placed  in  the  superior  colliculus  of 
monkeys  in  order  to  determine  whether  the  secondary  visual  pathway  present  in 
the  rat,  cat,  tree  shrew,  and  squirrel  is  also  present  in  higher  primates. 
Utilizing  both  the  Fink-Heimer  and  Voneida  silver  impregnation  techniques  we 
have  demonstrated  that  the  superior  colliculus  sends  a  heavy  projection  to 
the  inferior  portion  of  the  pulvinar,  a  connection  which  appears  to  be  homol- 
ogous to  that  reported  in  non-primate  animals.   In  addition  the  colliculus 
sends  a  relatively  heavy  projection  to  the  nucleus  centralis  lateralis. 
Animals  have  now  been  prepared  with  lesions  placed  either  superficially  or 
deep  in  the  superior  colliculus  to  determine  if  these  two  pathways  can  be 
dissociated.   Preliminary  results  from  another  study  indicate  that  the  pre- 
tectum,  also  involved  in  vision,  projects  to  the  parietal  cortex  through  the 
lateral  posterior  nucleus,  suggesting  still  another  visual  pathway. 

The  evidence  cited  above  in  support  of  a  transcortical  pathway  from 
striate  through  prestriate  to  inferotemporal  cortex  favors  a  sequential  acti- 
vation model  for  object  vision.   This  raises  the  question  of  whether  or  not 
such  a  model  can  be  extended  beyond  the  visual  system  to  encompass  stimulus- 
reward  associative  learning.   Translated  into  functional  anatomical  terms, 
the  question  is  whether  visual  objects  might  gain  motivational  and  emotional 
significance  through  an  interaction  between  the  inferotemporal  cortex  and  the 
limbic  system.   The  three  major  telencephalic  outputs  from  the  inferoteitporal 
area  are  (a)  to  the  orbital  frontal  cortex,  (b)  to  the  temporal  pole  and 
amygdala,  and  (c)  to  the  fusiform-hippocampal  gyrus  and  hippocampus.  As  a 
start  toward  investigating  the  possible  role  of  these  inferotemporal-limbic 


49 


pathways  in  visual  associative  learning,  three  groups  of  animals,  each  with 
damage  to  a  different  one  of  the  three  limbic  structures,  were  cortpared  with 
operated  and  unoperated  controls  in  object  reversal  learning.   This  task  was 
chosen  because  of  its  presumed  sensitivity  to  associative  learning  processes. 
The  results  indicate  that  whereas  the  hippocampus,  and  by  implication,  pathway 
(c) ,  is  probably  not  involved  in  visual  associative  learning,  both  of  the 
other  limbic  structures,  and  by  implication,  both  of  the  other  pathways,  are 
intimately  involved.   Furthermore,  these  two  pathways  (a  and  b)  probably 
serve  different  functions  in  visual  learning,  since  the  two  lesions  (orbital 
frontal  and  temporal  pole  plus  amygdala)  yielded  a  double  dissociation  of 
deficits.   Specifically,  the  frontal  group  was  more  impaired  in  suppressing 
or  abandoning  old  habits,  while  the  temporal  group  was  more  impaired  in 
establishing  new  ones. 

Frontal  Cortical  Mechanisms  in  Spatially  Directed  Responding. 

Previous  research  addressed  itself  to  the  problem  of  determining 
whether  the  delay,  the  spatial  features,  or  a  combination  of  the  two  was  the 
critical  factor  responsible  for  the  classical  delayed-response  deficit  pro- 
duced by  ablation  of  the  cortex  in  the  monkey's  principal  sulcus.   The  re- 
sults of  several  studies  have  established  that  lesions  in  the  principal  sulcus 
result  m  marked  impairments  only  when  a  task  requires  both  spatial  and 
mnemonic  strategies  for  its  solution.   Vftien  either  a  purely  mnemonic  or  purely 
spatial  ability  is  called  for  in  a  test,  the  test  is  no  longer  sensitive  to 
the  disorder  produced  by  ablation  of  the  principal  sulcus  but  rather  to  that 
produced  by  ablation  of  the  arcuate  cortex.   These  studies  of  small  focal 
lesions  on  a  variety  of  spatial  and  nonspatial  measures  revealed  an  unantici- 
pated specialization  of  function  within  the  dorsolateral  region  and  thus  dis- 
pelled the  prevalent  conception  of  a  unitary  dorsolateral  mechanism. 

These  findings  have  also  led  to  a  reformulation  of  the  deficit  clas- 
sically produced  by  frontal  lesions  as  a  modality-specific  memory  loss.   One 
way  to  conceptualize  this  loss  is  in  sensory-analytic  terms.   The  fact  that 
delayed-response  tasks  generally  lack  salient  exteroceptive  cues  to  guide 
spatial  orientation  has  led  many  investigators  to  conclude  that  proprioceptive 
cues  are  involved  m  solving  such  tasks  and  hence  to  the  view  that  proprio- 
ception IS  disrupted  by  frontal  lesions.   Another  way  to  conceptualize  the 

rlTr-L^T'TV-  !"""'  '"  '"  ^"^  °^  ^  "P^^^^l  ^^nosia,  which  is  not 

iTtT^^l^   ^°   <^^f^=^ent  sensation.   To  assess  the  relative  merits  of  these  two 
contrasting  views,  monkeys  with  dorsolateral  prefrontal  lesions  and  normal 

two^oi^r''^  T"?^  ""^  """^   ^°   ^^^  ^^^^^  5oal  box  in  a  locomotor  T-Maze  under 
two  conditions  of  illumnation  -  dimly  lit  and  well  lit.   According  to  the 
sensory  hypothesis ,  monkeys  with  frontal  lesions  should  have  greater  diffi- 
culty m  learning  the  runway  response  in  the  dark  than  in  the  light,  since  in 
the  former,  they  must  rely  to  a  greater  degree  on  proprioceptive  cues!  Ac- 
cording to  the  view  that  the  deficit  is  "gnostic"  rather  thL  sen'S 
frontal  monkeys  should  perform  as  well  as  normals  in  the  dark  but  mSht  be 
TSs"s"tudris  Itilf  in"'"'  Visual-spatial  cues  are  available  to  c^Jase  them. 
the%ienhat  S  '  r  ntrSrcifis^^  ^\'''^'''   T"^  ^^^°"^^^  ^^^^"- 
to  a  gnostic  function.   Moreote^  Sett^  Tro^   "SSa ftLr^rfai:^  JnteT 
polated  between  regular  training  trials  indicate  that  the  frontal  moLe^  do 

50 


indeed  pay  attention  to  Lhe  visual-spatial  cues  in  iihe  lighted  milieu  in 
which  they  are  impaired  while  utilizing  proprioceptive  cues  in  the  dark 
where  they  are  not.   This  is  the  first  evidence  of  its  kind  to  dissociate  the 
sensory  and  gnostic  modes  of  spatial  learning  in  frontal  monkeys. 

Cerebral  mechanisms  for  functional  recovery  after  brain  injury. 

The  study  of  the  cerebral  cortex  in  the  adult  monkey  is  intri- 
guing because  its  removal  produces  selective,  reliable,  and  on  some  tests, 
irrecoverable  behavioral  impairments.   The  investigation  of  cortex  in  the 
infant  monkey ^  by  contrast,  interests  us  precisely  because  its  removal  fails 
to  result  in  such  deficits.   The  difference  between  the  study  of  lesions  in 
the  infant  and  in  the  adult  is  more  tiian  one  of  a  dissimilarity  of  outcome , 
however,  for  the  two  types  of  investigations  pose  quite  different  problems. 
Whereas  the  essential  question  confronting  the  investigator  of  cortical  func- 
tion in  the  adult  is  the  nature  of  processes  intrinsic  to  the  damaged  sub- 
strate, the  task  confronting  tlie  student  of  the  early  brain-injured  is  the 
understanding  of  the  capacities  of  residual  areas,  since  presiomably  these  are 
the  areas  responsible  for  sustaining  the  functions  of  the  cortex  which  has 
been  removed.   Thus,  our  investigations  are  concerned  with  identifying  the 
neural  substrates  which  mediate  behavioral  recovery  in  young  brain-damaged 
animals , 

On  the  basis  of  studies  involving  selective  lesions  of  the  prefrontal 
cortex  in  infancy  we  have  been  able  to  identify  two  expressly  different  pat- 
terns of  recovery.   We  found  that  monkeys  given  orbital  lesions  in  infancy 
were  initially  as  impaired  as  monkeys  given  the  same  lesions  as  adults  but 
that  later  in  development  the  early-operated  monkeys  gave  evidence  of  dramatic 
recovery.   By  contrast,  monkeys  given  dorsolateral  lesions  as  infants  were 
initially  unimpaired  but  later  in  life  this  picture  of  normalcy  gave  way  to 
one  of  retarded  development.   On  the  basis  of  such  results  we  have  proposed 
that  there  is  a  central  principle  governing  whether  or  not  recovery  will 
occur,  approximately  when  it  will  occur,  and  whether  it  will  follow  the  pro- 
gressive or  regressive  pattern.   The  principle  concerns  the  maturational 
status  of  functionally  related  areas  that  remain  \indamaged  by  the  early  brain 
injury.   If  there  remains  iindamaged  a  related  area  which  is  relatively 
"uncommitted"  to  its  own  course  of  development  at  the  time  of  brain  injury, 
then  recovery  will  ensue.   If,  on  the  other  hand,  the  surviving  tissue  is 
already  "committed"  or  relatively  mature,  then  presumably  it  will  have  lost 
this  capacity  for  reorganization,  and  hence  will  be  unable  to  take  on  new 
functions.   Regarding  the  prefrontal  cortical  areas,  the  available  evidence 
suggests  that  the  orbital  cortex  becomes  "committed"  considerably  earlier  in 
ontogeny  than  does  the  dorsolateral  area.   Thus,  it  seems  reasonable  to 
suppose  that  in  monkeys  given  orbital  lesions  in  infancy,  the  remaining  dorso- 
lateral cortex  could  come  to  assume  the  functions  of  the  orbital  cortex  but 
that  the  orbital  region  could  not  reciprocate  for  damage  to  the  dorsolateral 
cortex.   The  full  expression  of  compensatory  readjustment  would  be  delayed, 
of  course,  until  the  compensatory  structure  itself  attained  functional 
maturity.   Thus,  the  finding  that  dorsolateral  lesions  do  not  produce  serious 
impairments  in  monkeys  until  they  reach  two  years  of  age,  together  with  the 
fact  that  only  monkeys  given  orbital  lesions  as  infants  show  recovery  at  the 
two-year  stage  provide  strong  evidence  for  this  view. 

51 


Another  aspect  of  Uiis  problem  concerns  the  status  of  subcortical 
structures  during  development.   It  is  well  established  that  the  prefrontal 
cortex  is  anatomically  and  functionally  related  to  the  caudate  nucleus   The 
dorsolateral  cortex,  for  exairple,  projects  to  the  anterodorsal  sector  of  the 
head  of  the  caudate  nucleus.   It  is  of  interest,  therefore,  that  lesions 
placed  in  this  part  of  the  caudate  in  infants  produces  serious  impairments 
on  just  those  tasks  and  at  just  those  ages  when  dorsolateral  cortical  lesions 
do  not   We  interpret  this  finding  to  mean  that  the  caudate  nucleus  becomes 
functionally  mature  earlier  in  development  than  the  dorsolateral  cortex  and 
that  it  is  capable  of  mediating  many  of  the  behaviors  that  the  dorsolateral 
cortex  will  ultimately  assume.  According  to  this  view,  the  caudate  does  not 
"take  over"  the  functions  in  a  compensatory  sense  but  at  early  ages  is  the 
structure  primarily  responsible  for  carrying  out  these  functions.   In  the 
course  of  development,  these  functions  become  "encephalized" ,  so  to  speak, 
with  the  maturation  of  the  cortex  and  the  caudate  then  loses  its  functional 
autonomy . 

These  studies  have  been  profitable  from  several  points  of  view. 
First,  they  have  provided  a  new  line  of  evidence  to  support  the  theory  that 
there  are  two  functionally  distinct  subdivisions  of  the  prefrontal  cortex. 
Secondly,  they  provide  some  clues  as  to  the  limiting  factors  and  hence  to  the 
mechanisms  underlying  recovery  of  function  in  developing  organisms.  Thirdly, 
they  indicate  something  about  the  normal  course  of  brain  development,  a  sub- 
ject about  which  little  is  known.  Finally,  these  investigations  have  bridged 
a  gap  previously  existing  between  animal  studies  and  the  clinical  literature. 
The  present  results  parallel  the  findings  in  man  by  establishing  evidence  for 
both  progressive  and  regressive  sequelae  of  early  injury  to  the  brain.   In 
this  kind  of  correspondence  lies  the  hope  that  the  outcome  of  investigations 
on  nonhuman  forms  can  ultimately  be  extrapolated  to  conditions  of  develop- 
mental neuropathology  in  man. 

Cortico-subcortical  mechanisms  in  the  regulation  of  behavior. 

One  of  the  siibcortical  structures  having  intimate  anatomical 
relationships  with  the  prefrontal  cortex,  particularly  with  the  orbital  sys- 
tem, is  the  hypothalamus.   While  many  studies  have  demonstrated  similarities 
between  the  frontal  cortex  and  the  hypothalamus  in  the  motivational  and  emo- 
tional functions  which  they  siobserve,  none  has  considered  whether  or  not  there 
are  also  similarities  in  cognitive  f imctions .   We  did  so  in  a  recent  study 
which  involved  placing  lesions  in  the  hypothalamus  of  monkeys  and  testing 
them  on  a  battery  of  tests  of  frontal-lobe  function.   Large  lesions  involving 
different  divisions  of  the  hypothalamus  resulted  in  a  pattern  of  deficits 
which  are  characteristic  of  damage  to  the  orbital  frontal  system.   Smaller, 
selectively  placed  lesions,  though  resulting  in  impairments,  did  not  yield  a 
pattern  of  deficits  unequivocally  characteristic  of  one  or  the  other  of  the 
frontal-lobe  systems.   Further  analysis  of  the  anatomical  and  the  behavioral 
data  is  underway  to  attempt  to  factor  out  the  discrepancies. 

The  medial  dorsal  nucleus  of  the  thalamus  is  another  subcortical 
structure  having  divisions  which  are  differentially  anatomically  related  to 
the  dorsolateral  or  the  orbital  frontal  cortex.   It  would  be  expected  that 


this  nucleus  would  have  functions  similar  to  those  of  frontal  cortex,  and 
that  the  functions  of  its  two  divisions  would  be  dissociable.  However,  in 
several  studies,  some  of  them  our  own,  even  very  large  lesions  involving 
virtually  all  of  this  nucleus  have  not  resulted  in  impaired  performance  on 
tests  of  frontal-lobe  function.  Nevertheless,  since  the  anatomical  relation- 
ships are  so  compelling,  we  undertook  to  investigate  this  problem  again  with 
slightly  different  procedures.   The  results  of  this  study  clearly  indicate 
that  lesions  in  this  nucleus  can  result  in  profound  deficits  on  these  tasks. 
To  determine  which  factor  is  critical  in  producing  the  impairment  is  the 
subject  of  current  work. 

Somatosensory  Perception. 

This  year  an  attempt  was  made  to  localize  more  precisely  the  part  of 
the  anterior  removal  in  the  postcentral  gyrus  which  was  responsible  for  a 
profound  somatosensory  deficit.  On  the  basis  of  electrophysiological  studies 
revealing  two  separate  and  detailed  representations  of  the  hand  within  the 
area  of  the  anterior  removal,  the  area  was  divided  into  two  parts  and  the 
subareas  characterized  by  slowly-adapting  and  quickly-adapting  units  were 
separately  removed.  A  deficit  of  the  same  magnitude  and  generality  as  that 
following  the  total  anterior  removal  was  found  after  destruction  of  the 
slowly-adapting  population,  whereas  a  milder  impairment  affecting  only  the 
first  (softness)  and  the  last  (roughness)  tasks  of  the  series  was  produced 
by  destruction  of  the  quickly-adapting  units. 

The  nature  of  the  impairment  after  the  anterior  postcentral  lesion 
was  explored  in  several  ways.  As  described  last  year,  we  found  that  monkeys 
with  this  lesion  (or  even  with  more  extended  removals  encompassing  the  entire 
postcentral  gyrus  and  parietal  operculum  of  both  hemispheres)  either  retained 
or  quickly  recovered  normal  sensitivity  of  the  hand  to  punctate  tactile 
stimuli,  as  tested  by  a  graded  series  of  modified  von  Prey  hairs.   Thus, 
their  deficits  on  the  original  battery  of  tasks  could  not  be  ascribed  to  a 
simple  hypesthesia.   This  result  led  us  to  investigate  the  effect  of  varia- 
tions in  the  procedures  which  had  revealed  the  severe  deficits.   We  escplored 
in  one  group  of  animals  the  effects  of  intensive  preoperative  training  on  all 
tasks,  and  in  another,  the  effects  of  allowing  a  recovery  period  of  six  months 
following  the  anterior  postcentral  removal.  Neither  of  these  modifications 
ameliorated  the  deficits,  thus  providing  strong  support  for  our  original 
finding  of  an  impairment  which  was  much  more  severe  than  any  reported  by  other 
investigators  who  have  studied  the  effects  of  postcentral  removals  with  tasks 
much  like  the  ones  we  employed.   We  therefore  believe  that  the  lesions  made 
previously  by  others  might  have  spared  tissue  in  the  depths  of  the  central 
sulcus,  the  siibarea  which  our  experiment  indicated  was  the  most  important. 
The  fact  that  our  procedural  variations  did  not  ameliorate  the  deficit  sug- 
gests that  the  lesion  causes  a  loss  of  somatosensory  capacity,  rather  than  a 
modality-specific  learning  disability  or  a  deficit  secondary  to  the  ataxia 
commonly  found  in  the  weeks  following  a  postcentral  ablation.   But  how  to 
characterize  this  postulated  loss  of  capacity  (since  it  is  not  a  loss  of 
tactile  sensitivity,  as  noted  above)  remains  unclear.   There  is  evidence  from 
electrophysiological  studies  suggesting  that  it  may  be  primarily  kinesthetic 
in  nature,  and  future  experiments  will  explore  this  possibility. 


53 


One  research  project  explored  the  effects  of  lesions  in  the  postcen- 
tral gyrus,  the  parietal  operculum,  and  the  posterior  parietal  "association" 
area  on  a  type  of  somatosensory  discrimination  not  hitherto  studied  in  our 
laboratory,  namely,  the  perception  of  differences  in  temperature.   Monkeys 
were  trained  by  a  series  of  steps ,  starting  with  a  task  involving  perception 
of  thermal  pain,  then  a  gross  temperature  discrimination  in  the  non-painful 
range,  and  finally  a  series  of  threshold  determinations  which  terminated  when 
the  animal  could  reliably  discriminate  a  difference  of  less  than  2°  C.  in  the 
cool  range  (24°  vs.  26°) .   Compared  with  a  normal  control  group  tested  for 
retention,  deficits  in  the  operated  groups  have  been  found  in  trials  to  cri- 
terion on  the  painful  and  on  the  non-painful  gross  discriminations,  as  well 
as  in  the  trials  taken  to  meet  the  final  threshold  criterion.   However,  all 
animals  eventually  reached  this  final  criterional  level,  thus  indicating  that 
the  capacity  for  discriminating  fine  temperature  differences  still  existed. 
The  operated  groups  which  showed  the  above-mentioned  deficits  had  either  bi- 
lateral parietal  lobectomy,  bilateral  removal  of  the  postcentral  gyrus  and 
the  parietal  operculum,  or  bilateral  removal  of  the  postcentral  gyrus  plus 
contralateral  removal  of  the  parietal  operculum.   Other  groups  whose  lesions 
did  not  involve  the  postcentral  gyrus  in  both  hemispheres  failed  to  show 
significant  deficits,  although  a  bilateral  postcentral  lesion  by  itself  was 
likewise  insufficient  to  produce  impairment. 

It  appears  from  these  results  that  temperature  perception,  like  that 
of  simple  touch,  is  extremely  resistant  to  cortical  lesions,  and  that  these 
forms  of  somatosensory  discrimination  are  in  this  respect  very  different  from 
those  involving  softness ,  texture ,  size ,  or  shape  cues . 

Schizophrenia: 

A  review  of  the  literature  on  the  offspring  of  schizophrenics  was 
undertaken.   The  various  studies,  taken  as  a  whole,  indicate  that  there  is 
an  increased  incidence  of  two  types  of  pathological  character  structures  in 
these  offspring,  besides  the  increased  incidence  of  schizophrenia.   There  is 
a  high  incidence  of  antisocial  characters ,  appearing  as  impulsive ,  hyper- 
active ,  delinquent  children,  and  as  adult  psychopaths  or  "schizoid  psycho- 
paths." There  is  also  a  schizoid  group  appearing  as  withdrawn,  anxious  chil- 
dren and  as  eccentric,  socially  isolated  adults.   The  pathological  types  in 
in  the  young  offspring  of  schizophrenics  were  found  to  be  similar  to  the 
types  found  in  retrospective  studies  of  a  group  of  pre-schizophrenics. 

Previous  studies  of  social  class  and  schizophrenia  have  demonstrated 
a  relationship  between  the  two  but  have  been  unable  to  dissect  out  the  factors 
mediating  the  relationship.   Employing  the  data  from  our  Denmark  studies,  we 
have  used  the  technique  of  adoption  to  separate  the  roles  of  genetic  and 
environmental  effects.   Our  findings  indicate  that:   (1)  the  relationship 
between  schizophrenia  and  lower  social  class  is  not  clearcut  in  our  popula- 
tion, (2)  that  the  tendency  for  schizophrenics  to  be  of  lower  socioeconomic 
class  is  the  consequence  of  their  "downward  drift",  and  (3)  that  lower  class 
rearing  does  not  appear  to  provoke  or  induce  schizophrenia.   The  generality 
of  these  findings  is  limited  because  of  the  special  nature  of  the  populations 
employed;  these  limitations  are  discussed  in  the  summary  of  this  research. 


54 


In  further  analyses  of  our  Danish  siobjects,  we  found  that  individuals 
who  had  a  proband  biological  relative  in  the  schizophrenia  spectrum  emigrated 
much  less  frequently  than  control  subjects.   This  finding  was  surprising 
since  the  literature  on  the  relation  between  migration  and  schizophrenia  sug- 
gests that  schizophrenics  emigrate  more  often  than  controls.   We  interpret 
this  finding  to  mean  that  individuals  who  harbor  genes  associated  with  schiz- 
ophrenia have  less  initiative,  are  less  adventurous,  and  more  averse  to 
abrupt  change  than  are  other  persons.   In  fact,  their  behavior  parallels  a 
trait  called  neophobia ,  which  schizophrenics  show  in  certain  experimental 
tasks . 

We  also  came  up  with  the  surprising  finding  that  on  multiple  reaction 
time  tasks,  our  subjects  who  were  reared  by  schizophrenia  spectrum  parents 
performed  more  poorly  than  subjects  not  reared  by  such  parents.   Since  re- 
action time  is  one  of  the  best  discriminators  of  schizophrenics  and  controls, 
and  since  genes  are  implicated  in  schizophrenia,  one  might  have  expected  an 
association  between  relatedness  to  a  schizophrenic  and  poor  reaction  time , 
but  this  was  not  the  case. 

Our  adoption  study  in  New  York  is  at  the  point  of  having  concluded 
almost  all  the  data  collection.   Our  Israeli  material  is  still  being  analyzed, 
but  already  many  new  significant  findings  have  turned  up.   These  will  be 
reported  next  year. 

Previous  findings  had  indicated  that  chronic  and  acute  schizophrenics 
do  not  exhibit  a  generalized  deficit  in  the  responsivity  of  the  autonomic 
nervous  system,  but  show  such  a  deficit  selectively,  particularly  in  response 
to  meaningful  stimuli  and  to  "stressors"  such  as  task  performance.   In  a 
study  of  monozygotic  twins,  most  of  whom  were  discordant  for  schizophrenia, 
we  found  that  this  specific  deficit  in  autonomic  responsivity  was  correlated 
with  the  severity  of  symptoms  and  behavioral  disturbance. 

Other  Psychopathology. 

Average  evoked  response  studies  of  minimal  brain  dysfunction  (MBD) 
children  showed  increased  amplitudes,  especially  at  high  stimulus  intensities, 
in  comparison  with  age-matched  controls.   In  MBD  children  who  showed  a  pos- 
itive clinical  response  to  amphetamine,  AER  diminished  with  drug  treatment; 
in  nonresponders ,  AER  increased. 

Similar  individual  differences  in  drug  response  were  seen  in  studies 
of  L-dopa  infusion  in  patients  with  affective  disorders.   In  both  studies,  as 
well  as  in  studies  of  attention  in  normal  subjects,  early  and  late  AER  com- 
ponents behaved  quite  differently,  suggesting  the  possibility  of  some  bio- 
chemical dissection  of  the  as  yet  poorly  defined  AER.   Further,  the  finding 
of  interactions  between  intensity  response  functions  and  level  of  attention 
makes  possible  some  neurophysiological  assessment  of  attention. 

It  was  found  that  lithium  is  of  no  appreciable  therapeutic  benefit 
for  minimally  brain  dysfunctioned  children  refractory  to  other  forms  of 
treatment.   Our  findings  indicate  that  MBD  children  appear  to  be  "augmenters"; 


55 


controls  do  not  "augment."  Furthermore,  it  appears  that  MBD  children  who 
respond  to  stimulant  medication  demonstrate  diminished  augmentation  with  such 
treatment  whereas  non-responders  show  increased  augmentation.   We  have  found 
apparent  biochemical  correlates  of  differences  in  conditioning  in  inbred 
strains  of  rats.   Preliminary  findings  are  that  animals  who  avoid  with  dif- 
ficulty but  who  respond  to  amphetamines  with  increased  rates  of  conditioning 
show  diminished  rates  of  norepinephrine  turnover.   This  finding  remains  to 
be  confirmed. 

The  Unit  on  Psychophysiology  has  been  active  in  the  development  of 
systems  for  on-line  real-time  collection  of  psychophysiological  and  electro- 
encephalographic  data  directly  from  human  subjects  or  from  analog  tape.   The 
combination  of  the  real-time  data  collection  programs,  on-time  interactive 
data  editing  programs  and  statistical  analysis  within  the  same  computer  - 
all  operating  together  on  a  time-share  basis  -  make  the  SEL  system  one  of  the 
most  sophisticated  psychophysiological  experimental  systems  yet  developed. 

Behavioral  Development. 

In  one  study,  kibbutz  and  residential  institution  were  compared  with 
respect  to  the  time  spent  by  caretakers  with  their  infants  and  in  behaviors 
by  caretakers  to  infants  and  by  infants  to  their  caretakers.   The  analysis 
was  performed  separately  for  periods  spent  in  caregiving  (feeding,  diapering, 
dressing,  bathing)  and  for  periods  when  caretakers  were  in  their  infants' 
vicinity  but  not  ministering  to  their  physical  needs  ("pure-social  time"). 

Analyses  of  the  periods  caretakers  spent  in  their  infants '  vicinity 
showed  that,  compared  to  kibbutz  caretakers,  institution  caretakers  spend 
about  twice  as  much  time  in  ministering  to  their  infants'  physical  needs  - 
caregiving,  and  about  three  times  as  much  time  in  the  vicinities  of  their 
charges  when  not  ministering  to  those  needs  -  pure-social  time.   This  differ- 
ence appears  to  reflect  the  facts  that  kibbutz  mothers  do  much  of  the  care- 
giving during  the  first  8  months  of  their  infants'  lives  -  the  period  inves- 
tigated, and  that  institution  caretakers  are  scored  as  being  near  an  infant 
when  they  minister  to  nearby  children. 

Compared  to  kibbutz  caretakers,  institution  caretakers  showed  more 
Smiles  and  Fine-contact  responses.   However,  in  the  institution,  the  care- 
takers were  the  only  ones  who  ministered  to  their  charges  while,  in  the 
kibbutz,  caretakers  shared  this  role  with  mothers. 

With  respect  to  infant  behaviors  to  their  caretakers  while  receiving 
physical  care  institution  infants  showed  more  looking  at,  smiling,  and  vo- 
calizing to  their  caretakers,  but  these  differences  dropped  out  when  adjust- 
ment was  made  for  differences  in  caregiving  time. 

•    .   In. periods  when  institution  and  kibbutz  caretakers  were  not  minister- 
ing to  their  infants  '  physical  needs,  institution  caretakers  sho^  ^re  Fine- 
contact  Talk,  and  Gross-contact  behaviors  than  did  kibbutz  caret^e^  but 

S\he  vrci:;rty  :f':^:1h'if  ^^^:.  ^^^  ^^°-^  --  -^^-^ed  forlim^sp^nt 
m  the  vicinity  of  the  children,  the  caretakers  were  found  to  differ  only  in 


56 


the  incidence  of  Gross-contact;  institution  caretakers  showing  more  of  this 
behavior  at  two  months,  the  same  amount  at  six  months,  and  less  at  eight 
months.   During  "pure-social"  settings,  no  differences  were  found  between 
groups  in  infant  behaviors  to^  those  caretakers. 

Within  the  two  settings,  caregiving  and  pure-social,  the  correlations 
between  caretaker  and  infant  behaviors  were,  overall,  higher  for  the  kibbutz 
than  for  the  institution  environment,  and  the  within-setting  correlations 
were  higher  than  the  between-setting  correlations  for  kibbutz  infants ,  while 
they  were  not  at  all  different  for  institution  infants.  Thus,  as  a  unit, 
kibbutz  infants  and  caretakers  appeared  to  behave  differently  in  pure-social 
than  in  caregiving  periods,  but  institution  pairs  did  not  behave  differently. 
This  same  overall  pattern  holds  as  well  for  infant  behavior  intercorrelations 
and  for  caretaker  behavior  intercorrelations.   This  pattern  is  therefore  a 
general  one. 

Within  the  kibbutz,  mothers  spent  more  time  than  did  caretakers  with 
their  infants  during  the  first  8  months  of  life:   in  caregiving  settings, 
where  caretaker  time  remains  constant  through  the  eight  months,  mothers  spent 
50  times  as  much  time  at  two  months,  and  twice  as  much  time  at  eight  months; 
in  pure-social  settings,  where  both  mothers  and  caretakers  spent  increasing 
time  with  their  infants  with  age,  mothers  spent  about  twice  as  much  time  with 
their  infants  as  did  caretakers.  After  behavior  scores  were  adjusted  for 
pure-social  time  in  the  presence  of  mother  and  caretaker,  it  was  found  that 
more  Vocal  sounds  and  Motor  acts  were  exhibited  by  infants  to  their  mothers 
than  to  their  caretakers.  Correlations  within  and  between  caregiving  and 
pure-social  periods  were  invariably  of  higher  magnitudes  between  mother  and 
infant  behaviors  than  they  were  between  caretaker  and  infant  behaviors .   This 
result  suggests  a  better  organization  between  the  behaviors  of  a  mother  and 
her  infant  than  between  a  caretaker  and  the  same  infant. 

In  a  comparison  of  the  kibbutz  with  two  other  environments ,  that  of 
the  youngest-child  and  that  of  only-child  family  (both  urban  middle-class)  , 
the  correlational  pattern  between  the  behaviors  of  a  mother  and  her  infant 
was  found  to  be  reliably  higher  in  magnitude  in  the  kibbutz  than  in  either 
the  youngest-  or  the  only-child  environments .   Correlational  patterns  between 
adult  and  infant  behaviors  were  reliably  higher  for  older  (8  months)  infants 
than  for  younger  (2  months)  infants. 

Perceptual  Development. 

An  investigation  which  compared  the  efficacy  of  (a)  repetitive , 
(b)  color-varying,  and  (c)  form-varying  visual  reinforcers  in  maintaining  the 
operant  behavior  of  three-month-olds  demonstrated  that  form  variation  was 
more  effective  than  color  variation  and,  hence,  that  the  three -month-old  is 
perhaps  more  sensitive  to  form  than  color  differences .   A  second  investigation 
sought  to  determine  which  features  (eyes,  nose/mouth,  contour)  predominate  in 
the  four-month-olds  perception  of  the  human  face  and  to  what  extent  they  are 
seen  as  isolated  elements  or  as  structured  configurations.   Previous  research 
had  yielded  equivocal  results  regarding  the  discriminability  of  regular  from 
scrambled  f<gces  and  "eyes-only"  from  eyeless  faces  up  to  four  months  of  age. 


57 


In  the  present  experiment  total  fixation  time  to  a  regular  schematic  face  was 
compared  for  groups  of  infants  following  prolonged  exposure  to  differing  dis- 
tortions of  the  face  (presumably,  the  greater  the  perceived  difference  between 
the  regular  face  and  the  previously  familiarized  distortion,  the  longer  the 
looking  time  to  the  former) .   The  distortions  were  applied  to  four  areas  - 
eyes,  nose/mouth,  contour,  and  all  features  combined  -  and  were  of  four  gen- 
eral types:   (a)  elimination  of  feature,  (b)  scrambling,  (c)  positional  dis- 
placement, and  (d)  orientation  change.   A  control  group  was  given  prolonged 
exposure  to  the  regular  face.   Preliminary  analysis  of  the  data  indicates  that 
in  the  face  perception  of  the  four-month-old  (1)  the  eyes  are  more  salient 
than  the  nose/mouth,  (2)  the  orientation  of  the  contour  more  critical  than  the 
orientation  of  the  features,  and  (3)  the  horizontal  arrangement  of  the  eyes 
more  important  than  their  precise  orientation. 

This  experiment  on  the  determinants  of  reinforcer  efficacy  demonstrates 
that  visual  change  is  more  effective  in  maintaining  the  infant's  commerce  with 
the  surround  than  visual  redundancy,  and  suggests  that  an  environment  contain- 
ing much  visual  contrast  and  variation  will  recruit  more  of  the  infant's  at- 
tention than  a  homogeneous  environment,  and  that  this  is  perhaps  a  prime  req 
uisite  for  early  discriminative  learning. 


Communication  Processes . 


I 


Psycholinguistic  research  in  the  Laboratory  focuses  on  speech  percep 
tion,  its  guiding  hypothesis  holding  that  listeners  process  "chunks"  of  speech 
which  are  identified  on  the  basis  of  intonational  patterns.   These  units, 
phonemic  clauses,  are  held  in  short-term  memory  and  processed  as  patterns  of 
sound,  syntax,  and  sense.   As  a  subject  listens  to  speech  a  gradient  of  pu- 
pillary dilatation  occurs  over  the  course  of  a  phonemic  clause,  while  it  is 
being  loaded  into  short-term  memory . 

Since  the  pupil  is  richly  and  complexly  innervated  and  a  variety  of 
processes  are  affecting  its  moment-to-moment  diameter,  signal  averaging  tech- 
niques are  required  in  order  to  separate  out  the  hypothesized  psycholinguistic 
effect  from  "noise."  The  course  of  the  project  this  year  has  involved  re- 
peated attempts  to  match  a  set  of  experimental  stimuli  to  a  Line  computer 
program  in  such  a  fashion  as  to  be  able  to  test  the  pupil  diameter  hypothesis. 

With  respect  to  listener  responses,  attention  this  year  has  focused 
on  its  developmental  aspects.   It  had  been  found  earlier  that  adult-type 
listener  responses  are  quite  rare  in  small  children.   They  seem  to  be  confined 
to  a  fairly  limited  number  of  situations  where  the  speaker's  need  for  them  is 
especially  strong  so  that  he  all  but  demands  them.   In  addition,  many  of  the 
children's  responses  are  quite  different  from  the  adult  ones:   they  are  likely 
to  involve  very  slight  movements,  visible  to  the  observer  only  on  repeated 
viewings  of  the  videotape,  and  thus  difficult  to  conceive  as  communicative 
in  the  ongoing  conversation.   Also,  many  of  the  responses  in  children  are  de- 
layed, unlike  those  of  adults,  indicating  perhaps  a  slower  rate  of  understand- 
ing speech.   One  expectation  based  on  past  work  has  been  confirmed:   individual 
differences  in  this  sort  of  behavior  are  very  large.   In  spite  of  the  varia- 
bility, younger  children  clearly  emit  fewer  listener  responses  than  adoles- 
cents and  adults . 

58 


The  listener  response  appears  to  have  a  dual  role,  one  for  the  speak- 
er's benefit  (that  is,  to  let  the  speaker  know  that  he  is  explaining  things 
understandably) ,  and  the  other  for  the  listener's  benefit.   This  latter  seems 
especially  true  of  movements  so  small  as  to  serve  no  communicative  function 
for  the  speaker.   These  two  roles  point  to  futnre  research  in  two  directions, 
one  toward  language  development  at  later  ages ,  and  the  other  toward  social 
development,  with  special  attention  to  educational  maturity  and  to  develop- 
mental diagnosis. 

Thought  Processes. 

In  an  experiment  in  which  a  computer  program  controlled  a  special 
adaptation  of  the  traditional  selection  paradigm  of  the  attribute  identifica- 
tion task,  tlie  amount  of  work  required  to  elicit  sufficient  information  for 
a  solution  was  found  to  be  a  far  less  important  determiner  of  the  total  effort 
than  were  tlie  redundant  inquiries  made  before  the  correct  interpretation  was 
produced . 

Work  continues  in  the  direction  of  increasing  the  computer's  partic- 
ipation in  administering  typical  psychological  experiments.   The  present  pro- 
gram participates  in  four  stages  of  this  task:   (1)  it  automatically  applies 
a  4  X  4  factorial  design  with  constrained  randomization  of  a  sequence  factor 
as  it  assigns  Ss  to  tasks;  (2)  it  manages  the  instructions  to  S  and  tests  for 
comprehension;  (3)  it  administers  the  assigned  display  sequence  and  records 
S's  responses;  (4)  it  provides  a  typed  summary  data  report  immediately  after 
each  run. 

This  program  executes  the  reception  paradigm  of  an  attribute  identi- 
fication task  designed  to  evaluate  a  person's  ability  to  perform  three  types 
of  reasoning:   (1)  inference  from  knowledge  of  a  sufficient  set  of  relevant 
factors,  (2)  inference  from  knowledge  of  a  sufficient  set  of  irrelevant  fac- 
tors, (3)  inference  from  knowledge  of  a  combination  of  relevant  and  irrelevant 
factors  that  is  just  sufficient  to  support  a  conclusion.   Only  about  one-third 
of  the  number  of  subjects  planned  for  this  experiment  have  completed  their 
assignments;  it  is  too  early  to  hazard  a  guess  about  its  outcome. 

An  Attribute  Identification  System  (a  computer  simulation)  that 
"solves"  this  type  of  problem  by  heuristics  specified  in  current  theories  has 
been  developed  to  provide  sufficiency  tests  on  any  theory  that  is  appropriately 
explicit  and  concise.   The  heuristics  of  two  theories  -  Restle's  "hypothesis 
testing"  theory  with  replacement  and  the  "local  consistency"  theory  -  have 
been  tested  and  found  to  agree  only  moderately  well  with  the  means  and  stand- 
ard deviations  obtained  from  human  subjects.   However,  certain  extensions  of 
the  "local  consistency"  result  in  matches  that  do  not  differ  significantly 
from  hviman  performances.   This  type  of  testing  merits  considerable  extension. 

Perception. 

Perception  of  Time  and  Form. 

Normal  individuals  often  experience  a  transient  disorientation 
for  time  and  place  when  awakened  from  a  deep  sleep.   Young  adults  were  awakened 

59 


periodically  during  the  night  and  tested  briefly  for  the  ability  to  discrim- 
inate short  time  intervals.  Initially  no  clear-  effect  of  depth  of  sleep  was 
evident,  but  with  more  coirplete  data  a  moderate  slowing  in  the  subjective  rate 
of  passage  of  time  was  detected.  This  effect  is  not  closely  associated  with 
variations  in  body  temperature,  EEG,  or  other  physiological  indicators.  Al- 
though stable  in  spite  of  differences  in  gross  physiological  state,  the  time 
sense  appears  to  change  in  a  way  similar  to  habituative  or  adaptational  shifts 
characteristic  of  basic  perceptual  processes. 

Investigation  of  the  physiological  basis  and  developmental  aspects  of 
visual  form  discrimination  has  grown  enormously  in  recent  years.   A  difficulty 
hampering  this  effort,  however,  has  been  the  lack  of  a  psychologically  adequate 
means  of  specifying  the  essential  parameters  involved.   The  concepts  of 
Euclidean  geometry  generally  used  were  derived  initially  in  connection  with 
surveying  and  other  problems  of  physical  measurement  not  primarily  concerned 
with  biologically  relevant  shapes  and  patterns.   But  perceptual  processes  pre- 
siomably  evolved  in  relation  to  the  necessity  for  discriminating  irregular  and 
varying  patterns  of  curvatures  and  densities  rather  than  points,  straight 
lines,  and  right  angles.   A  preliminary  test  of  the  applicability  of  a  bio- 
logically-oriented geometry  of  form  to  the  perception  of  the  orientation  of 
ellipses  has  been  undertaken.  This  geometry  postulates  a  basic  parameter,  the 
symmetric  axis,  which  was  varied  in  the  ellipses  used.   The  precision  of  judged 
orientation  was  significantly  correlated  with  the  length  of  the  symmetric  axis 
rather  than  with  the  lengths  of  the  major  diameter  and  focal  axis,  which  are 
conventional  geometric  properties  of  the  ellipse.   The  relationship  of  response 
to  the  ratio  of  major  and  minor  diameters  was  equally  good,  but  this  ratio  is 
specific  to  a  limited  class  of  forms.   The  importance  of  the  symmetric  axis  is 
that  it  is  a  property  of  all  forms.   If  tlie  concepts  involved  in  this  geometry 
have  general  applicability,  they  could  be  of  great  utility  in  understanding 
the  development  of  form  perception. 

Creativity. 

The  objective  of  this  research  has  been  to  examine  the  validities  of 
several  well-known  paper-and-pencil  tests  alleged  to  measure  "creative  poten- 
tial" by  comparing  them  to  two  criterion  measures  of  "manifest  creativity"  in 
science  and  to  a  number  of  variables  theoretically  related  to  the  concept  of 
scientific  creativity.   Since  the  meaningfulness  of  criterion  measures  in  this 
field  has  been  questioned,  an  additional  objective  was  to  examine  the  construct 
validities  of  the  criteria  themselves  by  relating  them  to  the  same  reference 
variables  as  used  in  the  assessment  of  the  test  measures.   The  principal  find- 
ings were:   (1)  that,  although  the  evidence  of  construct  validity  was  generally 
favorable  for  both  criteria,  one  criterion  (an  index  of  social  recognition) 
consistently  behaved  more  in  accord  with  theoretical  expectation  than  did  the 
other  (an  evaluation  of  a  science  fair  project) ;  and  (2)  that  there  was  no 
evidence  for  the  validity  of  any  of  six  creativity  tests  -  none  were  related 
to  either  of  the  criteria  or  to  any  of  the  reference  variables  in  the  expected 
manner.  ^ 

Noting  that  all  of  the  tests  which  they  had  investigated  had  been  de- 
rived from  theories  which  conceptualize  creativity  as  an  ability  trait  ^e 
investigators  decided  to  examine  an  alternative  approach.  Many  theorists  have 


i 


conceptualized  creativity  as  a  personality  trait  and  have  presented  descrip- 
tions of  the  "creative  personality."   These  theoretical  descriptions  were 
utilized  in  the  construction  of  an  illustrative  personality  test  of  creativity. 
The  validity  of  this  test  was  then  assessed  using  the  same  procedures  that 
had  earlier  been  applied  in  the  evaluation  of  the  ability  tests . 

The  findings  indicated  that  the  creative  personality  test  pos- 
sessed a  high  degree  of  construct  validity.   It  was  found  to  be  positively 
associated  with  the  recognition  measure  and  with  measures  of  achievement  in 
science  and  in  other  creative  areas  of  endeavor  (e.g.,  art,  literature,  music), 
with  self -ratings  of  creativity,  and  with  several  personality  traits  theoreti- 
cally related  to  the  concept  of  creativity.   As  hypothesized,  it  was  unrelated 
to  any  measures  of  academic  aptitude  or  academic  achievement. 

Taken  together  with  the  earlier  results,  these  findings  raise  serious 
questions  about  the  utility  of  theories  which  conceptualize  creativity  as  an 
ability  trait  and  support  the  conceptualization  of  creativity  as  a  personality 
trait. 

Some  corollary  findings  were  uncovered  with  regard  to  the  personality 
functioning  and  psychiatric  help-seeking  of  the  sample  of  high  and  low  crea- 
tive subjects:   (1)  The  prevalence  of  psychiatric  help-seeking  in  the  entire 
sample  was  remarkably  high,  23%,  as  compared  to  6  percent  of  college  students 
in  general.   (2)   Specific  problems  of  adjustment  to  college,  e.g.,  feeling 
out  of  place  or  having  low  grades,  appeared  to  be  the  primary  source  of  mo- 
tivation for  help-seeking.   (3)   The  functioning  of  students  who  received 
psychiatric  treatment  at  college  tended  to  decline  rather  than  to  improve  over 
time.  This  decline  was  not  confined  to  any  particular  area  of  functioning, 
and  the  extent  of  change  was  strongly  related  to  both  intensiveness  and  du- 
ration of  treatment.   Students  who  received  more  than  20  sessions  of  psycho- 
therapy exhibited  the  greatest  negative  change;  those  who  received  fewer  than 
five  sessions  of  vocational  counseling  actually  changed  in  a  positive  direc- 
tion.  (4)   An  interaction  was  found  between  mental  health  status  during  high 
school  and  type  of  college  attended.   Students  who  evidenced  psychiatric  prob- 
lems during  high  school  and  attended  extremely  selective,  competitive  colleges 
were  very  likely  to  experience  adjustment  problems,  to  enter  treatment,  and 
to  become  increasingly  impaired.   Conversely,  students  already  impaired  and 
who  attended  less  selective  colleges,  tended  not  to  experience  adjustment 
problems,  not  to  enter  treatment,  and  to  improve  over  time.   Among  students 
who  appeared  psychiatrically  healthy  d\iring  high  school,  those  who  were  most 
talented,  forceful,  and  well-integrated  were  the  ones  most  likely  to  become 
frustrated  at  college,  to  enter  treatment,  and  to  become  psychiatrically  im- 
paired.  In  the  help-seeking  group  as  a  whole,  students  who  already  had  clear 
psychiatric  problems  during  high  school  were  a  minority,  representing  about 
one-third  of  the  group. 


61 


ANNUAL  REPOR.T  OF  THE  LABORATORY  OF  SOCIO -ENVIRONMENTAL  STUDIES 

National  Institute  of  Mental  Health 

July  1,  1971  through  June  30,  1972 

Melvin  L.  Kohn,  Chief 

Dr.  William  Caudill,  a  valued  member  of  the  Laboratory  since  1960, 
died  of  cancer  on  March  24,  1972. 

Caudill  had  the  anthropologist's  faith  that  nothing  is  ever  explained 
until  you  understand  it  in  context  of  the  system  of  which  it  is  a  part.   He 
combined  this  faith  with  an  adamant  unwillingness  to  accept  half-truths  and 
superficial  solutions.   Whatever  he  studied- -whether  it  was  the  adjustment 
of  Japanese-Americans  in  Chicago  during  World  War  II,  the  social  structure 
of  the  mental  hospital,  the  interrelationship  of  biological,  personality, 
and  cultural  systems,  or  the  transmission  of  culture  from  mother  to  child- - 
the  same  qualities  stand  out.   He  wouldn't  let  go  of  a  problem  at  the  point 
where  most  scholars  would  long  since  have  thought  they  had  found  the  answer. 
He  always  had  to  discover  the  real  reasons  why  things  fit  together,  not 
just  the  apparent  reasons.   And  so  he  leaves  behind  not  only  an  impressive 
set  of  scholarly  achievements,  but  also  a  model  of  scholarship,  of  inquiry, 
of  the  pursuit  of  truth,  for  all  of  us  to  treasure  and  to  emulate. 

At  the  time  of  his  death,  Caudill  was  deeply  involved  in  a  major 
cross-national  study  of  how  culture  is  transmitted  from  mother  to  child. 
In  essence,  it  is  a  longitudinal  observational  study  in  Japan  and  the  United 
States  of  the  behavior  of  parents  and  children.   During  1961-64,  thirty 
Japanese  and  thirty  American  middle-class  mother-infant  pairs  were  selected 
for  systematic  observation.   The  infants  were  first-born,  normal  babies,  and 
were  three-to-four  months  of  age  at  the  time  of  observation.   The  first 
twenty  Japanese  and  the  first  twenty  American  cases  were  selected  for  follow- 
up  study  at  2\   years  of  age,  and  observations  in  the  home  were  completed 
during  1963-67.   These  same  children  were  studied  for  a  third  and  final  time 
at  six  years  of  age  during  1967-70,  and  all  observations  have  been  completed. 

Caudill  discovered  that  even  by  three-to-four  months  of  age  Japanese 
and  American  infants  show  characteristic,  culturally-appropriate  differ- 
ences in  behavior.   He  also  demonstrated  that  these  differences  are  meaningfully 
linked  to  observed  differences  between  Japanese  and  American  mothers'  child- 
rearing  practices.   His  interpretation  was  that  the  imprint  of  culture-- 
transmitted  from  mother  to  child--could  be  seen  even  at  this  early  age. 
This  interpretation  was  buttressed  by  a  study  of  Japanese-American  mothers, 
which  found  them  to  be  much  more  like  other  American  than  like  Japanese 
mothers  in  their  style  of  interaction  with  their  infants;  correspondingly, 
Japanese-American  babies  behave  more  like  other  American  babies  than  like 
Japanese  babies.   The  data  thus  argue  against  a  genetic  interpretation  of 
the  behavioral  differences  between  Japanese  and  American  infants.   Instead, 
they  suggest  that  characteristic  differences  in  the  behavior  of  Japanese 
and  American  infants  stem  from  culturally-prescribed  differences  in  maternal 
practices. 

63 


Shortly  before  his  death,  Caudill  completed  preliminary  analyses 
of  the  data  gathered  when  the  children  were  2%  years  of  age.   The  analyses 
give  a  striking  indication  of  continuity  in  cultural  differences  in  the 
behavior  of  both  mothers  and  children.   These  preliminary,  cross-sectional 
comparisons  do  not  yet  take  advantage  of  the  longitudinal  nature  of  the 
data.   But  they  do  indicate  that  processes  of  cultural  transmission  begun 
at  so  early  an  age  probably  have  great  continuity. 

Caudill  had  intended  to  continue  these  analyses  on  three  levels-- 
a  cross-cultural  analysis  of  continuities  and  discontinuities  in  child- 
rearing  practices  and  child  behavior;  a  more  detailed  statistical  appraisal 
of  situational  variability  in  mother-child  interaction;  and  a  clinical 
assessment,  on  a  case  by  case  basis,  of  the  individual  families.   It  is  a 
sad  truth  that  much  of  what  he  intended  cannot  be  carried  through  by  anyone 
else;  it  required  his  first-hand  knowledge  of  the  data  and  his  unique 
combination  of  statistical  and  clinical  skills.   But  the  main  thrust  of  the 
intended  statistical  analysis  can  be  carried  out,  and  Caudill 's  long-term 
collaborator,  Carmi  Schooler,  has  agreed  to  do  so.   And  Caudill 's  wife, 
Mie,  who  did  many  of  the  observations  in  Japan,  may  do  a  more  intensive 
analysis  of  the  individual  families. 


i 


It  has  been  a  difficult  year,  perhaps  the  most  difficult  in  the 
history  of  the  Laboratory.   Even  before  William  Caudill 's  tragic  illness, 
the  tone  of  life  had  been  one  of  struggling  against  adversity.   As  is  now 
almost  habitual,  we  have  had  to  keep  our  research  going  with  barely  adequate 
personnel  arrangements.   This  year  we  also  faced  the  very  real  danger  that 
a  major  new  endeavor,  Leonard  Pearlin  and  Frederic  Ilf eld's  study  of  the 
social-structural  origins  of  stress,  might  not  be  funded.   The  uncertainty 
led  to  considerable  anxiety,  not  only  for  these  investigators,  but  for 
everyone  else  who  cares  about  NIMH's  ability  to  continue  supporting  social 
science  research  in  its  Intramural  program.   The  issue  has  been  favorably 
resolved,  at  least  for  the  present. 

The  remainder  of  this  report  summarizes  the  accomplishments  of  the 
Laboratory  this  past  year.   We  simply  note  in  passing  those  studies  in 
which  the  principal  activities  were  data-collection  or  the  preparation  of 
data  for  analysis--specif ically,  Carmi  Schooler's  experimental  studies  of 
the  social,  psychological,  and  physiological  functioning  of  schizophrenic 
patients;  Gordon  Allen's  research  on  behavior  genetics;  and  Lindsley 
Williams's  analysis  of  the  relationships  between  urban  social  structure  and 
individual  psychological  functioning. 

THE  DEVELOPMENT  OF  PROSOCIAL  BEHAVIORS 

( OR  KINDNESS  COMETH^ ) 

h.v.  h  °''^''  ^  "'^^^'^  °^  ^^^''''  ''^^'^"  ^'^^^   ^^^^°"  ^"'i  Caroline  Zahn  Waxier 
have  been  engaged  in  research  on  the  development  of  prosocial  behaviors  in 
young  children,  that  is,  studies  aimed  at  identifying  conditions  that  ai" 


64 


or  hinder  the  development  of  concern  for  other  persons.   Details  of  their 
substantive  findings  have  been  reported  in  previous  annual  reports.   A 
general  conclusion  from  their  experiments,  one  relevant  to  their  present 
plans  for  extending  this  program  into  investigations  involving  older 
children,  is  that  the  child's  learning  and  practicing  of  altruism  is 
largely  a  function  of  the  parents'  or  teachers'  own  capacities  for  commit- 
ment to  altruism.   Children  under  the  care  and  tutelage  of  adults  whose 
commitment  was  only  at  the  level  of  verbalized  moral  principles  expressed 
altruism  only  in  the  form  of  moral  judgments  and  principles.   They  did  not 
develop  altruism  when  they  were  cared  for  by  adults  who  were  warmly  altruistic 
toward  other  people  but  who  treated  them  coldly  and  unempathically.   When 
the  caretakers  were  genuinely  responsive  to  others'  needs  for  help  and 
comfort,  verbalized  their  values  regarding  respect  for  others,  and  were 
warmly  responsive  to  the  child,  the  children  developed  altruism,  generalized 
both  in  principle  and  in  behavior. 

Experimentally  contrived  social  situations  are  widely  used  in  the 
investigation  of  children's  social  learning,  yet  there  are  few  guidelines 
or  criteria  for  determining  what  kinds  of  laboratory  manipulations  are 
effective  and  valid  representations  of  social  processes.   Yarrow  and  Waxier 
have  therefore  made  the  experimental  situation  itself  an  object  of  study. 
Through  planned  variations  in  their  own  experimental  procedures,  and  from 
an  analysis  of  the  research  literature,  they  have  demonstrated  that  findings 
vary  as  the  dimensions  of  the  experimental  situation  vary.   Conclusions  emd 
generalizations  arrived  at  from  a  large  body  of  experiments,  all  using 
structurally  similar  situations,  may  have  much  less  theoretical  generality 
than  is  often  assumed.   Furthermore,  experimental  situations  devised  for 
young  children  do  not  always  have  the  same  meaning  to  children  as  to  inves- 
tigators.  Similarly,  situations  assumed  to  be  conceptually  equivalent  are 
not  always  so. 

The  data  discussed  by  Yarrow  and  Waxier  show  that  such  facets  of  the 
experimental  situation  as  ambiguity,  bizarreness,  test-like  quality,  and 
artificiality  or  reality  have  significant  effects  on  children's  responding. 
Further,  although  various  experimental  situations  produce  similar  behaviors 
in  children,  the  cognitive  and  affective  accompaniments  of  these  behaviors 
are  not  always  the  same,  nor  do  they  always  conform  to  what  the  investigator 
has  assumed. 

As  Yarrow  and  Waxier  plan  for  extending  their  studies  to  older 
children,  many  new  experimental  difficulties  arise,  particularly  in  making 
laboratory  situations  plausible  and  meaningful.   These  limitations  push  for 
the  development  of  new  experimental  approaches  to  field  designs.   Their 
current  work  on  observational  procedures  in  fluid  settings,  such  as  in  the 
family,  is  providing  methodological  footings  to  aid  them  in  extending  their 
studies  of  prosocial  behavior;  this  work  should  contribute  as  well  to  basic 
methodology  in  social  research, 

DEVELOPMENT  OF  SELF-CONCEPTION  IN  CHILDREN 

In  past  reports  about  Morris  Rosenberg  and  Roberta  Simmons 's  study 
of  self-esteem  in  black  and  white  children,  we  emphasized  their  finding 

65 


that  black  children's  levels  of  self-esteem  are  as  high  as  are  those  of 
white  children--despite  the  widespread  belief  to  the  contrary  among  social 
scientists  and  laymen  alikeo   Now,  with  the  completion  of  their  analyses 
(soon  to  be  published  as  a  monograph  by  the  American  Sociological  Association), 
it  is  possible  to  address  the  theoretically  more  important  question:  just 
what  does  matter  in  determining  levels  of  self-esteem  of  both  black  and  white 
children? 

The  findings  consistently  emphasize  the  impact  of  the  immediate 
social  environment  on  the  child's  self-esteemo   Of  particular  importance  is 
the  concordance  or  discordance  of  the  individual's  social  characteristics 
with  those  of  the  people  with  whom  he  interacts.   Consequences  of  contextual 
consonance  or  dissonance  are  varied,  some  beneficial,  others  injurious. 
For  example,  at  the  secondary  school  level,  black  children  attending  pre- 
dominantly black  schools  are  more  likely  than  are  black  children  in  pre- 
dominantly white  schools  to  have  high  self-esteem;  but  they  are  also  more 
likely  to  obtain  low  marks  in  school.   Whatever  its  other  costs,  then,  a  con- 
sonant social  context  appears  to  protect  the  self-esteem  of  the  black  child. 
A  black  child  in  a  racially  segregated  context  has  little  direct  exposure 
to  white  children,  and  is  thus  unlikely  to  experience  direct  prejudice. 
He  is  exposed  to  circumstances  that  are  less  likely  to  make  him  aware  of 
the  deprecatory  views  of  whites.   If  he  comes  from  a  separated/never-married 
family,  he  is  less  likely  to  feel  deep  personal  shame  at  the  fact,  since 
the  stigma  attached  to  this  family  type  is  less  strong  in  this  environment. 
Although  his  school  performance  tends  to  be  poorer  than  that  of  whites, 
he  is  not  necessarily  disturbed  by  this,  for  he  usually  compares  himself 
with  others  of  his  race.   Finally,  a  consonant  social  environment  is  more 
hospitable  to  the  use  of  certain  psychological  mechanisms  for  protecting 
self-esteem. 

In  this  study,  four  protective  mechanisms  have  been  observed:  the 
inflation  mechanism  (e.g, ,  the  tendency  for  children  to  believe  that 
society  ranks  their  race,  religion,  or  father's  occupation  higher  than  it 
actually  does);  selective  interpretation  (e.g.,  the  child  who  does  poorly 
in  school  is  not  likely  to  believe  that  low  marks  signify  low  intelligence); 
selective  perception  (e.g.,  the  child  who  does  poorly  in  school  perceives 
his  parents  as  considering  him  intelligent);  and  value  selectivity  (e.g., 
the  academically  unsuccessful  child  is  less  likely  to  stake  his  feeling 
of  self -worth  on  intelligence).   All  these  protective  mechanisms  are  espe- 
cially likely  to  be  employed  in  consonant  social  contexts,  which  are 
particularly  hospitable  to  their  use. 

Finally,  the  individual's  self-attitude  is  strongly  influenced  by 
his  perception  of  other  people's  evaluations  of  him;  this  will  be  especially 
true  for  those  who  play  an  important  role  in  his  life.   In  this  respect, 
the  black  child  appears  to  fare  as  well  as  the  white.   Black  children  are 
just  as  likely  as  whites  to  believe  that  their  mothers,  friends,  and 
teachers  hold  favorable  opinions  of  them.   Furthermore,  these  perceptions 
are  at  least  as  strongly  related  to  the  self-esteem  of  black  as  of  white 
children.   These  processes  thus  serve  to  protect  the  self-esteem  of  the 
black  child  against  the  deprivations  to  which  he  is  subjected. 


66 


In  sum,  the  data  suggest  that  the  immediate  environment  of  the 
child  constitutes  an  important  crucible  within  which  his  self-image  is 
forged.   Even  in  a  hostile  larger  environment,  this  immediate  environment 
can  be  protective  of  the  child's  self-esteem. 

HEALTH  ORIENTATIONS  OF  CHILDREN 

From  comparisons  of  mothers'  and  children's  definitions  of  illness, 
John  Campbell  found  that  with  increasing  maturity  people  typically  adopt 
a  more  sophisticated  definition  of  illness,  one  that  is  broader,  more 
psychosocial ly  oriented,  more  precise,  and  more  subtle.   Using  a  composite 
measure  of  definitional  sophistication,  he  found  that,  with  age  statisti- 
cally controlled,  the  correlacion  between  mothers'  and  children's  "sophisti- 
cation" scores  were  negligible.   This  evidence  provides  little  support  to 
the  idea  that,  in  defining  illness,  the  child  adopts  his  mother's  conceptual 
style.  Moreover,  correspondence  between  mother  and  child  in  definitional 
sophistication  was  not  enhanced  by  facets  of  the  mother-child  relationship 
that  one  would  expect,  from  past  research,  to  be  favorable  to  the  inter- 
generational  transmission  of  attitudes  and  concepts.   To  a  considerable 
extent,  then,  children's  concepts  of  illness  develop  from  their  own  exper- 
iences, rather  than  from  the  direct  transmission  of  maternal  concepts. 

Although  children  may  not  directly  adopt  their  mothers'  conceptions 
of  illness,  mothers  do  serve  as  gatekeepers  for  the  child,  legitimizing 
his  illness  or  imposing  a  label  of  illness  on  him;  this  is  particularly 
true  for  younger  children.   Furthermore,  after  age  differences  are 
statistically  eliminated,  the  child's  propensity  to  view  the  behavior  of 
other  family  members  as  critical  in  defining  illness  is  clearly  linked  to 
his  past  health  history--the  healthier  the  child  has  been,  the  less  likely 
he  is  to  view  the  behavior  of  other  family  members  as  critical  in  defining 
illness. 

Another  dimension  of  the  illness  concept  is  whether  or  not  a  child 
will  interpret  particular  symptoms  as  indicating  that  he  is  ill.   In  general, 
both  mothers  and  children  think  that  they  are  less  vulnerable  than  other 
people  to  illness.   This  tendency  is  enhanced  with  age.   Above  and  beyond 
the  effects  of  age,  the  principal  determinants  of  whether  or  not  a  child 
will  interpret  a  given  set  of  symptoms  as  indicating  that  he  is  ill  are 
his  perception  of  whether  or  not  illness  brings  rewards,  his  assessment  of 
his  mother' s  own  approach  to  being  sick,  and  his  own  standards  for  function- 
ing in  the  sick  role.   If  he  sees  his  mother  as  more  attentive,  affectionate 
and  indulgent  when  he  is  sick,  if  he  reports  that  she  herself  readily 
accepts  the  sick  role,  and  if  he  thinks  that  it  is  acceptable  to  express  one's 
emotions  openly  when  sick,  then,  given  specified  signs  and  symptoms,  he  is 
more  likely  to  see  himself  as  ill.   In  short,  to  the  degree  that  a  child 
perceives  the  general  milieu  as  providing  support  for  adopting  the  sick  role, 
he  will  readily  attribute  illness  to  himself. 

THE  SOCIAL-STRUCTURAL  ORIGINS  OF  STRESS 

As  reported  in  some  detail  last  year,  Leonard  Pearlin  and  Frederic 
Ilfeld  are  in  the  midst  of  a  large-scale  study  of  the  social  origins  of 

67 


stress,  i.eo,  emotional  burdens  experienced  by  individuals  from  which 
they  attempt  to  remove  themselves.   The  main  thrust  of  their  investigation 
is  to  trace  the  influence  of  social  structure--especially  race,  class,  sex, 
and  age- -on  people's  exposure  to  potentially  stressful  situations,  their 
experiencing  these  situations  as  stressful  or  nonstressful,  their  modes  of 
coping  with  stressful  situations,  and  the  longer-term  consequences  of  these 
experiences. 

The  principal  accomplishments  of  the  project  this  year  have  been  a 
refined  conceptualization  of  the  stress  process,  particularly  of  coping, 
and  the  development  and  pretesting  of  a  complex  interview  schedule.   The 
final  wave  of  pretests  was  conducted  in  Chicago  by  a  professional  survey 
organization,  using  a  random  sample  of  100  respondents.   These  pretest 
interviews  made  possible  the  sharpening  of  questions  and  development  of 
indices.   Statistical  analysis  of  these  interviews  also  demonstrated  that 
it  is  possible  for  respondents  to  differentiate  among  potentially  stress- 
arousing  experiences  and  to  distinguish  between  situationally-induced 
stress  and  more  pervasive  anxiety.   For  example,  a  majority  of  people  who 
report  problematic  experiences  in  one  area  of  life  do  not  report  them  in 
others;  of  those  who  say  they  do  have  problems  in  one  or  another  area, 
most  say  that  the  problematic  experiences  do  not  create  felt  stress;  and 
of  those  reporting  stressful  reactions  in  one  area,  most  are  likely  to 
report  none  in  other  areas.   This  independence  of  responses  to  different 
parts  of  the  interview  insures  that  statistical  analyses  of  the  stress- 
process  can  be  meaningful. 

The  study  is  scheduled  to  go  into  the  field  shortly.   It  is  to  be 
conducted  in  Chicago,  the  goal  being  to  interview  a  representative  sample 
of  2,000  people,  plus  special  subsamples  of  another  300, 

THE  DEVELOPMENT  OF  CONSCIENCE 

In  his  experimental  studies  of  conscience-development  in  young 
children,  Roger  Burton's  focus  this  year  has  been  the  investigation  of  how 
a  mother's  presence  in  the  experimental  situation  and  her  specific  child- 
rearing  practices  are  related  to  her  child's  behavior  in  a  test  of  cheating. 
A  child's  performance  on  a  simple  game  of  motor  skill  provided  measures  of 
his  honesty  or  dishonesty  in  the  face  of  a  strong  temptation  to  cheat. 
Deviation  from  the  rules  of  the  game  was  necessary  to  achieve  a  good  score. 
All  children  were  first  tested  alone.   A  week  later,  their  mothers  were 
chlS  l°Jf   r   '5^  while  they  were  retested.   Interactions  of  mother  and 
child  were  observed  from  behind  one-way  mirrors. 

Ph.n..H^^"^K^^'''  T^^^""^   "^^^  present,  significant  numbers  of  children 
changed  m  their  observance  of  the  rules;  the  majority  changed  to  cheating 

oX2TslVe:T,olTTn,-t''   '^°"''^^''  ^  control^group  reteLed  alone  S 
ocnerwise  identical  conditions  remained  stable  in  either  chpflt-inc  r,-,-  k^,-„„ 
honest.   Among  children  who  cheated  only  when  mother  was  prlsei^'  tLre  ' 

silJen^^S^Se^tlndicatiS^  :;rt:in  ::iuct"  'T^'T'   ''^"  ^°"^  ^°"- 
hand,  some  children  who  ^ad^LS^^^    HLrint^^^edt^^i:"'^ 


mothers'  presence.   These  contradictory  processes  do  not  support  the  notion 
that  the  presence  of  an  adult  will  necessarily  result  in  what  has  been 
described  as  "externalization  of  conscience"  or  "transfer  of  superego,"  in 
which  the  child  shifts  responsibility  for  control  from  himself  to  the 
adult. 

Reviews  of  research  on  conscience  development  have  often  concluded 
that  parental  warmth  is  positively  associated  with  early  and  strong  develop- 
ment of  conscience.   In  this  study,  though,  maternal  warmth  was  related  to 
cheating,  under  both  experimental  conditions.   Further  analyses  that  dis- 
tinguished those  expressions  of  warmth  contingent  on  the  child's  behavior 
in  the  game  from  noncontingent  warmth  provided  a  clearer  understanding 
of  the  processes  involved.   Noncontingent  warmth,  a  measure  similar  to 
"general  warmth"  as  usually  employed,  was  unrelated  to  any  of  the  measures 
of  the  child's  behavior,  whereas  contingent  warmth  was  significantly  related 
to  cheating,  whether  or  not  the  mother  was  present  in  the  experimental  sit- 
uation.  These  findings  suggest  that  the  broad  notion  of  warmth,  which  has 
served  as  the  basis  for  assessing  the  nurturant  relationship,  may  be  mis- 
leading.  Warmth  may  be  more  adequately  conceptualized  as  a  specific  resource 
that  is  manipulated  rather  than  as  a  general  quality  of  a  relationship.   The 
data  do  fit  predictions  from  social  learning  principles  that  a  mother's 
requiring  successful  achievement  as  a  condition  for  showing  warmth,  or 
withholding  emotional  support  when  the  child  performs  badly,  would  lead  to 
cheating. 

Besides  warmth,  the  mother's  behavior  was  scored  in  the  areas  of 
rejection,  dominance,  harmony,  and  achievement  orientation.   The  findings 
generally  indicate  that  the  more  the  mother  focused  her  attention  on 
achievement  and  directed  the  child  toward  achievement,  the  more  likely  was 
the  child  to  cheat.   This  general  pattern  received  confirmation  from  a 
factor  analysis  of  the  rearing  measures, 

THE  SOCIAL  PSYCHOLOGICAL  CORRELATES  OF  OCCUPATION 

The  most  recent  analyses  of  Melvin  Kohn  and  Carmi  Schooler's  data  on 
the  social  psychology  of  occupation  have  centered  on  whether  occupation 
affects  or  only  reflects  personality.   Their  approach  to  this  problem  is 
based  on  studying  dimensions  of  occupation,  in  contrast  to  the  traditional 
approach  of  studying  some  one  occupation.   To  disentangle  the  intercorrelated 
dimensions  of  occupation,  they  have  secured  a  large  sample  of  men,  inventoried 
their  job  conditions,  and  differentiated  the  psychological  concomitants  of 
each  facet  of  occupation  by  statistical  analysis. 

Virtually  all  of  the  many  occupational  conditions  examined  in  this 
study  are  significantly  related  to  one  or  another  facet  of  psychological 
functioning.   But  relatively  few  occupational  conditions- -thirteen  in  all-- 
are  significantly  related  to  more  than  one  facet  of  psychological  functioning, 
independently  of  education  and  of  all  the  other  pertinent  dimensions  of  occu- 
pation.  Although  few  in  number,  these  occupational  conditions  are  sufficient 
to  define  the  structural  imperatives  of  the  job,  for  they  identify  the  man's 
organizational  locus,  his  opportunities  for  occupational  self -direction, 

69 


the  principal  job  pressures  to  which  he  is  subjected,  and  the  principal 
uncertainties  built  into  his  job.   These  occupational  conditions  have  an 
appreciable  bearing  on  men's  subjective  reactions  to  their  jobs,  their 
values,  their  orientation  to  self  and  to  society,  and  even  their  intellectual 
functioning. 


Kohn  and  Schooler's  preferred  explanation  of  the  linkages  between 
occupational  conditions  and  psychological  functioning  is  that  job  conditions 
affect  men's  orientations  to,  and  behavior  in,  both  occupational  and  non- 
occupational realms  of  life.   But  there  are  other  possible  interpretations, 
which  they  have  tested.  The  two  most  important  are  that  the  findings  re- 
flect a  tendency  for  men  to  mold  their  conditions  of  work  to  meet  their 
needs  and  values,  and  that  men  are  selectively  recruited  to  and  retained 
in  jobs  to  which  they  are  well  suited. 

Job  molding.   Several  lines  of  evidence  suggest  that  men's  molding 
of  their  jobs  can  take  place  only  within  rather  narrow  limitations.   Most 
important  of  all  the  evidence:  occupational  conditions  are  structurally 
interrelated.   Thus,  a  man  who  does  substantively  complex  work  stands  a 
greater  risk  of  being  held  responsible  for  things  outside  of  his  control 
than  does  a  man  who  works  at  simpler  tasks.   The  risk  increases  if  the  job 
is  not  only  substantively  complex  but  also  time-pressured,  and  increases 
further  if  the  man  stands  high  on  the  supervisory  ladder  or  is  an  owner. 
From  this  perspective,  an  increased  risk  of  being  held  responsible  for 
things  outside  of  one's  control  is  the  price  one  pays  for  holding  an  inter- 
esting and  responsible  job.   Each  of  the  other  occupational  conditions  can 
also  be  seen  as  part  of  an  interlocking  network.   This  structural  interre- 
latedness  means  that  one  has  to  accept  some  occupational  conditions  as  the 
price  for  securing  others. 

Selective  recruitment  and  retention.   To  deal  with  the  possibility 
that  the  relationships  between  occupational  conditions  and  psychological 
functioning  come  about  because  of  selective  recruitment  and  retention,  the 
investigators  reconstructed  each  respondent's  job  history.   The  emphasis 
was  on  one  pivotal  facet  of  occupation  that  could  be  reliably  assessed,  the 
substantive  complexity  of  the  job.   The  question  is:  To  what  extent  has 
the  substantive  complexity  of  men's  jobs  been  influenced  by  their  psycho- 
logical functioning,  and  to  what  extent  has  their  psychological  functioning 
been  influenced  by  the  substantive  complexity  of  their  jobs? 

The  analyses  indicate  that  psychological  functioning  plays,  at  most, 
a  small  part  in  determining  the  substantive  complexity  of  men's  past  and 
present  jobs.  Moreover,  no  matter  which  aspect  of  psychological  functioning 
is  examined,  it  is  more  affected  by,  than  a  determinant  of,  the  substantive 
complexity  of  the  job.   Occupational  self -selection  undoubtedly  does  take 
place,  but  does  not  provide  the  major  explanation  of  the  findings.   There 
IS  a  continuing  interplay,  throughout  the  career,  between  man  affecting 
job  and  job  affecting  man. 

These  findings  have  several  implications.   First  and  most  generally, 
they  contribute  to  the  growing  sense  that  we  have  for  too  long  fixated  on 

70 


I 


the  importance  of  early,  especially  childhood,  experience  in  the  shaping  of 
personality^   The  potentiality  for  change  persists  throughout  men's 
occupational  careers. 

Second,  the  findings  should  help  reshape  our  conceptions  about  what 
is  important  in  occupational  experience.   Variables  that  have  been  at  the 
center  of  interest  in  the  study  of  occupations- -status,  interpersonal 
relationships,  organizational  structure—prove  to  be  less  pertinent  for 
psychological  functioning  than  do  the  immediate  realities  of  men's  jobs. 

Third,  the  findings  provide  some  insight  into  the  processes  by 
which  occupational  efxperience  affects  psychological  functioning.   The 
linkages  between  particular  facets  of  occupational  experience  and  particular 
facets  of  psychological  functioning  suggest  that  men  learn  to  cope  with  the 
realities  of  their  jobs  and  then  generalize  these  lessons  to  nonoccupational 
realities.   These  findings  thus  argue  for  a  learning-generalization  model, 
as  opposed  to  a  reaction-formation  or  compensatory  model. 

Finally,  these  findings  bear  directly  on  the  issue  of  whether  men 
similarly  located  in  the  structure  of  society  come  to  share  beliefs  and 
values  because  they  have  experienced  similar  conditions  of  life  or  because 
of  some  process  of  value- transmission.   Marx  and  the  structuralists  would 
have  us  believe  that  the  former  is  basic,  theorists  as  diverse  as  the 
"human  relations  of  industry"  and  "culture  of  poverty"  schools  stress  the 
latter.   These  findings  come  down  solidly  in  support  of  the  structuralists. 
Men  learn  from  their  own  experience.   Social  structure  matters  because  it 
helps  shape  this  experience. 


71 


Annual  Report  -  July  1,  1971  -  June  30,  1972 

Laboratory  of  Brain  Evolution  and  Behavior 

National  Institute  of  Mental  Health 

Paul  D.  MacLean,  M.D.,  Chief 


By  July  1,  1972,  the  Laboratory  of  Brain  Evolution  and 
Behavior  will  have  spent  one  year  in  its  new  quarters  at  the 
NIH  Animal  Center  near  Poolesville,  Md.   This  splendidly  equipped 
and  beautifully  situated  laboratory,  for  which  planning  began  in 
1958,  makes  provision  for  large  indoor  and  outdoor  quasi-natural 
habitats  for  research  on  evolutionary,  developmental,  and 
ecological  factors  relating  to  brain  function  and  behavior  of 
animals.   With  this  multifaceted  approach,  the  Laboratory 
represents  a  unique  facility  and  a  new  departure  in  brain  research. 
The  relevance  of  comparative  animal  studies  to  programs  concerned 
with  mental  health  is  readily  appreciated  when  it  is  realized 
that  in  its  evolution  the  human  brain  expands  along  the  lines  of 
three  basic  patterns  common  to  all  mammals. 

The  move  into  the  new  buildings  went  smoothly  so  that  there 
was  virtually  no  interruption  in  the  ongoing  experiments  conducted 
indoors.   One  of  the  major  research  efforts  of  the  program  is  to 
develop  prototypes  for  outdoor  habitats.   The  pond  for  the  wild 
fowl  habitat  is  nearing  completion,  and  an  uplands  habitat,  also 
near  completion,  has  the  promise  of  affording  an  inexpensive 
means  and  labor-saving  method  for  enclosing  large  areas  for 
small  mammals.   The  main  laboratory  building  is  especially 
designed  to  allow  easy  access  for  the  investigators  to  the  out- 
door habitats . 

Several  Calhoun-type ,  indoor  habitats  are  available  for 
observations  on  small  mammals.   One  of  them  has  been  especially 
designed  as  a  prototype  for  a  "socioenvironmeter"  that  will  partly 
compensate  for  the  limitation  of  observers  to  record  continuously 
the  activities  of  many  animals .   It  provides  an  automated  data 
acquisition  system  which  records  the  place,  time,  and  direction 
of  movements  of  animals  in  various  compartments  of  the  habitat 
set  aside  for  nest  boxes,  feeding,  and  drinking.   Instrumental 
behaviors  can  also  be  continuously  recorded.   It  is  estimated 
that  the  performance  capacity  of  the  system  is  equivalent  to 
that  of  900  observers. 

The  Laboratory's  first  year  in  its  new  quarters  has  been 
remarkable  because  of  the  lack  of  frustrations  and  inconveniences 
usually  experienced  in  settling  into  new  buildings.   The  morale 
of  the  Laboratory  has  also  benefited  by  lively,  weekly  seminars 


73 


and  enthusiastic  visits  by  scientists  from  this  country  and 
abroad.   Finally,  as  mentioned  in  the  individual  reports,  the 
year  has  been  further  notable  because  of  signal,  scientific 
recognitions  of  certain  members  of  the  senior  staff. 

Section  on  Comparative  Neurophysiology  and  Behavior 
Paul  D.  MacLean,  Chief 

In  its  evolution  the  human  forebrain  has  expanded  along  the 
lines  of  three  basic  patterns  characterized  as  reptilian,  paleo- 
mammalian  and  neomammalian.   In  this  respect  it  has  similarities 
to  the  brains  of  all  higher  mammals.   The  three  basic  brain  types 
are  radically  different  in  chemistry  and  structure,  and  in  an 
evolutionary  sense  are  eons  apart.   Despite  extensive  investi- 
gation under  standard  laboratory  conditions  disappointingly  little 
has  been  learned  about  the  functions  of  the  two  evolutionary  older 
formations  of  the  brain.   With  its  new  facilities  at  the  Poolesville 
Center  the  Section  on  Comparative  Neurophysiology  and  Behavior 
will  be  able  to  conduct  comparative  brain  and  behavioral  studies 
on  animals  living  under  semi-natural  conditions.   Studies  of  this 
kind  have  the  potential  of  revealing  brain-and-behavior  relation- 
ships that  would  not  be  seen  in  the  confines  of  a  laboratory. 

STUDIES  ON  THE  STRIATAL  COMPLEX.   In  mammals  the  striatal 
complex  (corpus  striatum  +  globus  pallidus)  represents  the  major 
counterpart  of  the  reptilian  forebrain.   The  reported  findings 
that  large  destructive  lesions  of  the  striatal  complex  may  result 
in  no  motor  incapacity  is  evidence  against  the  clinical  view  that 
It  primarily  subserves  motor  functions.   Projects  of  this  Section 
are  designed  to  test  the  hypothesis  that  the  striatal  complex 
plays  a  basic  role  in  genetically  constituted  forms  of  behavior 
such  as  establishing  and  defending  territory,  hunting,  homing 
mating,  breeding,  and  forming  social  hierarchies.   Experimental 
work  of  this  kind  is  also  calculated  to  reveal  information  about 
neural  mechanisms  underlying  compulsive,  repetitious,  ritualistic, 
imitative  and  other  propendent  forms  of  behavior. 

Species-specific  and  imitative  behavior.   A  long-term  study 
IS  utilizing  the  innate  genital  display  behavior  of  the  squirrel 
monkey  as  a  means  of  identifying  parts  of  the  brain  involved  in 
species-specific  behavior  and  associated  imitative  factors. 
Large  bilateral  lesions  in  many  parts  of  the  brain  have  no  effect 
on  the  display   In  the  past  year,  additional  evidence  has  been 
^l^^i^^v  ^^        lesions  of  the  pallidal  part  of  the  striatal  complex 
may  markedly  alter  or  abolish  display  behavior,  although  there  is 
no  evident  motor  incapacity.   The  results,  therefore,  indicate 
that  the  striatal  complex  may  be  part  of  a  neural  repository  for 
species-specific  forms  of  behavior.  ' 


74 


Since  the  display  behavior  also  involves  imitative  factors, 
the  above  findings  are  relevant  to  the  important  question  of 
neural  mechanisms  of  imitation,  about  which  almost  nothing  is 
known.   Imitation  serves  in  many  ways  to  maintain  group  identity 
and  to  promote  group  survival.   The  devastating  effects  of  an 
incapacity  for  natural  imitation  are  illustrated  by  cases  of 
childhood  autism.   Since  the  early  19th  Century,  emphasis  has 
been  given  to  the  use  of  imitation  for  training  mentally 
retarded  children, 

Effects  of  6-hydroxydopamine  on  striatal  function. 
6-Hydroxydopamine  (6-OHDA)  is  known  to  destroy  dopaminergic 
endings  in  the  corpus  striatum.   Experiments  have  been  performed 
in  which  squirrel  monkeys  are  challenged  by  parenteral  injections 
of  L-dopa  or  apomorphine  after  the  deposit  of  6-OHDA  powder  in 
the  corpus  striatum.   Under  such  conditions,  monkeys  that  are 
apparently  unaffected  by  6-OHDA  alone,  develop  athetoid  movements 
and  other  dyskinesias.   It  has  been  shown  that  the  same  symptoms, 
(e.g.,  athetoid  movements  of  the  contralateral  foot)   can  be 
elicited  when  animals  are  challenged  a  year  later.   The  results 
are  compatible  with  the  clinical  hypothesis  that  dyskinesias 
seen  in  the  treatment  of  Parkinson's  disease  with  L-dopa  may 
be  the  result  of  a  hypersensitivity  of  striatal  dopamine 
receptors . 

Effect  of  6-OHDA  on  striatal  fluorescence.   The  use  of  the 
technique  of  Falck  and  Hillarp  has  revealed  that  in  the  foregoing 
type  of  experiment  the  deposit  of  6-OHDA  powder  in  the  striatum 
may  result  in  a  loss  of  fluorescence  for  a  distance  of  about 
2  mm  from  the  center  of  the  lesion.   In  addition,  this  experimental 
approach  has  provided  new  information  about  the  course  of 
nigrostriatal  dopaminergic  fibers  in  the  monkey.   Axons  with 
injured  terminals  show  up  as  brightly  fluorescent  beaded  fibers. 
The  main  contribution  of  fibers  to  the  rostral  striatum  appears 
to  follow  the  course  of  the  ansa  lenticularis .   Some  fibers  fan 
out  in  the  globus  pallidus  in  their  approach  to  the  putamen 
and  caudate,  whereas  others  veer  from  the  ansa  and  follow  the 
internal  capsule. 

Additional  findings.   In  extending  the  comparative  study  of 
striatal  functions,  some  pilot  experiments  are  being  conducted 
on  the  effects  of  lesions  of  the  paleostriatum  in  reptilian  and 
avian  forms.   Tom  turkeys  are  being  used  in  one  set  of  experiments 
because  the  group  gobbling  response  (G.G.R.)  provides  a  paradigm 
for  investigations  on  imitative  behavior.   Preliminary  findings 
indicate  that  a  unilateral  vascular  lesion  of  the  paleostriatum 
may  be  sufficient  to  produce  a  marked  alteration  of  the  G.G.R. 


75 


STUDIES  ON  LIMBIC  SYSTEM.   The  mammalian  limbic  system 
(limbic  cortex  H-  its  primary  brain-stem  connections]  represents 
an  inheritance  from  lower  mammals.   The  Section's  research  on  the 
limbic  system  has  continued  to  focus  on  the  important  question  of 
the  nature  and  function  of  intero-  and  exteroceptive  inputs  to 
the  limbic  cortex. 

Interoceptive  inputs.   In  a  microelectrode  study  of  vagal 
projections  to  the  limbic  cortex  an  improved  method  has  been 
devised  for  applying  stimuli  to  the  vagus  nerve  in  chronically 
prepared  awake,  sitting  squirrel  monkeys.   Additional  evidence 
has  been  obtained  that  vagal  volleys  evoke  discharges  of  units 
in  the  middle  part  of  the  cingulate  gyrus  with  latencies  ranging 
from  10-40  msec.   The  observations  gain  added  significance  from 
the  finding  that  intravenous  microinjections  of  serotonin,  a 
known  excitant  of  visceral  receptors,  affects  the  firing  of  18% 
of  units  in  the  same  cortical  region,  with  the  ratio  of  excitatory 
to  inhibitory  effects  being  3  to  1.   The  present  results  are  to 
be  considered  in  the  light  of  the  known  autonomic  functions  of 
the  cingulate  cortex  and  the  alleged  role  of  this  part  of  the 
limbic  system  in  morphine  addiction. 

Two  incidental  observations  in  connection  with  this  study 
should  be  mentioned:  (1)  Information  has  been  obtained  for  the 
first  time  about  the  physiological  effects  of  intravenous  serotonin 
in  the  monkey,  with  penile  erection  being  one  of  the  manifestations i 
ihis  latter  finding  which  has  not  heretofore  been  described  in 
any  species,  invites  further  investigation  in  regard  to  the 
disputed  role  of  parachlorophenylalanine  (a  serotonin  depletor)  in 
sexual  arousal  of  animals  and  man.  (2)  Attention  is  drawn  to 
Project  No.  M-LBEB-CN-5 ,  describing  the  case  of  a  monkey  in  which 
premature  ventricular  contractions,  ECG  signs  of  myocardial 
infarction,  and  cardiac  myocytolysis  developed  following  vagal 
in^tS^?t^h;  f"^   significance  of  this  finding  is  to  be  considered 
m  the  light  of  growing  clinical  evidence  that  a  sizeable 


nS?her^?L°^-^^^^T^  ^^^"^  ^^°"^  ^^^^^  myocardial  ischemia  show 
infarction    ^""^  °^  coronary  thrombosis  nor  gross  myocardial 


Exteroceptive  connections.   Although  more  is  known  ahoni-  i-h^ 
anatomy  and  physiology  of  the  olfactory^npSt  to  the  TimSic  cortex 
than  other  sensory  systems,  information  is  lackLg  aboifthe 
influence  of  various  components  of  the  olfactory  prelections  on 
behavior   The  development  of  an  improved  olfactometer  wi?S  a 
fully  automated  system  for  testing  olfactory  disc?imina5on  in 

Change  in  detection'tSLjo^SrfoS'So^rs^burSvrno  SSntJon'^ 
of  an  overlearned  discrimination  task.   RelearnJng  S?  the  ^^°'' 
discrimination,  however,  is  eventually  possible'^LSicating  that 


76 


other  projections  of  the  olfactory  bulb  afford  a  partial 
restitution  of  function.   The  present  study  provides  essential 
background  for  planned  investigations  on  (1)  neural  mechanisms 
required  for  the  discrimination  of  pheromones;  (2)  the  role  of 
olfactory  cues  in  "bait  shyness"  (Project  No.  M-LBEB-CN-9) ;  and 
(3)  the  sensory  control  of  fighting  behavior  (Project  No. 
M-LBEB-CN-11) . 

Section  on  Comparative  Biopsychology 
Walter  C.  Stanley,  Chief 

This  Section  conducts  comparative  and  ontogenetic  studies 
for  the  purpose  of  gaining  insights  into  adaptive  and  maladaptive 
behavior  of  human  beings.   A  basic  question  is,  "How  do  the 
consequences  of  early  behavior  affect  later  behavior?"   Dogs  are 
used  as  experimental  subjects  because  they  have  a  greater 
psychological  affinity  to  man  than  any  other  domesticated  animal 
and  are  ideally  suited  to  biopsychological  studies  of  the  develop- 
ment of  social  learning  and  motivation.   Previous  investigations 
of  this  Section  have  shown  that  puppies  under  2  weeks  of  age  are 
capable  of  learning  by  classical  and  operant  conditioning.   The 
results  suggest  that  in  terms  of  the  fundamental  process,  neo- 
natal learning  is  continuous  with  that  of  adult  learning.   This 
conclusion  has  far  reaching  implications  because  it  means  that 
neonatal  learning  takes  place  before  the  myelination  of  cortical 
structures. 

Temporal  organization  of  neonatal  ingestive  behavior.   Data 
on  stimulus  control  in  neonatal  dogs  indicate  that  under  some 
conditions  inhibitory  processes  are  either  weak,  transient,  or 
absent  in  the  very  young.   Either  the  presentation  or  omission  of 
a  strong  positive  reinforcer  such  as  milk  can  be  scheduled  so  that 
sucking  at  a  high  rate  slows  to  a  low  rate.   Previously,  reliable 
low  rate  sucking  has  been  obtained  only  for  short  periods .   In 
the  past  year,  the  use  of  a  computer-controlled,  milk-delivery 
schedule  has  made  it  possible  to  train  subjects  to  slow  their 
sucking  so  that  milk  is  obtained  50  to  99  percent  of  the  time. 
The  schedule  that  results  in  this  reliable  effect  combines  the 
response-suppressing  properties  of  multiple  milk  deliveries  with 
the  response-maintaining  properties  of  single  milk  presentations. 
These  findings  clearly  demonstrate  that  infant  dogs  have  the 
capacity  to  suppress  responses. 

Effective  stimulus  sites  for  milk  reinforcement.   Milk  obtained 
by  the  normal  intraoral  route  serves  as  a  reinforcer  in  a  variety 
of  learning  tasks  involving  different  response  requirements  in 
neonatal  dogs.   Intragastric  injection  of  milk,  however,  is  in- 
effective in  producing  and  maintaining  learned  key-lifting,  al- 
though it  is  sufficient  to  maintain  a  nipple  latch  and  to  initiate 

77 


sucking.   In  view  of  these  findings  it  was  significant  to  learn 
whether  or  not,  the  oral  ingestion  of  milk  would  still  be  an  ef- 
fective reinforcer  it  it  did  not  enter  the  stomach.   Findings  on 
an  esophagostomized  puppy  resulted  in  an  affirmative  answer  to 
this  question. 

Maladaptive  adjunctive  behavior  in  neonates.   If  a  neonatal 
dog  is  required  to  head-lift  a  key  many  times  before  obtaining 
milk  from  a  nipple,  other  responses  tend  to  occur  right  after 
each  milk  reinforcement.   Such  adjunctive  behaviors  may  be  of  a 
normal  kind  such  as  crawling  away  from  the  nipple  or  may  be 
maladaptive  hypertonic  states  that  interfere  with  getting  more 
milk.   The  maladaptive  behavior  is  characterized  by  lingual 
spasms  in  which  the  tongue  is  pressed  against  the  roof  of  the 
mouth  (TOR)  or  on  the  floor  of  the  mouth  (TOP) .   In  addition, 
there  usually  are  dyskinesias  of  the  head,  trunk,  and  limbs.   It 
was  found  that  the  experimenter  could  produce  the  TOR  response 
by  applying  repetitive  pressure  below  the  tongue,  and  the  TOP 
response  by  repetitive  insertion  of  a  nipple  above  the  tongue. 
These  functionally  induced  dyskinesias  possibly  reflect  the 
incomplete  maturation  of  the  basal  ganglia  and  suggest  how  some 
childhood  tics  might  stem  from  maladaptive  behaviors  acquired 
during  the  nursing  phase. 

Discriminated  instrimiental  crawling  in  neonatal  dogs.   Neo- 
natal dogs  are  capable  of  acquiring  stable  differential  crawling 
responses  to  tactual  or  thermal  cues  presented  on  successive 
trials  with  only  one  of  the  cues  being  associated  with  milk 
reinforcement.   Training  on  a  new  discrimination  task  is 
facilitated  by  inclusion  of  a  previously  positive  cue,  but  is 
unaffected  by  a  previously  negative  one.   The  findings  agree 
with  earlier  observations  that  neonatal  dogs,  unlike  adults, 
are  not  influenced  by  negative  cues. 

Attachment  behavior.   Attachment  behavior  is  operationally 
defined  as  behavior  initiated  and  maintained  by  reinforcing  effects 
of  social  stimulation.   It  has  previously  been  shown  that  contact 
and  interaction  with  a  person  can  serve  to  maintain  approach 
behavior  m  a  variety  of  breeds  of  dogs.   In  juvenile  Basenji 
puppies  approach  behavior  previously  established  by  the  presence 
of  a  passive  person  extinguishes  at  the  same  rate  whether  or  not 
exposure  to  the  person  has  been  on  a  continuous  or  intermittent 
schedule. _  Recent  experiments  have  shown  that  beagle  puppies, 
under  similar  test  conditions,  fail  to  show  extinction.   This  out- 
come IS  quite  the  reverse  of  what  is  found  in  beagle  puppies 
reared  m  total  isolation.   In  this  case,  the  presence  of  a  pass- 
ive person  results  m  an  improvement  of  running  behavior  with 
vnn^fn   K^^^   '  ^^^5^^^  ^^  the  absence  of  this  stimulus,  the 
running  behavior  habituates  and  extinguishes.   The  different 
findings  m  the  two  test  situations  possibly  reflects  the  important 

78 


role  of  early  exposure  to  human  handling. 

Section  on  Behavioral  Systems 
John  B.  Calhoun,  Chief 

The  research  of  this  Section,  with  its  emphasis  on  ecology, 
attempts  to  gain  a  better  understanding  of  the  interrelation- 
ships of  organisms  and  their  environment.   Studies  in  this  area 
have  a  special  urgency  because  of  the  exponential  growth  of  the 
world's  population  with  its  associated  psychopathology ,  depletion 
of  natural  resources,  and  the  pollution  of  the  environment. 

Rats  and  mice  are  used  as  experimental  subjects  because  of 
the  extensive  knowledge  of  their  biology  and  behavior  and  because 
of  their  short  reproductive  cycles.   Observations  are  made  on  (1) 
large  populations,  (2)  small  groups,  and  (3)  animals  in  isolation. 

The  research  of  the  past  year  has  been  mainly  concerned  with 
obtaining  additional  behavioral  and  chemical  data  on  members  of  a 
large  population  of  about  2,000  mice  that  exhausted  its  capacity 
for  continued  procreation.   This  population  initially  began  with 
four  pairs  of  mice  which  were  introduced  into  a  habitat  of  16 
"living  units"  consisting  of  nesting  boxes,  nesting  materials, 
food,  water,  and  "public  space."   Population  growth  terminated 
when  the  density  reached  about  180  mice  per  unit,  representing 
about  20  times  the  number  of  mice  that  would  be  expected  to 
inhabit  this  amount  of  space  under  ordinary  conditions.   In  the 
beginning  the  units  had  been  occupied  by  well-organized  social 
groups  exhibiting  adequate  territorial,  reproductive,  and  maternal 
behavior.   When  the  number  of  progeny  exceeded  by  five  times  the 
number  of  animals  in  the  original  socially  organized  groups,  there 
were  four  behaviorally  distinct  types  of  males:  Cll  territorial, 
dominant  males;  (2)  males  that  infrequently  left  the  nesting 
boxes  and  grew  to  maturity  without  developing  normal  social  and 
reproductive  behavior  (hereafter  identified  as  "nest  dwellers"); 
(3)  males  that  congregated  in  large  numbers  in  the  public  spaces; 
and  (4)  v/ithdrawn,  isolated  animals. 

Irreversible  behaviors  resulting  from  crowding.   Represent- 
ative mice  of  the  four  above  types  were  reconstituted  in  optimal 
sized  groups  in  new  habitats  containing  four  living  units.   In 
these  groups  the  same  kinds  of  abnormal  behavior  persisted,  with 
a  resultant  failure  to  form  a  stable,  structured  social  organiza- 
tion.  Reconstituted  groups  of  males  and  females  from  the  over- 
crowded habitat  showed  impaired  reproductive  behavior:  less  than 
the  expected  number  of  females  became  pregnant;  those  that  went 
to  term  made  poor  nests  and  appeared  incapable  of  nursing  and 
retrieving  their  young,  with  the  result  that  only  a  few  pups 


79 


survived.   The  provision  of  normal  females  did  not  improve  the 
sexual  behavior  of  the  males.   When  females  from  the  overcrowded 
habitat  were  paired  with  normal  stud  males  in  individual  cages, 
reproduction  was  more  successful,  but  there  was  more  than  the 
expected  number  of  cases  of  embryo  resorption  and  spontaneous 
abortion,  as  well  as  instances  of  maternal  neglect  and  cannibalism. 

The  apparent  irreversible  behavioral  changes  of  animals 
exposed  to  the  crowding  serves  as  a  v/arning  of  possible  similar 
consequences  to  human  beings  living  under  congested  conditions. 

Catecholamine  metabolism.   On  the  basis  of  an  earlier  study- 
it  was  expected  that  representatives  of  the  different  behavioral 
types  in  the  overcrowded  habitat  m.ight  show  differences  in  levels 
of  catecholamine  synthesizing  enzymes.   Assays  were  made  of  the 
levels  of  tyrosine  hydroxylase  (TOH)  and  phenylethanolamine-N- 
methyl  transferase  (PNMP)  in  the  brain  and  adrenal  glands.   The 
animals  that  lived  singly  or  in  pools  showed  a  significantly 
higher  TOH  activity  in  the  brain  and  a  higher  PNMP  activity  in 
the  adrenals  than  the  dominant  animals.   Interestingly,  the 
socially  uninvolved  nest-dwellers  had  enzyme  levels  comparable 
to  the  successful  dominant  animals. 

While  on  the  subject  of  chemistry  it  may  be  pointed  out  that 
previous  studies  in  this  Section  showed  that  rats  maturing  in 
crowded  populations  exhibited  marked  increases  in  vitamin  A 
content  of  the  liver.   This  finding,  together  with  the  abnormal 
behaviors  observed  in  these  animals ,  should  serve  as  a  caveat 
in  regard  to  the  desirability  of  large  doses  of  vitamins  that 
has  recently  been  proposed  in  writings  on  orthomolecular 
psychiatry. 

Social  velocity.   Social  velocity  refers  to  "a  measure  of 
the  degree  of  physical  activity  and  alertness  of  an  animal." 
Observations  on  groups  of  animals  ranging  from  four  to  two 
thousand  indicate  that  as  the  group  size  increases  beyond  an 
optimiom,  social  velocity  decreases.   In  groups  in  which  members 
have  lost  their  capacity  for  effective  social  organization  most 
individuals  exhibit  a  reduced  velocity  approaching  a  minimiom 
value. 

Rhythms  of  spontaneous  behavior  (RSB) .   The  behavior  of  an 
animal  over  time  consists  of  a  sequence  of  discrete  behavioral 
states,  each  of  which  starts,  continues,  and  then  stops,  after 
which  It  IS  replaced  by  another  behavior.   A  previous  analysis  of 
data  derived  through  the  use  of  a  RSB  apparatus  led  to  the 
Identification  and  calculation  of  five  probabilities  concerning 
the  initiation,  continuance,  termination,  and  sequencing  of 
behavioral  states.   In  the  large  population  of  mice  described 
above,  sixteen  groups  were  identified,  each  of  which  exhibited 

80 


a  distinctive  24-hour  cycle  of  activity.   These  findings  indicate 
that  when  an  increase  in  population  leads  to  an  interference  with 
access  to  resources,  there  is  a  capacity  of  the  social  system  to 
reduce  conflicts  by  utilizing  resources  at  different  times.   The 
"socioenvironmeter"  described  in  the  introductory  section  on 
habitats  will  provide  an  improved  means  for  investigating  sequences 
of  behavior  in  social  groups. 


81 


AnniJial  Report  of  the  Laboratory  of  Cerebral  Metabolism 

National  Institute  of  Mental  Health 

Louis  Sokoloff,  Chief 

July  1,  1971  through  June  30,  1972 

The  Laboratory  of  Cerebral  Metabolism  has  continued 
during  the  past  year  to  carry  out  investigations  in  its 
established  research  projects  with  no  major  reorganizations  or 
re-orientations.   Substantial  progress  has  been  made  in  most  of 
these  projects  so  that  despite  the  maintenance  of  the  same  goals, 
the  actual  research  activities  have  progressed  to  new  and  more 
clearly  defined  questions  at  more  advanced  levels.   The  program 
of  the  Laboratory  is  still  broad  and  divided  among  the  three 
Sections,  each  pursuing  its  own  specific  research  problems.   The 
Sections  benefit,  however,  from  their  membership  in  the 
Laboratory  through  the  communality  of  service  modules  and  major 
items  of  equipment,  the  exchange  of  theoretical  and  techno- 
logical knowledge,  and  continued  education  provided  by  the 
Laboratory  seminar  program. 

Section  on  Developmental  Neurochemistry 
Louis  Sokoloff,  Chief 

This  Section  has  continued  to  pursue  a  broad  program  of 
investigations  of  normal  and  pathological  mechanisms  underlying 
normal  and  abnormal  growth,  development,  and  maturation  of  the 
central  nervous  system.   These  studies  are  carried  out  at  both 
the  physiological  and  biochemical  levels.   Although  the 
emphasis  is  on  basic  and  fundamental  mechanisms,  there  is  full 
recognition,  consideration,  and  concern  about  the  relevance  of 
all  findings  to  the  prevention  and  treatment  of  CNS  diseases  of 
developmental  origin. 

The  thyroid  hormones  are  known  to  play  an  essential  role 
in  the  development  and  maturation  of  the  nervous  system. 
Thyroid  deficiency  in  early  postnatal  life  leads  to  physical 
dwarfism  and  mental  retardation,  a  condition  known  as  cretinism. 
The  elucidation  of  the  mechanism  of  action  of  thyroxine,  the 
major  thyroid  hormone,  has  been  a  long  and  continued  interest  of 
the  Section,  and  its  studies  led  several  years  ago  to  the 
discovery  that  thyroid  hormones  stimulated  protein  synthesis. 
This  action  is  now  recognized  as  the  basis  of  many  of  the 
numerous  and  diverse  physiological  effects  of  the  hormones.   The 
Section  has  been  engaged  in  studies  of  the  molecular  mechanisms 
of  the  thyroxine  stimulation  of  protein  synthesis  in  brain  and 
other  tissues.   It  has  been  found  that  the  stimulation  of 
protein  synthesis  is  not  a  direct  effect  of  the  hormone  on  the 
process  of  protein  synthesis  but  is  mediated  by  the  product  of 
a  prior  energy-dependent  reaction  between  the  hormone  and  the 
mitochondrial  fraction  of  the  cell.   These  studies  led  to  the 


83 


explanation  of  the  loss  of  thyroxine-sensitivity  which  occurs  in 
brain  as  the  brain  matures  and  the  failure  of  thyroxine  treatment 
to  reverse  the  mental  retardation  of  cretinism  after  a  critical 
age  is  achieved.   Mitochondria  of  immature  brain  are  capable  of 
reacting  with  the  hormone  in  the  initial  essential  reaction,  but 
the  mitochondria  of  mature  brain  have  lost  this  capability.   The 
identity  of  the  active  product  of  the  thyroxine-mitochondrial 
reaction  and  the  chemical  nature  of  this  reaction  are  obviously 
key  questions  to  be  resolved,  and  the  pursuit  of  these  questions 
are  major  goals  of  the  Section.   Substantial  progress  has  been 
made  in  determining  the  properties  of  the  active  factor,  and 
these  properties  have  been  utilized  to  design  purification 
procedures.   Its  exact  identity  is  still  unknown,  but  steady 
progress  has  been  made. 

Progress  in  these  studies  was  unfortunately  temporarily 
interrupted  during  the  last  year  by  two  reports  in  the  literature 
which  claimed  evidence  that  thyroxine  could  stimulate  protein 
synthesis  directly  without  involvement  of  any  prior  reaction  with 
mitochondria.   Because  of  the  importance  of  these  claims  to  the 
basis  of  the  Section's  investigations,  it  was  necessary  to 
examine  these  alleged  effects.   Extensive  studies  in  this 
Laboratory  have  proved  beyond  any  doubt  that  these  mitochondria- 
independent  effects  are  not  effects  on  protein  synthesis  but  are 
technical  artifacts  in  the  procedures  used  by  the  other 
investigators.   The  nature  of  the  artifacts  has  been  definitely 
established  and  identified,  and  the  results  of  these  studies 
will  be  published  as  an  example  of  the  hazards  of  uncritically 
studying  chemical  reactions  with  radioactive  compounds  without 
establishing  the  chemical  identity  of  the  radioactive  substrates 
and  products  of  the  presumed  chemical  reaction.   This  is  a 
timely  warning  in  this  age  of  the  widespread  use  of  radio- 
isotopes in  biochemical  investigations. 

Studies  have  been  continuing  on  defining  the  differences 
between  mature  and  immature  brain  mitochondria.   One  of  the 
differences  which  was  previously  found  in  this  Laboratory  was 
xn  regard  to  their  content  of  D-P-hydroxybutyrate  dehydrogenase, 
an  enzyme  whxch  is  important  in  the  utilization  of  ketone  bodies. 
This  enzyme,  which  IS  confined  only  to  the  mitochondrial 
fraction  of  the  cell,  is  low  in  the  brain  at  birth,  rises  to  a 
peak  during  maturation,  and  then,  in  contrast  to  other  mito- 
chondrial oxidative  enzymes  which  remain  constant   declines 
again  in  the  mature  brain.   Since  starvation  prodAcelan  increase 
in  availability  of  the  substrate  for  this  enzyme  aSa  ?esint  n? 
fat  degradation,  it  is  likely  that  this  enzyme  is  of  ma ior 
importance  for  the  protection  of  the  brain  from  nu?ri??onal 
deficiency  during  starvation.   Recent  studies  in  thT^iK    ^ 
have  Shown  that  the  entire  developmental  patLJn  ^^^^^^^aboratory 
ie^!^",^-^"g  maturation  is  acc^lL^a'^ed'a'nHhi^ted'on  t^he^'"^' 


time  scale  to  a  younger  age  in  infantHT  v,     ^^^"ed  on 
y    uiigei  dge  in  mtantile  hyperthyroidism. 


On 


84 


the  other  hand,  thyroxine  acting  directly  on  the  enzyme  inhibits 
its  activity  by  competitive  inhibition  of  the  affinity  of  the 
enzyme  for  its  substrates.   These  results  suggest   that  on  one 
hand  thyroxine  promotes  and  accelerates  the  biochemical 
maturation  of  the  brain  but,  on  the  other  hand,  may  reduce  the 
resistance  of  the  brain  to  nutritional  insufficiency. 
Furthermore,  the  action  of  thyroxine  on  this  dehydrogenase  may 
serve  as  a  model  for  its  primary  mechanism  of  action.   Studies 
are  currently  in  progress  directed  at  the  solubilization  and 
purification  of  the  enzyme  so  that  definitive  studies  of  the 
mechanism  of  its  inhibition  by  thyroxine  can  be  studied  at  the 
molecular  level. 

The  interaction  of  thyroxine  with  mitochondria  has  long 
been  known  to  release  latent  mitochondrial  ATPase  activity.   In 
contrast,  studies  in  this  Laboratory  have  demonstrated  that  the 
hormone  inhibits  microsomal  ATPase  activity.   Microsomes  have  a 
number  of  ATPases  which  are  stimulated  by  various  ions  and  are 
believed  to  be  involved  in  the  transport  of  the  ions  in  and  out 
of  the  cells.   Ion  transport  is  fundamentally  involved  in  the 
maintenance  of  membrane  potential  and  excitability  as  well  as 
many  other  cellular  functions.   Thyroxine  inhibits  all  the  ion- 
stimulated  ATPases.   The  effect  was  originally  found  with  liver 
microsomes,  but  studies  in  the  last  year  have  shown  that  the 
effect  is  even  more  prominent  in  brain  preparations.   This  effect 
may  be  related  to  some  of  the  changes  in  CNS  function  in  thyroid 
disease  states.   The  mechanism  of  the  effect  remains  under  study. 

Protein  synthesis  in  brain  is  relatively  high  early  in 
life  and  declines  progressively  during  development  until  it 
reaches  a  relatively  low  level  at  birth.   Much  of  this  decline 
is  attributable  to  a  change  in  the  protein  synthetic  activity 
of  the  ribosomes.   It  is  interesting  that  the  decline  in 
protein  synthetic  activity  bears  an  almost  inverse  relationship 
to  the  development  of  the  hormone-sensitive  cyclic  AMP  system 
in  the  brain.   Since  cyclic  AMP  is  now  known  to  act  by  stimu- 
lating protein  kinase,  an  enzyme  which  phosphorylates  proteins, 
the  possibility  has  been  considered  that  the  change  in  ribosomal 
activity  reflects  the  effects  of  phosphorylation  of  brain 
ribosomal  proteins.   Recently  initiated  studies  have  shown  that 
brain  ribosomal  proteins  can,  in  fact,  be  phosphorylated  by 
cyclic  AMP-stimulated  protein  kinase.   Studies  are  currently  in 
progress  to  determine  whether  there  are  age-related  changes  in 
this  process . 

Collaborative  studies  with  Dr.  Neil  H.  Raskin,  Department 
of  Neurology,  University  of  California,  on  the  biochemical 
mechanisms  of  alcohol  tolerance  and  the  alcohol-withdrawal 
syndrome  are  continuing.   This  project  was  responsible  for  the 
first  demonstration  of  alcohol  dehydrogenase  in  brain.   Recent 
studies  have  shown  that  chronic  alcohol  intake  causes  a  rise  in 


85 


the  brain  enzyme  level  of  about  50%.   Whether  this  rise  can 
explain  the  development  of  tolerance  to  alcohol  and  can  contributei 
to  the  symptoms  associated  with  alcohol  withdrawal  is  still  under 
study. 

Studies  of  the  changes  in  local  cerebral  blood  flow  with 
maturation  of  the  brain  have  been  completed.   These  studies  have 
demonstrated  that  blood  flow  in  gray  matter  is  low  at  birth  and 
rises  as  neuronal  activity  increases  with  maturation  of  the 
brain.   Blood  flow  in  white  matter  is  also  low  at  birth,  rises 
to  a  peak  at  the  time  of  maximum  rate  of  myelin  synthesis,  and 
then  declines  again  as  maturation  is  achieved.   The  changes  in 
blood  flow  probably  reflect  the  changes  in  energy  metabolism 
associated  with  the  energy  demands  for  biosynthetic  and 
functional  activities.   The  cerebral  circulation  in  the  newborn 
has  been  found  to  be  markedly  more  sensitive  to  even  moderate 
increases  in  the  oxygen  content  of  inspired  air  than  it  is  later 
m  life.   Studies  have  been  completed  which  show  that  continuous 
exposure  to  these  elevated  oxygen  concentrations  in  the  immediate 
postnatal  period  retards  brain  growth,  nucleic  acid  synthesis 
and  cell  proliferation.   These  results  indicate  that  oxygen   ' 
therapy  in  the  newborn  for  various  respiratory  and  cardiovascular 
diseases  can  be  deleterious  to  brain  maturation  and  should 
therefore,  be  used  with  caution.  ' 

^u  ^ifnificant  progress  has  been  made  in  the  development  of 
a  method  for  the  simultaneous  quantitative  determination  of 
glucose  utilization  in  all  the  discrete  component  structures  of 
the  brain  in  animals.   The  method  is  almost  ready  for  use  in 
^nH  i^^h°i  *^^  influence  of  various  physiological,  pharmacological, 
and  pathological  states  on  local  energy  metabolism.   It  is  hojed 
that  such  studies  can  be  initiated  in  the  coming  year. 

Section  on  Myelin  Chemistry 
Marian  W.  Kies,  Chief 

continue^!?!  ^nv  11^^   T^""  ^^^   Section  on  Myelin  Chemistry  has 
continued  its  investigation  of  the  relationship  between 
structure  and  activity  of  myelin  basic  protein  (MyBP)  and  the 
mechanisms  involved  in  the  pathogenesis  of  experimental  allergic 
fold'Surpolf'^The^'^'l--  ""^^'^^^  ^^^^^^  on^MyBrserve  a'^^L''^ 

:    1°  L--Ft-^"°-  ^^  ----a!--- 

reSrSto  ?he  h?o?  ""^^^^^J^  ^as  important  implications  with 
a:?:ii;ne\':acti^n°^in  ?h^CNs!  °'  "^""  ^"  ^^^  ^"^^^^^  °^  - 

19  argin^nes'^irthe  rnvMi'T'"^  ''^  °'^"""  *^^*  °"^  °f  ^he  18  or 
arginmes  m  the  myelin  basic  protein  molecule  was  partially 


•methylated,  and  it  was  suggested  that  partial  methylation  of  a 
single  basic  residue  might  explain  the  microheterogeneity  of 
myelin  basic  protein  first  observed  by  Dr ,  Martenson.   That 
methylation  of  one  residue  could  not  explain  all  of  the  observed 
microheterogeneity  was  obvious  because  of  the  existence  of  more 
than  three  components  in  the  total  protein.   Mrs.  Deibler 
undertook  the  difficult  task  of  developing  an  analytical 
procedure  for  the  detection  of  methylated  amino  acid  derivatives 
in  protein  hydrolysates .   Her  analyses  of  the  methylated 
arginines  in  the  components  of  guinea  pig  myelin  basic  proteins 
demonstrated  that  the  ratio  of  monomethylarginine  to  dimethyl- 
arginine  remains  constant,  bearing  out  the  contention  of  this 
Laboratory  that  methylation  of  arginine  107  cannot  explain  the 
observed  microheterogeneity.   The  method  which  Mrs.  Deibler 
developed  for  these  analyses  is  a  general  technique  for 
determining  methylated  derivatives  of  amino  acids  and  will  be 
useful  for  detection  of  these  compounds  in  other  proteins  as 
well . 

Attempts  by  Dr.  Alvord  and  co-workers  to  correlate  charge 
heterogeneity  with  the  multiple  precipitin  lines  which  they  had 
observed  in  immunoelectrophoretic  patterns  of  antigen-antibody 
reactions  involving  myelin  basic  protein  were  not  successful. 
However,  the  observation  that  three  precipitin  lines  are  present 
in  immunodiffusion  patterns  obtained  with  each  of  the  individual 
components  strongly  suggests  that  partial  methylation  of  Arg  107 
may  be  the  cause  of  the  multiple  lines.   If  so,  the  major 
antigenic  site  on  the  molecule  must  contain  this  residue. 
(Antigenic  site  in  this  context  refers  to  antibody-combining 
site,  rather  than  to  encephalitogenic  site.) 

Last  year  this  Laboratory  reported  that  certain  rodent 
myelins  were  different  from  other  mammalian  myelins  in  that  they 
contained  two  different  size  basic  proteins.   Studies  of  these 
two  rat  proteins  indicated  that  they  differed  in  size  by  about 
40  amino  acid  residues.   By  analogy  with  published  information 
on  amino  acid  compositions  of  bovine  and  human  myelin  basic 
proteins.  Dr.  Martenson  predicted  the  location  and  nature  of  the 
deletion  which  accounts  for  the  differences  between  the  large 
and  small  molecules.   Tryptic  peptide  analysis  of  rat  S  protein 
confirmed  this  prediction.   Although  the  deletion  does  not 
prevent  the  small  protein  from  functioning  satisfactorily  as  a 
structural  protein  of  myelin,  it  markedly  modifies  the 
encephalitogenic  site  known  to  be  responsible  for  its  activity 
in  guinea  pigs.   Myelin  BPs  have  also  been  isolated  from  CNS 
tissue  of  the  submammalian  species  chicken,  turtle,  frog,  carp, 
and  shark.   All  were  inactive  when  tested  in  guinea  pigs  and, 
therefore,  like  the  small  rat  myelin  basic  protein,  probably 
have  modified  tryptophan  regions.   Three  of  these  proteins — 
chicken,  turtle,  and  frog — are,  however,  encephalitogenic  in 
rats,  as  is  the  small  rat  protein.   Thus  it  is  clear  that  the 


87 


sequence  responsible  for  encephalitogenic  activity  in  rats  is 
different  from  the  encephalitogenic  site  active  in  guinea  pigs. 

Previous  studies  in  this  Laboratory  demonstrating  that 
guinea  pigs  can  be  made  tolerant  to  the  encephalitogenic  activity 
of  MyBP  through  pre- immunization  with  moderate  amounts  of  this 
protein  in  the  absence  of  mycobacteria  have  been  extended  to 
include  experiments  on  therapy.   Guinea  pigs  in  which  clinical 
signs  of  EAE  have  already  been  established  were  given  multiple 
daily  injections  of  basic  protein  in  incomplete  adjuvant.   The 
first  therapy  trials  were  carried  out  on  inbred  Strain  13  guinea 
pigs.   The  uniformly  successful  results  (9  of  10  guinea  pigs 
responded  favorably  to  treatment)  were  surprising  in  view  of 
earlier  observations  by  Dr.  Alvord  that  treatment  was  only 
partially  successful.   The  effectiveness  of  treatment  was 
confirmed  in  two  more  experiments.   Because  of  earlier  reports 
of  partial  success  in  treatment  of  Hartley  guinea  pigs  after 
EAE  had  developed,  similar  experiments  were  carried  out  with 
outbred  NIH  guinea  pigs,  and  it  was  also  found  that  treatment 
was  much  less  effective  in  these  animals  (only  3  of  9  animals 
responded  favorably  to  treatment  with  encephalitogen) .   The 
possibility  that  immune  response  genes  are  somehow  related  to 
(and  controlled  by?)  genetic  factors  has  been  suggested  by 
recent  work  on  simple  synthetic  antigens.   Thus  this  observation 
may  have  considerable  significance,  especially  in  view  of  recent 
reports  that  the  distribution  of  histocompatibility  antigens  in 
multiple  sclerosis  patients  is  different  from  the  distribution 
of  these  antigens  in  a  normal  population.   Further  studies  on 
genetic  relationships  involved  in  experimental  autoimmune 
disease  of  the  CNS  are  in  progress. 

Section  on  Membrane  Chemistry 
Louis  Sokoloff ,  Acting  Chief 

A  number  of  laboratories,  including  this  Section,  have 
observed  that  acetylcholine  stimulates  the  incorporation  of 
phosphate  into  phosphatidic  acid  and  phosphatidylinositol  in 
preparations  from  neural  tissues.   Phosphatidylinositol  is  an 
important  phospholipid  component  of  membranes,  and  it  is  widely 
believed  that  this  biochemical  effect  is  related  to  the  mechanism 
of  action  of  the  neurotransmitter  at  the  specific  receptor  site 
on  the  membrane  of  the  effector  cell.   The  mechanism  of  the 
action  of  acetylcholine  on  phosphoinositide  metabolism  is  still 
^"o^°T"k.?':'^  previous  workers  in  this  Section  proposed  that 


R^r.^  +  =.+  ^-    •   .,   -^™"l^te  phosphatidylinositol  turnover 
Recent  studies  in  this  Laboratory  have  implicated  calcium  Ions 


in  phosphatidylinositol  turnover.   EGTA,  a  potent  chelator  of 
Ca^+j  has  been  found  to  markedly  inhibit  ^^P  incorporation  into 
phosphatidylinositol,  and  this  inhibition  can  be  reversed 
specifically  by  the  addition  of  excess  Ca"^"^.   Evidence  has  also 
been  obtained  that  Ca2+  stimulates  the  hydrolysis  of  phosphatidyl- 
inositol.   In  other  words,  Ca2+  appears  to  have  actions  similar  to 
the  mechanisms  postulated  for  acetylcholine.   This  suggests  the 
possibility  that  the  action  of  acetylcholine  on  phosphatidyl- 
inositol  turnover  is  mediated  via  an  effect  on  free  Ca2+  levels. 
Preliminary  studies  indicate,  in  fact,  that  EGTA  also  blocks  the 
effects  of  acetylcholine.   Studies  are  continuing  to  determine 
the  role  of  Ca2+  in  the  mechanism  of  action  of  acetylcholine. 


89 


Annual  Report  of  the 

Laboratory  of  General  and  Comparative  Biochemistry 

National  Institute  of  Mental  Health 

Guilio  L.  Cantoni,  Chief 

S.  Harvey  Mudd,  Acting  Chief 

The  research  program  of  the  Laboratory  has  continued  to 
develop  favorably  during  the  current  year.   Dr.  Cantoni,  Chief 
of  the  Laboratory,  is  spending  the  year  on  sabattical  leave  at 
the  Institute  of  Embryology,  University  of  Rome,  Rome,  Italy 
pursuing  problems  of  gene  action  and  differentiation  in 
eukaryotic  cells. 

Dr.  Cantoni 's  collaborators  have  continued  fruitfully 
investigations  which  had  previously  been  initiated.   Dr.  Boeker 
has  succeeded  in  elucidating  the  subunit  structure  of  a  homogeneous 
preparation  of  seryl  tRNA  synthetase  and  supplied  kinetic  and 
other  data  bearing  upon  the  mechanism  of  interaction  between  small 
molecular  weight  substrates,  the  enzyme  protein,  and  the  acceptor 
RNA.   Detailed  understanding  of  these  sorts  of  interactions  are 
expected  to  shed  light  upon  a  problem  central  to  many  of  the  major 
problems  in  biology,  i.e.  the  general  area  of  nucleic  acid-protein 
recognition  and  interaction.   Dr.  Haberkern  has  developed  a  method 
of  purifying  the  enzyme  in  calf  thymus  extracts  which  hydro lyzes 
specifically  the  RNA  portion  of  RNA-DNA  hybrids.   The  purified 
enzyme  has  been  vised  to  characterize  the  substrate  acted  upon  and 
the  products  formed  by  this  unique  enzyme.   The  biological  role 
of  this  widely  distributed  enzyme  represents  a  major  puzzle,  the 
answer  to  which  will  surely  be  useful  in  understanding  normal  and 
abnormal  processes  of  information  transfer  in  biological  systems. 
Dr.  Schmidt  has  taken  the  first  steps  toward  a  study  of  spermidine 
metabolism  in  mammalian  brain.   There  is  increasing  evidence  that 
this  compound,  or  related  ones,  may  play  a  role  in  the  regulation 
of  growth  processes  and  the  early  indications  coming  from  the  work 
of  Dr.  Schmidt  that  there  may  be  a  correlation  between  the  rate 
of  spermidine  formation  and  the  times  of  most  rapid  brain  tissue 
formation  and  myelinization  raise  important  questions  which  will 
surely  stimulate  a  great  deal  of  work. 

Studies  on  the  interactions  between  «-lactalbumin  and  A- 
protein  are  continuing  in  Dr.  Klee's  laboratory  with  the  collabo- 
ration of  Drs.  K.  S.  Iyer  and  C.  B.  Klee.   The  A-protein  has 
been  found  to  be  a  component  of  the  synaptosomal  membrane  and  can 
readily  be  prepared  in  a  soluble  form  from  this  source.   Although 
this  partially  purified  preparation  is  functionally  indistinguish- 
able from  the  A-protein  found  in  milk,  the  membrane  bound  activity 
does  not  interact  with  a-lactalbumin.   Whether  this  is  a  problem 


91 


of  accessibility  or  of  modified  properties  of  the  A-protein 
itself  remains  to  be  determined,  as  does  the  function  of  the 
A-protein  in  synaptosomes.   a-Lactalbumin  has  been  prepared  in 
the  form  of  a  mixed  crystal  with  the  homologous  egg  white  protein, 
lysozyme.   These  mixed  crystals  may  be  useful  in  delineation  of 
the  degree  of  relationship  between  the  conformation  of  these  two 
proteins.   Studies  on  the  guanidination  of  a-lactalbumin  have  been 
initiated  with  the  dual  aim  of  preparing  a  radioactively  tagged 
protein  for  membrane  binding  studies  and  of  understanding  the 
role  of  amino  groups  in  the  A-protein-a-lactalbumin  interaction. 
The  protein  may  be  almost  completely  guanidinated  without 
appreciable  loss  of  activity  so  that  a  biologically  active 
derivative  of  high  radioactivity  can  easily  be  prepared.   Complete 
guanidination  is,  however,  accompanied  by  large  conformational 
changes,  aggregation,  and  loss  of  activity.   These  changes  are 
currently  being  studied  and  may  provide  some  clues  to  the 
structural  basis  of  ot-lactalbumin  activity.   As  discussed  last 
year,  these  studies  are  all  aimed  at  gaining  an  understanding  of 
the  manner  in  which  the  specific  function  of  one  protein  may  be 
modified  through  interaction  with  a  second  protein,  a  mechanism 
which  opens  interesting  and  largely  unexplored  evolutionary 
possibilities . 

Dr.  Merril  and  his  co-workers  have  performed  a  number  of 
investigations  on  the  effect  of  bacterial  viruses  on  human  cells. 
Such  studies  were  first  made  with  the  virus,  lambda,  and  hvutian 
skin  fibroblast  cells  grown  in  tissue  culture.   The  studies 
included  electronmicroscopic  observations  which  indicated  that 
the  cells  are  capable  of  taking  up  whole  virus,  DNA-RNA  hybridi- 
zation which  indicated  that  the  viral  genome  was  being  transcribed 
and,  finally,  assays  for  the  presence  of  an  enzyme  to  document 
translation  of  the  viral  genome.   The  human  fibroblasts  used  were 
from  a  child  with  galactosemia,  a  disease  associated  with  mental 
retardation  and  caused  by  a  defect  in  a  specific  galactose  trans- 
ferase enzyme.   A  bacterial  virus  lambda  derivative,  Xpgal, 
appears  to  be  capable  of  correcting  the  biochemical  defect  in  the 
cultured  galactosemic  human  fibroblasts.   Investigations  are 
currently  underway  to  define  the  variables  in  this  system.   These 
studies  have  already  led  to  the  finding  that  the  fetal  calf  serum 
used  for  growing  cells  in  tissue  culture  contains  bacterial  viruses. 
Similar  serum  is  used  to  grow  cells  for  vaccine  production  and 
the  possibility  of  inadvertant  exposure  of  large  numbers  of 
persons  to  these  viruses  certainly  deserves  further  exploration. 

As  a  consequence  of  the  finding  that  bacteriophage  are 
present  in  fetal  calf  serum,  a  survey  was  initiated  to  determine 
the  possible  presence  of  these  viruses  in  other  mammals.   The 
presence  of  viruses  which  can  form  plaques  on  Escherichia  coli  C 
was  soon  demonstrated  in  blood  samples  obtained  from  members  of 
our  staff  and  from  NIH  Blood  Bank  donors  whose  occupation  does 
not  involve  chronic  exposure  to  high  concentrations  of  virus. 


92 


[ 


studies  have  been  started  to  determine  how  these  viruses  get 
into  the  blood  and  the  possible  effects  they  might  have. 

As  indicated  by  the  very  great  amount  of  interest  and 
publicity  which  attended  publication  of  the  early  results  of 
these  studies,  the  work  of  Dr.  Merril  and  his  collaborators  has 
opened  a  variety  of  possibilities  for  further  investigation. 
Experimental  manipulation  of  the  genetic  material  within  human 
cells  should  be  useful  in  a  great  many  studies  of  gene  regulation, 
differentiation,  and  other  basic  biological  problems.   The  fact 
that  human  (and  calf)  blood  normally  contains  viruses,  raises  a 
host  of  questions  ranging  from  the  immediate  practical  conse- 
quences for  vaccine  production  to  longer  range  problems  of  the 
role  of  these  hiterto  undetected  biological  agents  in  human  health 
and  disease. 

The  research  in  the  Section  on  Alkaloid  Biosynthesis  has 
continued  to  focus  on  the  metabolism  of  sulfur  containing  amino 
acids.   Drs.  Giovanelli  and  Datko  have  used  the  plant  enzyme 
system  which  our  previous  studies  had  shown  could  utilize  a 
variety  of  0-alkylhomoserine  derivatives  as  well  as  0-phosphoryl- 
homoserine  to  set  up  a  very  sensitive  enzyme  assay  for  activated 
homoserine  derivatives .   This  assay  has  been  used  to  search  for 
such  compounds  present  naturally  in  plants.   It  has  now  been 
shown  that  plants  contain  a  compound,  preliminarily  characterized 
as  0-phosphorylhomoserine,  whereas  0-oxalyl-,  0-malonyl,  and 
O"succinylhomoserine  are  not  present.   This  finding  provides 
direct  evidence  to  support  the  previous  indications  of  a  key  role 
for  0-phosphorylhomoserine  in  cystathionine  biosynthesis  by  green 
plants.   Thus,  a  major  uncertainty  as  to  which  enzyme  reactions 
are  physiologically  important  in  plant  sulfur  amino  acid  metabolism 
has  been  resolved. 

The  studies  of  the  plant  toxin,  rhizobitoxine,  have  been 
refined  and  applied  to  a  more  favorable  experimental  system. 
Using  this  systan,  it  has  been  shown  that  rhizobitoxine  inhibits 
the  enzyme  B-cystathionase  in  vivo,  and  that  one  physiological 
consequence  of  the  inhibition  of  this  enzyme  is  an  accumulation 
of  cystathionine.   No  severe,  sustained,  impairment  of  methionine 
formation  occurs,  a  result  predicted  if  cystathionine  is  normally 
present  well  below  saturating  concentrations.   If  further  studies 
show  that  the  enzyme  acetylhomoserine  sulfhydrase,  is  not  inhibited 
by  rhizobitoxine,  a  potent  tool  will  be  available  to  decide  whether 
the  transsulfuration  or  the  direct  sulfhydration  pathway  is  more 
important  in  plant  homocysteine  biosynthesis. 

Finally,  continuing  studies  of  homocystinuria  in  humans  have 
led  during  the  current  year  to  definition  of  anew  inborn  error 
of  metabolism,  one  which  may  be  associated  in  at  least  some  cases 


93 


with  a  reversible  form  of  schizophrenia.   Investigations  of  the   ( 
means  whereby  large  doses  of  pyridoxine  alleviate  the  biochemical 
abnormalities  in  some  individuals  with  cystathionine  synthase 
deficiency  appear  to  be  providing  a  sound  experimental  basis 
for  the  possibility  that  hereditary  enzyme  deficiency  diseases 
may  be  treated  by  specific  stimulation  of  the  deficient  enzyme 
activity. 


94 


ANNUAL  REPORT  OF  THE  LABORATORY  OF  NEUROBIOLOGY 

■NATIONAL  INSTITUTE  OF  MENTAL  HEALTH 

Ichiji  Tasaki,  Chief 

The  Lahoratory  of  Neurobiology  has  carried  on  investigations  of  the 
nervous  system  on  two  different  levels:   studies  of  the  process  of  excitation 
in  the  nerve  menibrane  and  the  analysis  of  function  of  one  part  of  the  brain, 
the  superior  colliculus.. 

Experiments  on  nerve  utilize  optical  methods,  especially  fluorescence,  to 
study  the  nature  and  organization  of  the  membrane  macromolecules  and  how 
they  change  during  excitation.   Squid  giant  axons  and  crab  or  lobster  nerves 
are  stained  with  fluorescent  dyes  and  then  the  characteristics  of  the 
fluorescent  light  coming  from  the  nerve  are  analyzed.   The  intensity,  spectrum, 
and  fluorescence  polarization  of  the  emitted  light  give  useful  information  as 
to  the  state  of  the  macromolecules  in  the  membrane.   It  has  been  found  for 
example,  that  the  membrane  has  a  highly  organized,  regular,  rigid  structure. 
Evidence  has  been  accumulated  in  support  of  the  macromolecular  theory  of 
nerve  excitation  which  postulates  a  hydrophobic-hydrophilic  transition  of 
the  membrane  during  the  action  potential. 

Experiments  on  the  central  nervous  system  have  investigated  the  role  of 
the  superior  colliculus  in  behavior.   Responses  of  single  cells  have  been 
studied  while  an  awake  monkey  fixated  a  point  of  light  or  made  rapid  eye 
movements  from  one  point  of  light  to  another.   Cells  in  the  upper  layers  of 
the  colliculus  have  large  receptive  fields  but  are  insensitive  to  many 
stimulus  parameters.   About  half  of  these  cells  respond  more  vigorously  to 
a  spot  of  light  when  the  monkey  is  required  to  pay  attention  to  the  spot  of 
light.   Cells  in  the  intermediate  layers  discharged  before  eye  movements  to 
the  same  area  of  the  visual  field  where  the  receptive  fields  of  the  cells  in 
the  upper  layers  were  found.   Lesions  of  these  cells  in  upper  and  middle 
layers  did  not  decrease  the  accuracy  of  an  eye  movement  but  did  lead  to  a 
longer  latency  to  make  the  eye  movement .   These  experiments  suggest  that  the 
primate  superior  colliculus  is  not  critical  for  eye  movement  guidance  but 
instead  contributes  to  a  shift  of  visual  attention  and  facilitates  eye  move- 
ment toward  important  areas  of  the  visual  field. 


95 


I 


Annual  Report  of  the  Laboratory  of  Neurochemistry 

National  Institute  of  Mental  Health 

Seymour  Kaufman,  Chief 

During  the  last  year,  significant  progress  was  made  in  all 
of  the  major  research  areas  of  interest  to  the  Laboratory. 
Indeed,  in  one  of  these  areas,  ±.e.,    analysis  at  the  molecular 
level  of  the  enzymatic  defect  in  phenylketonuria  and  hyperphenyl- 
alaninemia,  the  results  obtained  during  the  last  year  represent 
the  culmination  of  one  of  the  lines  of  investigation  that  was 
initiated  17  years  ago.   At  that  time,  the  phenylalanine  hydrox- 
ylating  system  was  selected  for  intensive  investigation  for  two 
reasons:   a)  it  was  known  to  catalyze  a  relatively  new  type  of 
oxidative  reaction,  i^.e.  ,  the  incorporation  of  molecular  oxygen 
into  an  organic  molecule;  an  understanding  of  the  mechanism  of 
action  of  this  kind  of  enzyme  would  expand  our  knowledge  of  how 
molecules  are  oxidized  in  the  cell;   b)  it  was  known  that  the 
lack  of  this  activity  in  the  disease,  phenylketonuria  (PKU) ,  leads 
to  mental  retardation.   Implicit  in  this  undertaking  was  the  faith 
that  knowledge  of  the  normal  enzyme  system  would  contribute  to 
our  understanding  of  the  disease . 

One  of  the  earlier  applications  of  our  increasing  basic 
knowledge  about  the  hydroxylating  system  was  the  precise  delinea- 
tion of  the  defect  in  PKU.   As  it  became  apparent  from  our 
earlier  work  that  the  system  that  catalyzes  the  hydroxylation  of 
phenylalanine  to  tyrosine  is  a  complex  one,  consisting  of  at  least 
three  essential  components,  i^.e. ,  two  enzymes,  phenylalanine 
hydroxylase  and  dihydropteridine  reductase,  and  the  cofactor, 
tetrahydrobiopterin,  it  also  became  clear  that  the  lack  of  any 
one  of  these  components  could  be  responsible  for  the  lack  of  the 
overall  hydroxylating  activity  in  PKU.   We  showed  that  the  reduc- 
tase and  the  cofactor  are  present  in  normal  amounts  in  biopsy 
liver  samples  from  PKU  patients  and  that  the  hydroxylase  is  non- 
functional.  This  work  established  for  the  first  time  that 
phenylalanine  hydroxylase  is  the  affected  component  in  PKU. 

The  next  question  that  demanded  an  answer  is  "What  is  the 
nature  of  the  mutation  in  PKU  that  leads  to  a  non-functional 
hydroxylase?"   One  of  the  classical  approaches  to  this  kind  of 
problem  is  to  prepare  antibodies  to  the  normal  enzyme  and  to 
determine  if  the  mutation  leads  to  the  production  of  an  altered 
protein  which  is  devoid  of  the  normal  enzyme  activity,  but  can 
still  cross-react  with  the  antibodies.   This  is  the  approach  that 
we  have  followed. 

One  of  the  requisite  steps  in  this  line  of  investigation  is 
to  prepare  the  pure  antigen,  in  this  case,  phenylalanine  hydrox- 
lase .   In  the  ideal  application  of  this  method,  the  pure  hydroxylase 

97 


from  normal  human  liver  would  be  used  as  the  antigen.   The  un- 
availability of  fresh,  normal  human  liver  precluded  our  following 
the  ideal  course  and  instead,  we  have  attempted  to  use  the  normal 
rat  liver  enzyme  as  the  antigen. 

Pure  rat  liver  phenylalanine  hydroxylase  (described  in  last 
year's  report),  was  injected  into  sheep.   The  antiserum  produced 
by  the  sheep  to  this  foreign  protein  contained  antibodies  to  the 
hydroxylase.   When  tested  against  either  crude  rat  liver  or  normal 
human  liver  extract,  using  the  double-diffusion  technique,  only  a 
single  precipitin  line  was  produced,  proving  that  the  antibodies 
were  specific  for  phenylalanine  hydroxylase  and  that  the  anti- 
bodies to  the  rat  liver  hydroxylase  could  cross-react  with  the 
normal  human  enzyme . 

These  antibodies  were  used  to  look  for  cross-reacting  material 
(CRM)  in  a  biopsy  liver  sample  from  a  single  PKU  patient  and  from 
a  single  hyperphenylalaninemic  patient.   In  neither  of  these 
samples  could  any  CRM  be  detected.   The  tests  were  sensitive 
enough  to  detect  CRM,  if  any  were  present,  at  the  level  of  5%  of 
the  normal  enzyme . 

These  results  permit  several  important  conclusions  to  be 
drawn  about  the  molecular  defect  in  these  two  diseases.   First, 
they  provide  the  final  proof  that  phenylalanine  hydroxylase  is 
the  affected  component  in  PKU,  as  well  as  in  hyperphenylalaninemia, 
thus  extending  and  corroborating  our  previous  conclusions. 
Second,  they  show  that  in  PKU,  the  mutation  is  either  of  the 
deletion  type,  in  which  no  gene  product  is  made  (hence  no  detec- 
table CRM) ,  or  it  is  a  mutation  in  the  gene  that  determines  the 
structure  of  the  hydroxylase.   In  the  latter  case,  the  product 
of  the  mutated  gene  would  be  so  altered  that  it  is  devoid  of 
hydroxylase  activity  and  of  its  ability  to  cross-react  with  the 
antibodies . 

In  the  case  of  hyperphenylalaninemia,  additional  data  are 
available  that  help  in  the  delineation  of  the  genetic  events  that 
lead  to  the  disease.   Our  previous  work  showed  that  liver  samples 
from  patients  with  this  disease  have  about  5%  of  the  normal  level 
of  hydroxylase.   By  a  more  sensitive  immunological  test  than  the 
double-diffusion  technique,  we  have  detected  CRM  in  a  liver  ex-    j 
tract  from  a  hyperphenylalaninemic  subject.   Furthermore,  we  have 
shown  that  one  of  the  kinetic  properties  of  the  hydroxylase,  i.e., 
its  Km  for  phenylalanine,  is  different  from  that  of  the  normaT  ~ 
enzyme . 

These  results  indicate  that  this  disease  is  caused  by  a 
mutation  in  the  structural  gene  for  phenylalanine  hydroxylase. 
The  altered  protein  produced  has  the  following  properties:         ^ 

98 


a)  it  has  only  about  5%  of  the  normal  hydroxylase  activity; 

b)  it  has  a  significantly  lower  Km  for  phenylalanine; 

c)  it  interacts  with  antibodies  to  the  normal  enzyme,  but  the 
antibody-antigen  complex  does  not  precipitate  completely  nor 
does  it  lose  all  of  its  catalytic  activity. 

The  antibodies  to  pure  phenylalanine  hydroxylase  are  a 
powerful  tool  in  the  analysis  of  the  nature  of  the  defect  in 
these  diseases.   At  the  present  time,  the  only  serious  impediment 
to  a  more  detailed  analysis  is  the  limited  availability  of  suit- 
able tissue  biopsy  samples. 

In  the  area  of  the  regulation  of  normal  phenylalanine 
hydroxylase  activity,  an  important  advance  was  made  during  the 
last  year.   It  was  found  that  certain  phospholipids,  such  as 
lysolecithin,  can  stimulate  the  activity  50-fold.   Long-chain 
fatty  acids  show  some  activation,  whereas  lecithin  is  a  potent 
inhibitor.   These  results  indicate  that  lipids  may  play  an  im- 
portant role  in  the  regulation  of  the  hydroxylase  activity  in 
vivo .   They  point  to  the  possibility  that  a  secondary  consequence 
of  certain  diseases,  such  as  diabetes,  and  of  altered  nutritional 
states,  such  as  starvation  or  excessive  sucrose  intake  could,  by 
virtue  of  their  effects  on  lipid  metabolism,  lead  to  significant 
changes  in  the  activity  of  the  hydroxylase. 

The  marked  activation  of  the  hydroxylase  by  certain  phospho- 
lipids should  also  be  useful  in  attempts  to  detect  the  hydroxylase 
activity  in  tissues  that  are  more  readily  accessible  than  liver. 
If  the  activity  could  be  detected  in  these  tissues  (e.g.,  skin, 
blood  cells) ,  this  test  could  facilitate  the  diagnosTs~of  genetic 
diseases  that  are  characterized  by  low  levels  of  the  hydroxylase. 

During  the  last  year,  we  have  undertaken  a  new  problem,  an 
investigation  of  brain  tryptophan  hydroxylase.   This  enzyme, 
which  utilizes  the  pterin  cofactor  that  was  previously  discovered 
in  this  laboratory,  is  believed  to  catalyze  the  i"ate-limiting 
step  in  the  biosynthesis  of  the  neurotransmitter,  serotonin. 
Since  alterations  in  the  brain  level  of  serotonin  have  been  im- 
plicated in  such  diverse  activities  as  sleep,  agression,  sexual 
behavior  and  drug  addiction,  it  is  clear  that  this  hydroxylase 
may  play  an  important  role  in  modulating  behavior. 

Although  the  project  is  still  in  its  infancy,  it  has  already 
led  to  significant  insight  into  the  parameters  that  can  regulate 
the  activity  of  the  hydroxylase.   Based  on  our  previous  work 
with  the  other  pterin-dependent  hydroxylases,  we  were  able  to 
predict  with  a  high  degree  of  accuracy  several  of  the  important 
properties  of  this  enzyme .   One  of  these  is  that  the  Km  for 


99 


tryptophan  varies  dramatically  with  the  pterin  cof actor  used;  in 
the  presence  of  the  natural  cof actor,  the  Km  is  only  one-sixth 
as  large  as  it  is  in  the  presence  of  the  cof actor  analogue.   This 
finding  clarifies  what  appeared  to  be  an  absurd  situation:   that 
the  previously  accepted  Km  value  for  tryptophan  (determined  only 
in  the  presence  of  the  cof actor  analogue)  was  10  times  higher  than 
the  probable  brain  levels  of  tryptophan.   If  this  were  the  actual 
in  vivo  situation,  tryptophan  hydroxylase  would  be  severely 
limited  by  availability  of  tryptophan.   Based  on  our  new  value 
for  the  Km  for  tryptophan,  this  enzyme  appears  to  operate  with 
no  unique  limitation  of  substrate  availability. 


Another  important  property  of  the  enzyme  that  was  demon- 
strated was  inhibition  of  its  activity  by  excess  tryptophan.   It 
may  be  possible  to  exploit  this  property  in  the  treatment  of  the 
disease,  malignant  carcinoid  syndrome,  which  is  characterized  by 
excessive  serotonin  production.   If  high  tryptophan  levels  can 
be  achieved  in  vivo,  tryptophan  hydroxylase  shoule  be  inhibited 
and  the  exces¥  serotonin  production  may  be  partially  controlled. 

In  the  area  of  skeletal  muscle  hypertrophy,  we  have  found 
the  earliest  biochemical  change  yet  detected  in  this  adaption 
process  -  an  increased  turnover  of  phospholipids.   The  change 
is  detectable  within  2  hours  of  the  onset  of  hypertrophy,  pre- 
ceding by  about  one  day  any  of  the  previous  biochemical  changes 
that  have  been  documented.   The  alteration  appears  to  be  specific 
to  hypertrophy;  rats  subjected  to  acute  exercise  and  an  endurance 
training  program  do  not  show  this  change . 

In  the  Section  on  Biophysical  Chemistry,  the  study  of 
membrane-specific  proteins  has  been  extended  to  two  new  important 
areas.   The  amount   of  insulin-receptor  protein  in  the  membranes 
of  liver  cells  of  obese  hyperglycemic  mice  has  been  determined. 
The  concentration  of  insulin-receptors  was  found  to  be  reduced 
3-  to  6-fold  per  mg  of  membrane  protein  in  the  obese  mouse  as 
compared  to  normal  litter-mate  controls.   This  is  the  first  demon- 
stration of  altered  membrane  receptor  concentration  in  a  disease 
state.   The  findings  suggest  that  there  may  be  a  wide  variety  of 
disease  states  that  are  receptor  diseases. 

In  another  organ,  the  kidney,  it  was  found  that  the  isolated 
brush  border  membranes  are  enriched  in  a  highly  stereospecif ic 
binding  site  for  phlorizin,  a  glucose  analogue  that  inhibits  renal 
tubular  reabsorption  of  glucose.   All  of  the  evidence  indicates 
that  this  site  is  the  one  that  binds  glucose  during  transport . 
This  identification  should  permit  the  isolation  of  the  glucose 
carrier  and  should  facilitate  the  determination  of  the  mechanism 
of  glucose  transport . 


100 


I 


Annual  Report  of  the  Laboratory  of  Neurophysiology 

National  Institute  of  Mental  Health 

Edward  V.  Evarts,  M.D.,  Chief 

July  1,  1971  ~  June  30,  1972 


This  summary  of  the  research  program  of  the  Laboratory  of 
Neurophysiology  will  describe  three  areas  of  ongoing  research: 
1)  Cellular  Physiology,  2)  Central  Control  of  Movement  and  3) 
Neural  Correlates  of  Learning  and  Memory. 

I:   Cellular  Physiology.   This  area  includes  the  work  of 
Carpenter  and  Rapoport.   Carpenter's  work  has  been  centered  on 
two  general  problems.   The  first  concerns  the  mechanisms  which 
allow  nerve  cells  to  respond  to  changes  of  temperature.   A 
second  area  of  Carpenter's  research  has  dealt  with  the  state  of 
ions  and  water  in  living  cells. 

In  his  work  on  thermosensitivity ,  Carpenter  has  made  ex- 
tensive use  of  the  large  neurons  in  the  marine  molluscs,  Aplysia 
and  Navanax .   In  Aplysia  neurons  thermosensitivity  is  imparted 
to  each  cell  by  at  least  two  separate  mechanisms.   The  first, 
an  electrogenic  sodium  pump,  causes  the  cell  membrane  potential 
to  increase  with  temperature.   The  second  mechanism  tends  to 
depolarize  and  excite  the  cell  with  warming  as  a  result  of  a 
greater  temperature  dependence  of  the  passive  permeability  of 
the  membrane  to  sodium  than  to  potassium. 

A  related  problem  investigated  in  the  same  species  is  the 
ionic  basis  of  pacemaker  discharge  in  Aplysia  neurons.   The 
endogenous  pacemaker  activity  can  be  adequately  explained  by  a 
model  containing  a  voltage  and  time  varying  potassium  conduc- 
tance in  the  face  of  a  high  resting  sodium  conductance.   Meta- 
bolic processes  influence  discharge  dramatically  but  are  not 
directly  responsible  for  discharge.   The  electrogenic  sodium 
pump  does  not  underlie  the  bursting  discharge  characteristic 
of  some  neurons,  as  has  been  suggested  by  others.   A  metabolic 
regulation  of  membrane  conductance  is  important,  but  only  in 
maintenance  of  a  high  membrane  resistance  which  is  necessary 
for  normal  pacemaker  discharge. 

These  studies  of  Carpenter  are  aimed  at  providing  an  under- 
standing of  the  elementary  ionic  and  metabolic  mechanisms  of 
nerve  cells.   In  the  case  of  neuronal  thermosensitivity  he  has 
nov;  isolated  several  temperature  dependent  processes  which  can 
be  tested  in  mammalian  preparations. 

101 


The  study  of  the  ionic  basis  of  neuronal  pacemaker  dis- 
charge also  ha;s  relevance  to  the  mammal.   The  neuronal  pacemaker 
functions  in  a  manner  very  similar  to  that  of  the  heart.   In 
addition,  there  is  accumulating  a  considerable  body  of  evidence 
suggesting  that  there  may  be  endogenous  activity  of  neurons  in 
vertebrates  as  well  as  invertebrates. 

A  second  general  area  of  Carpenter's  work  concerns  the 
state  of  ions  and  water  in  living  cells.   His  results,  to  date, 
in  studies  of  this  problem  suggest  that  ions  in  nerve  Cell 
bodies  exist  in  a  very  different  state  from  those  in  axons.  If 
this  be  true  it  is  necessary  to  re-examine  many  of  the  concepts 
which  were  developed  to  explain  electrical  events  in  axons  and 
which  have  been  assumed  to  apply  to  all  excitable  tissues  on 
the  assumption  that  all  ions  are  free.   Moreover,  it  seems  very 
possible  that  the  state  of  ions  in  most  cell  bodies  may  be  more 
like  that  in  Aplysia  neurons  than  that  in  squid  axons  since  the 
cell  bodies  contain  many  more  membraneous  structures  and  a  hiqher 
concentration  of  organic  molecules  (which  are  probably  the  site 
of  the  ion  and  water  binding).   His  observations,  therefore, 
may  have  relevance  to  all  types  of  cells. 

Dr.  Stanley  Rapoport's  work  has  been  concentrated  on  two 
major  topics.   The  first  of  these  concerns  the  electrical,  ionic 
and  physical  properties  of  muscle.   The  second  area  of  Rapoport's 
work  has  dealt  with  transport  mechanisms  across  membranes.   His 
work  on  electrical,  ionic  and  physical  properties  of  muscle  is 
aimed  at  providing  knowledge  of  mechanical  properties  of  the 
sarcolemma  myofibrils,  and  of  their  relative  contribution  to 
tension  as  a  function  of  stretch.   This  knowledge  is  required 
to  understand  the  process  of  contraction  and  of  the  resistance 
of  the  muscle  to  stretch  under  physiological  conditions.   Cor- 
relation between  electromicroscopic  structure  of  the  sarcolemma 
and  myofibrils  and  their  properties  permits  a  better  understand- 
ing of  the  molecular  forces  regulating  tension. 

Stretch  prolongs  frog  muscle  survival  and  stimulates  muscle 
metabolism.   These  effects  have  not  been  related  up  to  now,  but 
the  present  work  shows  that  they  may  be  related  through  the  stim- 
ulation of  the  Na  pump  by  stretch.   The  Na  pump  will  determine 
ionic  contents  of  the  muscle,  and  these  in  turn  may  determine 
membrane  potential  and,  therefore,  contraction  threshold.   The 
effect  of  stretch  in  frog  sartorius  is  relevant  to  the  problem 
of  stretch-induced  muscle  hypertrophy. 

Dr.  Rapoport's  work  on  transport  mechanisms  across  membranes 
has  provided  a  new  model  for  blood-brain  barrier  breakdown.   It 
proposes  that  the  barrier  can  be  broken  down  irreversibly,  as 
it  has  in  the  past,  or  reversibly,  by  shrinkage  of  endothelium 


102 


I 


cells  because  of  osmotic  action.   The  reversible  breakdown  of 
the  barrier  could  be  of  significance  to  the  treatment  of  cere- 
bral diseases  by  facilitating  drug  passage  into  the  brain, 

2;   Central  Control  of  Movement.   This  area  of  the  Labo- 
ratory's research  program  includes  the  work  of  DeLong  on  the 
pasal  ganglia,  of  Miles  on  the  cerebellum  and  of  Evarts  on  the 
sensorimotor  areas  of  the  cerebral  cortex.   Their  studies  have 
involved  the  use  of  the  method  of  single  unit  analysis  to  un- 
cover the  way  in  which  nerve  cells  function  in  the  initiation 
and  control  of  movement. 

In  DeLong 's  studies  on  the  functional  role  of  the  basal 
ganglia  in  the  control  of  movement  and  posture,  monkeys  were 
trained  to  exert  a  steady  pushing  or  pulling  force  on  a  rigid 
rod  positioned  in  front  of  the  hand,  and  then  to  rapidly  re- 
verse the  direction  of  the  force  on  presentation  of  a  visual 
stimulus.   Extracellular  recordings  were  then  carried  out  during 
the  execution  of  the  task.   The  globus  pallidus  was  studied  in 
greatest  detail  initially.   In  subsequent  studies  recordings 
have  been  made  in  the  putamen  and  caudate  as  well.   In  these 
latter  nuclei,  unit  discharge  was  also  found  to  precede  the  arm 
movements,  especially  in  the  putamen.   A  functional  organiza- 
tion was  observed  in  both  the  pallidum  and  the  caudate-putamen 
whereby  the  majority  of  movement-related  units  are  located  in 
those  regions  which  receive  their  input  from  the  sensorimotor 
cortex.   Studies  on  the  function  of  the  corpus-striatum  are  of 
relevance  to  the  program  of  the  Institute  since  these  regions 
of  the  brain  appear  to  have  important  integrative  as  well  as 
purely  motor  functions  which,  when  disturbed  as  in  disease,  pro- 
duce disturbances  of  movement,  motivation,  and  affect.   Current 
theories  suggest  that  the  site  of  action  of  L-Dopa,  which  abol- 
ishes symptoms  in  the  majority  of  Parkinsonian  patients,  is  upon 
the  cells  of  the  caudate  and  putamen  via  a  dopaminergic  nigro- 
striatal  pathway.   An  understanding  of  the  normal  functioning 
of  the  corpus  striatum  should  provide  a  firm  basis  for  studies 
on  the  effects  of  disease  and  pharmacologic  agents  on  these 
structures. 

In  Miles'  studies  on  the  role  of  the  cerebellum  in  the  gen- 
eration of  saccadic  eye  movements,  microelectrode  recordings  are 
made  in  the  cerebellum  of  conscious  monkeys  and  a  search  is  made 
for  individual  units  whose  firing  patterns  correlate  with  the 
animal's  saccadic  eye  movements.    The  animal  is  trained  to 
press  a  bar  which  switches  on  a  small  spot  of  light  on  a  screen 
facing  him,  and  he  must  release  the  bar  when  this  light  dims. 
Successful  performance  is  rewarded  with  a  drop  of  water,  and 
all  the  animal's  fluid  intake  is  earned  by  working  at  this  task. 


103 


Using  this  approach,  four  monkeys  have  been  trained  to  fixate 
a  small  spot  of  light  and  maintain  this  fixation  even  when  the 
spot  changes  position.   Thus  it  is  possible  to  induce  the  animal 
to  generate  saccadic  eye  movements  of  known  magnitude  and  direc- 
tion merely  by  changing  the  position  of  the  fixation  target. 

To  date,  single  unit  recordings  have  been  made  from  the 
cerebellar  vermal  cortex  and  sub-cortical  nuclei  in  one  monkey 
performing  the  controlled  eye  movements.   Seventeen  units  were 
found  to  relate  to  saccade  eye  movements.   The  site  of  these 
cells  was  marked  with  small  electrolytic  lesions  and  has  yet  to 
be  confirmed  with  histology,  but  it  is  felt  with  reasonable  cer- 
tainty that  they  probably  all  lie  within  the  fastigial  nuclei. 
No  Purkinje  cell  firing  was  observed  to  correlate  with  these  eye 
movements.   The  main  characteristics  of  saccade-related  firina 
apparent  thus  far  are: 

a)  It  is  usually  directionally  selective,  showing  a  burst 
during  ipsilateral  saccades  and  either  suppression  or  no  re- 
sponse during  contralateral  saccades.   Occasional  units  generate 
a  burst  during  all  saccades. 

b)  This  burst  can  start  before  the  saccade,  but  the  exact 
time  relationships  remain  to  be  estimated. 

^  ^  ""l    ^'^^^   magnitude  of  these  bursts  is  related  to  the  magni- 
llf.t   ?   the  saccades  and  there  seems  to  be  an  optimum  eye  move- 
ment for  which  responses  are  maximal,  and  larger  or  smaller  sac- 
cades are  associated  with  less  vigorous  activity. 

d)   At  least  in  some  units,  the  saccade-related  burst  is 
not  very  sensitive  to  the  initial  start  position  of  the  eye. 

tion  ITi-T/^   °^  ""^^""^^    ^^^    ^^^^^  ^ith  the  functional  organiza- 

initiate  movement,  what  areas  cnntr-oi  =.r,^    ^reas  or  tne  cortex 
;:.nH  hr>,,   1-v.,.^^  wnaL.  dreas  control  and  regulate  movement. 

PTB  outDUt  S!or  ?^  ?   ^"^""""^^ys  have  shown  that  motor  cortex 
ulus  ocSrs  aSut  ?ni  r""  ,'"?r"'^"'=  t'^iW^s-J  by  a  visual  stim- 


104 


than  visual,  reaction  time  may  be  considerably  shorter.   Pre- 
vious studies  by  others  demonstrated  that  when  subjects  made 
responses  to  displacement  of  the  arm,  reaction  time  was  as  short 
as  50  msec.   Results  from  recordings  in  sensorimotor  cortex  of 
the  monkey  when  the  animal  makes  a  movement  in  response  to  an  in- 
put delivered  to  the  hand  showed  that  under  these  circumstances 
motor  cortex  pyramidal  tract  neurons  can  discharge  at  much  shorter 
latency  than  is  the  case  for  movements  initiated  by  a  visual 
stimulus.   In  the  experiments  carried  out  in  man,  it  had  been 
observed  that  muscular  responses  dependent  upon  the  voluntary  set 
of  the  subject  occur  50  msec  following  stimulus.   In  the  experi- 
ments on  monkeys,  changes  in  muscle  activity  depending  upon  the 
set  of  the  animal  occur  at  a  latency  of  approximately  35  msec 
following  the  stimulus.   These  changes  in  muscle  activity  were 
preceded  by  activity  of  neurons  in  motor  cortex.   Recordings 
from  the  motor  cortex  reveal  that  pyramidal  tract  neurons  became 
active  at  latencies  as  short  as  20  msec  following  a  stimulus  to 
the  hand.   Non-pyramidal  tract  neurons  of  motor  cortex  became 
active  even  earlier,  and  neurons  of  the  postcentral  gyrus  were 
active  at  still  shorter  latencies  of  10-12  msec  following  the 
stimulus  to  the  hand.   In  interpreting  these  observations  on  man, 
it  was  proposed  that  very  short  reaction  times,  dependent  upon  the 
voluntary  set  of  the  subject,  might  involve  a  setting  of  spinal 
reflexes.   The  present  observations  showing  changes  in  motor  cor- 
tex output  at  very  short  latencies  would  suggest  that  in  addition 
to  a  presetting  of  spinal  reflex  mechanisms,  such  short  latency 
responses  dependent  on  voluntary  set  may  also  involve  pre-setting 
of  cortical  mechanisms. 

The  importance  of  this  observation  is  that  it  shows  that  a 
quick  output  from  motor  area  is  not  an  automatic  consequence  of 
input  but  that  it  can  be  modified  or  gated  depending  on  the  voli- 
tional goals  of  the  subject.   It  seems  possible  that  certain 
cells  in  the  motor  area  are  more  or  less  directly  tied  to  the  in- 
put and  that  neuronal  networks  within  the  cerebral  cortex  are 
able  to  facilitate  or  prevent  the  transmission  of  these  patterns 
of  discharge  to  the  pyramidal  tract  output  from  the  cortex.   The 
time  available  for  this  switching  to  take  place  is  brief  and  this 
fact  means  that  analysis  of  the  mechanisms  underlyina  the  gating 
on  or  off  of  motor  output  may  be  approached  more  effectively  than 
has  heretofore  been  possible. 

A  number  of  formulations  concerning  the  nature  of  mental 
disorder  in  patients  have  proposed  a  disturbance  in  the  cerebral 
mechanisms  which  underlie  the  maintenance  of  "set"  or  "attention." 
It  appears  that  the  present  neurophysiological  experiments  on 
monkeys  begin  to  get  at  mechanisms  which  are  close  to  the  atten- 
tional  and  set  determining  mechanisms  of  the  brain.   If  these 
mechanisms  can  be  better  understood,  it  seems  possible  that  they 


105 


will  lead  to  a,  sounder  understanding  of  a  variety  of  disturbances 
of  psychological  function. 

3.   Neural  Correlates  of  Learning  and  Memory.  This  third 
general  area  of  the  Laboratory's  program  includes  the  work  of 
Niki  and  Mortimer.   Niki  is  studying  the  way  in  which  single 
nerve  cells  of  the  prefrontal  cortex  operate  in  the  performance 
of  "delayed  alternation,"  a  task  involving  short  term  memory, 
and  Mortimer  has  been  investigating  cerebellar  activity  occurring 
in  association  with  the  startle  response  in  the  monkey,  with  a 
view  to  obtaining  information  on  the  modifications  of  cerebellar 
discharge  associated  with  habituation  of  this  response.   Ulti- 
mately, Mortimer  is  interested  in  studying  the  role  of  the  cere- 
bellum in  motor  learning. 

Niki's  studies  have  revealed  the  existence  of  prefrontal 
neurons  which  discharge  differently  depending  on  the  movement 
(rightwards  or  leftwards)  which  the  monkey  must  make  several 
seconds  later.   These  cells  may  possibly  be  involved  in  regis- 
tration of  short-term  spatial  memory. 

Mortimer's  studies  have  dealt  with  the  temporal  sequence  of 
cerebellar  activity  in  relation  to  the  initiation  and  control  of 
movements.   The  general  objective  of  this  research  is  to  under- 
stand the  relationship  between  the  cerebellar  cortex  and  the 
cerebellar  nuclei  in  the  control  and  initiation  of  movement. 
More  specifically,  the  aim  is  to  discover  the  functional  role  of 
direct  afferent  inputs  to  the  nuclei.   In  higher  vertebrates  the 
deep  cerebellar  nuclei  provide  the  major  output  from  the  cere- 
bellum.  The  cells  of  these  nuclei  are  controlled  by  two  major 
inputs:  an  inhibitory  input  from  the  output  Purkinje  neurons  of 
the  cerebellar  cortex  and  an  excitatory  input  from  the  collaterals 
of  afferents  to  the  cortex.   Two  hypotheses  have  been  proposed  for 
the  functional  operation  of  the  cerebellum.   In  the  first  hypoth- 
esis, the  direct  excitatory  input  to  the  nuclei  is  considered  to 
provide  only  a  steady  level  of  background  facilitation;  changes 
in  nuclear  activity  then  reflect  changes  in  the  inhibitory  input 
from  Purkinje  cells.   An  alternative  hypothesis  is  that  the  cere- 
bellar cortex  output  is  superimposed  upon  an  ongoincr  nuclear  dis- 
charge evoked  by  its  direct  afferent  input. 

Recordings  of  cerebellar  Purkinje  and  nuclear  cells  revealed 
a  temporal  sequence  of  neuronal  activity  following  the  stimuli, 
in  which  changes  in  nuclear  cell  discharge  preceded  the  earliest 
changes  in  Purkinje  cell  activity.   Virtually  all  nuclear  cells 
responded  with  a  short-latency  burst  of  spikes,  which  occurred 
several  milliseconds  before  the  earliest  change  in  EMG  activity 
associated  with  the  startle  response.   Shortly  after  the  onset 
of  the  EMG  response,  increases  and  decreases  in  Purkinje  dis- 
charge rate  were  observed.   These  findings  suggest  that  direct 

106 


excitatory  input  to  the  nuclei  is  capable  of  initiating  activity, 
which  is  modified  after  a  delay  by  the  inputs  from  Purkinje 
cells.   It  is  possible  that  the  early  nuclear  discharge  contrib- 
utes to  the  initiation  of  motor  activity  associated  with  the 
startle  response. 


107 


Annual  Report  of  the  Section  on  Technical  Development 

National  Institute  of  Mental  Health 

national  Institute  of  Neurological  Diseases  and  Stroke 

July  1,  1971  -  June  30,  1972 

James  S.  Bryan,  Chief 


During  the  past  12  months,  the  Section  on  Technical  Development 
continued  to  fulfill  its  traditional  role  of  support  of  NIMH  and  NINDS 
research  efforts.  Continuing  assistance  was  made  available  in  shop 
help,  special  purpose  instruments,  instrumentation  systems,  and  assistance 
in  computer  oriented  research  and  digital  instrumentation. 

The  major  load  on  the  Section  in  the  past  year  has  continued  to  he 
related  to  support  of  computer  installations,  principally  the  Building  10 
8lOB  system  which  is  now  beginning  to  work  with  reasonable  reliability 
in  on-line  experiments,  and  the  rat-colony,  data-collection  system  at 
Poolesville  which  has  occupied  us  with  problems  of  maintenance,  expansion 
and  modification. 

The  Section  continues  as  before  to  support  three  laboratory  computers 
for  general  use.  Table  I  gives  a  breakdown  of  their  usage  by  Institute. 
Table  II  shows  a  breakdown  of  Section  activity  by  laboratory.  As  usual, 
almost  all  research  within  the  Section  has  involved  collaboration  with 
laboratories  in  NIMH  and  NINDS  and  is,  therefore,  reported  as  part  of  the 
projects  in  the  laboratories  involved.  Exceptions  to  the  foregoing  include 
a  small  but  continuing  effort  in  neural  modeling  in  collaboration  with  the 
Laboratory  of  Applied  Studies,  DCRT,  and  development  of  equipment  to 
investigate  the  nature  of  motor  deficits  in  patients  with  either  dystonia 
or  Parkinson's  disease. 

The  equipment  to  measure  motor  dysfunction  has  progressed  to  the  point 
of  carrying  out  a  few  exploratory  measurements  on  Parkinson  patients  made 
available  by  the  Section  on  Experimental  Therapeutics,  Laboratory  of 
Clinical  Science,  NIMH.  The  results  of  these  measurements  encourage  us  to 
believe  that  we  shall  be  able  to  characterize  a  patient ' s  dysfunction  in 
terms  of  motor-system  damping  expressed  as  a  time-varying  parameter,  which 
in  turn  should  yield  insight  into  the  nature  of  function  and  dysfunction 
in  the  gamma  motor  system.  Since  our  initial  measurements  revealed  in- 
adequacies in  the  torque  motor  used  in  the  experiments,  the  system  is  now 
being  reworked  with  a  new  motor  in  a  form  to  be  used  in  Building  10  for 
routine  data  collection  with  patients .  This  system  should  be  operational 
by  July  1,  1972. 

A  total  of  151  projects  were  completed  in  the  last  year.  A  large 
portion  of  these  consisted  of  routine  fabrication  of  various  chambers,  baths. 


109 


electrode  holders,  and  jigs  for  experimental  use  as  well  as  many  small 
electronic  devices. 

Major  systems  included: 

(1)  Preparation  of  a  large -animal  EEG  telemetry  system  with 
one -half  m.ile  range  for  study  of  sleep  patterns  in  free 
ranging  wild  animals  -  Laboratory  of  Psychotiology,  MTMH, 
(in  process) . 

(2)  Development  of  electronics  for  scanning  microspectrophotometer 
in  collaboration  with  the  Section  on  Sensory  Physiology, 

Laboratory  of  Neurophysiology,  WIWDS . 

(3)  Projecting  densitometer  for  quantitative  evaluation  of 
autoradiograms  -  Laboratory  of  Experimental  Neurology,  WINDS. 

{k)     Portable . System  for  Infant  Learning  Experiments  -  Section  on 
Perception,  Laboratoiy  of  Psychology,  NIMH,  (in  process). 

(5)  Collaborative  activity  with  the  Section  on  Pathology, 

Perinatal  Research  Branch,  NIWLS  in  the  development  of  a 
computerized  image  analysis  system  for  grain  counting  in 
autoradiograms . 


TABLE  I 


LABORATORY  COMFOTER  UTILIZATION 


NIMH 


Classic  LINC 

MicroLINC 

PDP-12 


NINDS 

NICHD 

TOTAL  HOURS 

0 

0 

2920 

2li 

0 

1912 

6ofo 

3fo 

228U 

110 

/ 


TABLE  II 


APPORTIOJMMENT  OP  EFFORT 


ENGIHEERING  &  FABRICATION  TIME 


MAJOR  USERS 


LABORATORY  OR  BRAWCH 

NIMH  8IOB  Computer  (includes  Programmer)  -  -  -  - 

Psychologj^  ICTMH  ------------   --- 

Clinical  Psychobiology,  NIMH  -------  -- 

Brain  Evolution  &  Behavior,  NIMH  -------  - 

Office  of  the  Director,  NINDS   --------- 

Technical  Development,  NIMH-NINDS   -  -  -  

Neurophysiology,  NINDS   ------   ------ 

Experimental  Neurology,  NINDS  -----  ---- 

Adult  Psychiatry,  NIMH 

Behavioral  Biology,  NICHD  _---  ---- 

Biophysics,  NINDS   ---  __--_--_ 

General  &  Comparative  Biochemistry,  NIMH  -  -  -  ~ 
Neuropathology  &  Neuroanatoraical  Sciences,  NINDS 

Clinical  Science,  NIMH --- 

Neurochemlstry,  NIIVE  ----------  --- 

Molecular  Biology,  NINDS --- 

Neural  Control,  NINDS  _-- 

Intramural  Research,  NINDS  ----------- 

Neurophysiology,  NIMH  ------------- 

All  other  NINDS  Labs  -------------- 

All  other  NIMH  Labs 


HOURS 

PERCENT 

5292 

19.17 

36U2 

13.19 

320i^ 

11.6 

23i^0 

QM 

1856 

6.72 

1663 

6.02 

lh9h 

^.hl 

1380 

^.99 

136U 

k.9h 

1096 

3.97 

969 

3.51 

hh9 

1.62 

h31 

1.58 

35^ 

1.28 

328 

1.18 

322 

1,16 

310 

1.12 

30ij- 

1,10 

301 

1.09 

297 

1.07 

172 

.62 

NIMH  (Total) 
NINDS  (Total) 
NICHD  (Total) 


TOTAL"* 


18,509     67.05 

7,999  28.97 

1,096  3.97 


27,60k  100.0 


Not  included  in  the  foregoing  totals  or  in  the  breakdown  by  laboratory 
are  8OO  hours  spent  in  routine  maintenance  internal  to  the  Section,  and 
the  time  of  the  Section  Chief. 


Ill 


ANNUAL  REPORT 

MENTAL  HEALTH  INTRAMURAL  RESEARCH  PROGRAM  - 
Division  of  Clinical  and  Behavioral  Research,  and 
Division  of  Biological  and  Biochemical  Research 

NATIONAL  INSTITUTE  OF  MENTAL  HEALTH 

July  1,  1971  -  June  30,  1972 


VOLUME  II 
Individual  Project  Reports 


ANNUAL  REPORT 
MENTAL  HEALTH  INTRAMURAL  RESEARCH  PROGRAM  - 
Division  of  Clinical  and  Behavioral  Research,  and 
Division  of  Biological  and  Biochemical  Research 
NATIONAL  INSTITUTE  OF  MENTAL  HEALTH 

July  1,  1971  -  June  30,  1972 


TABLE  OF  CONTENTS 
VOLUME  II  -  Individual  Project  Reports 

DIVISION  OF  CLINICAL  AND  BEHAVIORAL  RESEARCH  Page 

Office  of  the  Director 

M-0D-CI-5(c)     Studies  in  Schizophrenic  Conditions:   Psychosocial 

and  Biological  Interrelationships 1 

M-OD-SW-1       Conflict  between  the  Parents  of  Schizophrenics....     5 
ADULT  PSYCHIATRY  BRANCH 


Office  of  the  Chief 


M-AP (C) -14-1    Conceptualization  and  Dimensional  Evaluation  of 

Schizophrenia 7 

M-AP (C) -14-2    Principles  for  Scoring  Communication  Defects  and 
Deviances  of  Parents  of  Schizophrenics  in 
Psychological  Test  Transactions 11 

M-AP  (C)  -14-3    Cross-cultural  Family  Studies 15 

M-AP (C) -14-8    A  Study  of  the  Separation  Process  in  Adolescents 

and  Their  Families 17 

M-AP (C) -14-9    The  Conceptualization  of  Lasting  Dyadic 

Relationships 25 

Family  Studies  Section 

M-AP (C) -15-3    Evaluation  of  Family  Dynamics  with  Conjoint  Family 

Art  Procedures 29 

M-AP(C)-15-5    Family  Art  Therapy 33 

M-AP (C) -15-8    Systematic  Analysis  of  Family  Art  Evaluations 35 


ftPULT  PSYCHIATRY  BRANai  (cont'd)  Page 

Family  Studies  Section  (cont'd) 

M-AP (C) -15-9    Systematic  Analysis  of  Brazilian  Family  Art 

Evaluations  :   A  Replication. 39 

M-AP (C) -15-10   Sources  of  Variance  in  the  Cross-Cultural 

Application  of  an  Objective  System  for  Analyses 

of  Pictures  Drawn  by  Patients  and  Their  Families . .    43 

Section  on  Psychiatric  Assessment 

M-AP (C) -16-1    WHO  International  Pilot  Study  of  Schizophrenia....  47 

M-AP (C) -16-3    Comparative  Studies  of  Functional  Psychoses 51 

M-AP (C) -16-4    Empirical  Grouping  of  Psychiatric  Patients 55 

M-AP  (C)  -16-5    Serum  Enzymes  in  Acute  Psychotic  States 57 

M-AP (C) -16-6    Psychiatric  History  Study:   The  Nature  and 

Reliability  of  the  Data 59 

M-AP  (C) -16-7    The  Evaluation  of  Outcome  in  Schizophrenia 61 

M-AP  (C) -16-8    Psychobiology  of  Cortisol  Metabolism 63 

M-AP  (C) -16-9    Research  Interviews:   Are  They  Valid? 67 

M-AP  (0-16-10   The  Recovery  Process  and  Research  Data  in  Acute 

Psychosis 69 

M-AP (C) -16-11   Investigation  of  the  Schizophrenic  Process  Through 

Art  Productions  of  Acutely  Psychotic  Patients 71 

Section  on  Personality  Development 

M-AP (C) -17-1    A  Study  of  Problems  in  Growth  and  Adaptation  in 

the  Personaltiy  Development  of  the  Adolescent 73 


M-AP (C) -17-2    Adolescent  Ego  Development  in  Normal  Families, 


81 


M-AP (C) -17-3    Studies  of  Psychogalvanic  Response  in  Family 

Therapy .....". 83 

M-AP (C) -17-4    A  Follow-up  Study  of  37  Families  Treated  in  the 

Study  of  Adolescent  Identity. 87 

M-AP (C) -17-5    Cognition  and  Identity  Development  in  Early  and 

Late  Adolescence :   Longitudinal  Studies 89 


II 


ADULT  PSYCHIATRY  BRANCH  (cont'd)  ^^9^ 

Section  on  Experimental  Group  and  Family  Studies 

M-AP(C)-18-2  Coordination  "Micro-Codes"  in  Family  Consensual 
Experience:  A  Study  of  the  Responses  to  Speech 
Hesitancy  and  Fluency  in  Family  Interaction 93 

M-AP(C)-18-3    The  Effects  of  Progressive  Isolation  of  an 

Individual  from  his  Perceptual  Functioning:   Use  of 
a  Teletype-LINC  Apparatus  to  Study  the  Reciprocal 
Relationship  of  Family  Interaction  and  Individual 
Thinking 95 

M-AP(C)-18-6    Nurse-Doctor-Patient  Interaction:  An  Experimental 
Study  of  its  Role  in  Patient  Acculturation  on 
Psychiatric  Wards 99 

M-AP (C) -18-10   The  Effect  of  Stimulus  Materials  on  Family  Problem 

Solving. 103 

M-AP (C) -18-12   Family  Views  of  Its  Social  Environment:   Effects 

on  Family  Therapy  Process 105 

M-AP (C) -18-13   Values  and  Atmosphere  on  a  Psychiatric  Ward: 

Basic  Dimensions  and  Institution  Comparisons 109 

M-AP (C) -19-1    Comparative  Studies  of  Discordant  Siblings  in 

Families  of  Schizophrenic,  Juvenile  Delinquent  and 
Well-adjusted  Yo\mg  Adults Ill 

M-AP (C) -19-2    Studies  in  the  Development  of  Personality  and 

Psychopathology  in  Identical  Twins  Discordant  for 
Schizophrenia 113 

M-AP (C) -19-5    The  Distribution  and  Concomitants  of  Schizophrenia, 
and  Other  Psychopathologies ,  in  a  Systematic 
Sample  of  15,909  Twin  Pairs 117 

M-AP (C) -19-6    The  Twin  Intrapair-Comparative  Technique  in  the 
Study  of  the  Determinants  of  Early  Personality 
Development 121 

M-AP  (0-20-1    Recognizing  and  Interpreting:   A  Differentiation 

of  Perceptual  and  Cognitive  Patterns 127 

M-AP (C) -20-4    The  Consensus  Rorschach  and  Focused  Feedback  as  a 

Clinical  Procedure 129 

M-AP  (0-20-5    Psychological  Studies  of  Patients  with  Affective 

Disorders 133 


ADULT  PSYCHIATRY  BRANCH  (cont'd)  Page 

Section  on  Experimental  Group  and  Family  Studies  ( cont ' d) 

M-AP(C)-20-6    Psychological  Deficits  in  Selected  Neurological 

Disorders 135 

M-AP(C)-21-2    Studies  of  Perceptual  and  Cognitive  "Styles"  in 

Psychiatric  and  Non-psychiatric  Sxibjects 137 

M-AP(C)-21~4    Perceptual  and  Cognitive  Style  in  Normal  Twins....   141 


CHILD  RESEARCH  BRANCH 

M-CR-10  (c)      Relations  of  Preschool  and  Child  Behavior  to 

Earlier  Parent  and  Child  Characteristics 143 

M-CR-11  (c)      Relations  between  Himan  Neonatal  Behavior  and 

Later  Development , 147 

M-CR-12  (c)      Developmental  Patterns  in  the  Young  Family 151 

M-CR-22  (c)      Offspring  Effects  on  Parents 156 

M-CR-23  (c)      Determinants  and  Dimensions  of  Mother-Infant 

Interaction 159 

M-CR-24  Cc)      Structure  and  Correlates  of  Preschool  and  Child 

Behavior 163 


LABORATORY  OF  CLINICAL  PSYCHOBIOLOGY 


Section  on  Clinical  Studies 

M-CP(C)-18-3    Biochemical  and  Pharmacological  Studies  of  Sleep..   165 

M-CP(C)-18-8    Psychophysiological  Studies  of  Sleep  and  Waking  in 

Normal  Subjects 169 

M-CP(C) -18-69    Longitudinal  Studies  of  Sleep  and  Concomitant 

Biological  Changes  in  Psychiatric  Patients 175 

Section  on  Comparative  Studies 

M-CP-18-6       Comparative  Studies  of  Sleep 179 

M-CP-18-7       Factors  Affecting  Intraspecific  and  Predatory 

Aggression  in  the  Rat 185 


LABORATORY  OF  CLINICAL  SCIENCE  Page 

Office  of  the  Chief 

M-CS-OC  (C) -04   Studies  of  the  Interrelationships  of  the  Nervous 

and  Circulatory  Systems 191 

M-CS-OC (C) -15   Studies  of  Pinched-off  Nerve  Endings  (Synaptosomes) 
as  a  Model  System  for  Investigating  the  Transport, 
Binding  and  Metabolism  of  Monoamines 193 

M-CS-OC (C) -19   Metabolism,  Distribution  and  Biochemical  Effects 

of  Psychoactive  Drugs 195 

M-CS-OC  (C) -20   Histochemical  Studies  of  Biogenic  Amines 197 

Section  on  Medicine 

M-CS-M(C)-08    Formation,  Release,  Disposition  and  Metabolism  of 

Biogenic  Amines 201 

M-CS-M(C)-11    False  Neurochemical  Transmitters 205 

M-CS-M(C) -12    Growth  Characteristics  or  Aminergic  Neurons 207 

Section  on  Psychiatry 

M-CS-Ps (C) -18   Biochemical  and  Behavioral  Factors  in  Affective 

Disorders 211 

Section  on  Pharmacology 

M-CS-Ph-05      Biochemistry  and  Pharmacology  of  the  Adrenergic 

Nervous  System 223 

M-CS-Ph-06      Tryptamine  and  Ohter  Biogenic  Amines  and 

Psychoactive  Drugs 227 

M-CS-Ph-07      Biochemical  and  Pharmacological  Studies  on  the 

Pineal  Gland 229 

Section  on  Experimental  Therapeutics 

M-CS-ET-01      Biochemistry,  Pharmacology  and  Physiology  of 

Cerebral  Amines 231 


LABORATORY  OF  PSYCHOLOGY  Page 

Office  of  the  Chief 

jyi_p_C-(c) -12     Studies  of  Heredity  and  Environment  in 

Schizophrenia. „  .  .  . ,  .  .  .  239 

M-P-C-  (C)  -15     Reaction  Time  in  Schizophrenia 243 

M-P-C-(C)-17     Psychophysiological  Responsivity  in  Schizophrenia.  245 

M-P-C-(C)-36     Psychological  Correlates  of  Cortical  Evoked 

Responses 249 

M-P-C- (C) -39     Study  of  Heredity  and  Environmental  Factors  in 

Schizophrenia 255 

M-P-C- (C) -40     Changes  in  Neurological  and  Psychological 
Functioning  in  Children  with  Minimal  Brain 
Dysfunction  Receiving  D-amphetautiine 257 

M-P-C- (C) -43     Lithium  as  a  Therapeutic  Agent  in  Hyperkinetic 

Behavior  Disorders  of  Childhood. 259 

M-P-C- (C) -44     Individual  Differences  in  Eye  Movement  Search 

Patterns 261 

M-P-C- (C) -45     The  Offspring  of  Schizophrenics:   Markers  of  a 

Schizophrenic  Disposition. 253 

M-P-C- (C) -46     Psychophysiological  Changes  During  the  Menstrual 

Cycle 265 

M-P-C- (C) -47     Psychophysiological  Concomitants  of  Minimal  Brain 

Dysfunction  in  Children 267 

M-P-C- (C) -48     Autonomic  Functioning  in  mz  and  dz  Twins 269 

Section  on  Early  Learning  and  Development 

M-P-D-(C)-30  Stimulus  Conditions,  Infant  Behaviors  ,  Caretaker- 
child  Interaction,  and  Social  Learning  in  Diverse 
Child-rearing  Environments 271 

M-P-D-(C)-34     Contextual  Determinants  of  Stimulus  Power 

(Formerly:   Deprivation  and  Satiation  of  Social 

Stimuli  as  Determinants  of  Their  Reinforcing 

Efficacy) 277 

M-P-D-(C)-42     Evaluation  of  Concepts  Employed  for  Early  Learning 

and  Development 279 


LABORATORY  OF  PSYCHOLOGY  (cont'd)  Page 

Section  on  Personality 

M-P-P-(C)-6      The  Investigation  of  Some  Formal  Characteristics 

of  Speech 281 

M-P-P-(C)-22     Development  of  Potentially  Creative  Scientists: 
Personality  Characteristics  Associated  with 
Creative  Performances 285 

M-P-P-(C)-40     Body  Movement  as  Expression  of  Change  in 

Psychological  Tension  States 289 

M-P-P-(C)-41     Survey  of  Literature  on  Emotional  Communication...  291 

M-P-P-(C)-42     Precocious  Science  Students  in  Psychiatric 

Treatment:   a  Longitudinal  Study   (Formerly: 
Psychotherapy  Research:   Models  and  Conceptions)..  293 

M-P-P-(C)-43     Test  and  Performance  Measures  of  Creativity  in 

Science  (Formerly:   Measures  of  Creative  Ability 

in  Science) 297 

M-P-P-(C)-44     Psychodynamic  and  Instrumental  Learning  Models: 
Implications  for  Personality  Theory  and 
Psychotherapy 301 

M-P-P- (C) -45     Developmental  Factors  in  Conversational  Behavior..  303 

M-P-P-(C)-46     Stimulus  Intensity  Modification:   Neurophysiologic 

and  Psychoanalytic  Relationships 307 

Section  on  Higher  Thought  Processes 

M-P-A-16         A  Study  of  the  Means-end  Thought  Processes  in 

Hxoman  Subjects 309 

Section  on  Neuropsychology 

M-P-B-2          Analysis  of  the  Relationship  Between  Problem- 
solving  Behavior  and  Certain  Cortical  and 
Subcortical  Structures  in  the  Sub-human  Primate 
Brain 313 

M-P-B-5  Neural  Mechanisms  in  Vision 317 

M-P-B-7  Histological  Analysis  of  Cerebral  Lesions  and 

Intra-cerebral  Connections  in  Primates 321 

M-P-B-14         The  Neural  Regulation  of  Appetitive  Behavior 325 


VII 


LABORATORY  OF  PSYCHOLOGY  (cont'd)  Page 

Section  on  Neuropsychology  (cont'd) 

M-P-B-16         Cerebral  Mechanisms  Underlying  Functional 

Plasticity  in  the  Developing  Organism 327 

Section  on  Perception 

M-P-L-5  Individual  Differences  in  Normal  Perceptual 

Processes 331 

M-P-L-7  Perceptual  Adaptation 333 

M-P-L-9  Discriminative  and  Conceptual  Behavior  in 

Preschool  Children 335 

M-P-L-10         Discriminative  and  Conceptual  Behavior  in 

Infancy 337 

M-P-L-12         Cortical  Mechanisms  in  Somesthesis 341 


LABORATORY  OF  SOCIO-ENVIRONMENTAL  STUDIES 

M-S-C-11         Social  Psychological  Correlates  of  Occupational 

Position 345 

M-S-D-10         Research  on  the  Processes  of  Internalization  of 

Rules  ,  Standards  ,  and  Values 351 

M-S-D-15         Occupational  Experiences  of  Musicians 357 

M-S-D-23         Observational  Learning  from  Nurturant  and 

Nonnurturant  Models 359 

M-S-D-26         An  Observational  Study  of  Maternal  Models 363 

M-S-D-28         A  Comparison  of  Methods  of  Obtaining  Data  on 

Parent  and  Child  Behavior 367 

M-S-P(C)-23      Cultural  and  Psychodynamic  Factors  in  the 

Occurrence  and  Treatment  of  Psychiatric  Illnesses 

in  Japan ,  Taiwan,  and  the  United  States 371 

M~S-P(C)-27      Parental  Care  and  Child  Behavior  in  Japan  and  the 

United  States 375 

M-S-P(C)-38      The  Interrelationships  between  Social  Interaction, 
Psychological  Functioning,  Perceptual  Style, 
Physiological  Arousal  and  Personal  History  Factors 
Among  Schizophrenics 379 

VIII 


LABORATORY  OF  SOCIO-ENVIRONMENTAL  STUDIES  (cont'd)  Page 

M-S-PS-1      Health  Orientations  of  Parents  and  Children 383 

M-S-S-12      Developmental  Study  of  the  Self-image 387 

M-S-SP-3      Variables  Affecting  Twin  Birth  Frequencies 391 

M-S-SP-4      Individual  Differences  in  Survival  and  Reproduction 

Among  Old  Colony  Mennonites  in  Mexico 393 

M-S-SP-5      Social  Origins  of  Stress 395 

M-S-SP-6      Studies  of  Evolution  of  Reacting  Chemical  Mixtures 

Under  Nearly  Steady-State  Conditions 399 

DIVISION  OF  BIOLOGICAL  AND  BIOCHEMICAL  RESEARCH 
Office  of  the  Director 
M-OD-BBR-2    Characteristics  of  Membranes  in  Muscle 401 


LABORATORY  OF  BRAIN  EVOLUTION  AND  BEHAVIOR 

Section  on  Comparative  Neurophysiology  and  Behavior 

M-LBEB-CN-1   Neural  Substrate  of  Mirror  Display  in  Squirrel 

Monkey  (Saimiri  Sciureus) 403 

M-LBEB-CN-2   Unit  Study  of  Interoceptive  Inputs  to  the  Cingulate 

Cortex  of  Squirrel  Monkey. 407 

M-LBEB-CN-3   Effect  of  Intravenous  Injections  of  5-Hydroxy- 

tryptamine  (Serotonin)  on  Unit  Activity  of  Cingulate 
Cortex  of  Awake  Squirrel  Monkeys  (Saimiri  Sciureus) . .  409 

M-LBEB-CN-4   Physiological  Effects  of  Intravenous  Administration 
of  Serotonin  (5-Hydroxytryptamine)  in  Awake  Squirrel 
Monkey  (Saimiri  Sciureus) 411 

M-LBEB-CN-5   ECG  Changes  and  Myocardial  Myocytolysis  Following 

Vagal  Stimulation  in  Awalce,  Sitting  Squirrel  Monkey 
(Saimiri  Sciureus) 413 

M-LBEB-CN-6   Transsynaptic  Cellular  Degeneration  Following  Vagal 

Nerve  Section  in  the  Newborn  Rabbit 415 

M-LBEB-CN-7   Exploratory  Study  on  Actions  of  Biogenic  Amines  in 

Squirrel  Monkeys 417 


IX 


LABORATORY  OF  BRAIN  EVOLUTION  AND  BEHAVIOR  (cont'd)  Page 

Section  on  Comparative  Neurophysiology  and  Behavior  ( cont ' d) 

M-LBEB-CN-S   Neural  S'jbstrate  of  Olfaction  in  the  Rat 421 

M-LBEB-CN-9   Taste  and  Location  Aversion  in  Bait  Shyness 423 

M-LBEB-CN-10   Aggression  and  Defense  in  Rats  With  Septal  Lesions..  425 

M-LBEB-CN-11   Sensory  Control  of  Fighting  in  Mice 427 

M-LBEB-CN-12   Reinforcing  Properties  of  Nesting  Material  During 

Gestation  in  Rats 429 

M-LBEB-CN-13   Functions  of  Avian  Paleostriatal  Complex. 

I.   Question  of  its  Role  in  Imitative  Behavior 431 

M-LBEB-CN-14  Behavioral  Effects  of  Hippocampal  Destruction  in  the 

Virginia  Opossum  (Didelphis  Virginiana) 433 

Section  on  Comparative  Biopsychology 

M-LBEB-CB-1   Temporal  Organization  of  Feeding  Sequences  and 

Sucking  Behavior  in  Infant  Dogs 435 

M-LBEB-CB-2   Behavioral  Effects  of  Response-contingent  Intra- 
gastric Versus  Intraoral  Milk  Injection  in  Infant 
Beagle  Dogs , 439 

M-LBEB-CB-3   Schedule-induced  Maladaptive  Adjunctive  Behavior 

in  Infant  Beagle  Dogs 441 

M-LBEB-CB-4   Capacity  for  Learning  in  Neonatal  Dogs :   Parametric 

Studies 445 

M-LBEB-CB-5   Excitatory  and  Inhibitory  Processes  in  Discriminated 

Instrumental  Behavior  of  Neonatal  Beagle  Dogs 447 

M-LBEB~CB-6   Instrumental  Escape  and  Avoidance  Learning  in 

Neonatal  Mongrel  Cats 449 

M-LBEB-CB-7   Attachment  Behavior  in  Beagle  Dogs  as  a  Function  of 

Social  Reinforcement 451 

M-LBEB-CB-8   Behavioral  Mathematics  and  the  Logic  of  Measurement.   453 

M-LBEB-CB-9   Automated  Apparatus  for  the  Biopsychological  Study 

of  Behavior 455 

Section  on  Behavioral  Systems 

M-LBEB-BS-1   Vitamin  A  Induced  Alteration  of  Social  Behavior. ....   457 

X 


LABORATORY  OF  BRAIN  EVOLUATION  AND  BEHAVIOR  (cont'd)  Page 

Section  on  Behavioral  Systems  (cont'd) 

M-LBEB-BS-2    Social  Velocity 461 

M-LBEB-BS-3   The  Overliving  of  a  Mouse  Population 463 

M-LBEB-BS-4   Role  of  Prior  Social  Experience  in  Altering  Adaptive 

Behavior 467 

M-LBEB-BS-5   Modification  of  Catecholamine  Metabolism  in  a  Crowded 

Mouse  Population 471 

M-LBEB-BS-6   Socially  Induced  Dissolution  of  Reproductive 

Capacities  in  Mice 473 

M-LBEB-BS-7   Rhythms  of  Spontaneous  Behavior. 477 

M-LBEB-BS-8   An  Automated  System  for  Monitoring  in-context 

Behavior 479 

M-LBEB-BS-9    Population,  Space  and  Mental  Health 483 


LABORATOPY  OF  CEREBRAL  METABOLISM 

Section  on  Developmental  Neurochemistry 

M-CM-DN-1     The  Mechanism  of  Action  of  Thyroxine  and  its 

Relation  to  Cerebral  Metabolism 487 

M-CM-DN-2     Studies  on  Regional  Cerebral  Circulation  and 

Metabolism 495 

M-CM-DN-3     Biochemical  Bases  of  Alcohol  Addiction 501 

M-CM-DN-4     Regulation  of  Protein  Synthesis  in  the  Brain 505 

Section  on  Myelin  Chemistry 

M-CM-MyC-1    Biochemical  Studies  on  Myelin  and  Myelin  Basic 

Protein 509 

M-CM-MyC-2    Immunological  Studies  on  Experimental  Allergic 

Encephalomyelitis  (EAE) 513 

M-CM-MyC-3    Studies  on  Delayed  Hypersensitivity  in  EAE 517 


LABORATORY  OF  CEREBRAL  iVJETABOLISM   (cont'd)  Page 

Section  on  Membrane  Chemistry 

M-CM-MeC-1    Study  of  the  Modulation  of  Central  Nervous  System 
Metabolism  and  Function  through  Alterations  in 
Membrane  Permeability  and  Transport 521 


LABORATORY  OF  GENERAL  AND  COMPARATIVE  BIOCHEMISTRY 

Section  on  Proteins 

M-LGCB  16B    Amino  Acid  tRNA  Synthetases.   Their  Role  in  Protein 

Synthesis  ,  and  Interaction  with  tRNA 525 

M-LGCB  18     Studies  on  the  Structure  and  Function  of  Thetin- 

Homocysteine  Methylpherase  and  Lactose  Synthetase. . .   529 

M-LGCB  35     Studies  on  Protein  Conformation  and  Limited 

Proteolysis 533 

M-LGCB  56     Determination  of  the  Effect  of  Small  Viruses  and 
Their  Nucleic  Acids  on  the  Biochemistry  of  Living 
Organisms 537 

M-LGCB  58     Ribonuclease  Specific  for  RNA-DNA  Hybrids 541 

M-LGCB  59     Spermidine  Synthesis  in  Rat  Brain 543 

Section  on  Alkaloid  Biosynthesis 

M-LGCB  43     Homocystinuria:   Methionine  Metabolism  in  Mammals...  545 

M-LGCB  48     Transsulf  uration  in  Higher  Plants 549 


LABORATORY  OF  NEUROBIOLOGY 

M-NB-1        Transient  Changes  in  Extrinsic  Fluorescence  of  Nerve 

Produced  by  Electric  Stimulation.  .  .- 553 

M-NB-2        Sensory-motor  Integration  in  the  Primate  Visual 

System 559 

M-NB-3        Metabolic  Activity  of  Nuclear  Proteins  from  Rat 

Brain  Cells 563 


LABORATORY  OF  NEUROCHEMISTRY  Page 

M-NC-1        The  Conversion  of  Phenylalanine  to  Tyrosine..........  565 

M-NC-2        Biosynthesis  of  Catecholamines 569 

M-NC-4        The  Biochemical  Basis  of  Skelet=;l  Muscle 

Hypertrophy 573 

M-NC-5        The  Process  of  Lysogeny 575 

M-NC-6        Physicochemical  Investigations  of  Biofunctional 

Structures  of  Glycosaminoglycans  and  Glycolipids 579 

M-NC-7        The  Role  of  the  Cell  Membrane  in  Cellular 

Organization ,  A  Molecular  Study 583 

M-NC-8        Biological  and  Biochemical  Models  for  the  Genetic 

Disease ,  Phenylketonuria  (PKU) 587 

M-NC-9        The  Conversion  of  Tryptophan  to  5-Hydroxy 

Tryptophan 589 


LABORATORY  OF  NEUROPHYSIOLOGY 

M-NP-3        Electrical,  Ionic  and  Physical  Properties  of  MuscIf  ,  593 

M-NP-8        Transport  Mechanisms  Across  Membranes 597 

M-NP-47       The  Ionic  and  Metabolic  Basis  of  Neuronal 

Thermosensitivity 601 

M-NP-48       The  State  of  Ions  and  Water  in  Living  Cells 605 

M-NP-63       The  Functional  Organization  of  the  Sensorimotor 

Cortex  in  the  Initiation  and  Control  of  Movement.....  609 

M-NP-65       Functional  Role  of  the  Basal  Ganglia  in  the  Control 

of  Movement  and  Posture 615 

M-NP-66       The  Role  of  the  Cerebellum  in  the  Generation  of 

Saccadic  Eye  Movements 619 

M-NP-67       Temporal  Sequence  of  Cerebellar  Activity  in  Relation 

to  the  Initiation  and  Control  of  Movements 623 

M-NP-68       Studies  on  the  Neuronal  Activity  of  the  Prefrontal 

Cortex 625 


Serial  No.  M-0D-CI-5(c) 

1.  Office  of  Director 

2.  Division  of  Clinical  and 

Behavioral  Research. 

3.  Bethesda,  Maryland 

PHS-HSMM-raMH 
Individual  Project  Report 
July  1,  1971  through  June  30^  I972 

Project  Title:  Studies  in  Schizophrenic  Conditions:  Psychosocial  and 
Biological  Interrelationships 

Previous  Serial  Number:  Same 

Principal  Investigator:  David  Shakow 

ther  Investigators :  None 
Cooperating  Units :  None 

-an  Years : 


Total : 

1.50 

Professional: 

.90 

Other: 

.60 

Project  Description: 

Objectives:  To  bring  together  a  large  body  of  experimental  data  on  schizo- 
phrenia collected  over  several  decades  into  a  book  (with  attendant  individual 
papers)  which  develops  a  theory  of  schizophrenia,  particularly  of  the  psycho- 
biology  of  schizophrenia,  centered  around  a  concept  of  segmentalization .  A 
detailed  analysis  of  the  body  of  experimental  data  already  available  from 
Worcester  State  Hospital  studies  and  some  new  data  gathered  on  our  wards  at 
NTMH  and  at  St.  Elizabeths  Hospital  will  be  used. 

'Methods  Employed:  In  relation  to  the  already  accimiijlated  materials  in  the 
L-ea  of  physiology,  psychophysiology,  and  psychology,  the  usual  methods  of 
catistical  and  conceptual  analysis  are  used.   Some  parts  of  the  relevant 

vzperimental  literature  will  be  used  for  further  differentiation  of  the 
laterial.   Related  studies  being  carried  out  by  other  investigators  in  the 

Laboratory  of  Psychology  and  elsewhere  in  NIMH  on  schizophrenic,  senescent, 

and  brain-damaged  subjects  will  be  used  in  these  studies  for  control  purposes. 

Major  Findings:  During  the  year  a  major  effort  has  gone  into  the  further 
analysis  and  organization  of  data  in  the  physiological,  psychophysiological, 
and  psychological  aspects  of  schizophrenia,  with  a  view  toward  developing  a 
unified  theory  of  schizophrenia.  Special  effort  has  been  extended  to  develop 
further  the  segmental  set  theory  and  the  detailed  presentation  of  a  theory 
of  language  in  schizophrenia. 


S i gnificance  to  Biomedical  Research  and  the  Program  of  the  Institute :   The 
studies  mentioned  above  will  contribute  to  the  understanding  of  the  phenomena 
of  schizophrenia  and  eventually  to  a  comprehensive  theory  of  schizophrenia. 

Proposed  Course  of  Project:  Continued  analysis  of  both  published  and  still 
unpublished  data^  in  the  context  of  the  analysis  of  relevant  data  from  studies 
of  others  at  NIH  and  elsewhere. 

Honors  and  Awards : 

Special  Recognition  Mental  Health  Awards  for  distinguished  achievement 
in  the  mental  health  field.   Conferred  on  the  occasion  of  the  25th  anni- 
versary of  the  enactment  of  the  National  Mental  Health  Act. 

First  Annua].  Distinguished  Scientist  Awards  conferred  by  Section  IIIj 
Division  12  (Clinical  Psychology)^  of  the  American  Psychological  Asso- 
ciation^ for  notable  contribution  to  psychopathology. 

Third  Annual  Seymour  D.  Vestermark  Memorial  Awards  for  outstanding 
contributions  to  mental  health  education  and  research;  cosponsored  by 
the  American  Psychiatric  Association  and  the  National  Institute  of 
Mental  Health.   Lecture  presented,  "The  education  of  the  mental  health 
researcher:  Encouraging  potential  development  in  man." 

Thomas  Salmon  Medal  of  the  New  York  Academy  of  Medicine,  on  the  occasion 
of  the  TS^fch  anniversary  celebration  of  the  New  York  State  Psychiatric 
Institute,  for  distinguished  service  in  psychiatry. 

Publications : 

Shakow,  D.  :  Some  observations  on  the  psychology  (and  some  fewer,  on  the 
biology)  of  schizophrenia.   J.  Nerv.  Ment.  Dis .  I53:   3OO-316,  I97I. 

Shakow,  D. :  The  Worcester  State  Hospital  research  on  schizophrenia 
(abbreviated  version).   In  Offer,  D.,  and  Freedman,  D.X.  (Eds.): 
Modern  Psychiatry  and  Clinical  Research:  Essays  in  Honor  of  Roy  R. 
Grinker,  Sr.   New  York,  Basic  Books,  1972,  pp.  174-207. 

Shakow,  D. :  Conference  on  psychiatric  education:  The  contribution  of 
psychology  in  the  teaching  of  psychiatry  to  medical  students.   J.  Nei-v. 
Ment.  Dis.  l^k:     I73-I79,  I972. 

Shakow,  D. :  The  Worcester  State  Hospital  research  on  schizophrenia 
(1927-19^+6).  Monograph,  J.  Abn.  Psychol.  ,  in  press. 

Shakow,  D. :  Discussion  of  Holzman's  and  Silverman's  contributions  on 
perception  in  schizophrenia.   Proceedings  of  the  Conference  on  Schizo- 
phrenia: The  Implications  of  Research  Findings  for  Treatment  and 
Teaching,  May  30- June  2,  1970,  in  press. 


Shakow,  D. :  The  education  of  the  mental  health  researcher:  Encouraging 
potential  development  in  man.   Arch.  Gen.  Psychiat.,  in  press. 

Shakow,  D. :  Hermann  ETbbinghaus.  McGraw-Hill  Encyclopedia  of  World 
Biography.   New  York;  McGraw-Hill,  in  press. 

Shakow,  D. :  Some  observations  on  the  psychology  (and  some  fewer,  on  the 
biology)  of  schizophrenia  (abbreviated  version).   D.  Uznadze  Institute 
of  Psychology,  Academy  of  Sciences  of  the  Georgian  S.S.R.,  Tbilisi, 
U.S.S.R. ,  in  press. 

Shakow,  D. :  Some  dilemmas  in  psychology.  Festschrift  in  honor  of 
A.  D.  Zurabashvili .   Academy  of  Sciences  of  Georgian  S.S.R. ,  Tbilisi, 
U.S.S.R. ,  in  press. 


Serial  No.  M-OD-SW-1 

1.  Office  of  the  Director,  DCBR 

2<,  Section  on  Social  Work 

3.  Bethesda,  Maryland 


PHS-HSMHA-4JIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 


Project  Title:  Conflict  between  the  Parents  of  Schizophrenics 
Principal  Investigator;  Carol  F.  Hoover,  Social  Worker 

Cooperating  Units;  Sections  on  Psychiatric  Assessment,  Family  Studies  and 

Personality  Development  in  Adult  Psychiatry  Branch,  DCBR. 
Center  for  Population  Research,  National  Institute  of 
Child  Health  and  Development. 

Man  Years; 

Total:  .5 
Professional;  .3 
Other ;        . 2 

Project  Description; 

Objective;  To  Investigate  levels  of  marital  conflict,  acknowledged 
anger  and  styles  of  coping  with  disagreement  characteristically  reported  by 
the  parents  of  schizophrenics,  as  compared  to  parents  of  maladjusted  and 
parents  of  community  young  people.  Conflict  over  children,  particularly 
index  patient  coiq>ared  to  his  siblings  and  to  the  offspring  of  community 
families,  is  a  particular  focus.  Marital  dominance  and  perceived  couple 
interaction  are  also  studied. 

Method  Employed:  A  70-itera  card  sort  is  administered  to  each  couple 
on  two  separate  occasions  a  week  apart.  This  procedure  is  scored  to  Indicate 
conflict  ratio  and  coping  mechanisms.  Marital  disagreements  which  Involve 
particular  children  are  also  reported. 

Major  Findings;  A  total  of  154  individuals  have  been  tested,  either 
at  the  N.I.M.H.  or  their  own  homes.  These  Include  30  couples  from  the 
community,  located  through  city  directories,  25  couples  with  maladjusted 
children,  and  22  couples  who  have  schizophrenic  offspring  hospitalized  at 
the  N.I.M.H.  or  elsewhere  in  the  area.  Each  of  these  parent  couples  has  two 
or  more  children  between  the  ages  of  13  and  27. 

Data  from  this  group  of  subjects  is  now  being  prepared  for  analysis. 


Serial  No.  M-AP(C)-ltt..l 

1.  Adult  Psychiatry  Branch 

2.  Office  of  the  Chief 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  20,  1972 

Project  Title;  Conceptiialization  and  Dimensional  Evaluation  of  Schizophrenia. 

Principal  Investigators;  Lyman  C.  Wynne,  M.D.,  Ph.D.,  Margaret  T.  Singer,  Ph.D., 

and  John  Strauss,  M.D. 

Other  Investigators;  Helm  Stierlin,  M.D.,  Ph.D.j  Winfield  Scott,  Ph.D.; 

Margaret  Toohey;  T.  W.  Carpenter,  M.D.;  Monte  Buchsbaum, 
M.D.  (Laboratory  of  Psychology);  John  Bartko,  Ph.D. 
(Biometry  Branch). 

Cooperation  Units;  World  Health  Organization,  Geneva,  Switzerland;  Spring  Grove 
State  Hospital,  Maryland;  Prince  George  County  General 
HospiteuL;  Laboratory  of  Psychology;  Division  of  Computer 
Research  and  Technology,  Biometry  Branch. 

Man  Years  (not  included  in  cooperation  pro^jects); 

Total ;  . 5 
Professional;  .3 
Other;         .2 

Project  Description; 

Objectives;   (l)  This  project  aims  to  conceptualize  major  features  of 
schizophrenic  disorders  along  continua  or  dimensions  in  such  a  vay  that  patients 
can  be  evaluated  on  the  basis  of  data  obtained  and  compared  from  (a)  symptom- 
oriented  research  interviews  and  rating  scales  (see  M-AP  C)-l6-l;  -l6-2); 
(b)  individual  research  interviews  oriented  to  formal  or  stylistic  variables 
especially  thought  disorder;   (c)  psychotherapeutic  work  with  schizophrenics 
and  their  families  (see  M-AP(C)-15-lt );   (d)  interviews  and  records  about 
pre-morbid  history,  kind  of  onset,  and  type  of  course  of  illness,  especially 
thought  disorder;   (e)  projective  test  scorings  and  evaluations  (see  M-AP(C) 
-ll*-2;  -llt-5);   (f)  scores  from  tests  of  sensory,  perceptual,  congitive  and 
psychophysiological  variables  (see  M-AP(C)-21-52) . 

(2)  To  apply  these  various  methods  to  patients  from  (a)  a  variety  of 
cultures;  (b)  a  variety  of  social  class,  educational  and  occupationsuL  back- 
grounds; (c)  a  variety  of  families,  and  to  study  how  these  social  variables 
do  and  do  not  affect  the  individual  features  of  the  various  forms  of  schizo- 
phrenic disorder. 


4 


Serial  No.  M-AP(C)-14-1 

Broadly  speaking,  this  project  draws  upon  and  helps  to  integrate  data 
concerning  schizophrenia  obtained  in  a  number  of  projects  in  the  Branch  and  is 
especially  concerned  with  developing  improved,  more  comprehensive  concepts  and 
theories  of  schizophrenia.   Especially  relevant  are  M-AP(C)-14-2,  3,  5,  6;  16- 
1,  4;  21-2,  4. 

Me thod s  Emp loyed ;   Work  is  continuing  on  the  conceptualization  and 
definition  of  a  series  of  dimensions  to  which  a  variety  of  rating  scales  and 
test  measures  can  be  applied.   These  dimensions  fall  into  five  main  clusters: 
f^)    arousal,  including  alertness,  energy  level,  and  volitional  and  affective 
states;  (2)  selectively  with  which  attention  is  focused,  irrelevant  stimuli 
are  excluded;  (3)  transactional  sharing  of  foci  of  attention  in  which  two  or 
more  persons  look  at  the  same  events,  ideas,  or  feeling  states  together,  with 
differences  along  the  dimensions  of  (a)  active  (doing)  versus  passive  (under- 
going) ways  of  relating  to  other  persons  and  stimuli,  and  (b)  variations  in 
emotional  closeness  and  distance;  (4)  organization  of  the  boundaries  and  con- 
tents of  the  person's  sense  of  self  and  sense  of  identity;  and  (5)  patterns  of 
variations  in  the  above  features  through  time  in  major  or  segmental  "sets." 
The  specific  methods  used  are  described  in  the  various  projects  listed  above 
which  are  brought  together  for  purposes  of  conceptualization  and  theory  for- 
mation in  this  project. 

A  major  activity  currently  under  way  is  to  develop  procedures  for  com- 
puterized analysis  of  the  various  kinds  of  data  which  have  been  generated. 
Data  have  been  obtained  from  over  1,000  subjects  in  various  forms;  most  of  this 
has  now  been  coded  into  complex  computerized  data  files. 

Maj or  Findings :   As  data  analysis  is  being  completed,  the  formulation 
and  publication  of  findings,  concepts,  and  theory  are  actively  in  progress.  A 
number  of  types  of  publications,  both  brief  and  lengthy,  are  being  organized 
and  edited  for  publication. 

Significance  to  Mental  Health  Research;   The  systematic  evaluation  of 
schizophrenic  symptoms  and  processes  is  a  fundamental  necessity  for  further 
progress  in  this  major  area  of  psychiatry.   This  research  program  endeavors 
to  bring  together  experimental  and  clinical  approaches  and  to  apply  these  to 
a  variety  of  patients  from  different  backgrounds.  Too  often  in  the  past, 
sophisticsted,  experimental  approaches  have  been  related  onlv  to  highly  unsyste- 
matic and  vague  clinical  evaluations,  and  only  one  or  two  variables  of  patients 
have  been  studied  in  most  research  programs  on  schizophrenics.   For  background 
may  be  included  in  a  given  study.   This  piecemeal  approach  to  the  study  of  schi- 
zophrenics has  led  to  many  seeming  contradictions  in  findings  and  in  concepts 
which  are  difficult  or  impossible  to  resolve  because  the  data  obtained  are  not 
comparable  from  one  study  to  the  next.   The  present  nroject  is  conceived  as  a 
long-term  program  for  developing  assessment  methods  to  a  higher  level  of  refine- 
ment and  reliability  than  is  presently  available,  and  to  increase  the  effort  to 
apply  and  concentualize  these  methods  in  relation  to  a  broader  spectrum  of  pati- 
ents.  These  methods  of  data  collection  lend  themselves  to  computerized  data 
processing  which  permit  the  asking,  and  answering,  of  many  research  questions 
previously  inaccessible  to  investigation. 


Serial  No.  M-AP(C)-14-l 


Proposed  Course  of  Project;   The  data  for  this  work  are  essentially 
in  hand,  although  it  would  be  desirable  to  continuing  with  the  follow-up  of 
some  patients  and  families;  collaboration  in  this  follow-up  and  in  some  aspects 
of  data  analysis  and  writing  -up  of  the  work  will  continue  during  the  coming 
year.   However,  this  extensive  program  is  now  basically  completed.   Each  aspect 
of  the  project  will  be  of  groups  both  within  the  Branch  program  and  outside 
the  Branch,  as  in  the  WHO  International  Pilot  Study  of  Schizophrenia  (see  M- 
AP(C)-16-1).   The  current  emphasis  is  on  multivariate  computerized  analysis  of 
the  large  amount  of  diverse  data  which  have  been  assembled.   The  concepts  and 
findings  in  this  program  are  being  assembled  for  publication  in  book  form. 

Publications: 

(1)  Wynne,  L.C.:   The  Injection  and  Concealment  of  Meaning: 
Difficulties  in  achieving  consensual  validation  in  the  familial  and  Psycho- 
therapeutic Relationships  of  Schizophrenics.   Presented  at  the  fourth  Inter- 
national Sjrmposlum  on  the  Psychotherapy  of  Schizophrenia,  Turku,  Finland, 
August  6,  1971;  to  be  published  by  Excerpta  Medica,  Amsterdam,  1972. 

(2)  Wynne,  L.C.:  Emerging  Trends  in  Family  Research  on  Schizophrenia, 
in  M.  Katz,  R.  Littlestone,  L.  Mosher,  H.  Tuma,  and  M.  Rooth  (eds.):  Schizo- 
phrenia:  Implications  of  Research  for  Treatment  and  Training,  N.Y.:   Basic 
Books,  1972. 


Serial  No.  M-AP(C)-14-2 

1.  Adult  Psychiatry  Branch 

2.  Office  of  the  Chief 

3.  Bethesda,  Mairyland 

PHS  -HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:   Principles  for  Scoring  Communication  Defects  and  Deviances  of 
Parents  of  Schizophrenics  in  Psychological  Test  Transactions. 

Principal  Investigators:   Ljmian  C  Wynne,  M,D.,  Ph.D.  and  Margaret  T.  Singer, 

Ph.D. 

Other  Investigators:  Winfield  Scott,  Ph.D.;  John  Bartko,  Biometry  Branch,  NIMH; 
Margaret  Toohey. 

Cooperating  Units :   Section  on  Twin  and  Sibling  Studies,  APB;  Biometry  Branch, 

NIMH;  MRC  Social  Psychiatry  Unit,  Maudsley  Hospital,  London. 

Man  Years : 

Total:  2.0 
Professional:  1.1 
Other :         0.9 

Project  Description: 

Objectives :   To  apply  previously  developed  theories  about  parental  communi- 
cation for  evaluating  protocols  of  psychological  test  transactions   to  pinpoint 
selectively  certain  features  of  parental  behavior  which  can  be  reliably  and 
quite  quickly  scored  from  psychological  tests,  particularly  the  Rorschach,  TAT, 
and  Object  Sorting  tests;  to  evaluate  inter-rater  reliability  using  the  scoring 
manuals;  and  to  evaluate  the  effectiveness  with  which  the  scoring  manuals  can 
be  used  to  differentiate  parents  of  psychiatrically  different  offspring. 

Methods  Employed:   In  previous  studies,  l^nne  and  Singer  have  developed  a 
series  of  principles  for  evaluating  the  forms  in  which  persons  engage  and  com- 
municate in  interpersonal  relationships;  parental  styles  of  communicating  in 
standardized  situations  are  hypothetically  linked  to  the  occurrence  and  form 
of  schizophrenic  disorders  in  offspring.   Wynne  and  Singer  have  hypothesized 
that  communication  problems  of  parents  could  affect  the  development  of  core  ego 
functions  which  are,  in  fact,  impaired  in  schizophrenics,  including,  most  im- 
portantly, defects  and  deviances  in  the  manner  in  which  foci  of  attention  are 
shared.   These  problems  lead  directly  into  a  variety  of  other  schizophrenic 
difficulties  in  such  areas  as  the  use  of  language,  task  orientation  and  inter- 
personal relations . 

In  evaluating  these  hypotheses ,  psychological  test  materials  have  been 
evaluated  in  ways  quite  different  from  their  traditional  use.   The  emphasis  in 
the  present  approach  is  to  regard  these  test  protocols  as  "interpretive  trans- 


11 


Serial  No.  M-AP(C)-14-2 

actions"  in  which  they  are  considered  samples  of  communication  obtained  in  a 
relatively  standardized  way  in  which  the  how  (form)  aspects  are  given  more 
emphasis  than  the  what  (content)  aspects  of  attending  and  communicating.   Par- 
ental junctioning  in  test  transactions  is  studied  with  the  viewpoint  that  the 
forms  of  this  functioning  (not  the  content)  have  certain  counterparts  in  daily 
parental  roles  with  the  growing  child,  namely,  showing  the  child  (or,  in  the 
test  situation  of  the  individual  Rorschach,  the  tester-listener)  where  to  look, 
what  it  is  he  is  to  try  to  understand  with  the  parent,  and  how  he  demonstrates   ( 
his  or  her  overall  roles  as  a  reasoning,  communicating  person.   The  tests  were 
used  to  infer  the  effect  the  parent  has  on  the  other  person  transacting  with 
him  or  her,  and  to  analyze  how  the  parent  shares  or  fails  to  share  a  focus  of 
attention  with  another  person. 

The  scoring  manuals  have  been  designed  for  use  with  the  Object  Sorting 
test,  individual  Rorschach  and  TAT.   It  is  necessary  that  records  of  subject- 
tester  transactions  be  as  nearly  verbatim  as  possible.   In  the  Rorschach  scoring 
manual  there  are  three  main  clusters  of  categories  which  are  scored:   closure 
problems,  disruptive  behavior,  and  peculiar  perception  and  verbalization.  Under 
these  main  headings  there  are  41  specific  categories  which  can  be  used  to  score 
each  response  in  the  Rorschach.   Similarly,  somewhat  different  categories  have 
been  applied  to  TAT  protocols  and  Object  Sorting  test  protocols. 

Rorschach  data  from  a  sample  of  239  families  (731  individuals)  have  now 
been  analyzed  with  this  scoring  procedure.   One  hundred  and  fifteen  families 
were  tested  in  Bethesda  in  the  APB  program  plus  25  pairs  of  parents  tested 
earlier  by  Wender  and  Rosenthal  (biologic  and  adoptive  parents  of  schizophrenics 
and  adoptive  parents  of  normals),  40  in  London,  and  59  in  Houston.   In  this 
sample,  a  diagnostic  diversity  of  patients  of  both  sexes  was  included,  as  well 
as  considerable  social  class  and  education  variability.   In  the  Bethesda  samples, 
each  parent  and  offspring  was  given  a  psychiatric  diagnosis  so  that  communica- 
tion deviance  scores  and  diagnosis  could  be  compared  for  each  individual  and 
for  parents  compared  to  offspring.   Sub-groups  of  families  have  been  parcelled 
out  for  special  study.   This  approach  has  been  facilitated  by  computerization 
of  the  data  (see  M-AP(C)-14-1)  factor  analyses,  multiple  regression  analyses, 
and  a  stepwise  multiple  discriminant  analysis  of  the  data  have  been  carried 
out  in  order  to  assess  the  significance  of  various  demographic  and  clinical 
variables  and  the  relative  importance  in  various  discriminations,  of  the  par- 
ticular categories  in  the  scoring  manual. 


i 


Major  Findings :  A  high  degree  of  inter-rater  reliability  was  achieved  in 
using  the  Rorschach  scoring  system.   All  protocols  were  scored  entirely  blindly, 
without  any  information  about  the  diagnosis  or  relationships  of  any  subject 


The  central  research  hypothesis  was  decisively  confirmed:  in  these  intact 
families,  the  frequency  of  communication  deviances  of  parents  was  significantly 
related  to  the  severity  of  psychiatric  illness  in  the  offspring,  and  when  other 
variables  are  held  constant  statistically  this  relationship  remains.  A  large 
number  of  new  findings  are  emerging  from  these  data  analyses  and  are  being  pre- 
pared for  publication.  Especially  noteworthy  is  the  finding  that  the  diagnosis 
of  the  offspring  in  all  25  families  tested  by  Wender  and  Rosenthal  were  correctly 


i 


I 


12 


Serial  No.  M-AP(C)-14-2 

identified  from  parental  Rorschachs ,  including  all  nine  offspring  who  were 
adoptive  schizophrenics. 

Significance  for  Mental  Health  Research:   This  work  has  developed  systema- 
tic, reliable  scoring  methods  which  are  simple  enough  to  be  used  by  relatively 
untrained  raters,  but  which  make  significant  differentiations  of  parental  be- 
havior.  The  scoring  methods  have  been  directly  derived  from  a  comprehensive 
theory  of  psychological  development  within  the  family  context  which  has  been 
described  in  detail  in  a  series  of  papers . 

Proposed  Course  of  Project:   The  concepts  and  findings  in  this  study  are 
being  reported  in  a  series  of  papers  and  in  book  form.   The  multivariate  analy- 
ses of  the  data  is  in  its  final  stages.   The  scoring  procedure  and  manuals  are 
being  modified  on  the  basis  of  the  findings  in  the  present  study.   The  scoring 
procedure  will  then  be  applied  to  new  samples  of  parents  of  different  diagnos- 
tic, educational,  social,  and  cultural  backgrounds  to  discover  what  the  limits 
of  these  procedures  are  as  a  predictive  and  screening  device,  applicable  to 
the  identification  of  "high-risk"  versus  "low-risk"  subjects.   Also,  the  proce- 
dure is  being  used  with  various  special  families  such  as  adoptive  families  with 
families  with  and  without  a  schizophrenic  offspring.   Such  work  will  be  valuable 
in  elucidating  the  genetic  versus  the  "learning"  aspects  of  schizophrenic  dis- 
orders.  One  study  is  currently  in  progress  in  V7hich  the  Rorschach  scoring 
manual  is  also  being  applied  to  a  sample  of  parents  of  Japanese  schizophrenics 
(see  M-AP(C)-14-3). 

Publications : 

1.  Wynne,  Lyman  C.  and  Singer,  M.  T. ,  Schizophrenics  and  their  Families: 

II.  Research  Methods,  Brit.  J.  of  Psychiatry,  1972,  in  press. 

2.  Wynne,  Lyman  C.  and  Singer,  M.  T. ,  Schizophrenics  and  Their  Families: 

III.  Recent  Rorschach  Communication  Findings,  Brit.  J.  Psychiatry, 
1972,  in  press . 


13 


I 


Serial  No.  M-AP(C)-14-3 

1.  Adult  Psychiatry  Branch 

2.  Office  of  the  Chief 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   Cross -Cultural  Family  Studies 

Principal  Investigators :  Lyman  C.  Wynne,  M.D.,  Ph.D.  and  Margaret  T.  Singer, 

Ph.D. 

Other  Investigators :  Mieko  Caudill ;  Dr.  Kenji  Sakamoto,  Kyoto  University 

Medical  School,  Kyoto,  Japan;  Dr.  Y.  Kasahara,  Psychiatry 
Clinic,  Kyoto  University,  Kyoto,  Japan;  Dr.  S.  Kuromaru, 
Kobe  Medical  School,  Kobe,  Japan  Dr.  William  Caudill, 
Laboratory  of  Socio -Environmental  Studies. 

Cooperating  Units :    Kyoto  University  Medical  School,  Kyoto,  Japan;  Sakamoto 
Psychiatric  Hospital,  Osaka,  Japan;  Psychiatric  Clinic, 
Kyoto  University,  Kyoto,  Japan;  Kobe  Medical  School, 
Kobe,  Japan;  Section  on  Personality  and  Environment, 
Laboratory  of  Socio-Environemntal  Studies,  NIMH. 

Man  Years 


Total:  .6 

Professional:     .4 
Other:  .2 

Project  Description: 

Objectives :   To  determine  whether  criteria  for  differentiating  families 
of  schizophrenics  and  other  kinds   of  families  apply  cross -culturally  and  thus 
have  generalized  validity;  to  specify  features  of  schizophrenics  and  their 
families  which  are  and  are  not  cross -culturally  general;  to  study  how  varia- 
tions in  the  sibling  order  of  schizophrenics  are  related  to  cultural  patterns 
of  family  life. 

Methods  Employed:   Clinical  data  and  psychological  tests  have  been 
obtained  from  a  sample  of  normal  control  families  and  families  of  schizophrenics 
in  Japan,  and  earlier,  in  Lebanon. 

This  year  emphasis  was  placed  on  examination  of  the  Japanese  data. 
Psychological  test  protocols  have  been  received  from  families  of  50  late 
adolescent  and  young  adult  Japanese  psychiatric  patients  and  from  the  parents 
of  20  childhood  psychiatric  patients  and  normal  controls.   These  Japanese 
protocols  are  being  translated  and  scored  by  Mrs.  Mieko  Caudill,  a  native 
Japanese,  with  the  manual  described  in  M-AP(C)-14-2 ,  with  the  translated 
protocols  also  studied  by  Dr.  Margaret  T.  Singer. 


15 


Serial  No.  M-AP(C)-14-3 

This  year  special  attention  has  been  given  to  a  detailed  examination 
of  the  problems  of  translating  communication  samples,  as  found  in  verbatim 
Rorschach  records,  from  Japanese  to  English  and  vice  versa.   This  study, 
conducted  with  investigators  from  both  countries  revealed  much  about  the 
latent  value  assumptions  and  implicit  communication  processes  in  both 
cultures.   Extensive  discussions  were  also  carried  out  on  the  problems  of       J 
achieving  diagnostic  comparability  on  Japanese  and  American  patients.  U 

tfajor  Findings:  The  project  is  still  in  progress.   The  preliminary 
findings  indicate  that  the  scoring  manuals  developed  in  the  NIMH  research  can 
be  used  with  these  highly  diverse  psychological  test  samples  obtained  in  Leba- 
non and  Japan.   Two  papers  on  the  special  problems  of  conducting  family  therapy 
with  large,  extended  families  in  a  non-Western  cultural  setting  (Lebanon)  have 
been  prepared . 

Significance  to  Mental  Health  Research:   The  cross-cultural  approach 
will  very  greatly  strengthen  the  significance  of  the  findings  concerning  the 
families  of  schizophrenics  which  have  been  obtained  from  American  samples  in 
the  Adult  Psychiatry  Branch  program.   The  patient-family  links  which  have  been 
studied  in  this  research  are  concerned  with  forms  of  thinking  and  communicating, 
rather  than  the  content  of  thinking,  so  that,  theoretically,  the  methods  of 
scoring  should  be  applicable  regardless  of  cultural  background  or  other 
variables  if  there  are  characteristic  forms  in  which  families  of  schizophrenics 
related  and  live  with  one  another.   Because  of  translating  and  other  difficulties 
there  have  been  questions  raised  in  many  quarters  whether  psychological  tests    f 
and  interview  materials  can  be  meaningfully  compared  cross -culturally .   The 
present  study  indicates  that  such  work  is  practicable,  if  certain  procedures 
and  standards  are  used  in  translating  and  in  obtaining  the  original  protocols , 
but  scrutiny  of  the  translating  problems  is  valuable  in  its  own  right  because 
it  facilitates  understanding  of  cross-cultural  differences. 

Proposed  Course  of  Project:   Data  collection  in  Japan  by  Drs .  Sakamoto, 
Kasahara,  and  Kuromaru  in  Japan  is  almost  complete.   Interpretation  of  the 
findings,  completion  nf  publications  on  methodologic  and  substantive  findings, 
and  further  planning  of  the  collaborative  work  is  in  progress. 

Publications : 

(1)  Wynne,  L.C.,  Caudill,  M.  ,  Kasahara,  Y.  ,  Kuromaru,  S.,  Higa,  M.  , 
and  Singer,  M.T. :  Problem  in  the  Cross-cultural  Study  of  Psychopathology : 
A  Comparison  of  Japanese  and  American  Disorders  of  Thinking  and  Communication. . 
Lebra,  W.  (ed.):  Mental  Health  Research  in  Asia  and  the  Pacific,  Honolulu:      j 
East-West  Center  Press,  in  press,  1972.  ''I 


16 


Serial  No.  M-AP(C)  14-8 

1.  Adult  Psychiatry  Branch 

2.  Office  of  the  Chief 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:  A  Study  of  the  Separation  Process  in  Adolescents  and  Their 
Families 

Previous  Serial  Number:  M-AP(C)-15-2 

Principal  Investigator:   Helm  Stierlin,  M.D.,  Ph.D. 

Other  Investigators:   Stanley  I.  Hirsch,  Richard  M.  MacDonald,  M.D.,  Kent 
Ravenscroft.  Jr.,  M.D.,  Robert  J.  Savard,  Ph.D., 
Miss  Elizabeth  Sherwood,  John  S.  Strauss,  M.D.,  and 
Lyman  C.  Wynne,  M.D.,  Ph.D. 

Cooperating  Units:  Section  on  Clinical  Psychology;  Section  on  Perceptual 
and  Cognitive  Studies;  Section  on  Psychiatric  Assess- 
ment (Adult  Psychiatry  Branch,  NIMH). 

Man  Years: 

Total:  7.3 
Professional:  5.5 
Others:        1.8 

Project  Description: 

Objectives; 

The  basic  objectives  of  this  study  have  remained  the  same  as  stated  in  the 
report  of  last  year:   To  investigate,  at  the  clinical  and  research  levels, 
the  individual  and  family  factors  which  may  further  or  jeopardize  the  separa- 
tion process  throughout  adolescence.   By  tapping  a  large  available  reservoir 
of  students  with  school  problems,  the  study  makes  use  of  an  adolescent  high 
risk  population  who,  over  the  following  five  years,  will  or  will  not  develop 
either  in  a  psychotic  or  sociopathic  direction.   Understanding  and  possibly 
differentiating  the  separation  course  of  these  two  patient  groups  is  the 
main  goal.   This  includes  a  grasp  of  these  patients'  family  and  peer  rela- 
tions as  they  unfold  in  time.   The  project  builds  on  many  of  the  findings 
which  Drs.  Lyman  C.  Wjmne  and  Margaret  T.  Singer  and  their  associates  have 
reported  during  the  last  decade.   It  addresses  itself  now  to  experimential 
factors  which  may  allow  certain  high  risk  adolescents  to  steer  clear  of 
serious  psychopathology  while  causing  others,  of  seemingly  equal  or  even 
lower  risk,  to  succumb  to  such  psychopathology. 


17 


Serial  No.  M-AP(C)  14-8 

Within  the  framework  of  this  broad  objective,  the  study  tries  further  to 
throw  light  on  several  specific  related  issues.   These  are: 

(a)  Parental  perceptions  and  expectations  which  specifically  bear  on  their 
children's  separation,  e.g.  their  ability  and  willingness  to  seek  partners 
outside  the  family  or  to  take  on  responsible  jobs.   We  have  become  increas- 
ingly impressed  with  the  .importance  of  such  perceptions  as  factors  which 
either  inhibit  or  promote  their  children's  moves  toward  autonomy. 

(b)  The  individual  and  family  dynamics  of  runaway  adolescents.   Twenty- 
six  out  of  37  index  adolescents  seen  in  this  project  had  run  away  from  home 
at  least  one  full  day  and  night,  before  they  had  turned  17  (some  of  them 
have  run  away  frequently,  getting  as  far  away  as  Florida,  California,  and 
Canada).   The  project  offered  a  unique  chance  to  study  in  depth  this  group 
of  runaways. 

(c)  The  often  divergent  developmental  course  of  siblings  who  appear  close 
in  age  and  who  at  first  sight,  appear  exposed  to  similar  family  influences. 

(d)  The  sequela  of  an  early  precocious  and  overstimulated  development. 

(e)  Psychological  and  perceptual  sequelae  of  teenage  drug  abuse. 

(f)  The  potential  problems  and  limits  inherent  in  various  treatment 
approaches-but  mainly  individual, couple — and  family  therapy — as  used  during 
a  crucial  juncture  in  an  adolescent's  life  and  separation  process. 

(g)  The  impact  of  the  adolescent's  separation  on  the  parent's  image  and  life 
style. 

(h)   The  role  of  the  peer  group  in  facilitating  or  hindering  the  adolescent's 
growth  and  separation. 

An  additional  number  of  families  were  seen  in  screening  sessions  only. 
These  families,  too,  were  made  subject  to  predictions  so  that  they  could  be 
followed  up  and  could  serve  as  untreated  controls  to  the  treated  index 
patients  and  families. 

No  new  families  were  admitted  during  the  last  year  and  the  major  focus 
shifted  to  the  final  follow-up  interviews  carried  out  by  Drs.  Stierlin  and 
Savard.   So  far,  approximately  twenty  of  the  follow-up  interviews  have  been 
carried  out,  most  of  them  in  the  families'  homes.   In  these  interviews, 
index  patients,  siblings  close  in  age,  and  the  two  parents  were  seen  for 
approximately  50  minutes  each.   The  asessments  directed  to  them  covered 
the  areas  of  earlier  made  predictions.   Following  these  individual  follow-up 
xnterviews,  all  family  members  were  asked  to  listen  to  excerpts  from  audio 
or  (.when  available)  video-tapes  made  at  earlier  conjoint  family  sessions 
and  dating  back  up  to  five  years. 


18 


Serial  No.  M-AP(C)-14-8 

Methods  Employed: 

Adolescents  of  age  15  and  16  who  attend  public  schools  in  Montgomery  County 
(Maryland)  supplied  the  bulk  of  our  patient  material,  in  addition  to  those 
referred  to  us  by  private  psychiatrists  and  various  social  and  psychiatric 
agencies.   The  various  referral  sources  sent  us  adolescents  who  demonstrated 
school  problems  and  whose  families  appeared  willing  to  engage  in  family 
therapy.   It  was  assumed  that  these  students  represented  a  high  risk  popula- 
tion both  in  the  direction  of  schizophrenia  and  in  the  direction  of  socio- 
pathic  development.   Mostly  unbroken  families  were  accepted.   At  the  initial 
screening  appointment,  the  family  was  seen  as  a  group  for  50  minutes  and  then 
the  couple  and  designated  patient  were  seen  each  for  one-half  hour.   If  the 
family  qualified  and  was  willing  to  participate  in  the  treatment  and  research 
project,  the  patient  was  admitted  to  Unit  3-West  where  he  received  or  still 
receives  individual  psychotherapy,  usually  three  times  a  week.   The  family 
was  seen  in  once-  or  twice-weekly  family  therapy  sessions.   Couple  therapy 
once  a  week  became  mandatory.   Individual  psychotherapy  for  family  members 
was  offered  when  necessary  and  feasible.   On  the  ward,  the  intensive  therapy 
of  the  individual  adolescent  was  supplemented  by  an  intensive  milieu  program. 
No  time  limits  were  set  to  the  individual  or  family  treatment  except  for 
those  dictated  by  the  lengths  of  the  therapists'  stay  at  NIl-lH. 

After  the  first  screening  interview  the  available  historical,  social,  and 
dynamic  data  about  the  family  were  summarized  and  a  fairly  detailed  predic- 
tion was  made  about  the  index  patient.   This  prediction  included  ten  major 
items  such  as  employment  in  five  years,  psychiatric  contacts  and  diagnoses, 
suicidal  tendencies,  delinquent  tendencies,  etc.   The  ensuing  family  and 
individual  therapy  was  then  used  to  obtain  a  more  comprehensive  picture  of 
the  family  dynamics  as  they  bore  on  the  adolescent's  separation  problem  and 
further  development.   The  following  areas  were  carefully  observed  and 
assessed: 

(1)  The  prevailing  parental  perceptions  and  expectations,  particularly 
insofar  as  these  bear  on  the  adolescent's  separation. 

(2)  All  data  pertaining  to  runaway  episodes  of  adolescents,  e.g.  overt  or 
covert  parental  encouragement,  the  context  of  the  running  away  episode, 
antecedents,  peer  contacts,  etc. 

(3)  The  communication  patterns  within  the  family.   We  tried  to  establish  how 
much  each  family  was  bound  to  sabotage  a  pooling  of  resources. 

(4)  The  nature  of  the  family's  alignments,  their  relative  shifts  and  incon- 
sistencies, their  strengths,  and  their  overt-  or  covertness. 

(5)  Family  boundaries.   We  tried  to  assess  how  the  family  is  integrated  within 
the  community  and  how  much  it  might  put  obstacles  in  the  way  of  the  adoles- 
cent's associating  with  peers,  teachers,  and  other  figures  outside  the  family. 


19 


Serial  No.  M-AP(C)-14-8 

(6)  Patterns  of  psychological  exploitation:   The  various  ways  in  which  a  child 
(more  or  less  covertly)  was  recruited  to  serve  his  parents  in  ways  which  inter- 
fered with  his  own  growth  and  separation. 

(7)  We  tried  to  be  alert  to  all  data,  implicit  and  explicit,  which  could 
throw  light  on  the  parents'  roles  in  the  adolescent's  separation  and,  in  par- 
ticular, on  their  own  separation  problems  when  they  were  adolescents 
themselves. 

(8)  Through  an  actively  and  empathically  conducted  family  therapy,  we  tried 
to  get  an  indication  of  how  much  the  family  might  be  capable  of  changing  its 
patterns  and  thereby  facilitate  the  adolescent's  separation.   Also,  by  focus- 
ing on  the  evolving  transferences,  we  tried  to  get  further  clues  about  the 
parents'  own  separation  problems. 

On  the  basis  of  these  assessments,  which  were  supplemented  by  an  individual 
interview  with  each  family  member,  we  made,  at  the  end  of  the  treatment 
period,  second  step  predictions  about  the  adolescent's  prospective  life  style 
at  the  age  of  21.   These  predictions  covered  the  same  items  as  those  made 
immediately  after  the  screening  session,  but  they  were  now  amplified.   Also, 
we  supplemented  them  by  a  narrative  kind  of  prediction  which  dealt  with  the 
question  of  how  much  the  index  would  become  restricted  or  nonrestricted, 
active  or  more  passive.   In  cases  where  there  were  two  siblings  closely  re- 
lated in  age,  the  two  of  them  were  covered  by  predictions.   It  was  expected 
that  the  later  confirmation,  partial  confirmation,  or  refutation  of  our  pre- 
dictions would  deepen  our  insights  and  sharpen  our  hypotheses  about  the 
adolescent  separation  process.   The  comparison  between  the  first  step  and 
second  step  predictions,  as  outlined  above,  appeared  as  a  useful  means  of 
alerting  us  to  possible  sources  of  predictive  error  at  this  early  stage  of 
the  research  project. 

While  the  principal  clinical  investigator  tried  to  make  five-year  predictions 
based  on  the  assessment  of  presumably  crucial  and  lasting  family  features,  as 
mentioned  earlier,  additionally  obtained  Rorschach  tests,  TAT,  cognitive  and 
perceptual  style  procedures  of  all  family  members,  as  well  as  the  audio  and 
video  tapes ,  provided  material  for  independent  evaluations  and  predictions 
to  be  made  either  then  or  at  later  stages  of  the  project.   The  availability 
of  these  test  procedures  made  it  further  possible  to  utilize  these  families 
for  other  ongoing  research  projects  of  the  Adult  Psychiatry  Branch,  as 
described  elsewhere. 

Further,  a  standardized  diagnostic  inventory  was  made  in  accord  with  guide- 
lines developed  by  Drs.  John  Strauss  and  Will  Carpenter  on  all  newly  admitted 
index  patients.   This  should  provide  us  with  a  further  means  to  check  out 
(subjectively  tinged)  dynamic  family  data  against  other  independently  obtained 
and  more  standardized  data. 

Altogether  37  index  patients  and  their  families  have  so  far  been  included  in 
the  program.   An  additional  number  of  families  were  seen  in  screening  sessions 
only.   These  families,  too,  were  made  subject  to  predictions  so  that  they 


20 


Serial  No.  M-AP(C)-14-8 

could  be  followed  up  and  could  serve  as  untreated  control  to  the  treated 
index  patients  and  families. 

No  new  families  were  admitted  during  the  last  year  and  the  major  focus  shifted 
to  the  final  follow-up  interviews,  carried  out  by  Drs.  Stierlin  and  Savard. 
So  far,  approximately  twenty  of  the  follow-up  interviews  have  been  carried 
out,  most  of  them  in  the  families'  homes.   In  these  interviews,  index  patients, 
siblings  close  in  age,  and  the  two  parents  were  seen  for  approximately  fifty 
minutes  each.   The  questions  and  assessments  directed  to  them  covered  the 
areas  of  earlier  made  predictions.   Following  these  individual  follow-up  in- 
terviews, all  family  members  were  asked  to  listen  to  excerpts  from  audio  or 
(when  available)  video  tapes  made  at  earlier  conjoint  family  sessions  and 
dating  back  up  to  five  years. 

The  family  members  were  then  encouraged  to  reflect  together  on  how  the  situa- 
tion conveyed  by  the  tape  excerpt  did  still  exist  and  on  how  they  all  had 
changed  or  not  changed.   In  the  ensuing  discussion  there  emerged  often  items 
and  issues  which  had  not  been  covered  in  the  preceding  individual  follow-up 
interviews . 

Until  now,  five  out  of  the  originally  treated  37  families  have  refused  to  be 
interviewed.   It  is  hoped  that  most  of  the  remaining  families  can  still  be 
interviewed  during  the  current  fiscal  year  so  that  the  senior  investigator 
can  devote  the  major  part  of  the  next  year  to  the  evaluation  of  the  data 
obtained. 

Maj  or  Findings : 

Many  major  findings  cannot  be  expected  before  the  follow-up  data,  just  men- 
tioned, can  be  fully  evaluated.   Nonetheless,  the  following  interesting  find- 
ings have  already  been  noted  and  either  published  or  are  ready  for  publication. 

1.  The  two  major  patterns  in  adolescence,  called  centripetal  and  centrifugal, 
which  were  mentioned  in  last  year's  report,  have  been  further  refined.   With 
an  ongoing  focus  on  these  differing  separation  patterns,  the  conceptual  frame- 
work which  emerged  last  year  was  further  developed.   Crucial  to  this  framework 
is  the  concept  of  transactional  parental  modes  which  all,  albeit  in  different 
ways,  contribute  to  a  distorted  separation  of  adolescent  children.   They 
operate  via  parental  perceptions  and  expectations  but  also  imply  more  basic 
and  mutual  relational  ways  and  styles. 

2.  In  line  with  the  above,  differing  separation  conflicts  of  adolescent  child- 
ren could  be  more  clearly  delineated.   The  differing  implications  for  the 
parent's  and  adolescent's  growth  and  the  resulting  differing  indications  for 
therapeutic  intervention  in  separation  conflicts  have  been  spelled  out. 

3.  The  role  of  parental  perceptions  and  expectations  for  the  development  of 
crucial  identificatory  processes  in  the  adolescent  has  been  further  clarified. 
In  particular,  certain  interpersonal  factors  bearing  on  varying  forms  of  in- 
ternalizations (which  include  incorporations,  introjections ,  and  identifica- 
tions) could  be  systematically  described. 

21 


Serial  No.  M-.\P CC) -14-8 

4.  The  five  different  types  of  runaways  which  were  mentioned  in  last  year's 
report  could  be  more  convincingly  linked  to  characteristic  family  djmamics. 
This  has,  in  turn,  further  illuminated  the  transactions  which  cause  parents 
and  adolescent  children  to  separate  or  not  to  separate. 

5.  Mainly  in  collaboration  with  Dr.  Kent  Ravenscroft  the  adolescent's  family 
dynamics  and  separation  patterns ,  as  above  conceptualized,  have  been  examined 
in  their  relevance  for  the  adolescent's  peer  relations. 

6.  The  above  findings  and  conceptualizations  have  helped  to  clarify  the  family 
dynamics  and  separation  patterns  of  potential  schizophrenics. 

Significance  to  Mental  Health  Research: 

This  study  builds  on  findings  about  the  structures,  communication  patterns, 
and  boundaries  of  families  with  disturbed  offspring  which  have  been  made  in 
the  Adult  Psychiatry  Branch  during  the  past  decade.   With  the  focus  on  longi- 
tudinal development  and  the  separation  process  in  adolescence,  this  study 
tries  to  assess  the  significance  of  various  -  mainly  experiential  -  factors 
in  the  actual  outbreak  of  schizophrenia  and  other  disturbances  during  late 
adolescence,  a  period  which  is  known  to  be  fateful  in  an  individual's  per- 
sonality development  and  which  yields  a  high  percentage  of  first  schizophrenic 
breaks.   The  new  focus  on  runaways  appears  commensurate  with  the  increasing 
social  importance  of  this  patient  group. 

In  the  present  study,  family  therapy  is  used  as  a  diagnostic  instrument.   At 
the  same  time,  it  is  tried  out  as  a  possibly  efficient  and  most  economic  tool 
in  the  prevention  of  the  major  disasters  of  late  adolescence, 

Proposed  Course  of  Project: 

A  major  effort  is  now  being  made  to  finish  up  the  follow-up  interviews  on 
the  approximately  forty  families  who  have  passed  through  this  project.   After 
these  data  have  been  obtained,  it  is  hoped  that  the  project  can  be  completed 
within  the  next  fiscal  year. 

Honors  and  Awards : 

Stierlin,  H. :   "Family  Djmamics  and  Separation  Patterns  of  Potential  Schizo- 
phrenics." Paper  presented  at  the  IVth  International  Symposium  on 
Psychotherapy  of  Schizophrenia,  Turku,  Finland,  August  6,  1971. 

By  invitation,  participated  (via  extemporaneous  lectures)  in  the  Seminar  on 

Family  Therapy,  sponsored  jointly  by  the  Danish  Psychological  Association, 
Danish  Psychoanalytic  Society,  and  the  Danish  Psychiatric  Society, 
Copenhagen,  Denmark,  August  8-10,  1971. 


22 


Serial  No.  M-AP(C)-14-8 

Publications: 

Levi,  L.  D. ,  Stierlin,  H. ,  and  Savard,  R.  J.:   Fathers  and  sons:   The  inter- 
locking crises  of  integrity  and  identity.   Psychiatry  35:  48-55,  1972. 

Stierlin,  H. ,  Levi,  L.  D. ,  and  Savard,  R.  J.:   Parental  perceptions  of  separat- 
ing children.   Family  Process  10:  411-427,  1971. 

Silverman,  J.,  Buchsbaum,  M. ,  and  Stierlin,  H. :   Sex  differences  in  perceptual 
differentiation  and  stimulus  intensity  control.   In  press.  Journal  of  Person- 
ality and  Social  Psychology. 

Stierlin,  H. :   Family  dynamics  and  separation  patterns  of  potential  schizo- 
phrenics.  In  press,  Y.  Alanen  (ed.):   Proceedings  of  the  Fourth  International 
Symposium  on  Psychotherapy  of  Schizophrenia,  Excerpta  Medica. 

Stierlin,  H. :   Interpersonal  aspects  of  internalizations.   In  press.  Interna- 
tional Journal  of  Psycho-Analysis. 

Stierlin,  H.,  and  Ravenscroft,  Jr.,  K. :   Varieties  of  adolescent  "separation 
conflicts."   In  press,  British  Journal  of  Medical  Psychology. 


23 


Serial  No.   M-AP(C)-14-9 

1.  Adult  Psychiatry  Branch 

2.  Office  of  the  Chief 

3.  Bethesda,  Maryland 


I 


I 


PHS-HSMHA-NIMR 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 


Project  Title:   The  Conceptualization  of  Lasting  Dyadic  Relationships 

Previous  Serial  Number:   M-AP(C)-15-6 

Principal  Investigator:   Helm  Stierlin,  M.D.,  Ph.D. 

Other  Investigators:   None 

Cooperating  Units :   None 

Man  Years: 

Total:  .3 
Professional:  .2 
Others:        .1 

Project  Description: 

Objectives: 

This  project  seeks  to  contribute  to  the  theoretical  base  for  the  compara- 
tive analysis  of  a  wide  variety  of  human  relationships.   It  grew  out  of 
conceptualizations  which  the  investigator  developed  before  he  joined  the 
Adult  Psychiatry  Branch  six  years  ago  and  which  were  published  in  book 
form  (Conflict  and  Reconciliation.   New  York:   Doubleday-Anchor,  1969; 
New  York:   Science  House,  1969).   The  focus  continues  to  be  on  the  ongoing 
transaction  between  two  persons  who  are  considered  as  subjects  -  that  is, 
as  centers  of  an  individual  orientation  toward  the  self,  the  world,  and 
the  other  -  and  who  are  changed  while  the  relationship  unfolds.   The 
phenomenology  and  dynamics  of  psychological  exploitation  appear  here 
particularly  significant.   The  implications  of  a  dyadic  model  for  the 
better  understanding  of  family  and  group  relationships  are  being  explored. 
Also,  creativity  as  a  response  to  a  binding  and  conflictual  interpersonal 
field  has  been  made  a  special  focus  of  study. 

Methods  Employed: 

Study,  critical  evaluation  and  integration  of  a  wide  range  of  ideas  and 
findings  reported  in  the  literature  of  human  relationships.   At  the  same 
time,  the  project  relies  increasingly  on  the  clinical  experiences  and  ob- 
servations provided  through  the  clinical  service  of  the  Adult  Psychiatry 
Branch  and  particularly  the  ongoing  family  therapies.   Increasingly,  the 


25 


Serial  No.    M~AP(C)"14--9 

issues  raised  and  described  in  Project  M--AP(C)-.14-8  have  influenced  the 
here-described  conceptual  efforts. 

Major  Findings; 

(1)  The  concept  of  psychological  exploitation  has  been  further  developed 
and  clarified  and  has  been  integrated  with  the  concept  of  transactional 
modes.   This  is  then  expected  to  refine  the  conceptual  base  for  an  under- 
standing of  those  separation  vicissitudes  which  are  the  concern  of  Project 
M-AP(C)-14-8  and  which  have  been  describad  there, 

(2)  Various  more  or  less  related  subjects,  mentioned  already  in  the  pre- 
vious report,  have  been  further  worked  on.   These  include  a  paper  on  the 
German  poet  Friedrich  Ho'lderlin  (1770-1848),  who  became  clinically  schizo- 
phrenic in  his  mid-thirties,  a  paper  on  the  quest  for  the  self-actualiza- 
tion of  the  therapist,  and  others. 

Significance  to  Mental  Health  Research: 

This  conceptual  work  is  relevant  to  the  understanding  of  schizophrenia  as 
a  transactional  thought  disorder.   Beyond  that,  it  seeks  to  illuminate 
various  mental  disorders  as  being  linked  to  special  types  of  human  rela- 
tionships.  The  complexities  of  human  relationships,  it  appears,  have  far 
outdistanced  the  conceptualizations  so  far  at  our  disposal.   This  project 
tries  to  reduce  the  conceptual  lag  in  this  area.   The  concept  of  psycho- 
logical exploitation  seems  relevant  to  many  pressing  social  issues. 

Proposed  Course  of  Project; 

The  principal  investigator  is  in  the  process  of  pulling  the  thoughts  and 
themes  developed  under  this  project  into  book  form. 

Honors  and  Awards ;   None 

Publications: 

Stierlin,  H. ;  _  Lyrical  Creativity  and  Schizophrenic  Psychosis  as  Reflected 
in  Friedrich  Holderlin's  Fate„  In  George,  E.  (Ed. ) ;  Holderlin,  The  Early 
Mooern.   Ann  Arbor,  University  of  l^chigan  Press,  in  pTiil^ 

^^'^n^'^^n'."''  ^®  '^^V^ct  of  Relational  Vicissitudes  on  the  Life  Course 
of  One  Schizophrenic  Quadruplet.  In  Kaplan,  A.  (Ed. ) ;  Genetic  Factors 
in  Schizophrenia.   Springfield,  111.,  Charles  C.  Thomas,  1972. 

Stierlin,  H. :   The  Interlocking  Quest  for  Self-Actualization  and  Philoso- 

S;'^i,tr^T'';  ^".^""°-'  ^'    ^Ed.);   Ihe  Self-Actualization  of  the 
Therapist.   San  Francisco,  Jossey-Bass,  in  press. 

Stierlin,  H. ;  "The  Bed  -  Secret  Weapon  of  the  Revolution?"  Book  Review 
|f^Cooper.s^^,e_p^^th^^        P^^^gh^the^  and  Social  Science 

26 


Serial  No.  M-APCC)-14-9 

Stierlin,  H. :   Book  Review  of  A.  Lorenzer's  Destruction  and  Reconstruc- 
tion of  Language.   Accepted  for  publication  in  The  International  Journal 
of  Psycho-Analysis,  and  in  Psyche. 

Stierlin,  H. :   Book  Review:   Some  Comments  on  Reimut  Reiche's  Critique  of 
Charles  Socarides'  The  Overt  Homosexual.   Accepted  for  publication  in 
Psyche. 


27 


Serial  No.  M-AP(C)-15-3 

1.  Adult  Psychiatry  Branch 

2.  Family  Studies  Section 

3.  Bethesda,  Maryland 


PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 


Project  Title:   Evaluation  of  Family  Dynamics  with  Conjoint  Family  Art  Pro- 
cedures 

Previous  Serial  Number:   SAME 

Principal  Investigator:  Hanna  Yaxa  Kwiatkowska 

Other  Investigators:   NONE 

Cooperating  Units:   Section  on  Adolescence  and  The  Family;  Unit  on  Longi- 
tudinal Studies 


Man  Years : 

Total:  - 

0.56 

Professional: 

0.36 

Others: 

0.2 

Project  Description: 

Objectives:  The  purpose  of  the  project  is:  (1)  To  evaluate  families  through 
a  technique  in  which  art  media  are  used  as  a  mode  of  communication  and  self- 
expression  in  order  to  compare  (a)  different  families  in  which  one  or  more  of 
the  offspring  is  afflicted  with  one  of  a  variety  of  mental  illnesses  (schizo- 
phrenic, psychoneurotic,  or  delinquent)  as  well  as  normal  families,  and  (b) 
different  members  within  a  family;  (2)  to  evaluate  through  the  same  technique 
changes  occurring  in  the  course  of  family  psychotherapy  by  repeating  these 
procedures  in  periodic  follow-ups  during  the  treatment  and  after  discharge. 

Methods  Employed:  All  members  of  a  family  are  seen  jointly  in  art  evaluation 
sessions.   The  family  is  introduced  to  easy  art  media  with  no  emphasis  on 
artistic  achievement.   The  structure  of  the  session  combines  spontaneous  self- 
expression  with  standardized  procedures:   (a)  free  picture;  (b)  family  por- 
traits; (c)  abstract  family  portraits;  (d)  individual  pictures  started  with 
the  help  of  a  scribble;  (e)  picture  done  by  the  family  jointly  and  started 
with  the  help  of  a  scribble.   These  procedures  are  d^evised  for  the  comparison 
of  different  families.   The  sessions  are  conducted  by  the  art  therapist  with 
a  cooperating  investigator,  a  psychiatrist  or  other  staff  member  as  partici- 
pant observer.  All  the  sessions  are  tape  recorded,  some  of  them  video  taped 
for  a  better  study  of  family  interaction.  Abstracts  of  all  the  sessions,  des- 
cribing the  families '  transactions,  their  comments  and  discussions  of  their 


29 


Serial  No  M-AP(C)-15-3 


pictures  as  well  as  special  observations  of  the  investigators,  are  dictated 
upon  completion  of  the  session;  the  art  productions  and  tapes  of  the  ses- 
sions are  studied  for  more  accurate  analysis.   Each  family  is  seen  in  a  single 
evaluation  session  as  close  as  possible  after  admission.   Long  term  patients 
and  their  families  are  seen  in  a  second  family  art  evaluation  after  a  minimum 
of  six  months  of  conjoint  family  therapy  or  at  termination  of  treatment. 

The  families  admitted  to  Unit  3  West  continue  to  participate  in  family 
art  evalifitions.  As  in  previous  years  the  arc  therapist  had  as  minimal  as 
possible  contact  with  the  patient  or  family  prior  to  the  evaluation  in  order 
not  to  be  biased  by  information  from,  other  sources. 

Major  Findings:  The  investigated  patient  population  in  the  period  from 
July  1,  1971  consisted  of  a  great  majority  of  adolescents  with  behavioral 
problems  such  as  delinquency  and  drug  usage.   The  investigation  of  phenomena 
specific  to  families  of  patients  with  these  types  of  mental  disorders  contin- 
ues. 

It  was  observed  that  many  of  these  families  required  about  double  the 
length  of  time  usually  needed  for  an  evaluation  session  and  produced  a  great 
deal  of  pictorial  and  verbal  material.   While  the  pictures  were  impressively 
revealing  of  the  families'  dynamics,  the  investigators  were  amazed  at  the 
difficulty  these  families  had  in  recognizing  the  problems  and  interrelation- 
ships so  vividly  displayed.   The  quantity  of  material  by  itself  overwhelmed 
the  investigators,  but  even  careful  study  of  tapes  rarely  revealed  a  deeper 
engagement  of  the  family. 

In  the  joint  endeavor  (see  Method  (e)  above),  the  fathers  made  ineffec- 
tive efforts  at  leadership  and  were  frequently  sabotaged  by  the  mothers.   The 
joint  production  was  usually  of  an  inferior  quality  than  the  family  members' 
individual  ones. 

The  separation  issue  was  repeatedly  revealed  in  the  pictures  of  the 
families  of  this  same  group  of  adolescents.   These  adolescents  underlined  in 
their  family  portraits  their  desire  for  complete  separateness  from  the  family 
unit,  but  upon  closer  investigation  one  discovers  that  there  is  an  ambiguity 
in  these  representations:   the  adolescent  pictures  himself  either  outside  of 
the  carefully  delimited  world  of  the  family,  yet  somehow  still  closely  at- 
tached to  it  or  in  complete  unreality  such  as  hazy,  drugged  fantasy  world  or 
on  a  desert  island. 

On  the  other  hand,  we  noticed  the  opposite  tendency  in  the  parents.   The 
myth  of  happiness  and  unity  of  the  family  was  predominant,  with  only  hints  at 
scapegoating  the  index  patient.   Their  pictures  underlined  the  unity  of  the 
family  and  encircled  tightly  the  family  world. 

As  in  preceding  years,  the  family  art  evaluation,  basically  a  research 
proced«re  has  also  presented  clinical  advantages.   The  pictures  displayed  at 
clinical  conferences  illustrate  the  family  members'  problems,  their  trans- 


30 


Serial  No,  M-AP(C)-15-3 


actional  style,  and  their  perception  of  each  other.   The  clinicians  can 
visualize  and  focus  on  specific  issues  represented  in  the  concrete  and  dur- 
able form  of  the  graphic  projections.   These  issues  can  also  be  further 
worked  on  in  family  or  individual  therapy. 

Significance  to  Mental  Health  Research;   The  development  of  this  technique 
continues  to  give  additional  dynamic  understanding  of  family  relations  to 
projects  of  the  Adult  Psychiatry  Branch  of  NIMH.   The  hypotheses  based  on 
the  empirical  findings  obtained  through  family  art  evaluations  have  been 
scientifically  investigated  by  systematic  computer  analysis  of  the  material 
and  described  as  a  separate  project,  (M-AP(C)-15-8). 

The  researchers'  and  clinicians'  interest  in  this  technique  continues 
to  increase  in  the  United  States  and  abroad.  As  a  result  of  the  development 
of  our  work  at  NIMH,  a  graduate  course  in  Family  Art  Techniques  leading  to 
a  Master's  Degree  is  offered  by  the  Graduate  School  of  Arts  and  Sciences  at 
George  Washington  University  and  at  Washington  School  of  Psychiatry. 

Seminars  on  family  art  techniques,  reprints  of  papers,  and  consultations 
continue  to  be  requested. 

Proposed  Course;   To  continue  to  investigate  systematically  the  findings  des- 
cribed above  with  the  goal  of  categorizing  the  families  where  these  character- 
istics appear  most  prominently. 

It  is  hypothesized  that  the  unresolved  separation  of  these  fathers  and 
mothers  from  their  own  parents  would  be  crucial  in  the  problems  of  separation 
of  their  offspring.   Special  additional  art  procedures  are  being  planned  for 
this  purpose. 

Honors  and  Awards ;   By  invitation  of  the  American  Psychological  Association, 
a  paper,  EVALUATION  OF  FAMILIES  WITH  SCHIZOPHRENIC  TWINS  THROUGH  FAMILY  ART 
PROCEDURES  by  Hanna  Yaxa  Kwiatkowska  and  Loren  R.  Mosher,  M.D.,  was  presented 
at  the  Annual  Meeting  in  Washington,  D.C.  in  September  1971. 

An  Exhibit,  EVALUATION  OF  FAMILY  DYNAMICS  THROUGH  CONJOINT  FAMILY  ART 
PROCEDURES  by  Hanna  Yaxa  Kwiatkowska,  was  presented,  also  by  invitation  at  the 
World  Congress  of  Psychiatry  in  Mexico  City  in  December  1971. 

Publications;   FAMILY  ART  EVALUATION:  Use  in  Families  with  Schizophrenic 
Twins  by  Loren  R.  Mosher,  M.D.  and  Hanna  Yaxa  Kwiatkowska,  B.S.,  published  in 
the  Journal  of  Nervous  and  Mental  Diseases  in  the  September  issue,  Vol.  153, 
No.  3,  1971. 


31 


Serial  No.  M-AP(C)-15-5 

1,  Adult  Psychiatry  Branch 

2,  Family  Studies  Section 

3,  Bethesda,  Maryland 


PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 


Project  title:   Family  Art  Therapy 

Previous  Serial  Number:   SAME 

Principal  Investigator:   Hanna  Yaxa  Kwiatkowska 

Other  Investigators:  NONE 

Cooperating  Units:   NONE 

Man  Years: 

Total:         0 
Professional:   0   (inactive) 
Other:         0 

Project  Description: 

Objectives ;   (a)  To  further  investigate  the  pilot  study  where  family  art  thera- 
py is  used  as  the  sole  therapy  with  families  of  adolescents  from  different 
diagnostic  groups;  (b)  To  use  this  approach  with  families  of  different  socio- 
economic backgrounds. 

Mathods  Employed:  All  members  of  a  nuclear  family  are  seen  jointly  in  family 
art  psychotherapy  by  the  art  therapist  and  the  collaborating  psychiatrist. 
Art  media  are  offered  to  the  family  as  a  means  of  communication  and  self- 
expression;  artistic  or  aesthetic  considerations  are  not  emphasized.   In  some 
of  the  sessions  (at  the  beginning  of  treatment  and  repeated  every  six  months) 
art  evaluation  procedures  are  used.   These  procedures  combine  free  expression 
with  standardized  tasks  and  their  purpose  is  to  gauge  the  course  of  therapy 
periodically.   Otherwise  the  family  is  largely  left  to  structure  the  session; 
they  are  encouraged  to  draw  or  paint  whatever  comes  to  mind.   All  sessions  are 
tape  recorded;  abstracts  describing  the  family's  interaction  and  the  analysis 
of  the  pictorial  and  verbal  material,  as  well  as  the  therapists'  subjective 
reactions,  are  dictated  by  both  therapists.   In  the  course  of  therapy  at  least 
one  session  is  video  taped. 

tfajor  Findings ;   No  family  was  investigated  this  year,  but  a  study  based  on  a 
"blind"  analysis  by  eminent  psychiatrists  and  analysts  of  pictorial  material 
obtained  from  long  term  family  art  psychotherapy  and  chronologically  arranged 
was  completed  and  presented  by  invitation  at  the  American  Psychiatric  Associa- 


33 


Serial  No  M-AP(C)-15-5 

tion  meetings  under  the  title  "Blind  Evaluation  of  Pictures  in  Family  Psycho- 
therapy: Their  Communicative  Power,"  This  study  demonstrated: 

1.  The  blind  judgements  drawn  from  pictures  only,  without  any  verbal 
content  were  astonishingly  accurate  as  to  identity  of  index,  diagnosis, 
course,  and  outcome  of  therapy. 

2,  The  observations  of  the  judges  brought  more  clarity  on  the  reasons 
for  a  successful  achievement  of  the  therapy  and  helped  the  therapists  to 
gain  a  more  precise  understanding  of  their  experience  with  this  family. 

Proposed  Course:   To  complete  for  publication  the  monograph  "The  Use  of  Drawing 
and  Painting  as  a  Primary  Mode  of  Communication  in  the  Family  Therapy  of 
Schizophrenia. " 

Honors  and  Awards :  An  exhibit,  "Pictures  Help  a  Regressed  Schizophrenic 
Patient  to  be  Heard  and  Understood"  by  Hanna  Yaxa  Kwiatkowska,  was  presented 
by  invitation  at  the  Exhibition  of  Psychopathological  Art  at  the  Fifth  World 
Congress  of  Psychiatry  in  Mexico  City. 

Publications:  NONE 


3i^ 


Serial  No,  M-AP(C)-15-8 

1.  Adult  Psychiatry  Branch 

2.  Family  Studies  Section 

3.  Bethesda,  Maryland 


PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 


Project  Title:   Systematic  Analysis  of  Family  Art  Evaluations 

Previous  Serial  Number:   SAME 

Principal  Investigators:   James  K.  Dent,  Ph.D.  and  Hanna  Yaxa  Kwiatkowska 

Other  Investigators:   Lyman  C.  Wynne,  M.D.,  Ph.D.,  Margaret  T.  Singer,  Ph.D. 

Cooperating  Units:   Section  on  Personality  Development,  Section  on  Twin  and 

Sibling  Studies,  Section  on  Clinical  Psychology,  Division 
of  Computer  Research  and  Technology. 

M&n  Years : 

Total:  0.35 
Professional:  0.20 
Other:        0.15 

Project  Description: 

Objectives :   The  overall  objective  is  to  explore  systematically  the  materials 
available  from  the  Family  Art  Evaluations  which  have  been  introduced  by  Mrs. 
Hanna  Kwiatkowska  and  conducted  for  several  years.   Such  an  analysis  is  aimed 
at  improving  diagnostic  procedures  and  increasing  our  understanding  of  the 
social  psychological  dynamics  of  psychopathology .   In  presenting  the  specific 
objectives,  the  longer  range  of  objects  are  listed  first;  the  immediate  ob- 
jectives are  listed  last. 

A.  Family  Dynamics  and  Psychopathology. 

1.  To  differentiate,  through  the  characteristics  of  their  art  pro- 
ductions, families  in  which  the  index  is  diagnosed  as  process  schizo- 
phrenic, reactive  schizophrenic,  psychoneurotic,  and  so  forth. 

2.  To  distinguish  role  positions  in  the  family  (father,  mother, 
sibling,  etc.),  as  revealed  by  their  pictures  (such  as  family  portraits) 
and  transactions. 

B.  Diagnostics  (A  Manual  for  the  use  of  the  Family  Art  Evaluations). 
1.   To  specify  the  relation  of  the  diagnosis  of  the  index  to  the 


35 


Serial  No.  M-AP(C)-15-8 


characteristics  of  his  own  art  productions  and  those  of  his  family. 

2.   To  determine  which  characteristics  of  the  art  productions  appear 
to  represent  transient  symptoms  and  which  represent  more  enduring  per- 
sonality characteristics. 

C.  Measurement  Objectives. 

1.  To  develop  objective  rating  systems  for  pictures  and  family 
transactions  in  the  Family  Art  Evaluation  method. 

2.  To  determine  the  interrater  agreement  and  the  internal  consis- 
tency of  the  scales  used. 

3.  To  construct  by  combining  scales,  variables  having  stronger  met- 
ric power. 

4.  To  analyze  the  significance  of  variables  like  artistic  talent 
and  intelligence  which  may  confound  the  relation  between  diagnostic 
variables  and  characteristics  of  the  art  productions.   It  is  important 
to  separate  the  evidence  of  psychopathology  in  a  picture  from  the  influ- 
ence of  intelligence  or  artistic  talent. 

Methods  Employed:  Our  methods  were  described  in  detail  last  year.   In  sum- 
mary, the  pictures  are  blinded,  randomized,  and  rated;  one  picture  in  four 
is  check  rated  for  studies  of  interrater  agreement.  A  variety  of  statisti- 
cal techniques  are  being  used,  depending  upon  specific  objectives. 

"Blind"  ratings  of  pictures  represent  an  independent  measure  of  the  men- 
tal status  of  an  individual  at  a  particular  point  in  time.  It  is  our  plan  to 
correlate  these  ratings  with  other  data.  Correlation  with  diagnosis  and  fam- 
ily characteristics  such  as  socio-economic  status  will  be  greatly  facilitated 
because  some  of  these  data  have  already  been  compiled  in  connection  with  the 
research  done  by  Dr.  Lyman  C.  Wynne. 

Major  Findings;   Factor  analyses  across  pictures  reveals  that  there  are  some 
expected  dimensions  which  are  prominent  and  stable.   For  example,  there  is  a 
dimension  that  might  be  labelled  "bizarreness"  which  is  always  first  or 
second  in  explaining  variance  regardless  of  how  the  factor  analysis  is  con- 
ducted.  However,  there  are  many  more  independent  dimensions  than  was  antici- 
pated; that  is,  even  though  interrater  agreement  is  high,  relations  among 
dimensions  tend  to  be  low.   The  characteristics  of  the  pictures  are  not  easily 
summarized  in  a  few  dimensions. 

Factor  analysis  across  individuals  indicated  that  there  are  a  few  dimen- 
sions which  might  be  labelled  "trait"  dimensions.   They  extend  across  the 
various  procedures,  across  two  F.A.E. 's,  and  are  correlated  with  intelligence 
and  artistic  talent.  An  example  of  such  a  dimension  is  the  use  of  color. 
However,  unexpectedly , "bizarreness"  is  not  such  a  dimension;  that  is,  an 


( 

I 


36 


Serial  No.  M-AP(C)-15-8 

individual  who  produces  a  bizarre  "first  free"  picture  is  not  likely  to  show 
"bizarBeness"  in  his  last  picture. 

There  are  a  large  number  of  dimensions  which  show  significant  differences 
between  patients  and  siblings.   These  differences  are  almost  always  as  one 
would  predict;  for  example,  patients'  pictures  are  more  likely  to  be  "bizarre." 
Comparisons  between  offspring  and  their  parents  are  difficult  because  the 
parents  tend  to  show  less  artistic  talent.   Further  analyses  of  talent-free 
dimensions  are  required. 

Significance  to  Mental  Health  Research:   Since  the  art  production  is  an  inde- 
pendent, enduring  representation  of  the  mental  status  of  an  individual  (or 
family)  at  a  moment  in  time  and  in  a  structured  family  setting,  it  is  a  valu- 
able datum  both  for  enhancing  our  diagnostic  methods  and  for  investigating 
family  dynamics  in  relation  to  mental  disorder. 

The  usefulness  of  "drawing  tests"  for  individual  diagnosis  is  widely 
recognized.   Considerable  research  has  been  done  on  the  Draw-A-Person  test. 
More  recently  there  have  been  efforts  to  use  other  types  of  art  productions. 
Although  the  literature  is  full  of  ideas  about  how  to  diagnose  mental  illness 
from  pictures,  most  of  the  research  has  been  concerned  with  a  much  simpler 
and  less  useful  task,  viz.:   To  predict  whether  a  person  is  mentally  ill. 
Only  a  few  systematic  studies  (e.g.,  that  of  Dr.  Robert  Kaye)  have  been  con- 
cerned with  trying  to  specify  what  aspects  of  a  picture  are  predictive  of 
what  kinds  of  mental  disorder,  and  there  have  been  no  statistical  studies  of 
family  dynamics  as  seen  through  the  art  productions  of  the  whole  family. 

On  the  side  of  family  dynamics,  there  is  a  rich  body  of  research  findings. 
Many  of  the  concepts  in  this  literature  are  used  in  the  present  study.  More- 
over, the  material  is  being  coded  for  the  computer  in  the  same  format  as  for 
other  studies  in  the  Adult  Psychiatry  Branch,  and  this  will  greatly  facili- 
tate the  comparison  and  integration  of  findings. 

Proposed  Course:  Analyses  of  diagnostic  groups  will  be  conducted.  We  will 
use  a  diagnostic  system  developed  by  L.  C.  Wynne  together  with  data  collected 
in  connection  with  M-AP(C)-14-6,  Pilot  Study  in  Records  Codification.  We  will 
also  use  a  diagnostic  system  modeled  on  the  work  of  Donald  F.  Klein  of 
Hillside  Hospital,  New  York  City. 

Honors  and  Awards ;  NONE 

Publications:  NONE 


37 


1 


Serial  No.  M-AP(C)-15-9 

1.  Adult  Psychiatry  Branch 

2.  Family  Studies  Section 

3.  Bethesda,  Maryland 


PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:   Systematic  Analysis  of  Brazilian  Family  Art  Evaluations:  A 
Replication. 

Previous  Serial  Number:   SAME 

Principal  Investigators:   Hanna  Yaxa  Kwlatkowska  and  James  K.  Dent,  Ph.D. 

Other  Investigators:   Dr.  Carlos  Paes  de  Barros,  Dr.  Aroldo  Rodriques, 

Sylvia  Beatriz  Machado  Joffely,  Vera  Polio  Flores, 
Luiz  Duprat. 

Cooperating  Units:   Institute  of  Psychology  of  the  Catholic  University  in  Rio 
de  Janeiro,  Brazil,  Department  of  State  Committee  on  Inter- 
national Exchange  of  Persons  (Fulbright  Commission). 

Man  Years : 

Total:  0.10 
Professional:  0.05 
Others:        0.05 

Project  Description: 

Objectives :   The  overall  objective  is  to  explore  the  differences  and  similari- 
ties appearing  in  the  systematic  analysis  of  pictorial  material  obtained  from 
Brazilian  families  with  the  material  obtained  from  American  families,  here, 
in  the  identically  structured  situation  of  the  "Family  Art  Evaluation. "  The 
specific  objectives  are: 

1.  To  investigate  and  compare  the  characteristics  of  pictures  drawn  by 
Brazilian  families  where  a  family  member  has  a  specific  psychiatric 
diagnosis  with  the  characteristics  of  pictures  of  diagnostically  similar 
families  in  the  United  States. 

2.  To  define  if  eventual  differences  observed  through  this  analysis 
could  be  attributed  to  cultural  variations. 

3.  To  study  the  differences  in  roles  of  family  members  in  both  countries 
as  seen  in  the  different  procedures  of  the  family  art  evaluations.   E.G., 
in  her  work  with  Brazilian  families  Mrs.  Kwiatkowska  has  observed  that 
the  family  portraits  of  Brazilian  families  frequently  include  the  exten- 


39 


Serial  No.  M~AP(C)-15-9 

ded  family,  thus'  bringing  to  light  the  roles  of  substitute  parents.   Is  there 
a  correlation  between  the  recurrent  inclusion  of  such  substitute  parent  in  the 
family  portraits  and  the  degree  of  pathology  in  the  family?  What  is  the  role 
of  the  natural  parents  in  such  families? 

(4)  To  investigate  and  compare  the  interrater  agreement  on  the  same  items 
of  the  rating  system  in  the  United  States  and  Brazil.   This  could  also  shed 
light  on  cultural  differences. 

Methods  Em.ployed:   The  manual  used  for  the  NIMH  study  was  translated  into 
Portuguese  by  the  Staff  of  the  Institute  of  Psychology  at  the  Catholic  Univer- 
sity in  Rio  de  Janeiro.   It  was  edited  by  Hanna  Yaxa  Kwiatkowska;  staff  mem- 
bers were  trained  by  her  personally  to  conduct  a  study  parallel  to  the  NIMH 
study. 

A  psychologist,  Mrs,  Vera  Polio  Flores,  with  the  consultantship  of  Miss 
Sylvia  Beatriz  Machado  Joffely,  is  in  charge  of  the  study  and  under  the  direc- 
tion of  Dr.  Carlos  Paes  de  Barros,  Chairman  of  the  Department  of  Psychology. 
Other  staff  members  of  the  Institute  were  designated  as  coordinators  and 
trainers  of  the  raters.   The  ratings  were  done  by  students  as  part  of  their 
regular  curriculum  for  credit.   Dr.  Aroldo  Rodriques,  Research  Psychologist, 
is  a  consultant  for  the  statistical  aspect  of  the  study. 

The  patients  referred  to  the  Clinic  at  the  Institute  of  Psychology  are 
mostly  children  or  adolescents  in  their  early  teens.   Jointly  with  their  fami- 
lies they  all  have  a  family  art  evaluation  as  part  of  their  routine  psycholo- 
gical work-up.   A  considerable  amount  of  material  has  been  accumulated  since 
the  evaluations  were  introduced  there  in  1966.   In  selecting  sample  families 
for  the  present  study  we  were,  nevertheless,  limited  by  the  age  group;  we  did 
not  want  to  include  families  where  the  index  would  be  less  than  ten  years  old. 
Diagnostically  the  sample  includes  families  of  severely  neurotic  or  behavior 
problem  children,  all  out-patients  at  the  Clinic.   Records  of  all  investigated 
Brazilian  families  were  obtained  and  translated  from  Portuguese  into  English 
in  order  to  obtain  data  (symptoms,  onset,  premorbid  history)  to  be  used  in 
establishing  diagnoses  of  the  Brazilian  subjects. 

Major  Findings;  Factor  analyses  reveal  that  there  are  some  similarities  with 
and  some  differences  from  the  factor  structure  of  pictures  drawn  by  our  fami- 
lies here  in  Bethesda. 

Significance  to  Mental  Health  Research:  Family  art  evaluations  provide  a 
situation  which  offers  a  good  deal  of  stability  in  the  manner  material  is 
gathered  for  comparative  studies.  The  basic  material  (pictures)  is  collected 
in  an  experimental  setting  structured  as  identically  as  possible  with  the 
NIMH  setting.  The  methods  used  for  the  computer  analysis  of  these  data  are 
also  identical.  The  possible  flaws  in  the  translation  and  interpretation  of 
the  scoring  manual,  whether  of  linguistic  or  cultural  nature  are  being  inves- 
tigated in  a  separate  study  (M-AP(C)-15-10  "Sources  of  Variance  in  Cross- 
cultural  Application  of  an  Objective  System  for  Analyses  of  Pictures  Drawn  by 


ko 


{ 

I 


Serial  No.  M-AP(C)-15-9 


Patients  and  their  Families"). 

Proposed  Course:   Further  analysis  awaits  the  clarification  of  certain  omis- 
sions and  discrepancies  in  the  Brazilian  data.   Communication  about  these 
discrepancies  is  difficult  when  one  is  dependent  upon  letter  writing.   We 
have  been  fortunate  in  the  past  that  Mrs.  Kwiatkowska  was  able  to  visit  the 
Institute  and  establish  face-to-face  communications. 

Honors  and  Awards ;   NONE 

Publications:  NONE 


I 


kl 


Serial  No.  M-AP(C)-15-10 

1.  Adult  Psychiatry  Branch 

2.  Family  Studies  Section 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:  Sources  of  Variance  in  the  Cross-Cultural  Application  of  an 
Objective  System  for  Analyses  of  Pictures  Drawn  by  Patients 
and  Their  Families. 

Previous  Serial  Number:   SAME 

Principal  Investigators:   James  K.  Dent,  Ph.D.  and  Hanna  Yaxa  Kwiatkowska 

Other  Investigators:   Dr.  Carlos  Paes  de  Barros,  Dr.  Aroldo  Rodrigues, 

Sylvia  Beatriz  Valerio  Machado  Joffely,  Vera  Polio 
Flores 

Cooperating  Units:   Institute  of  Psychology  of  the  Catholic  University  of 
Rio  de  Janeiro,  Brazil 

Man  Years: 

Total:  0.04 
Professional:  0.04 
Others:       0.00 

Objectives :  A  system  has  been  developed  for  objectively  classifying  pictures 
drawn  by  patients  and  by  members  of  their  families  in  the  Family  Art  Evalua- 
tions at  NIMH  (M-AP(C)-15-8).   This  rating  system  which  consists  of  about 
fifty  dimensions  has  been  translated  into  Portuguese  and  is  being  used  to 
describe  pictures  drawn  by  mental  patients  and  their  families  in  Brazil, 
(M-AP(C)-15-1).   In  application,  the  two  measurements  may  not  be  equivalent 
for  several  reasons: 

(a)  Various  pictorial  symbols  may  have  different  significances  in  culture 
A  (American)  from  those  in  culture  B  (Brazilian). 

(b)  The  English  and  Portuguese  translations  may  not  be  equivalent. 

(c)  Research  group  A  may  have  particular  frames  of  references  not  common 
to  their  own  culture. 

(d)  Research  Group  B  may  also  have  particular  frames  of  references. 

The  objective  of  this  project  is  to  begin  to  sort  out  some  of  these  various 
sources  of  error  and  variance. 


^3 


Serial  No.  M-AP(C)-15-10 

Methods  Employed':   Sixty-eight  pictures  selected  at  random  from  about  one 
thousand  pictures  (American  families)  have  been  or  are  being  rated  as  follows: 

Ratings  1  and  2: 

Two  members  of  research  group  A  have  independently  rated  each  of  the  pic- 
tures using  the  English  translation. 

Rating  3: 

These  raters  discussed  their  differences  and  prepared  a  check  rating  repre- 
senting the  best  judgment  of  research  group  A  for  each  picture. 

Rating  4: 

Using  the  English  translation,  the  pictures  have  been  rated  by  two  American 
college  student  volunteers  working  alone  (no  contact  with  the  research 
group),  each  doing  about  half  of  the  pictures. 

Rating  5: 

Using  the  Portuguese  translation,  a  bilingual  American  college  student 
volunteer  rated  the  pictures  alone  (no  contact  with  the  research  group). 

Ratings  6,  7,  and  8: 

These  are  like  ratings  1,  2,  and  3  but  are  being  done  by  Brazilian  members 
of  research  group  E  in  Brazil,  from  slides  of  the  same  pictures  rated  at 
NIMH. 

For  the  50  dimensions  in  the  rating  system,  comparison  among  these 
ratings  should  permit  us  to  isolate  translation  difficulties  and  some  of  the 
group  effects.   Presumably  differences  not  attributable  to  these  two  sources 
of  variance  represent  cultural  factors  in  interpretation  or  individual  rater 
biases.   (A  study  of  individual  rater  biases  is  included  in  M-AP(C)-15-8) . 
Because  of  the  small  number  of  pictures  and  of  having  only  one  bilingual  rater, 
the  results  will  have  to  be  considred  tentative.   This  project  is  essentially 
a  pilot  study  for  this  type  of  investigation. 

Major  Findings:   The  Brazilians  were  able  to  rate  only  about  half  of  the  pic- 
tures we  sent  them.   Analysis  of  this  half  indicated  clearly  which  dimensions 
have  a  constant  meaning  in  both  centers,  which  have  different  meanings  but  are 
reliable  within  centers  (translation  problems),  and  which  dimensions  are  so 
poorly  defined  they  have  little  meaning  in  either  center. 

Proposed  Course;   Findings  will  be  written  up  in  the  next  fiscal  year. 

Significance  to  Mental  Health  Research:   The  precise  description  of  mental 
disorders  across  cultures  is  hampered  by  a  paucity  of  culture-free  methods  of 


( 


kk 


Serial  No.  M-AP(C)-15-10 

assessment.   Frequently  the  problem  is  dealt  with  by  using  the  inferential 
judgments  of  particular  clinicians  who  evaluate  patients  in  two  or  more  cul- 
tures. Agreement  among  them  about  particular  patients  is  interpreted  as 
constancy  in  measurement.   This  system  which  is  biased  by  language,  dialect 
and  status  problems  may  not  provide  replicable  descriptions;  i.e.  there  are 
no  assurances  that  another  group  of  clinicians  with  differing  backgrounds 
would  provide  the  same  description,  or  even  a  common  one. 

At  the  other  extreme,  one  is  impressed  by  the  almost  universal  under- 
standing and  appreciation  of  works  of  art.   The  messages  of  enduring  repre- 
sentations of  art  seem  on  the  one  hand  to  be  an  expression  of  the  different 
cultures  and  on  the  other  hand  to  convey  emotions  universally  accessible.   One 
is  also  impressed  with  the  high  quality  of  communication  in  pure  science. 
Where  ideas  are  precisely  defined  in  observable  terms  cross-cultural  communi- 
cation is  facilitated.   For  these  reasons  objective  descriptions  of  art  pro- 
ductions may  be  an  important  way  of  achieving  cross-cultural  communication  in 
description  of  mental  disorders.   In  addition  to  being  tangible  the  communica- 
tion is  not  limited  and/or  biased  by  the  language  or  dialect  problem  and  the 
professional  has  a  direct  access  to  the  experience  of  the  patient. 

Honors  and  Awards ;  NONE 

Publications;   NONE 


h5 


Serial  No.  M-AP(C)-16-1 

1.  Adult  Psychiatry  Branch 

2.  Psychiatric  Assessment  Section 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:  WHO  International  Pilot  Study  of  Schizophrenia 

Previous  Serial  Number:  M-AP(C)-16-1 

Principal  Investigators:  John  S.  Strauss,  M.D. 

William  T.  Carpenter,  Jr.,  M.D. 
Lyman  C.  Wynne,  M.D.,  Ph.D. 

Cooperating  Units:  John  Bartko,  Ph.D.,  Biometrics  Branch 
Prince  Georges  General  Hospital 
Spring  Grove  State  Hospital 
Morris  Cafritz  Memorial  Hospital 
World  Health  Organization 

Man  Years: 

Total:  2.0 
Professional:  1.0 
Other:        1.0 

Project  Description: 

Objectives:  (1)  To  develop  standard  interview  and  rating  schedules  that 
can  be  used  cross-culturally  for  the  evaluation  of  psychotic  patients. 
(2)  To  evaluate  a  cohort  of  patients  from  the  catchment  area  of  Prince 
Georges  County,  Maryland  with  these  Instruments  and  to  compare  these  findings 
with  similar  evaluations  being  carried  out  by  investigators  In  eight  other 
psychiatric  centers  in  Colombia,  Czechoslovakia,  Denmark,  Great  Britain,  India, 
Nigeria,  Taiwan  and  the  USSR.  (3)  To  work  toward  a  consensus  with  investigators 
from  these  other  countries  about  criteria  derived  from  the  interview  Instruments, 
for  classifying  patients  as  schizophrenic.  (4)  To  compare  these  WHO  diagnostic 
evaluations  with  clinical  evaluations  and  ratings  of  the  same  patients  made  with 
other  methods  such  as  the  Lorr  IMPS  scale  and  projective  tests.  (5)  To  compare 
social  and  demographic  data  on  patients  evaluated  by  the  standard  instruments 
to  understand  more  completely  how  these  factors  are  related  to  schizophrenia 
as  defined  through  the  use  of  the  standard  diagnostic  schedules.  (6)  To 
compare  course  of  illness  in  patients  from  the  collaborating  centers  by 
conducting  a  follow-up  study  on  patients  seen  in  the  original  sample. 

Methods  Employed:  Standardized  forms  have  been  developed  for  evaluating 
mental  status,  history,  social  function,  and  outcome.  Initial  evaluations 
were  completed  using  these  forms  on  135  patients  from  each  center.  Data 
is  being  analyzed  to  compare  the  patients  from  the  nine  centers  in  terms 


^7 


Serial  No.  M-AP(C)-16-1 

of  initial  diagnosis,  social  function,  and  follow-up  status.  Alternative 
diagnostic  techniques  have  been  applied  to  evaluate  their  validity. 

Major  Findings:  In  the  past  year  the  final  draft  of  Volume  One  of  the  IPSS 
report  has  been  prepared.  This  report  described  methods  and  findings  of  the 
first  phases  of  the  IPSS.  These  phases  include  (1)  the  preparation,  translation, 
pretesting,  and  revision  of  the  data  collection  instruments;  (2)  the  application 
of  these  instruments  to  1,202  patients  in  nine  different  centers;  (3)  the  evalu-  ^ 
ation  of  reliability  of  the  interview  schedules;  and  (4)  diagnostic  comparisons 
of  the  patients  seen  in  the  nine  centers. 

The  preparation  and  translation  of  data  collection  schedules  of  this  kind  with 
collaboration  of  psychiatrists  from  nine  centers  is,  in  itself,  a  significant 
contribution  to  the  methodology  available  to  future  cross-cultural  studies. 
In  evaluating  the  applicability  and  reliability  of  the  schedules,  two  findings 
were  especially  significant.  First,  it  was  possible  to  use  the  same  standard- 
ized mental  status  interview  (in  translation  where  necessary)  in  all  of  the 
collaborating  centers  and  reliability  of  ratings  within  each  of  the  centers  was 
high.  The  reliability  of  the  ratings  across  centers  was  at  a  lower  but  still 
acceptable  level.  Because  history  and  social  description  data  had  to  be 
collected  in  different  ways  in  the  different  centers,  and  because  these  data 
depend  so  much  for  their  psychiatric  significance  on  the  cultural  milieu.  It 
was  more  difficult  to  evaluate  the  comparability  of  these  kinds  of  Information 
from  center  to  center.  However,  the  schedules  provided  a  useful  means  of 
collecting  these  data  and  represent  a  first  step  towards  the  development  of 
comparable  methodology  in  this  area  as  well.  ' 

The  comparison  of  similarities  and  differences  in  patient  types  seen  in  the 
different  centers  has  been  given  considerable  attention.  The  Inherent  complexity 
of  such  a  comparison,  even  of  patients  within  one  center,  is  often  under- 
estimated, but  was  highlighted  by  the  cross-cultural  nature  of  this  project. 
Three  different  methods  for  defining  diagnostic  types  were  used.  The  results 
of  these  three  different  methods  were  then  compared.  In  the  first  diagnostic 
method,  the  Interviewing  psychiatrist  assigned  the  patient  to  one  of  the  conmonly 
used  clinical  diagnostic  categories.  The  categories  defined  by  the  Inter- 
national Classification  of  Diseases  were  those  most  frequently  used;  however, 
some  centers  tended  to  use  special  diagnostic  categories.  Analysis  of  symptom 
profiles  of  the  different  diagnostic  types  showed  broad  similarities  across 
centers  for  the  general  diagnostic  categories  such  as  schizophrenia,  and  manic- 
depressive  psychosis.  It  indicated  further  that  patients  with  some  of  the 
common  defining  characteristics  of  these  diagnostic  categories  were  seen  In  all 
centers.  Comparison  of  symptom  profiles  to  diagnostic  labels  applied  by 
investigators  from  the  centers  also  clarified  many  differences  in  the  way  in     . 
which  psychiatrists  from  different  centers  used  symptom  information  in  reaching  ' 
a  diagnosis. 

A  second  diagnostic  method  used  to  analyze  the  types  of  patients  seen  in  this 
study  was  a  computer  program  developed  to  simulate  clinical  diagnoses  as  they 
might  be  made  by  the  psychiatric  school  led  by  Kurt  Schneider.  Using  data  from 
the  mental  status  examination  and  psychiatric  history,  this  computer  method 


U8 


Serial  No.  M-AP(C)-T6-1 

(Catego)  was  able  to  duplicate,  to  some  extent,  the  broad  clinical  diagnoses 
such  as  schizophrenia,  and  psychotic  depression  given  to  the  patients  by  the 
investigators  in  the  centers.  This  method  represents  considerable  progress  in 
developing  a  technique  for  applying  diagnoses  to  patients  which  can  be  applied 
in  different  centers  with  complete  reliability. 

The  third  method  used  for  assigning  patients  to  diagnostic  categories  employed 
cluster  techniques.  With  these  mathematical  techniques  for  defining  groups  of 
patients,  it  was  possible  to  arrive  at  categorizations  that  were  somewhat 
similar  to  both  clinical  and  Catego  diagnoses.  The  cluster  techniques  also 
provided  a  means  for  defining  certain  subgroups  of  patients  that  were  seen  in 
only  one  or  two  centers.  The  results  of  these  three  methods  were  compared  and 
combined  to  describe  basic  similarities  and  differences  among  patients  seen  in 
the  different  centers. 

The  data  from  the  study  is  also  being  used  as  source  for  other  closely  related 
investigations:  (M-AP(C)-16-3,  M-AP(C)-16-4) .  These  studies  involve  more 
intensive  investigation  of  certain  aspects  of  the  data  obtained  during  the  IPSS 
and  comparison  of  these  data  with  similar  information  obtained  from  other 
sources. 

Significance  to  Mental  Health  Research  and  the  Program  of  the  Institute: 
The  difficulty  in  comparing  psychiatric  patients  from  different  cultures  has 
made  it  impossible  to  evaluate  accurately  the  etiological  importance  of  cultural 
factors  in  psychiatric  disorder.  The  absence  of  standard  methods  for  evaluation 
and  diagnosis  of  psychiatric  patients  has  also  made  it  difficult  to  ccri'pare 
incidence  and  prevalence  rated  in  different  cultures  and  to  compare  usefulness 
of  treatment  methods  employed  in  different  centers.  Until  these  comparisons 
can  be  performed,  it  is  not  possible  to  test  many  crucial  hypotheses  regarding 
the  nature  and  etiology  of  psychiatric  disorders.  The  difficulties  in  estab- 
lishing standard  instruments  are  considerable,  not  only  in  the  writing  and 
testing  of  such  Instruments,  but  in  the  extensive  negotiations  and  communications 
necessary  with  the  various  Investigators  from  different  countries  with  diverse 
backgrounds  and  orientations.  Nevertheless,  in  this  study  it  has  been  possible 
to  develop  such  Instruments  that  can  be  applied  in  a  useful  way  in  a  variety  of 
cultural  settings.  These  Instruments  were  used  with  patients  in  nine  different 
countries  and  proved  to  be  applicable  and  useful  for  this  purpose. 

While  methods  of  evaluating  patient  characteristics  must  be  developed  in  order 
to  perform  cross-cultural  studies,  it  is  also  essential  to  develop  methods  for 
categorizing  patients  once  their  characteristics  have  been  elicited  and  rated. 
In  the  current  studies,  three  different  methods  were  used  to  categorize  patients 
and  to  compare  patient  types  among  the  different  centers.  Through  applying 
these  methods,  it  is  possible  to  show  in  what  sense  patients  seen  in  the  differ- 
ent centers  are  similar  and  in  what  sense  they  are  unique.  The  combinations 
of  these  methods  can  also  be  used  to  determine  in  what  sense  the  statement, 
"schizophrenia  is  found  in  all  of  the  nine  centers,"  is  true,  and  in  what  sense 
the  statement  omits  recognition  of  real  differences  of  "schizophrenic"  patients 
from  the  different  centers. 


k9 


Serial  No.  M-AP(C)-16-1 

The  completion  of  a  follow-up  study  on  the  patients  originally  interviewed  adds 
the  crucial  dimension  of  course  of  illness  to  the  evaluation.  By  having 
standardized,  comparable  infcnnation  on  patients  from  different  countries  at 
two  points  in  time,  it  will  be  possible  to  compare  course  of  illness  cross- 
culturally  and  to  investigate  further  the  use  of  outcome  of  psychiatric  illness 
to  validate  the  original  diagnoses. 

Proposed  Course  of  the  Project:  In  the  coming  year  the  data  from  the  ^ 
follow-up  phase  of  the  IPSS  will  be  further  analyzed  and  preparation  of  Volume 
Two  of  the  IPSS  report  will  be  undertaken  reporting  follow-up  results  and  several 
substudies  from  the  early  phases  of  the  IPSS. 


50 


Serial  No.  M-AP(C)-16-3 

1.  Adult  Psychiatry  Branch 

2.  Psychiatric  Assessment  Section 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:  Comparative  Studies  of  Functional  Psychoses 

Previous  Serial  Number:  M-AP(C)16-3 

Principal  Investigators:  William  T.  Carpenter,  Jr.,  M.D. 

John  S.  Strauss,  M.D. 

Cooperating  Units:   John  Bartko,  Ph.D.,  Biometrics  Branch,  Prince  Georges 
General  Hospital,  Spring  Grove  State  Hospital,  Morris 
Cafritz  Memorial  Hospital,  World  Health  Organization, 
3-E  and  4-W  Nursing  Units,  Clinical  Center,  NIH,  Section 
on  Psychiatry,  Laboratory  of  Clinical  Science. 

Man  Years : 

Total:  0,4 
Professional:  0.3 
Others:        0.1 

Project  Description: 

Objectives :  (1)  To  utilize  standard  interview  and  rating  schedules  to 
collect  data  on  manic-depressive  patients.  (2)  To  utilize  this  data  and 
data  collected  on  a  larger  group  of  schizophrenic  patients  in  a  comparable 
manner  to  investigate  similarities  and  differences  in  symptomatology  within 
these  diagnostic  categories.   (3)  To  provide  a  sufficiently  large  sample  of 
manic-depressive  patients  to  enable  comparison  with  similarly  diagnosed 
patients  from  other  field  centers  in  the  WHO  International  Pilot  Study  of 
Schizophrenia.   (4)  To  obtain  data  with  which  to  test  the  hypothesis  that 
many  of  the  usually  accepted  criteria  for  a  depressive  illness  (i.e.,  biological 
signs,  psychosomatic  complaints,  sleep  difficulties,  decrease  in  libido,  etc.) 
do  not  have  high  order  discriminatory  function  between  depression  and  other 
forms  of  mental  disturbances.  (5)  To  generate  a  sufficient  sample  of  depressed 
patients  to  explore  the  hypothesis  that  a  diagnosis  of  schizophrenia  is  often 
used  for  a  person  who  otherwise  is  comparable  to  a  psychotic  depression  but 
has  a  bizarre  delusion  or  the  presence  of  an  hallucinatory  phenomena  which 
many  clinicians  in  practice  do  not  identify  as  part  of  a  depressive  illness. 
(6)  To  elucidate  the  concept  of  schizo-affective  schizophrenia  by  examining 
the  signs  and  symptoms  present  in  cases  so  diagnosed  comparing  them  with 
depressed  patients  and  schizophrenic  patients  during  illness  and  through 
a  follow-up  period.  (7)  To  test  empirically  current  diagnostic  systems  for  the 
psychoses. 


51 


Serial  No.  M-AP(C)-16-3 

Methods  Employed:   The  standard  instruments  were  developed  for  the  WHO 
International  Pilot  Study  of  Schizophrenia,   They  were  developed,  revised,  and 
extensively  pretested  on  at  least  24  patients  from  centers  in  eight  countries 
and  have  been  used  in  the  past  year  on  a  cohort  of  135  patients  from  each 
center.   Four  basic  interview  forms  comprise  the  standard  instruments  and  are 
described  in  project  No.  M-AP(C)-16-1.   Using  these  schedules  on  a  sample  of 
patients  not  included  in  the  IPSS,  37  manic-depressive  patients  have  been  inter-- 
viev/ed  from  wards  3-E  and  4-W  in  the  Clinical  Center,  Nllffl.   Computerized       * 
statistical  methods  are  being  developed  to  analyze  the  data  collected  from  these 
groups  of  patients  to  develop  empirical  "clusters"  of  patients  based  on  the 
symptoms  they  demonstrate.   In  addition  the  material  on  certain  sub-groups  of 
patients  (i.e.,  schizo-af fective  schizophrenia)  will  be  examined  by  the  prin- 
cipal investigators  in  an  effort  to  clarify  descriptive  and  conceptual  aspects 
of  the  diagnostic  categories. 

Major  Findings:   It  has  been  possible  to  accumulate  systematic  symptom 
and  sign  data  on  large  groups  of  patients  assigned  to  various  functional 
psychotic  subcategories.   This  date  permits  testing  of  major  diagnostic  con- 
cepts and  to  contrast  symptom  profiles  among  various  diagnostic  categories. 
The  most  important  finding  to  data  comes  from  the  first  empiric  investigation 
of  Kurt  Schneider's  diagnostic  concept.   Schneider's  identification  of  patho- 
gnomonic symptoms  of  schizophrenia  has  influenced  diagnostic  practices  through- 
out most  of  the  world.   Despite  general  acceptance  for  over  forty  years,  his 
diagnostic  system  has  never  been  empirically  tested.   Using  the  patient  data 
described  above,  we  were  able  to  demonstrate  that  the  first  rank  symptoms  are 
not  pathognomonic  for  schizophrenia,  but  occur  in  one-third  of  manic-depressive 
patients  and  in  ten  percent  of  neurotic  and  character  disorder  patients.  We 
have  been  able  to  replicate  these  findings  with  the  data  from  each  of  the  other 
eight  centers  in  the  IPSS, 

These  data  have  been  used  with  a  number  of  diagnostic  procedures  to  iden- 
tify groups  of  patients  to  test  hypotheses  related  to  outcome  in  schizophrenia 
(see  Project  Serial  No.  M-AP(C)-16-7) . 

Significance  to  Mental  Health  Research  and  the  Program  of  the  Institute : 
There  is  a  paucity  of  data  in  functional  psychoses  using  standardized  inter- 
view techniques.   Evaluating  diagnostic  groups  and  comparing  them  with  similar 
groups  from  the  various  field  centers  in  the  WHO  International  Pilot  Study  of 
Schizophrenia  offers  an  opportunity  to  clarify  the  use  and  misuse  of  the 
diagnostic  categories  and  to  describe  more  clearly  phenomena  represented  in 
each  and  the  distinguishing  features  of  the  various  diagnostic  categories. 
The  ability  to  identify  homogeneous  and  comparable  groups  in  various  centers 
IS  fundamental  for  all  human  research  of  the  psychoses. 

Proposed  Course  of  the  Proiect-  During  the  coming  year  we  will  test  other 
diagnostic  concepts.   We  will  use  follow-up  information  and  premorbid  data  in 
an  effort  to  validate  and  invalidate  diagnostic  groups.   Mathematical  approaches 
to  this  data  can  help  identify  the  critical  symptom  variables  in  diagnosing. 
Revision  of  diagnostic  concepts  will  follow  in  order  to  maximize  their  ability 
to  discriminate  between  patient  groups  based  on  signs  and  symptoms  that  occur 
frequently  and  are  readily  observed  by  clinicians, 

52 


Serial  No.  M-AP(C)-16-3 

Presentations:  Presented  by  Dr.  William  T,  Carpenter,  Jr, 

1.  The  Search  for  Pathognomonic ity  in  Schizophrenia,  presented  to  the 
Eleventh  Annual  Conference  of  the  Mental  Health  Career  Development 
Program,  New  Orleans,  Louisiana,  1972. 

2.  Pathognomonic ity  in  Schizophrenia:  An  Empiric,  Cross-Cultural 
Investigation  of  Kurt  Schneider's  Diagnostic  Concept,  presented  at 
the  Annual  Meeting  of  the  American  Psychiatric  Association,  1972. 

3.  Diagnostic  Concepts  in  Schizophrenia,  presented  to  the  Department  of 
Psychiatry,  University  of  Kentucky  Medical  School,  1972. 


53 


Serial  No.  M-AP(C)-16-A 

1.  Adult  Psychiatry  Branch 

2.  Psychiatric  Assessment  Section 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:   Empirical  Grouping  of  Psychiatric  Patients 

Previous  Serial  Number:   M-AP(C)-16-4 

Principal  Investigators:   John  S.  Strauss,  M.D.,  John  Bartko,  Ph.D., 

William  T.  Carpenter,  M.D. 

Cooperating  Units:   Biometrics  Branch,  NIMH,  Computer  Center,  NIH,  World 
Health  Organization 

Man  Years: 

Total:  0.3 
Professional:  0.2 
Other:         0.1 

Project  Description: 

Objectives:   (1)  To  develop  methods  for  grouping  psychiatric  patients 
empirically.   (2)  To  determine  whether  patients  as  defined  by  their  symptoms 
fall  into  natural  groups  or  vary  along  continua.   (3)  To  evaluate  methods 
commonly  used  for  the  empirical  grouping  of  patients. 

Methods  Employed:   In  the  process  of  analyzing  the  data  generated  by  the 
WHO  IPSS  (M-AP(C)-16-1) ,  some  difficulties  with  commonly  used  clustering  and 
factoring  procedures  for  grouping  patients  became  apparent.   The  investigators 
have  used  a  series  of  statistical  techniques  to  locate  where  in  the  process 
of  data  analysis  the  difficulties  arose  and  to  understand  the  relationships 
between  cluster  techniques  and  the  underlying  discrete  or  continuous  structure 
of  data. 

Major  Findings:   The  results  of  the  commonly  used  clustering  and  factoring 
techniques  for  grouping  psychiatric  patients  have  been  demonstrated  to  be  less 
stable  than  is  generally  recognized.   It  has  been  possible  to  identify  the 
variables  that  are  significant  in  causing  this  instability.   The  inability  of 
even  the  improved  techniques  to  create  stable  clusters  from  psychiatric  data 
suggests  that  psychiatric  patients  may  represent  continua  rather  than  discrete 
categories. 

Significance  to  Mental  Health  Research  and  the  Program  of  the  Institute: 
Because  of  the  unreliability  of  psychiatric  diagnoses  and  their  limited 
utility,  many  investigators  have  turned  to  mathematical  models  to  define  more 
meaningful  groups  of  psychiatric  patients.   These  efforts  may  one  day  be 

55 


Serial  No.  M-AP(C)-16-4 

important  in  defining  groups  of  patients  with  similar  causes  and  courses  of 
their  disorders  and  similar  responses  to  treatment  and  thus  provide  consider- 
able progress  in  research,  treatment,  and  prevention  of  psychiatric  disorders. 
The  mathematical  models  currently  in  use  have  many  weaknesses  that  must  be 
recognized  and  eliminated  before  such  a  step  can  take  place.   By  comparing 
different  methods  of  data  analysis  with  the  same  group  of  patients,  we  have 
identified  some  of  these  weaknesses,  attempted  to  develop  a  more  useful  tech- 
nique of  data  analysis  with  more  meaningful  and  stable  output  and  to  use  this 
technique  to  study  how  appropriate  typological  diagnostic  concepts  are  to  the 
nature  of  psychiatric  disorder. 

Proposed  Course  of  the  Project:   The  work  completed  has  been  prepared  for 
publication.   Further  efforts  continue  along  two  major  directions:   (1)  the  use 
of  different  techniques  to  define  more  of  the  problem  areas  and  to  develop 
more  satisfactory  methods  for  grouping  patients;   (2)  an  alternate  direction, 
the  developing  of  dimensions  of  psychiatric  function  for  Identifying  psychiat- 
ric patients  rather  than  attempting  to  place  patients  into  discrete  groups. 

Publications:   Bartko,  J.  J.,  Strauss,  J.  S. ,  Carpenter,  W.  T.,  Jr.: 
An  evaluation  of  taxometric  techniques  for  psychiatric  data.   Classification 
Society  Bulletin,  2(3),  1971. 

Presentations :   Diagnostic  Models  and  the  Nature  of  Psychiatric  Disorder. 
Invited  paper  presented  at  the  Annual  Meeting  of  the  Classification  Society, 
Chicago,  April  24,25,  1972,  by  John  S.  Strauss,  M.D. 


56 


Serial  No.  M-AP(C)-16-5 

1.  Adult  Psychiatry  Branch 

2.  Psychiatric  Assessment  Section 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:   Serum  Enzymes  in  Acute  Psychotic  States 

Previous  Serial  Number:   M-AP(C)-16-5 

Principal  Investigators:   John  S.  Strauss,  M.D.;  Herbert  Meltzer,  M.D.; 

William  T.  Carpenter,  Jr.,  M.D. 

Man  Years : 

Total:  0.2 
Professional:  0.1 
Others:        0.1 

Project  Description: 

Objectives:   In  an  attempt  to  determine  relationships  between 
biochemical  findings  and  psychotic  conditions.  Dr.  Meltzer  has  demonstrated 
that  creatine  kinase  and  serum  aldolase  levels  are  often  elevated  in  acute 
psychotic  states.   The  objective  of  this  project  is  to  determine  more 
precisely  in  which  psychotic  conditions  these  enzymes  are  elevated.  By  the 
use  of  standardized  diagnostic  interviews  to  obtain  information  on  a  wide 
variety  of  symptoms  and  environmental  conditions  it  will  be  possible,  using 
a  sample  of  patients  to  define  more  clearly  the  correlations  of  individual 
symptoms  with  enzyme  elevations.   It  will  be  possible  in  this  way  to  evaluate 
how  reliably  these  enzyme  methods  differentiate  schizophrenic  patients  from  other 
psychotic  and  borderline  conditions. 

Methods  Employed:  A  series  of  patients  is  being  interviewed  using 
standardized  mental  status,  history  and  social  description  interviews. 
Blood  is  drawn  at  the  time  of  the  mental  state  interview  and  analyzed  employing 
methods  currently  in  use  by  Dr.  Meltzer  for  determining  serum  aldolase  and 
creatine  kinase. 

Major  Findings;   An  initial  sample  of  patients  has  been  tested  with  the 
techniques  described  and  preliminary  findings  suggest  that  degree  of 
"cognitive  disorganization"  as  defined  by  a  group  of  mental  status  items, 
correlates  more  closely  than  other  parameters  with  elevated  enzyme  levels. 

Significance  to  Mental  Health  Research  and  Program  of  the  Institute: 
There  is  much  interest  in  determining  whether  schizophrenia  and  other  psycho- 
tic conditions  can  be  related  to  particular  biochemical  and  other  physiological 
measures.   Although  there  is  some  evidenze  for  such  relationships  in  regard 

57 


Serial  No.  M-AP(C)-16-5 

to  certain  affective  psychoses,  evidence  for  similar  relationships  in  schizo-    ■ 
phrenia  is  mere  controversial.   Dr.  Meltzer  has  been  able  to  demonstrate        ■ 
relationships  between  creatine  kinase  and  serum  aldolase  in  psychotic  condi-     ■ 
tions  but  it  is  not  clear  yet  to  what  extent  elevations  in  these  enzymes  are 
related  to  (1)  the  acuteness  of  the  psychotic  conditions,  and  (2)  particular 
clinical  pictures.   In  the  present  study,  it  will  be  possible  to  help  clarify 
some  of  these  relationships  as  well  as  to  evaluate  by  replication  Dr.  Meltzer 's 
earlier  work. 

Proposed  Course  of  the  Project;   A  larger  series  of  patients  is  being 
evaluated.   On  completion  of  the  data  collection,  sjTuptom  patterns  will  be 
compared  to  the  results  of  the  enzjnne  determinations  to  see  whether  a 
meaningful  relationship  exists. 


58 


Serial  No.  M-AP(C)-16-6 

1.  Adult  Psychiatry  Branch 

2.  Psychiatric  Assessment  Section 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:   Psychiatric  History  Study:  The  Nature  and  Reliability  of  the 
Data 

Previous  Serial  Number:  M-AP(C)-16-6 

Principal  Investigators:   John  S.  Strauss,  M.D.,  William  T.  Carpenter,  Jr.,  M.D. 

Other  Investigators:   Ruth  E.  Boesman,  R.N. 

Cooperating  Units:   John  Bartko,  Ph.D.,  Biometrics  Branch,  Nursing  Units, 
4-E,  4-W,  3-E,  3-W,  NIH,  Clinical  Center 

Man  Years : 

Total:         0.1 
Professional:   0.07 
Others:        0.03 

Project  Description: 

Objectives :   (1)  To  identify  different  types  of  data  ordinarily  obtained 
in  psychiatric  history  interviewing.   (2)  To  study  the  reliability  for  these 
data  as  obtained  from  the  patient  compared  to  that  obtained  from  his  relative. 
(3)  To  study  the  effect  of  when  in  the  course  of  hospitalization  data  is  ob- 
tained on  the  nature  of  the  data  elicited.  (4)  To  learn  how  psychiatric 
history  is  obtained  in  various  psychiatric  settings.   These  data  will  be  used 
to  examine  the  hypothesis  that  there  is  a  greater  variability  in  psychiatric 
history  information  than  is  usually  expected  and  that  the  nature  of  the  data 
obtained  relates  to  the  degree  of  variation. 

Methods  Employed:  Standardized  psychiatric  history  and  social  description 
interview  schedules  developed  for  the  International  Pilot  Study  of  Schizophrenia 
were  utilized  in  interviewing.   The  first  20  admissions  to  one  of  the  psychia- 
tric nursing  units  who  also  had  relatives  available  as  informants  were  inter- 
viewed.  The  patient  and  relative  were  interviewed  within  one  week  of  admission 
and  again  six  weeks  later.   The  same  interview  schedules  were  used  in  each 
interview  and  the  interviewing  was  rotated  between  the  three  investigators 
listed  above  in  an  effort  to  keep  the  interviewer  as  naive  as  possible  to 
patient  information  other  than  that  obtained  during  the  interview. 

A  questionnaire  was  sent  to  a  large  number  of  facilities  that  admit 
psychiatric  patients  in  the  United  States.   This  questionnaire  requested 


59 


Serial  No.  M-AP(C)-16-6 

information  about  who  interviews  whom  and  at  what  time  to  obtain  psychiatric 
history  information.   Data  has  been  collected  from  20  patients  and  their 
relatives  and  is  being  analyzed  to  determine  reliability.   Narrative  summaries 
of  the  interviews  and  certain  key  items  are  being  examined  by  the  investigators 
in  order  to  determine  comparability  of  the  less  structured  aspect  of  psychiatric 
history  evaluation. 

Major  Findings;  Results  show  that  data  obtained  by  structured  questions 
is  most  reliable.   Several  areas  of  data  such  as  duration  of  illness,  acuteness 
of  onset  and  precipitating  factors  have  low  reliability.   These  findings  chal- 
lenge the  validity  of  many  concepts  of  psychiatric  disorder  that  are  based  on 
results  from  unstructured  collection  of  these  data. 

Significance  to  Mental  Health  Research  and  the  Program  of  the  Institute: 
The  relationship  of  past  experience  to  present  behavior  is  fundamental  to  most 
psychological  theories  of  behavior  and  mental  function.   There  is  a  paucity 
of  data  testing  the  reliability  and  validity  of  background  information  obtained 
from  psychiatric  patients  and  their  families.   This  study  will  attempt  to 
identify  the  various  means  of  collecting  past  history  from  psychiatric  inpa- 
tients in  various  settings  and  to  identify  the  pitfalls  involved  in  interpret- 
ing this  information. 

Proposed  Course  of  the  Project:   The  findings  are  being  prepared  for 
publication. 


60 


Serial  No.  M~AP(C)-16-7 

1.  Adult  Psychiatry  Branch 

2.  Psychiatric  Assessment  Section 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:   The  Evaluation  of  Outcome  in  Schizophrenia 

Previous  Serial  Number:   None 

Principal  Investigators:   John  S.  Strauss,  M.D. 

William  T.  Carpenter,  Jr.,  M.D. 

Man  Years: 

Total:  1.1 

Professional:  0.8 

Other:  0.3 

Project  Description: 

Objectives;   (1)  To  describe  the  characteristics  of  outcome  in  schizo- 
phrenia.  (2)  To  study  the  predictors  of  outcome  in  schizophrenia  including 
premorbid  history,  social  background,  duration  of  illness,  diagnosis,  and 
symptomatology.   (3)  To  use  outcome  measures  as  means  for  evaluating  the 
validity  of  different  diagnostic  systems. 

Methods  Employed:   Two-year  follow-up  results  from  the  patients  seen  by 
the  staff  of  the  Psychiatric  Assessment  Section  for  the  International  Pilot 
Study  of  Schizophrenia  (M-AP(C)-16-1)  were  rated  with  scales  developed  for 
the  study.   These  outcome  results  were  compared  with  patient  diagnoses  as  de- 
termined by  the  criteria  of  the  Diagnostic  and  Statistical  Manual  of  the  APA, 
Kurt  Schneider's  first  rank  symptoms,  and  Langfeldt's  criteria  for  true 
schizophrenia.   Outcome  results  were  also  compared  with  individual  symptoms  and 
sixteen  items  rating  areas  of  premorbid  functioning. 

Major  Findings:   Results  showed  that  outcome  itself  is  not  a  unitary 
concept,  but  consists  of  at  least  four  dimensions:   social  functioning,  sjrmp- 
tomatology,need  for  hospitalization,  and  ability  to  work.   Each  of  these 
variables  was  independent  enough  from  the  others  to  suggest  that  outcome 
represents  an  open-linked  system  comprised  of  several  semi-independent  variables. 
This  view  of  outcome  was  further  supported  by  the  fact  that  each  area  of  outcome 
was  best  predicted  by  the  corresponding  area  of  premorbid  function:   outcome 
social  function  by  premorbid  social  function,  outcome  symptoms  by  previous 
duration  of  symptoms,  outcome  need  for  hospitalization  by  previous  hospitaliza- 
tion, and  outcome  ability  to  work  with  previous  ability  to  work.   On  the  other 
hand,  none  of  the  diagnostic  systems  or  individual  sjmiptoms  were  able  co  predict 
outcome  to  a  significant  degree.   Together,  these  findings  suggest  that  outcome 

61 


% 


Serial  No.  M-AP(C)-16-7 

( 
is  far  more  determined  by  longitudinal  dimensions  of  function  than  by  particular 
sjrmptoms  or  sjiaptom  patterns. 

Significance  to  Mental  Health  Research  and  the  Program  of  the  Institute; 
There  has  been  much  doubt  whether  certain  symptom  patterns  are  adequate  to  define 
psychiatric  "diseases"  with  predictable  outcomes.   Such  a  conception  would  imply 
a  concept  of  psychiatric  disorder  very  similar  to  many  medical-surgical  illnesse 
The  current  study  suggests  that  this  conception  of  psychiatric  disorder  is  in- 
correct and  that  the  major  determinants  of  outcome  are  enduring  personality 
structures  rather  than  a  particular  "disease"  process.   This  implies  that  the 
causes  and  treatments  for  prolonged  disability  might  best  be  aimed  at  personality 
variables  rather  than  at  a  supposed  disease  process. 

Proposed  Course  of  the  Project;   The  initial  sample  of  140  patients  is 
being  augmented  by  addition  of  the  patients  admitted  to  the  4-East  clinical- 
research  ward.   More  intensive  investigation  into  the  functional  determinants 
of  outcome  will  be  carried  out  to  understand  the  outcome  process  more  clearly. 

Publications;   Strauss,  J.S.;  Carpenter,  W.T.,  Jr.   The  Evaluation  of 
Outcome  in  Schizophrenia,   To  be  published  in  Life  History  Research  in  Psycho- 
pathology,  Vol.  3.   Edited  by  Thomas,  A.,  Roff,  M. ,  and  Ricks,  D.F.   University 
of  Minnesota  Press ,  Minneapolis  . 

Presentations;  Presented  by  John  S.  Strauss,  M.D. 

1.  The  Fate  of  Schizophrenic  Patients,  presented  at  the  Annual  Meeting  of  the 
Mental  Health  Career  Development  Program.  New  Orleans,  March  1972. 

2.  The  Evaluation  of  Outcome  in  Schizophrenia,  presented  at  the  annual  meeting 
of  the  Society  for  Study  of  Life  History  and  Psychopathology.  New  York,  April 
14-15,  1972. 

3.  Diagnostic  Criteria  and  Outcome  in  Schizophrenia,  presented  at  the  annual 
meeting  of  the  American  Psychiatric  Association.  Dallas,  May  1-5,  1972. 


62 


C 

i 


Serial  No.  M-AP(C)-16-8 

1.  Adult  Psychiatry  Branch 

2.  Psychiatric  Assessment  Section 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:  Psychobiology  of  Cortisol  Metabolism 

Previous  Serial  Number:  None 

Principle  Investigator:  William  T.  Carpenter,  Jr.,  M.D. 

Other  Investigators:  William  E.  Bunney,  M.D.,  John  S.  Strauss,  M.D., 
Laurence  Drell ,  M.D. 

Cooperating  Units:  Section  on  Psychiatry,  Laboratory  of  Clinical  Science, 
Section  on  Cognitive  and  Perceptual  Studies,  APB 

Man  Years: 

Total:        .2 
Professional:  .15 
Other:        .05 

Project  Description: 

Objectives:  (1)  To  utilize  sophisticated  techniques  for  determining 
metabolism  of  Cortisol  in  psychiatric  patients.  (2)  To  evaluate  manic- 
depressive  patients  with  a  battery  of  investigations  that  provide  comprehensive 
information  regarding  their  Cortisol  metabolism.  (3)  To  investigate  the  re- 
lationship between  Cortisol  metabolism,  psychophysiology,  and  psychopathology. 
(4)  To  determine  if  Cortisol  variability  relates  to  schizophrenic  diagnostic 
subgroups  or  outcome. 

Methods  Employed:  Radioisotope  dilution  methodology  was  used  to  determine 
production  rates  and  metabolic  clearance  rates  of  Cortisol.  Plasma  concentra- 
tion at  various  hours  of  the  day  and  24-hour  urinary  output  of  Cortisol  was 
determined  with  routine  laboratory  procedures. 

Standardized  clinical  assessment  techniques  are  now  being  employed  to  give 
detailed  clinical  information  to  relate  to  steroid  variability.  Perceptual  and 
cognitive  test  procedures  are  being  carried  out  in  collaboration  with 
Dr.  Buchsbaum. 

In  a  cohort  of  depressed  patients,  it  was  determined  that  central  mech- 
anisms controlling  Cortisol  metabolism  functioned  abnormally.  The  mechanisms 
which  determine  response  to  dexamethasone  suppression,  methopyrapone  stimula- 
tion, ACTH  stimulation  and  circadian  rhythm  were  intact  in  depressed  patients. 
However,  determining  metabolic  clearance  rates  and  production  rates  of  Cortisol 

63 


SeriP.l  No.  M«AP(C)-16-8 

suggests  that  depressed  patients  produce  more  Cortisol  and  metabolize  it  more 
rapidly,  while  maintaining  normal  plasma  concentration.  On  recovery,  these  same 
patients  reduce  their  production  rates  while  maintaining  an  abnormally  high 
metabolic  clearance  rate,  and,  consequently,  reduced  plasma  concentration. 
These  findings  suggest  two  interesting  possiblities :  (1)  That  psychological 
and  biological  effects  of  rapid  turnover  of  Cortisol  may  be  critical  in  de- 
pressive illness;  and  (2)  the  finding  of  reduced  plasma  concentration  and 
production  rate  on  recovery  v^lle  an  increased  clearance  rate  is  maintained, 
suggests  the  possibility  that  relative  adrenal  insufficiency  may  be  related  to 
the  biological  vulnerability  to  depression. 


Significance  to  Mental  Health  Research  and  the  Program  of  the  Institute: 
The  results  of  this  work  have  focused  attention  on  the  need  for  sophistication 
in  technical  approaches  to  Cortisol  research  in  psychiatry.  Static  measures 
alone  (e.g.,  plasma  concentration  for  24-hour  excretion  rate)  may  be  misleading 
about  the  physiologic  activity  of  Cortisol.  Findings  to  date  require  a  re- 
consideration of  Cortisol  metabolism  regarding  manic-depressive  disorders.  The 
possibility  of  relative  adrenal  insufficiency  in  depressive  disorders  reopens 
an  area  of  research  which  has  been  dwarfed  by  the  number  of  findings  based  on 
static  measures  suggesting  either  normal  or  Increased  adrenal  function  with 
depressive  Illness.  If  there  is  a  biological  vulnerability  based  on  adrenal 
insufficiency,  this  may  be  obscured  by  stimulated  Cortisol  production  during 
the  distress  of  depressive  illness.  Studying  patients  during  recovered,  low 
stress  periods  provide  an  opportunity  to  identify  basic  biological  dispositions. 

Proposed  Course  of  Project:  Studies  of  Cortisol  metabolism  are  being 
incorporated  into  the  4-East  clinical  unit's  research  program.  In  keeping  with 
the  major  thrust  of  the  work  on  4-East,  there  will  be  careful  attention  to  the 
clinical  variables  related  to  altered  steroid  metabolism  and  the  possibility 
of  using  biological  variables  such  as  steroid  metabolism  as  validating  criteria 
to  test  classifcation  systems.  The  relationship  between  steroids,  psychopath- 
ology  and  psychophysiology  will  be  investigated  in  collaboration  with  the 
Section  on  Perceptual  and  Cognitive  Studies,  APB. 

Honors  and  Awards:  None 

Publications: 

Carpenter,  W.  T.,  Jr.,  Bunney,  W.  E.:  Adrenal  Cortical  Activity  in 
Depressive  Illness,  Amer.  J.  Psychiat.  128:  31-40,  1971. 

Carpenter,  W.  T.,  Jr.,  Bunney,  W.  E.:  Dirunal  Rhythm  of  Cortisol  in 
Mania,  Arch.  Gen.  Psychiat.  25^:  270-273,  1971. 

Carpenter,  W.  T.,  Jr.,  Bunney,  W.  E.:  Behavioral  Effects  of  Cortisol 
in  Man,  Seminars  in  Psychiatry  3:  421-434,  1971. 

Carpenter,  W.  T.,  Jr.,  Strauss,  J.  S.,  Bunney,  W.  E.:  The  psychobiology 
of  Cortisol  Metabolism:  Clinical  and  Theoretical  Implications,  to' be  published 
in  Psychiatric  Aspects  of  Medical  Drugs,  R.  I.  Shader  (ed.).  Raven  Press, 


I 


6k 


Serial  No.  M-AP(C)-16-8 

Presentations: 

The  Serotonin  Depletion  Hypothesis  in  Depressive  Disorder,  presented  by 
Dr.  Carpenter  to  the  Tenth  Annual  Conference  of  the  Mental  Health  Career 
Development  Program,  Tucson,  Arizona,  1971. 


65 


Serial  No.  M-AP(C)-16-9 

1.  Adult  Psychiatry  Branch 

2.  Psychiatric  Assessment  Section 

3.  Bethesda,  Maryland 


PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 


Project  Title:   Research  Interviews:  Are  They  Valid? 

Previous  Serial  Number:   None 

Principal  Investigators:   Michael  H.  Sacks,  M.D. 

John  S.  Strauss,  M.D. 


William  T.  Carpenter,  Jr.,  M.D, 


Man  Years : 

Total: 

.2 

Professional: 

as 

Other : 

.05 

Project  Description: 

Objectives :   To  test  the  validity  of  structured  mental  status  interviews 
used  for  research  and  clinical  purposes. 

Methods  Employed:   Twenty  patients  admitted  to  a  research  unit  for  acutely 
psychotic  patients  were  interviewed  within  the  first  week  of  admission  using 
the  Psychiatric  Assessment  Interview  (PAI),  a  modification  of  the  Present  State 
Examination  (PSE)  used  in  the  International  Pilot  Study  of  Schizophrenia.   Two 
weeks  after  admission,  the  patient's  psychiatrist  filled  out  a  PAI  schedule 
utilizing  information  obtained  from  the  patient,  family,  spouse,  nursing  staff, 
etc.   The  initial  evaluation  interview  and  the  schedule  completed  on  the  basis 
of  all  information  available  was  then  compared. 

Major  Findings:    (1)  The  ratings  on  the  two  week  PAI  generally  described 
more  pathology  than  those  from  the  initial  PAI.   (2)  This  difference  was 
especially  marked  for  observed  behavioral  data  (signs)  and  minimal  for  reported 
symptoms.   (3)  Patient  classifications  based  on  the  two  interviews  were  iden- 
tical for  each  patient  if  a  diagnostic  system  such  as  Kurt  Schneider's  symptoms 
as  criteria  were  used.   For  those  systems  such  as  cluster  analysis  depending 
more  on  both  signs  and  symptoms,  patient  classification  often  changed  markedly 
from  the  initial  to  the  second  interview.   (4)  Diagnostic  categories  such  as 
catatonic  schizophrenia  which  are  most  dependent  on  behavioral  ratings  were 
especially  likely  to  change  when  initial  interview  and  the  second  schedule 
were  compared. 

Significance  to  Mental  Health  Research  and  the  Program  of  the  Institute: 
Structured  mental  status  interviews  have  become  a  major  instrument  in  studies 

67 


Serial  No.  M-AP(C)-16-9 


of  psychiatric  patients.   They  have  been  used»  for  example,  as  basic  data  col- 
lection instruments,  the  International  Pilot  Study  of  Schizophrenia  and  the 
United  States-United  Kingdom  Study  of  Psychiatric  Disorder.  With  structured 
interviews  of  demonstrated  reliability,  large  amounts  of  data  accumulated  by 
different  psychiatrists  at  different  centers  can  be  collected  and  compared. 
However,  the  degree  to  which  these  interviews  provide  data  that  accurately 
reflects  all  information  available  about  the  patient's  current  psychiatric 
status  has  not  previously  been  evaluated.   The  results  of  the  present  study 
suggest  that  for  certain  diagnostic  systems  and  certain  psychiatric  conditions 
such  mental  status  interviews  are  very  adequate,  but  for  these  diagnostic 
system.s  or  psychiatric  conditions  depending  more  on  observed  behavior,  results 
from  strucured  interviews  must  be  accepted  with  reservation. 


Serial  No.  M-AP(C)-16-10 

1.  Adult  Psychiatry  Branch 

2.  Psychiatric  Assessment  Section 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:  The  Recovery  Process  and  Research  Data  in  Acute  Psychosis 

Previous  Serial  Number:  None 

Principal  Investigators:  Michael  Sacks,  M.D. 

William  T.  Carpenter,  Jr.,  M.D. 
John  S.  Strauss,  M.D. 

Man  Years: 

Total:  .2 

Professional:  .18 

Other:  .02 

Project  Description: 

Objectives:  (1)  To  define  the  different  phases  of  the  psychotic  process 
as  the  patient  moves  from  severe  decompensation  toward  recovery.  (2)  To 
describe  the  kinds  of  research  Investigations  the  patient  is  able  to  par- 
ticipate in  as  he  passes  through  these  phases,  and  the  implications  of  this 
phasic  process  for  interpreting  results  of  research  on  psychosis. 

Methods  Employed:  Acutely  psychotic  patients  were  observed  during  the 
course  of  their  Illnesses  as  they  participated  or  failed  to  participate  in 
different  research  projects.  Independent  behavior  ratings  were  compared  with 
the  patients'  research  performances.  These  observations  were  supplemented 
by  interviews  with  the  patient,  held  prior  to  discharge,  regarding  his  views 
on  the  research  procedures. 

Major  Findings:  Distinct  phases  of  patient's  illness  have  been  identified. 
The  three  phases  are:  (1)  The  out-of-contact  phase  during  which  patients 
typically  were  unaware  of  research  expectations.  Thought  processes  are 
fragmented  and  delusional.  During  this  time  the  patient  is  unavailable  for 
any  kind  of  research  that  involves  active  cooperation  with  another  person  or 
cognitive  engagement  in  a  task.  (2)  Double-awareness  phase  during  which 
the  patient  is  still  delusional,  but  has  become  aware  of  the  ward  research 
program.  A  capacity  for  insight  of  his  symptoms  has  begun  and  the  patient 
begins  to  modify  his  behavior  despite  severe  symptoms.  Participation  and 
cooperation  in  complex  research  tasks,  although  tedious,  are  now  possible 
even  though  delusional  interpretations  of  procedures  may  suggest  a  danger 
to  the  patient  and.  In  fact.  Influence  the  way  in  which  he  takes  the  test. 
(3)  The  recovery  phase  during  which  the  patient  is  able  to  realistically  perceive 
and  evaluate  the  research  and  his  participation  in  it  comes  with  significant 
clinical  improvement.  When  the  patient  fails  to  cooperate  In  research  procedures, 


Serial  No.  M-AP(C)-16-10 


1 

nit  I 

I 


he  has  clear  reasons  for  refusing— which  reflect  his  attitude  toward  the  un 
or  his  doctor.  Themes  about  the  research  which  were  present  in  delusional 
form  during  earlier  phases  may  continue,  but  are  now  expressed  more 
rationally  in  a  therapeutic  relationship.  Research  that  can  be  carried  out  is 
restricted  by  the  phase  through  which  the  patient  is  passing.  In  the  more 
disturbed  phase,  no  information  is  obtainable  about  either  response  or  other 

5S  reqi 

spects 


aisturoea  pnase,  no  inrormation  is  obtainable  about  either  response  or  other  ■ 
measures  requiring  active  collaboration  of  the  patient;  as  the  patient  improves* 
more  aspects  of  his  function  can  be  evaluated.  ■! 

I 


Significance  to  Mental  Health  Research  and  the  Program  of  the  Institute: 
The  major  focus  of  experimental  research  on  psychosis  in  the  past  has 
often  been  on  chronic  patients.  Only  recently  has  greater  attention  been 
directed  toward  the  acute  patient.  This  study  attempts  to  define  phases  of 
the  acute  process  and  to  demonstrate  their  interrelationship  to  the  research 
findings  and  conclusions  that  can  be  drawn  from  them.  Identifying  the  psycho- 
logical set  during  collection  of  data  provides  a  framework  for  interpreting 
results  which  enriches  the  disease  model  or  simple  behavioral  rating  approach. 


TO 


Serial  No.  M-AP(C)-16-11 

1.  Adult  Psychiatry  Branch 

2.  Psychiatric  Assessment  Section 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:   Investigation  of  the  Schizophrenic  Process  Through  Art 
Productions  of  Acutely  Psychotic  Patients 

Previous  Serial  Number:   None 

Principal  Investigator:  Harriet  Wades on 

Cooperating  Unit:  4-East  Nursing  Unit,  Clinical  Center,  NIH 

Man  Years : 

Total:  0.6 
Professional  0.5 
Other:        0.1 

Project  Description: 

Objectives;   (1)  To  obtain  art  productions  from  acutely  psychotic  patients 
at  intervals  during  the  course  of  their  hospitalization  and  follow-up.   (2)  To 
utilize  the  art  productions  in  conjunction  with  other  clinical  assessments  for 
the  purpose  of  diagnosis.   (3)  To  compare  and  study  the  art  productions  and  the 
patients'  associations  to  them  in  order  to  gain  a  greater  understanding  of  the 
schizophrenic  process  by:  (a)  investigating  longitudinal  changes  by  comparing 
pictures  made  during  acute  psychosis,  recovery,  and  follow-up;  (b)  studying, 
in  detail,  delusions,  hallucinations,  and  other  manifestations  of  schizophrenic 
thinking  as  revealed  in  the  art  productions;  (c)  comparing  art  productions  of 
different  patients  with  one  another  in  order  to  delineate  subgroups  of  schizo- 
phrenic ideation;  (d)  contrasting  the  art  productions  of  schizophrenic  patients 
with  those  of  manic  and  depressed  patients. 

Methods  Employed;  All  patients  on  a  research  ward  for  the  study  of  acute 
schizophrenia  are  evaluated  in  individual  art  therapy  sessions  shortly  after 
admission,  just  prior  to  discharge,  and  at  follow-up.   Some  patients  have  add- 
itional sessions  during  the  course  of  hospitalization  if  there  is  marked  change 
in  the  patient's  condition.   Patients  are  provided  with  simple  media  and  en- 
couraged to  express  themselves  freely  and  to  free  associate  to  their  pictures. 
At  each  session  they  are  requested  to  make  three  pictures:  (1)  whatever  they 
want  to  draw;  (2)  a  self  portrait;  (3)  a  picture  of  the  illness.   If  there  is 
indication  that  a  patient  is  hallucinating  or  has  in  the  past,  he  is  asked  to 
make  a  picture  of  it.   If  there  are  other  pictures  that  patients  particularly 
want  to  produce,  either  during  the  session  or  at  another  time,  they  are  encour- 
aged to  do  so  and  to  discuss  them  with  the  investigator.   To  date  18  patients 


71 


i 


Serial  No.  M-AP(C)-16-11 

have  been  studied.   Each  session  is  recorded  on  audiotape  and  a  suirrmary  is 
written  by  the  investigator. 

Ma.jor  Findings:   Although  it  is  too  early  to  report  any  solid  findings, 
certain  trends  have  appeared  which  are  being  studied  further.   The  parameter 
of  organization  in  the  pictures  seems  to  be  particularly  revealing  of  intra- 
psychic states.   The  changes  in  balance  between  richness  and  impoverishment 
in  the  pictures  (the  latter  is  often  indicative  of  depression  [H,  Wadeson, 
Characteristics  of  Art  Expression])  both  within  the  same  patient  and  among 
patients  provides  important  data  on  the  process  of  the  illness.   Changes  in 
self-concept  during  the  course  of  psychosis  and  recovery  and  differences  in 
self-concept  among  patients  is  an  important  discriminator.   Pictures  of  hal- 
lucinations, delusional  systems,  and  other  manifestations  of  schizophrenic 
functioning  are  extremely  useful  in  furnishing  greater  understanding  of  the 
patient's  experience  of  his  psychosis. 

Significance  to  Mental  Health  Research  and  the  Program  of  the  Institute; 
There  is  little  data  of  a  comparative  nature  on  the  art  productions  of  any 
particular  population.  Most  of  the  writing  in  this  area  is  directed  toward 
therapeutic  benefits  rather  than  diagnosis  and  evaluation.  Where  such  reports 
exist,  they  are  primarily  speculative  and  do  not  report  characteristics  of  a 
designated  population  that  has  been  studied  systematically.   The  purpose  of 
this  project  is  to  help  counter  this  lack.   In  a  broader  sense,  although  the 
outward  manifestations  of  acute  schizophrenia  are  readily  studiable,  (symptoms,  | 
progress,  etc.)  the  inner  experience  of  the  affected  individual  is  much  less 
accessible.   Hopefully,  this  investigation  will  provide  data  in  this  area. 
Finally,  in  conjunction  with  other  parameters  of  assessment,  it  is  hoped  that 
the  data  obtained  from  the  art  evaluations  will  add  to  the  clarity  of  differ- 
ential diagnostic  dimensions  in  acute  schizophrenia. 

Proposed  Course  of  the  Project:   During  the  coming  year  the  sample  will 
be  enlarged  and  the  developing  trends  investigated  systematically.   Also,  new 
trends  will  be  noted  and  studied.   In  addition,  the  data  from  this  project  will 
be  compared  with  data  from  art  productions  of  manic  and  depressed  patients,  of 
which  the  investigator  has  accumulated  an  abundance  on  past  projects. 

Publications ; 

Wadeson,  Harriet:  Characteristics  of  Art  Expression  in  Depression.  J.  Nerv. 

Ment.  Pis.,  153(3),  Sept.  1971. 
Wadeson,  Harriet,  Fitzgerald,  Roy:  Marital  Relationship  in  Manic-Depressive 

Illness:  Conjoint  Psychiatric  Art  Evaluations.  J.  Nerv.  Ment.  Dis. ,  153 (3), | 

Sept.  1971.  ■ 

Wadeson,  Harriet:  Conjoint  Marital  Art  Tlierapy  Techniques.  Psychiatry.  Feb. 

1972. 
Wadeson,  Harriet:  Portraits  of  Suicide.  Publication  of  exhibit.  Annual  Meeting, 

American  Psychiatric  Association,  Washington,  D.C.,  May  1971. 

Awards :  Rush  Bronze  Medal  Award 


72 


Serial  No.  M-AP(C)-17-1 

1.  Adult  Psychiatry  Branch 

2.  Section  on  Personality  Development 

3.  Bethesda,  Maryland 


PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:   A  Study  of  Problems  in  Growth  and  Adaptation  in  the 
Personality  Development  of  the  Adolescent 

Previous  Serial  Number:   None 

Principal  Investigator:   Roger  L.  Shapiro,  M.D. 

Other  Investigators:   Carmen  Amoros-Cabrera,  M.S.W.;  Carl  Feinstein,  M.D. ; 
Stuart  Hauser,  M.D. ;  Richard  MacDonald,  M.D. ; 
Winfield  Scott,  Ph.D.;  Robert  Winer,  M.D. ;  and 
John  Zinner,  M.D. 

Cooperating  Units:  Unit  3-West 

Man  Years 

Total:   3.9 
Professional:   3.3 
Other:  .6 

Project  Description: 

Objectives.   Our  investigation  of  personality  development  in  the 
individual  adolescent  focuses  upon  study  of  the  family  group  and  the  social 
group  of  which  he  is  a  part.   We  assume  that  there  is  a  correspondence 
between  the  structure  of  the  individual  personality  system  and  the  structure 
of  external  reality  which  has  impinged  on  that  personality  throughout 
development,  especially  the  social  system  and  its  subsystems.   Personality 
theory  generally  relies  heavily  on  the  individual's  account  of  his  own 
developmental  experience  in  interpersonal,  family,  and  group  situations, 
to  understand  his  personality  formation  and  functioning.   In  our  program 
of  research  we  observe  directly  the  individual  adolescent  in  interaction 
with  his  family  group  and  social  group.   These  observations  provide  an 
objective  measure  against  which  to  assess  the  individual's  statements  about 
his  own  experience.   Such  observations  are  a  necessary  step  in  verification 
of  theory  postulating  social  determinants  of  personality  functioning.   In 
addition,  such  observations  clarify  the  individual's  psychological  meaning 
to  significant  others.   This  is  crucial  to  understanding  their  behavior 
towards  him  and  its  effect  upon  his  psychological  functioning. 

Methods .   Our  early  studies  of  adolescents  in  emotional  crises  over 
separation  from  their  families  included  psychotherapy  of  hospitalized 
adolescents  and  research  interviewing  and  psychological  testing  of  the 
adolescent  and  his  parents  separately.   A  comparison  group  of  adolescents 

73 


Serial  No.  M-AP(C)-17-1 

1.  Adult  Psychiatry  Branch 

2.  Section  on  Personality  Development   ' 

3.  Bethesda,  Maryland 

who  were  developing  normally  was  studied  in  individual  interviews  and 
family  interviews.  A  difference  was  found  between  patient  families  and 
normal  families  in  the  capacity  to  tolerate  autonomous  behavior  in  the         i 
adolescent  and  none-the-less  maintain  relatedness  to  him;  that  is,  the         i 
patient  families  manifested  difficulties  in  these  areas  while  the  normal 
families  did  not. 

We  noticed  repeated  discrepancies  in  the  patient  families  between 
the  adolescent's  statements  about  parental  attitudes  towards  his 
independent  functioning  and  the  parents'  own  statements  of  attitude  toward 
independent  behavior  in  the  adolescent.   We  became  interested  in  these 
discrepant  views  and  in  order  to  investigate  them  further,  began  to  study 
the  adolescent  and  his  parents  in  interaction.   We  added  conjoint  family 
therapy  to  our  treatment  program.   We  could  now  observe  directly  transactions 
between  adolescent  and  parents.   This  has  remained  a  major  focus  of  our 
study.  We  have  developed  methods  for  defining  characteristics  of  parent- 
adolescent  interaction  and  formulating  the  relation  of  these  behaviors  to 
the  identity  problem  of  the  adolescent.   We  define  characteristics  of  the 
boundary  between  the  family  and  the  individual  adolescent.  We  find  a 
relation  between  this  and  the  nature  of  self  boundaries  which  have  developed 
within  the  adolescent.   In  addition,  we  consider  how  characteristics  of 
self  boundaries  in  the  adolescent  determine  the  role  boundaries  he  establishes  \ 
in  new  interpersonal  and  group  situations. 

The  unique  feature  of  our  research  is  the  design  and  conduct  of  a 
program  in  which,  in  addition  to  intensive  individual  study  of  the  adolescent, 
he  is  studied  within  his  family  group  and  in  his  role  behavior  in  a  group 
situation  in  the  treatment  unit  or  (in  the  case  of  our  normal  sample)  in 
the  school.   For  the  past  two  years  our  psychiatric  unit  has  had  an 
entirely  adolescent  population  which  has  greatly  facilitated  our  ability 
to  study  the  role  the  adolescent  takes  in  peer  relations  and  authority  re- 
lations in  the  group  life  of  the  residential  treatment  unit. 

During  the  past  four  years  we  have  worked  with  normal  adolescents  at 
the  Sidwell  Friends  School  in  Washington.   For  purposes  of  comparison,  we 
have  studied  these  adolescents  in  situations  similar  to  those  in  which  we 
study  disturbed  adolescents.   We  have  seen  them  in  individual  research 
interviews,  in  family  study  groups  with  their  parents,  and  in  weekly 
groups  studying  peer  relations  and  authority  relations  in  the  school  setting,  i 

The  adolescents  we  have  hospitalized  in  our  treatment  unit  have  been 
between  ages  14-21  with  a  wide  range  of  disorders.   These  have  included 
adolescents  manifesting  a  variety  of  behavior  disorders  including  school 
and  work  failure,  drug  problems,  sexual  disturbances,  running  away,  and 
other  kinds  of  antisocial  acting  out;  we  have  also  studied  adolescents 
with  neurotic  disturbances  manifested  by  anxiety  symptoms  and  depression. 


Serial  No.  M-AP(C)-17-1 

as  well  as  adolescents  with  borderline  disorders  or  psychoses.   We  have 
treated  these  adolescents  and  their  families  for  periods  ranging  from 
6  months  to  2  years,  first  as  inpatients,  later  as  outpatients. 

Our  residential  treatment  program  includes  individual  psychotherapy 
for  the  adolescent,  conjoint  family  therapy,  and  study  of  the  hospital 
group  in  which  the  adolescent  lives  and  works.   It  combines  three  hours 
per  week  of  individual  psychotherapy  for  the  adolescent  with  a  weekly 
one-hour  conjoint  family  therapy  session;  one  hour  per  week  of  marital 
therapy  for  the  parents;  and  four  patient-staff  meetings  per  week,  including 
one  which  is  a  study  group  examing  peer  relations  and  authority  relations 
on  the  psychiatric  unit.   This  program  has  evolved  over  the  past  12  years 
during  which  time  increasing  integration  of  the  functions  of  study  and 
treatment  has  occurred.   We  have  designed  the  program  to  study  situations 
which  articulate  the  psychological  maturation  of  the  individual  adolescent 
with  hisexperience  within  his  family,  within  his  peer  group,  and  within 
the  social  institution  of  which  he  is  a  part. 

We  define  the  following  tasks  which  we  implement  within  the  program: 

(1)  To  explore  and  modify  the  internalizations  of  childhood  experience 
which  have  rendered  the  adolescent's  ego  vulnerable  and  unable  to  develop 
relative  autonomy  and  individuation.   This  is  the  task  of  individual 
psychotherapy . 

(2)  To  explicate  and  modify  the  actuality  of  current  family  dynamics 
which  are  interfering  with  adolescent  individuation  and  separation.   This 
includes  clarification  of  the  nature  of  the  boundary  between  the  parents 
as  a  marital  pair  and  the  adolescent.   This  is  the  task  of  conjoint  family 
therapy  and  marital  therapy. 

(3)  To  study  and  modify  the  adolescent's  functioning  in  a  new 
social  organization  away  from  the  family  in  which  he  has  the  opportunity 
to  develop  a  more  mature  and  responsible  relationsHjp  to  peers  and  to 
authority  figures  than  was  present  in  his  family  relations.   This  is  the 
task  of  the  unit  study  group. 

The  task  we  define  for  the  individual  psychotherapy  situation  includes 
study  of  the  internalizations  of  the  adolescent  through  his  projections 
in  the  transference.   In  our  patients  these  internalizations  interfere  with 
capacities  maturing  in  the  adolescent  for  making  new  relationships  outside 
of  the  family.   We  define  characteristics  of  the  adolescent's  internal 
objects  which  militate  against  new  relationships  through  engendering  anxieties 
over  separation,  sexual  anxieties,  or  anxieties  deriving  from  deficient 
models  for  adult  roles  and  relationships.   These  characteristics  of  inner 
objects  are  externalized  in  transference  phenomena  and  their  study  is  a 
central  task  in  the  work  of  psychotherapy. 


75 


Serial  No.  M-AP(C)-17-1 

The  integration  of  individual  psychotherapy  with  family  therapy 
includes  study  of  the  correspondence  between  transference  phenomena  in 
individual  therapy  and  the  actual  current  parent-adolescent  relationship 
family  therapy. 


1 

cond  Hi 


We  utilize  the  conjoiiit  family  therapy  situation  to  implement  the  se 
task  defined  above,  that  of  explicating  and  modifying  the  actuality  of 
current  family  dynamics  which  are  interfering  with  adolescent  individuation 
and  separation.   The  boundary  between  the  individual  adolescent  and  his 
family  as  a  group  is  studied.  We  conceptualize  transactions  across  this 
boundary  through  use  of  the  concept  of  delineation  and  through  a  related 
concept,  that  of  unconscious  assumptions  in  the  family  as  a  group. 

Delineation  is  a  concept  closely  linked  to  observable  behavior.   We 
define  as  delineations,  behaviors  through  which  one  family  member  communicates 
explicitly  or  implicitly  his  perceptions  and  attitudes — infact,  his  mental 
representation  of  another  family  member — to  that  other  person.   Through  use 
of  the  concept  of  delineation  we  make  formulations  involving  three  levels 
of  inference  from  observations  of  family  interaction.   A  first  level  of 
inference  is  that  specified  behaviors  in  one  person  imply  a  particular 
delineation  of  the  other  person. 

A  second  level  of  inference  is  about  the  determinants  of  delineation. 
Delineations  may  communicate  a  view  of  the  other  person  which  appears  to 
be  predominantly  determined  by  his  reality  characteristics.   However,  in 
the  families  of  disturbed  adolescents  we  find  that  delineations  frequently 
communicate  a  view  of  the  other  person  which  is  predominantly  determined  by 
mobilization  of  anxiety  and  defense  in  the  delineator.   We  call  these 
defensive  delineations.   We  pay  particular  attention  to  the  parents' 
defensive  delineations  of  the  adolescent.  When  parents'  delineations  are 
observed  to  be  distorted,  stereotyped,  and  over-specific,  contradictory, 
or  otherwise  incongruent  with  the  range  of  behaviors  manifested  by  the 
adolescent,  we  make  the  inference  that  these  delineations  serve  defensive 
aspects  of  the  parents'  personality  functioning.   That  is,  they  are  not 
simply  realistic  responses  to  the  current  characteristics  of  the  adolescent 
but  are  behaviors  through  which  parents  defend  against  anxiety.   We  find 
that  these  parents,  through  their  defensive  delineations,  seek  to  hold  the 
adolescent  in  a  relatively  fixed  role  which  serves  to  mitigate  their  own 
anxiety.   Projective  identification  is  of  central  importance  as  a  mechanism 
of  defensive  delineation. 

In  addition,  we  make  a  third  level  of  inference,  that  of  characteristics 
of  the  family  group  as  a  whole.   From  excerpts  of  family  interaction 
containing  defensive  delineations,  we  accrue  evidence  of  shared  or  comple- 
mentary characteristics  of  the  family  as  a  group  and  of  the  unconscious 
determinants  of  these  characteristics.  We  consider  coordinated,  shared 
complementary  behavior  in  the  family  to  be  evidence  of  a  level  of  unconscious 
fantasy  and  defense  in  the  family  group  organized  around  particular 
unconscious  assumptions. 


76 


Serial  No.  M-AP(C)-17-1 

The  third  task  defined  above  is  that  of  study  and  modification  of  the 
adolescent's  functioning  in  a  new  social  organization  away  from  the  family 
in  which  he  has  the  opportunity  to  develop  new  roles  and  a  new  relationship 
to  peers  and  to  authority  figures.   The  situation  we  have  developed  in  our 
program  for  implementation  of  this  task  is  the  Unit  Study  Group.   This  is 
an  intergroup  meeting  consisting  of  all  of  the  patients,  the  chief  psychiatric 
nurse  representing  the  nursing  staff,  the  unit  administrator  representing 
the  individual  and  family  therapi.?ts,  and  the  clinical  director  representing 
the  research  project  chiefs  and  senior  psychiatric  staff.   The  task  of  this 
meeting  is  study  of  authority  relations  and  peer  relations  in  the  group 
life  of  the  psychiatric  unit.   This  is  not  a  decision-making  meeting,  but 
one  in  which  the  dynamics  of  roles  and  role  relationships  are  studied, 
including  attitudes  toward  those  in  authority  roles.   The  work  of  the  meeting 
is  the  examination  of  roles  individuals  take  or  are  put  into  by  the  group 
in  the  hospital  with  whom  they  live  and  work.   A  whole  range  of  issues  of 
group  life  in  the  hospital  are  discussed  in  the  meeting.   In  particular, 
phenomena  defining  the  boundaries  of  the  self  are  attended  to  in  the  group, 
the  roles  taken  by  the  patients  and  the  new  roles  which  evolve  in  their 
relations  with  each  other  and  with  authority. 

In  a  new  investigation.  Dr.  Robert  Winer  is  continuing  his  study  of 
the  use  of  mind-altering  drugs  by  youth  in  a  multi-faced  research  project. 
Relying  primarily  on  interview  data,  he  is  explaining  the  meaning  of 
drug  use  to  adolescents  and  to  their  families.   The  study  is  at  present 
proceeding  on  four  fronts,  with  a  fifth  area  to  be  investigated  in  the 
future. 

Three  of  the  sub-studies  focus  on  the  hospitalized  adolescent  population. 
While  drug  use  was  not  a  criteria  for  admission  to  the  ward,  two-thircfe  of 
the  patients  have  made  extensive  use  of  "street-drugs"  prior  to  their 
admission  here.   The  first  sub-study  consists  of  interviews  with  each  of 
in-patients  in  which  the  primary  focus  is  on  motivational  aspects  of  their 
drug  use.   Clear  patterns  of  social  and  interpsychic  determinants  of  drug 
use  are  becoming  apparent,  and  it  appears  that  the  more  disturbed  adolescents 
primarily  used  drugs  in  attempts  to  resolve  internal,  rather  than  external, 
conflict.   The  impact  of  the  adolescents'  peer  mileau,  both  prior  to  and 
during  hospitalization,  on  their  attitudes  about  drug  use  is  significant. 
Normative  peer  expectations  provide  a  baseline  for  adolescents  from  which 
they  judge  their  own  behavior. 

The  second  sub-study  involves  interviews  of  these  adolescents  with 
their  families.   As  these  families  are  also  seen  weekly  in  ongoing  family 
therapy,  data  from  the  research  interviews  will  be  correlated  with  material 
obtained  from  family  therapists.   In  these  interviews  areas  focused  on 
include  the  family  members'  attitudes  and  fantasies  about  drug  use,  and 
the  families'  past  and  present  modes  of  responding  to  the  adolescent's 
known  or  suspected  drug  use,  including  modes  of  response  within  the  research 
sessions.   It  is  becoming  clear  that  the  parents'  own  conflict  over  drug 
use  finds  expression  in  the  adolescents'  behavior;  that  conflict  over 
drug  use  becomes  a  focal  point  in  the  family  for  the  negotiation  of  broader 

77 


Serial  No.  M-AP(C)-17-1 


m 


family  conflicts;  and  that,  more  specifically,  a  frequently  found  conspiracy 
of  silence  in  the  family  on  the  drug  use  issue  reflects  the  family's  abortive 
efforts  toward  integration. 

The  third  sub-study  examines  the  adolescents'  experience  with  their 
pro~tem  family,  the  psychiatric  staff,  in  working  through  conflict  over 
drug  use.   Patterns  observed  in  the  family  sub-study  are  also  seen  in  this 
arena.   Since  the  psychiatric  staff  is  committed  to  the  fact  of  finding 
constructive  means  for  dealing  with  drug  use,  it  is  possible  to  explore 
the  interaction  of  the  adolescents'  attitudes,  values,  and  behavior  with 
those  of  the  staff. 

A  fourth  sub-study  is  explaining  motivational  aspects  of  drug  use  in 
a  group  of  late  adolescents  and  young  adults  who  have  made  extensive  use 
of  mind-altering  drugs ,  but  who  have  not  sought  or  received  psychiatric 
help.   While  the  importance  of  intrapsychic,  as  opposed  to  social  deter- 
mination of  drug  use  is  important  here,  as  in  the  hospitalized  group,  the 
specific  nature  of  the  determinants  appear  to  differ,  being  apparently 
more  related  to  the  working  through  of  appropriate  life  stage  conflicts 
than  to  the  resolution  of  neurotic  conflict. 

Finally,  an  anticipated  sub-study  will  investigate  data  obtained 
in  group  meetings  with  non-hospitalized  youths  who  have  made  extensive 
use  of  drugs.   The  emergence  of  group  attitudes,  and  their  impact  on 
individual  members  will  be  explored. 

Major  Findings.   The  methods  of  observation  and  inference  which  have 
been  described  are  utilized  to  define  in  each  of  our  adolescent  patients 
the  characteristics  of  his  internal  psychological  boundaries  and  the 
relation  of  these  to  characteristics  of  the  boundaries  between  the  individual 
adolescent,  his  family,  his  peers,  and  authorities  in  the  institution 
in  which  he  lives.  We  find  in  examining  the  boundary  between  the  adolescent 
and  his  family  that  parental  delineations  of  the  adolescent  are  determined 
by  defensive  needs  in  the  parents  rather  than  by  realistic  perceptions  of 
the  adolescent.   These  defensive  needs  in  the  family  are  the  key  to 
formulations  of  the  unconscious  assumptions  of  the  family  as  a  group. 

We  find  in  the  unit  study  group  that  patients  tend  to  repeat  roles 
they  have  taken  and  are  taking  in  their  families .   In  the  work  of  the 
group  we  examine  this  phenomenon  and  explore  with  the  adolescents  the 
degree  to  which  new  possibilities  in  role  behavior  are  available  to  them 
in  relation  to  peers  and  to  people  in  authority  roles  in  the  institution. 
We  find  the  range  of  role  behavior  limited  and  difficult  to  change  in  the 
patient  group.   They  are  an  extremely  dependent  group.   They  manifest  a 
range  of  responses  of  anxiety,  rage,  suspiciousness  and  fear  of  exploitation 
in  relation  to  authority.   These  responses  prove  to  be  highly  resistant  to 
change.   In  contrast  we  find  in  the  group  of  normal  adolescents  in  the 
classroom  study  group  at  Sidwell  Friends  School  greater  capacity  to  take 
and  maintain  work  leadership  in  the  group  and  to  cooperate  with  authority. 


78 


Serial  No.  M-AF(C)-17-1 

They  show  more  flexibility  in  role  behavior,  more  capacity  to  experiment 
in  the  group,  and  less  suspiciousness  and  anger.   We  are  now  beginning 
detailed  comparisons  of  these  group  behaviors. 

Significance  to  Mental  Health  Research.  This  study  now  includes  methods 
and  findings  for  studying  the  adolescent  peer  group  as  well  as  studying 
the  adolescent  and  his  family.   With  these  methods  we  will  more  fully 
comprehend  adolescent  personality  development  from  the  perspective  of 
identity  formation.   Our  findings  thus  far  clearly  indicate  that  the  presence 
of  impaired  development  of  adolescent  ego  autonomy  reflects  impaired 
parental  ego  functions.   We  want  to  consider  in  what  ways  and  to  what  extent 
the  peer  group  can  be  used  to  alter  and  mitigate  deleterious  consequences 
of  family  relationships.   We  are  interested  in  the  implications  of  these 
findings  both  for  the  highly  important  task  of  deepening  our  understanding 
of  disturbance  in  adolescence  and  for  improving  our  techniques  of  therapy 
and  rehabilitation. 

Proposed  Course  of  Project.    Next  year  we  will  introduce  a  more 
systematic  study  of  the  individual  therapy  of  the  adolescent  himself.   We 
want  to  expand  the  observations  in  individual  therapy  from  which  we  infer 
the  characteristics  of  the  self  boundaries  of  the  adolescent.   We  also 
want  to  focus  upon  evidence  of  the  individual's  internalization  of 
experiences  in  the  family  group  and  the  unit  study  group  as  it  is  mani- 
fested in  individual  therapy.   In  addition,  we  will  continue  more  detailed 
comparison  of  behavior  of  adolescents  in  the  psychiatric  unit  study  group 
and  the  classroom  study  group  at  Sidwell  Friends  School.   We  will  also 
continue  the  study  of  adolescent  drug  use  in  the  ways  that  have  been  discussed. 

Honors  and  Awards : 

Roger  L.  Shapiro,  M.D. ,  Principal  Investigator: 

Director  of  a  Group  Relations  Conference,  sponsored  by  The  A.  K. 
Rice  Institute  of  The  Washington  School  of  Psychiatry,  Amherst 
College,  August  27-September  1,  1971. 

Senior  Staff,  Conference  on  Authority  and  Leadership,  sponsored 
by  the  Centre  for  Applied  Social  Research  of  the  Tavistock 
Institute  of  Human  Relations,  London.   University  of  Leicester, 
England,  April  5-18,  1972. 

Senior  Staff,  Group  Relations  Conference,  sponsored  by  The  A.  K. 
Rice  Institute  of  The  Washington  School  of  Psychiatry,  Mount 
Holyoke  College,  June  3-16,  1972. 


79 


Serial  No,  M-AP(C)-17-1 

Presentations: 

Roger  L.  Shapiro,  M.D. ,  Principal  Investigator: 

"The  Adolescent,  the  Family,  and  the  Group:   Boundary 

Considerations."   Presented  at  the  17th  Annual  Chestnut 
Lodge  Symposium,  Rockville,  Maryland,  October  8,  1971, 
and  at  Tufts  New  England  Medical  Center,  Boston,  Massachusetts, 
December  16,  1971, 

Publications : 

Shapiro,  R.  L.  Adolescence  and  the  Family.  In  the  Proceedings  of 
the  Ninth  Annual  Conference  on  The  Handicapped  Child.  Alfred  I. 
DuPont  Institute,  Wilmington,  Delaware,  1971. 

Shapiro,  R.  L.  and  Zinner,  J.   Family  Organization  and  Adolescent 
Development.   Task  and  Organization,  ed.  Eric  Miller. 
Tavistock  Publications.   In  press. 

Zinner,  J.  and  Shapiro,  R.  L.   Projective  Identification  as  a  Mode 
of  Perception  and  Behavior  in  Families  of  Adolescents.   Int.  J. 
of  Psychoanalysis.   In  press. 


Serial  No.  M-AP(C)-17-2 

1.  Adult  Psychiatry  Branch 

2.  Section  on  Personality  Development 

3.  Bethesda,  Maryland 


June  1,  1971  through  June  30,  1972 

Project  Title:   Adolescent  Ego  Development  in  Normal  Families 

Previous  Serial  Number:   NONE 

Principal  Investigator:   Roger  L.  Shapiro j  M.D. 

Other  Investigators:   Stuart  Hauser,  M.D. ;  John  Zinner,  M.D. 

Cooperating  Units:   Sidwell  Friends  School,  Washington,  D.  C. 

Man  Years : 

Total:   .7 
Professional:   .6 
Other:   .1 

Project  Description: 

Objectives.   This  study  attempts  to  specify  some  of  the  crucial 
determinants  of  identity  formation  in  normal  adolescents.   We  hypothesize 
that  delineations  of  the  adolescent  by  his  family  and  his  peer  group 
provide  much  of  the  content  of  his  self  concept  and  that  the  manner  in  which 
the  delineation  is  communicated  will  influence  the  way  in  which  it  is 
internalized.   We  further  hypothesize  that  the  adolescent  will  utilize 
peer  group  experience  in  an  attempt  to  reorganize  conflicting  elements 
in  his  self  concept  which  have  derived  from  conflicting  elements  within 
his  family.   We  hope  to  specify  in  detail  in  what  ways  peer  group  experience 
allows  for  development  of  new  and  innovative  aspects  of  identity  and  in 
what  ways  it  is  conditioned  and  limited  by  past  and' present  family  interactions. 

Methods  Employed.   During  this  year  two  classroom  study  groups  were 
formed  at  Sidwell  Friends  School.   These  groups  were  composed  of  10  students, 
ages  14-17,  in  the  9th  to  12th  grades  of  the  Sidwell  Middle  School;  a  teacher 
and  a  principal,  or  dean;  and  Dr.  Stuart  Hauser  as  group  consultant.   The 
task  of  the  group  was  to  study  authority  relations  and  peer  relations  in  the 
school,  making  observations  about  group  formation,  individual  roles  in  the 
group,  relations  to  authority  in  the  group  as  we  have  with  the  Unit  Study  Group 
on  the  adolescent  inpatient  unit.   Particular  attention  was  paid  to  the 
capacity  of  these  adolescents  to  define  themselves  verbally  in  relation  to 
authority  figures  and  peers.   The  range  of  attitudes  toward  self  and  others 
and  capacity  to  tolerate  differences  and  to  work  with  the  boundaries  established 
by  authority  were  foci  of  attention.   Tne  groups  met  for  13  weekly  sessions 
of  an  hour. 

81 


Serial  No.  M-AP(C)-17-2 

Major  Findings.   In  the  Classroom  Study  Group  far  less  anxiety  and 
inhibition  was  seen  in  group  function  and  activity  than  was  seen  in  the 
Unit  Study  Group.   The  students  were  quickly  highly  verbal  and  involved  in 
clearly  defined  ways.   The  principal  and  the  teacher  had  difficulty 
representing  their  actual  school  roles  in  the  group  and  still  feeling 
a  part  of  the  group.   Their  presence  focused  much  of  the  group's  attention  on 
authority  relations  although  explicit  discussion  of  attitude  toward  teachers 
and  school  administration  was  far  less  common  than  expression  of  implicit 
attitudes.   The  Classroom  Study  Groups  demonstrate  the  feasibility  of  such 
groups  in  the  Sidwell  School  setting.   This  is  the  second  year  of  working 
with  such  groups,  following  last  year's  tliddle  School  Group,  also  done  with 
Dr.  Hauser, 

Significance  to  Mental  Health  Research.   The  study  of  peer  relations 
and  of  family  relations  of  normal  adolescents  provides  a  contrast  to  our 
studies  of  peer  relations  and  of  family  relations  of  disturbed  adolescents. 
This  increases  the  precision  of  our  formulations  of  the  pathological 
processes  in  adolescent  disturbance  and  thereby  contributes  to  a  better 
understanding  of  the  etiology  of  adolescent  personality  disorder.   At  the 
same  time  the  study  provides  data  on  the  ways  in  which  peer  and  school 
experience  contributes  to  normal  identity  formation  and  thereby  contributes 
to  an  understanding  of  normal  development. 

Proposed  Course  of  Project.   We  want  to  begin  to  analyze  the  develop- 
ment and  processes  within  these  groups  in  more  detail,  and  in  relation  to 
our  patient  groups  (the  unit  study  group) . 


82 


Serial  No.  M-AP(C)-17-3 

Adult  Psychiatry  Branch 

Section  on  Personality  Development 

Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:   Studies  of  Psychogalvanic  Response  in  Family  Therapy 

Previous  Serial  Number:    M-AP(C)-17-3 

Principal  Investigator:    John  Zinner,  M.D. 

Other  Investigators:    David  Reiss,  M.D.  and  Roger  Shaprio,  M.D. 

Cooperating  Units:    Experimental  Group  and  Family  Studies  Section,  APB; 
Unit  3-West 

Man  Years 

Total:   1.25 
Professional:    .50 
Other:    .75 

Project  Description: 

Objectives;   The  family  psychophysiology  project  was  initiated  to  provide 
quantifiable  information  about  subjective  experience  during  family  interaction 
that  would  supplement  self  reports  of  family  members  and  inferences  made  from 
observable  behavior. 

Studies  of  interaction  in  families  of  emotionally  disturbed  adolescents 
carried  out  by  this  section  in  the  past  and  concurrently  have  consistently 
focused  attention  on  the  subjective  experience  by  family  members  of  one  another 
as  important  determinants  of  family  group  behavior.   In  particular,  we  have 
found  clinically  that  family  members  often  behave  in  such  a  way  as  to  reduce 
anxiety  in  the  family  group  as  a  whole  or  within  particular  members.   In  the 
case  of  emotionally  disturbed  adolescents  the  psychopathologic  outcome  may  de- 
rive at  least  in  part  from  the  patient's  attempts  to  diminish  parental  anxiety 
over  parental  intrapsychic  conflict. 

Because  family  members  may  not  be  aware  of  anxiety  during  family  sessions 
and  because  anxious  members  may  choose  to  remain  silent  and  not  report  their 
feelings  or  demonstrate  it  overtly  in  their  behavior,  we  undertook  to  monitor 
continuously  autonomic  indicators  of  anxiety  during  family  therapy  sessions. 
The  study  therefore  adds  a  psychophysiologic  dimension  to  our  ongoing  investi- 
gations of  the  interplay  between  subjective  experience  and  behavior  in  family 
interaction.   Since  the  unit  of  study  is  conjoint  family  therapy,  an  opportunity 
is  provided  for  exploration  of  the  process  of  family  therapy  witihin  individual 
sessions  and  on  a  long  term  basis,  as  well  as  the  physiologic  reactions  of  family 
members  to  the  interventions  of  the  psycho-therapists. 

83 


Serial  No,  M-AP(C)-17-3 

Method.   The  sample  consists  of  families  of  adolescent  patients  admitted 
to  our  treatment  program  as  well  as  families  of  "normal"  adolescents  inter- 
viewed in  the  "Sidwell  Project." 

The  Psychophysiologic  variable  selected  for  initial  study  was  the  galvanic 
skin  response  (GSR)  which  is  known  to  be  a  rather  good  indicator  of  anxiety 
occurring  in  an  interpersonal  context.   In  addition,  the  GSR  has  the  value  of 
being  discrete,  unidirectional,  easily  visualizable  and  proportional  in  ampli- 
tude to  the  experienced  intensity  of  the  emotional  stimulus. 

During  conjoint  family  interviews,  the  GSR  of  family  members  and  thera- 
pists are  monitored  continuously  on  a  Grass  Polygraph  by  way  of  electrodes 
attached  to  two  fingers  of  each  subject's  non-dominant  hand.   A  timing  device 
and  polygraphic  recording  of  speech  permits  the  accurate  synchronization  for 
retrieval  of  physiologic  responses  and  concurrent  verbal  behavior.   In 
addition,  sessions  may  be  video-taped  using  a  split-screen  technique  which 
records  and  displays  simultaneously  both  the  family  in  interaction  and  the 
polygraph  record.   Playback  of  these  videotapes  permits  an  analysis  of  the 
sequential  unfolding  of  family  behavior  and  subjective  experience  of  family 
members . 

Progress  and  Major  Findings.   A  small  sample  of  families  of  "normal"  and 
"hospitalized"  adolescents  has  been  monitored  physiologically  during  family 
sessions.   Each  family  has  been  tested  on  at  least  two  occasions  to  evaluate 
the  stability  of  the  physiologic  variables.   There  is  a  close  relationship, 
between  occurrence  of  GSRs   and  the  operation  of  psychological  defense 
mechanisms.   GSRs  can  be  peripheral  indicators  of  central  anxiety  "signals." 
These  are  subjective  phenomena  which  stimulate  the  operation  of  psychological 
defenses  preventing  the  eruption  of  a  greater  intensity  of  anxiety.   Psycho- 
logical defenses  which  limit  anxiety  limit  the  further  occurrence  of  GSRs. 
In  the  family  therapy  situation,  however,  there  are  stimuli  beyond  the  control 
of  the  family,  such  as  therapists'  interpretations,  which  challenge  defense 
mechanisms  and  generate  anxiety,  with  a  corresponding  increase  in  GSR  ampli- 
tude and  frequency.   Individuals  in  whom  anxiety  is,  in  general,  poorly  bound 
demonstrate  marked  degrees  of  GSR  activity  on  polygraph  records.   At  the  other 
end  of  the  spectrum  are  those  individuals  with  hypertrophed  defense  operations, 
marked  ego  restriction  and  almost  quiescent  electrodermal  activity.   Thus  the 
physiologic  recordings,  conform  to  psychoanalytic  concepts  of  anxiety  which 
postulate  that  primitive  arousal  mechanisms  are  incorporated  and  modulated  by 
the  ego  so  that  they  may  perform  a  signal  function  for  the  operation  of  psycho- 
logical defenses. 

This  year,  all  the  physiologic  data  has  been  scored  as  have  the  transcribed! 
audiotapes  of  the  family  sessions.   The  data  has  been  reduced  in  a  search  for 
new  physiologic  variables  which  would  be  relevant  to  testing  of  hypotheses 
derived  from  clinical  theory.   Most  variables  used  in  the  literature  were  not 
useful  for  this  purpose.   Variables  developed  in  our  study  which  measure  rela- 
tive rather  than  absolute  degrees  of  electrodermal  activity  are  more  valid. 
In  the  coming  year  these  new  physiologic  variables  will  be  employed  in  tests 
of  hypotheses  related  to  family  interaction.   One  such  experiment  is  being 
planned  in  collaboration  with  the  alcohol  Research  Center  at  St.  Elizabeth's 
Hospital.   In  this  instance,  physiologic  measures  will  test  the  stabilizing 

8^ 


Serial  Ho.  M-AP(C)-17-3 

effect  of  drinking  behavior  of  marital  dyads  in  which  one  or  both  members 
are  alcoholics. 


85 


I 


Serial  No.  M-AP(C)-17-4 

1.  Adult  Psychiatry  Branch 

2.  Section  on  Personality  Development 

3.  Bethesda,  Maryland 


PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   A  Follow-Up  Study  of  37  Families  Treated  in  the  Study 
of  Adolescent  Identity 

Previous  Serial  Number:   M-0D-CI-SW-9(c) 

Principal  Investigators:   Carmen  Amoros-Cabrera,  M.S.W.  and  Roger  Shapiro,  M,D. 

Other  Investigators:   Carl  Feinstein,  M.D. 

Cooperating  Units:   Unit  3-West 

Man  Years 

Professional:   .40 
Other:   .20 
Total:   .60 

Project  Description: 

Objectives.   To  obtain  information  about  the  current  adjustment  of 
the  adolescent  and  his  family  as  related  to  (1)  the  problems  that  motivated 
their  admission  to  the  project,  and  (2)  their  individual  perceptions  of 
the  effects  of  therapy  and  the  relationship  of  therapy  to  any  changes  that 
may  have  taken  place. 

Methods  Employed.   The  family  group,  the  adolescent,  and  the  parents 
are  seen  in  separate  interviews  with  the  goal  of  providing  information 
which  will  allow  for  the  isolation  and  identification  of  various  factors 
comprising  the  therapeutic  experience,  such  as  the  impact  of  the  adolescent's 
hospitalization,  ward  milieu,  family  therapy,  couples  therapy,  and  individual 
therapy.   The  outcome  of  each  aspects  of  the  therapeutic  program  is 
emphasized,  and  outcomes  will  be  evaluated  for  a  number  of  categories  still 
being  defined. 

Progress.   Sixteen  families  have  been  seen  in  the  follow-up  study 
this  past  year,  and  a  paper  was  written  on  the  preliminary  findings 
focusing  on  couple's  therapy  with  the  parents  and  their  status  at  follow-up 
interview.   While  adolescence  and  adolescent  turmoil  are  frequently  seen 
as  an  opportunity  for  the  growth  and  development  of  the  child,  little 
attention  has  been  given  the  possibilities  of  change  for  the  parent  during 
his  child's  adolescence.   The  findings  of  our  study  indicate  that  parents, 

87 


Serial  No.  M-AP(C)-17-4 

precipitated  intp  couple's  psychotherapy  by  the  adolescent  turmoil  of  their 
children,  have  considerable  capacity  for  psychic  change  at  that  time. 

On  the  basis  of  follow-up  interviews  and  evaluation  of  data  from 
long-term  therapy  with  22  parental  pairs,  three  stages  of  regression  and 
progression  through  which  these  couples  pass  during  the  therapeutic  process 
were  defined:   (1)  loosening  of  ties  to  the  original  family,  (2)  renewed 
adolescence  and  early  m.arriage,  and  (3)  return  to  parenting. 

Of  the  27  follow-up  cases,  there  was  evidence  of  drug  use  in  11  of 
the  index  patients  (the  adolescent).   Using  a  scale  of  -5  to  +5  to 
evaluate  adjustment,  each  adolescent  was  rated  for  factors  such  as  capacity 
for  independent  living,  socialization,  heterosexual  adjustment,  ability  to 
handle  finances,  productive  application  of  time  and  energy,  and  sustained 
level  of  health.   The  results  were: 


1 

case 

+5 

5 

cases 

+4 

1 

case 

+3 

1 

case 

+1 

1 

case 

0 

1 

case 

-3 

1 

case 

-4 

Of  these  cases,  six  continued  in  therapy  after  discharge  as  we  recommended. 
Five  of  them  had  married  and  seemed  to  be  functioning  adequately  in 
relation  to  their  family  responsibility;  4  of  the  11  had  completed  college 
and  were  successfully  employed.   T\i?o  adolescents  showed  no  indication  of 
progress.   One  continued  to  be  extremely  delinquent,  a  child  of  very  unstable 
parents,  and  his  involvement  with  drugs  has  become  increasingly  serious. 
The  other  had  presented  clear  indications  of  psychotic  content  since 
admission,  had  shown  marked  recovery  periodically,  but  had  failed  to  sustain 
an  adequate  level  of  functioning  and  was  hospitalized. 

Significance  for  Mental  Health  Research.  We  are  particularly 
interested  in  learning  about  the  success  of  the  therapeutic  plan  in 
clarifying  the  index  patient's  identity  problems  and  in  understanding  and 
modifying  the  parents'  delineations  of  the  adolescent.   This  study  will 
be  useful  in  isolating  factors  contributing  to  the  precipitation  of  serious 
adjustment  problems  during  adolescence  and  in  evaluating  the  outcome  of  a 
treatment  program  derived  from  research  findings. 

Proposed  Course  of  Project.   A  paper  is  being  developed  on  the  three 
phases  of  couple's  therapy.   A  predictive  criteria  is  being  developed  to 
relate  to  anticipated  progress  after  discharge.   A  correlation  between 
index  patient  progress  and  parents  progress  is  being  made,  and  we  are 
studying  the  siblings  of  index  patients  in  terms  of  the  development  of 
siblings  with  "static  parents"  versus  that  of  siblings  with  "dynamic  parents.' 
We  are  also  assessing  the  impact  of  parental  therapy  on  the  quality  of 
interaction  between  parents  and  younger  siblings  when  those  siblings 
reach  adolescence. 


Serial  No,  M-AP(C)-17-5 

1.  Adult  Psychiatry  Branch 

2.  Section  on  Personality  Development 

3.  Bethesda,  Maryland 


PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 


Project  Title:   Cognition  and  Identity  Development  in  Early  and  Late 
Adolescence:   Longitudinal  Studies 

Principal  Investigator:   Stuart  T.  Hauser,  M.D. 

Other  Investigators:   Roger  L.  Shapiro,  M.D. 

Cooperating  Units:   Ward  3-West,  Normal  Volunteer  Office 

Man  Years : 

Total:   .50 
Professional:   .30 
Other:   .20 

Project  Description: 

Objectives.   An  earlier  longitudinal  study  of  identity  formation  in 
lower  socio-economic  class  boys  (Hauser,  S.  T.,  Black  and  White  Identity 
Formation,  N.  Y.,  Wiley,  1971)  suggested  several  areas  for  further  investi- 
gation.  A  clear  difference  in  identity  formation  patterns  was  found 
between  the  black  and  white  adolescent  subjects.   Two  questions  of  interest 
emerging  from  this  earlier  investigation  and  orienting  the  current  studies 
were: 

1.  What  variants  of  identity  formation  are  found  in  other  groups  of 
adolescents,  such  as  girls,  other  social  classes,  and  psychiatric  patients? 

2.  What  are  other  aspects  of  psychological  functioning  which  are 
associated  with  varying  identity  formation  patterns?   In  particular, 
cognitive  processes  appear  to  be  related  to  modes  of  self-image  perception. 
How  then  are  these  cognitive  areas  linked  with  identity  development 
patterns,  more  complex  patternings  of  self-images?  Are  certain  cognitive 
or  perceptual  processes  more  powerfully  linked  to  identity  development? 

Methods  Employed.   To  approach  the  preceding  questions,  several 
populations  of  subjects  are  being  sampled: 

1.   Adolescent  male  and  female  patients  of  middle  and  upper  socio- 
economic class  status  (24  subjects). 


Serial  No.  M-AP(C)~17-5 

2.   Adolescent  male  and  female  high  school  and  early  college  age 
students,  also  of  middle  and  upper  socio-economic  class  status  (35  subjects), 

Each  of  the  subjects  from  these  samples  is  studied  longitudinally  for 
two  years,  being  seen  every  six  months.   The  sequences  of  meetings  and 
instruments  used,  with  rationale  for  their  use,  is  the  following: 

1.  Groups  of  seven  to  eight  subjects  from  each  of  the  samples 
meet  with  the  senior  investigator  for  a  series  of  four  meetings,  focused 
around  "the  study  of  roles  and  perceptions  of  the  self  and  others  in  the 
group." 

2.  From  the  tapes  of  these  meetings,  a  separate  Q-sort  deck  is 
generated  for  each  group.   The  deck,  consists  of  3X5  cards,  on  each  being 
an  "I"  statement  made  by  a  group  member  which  reflected  a  particular 
personal  emotional,  ideological,  or  general  descriptive  position  about 
himself.   There  is  an  equal  number  of  statements  from  each  group  member, 
including  the  leader. 

3.  Each  subject  is  individually  interviewed  following  the  conclusion 
of  the  four  group  meetings,   the  thrust  of  the  individual  sessions  being 
around  self-conceptions,  current  and  past.   Inquiry  is  also  along  the 
lines  of  developmental  and  family  history. 

4.  The  following  week  the  subject  takes  the  Q-sort  task.   In  this 
method  he  is  asked  to  sort  the  deck  from  his  group  (described  in  #2,  above) 
for  a  series  of  seven  different  self-images.   These  include  self-images 
from  temporal,  idealized,  and  peer  realms.   There  are  a  total  of  seven 
self-images,  always  requested  in  the  same  order  by  the  experimenter. 

5.  In  the  following  testing  one  to  three  weeks  after  the  Q-sort, 

the  subject  is  tested  with  a  series  of  cognitive  measures.   The  techniques, 
their  rationale  and  their  order  of  being  taken  are: 

a.  The  Pettigrew  Category  Width  Scale.   This  is  to  measure  the 
breadth  or  narrowness  of  a  subject's  categories. 

b.  The  Concealed  Figures  Test.   For  determination  of  degree  of 
field  articulation,  of  "differentiation." 

c.  The  Object  Sorting  Test.   To  determine  the  size  and  number 
of  categories  generated  by  a  subject;  and,  in  addition,  to  analyze  his 
reasons  underlying  his  categories  (conceptualizations) . 

d.  The  Twenty  Questions  Task.   To  measure  the  type  and  degree 
of  efficiency  of  a  subject's  problem-solving  strategy. 

e.  Draw-A-Person  Task.   The  drawing  of  persons  obtained  will  be 
analyzed  using  the  scales  devised  by  Witkin  and  Associates  for  measurement 


90 


Serial  No.  M-AP(C)-17-5 

of  "sophistication  of  body  image,"  a  variable  highly  associated  with 
differentiation. 

Steps  three  through  five  are  repeated  every  six  months  for  a  two-year 
period.   Thus  each  subject  will  be  interviewed  and  tested  a  total  of 
four  times . 

The  self-image  measurements  which  are  being  obtained  from  these 
instruments  include  correlational  indices,  general  measures  of  relatedness 
and  of  discrimination  (all  obtained  from  the  Q-sorts) ;  indices  of  the 
sources  of  self-image  components  (also  from  the  Q-sorts) .   Specific 
cognitive  variables  from  each  of  the  cognitive  instruments  are  simultaneously 
being  determined. 

Techniques  for  analyzing  the  complex  data  is  along  several  lines  in 
order  to  investigate  inter-relationships  of  the  variables  at  single  points 
in  time,  and  over  time;  and  to  investigate  consistencies  within  individual 
subjects  and  between  groups  of  subjects.   Two  basic  statistical  tools  will 
be  analyses  of  variance  and  factor  analyses.   Both  these  approaches  and 
their  implementation  have  been  worked  out  with  Dr.  John  Bartko,  statistical 
consultant,  and  the  computer  center. 

Major  Findings.   At  this  point  three  to  four  waves  of  interviews  and 
testings  have  been  completed  on  most  of  the  controls  and  patients.   The 
data  obtained  from  the  first  round  has  been  analyzed  for  measures  noted 
earlier.   Correlational  analyses  of  the  Q-sort  data  are  completed  and 
have  been  written  up  in  "The  Differentiation  of  Adolescent  Self-images," 
to  be  presented  at  the  annual  American  Psychiatric  Association  meetings. 
The  major  finding  is  in  the  differential  sensitivity  of  various  self-images 
(idealized,  temporal,  peer)  to  variables  of  sex  and  patienthood.   Implications 
of  these  differences  are  being  studied,  and  further  elaborated. 

A  second  aspect  of  the  sample  is  in  the  black-white  comparative 
studies.   Data  from  the  original  New  Haven  sample  was  re-analyzed  using 
new  tools:   information  statistics  (for  analysis  of  structural  complexity 
of  self-image  and  over-all  relatedness)  and  drawing  analyses  for  study 
of  differentiation.   The  structural  complexity  analysis  of  the  older 
longitudinal  data  is  consistent  with  lessened  structural  complexity 
(more  polarized)  self-image  for  several  of  the  blacks'  images. 

Significance  to  Mental  Health  Research.   These  studies  are  directed 
toward  an  increasingly  intensive  analysis  of  self  images  from  several 
perspectives:   Their  "inner   characteristics  of  meaning  and  structure,  their 
relation  to  one  another,  their  modes  of  change  over  time,  their  relation 
to  other  modes  of  personality  functioning  which  appear  highly  relevant, 
such  as  cognitive  processes.   One  important  application  of  such  quantitative 
studies  is  as  a  means  of  following  the  course  of  an  adolescent  during 
psychotherapy  comparing  other  measures  with  independent  observations  such 
as  those  of  nurses  or  the  patient's  therapist.   A  second  application  is  to 


91 


Serial  No.  M-AP(C)-17-5 

the  comparison  of  adolescent  development  with  and  without  psychotherapy, 
and  under  different  modes  of  psychotherapy  (half  the  patient  population 
is  receiving  only  group  therapy,  the  other  half  is  in  group  and  individual 
therapy) . 

The  operationalizing  of  major  concepts  such  as  "identity  formation" 
and  "psychosocial  moratorium"  is  still  a  third  important  consequence  of 
this  kind  of  research.   Through  such  operationalizing  the  concepts  are  given 
clearer  empirical  definition  and  rendered  more  susceptible  to  rigorous 
quantitative  research.   Moreover,  the  way  is  opened  to  study  of  these 
much  discussed  phenomena  (identity  development)  in  many  varied  groups 
ranging  from  ones  within  our  own  culture — ethnically ,  racially ,  psychia- 
trically,  socio-economically  differentiated — to  cross-cultural  comparisons. 

Course  of  the  Research.   The  plan  is  to  complete  data  collection 
for  a  two-year  period  on  all  of  the  subjects.   This  will  involve  four 
waves  of  interviews  and  testings  on  each  subject.   The  complex  data  is 
being  analyzed  using  analysis  of  variance  models :   two  and  three-way 
ANOVA's  for  cross-sectional,  and  repeated  measures  model  for  longitudinal. 
A  second  facet  of  the  research  is  content  analysis  of  the  interview 
materials  along  the  lines  of  different  self-images  and  their  changes. 
A  technique  involving  quantitative  analysis  of  five-minute  interview 
segments  has  been  developed  and  applied  with  the  help  of  the  late  Dr.  William 
Caudill. 

A  preliminary  outline  for  the  eventual  integration  of  the  findings 
in  monograph  form,  "Lines  of  Adolescent  Development,"  has  been  written 
up.   Specific  discussions  of  new  methodological  and  substantive  findings 
during  the  progress  of  the  studies  are  complete.   The  first  of  these 
papers,  "The  Differentiation  of  Adolescent  Self-images,"  is  to  be  presented 
at  the  annual  APA  meetings. 

Honors  and  Awards : 

1.  Hauser,  S.  T.  and  Shapiro,  R,  L.   "Differentiation  of  Adolescent 
Self-images."   Presented  at  the  Adult  Psychiatry  Branch  Seminar,  NIMH, 
March,  1972. 

2.  Hauser,  S.  T.  and  Shapiro,  R.  L.  "Differentiation  of  Adolescent 
Self-images,"  presented  at  the  Annual  Meeting  of  the  American  Psychiatric 
Association,  Dallas,  Texas,  1972. 

3.  Hauser,  S.  T.   "Black  and  White  Identity  Formation."  Presented 
to  Grand  Rounds,  St.  Elizabeths  Hospital,  November  1971. 

4.  Hauser,  S.  T.  Recipient  of  Research  Scientist  Development  Award 
Grant. 


92 


Serial  No.  M-AP(C)-18-2 

1.  Adult  Psychiatry  Branch 

2.  Section  on  Experimental 
Group  and  Family  Studies 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  -  June  30,  1972 

Project  Title:  Coordinating  "Micro-Codes"  in  Family  Consensual  Experience: 
A  Study  of  the  Responses  to  Speech  Hesitancy  and  Fluency 
in  Family  Interaction. 

Previous  Serial  Number:  M-AP(C)-18-2 

Principal  Investigator:  David  Reiss,  M.D. 

Other  Investigators:  None 

Cooperating  Units:  None 

Man  Years: 

Total:  .  1 
Professional:  .0 
Other:        .1 

Project  Description: 

Objective:  The  card-sorting  experiment  and  previous  studies  by  Reiss 
as  well  as  by  Strodtbeck,  Mishler,  and  Waxier,  et  al. ,  support  the  notion 
that  families  can  be  distinguished  by  the  shared  experience,  of  their 
members,  of  their  environment.   Furthermore,  it  appears  as  if  this  shared 
experience  serves  as  a  major  regulator  of  moment-by-moment  family  interaction 
in  a  variety  of  settings.   In  order  to  maintain  such  consensual  experience 
and  to  utilize  it  to  deal  with  environment  events  as  they  occur  on  a  moment- 
by-moment  basis,  family  members  must  be  exquisitely  sensitive  to  each  other's 
ideas  and  feelings  at  all  times.   The  project  was  part  of  a  card-sorting 
experiment  in  which  family  members  could  communicate  only  by  voice;  thus 
each  member  had  to  utilize  the  others'  vocalizations  to  remain  continuously 
integrated  in  this  delicately  balanced  family  process.  Recent  experimental 
evidence  suggests  that  family  members  may  utilize  changes  in  each  other's 
patterns  of  speech  hesitancy  and  fluency  for  this  purpose.  We  postulated 
that  all  families  will  show  significant  moment-by-moment  response  to  changes 
in  the  fluency  patterns  of  each  member.  However,  some  families — which  we 
have  termed  "environment-sensitive" — are  predicted  to  respond  to  hesitant 
speech  as  a  signal  pointing  to  a  difficulty  or  incogrulty  perceived  by  the 
speaker  in  the  laboratory  puzzle  itself.  Other  families — ^we  call  them 


93 


Serial  No.  M-AP(C)-18-2 

"consensus-sensitive" — ^will  interpret  hesitancy  as  a  sign  of  the  speaker's 
perception  of  or  response  to  the  family  itself.  These  family  types  are 
defined  by  a  consensual  experience  model  and  identified  by  their  non-verbal 
performance  on  a  card-sorting  procedure.   Thus,  this  study  is  a  further  test 
of  the  consensual  experience  model  which  predicts  that  family  members  will 
respond  to  minimal  changes  in  each  other's  speech  in  ways  determined  by 
their  over-all  shared  experience  of  the  environment.   These  minimal  speech 
changes  could  then  be  viewed  as  a  personal,  family  "micro-code"  serving  to 
regulate  its  interaction  in  moment-by-moment  harmony  with  its  shared  experi- 
ences and  views. 

Method ;  The  verbal  interaction  in  the  second  family  problem  of  the 
card-sorting  task  was  recorded  on  a  specially  prepared  4-channel  tape  record- 
ing system  and  transcribed  by  polygraph  to  give  a  visual,  objective  record 
of  patterns  of  vocalization.  A  timing  signal  permitted  coordination  of  the 
polygraph  record  with  a  tjrpescript  of  the  content  of  the  family's  discussion. 
Changes  in  fluency  were  measured  by  methods  of  Boomer  and  Dittman,  and 
Goldman-Eisler,  using  the  polysraph  record.   The  family's  response  to  fluency 
changes  in  any  member  was  measured  using  interaction  codes  developed  by  Reiss 
and  Mlshler  and  Waxier,  using  the  typescript,  and  also  measures  of  the  card 
sort  and  trial  times. 

Progress:  All  the  polygraph  and  typescript  records  have  been  obtained. 
The  Boomer  and  Dittman  scoring  procedures  have  been  successfully  adapted  for 
use  with  the  data  collected  in  this  study.   In  addition,  the  Level  of 
Abstraction  Code,  from  previous  work  by  Reiss,  and  the  Responsiveness  Code, 
from  work  by  Mishler — two  coding  procedures  for  measuring  verbal  interaction — 
have  been  adapted  for  the  present  project.   All  three  coding  procedures  are 
nearly  complete.  Programming  has  begun  to  utilize  Attneave's  information 
transmission  statistic  to  analyze  relationships  among  the  three  codes 
through  time.   Coding  procedures  have  continued  very  slowly  during  the  past 
year.   Completion  of  this  project  is  being  hampered  by  lack  of  adequate 
number  of  research  support  staff. 


9h 


Serial  No.  M-AP(C)-18-3 

1.  Adult  Psychiatry  Branch 

2.  Section  on  Experimental 
Group  and  Family  Studies 

3.  Bethesda,  Maryland 


PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  -  June  30,  1972 

Project  Title:  The  Effects  of  Progressive  Isolation  of  an  Individual 
From  His  Family  on  His  Perceptual  Functioning:  Use  of 
a  Teletype-LINC  Apparatus  to  Study  the  Reciprocal  Rela- 
tionship of  Family  Interaction  and  Individual  Thinking. 

Previous  Serial  Number:  M-AP(C)-18-3 

Principal  Investigator:  David  Relss,  M.D. 

Other  Investigators:  None 

Cooperating  Units:  None 

Han  Years: 

Total:  .1 
Professional:  .0 
Other:        .1 

Project  Description: 

Objective:  Previous  experiments  in  this  Section  have  demonstrated  that 
family  Interaction  does  have  a  specific,  predictable  short-term  effect  on  the 
thinking  and  perception  of  its  members.  A  critical  question  is:  of  all  the 
flux  and  nuance  of  family  interaction,  which  aspects  are  the  most  critical 
for  regulating  the  thought  and  perception  of  its  members.   In  the  card-sorting 
and  micro-code  experiments.  Dr.  Reiss  explored  the  role  of  various  details  of 
the  vocalized  portion  of  family  interaction — excluding  all  forms  of  non-vocal 
performance.   In  the  current  experiment,  the  question  is:  to  what  extent  do 
families  differ  In  the  amount  of  objective  information — concerning  the 
problem  solution — they  can  obtain  and  distribute  among  its  members;  and, 
further,  how  does  this  obtained  and  distributed  Information  reeulate  per- 
ceptual processes  in  their  members.   In  other  words,  in  what  way  does  an 
individual's  perceptual  process — occurring  in  the  midst  of  a  familv  problem- 
solving  task — deoend  on  the  quality  and  quantity  of  information  provided  him 
about  the  problem  by  his  family,  disregarding  all  other  aspect  of  the  family 
interaction  of  which  he  is  a  part.   It  is  predicted  that  families  will  differ 
in  the  amount  of  relevant  information  they  can  discover  about  the  problem, 
their  effectiveness  in  distributing  it  to  all  members  of  the  family  and  the 


95 


Serial  No.  M-AP(C)-18-3 


use  each  member  makes  of  Information  provided  to  him  by  others  in  the  family. 
Specifically,  we  expect  families  we  have  designated  as  environment-sensitive 
will  extract  a  great  deal  of  problem-relevant  Information  from  their  environ- 
ment, will  effectively  distribute  it  amongst  members  in  the  family  and  each 
member  will  utilize  the  information  insofar  as  it  assists  him  in  a  logical, 
consistent  and  comprehensive  problem  solution.   Individuals  in  families 
designated  as  consensus-sensitive  will  work  to  obtain,  distribute,  and 
utilize  problem-relevant  information  only  insofar  as  it  permits  a  family 
solution  at  a  desired  level  of  wlthin^member  agreement.   In  the  present 
experiment  the  procedure  progressively  isolates  each  member  from  his  family. 
In  the  first  condition  all  information  obtained  by  all  members  about  the 
problem  is  transmitted  Immediately  to  each  individual  along  with  the  identity 
of  the  family  member  who  obtained  lt~the  "public  mode";  in  the  second 
condition  the  information  is  transmitted  after  a  variable  delay  without  the 
identity  of  the  member  who  obtained  It — the  "anonymous  mode";  in  the  third 
condition  no  Information  is  transmitted  between  members—the  only  information 
available  to  each  monber  is  what  he  obtains  himself  and  that  provided  by  an 
Impersonal,  extra-family  source — the  "standard  mode."  It  is  predicted  that 
members  in  environment-sensitive  families  will  maximally  utilize  information 
from  any  source  whereas  members  in  consensus-sensitives  will  utilize  informa- 
tion from  their  past  when  it  comes  from  an  impersonal  source.   In  order  to 
provide  immediate  and  standardized  information  transmission  between  the  family 
members  and  between  the  family  and  the  impersonal  environment  a  teletype-LINC 
apparatus  was  constructed  and  programmed.   This  permitted  the  conduct  of 
experiments  entirely  under  the  control  of  computer.   It  further  permitted 
every  item  of  family  interaction,  i.e.  transmission  of  information  by  use  of 
teletypes,  to  be  precisely  recorded  in  time.   Thus,  at  the  conclusion  of  the 
experiment  it  is  possible  to  know  not  only  what  interaction  has  occurred  but 
precisely  when.   This  will  permit  an  exact  correlation  of  the  various  events 
comprising  the  flux  of  family  interaction  in  this  experimental  setting.   The 
teletype-LINC  apparatus  represents  a  major  innovation  in  experimental  social 
psychology  and  this  project,  in  addition  to  its  exploration  of  a  particular 
hypothesis  about  family  interaction,  serves  as  an  Initial  study  of  this 
innovation. 

Method:  Four  family  members,  the  parents  and  two  children,  are  seated 
in  booths  so  they  cannot  see  each  other.   Each  has  a  teletype  and  is  Instructed 
in  its  use.   They  are  told  that  they  must  discover  a  class  of  symbol  sequences 
that,  when  typed,  will  result  in  plus  (+)  being  typed  in  return — automatically. 
Their  understanding  is  that  the  plusses  are  typed  in  a  systematic  way  and 
their  job  is  to  discover  the  system  or  pattern.   Each  member  is  given  an 
example  (e.g.  CSTTTTTTTS  which  represents  the  class  of  "plus  sequences" 
beginning  with  CS  followed  by  n  number  of  Ts  and  concluding  with  an  S) ,   Then 
each  member  tries  out  his  own  sequences  in  turn.   In  the  "public  mode"  each 
sequence  Is  automatically  typed,  immediately,  on  the  other  members'  teletypes, 
with  a  symbol  indicating  whose  sequences  It  was  and  when  it  received  a  plus 
or  not.   In  the  "anonymous  mode"  the  sequence  is  typed,  along  with  its  plus  or 
minus,  after  a  variable  delay  in  a  way  concealing  its  authorship.   In  the 


96 


Serial  No.  M-AP(C)-18-3 

"standard  mode"  the  sequence  t5rped  by  each  member  Is  not  typed  on  anyone 
else's  teletype;  instead,  a  sequence  from  a  standard  library,  stored  in  the 
computer,  is  typed  on  everyone  else's  teletype.,   Each  mode  is  introduced  by 
detailed  instructions  and  considerable  practical  experience  for  the  family 
so  that  they  become  fully  familiar  with  its  distinctive  features  before 
beginning  the  actual  problem-solving.  Preceding  and  following  each  experi- 
mental problem  each  member  is  given  a  objective  test  of  his  ability  to 
predict  the  class  of  sequences  that  will  get  a  plus;  this  serves  as  a  test 
of  his  ability  to  recognize  relevant  patterns. 

Progress;  In  the  first  study,  four  families  designated  as  consensus- 
sensitive  were  compared  with  four  environment-sensitive  families.  The 
distinction  between  these  two  groups  was  made  by  the  use  of  card-sorting 
procedure.  The  consensus-sensitive  families  were  those  that  sought  to 
achieve  consensus  at  the  price  of  accurate  problem  solution.  The  two  groups 
were  carefully  matched  for  a  number  of  variables  including  intelligence  and 
social  class.   The  results  were  very  striking  and  clear  even  though,  in  this 
pilot  study,  the  sample  was  small.  We  used  a  matched-pair  design  in  which  an 
environment-sensitive  family  was  matched  with  an  consensus-sensitive  family. 
In  each  pair  the  consensus-sensitive  family  showed  a  progressive  improvement 
in  problem-solving  ability  as  intermember  access  was  reduced  from  the  public, 
to  the  anon3rmous  to  the  standard  mode.   In  sharp  contrast  each  environment- 
sensitive  family  showed  no  change  or  a  slight  decline  in  problem-solving 
ability  as  intermember  access  was  reduced. 

A  second  study,  using  a  wider  sample  of  15  families,  studied  the  more 
detailed  processes  of  hypothesis  testing  in  the  two  groups  of  families. 
Correlational  studies  suggested  that  members  in  families  with  a  marked  deficit 
in  the  public  mode  relative  to  the  standard  mode,  used  others'  h3rpotheses  as 
a  basis  for  their  own  hypothesis  testing  less  often  than  members  in  families 
without  such  a  relative  deficit.  Moreover,  in  the  public  deficit,  members 
were  less  willing  to  risk  the  construction  of  incorrect  hypotheses.  These 
findings  were  predicted  by  a  consensual  experience  model:   It  states  that 
members  in  environment-sensitive  families  (with  no  public  deficit)  use  each 
others'  experiences  with  the  environment  as  a  way  of  augmenting  their  ovra 
experience  and  understanding  of  it,  whereas  consensus-sensitive  families, 
since  they  are  oriented  to  achieving  an  agreed-unon  internal  version  of 
experience,  tend  to  ignore  the  others  interaction  with  the  environment.  The 
unwillingness  of  these  individuals  to  risk  negative  feedback,  for  their 
hjrpotheses.  confirms  our  view  that  they  experience  negative  feedback  as 
censorious  rather  than  information-giving;  this  attitude  is  consistent  with 
their  vi«w  of  the  environment  as  hostile  and  unknowable. 

After  completing  the  two  studies  described  above,  the  program  for  the 
teletype  experiment  was  substantially  revised  to:   (a)  make  the  three  modes 
more  nearly  identical  in  the  type  and  quantity  of  feedback  for  subjects' 
hypotheses  and  (b)  to  more  completely  automate  the  procedure;  this  now 
includes  some  automatic  instruction  and  testing  of  subjects.   Pre-experimental 
trials,  during  the  past  year,  have  indicated  that  the  changes  have  improved 

91 


Serial  No.  M-AP(C)-18-3 


the  efficiencYs  standardization  and  comprehensibility  of  the  procedure. 
Serious  delays  in  completing  data  collection  have  been  caused  by  lack  of 
adequate  number  of  research  support  staff. 


Honors  and  Awards; 

1.   Reiss,  D. :  Invited  address.   "The  Faiaily's  View  of  Its  Environment; 
Laboratory  Studies  of  Its  Origins  and  Functions."  Faculty  of  the 
Department  of  Psychiatry,  Montefiore  Hospital  and  Medical  Center, 
Bronx,  New  York,  March,  1972. 


Publications: 

1.  Reiss,  D. :  Intimacy  and  problem  solving:  An  automated  procedure 
for  testing  a  theory  of  consensual  experience  in  families. 
Arch.  Gen.  Psychiat.  25:  442-455,  1971. 

2.  Reiss,  D. :  Varieties  of  consensual  experience  I.   A  theory  for 
relating  family  interaction  to  individual  thinking.   Fam.  Process 
10:  1-28,  1971. 

3.  Reiss,  D. :  Varieties  of  consensual  experience  II.   Dimensions  of 

a  family's  experience  of  its  environment.   Fam.  Process,  10;  28-35, 
1971. 

4.  Reiss,  D. :  Varieties  of  consensual  experience  III.   Contrast 
between  families  of  normals,  delinquents  and  schizophrenics. 
J.  Nerv.  Ment.  Pis.  152:  73-95,  1971. 

5.  Reiss,  D. :   Competing  hypotheses  and  warring  factions;  Applying 
knowledge  of  schizophrenia.   Schizo.  Bull.   In  press. 


Serial  No.  M-AP(C)-18-6 

1.  Adult  Psychiatry  Branch 

2.  Section  on  Experimental 
Group  and  Family  Studies 

3.  Bethesda,  Maryland 


PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  -  June  30,  1972 

Project  Title:  Nurse-Doctor-Patlent  Interaction:  An  Experimental  Study 
of  Its  Role  In  Patient  Acculturation  on  Psychiatric  Wards. 

Previous  Serial  Number:  M-AF(C)-18-6 

Principal  Investigator:  David  Relss,  M.D. 

Other  Investigators:  None 

Cooperating  Units:  Richard  Almond,  M.D. ,  Department  of  Psychiatry, 

Stanford  University  Medical  School,  Palo  Alto,  California 

Man  Years: 

Total:  .8 
Professional:  .6 
Other:        .2 

Project  Description: 

Objectives:  The  major  objective  of  the  study  is  the  direct  measurement, 
under  controlled  conditions,  of  nurse-doctor-patient  interaction  as  it  occurs 
on  psychiatric  wards.  The  hypotheses  of  the  study  are  derived  from  previous 
work  by  Dr.  Almond  which  suggest  that  particular  forms  of  nurse-doctor- 
patient  interatlon  are  crucial  to  inducing  change  and  improvement  in  patients. 
Moreover,  his  previous  studies  suggest  that  certain  value  orientations  by 
the  staff  serve  to  control  or  perpetuate  these  crucial  interactions  and  many 
patients,  after  modifying  their  behavior  during  interaction  with  professional 
staff  (and  other  patients),  accept  these  values.  This  study  seeks  to  relate 
value  orientations  of  the  staff,  concerning  t3rpes  and  process  of  treatment 
as  well  as  personal  preferences  for  t3rpe8  of  interaction  in  group  involve- 
ment, with  the  way  they  interact  with  each  other  and  with  patients.   Specif- 
ically, we  attempt  to  predict  how  a  nurse  and  doctor  will  Interact  with 
each  other  from  a  knowledge  of  their  value  orientations;  then  we  seek  to 
predict  how  the  nurse-doctor  dyad  will  Interact  with  a  patient,  based  on 
their  behavior  when  interacting  as  a  dyad.  This  is  the  first  direct  experi- 
mental study  of  Interpersonal  processes  amongst  psychiatric  personnel  and 
therefore  the  project  also  serves  the  general  purpose  of  examining  the  value 
of  experimental  techniques  in  this  area  of  clinical  Investigation. 


99 


Serial  No.  M-AP(C)-18-6 


Method :  Dr.  Almond  has  modified  a  questionnaire  he  used  in  his  original 
studies  in  New  Haven.   It  has  a  broader  range  of  items  and  is  now  suitable 
for  administration  to  nurses  and  doctors  as  well  as  patients.  The  results 
of  this  questionnaire  were  used  to  evaluate  nurses'  and  doctors'  value 
orientations.  These  orientations,  in  turn,  were  used  to  predict  nurse-doctor 
interaction.  Two  value  orientations  were  selected  as  independent  variables. 
1)  the  subjects'  expressed  valuation  of  social  openness  and  involvement  in 
the  ward  (SOWI)  by  patients  and  staff;  2)  the  subjects'  expressed  wish  to  be 
included  in  the  control  groups  (FIRO).   Sixteen  nurse-doctor  dyads  were 
formed  so  that  they  could  be  divided  into  four  subsamples  of  equal  size; 
8  dyads  were  highly  discrepant  on  SOWI  (snore  higher)  and  8  had  similar 
scores;  half  of  each  of  these  subsamples  had  highly  discrepant  FIRO  scores 
(more  higher)  and  half  were  the  same.   Each  dyad  was  tested  separately  in  a 
small-group-type  laboratory  where  they  were  isolated  in  booths  and  could 
communicate  only  by  microphone.  They  worked  on  a  standard  set  of  problems, 
provided  by  the  experimenter,  requiring  them  to  group  a  set  of  fictitious 
patients  into  activity  groups.  After  a  series  of  such  problems,  they  were 
joined  by  a  patient  and  continued  to  work  on  a  set  of  similar  problems  as  a 
triad.  A  number  of  objective  indices  of  social  interaction  in  the  dyads  and 
triads  were  derived  from  the  card  placements  and  objectively  recorded  times 
of  various  phases  of  the  experimental  task.  These  variables  sought  to 
measure  the  extent  to  which  the  dyads  and  triads  1)  agreed  or  disagreed  on 
problem  solutions;  2)  blindly  followed  a  potent  leader  or  worked  inter- 
dependently  with  each  individual  making  a  substantial  contribution;  3) 
utilized  the  full  range  of  ideas  elaborated  by  each  person  working  alone; 
4)  "objectified  or  dimensionalized"  the  problem  rather  than  seeing  each 
fictitious  patient  and  grouping  as  unique  and  personal. 

Progress:  Data  analysis  and  written  reports  are  complete.  The  basic 
findings  are  these:  There  is  a  substantial  difference  in  the  effects  of 
independent  variables  early  in  the  task,  when  the  nurse  and  doctor  are  being 
acquainted  and  where  the  dyad  meets  the  patients  for  the  first  time,  and 
later  in  the  task  when  all  three  have  been  working  together.  The  findings 
are  these:   1)  Where  the  nurse  has  a  tendency  to  dominate  groups  and  the 
doctor  wants  to  be  dominated  (FIRO  compatibility)  and  the  nurse  has  higher 
SOWI  values,  the  doctor  and  nurse  form  a  very  tight  consensus  but  are  unable 
to  include  or  assimilate  the  patient.  Here  the  dominant  nurse  shows  evidence 
of  using  her  more  differentiated  values  as  a  club  forcing  the  doctor  to  accept 
her  views.   These  findings  were  also  obtained  where  the  nurse  and  doctor  are 
equal  in  values  and  neither  is  dominating  or  wishes  to  be  dominated  (FIRO 
incompatible) .   Here  the  lack  of  any  differences  between  the  two  on  value 
orientation  appears  to  produce  an  enui  exaggerated  by  incompatibility  and 
papered  over  by  an  artificial  consensus.   2)  Where  the  nurse  and  doctor 
are  equal  in  values  and  FIRO  compatible,  and  where  the  nurse  is  superior  in 
values  and  the  dyad  is  FIRO  incompatible,  the  nurse  and  doctor  form  a 
flexible  and  varying  consensus  and  very  effectively  include  the  patient  in 
this  consensus.   In  the  former,  interpersonal  compatibility  enables  the  dyad 
to  reach  an  affable  agreement  which  is  well  able  to  include  a  third  person. 
In  the  latter,  some  interpersonal  incompatibility  focusses  the  dyad  away 

100 


Serial  No.  M-AP(C)-18-6 


from  the  task  of  simply  gratifying  one  another.  Rather  they  concentrate  on 
preparing  for  the  patient's  entrace.  The  nurse's  high  SOWI  values  enable 
her  to  take  an  important  role  in  assimilating  the  patient  when  he  does  arrive. 
The  findings  indicate  that  both  independent  variables  are  Important  and  have 
an  interacting  effect.  A  difference  in  values  appears  crucial  for  stimulat- 
ing the  nurse-doctor  dyad  to  consider  various  approaches  and  reach  a  meaning- 
ful consensus;  however,  if  the  nurse  tends  to  dominate  the  dyad  and  the 
doctor  acquiesce,  the  nurse  will  use  her  distinctive  value  position  as  a 
club.  Tension  between  nurse  and  doctor  will  be  papered  over  with  a  forced 
consensus  and  the  patient  will  be  excluded. 


101 


Serial  No.  M-AP(C)-18-10 

1.  Adult  Psychiatry  Branch 

2.  Section  on  Experimental 
Group  and  Family  Studies 

3.  Bethesda,  Maryland 


PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  -  June  30,  1972 

Project  Title:  The  Effect  of  Stimulus  Materials  on  Family  Problem  Solving. 

Previous  Serial  Number:  M-AP(C)-18-10 

Principal  Investigator:  David  Relss,  M.D. 

Other  Investigators:  None 

Cooperating  Units:  None 

Man  Years: 

Total:  .1 
Professional:  .1 
Other:         .0 

Project  Description: 

Objective:  In  the  work  done  in  our  laboratory  almost  all  family 
problem-solving  tasks  have  utilized  pattern  recognition  tasks  in  which 
patterned  stimuli  have  been  generated  by  one  or  another  type  of  finite  state 
grammar  (as  originally  described  by  Chomsky  and  Miller).   These  problem 
materials  have  a  ntimber  of  advantages  for  studying  complex  perceptual  and 
cognitive  processes.  Nonetheless,  they  represent  a  restricted  model  of  the 
types  of  stimulus  experience  families  may  encounter  In  their  everyday  lives. 
Tt  is  important  to  establish  that  our  findings  concerning  family  problem 
solving  can  be  generalized  to  different  kinds  of  stimuli.  Other  feattires 
of  the  card-sorting  procedure,  such  as  the  partial  self -administration 
features,  ease  of  observer  recording  of  sorting  performance,  uniformity  of 
physical  characteristics  of  the  stimulus  materials.  Isolation  in  booths, 
have  solved  a  number  of  long-standing  methodological  problems.   Thus,  it 
seemed  imprudent  to  change  the  basic  card-sorting  procedure  itself.  However, 
a  change  of  the  content  of  the  cards  seemed  useful  to  test  the  generality  of 
our  findings. 

Method;  Accordingly,  we  designed  a  procedure,  adapted  from  Tlen's 
Organic  Integrity  Test,  which  required  subjects  to  sort  cards  according  to 
objects  pictured  on  the  cards.  Three  sets  of  15  cards  were  developed:  two 
were  used  for  initial  and  final  individual  task  and  a  third  for  a  family 


103 


Serial  No.  M-AP(C)-18-10 


task  between  the  individual  tasks.  Thus,  the  procedure  has  the  same  formal 
structure  as  the  letter  syllable  and  number-sorting  tasks.   In  each  of  three 
tasks  the  cards  can  be  grouped  in  at  least  three  ways:  by  color  of  object, 
use  of  object  (e.g.  tool,  wearing  apparel  or  sporting  equipment)  or  by  sex 
of  user  (male,  female  or  neutral).  A  maximally  effective  sort  would  pre- 
sumably use  one  of  these  three  with  complete  consistency  (corresponding  to 
recognizing  the  finite  state  grammar  in  the  basic  sorting  procedure).  Also, 
families  could  vary  in  the  amount  of  sorting  similarity  between  members  and 
across  trials.  Therefore,  the  same  variables  of  problem-solving  ability, 
coordination  and  closure  were  obtainable  from  this  procedure  as  the  basic 
procedure. 


Progress;  Data  collection  is  continuing. 


lOi^ 


Serial  No.   M-AP(C)-18-12 

1.  Adult  Psychiatry  Branch 

2.  Section  on  Experimental 
Group  and  Family  Studies 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  -  June  30,  1972 

Project  Title:  Family  Views  of  Its  Social  Environment:  Effects  on 
Family  Therapy  Process. 

Previous  Serial  Number:  None 

Principal  Investigator:  David  Relss,  M.D. 

Other  Investigators:  Ronald  Costell,  M.D.  and  Loann  Drake 

Cooperating  Units:  Section  on  Personality  Development,  APB,  IR,  NIMH 

and  Psychiatric  Institute  of  the  District  of  Columbia 

Man  Years: 

Total:        2.0 
Professional:   1 
Other:         1 

Project  Description: 

Objective:  During  the  past  6  years  a  series  of  laboratory  studies  have 
revealed  that  families — functioning  as  a  group — develop  shared  and  vivid 
concepts  of  the  structure  of  the  larger  social  community  in  which  they  live 
and  work.   Some  families  see  their  social  environment  as  being  patterned 
and  engrossing.  Other  families  see  their  social  environment  as  threatening, 
chaotic  and  overwhelming.  Evidence  suggests  that  these  shared  family 
constructions  of  their  environment  are  typical  and  enduring  and  dominate  a 
family's  response  to  any  novel  or  stressful  challenge  in  their  social 
environment.  We  hjrpothesize  that  this  is  particularly  true  when  a  family 
must  Involve  Itself  in  an  entirely  new  social  community.  Then,  their  typical 
reaction  patterns  play  a  major  role  in  shaping  their  adaptations  to  and 
involvement  in  the  Institution^  social  processes.  This  kind  of  encounter 
between  family  and  the  new  institution  is  very  well  exemplified  by  a 
psychiatric  hospital  that  emphasizes  family  treatment.  When  the  index 
member  is  admitted  to  the  hospital,  the  whole  family  is  actively  engaged  in 
the  treatment  program.  Thus,  the  family — as  a  group — must  orient  itself  to 
a  set  of  novel  and  stressful  challenges.  This  study  is  designed  to  test  the 
relationship  between  family  reaction  patterns,  as  measured  in  the  laboratory, 
and  their  adaption  during  the  first  six  weeks  of  family-oriented  in-patient 
psychiatric  treatment.  The  laboratory  measures  will  be  used  to  predict  the 

105 


Serial  No.  M-AP(C) -18-12 


degree  to  which  the  family  will  become  involved  and  engrossed  in  the  treat- 
ment program  or  withdraw  and  protect  itself  from  the  hospital  eomnunity  and 
its  programs.  The  interaction  between  family  and  hospital  will  also  be 
viewed  as  protypical  of  interactions  between  families  and  a  variety  of 
institutions  in  their  social  environment.  Later,  we  plan  studies  of  the 
interaction  between  families  and  schools  and  families  and  occupational 
settings. 

Methods  One  independent  variable  is  the  family's  problem-solving 
behavior  in  the  laboratory.  Based  on  this,  a  family  can  be  placed  in  one  of 
three  categories!   environment-sensitive,  consensus-sensitive  and  distance- 
sensitive.  The  second  variable  is  institution;  the  families  are  either 
admitted  to  the  Psychiatric  Institute  or  NIMH.   It  is  planned  to  set  up  a 
system  whereby  families  can  be  randomly  assigned  to  one  or  the  other 
institution  with  a  stratification  procedure  that  assures  family  comparability 
along  several  dimensions.  Thus,,  the  basic  design  is  a  3  (family  types)  x  2 
(institutions)  factorial  one. 

The  dependent  variables  are  selected  to  measure  various  aspects  of  the 
family's  adaptation  to  the  hospital  community  and  its  treatment  program. 
Several  of  the  procedures  utilize  the  family  interaction  laboratory  but  are 
specifically  designed  to  measure  the  family's  perception  or  collective 
experience  of  the  hospital  social  community.  The  most  important  is  the  Ward 
Perception  Q-Sort.  Our  theory  states  that  a  family's  t3^ical  approach  to 
construing  novel  social  situations  will  determine  its  shared  experience  of 
the  ward  community.  This  shared  experience  is  a  variable  intervening 
between  family  type  and  adjustment  to  the  treatment  program.  The  Ward 
Perception  Q-Sort  is  intended  as  a  direct  estimate  of  this  shared  perception 
in  the  family.   Specifically,  it  measures  four  aspects  of  the  family's  shared 
perceptions!  accuracy,  stereotypy  coherence  and  the  similarity  between 
members.  The  procedure  requires  family  members,  each  individual  in  his  own 
booth,  to  sort  a  group  of  36  cards  into  7  categories.  Each  card  contains  a 
description  that  might  be  applicable  to  the  psychiatric  ward  and  the  7 
categories  are  labeled  in  descending  order  from  "most  characteristic"  to 
"least  characteristic."  The  family  is  urged  to  discuss  together,  thru  an 
intercom,  how  to  categorize  the  cards.  Objective  scores  are  computed  to 
estimate  the  four  aspects  of  family  perception  from  their  sorts. 

Two  other  procedures  permit  a  direct  assessment  of  family-hospital 
interaction;  they  are  utilized  directly  on  the  ward.  Both  depend  on  the 
family's  participation  in  a  multiple-family  therapy  group— a  major  treatment 
modality  at  both  the  Psychiatric  Institute  and  NIMH. 

The  first  procedure  is  direct  observation  and  measurement  of  the 
family's  interaction  with  other  family  and  psychiatric  staff  in  the  group. 
Over  a  series  of  sessions  the  family's  seating  arrangement  and  the  frequency 
and  direction  of  their  speech  will  be  carefully  recorded  by  an  observer. 
The  family's  engagement  and  involvement  in  the  ward  community  will  be  indexed 
by  its  willingness  to  disperse  itself  physically  in  a  group  rather  than  stay 

106 


Serial  No.  M-AP(C)-18-12 


huddled  together  in  adjoining  seats;  it  will  also  be  indexed  by  frequent 
speech  directed  at  many  individuals. 

The  second  procedure  is  the  sociometric  technique.  It  too  is  being 
used  as  a  measure  of  family  engagement  and  involvement.  In  particular,  we 
are  interested  in  the  experiential  boundary  the  family  constructs  between 
itself  and  the  rest  of  the  community.  Family  members  are  asked  to  choose 
others  in  the  multiple  family  group  whom  they  like  and  know  well.  Imper- 
meable boundaries  will  be  indicated  by  families  who  choose  few  others  and 
where  members  choose  others  in  the  same  family.  Members  in  families  with 
impermeable  boundaries  should  also  be  the  object  of  choice  by  few  others, 
outside  the  family,  in  the  multiple  family  group. 

A  third  procedure  is  a  group  cohesiveness  questionnaire  adapted  from 
studies  of  outcome  and  process  in  therapy  groups  of  unrelated  members.  This 
is  used  to  estimate  the  family's  subjective  sense  of  being  involved  in  the 
multiple  family  group. 

A  fourth  procedure  is  the  Family  Perception  Procedure.  This  procedure 
is  aimed  at  assessing,  from  a  different  perspective,  the  character  of  the 
family's  experience  of  the  social  community— in  this  sense  supplementing 
the  Ward  Perception  Q-Sort.  Here,  a  family  is  tested  immediately  following 
a  multiple-family  group  meeting.  Members,  working  together,  are  asked  to 
make  a  number  of  distinctions  between  different  families  and  between  differ- 
ent members  of  the  same  family.  Following  general  procedures  outlined  by 
George  Kelly,  an  estimate  is  made  of  the  number,  complexity  and  character  of 
the  dimensions  the  family  uses  to  discriminate  between  individuals  and 
families  within  the  group.  Here,  we  attempt  to  distinguish  between  simple, 
moralistic  and  superficial  distinctions  and  complex,  flexible  and  psycho- 
logically insightful  distinctions. 

Overall,  we  have  made  the  following  predictions.  Environment-sensitive 
families — who  can  develop  progressively  more  complex,  subtle  and  accurate 
solutions  to  laboratory  problems,  will  show  simple  kinds  of  evaluations  of 
the  ward  social  community  on  the  Q-Sort  and  Family  Perception  Procedure. 
They  will  also  show  evidence  of  greater  engagement  and  involvement  in  the 
therapeutic  process.  Consensus-sensitive  families — who  force  an  early 
agreement  among  themselves  on  simple  and  stereotyped  solutions  to  laboratory 
puzzles— will  show  similar  characteristics  in  their  conceptions  of  the  social 
community  on  the  ward  and  remain  isolated  and  distant  from  the  therapeutic 
program. 

Progress;  Two  major  achievements,  crucial  to  the  success  of  this 
project,  have  been  accomplished  during  this  first  year  of  the  study.  First, 
a  well  worked  out  collaboration  has  been  established  with  the  Psychiatric 
Institute  and  the  Section  on  Personality  Development.  This  has  included 
review  of  the  project  with  professional  staff  and  patients,  testing  of 
families  and  establishing  multiple-family  groups  suitable  for  study.  The 
problem  of  setting  up  a  random  assignment  procedure  must  wait  until  the 

107 


Serial  No.   M-AP(C) -18-12 


future  of  the  Adult  Psychiatric  Branch  and  Unit  3  West  is  secure.   Second, 
all  procedures  for  measuring  the  dependent  variables  are  new  in  some 
respect — either  they  have  never  been  tried  before  or  they  have  never  been 
applied  to  families.   Thus,  during  the  past  year  we  have  been  engaged  in 
extensive  and  intensive  pilot  testing  and  all  procedures  show  evidence  of 
being  practicable  and  reliable. 


108 


Serial  No.  M-AP(C) -18-13 

1.  Adult  Psychiatry  Branch 

2.  Section  on  Experimental 
Croup  and  Family  Studies 

3.  Bethesda,  Maryland 


PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  -  June  30,  1972 


Project  Title:  Values  and  Atmosphere  on  a  Psychiatric  Ward:  Basic 
Dimensions  and  Institution  Comparisons. 

Previous  Serial  Number:  None 

Principal  Investigator:   Ronald  Costell,  M.D. 

Other  Investigators:     David  Reiss,  M.D. 

Cooperating  Units:  NIH  Nursing  Administration,  Nursing  Units  3  West,  3  East, 
4  West,  4  East,  and  Psychiatric  Institute  of  the 
District  of  Columbia 

Han  Years: 

Total:  .9 
Professional:  .4 
Other:        .5 

Project  Description: 

Objective;  Studies  of  psychiatric  wards  indicate  that  the  attitudes 
and  values  of  staff  and  patients  with  regard  to  therapy-related  behaviors 
play  an  important  role  in  defining  the  therapeutic  milieu  and  the  nature  of 
therapeutic  transactions  between  patients  and  treatment  staff.  This  study 
seeks  to  explore  the  relation  between  therapeutic  milieu  attitudes  and 
values  and  aspects  of  Individual  disposition  toward  interpersonal  relations. 
In  addition,  the  study  seeks  to  explore  the  relation  between  these  two 
domains  and  the  ways  in  which  individuals  perceive  the  ward  atmosphere. 
These  relations  are  explored  through  analysis  of  a  composite  questionnaire. 
Therapeutic  milieu  attitudes  and  values  are  represented  on  the  questionnaire 
by  several  previously  studied  scales  includluK  the  Almond  Social  Openness- 
Ward  Involvement  Scale,  and  the  Therapeutic  Ideology  Scale  of  Strauss. 
Individual  interpersonal  disposition  items  are  represented  by  the  A-B 
Therapist  Scale  of  Whltehom  and  Betz,  the  FIRO-B  scales  of  Schutz  and  the 
Machiavellianism  Scale  of  Gelst  and  Christe.  The  Ward  Atmosphere  Scale  of 
Moos  provides  the  measure  of  perception  of  the  social  atmosphere  of  the 
ward.   Exploration  of  therapeutic  milieu  attitudes  and  values,  and  of 
interpersonal  relations  disposition  in  conjunction  with  another  study,  in 
1969,  provided  interesting  factor  analytic  factor  clusters  from  two 

109 


Serial  No.  M-AP(C) -18-13 


institutions.   In  the  current  study  we  plan  to  assess  the  reliability  of 
these  factors  over  time  and  extend  the  perspective  of  the  study  to  percep- 
tions of  ward  atmosphere. 

Method!  The  composite  questionnaire  is  to  be  administered  to  inpatients, 
nursing  staff  and  professional  staff  on  the  four  psychiatric  units  at  NIMH 
and  to  similar  groups  at  a  large  private  psychiatric  hospital,  the 
Psychiatric  Institute  of  D.C.   Individuals  from  both  hospitals  participated 
in  the  1969  study.  The  data  consisting  of  score  values  on  the  various  com- 
ponent scales  will  be  factor  analyzed  using  the  principal  components  method. 
Reliability  of  Che  questionnaire  components  and  factor  structure  obtained  in 
the  1969  study  will  also  be  assessed.  The  total  sample  of  respondents  will 
be  about  250. 

Progress;  Questionnaire  materials  allowing  for  direct  IBM  card  punching 
from  the  forms,  and  computer  program  for  extracting  the  scale  scores  have 
been  prepared  and  pretested.  The  questionnaires  have  currently  been  distri- 
buted on  all  of  the  four  NIMH  wards,  and  preparations  are  underway  to 
distribute  the  questionnaire  at  the  Psychiatric  Institute  of  D.C. 


110 


Serial  No.  M-AP(C)   19-1 

1.  Adult  Psychiatry  Branch. 

2.  Section  on  Twin  &  Sibling  Studies 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 
Individual  Progress  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   Comparative  Studies  of  Discordant  Siblings  in  Families  of 
Schizophrenic,   Juvenile  Delinquent  and  Well— adjusted 
Young  Adults 

Previous  Serial  Number:   same 

Principal  Investigator:  William  Pollin,  M.D. 

Other  investigator:   Martha  Werner,  M.A. 

Cooperating  Units: 

University  of  California-Davis,  Dr.  Joe  P.  Tupin 
University  of  Connecticut,  Dr.  James  R.  Stabenau 

Man  Years  (Computed  for  the  12  month  period) 

Total:  .5 
Professional:  .3 
Other:         .2 

Project  Description: 

Objectives,  Methods  Employed.  Patient  Material,  and  Major  Findings 
of  this  study  have  been  extensively  described  in  previous  years'  reports. 
At  present,  activities  are  limited  to  completion  of  ten-year  followup 
home  visits,  and  integration  and  preparation  of  the  data  for  monograph 
publication. 

Significance  to  Mental  Health  Research;   This  project,  along  with  the 
other  ongoing  studies  in  schizophrenia  concurrently  under  way  in  the  Section 
are  all  addressed  to  the  two  major  goals  of  helping  to  define  etiologic 
factors  relevant  to  schizophrenia,  and  more  basically,  determinants  of 
personality  formation.  As  such,  they  are  relevant  to  major  ongoing  questions 
ef  the  determinants  of  mental  health  and  emotional  illness. 

Proposed  Course  of  Project:   Integration  of  sibling  data  with  that  from 
twin  studies  (19-2  and  19-5  below)  for  monograph  publication. 

Honors  and  Awards;   Publications: 


111 


Serial  No.  M-AP(C)   19-2 

1 .  Adult  Psychiatry  Branch 

2.  Section  on  Twin  &  Sibling  Studies 

3.  Bethesda,  Maryland 

PHS-HSMA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   Studies  in  the  Development  of  Personality  and  Psychopathology 
in  Identical  Twins  Discordant  for  Schizophrenia 

Previous  Serial  Number:   same 

Principal  Investigator:   William  Pollin,  M.D. 

Other  Investigators:   none 

Cooperating  Units: 

A.  NIMH: 

Social  Service  Department  (Eleanor  Dibble) 

Computer  Systems  Branch,  Office  of  Adm  inistrative  Management  (Nils 

Mattsson) 
Center  for  Studies  of  Schizophrenia,  CRB,  ERPC  (Dr.  Loren  Mosher) 

B.  The  George  Washington  University,  Department  of  Psychology  Graduate 

Facility  (Mrs.  Mae  Leisinger,  Dr.  Malcolm  L.  Meltzer) 
Galesburg  State  Research  Hospital,  Galesburg,  111.  (Dr.  Harold  Himwich) 

Man  Years  (computed  for  the  12  month  period) 

Total:  1.3 
Professional:  1.1 
Other:         .2 

Project  Description: 

Objectives : 

In  identical  twins  discordant  for  schizophrenia,  genetic,  racial,  ethnic, 
social  class  and  a  variety  of  other  variables  which  have  seemed  to  bear  some 
relationship  to  the  pathogenesis  of  this  illness  are  constant  for  both  twins. 
Therefore,  in  studying  pairs  in  which  one  twin  is  schizophrenic  and  the  other 
is  not,  there  exists  an  unusually  favorable  situation  within  which  to  attempt 
to  determine  what  life  history  events,  family  relationship  patterns  and  non- 
genetic  biologic  factors  play  a  role  in  the  etiology  of  this  illness,  and  in 
what  manner.   In  addition,  a  new  method  of  analyzing  and  comparing  twin  and 
control  data  has  made  it  possible  to  define  probable  genetic  factors  which 
predispose  to  schizophrenia.   The  overall  picture  of  schizophrenia  patho- 
genesis which  is  then  possible  enables  one  to  aim  at  a  more  rational  approach 
to  development  of  new  treatment  modalities. 


113 


Serial  No.  M-AP(C)   19-2 

Methods  Employed; 

Previous  reports  have  described  the  intensive  multidisciplinary  in- 
patient work-up  of  a  total  of  25  families  with  identical  twins  admitted  for 
evaluation  to  the  Clinical  Center. 

During  the  past  year,  Mrs.  Mae  Leisinger,  working  on  her  Ph.D.  disser- 
tation under  my  supervision,  tested  a  series  of  hypotheses  relating  schizo- 
phrenia to  family  interaction  and  pathology.   The  conceptual  frame  of  refer- 
ence was  that  shared  unconscious  pathology  of  the  family  system  generates 
interlocking  tensions  which  are  reduced  and  projected  onto  a  particular  mem- 
ber.  This  member's  fragmentation  of  experience,  identity  diffusion,  dis- 
turbance of  motor  perception  and  distortion  of  thought  and  affect  —  some 
of  the  salient  characteristics  of  schizophrenia  —  are  hypothesized  to  re- 
flect to  a  maximum  degree  the  distortions  clinically  resident  in  other  family 
members  and/or  their  relationship  with  one  another.   To  test  these  hypotheses, 
an  additional  group  of  ten  local,  community  resident  families  with  "normal" 
twin  pairs  were  given  the  same  TAT  and  Leary  Interpersonal  Testlist  procedures 
previously  employed  with  the  series  of  families  of  MZ  pairs  discordant  for 
schizophrenia,  and  the  resultant  N  of  30  families  (120  individuals)  analyzed. 
Each  individual  described  himself,  his  hypothetical  ideal  self,  and  each  of 
the  three  other  family  members;  specialized  scoring  systems  were  used  to 
measure:   1)  the  level  of  conscious  communication;  2)  the  level  of  private 
perception  versus  pre-conscious  symbolic  representation;  and  3)  the  level  of 
values  or  ego  ideal . 

Patient  Material: 


See  previous  reports  for  details.   Fifteen  monozygotic  twin  pairs  dis- 
cordant for  schizophrenia  and  their  families  (one  pair  became  concordant) ; 
20  control  twin  families. 

Major  Findings: 

Previous  reports  have  described  earlier  findings.   Differences  distin- 
guishing index  schizophrenic  from  non-schizophrenic  co-twin  controls  in  dis- 
cordant pairs  have  included  family  perception  and  relationship  differences, 
life  history  and  non-genetic  constitutional  differences;  and  biochemical 
findings  apparently  related  to  schizophrenic  genotypes  involving  catechol- 
amine metabolism. 

New  findings  this  past  year  involved  family  interaction  data.   It  was 
found  that  individuals  in  the  schizophrenic  families  unconsciously  perceive 
themselves  as  very  similar  ~  father  similar  to  mother  and  parents  similar  to 
offspring.   Normal  family  members,  instead,  portray  themselves  as  different 
one  from  the  other  within  the  families  with  the  father  particularly  being 
perceived  as  exhibiting  a  well-differentiated  role  identity.   The  data  suggest 
that  the  normal  father  is  the  family  member  who  customarily  disentangles  the 
family  group,  but  the  fathers  of  schizophrenics  seem  unable  to  do  this.   This 
similarity  is,  however,  either  unrecognized  or  unadmitted.   This  blurring  of 
sex  role  differences  seems  to  skew  the  family  system,  and  the  family  is  seen 
to  have  an  "undifferentiated  ego  mass"  as  previously  described  by  Bowen. 
Further,  there  is  substantial  evidence,  consistent  with  Laing's  formulations 

lli^ 


Serial  No,  M-APCC)   19-2 

that  the  parents  perceive  the  schizophrenic  in  terms  that  misdefine  him  to 
himself.   In  particular,  the  parental  message  for  the  schizophrenic  is  that 
he  is  passive  and  instrumentally  unable  to  master  his  environment.   These 
observations  are  consistent  with  those  of  Tienari  and  Kallmann,  and  with  the 
earlier  clinical  observations  by  this  group,  who  had  reported  a  pattern  in  the 
discordant  MZ  pairs,  beginning  in  the  earliest  years,  by  which  the  index  was 
rigidly  imprinted  with  a  role  expectation  of  incompetence  and  dependence.  The 
question  quickly  arises  as  to  the  extent  to  which  this  familial  perception  of 
the  schizophrenic  as  passive  and  incompetent  is  based  on  the  reality  of  the 
results  of  his  illness.   To  some  extent  this  must  be  the  case.   However,  a 
most  interesting  relationship  between  such  disconfirmation  of  the  index,  and 
parental  intrapsychic  repression,  strongly  suggests  that  this  is  not  the 
entire  story.   The  higher  the  degree  of  parental  repression,  the  greater  the 
degree  of  parental  disconfirmation  of  the  index  twin.   This  finding  presents 
an  interesting  parallelism  to  the  formulation  of  defensive  delineations  pre- 
viously proposed  by  Roger  Shapiro's  group,  and  suggests  that  the  disconfirma- 
tion is  in  part  a  process  that  is  meeting  unconscious  psychological  needs 
of  the  parent.   Leisinger  suggests  "One  may  analogize  from  the  wit  of  G.  B. 
Shaw  who,  as  Eliza  in  Pygmalion,  says,  "The  difference  between  a  flower  girl 
and  a  lady  is  not  how  she  behaves,  but  how  she  is  treated,'  to  say,  the 
difference  between  a  schizophrenic  and  another  twin  is  not  how  he  responds, 
but  how  he  is  perceived."  Clearly  this  is  not  the  whole  story,  but  the 
interesting,  statistically  significant  relationship  between  parental  repress- 
ion and  the  above  findings  strongly  suggest  that  it  is  part  of  the  story. 

Significance  to  Mental  Health  Research: 

Previous  analysis  has  focused  on  the  significance  of  defining  a)  non- 
genetic  constitutional  contributions  toward  the  pathogenesis  of  schizophrenia, 
and  b)  a  characteristic  pre-illness  life  course  preceding  schizophrenia. 
The  findings  of  the  past  two  years  suggest  some  of  the  genetically  determined 
biological  factors  which  contribute  to  predisposition  to  this  psychosis,  and 
help  establish  by  quantitative  rather  than  clinical  data  some  of  the  relevant 
family  processes . 

Proposed  Course  of  Project: 

Continuing  analysis  of  multidisciplinary  data  with  further  efforts  to 
trace  central  relationships  involved.   Replication  study  as  described 
below  (19-5),  with  focus  on  newly  available  biochemical  possibilities, 
including  DMJ  determinations  (Himwich)  and  collaborative  methyl  transferase 
determinations  (Wyatt  and  Himwich) . 

Honors  and  Awards : 

Pollin,  William:   Guest  lecturer,  Northern  Virginia  Mental  Health  Center 

Pollin,  William:   Guest  lecturer.  The  George  Washington  University, 
Department  of  Psychology  Graduate  Facility. 


115 


Serial  No.  M-AP(C)   19-2 


Publications ; 


Pollin,  W.:   The  pathogenesis  of  schizophrenia:   Possible  relationships 
between  genetic,  biochemical  and  experiential  factors.   (In  press. 
Arch.  Gen.  Psychiat.) 

Pollin,  W. :   A  new  approach  to  the  use  of  twin  study  data  in  studies  of 
the  pathogenesis  of  schizophrenia  and  neurosis.   In  Kaplan,  A.  (Ed.): 
Genetic  Factors  in  Schizophrenia.   Springfield,  111.,  Charles  C.  Thomas, 
1972^  pp.  374-379. 

Pollin,  W.   A  possible  genetic  factor  related  to  psychosis.   Reprinted 
in  Vestnik  Proceedings  Academy  of  Medical  Science  of  USSR  5:  57-59, 
1971. 

Pollin,  W. :  Genetic  and  environmental  determinants  of  neurosis.  In 
Kaplan,  A.  (Ed.):  Human  Behavior  Genetics .  (In  press,  Springfield, 
111.,  Charles  C.  Thomas) 


116 


Serial  No.  M-AP(C)   19-5 

1.  Adult  Psychiatry  Branch 

2.  Section  on  Twin  &  Sibling  Studies 

3.  Bethesda,  Maryland 

PHS-HSMHA-Nim 
Individual  Progress  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   The  Distribution  and  Concomitants  of  Schizophrenia,  and 

Other  Psychopathologies,  in  a  Systematic  Sample  of  15,909 
Ts'/in  Pairs 

Previous  Serial  Number:   Same 

Principal  Investigator:   William  Pollin,  M.D. 

Other  Investigator:   Stephen  Cohen,  M.D. 

Cooperating  Units: 

A.  NIMH: 

Social  Work  Department,  Mrs,  Eleanor  Dibble 

B.  National  Academy  of  Sciences /National  Research  Council,  Dr.  Z,  Hrubec 
Georgetown  University,  Dr.  Martin 

Human  Genetics  Branch,  NIDR,  Mr.  Webster  Leyshon 

Man  Years  (Computed  for  the  12  month  period) 

Total:       1.9 
Professional:  1.0 
Other:         .9 

Project  Description: 

Objectives : 

1.  To  identify,  contact,  and  recruit  a  replication  sample  for  a  new 
study  into  the  pathogenesis  of  psychosis.   (See  19-2) 

2.  To  determine  which  of  the  differentiating  factors  previously  uncover- 
ed in  our  study  of  a  series  of  identical  twins  discordant  for  schizophrenia 
can  be  validated  by  analyzing  a  much  larger  systematic  series  of  twins  dis- 
cordant for  schizophrenia. 

3.  To  determine  which,  if  any,  of  these  factors  are  specifically  rele- 
vant to  schizophrenia,  and  which  instead  may  predispose  toward  non-schizo- 
phrenic psychosis,  or  non-psychotic  psychopathology . 

4.  To  evaluate  the  relative  genetic  component  in  the  etiology  of  schizo- 
phrenia, in  comparison  to  other  psychopathologies;  in  particular,  affective 
psychosis . 

Methods  Employed: 

In  a  National  Research  Council  sample  of  15,909  pairs  of  male  twins,  both 
of  whom  served  in  the  Armed  Forces,  and  for  whom  extensive  medical  follow-up 


117 


Serial  No.  M-APCO   19-5 

is  available,  all  subjects  were  located  who  were  computerized  as  showing 
any  psychiatric  diagnosis,  or  were  separated  from  the  Service  in  such  a 
manner  as  to  indicate  disabling  psychopathology.   Following  analysis  of  the 
computer  data,  individual  charts  of  the  first  subgroup  of  patients,  com- 
prising 420  pairs  with  one  or  both  diagnosed  Schizophrenic  Reaction,  Involu- 
tional Psychotic  Reaction,  Affective  Reaction,  and  Other  Psychotic  Reactions 
were  called  in  from  various  parts  of  the  country  and  thoroughly  reviewed  by  a 
team  of  three  psychiatrists-.   Those  charts  that  fulfill  certain  rigid  diagnos- 
tic criteria  for  Schizophrenia  and  Manic  Depressive  psychosis  have  been 
identified  and  form  the  nuclear  sample  for  further  study. 

Recruitment  letters  have  been  sent  by  the  NAS/NRC  Follow-Up  Agency  to 
those  twin  pairs  who  met  our  criteria,  inquiring  as  to  their  availability  for 
participation  in  the  study  either  in  their  home  community  or  in  Bethesda. 
Blood  samples  for  zygosity  detennination  have  been  analyzed  for  pairs 
responding  positively. 

Because  of  a  disappointingly  low  yield  in  the  affective  psychosis  cate- 
gory State  Departments  of  Mental  Hygiene  were  contacted  nationwide.   Three 
states  currently  maintain  twin  registries  (California,  North  Carolina  and 
New  York) .   A  total  of  366  possible  referrals  from  the  first  two  of  these 
states  have  been  received  and  are  in  the  process  of  chart  diagnostic  review. 

Patient  Material: 

Working  with  data  obtained  from  42  states'  vital  statistic  offices,  the 
NAS/NRC  located  54,000  pairs  of  male  twins,  born  between  the  years  1917  and 
1927.   Of  these,  15,909  pairs  were  identified  by  the  Veterans  Administration 
as  both  having  served  in  the  Armed  Services.   These  twins  represent  a  cohort 
born  in  the  decade  1917-1927,  and  now  range  in  age  from  45  through  55;  thus 
the  age  of  maximal  risk  for  the  development  of  schizophrenia  has  been  passed. 
We  are  currently  vjorking  with  the  420  pairs  of  the  15,909  pairs  for 
whom  data  are  available,  in  which  one  or  both  twins  have  been  listed  as  show- 
ing the  diagnosis  of  Schizophrenia,  Involutional  Psychotic  Reaction, 
Affective  Reactions,  and  Other  Psychotic  Reactions.   We  will  subsequently 
review  the  charts  of  twins  with  diagnosis  for  psychoneurosis  and  a  group 
still  to  be  selected  to  serve  as  normal  controls. 

Of  229  California  twins  referred  with  possible  Affective  Psychosis 
diagnosis,  68  charts  were  selected  as  most  likely  candidates  and  sent  to 
us  for  current  review. 

Major  Findings: 

1.  The  yield  of  potential  MZ  pairs  discordant  for  Affective  Psychosis, 
a  key  control  group  In  our  planned  replication  study,  has  been  disappoint- 
ingly small,  even  after  extension  to  three  state  hospital  systems,  and  it 
may  be  necessary  to  give  up  this  phase  of  the  contemplated  study  design. 

2.  A  systematic  review  of  the  claims  files  of  all  420  veteran  twin 
pairs  from  the  NAS/NRC  twin  panel  of  15,909  pairs  where  one  or  both  twins 
had  a  psychotic  diagnosis  revealed  that  the  MZ  pairwise  concordance  rate  for 
schizoaffective  disorder  is  more  than  two  times  higher  than  that  of 

118 


I 


Serial  No.  M-AP(C)   19-5 

schizophrenia,  but  not  significantly  different  from  that  of  manic  depressive 
illness.   Monozygotic  twins  concordant  for  schizoaffective  disorder  had 
affective  symptomatology  equal  to  that  of  manic  depressive  twins  and  schizo- 
phrenic symptomatology  equal  to  that  of  the  schizophrenic  twins.   For  both 
twins  in  MZ  pairs  concordant  for  illness,  schizoaffective  psychosis  has  a 
mean  age  of  onset  which  is  earlier  than  both  manic  depressive  psychosis  and 
schizophrenia.   Seven  of  21  (33%)  MZ  index  schizoaffective  committed  suicide, 
as  opposed  to  none  of  the  18  manic  depressives  and  3  of  the  100  index 
schizophrenic  twins. 

3.   From  the  NAS  computer  tape,  5,256  psychopathology  diagnoses  were 
initially  identified  in  3,614  individuals.   These  included  the  following 
subgroups  of  monozygotic,  discordant  pairs;  401  pairs  discordant  for  psycho- 
neurosis,  112  personality  disorders,  166  for  psychophysiologic  disorders, 
23  affective  disorders,  and  354  pairs  discordant  for  other  psychopathology, 
in  addition  to  the  previously  described  69  MZ  pairs  discordant  for  schizo- 
phrenia.  Subsequent  intensive  chart  review  by  a  team  of  three  psychiatrists 
has  significantly  refined  these  initial  findings.   For  the  first  time,  a 
common  clinical  yardstick  has  been  applied  to  all  subjects  reviewed,  and 
obvious  errors  located  and  corrected.   In  the  840  charts  reviewed  there  were 
268  charts  where  changes  in  zygosity,  diagnosis  or  disease  course  were  made. 

Significance  to  Mental  Health  Research; 

1.  The  findings  concerning  schizoaffective  psychosis  help  clarify  the 
diagnostic  relationships  of  various  types  of  psychosis.   Specifically,  the 
revised  findings  help  document  the  conclusion  that  there  may  be  a  signifi- 
cantly greater  genetic  factor  contributing  to  the  pathogenesis  of  affective 
as  compared  to  schizophrenic  psychosis.   They  also  indicate  that  the  genetic 
mechanisms  contributing  to  schizoaffective  schizophrenia  overlap  with,  or 
include,  those  of  affective  as  well  as  schizophrenic  psychosis. 

2.  Identification  of  the  sought  for  groups  of  MZ  twins  discordant  for 
different  psychopathologies  would  provide  populations  admirably  suited  for 
testing  several  major  related  hypotheses  concerning  schizophrenia.  We  have 
previously  described  a  constellation  of  familial,  life  history,  and  biolog- 
ical factors,  derived  from  intramural  studies  and  the  world  literature,  which 
has  differentiated  identical  twins  who  become  schizophrenic  from  their  co— twins 
who  do  not.   Comparison  of  the  sample  of  MZ  pairs  discordant  for  several  of 
the  other  psychopathologies,  will  make  it  possible  a)  to  clarify  and  inte- 
grate into  a  conceptual  schema  those  differentiating  features  which  we 
replicate;  and  b)  to  determine  which,  if  any,  subgroup  of  these  differentiating 
factors  may  be  specific  for  schizophrenia,  and  which,  on  the  other  hand,  are 
related  to  psychopathology  in  general. 

Proposed  Course  of  Project: 

1.  Continuing  evaluation  of  additional  state  referrals,  and  completion 
of  analysis  of  chart  review. 

2.  Questionnaire  evaluation  of  selected  subsamples  of  the  above- 
described  MZ  pairs  discordant  for  different  definable  psychopathologies, 

3.  Direct  study  of  appropriately  selected  subsamples  to  test 
previously  described  hypotheses. 


119 


Serial  No.  M-AP(C)   19-5 

Honors  and  Awards : 

None 

Publications : 

Cohen,  S.,  Allen,  M. ,  Pollin,  W.  and  Hrubec,  Z.   The  relationship  of 
schizoaffective  psychosis  to  manic  depressive  psychosis  and 
schizophrenia:   Findings  in  15,909  veteran  twin  pairs.   (In  press. 
Arch .  Gen ,  Psychiat . ) 

Allen,  M. ,  Cohen,  S.,  Pollin,  W.   Schizophrenia  in  veteran  twins,  a 
diagnostic  review.   Am.  J.  Psychiat.  28:  936-945,  1972 


120 


Serial  No.  M-APCC)   19-6 

1.  Adult  Psychiatry  Branch 

2.  Section  on  Twin  &  Sibling  Studies 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 
Individual  Project   Report 
July   1,    1971   through  June   30,    19  72 

Project  Title:   The  Twin  Intrapair-Comparative  Technique  in  the  Study  of 
the  Determinants  of  Early  Personality  Development 

Previous  Serial  Number:   same 

Principal  Investigators:   Donald  J.  Cohen,  M.D.  and  William  Pollin,  M.D. 

Co-principal  Investigator:   Eleanor  Dibble 

Research  Associate:   Anna  Nichols 

Cooperating  Units: 

Section  on  Scientific  Applications,  AMCS ,  NIMH,  Messrs.  Nils  Mattsson, 

Robert  Rawlings ,  Jr.,  Darryl  E.  Bertolucci,  Richard  Fabsitz 
Social  Work  Department,  NIMH 
Child  Research  Branch,  NIMH  (Nursery  School),  Dr.  Charles  Halverson  and 

Gail  Inoff  (M-CR-24  (C)) 
Georgetown  University,  Washington,  D.C.,  Dr.  Martin  Allen 
Children's  Hospital,  Washington,  D.C.,  Drs.  Beale  Ong,  Jerome  Haller, 

and  Ann  Lodge 
Human  Genetics  Branch,  NIDR,  Mr.  Webster  Leyshon 
Department  of  Pathology,  NIH,  Dr.  Louis  Thomas 

Man  Years  (computed  for  the  12  month  period) 

Total:  2.1 
Professional:  1.2 
Other:         .9 

Project  Description: 

Objectives: 

1.   To  develop  methodologies  for  the  study  of  the  antecedents  of  person- 
ality in  preschool  children,  based  especially  on  the  comparative  study  of 
pairs  of  twins.   To  study  differences  between  children  in  relation  to  a) 
non-genetic  biological  differences  between  the  twins,  i.e.  differences  in  the 
congenital  endowment  of  the  children  and  early  differences  during  the  first 
weeks  of  life;  b)  parental  personalities  and  behaviors,  specifically,  differ- 
ences in  relationship  and  perceptions  of  parents  to  Twin  A  versus  Twin  B; 
c)  the  impact  of  such  differences  in  parent-child  relationships,  and  of  differ- 
ent experiences  such  as  illness  or  surgery,  on  the  children;  and  d)  the  origins 
of  and  differences  between  the  children  in  relation  to  behavior  problems. 


121 


Serial  No,  ,M-AP(C}   19-6 

2.   To  study  the  developmental  roots  of  personality  and  family  character- 
istics which  have  been  related  in  our  other  studies  on  schizophrenia  and  psycho- 
pathology  to  the  origins  of  serious  mental  illness. 


Methods  Employed: 

(1)   Longitudinal  Study.   Local  obstetricians,  officers  of  Mothers  of 
Twins  Clubs,  and  mothers  familiar  with  our  program,  have  referred  families  to 
the  research  program  at  various  times  during  the  gestation  of  the  twins  or  soon 
after  birth.   Families  were  seen  while  the  children  were  still  unborn,  and  have 
been  followed  since  that  time.   The  children's  current  ages  in  this  cohort  of 
12  sets  of  twins  range  between  almost  1  year  of  age  and  almost  6  years  of  age. 
The  children  in  this  cohort  and  their  families  have  been  studied  with  the  fol- 
lowing procedures:   Developmental  evaluation  and  Bayley  testing;  neurological 
evaluation;  psychiatric  diagnostic  evaluations  of  the  twins  and  parents;  fam- 
ily records;  information  from  the  Experimental  Nursery  School  of  the  National 
Institute  of  Mental  Health  in  which  the  children  are  enrolled  at  age  2-1/2 
years  for  one  day  of  studies;  evoked  cortical  potentials;  projective  psycholog- 
ical testing;  and  social  work  evaluations.   The  children  and  the  parents  are 
seen  at  regular  intervals  of  from  3  to  6  months  for  evaluation  and  interview. 
Special  forms  have  been  developed  for  the  taking  of  developmental  history, 
family  history,  rating  of  behavior  during  Rorschach  testing,  and  ratings  of 
the  children  in  experimental  situations. 


I 

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(2)   Epidemiological  Study.   On  the  basis  of  our  studies  on  psychopathol 
and  on  the  longitudinal  study  of  normal  twin  development,  we  have  initiated 
a  new  study  titled  "Childhood  Personality  Development:   Twins  and  the  Antece- 
dents of  Personality."   This  epidemiological  investigation  aims  at  exploring 
the  hypotheses  and  conclusions  from  the  previous  studies  and  extends  the  size 
of  the  sample,  explicates  and  operationally  defines  particular  variables  that 
have  emerged  from  clinical  observations ,  and  uses  newly  devised  psychological 
instruments.   The  study  employs  a  battery  of  psychological  questionnaires  and 
instruments,  some  newly  devised  and  others  adapted  from  other  workers,  with  a 
population  that  will  include  approximately  600  families  with  twins  between 
the  ages  of  1  year  and  6  years  of  age.   The  major  focus  will  be  on  twins  who 
are  monozygotic.   The  sample  will  be  drawn  from  volunteers  from  Mothers  of 
Twins  Clubs,  locally  and  nationally.   Parents  who  volunteer  will  be  sent  by 
mail,  in  two  phases,  a  series  of  questionnaires  and  forms,  which  they  will 
return  when  completed.   The  9  forms,  which  we  call  the  psychological  instrument, 
includes  the  following: 

1.  Release  of  Information  Form.  This  is  a  relatively  standardized  form 
which  gives  permission  for  communication  with  the  family's  obstetrician, 
pediatrician,  hospitals,  and  schools. 

2.  Family  Background.   This  form  contains  questions  about  demographic  in- 
formation and  physical  similarities  between  the  children.   Socioeconomic 
questions  allow  for  the  determination  of  social  position  and  socioeconomic 
class  (using  the  Hollingshead  two-factor  index  of  social  position) .   A 
series  of  questions  about  the  children's  physical  similarity  (height, 
weight,  etc.)  and  about  whether  or  not  they  are  confused  by  members  of  the 
family  and  strangers  allows  for  the  determination  of  probable  zygosity. 
The  similarity  and  zygosity  indices,  newly  devised  by  us,  are  based  on 

122 


Serial  No.  M-AP(C)   19-6 

previous  experience  with,  twins  and  work,  done  on  determination  of  zygosity 
with  adults.   Validation  will  be  achieved  to  collaborate  with  studies 
that  have  performed  blood  typing  for  zygosity. 

3.  Pregnancy,  Delivery  and  First  Month,  of  Life.   This  form  has  a  series 
of  questions  relating  to  problems  during  the  pregnancy,  problems  during 
delivery,  and  problems  during  the  first  month  of  life  for  the  children. 
Pregnancy  form  includes  questions  such  as  length  of  the  pregnancy,  diffi- 
culties during  pregnancy,  and  medication  during  pregnancy.   The  delivery 
section  relates  to  birth  weight,  problems  during  the  first  week  of  life, 
and  time  of  first  sustained  contact  between  parents  and  children.   The 
first  month  of  life  section  is  an  elaboration  of  a  scale  which  we  have 
previously  developed  in  our  longitudinal  study  on  the  development  of  twins, 
The  parents  are  asked  questions  in  six  operationally  defined  areas  of 
functioning,  including  attentiveness ,  calmness,  bodily  functions,  general 
overall  development,  and  health.   Indices  have  been  developed  for  scoring 
difficulties  during  pregnancy , delivery  and  first  month  of  life  for  each 
child.   In  addition,  general  questions  about  parental  attitudes  and  con- 
cerns are  scored  separately. 

4.  Twin  Development  During  the  First  Years  of  Life.   This  form  contains 
broad  variables  which  have  been  found  to  be  most  relevant  from  our  longi- 
tudinal study  of  children,  and  is  an  operational  statement  of  the  inter- 
twin  comparison  method.   Each  item  is  a  question  stated  in  the  following 
way:  Which  child  shows  more  of  a  particular  characteristic,  for  example, 
which  child  was  more  cuddily.   Respondent  specifies  two  things:   which 
child  shews  more  of  the  personality  attribute  and  how  big  a  difference 
existed  between  the  two  children  in  relation  to  the  personality  attribute. 
Three  age  periods  are  covered:   first  year  of  life,  second  year  of  life, 
and  current . 

5.  The  Childhood  Personality  Scale.   This  form  is  derived  in  part  from 
the  work  of  Drs.  Earl  Schaefer  and  Richard  Q.  Bell  (Infant  Behavior  Scale). 
It  relates  to  each  child's  characteristic  behavior  during  the  preceeding 
two  months.   Both  socially  desirable  and  socially  undesirable  character- 
istics are  represented.   The  positive  or  socially  desirable  character- 
istics include  verbal  expressiveness,  social  response,  inquisitiveness , 
vigor,  etc.   Negative  characteristics  include  monotonous  behavior,  irrit- 
ability, destructibility ,  passivity,  etc. 

6.  Parents  Report.   This  form  concerns  the  way  a  parent  feels  he  acts 
towards  the  child  and  a  sense  of  how  the  ideal  parent  would  act  towards 
the  same  child.   Concepts  are  derived  from  Drs.  Earl  Schaefer' s  and 
Richard  Bell's  studies  of  parenting,  and  include  concepts  from  their 
home  behavior,  parent  behavior,  and  communication  of  marriage  inventories. 
Each  item  is  stated  in  the  following  form:   I  see  the  child's  good  points 
and  faults.   The  respondent  states  whether  this  is  an  accurate  description 
of  his  behavior,  using  a  6-point  scale,  and  also  states  how  the  ideal 
parent  would  act  toward  the  child. 

7.  Recent  Family  Changes.   This  form  assesses  the  family's  perception  of 
its  adaptation  and  of  the  current  family  situation  to  which  they  feel  the 
children  are  exposed.   Specific  problem  areas,  as  well  as  general  adap- 
tation, are  covered  by  separate  questions.   Specific  areas  include  family 
migration,  recent  losses,  problems  of  marriage  and  finance,  physical 

123 


Serial  No.  M-AP(C)   19-5 

illness,  etc.   The  family  is  also  asked  to  rate  the  degree  to  which  the 
children  are  under  stress,  how  well  the  children  are  coping  with  the 
stress,  and  an  overall  rating  of  the  children's  health.   They  are  also 
asked  to  rate  similar  questions  for  each  of  the  adults.   Quantitative 
scores  are  derived  from  reports  by  both  the  father  and  mother  of  the 
degree  of  family  stress. 

8.  Behavior  Problems.   This  form  is  derived  from  our  clinical  experience. 
The  National  Institute  of  Mental  Health  Psychopharmacology  Study  Section's 
instrument  for  behavioral  assessment  of  children,  Keith  Conner's  studies, 
and  the  work  of  other  epidemiological  investigators  of  childhood  psycho- 
pathology.   The  form  consists  of  items  which  describe  particular  problems 
of  behavior.   The  respondent  assesses  whether  the  particular  child  has 
this  problem,  using  a  4-point  scale.   The  form  can  be  scored  using  factors 
derived  in  other  studies,  for  example,  Conner's  factors,  quantitative 
scores  relevant  to  the  psychiatric  classification  system  developed  by 

the  Group  for  the  Advancement  of  Psychiatry.   Thus,  severity  and  particu- 
lar areas  of  psychopathology  are  scored. 

9.  General  Comments.   This  form  consists  of  a  general  question  which  is 
open-ended  to  allow  families  to  fill  in  other  information  which  they 
think  is  of  relevance. 

Both  mother  and  father  complete  psychological  forms.    The  mother  alone 
completes  the  Release  of  Information  form,  the  Family  Background  form, 
and  the  Pregnancy,  Delivery  and  First  Month  of  Life  form.   The  mother 
and  father  individually  complete  the  following  instruments:   Twin  Develop- 
ment During  the  First  Years  of  Life,  Parents  Report,  Recent  Family  Changes, 
Behavior  Problems,  and  General  Comments.   The  father  completes  a  separate 
form  about  his  attitudes  towards  the  pregnancy,  which  is  derived  from  the 
larger  form  Pregnancy,  Delivery,  and  First  Month  of  Life,  which  is 
completed  only  by  the  mother. 

Collaborative  arrangements  have  been  established  with  the  Section  on 
Scientific  Applications,  Computer  Systems  Branch,  NIMH  for  data  reduc- 
tion and  computer  analysis  of  the  data. 

Patient  Materials : 

The  longitudinal  development  of  twins  study  consists  of  a  cohort  of  12 
sets  of  twins,  10  monozygotic  and  2  dizygotic.   The  cohort  for  the  epidemio- 
logical study  will  consist  of  approximately  600  sets  of  twins,  100  dizygotic, 
approximately,  and  the  remainder  monozygotic. 

Maj  or  Findings : 

(A)  Longitudinal  study: 

Eight  of  the  sets  of  twins  followed  from  the  time  of  diagnosis  of  twin- 
ing in  pregnancy  through  the  current  ages  of  2-1/2  to  6  have  been  in  the  Child 
Research  Branch,  NIMH,  nursery  school.   By  June  1,  1972,  all  10  sets  of  twins 
from  this  major  cohort  above  the  age  of  3  will  have  been  seen  in  the  nursery 
school.   In  addition,  they  have  all  had  the  scheduled  developmental  evalua- 
tions, psychiatric  interviews,  social  work  evaluations,  and  projective  testing. 
In  general,  these  studies  have  shown  a  developmental  sequence  and  set  of 
interactions  between  constitution  and  family  perception  and  behavior. 


124 


i 


Serial  No.  M-AP(C)   19-6 

In  general,  the  child  was  more  competent  physiologically  and  behaviorally  as 
a  newborn  tends  td  develop  into  the  more  articulate,  coping,  and  socially 
competent  preschooler.   In  contrast,  his  less  well-endowed  sibling  tends  to 
become  more  fearful  and  insecure.   An  important  aspect  of  this  developmental 
pattern  relates  to  the  better  endowed  child's  ability  to  be  both  highly  atten- 
tive to  external  stimulation  and  at  the  same  time  to  be  relatively  calm. 
The  child  who  is  more  calm  and  attentive  is  not  only  seen  as  less  vulnerable 
by  parents,  but  he  also  tends  to  have  fewer  physical  difficulties  during 
the  first  years  of  life. 

(B)  Epidemiological  study: 

This  study  has  just  emerged  from  the  pilot  testing  phase.   The  major  re- 
sults of  this  phase  has  been  to  perfect  the  psychological  instrument  and  to 
establish  its  usefulness. 

Proposed  Course  of  Project: 

The  project  will  continue  to  study  longitudinally  the  development  of  the 
children  in  the  longitudinal  cohort.   It  will  be  of  particular  interest  to 
follow  these  children  as  they  move  into  more  formal  schooling  and  through  the 
oedipal  and  latency  stages.   A  major  focus  of  activity  will  be  in  relation  to 
the  large  scale,  epidemiological  investigation  of  personality  development  of 
twins . 

Significance  to  Mental  Health  Research: 

The  longitudinal  study  of  twins  has  offered  the  opportunity  to  study  in 
depth  the  contributions  of  genetic,  non-genetic  but  congenital,  and  early 
experiential  variables  to  the  development  of  personality.   This  has  made  pos- 
sible the  delineation  of  variables  related  both  to  vulnerability  and  to 
competence.   The  central  role  of  arousal  and  the  modulation  of  arousal,  as 
well  as  the  varieties  of  ways  in  which  children  and  families  can  cope  with 
stressful  situation  articulates  with  our  other  studies  on  schizophrenia.   As 
the  children  in  the  longitudinal  cohort  enter  the  oedipal  and  latency  stages, 
we  will  have  the  opportunity  to  observe  the  increasingly  complex  structural- 
ization  of  their  behavior  as  they  develop  more  complex  coping  and  defense 
systems.   The  epidemiological  study  of  twins  will  provide  a  major  testing 
ground  of  many  of  our  hypotheses  about  genetic  and  non-genetic  antecedents  of 
personality,  with  particular  relation  to  our  interest  in  the  first  months  of 
life,  family  perception,  and  the  development  of  competence.   We  believe,  also, 
that  the  psychological  instrument  which  we  have  developed  will  have  broad 
application  in  other  studies  which  aim  at  understanding  the  social  and  emo- 
tional development  of  children  during  the  first  years  of  life. 

Honors  and  Awards: 

None 

Publications : 

Cohen,  D. ,  Allen,  M. ,  Pollin,  W.  et  al . :  Personality  development  in 
twins:  Competence  in  the  newborn  and  preschool  periods.  (In  press, 
J.  Amer.  Acad.  Child  Psychiat.) 

125 


n 


Serial  Number:   M-AP(C)-20-l 

1.  Adult  Psychiatry  Branch 

2.  Section  on  Clinical  Psychology 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:   Recognizing  and  Interpreting:   A  Differentiation  of 
Perceptual  and  Cognitive  Patterns 

Previous  Serial  Number:   None 

Principal  Investigator (s) :   Winfield  H.  Scott,  Ph.D. 

Other  Investigators:  Monte  Buchsbaum,  M.D. 

Cooperating  Units:   Laboratory  of  Psychology,  Division  of  Computer  Research 
and  Technology 

Man  Years:   (1971-1972) 

Total:   .20 
Professional:   .10 
Other:   .10 

Project  Description: 

Objectives:   The  purpose  of  the  research  is  to  study  contrasting  approaches 
to  Rorschach  responding,  as  a  way  of  studying  individual  differences  in 
thinking  and  perceiving,  to  study  the  relationships  between  these  con- 
trasting approaches  and  contrasting  varieties  of  symptom  formation  in 
psychiatric  patients  and  differing  patterns  of  performances  on  laboratory 
measures  of  perceptual  and  cognitive  variables  among  psychiatric  patients 
and  normal  subjects.   In  earlier  work,  two  different  approaches  to  Rorschach 
responding  were  identified.  The  first,  the  "Recognitory"  approach,  is  one  in 
which  subjects  tend  to  respond  to  qualities  of  blots  with  associations  to 
things  previously  seen.   In  the  contrasting  "Interpretive"  approach, 
subjects  attribute  qualities  to  the  blots  which  are  not  innate  in  them, 
qualities  such  as  movement  and  depth,  and  these  become  important  determinents 
of  responses.   Both  approaches  can  be  observed  among  normal  subjects  as  well 
as  psychiatric  patients.  The  objectives  of  continuing  work  on  the  project 
are  to  refine  definitions  of  the  contrasting  approaches,  to  study  their 
relationships  to  clinical  symptomatology  in  psychiatric  patients  and  to 
laboratory  measures  of  perceptual  and  cognitive  variables  among  both  normal 
subjects  and  subjects  who  are  psychiatrically  impaired. 

Methods  Employed:   Normal  subjects  and  psychiatric  patients  are  administered 
the  Rorschach  in  a  strictly  routinized  fashion.   In  addition,  they  are 
administered  other  psychological  tests,  including  the  Wechsler  Adult 
Intelligence  Scale  and  measures  of  a  variety  of  perceptual  and  cognitive 


127 


Serial  Number:  M-AP(C)-20-l 
variables.  A  scoring  system  has  been  developed  for  interpretive  and 
recognitory  features  on  the  Rorschach.  Thus  statistical  analyses  are 
possible  to  do  on  the  relationship  between  approaches  to  Rorschach  re- 
sponding and  performances  on  the  laboratory  measures  of  perceptual  and 
cognitive  variables. 

Major  Findings:    Factor  analyses  have  been  carried  out  on  the  associations 
of  the  interpretive  and  recognitory  features  in  the  Rorschach  protocols  of 
20  college  students,  v7ho  were  normal  volunteers.  While  the  recognitory 
features  have  emerged  in  a  single  factor,  the  interpretive  features  are 
divided  into  two  different  factors,  which  appear  to  reflect  different 
styles  of  thinking  and  perceiving.   The  component  elements  of  the  first 
interpretive  factor  suggests  that  subjects  with  high  scores  on  this 
factor  tend  to  think  and  perceive  in  terms  of  ongoing  processes,  movement 
and  change.   In  contrast,  it  suggested  that  subjects  with  high  scores  on 
the  second  interpretive  factor  tend  to  objectify  processes,  to  think  in 
terms  of  fixed  outcomes  of  actions,  and  to  think  of  objects  in  terms  of    j 
their  uses.   Subjects  with  high  scores  on  the  recognitory  factor  think 
and  perceive  heavily  under  the  influence  of  concrete  features  of  external 
stimuli,  even  to  the  point  of  stimulus-boundedness .   A  few  relationships 
have  been  established  among  these  normal  subjects  between  interpretive 
tendencies  and  performances  on  some  laboratory  measures  of  perceptual  and 
cognitive  variables.   Subjects  who  are  given  high  global  ratings  on 
interpretiveness  also  have  high  scores  on  an  Embedded  Figures  test,  and 
on  a  size  estimation  test.  They  have  lower  scores  on  the  Category  Width 
test.   Interpretive  tendencies  appear  to  be  associated  with  field  inde- 
pendence . 

Significance  to  Mental  Health  Research:   The  research  may  allow  development 
of  new  systems  of  classifying  patients  in  terms  of  diagnostic,  therapeutic 
and  prognostic  variables  which  are  associated  with  fundamental  aspects  of 
psychophysiological  functioning. 

Proposed  Course  of  Project:   Both  psychological  test  data  and  data  on 
perceptual  and  cognitive  variables  have  been  gathered  on  a  population  of 
twins.   It  is  proposed  to  study  the  relationship  between  interpretive  and 
recognitory  tendencies  and  laboratory  measures  in  this  population  in  an 
attempt  to  establish  other  relationships  between  perceptual  and  cognitive 
functioning  and  approaches  to  Rorschach  responding.   In  addition,  data 
are  being  gathered  on  a  variety  of  acutely  psychotic  patients,  in  order  to 
study  variations  in  approaches  to  Rorschach  responding  among  these  patients. 

Honors  and  Awards:   None 

Publications: 


Ulatowska,  Hanna  and  Scott,  Winfield  H.   Linguistic  indicators  of 
perceptual  style.   Linguistics,  (in  press). 


128 


Serial  Number:   M-AP(C)-20-4 

1.  Adult  Psychiatry  Branch 

2.  Section  en  Clinical  Psychology 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:  The  Consensus  Rorschach  and  Focused  Feedback  as  a 
Clinical  Procedure 

Previous  Serial  Number:   None 

Principal  Investigator(s) :  Winfield  H.  Scott,  Ph.D.,  Elizabeth  B.  Sherwood, 

M.A.,  Carol  A.  Langsner 

Other  Investigators:   None 

Cooperating  Units:   Section  on  Personality  Development 

Man  Years:  (1971-1972) 

Total:   1.00 
Professional:   .8 
Other:   .2 

Project  Description: 

Objectives:   The  main  objective  of  the  research  is  to  study  the  family  as 
a  small  group,  in  order  to  identify  salient  differentiating  features  of 
families  which  may  have  effects  on  the  functioning  of  their  individual 
members.  A  second  purpose  is  to  explore  the  use  of  the  Consensus  Rorschach 
and  video  and  audio  tape  feedback  as  a  clinical  technique  which  may  be 
used  in  the  assessment  of  families.   Any  family  can  be  regarded  as  a  small 
group,  like  other  small  groups  which  have  tasks  to  perform,  requiring  a 
differentiation  of  roles.   Each  family  has  unique  features  which  are  likely 
to  effect  the  functioning  of  the  family  as  a  whole,  and  the  functioning  of 
its  individual  members  as  well.   The  Consensus  Rorschach  provides  a  x%fay 
of  studying  these  features  under  conditions  which  are  standardized,  but 
which  provide  families  with  an  opportunity  to  express  important  features  of 
the  group  freely.   The  current  work  also  involves  exploration  of  the 
potential  applications  of  the  Consensus  Rorschach  to  clinical  assessment. 
The  family  are  made  part  of  the  diagnostic  team  in  that  they  are  asked  to 
review  their  own  performance  during  "feedback"  sessions.   In  these  sessions 
psychologists  lead  the  family  members  in  a  discussion  of  their  performance 
through  the  use  of  videotape  or  audiotape  replay  of  the  Consensus  Rorschach 
procedure.   A  major  objective  of  the  research  is  to  examine  the  effective- 
ness of  the  feedback  procedure  in  changing  the  performance  of  family 
members  in  a  subsequent  administration  of  the  Consensus  Rorschach. 


129 


Serial  Number:   M-AP(C)-20-4 

Methods:   Each  family  admitted  to  3-West  is  asked  to  participate  in  the 
project.   Both  parents,  the  index  patient  and  the  one  sibling  closest 
in  age  to  the  patient  take  part  in  the  Consensus  Rorschach.  They  are 
required  to  see  how  many  agreements  they  can  reach  about  what  an  inkblot 
looks  like.  The  procedure  is  recorded  on  both  videotape  and  audiotape. 
Each  family  is  randomly  assigned  to  one  of  four  different  "feedback" 
conditions.  Depending  uppn  the  condition  to  which  they  are  assigned, 
families  review  their  performances  on  videotape  or  on  audiotape,  with  or 
without  psychologists  present  with  them.  At  a  third  session,  the 
Consensus  Rorschach  is  repeated,  as  is  a  paper  and  pencil  test.   The  pro- 
cedure produces  data  bearing  on  different  effects  of  different  feedback 
conditions,  as  well  as  on  the  differences  among  families  in  various  aspects 
of  performance  on  the  Consensus  Rorschach  procedure  itself. 

Major  Findings:   In  the  experimental  situation,  families  can  be  regarded 
as  small  work  groups.  Families  who  have  gone  through  the  procedure  - 
families  of  psychiatrically  impaired  adolescent  children  -  are  regularly 
unproductive  or  underproductive  in  the  Consensus  Rorschach  procedure.  But 
the  reasons  for  low  productivity  vary  from  one  family  to  another,  and 
their  identification  provides  a  way  of  characterizing  families  and  de- 
scribing salient  features  of  those  families  as  small  groups.   In  some 
families,  productivity  is  low  because  of  relentless  competitiveness  among 
family  members  which  prevents  them  from  organizing  around  the  task  of 
reaching  agreements,  or  precludes  their  modifying  their  individual  per- 
ceptions sufficiently  to  reach  agreements.   In  other  families,  productivity 
is  low  because  percepts  are  not  sufficiently  differentiated  for  clear 
identification  of  real  agreements  to  occur.   In  other  instances,  productivity 
is  low  because  of  difficulties  in  permitting  appropriate  role  differentiation 
to  occur,  or  because  of  the  family's  great  discomfort  in  the  test  situation. 
Clinical  observation  would  suggest  that  these  differences  may  relate  to 
the  particular  kinds  of  impairment  in  functioning  demonstrated  by  the 
adolescent  offspring. 

Significance  to  Mental  Health  Research:   The  project  may  result  in 
identification  of  features  of  families  which  are  likely  to  have  effects 
on  the  functioning  of  individual  members.   It  may  also  result  in  a  technique 
useful  to  apply  as  a  part  of  the  clinical  evaluation  of  families  prior  to 
their  beginning  in  family  therapy.   It  is  likely  that  performance  on  the 
Consensus  procedure  and  in  the  feedback  session  will  have  prognostic  value, 
providing  a  basis  for  estimating  the  capacity  of  the  family  to  engage  in 
the  process  of  regarding  itself  as  a  group  which  has  effects  on  its 
individual  members.  Moreover,  the  project  provides  a  way  of  assessing 
the  effects  of  various  "feedback"  procedures  now  widely  used  in  clinical 
settings . 


I 


130 


Serial  Number:  M-AP(C)-20-4 

Proposed  Course  of  Project;   Eight  out  of  an  experimental  series  of  20 
families  have  gone  through  the  three  sessions  of  the  procedure.  As  other 
families  become  available  for  study,  they  will  be  tested.   Work  is 
underway  to  modify  the  scoring  system  developed  by  Dr.  Nathene  Loveland 
for  evaluation  of  communication  deviances  occuring  in  test  sessions. 

Honors  and  Awards;   None 

Publications;    None 


131 


Serial  Number:  M-AP(C)-20-5 

1.  Adult  Psychiatry  Branch 

2.  Section  on  Clinical  Psychology 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:   Psychological  Studies  of  Patients  V7ith  Affective  Disorders 

Previous  Serial  Number:   None 

Principal  Investigator (s) :   Edward  F.  Donnelly,  Ph.D.,  Dennis  L.  Murphy,  M.D. 

Other  Investigators:   Winfield  H.  Scott,  Ph.D.,  James  K.  Dent,  Ph.D. 

Cooperating  Units:   The  Laboratory  of  Clinical  Science,  Section  on  Psychiatry 

Man  Years:   (1971-1972) 

Total:   .45 
Professional:   .4 
Other:   .05 

Project  Description: 

Objectives;   The  purpose  of  the  research  is  to  study  differences  in 
psychological  test  response  patterns  between  patients  with  affective  dis- 
turbances and  other  psychiatric  patients,  and  to  explore  the  relationship 
between  test  response  patterns  and  a  range  of  clinical  and  experimental 
variables  among  patients  with  affective  disturbances.   A  major  goal  is 
to  clarify  distinctions  between  patients  with  unipolar  and  bipolar 
affective  disturbances. 

Methods:   Psychological  test  productions  of  patients  with  a  variety  of 
affective  disturbances  constitute  the  basic  data  for  differentiation  of 
subgroups.   The  test  data  include  both  objective  and  projective  personality 
tests,  as  well  as  an  intelligence  scale.   Patterns  of  psychological  test 
data  are  studied  in  relation  to  aspects  of  premorbid  adjustment,  course  of 
illness  during  hospitalization,  and  adjustment  following  hospitalization. 

Major  Findings:    Differences  have  been  observed  in  the  test  response 
patterns  of  patients  with  unipolar  depressions  on  one  hand,  and  bipolar 
patients  -  whether  depressed  or  manic  -  on  the  other.   On  the  Rorschach, 
patients  with  unipolar  depressions  develop  responses  which  are  dynamically 
expressive  communications  while  bipolar  patients  develop  responses  which 
are  concretely  related  to  the  inkblots.   During  the  past  year,  it  has  been 
established  that  among  patients  hospitalized  for  depression,  a  group  of 
unipolar  patients  can  be  differentiated  from  a  group  of  bipolar  patients 
on  the  basis  of  patterns  of  responses  to  the  MMPI .  Moreover,  there  is  a 
difference  between  unipolar  and  bipolar  depressed  patients  in  the  relation- 
ship between  scores  on  a  depression  scale  of  the  MMPI  and  ratings  for 

133 


Serial  Number:  M-AP(C)-20-5 

depression  on  the  Bunney-Hamburg  scales.  While  there  was  a  significant 
relationship  between  the  two  for  unipolar  patients,  there  is  not  for 
bipolar  patients.  This  would  suggest  that  there  may  be  a  difference 
between  the  subjective  experience  of  depression  and  outward  manifestations 
of  depression  in  behavior  among  bipolar  patients. 

Significance  to  Mental  Health  Research:  The  research  may  contribute  to 
a  refined  classification  of  patients  with  affective  disturbances  related 
to  psychological  test  performances,  patterns  of  perceptual  and  cognitive 
functioning,  aspects  of  premorbid  functioning  and  post-morbid  adjustment. 

Proposed  Course  of  Project:   Further  analyses  will  be  done  on  data  at 
hand,  and  additional  data  will  be  accumulated  on  new  patients  admitted 
to  the  Clinical  Center  for  the  treatment  of  depression. 

Honors  and  Awards:   None 


Publications:   None 


1 


13^^ 


Serial  Number:   M-AP(C)-20-6 

1.  Adult  Psychiatry  Branch 

2.  Section  on  Clinical  Psychology 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  I,    1971  through  June  30,  1972 

Project  Title:   Psychological  Deficits  in  Selected  Neurological  Disorders 

Old  Title:   Psychological  Assessment  of  Deficits  in  Affective  Psychosis, 
Epilepsy  and  Schizophrenia 

Previous  Serial  Number:   None 

Principal  Investigator (s) :   Edward  F .  Donnelly,  Ph.D.,  Thomas  N.  Chase,  M.D. 

Other  Investigators:   Norton  M.  Hadler,  M.D.,  Max  A.  Baker,  M.D.  and 
Carol  A.  Langsner 

Cooperating  Units:   Laboratory  of  Clinical  Science,  NIMH  and  Arthritis  and 
Rheumatic  Branch,  NIA^LD 

Man  Years:   (1971-1972) 

Total:   .40 
Professional:   .30 
Other:   .10 

Project  Description: 

Objectives:   The  objective  of  the  research  is  to  study  patterns  of  deficit 
in  personality,  intellectual,  cognitive  and  perceptual  functioning  in 
various  neurological  and  psychiatric  disorders,  and  to  study  drug- related 
changes  in  patterns  of  deficit. 

Methods:   Patients  with  various  neurological  disorders  such  as  Parkinson's 
disease,  Huntington's  disease  and  Down's  syndrome  are  studied  with 
psychological  measures  of  intellectual,  personality  and  central  nervous 
system  functioning.   These  include  the  Halstead-Reitan  Battery,  the  MMPI 
and  the  Wechsler  Adult  Intelligence  Scale.   Behavioral  observations  are 
recorded  on  the  Bunney-Hamburg  scale. 

Major  Findings:   A  study  of  the  possible  effects  of  L-dopa  on  intellectual 
and  memory  functioning  reveals  that  I.Q.  increments  reported  by  prior 
studies  can  be  explained  as  a  function  of  practice  effect,  a  variable 
difficult  to  control  in  longitudinal  studies  requiring  testing  and  retesting. 
A  long  term  followup  of  patients  on  L-dopa  therapy  suggests  that  there  are 
no  deleterious  effects  on  intellectual  functioning,  although  there  is  a 
slight  (and  non  significant)  decline  in  the  scores  on  the  Comprehension 
subtest  of  the  WAIS  for  a  portion  of  the  patients. 


135 


Serial  Number:   M-AP(C)-20-6 

Significance  to  Mental  Health  Research:   From  both  clinically  and 
empirically  derived  data,  there  have  been  claims  for  the  improvement  in 
intellectual  functioning  attributed  to  treatment  with  L-dopa.   Observations 
would  suggest,  however,  that  the  improvement  can  more  likely  be  attributed 
to  practice  effect  on  the  tests  than  to  L-dopa  induced  effects. 

Proposed  Course  of  Project:   It  is  anticipated  that  during  the  coming  year, 
patients  with  a  variety  of  neurological  disorders  will  be  studied  to 
establish  what  aspects  of  intellectual  and  personality  functioning  may 
be  effected  by  the  neurological  disorders.   In  addition,  the  effects  of 
drugs  on  the^e  patterns  of  deficit  will  be  studied. 

Honors  and  Awards:   None 


Publications: 


Chase,  T.N.,  Watanabe,  A.M.,  Brodie,  H.K.H.  and  Donnelly,  E.F. 
Huntington's  Chorea:   Effect  of  serotonin  depletion.  Archives  of 
Neurology,  26:  282-284,  1972. 


^ 


136 


Serial  No.  M-AP(c)-21-2 

1.  Adult  Psychiatry  Branch 

2.  Section  on  Perceptual  and 
Cognitive  Studies 

3.  Bethesda,  Maryland 

PHS  -HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  -  Jujie  30,  1972 

Project  Title:   Studies  of  Perceptual  and  Cognitive  "Styles"  in  Psychiatric 

and  Non-psychiatric  Subjects. 
Previous  Serial  Number:   Same 
Principal  Investigator:  Monte  Buchsbaum,  M.D. 

Other  Investigators:     Lyman  C.  Wynne,  M.D.,  Ph.D.,;  Stephen  Landau,  M.D. 
Thomas  Bittker,  M.D.;  John  S.  Strauss,  M.D.;  Dennis 
Murphy,  M.D.;  Frederick  K.  Goodwin,  M.D.;  and 
William  P.  Carpenter,  Jr.  M.D. ,  Helm  Stierlin,  M.D. , 
Ph.D. 

Cooperating  Units :   Laboratory  of  Psychology,  NIMH 


Man  Years: 

Total; 

2.0 

Professional: 

1.0 

Other : 

1.0 

Project  Description: 

Objectives;   To  relate  individual  differences  in  sensory  perception  and 
cognitive  functioning  in  human  subjects  to  psychiatric  clinical  dimensions 
and  to  neurophysiological  measures;  to  develop  and  implement  clinically 
valuable  computerized  measures  of  perceptual  and  cognitive  functions . 

Methods  Employed;   Research  in  this  section  focuses  on  disturbances  in  per- 
ceptual and  cognitive  behavior  in  psychiatric  patients.  Its  work  is  closely 
coordinated  with  basic  electrophysiological  and  perceptual  research  in  the 
Unit  of  Psychophysiology,  Laboratory  of  Psychology,  NIMH. 

The  finding  of  perceptual  and  attentional  deficits  in  a  variety  of 
psychiatric  patient  groups  has  encouraged  the  development  of  theories  of 
psychiatric  illness  and  personality  structure  based  on  perceptual  style. 
However,  the  psychiatric  patient's  report  of  his  perceptions  might  reflect 
poor  motivation,  poor  cooperation,  failure  to  attend  to  instructions  or  in- 
ability to  communicate  with  the  examiner,  rather  than  any  actual  perceptual 
difference.   For  this  reason  the  section  has  emphasized  electrophysiological 
correlates  of  perceptual  behavior  using  averaged  evoked  response  techniques. 

Major  Findings;  Affective  Disorders.  Off -drug  average  evoked  response 
data  have  been  collected  on  a  population  of  83  bipolar  and  unipolar  patients 
and  ^4-8  mat-ched  normal  controls.  Earlier  findings  that  bipolar  patients 


137 


Serial  Wo.  M-AP(c)-21-2 

5.  Narcotic  Addicts.  A  group  of  narcotic  addicts  in  a  methadone 
research  program  at  the  VeterajD.s  Administration  Hospital  is  being  studied 
both  on  and  off  methadone  treatment  on  a  single  blind  basis.  Our  interest 
in  this  group  stems  from  study  of  a  perceptual  dimension  termed  "stimulus 
intensity  control".   This  dimension  is  based  on  a  series  of  studies  of 
individual  differences  in  responsiveness  to  sensory  stimulation.   Two  differ- 
ent ways  of  accepting  sensory  input ha-ve  been  hypothesized:  the  "augmenter" 
who  tends  to  increase  the  perceived  intensity  of  stimuli  and  the  "reducer" 
who  tends  to  decrease  it.  Reducing,  like  habituation,  may  represent  attempts 
to  cope  with  sensory  overload.   The  stimulus  intensity  control  is  being 
inferred  for  measurements  of  the  average  evoked  response  to  varying  inten- 
sities of  auditory  and  visual  stimulation.  Opiates,  which  modify  responses 
to  painful  or  intense  stimulation,  would  be  expected  to  affect  the  evoked 
response  at  high  intensities  differently  than  low  intensities.  We  have 
further  hypothesized  that  narcotic  addicts  may  differ  from  the  control  popu- 
lations in  their  baseline  off -drug  electrophysiological  response  to  stimuli 
of  various  intensities.  Tests  of  prognostic  and  diagnostic  significance 
might  develop  from  this  program. 

Significance  to  Biomedical  Research  and  the  Program  of  fahe  Institute; 
This  project,  in  helping  to  give  a  neurophysiological  basis  to  psychiatric 
diagnosis  and  prognosis,  contributes  to  the  effort  to  understand  the 
mechanisms  of  psychiatric  disease. 

Proposed  Course  of  the  Project: 

1.  Comparison  of  clinical  groups.  During  the  next  year,  extensive 
analysis  of  data  collected  on  affective  disorder,  schizophrenic  and  normal 
populations  will  be  analyzed.  New  mathematical  techniques  being  developed 
for  the  analysis  of  evoked  response  will  be  applied  to  this  pool  of  data. 

2.  Patient  testing.  We  will  continue  to  test  patients  with  affective 
disorders  and  schizophrenia.  Several  new  drug  studies  are  planned  with  the 
affective  disorder  patients  and  emphasis  will  be  on  collecting  off -drug  data 
on  schizophrenic  patients . 

3.  Twin  studies  will  enter  a  data  analysis  phase  with  emphasis  both 
on  the  determining  Mz  and  Dz  differences  and  using  psychophysiological  and 
psychophysical  data  to  predict  perceptual  differences  in  Mz  pairs. 

k.     Collaboration  with  the  Unit  on  Psychophysiology  will  continue 
on  basic,  perceptual  and  psychophysiological  research  on  attention, 
habituation  and  stimulus  intensity  in  order  to  increase  our  biochemical, 
psychological  and  clinical  meaning  of  certain  a^^erage  evoked  response 
components  and  their  parametric  changes . 

Honors  and  A.-rarls:   jlone. 


138 


Serial  No.  M-AP(c)  -  21-2 

showed  larger  amplitude  evoked  responses  and  especially  at  higher  inten- 
sities ("augmentation")  in  comparison  with  unipolar  patients  have  heen 
replicated.  Of  special  interest  is  the  finding  that  the  "bipolar  -unipolar 
difference  was  the  greatest  among  patients  with  early  onset  of  symptoms 
(less  than  age  ko)   since  several  investigators  have  demonstrated  a  greater 
genetic  component  in  the  affective  illness  in  the  early  onset  vs.  late 
onset  patients.  In  addition  to  the  amplitude  findings,  changes  in  evoked 
response  latency  across  stimulus  intensity  have  also  been  found.  Age,  sex, 
biochemical  data  and  behavioral  ratings  collected  in  conjtmction  with  the 
evoked  response  data  are  also  undergoing  analysis. 

2,  Schizophrenic  patients.  A  battery  of  tests  including  four  average 
evoked  response  measures,  perceptual  tests,  autonomic  physiology  and  psycho- 
motor function  have  been  collected  so  far  on  fifteen  schizophrenic  patients 
off  drugs.  Data  collection  will  continue  until  a  larger  sample  is  collected. 

3.  Twin  studies.  In  order  to  assess  the  relative  importance  of  genetic 
and  environmental  backgrounds,  monozygotic  and  dizgotic  normal  twins  are 
being  studied  using  measures  of  autonomic  and  psychomotor  functioning,  average 
evoked  response  procedures,  a  battery  of  perceptual  tests,  questionnaires  and 
interview  data.  Thus  far  approximately  60  twin  pairs  have  been  tested.  The 
project  is  currently  entering  the  data  analysis  phase.  In  addition  family 
groups,  both  normal  and  psychiatric,  have  also  been  evaluated. 

k.     Constancy  of  perceptual  effects.  Do  the  perceptual  differences 
observed  in  psychiatric  patients  reflect  an  underlying  and  fixed  biological 
characteristic  or  are  they  related  to  the  attentional,  affective  and  autonomic 
arousal  state  of  the  individual  at  the  moment  of  the  perceptual  behavior? 
At  a  clinical  level  our  approach  to  this  problem  is  to  compare  two  clinical 
groups,  those  with  affective  disorders  and  those  with  schizophrenia  using 
only  periods  when  the  patients  are  off  drugs.  Comparisons  are  made  between, 
on  the  one  hand  correlations  between  perceptual  behavior  and  day  to  day 
clinical  rating,  and  on  the  other  hand  correlations  between  perceptual 
behavior  and  historical,  demographic,  and  genetic  features.  In  comparing 
perceptual  behavior  in  periods  of  mania  or  depression  in  cyclic  patients 
with  periods  of  depression  in  unipolar  depressed  patients,  diagnostic 
categories  determined  by  patient  history  appear  to  be  more  closely  related 
to  perceptual  behavior  and  neurophysiological  data  than  current  patient 
mood  as  measured  by  nurse  or  physician  ratings.  Similar  analyses  will  be 
done  on  the  data  from  the  schizophrenic  patients.  The  effects  of  "state 
variables"  such  as  attention  and  arousal  are  also  being  studied  in  normal 
populations.  Comparisons  of  the  effects  of  muscle  tension,  painful  stimula- 
tion and  shifts  of  attention  toward  or  away  from  evoked  response  stimuli 
have  demonstrated  the  importance  of  each  of  these  factors  but  also  have 
highlighted  the  importance  of  underlying  individual  differences  in  the 
habitual  deployment  of  attention  or  channeling  of  arousal. 


139 


Serial  No.  M-AP-(c)  21-2 

Publications: 

Buchsbaum,  M. :  Average  evoked  response  techniques  and  applications .  Schiz. 
Bull.  Winter,  1970.  pp.  10-18. 

Buchsbaunij  M.,  King,  C.  and  Henkin,  R.  I,:  Average  evoked  responses  and 

psychophysical  performance  in  patients  with  pseudohypoparathyroidism. 
J.  Keurol.  Neurosurg.  Psychol.  In  press. 

Buchsbaum,  M.,  Goodwin,  F.,  Murphy,  D«,  and  Borge,  G.  AER  in  affective  dis- 
orders. Ajner.  J.  Psychiat,  128:   19-25.  1971. 

Borge,  G.,  Buchsbaum,  M.,  Goodwin,  F.,  Murphy,  D.,  and  Silverman,  J.: 

Neuropsychological  correlates  of  affective  disorders.  Arch.  Gen. 
Psychiat.  2k:     501-50^+,  1971. 


Gillin,  J.  C,  Jacobs,  L.  S.,  Fram,  D.  H. ,  Williams,  R. ,  Buchsbaum,  M.  and 
Snyder,  F.  Partial  REM  phase  deprivation  and  schizophrenia:  An 
experimental  reappraisal.  Arch.  Gen.  Psychiat.  In  press. 

Silverman,  J.,  Buchsbaum,  M.  and  Stierlin,  H. :  Sex  differences  in 
perceptual  differentiation  and  stimulus  intensity  control. 
J.  Persc  Soc.  Psychol,  In  press. 


ito 


Serial  No.  M-AP(c)  -  21-U 

1.  Adult  Psychiatiy  Branch 

2.  Section  on  Perceptual  and 
Cognitive  Studies 

3.  Bethesda 


PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,   1971  -  June  30,   1972 

Project  Title:   Perceptual  and  cognitive  style  in  normal  twins. 

Previous  Serial  Number:   Same, 

Principal  Investigator:  Monte  Buchsbaum,  M.D. 

Other  Investigators:     Lyman  C.  Wynne,  M.D.,  Ph.D. 
Theodore  P.  Zahn,  Ph.D. 
Stephen  Landau,  M.D. 
Winfield  Scott,  Ph.D. 
William  Pollin,  M.D. 

Cooperating  Units:   Unit  on  Psychophysiology,  LP  -  NIMH 


Man  Years: 

Total: 

3.0 

Professional: 

1.5 

Other: 

1.5 

Project  Description: 

Objectives;  Evaluation  of  the  heritability  and  interaction  of  several 
sensory,  perceptual  and  cognitive  fimctions  in  normal  volimteer  tivins . 

Methods  Employed: 

1)  Rod  and  frame  measure  of  field  dependence-independence. 

2)  Measure  of  scanning:   direct  monitoring  of  eye  movements  during 
a  size  estimation  task. 

3)  Auditory  and  -visual  cortical  evoked  response  measures  designed  to 
evaluate  the  effect  of  stimulus  intensity,  stimulus  contrast, 
evoked  response  stability  and  cortical  response  symmetry. 

k)  Rorschach  inkblot  test. 

5)  Psychiatric  background  interview. 

6)  Clinical  rating  scales  (M-AP(c)-l^-l). 

7)  Blood  typing  for  zygosity  (M-AP(c)-16-1). 

8)  Autonomic  and  psychomotor  functioning. 

9)  Wise  IQ  test. 

Sixty  twin  pairs  have  been  tested  to  date.  Preliminary  examination  of 
the  data  has  revealed  predicted  similarities  in  the  monozygotic  twins  which 
are  not  found  in  dizygotic  pairs.  This  is  particularly  apparent  for  the 
cortical  evoked  response  wave  forms  and  the  stimulus  intensity  response 
amplitude  functions  augmenting-reducing  concept.  Data  analysis  will  soon 
begin. 

ll^l 


Serial  No.  M-AP(C)-21-U 

Significance  to  Biomedical  Research  and  the  Program  of  the  Institute; 

The  concepts  of  field  dependence-independence  and  stimulus  intensity 
control  have  been  relevant  in  predicting  and  explaining  individual  differ- 
ence in  pain  tolerance,  sensory  isolation,  tolerance  and  response  to 
stimulus  overload.  Preliminary  studies  here  at  the  NIMH  have  revealed  that 
there  are  fami.lial  tendencies  in  perceptual  styles  as  measured  by  standard 
psychophysiologic  tasks  and  cortical  evoked  responses.  One  method  of 
further  elucidating  the  heritable  nature  of  perceptual  style  is  to  investigate 
several  perceptual  functions  in  groups  of  monozygotic  and  dizygotic  twins. 
This  will  allow  us  to  draw  some  conclusions  as  to  what  aspects  of  perception 
are  genetically  transmitted  and  which  ones  are  learned  or  modified  by 
environmental  experiences , 

Proposed  Course  of  Project;   The  cujrrent  project  was  designed  to  run  for 
three  years.  This  will  result  in  approximately  100  twin  pairs  tested  at  the 
end  of  that  time.  This  large  number  is  necessary  in  order  to  arrive  at 
meaningful  and  significant  conclusions  about  the  objectives  of  the  study. 

Honors  and  Awards;  None, 

Publications ;  None . 


142 


Serial  No.  M-CR-10  (c) 

1.  Child  Research  Branch 

2.  Child  Behavior 

3.  Bethesda,  Maryland 


PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 


Project  Title:   Relations  of  Preschool  Behavior  to  Present  and  Earlier 
Parent  and  Child  Characteristics 

Previous  Serial  Number:   SiME 

Principal  Investigator:   Charles  F.  Halverson,  Jr. 

Other  Investigators:   Mary  F.  Waldrop,  Richard  Q.  Bell 

Cooperating  Units:   Section  on  Twin  and  Sibling  Studies,  Adult  Psychiatry 
Branch,  NIMH  [M-AP(C)-19-6] 

Man  Years: 

Total:   9.0 
Professional:   2.2 
Other:   6.8 

Project  Description: 

Objectives: 

To  describe  reliable  and  consistent  measures  of  parent  and  child  charac- 
teristics at  the  early  preschool  level  to  serve  as  developmental  markers  in 
the  overall  branch  longitudinal  research  program,  which  includes  studies  of 
early  marriage,  newborns,  early  mother- infant  interaction,  and  behavioral  de- 
velopment in  the  first  year  of  life.   To  organize  and  describe  patterns  of  be- 
havior and  individual  differences  in  young  children  through  experimental  and 
naturalistic  studies  at  various  age  periods  in  the  preschool  and  early  school 
years.   Specifically,  the  object  is  to  measure  varieties  of  play,  social  de- 
velopment, peer  behavior,  assertiveness,  cognition,  and  attentional  processes 
in  young  children,  and  to  measure  relevant  parental  characteristics. 

Methods  Employed: 

The  final  sample  for  the  cohort  presently  being  studied  by  the  Branch, 
Cohort  II,  will  consist  of  approximately  130  early  preschool-age  children  and 
their  parents.   Explicit  methodology  of  the  research  nursery  school  has  been 
described  in  earlier  annual  reports.  Groups  of  five  children  ranging  in  age 
from  two  and  a  half  to  three  years  of  age  attend  nursery  school  for  four  weeks. 
Behavior  measures  are  obtained  by  direct  counts  and  timing.   Play  and  peer 

li^3 


Serial  No.  M-CR-10  (c) 

behavior  are  also  the  basis  for  more  global  ratings  of  personality  and  social 
development.  Measurement  is  directed  toward  attentional  behavior  in  free  and 
semi-structured  play  settings,  social  behavior  in  several  contexts,  and  toward 
the  quality  and  quantity  of  vigorous  and  assertive  behaviors  in  various  exper- 
imental situations.   Cognitive  and  intellectual  development  is  assessed  in 
Individual  tests  and  from  analyses  of  ongoing  speech  and  play  behavior. 

The  basic  methodological  considerations  are  (a)  the  stability  of  measures 
of  play  behavior  during  the  four-week  period,  (b)  construct  validity  of  the 
cognitive  and  play  variables,  and  (c)  cross- setting  generality  of  the  various 
constructs.  The  planned  analysis  of  the  data  calls  for  checking  relations 
between  the  various  kinds  of  measures  (observations,  ratings,  experimental 
procedures)  in  different  settings  (indoor  free  play,  rest,  outdoor  free  play). 
This  check  will  then  provide  the  basis  for  composite  variables  describing 
more  general  characteristics  of  the  child. 

All  the  preschool  children  in  this  cohort  of  the  longitudinal  study,  in- 
cluding those  who,  for  various  reasons,  cannot  attend  a  full,  four-week 
session  of  nursery  school,  are  observed  in  a  one-half-day  session  of  free 
play.  This  session  precedes  each  regular  four-week  session.   The  child  and 
mother  are  individually  transported  to  the  research  nursery  school  where,  in 
the  absence  of  peers,  detailed  records  of  the  changes  in  play  brought  about 
by  the  entrance  of  strangers  and  the  departure  of  the  mother  to  another  room 
are  obtained.  The  mother  is  also  interviewed  about  her  child's  social  behav- 
ior and  level  of  behavioral  and  social  competence.   At  this  time,  the  first 
in  a  series  of  detailed  reviews  of  the  child's  and  parent's  activities  for  a 
week  are  obtained  from  the  mother.   By  the  end  of  the  nursery  school  group, 
each  mother  has  provided  us  with  descriptions  of  three  weeks  in  the  child's 
and  parent's  lives.  From  these  records  we  hope  to  check  for  relations  between 
relevant  parental  behavior  and  the  child's  functioning  in  nursery  school,  as 
well  as  provide  criterion  data  for  material  gathered  on  the  parents  at  earlier 
points  in  time.   Additional  parent  information  is  obtained  by  other  interviews 
and  rating  procedures. 

Data  collection  on  the  main  cohort  of  preschool  children  from  our  longi- 
tudinal sample  has  now  been  underway  for  two  years  and  will  continue  to  July, 
1973,  to  reach  a  total  sample  of  approximately  65  males  and  65  females.  These 
cases  are  extremely  valuable  since,  for  most,  newlywed  data  have  been  obtained 
on  the  parents,  and  the  infant  and  mother- infant  pairs  have  been  studied  in 
the  first  year  of  life.   Currently,  we  have  seen  90  of  Cohort  II,  two-thirds 
of  the  core  sample  that  we  anticipate  can  be  seen.   Case  loss  in  the  first 
two  years  (moving  out  of  the  area,  unable  to  contact,  illness,  etc.)  continues 
to  be  approximately  25  percent. 

Major  Findings: 

No  analyses  or  results  other  than  reliabilities  can  be  carried  out  for 
this  project  until  all  the  subjects  have  been  seen.  Several  reports  are  in 
preparation  based  on  previously  seen  longitudinal  samples.  Earlier  reports 
have  described  studies  based  on  a  sample  of  children  who  had  been  studied 

Ikk 


Serial  No.  M-CR-10  (c) 

previously  as  newborns,  in  the  research  nursery  school  at  two  and  a  half  years 
of  agQ  and  at  age'  seven  and  a  half,  using  a  battery  of  cognitive  tests  and  an 
assessment  of  play  behavior.  We  are  now  collating  these  studies  in  a  report 
for  publication  that  shows  children  who  were  effective  and  assertive  in  pre- 
school barrier  situations  later,  at  seven  and  a  half,  were  the  ones  who  (a) 
had  higher  verbal  intelligence  and  showed  more  imagination  in  play  (cognitive 
domain) ,  (b)  were  more  dominant  in  initiating  peer  contacts  and  were  more  vig- 
orous, less  fearful  and  coped  better  with  new  situations  (play  domain).   Also, 
high  verbal  males  and  females  were  high  in  verbal  IQ,  social  maturity,  and  in 
amount  of  time  exploring  the  free  play  environment. 

Also,  a  paper  has  been  published  delineating  the  rating  system  for  the 
assessment  of  the  hyperactivity  factor  in  preschool  children.   Six  facets  of 
hyperactivity  and  three  of  withdrawal  can  be  identified  via  teacher's  rating 
scales  and  then  combined  into  two  factor  scores.  The  scores  can  be  used  to 
identify  hyperactive  or  withdrawn  children  in  various  treatment  settings. 

We  are  also  continuing  a  collaboration  begun  in  1970  with  the  Section  on 
Twin  and  Sibling  Studies  of  the  Adult  Psychiatry  Branch,  NIMH  [M-AP(C) - 19-6] . 
We  are  now  studying  sets  of  twins  that  are  part  of  a  study  of  the  early  con- 
genital and  experiential  contributors  to  development.  To  date  we  have  assessed 
six  pairs  of  twins  in  a  cohort  of  approximately  ten  pairs  intensively  studied 
from  birth  on.   The  final  plan  will  be  to  relate  our  nursery  school  behavior 
to  data  collected  by  the  collaborating  section  on  genetic,  physiological,  and 
behavior  variables  during  the  early  years.   A  preliminary  clinical  report  based 
on  the  first  five  pairs  of  twins  has  been  accepted  for  publication. 

Significance  to  Bio-Medical  Research  and  the  Program  of  the  Institute: 

The  identification  of  stable  patterns  of  preschool  behavior  in  the  areas 
of  assertiveness,  response  to  caretakers,  interaction  with  peers,  and  cogni- 
tive performance  is  important  for  the  description  of  variations  in  human  de- 
velopment.  In  addition,  the  several  different  developmental  patterns  associ- 
ated with  hyperactive,  impulsive  behavior  may  provide  some  evidence  about  the 
early  or  congenital  contributors  to  impulse -control  problems.   This  type  of 
behavior  problem  is  one  of  the  most  frequent  bases  for  referral  of  children 
to  child  guidance  clinics.   Studies  of  twins  and  behavioral  activity  in  the 
preschool  period  provide  additional  evidence  of  the  interface  between  genetic, 
physiological,  and  behavioral  dimensions.   The  present  longitudinal  cohort 
even  makes  it  possible  to  extend  our  studies  of  precursors  to  a  phase  in  the 
life  cycle  prior  to  the  infant's  birth  --  the  preparental  period.   The  planning 
of  mental  health  programs,  both  diagnostic  and  remedial,  will  depend  on  such 
reliable  information  about  development.   The  understanding  of  early  develop- 
mental processes  can  lead  to  appropriate  early  intervention  that  would  be  more 
effective  than  diagnosis  and  treatment  occurring  at  a  much  later  point  in  time. 

Proposed  Course  of  the  Project: 

Data  collection  has  been  underway  for  two  years,  and  will  continue  for 
one  more  year.  An  additional  two  years  will  be  necessary  for  the  reduction 


Serial  No,  M-CR-10  (c) 

and  analysis  of  the  vast  amount  of  data  obtained.   Analyses  of  the  preparatory 
study  will  continue  and  further  reports  will  be  prepared. 

Honors  and  Awards:   None 

Publications: 

Bell,  R.  Q.,  Waldrop,  M.  F.,  and  Weller,  G.  M.:   A  rating  system  for  the 
assessment  of  hyperactive  and  withdrawn  children  in  preschool  samples. 
Amer.  J.  Orthopsychiat .  42:   23-34,  1972. 


1^6 


Serial  No.  M-CR-11  (c) 

1.  Child  Research  Branch 

2.  Infant  Development 

3.  Bethesda,  Maryland 


PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:  Relations  between  Human  Neonatal  Behavior  and  Later 
Development 

Previous  Serial  Number;  Same 

Principal  Investigator:  Raymond  K.  Yang 

Other  Investigators:  Richard  Q.  Bell 

Cooperating  Units:  None 

Man  Years: 

Total:  k.k3 
Professional:  3.25 
Other:       1.20 

Project  Description: 

Objectives : 

This  is  a  psychophysiological  and  behavioral  study  of  human  neonates, 
designed  to  provide  measures  of  stable  individual  differences  reflecting 
congenital  characteristics  of  infants  bom  to  families  in  the  Branch  Longitu- 
dinal Study.  The  data  are  to  be  used  to:  l)  identify  stable  measures  charac- 
terizing the  human  newborn;  2)  identify  continuities  and  discontinuities 
between  the  newborn  period  and  later  periods  of  development;  and,  3)  describe 
the  fashion  in  which  newborn  characteristics  interact  with  parental  variables 
in  producing  later  outcomes. 

Methods  Employed: 

This  section  is  currently  reducing  data  (collected  from  I967  to  1970  on 
the  Branch  Longitudinal  series.  Cohort  II)  to  forms  amenable  to  computer 
analyses.  Data  was  obtained  from  I38  human  newborns.  Each  infant  was 
observed  in  a  hospital  nursery  and  continuous  recordings  of  selected  psycho- 
physiological and  behavioral  functions  were  obtained  during  two  consecutive 
interfeeding  periods  between  50  and  72  hours  of  age.  The  functions  and 
responses  recorded  were:  heart  rate,  respiratory  rate,  galvanic  skin  potential, 
electro -oculogram,  skin  temperature,  body  motility,  tactile  threshold,  a 
righting  reflex  (the  prone  head  response) ,  characteristics  of  non-nutritive 

IU7 


Serial  No.  M-CR-U  (c) 

sucking,  reaction  to  interruption  of  sucking,  and  pliyslclogical  and  behavioral 
changes  due  to  swaddling. 

This  section  also  has  complete  hospital  records  of  the  anesthetics  and 
analgesics  given  the  mothers  of  the  infants  during  labor  and  delivery.   In 
future  analyses  it  is  intended  that  these  data  will  serve  as  a  possible 
mediator  of  relations  established  between  the  newborn,  and  later  periods  of 
development . 

Major  Findings ; 

The  year  was  devoted  entirely  to  data  reduction.  Tiie   section  faced  the 
somewhat  fonnidable  task  of  reducing  by  hand  ncre  than  35,000  feet  of 
poly graphic  tracings  to  data  that  could  be  analyzed  by  computer.  This  task 
has  been  accomplished  and  the  section  has  near  completion  an  analysis  of 
heart  rate  responses  to  threshold  intensity  tactile  stimuli  (determined  by 
behavioral  response) .  Analyses  indicated  that  the  exclusive  response  was  a 
monophasic  acceleration  above  prestimulus  levels  that  did  not  reach  its  peak 
magnitude  until  9-15  seconds  past  stimulus  onset.  No  heart  rate  responses 
were  associated  with  sub-threshold  stimulus  intensities.  Repetitive  presenta- 
tions of  threshold  levels  were  characterized  by  a  very  rapid  decrement  in 
heart  rate  response ,  most  of  the  decrement  occurring  between  the  first  and 
second  stimulus  presentation.  Neither  threshold  intensity  nor  magnitude  of 
the  heart  rate  response  was  affected  by  sex  of  the  infant  or  sleep  state 
(active  or  quiet) .  There  was  a  slight  tendency  for  males  and  females  to 
continue  their  behavioral  responses  to  repetitive  presentations  of  the 
stimulus  during  active  sleep. 

Significance  to  Biomedical  Research  and  the  Program  of  the  Institute; 

Results  from  an  earlier  publication  (Bell,  Weller  and  Waldrop,  Monogr. 
of  the  Soc.  for  Res.  in  Child  Develpm. ,  1971,  Vol.  36,  Nos.  1-2)  suggest  that 
paradoxical  shifts  in  relations  may  occur  between  measures  obtained  during 
the  newborn  period  and  during  the  preschool  period  (2-l/2  to  3  years) : 
prognostically  healthy  signs  at  the  newborn  period  (vigorous  respiration  and 
reflex  responsiveness)  were  positively  related  to  watching  others  rather  than 
participative  behavior  at  the  nursery  school  period.  These  results  were 
reported  at  a  symposium  on  stress  in  Stockholm,  at  the  International  Congress 
of  Psychology,  in  the  Netherlands,  and  at  a  symposium  of  the  American 
Psychological  Association.  A  discussant  at  the  latter  symposium  remarked 
that  the  same  type  of  paradoxical  shift  between  early  and  later  behaviors 
had  been  uncovered  in  two  other  longitudinal  studies,  though  this  section's 
data  on  the  newborns  were  from  an  earlier  point  in  development.  Thus  it  now 
appears  that  there  is  convergent  evidence  that  relations  between  congenital 
behaviors ,  or  other  behaviors  manifest  in  the  first  year  of  life ,  and  later 
development , are  of  a  different  and  much  more  complex  nature  than  has 
heretofore  been  surmised. 

The  elucidation  of  variables  and  relations  such  as  these  are  useful  not 
only  in  describing  continuities  in  development,  but  also  in  locating  areas 

li+8 


Serial  No.  M-CR-11  (c) 

of  behavior  in  which  reliable  prognostic  indicators  of  later  behavior  can  be 
found.  The  data,  currently  being  reduced  to  analyzable  forms,  will  provide 
an  opportunity  to  expand  the  areas  in  which  this  search  can  be  made  (extensive 
physiological  and  sleep  data  were  not  previously  available)  as  well  as  to 
provide  an  opportunity  to  replicate  the  Bell,  Weller  and  Waldrop  findings. 

Proposed  Course  of  the  Project; 

The  major  data  reduction  task  should  be  completed  early  in  the  year. 
At  that  time,  within-phase  analyses  will  be  undertaken  to  ascertain  those 
variables  and  areas  of  newborn  behavior  that  might  provide  fruitful  relation- 
ships to  data  obtained  with  other  phases  of  the  longitudinal  study.  Once 
this  is  done,  it  should  be  possible  to  analyze  and  report  on  relations 
between  these  newborn  measures  and  later  behavior  at  three-  and  eleven-months 
postpartum,  the  latter  obtained  by  one  other  team  in  the  longitudinal  study. 
Relations  between  newborn  and  preschool  characteristics  cannot  be  determined 
until  1975 )   since  data  gathering  at  this  later  phase  will  not  be  completed 
until  1973 >  and  reduction  of  the  data  will  not  be  completed  until  two  years 
later. 

Honors  and  Awards:  None 

Publications : 

Bell,  R.Q:  Human  neonatal  behavior  as  a  predictor  of  behavior  in 
childhood  stress  situations.  In  L.  Levy  (Ed.),  Society,  stress 
and  disease;  childhood  and  adolescence.  Oxford  University  Press : 
Oxford,  England,  to  appear  in  1972. 


Ik9 


Serial  No.  M-CR-12  (c) 

1.  Child  Research  Branch 

2.  Section  on  Family  Development 

3.  Bethesda,  Maryland 

PHS-HSMHA~NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  197  2 

Project  Title:   Developmental  Patterns  in  the  Young  Family 

Previous  Serial  Number:   SAME 

Principal  Investigator:   Robert  G.  Ryder 

Other  Investigators:    David  H.  Olson,  John  S.  Kafka,  and 

Walter  Sceery 

Man  Years : 

Total:  5.92 
Professional:  2.52 
Other:         3.40 

Project  Description: 

Objectives: 

To  describe  and  formulate  variations  in  relationships 
among  young  married  couples;  to  describe  and  explicate  the 
developmental  history  of  differing  patterns  of 
relationships;  to  integrate  sub-cultural,  social,  and 
personality  phenomena  into  a  comprehensive  view  of  intimate 
human  relationships,  to  investigate  correspondence  among 
marriage  patterns,  attributes  of  offspring  and  patterns  of 
parent-child  interaction. 

Methods  Employed : 

Most  of  the  data  presently  being  studied  were 
previously  collected  from  a  sample  of  2,162  young  married 
couples  from  the  Washington,  D.C.  metropolitan  area.  The 
quantitative  portion  of  this  body  of  data  has  largely  been 
collated  and  organized  into  computer  files  from  which 
substantive  analyses  can  be  undertaken.  The  qualitative 
data,  consisting  primarily  of  written  records  and  reports, 
has  been  altered  to  protect  confidentiality,  and  recorded  on 
microfilm.  Original  copies  of  most  written  material  have 
been  placed  in  federal  storage,  and  will  be  destroyed   after 


151 


Serial  No.  M-CR-12  (c) 
the  completeness  of  the  microfilm  copies  has  been  definitely 
established. 

Present  data  collection  is  limited  to  marriage  followup 
studies  of  couples  whose  children  have  reached  the  preschool 
phase  of  the  Branch  longitudinal  study,  a  group  of  about  80 
couples  so  far.  Data  collection  includes  interaction 
procedures,  questionnaires  and  an  interview. 

The  Qualitative  Unusual  Event  Sorting  Technique 
(QUEST) ,  developed  in  FY  1971,  has  been  used  to  generate 
clusters  among  self  descriptive  terms  provided  by  subjects. 
All  cases  are  presently  being  scored  for  these  clusters. 
QUEST  is  presently  being  used  to  generate  a  set  of  clusters 
from  codings  of  subjects'  written  essays  about  their 
marriages . 

A  new  technique  for  studying  interaction  sequences  is 
being  developed,  for  use  with  interaction  data  from  this  and 
other  projects.  This  Sequence  Correlation  Procedure  (SCP) 
departs  greatly  from  traditional  procedure,  which  generates 
transitional  probabilities,  requires  a  great  deal  of  data, 
and  can  yield  umvieldy  results.  Useful  but  somewhat 
different  kinds  of  information  seem  obtainable  vrith 
substantially  more  economy  from  SCP,  VJhile  more 
conventional  procedure  treats  a  sequence  of  events,  in 
effect,  as  a  matrix,  SCP  specifies  a  sequence  as  simply  a 
vector,  with  consequent  reduction  in  the  numerical 
complexity  of  results.  SCP  should  also  make  it  possible  to 
uncover  sequential  patterns  embedded  in  a  context  of 
irrelevant  events,  which  might  be  lost  using  other 
procedures . 

Major  Findings : 

Preliminary  intercorrelations  among  all  presently 
scored  questionnaire  variables  indicates  a  far  higher  number 
of  significant  relationships  than  v/ould  he  expected  by 
chance.  The  organization  of  these  relationships  into 
dimensions,  to  be  revised  by  an  iterative  process,  is  in 
progress . 

Longitudinal  data  has  been  used  to  partially  replicate 
findings  from  other  laboratories  that  having  a  child  is 
related  to  a  decrease  in  self  reports  of  "marriage 
satisfaction".  One  such  study  also  reports,  in  effect,  that 
couples  initially  high  in  "marriage  satisfaction"  shov;  the 
greatest  decrease.  The  analysis  completed  in  the  present 
project  also  shows  a  decrease  in  "marriage  satisfaction" 
that  is  greater  for   couples   who   have   a   child   than   for 


152 


Serial  No.  M-CR-12  (c) 

couples  who  do  not  have  a  child  in  the  same  time  interval, 
and  indicates  that  the  most  consistent  content  involved  in 
this  relationship  is  the  \\-ife's  self  report  that  her  husband 
is  inattentive  to  her.  IJomen  who  have  a  child,  as  compared 
with  women  who  do  not  in  the  same  time  interval,  become  more 
likely  to  report  that  husbands  do  not  pay  enough  attention 
to  them.  There  was  no  evidence  whatever  to  support  the  view 
that  this  effect  was  related  to  one's  initial  scores  on 
"marriage  satisfaction" . 

Longitudinal  data  are  also  being  used  at  present  to 
investigate  changes  in  reported  sexual  behavior  and  interest 
in  the  first  few  years  of  marriage.  There  appears  to  be  a 
general  decline  in  both  reported  activity  and  interest 
between  the  spouses,  somevrhat  greater,  on  the  average,  for 
the  wife  than  for  the  husband. 

Interaction  data  from  the  Color  Matching  Test  has  been 
factored  and  the  factors  replicated.  The  resulting 
dimensions  are  presently  being  adjusted  to  an  optimal 
profile  rotation,  i.e.,  a  rotation  which  maximally 
differentiates  among  couples,  versus  the  standard 
rotational  aim  of  maximally  differentiating  among  variables. 
It  appears  that  three  or  four  dimensions  are  stable  among 
samples  of  about  200  couples,  as  compared  with  two  or  three 
dimensions  from  the  much  smaller  samples  previously 
employed.  Interaction  data  are  still  being  coded  from  the 
Inventory  of  Marital  Conflict,  and  the  Inventory  of  Family 
Conflict.  Data  from  the  Inventory  of  Family  Conflict  is 
still  being  collected,  since  this  procedure  is  used  with 
longitudinal  couples  whose  children  are  presently  going 
through  the  Child  Research  Branch  nursery  school. 

Consideration  of  previous  experience  with  interaction 
procedures  has  led  to  a  report  by  David  Olson  called  "The 
Power lessness  of  Family  Power",  in  which  he  notes  the 
extremely  poor  correspondence  of  alleged  power  measures 
collected  from  different  sources.  The  principal 
investigator  has  completed  a  conceptual  work  attempting  to 
delineate  just  what  is  meant  by  the  word  "power".  A 
principal  conclusion  was  that  power  is  best  viev;ed  as  a 
psychological  concept  involving  motivation.  "A"  is  said  to 
have  power  over  "B"  if  "A"  can  get  "B"  to  do  something  "A" 
wants  done  and  "B"  does  not  want  done.  Three  varieties  of 
power  were  defined:  contingency  power,  cost-effectiveness 
power,  and  resource  power. 

Work  was  also  advanced  on  global  descriptions  of 
particular  marriage  patterns.  Adequate  preliminary  coding 
reliability  was   established  for  locating  spouses  in  a  five 


153 


Serial  No.  M-CR-12  (c"i 


dimensional  inferential  framework.  Husbands  vrere  considered 
according  to  attributed  effectiveness  and  impulse  control, 
and  wives  according  to  "dependency" ,  attitude  toward 
attention  and  orientation  toward  the  marriage. 

An  impressionistic  report  of  marriages  in  v/hat  has  been 
called  the  counter  culture  has  also  been  completed.  Aspects 
emphasized  in  this  report  are  a  return  of  conventionality, 
demystification  of  sexuality,  a  general  approach  to  tension, 
and  a  psychology  of  plenty.  Conceptual  links  among  these 
facets  were  noted. 


Significance   to  Bio-Medical  Research  and  the  Program  of  the 
Institute; 

There  continues  to  be  a  growing  interest,  in  the 
general  marriage  and  family  field,  in  the  substantive 
findings  and  methodological  advances  of  this  project.  A 
significant  contribution  to  knowledge  about  concomitants  of 
child  bearing  is  one  substantive  matter  of  widespread 
interest.  A  popular  enthusiasm  for  measures  of  family  power 
is  likely  to  be  effected  by  the  more  conservative  viev?  we 
find  supported  by  our  data.  A  serious  need  for 
dispassionate  views  of  the  family  implications  of 
alternative  life-styles  is  answered  in  part  by  the  project 
work  on  unconventional  couples . 

The  primary  significance  of  the  project  continues  to  be 
in  progressing  toward  more  differentiated  ways  of  describing 
and  viewing  intimate  relationships,  which  should  be  useful 
to  those  dealing  clinically  or  by  way  of  research  with 
married  couples,  and  in  cooperating  v/ith  other  projects  in 
the  Child  Research  Branch  in  attempting  to  demonstrate 
predictive  relationships  between  kinds  of  young  married 
couples  and  their  subsequent  offspring. 

Proposed  Course  of  Project; 

Activities  for  the  coming  fiscal  year  will  continue  to 
consist  primarily  of  working  v/ith  the  data  in  hand- 
Quantitative  and  quasi-clinical  studies,  studies  of 
particular  relationship  patterns,  and  comprehensive  studies 
of  dimensionality  are  to  be  carried  forv/ard  with  a  view  to 
eventual  integration. 


15h 


Serial  No.  M-CR-12  (c) 


Honors  and  Awards ; 

The  principal  investigator  was  nominated  to  be 
president  of  the  Groves  Conference  on  Marriage  and  the 
Family. 

Publications : 


DuPont,  R.L.,  Ryder,  R.G.  and  Grunebaum,  H. :   An  Unexpected 
Result  of  Psychosis  in  Marriage.   American  Journal  of  Psychiatry, 
128:   6,  735-739,  1971 

Kafka,  J.S.:   Discussion  of:   An  Unexpected  Result  of 
Psychosis  in  Marriage.   American  Journal  of  Psychiatry, 
128:   738-739,  1971 

Kafka,  J.S.:   Paradox,  Time  and  Object  Constancy. 
Scientific  Bulletin  of  the  British  Psycho-Analytical 
Society,  331   23-39,  1972 

Kafka,  J.S.:   Report  on  Panel  on  "The  Experience  of  Time". 
Journal  of  the  American  Psychoanalytic  Assn.  (in  press)  1972 

Olson,  D.H. :   The  Powerlessness  of  Family  Power:   Empirical  and 
Clinical  Considerations,  Science  and  Psychoanalysis, 
22:   139-147,  1972 

Olson,  D.H.:   Empirically  Unbinding  the  Double  Bind: 

Review  of  Research  £  Conceptual  Reformulation.   Family  Process, 

II:   1,  69-94,  1972 

Olson,  D.H.  and  Rabunsky,  C.C.:   Validity  of  Four  Measures 
of  Family  Power,  Journal  of  Marriage  and  The  Family, 
(in  press)  1972 

Ryder,  R.G.:   Dimensional  Structure  of  SPAT  (The  Spouse 
Adjective  Test)  Catalog  of  Selected  Documents  in  Psychology, 
1:   17,  1971  ~ 

Ryder,  R.G.:   What  is  Power?   Definitional  Considerations 
and  some  Research  Implications.   Science  and  Psychoanalysis, 
22:   36-52,  1972  


155 


Serial  No.  M-CR-22(c) 

1.  Child  Research  Branch 

2.  Infant  Development 

3.  Bethesda,  Maryland 


PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 


Project  Title:   Offspring  Effects  on  Parents 

Previous  Serial  Number:   Same 

Principal  Investigator:   Richard  Q.  Bell 

Other  Investigators:   Lawrence  V.  Harper,  University  of  California  at  Davis 

Cooperating  Units:   DCRT,  Computation  and  Data  Processing  Branch 

Man  Years : 

Total:  1.0 
Professional:  .4 
Other :         . 6 

Project  Description: 

Objectives ; 

To  review  the  literature  for  evidence  of  offspring  effects  on  parents; 
to  provide  a  conceptual  scheme  to  organize  findings;  to  initiate  studies 
in  areas  crucial  to  theories  of  early  development. 

Methods  Employed; 

Literature  search,  concept  development,  and  development  of  research 
methods  relevant  to  offspring  effects  on  parents . 

Major  Findings: 

In  last  year's  report  we  mentioned  efforts  to  locate  hierarchies  of 
infant  and  maternal  behaviors  from  home  observation  data  between  the  first 
and  ninth  week  of  life.   Inspection  of  data  from  a  computer  program  pre- 
pared by  DCRT  for  analyzing  temporal  contingencies  in  mother-infant  inter- 
actions, indicates  our  searching  method  is  valid.  This   method  consists  of 
scanning  computer-plotted  frequency  distributions  that  show  the  frequency 
of  first  occurrences  of  one  category  of  responses  after  varying  intervals 
following  occurrences  of  responses  in  another  category.   Scanning  resulted 
in  finding  non-random  distributions  for  a  substantial  number  of  our  cases 


156 


Serial  No.  M-CR-22(c) 

for  a  sequence  known  to  exist  in  the  data  on  the  basis  of  previous  studies. 
That  is,  crying  should  follow  fussing  at  other  than  random  intervals,  and 
more  frequently  than  fussing  follows  crying.   This  proved  to  be  the  case, 
following  which  we  searched  for  other  elements  in  the  sequence  that  have 
not  already  been  established  in  prior  studies.   It  was  found  that  vocal- 
izing usually  precedes  fussing,  but  not  the  reverse,  whereas  general 
movement  can  either  precede  or  follow  vocalization. 

Thus,  looking  at  the  infant  data  alone,  it  appears  we  have  located  an 
ordered  response  repertoire.  We  can  now  take  the  step  of  checking  this 
repertoire  for  age  changes .   Components  that  show  age  changes  can  then  be 
checked  for  the  influence  of  maternal  responses.   In  this  way  we  can  proceed 
to  test  the  hypothesis  that  infants  and  parents  respond  to  each  other,  not 
only  in  terms  of  single  events,  but  also  in  terms  of  each  other's  reper- 
toires.  The  research  approach  was  reported  at  the  April  1972  meeting  of 
the  Committee  of  Correspondents  on  Infancy. 

Lawrence  Harper  has  completed  a  paper  reviewing  all  sources  of  data 
relevant  to  the  human  infant's  effect  on  parents  or  caretakers.   This  paper 
paralleled  a  previous  review  carried  out  on  infra-human  mammals,  and  showed 
that  the  effect  of  the  young  ranged  from  the  impact  on  the  physiology  of 
the  mother  through  to  alteration  of  the  relationship  of  the  parents  to 
their  physical  and  social  environment,  just  as  was  the  case  in  infra-human 
primates.   One  of  the  challenging  conclusions  that  Dr.  Harper  wasable  to 
reach  in  the  review  of  the  paper  on  primates  was  that  the  young  had  played 
a  vital  role  in  the  radiation  of  species  into  different  environments,  and 
that  the  innovative  and  exploratory  activities  of  the  young  offset  normal 
cultural  transmission.   Even  in  the  primate  colonies,  cultural  transmission 
from  adults  is  conservative  and  operates  to  restrict  the  range  and  flexi- 
bility of  animal  troups .   Though  the  evidence  was  of  a  different  nature, 
similar  conclusions  could  be  reached  at  the  human  level. 

Significance  to  Biomedical  Research  and  the  Program  of  the  Institute; 

This  series  of  conceptual,  methodological  and  empirical  contributions 
is  intended  to  bring  about  a  revision  of  socialization  theory  and  research 
methods  that  have,  in  the  main,  proved  relatively  unproductive  in  recent 
years.  The   revised  approach  may  make  it  possible  to  launch  socialization 
research  on  a  course  that  corresponds  better  to  the  realities  of  parent- 
child  interaction,  and  thus  increase  the  likelihood  of  generating  more 
consistent  results  than  in  the  past.   Socialization  research  is,  in  turn, 
the  basis  for  advice  to  parents  as  well  as  the  basis  for  many  social  and 
family-oriented  action  programs. 

Proposed  Course  of  the  Project: 

All  papers  from  this  project,  along  with  contributions  to  the  field 
from  other  authors,  are  being  collated  in  a  volume  of  readings  on  the 
effects  of  the  young  on  their  parents.   Ihe  analyses  of  mother-infant  inter- 
actions will  be  continued  with  the  objective  of  locating  parent  response 


15T 


Serial  No.  M-CR-22(c) 

hierarchies,  and  ascertaining  how  these  interact  with  infant  behavior 
repertoires  in  the  production  of  age  changes . 

Honors  and  Awards ; 

Richard  Bell  was  invited  to  be  the  keynote  speaker  at  the  first  of  a 
series  of  annual  conferences  on  the  origins  of  behavior,  sponsored  by 
the  Educational  Testing  Service. 

Publications : 

Bell,  R.  Q.:   Reduction  of  the  stress  in  child  rearing.   In  Levy,  L. 
(Ed.):   Society,  Stress,  and  Disease:   Childhood  and  Adolescence. 
Oxford,  England,  Oxford  University  Press,  In  press. 


158 


Serial  No.  M-CR-23  (c) 

1.  Child  Research  Branch 

2.  Section  on  P&rent- Infant  Behavior 

3.  Bethesda,  Maryland 

EHS-HSMHA-Un^lH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:  Determinants  and  Dimensions  of  Mother- Infant  Interaction 

Previous  Serial  Number:  Same 

Principal  Investigator:  Howard  A.  Moss 

Other  Investigators:  Sandra  J.  Jones 

Cooperating  Units:  None 

Man  Years: 

Total:  i+.17 
Professional:  1.17 
Other:        3.00 

Project  Description: 

Objectives ; 

The  major  objectives  of  this  research  are  to  identify  primary  dimensions 
of  mother-infant  interaction,  to  illuminate  the  determinants  of  these  inter- 
action patterns,  and  to  relate  these  findings  to  data  provided  by  other  com- 
ponents of  the  Branch  longitudinal  program,  including  the  early  behavioral 
makeup  of  the  infant,  the  preparental  relationship  of  the  mother  and  father, 
and  the  mother's  early  experience  with  her  own  family.  In  addition,  the  data 
obtained  from  the  mother-infant  study  vill  be  used  to  predict  nursery  school 
behavior  when  the  children  are  studied  at  2^  years  of  age. 

Methods  Employed: 

The  data  collection  for  this  project  on  mother-infant  behavior  was  initi- 
ated in  September,  19^7  and  completed  by  October,  1970.  Although  most  of  the 
reliability  data  was  collected  throughout  the  course  of  the  study,  there  vere 
some  cases  studied  through  January,  1971,  for  the  purpose  of  obteiining  addi- 
tional reliability  information  on  sane  of  the  procedures.  The  sample  consists 
of  121  mother-infant  pairs  from  the  second  cohort  of  the  Branch's  longitudinal 
program. 

All  the  procedures  administered  in  the  main  longitudinal  study  of  mother- 
infant  interaction  have  been  described  in  detail  in  previous  annual  reports. 

159 


Serial  No.  M-CR-23  (c) 
Therefore  this  annual  report  i-Till  only  provide  a  summarj-. 

(1)  Interviews  and  questionnaires  were  administered  to  the  expectant 

mother  during  the  last  trimester  of  pregnancy. 

(2)  Two  six-hour  home  observations  were  made  of  mother-infant  interaction 
at  three  months  of  age. 

(3)  Postpartum  interviews  and  questionnaires  were  administered  to  the 
mother  when  the  infant  was  about  3<^  months  of  age.  ^.-Jhile  these  pro- 
cedures were  being  administered,  the  infant  was  studied  in  a  labora- 
torj'-  situation  using  procedures  that  involved  vocal  conditioning, 
visual  attention,  resistance  to  cuddling,  and  muscle  tonus. 

(h)     \lhen   the  infant;  was  eleven  months  old,  a  home  visit  was  made  durirg 
\7hich  the  mother  was  interviewed  and  the  child  was  observed  in  struc- 
tured situations  and  in  free  play.   Observations  dealt  with  reaction 
to  strangers,  separation  from  the  mother,  imitation,  socialization, 
exploratory  behavior,  etc. 

In  addition,  we  have  completed  data  collection  on  a  subsample  of  36  second- 
born  mother-infant  pairs  for  whom  we  have  antecedent  data  on  the  first-born. 
Two  six-hour  home  observations  of  matemal-infant  interaction  were  made  using 
the  same  measures  employed  in  studying  the  first-born  sample.  Folloid.ng  the 
second  obsei*vation,  the  mother  was  interviewed  briefly  about  differences  and 
similarities  between  her  experiences  with  her  two  infants. 

The  majority  of  the  staff  effort  for  the  past  year  has  been  devoted  to 
coding,  processing,  and  carrying  out  preliminarj^  analyses  of  data.  Under  a 
contract.  Dr.  Elizabeth  Hillenbrand  has  completed  ratings  on  the  121  postpartum 
interview  tapes.  The  principal  investigator  conducted  both  the  pregnancy  and 
postpartum  interviews  but  rated  only  the  pregnancy  tapes.  Thus,  independence 
of  ratings  between  these  two  sets  of  data  is  being  maintained. 

The  i^l  heme  observation  variables  and  the  I7  global  variables  from  the 
home  observations  have  been  standardized  to  correct  for  any  differences  between 
observers.  Fifty- six  new  combination  and  contextual  variables  from  the  home 
observations  have  been  generated  based  on  patterns  and  sequences  of  scores. 
These  will  eventually  be  used  \j±th   our  other  measures  in  both  our  cross-sec- 
tional and  longitudinal  analyses. 

In  addition,  data  preparation  has  been  completed  for  the  pregnauicy  and 
postpart'.in  questionnaires,  the  traditional  family  values  questionnaire,  the 
pregnancy  and  postpartum  interview  ratings,  and  the  laboratory  studies  on  vocal 
conditioning,  visual  attention,  muscle  tonus,  and  resistance  to  cuddling.  The 
eleven-month  study  variables  have  been  coded,  reliabilities  for  the  three  ob- 
servers have  been  calculated,  and  the  approximately  90  variables  remaining  are 
in  the  process  of  being  put  on  IH'I  cards  to  be  added  to  the  data  decl:  for  each 
subject. 

160 


Serial  No.  M-CR-23  (c) 

Sir;nlficance  to  Bio-Medical  Research  and  the  Prop;ragi  of  the  Institute; 

The  data  collected  from  this  project  should  provide  basic  information  con- 
cerning the  extent  to  which  initial  response  tendencies  in  infants  and  various 
parental  characteristics  conjointly  contribute  to  early  mother-infant  inter- 
action patterns.  From  these  data  we  can  begin  to  determine  the  variance  in  the 
mother-infant  interaction  that  is  attributable  to  infant  characteristics,  as 
well  as  the  variance  associated  with  particular  maternal  predispositions.  The 
results  of  these  studies  should  also  help  us  understand  the  development  of  the 
mother's  and  infant's  attachment  toward  one  another;  the  emergence  of  social 
behavior  and  responsiveness  in  the  young  child;  and  some  of  the  developmental 
antecedents  of  cognitive  functioning.  The  results  should  also  provide  informa- 
tion concerning  the  basic  dynamics  of  early  personality  functioning. 

Prcrposed  Course  of  Project; 

Data  processing  should  be  completed  for  all  but  the  second-born  sample 
during  the  coming  year.  All  within-stage  analyses  of  the  mother-infant  materi- 
al and  the  construction  of  the  final  set  of  variables  to  be  used  in  the  cross- 
sectional  and  longitudinal  analyses  should  also  be  completed.  The  last  year  has 
been  concentrated  on  data  analyses.  In  the  coming  year  our  efforts  will  turn  to 
the  reporting  and  publication  of  findings. 

Honors  and  Awards; 

None 

Publications; 

Jones,  S.  J.  Test  of  Bogartz's  model  on  binary  prediction  by  children. 
Psychonomic  Science,  In  Press. 


161 


Serial  No.  M-CR-24  (c) 

1.  Child  Research  Branch 

2.  Child  Behavior 

3.  Bethesda,  Maryland 


PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 


Project  Title:   Structure  and  Correlates  of  Preschool  and  Child  Behavior 

Previous  Serial  Number:   SAME 

Principal  Investigator:   Charles  F.  Halverson,  Jr. 

Other  Investigators:   Mary  F.  Waldrop 

Cooperating  Units:   None 

Man  Years: 

Total: 

Professional: 

Other: 

Project  Description: 

This  project  has  been  incorporated  in  M-CR-IO  (c) . 


163 


Serial  No.  M-CP(C)-18-3 

1.  Laboratory  of  Clinical  Psychobiology 

2.  Section  on  Clinical  Studies 

3.  Bethesda,  Maryland 


PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 


Project  Title:   Biochemical  and  Pharmacological  Studies  of  Sleep 
Previous  Serial  Number;  Same 


Principal  Investigator: 
Other  Investigators: 


Frederick  Snyder,  M.D. 

William  E.  Bunney,  Jr.,  M.D.,  David  H.  Fram,  M.D., 
J.  Christian  Gillin,  M.D.,  Frederick  K.  Goodwin,  M.D., 
Robert  M.  Post,  M.D.,  Richard  J.  Wyatt,  M.D., 


Joel  Kotin,  M.D.,  Leonard  S. 
Robert  I.  Henkin,  M.D. 


Jacobs,  M.D.  and 


Cooperating  Units: 


Section  on  Psychiatry,  Laboratory  of  Clinical  Science,  NIMH 
Laboratory  of  Clinical  Psychopharmacology,  SMR 
Experimental  Therapeutics,  National  Heart  and  Lung 
Institute,  NIH 


Man  Years  C1971): 

Total :        3 
Professional:    1  1/2 
Other:         1  1/2 

Project  Description: 

Objectives: 

Experimental  findings  over  the  past  several  years  promise  under- 
standing of  the  basic  biochemical  processes  underlying  sleep,  and  over 
the  same  period  increasingly  clear  demonstrations  of  the  severity  of 
sleep  disturbances  in  many  psychiatric  patients  indicate  the  need  for 
better  means  of  alleviation.  These  practical  and  theoretical  aspects 
are  closely  linked,  for  if  biochemical  understanding  of  sleep  could  be 
achieved,  rational  treatment  of  its  disturbance  would  surely  follow. 

The  work  of  Jouvet  and  others  in  cats  suggests  that  non-REM  sleep 
is  somehow  related  to  serotonin  metabolism,  while  REM  sleep  has  a 
particular  relationship  to  norepinephrine.  Among  the  evidence  for 

165 


Serial  No.  M-CP(C)-18~3,  Page  2 


these  conclusions  is  a  specific  reduction  in  non-REM  sleep  after 
parachlorophenyl alanine  (PCP)  administration,  as  well  as  the  specific 
reduction  of  REM  sleep  by  monoamine  oxidase  inhibitors  (MAOI).  Pre- 
vocative  as  these  findings  are,  their  human  relevance  was  uncertain 
so  long  as  comparable  studies  had  not  been  carried  out  in  man,  and 
this  has  been  the  primary  aim  of  our  own  efforts  over  the  past 
several  years,. 

Contrary  to  findings  in  the  cat,  we  have  reported  that  therapeutic 
doses  of  parachlorophenylalanine  (PCP),  an  inhibitor  of  serotonin 
synthesis,  produces  marked  suppression  of  REM  sleep  without  diminution 
of  total  sleep,  an  effect  which  is  reversed  by  5-hydroxytryptophan 
(5-HTP)  the  serotonin  precursor  which  by-passes  the  PCP  inhibition 
of  serotonin  synthesis.  On  the  other  hand,  we  have  found  that 
inhibitors  of  catecholamine  synthesis,  alpha  methyl  paratyrosine 
(AMPT)  or  alpha  methyl  phenyl  alanine  (AMPHe)  have  the  effect  of 
elevating  REM  sleep  levels  without  significant  change  in  non-REM  sleep. 
We  have  found  that  oral  dosages  of  L-Dopa,  presumably  elevating 
central  Dopamine  concentrations,  also  diminish  REM  sleep.  Thus, 
both  serotonergic  and  adrenergic  systems  would  appear  to  influence  the 
occurrence  of  REM  sleep,  but  in  ways  quite  opposite  to  those  implied 
by  previous  studies  in  the  cat. 

While  the  main  implications  of  these  findings  are  being  pursued  by 
Dr.  Wyatt  at  his  new  sleep  laboratory  in  the  Laboratory  of  Clinical 
Psychopharmacology,  SMR,  several  related  issues  continue  to  be 
followed  up  here  during  the  past  year  in  a  number  of  separate  studies. 

Patient  Material : 


4  medical  patients 

15  psychiatric  patients 

5  normal  volunteers 


Methods  and  Findings: 

A.  Effects  of  Intravenous  DOPS  and  5-HTP  during  Sleep 

A  new  approach  to  studying  the  biochemistry  of  human  sleep  involving 
the  intravenous  infusion  of  drugs  during  sleep  with  simultaneous 
monitoring  of  sleep  patterns  was  described  in  last  year's  report 
together  with  first  results.  REM  onset  infusions  of  L-Dopa, 
25-50  mg.  shortened  the  first  REM  period,  while  pre-REM  infusions 
delayed  the  onset  of  the  first  REM  period  in  patients  pretreated  with 
a  peripheral  decarboxylase  inhibitor. 


166 


Serial  No.  M-CPCC)-18-3,  Page  3 

During  the  past  year  the  same  approach  has  been  extended  to  two 
other  drugs  affecting  amine  synthesis,  DORA  (an  unnatural  amino 
acid  thought  to  be  decarboxylated  directly  to  norepinephrine  without 
conversion  to  dopamine)  and  5-HTP  (the  immediate  precursor  of 
serotonin.  In  the  present  studies  eight  depressed  patients,  pretreated 
with  a  peripheral  decarboxylase  inhibitor  (MK-486,  50  mg.  t.i.d.) 
were  given  a  total  of  22  DOPS  infusions  (50-150  mg.),  11  5-HTP 
infusions,  and  28  placebo  infusions.  In  contrast  to  L-Dopa,  neither 
DOPS  nor  5-HTP  effected  REM  latency  or  the  length  of  the  first  REM 
period.  There  were  no  differences  in  the  overall  nightly  sleep 
patterns  compared  with  placebo  infusion.  Larger  doses  of  both  drugs 
will  be  used  in  further  trials. 

B.  Effects  of  Histidine  on  Sleep 

As  reported  last  year,  20  gm/day  doses  of  L-histidine,  the  amino  acid 
precursor  of  histamine,  did  not  appear  to  have  any  effects  on  the 
sleep  patterns  of  narcoleptic  patients,  discouraging  the  possibility 
that  histamine  is  particularly  implicated  in  the  biochemistry  of 
sleep  and  waking.  Although  that  issue  has  been  dormant  for  most  of 
the  past  year,  Drs.  Gill  in  and  Henkin  have  now  revived  it  by 
beginning  a  series  of  studies  at  higher  dosages  of  L-histidine 
(32  gm/day)  in  normal  volunteer  subjects. 

C.  The  Effects  of  Carbohydrate  Active  Steroids  (CAS)  on  Human  Sleep 

Pursuant  to  last  year's  work  demonstrating  significant  reductions 
of  REM  sleep  after  moderately  high  pharmacological  dosages  of 
prednisone  in  normal  volunteers,  Drs.  Gillin  and  Henkin  are  now 
examining  the  effects  of  carbohydrate  active  steroids  both  in  normals 
and  in  patients  with  adrenal  cortical  insufficiency. 

The  effects  of  CAS  were  studied  in  four  patients  (three  with 
Addison's  Disease  and  one  with  panhypopituitarism),  on  and  off 
hormonal  replacement  therapy,  as  well  as  in  five  male  volunteers 
during  baseline  conditions  and  while  receiving  metyrapone  (reduces 
Cortisol  production  by  inhibition  of  adrenal  11-B-hydrosylation). 
In  both  patients  and  volunteers  decreased  CAS  was  associated  with 
significant  increase  in  high-voltage  slow-wave  proportions  of  sleep 
and  REM  density  (the  intensity  of  rapid  eye  movement  during  REM 
sleep).  The  effects  of  increased  CAS  were  studied  in  three 
volunteers  by  oral  administration  of  prednisone  12.5  gm.  4  times/day 
and  in  5  volunteers  by  intravenous  infusions  of  ACTH.  In  both 
situations  increased  CAS  resulted  in  significant  decreases  in  REM 
and  REM  %  and  increase  in  REM  latency.  In  addition,  prednisone 
significantly  reduced  stage  3,  and  ACTH  reduced  total  sleep.  Since 
the  same  results  were  found  in  the  hypopituitary  patients  as  in  the 
Addisonians,  the  results  suggest  that  increased  slow-wave  sleep 

167 


Serial  No.  M-CP(.C)-18-3,  Page  4 


following  decreased  CAS  is  independent  of  ACTH. 

D.  Effects  of  L-Kynurenine  on  Human  Sleep 

Earlier  work  here  failed  to  explain  why  two  precursors  of  serotonin, 
L-tryptophan  and  5-HTP,  did  not  have  the  same  effects  on  human 
sleep.  Since  kynurenine  is  the  largest  metabolic  pathway  for 
tryptophan,  it  was  of  interest  to  examine  the  effects  of 
L-kynurenine  administration  itself.  Although  this  study  still 
continues,  data  from  the  first  three  subjects  given  this  substance 
in  doses  of  2  gin.  before  bedtime  have  not  yielded  any  apparent 
effects  on  sleep  patterns. 

E ,  Effects  of  ^  tetrahydrocannabinol  on  the  Sleep  of  Psychiatric 
Patients 

In  connection  with  therapeutic  trials  of  A ^tetrahydrocannabinol 
we  have  examined  sleep  effects  in  three  depressed  psychiatric 
inpatients.  The  only  consistent  result,  noted  in  all  three 
patients,  was  a  considerable  reduction  of  REM  time  on  the  first 
night  of  drug  administration,  but  not  on  succeeding  nights. 
Additional  subjects  are  being  studied. 

Significance  to  Mental  Health  Research: 

These  studies  contribute  to  the  present  worldwide  effort  to  unravel 
the  complex  relationships  of  brain  monoamines  to  sleep  and  to  mental 
illness.  They  also  begin  to  demonstrate  the  possible  effects  of  stress 
and  increased  corticosteroid  levels  in  disturbing  those  mechanisms. 

Proposed  Course  of  Project: 

The  collaboration  of  this  Laboratory  in  such  biochemical  and 
pharmacological  studies  of  sleep  will  probably  be  limited  to  completion 
of  the  above  studies  and  others  immediately  following  from  them.  In 
the  meantime,  two  of  our  alumni,  Drs.  Wyatt  and  Gillin,  have  launched 
a  full  scale  effort  along  the  same  lines  at  the  Laboratory  of  Clinical 
Psychopharmacology,  SMR,  where  this  work  will  undoubtedly  continue. 

Publications: 

Gillin,  J.C.,  Jacbos,  L.S.,  Fram,  D.H.  and  Snyder,  F.:  Acute  effect 
of  a  glucocorticoid  on  normal  human  sleep.  Nature,  in  press  1972. 

Wyatt,  R. ,  Fram,  D.H.,  Buchbinder,  R.  and  Snyder,  F.:  Treatment  of 
intractable  narcolepsy  with  a  monoamine  oxidase  inhibitor. 
New  Eng.  J.  Med.  285:   987-991,  1971. 


168 


n 


Serial  No.  M-CPCC)-18-8 

1.  Laboratory  of  Clinical  Psychobiology 

2.  Section  on  Clinical  Studies 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:  Psychophysiological  Studies  of  Sleep  and  Waking  in 
Normal  Subjects 

Previous  Serial  Number:  same 

Principal  Investigator:  Frederick  Snyder,  M.D. 

Other  Investigators:  Redford  B.  Williams,  Jr.,  M.D.,  J.  Christian  Gillin, 
M.D.,  Monte  S.  Buchsbaum,  M.D.,  Robert  I.  Henkin,  M.D. 
Thomas  E.  Bittker,  M.D.,  Friedhelm  Lamprecht,  M.D. 
Frederick  G.  Wooten,  M.D.,  Lyman  C.  Wynne,  M.D.,  Ph.D. 
Wybren,  De  Jong,  M.D.  and  David  P.  Henry,  M.D. 

Cooperating  Units:  Adult  Psychiatry  Branch,  Laboratory  of  Clinical  Science 
and  Laboratory  of  Psychology,  CBRD,  NIMH 
Laboratory  of  Clinical  Psychopharmacology,  SMD,  NIMH 
Experimental  Therapeutics,  National  Heart  and  Lung 
Institute 

Man  Years:  (1971) 

Total :        3 
Professional:   1  1/2 
Other:        1  1/2 

Project  Description; 

Objectives: 

This  heading  encompasses  a  number  of  varied  studies  each  concerned  with 
one  or  another  aspect  of  normal  psychophysiology.  One,  carried  out  by 
Dr.  Redford  Williams  and  numerous  collaborators  examines  the 
cardiovascular  correlates  of  varying  transactional  behavior.  A  second, 
undertaken  by  Drs.  Christian  Gillin  and  Monte  Buchsbaum  searches  for 
variations  in  auditory  evoked  potentials  across  the  night  of  sleep. 
A  third  project,  extending  existing  data  on  the  relationship  between 
plasma  growth  hormone  levels  and  stages  of  sleep  to  middle-aged  and 


169 


Serial  No.  M-CPCC)-18-8,  Page  2 


older  subjects,  has  been  completed  during  the  past  year  and  is 
awaiting  publication.  Finally,  a  fourth  study  looking  for 
regularly  periodic  variations  in  waking  psychophysiology  under- 
taken in  collaboration  with  the  Department  of  Psychophysiology  at 
Walter  Reed  Army  Institute  of  Research  had  to  be  abandoned  when 
one  of  the  collaborators  left  the  Arir^y  and  the  other  was  reassigned 
to  different  duties. 

Patient  Material : 


40  normal  control  subjects 
8  psychiatric  patients 

Methods  and  Findings: 

A.  Cardiovascular  Correlates  of  Varying  Transactional  Behaviors 

In  these  studies  two  cardiovascular  measures  (heart  rate  and 
blood  flow)  are  recorded  during  baseline  periods  (a  vigilance 
task)  and  three  experimental  conditions  as  follovjs: 

Cl)  A  vigilance  task  eliciting  attentive  observation  of 
external  stimuli. 

(2)  An  interview,  promoting  interaction  with  another  person. 

(3)  A  cognitive  task  (mental  arithmetic  or  a  word  association 
test)  directing  attention  inward. 

In  a  first  study,  the  two  cardiovascular  measures  were  examined  in 
8  normal  and  8  psychiatric  patients  (5  schizophrenic  and  3 
depressives)  in  conjunction  with  interviews  and  word  association 
tests.  Not  surprisingly,  baseline  heart  rates  and  forearm  blood 
flows  were  significantly  higher  in  the  patient  group  and  increases 
in  heart  rate  were  significantly  greater  regardless  of  condition. 
While  normals  showed  significant  increases  in  blood  flow  during  the 
word  association  test,  patients  did  not  ~  perhaps  due  to  their 
already  high  baseline  levels,  or  perhaps  related  to  their  difficulty 
in  sustaining  attention  to  the  experimental  task.  Changes  in  forearm 
blood  flow  during  an  interview  were  quite  unexpected  in  both  normals 
and  patients,  being  the  first  instance  of  decreased  forearm  blood 
flow  in  response  to  any  psychological  stimulus. 

Consistent  results  were  obtained  from  a  second  study  in 
collaboration  with  Drs.  Wynne,  Buchsbaum,  Bittker  and  Singer  in  20 
normal  subjects  representing  either  "augmenters"  or  "reducers"  of 
auditory  evoked  potentials.  As  measured  by  simultaneous  recording 


170 


Serial  No.  M-CP(C)-18-8,  Page  3 

of  systolic  and  diastolic  blood  pressure,  heart  rate,  forearm 
blood  flow  and  finger  pulse  volume,  significantly  different 
patterns  of  cardiovascular  activation  were  obtained  under  the 
three  experimental  conditions  of  outward  vigilance,  interview  and 
mental  arithmetic.  Forearm  blood  flow  provided  the  best  differ- 
entiation, since  it  again  went  up  during  mental  arithmetic 
(attention  inward),  but  down  during  vigilance  (attention  outward). 

This  finding  (and  related  sub-findings)  suggests  that  depending 
upon  which  cardiovascular  parameter  one  chose  to  look  at,  one  could 
say  that  any  one  of  the  three  experimental  conditions  was  the  more 
stressful  in  that  it  resulted  in  a  larger  response.  A  consideration 
of  the  pattern  of  response,  however,  suggests  that  behaviors 
associated  with  attentive  observation  of  the  environment  give 
rise  to  a  pattern  of  response  resembling  that  of  peripheral 
sympathetic  nerve  activation,  while  rejection  of  environmental 
stimuli  seems  to  give  rise  to  a  pattern  of  response  resembling 
that  ensuing  from  adrenal  medullary  activation. 

Support  for  the  above  interpretation  was  provided  by  the  second 
finding  that  subjects  with  increased  FBF  during  the  interview 
differed  significantly  in  cardiovascular  response  from  those 
subjects  with  decreased  flow.  Contributing  independently  to  this 
difference  was  the  greater  degree  of  attentiveness  to  the 
interviewer  observed  in  subjects  with  decreased  FBF  during  the 
interview. 

If  attentiveness  to  environmental  stimuli  is  an  important  determinant 
of  cardiovascular  response,  then  persons  who  differ  in  terms  of 
characteristic  ways  of  attending  to  stimuli  might  be  expected  to 
differ  in  terms  of  the  cardiovascular  parameters  under  study. 
Augmenters  In  the  present  study  differed  from  reducers  both  in 
terms  of  cardiovascular  response  to  the  experimental  conditions 
and  in  terms  of  resting  levels  of  the  five  cardiovascular  parameters. 
In  general  these  differences  were  reflected  in  higher  FBF  and 
heart  rate  for  augmenters  in  terms  of  both  resting  levels  and 
responses  to  experimental  conditions. 

B.  Auditory  Evoked  Potentials  during  Sleep 

Previous  work  of  Dr.  M.  Buchsbaum  and  others  has  shown  that  certain 
normal  persons  tend  to  show  exaggerated  increases  in  evoked  potentials 
to  increasing  intensity  of  auditory  stimulus  ("augmenters")  while  others 
tend  to  dampen  their  responses  at  the  higher  intensities  ("reducers"). 
Collaborative  studies  begun  by  Dr.  C.  Gill  in  while  he  was  a  member  of 
our  staff  with  Dr.   M.  Buchsbaum  still  continues  to  search  for  changes 
in  auditory  evoked  potentials  across  the  night  of  sleep,  looking  for 
differential  tendencies  to  augment  or  reduce  related  to  the  several 

171 


Serial  No.  M-CP(C)-18--8,  Page  4 


EE6  stages  of  sleep, 


Following  a  night  of  adaptation  to  the  sleep  laboratory  and  the 
auditory  click  stimuli,  auditory  evoked  potentials  are  collected 
and  averaged  by  computer  for  each  of  the  EEG  sleep  stages  across 
two  or  three  nights.  Pilot  results  suggested  a  clear  trend  toward 
reducing  of  evoked  potentials  in  the  progression  from  REM  sleep 
through  successive  phases  of  non-REM  sleep  (stages  2  to  4).  Data 
has  been  collected  from  8  additional  subjects  during  the  past  year, 
but  analysis  is  not  yet  completed. 

C .  Growth  Hormone  Release  during  Sleep  in  Relation  to  Subjects'  Age 
and  to  Acromegaly 

One  of  the  most  dramatic  findings  of  recent  sleep  research  has  been 
that  of  an  apparent  association  between  high-voltage  slow-wave 
stages  of  sleep  (stages  3  and  4)  and  peaks  of  plasma  growth  hormone. 
Until  now  that  evidence  had  been  limited  to  young  adult  sublects  who 
happen  to  have  large  portions  of  slow-wave  sleep  and  might  be  expected 
to  have  high  levels  of  growth  hormone.  In  collaboration  with 
Dr.  R.  Henkin  of  the  Experimental  Therapeutics  Branch,  NHLI,  during 
the  past  year  we  have  studied  such  relationships  in  middle-aged  and 
older  subjects,  who  typically  have  much  less  slow-wave  sleep  as  well 
as  lower  levels  of  plasma  growth  hormone.  In  addition,  studies 
have  been  conducted  on  acromegalic  patients  who  have  elevated  growth 
hormone  levels  throughout  the  night.  The  results  of  studies  in  10 
middle-aged  or  older  normal  controls  and  6  acromegalic  patients  have 
been  reported  in  a  paper  published  in  Endocrinology.  Although  7 
of  the  10  older  normals  showed  at  least  one  peak  of  growth  hormone 
early  in  the  sleep  period  regardless  of  whether  they  had  phases  of 
high-voltage  slow-wave  sleep  at  that  time,  3  of  the  4  subjects  over 
50  years  of  age  failed  to  show  sleep  peaks  of  growth  hormone  despite 
the  presence  of  high-voltage  slow-wave  sleep.  The  sleep  patterns  of 
the  acromegalic  patients  were  essentially  normal  for  their  ages. 
While  they  showed  the  expected  elevations  of  growth  hormone  levels 
throughout  the  night,  none  exhibited  any  discrete  peaks  of  hormone 
level  generally  found  in  normals.  Thus,  these  findings  suggest  that 
sleep-related  peaks  of  growth  hormone  tend  to  diminish  or  disappear 
with  advancing  years,  but  that  this  change  is  probably  not  directly 
related  to  the  age  associated  decrease  in  slow-wave  sleep. 

Significance  to  Mental  Health  Research: 

The  significance  of  Dr.  R.  Williams'  work  on  the  psychophysiology  of 
transactional  behaviors  stems  from  the  central  importance  of 
"physiological  arousal"  to  psychiatric  thinking.  This  work 
demonstrates  that  physiological  arousal  has  directional  properties. 


172 


Serial  No.  M-CPCC)-18-8.  Page  5 

depending  upon  whether  it  is  in  response  to  internal  or  external 
stimuli."  That  finding  may  help  to  clarify  much  past  confusion 
among  efforts  to  quantify  the  somatic  correlates  of  arousal. 

The  work  of  Drs.  C.  Gill  in  and  M.  Buchsbaum  on  auditory  evoked 
potentials  during  sleep  promises  to  add  a  significant  dimension  to 
present  knowledge  of  the  human  neurophysiology  of  sleep.  By  means 
not  applicable  to  human  subjects,  a  vast  amount  of  recent 
neurophysiology  has  begun  to  identify  differences  in  the  function 
of  the  brain  in  relation  to  the  several  electrographic  stages  of 
sleep.  The  evoked  potential  technique  is  one  of  a  few  means  by 
whicR  similar  conclusions  might  be  reached  concerning  human  brain 
function. 

The  studies  of  growth  hormone  release  during  sleep  in  older  normals 
and  acromegalics  serve  to  confound  previous  assumptions  about 
a  direct  relationship  between  growth  hormone  peaks  and  high-voltage 
slow-wave  sleep.  By  demonstrating  dissociation  of  the  two  under 
certain  natural  conditions  our  work  implies  that  they  are  not 
directly  related. 

All  of  these  studies  illustrate  the  necessity  for  the  most  searching 
possible  understanding  of  normal  relationships  between  behavioral 
and  physiological  variables  as  prerequisite  for  the  interpretation 
of  abnormal  ones. 

Proposed  Course: 

One  additional  study  involving  Drs.  R.  Williams,  M.  Buchsbaum, 
R.  Wooten  and  D.  Henry  is  planned  this  year  in  which  they  will  carry 
out  simultaneous  measures  of  forearm  blood  flow,  heart  rate, 
blood  epinephrine,  norepinephrine  and  DBH  levels  during  another 
vigilance  task  (continuous  performance  test)  and  mental  arithmetic. 
Some  subjects  will  be  normals  who  have  been  identified  as  either 
"augmenters"  or  "reducers,"  and  others  will  represent  extremes  of 
"field  dependence"  or  "field  independence." 

Since  Dr.  R.  Williams  is  leaving  the  laboratory  this  June  and 
Dr.  C.  Gill  in  has  already  formally  left  to  join  the  Laboratory  of 
Clinical  Psychopharmacology,  Division  of  Special  Mental  Health 
Research,  St.  Elizabeths'  Hospital,  no  further  studies  under  this 
category  are  contemplated  during  the  next  year. 


173 


Serial  No.  M-CP(C)-18-8,  Page  6 

Publications: 

Carlson,  H.E.,  Gillin,  J.C.,  Gorden,  P.  and  Snyder,  F.:  Absence  of 
sleep-related  growth  hormone  peaks  in  aged  normal  subjects  and  in 
agromegaly.  Endocrinology,  in  press. 

Snyder,  F.:  Psychophysiology  of  human  sleep.  Clin.  Neurosurg. 
18:   503-536,  1971, 

Snyder,  F.  and  Scott,  J.:  Psychophysiology  of  sleep.  In:  Greenfield,  N. 
and  Sternbach,  R.  (eds.),  Psychophysiology.  New  York:  Holt,  Rinehart  and 
Winston,  Inc.,  1972. 

Awards :  None 


rjk 


Serial  No.  M-CP(C)-18-69 

1.  Laboratory  of  Clinical  Psychobiology 

2.  Section  on  Clinical  Studies 

3.  Bethesda,  Maryland 


PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:  Longitudinal  Studies  of  Sleep  and  Concomitant  Biological 
Changes  in  Psychiatric  Patients 

Previous  Serial  Number:  Same 

Principal  Investigator:  Frederick  Snyder,  M.D. 

Other  Investigators:  Bernard  L.  Frankel ,  M.D.,  Redford  B.  Williams,  Jr., 
M.D.,  Winfield  H.  Scott,  Ph.D.,  Robert  D.  Coursey, 
Ph.D.,  John  J.  Strauss,  M.D.  and 
William  T.  Carpenter,  Jr.,  M.D. 

Cooperating  Units:  Section  on  Clinical  Psychology,  CBRA 

Section  on  Psychiatric  Assessment,  CBRA 

The  Department  of  Psychology,  University  of  Maryland 

Man  Years  C1971): 

Total:  3.5 
Professional:  1.5 
Other:         2.0 

Project  Description: 

Objectives: 

The  continuing  purpose  of  this  project  is  that  of  seeking  objective 
correlates  of  mental  illness  which  will  provide  quantifiable 
assessments  of  clinical  course  and  effectiveness  of  therapeutic 
efforts  over  a  broad  spectrum  of  diagnostic  entities.  The  collection 
of  all-night  sleep  patterns  from  psychiatric  inpatients  has  been 
suspended  during  the  past  year,  while  analysis  of  data  collected  in 
previous  years  remains  to  be  completed.  In  collaboration  with  the 
Section  on  Psychiatric  Assessment,  APB,  longitudinal  studies  of  a 
waking  psychopysiological  measure,  forearm  blood  flow  continue  on 
acutely  psychotic  patients.  In  the  meantime,  the  primary  emphasis 
of  the  project  has  shifted  to  sleep  studies  of  an  outpatient 
category  which  has  been  very   little  investigated  previously,  that 
of  primary  insomniacs.  The  latter  studies  are  being  carried  out  in 
conjunction  with  therapeutic  trials  of  cerebral  electrotherapy. 

175 


Serial  No.  M-CPCC)-18-69,  Page  2 


Methods  Employed: 


On  the  inpatient  side  of  this  project,  forearm  blood  flow,  a  measure 
reputed  to  be  related  to  variations  in  arousal  or  anxiety,  has  been 
obtained  on  a  serial  basis,  two  or  three  times  per  week,  from 
selected  psychiatric  inpatients  going  through  acute  psychotic  episodes. 
In  such  manner  seven  patients  have  now  been  followed  throughout  their 
entire  clinical  courses  here  at  the  Clinical  Center. 

The  outpatient  studies  of  insomniacs,  so  far  encompassing  fifteen 
patients,  involve  the  following  protocol.  After  completion  of 
initial  psychiatric  evaluation,  clinical  psychological  testing  by 
Dr.  Scott  of  APB  and  additional  psychological  testing  by 
Dr.  Coursey  of  the  University  of  Maryland,  all-night  electrographic 
sleep  records  are  obtained  for  five  consecutive  nights.  At  the 
completion  of  that  baseline  period  patients  receive  two  courses  of 
cerebral  electrotherapy  totalling  thirty  daytime  sessions  over  a 
seven  week  period,  including  intervals  at  two  different  pulse 
frequencies.  Throughout  the  study  interval  patients  complete  an 
eleven  item  questionnaire  each  morning  to  provide  subjective        i 
assessment  of  the  quality  of  their  sleep.  Twenty-four  hour  urine     ' 
samples  to  be  analyzed  for  17-hydroxy  steroid  levels  are  collected 
during  the  baseline  period  and  again  after  completion  of  the 
treatment  course.  At  the  end  of  the  treatment  interval  five 
additional  nights  of  sleep  recordings  are  carried  out  in  our  laboratory. 
Both  pre-  and  post-treatment  sleep  records  are  compared  to  those  of 
age-matched  normal  control  studies  under  the  same  conditions. 

Patient  Material : 


18  patients  (3  schizophrenics  and  15  insomniacs) 

Major  Findings: 

The  longitudinal  measures  of  forearm  blood  flow  completed  during  the 
past  year  have  been  consistent  with  the  findings  described  in  two 
patients  in  last  year's  report.  In  each  case  marked  increases  in 
forearm  blood  flow  have  preceded  onset  of  major  changes  in  clinical 
status,  usually  improvement,  but  in  a  few  instances  exacerbation  of 
illness. 

Data  from  the  first  seven  insomniac  patients  has  been  analyzed 
with  the  following  results: 

(1)  Compared  to  age  and  sex-matched  controls  the  insomniacs  did 

indeed  take  longer  (p<:.05)  to  fall  asleep,  spent  less  (p<:.05) 
time  in  bed  actually  asleep,  and  they  also  awakened  more 
frequently  during  the  night  after  falling  asleep.  In  addition, 

176 


Serial  No.  M-CP(C) -18-69,  Page  3 

there  were  trends  toward  decreased  REM  latency,  increased  REM 
sleep  percentage  and  decreased  delta  sleep  in  the  insomniacs, 
but  these  have  not  been  statistically  significant  in  the 
subsample  so  far  analyzed. 

(2)  Using  a  two-tailed  paired  t-test  to  compare  pre-  and  post- 
treatment  sleep  record  parameters,  there  were  no  significant 
changes  in  (a)  time  to  fall  asleep;  (b)  amount  of  actual  sleep, 
number  or  total  duration  of  nocturnal  awakening,  REM  latency, 
or  percentages  of  sleep  spent  in  particular  EEG  stages.  Also, 
there  were  no  significant  changes  in  the  patients'  subjective 
evaluations  of  their  sleep  or  in  depression  and  anxiety  self- 
rating  scales. 

Significance  to  Mental  Health  Research: 

As  recently  reviewed  (Electroencephalographic  Studies  of  Sleep  in 
Psychiatric  Illness),  the  worldwide  effort  over  the  past  decade  to 
objectify  the  nature  of  sleep  disturbances  in  various  psychiatric  conditions 
does  not  appear  to  demonstrate  specific  or  inherent  anomalies  of  sleep 
in  any  diagnostic  category.  Rather,  it  would  seem  that  the  sleep 
abnormalities  thus  far  found  in  all  groups  simply  reflect  the  intensity 
and  duration  of  anxiety  and  hyperarousal  accompanying  various  conditions. 
Thus,  sleep  patterns  may  provide  highly  tangible  indicators  of  the 
degree  of  patients  internal  distress  at  various  phases  of  illness,  but 
two  deficiencies  of  present  knowledge  remain  to  be  remedied.  For  one, 
other  objective  indicators  of  waking  anxiety  are  needed  with  which  to 
correlate  changes  in  sleep  patterns.  The  forearm  blood  flow  measure  we 
have  been  examining  may  be  one  such  indicator.  Secondly,  much  more 
information  is  needed  about  sleep  patterns  in  nonhospi tali  zed  and  less 
severely  ill  patients,  or  in  normal  individuals  undergoing  periods  of 
unusual  life  stress.  Our  present  studies  of  insomniac  patients 
contribute  to  the  second  goal ,  and  constitute  one  of  the  first  serious 
efforts  to  investigate  that  very  common  but  poorly  understood  problem. 

Proposed  Course  of  Project: 

Data  analysis  from  our  extensive  earlier  studies  of  sleep  in  inpatient 
schizophrenics  and  depressives  will  be  completed  as  will  that  from 
our  current  trials  of  electrosleep  in  insomniacs.  It  is  hoped  that 
during  the  next  year  the  series  of  insomniacs  studied  can  be  enlarged, 
the  measures  applied  to  their  sleep  extended  to  include  a  variety  of 
autonomic  as  well  as  EEG  indices,  and  alternative  therapeutic 
approaches  explored,  such  as  relaxation  feed-back  training  and  behavioral 
conditioning.  Efforts  will  continue  to  find  research  access  to  patients 
suffering  from  acute  and  chronic  anxiety  states,  and  to  normal  subjects 
under  conditions  of  unusual  stress.  In  this  last  connection,  we  are 


177 


// 


Sena!  No.  M-CP(C) -18-69,  Page  4 


about  to  undertake  a  study  of  EEG  sleep  patterns  in  patients  prior  to 
and  following  open  heart  surgery  in  collaboration  with  NHLI.  As 
noted  elsewhere,  the  effects  of  chronic  stress  on  sleep  are  also  being 
tested  experimentally  in  laboratory  animal  studies. 

Publications: 

Kupfer,  D.J.,  Wyatt,  R.J.,  Snyder,  F.,  Mould,  G.P.  and  Curry,  S.H.: 
Chlorproraazine  Plasma  levels  and  sleep  in  psychiatric  patients. 
Coniiiun.  Behav.  Biol.  6:   237-240,  1971. 

Snyder,  F.:  Electroencephalographic  studies  of  sleep  in  psychiatric 
disorders.  To  be  published  in  the  Proceedings  of  the  First 
International  Congress  of  the  Association  for  the  Psychophysiological 
Study  of  Sleep,  Bruges,  Belgium,  in  press,  1972. 


178 


^ 


Serial  No.  M-CP-18-6 

1.  Laboratory  of  Clinical  Psychobiology 

2.  Section  on  Comparative  Studies 

3.  Bethesda,  Maryland 


PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:  Comparative  Studies  of  Sleep 

Previous  Serial  Number:  Same 

Principal  Investigator:  Frederick  Snyder,  M.D. 

Other  Investigators:  Thomas  C.  Douthitt,  Ph.D.,  Nellie  Bugbee  and 
Burr  S.  Eichelman,  Ph.D.,  M.D. 

Cooperating  Units:  Section  on  Technical  Development,  IRPD,  NIMH 
Laboratory  of  Clinical  Science,  CBRD,  NIMH 
National  Zoological  Park 

Man  Years  (1971): 

Total:  3  1/2 
Professional:  1  1/2 
Other:        2 

Project  Description: 

Objectives: 

The  general  objective  of  this  project  is  to  explore  the  phylogenetic 
manifestations  and  adaptive  functions  of  sleep  by  systematic 
comparative  study  in  a  broad  variety  of  animal  forms  under  varied 
experimental  conditions.  This  first  required  the  development  of 
suitable  instrumentation  and  methodology  for  the  recording  of 
electrophysiological  patterns  from  unrestrained  animals  in  relatively 
spacious  enclosures  and  over  extended  time  intervals.  The  achievement 
of  a  suitable  radio-telemetry  system  for  that  purpose  was  described  in 
last  year's  report,  together  with  the  first  results  from  its 
application. 

The  past  year  has  been  occupied  with  much  more  extensive  data 
collection  from  several  species  of  primitive  mammals  under  a  wider 
variety  of  experimental  conditions.  Further  refinement  of  the 
telemetry  system  has  permitted  the  first  assessment  of  sleep  patterns 
under  quasi-natural  conditions  in  a  large,  out-door  enclosure. 


179 


Serial  No.  M-CP-18-6,  Page  2 


Beginnings  have  been  made  at  developing  techniques  for  much 
longer  range  telemetry  which  should  permit  the  study  of  sleep  patterns 
in  entirely  free-roaming  animals.  Finally,  special  emphasis  is 
being  directed  to  animal  models  of  the  effects  of  chronic  stress 
upon  sleep  patterns. 

Methods  Employed: 

Electroencephalographic  sleep-waking  patterns  are  obtained  from 
animal  subjects  either  by  implanted  radio-telemetry  or  by  cables  attached 
to  implanted  electrodes.  After  at  least  ten  days  recovery  from  surgery 
animals  are  acclimated  to  conditions  of  life  in  64  cubic  feet,  sound 
shielded  enclosures  under  constant  conditions  of  temperature,  a 
standardized  12/12  light  cycle,  and  feeding  at  the  same  time  each  day. 
Without  further  disturbance  to  the  animal,  recordings  are  then  obtained 
over  24-hour  periods  two  or  more  days  each  week  for  at  least  one  month 
prior  to  experimental  modification  of  conditions.  Records  are  scored 
in  30  second  epochs  in  terms  of  waking,  transitional  sleep,  slow-wave 
sleep  and  REM  sleep.  Since  gross  body  movement  and  feeding  are 
identifiable  from  characteristic  artefacts,  the  records  actually  provide 
a  quantitative  profile  of  the  animals'  entire  daily  life. 

At  the  completion  of  baseline  recording,  environmental  conditions  are 
varied  in  one  or  another  respect,  thus  far  including  the  following: 
Cl )  alterations  of  the  light  cycle  (24-hours  light  or  24-hours 
darkness);  (2)  introduction  of  co-specific  animals  of  the  same  or 
opposite  sex;  (3)  changes  of  ambient  temperature;  (4)  modifications  of 
quantity  or  nature  of  diet;  (5)  reduction  in  size  of  available  living 
space;  and  (6)  experimental  stress. 

Major  Findings: 

A .  Technical  Aspects. 

1 .  Improvement  of  telemetry  signal  strength 

Attempts  earlier  this  year  to  apply  the  low  powered,  implanted 
telemetry  system  to  opossums  living  in  our  large,  out-door  enclosure 
at  the  National  Zoo  were  unsuccessful,  since  the  signal  strength  was 
too  weak  to  be  reliable  for  continuous  24-hour  reception.  After 
various  attempts  to  remedy  that  problem,  a  solution  was  finally 
achieved  by  incorporating  a  small,  powdered  iron  core  into  the 
transmitter,  thus  increasing  signal  strength  several  fold  without 
increase  in  power  consumption  or  necessary  battery  weight.  With 
that  recent  innovation,  recordings  are  now  being  successfully 
obtained  on  a  routine  basis  from  animals  living  undisturbed  in 
a  10,000  square  feet  out-door  enclosure  over  intervals  of  three  to 
four  months. 


180 


Serial  No.  M-CP-18-6,  Page  3 

2.  Development  of  a  telemetry  system  for  studies  of  free- 
roaming  animals 

The  ultimate  step  beyond  our  present  capability  to  study  animals 
under  the  quasi-natural  conditions  described  above  would  be  the 
ability  to  obtain  similar  records  from  completely  free-ranging 
animals  without  at  all  disturbing  their  natural  patterns  of  behavior. 
This  would  require  long-range  physiological  telemetry  capabilities 
for  recording  el ectroencephal ©graphic  patterns  at  distances  of  at 
least  one-half  mile,  as  well  as  tracking  telemetry  for  following 
them  over  still  greater  distances.  The  tracking  telemetry 
techniques  have  been  extensively  used  for  wildlife  studies  and 
this  equipment  is  commercially  available.  Mr.  James  Bryan, 
Chief,  Section  on  Technical  Development,  is  attempting  to  meet  the 
challenge  of  long-range  physiological  telemetry  for  us  by  designing 
a  short-range  implanted  telemetry  package  together  with  a  much 
higher  powered,  "booster"  transmitter,  which  will  be  attached  to  the 
animals  by  the  neck  collar.  The  first  field  test  of  that  system  is 
now  underway  at  the  Pool esvi lie  animal  facility. 

B.  Phylogenetic  Studies 

As  described  in  last  year's  report,  primary  emphasis  has  thus  far 
been  given  to  intensive  study  of  sleep  in  a  number  of  primitive 
maranals,  the  hope  being  that  this  will  yield  insights  concerning 
the  prototypical  characteristics  of  mammalian  sleep.  Data  has  now 
been  collected  and  analyzed  from  more  extensive  series  of  four 
species:  the  native  marsupial,  Didelphis;  two  insectivores,  Centetes 
ecaudatus  and  Erinaceus  europaeus;  and  the  primitive  rodent, 
Aplodontia  rufa"!  Results  to  date  point  to  some  similarities  and 
other  differences  in  the  sleep  of  these  animals.  It  is  prominent 
in  the  captive  lives  of  all:  55-65%  of  every  24-hour  period  in 
Centetes,  Erinaceus  or  Aplodontia,  and  up  to  85%  in  Didelphis.  However, 
the  patterning  of  sleep  through  the  24-hours  and  its  relation  to  the 
light-dark  cycle  differs  considerably  among  them.  Erinaceus  appears 
to  be  essentially  a  monophasic  sleeper,  with  sleep  almost  uninterrupted 
throughout  the  light  phase  of  the  cycle,  while  at  the  other  extreme, 
Aplodontia  is  regularly  polyphasic,  with  a  clock-like  alternation 
between  sleep  and  waking  5-6  times  each  day,  and  with  very  little 
regard  to  light  or  darkness.  The  Tenrec,  Centetes.  is  an  irregularly 
polyphasic  sleeper  with  only  slightly  more  sleep  interspersed  during 
the  dark  than  during  light,  while  the  opossum's  small  portion  of 
waking  is  mainly  in  one  nocturnal  block. 


181 


Serial  No.  M-CP-18-5,  Page  4 

In  terms  of  the  percentages  of  REM  sleep  within  total  sleep,  extremes 
of  18  to  30%  occur  in  the  two  most  closely  related  forms,  Erinaceus  and 
Centetes,  while  the  two  most  remote,  Pi  del  phis  and  Aplodontia  have  the 
similar  proportions  of  23  end  21%  respectively  (also  very  similar  to 
the  average  figure  in  another  relatively  primitive  mammal,  Homo  sapiens). 
These  results  from  pnmitive  mammals  lead  us  to  suspect  that  variations 
in  patterns  of  mammalian  sleep  have  less  to  do  with  broad  phylogenetic 
relationships  than  with  specialized  evolutionary  adaptations,  a  point  of 
view  elaborated  In  an  "ecological -adaptive"  hypothesis  of  sleep  function 
in  a  recent  publication  (Evolutionary  Theories  of  Sleep:  What,  Which, 
and  Whither?). 

From  the  foregoing  perspective  it  is  now  of  interest  to  explore  the  sleep 
characteristics  of  some  of  the  more  highly  specialized  end  products  of 
mammalian  evolution,  where  sleep  patterns  could  be  expected  to  be  most 
diverse  in  ways  related  to  the  overall  life  adaptations  of  different 
forms.  To  that  end,  during  the  past  year  we  have  begun  telemetric  studies 
of  sleep  in  ungulates  at  the  Poolesville  animal  facility,  starting  with 
the  domestic  goat.  The  goat  is  exclusively  a  nocturnal  sleeper,  but  in 
the  data  collected  so  far  has  averaged  less  than  3  hours  sleep  per 
night,  and  only  9%  of  that  has  been  REM  sleep.  Plans  to  attempt  similar 
studies  of  more  e.xot1c  ungulates  will  be  described. 

C.  Experimental  Modification  of  Sleep  in  Primitive  Mammals 

Effects  of  varying  environmental  conditions  upon  primitive  sleep  patterns 
have  thus  far  been  most  extensively  studies  in  Erinaceus,  and  to  a  lesser 
extent  in  the  other  species  enumerated.  Experimental  manipulations  in  the 
case  of  Erinaceus  has  included;  (1)  introduction  of  a  co-specific  animal 
of  the  opposite  sex  into  the  recording  chamber,  (2)  substitution  of 
continuous  light  or  continuous  darkness  for  the  standard  cycle; 
(3)  total  food  deprivation  for  one  day;  (4)  reduction  in  amount  of  living 
space  from  54  to  8  cubic  feet;  (5)  removal  of  the  log  used  as  a  nesting 
place;  and  Ijo)   successively  lower  temperatures  until  the  point  of 
hibernation.  The  only  experimental  condition  which  clearly  decreased 
the  proportion  of  waking  was  reduction  In  enclosure  size,  a  change  of 
about  9%.  Since  most  animal  sleep  studies  are  done  in  small  enclosures, 
their  estimates  of  total  sleep  may  be  inflated,  a  point  that  should 
become  clearer  when  we  make  similar  measures  of  hedgehog  sleep  in  our 
large,  out-door  enclosure.  Although  we  expected  that  continuous  dark 
might  increase  the  duration  of  waking  in  this  strongly  nocturnal 
animal,  there  was  no  change,  yet  continuous  light  did  result  in  a 
moderate  increase  in  total  sleep.  All  other  variables  described 
resulted  in  Increased  waking,  with  increments  ranging  from  5%  during 
a  day  of  food  deprivation  to  20%  when  ambient  temperature  was  lowered 
to  41  F.  Similar  decreases  In  sleep  to  food  deprivation  and  lower 
ambient  temperatures  were  demonstrated  in  Aplodontia.  Either  increases 
or  decreases  in  total  sleep  of  Erinaceus  in  response  to  these 


182 


Serial  No.  M-CP-18-6,  Page  5 

experimental  conditions  were  accompanied  by  decreased  proportions 
of  the  REM  phases,  most  marked  at  low  temperatures,  when  it  was  cut  in 
half.  The  same  was  true  of  Aplodontia  only  with  respect  to  food 
deprivation. 

The  low  temperature  study  reflects  our  interest  in  the  possible  relation- 
ship between  sleep  and  hibernation.  Specifically,  we  expected  to  find 
increasing  sleep  at  low  temperatures,  finally  giving  way  to  a  smooth 
transition  from  sleep  into  hibernation.  In  the  one  hedgehog  in  which 
hibernation  has  occurred  thus  far,  just  the  opposite  occurred.  Total 
sleep  decreased  progressively  as  ambient  temperature  was  lowered, 
so  that  the  dropping  out  of  cerebral  electrical  activity  signaling 
hibernation  actually  occurred  directly  out  of  waking. 

The  experimental  comparison  of  greatest  interest  has  been  that  between 
animals  living  under  standard  laboratory  conditions  and  those  living 
under  quasi-natural  conditions  in  the  out-door  enclosure.  Technical 
problems  prevented  that  comparison  until  recently,  but  the  first  two 
studies  of  this  nature  have  now  been  completed  in  opossums.  No  very 
striking  differences  in  sleep  patterns  of  those  animals  appeared  in  those 
studies,  except  for  variations  apparently  related  to  intercurrent 
weather  conditions.  On  two  days  when  temperatures  averaged  below  40°F 
waking  was  reduced  to  about  15%,  compared  to  30-40%  in  other  recordings 
from  this  animal.  By  contrast,  several  episodes  of  rain  were  associated 
with  almost  continuous  waking  in  the  same  specimen.  During  the  next 
year  we  shall  be  looking  for  similar  responses  to  naturally  occurring 
events  in  the  zoo  enclosure,  as  well  as  experimentally  manipulating 
that  situation  by  varying  modes  of  feeding,  introducing  co-specific 
animals  of  the  same  or  opposite  sex,  or,  with  proper  safeguards, 
introducing  a  natural  predator  of  the  opossum,  such  as  a  dog  or 
coyote,  to  observe  the  effects  of  a  natural  stress. 

D.  Effects  of  Chronic  Immobilization  Stress  on  Sleep  of  the  Rat 

The  possible  effects  of  chronic  stress  on  sleep  patterns  is  an  issue 
directly  relevant  to  interpretation  of  abnormalities  found  in  the  sleep 
of  psychiatric  patients,  but  one  which  could  not  be  experimentally 
tested  in  human  subjects.  Our  efforts  to  examine  that  question  in  monkeys 
by  means  of  adversive  conditioning  had  to  be  given  up  when  collaborative 
arrangements  with  scientists  at  the  Walter  Reed  Institute  of  Research 
proved  unworkable,  since  we  have  no  suitable  facilities  for  monkey 
studies  in  thts  Laboratory.  We  turned,  therefore,  to  the  use  of  another 
well  standardized  experimental  model  of  stress,  that  resulting  from 
tmmobiltzatton  restraint  in  the  albino  rat.  Recent  studies  here  and 
in  other  NIMH  laboratories  have  demonstrated  marked  and  persistent 
changes  in  rat  behavior  (increased  irritability  and  shock-induced 
fighting)  as  well  as  elevations  of  brain  norepinephrine  levels  and 


183 


Serial  No.  M-CP-18-6,  Page  6 


blood  pressure  after  one  month  of  immobilization  stress  administered 
two  hours  each  day.  The  same  effects  are  still  apparent  15  days  after 
the  stress  period.  Hence s  we  have  set  out  to  determine  whether 
comparable  stress  will  be  reflected  in  the  24-hour  sleep  patterns. 
Since  the  telemetric  technique  appeared  to  have  no  advantages  for  this 
purpose,  recording  is  being  done  by  wire  cables  connected  to  implanted 
electrodes.  After  five  days  baseline  recording,  daily  immobilization 
periods  are  carried  out  for  the  next  30  days,  while  24-hour  sleep 
patterns  are  sampled  three  days  per  week.  Control  animals  not  subjected 
to  the  daily  stress  are  housed  and  recorded  in  the  same  fashion. 

A  pilot  study  by  this  means  in  one  rat  yielded  some  of  the  most 
dramatic  changes  in  sleep  patterns  so  far  observed  after  any  experimental 
manipulations.  Total  sleep  and  REM  were  reduced  from  the  outset  of  the 
stress,  but  after  15  days  REM  sleep  abruptly  disappeared  entirely, 
remaining  absent  for  the  remainder  of  the  stress  period  and  for  at  least 
one  week  afterward.  The  same  procedure  is  now  almost  completed  in 
groups  of  six  stressed  rats  and  six  controls,  with  results  which  appear 
to  be  consistent  but  perhaps  somewhat  less  striking.   This  time 
special  attention  will  be  devoted  to  the  period  of  recovery  from  stress 
to  determine  the  time  course  of  sleep  normalization,  and  whether 
there  is  evidence  of  rebound  compensation  for  the  lost  REM  sleep,  such 
as  we  have  described  in  recovering  depressive-psychotics,  but  have 
failed  to  find  in  recovering  schizophrenics. 

Significance  to  Mental  Health: 

Despite  its  obvious  importance  in  human  life  and  its  particular 
disturbance  in  psychiatric  illness,  the  general  biological  significance 
of  sleep  is  still  entirely  obscure.  The  investigations  described  are 
among  efforts  proceding  all  over  the  world  to  remedy  that  deficiency 
by  careful  phylogenetic  comparison  and  experimental  analysis. 

Proposed  Course  of  Project: 

Work  will  continue  on  all  of  the  fronts  described.  In  addition,  the 
principal  investigator  will  take  advantage  of  a  foreign  work  assignment 
to  attempt  studies  of  sleep  patterns  in  a  number  of  larger  African 
mammals  by  means  of  long-range  telemetry. 

Publications: 

Snyder,  F. :  Evolutionary  theories  of  sleep:  What,  which,  and  whither? 
To  be  published  in  the  Proceedings  of  the  First  International  Congress 
of  the  Association  for  the  Psychophysiological  Study  of  Sleep,  in  press. 

Awards :  None 


18^ 


J 


Serial  No.  M-CP-18-7 

1.  Laboratory  of  Clinical  Psychobiology 

2.  Section  on  Comparative  Studies 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:  Factors  Affecting  Intraspecific  and  Predatory  Aggression 
in  the  rat 

Previous  Serial  Number:  Same 

Principal  Investigator:  Burr  S.  Eichelman,  Jr.,  M.D.,  Ph.D. 

Other  Investigators:  Nguyen  Bich  Thoa,  Ph.D.,  Jorge  Perez-Cruet,  M.D., 
Redford  B.  Williams,  Jr.,  M.D.,  Friedhelm 
Lamprecht,  M.D.  and  Keng-Yong  L.  Ng,  M.D. 

Cooperating  Units:  Office  of  the  Chief.  Laboratory  of  Clinical  Science,  CBRD, 
NIMHj  Section  on  Medicine,  Section  on  Psychiatry  and 


Section  on  Experimental  Therapeutics,  Laboratory  of 
Clinical  Science,  CBRD,  NIMH 


Man  Years  (1971): 


Total : 

1 

.5 

Professional : 

1 

.4 

Other: 

.1 

Project  Description: 

Objectives: 

This  project  is  designed  to  provide  an  overview  of  aggressive  behavior 
in  the  rat,  an  overview  encompassing  strain  characteristics  and  types 
of  aggressive  behavior,  as  well  as  their  pharmacological  and  neuro- 
anatomical  correlates.  The  information  from  these  studies  is  also 
being  contrasted  with  mouse  aggression. 

Methods  Employed: 

The  studies  center  around  three  behavioral  tests:  shock-induced 
aggression,  jump-flinch  thresholds  to  pain,  and  mouse-killing 
behavior.  The  first  two  paradigms  have  already  proved  fruitful  as 
areas  of  research  in  delineating  aggressive  behavior  (Eichelman,  B.: 
J.  Comp.  Physiol.  Psychol.  74:331-339,  1971).  Ancillary  techniques 


185 


.y; 


Serial  No.  M-CP-iS-?,  Page  2 


employed  utilize  cannula  and  intraci sternal  application  of 
pharmacologically  active  drugs,  surgical  excision  or  lesioning, 
monitoring  of  blood  pressure  (rat  tail),  and  monoamine  or  related 
enzyme  measurements. 

Sub-projects: 

(1)  Strain  Variability.  This  is  a  continuation  of  the  comparative 
study  of  rat  strains  in  relation  to  shock-induced  aggression, 
pain  thresholds  and  mouse-killing  behavior.  There  is  a 
significant  variation  in  aggression  as  well  as  in  the  response 
to  footshock.  Osborne-Mendel  rats  (NIH)  demonstrate  a  group 
probability  of  0.5  for  mouse-killing  and  shock-induced  fighting 
contrasted  vn'th  NIH  Wistar  which  do  not  show  mouse-killing, 

but  fight  at  0.5  or  Sprague-Dawley  rats  which  have  a  killing 
probability  of  0.1  and  fight  0.2.  As  suggested  by  Wistar 
strain  studied,  there  is  no  correlation  between  high  fighting 
pairs  in  the  shock-induced  paradigm  and  the  predatory  behavior 
of  mouse-killing  either  within  or  between  strains.  Between 
10  to  20  strains  will  be  reported  on  at  the  termination  of  this 
study.  This  material  will  allow  for  the  appropriate  selection 
of  strains  to  study  in  terms  of  high  or  low  levels  of  irritable 
or  predatory  aggression. 

An  ancillary  project  related  to  an  automated  system  of  measuring 
isolation-induced  aggression  in  mice  has  proved  adequate  for 
short-term  observations,  but  inadequate  for  long-term 
monitoring.  This  project  has  been  terminated. 

(2)  Sensory  Input.  The  role  of  sensory  input  and  its  effect  on 
aggression  and  pain  threshold  has  been  studied  in  collaboration 
with  Miss  Nellie  Bugbee.  Total  olfactory  bulbectoiny  in  the  rat 
induces  mouse-killing  behavior.  This  has  been  validated  in  our 
laboratory,  however,  there  is  no  change  in  intraspecific  shock- 
induced  aggression.  Bulbecton^  does  lower  the  rat's  jump 
threshold  to  electric  shock,  demonstrating  that  an  interruption 
of  one  sensory  input  changes  the  behavior  response  to  another 
sensory  stimulus.  Removal  of  rat  vibrissae  substantially 
decreases  shock-induced  fighting,  while  blinding  and  decreasing 
hearing  produces  no  change  in  shock-induced  or  predatory 
aggression.  This  study  has  been  completed  and  will  be  published 
in  June,  1972.  However,  the  removal  of  vibrissae,  does  not 
effect  isolation-induced  aggression  in  mice,  as  shown  by  a  study 
done  in  collaboration  with  Dr.  B.  Slotnick  of  the  Laboratory  of 
Brain,  Evolution  and  Behavior,  NIMH. 


186 


Serial  No.  M-CP-18-7,  Page  3 


(3)  Experimental  Manipulation.  Hunger,  thirst,  and  prolonged 
swimming  do  not  alter  shock-induced  fighting  of  Sprague- 
Dawley  rats.  Conversely,  sleep  deprivation  or  chronic 
immobilization  increased  shock-induced  aggression.  The 
increased  aggression  seen  after  immobilization  is  correlated 
with  an  elevation  of  hypothalamic  norepinephrine  and  tyrosine 
hydroxylase,  but  not  serum  dopamine  B-hydroxylase. 

(4)  Pharmacological  Manipulations.  Catecholamine  levels,  turnover 
rates,  and  destruction  of  nerve  terminals  have  been  studied 

in  relation  to  irritable  aggression.  Both  6-hydroxydopamine 
(which  depletes  both  dopamine  and  norepinephrine  and  damages 
both  amines'  nerve  terminals)  and  6-hydroxydopa  (which  effects 
only  norepinephrine  metabolism  in  the  dose  used)  produce  an 
increase  in  shock-induced  aggression  which  persisted  up  to 
six  months.  This  effect  appears  specifically  related  to 
norepinephrine,  since  6-hydroxydopa  which  effects  only  norepine- 
phrine has  the  same  effect.  The  time  course  of  this  facilitation 
of  aggression  is  delayed  by  two-three  days  after  amine  depletion. 
This,  plus  the  fact  that  AMPT  (alpha-methyl -para-tyrosine)  and 
disulfiram  —  which  also  deplete  brain  norepinephrine,  but  do  not 
damage  terminals  —  do  not  alter  shock-induced  aggression, 
suggests  that  the  increase  in  aggression  may  be  related  to 
receptor  supersensitivity  rather  than  amine  depletion  per  se. 
Chronic  use  of  cations  such  as  rubidium  and  even  potassium  also 
increase  shock-induced  fighting  while  lithium  decreases  the 
attack  rate  and  cesium  or  sodium  do  not  change  it.  These 
results  are  now  being  studied  in  relation  to  effects  of  amine 
turnover  in  brain.  It  appears  that  an  increase  in  norepinephrine 
turnover  rate  is  associated  with  an  increase  in  shock-induced 
aggression. 

In  contradistinction,  spontaneous  aggression  in  the  rat  appears 
related  to  dopamine  metabolism  rather  than  to  norepinephrine, 
since  it  is  facilitated  by  apomorphine  and  also  by  dopa  plus 
a  peripheral  decarboxylase  inhibitor,  particularly  after 
6-hydroxydopamine  pretreatment.  This  facilitation  occurs  even 
in  the  presence  of  a  dopamine  B-hydroxylase  inhibitor  which 
prevents  the  synthesis  of  new  norepinephrine. 

These  pharmacological  studies  have  generated  a  unitary  theory 
on  irritable  aggression  in  the  rat  discussed  in  "Aggressive 
Monoamines,"  Biological  Psychiatry,  in  press. 


18t 


Serial  No,  M-.CP-18-7,  Page  4 


(5)  Hypertension.  Strain  differences  in  blood  pressure  and  aggression 
have  been  studied  in  the  rat.  These  parameters  appear  to  vary 
independently.  However,  brain  norepinephrine  metabolism 
differences  have  been  observed  in  the  Sprague-Dawley  deprived 
rats  of  the  Brookhaven  "sensitive"  and  "resistant"  strains 
developed  by  Dr.  L.K.  Dahl .  These  strains  differ  in  levels  of 
aggression  and  also  in  their  susceptibility  toward  hypertension. 
Their  catecholamine  metabolism  will  be  studied  in  greater  detail 
during  the  remainder  of  this  year. 

The  blood  pressure  changes  following  foot-shock  to  rats  alone 
or  in  pairs  noted  in  last  year's  report  has  been  shown  to  vary 
with  rat  strain.  Further,  the  decrease  in  tail  blood  pressure 
appears  related  to  peripheral  and  central  sympathetic  activity, 
while  the  increase  in  blood  pressure  seen  in  rats  shocked  alone 
appears  related  to  adrenal  function.  These  conclusions  were 
reached  by  studying  rats  treated  with  peripherally  or  centrally 
administered  6-hydroxydopamine  (to  deplete  norepinephrine  or 
dopamine)  and  with  adrenalectomy. 

The  cannula  study  for  examining  the  central  dopa-induced 
hypotensor  response  will  be  completed  during  the  remainder  of 
the  year. 

Significance  to  Bio-medical  Research  and  the  Program  of  the  Institute 

Aggression  in  the  rat  must  be  divided  into  at  least  three  categories: 
irritable  aggression,  spontaneous  aggression  and  predatory 
aggression.  Irritable  aggression  appears  to  develop  upon  central 
stimulation  of  norepinephrine  receptors.  Spontaneous  aggression 
appears  to  develop  upon  stimulation  of  central  dopamine  receptors. 
Predatory  aggression  appears  more  related  to  serotonin  and 
cholinergic  brain  metabolism.  Hypertension  and  irritable  aggression 
appear  only  randomly  related  in  the  rat,  but  both  may  show  correlations 
with  central  catecholamine  metabolism.  External  factors  such  as 
stress  may  chronically  alter  aggressive  behavior  and  brain  catechol- 
amine metabolism.  Expanding  knowledge  of  the  biology  of  aggression 
in  the  rat  offer  provocative  leads  for  future  studies  of  primate  and 
human  aggression. 

Proposed  Course  of  Project: 

Completion  of  the  above  studies. 


Serial  No.  M-CP-18-7,  Page  5 

Publications: 

Eichelraan,  B.,  Thoa,  N.B.  and  Ng,  K.Y.:  Facilitated  aggression 
in  the  rat  following  6-liydroxydopamine  administration. 
Physiol ofly  and  Behavior  8:   1-3,  1972. 

Eichelman,  B.  and  Thoa,  N.B.:  Aggressive  monoamines. 
Biological  Psychiatr^^,  in  press,  1972. 

Bugbee,  N.M.  and  Eichelman,  B.:  Sensory  alterations  and  aggressive 
behavior  in  the  rat.  Physiology  and  Behavior,  June  1972,  in  press. 

Thoa,  N.B.,  Eichelman,  B.  and  Ng,  K.Y.:  Effect  of  6-hydroxydopamine 
and  other  drugs  on  shock-induced  aggression  in  the  rat. 
Brain  Research,  in  press. 

Thoa,  N.B.,  Eichelman,  B.  and  Ng,  K.Y.:  Aggression  in  rats  treated 
with  dopa  and  6-hydroxydopam1ne.  Journal  of  Pharmacy  and  Pharmacology 
24:   337-338,  1972. 

Williams,  R.B.  and  Eichelman,  B.:  Social  setting:  Influence  on  the 
physiological  response  to  electric  shock  in  the  rat.  Science 
174:   613-614,  1971. 

Awards : 

A.E.  Bennett  Research  Award  in  Basic  Science,  1972,  from  the  Society 
of  Biological  Psychiatry. 


189 


t 


Serial  No.  M-CS-OC(C) -04 

1.  Laboratory  of  Clinical  Science 

2.  Office  of  the  Chief 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIH 

Individual  Project   Report 

July   1,    1971  through   June  30,    1972 

Project   title:      Studies   of   the   interrelationships   of   the   nervous 
and  circulatory  systems. 

Previous   Serial  Number:      Same 

Principal   Investigator:      Philippe  V.    Cardon 

Other   Investigators:        James  L.   Weiss,    Raymond    J.    Matta ,   Thomas 

N.   Chase,   G.    Frederick  Wooten,   Friedhelm 
Lamprecht,    Griff  T.    Ross,   August  Watanabe, 
Jorge  Perez-Cruet, 

Cooperating  Units:      Sections   on  Pharmacology,    Experimental 

Therapeutics,    Psychiatry,    and  Medicine,   LCS ; 
Reproduction  Research  Branch,    NICHHD; 
Department   of  Medicine,  University   of   Indiana. 

Man  Years:      Total  2,5 

Professional     2.5 
Other  None 

Project  Description: 

Objectives :      To  study   the   interaction  of   the   nervous   and 
circulatory  systems   and   the  effects   of   drugs   on  those  systems. 

Methods  Employed ;    Standard   non-traumatic   techniques   for 
assessing  well-known  circulatory   parameters    in  man.      Direct 
measurement   of   analogous   parameters    in  animals.      Electrical   re- 
cording of   peripheral  sympathetic   nerve  activity    in  animals. 
Enzymatic   assay   of   blood.      Radio-immune   assay   of    pituitary 
trophic   hormones    in  blood.      Standard   tests   of   renal   function. 

Major  Findings:    (1)    Effects   of   anti-parkinsonism  drugs 
other   than  direct  CNS   effects.      Three  clinical   studies,    each 
involving   5-10   patients  will   be  completed   by   the  end   of   the 
year,    but   data   analysis   has   not   been  completed,    because  the   pace 
of   acquiring  sufficient   data    is    limited   by   the   rate   at  which 
patients   receive  these  agents   for   therapeutic   reasons.      The 
studies   are:      (a)    Effects   of  L-dopa   on  plasma   renin  and 
aldosterone,       (b)    Effects   of  L-dopa   on  gonadotrophic   hormones, 


191 


Serial  No.    M-CS-OC (C) -04 

TSH .    and   growth   hormone,       (c)    Effects    of    0-methyl-Dopa    on  blood 
pressure   and    postural   circulatory   adjustments. 

In  three    patients   receiving   the   dopaminergic-stimulating 
drug   apomorphine,    the   following   rapidly   reversed    renal   ab- 
normalities   occurred:      50%   reduction   in  glomerular   filtration 
rate,    decreased   PSP   excretion,    and   azotemia,    without   albuminuria 
or   abnormal   sediment.      Further   studies    of    this   effect    in  monkeys 
have   begun. 

(2)    Factors    influencing  serum  dopamine-beta-hydroxylase 
activity    (DBH) ,       In  man  DBH  activity    increases   during   exercise, 
cold-pressor   stress,    and    in  response   to  the   presumed    psychic 
stress    of    being  studied    for   the   first    time.       In  animals    it    in- 
creases  during  hemorrhage,      Fusaric   acid,    known  to   inhibit  DBH 
activity    in  animals,    also    inhibits   DBH  activity    in  man. 

Significance   to  Biomedical  Research  and   the  Program  of   the 
Institute :      A   thorough   understanding   of   the   effects    of   anti- 
park  ins  oliism  drugs    is   essential   for   their   rational   use.      The 
studies    of  DBH  contribute   to   our   understanding   of   the   extent 
to  which   changes    in  serum  DHB   activity   are   an   index   of   changes 
in  sympathetic   nerve  activity. 

Proposed   course   of    project :    Further  studies   of   similar 
nature. 

Honors   and  Awards :      None 

Publications : 


Weiss,    J.L. ,    L.K.Y.    Ng ,    T.N.  Chase:      Long-lasting  dyskinesia 

induced    by    levodopa.      Lancet  1:1016,    1971. 

Weiss,  J.L.,  C.K.  Cohn,  T.N.  Chase:  Reduction  of  catechol-0- 
methyltransf erase  activity  by  chronic  L-dopa  therapy.  Nature 
234:218,    1971. 

Weiss,    J.L.    and   T.N.    Chase:  Levo-dopa    in   parkinsonism. 
Drugs   2:257,    1971. 


J 


Lemberger ,  L. ,  J.L.  Weiss,  A.M.  Watanabe,  I,M,  Galanter,  R.J, 
Wyatt ,  P.V.  Cardon:   Delta-9-tetrahydrocannabinol :   Temporal 
correlation  of  the  psychological  effects  and  blood  levels  after 
various  routes  of  administration.   New  Engl.  J.  Med.  286:685, 
1972, 


192 


Serial  No.  M-CS-0C(C)-16 

1.  Laboratory  of  Clinical  Science 

2.  Office  of  the  Chief 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:  Studies  of  pinched-off  nerve  endings  (synaptosomes)  as  a  model 
system  for  investigating  the  transport,  binding  and  metabolism  of 
monoami  nes . 

Previous  Serial  NunAer:  Same 

Principal  Investigator:  Robert  W.  Col  burn 

Other  Investigators:  L.  Keng-Yong  Ng  (Guest  Worker),  K.S.  Rajan  and  Irwin  J. 
Kopin 

Cooperating  Units:  Section  on  Experimental  Therapeutics,  LCS  and  Illinois 
Institute  of  Technology  Research  Institute  (Chicago) 

Man  Years:  Total  1.0 
Professional  1.0 
Other       None 

Project  Description: 

Obgectives:     Synaptosomes  isolated  from  whole  brain  represent  an  in  vitro 
system  similar  in  many  respects  to  that  present  In  living  organisms.  THIrrent 
basic  problems  being  investigated  with  this  system  are:  (1)  How  do  neurotrans- 
mitters pass  through  mentranes?  (2)  How  are  they  bound  within  vesicles? 
(3)  What  is  the  mechanism  for  their  release?  A  concurrent  study  involves 
investigation  of  the  effects  of  psychotomimetic  drugs  on  the  above  parameters 
for  neurotransmitter  substances. 

Methods  Employed:     Drugs  used  for  treatment  of  depression  or  mania  such  as 
desmethylimipramine,  lithium  or  narcotics  are  added  to  the  synaptosome  system. 
The  uptake,  binding  and  release  of  a  variety  of  neurotransmitter  substances  are 
measured;  alternatively,  drugs  are  given  in  vivo  prior  to  isolation  of  the 
synaptosomes.  The  chelation  chemistry  of  neurotransmitters  as  a  possible 
mechanism  for  binding  and  release  in  synaptosomes  is  studied. 

Major  Findings:     The  synaptosomes  take  up,  bind  and  release  monoamines 
such  as  norepinephrine  and  serotonin  much  as  they  function  in  in  vivo  or  in 
perfusion  experiments.  As  in  the  peripheral  sympathetic  nervous  system,  the 
route  of  norepinephrine  metabolism  varies  with  the  mode  of  its  release.  Uptake 
studies  with  neurotransmitters  are  of  importance  since  reuptake  is  a  major  means 
for  termination.  Recent  findings  with  the  in  vitro  synaptosome  system  provide 


193 


Serial  No.  M-CS-0C(C)-16,  Page  2 

evidence  that  dopamine  administration  at  high  doses  displaces  endogenous 
serotonin  from  its  storage  sites. 

Signifioanae  to  Biomedical  Research  and  the  Progrcan  of  the  Institute:     The 
drugs  altering  monoamine  function  have  proved  very  useful  in  modifying  mood. 
The  present  studies  provide  information  on  a  molecular  basis  concerning  drug 
action. 

Proposed  Course  of  Pros  eat:     With  the  above  system,  large  numbers  of  very 
similar  samples  can  be  prepared  and  will   be  used  in  comparing  a  wide  variety  of 
drugs  using  kinetic  methods  to  determine  active  mechanisms.     Synaptosomes  will 
be  further  fractionated  to  isolate  carrier  or  receptor  proteins. 

Honors  and  Awards:  Dr.  Ng  was  a  recipient  of  the  A.E.  Bennett  Award  for  basic 
research  of  the  effects  of  L-dopa  on  disposition  of  cerebral  monoamines  in  rat 
brain  homogenates. 

Publications: 

Colburn,  R.W.  and  Kopin,  I.J.:     Effects  of  reserpine  and  tyramine  on  release  of 
norepinephrine  from  synaptosomes.     Bioohem.  Phamaool.   21:  733-736,  1972. 

Ng,  L.K.Y.,  Colburn,  R.W.  and  Kopin,  I. J.:  Effects  of  L-dopa  on  uptake  and 
release  of  monoamines  and  amino  acids  by  synaptosomes  in  homogenates  of  rat 
brain.     J.   Pharmacol.   Exp.   Ther.,   in  press. 


ISk 


Serial  No.  M-CS-0C(C)-19 

1.  Laboratory  of  Clinical  Science 

2.  Office  of  the  Chief 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:  Metabolism,  distribution  and  biochemical  effects  of 
psychoactive  drugs 

Previous  Serial  Number:  Same 

Principal  Investigator:  Irwin  J.  Kopin  and  Julius  Axelrod 

Other  Investigators:  L.  Keng-Yong  Ng  (Guest  Worker),  Robert  W.  Colburn  and 
David  S.  Kreuz 

Cooperating  Units:  Sections  on  Pharmacology,  Experimental  Therapeutics  and 
Medicine,  LCS 

Man  Years:  Total  1.5 
Professional  1.1 
Other       0.4 

Project  Description: 

Methods  Employed:     (1)  Drugs  are  administered;  and  using  radioactivity  or 
chemical  methods,  the  levels  in  blood,  urine  and  feces  are  determined.  (2)  The 
alterations  in  amine  metabolism  are  assessed  by  examining  the  tissues  of  animals 
or  the  blood,  cerebrospinal  fluid  and  urine  of  man.  (3)  The  modification  of 
effects  of  one  drug  by  another  is  examined  in  animals. 

Major  Findings:     Tetrahydrocannabinol  persists  for  several  days  in  the 
blood  of  persons  receiving  the  drug.  Blood  levels  of  the  drug  and  its 
metabolites,  which  are  rapidly  formed,  correlate  well  with  the  euphoric  effects. 
Chronic  marihuana  smokers  metabolize  tetrahydrocannabinol  more  rapidly  than 
others,  and  formation  of  11 -hydroxy- tetrahydrocannabinol  may  mediate  the  effects 
of  the  drug. 

Signifioanae  to  Biomedical  Research  and  the  Frogram  of  the  Institute:     The 
problem  of  drug  usage  is  currently  a  major  concern.  The  studies  will  help  to 
elucidate  the  mechanisms  of  action  of  drugs  which  are  abused,  to  indicate  their 
possibly  toxic  effects  and  to  suggest  means  for  treatment  of  patients  suffering 
from  toxic  effects  of  the  drugs. 

Proposed  Course  of  Project:     Identification  of  metabolites,  estimation  of 
drug  effects  on  amine  metabolism  and  enzymes  concerned  with  amine  synthesis  and 
with  degradation  and  examination  of  drug  interactions  will  continue. 


195 


Serial  No.  M-CS-0C(C)-19,  Page  2 

Honors  and  Awards:     None 

Publications: 

DaviSj  J.M. ,  Kopin,  I.J.,  Lemberger,  L.  and  Axelrod,  J.:     Effects  of  urinary  pH 
on  amphetamine  metabolism.     Ann.  N.Y.  Acad.  Sai.   179:  493-501,  1971. 

Lemberger,  L.,  Axelrod,  J.  and  Kopin,  I.J.:     Metabolism  and  disposition  of 
delta-9-tetrahydrocannabinol   in  man.     Pharmacol.  Rev.   23:  371-380,  1971. 

Lemberger,  L.,  Axelrod,  J.  and  Kopin,  I.J.:     Metabolism  and  disposition  of 
tetrahydrocannabinols  in  naive  subjects  and  chronic  marijuana  users.     Ann.  N.Y. 
Acad.   Sai.    191:   142-154,   1971. 


I 


Lemberger,  L.,  Tamarkin,  N.R.,  Axelrod,  J.  and  Kopin,  I.J.:     Delta-9- 
tetrahydrocannabinol :     Metabolism  and  disposition  in  long-term  marihuana  smokers. 
Science  173:   72-74,  1971. 

Lemberger,  L.,  Weiss,  J.L.,  Watanabe,  A.M.,  Galanter,  I.M.,  Wyatt,  R.J.  and 
Cardon,  P.V.:     Delta-9-tetrahydrocannabinol :     Correlation  of  the  psychological 
effects  and  blood  levels  after  various  routes  of  administration.    Neu  Eng.  J. 
Med. J   in  press. 


196 


Serial  No.  M-CS-0C(C)-20 

1.  Laboratory  of  Clinical  Science 

2.  Office  of  the  Chief 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:     Histochemical  studies  of  biogenic  amines 

Previous  Serial  Number:     None 

Principal   Investigator:     David  M.  Jacobowitz 

Other  Investigators:     Andrew  K.S.  Ho  (Guest  Worker),  Paul  D.  Maclean, 

J.  Stephen  Richardson  (Guest  Worker)  and  Hiroshi  Watanabe.  |. 

Cooperating  Units:     Laboratory  of  Brain  Evolution  and  Behavior,  NIMH  1 1 

Man  Years:    Total  1.50  "I 

Professional     0.75  ,,, 

Other  0.75  H 

II' 
Project  Description:  '^*' 

Objectives :    To  localize,  at  a  cellular  level  by  use  of  histological 
techniques,  neurotransmitters  and  the  enzymes  and  receptors  concerned  with  their 
formation,  action  and  metabolism.    The  effects  of  drugs,  hormones  and  environ- 
mental changes  are  being  studied  using  tissues  from  animals  or  from  in  vitro 
organ  and  tissue  cultures.     The  techniques  allow  precise  localization  o? 
biochemical  changes  and  permit  study  of  interaction  of  different  neuro- 
transmitter systems  (e.g.,  adrenergic-cholinergic  interrelationships)  as  well 
as  correlations  with  behavioral  parameters. 

Methods  Employed:     (1)  The  morphological  procedure  involves  the  use  of  a 
highly  specific  fluorescence  histochemical  method  for  the  demonstration  of 
catecholamines  (norepinephrine,  epinephrine,  dopamine)  and  indoleamines 
(serotonin)  within  monoaminergic  nerves  and  cells.     (2)  Biochemical  assays  for 
norepinephrine,  dopamine  and  serotonin  are  available.     (3)  Enzymes  concerned 
with  biogenic  amine  synthesis  (tyrosine  hydroxylase,  dopamine-beta-hydroxylase, 
phenyl ethanol ami ne-N-methyl  transferase)  and  acetylcholine  synthesis  (choline 
acetyl  transferase)  and  degradation  (acetylcholinesterase)  are  assayed  in  the 
brain.     (4)  Behavioral  parameters  such  as  water  and  food  consumption, 
spontaneous  motor  activity,  rectal  temperature  and  aggressive  behavior  are 
measured. 

Major  Findings:     (1)  6-Hydroxydopa  stereotaxically  placed  in  the  rat 
lateral  ventricles  produces  a  graded  dose-dependent  decrease  in  spontaneous 
motor  activity,  water  and  food  consumption  and  norepinephrine  in  the  brain. 
Fluorescent  microscopy  of  brain  sections  shows  an  increase  of  fluorescence  in 

197 


Serial  No.  M-CS-0C(C)-20,  Page  2 

the  preterminal  nerve  trunks  in  noradrenergic  axons.  The  return  of  normal 
appetitive  and  locomotion  behaviors  despite  reduced  levels  of  norepinephrine 
suggests  that  other  unknown  factors  such  as  supersensitivity  are  Involved  in 
the  recovery  of  the  behaviors.  Two  to  three  days  after  injection  of  6-hydroxy- 
dopa,  there  appears  to  be  an  increase  in  the  tyrosine  hydroxylase  activity  and 
a  decrease  in  the  dopamine-beta-hydro)?ylase  activity  in  the  striatum. 

Histochemical  observations  reveal  a  system  of  monoaminergic  cell  bodies  in  the 
region  of  the  depleted  terminals  of  the  nucleus  dorsomedialis,  directly  below 
the  fasciculus  mamillothalamions. 

6-Hydroxydopa  injected  intraventricularly  causes  a  marked  and  persistent 
increase  in  the  number  of  attacks  occurring  during  shock-induced  fighting  in 
rats.  The  increase  in  attack  frequency  appears  to  be  correlated  with 
6-hydroxydopa ' s  effect  of  reducing  brain  norepinephrine  and  with  degeneration 
of  norepinephrine  terminals. 

(2)  On  the  basis  of  our  demonstration  that  reinnervation  occurs  in  denervated 
rat  irises  by  the  superior  cervical  ganglion  cultured  in  vitro,  we  now  have 
shown  that  cross  innervation  occurs  between  ganglia  and  irises  of  different 
species.  The  mouse  ganglion  is  capable  of  growing  nerves  onto  the  rat  and 
guinea  pig  iris;  the  rat  ganglion  reinnervates  the  guinea  pig  and  mouse  irises, 
thus  providing  the  first  demonstration  of  cross-species  reinnervation  in  vitro. 

Drugs  added  to  the  ganglion-iris  preparation  have  been  shown  to  influence  the 
nerve  terminals.  6~Hydroxydopami ne  appears  to  deplete,  and  probably  destroy, 
adrenergic  nerves  grown  in  organ  culture.  Cytochalasin  B  appears  to  disrupt 
and  reduce  the  number  of  adrenergic  nerves  in  the  iris  in  vitro. 

(3)  Histochemical  observation  of  the  rat  superior  cervical  ganglion  at  various 
time  intervals  after  application  of  vinblastine  to  the  ganglion  shows  that 
there  is  an  initial  marked  increase  in  the  catecholamine  fluorescence  in  the 
nonterminal  axons  within  the  ganglion  for  up  to  four  days;  thereafter,  the  axons 
are  normal.  The  adrenergic  terminals  within  the  ganglion  initially  are 
diminished  (24  hours)  but  are  subsequently  (four  to  14  days  after  treatment) 
markedly  increased  in  number.  The  noradrenergic  terminal  plexus  in  the  iris  is 
entirely  absent  between  one  and  40  days  after  vinblastine  application.  The 
occurrence  of  norepinephrine  uptake  into  the  nerves,  however,  demonstrates  the 
presence  of  the  nerve  fibers  and  suggests  that  "naked"  adrenergic  nerves  are 
present  without  all  the  synthetic  machinery  required  for  norepinephrine 
synthesis  and  storage. 

(4)  A  possible  localization  of  tryptamine  in  the  brain  was  investigated  by 
administration  of  tryptophan  in  the  presence  of  iproniazid  and  para- 
chlorophenyl alanine  to  rats.  No  unusual  localization  of  monoamine  fluorescence 
was  noted  in  catecholamine  or  serotonergic  nerves;  however,  green  fluorescence 
was  noted  in  the  capillary  endothelium  and  was  prevented  by  the  decarboxylase 
inhibitor  MK-486.  It  appears  that  tryptophan  is  capable  of  being  decarboxylated 
in  the  endothelium  of  the  brain  capillaries  to  form  tryptamine. 


Serial  No.  M-CS-0C(C)-20,  Page  3 

(5)  Newborn  rats  treated  with  dexamethasone  daily  for  one  week  show  a  marked 
increase  in  the  number  of  catechol  ami ne-containing  chromaffin  cells  in  the 
superior  cervical  ganglion.     The  increase  is  correlated  with  a  marked  increase 
in  the  phenyl ethanol ami ne-N-methyl  transferase  level  within  the  ganglion. 
Continued  treatment  for  12  days  appears  to  maintain  the  increased  numbers  of 
chromaffin  cells  within  the  ganglion  although  the  phenyl  ethanol ami ne-N-methyl 
transferase  activity  at  this  time  is  markedly  reduced.    Therefore,  enzyme 
induction  is  not  maintained  along  with  new  cell  formation.    After  one  month, 
the  catecholamines  in  the  new  cells  disappear. 

(6)  A  method  was  developed  whereby  small  cell -body  regions  of  the  brain  could 
be  taken  and  smeared  on  slides  and  visualized  the  same  day  without  freeze- 
drying  procedures.     The  procedure  will  enable  pin-point  localization  of 
monoaminergic  cell  bodies  (e.g.,  locus  coeruleus)  for  future  studies  in  cell 
culture  or  biochemical  analyses, 

(7)  Explants  of  substantia  nigra  grown  in  tissue  culture  have  been  shown  to 
survive  for  three  to  seven  days.     Histochemical  and  biochemical  studies  using 
uptake  of  dopamine-H'  indicate  viable  cell  bodies  and  varicose  terminals 
emanating  from  the  dopami ne-containing  cells. 

(8)  Studies  with  Gunn  rats,  a  genetically  abnormal  strain  of  rat  with  a 
parkinson-like  syndrome,  showed  by  fluorescence  microscopy  that  there  is  a  red 
fluorescent  substance  within  the  myelin  of  most  of  the  large  nerve  trunks  within 
the  brain  and  suggests  a  possible  porphyri n-1 i ke  substance  accumulating  in  the 
brain.     In  addition,  a  degenerative  pigment  cell  accumulation  is  observed  in  the 
cerebellum.     Furthermore,  many  noradrenergic-nerve  containing  regions  of  the 
brain  appear  to  contain  a  reduced  content  of  the  amine. 

(9)  Studies  of  the  adrenergic  innervation  within  the  autotranspl anted  hearts  of 
dogs  indicate  that  a  complete  adrenergi c-nerve  denervation  is  initially  obtained 
with  the  procedure.     Hearts  of  dogs  maintained  for  two  years  after  auto- 
transplantation  showed  a  moderate  reinnervation  of  nerves,  mainly  in  the  left 
atrium  and  ventricle  with  fewer  nerves  in  the  right  chambers;  transplanted 
hearts  and  other  organs  may  become  reinnervated  by  adrenergic  nerves. 

(10)  The  caudate  and  putamen  of  squirrel  monkeys  were  unilaterally  implanted 
with  6-hydroxydopamine  crystals  in  an  attempt  to  destroy  the  dopamine  terminals 
within  the  neostriatum;  gross  motor  deficits  were  noted.     The  brain  is  currently 
being  studied  for  the  extent  of  dopami nergi c-nerve  destruction.     It  appears  that 
most  of  the  caudate  and  about  one-half  of  the  putamen  contents  of  dopamine  were 
lost.     The  preterminal  dopamine  tracts  are  visualized  and  are  currently  being 
mapped. 

Signifioanoe  to  Biomedical  Reseopoh  and  the  Program  of  the  Institute:     Our 
Studies  attempt  to  elucidate  the  functions  of  catechol-  and  other  amines  in  the 
brain  and  periphery  in  normal  and  pathological  clinical  states.     Precise 
localization  of  biochemical  processes  is  a  major  advance  in  furthering  our 
understanding  of  the  role  of  particular  areas  of  brain  in  control  of  behavior 


199 


Serial  No.  M-CS-0C(C)-20,  Page  4 

and  movement  disorders  and  in  identifying  the  site  of  drug  action. 

Proposed  Course  of  Project:     Detailed  mappings  of  the  brain  catecholamine 
and  serotonergic  nerves  of  the  rat  brain  are  currently  being  done  for  future 
studies  using  drugs  and  lesions  in  order  to  reveal  specific  functions  of  the 
monoamines  at  various  sites  within  the  brain.  A  similar  mapping  of  the 
cholinergic  nerves  of  the  brain  will  also  be  undertaken. 

Honors  and  Awards:  None 

Publications:  None 


200 


Serial  No.  M-CS-M(C)-08 

1.  Laboratory  of  Clinical  Science 

2.  Section  on  Medicine 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:  Formation,  release,  disposition  and  metabolism  of  biogenic 
amines 

Previous  Serial  No.:  Same 

Principal  Investigator:  Irwin  J.  Kopin 

Other  Investigators:  Philippe  V.  Cardon,  Robert  W.  Col  burn,  Andr§  Dubois 
(Guest  Worker),  Michael  H.  Ebert,  Ingeborg  Hanbauer,  David  P.  Henry, 
Tomislav  KaziC  (Guest  Worker),  Friedhelm  Lamprecht,  Gertrude  D.  Maengwyn- 
Davies  (Guest  Worker),  L.  Keng-Yong  Ng  (Guest  Worker),  Stephen  D. 
Silberstein,  Ngueyn  B.  Thoa,  James  A,  Thomas  and  Virginia  K.  Weise. 

Cooperating  Units:  Section  on  Experimental  Therapeutics,  LCS  and  Units  on 
Psychosomatlcs  and  Analytical  Biochemistry  (Office  of  the  Chief),  LCS 

Man  Years:  Total  7.5 
Professional  6.0 
Other       1.5 

Project  Description: 

objectives:     (1)  To  determine  the  mechanisms  which  control  development 
and  plasticity  of  the  nervous  system.  (2)  To  study  the  molecular  basis  for 
control  of  synthesis,  storage,  release,  action  and  inactivation  of  aminergic 
transmitters.  (3)  To  quantify  metabolic  rates  for  neurotransmitters  and 
correlate  them  with  function,  drug  effects  and  environmental  influences. 

Methods  Employed:     Radioactive  amines  or  their  precursors  are  injected 
into  animals,  perfused  through  tissues  or  exposed  to  tissue  slices  in  vitrei 
and  the  metabolism  and  disposition  of  the  compounds  are  examined.  Enzymes 
concerned  with  synthesis  or  metabolism  are  assayed  in  various  tissues;  and  the 
effects  of  drugs,  procedures,  age,  etc.  are  determined. 

Major  Findings:    The  elevation  of  adrenal  medullary  enzymes,  which 
results  from  repeated  exposure  to  stress,  is  associated  with  an  enhanced  rate 
of  epinephrine  biosynthesis.  The  enzyme  levels  appear  to  be  controlled  by 
neuronal  and  hormonal  influences  which  involve  cyclic-AMP.  Immobilization 
stress  results  in  elevation  of  endogenous  norepinephrine  and  increased  fighting 
behavior.  Shock-induced  aggression  is  enhanced  by  destruction  by  6-hydroxy- 
dopamine  of  catechol aminergic  neurons  in  the  brain.  This  effect  is  reversed 
by  drugs  which  result  in  activation  of  the  dopaminergic  receptor. 


201 


Serial  No.  M-CS-M(C)-08,  Page  2 

Stimulation  of  sympathetic  nerves  results  in  release  of  dopamine-beta- 
hydroxylase  as  well  as  norepinephrine;  and  the  enzyme  can  be  used  to  study  the 
process  of  exocytcsis,  which  mediates  release  of  the  neurotransmitter.  In  the 
guinea  pig  vas  deferens  the  process  of  transmitter  and  enzyme  release  is 
enhanced  by  calcium  ions  and  phenoxybenzamine;  but  the  enhanced  release  is 
reversed  by  prostaglandin,  possibly  by  its  action  on  calcium  ions.  Stimulation- 
induced  release  of  neurotransmitters  appears  to  be  blocked  by  colchicine  or 
vinblastine,  drugs  which  interfere  with  the  integrity  of  the  neurotubular 
proteins.  Stimulation  of  the  hypogastric  nerves  results  in  accelerated 
synthesis  of  norepinephrine  in  the  vas  deferens  with  selective  release  of  the 
newly  formed  transmitter. 

Colchicine  and  vinblastine,  by  interacting  with  neurotubulin,  block  rapid 
axonal  transport.  These  drugs,  when  applied  to  the  superior  cervical  ganglion 
of  rats,  cause  elevation  in  levels  of  catecholamines  and  of  dopamine-beta- 
hydroxylase.  After  the  initial  increase  in  levels  of  the  enzyme,  the  amount 
of  dopamine-beta-hydroxylase  present  diminishes.  Postganglionic  section  or 
treatment  with  6-hydroxydopamine,  which  destroys  sympathetic  nerve  endings, 
results  in  a  similar  decline  in  dopamine-beta-hydroxylase  activity  with  a 
similar  decline  in  levels  of  tyrosine  hydroxylase.  Uptake  of  norepinephrine 
by  the  ganglia  in  vitro,   however,  increases  at  the  time  that  dopamine-beta- 
hydroxylase  and  tyrosine  hydroxylase  fall.  These  observations  suggest  that  as 
a  result  of  axonal  injury,  there  has  been  a  switch  in  metabolism  In  the  ganglia 
which  results  in  decreased  enzyme  production  and  enhanced  formation  of 
structural  components. 

Siqnifiaanoe  to  Biomedical  Researah  and  the  Program  of  the  Institute: 
Catecholamines  end  other  amines  play  an  important  role  In  normal  physiology. 
Alterations  In  synthesis,  activation,  Inactivation  or  metabolism  of  these 
substances  may  be  responsible  for  abnormal  clinical  states  or  may  explain  the 
mode  of  action  of  drugs  or  development  of  tolerance  or  addiction  to  drugs. 
Assessment  of  these  various  processes  is  important  in  determining  the  factors 
Influencing  physiology,  pharmacology  and  pathology  in  brain  and  other  organs. 

Proposed  Course  of  Project:     Continued  development  of  methods  to  Study 
control  and  to  quantify  synthesis  rates,  storage,  release  and  metabolic  routes 
of  the  catecholamines  in  isolated  tissues.  Intact  animals  and  man  and  the 
study  of  these  mechanisms  of  neurohumor  inactivation  in  various  clinical  states 
of  autonomic  and  mental  disorders  will  be  pursued.  Assessment  of  the  control 
of  enzymes  concerned  with  transmitter  synthesis  and  their  roles  in  control  of 
neuronal  function  will  be  further  studied. 

Honors  and  Awards:  Dr.  Kopin  presented  Invited  seminars  on  topics  in 
catecholamine  metabolism  and  synthesis  to  the  Department  of  Physiology/Schools 
of  Medicine  and  Dentistry,  Georgetown  University  (Washington)  and  to  the 
Department  of  Pharmacology/ Co liege  of  Medicine,  University  of  Arizona  (Tuscon). 
He  addressed  the  New  York  Heart  Association  Symposium  on  Regulation  of 
Catecholamine  Metabolism  in  the  Sympathetic  Nervous  System  (New  York)  and 
served  as  Discussant  at  the  conference  of  the  Psychobiology  of 


202 


Serial  No.  M-CS-M(C)-08.  Page  3 

Electroconvulsive  Treatment  (Dorado  Beach,  P.R.).     He  was  invited  to 
participate  on  the  Ad  Hoc  Panel  on  Cardiovascular  Metabolic  Effects  of  Space- 
flight at  the  NASA  Manned  Spacecraft  Center  (Houston)  and  to  chair  a  symposium 
on  Brain  Monoamines  and  Control  of  Anterior  Pituitary  Function  at  the  IV 
International  Congress  of  Endocrinology  (Washington).     He  participated  in  the 
Round  Table  Discussion  on  Studies  of  Neurotransmitters  at  the  Synaotic  Level 
(Budapest)  and  in  the  lUPS  Comnission  on  Neurotransmission  (Munich). 

Publications: 

Gewirtz,  G.P.;,  Kvetnansky,  R..  Weise,  V.K.  and  Kopin,  I.J.:     Effects  of  ACTH 
and  dibutyryl  cyclic-AMP  on  catechol  ami ne-synthesi zing  enzymes  in  the  adrenals 
of  hypophysectomized  rats.     Nature  230:  462-463,  1971. 

Johnson,  D.G. ,  Thoa,  N.B.,  Weinshilboum,  R. ,  Axelrod,  J.  and  Kopin,  I.J.: 
Enhanced  release  of  dopamine-beta-hydroxylase  from  symoathetic  nerves  by 
calcium  and  phenoxybenzamine  and  its  reversal  by  prostaglandins.    Proo.  Sat. 
Aoad.  Soi.   68:  2227-2230,  1971. 

Kopin,  I.J.  and  Silberstein,  S.D.:  Axons  of  sympathetic  neurons:  Transport  of 
enzymes  in  vivo  and  properties  of  axonal  sprouts  in  vitro.  Pharmaaol.  Rev.,  in 
press. 

Kvetnansky,  R.,  Gewritz,  G.P.,  Weise,  V.K.  and  Kopin,  I.J.:     Effect  of 
dibutyryl  cyclic-AMP  on  adrenal  catechol  ami ne-synthesi zing  enzymes  in 
repeatedly  immobilized  hypophysectomized  rats.     Endocrinology  89:  50-55,  1971. 

Kvetnansky,  R.,  Weise,  V.K.,  Gewirtz,  G.P.  and  Kopin,  I.J.:     Synthesis  of 
adrenal  catecholamines  in  rats  during  and  after  immobilization  stress. 
Endocrinology  89:  46-49,  1971. 

Lamprecht,  F.,  Eichelman,  B.S.,  Thoa,  N.B.,  Williams,  R.B.  and  Kopin,  I.J.: 
Ininoblizati on-induced  increase  in  rat  fighting  behavior  and  brain  catecholamine 
synthesis.     Science »  in  press. 

Thoa,  N.B.,  Eichelman,  B.S.  and  Ng,  L.K.-Y.:     Shock-induced  aggression: 
Effects  of  6-hydroxydopami ne  and  other  pharmacological  agents.     Brain  Res.,  In 
press . 

Thoa,  N.B.,  Johnson,  D.G.  and  Kopin,  I.J.:     Selective  release  of  newly 
synthesized  norepinephrine  in  the  guinea  pig  vas  deferens  during  hypogastric 
nerve  stimulation.     Eur.  J.  Pharmacol.  15:  29-35,  1971. 

Thoa,  N.B.,  Johnson,  D.G. ,  Kopin,  I.J.  and  Weiner,  N.:     Acceleration  of 
catecholamine  formation  in  the  guinea-pig  vas  deferens  after  hypogastric  nerve 
stimulation:     Roles  of  tyrosine  hydroxylase  and  new  protein  synthesis.    J. 

Pharmacol.  Exp.   Ther.   178:  442-449,  1971. 


203 


Serial  No.  M-CS-M(C)-08,  Page  4 

Thoa,  N.B.,  Wooten,  G.F.,  Axelrod,  J.  and  Kopin,  I.J.:     Inhibition  of  release 
of  dopamina-beta-hydroxvlase  and  norepinephrine  from  sympathetic  nerves  by 
colchicine,  vinblastine  or  cytochalasin-B.     Fpoo.  Nat.  Acad.  Sci.   69:  520-522, 
1972. 


20k 


Serial  No.  M-CS-M(C)-11 

1.  Laboratory  of  Clinical  Science 

2.  Section  on  Medicine 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:     False  neurochemical  transmitters 

Previous  Serial  Number:     Same 

Principal  Investigator:     Irwin  J.  Kopin 

Other  Investigators:     L.  Keng-Yong  Ng  (Guest  Worker),  Nguyen  B.  Thoa  and 

Virginia  K.  Weise  [ 

Cooperating  Units:     Unit  on  Psychosomati cs  (Office  of  the  Chief)  and  Section  t 

on  Experimental  Therapeutics,  LCS  I 

■J 
Man  Years:     Total  1.5 

Professional     1.0  ]" 

Other  0.5  j; 

Project  Description: 

Objeatives:     To  determine  the  consequences  of  neurochemical  transmitter 
replacement  by  relatively  inactive  substances,  "false  transmitters,"  in  the 
mechanism  of  action  of  drugs,  to  study  the  possible  role  of  these  substitute 
transmitters  in  disease  states  and  to  investigate  the  mechanism  of  transduction 
of  the  nerve  impulse  into  transmitter  release. 

Methods  Employed:     (1)  Radioactively  labeled  substances  which  are  known 
or  thought  to  accumulate  in  sympathetic  nerves  are  synthesized  and  purified. 
(2)  The  effect  of  precursors  of  false  transmitters  on  the  rate  of  synthesis 
of  catecholamines  is  determined  using  conversion  of  labeled  tyrosine  to 
octopamine  and  norepinephrine.     (3)  The  central  effects  of  L-dopa  have  been 
studied  in  animals  in  which  the  adreneraic  and  dopaminergic  neurons  have  been 
destroyed  with  6-hydroxydopamine.     This  permits  study  of  uptake  and  metabolism 
of  dopa  and  dopamine  in  serotonergic  neurons. 

Mas'or  Findings:     Amines  related  to  norepinephrine  can  replace  it  at  its 
binding  sites  and  thereby  influence  norepinephrine  synthesis,  storage  and 
release.     The  effects  deoend  on  the  time  after  administration.     Dopamine, 
formed  from  dopa,  in  serotonergic  neurons  can  displace  serotonin  and  diminish 
synthesis  and  release  of  this  indoleamine.     Dopamine  may  be  a  false 
serotonergic  transmitter  since  it  can  be  released  by  5-hydroxytryptophan. 


205 


Serial  No.  M-CS-M(C)-n,  Page  2 

Significance  to  Biomedical  Research  and  the  Program  of  the  Institute:     An 
understanding  of  the  mechanisms  for  binding  and  release  of  catecholamines  is 
basic  to  a  meaningful  hypothesis  of  the  events  related  to  the  activation  of 
transmitters  and  synaptic  transmission.     The  fact  that  a  number  of  inactive 
substances  chemically  related  to  norepinephrine  may  replace  it  provides  a  means 
for  modulating  the  effects  of  nerve  stimulation.     It  is  possible  that  after 
drug  administration  or  in  disease  states,  endogenously  formed  false  transmit- 
ters may  reduce  effectiveness  of  ??eurotransmission  through  certain  nervous 
pathways.     After  admini strati ori  of  Udopa,  accumulation  of  dopamine  and 
replacement  of  other  amines  may  result  In  hypotension  and  movement  disorders. 

Proposed  Course  of  the  Project:     Further  investigations  of  replacement  by 
false  transmitters  of  other  neurotransmitters  such  as  cholinergic  or  seroton- 
ergic false  transmitters  are  planned.     The  possible  existence  of  other 
molecular  substitutes  (hormones,  for  example)  will  also  be  investigated. 
Studies  of  the  possible  role  of  false  transmitters  in  drug  action  in  man  are 
planned. 

Honors  and  Awards:     Dr.  Kopin  presented  a  lecture  on  the  mode  of  action  of 
L-dopa  in  the  central  nervous  system  to  the  Department  of  Neurology/School  of 
Medicine,  University  of  Maryland  (Baltimore). 

Publications: 

Kopin,  I.J.:     Unnatural  amino  acids  as  precursors  of  false  transmitters.     Fed. 
Proc.    3":   904-907,  1971. 

Thoa,  N.B.,  Johnson,  D.G.  and  Kopin,  I.J.:     Inhibition  of  norepinephrine 
biosynthesis  by  alpha-methyl  amino  acids  in  the  guinea-pig  vas  deferens.     J. 

Pharmacol.   Exp.  Ther.   180:  71-77,  1972. 

Thoa,  N.B.,  Weise,  V.K.  and  Kopin,  I.J.:     Effect  of  L-dopa  on  methylation  of 
H3-norepinephrine  and  H3-histamine.     Bioahem.  Pharmacol,  t  in  press. 


206 


Serial  No.  M-CS-M(C)-12 

1.  Laboratory  of  Clinical  Science 

2.  Section  on  Medicine 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:  Growth  characteristics  of  aminergic  neurons 

Previous  Serial  No.:  None 

Principal  Investigator:  Irwin  J.  Kopin 

Other  Investigators:  Julius  Axelrod,  Kenneth  R.  Berv,  Floyd  E.  Bloom,  Ingeborg 
Hanbauer,  David  M.  Jacobowitz,  David  C.  Klein,  Stephen  0.  Silberstein  and 
Steven  A.  Vogel . 

Cooperating  Units:  Laboratory  of  Neuropharmacology,  NIMH;  Laboratory  of 

Biomedical  Sciences,  NICHD;  Unit  on  Histopharmacology  (Office  of  the  Chief) 
and  Section  on  Pharmacology,  Laboratory  of  Clinical  Science,  NIMH 

Man  Years:  Total  3.5 
Professional  3.0 
Other       0.5 

Project  Description: 

ObjeoHves:     The  development  of  i£  vitro  techniques  to  study  tissues  in 
isolation  permits  examination  of  factors  which  control  processes  of  growth  and 
influence  levels  of  functions  of  cells  (neurons). 

Methods  Employed:     Tissues  are  removed  from  animals  and  transferred  to 
vessels  where  they  are  maintained  in  culture  and  allowed  to  grow.  The 
constituents  of  the  culture  media  are  varied;  different  tissues  (such  as  super- 
ior cervical  ganglion  and  irises)  can  be  grown  together,  and  drugs  and  hormones 
can  be  added  to  the  media.  With  such  in  vitro  techniques,  the  rate  of  change  in 
enzyme  levels,  amine  content  and  uptake  processes  can  be  measured,  and  the 
effects  of  various  factors  on  growth  of  axonal  processes  can  be  assessed. 

Major  Findings:     Adrenal  glands,  superior  cervical  ganglia.  Irises  and 
pineal  glands  from  adult  rats  survive  for  up  to  two  weeks  in  organ  culture. 
When  ganglia  are  grown  in  contact  with  irises  or  pineal  glands,  axonal  processes 
grow  into  the  tissue.  When  the  ganglia  are  grown  alone,  however,  axonal  sprouts 
form  and  have  the  properties  of  nerve  endings  (uptake,  storage  and  release  of 
catecholamines).  The  axonal  sprouts  enter  tissues  and  carry  with  them  vesicles 
containing  dopamine-beta-hydroxylase  and  catecholamines.  Reinnervation  does  not 
appear  to  be  specific,  but  development  of  sprouts  can  be  prevented  by  drugs 
which  interfere  with  neurotubular  protein.  A  sensitive  and  specific  assay  for 


207 


Serial  No.  M-CS-M(C)-12,  Page  2 

nerve  growth  factor  has  been  developed;  nerve  growth  factor,  which  is  normally 
present  in  ganglia  and  other  tissues,  influences  the  rate  and  extent  of  axonal 
ramification. 

Conditions  which  enhance  release  of  catecholamines  (e.g.,  depolarization 
induced  by  elevated  potassium)  cause  induction  of  tyrosine  hydroxylase  and 
dopamine-beta-hydroxylase  in  adrenal  glands  and  ganglia. 

Signifiacmoe  to  Biomedical  Researah  and  the  Program  of  the  Institute: 
Understanding  the  factors  which  control  neuronal  growth  and  development  is 
essential  for  a  rational  approach  to  investigation  of  a  wide  spectrum  of 
physiologic  processes  (e.g.,  memory,  maturation,  endocrine  control)  and 
pathologic  conditions  (neural  retardation,  drug  influences  on  brain  development 
and  perhaps  a  number  of  neurologic  and  psychiatric  disorders).  The  study  of 
neurons  in  isolated  systems  permits  controlled  variations  of  the  cellular 
environment,  which  are  not  possible  in  the  intact  animal,  and  thus  allows  more 
definitive  indentifi cation  of  the  factors  involved  in  control  of  the  various 
functions. 

Proposed  Course  of  Project:     Tissue  from  brain  and  peripheral  sympathetic 
neurons  will  be  grown.  The  changes  in  uptake  processes,  enzyme  levels, 
neurotransmitter  formation  and  release  and  the  effects  of  other  cells  will  be 
examined.  The  rate  of  hormones,  the  effects  of  drugs  and  the  differences  in 
genetic  variants  will  be  investigated. 

Honors  and  Awards:  Dr.  Kopin  was  invited  to  present  a  lecture  on  recent  work 
relating  to  functional  innervation  by  sympathetic  nerve  fibers  grown  in  tissue 
culture  to  the  Department  of  Neurology/College  of  Physicians  and  Surgeons, 
Columbia  Univeristy  (New  York). 

Publications: 

Hanbauer,  I.,  Johnson,  D.G.,  Silberstein,  S.D.  and  Kopin,  I.J.:  Pharmacological 
and  kinetic  properties  of  uptake  of  norepinephrine-H^  by  superior  cervical 
ganglia  of  rats  in  organ  culture.  Neuro-pharmaoology ^   in  press. 

Johnson,  D.G.,  Gorden,  P.  and  Kopin,  I.J.:  A  sensitive  radioimmunoassay  for  75 
nerve  growth  factor  antigens  in  serum  and  tissues.  J.   Neuroohem.   18:  2355-2362, 
1971. 

Johnson,  D.G. ,  Weise,  V.K.,  Hanbauer,  I.,  Silberstein,  S.D.  and  Kopin,  I.J.: 
Dopamine-beta-hydroxylase  activity  during  sympathetic  reinnervation  of  rat  iris 
in  organ  culture.  Neurobioloay ,   in  press. 

Kopin,  I.J.,  Silberstein,  S.D.,  Johnson,  D.G.,  Hanbauer,  I.  and  Jacobowitz, 
D.M. :  Sympathetic  reinnervation  of  the  rat  iris  in  vitro.  In  Costa,  E. , 
Iversen,  L.L.  and  Paoletti,  R.  (Eds.):  Advances  in  Biochemical 
Psyohopharmacology J   Volume  VI.  New  York:  Raven  Press,  Inc.,  1972,  in  press. 


208 


I 


Serial  No.  M-CS-M(C)-12.  Page  3 

Silberstein,  S.D.:     Sympathetic  reinnervation  of  the  rat  iris  in  culture:     Role 
of  nerve  growth  factor  and  microtubular  protein.     Neurology ^   in  press. 

Silberstein,  S.D.,  Brimijoin,  S.,  Molinoff,  P.B.  and  Lemberger,  L.:     Induction 
of  dopamine-beta-hydroxylase  in  rat  superior  cervical  ganglia  in  organ  culture. 
J.   Neuroohem.    19,  919-921,  1972. 

Silberstein,  S.D.,  Johnson,  D.G.,  Hanbauer,  I.,  Bloom,  F.E.  and  Kopin,  I.J.: 
Axonal  sprouts  and  norepinephrine-H'  uptake  by  superior  cervical  ganglia  in 
organ  culture.     Ppoc.  Nat.  Acad.  Sai.j   in  press. 

Silberstein,  S.D. ,  Johnson,  D.G.,  Jacobowitz,  D.M.  and  Kopin,  I.J.:     Sympathetic 
reinnervation  of  the  rat  iris  in  organ  culture.    Proa.  Nat.  Aaad.  Soi.  68: 
1121-1124,  1971. 

Silberstein,  S.D.,  Lemberger,  L.,  Klein,  D.C.,  Axelrod,  J.  and  Kopin,  I.J.: 
Induction  of  adrenal  tyrosine  hydroxylase  in  organ  culture.     Neuropharmaoology^ 
in  press, 

Silberstein,  S.D.,  Shein,  H.M.  and  Berv,  K.R. :     Catechol -0-methyl  transferase 
and  monoamine  oxidase  activity  in  cultured  rodent  astrocytoma  cells.     Brain 
Res.f  in  press. 

Vogel,  S.A.,  Silberstein,  S.D.,  Berv,  K.R.  and  Kopin,  I.J.:     Stimulation-induced 
release  of  norepinephrine  from  rat  superior  cervical  ganglia  in  vitro.     Eur.  J. 
Fharmaool.f   in  press. 


209 


Serial  No.    M-CS-Ps(C)-18 

1.  Laboratory  of  Clinical  Science 

2.  Section  on  Psychiatry 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual   Project  Report 

July  1,  1971   through  June  30,  1972 

Project  Title:     Biochemical  and  behavioral   factors  in  affective  disorders 

Previous  Serial  Number:     Same 

Co-Principal   Investigators:     Dennis  L.  Murphy,  Frederick  K.  Goodwin 

Other  Investigators:  Max  A.  Baker,  Thomas  C.  Goldman,  Joel  Kotin,  Robert  Post, 
Halbert  Miller,  Steven  Ablon,  Gabrielle  Carlson, 
David  Fischer 

Biochemists:     Edna  K.  Gordon 

Other 

Collaborating 

Scientists:        William  E.  Bunney,  Jr.,  Monte  S.  Buchsbaum, 

Frederick  Snyder,  Richard  Wyatt,  Christopher  Gillin, 
Edward  Donnelly,  Michael  H.  Ebert,  Jorge  Perez-Cruet 

Psychiatric 

Social  Workers:     Yolande  Davenport,  Carol   F.  Hoover,  Walter  Sceery 

Psychiatric 

Consultants:  M.B.  Richmond,  P.  Chodoff,  M.L.  Adland,  H.A.  Myersberg 

Cooperating  Units:        Nursing,  Occupational  Therapy  Personnel  on  Wards 
3-East  and  4-West 

Man  Years:     Total  18.9 

Professional   10.9 
Other  8.0 

Project  Description: 

Ojjjectives      The  objective  of  these  projects  has  been  to  develop  a 
research  program  for  the  investigation  of  the  behavioral,  biochemical   and 
physiological   aspects  of  depressive  and  manic-depressive  patients. 

Behavioral  Objectives:     Behavioral  objectives  include  an  attempt  to 
delineate  some  of  the  central  problems  in  depression.     This  involves  an 


211 


Serial  No.  M-CS-Ps(C)-18,  Page  2 

intensive  analysis  of  the  environmental  and  psychological  events  occurring 
prior  to  and  during  the  development  of  depressive  and  manic  illness. 

Biochemical  and  Pharmacological  Objectives:  Biochemical  objectives  in- 
volve testing  the  hypothesis  that  norepinephrine,  dopamine  and/or  serotonin 
are  decreased  in  depressed  patients  and  are  increased  in  manic  patients.  An 
attempt  is  being  made  to  develoD  methods  for  studying  the  metabolism  of  the 
putative  neurotransmitters  in  humans.  In  part  this  involves  the 
utilization  of  Dharmacological  agents  which  affect  enzymes  involved  in  the 
synthesis  and  breakdown  of  these  neurotransmitters. 

Methods  Employed: 

1.  Both  manic-depressive  and  depressive  patients  are  selected  for  study. 
The  depressed  patients  demonstrate  feelings  of  hopelessness,  thoughts  of 
worthlessness,  preoccupation  with  death  and  dying,  and  difficulty  sleeping, 
while  the  manic  patients  often  show  flight  of  ideas,  grandiosity,   inappro- 
priate and  intrusive  behavior  and,  at  times,  euphoria. 

2.  Behavioral   and  biochemical   data  is  collected  on  a  longitudinal   basis 
throughout  the  course  of  each  patient's  hospitalization. 

3.  Behavioral   data  is  collected  by  a  nursing  research  team,  the  social 
worker,  and  ward  physicians. 

a.  The  nursing  research  team  is  trained  in  systematic  methods  of 
observation  and  recording.     At  the  end  of  each  morning  and  evening  shift,  two 
members  of  the  nursing  team  independently  rate  each  oatient  on  a  15-point 
scale.     The  scale  measures  the  amount  of  depression,   anxiety,  psychotic 
behavior,  physical   activity,  somatic  complaints  and  anger  which  are  manifes- 
ted during  the  8-hour  shift.     A  separate  scale  has  been  developed  for  the 
measurement  of  manic  symptomatology.     The  nurses  also  describe  the  patients' 
verbal   and  non-verbal   behavior  every  eight  hours. 

b.  The  staff  physicians  see  each  patient  in  individual   psychotherapy 
two  to  four  times  a  week.     The  physicians  dictate  information  following  a 
schedule  after  each  therapy  session. 

c.  The  social  worker  interviews  the  closest  relatives  of  each 
patient  and  sees  them  individually  on  a  weekly  basis. 

d.  Observations  are  made  by  the  nurses  concerning  the  patients' 
sleep  throughout  e\jery  night.     These  observations  are  recorded  at  half- 
hour  intervals. 

Biochemical   Data:     24-hour  urine  pools  are  collected  throughout  hospitali- 
zation for  the  determination  of  urinary  catecholamines  and  indoleamines  and 
their  metabolites.     Cerebrospinal   fluid  was  obtained  from  most  patients  and 
was  analyzed  for  the  metabolites  of  catechol-  and  indoleamines.     Some 
patients  were  qiven  doses  of  probenecid  as  a  research  procedure.     Probenecid 


212 


Serial   No.    M-CS-Ps(C)-18,  Page  3 

inhibits  the  active  transport  of  acid  metabolites  of  brain  amines,  5-hydroxy- 
indoleacetic  acid  .(5HIAA)  and  homovanillic  acid  (HVA),  the  major  breakdown 
products  of  serotonin  and  dopamine,  respectively.     The  CSF  levels  of  these 
acid  metabolites  are  closely  related  to  brain  levels  and  their  rate  of  accumu- 
lation during  probenecid  administration  can  be  used  as  an  indirect  index  of 
amine  turnover.     Blood  cells  and  serum  are  also  prepared  for  enzyme  and  bio- 
genic amine  level  measurements. 

Physiological  Data:     Some  of  the  patients  are  monitored  in  terms  of  their 

EEG  and  rapid  eye  movement  potentials  throughout  each  night  in  a  collaborative 

study  with  Dr.  Frederick  Snyder.     Cortical  evoked  potentials  are  studied  on 
most  patients  in  collaboration  with  Dr.  Monte  Buchsbaum. 

Pharmacological  Studies:     Active  medication  and  placebo  were  adminis- 
tered double-blind  in  a  non-random  design  to  many  of  the  patients,  with 
placebo  substitution  before  and  after  each  active  compound.     The  utilization 
of  placebo  substitution  increased  the  level  of  confidence  in  the  efficacy 
of  a  compound  in  an  individual   patient.     This  is  important  in  the  evaluation 
of  drug  effects  because  of  the  frequency  of  spontaneous  remissions  and  exacer- 
bations in  manic-depressive  illness. 

Major  Findings:     The  major  findings  in  the  Section  during  the  past  year 
are  reviewed  as  follows. 

1.  SEROTONIN  AND  BEHAVIOR:     AN  EVALUATION  OF  L-TRYPTOPHAN  AS  AN  ANTI- 
DEPRESSANT:    Evidence  primarily  from  British  studies  has  suggested  that 
depression  might  be  accompanied  by  brain  serotonin  depletion,  since  reduced 
cerebrospinal   levels  of  5-hydroxyindoleacetic  acid  has  been  found  in  depressed 
patients  and  several   studies  have  reported  that  L-tryptophan  was  an  effective 
antidepressant.     To  evaluate  whether  L-tryptophan  was  capable  of  significantly 
altering  serotonin  metabolism  in  man  and  whether  its  antidepressant  efficacy 
could  be  demonstrated  in  a  double-blind  study,  L-tryptophan  was  administered 
at  an  average  dose  of  9.6  gm/day  for  an  average  of  20  days  to  16  unipolar 
depressed  patients.     Thirteen  of  these  individuals  showed  no  change  or  became 
worse  on  L-tryptophan.     Only  three  patients  showed  a  decrease  in  either 
depression  or  psychosis  ratings.     None  of  these  three  individuals  showed  a 
relapse  when  placebo  was  substituted.     CSF  and  urinary  5-HIAA  levels  and 
platelet  serotonin  levels  were  increased  in  these  patients  during  L-tryptophan 
treatment.     The  lack  of  clinical   response  in  the  majority  of  these  patients, 
most  of  whom  later  improved  with  other  forms  of  treatment,  does  not  support 
the  suggestion  that  L-tryptophan  might  be  a  useful   antidepressant  agent. 
Similarly,  the  lack  of  clinical   change  despite  evidence  of  increased  peripheral 
and  central  serotonin  metabolism  in  response  to  L-tryptophan  administration 
does  not  support  the  hypothesis  that  a  functional   deficiency  in  brain  seroto- 
nin is  directly  involved  in  the  pathogenesis  of  depressive  disorders. 

2.  BIOGENIC  AMINES,  MEMORY  AND  MOOD:     Marked  changes  in  verbal   learning 
"capacity  and  memory  were  observed  to  accompany  mania  in  the  course  of  a 

longitudinal   study  of  cycling  manic-depressive  patients.     This  alteration 


213 


Serial   No.    M-CS-Ps(C)-18,      Page  4 

in  learning  was  shown  to  be  princioally  accounted  for  by  an  increased  occurr- 
ence of  idiosyncratic  verbal   associations  and  an  increased  turnover  of  all 
associations,  changes  which  appear  to  interfere  with  lonq-term  memory  opera- 
tions, particularly  retrieval.     The  possibility  that  these  cognitive  changes 
may  be  a  function  of  biogenic  amine-related  arousal   is  currently  under 
evaluation  in  a  series  of  studies  of  the  effects  of  drugs  which  affect  amines 
(L-DOPA,  L-tryptonhan,  alpha-methyl -para-tyrosine,   lithium  and  antidepressant 
agents)  on  serial  word-list  learning,  free  random  recall   and  word  association 
functions. 

3.  CELLULAR-LEVEL  STUDIES  OF  THE  EFFECTS  OF  PSYCHOACTIVE  DRUGS  ON 
ENZYME  ACTIVITY  AND  BIOGENIC  AMINE  METABOLISM  IN  MAN:     Assays   to  measure  not 
only  psychoactive  drug  levels  but  also  cellular-level  affects  of  these  drugs 
in  individual   patients  are  under  development.     Currently  in  regular  use  in 
this  Section  are  techniaues  measuring  mitochondrial   monoamine  oxidase   (for 
MAO-inhibiting  antidepressants),  amine  transport  kinetics   (for  tricyclic 
antidepressants),  cyclic  AMP  formation   (for  drugs  with  receptor-blocking 
properties)  and  amine  levels   (for  drugs  affecting  amine  storage  and  release). 
These  techniques  permit  very  precise  comparisons  of  individual   biochemical 
and  behavioral   responses  to  drugs.     They  have  also  led  to  such   "incidental" 
findings  as  a  reduced  level   of  monoamine  oxidase  activity  in  the  bipolar 
manic-depressive  patient  group,  and  the  discovery  of  increased  levels  of  the 
false  transmitter,  octopamine,  in  cells  from  patients  receiving  MAO-inhibitors 
and  in  some  depressed  patients  with  reduced  MAO  activity. 

4.  CSF  AMINE  METABOLITES  IN  AFFECTIVE   ILLNESS:     PROBENECID  STUDIES: 
A  major  focus  of  investigation  on  the  4-West  Clinical   Research  Unit,  in 
collaboration  with  the  Unit  on  Clinical   Biochemistry,  has  been  the  continued 
development  and  application  of  the  probenecid  technique  for  the  study  of  amine 
turnover  in  the  CNS.     To  date,  35  patients  with  affective  illness.  10  controls 
and  7  addicts  on  methadone  have  been  studied.     Differences  in  the  probenecid- 
induced  accumulation  in  the  CSF  of  5-HIAA,  HVA,  and  MHPG  (the  major  metabolites 
of  serotonin,  dopamine  and  norepinephrine,   respectively)  have  been  shown  to 
exist  between  diagnostic  groups  and  in  relation  to  different  drugs,   including 
L-DOPA,  L-tryptophan,  AMPT,  PCPA,  lithium  and  imioramine. 

5.  BASELINE  CSF  AMINE  METABOLITE  LEVELS  IN  AFFECTIVE  ILLNESS:     A  large 
series  of  depressed  patients   (55)  has  been  studied  under  controlled  conditions 
for  CSF  5-HIAA  and  HVA.     With  control   of  the  physical   activity  variable,  we 
have  been  unable  to  demonstrate  any  differences  in  5-HI.^A  between  depressed 
patients  and  a  carefully  selected  control   group.     HVA  has  been  found  to  be 
lower  in  depression  when  compared  to  manics  or  controls.     Similarly,  MHPG 

was  found  to  be  low  in  a  smaller  group  of  patients  with  retarded  depression 
when  compared  to  manics  or  controls. 

6.  SIMULATED  BEHAVIORAL  STATES  IN  PSYCHOBIOLOGICAL  STUDIES:     EFFECTS  ON 
CSF  AND  URINARY  AMINE  METABOLITES:     Studies  have  been  initiated  this  year  on 
the  4-West  Clinical   Research  Unit,  which  are  designed  to  help  clarify  the 
questions  concerning  whether  a  biological   abnormality  identified  in  association 
with  the  behavioral   state  (for  example,  mania  or  deoression)   is  primary 


Serial  No.  M-CS-Ps(C)-18,   Page  5 

(that  is,  reflecting  the  underlying  psychopathology)  or  is  secondary  to  some 
aspect  of  the  behavioral  state.  Moderately  depressed  patients  were  asked  to 
simulate  a  state  of  manic  excitement  and  hyperactivity  and  CSF  amine  metabol- 
ites were  studied  and  compared  with  baseline  conditions.  Both  5-HIAA  and 
HVA  in  the  CSF  were  substantially  increased  by  this  procedure,  suggesting  that 
the  level  of  psychomotor  activity  is  an  important  variable  determining  the 
level  of  these  amine  metabolites  in  the  CSF.  MHPG  and  cyclic-AMP  in  the  CSF 
were  not  elevated  by  this  simulated  mania  procedure. 

In  a  separate  preliminary  study  involving  a  moderate  exercise  procedure 
in  four  patients  (with  no  attempt  to  simulate  an  actual  mood  change)  we  have 
shown  a  large  increase  in  urinary  MHPG  (100-150%)  on  the  exercise  day  in  three 
out  of  the  four  patients.  For  the  group  as  a  whole,  the  change  was  statisti- 
cally significant. 

7.  COMPARISON  OF  THE  ANTIDEPRESSANT  EFFECTS  OF  IMIPRAMINE  AND  LITHIUM  IN 
UNIPOLAR  AND  BIPOLAR  DEPRESSED  PATIENTS:  A  total  of  52  patients  have  been 
studied  under  controlled  conditions.  Lithium  has  been  shown  to  be  a  more 
effective  antidepressant  in  bipolar  compared  to  unipolar  patients,  whereas 

the  reverse  appears  to  be  the  case  with  the  tricyclic  drugs. 

8.  BEHAVIORAL  AND  BIOCHEMICAL  EFFECTS  OF  THC  IN  MAN:  Tetrahydrocanna- 
binol (THC)  has  been  administered  chronically  (for  seven  days)  to  a  small 
group  of  depressed  patients  and  a  number  of  parameters  have  been  evaluated. 
Behaviorally,  little  or  no  antidepressant  effect  was  observed.  Two  of  the 
six  patients  experienced  clearly  dysphoric  reactions  with  increased  anxiety 
and  psychosis.  A  number  of  biological  effects  of  THC  are  under  collaborative 
investigation,  including  the  effects  of  THC  administration  on  microsomal 
enzyme  systems  in  liver,  effects  of  THC  on  the  distribution  of  metabolism  of 
labeled  THC,  and  its  effects  on  amine  metabolism. 

9.  BEHAVIORAL  AND  BIOCHEMICAL  STUDIES  OF  COCAINE  IN  DEPRESSION:  Cocaine, 
like  the  tricyclic  antidepressants,  is  a  powerful  inhibitor  of  the  reuptake  of 
amines,  potentiating  the  action  of  these  neurotransmitters  at  critical  central 
synapses;  thus,  theoretically,  it  should  have  antidepressant  properties.  An 
experimental  trial  of  cocaine  (both  orally  and  i.v.)  in  depressed  patients  has 
been  undertaken  in  order  to  further  evaluate  the  hypothesized  role  of  amines 

in  affective  illness.  Preliminary  results  suggest  that  cocaine  (particularly 
when  administered  i.v.)  has  definite  psychoactive  effects.  Its  effects, 
however,  are  not  clearly  antidepressant  but  rather  that  of  mobilizing  or 
activating  a  variety  of  affective  states.  The  effects  of  cocaine  on  the  uptake 
of  infused  norepinephrine  is  being  studied  by  Drs.  Et3ert  and  Kopin  using 
double  isotope  procedures. 

10.  FOLLOWUP  STUDIES  OF  MANIC-DEPRESSIVE  PATIENTS:  A  200-item  followup 
questionnaire  has  been  developed;  it  focuses  on  job,  family  and  social  adjust- 
ment and  on  psychiatric  symptomatology.  To  date,  60  former  patients  have  been 
interviewed;  in  addition,  in  50  of  these  cases,  the  spouse  or  significant  other 
was  also  interviewed.  Outcome  over  the  average  two-year  followup  period  has 
been  scored  for  each  patient.  In  a  group  of  20  patients  selected  on  the  basis 

215 


Serial  No.    M-CS-Ps(C)-18,      Page  6 

of  having  had  a  full   manic  episode  while  in  the  hospital,  no  correlation  was 
found  between  outcome  on  followup  and  the  severity  of  the  manic  episode  scored 
independently  during  hospitalization, 

11.  ASSESSMENT  OF  BEHAVIOR  AND  EGO   FUNCTION   IN  MANIC-DEPRESSIVE  PATIENTS: 
Further  studies  on  the  validation  of  a  new  milieu  rating  scale  for  manic  and 
depressive  behavior  have  been  completed.     Factor  analysis  of  the  scale  items 
has   confirmed  the  presence  of  two  major  subgroups  of  manic  patients  who 
manifest  different  behavioral   patterns  while  manic.     In  another  approach  to 
personality  assessment,  data  concerning  eqo  function  and  defensive  patterns 

has  been  collected  from  each  4-West  patient's  therapist  on  a  twice-weekly 
basis  over  the  last  year.     This  data  is  currently  under  analysis. 

12.  SLEEP  STUDIES:     In  collaboration  with  Drs .  Gillen  and  Snyder,  we 
have  continued  our  EEC  studies  of  sleep  in  depressed  and  manic  natients, 
particularly  focusing  on  the  effect  of  drugs  such  as  THC  and  cocaine.     In 
addition,  the  effects  of  amine  precursors  have  been  evaluated,  using  the 
novel   technigue  of  intravenous  infusion  during  undisturbed  sleep.     I.V.  L-DOPA 
was  found  to  suppress  REM  sleeo  and  to  delay  the  onset  of  the  first  REM  period. 
Threo-DOPS  and  5-HTP,  precursors  of  norepinephrine  and  serotonin,   respectively, 
have  been  studied  using  the  same  technique  and  no  significant  effects  on  sleep 
were  observed.     With  longitudinal   all   night  recordings,   it  was  demonstrated 
that  oral   cocaine  significantly  reduces  total   sleeo  and  rapid  eye  movement 
(REM)  sleep.     Studies  on  the  effects  of  chronic  oral  THC  administration  to 
depressed  patients  have  demonstrated  no  sianificant  sleep  changes,  except 
suppression  of  REM  sleen  on  the  first  night  of  the  drug. 

Proposed  Course  of  the  Project:     Durina  the  next  year  continued  emphasis 
will   be  given  to  the  further  development  of  methods  for  the  study  of  amine 
function  in  man  and  their  application  to  the  study  of  manic  depressive  illness. 

Studies  of  the  natural   course  of  manic-depressive  illness  will   be  expan- 
ded, using  follow-up  studies  as   the  major  focus.     An  attempt  will   be  made  to 
examine  psychobiological   correlates  of  the  predisposition  to  affective  illness 
by  studying  patients  with  past  histories  of  manic  or  depressive  illness,  and 
their  first  degree  relatives  during  normal   phases. 

Studies  in  the  area  of  drug  addiction  will   be  given  new  emphasis,   in 
collaboration  with  the  Office  of  the  Chief,  LCS.     These  studies  will   involve 
the  continued  assessment  of  amine  function  in  heroin  addicts  on  and  off 
methadone,  and  the  effects  of  amine  precursors  and  synthesis  inhibitors  on 
the  addictive  and  withdrawal   processes   in  man. 


2l6 


Serial  No.  M-CS-Ps(C)-18,  Page  7 

HONORS  AND  AWARDS 

Drs.  William  E.  Bunney,  Jr.,  Dennis  L.  ^lurphy  and  Frederick  K.  Goodwin 
were  chosen  as  First  Place  co-winners  of  the  Anna-Monika  Award  given  by  the 
Anna-Monika-Stiftung,  Dortmund,  Germany. 

Dr.  Bunney  presented  a  paper  on  "Psychobiological  Studies  of  Manic- 
Depressive  Illness"  in  Basel,  Switzerland,  a  paper  entitled,   "Studies  of 
L-DOPA,  L-tryptophan  and  alpha-methyl -para-tyrosine"  to  the  Vth  World 
Congress  of  Psychiatry,  in  Mexico  City,  Mexico,  a  paper  entitled  "Lack  of 
clinical   response  to  large  doses  of  L-tryptophan:     behavioral  and  metabolic 
studies"  at  the  Conference  on  the  Behavioral  Effects  of  Changes  in  Level  of 
Brain  Serotonin,  in  Palo  Alto,  California,  and  a  paper  entitled,   "CSF-MHPG 
in  Affective  Disorders"  to  the  American  College  of  Neuropsychopharmacology 
in  Las  Vegas,  Nevada.     In  addition,  at  the  4th  Annual  Taylor  Manor  Hospital 
Scientific  Symposium  in  Ellicott  City,  Maryland,  he  presented  a  paper 
entitled  "Psychobiological  Studies  of  Mania  and  Depression".     Dr.  Bunney 
will   present  a  paper  at  the  Annual  Convention  of  the  American  Medical 
Association  in  June. 

Dr.  Goodwin  presented  a  paper  at  the  Max  Planck  Institute,  Munich, 
Germany,  entitled:     "Current  status  of  amine  function  in  affective  illness", 
and  at  the  Annual  Meeting,  International  Group  for  the  Study  of  Affective 
Disorders  in  Zurich,  Switzerland,  he  presented  a  paper  on  "Amine  precursors 
and  synthesis  inhibitors  in  the  study  of  affective  illness".     At  a  Symposium 
of  the  American  Society  of  Clinical  Pharmacology  and  Therapeutics  in  Philadel- 
phia, he  presented  a  paper  entitled,  "Psychopharmacology".     He  also  presented 
a  paper  entitled  "Lithium  in  Depression"  at  the  V. A. -NIMH  Collaborative  Lithium 
Study  Meeting  in  New  Orleans.   "The  Psychobiology  of  Depression  -  Conceptual 
Issues"  was  presented  at  the  NIMH  Workshop  on  The  Psychology  of  Depression  in 
Arlie,  Virginia,  and  "The  Use  of  Probenecid  for  the  Study  of  Amine  Turnover 
in  Man"  was  presented  at  the  NIH  Clinical  Center  Grand  Rounds. 

Dr.  Goodwin  also  presented  a  paper  on  "Lithium  Response  in  Unipolar  vs.  Bipolar 
Depression"  at  the  Vth  World  Congress  of  Psychiatry  in  Mexico  City,  and  a  paper 
on  "Current  Psychobiological   Research  in  Affective  Illness"  at  the  Department 
of  Psychiatry,  Albert  Einstein  College  of  Medicine,  New  York.     Two  papers  - 
"The  Biology  of  Bipolar  Affective  Illness:  Studies  with  L-DOPA  and  alpha-methyl- 
para-  tyrosine",  and  "Problems  in  the  Study  of  Amine  Turnover  in  Man  -  The 
Probenecid  Technique"  were  presented  at  the  American  College  of  Neuropsycho- 
pharmacology (ACNP),  Las  Vegas,  Nevada. 

In  addition.  Dr.  Goodwin  will  be  presenting  the  following  papers.  "CSF  Amine 
Metabolites  in  Affective  Illness:  Probenecid  Studies",  Annual  Meeting, 
American  Psychiatric  Assn.,  Dallas,  and  "Psychopharmacology  of  the  Affective 
Disorders",  Hillside  Hospital,  New  York.  He  has  also  been  invited  to  present 
■a  paper  entitled,  "Methods  for  the  Study  of  Central  Amine  Function  in  Man"  at 
the  Annual  Meeting,  International  Group  for  the  Study  of  Affective  Disorders, 
San  Antonio,  Texas.     Dr.  Goodwin  participated  as  a  co-author  in  several  other 


217 


Serial   No.   M-CS-Ps(C)-"l8,  Page  8 

papers  presented  at  the  World  Congress  of  Psychiatry,  the  ACNP,  the  American 
Psychiatric  Assn.,   the  American  Psychosomatic  Society,  the  Association  for  the 
Psychophysiological   Study  of  Sleep,  and  others. 

Dr.  Murphy  presented  the  following  papers:     "A  Cellular  Model   for  Studies 
of  Biogenic  Amine  Metabolism  in  Mania"  at  the  American  College  of  Neuropsycho- 
Dharmacology  in  Las  Vegas,  Nevada;   "Differential   Behavior  and  Biochemical 
Responses   to  L-DOPA  in  Bipolar  Manic-Depressive  Patients"  at  the  Vth  World 
Congress  of  Psychiatry  in  Mexico  City,  and  "Studies  of  Platelet  and  Plasma 
Serotonin  in  Neuromuscular  Diseases"  at  the  American  Academy  of  Neurology  in 
St.  Louis,  Missouri.     Dr.   Murphy  was   invited  to  present  papers  on  different 
aspects  of  the  biological   and  behavioral   studies  of  affective  disorders  at 
Georgetown  University,  Johns  Hopkins  University,  The  University  of  California 
at  Los  Angeles,  the  University  of  Kentucky,   the  Philadelphia  Naval   Hospital, 
the  University  of  Utah  and  Rutgers  University.     He  will   be  presenting  a  paper, 
"Differential   Excretion  of  Catecholamine  Metabolites  After  L-DOPA  in  Depressed 
Patients"  at  the  American  Psychiatric  Assn.  Annual   Meeting  in  Dallas,  Texas 
in  May. 

In  addition.  Dr.  Murphy  discussed  the  Section's  studies  of  depression  on  an 
hour-long  nationwide  television  interview  on  the  Phil   Donahue  Show  in  Dayton, 
Ohio. 

Dr.   Perez-Cruet  presented  the  following  papers.     "Evidence  for  a  Balance 
in  the  Basal   Ganglia  between  Cholinergic  and  Dopaminergic  Activity"  at  the 
Federation  Meeting  in  Atlantic  City;   "Changes  in  Synthesis  Rate  of  Serotonin, 
Dopamine  and  Norepinephrine  after  Withdrawal   of  Chronic  Treatment  with  a-methyl- 
tyrosine   (aF-IT)   in  rats"  was  presented  at  the  American  Federation  for  Clinical 
Research  in  Philadelphia.     A  paper  was  presented  at  the  American  Society  for 
Pharmacology  and  Experimental  Therapeutics,   "Prostaglandin  E]    (PGEi)   Induces 
"Paradoxical"  Sleep,   Increases  Brain  Acetylcholine  (Ach)   Levels  and  Serotonin 
(5HT)  Turnover",  in  Burlington,  Vermont,  and  a  paper  on  "Stimulation  of  Sero- 
tonin Synthesis  by  Cecium  in  Rats"  at  the  Federation  Meetings  in  Atlantic  City. 

Dr.   Perez-Cruet  will   be  presenting  a  paper,   "Effects  of  Psychotropic  Drugs 
on  Subcellular  Levels  of  Amino  Acid  Precursors  and  Metabolism  of  Monoamines 
in  Brain"  at  the  5th  International  Congress  on  Pharmacology  in  San  Francisco. 

Dr.   Post  presented  a  paper,   "Simulated  Behavior  States  in  Psychobiological 
Research"  at  the  American  Psychosomatic  Society  meetings  in  Boston.     He  will 
present  a  paper  at  the  American  Psychiatric  Assn.  meetings  in  Dallas  entitled, 
"CSF  Amine  Metabolites,  Mood  and  Psychomotor  Activity",  and,  also  in  Dallas, 
will   present  a  paper  to  the  Association  for  the  Psychophysiological   Study  of 
Sleeo  entitled,   "Effect  of  Cocaine  on  Sleep  of  Depressed  Patients". 

Dr. ^Kotin  will   present  a  paper  at  the  meetings  of  the  American  Psychiatric 
Association  in  Dallas,  entitled,  "Tetrabydrocannabinol   (THC)  in  Depressed 

Patients". 


218 


Publications:  serial  no.    M-CS-Ps(C) -18,   Page   9 

Gershon,  E.S.;  Bunney,  W.E.,Jr. ,  Goodwin,  F.K.,  Murphy,  D.L.,  Dunner,  D.L., 
and  Henry,  G.M. :     Catecholamines  and  Affective  Illness:  Studies  with  L-DOPA 
and  Alpha-methyl -para- tyrosine.     In:  Ho,  B.T.  &  Mclsaac,  W.M.   (Eds.)  Brain 
Chemistry  and  Mental   Disease.  Plenum  Press,  New  York,  Vol.   I,  pp. 135-163, 
1971. 

Carpenter,  W.T.;  and  Bunney,  W.E.,Jr.:     Adrenal   Cortisol  activity  in 
depressive  illness.     Amer.  J_.  Psychiat.   128:63-72,  1971. 

Carpenter,  W.T.;  and  Bunney,  W.E.,Jr.:  Diurnal  rhythm  of  Cortisol  in  mania. 
Arch.   Gen.   Psychiat.     25:270-273,  1971. 

Beigel,  A.;  Murphy,  D.L.,  and  Bunney,  W.E.,Jr.:     The  manic-state  rating 
scale:     scale  construction,  reliability  and  validity.     Arch.  Gen.  Psychiat. 
25:256-262,   1971. 

Goodwin,  F.K.;  and  Bunney,  W.E.,Jr. :     Depressions  following  reserpine:     a 
reevaluation.     Seminars  in  Psychiatry.  3:435-448,  1971. 

Murphy,  D.L.;  and  Bunney,  W.E.,Jr.:     Total  body  potassium  changes  during 
lithium  treatment.     J..  Nerv.  Ment.  Dis..   152:381-389,  1971. 

Bunney,  W.E.,Jr. :     Biochemical  Research  in  Affective  Illness.     In:  Fieve,R.R. 
(Ed.)  Depression  in  the  70 's.     Modern  Theory  and  Research.     Excerpta  Medica 
Foundation,  New  York,  pp.  55-63,  1971. 

Bunney,  W.E.,Jr. ;  Goodwin,  F.K.  and  Murphy,  D.L.:     Current  Research  on 
L-DOPA  in  Depression  and  Mania.     In:     Malitz,  S.   (Ed.)  L-DOPA  and  Behavior. 
Raven  Press,  New  York,  1971. 

Goodwin,  F.K.;  Ebert,  M.,  and  Bunney,  W.E.,Jr.:  Mental  Effects  of  Reserpine 
in  Man.  In:  Shader,  R.I.  (Ed.)  Psychiatric  Complications  of  Medical  Drugs. 
Raven  Press,  New  York,   1971. 

Goodwin,  F.K.:     Behavioral   Effects  of  L-DOPA  in  Man.     In:     Shader,  R.I.    (Ed.) 
Psychiatric  Complications  of  Medical   Drugs.     Raven  Press,  New  York,  1971. 

Goodwin,  F.K.;  and  Post,  R.M.:     The  Use  of  Probenecid  in  High  Doses  for 
the  Estimation  of  Central  Serotonin  Turnover  in  Patients.     In:     Barchas,  J. 
and  Usdin,  E.   (Eds.)  Serotonin  and  Behavior.     Academic  Press,  New  York,  1972. 

Goodwin,  F.K.  and  Bunney,  W.E.,Jr.:     The  Biology  of  Bipolar  Affective  Illness. 
Studies  with  L-DOPA  and  Alpha-methyl-para-tyrosine.     In:     Gershon,  S.   and 
Bunney,  W.E.,Jr.   (Eds.)  Amines  and  Affective  Disorders.     (ACNP  Symposium) 
Plenum  Press,  New  York,  1972. 

Goodwin,  F.K.  and  Post,  R.M.:     Problems  in  the  Study  of  Amine  Turnover  in  Man 
-  The  Probenecid  Technique.     In:     Gershon,  S.  &  Bunney,  W.E.,Jr.    (Eds.) 
Amines  and  Affective  Disorders.   (ACNP  Symposium)  Plenum  Press,  New  York,  1972. 


219 


Serial   Mo.  M-CS-Ps(C)-18,  Page  10 

Borge,  G.;  Buchsbaum,  M.,  Goodwin,  F.K.   and  Murphy,  D.L.:     NeuroDsycholoqical 
correlates  of  affective  disorders.     Arch.  Gen.  Psych i at.  24:501-504,  1971. 

Dunner,  D.L.;  Gershon,   E.S.,  Goodwin,  F.K.,  Murphy,  D.L.   and  Bunney,  W.E.,Jr.: 
Excretion  of  17-hydroxycorticosteroids  in  unipolar  and  bipolar  depressed 
patients.     Arch.   Gen.   Psychiat.   26:360-363,  1972. 

Buchsbaum,  M.;  Goodwin,   F.K.,  Murphy,  D.L.   and  Borge,  G.:     Average  evoked 
responses  in  affective  disorders .     Amer.  J_.   Psychiat.   128:19-25,   1971. 

Henry,  G.M.;  Murphy,  D.L.,  and  Weinqartner,  H.:     Idiosyncratic  oatterns  of 
learning  and  word  association  during  mania.     Amer.  J_.  Psychiat.   128:564-574, 
1971. 

Beigel,  A.;   and  Murphy,  D.L.:     Assessing  clinical   characteristics  of  the  manic 
state.     Amer.  J_.   Psychiat.   128:688-699, '  1971 . 

Beigel,  A.;  and  Murphy,  D.L.:     Differences  in  clinical   characteristics 
accompanying  depression  in  unipolar  and  bioolar  affective  illness.     Arch. 
Gen.     Psychiat.   24:215-220,  1971. 

Goodwin,  F.K.:     Psychiatric  side  effects  of  Levodopa  in  man.     JAMA     218: 
1915,  1971. 

Dunner,  D.L.;  and  Goodwin,  F.K.:     The  effect  of  L-tryptophan  on  brain  sero- 
tonin metabolism  in  depressed  patients.     Arch.  Gen.   Psychiat.   26:364-366, 
1972. 

Goodwin,  F.K.;  Dunner,  D.L.,  and  Gershon,  E.S.:     Effect  of  L-DOPA  treatment 
on  brain  serotonin  metabolism  in  depressed  patients.     Life  Sci .     10:751,  1971. 

Gershon,  E.S.;  Dunner,  D.L.,  and  Goodwin,   F.K.:     Toward  a  biology  of  affective 
illness:     genetic  contributions.     Arch.   Gen.   Psychiat.   25:1,  1971. 

Dunner,.  D.L. ;  Cohn,  C.K.,  Gershon,   E.S.,  and  Goodwin,   F.K.:     Differential 
catechol -0-methyl -transferase  activity  in  unipolar  and  bipolar  affective 
illness.     Arch.  Gen_.   Psychiat.  25:348,   1971. 

Paul,  M.I.;  Cramer,  H.,  and  Goodwin,   F.K.:     Urinary  cyclic-AMP  in  depression 
and  mania:     effects  of  L-DOPA  and  lithium  carbonate.     Arch.  Gen.  Psychiat. 
24:327,   1971. 

Robinson,  D.S.;  Davis,  J.M.,  Niles,  A.,  Colburn,  R.W.,  Davis,  .i.N.,  Bourne, 
H.R.,  Bunney,  W.E.,Jr.,  Shaw,  D.M.   and  Coppen,  A.J.:     Ageina,  monoamines, 
and  monoamine  oxidase  levels.     Lancet     1:290-291,   1972. 

Donnelly,  E.F.;  Mignone,   R.J.,  Dent,  J.K.   and  Murphy,  D.L.:     Comparison  of 
temporal   lobe  epileptics  and  affective  disorders  on  the  Halstead-Rei tan 
test  battery.     J^.  Clin.   Psychol .    (In  press). 


220 


I 


Serial  No.M-CS-Ps(C)-18,  Page  11 

Lott,  I.T.;  Murphy>  D.L.  and  Chase,  T.N.:     Down's  syndrome:     central  mono- 
amine turnover  in  patients  with  diminished  platelet  serotonin.     Neurol . 
(In  press). 

Murphy,  D.L.:     Amine  precursors,  monoamine  oxidase  activity  and  false 
neurotransmitters  in  depressed  patients.     Amer.  J^.  Psych i at.   (In  press). 

Murphy,  D.L.  and  Weiss,  R.:  Reduced  monoamine  oxidase  activity  in  blood 
platelets  from  bipolar  depressed  patients.     Amer.  J_.  Psych i at.   (In  press). 

Perez-Cruet,  J.;  Tagliamonte,  A.,  Tagliamonte,  P.  and  Gessa,  G.L.: 
Differential  effect  of  p-chlorophenylalanine  (PCPA)  on  sexual  behavior  and 
on  sleep  patterns  of  male  rabbits.     Ri vista  di  Farmacol .  e  Terap.  11:27-34, 
1971. 

Tagliamonte,  A.;  Tagliamonte,  P.,  Perez-Cruet,  J.,  Stern,  S.  and  Gessa,  G.L.: 
Effects  of  psychotropic  drugs  on  tryptophan  concentration  in  the  rat  brain. 
J^.   Phamiacol .   Exp.  Ther.     177:475-480,  1971. 

Tagliamonte,  A.;  Tagliamonte,  P.,  Perez-Cruet,  J.  and  Gessa,  G.L.:     Increase 
of  brain  tryptophan  caused  by  drugs  which  stimulate  serotonin  synthesis. 
Nature  -  New  Biology,  229:125,  1971. 

Perez-Cruet,  J. ;  Tagliamonte,  A.,  Tagliamonte,  P.  and  Gessa,  G.L.:     Stimula- 
tion of  serotonin  synthesis  by  lithium.     J^.  Pharmacol .  Exp.  Ther.  178:325- 
330,  1971. 

Tagliamonte,  A.;  Tagliamonte,  P.,  Forn,  J.,  Perez-Cruet,  J.,  Krishna,  G. 
and  Gessa,  G.L.:  Stimulation  of  brain  serotonin  synthesis  by  dibutyryl- 
cyclic  AMP  in  rats.     J^.  Neurochem.     18:1191-1196,  1971. 

Sesame,  H.A.;  Perez-Cruet,  J.,  DiChiara,  G.,  Tagliamonte,  T.,  Tagliamonte, 
P.  and  Gessa,  G.L.:     Effect  of  methadone  on  dopamine  metabolism  in  rat 
basal   ganglia  and  its  relation  to  catalepsy.     Ri vista  di   Farmacol .  e^ 
Terap.     11:99-105,  1971. 

Perez-Cruet,  J.;  Murphy,  D.L.  and  Bunney,  W.E.,Jr.:     Changes  in  synthesis 
rate  of  serotonin,  dopamine  and  norepinephrine  after  withdrawal  of  chronic 
treatment  with  a-methyl-tyrosone  (aMT)  in  rats.     Clin.  Res.  19:735,  1971. 

Haubrich,  D.R.;  Perez-Cruet,  J.  and  Reid,  W.D.:     Prostaglandin  E-,   induced 
paradoxical  sleep  and  increase  in  brain  serotonin  turnover  in  rats.     Brit. 
J^.  Pharmacol.     (In  press). 

Perez-Cruet,  J.;  Tagliamonte,  A.,  Tagliamonte,  P.,  and  Gessa,  G.L.:     Changes 
in  brain  serotonin  metabolism  associated  with  fasting  and  satiation  in  rats. 
"Life  Sci.   11:31-39,   1972. 


221 


Serial   No.M-CS-Ps(C)-18,  Page  12 

Goodwin,  F.K.;  Murphy,  D.L.,  Dunner,  D.L.  and  Bunney,  W.E.,Jr.:  Lithium 
response  in  unipolar  vs.  bipolar  depression.     Amer.  J^.  Psych i at.    (In  press). 

Lott,  I.T.;  Chase,  T.N.  and  Murphy,  D.L.:     Down's  syndrome:     transport, 
storage,  and  metabolism  of  serotonin  in  blood  platelets.     Pediatric  Res. 
(In  press). 

Post,  R.M.;  Kotin,  J.  and  Goodwin,  F.K.:     The  relationship  between  psycho- 
motor activity  and  cerebrospinal   fluid  amine  metabolites  in  affective 
illness.     Amer.  J^.  Psychiat.   (In  press). 

Goodwin,  F.K.;  and  Ebert,  M.:  Lithium  in  Mania.  In:  Gershon,  S.  (Ed.) 
Lithium:  Its  Role  in  Psychiatric  Research  and  Treatment.  Plenum  Press, 
New  York,   1972   (In  press). 

Goodwin,  F.K.;  and  Bunney,  W.E.,Jr. :     The  Current  Status  of  Lithium  as  Used 
in  Psychiatry  and  as  a  Research  Instrument  in  Medicine.     In:     Gershon,  S. 
(Ed.)  Lithium:     Its  Role  in  Psychiatric  Research  and  Treatment.     Plenum 
Press,  New  York,   1972   (In  press). 

Kotin,  J.;  and  Goodwin,  F.K.:     Depression  during  mania:     clinical   observations 
and  theoretical   implications.     Amer.   J^.  Psychiat.   (In  press). 

Bunney,  W.E.,Jr.;  Murphy,  D.L.,  Goodwin,  F.K.   and  Borge,  G.F.:     The   "switch 
process"  in  manic-depressive  illness.     I.  A  systematic  study  of  sequential 
behavioral   change.     Arch .  Gen.  Psychiat.     (In  press). 

Bunney,  W.E.,Jr.;  Goodwin,  F.K.,  Murphy,  D.L.   and  House,   K.M. :     The   "switch 
process"  in  manic-deoressive  illness.     II.  Relationship  to  catecholamines, 
REM  sleep  and  drugs.     Arch.  Gen.   Psychiat.    (In  press). 


Bunney,  W.E.,Jr. ;  Goodwin,  F.K.   and  Murphy,  D.L.:     The  "switch  process"  in 
manic-depressive  illness.     III.  Theoretical   implications.     Arch.  Gen.   Psychiat. 

(In  press). 

Murphy,  D.L.;  Baker,  M.,  Goodwin,  F.K.,  Kotin,  J.  and  Bunney,  W.E.,Jr.: 
Behavioral  and  Metabolic  Effects  of  L-Tryptophan  in  Unipolar  Depressed 
Patients.  In:  Barchas,  J.  &  Usdin,  E.  (Eds.)  Serotonin  and  Behavior. 
Academic  Press,  New  York,  1972.  (In  press). 

Jacobs,  L.;  and  Kotin,  J.:  Fantasies  of  psychiatric  research.  Amer.  J. 
Ps^cMat.  128:1074,  1972.  ~ 

Bunney,  W.E.,  Jr.;  and  Murohy,  D.L.:  The  Switch  Process  and  Psychopathology. 
In:  Mendels,  J.  (Ed.)  Textbook  of  Biological  Psychiatry.  Academic  Press, 
New  York  (In  press) . 


222 


I 


Serial  No.  M-CS-Ph-5 

1.  Laboratory  of  Clinical  Science 

2.  Section  on  Pharmacology 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:   Biochemistry  and  pharmacology  of  the  adrenergic 
nervous  system 

Previous  Serial  Number:   None 

Principal  Investigators:   Roland  D.  Ciaranello,  Joseph  T.  Coyle, 
G.  Frederick  Wooten 

Other  Investigators:   Julius  Axelrod 

Man  Years:  Total  7.5 
Professional  4.5 
Others        3.0 

Project  Description: 

Objectives;   To  study  the  development  of  the  adrenergic 
nervous  system  in  the  brain.   To  examine  how  adrenergic 
biosynthetic  enzymes  are  transported  down  the  axon  and  released. 
To  examine  serum  dopamine- p-hydroxylase  levels  after  disease  and 
drug  treatment. 

Major  Findings:   A  sensitive  method  for  measuring  tyrosine 
hydroxylase  in  the  brain  has  been  developed  and  its  distribution 
described.   In  studies  on  the  development  of  the  adrenergic 
nervous  system  in  the  rat  brain  it  was  found  that  all  of  the 
biosynthetic  enzymes,  tyrosine  hydroxylase,  dopa  decarboxylase 
and  dopamine- p-hydroxylase  first  appear  15  days  after  gestation, 
mainly  in  the  cell  bodies.   This  is  followed  by  outgrowth  of 
nerve  terminal  18  days  after  gestation  and  appearance  and 
storage  of  noradrenaline  on  day  20  after  gestation.   Both 
tyrosine  hydroxylase  and  dopamine- p-hydroxylase  move  down  the 
axon  proximodistally  by  a  rapid  transport  process.   Microtubular 
elements  appear  to  be  involved  in  this  transport.   Repeated 
administration  of  reserpine  results  in  an  induction  of  tyrosine 
hydroxylase  and  dopamine- p-hydroxylase  but  no  change  in  rate  of 
transport.   Studies  on  release  process  were  carried  out  in 
collaboration  with  the  Section  on  Medicine  and  will  be  described 
by  Dr.  Kopin. 


223 


Serial  No.  M-CS-Ph-5,  page  2 

Serum  dopamine- p-hydroxylase  is  reduced  or  absent  in 
children  with  familial  dysautonomia.   In  normal  subjects  there 
was  a  gradual  increase  in  the  serum  enzyme  from  birth  to 
puberty.   After  stress  there  was  a  rapid  increase  in  dopamine- 
s-hydroxylase in  man. 

The  administration  of  dexamethasone  results  in  an 
induction  of  a  new  enzyme  in  the  sympathetic  ganglia  of 
newborn  rats. 

Preliminary  work  indicates  that  dopaminergic  cell  bodies 
in  the  substantia  nigra  can  be  grown  in  organ  culture. 

Significance  to  Biomedical  Research  and  the  Program  of 
the  Institute :   Studies  on  the  development  of  the  adrenergic 
nervous  system  in  the  brain  make  it  possible  to  carry  out 
investigations  on  how  these  developments  can  be  perturbed  and 
the  consequences.   Serum  dopamine- p-hydroxylase  studies  have 
given  insight  regarding  the  course  of  familial  dysautonomia 
and  should  make  possible  studies  of  other  neurological  diseases, 

Proposed  Course  of  Project:   Further  studies  will  be 
carried  out  to  examine  how  specific  proteins  are  transported 
down  the  axon  and  how  they  are  released.   The  factors 
influencing  dopaminergic,  noradrenergic  and  serotonergic  cell 
bodies  to  be  maintained  in  organ  culture  will  be  examined. 
Changes  in  serum  dopamine- p-hydroxylase  will  be  studied. 
Induction  and  suppression  of  the  adrenaline-forming  enzyme  in 
the  ganglia  and  organ  of  Zuckerkandl  will  be  examined. 

Honors  and  Awards:   Dr.  Axelrod  has  been  invited  to  give 
the  Harvey  Lecture  at  Rockefeller  University,  the  Scheuler 
Lecture  at  Tulane  University,  and  the  main  address  at  the 
General  Session  of  the  Federation  of  American  Societies  for 
Experimental  Biology.   He  also  received  an  Honorary  Sc.D. 
from  New  York  University  and  from  the  Medical  College  of 
Wisconsin;  the  Townsend  Harris  Medal  of  The  City  College  of 
New  York,  the  Myrtle  Wreath  Award  of  the  Hadassah  Society, 
and  the  Man  of  the  Year  Award  of  the  Montgomery  County  Chamber 
of  Commerce o 

Publications : 

Axelrod,  J. :   Methyltransf erase  enzymes  in  the  metabolism  of 
physiologically  active  compounds  and  drugs.   In  Brodie,  B.B. 
and  Gilette,  J.  (Eds.):   Handbook  of  Expalmental  Pharmacology. 
New  York,  Springer-Verlag,  1971,  pp.  609-620. 


22i| 


Serial  No.  M-CS-Ph-5,  Page  3 

Axelrod,  J.:  .  Noradrenaline:   fate  and  control  of  its 
biosynthesis.   In:   Les  Prix  Nobel.   Stockholm,  Impriraerieal 
Royal  P. A.  Norstedt  &  Soner,  1971,  pp.  189-208.   Science  173: 
598-606,  1971. 

Black,  I.B.,  Axelrod,  J.,  and  Reis,  D.J.:   Hypothalmic 
regulation  of  the  daily  rhythm  in  hepatic  tyrosine  transaminase 
activity.   Nature  (New  Biol.)  230:   185-187,  1971. 

Black,  I.B.  and  Reis,  D.J.:   Central  neural  regulation  by 
adrenergic  nerves  of  daily  rhythm  in  hepatic  tyrosine 
transaminase  activity.   J.  Physiol.  219:   267-280,  1971, 

Cohn,  C.K.  and  Axelrod,  J. :   Effect  of  estradiol  on  catechol-0- 
methyltransf erase  activity  in  rat  liver.   Life  Sci.  10: 
1351-1354,  1971. 

Coyle,  J.T.  and  Axelrod,  J.:   Development  of  the  uptake  and 
storage  of  L-['^H] norepinephrine  in  the  rat  brain.   J.  Neurochem. 
18:   2061-2075,  1971. 

Henry,  J.P. ,  Stephens,  P.M.,  Axelrod,  J.,  and  Mueller,  R.A. : 
Effect  of  psychosocial  stimulation  on  the  enzymes  involved  in 
the  biosynthesis  and  metabolism  of  noradrenaline  and  adrenaline. 
Psychosomat.  Med.  33:   227-237,  1971. 

Johnson,  D.G. ,  Thoa ,  N.B. ,  Weinshilboum,  R. ,  Axelrod,  J.,  and 
Kopin,  I.J. :   Enhanced  release  of  dopamine- p-hydroxylase  from 
sympathetic  nerves  by  calcium  and  phenoxybenzamine  and  its 
reversal  by  prostaglandins.   Proc.  Nat.  Acad.  Sci.  68: 
2227-2230,  1971. 

Molinoff,  P.B.,  Weinshilboum,  R. ,  and  Axelrod,  J.:  A  sensitive 
enzymatic  assay  for  dopamine- p-hydroxylase.  J.  Pharmacol.  Exp. 
Thcr.   178:   425-431,  1971. 

Mueller,  R.A. ,  Willard,  P.,  and  Axelrod,  J.:   Alterations  in 
norepinephrine  storage  in  inbred  rats  made  hypertensive  by 
triidothyronine  and  sodium  chloride.   Pharmacology  5: 
153-164,  1971. 

Weinshilboum,  R.  and  Axelrod,  J.:  Reduced  plasma  dopamine-p- 
hydroxylase  in  familial  dysautonomia.  New  Engl.  J.  Med.  285: 
938-942,  1971. 

Weinshilboum,  R.  and  Axelrod,  J.:   Serum  dopamine- p-hydroxylase 
decrease  after  chemical  sympathectomy.   Science  173:   931-934, 
1971. 


225 


Serial  No.  M-CS-Ph-5,  Page  4 

Weinshilboum,  R. ,  Kvetnansky,  R. ,  Axelrod,  J.,  and  Kopin,  I. J.  : 
Elevation  of  serum  dopamine- p-hydroxylase  activity  with  forced 
immobilization.   Nature   230:   287-288,  1971. 

Weinshilboum,  R.  ,  Thoa ,  N.B.  ,  Johnson,  D.G.  ,  Kopin,  LJ.,  and 
Axelrod,  J. :   Proportional  release  of  norepinephrine  and 
dopamine- p-hydroxylase  from  sympathetic  nerves.   Science 
174:   1349-1351,  1971. 

Cohn,  C.K.,  Vesell,  E.S.,  and  Axelrod,  J.:   Studies  of  a 
methionine-activating  enzyme.   Biochem.  Pharmacol.  21: 
803-809,  1972. 

Coyle,  J.T.  and  Axelrod,  J.:   Dopamine- p-hydroxylase  in  the  rat 
brain:   developmental  characteristics.   J.  Neurochem.  19: 
449-459,  1972. 

Ross,  S.B.,  Weinshilboum,  R. ,  Molinoff,  P.B.,  Vesell,  E.S.,  and 
Axelrod,  J.:   Electrophoretic  properties  of  dopamine-p- 
hydroxylase  in  several  tissues  from  three  species.   Mol. 
Pharmacol.  8:   50-58,  1972. 

Silberstein,  S.D.,  Brimijoin,  S,,  Molinoff,  P.B. ,  and 
Lemberger,  L. :   Induction  of  dopamine- p-hydroxylase  in  rat 
superior  cervical  ganglia  in  organ  culture.   J.  Neurochem. 
19:   919-921,  1972. 

Thoa,  N.B. ,  Wooten,  G.F. ,  Axelrod,  J.,  and  Kopin,  I.J.: 
Inhibition  of  release  of  dopamine- p-hydroxylase  and 
norepinephrine  from  sympathetic  nerves  by  colchicine, 
vinblastine,  or  cytochalasin-B.   Proc.  Nat.  Acad.  Sci.  69: 
520-522,  1972. 

Reis,  D.J.  and  Molinoff,  P.B. :   Brain  dopamine- p-hydroxylase: 
regional  distribution  and  effects  of  lesions  and  6-hydroxy- 
dopamine  on  activity.   J.  Neurochem.  19:   195-204,  1972. 


n 


226 


Serial  No.  M-CS-Ph-6 

1.  Laboratory  of  Clinical  Science 

2.  Section  on  Pharmacology 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:   Tryptamine  and  other  biogenic  amines  and 
psychoactive  drugs 

Previous  Serial  Number:   None 

Principal  Investigators:   Julius  Axelrod,  David  S.  Kreuz, 

Juan  M.  Saavedra  (Guest  Worker) 

Man  Years:   Total  2.5 

Professional    1.5 
Other  1.0 

Project  Description: 

Objectives :   To  develop  sensitive  methods  for  the 
measurement  of  normally  occurring  amines  and  psychoactive  drugs. 

Methods  Employed:   Biochemical,  pharmacological  and 
radioactive  tracer  techniques . 

Major  Findings;   A  specific  and  sensitive  enzyme  method 
for  measuring  tryptamine  in  tissues  was  developed.   This  amine 
was  found  to  occur  normally  in  brain  and  other  tissues. 
Injection  of  C   -tryptamine  into  the  brain  results  in  the 
formation  of  methyl-  and  dimethyltryptamine.   An  enzyme  that 
methylates  tryptamine  was  found  in  rat  and  human  brain  and  an 
unidentified  inhibitor  was  also  observed. 

After  its  repeated  administration,  tetrahydrocannabinol 
was  found  to  accumulate  in  the  fat  and  to  a  small  extent  in 
the  brain. 

Octopamine  was  found  to  occur  rormally  in  human  blood. 

Significance  to  Biomedical  Research  and  the  Program  of 
the  Institute!   The  occurrence  of  an  enzyme  that  can  make  a 
psychotomimetic  metabolite  from  normally  occurring  compounds 
(tryptamine)  has  implications  to  psychiatry.   The  accumulation 
of  THC  in  the  fat  might  be  potentially  harmful. 

Proposed  Course  of  Project;  Enzyme  methods  for  the 
development  of  other  amines  (phenylethanolamine)  will  be 

227 


Serial  No.  M-CS-Ph-6 ,  Page  2 

developed.   The  effect  of  drugs  on  tryptamine  levels  in  tissue 
will  be  examined.   Further  studies  on  the  tryptamine-methylating 
enzyme  will  be  made.   Blood  levels  of  octopamine  after  drugs  and 
various  disease  states  will  be  studied. 

Honors  and  Awards:   Dr.  Axelrod  has  been  invited  to  give 
the  main  lecture  at  the  American  College  of  Neuropsychopharmacology . 
He  also  received  the  Albert  Einstein  Achievement  Award  from 
Yeshiva  University,  and  the  Virchow  Medal,  and  has  been  elected 
Honorary  Member  of  the  American  Neurological  Association  and  the 
American  Psychopathology  Association. 

Publications : 

Davis,  J.M.,  Kopin,  I.J.,  Lemberger,  L. ,  and  Axelrod,  J:   Effects 
of  urinary  pH  on  amphetamine  metabolisn.   Ann.  N.Y.  Acad.  Sci. 
179:   493-501,  1971. 

Lemberger,  L.  ,  Axelrod,  J.,  and  Kopin,  I.J.  :   Metabolism  and 
disposition  of  delta-9-tetrahydrocannabinol  in  man. 
Pharmacol.  Rev.  23:   371-380,  1971. 

Lemberger,  L. ,  Axelrod,  J.,  and  Kopin,  I.J.:   Metabolism  and 
disposition  of  tetrahydrocannabinols  in  naive  subjects  and 
chronic  marijuana  users.   Ann.  N.Y.  Acad.  Sci.  191:   142-154, 
1971. 

Lemberger,  L. ,  Axelrod,  J.,  and  Kopin,  I.J. :   The  disposition 
and  metabolism  of  tryptamine  in  the  in  vivo  formation  of 
6-hydroxytryptamine  in  the  rabbit.   J.  Pharmacol.  Exp.  Ther. 
177:   169-176,  1971. 

Lemberger,  L. ,  Tamarkin,  N.R.,  Axelrod,  J.,  and  Kopin,  I.J. : 
Delta-9-tetrahydrocannabinol :  metabolism  and  disposition  in 
long-term  marihuana  smokers.   Science  173:   72-74,  1971. 

Molinoff,  P.B.  and  Axelrod,  J.:   Distribution  and  turnover  of 
octopamine  in  tissues.   J.  Neurochem.  19:   157-163,  1972. 

Saavedra,  J.M.  and  Axelrod,  J.:   Psychotomimetic  N-methylated 
tryptamines :   formation  in  brain  in  vivo  and  in  vitro.   Science 
175:   1356-1366,  1972. 

Silberstein,  S.D„,  Brimijoin,  S.,  Molinoff,  P.B. ,  Lemberger,  L. : 
Induction  of  dopamine- p-hydroxylase  in  rat  superior  cervical 
ganglia  in  organ  culture.   J.  Neurochem.  19:   919-921,  1972. 


228 


4 


Serial  No.  M-CS-Ph-7 

1.  Laboratory  of  Clinical  Science 

2.  Section  on  Pharmacology 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   Biochemical  and  pharmacological  studies  on 
the  pineal  gland 

Previous  Serial  Number:   None 

Principal  Investigators:   Takeo  Deguchi  (Guest  Worker) 

Other  Investigators:   Julius  Axelrod 

Man  Years:  Total  1.5 
Professional  1.5 
Other         0 

Project  Description: 

Objectives:   To  study  how  the  sympathetic  nervous  system 
transduces  biochemical  events  in  the  pineal  gland. 

Methods  Employed:   Biochemical,  pharmacological  and 
radioactive  tracer  techniques. 

Major  Findings:   A  sensitive  method  was  developed  to 
measure  the  enzyme  that  N-acetylates  serotonin  in  the  pineal 
gland.   Administration  of  dopa,  noradrenaline,  isoproterenol 
and  monoamine  oxidase  inhibitors  and  theophylline  caused  a 
marked  induction  (20-fold)  of  the  serotonin  N-acetylating  enzyme 
in  the  pineal.   This  elevation  in  enzyme  activity  is  blocked  by 
propranolol,  a  p-adrenergic  blocking  agent.   When  pineal  gland 
is  denervated,  p-adrenergic  agents  and  isoproterenol  cause  a 
superinduction  (100-fold)  of  the  acetylating  enzyme.   This 
induction  is  also  blocked  by  propranolol. 

Significance  to  Biomedical  Research  and  the  Program  of 
the  Institutel   None  that  is  immediately  apparent. 

Proposed  Course  of  Project:   The  phenomena  of  denervation 
sensitivity  will  be  further  examined.   The  isolation  of  the 
p-adrenergic  receptor  from  the  pineal  will  be  attempted.   The 
molecular  events  in  the  induction  of  N-acetyltransf erase  will 
be  examined. 


229 


Serial  No.  M-CS-Ph-7,  Page  2 

Honors  and  Awards:   Dr,  Axelrod  was  elected  Fellow  of 
the  American  Academy  of  Arts  and  Sciences  and  the  National 
Academy  of  Sciences.   He  was  also  asked  to  lecture  on  the  pineal 
gland  at  Howard  Medical  School. 

Publications:   None 


230 


Serial  No.  M-CS-ET-1 

1.  Laboratory  of  Clinical  Science 

2.  Section  on  Experimental  Therapeutics 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual   Project  Report 

July  1,  1971   through  June  30,  1972 

Project  Title:     Biochemistry,  Pharmacology  and  Physiology  of  Cerebral  Amines 

Previous  Serial  Number:     M-CS-ET-1;  M-CS-ET-2 

Principal   Investigator:     Thomas  N.  Chase 

Other  Investigators:     Jacob  A.  Brody,  Cal   K.  Cohn,  Robert  W.  Colbum, 
Hinrich  Cramer,  Edna  K.  Gordon,  Irwin  J.  Kopin, 
Paul  D.  Maclean,  Raymond  Matta,  Larry  Keng-Yong 
Ng  (Guest  Worker),  Elliott  S.  Vesell,  Roger 
Weir  (Guest  Worker),  and  James  L.  Weiss. 

Cooperating  Units:     Sections  on  Medicine  and  Pharmacology  and  Unit  on  Clinical 
Biochemistry,  Laboratory  of  Clinical  Science,  NIMH; 
Laboratory  of  Neurophysiology,  NIW;  Epidemiology  Branch, 
NINDS;  Department  of  Pharmacology,  Pennsylvania  State 
College  of  Medicine. 

Man  Years:     Total  3.0 

Professional       1.0 
Other  2.0 

Project  Description: 

Objectives: 

1.  To  study  the  transport,  metabolism,  storage,  release  and 
postsynaptic  interactions  of  monoamines  and  other  putative  central 
neurotransmi  tters . 

2.  To  examine  the  functional  role  of  monoamines  and  other  suspected 
neurohumoral  agents  in  the  central  nervous  system  of  normal  individuals 

and  in  patients  manifesting  neuropsychiatric  disease. 

3.  To  study  the  mechanism  of  action  and  therapeutic  efficacy  of 
drugs  which  influence  brain  function. 


231 


Methods  Employed:  serial  no.  m-cs-et-i 

1.  Preclinical  studies  utilize  a)  slices  or  homogenates  of  brain 
and  other  tissues  which  are  incubated  with  radioactively  labeled  amines  and 
related  compounds,  then  exposed  to  drugs,  other  amines  or  electrical 
stimulation;  b)  surgically  prepared  laboratory  animals  in  which  the 
concentration  of  labeled  and  endogenous  compounds  in  brain,  cerebrospinal 
fluid,  serum  and  urine  are  determined  under  various  experimental   conditions 
following  the  systemic  or  intracranial   injection  of  labeled  amines  and 
other  substances. 

2.  Clinical  studies  are  conducted  in  patients  with 
neuropsychiatric  disease  and  in  normal   volunteers.       Under  resting  conditions 
and  during  the  administration  of  drugs  or  procedures  believed  to 

influence  central  synaptic  mechanisms,  neurologic,  psychiatric  and  psychologic 
parameters  of  brain  function  are  correlated  with  the  results  of  a)  chemical 
assay  of  relevant  compounds  in  various  body  fluids  and  tissues,  b)  radio- 
isotope tracer  procedures  and  c)  electrical  measurement  of  spontaneous  and 
evoked  cortical  potentials  during  waking  and  sleep. 

Major  Findings:     Studies  carried  out  with  L.K.Y.  Ng,  R.  W.  Colburn 
and  I.J.   Kopin  indicate  that  5-hydroxytryptophan  enhances  the  release  of 
dopamine  and  serotonin  from  central  nervous  system  tissues.     This  action 
appeared  dependent  upon  the  decarboxylation  of  5-hydroxytryptophan  to 
serotonin,  since  it  could  be  blocked  by  the  addition  of  an  inhibitor  of 
L-amino  acid  decarboxylase.     Selective  destruction  of  catechol  ami ne- 
containing  neurons  with  6-hydroxydopamine  substantially  reduced  the  uptake 
and  release  of  labeled  serotonin.     These  results  suggest  that  dopamine 
may  be     released  by  serotonin  derived  from  the  decarboxylation  of 
5-hydroxytryptophan  in  catechol  ami nergic  neurons.     Conceivably,  a  portion 
of  exogenously  administered  5-hydroxytryptophan  may  enter  central 
catechol  ami nergic  terminals  and  undergo  decarboxylation  to  serotonin  with 
resultant  displacement  of  endogenous  catecholamines     from  vescicular 
stores.     This  mechanism  may  explain  certain  of  the  behavioral   and  neurologic 
effects  of  5-hydroxytryptophan  loading  in  man. 


J 


In  collaboration  with  L.K.Y.  Ng,  R.E.  Gelhard  and  P.D.  Maclean, 
attempts  have  been  made  to  produce  an  animal  model  of  naturally  occurring 
or  drug-induced  dyskinetic  disorders.  Following  unilateral   intracerebral  or 
intraventricular  injections  of  6-hydroxydopamine,  monkeys  displayed  a 
substantially  enhanced  susceptibility  to  involuntary  movement  disorders 
induced  by  L-dopa  (the  precursor  of  dopamine)  or  apomorphine  (a  dopamine 
receptor  stimulator).     These  observations  support  the  hypothesis  that 
denervation  hypersensitivity  of  central   catechol  ami nergic  receptors  may 
be  involved  in  the  production  of  dyskinesias  during  L-dopa  treatment  of 
patients  with  extrapyramidal  disease  and  suggest  that  6-hydroxydopamine 
pretreated  primates  may  provide  a  useful  paradigm  for  future  studies  of 
the  relationship  between  catechol amine-containing  neural  systems  and 
spontaneous  or  drug-induced  involuntary  movement  disorders  in  man. 


232 


Serial  No.   M-CS-ET-1 

In  an  attempt  to  determine  the  site  of  origin  of  monoamine 
metabolites  in  luntar  cerebrospinal  fluid,  ventricular-lumbar  infusion 
studies  with  radtoactively  labeled  substances  have  been  carried 
out  in  cats  with  Dr.  Roger  Weir.     Currently  available  data  indicate  that 
TOSt  5-hydroxyindoleacetic  acid  in  lumbar  spinal  fluid  derives  from 
brain  rather  than  spinal  cord  metabolism.  These  results  provide  a  more  certain 
rationale  for  the  use  of  metabolite  levels  in  human  lumbar  fluid  as  an  index 
of  cerebral  monoamine  metabolism. 

Recent  laboratory  experiments  indicate  that  high  doses  of 
S-dihydro^O'phenyl serine,  when  given  in  combination  with  the  peripheral 
decarboxylase  inhibitor  (MK  486),  substantially  elevates  brain  norepinephrine 
concentrations  without  affecting  dopamine  or  serotonin.     Since  no  toxic  effects 
were  observed,  clinical  trials  of  this  drug  combination  are  now  planned  in  an 
attempt  to  discern  the  relationship  between  norepinephrine  mediated  neural 
transmission  and  disorders  of  motor  and  behavioral  function. 

Studies  of  the  probenecid-induced  accumulation  of  monoamine 
metabolites  in  cerebrospinal  fluid  continue  to  yield  important  new  information 
concerning  the  role  of  aminergic  mechanisms  in  central  nervous  system 
disease.     Since  probenecid  inhibits  the  active  transport  of  homovanillic 
acid  (a  principal  metabolite  of  dopamine)  and  5-hydroxyindoleacetic 
acid  (the  major  product  of  serotonin  degradation)  from  the  central  nervous 
system,  the  probenecid-induced  rise  in  these  metabolites  should  afford  an 
index  to  their  rate  of  formation  as  well  as  to  the  central  turnover  of  the 
parent  amines.     Current  studies  in  patients  with  idiopathic  Parkinson's 
disease  indicate  that  basal  concentrations  and  probenecid-induced 
accumulations  of  homovanillic  acid  are  considerably  below  those  of 
control  subjects.    Although  steady  state  levels  of  5-hydroxyindoleacetic 
acid  did  not  differ  from  normal  values,  there  was  a  substantial 
diminunition  in  the  response  of  this  serotonin  metabolite  to 
probenecid.     Pretreatment  severity  of  parkinsonian  rigidity  and  bradykinesia, 
but  not  tremor,  correlated  inversely  with  the  probenecid-induced  rise  in 
both  monoamine  metabolites.    No  apparent  association  was  found,  however, 
between  the  therapeutic  response  to  L-dopa  and  either  the  severity  of 
parkinsonian  signs  or  the  magnitude  of  the  defect  in  monoamine 
metabolism.     These  results  cast  doubt  upon  the  prevailing  notion 
that  the  ability  of  L-dopa  to  ameliorate  parkinsonian  signs  is  solely 
contingent  upon  its  conversion  to  dopamine  in  surviving  dopaminergic  neurons. 

In  contrast  to  our  findings  in  naturally  incurring  Parkinson's 
disease,  normal  or  slightly  elevated  probenecid-induced  accumulations    of 
homovanillic  acid  were  found  in  patients  who  developed  parkinsonian  signs 
while  receiving  psychotropic  phenothiazines  or  related  neuroleptic  agents. 
These  observations  support  the  contention  that  pharmacologic  parkinsonism 
may  be  the  consequence  of  a  drug-induced  blockade  of  dopaminergic  receptors. 

Application  of  the  probenecid  technique  to  the  study  of  central 
monoaminergic  function  in  patients  with  Huntington's  chorea  revealed  a 


233 


Serial   No.    M-CS-ET-1 

substantial   reduction  in  homovaninic  acid  formation  but  no  abnormality 
in  the  turnover  of  5-hydroxyindoleacetic  acid.  Unlike  our  findings  in 
Parkinson's  disease,  however,  there  was  no  apparent  correlation  between  the 
degree  of  homovanillic  acid  abnormality  and  the  severity  of  motor  or 
behavioral  dysfunction. 

In  a  collaborative  study  with  H.  Cramer  and  L.K.Y.  Ng,  probenecid  was 
found  to  substantially  increase  adenosine-3' ,5' -monophosphate  (cyclic 
AMP)  levels  in  human  lumbar  spinal   fluid.  Since  experiments  in  the  laboratory 
animal   indicate  that  probenecid  does  not  affect  brain  cyclic  AMP  concentrations, 
our  clinical  observations  suggest  that  probenecid  may  act  to  inhibit  the 
efflux  of  this  nucleotide  from  the  spinal   fluid  compartment.  Use  of  probenecid 
to  estimate  central  cyclic  AMP  turnover  may  thus  contribute  to  our  under- 
standing of  the  role  of  this  substance  in  human  neurotransmission. 

An  improved  gas-liquid  chromotography  method  for  measuring  cerebro- 
spinal  fluid  levels  of  3-methoxy-4-hydroxyphenyl glycol   (MHPG),  a  major 
product  of  norepinephrine  metabolism,  has  been  applied  to  more  than  60  patients 
with  central  nervous  system  disease  in  collaboration  with  E.   K.  Gordon 
and  L.   K.  Y.  Ng.     MHPG  concentrations  were  similar  in  ventricular  and  lumbar 
spinal   fluid.     About  one-third  of  MHPG  from  either  source  occurred  as  the 
sulfate  conjugate.     The  administration  of  a-methyl para tyrosine  (an  inhibitor  of 
catecholamine  biosynthesis)     substantially  reduced  MHPG  levels  in  all 
patients  tested.     Since  relatively  little  intravenously  infused,  isotopically 
labelled  MHPG  enters     spinal   fluid,  our  results  suggest  that  MHPG  levels  in 
lumbar  fluid  may  provide  an  index  to  norepinephrine  metabolism  in  the  central 
nervous  system  of  man. 

Various  clinical   studies  of  the  effects  of  L-dopa  on  motor  and 
behavioral   function  continue.     A  comparative  evaluation  of  the  therapeutic 
efficacy  and  toxicity  of  L-dopa  alone  and  in  combination  with  a  peripheral 
decarboxylase  inhibitor  (MK  486)   in  stateside  patients  with  Parkinson's 
disease  and  in  Guamanians  with  parkinsonism-dementia  (in  collaboration  with 
J. A.  Brody)  has  been  expanded.     Currently  available  data  from  both  studies 
affirm  the  favorable  results  on  extrapyramidal   function  reported  last  year. 
No  effect  on  dementia  has  been  found  in  the  Guamanian  subjects.       An 
examination  of  the  antiparkinsonian  efficacy  of  L-dopa  in  schizophrenic 
patients  who  have  developed  extrapyramidal  signs  while  receiving  long-term 
neuroleptic  therapy  has  yielded  favorable  results  in  several   patients. 

A  therapeutic  trial  of  3-0-methyldopa  in  patients  with  Parkinson's 
disease  has  recently  been  concluded.  The  administration  of  this  dopa 
metabolite,  either  alone  or  in  combination  with  a  peripheral  decarboxylase 
inhibitor  (MK  486),  had  no  effect  on  parkinsonian  signs.     During  treatment 
with  high  doses  of  0-methyldopa,  levels  of  apparent  L-dopa  in  plasma  and 
homovanillic  acid  in  luntar  spinal   fluid  approximated  those  found  in 
patients  receiving  therapeutically  effective  doses  of  L-dopa.     These 
findings  raise  some  question  about  the  generally  assumed  mechanism  by 
which  L-dopa  exerts  its  antiparkinsonian  action. 


23i^ 


Serial   No.    M-CS-ET-1 

Tests  of  the  therapeutic  efficacy  of  fusaric  acid,  a  new  dopamine 
3-hydroxylase  inhibitor,  have  recently  been  conducted  in  patients  with 
various  extrapyramidal  disorders.    Use  of  this  drug  alone  or  together  with 
a  fixed  dose  of  L-dopa  failed  to  significantly  alter  parkinsonian  signs 
despite  markedly  reduced  serum  dopamine  g-hydroxylase  levels  as  measured 
by  R.  J.  Matta  and  C.  K.  Cohn. 

Parachlorophenylalanine,  a  potent  and  specific  depletor  of  brain 
serotonin,  was  given  to  6  patients  with  Idiopathic  parkinsonism.     Despite 
a  substantial  reduction  in  the  spinal  fluid  content  of  5-hydroxyindoleacet1c 
acid,  there  was  no  change  in  cardinal  parkinsonian  signs.     These  results  sug- 
gest that  the  decrease  in  serotonin  turnover  which  characteristically  attends 
Parkinson's  disease  may  be  a  secondary  phenomenon  of  little  consequence  to 
the  clinical  severity  of  this  disorder. 

A  study  of  the  effect  of  L-dopa  on  hepatic  microsomal  drug 
metabolizing  enzymes  has  been  conducted  in  collaboration  with  L.K.Y.  Ng, 
G.T.  Passananti,  and  E.  S.  Vessell.     Antipyrine  half-lives  In  plasma  were 
used  to  detect  changes  In  rates  of  drug  metabolism,  since  the  decline  In 
blood  antipyrine  concentrations  is  largely  dependent  upon  its  biotransforma- 
tion In  liver.     Our  results  indicate  that  chronic  treatment  with  L-dopa  and 
a-methyldopahydrazine  (MK  486),  but  not  with  L-dopa  alone,  significantly 
prolongs  mean  antipyrine  half-life. 

The  clinical  effects  of  drugs  which  act  relatively  specifically 
on  cerebral  amines  have  been  examined  in  patients  with  Huntington's 
disease.    L-tryptophan,  alone  or  in  combination  with  a  peripheral 
decarboj^lase  inhibitor,  failed  to  influence  either  the  motor  or  behavioral 
aspects  of  this  disorder.     Parachlorophenylalanine  in  doses  sufficient  to 
reduce  cerebrospinal   fluid  levels  of  5-hydroxyindoleacetic  acid  by  nearly  50%, 
was  also  ineffective.     In  view  of  these  results  as  well  as  those  obtained 
with  the  probenecid  test,  the  participation  of  serotonergic  mechanisms 
in  the  pathogenesis  of  Huntington's  chorea  would  seem  unlikely.  On  the  other 
hand,  L-dopa,  the  inmedlate  precursor  of  dopamine,  led  to  an  unmlstakeable 
Increase  in  the  severity  of  choreatic  movements  in  most  of  the  Huntington's 
chorea  patients,  while  a-methylparatyrosine,  a  specific  Inhibitor  of 
catecholamine  synthesis,  tended  to  ameliorate  hyperkinesias  in  these 
individuals.    The  effect  of  a-methylparatyrosine  was  markedly  potentiated 
by  the  conjoint  administration  of  haloperidol.     These  pharmacologic 
observations  are  not  necessarily  in  conflict  with  the  previously  described 
biochemical   findings  suggestive  of  a  reduction  in  central  dopamine  turnover 
in  Huntington's  disease.     Conceivably,  the  small  striatal  nerve  cells  which 
are  seen  to  degenerate  in  Huntington's  disease  are  host  to  dopaminergic 
terminals  from  the  nigrostriatal  system,  and  it  is  the  primary  reduction  in 
function  of  these  striatal  cells  which  gives  rise  to  the  involuntary 
movements  characteristic  of  this  disorder.  Diminished  dopamine  metabolism 
in  Huntington's  disease  might  thus  occur  only  as  a  secondary  phenomenon. 
This  functional  alteration  could  be  due  to  an  intemeuronal  feedback 
mechanism,  acting  in  the  opposite  direction  to  that  which  is  believed  to 
occur  during  treatment  with  psychotropic  phenothiazines    or  butyrophenone . 


235 


Serial   No.    M-CS-ET-1 

Significance     to  bioiTiedical   research  and  the  program  of  the  Institute; 
Biogenic  amines  appear  to  act  an  synaptic  mediators  in  certain  neuronal 
systems  within  the  central   nervous  system  of  man.     Alterations  in  these 
substances  have  recently  been  found  in  relation  to  several  extrapyramidal   and 
behavioral   disorders  and  have  led  to  discovery  of  drugs  which  reverse  both 
the  biochemical   and  clinical  defect.     This  approach  to  the  development  of 
new  pharmacologic  therapies  may  be  applicable  to  other  disorders  of  brain 
function. 

Proposed  Course  of  Project:     Current  studies  of  monoaminergic 
mechanisms  in  relation  to  naturally  occurring  and  drug-induced  neuro- 
psychiatric  disease  will  be  continued.  Special  emphasis  will  be  given  to 
phenothiazine-induced  extrapyramidal   disorders  (tardive  dyskinesias). 
Attempts  to  develop  improved  techniques  for  evaluating  the  metabolism  of 
suspected  neurotransmitters  in  the  human  central  nervous  system  will  be 
extended  to  include  acetylcholine,  y-aminobutyric  acid  and  the 
prostaglandins. 

Honors  and  Awards:     During  the  past  year  Dr.   Chase  was  elected  to 
the  Clinical   Research  Committee  of  the  NIH  Medical   Board  and  to  the 
Scientific  Advisory  Board  of  the  Committee  to  Combat  Huntington's  Disease. 
He  was  also  invited  to  serve  on  an  FDA  advisory  panel   on  Drug  Induced 
Dyskinesias.     He  chaired  the  session  on  "Biogenic  Amines"  at  the  Third  Annual 
Meeting  of  the  American  Society  for  Neurochemistry  in  Seattle,  March  20-23  and 
the  "Biochemistry  Session"  at  the  Centennial  Symposium  on  Huntington's  chorea 
in  Columbus,  March  26-28.     In  connection  with  the  latter  symposium.  Dr.  Chase 
served  as  Scientific  Assistant  Secretary  and  co-editor  of  the  Proceedings. 
Invitational   lectures  and  seminars  were  given  at  Einstein  Medical  College 
on  October  14,  at  the  University  of  Virginia  Medical   School,  November  18  and 
19,  and  to  a  symposium  on  "Order  and  Disorder  in  Movement"  at  the  First 
Annual  Meeting  of  the  Society  for  Neuroscience  in  Washington  on  October  29. 
Dr.  Chase  served  as  an  invited  discussant  for  papers  entitled  "The 
Association  of  Parkinsonism  and  Motor  Neuron  Disease",   "Side  Effects  of 
L-dopa  Related  to  Blood  Concentration"  and  "The  Effect  of  Chlorpromazine 
on  Striatal   Dopamine  Synthesis"  presented  at  the  Twenty-Fourth  Annual 
Meeting  of  the  American  Academy  of  Neurology  in  St.   Louis,  April   27-29. 
During  the  year  Dr.  Chase  read  papers  before  the  American  Society  for 
Neurochemistry,  American  Academy  of  Neurology,  Centennial  Symposium  on 
Huntington's  Chorea,  and  the  Annual  Meeting  of  the  International   Society 
for  Neurochemistry  in  Budapest, 

Publications: 

Weiss,  J.L.,  Ng,  L.K.Y.  and  Chase,  T.N,:     Long-lasting  dyskinesia  induced 
by  Levodopa.     Lancet  i_:1016-1017,  1971. 

Chase,  T.N,,  Schnur,  J. A.,  Brody,  J. A.  and  Gordon,  E.K.:     Parkinsonism- 
dementia  and  Amyotrophic  Lateral  Sclerosis  of  Guam:     Effect  of  probenecid 
on  monoamine  catabolite  levels  in  cerebrospinal   fluid.     Arch.  Neurol. 
25:9-13,   1971. 


236 


Serial   No.    M-CS-ET-1 

Vesell,  E.S.,  Ng,  L.K.Y.,  Passananti,  G.T.  and  Chase,  T.N.:     Inhibition  of 
drug  metabolism  by  L-dopa  in  combination  with  a  dopa  decarboj^lase  inhibitor. 
Lancet  2:370,  1971. 

Wyatt,  R.J.,  Chase,  T.N.,  Kupfer,  D.J.,  Scott,  J.,  Snyder,  F.,  Sjoerdsma,  A. 
and  Engelman,  K.:     Brain  catecholamines  and  human  sleep.     Nature  233:63-65, 
1971. 

Mendel! ,  J.R.,  Chase,  T.N.  and  Engel,  W.K.:     Amyotrophic  Lateral  Sclerosis: 
A  study  of  central  monoamine  metabolism  and  therapeutic  trial  of  L-dopa. 
Arch.  Neurol.  2^^:320-325,  1971. 

Weiss,  J.L.,  Cohn,  C.K.  and  Chase,  T.N.:     Catechol -0-methyl   transferase: 
Reduction  by  chronic  L-dopa  therapy.     Nature  234:218-219,  1971. 

Chase,  T.N.  and  Ng,  L,K.Y.:     Probenecid  test  in  Parkinson's  disease. 
Lancet  2:1265-1266,  1971. 

Schnur,  J. A.,  Chase,  T.N.  and  Brody,  J. A.:     Parkinsonism-dementia  of  Guam: 
Treatment  with  L-dopa.     Neurology  21:236-1242,  1971. 

Mendell,  J.R.,  Chase,  T.N.  and  Engel,  W.K.:     Amyotrophic  lateral  sclerosis: 
Metabolism  of  central  monoamines  and  treatment  with  L-dopa.     Trans.  Amer. 
Neurol.  Assn.  96:284-286,  1971. 

Weiss,  J.L.  and  Chase,  T.N.:     Levodopa  in  parkinsonism.     Drugs  2:257-261, 
1971. 

Chase,  T.N.,  Watanabe,  A.M.,  Brodie,  H.K.H.,  Donnelly,  E.F.:     Huntington's 
chorea:     Effect  of  serotonin  depletion.  Arch.  Neurol.  26^:282-284,  1972. 

Chase,  T.N.  and  Watanabe,  A.M.:     Methyl dopahydrazi ne  as  an  adjunct  to  L-dopa 
therapy  in  parkinsonism.     Neurology.     22^:384-392,  1972. 

Chase,  T.N.:     Drug-induced  extrapyramidal  disorders.     Chapter  22.  In 

Res.  Publ.  Assn.  Nerv.  Ment.  Pis.,  Vol.  50,  Williams  and  Wilkins,  Baltimore. 

In  press. 

Ng,  L.K.Y.,  Chase,  T.N.,  Colburn,  R.W.  and  Kopin,  I. J.:     L-dopa  in 
parkinsonism:     A  possible  mechanism  of  action.     Neurology.     In  press. 

Chase,  T.N.,  Ng,  L.K.Y.  and  Watanabe,  A.M.:     Parkinson's  disease: 
Modification  by  5-hydroxy tryptophan.     Neurology.     In  press. 

Lott,  I.T.,  Murphy,  D.L.  and  Chase,  T.N.:     Down's  syndrome:     Central 
monoamine  turnover  in  patients  with  diminished  platelet  serotonin. 
Neurology.     In  press. 

Cramer,  H.,  Ng,  L.K.Y.  and  Chase,  T.N.:     Effect  of  probenecid  on  cyclic 
AMP  levels  in  human  spinal   fluid.     J  Neurochem.     In  press. 


237 


I 


Serial  No.  M-P-C-(C)-12 

1.  Laboratory  of  Psychology 

2.  Section  of  the  Chief 

3 .  Bethesda 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:   Studies  of  heredity  and  environment  in  schizophrenia. 

Previous  Serial  Nxunber:   Same. 

Principal  Investigator:   David  Rosenthal 

Other  Investigators:   Paul  H.  Wender,  Seymour  S.  Kety  (Harvard) , 

Shmuel  Nagler  (Israel) ,  Fini  Schulsinger  (Denmark) . 

Cooperating  Units:   None. 

Man  Years : 

Total:  7.0 
Professional:  3.0 
Others:        4.0 

Project  Description: 

Objectives :   To  understand  how  hereditary  and  environmental  factors  interact 
to  make  for  schizophrenic  outcomes  of  varying  types  and  degrees . 

Methods  Employed;   1.   A  constructively  critical,  hypothesis-oriented  anal- 
ysis of  the  worthwhile  literature  on  heredity  and  environment  in  schizo- 
phrenia.  2.   An  intensive  multidisciplinary  study  of  a  family  with  one-egg 
quadruplet  daughters  concordant  as  to  schizophrenia  but  discordant  as  to 
severity  and  outcome.   This  study  was  published  in  book  form.   We  are  con- 
tinuing our  contacts  with  this  family  to  see  what  happens  in  the  clinical 
course  of  these  girls  and  how  the  course  is  related  to  earlier  and  current 
life  experiences.   3.   Studies  of  adoptees  and  their  biological  and  adoptive 
families.   4.   A  study  of  children  (of  schizophrenic  and  control  parents) 
reared  in  town  or  kibbutz  in  Israel. 

Major  Findings:   1.   The  analysis  of  the  literature  has  been  reported  in  a 
series  of  papers  and  in  the  study  of  the  quadruplets .  A  textbook  which  or- 
ganizes and  explicates  the  literature  on  the  genetics  of  behavioral  dis- 
orders, and  a  modified  version  of  this  book  have  been  piiblished.   2.   Sev- 
eral papers  on  our  adoption  studies  are  now  published.   The  studies  indicate 
that  hereditary  factors  contribute  to  the  development  of  schizophrenia,  and 
to  other  disorders  that  we  include  in  a  group  called  the  schizophrenia 
spectrum.   Several  articles  are  in  preparation  and  eventually  a  monograph 
will  be  written  on  the  adoption  studies.   Data  analysis  is  continuing. 
3.   One  hundred  subjects  in  the  Israel  study  have  been  examined,  and  the 

239 


Serial  No.  M-P-C-(C) -12,  p.  2. 

research  findings  are  currently  being  analyzed  and  evaluated.   Preliminary 
findings  indicate  that  offspring  of  schizophrenics  have  more  neuropatho- 
logical  signs  in  childhood  than  do  controls.   Two  subjects  have  had  a  break- 
down and  one  is  on  the  verge  of  breakdown.   All  three  have  a  schizophrenia 
parent. 

Significance  to  Bio-medical  Research  and  the  Program  of  the  Institute:   We 
have  resolved  a  chronic,  critical  problem  in  psychiatry  by  demonstrating 
beyond  any  reasonable  doubt  that  genetic  factors  are  importantly  involved  in 
the  etiology  of  schizophrenia  and  related  mental  disorders.   Moreover,  the 
evidence  thus  far  suggests  that  the  mode  of  genetic  transmission  is  polygenic 
or  a  dominant  single  gene  with  polygenic  modifiers. 

Proposed  Course  of  Project:   We  are  examining  additional  subjects  in  Denmark 
with  the  following  goals  in  mind:   1.   to  try  to  discriminate  gene  carriers 
and  non-gene  carriers  with  respect  to  personality  and  test  variables;  2.   to 
compare  the  fate  of  gene-carriers  who  are  reared  in  the  parental  home  as 
compared  to  those  reared  in  adoptive  homes;  3.   to  compare  Ss  who  have  a 
psychotic  biological  parent  but  who  are  reared  by  nonpsychotics  with  Ss 
whose  biological  parents  are  not  psychotic  but  who  are  reared  by  a  psychotic 
adoptive  parent;  4.   to  find  the  incidence  of  schizophrenic  spectrum  dis- 
order in  a  random  sample  of  the  Danish  population.   In  Israel,  our  goal  is 
to  prepare  a  volume  on  our  findings  and  their  theoretical  implications . 
During  this  year  we  will  carry  out  reexaminations  of  this  unique  sample  of 
subjects. 

Honors  and  Awards :   None . 

Publications : 

Rosenthal,  D. :   A  program  of  research  on  heredity  in  schizophrenia. 
Behav.  Sci.  16:   191-201,  1971.   (Republished  in  abbreviated  form: 
Mental  Health  Digest,  3[9]:   1-4,  1971.) 

Wender,  P.  H.,  Rosenthal,  D. ,  Zahn,  T.  P.,  &  Kety,  S.  S.:   The 
psychiatric  adjustment  of  the  adopting  parents  of  schizophrenics.   Amer. 
J.  Psychiat.  127:   53-58,  1971. 

Rosenthal,  D.:   Research  patterns  in  assessing  genetic  and  rearing 
factors  in  schizophrenia.   Vestnik  Akademii  Meditsinskikh  Nauk  SSR, 
(Journal  of  the  USSR,  Academy  of  Medical  Sciences)  Meditsina  (Publisher) 
#5:   42-46,  1971. 

Kety,  S.  S.,  Rosenthal,  D.,  Wender,  P.  H.,  &  Schulsinger,  F.:   Mental 
illness  in  the  biological  and  adoptive  families  of  adopted  schizophrenics. 
Amer.  J.  Psychiat.  128:   302-306,  1971. 

Rosenthal,  D.,  Wender,  P.  H.,  Kety,  S.  S.,  Welner,  J.,  &  Schulsinger,  F.: 
The  adopted-away  offspring  of  schizophrenics.   Amer.  J.  Psychiat.  128: 
307-311,  1971. 


Serial  No.  M-P-C- (C) -12 ,  p.  3. 

Rosenthal,  D. :   Foreword  (2).   In  Shields,  J.,  &  Gottesman,  I.  I.  (Eds.), 
Man,  mind  and  heredity:   Selected  papers  of  Eliot  Slater  on  psychiatry 
and  genetics .   Baltimore:   The  Johns  Hopkins  Press,  1971,  pp.  xix-xx. 

Rosenthal,  D.:   Three  adoption  studies  of  heredity  in  the  schizophrenic 
disorders.   Int.  J.  Men.  Health  1:   63-75,  1972. 


2iH 


Serial  No.  M-P-C-(C)-  #15 

1.  Laboratory  of  Psychology 

2.  Section  of  the  Chief 

3.  Bethesda 

PHS  -HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:  Reaction  time  in  schizophrenia. 

Previous  Serial  Number:  Same 

Principal  Investigator:  Theodore  P.  Zahn 

Other  Investigator:      Paul  Fedio 

Cooperating  Units :       Surgical  Neurology  Branch,  NINDS 

Section  on  Psychiatric  Assessment,  NIMH 

Man  Years:  .2 
Total: 

Professional:  .1 

Other:  .1 

Project  Description: 

Objectives:   To  study  deficits  in  attention  in  schizophrenia,  particularly 
as  maxilfested  in  difficulties  in  adopting  axid  maintaining  preparatory  sets. 
To  study  the  specificity  of  such  deficits  to  schizophrenia.  To  study 
possible  organic  and  genetic  determinants  of  such  deficits.  To  determine 
the  relation  between  such  deficits  and  the  severity  of  schizophrenic 
symptomatology. 

Methods  Employed;   (A)  A  reaction  time  (RT)  technique  which  puts  severe 
demands  on  attention  and  which  discriminates  well  between  schizophrenic 
and  non-schizophrenic  subjects  is  being  given  to  patients  before  and  after 
unilateral  temporal  lobectomy  for  the  relief  of  psychomotor  epilepsy. 
This  procedure  and  a  choice  technique  which  compared  RT  to  monaural  stimu- 
lation in  each  ear  and  responses  with  the  same  or  opposite  hand  have  also 
been  used  on  postoperative  temporal  lobe  followup  cases  and  normal  controls. 

(b)  Acute  schizophrenic  and  non-schizophrenic  patients  are  being 
tested  with  these  procedures  soon  after  admission,  on  discharge  from  the 
Clinical  Center  after  3-^  months  and  on  a  followup  6  months  to  1  year  later. 
The  results  will  be  compared  with  intensive  symptom  ratings. 


L 


2i^3 


M-P-C-(C)-  15,  page  2 

Major  Findings:      We  continue  to  find  that  about  half  of  the  temporal 
lobe  followup.  cases  give  essentially  normal  performance  despite  some 
apparent  personality  disturbance.  Most  patients  tested  10  -  15  days 
postoperatively  have  shown  a  decline  from  their  preoperative  performance 
level,  suggesting  a  possible  recovery  of  function  over  time.  The  followup 
cases  are  also  slower  in  choice  ET  but  further  analysis  of  the  data  is 
needed  to  determine  if  this  slowing  is  disproportionate  to  the  simple  RT 
level . 

Significance  to  Biomedical  Research  and  the  Program  of  the  Institute; 
These  studies  are  designed  in  part  to  explore  the  Jjossibility  of  a  biologi- 
cal basis  for  schizophrenia.  Since  patients  with  lesions  in  the  temporal 
lobe  frequently  exhibit  a  schizophrenic-like  personality  picture  and  since 
patients  with  other  types  of  brain  lesions  have  been  found  to  exhibit 
reaction  time  deficits  (but  of  different  types  than  those  shown  by  schizo- 
phrenics) the  reaction  time  performance  of  these  patients  might  indicate 
if  a  temporal  lobe  disturbance  is  possibly  involved  in  schizophrenia. 
The  reciction  time  studies  with  schizophrenics  add  to  our  knowledge  of  the 
specific  psychological  processes  involved  in  the  disorders  of  set  and 
attention  that  seem  to  be  important  aspects  of  the  schizophrenia  process. 

Proposed  Course  of  Project;   Further  collection  of  data  on  both  current 
and  followup  temporal  lobe  cases.  When  enough  data  have  been  collected 
the  effects  of  the  side  of  the  lesion  and  correlations  with  the  amount 
of  tissue  removed  can  be  determined.  Further  data  collection  on  schizo- 
phrenic and  non-schizophrenic  patients . 

Honors  and  Awards :  None. 

Publications:  None. 


2itU 


Serial  No.  M-P-C-(C)  -  #1? 

1.  Laboratory  of  Psychology 

2.  Section  of  the  Chief 

3.  Bethesda 


PHS  -HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June   30,  1972 


Project  Title:   Psychophysiological  Responsivity  in  Schizophrenia. 
Previous  Serial  Number:    Same 

Theodore  P.  Zahn 

Dayid  Rosenthal,  William  Pollin,  Loren  Mosher 


Principal  Investigator 
Other  Investigators : 
Cooperating  Units : 


Section  on  Twin  and  Sibling  Studies,  NIMH 
Section  on  Technical  Development,  MHIRP 
Section  on  Psychiatric  Assessment,  NIMH 


Man  Years: 


Total:      -  .5    -  ■   ,  £ 
Professional:   .2     -      ■ 
Other-         .3 

Project  Description: 

Objectives:   The  general  purpose  of  these  studies  is  to  investigate 
schizophrenic -normal  differences  in  the  relative  autonomic  respon- 
sivlty  to  various  stimuli,  the  relationship- of  autonomic  activity 
to  adequacy  of  performance  and  to  psychiatric  condition,  and  possible 
genetic  determinants . 

Methods  Employed;   1.  ^-.Peripheral  measures  of  autonomic  functioning,  namely 
GSR,  heart  rate,  finger  pulse  volume,  respiration  and  skin  temperature  are 
recorded  during  several  sessions  in  which  stimuli  are  presented  and  tasks 
are  performed  which  vary  in  the  demands  placed  on  the  subjects:   no  stimuli, 
simple  auditory  stimuli  with  no  response  reqiiired,  the  same  with  a  "casual" 
response  required,  reaction  time,  word  association,  mental  arithmetic,  and 
cold  presser.  Specific  and  non-specific  response  frequencies  and  amplitudes, 
baseline  values  and  baseline  changes  are  measured.   These  procedures  have 
been  used  with  identical  twins  discordant  or  concordant  for  schizophrenia 
and  their  parents  and  with  the  adoptive  and  biological  parents  of  schizo- 
phrenic patients  in  order  to  see  if  whatever  genetic  influence  there  is  in 
schizophrenia  is  manifested  in  autonomic  functioning. 

Currently,  acute  schizophrenic  and  non-schizophrenic  patients 
are  being  tested  on  a  shorter  version  of  the  above  proced\ires  soon  after 


2i+5 


M-P-C-(C)-  #17,  page  2 

admission,  at  discharge  from  tne  Clinical  Center  (3-^  months  later)  and  at 
a  6  month  to  1  year  followip. 

Methods  have  been  developed  in  our  laboratory  to  analyze  skin  con- 
ductance, heart  rate,  skin  temperature  and  finger  pulse  volume  data 
automatically  from  taped  analog  records  by  means  of  the  SEL  8lO  B 
computer. 

2.  A  large  scale  exploratory  correlational  analysis  using  both  uni- 
variate and  multivariate  (canonical)  correlations  of  the  psychophysiological 
variables  with  biochemical  and  psychiatric  data  collected  by  other 
investigators  is  being  carried  out  to  determine  the  interrelationships 
between  these  major  classes  of  variables. 

3.  Analyses  of  the  genetic  determinants  of  psychophysiological 
variables  on  the  data  from  the  twins  is  being  carried  out  by  a  method  of 
intra-class  correlation  which  attempts  to  control  for  any  consistent 
influence  of  psychopathology  on  the  dependent  variable. 

k.     The  variability  in  psychophysiological  functioning  is  of  increas- 
ing interest  to  investigators  in  this  field  as  possibly  reflecting  the 
operation  of  regulating  mechanisms.  In  addition  to  measuring  the  magnitude 
of  spontaneous  electrodermal  and  heart  rate  fluctuations,  analyses  of  the 
frequencies  of  heart  rate  variations  have  been  done  by  computing  power 
spectra  on  the  autocorrelation  functions.  Methods  are  being  developed  to 
compare  individual  subjects  with  respect  to  the  patterns  of  frequencies 
exhibited.  Since  examination  of  the  autocorrelations  suggest  an  auto- 
regressive  process,  methods  are  being  developed  to  fit  an  autoregresslve 
model  to  the  data  for  individual  subjects. 

5.  Skin  conductance  data  from  several  studies  are  being  reanalyzed 
using  a  "range  corrected"  measure  by  which  it  is  hoped  to  remove  some  of 
the  extraneous  variation  due  to  anatomical  factors  from  this  measure. 

Major  Findings:   1.  Previously  we  had  found  that  the  differences  between 
the  schizophrenic  and  non-schizophrenic  members  of  the  twin  pairs  were  simi- 
lar to  the  differences  between  unrelated  schizophrenic  and  normal  subjects 
in  that:   (a)  despite  equal  autonomic  responsivity  to  meaningless  stimuli, 
the  schizophrenics  were  significantly  hyporeactive  to  more  meaningful 
stimuli;  and  (b)  the  schizophrenics  showed  higher  arousal  levels  under 
nondemanding  conditions  but  the  controls  showed  a  greater  increase  in  arousal 
under  the  mild  stress  of  task  performance. 

2.  Preliminary  results  from  the  correlational  analyses  show  un- 
expected but  consistent  negative  correlations  between  electrodermal  and 
heart  rate  indices  of  arousal  and  urinary  measures  of  the  precursors  and 
metabolites  of  epinephrine  and  norepinephrine  (dopamine,  metanephrine, 
and  normetanephrine). 


2h6 


M-P-C-(C)-  #17,  page  3. 

3.   Premininary  axialyses  of  the  genetic  determination  of  psycho- 
physiological variables  has  shown  that  overall  autonomic  arousal  levels, 
variability  and  responsivity  seem  to  have  a  significant  genetic -familial 
component,  while  performance  measures  and  the  autonomic  response  to  demand 
do  not  show  appreciable  genetic  influence. 

h.     Most  subjects  show  significant  heart  rate  fluctuations  occuring 
at  U-8  cycles  per  minute  in  addition  to  sinus  arrhythmic  (15  -  20  cycles 
per  minute).   Some  of  the  twin  pairs  show  strikingly  similar  spectra. 

5.  Correlations  among  the  autonomic  perfonnance  and  behavioral 
variables  suggest  that  schizophrenics  with  high  resting  (non-specific) 
arousal  levels  have  poorer  performance  and  more  severe  symptomatology  than 
those  with  lower  arousal  levels,  while  the  relationships  of  task-produced 
increments  in  arousal  have  just  the  opposite  relationships  with  the  behavioral 
variables.  Similar,  but  much  less  marked  relationships  are  found  in  controls. 

6.  A  review  of  the  literature  on  the  relationships  of  autonomic 
phenomena  to  behavior  in  schizophrenia  has  revealed  much  support  for  the 
implication  from  our  research  that  there  is  no  generalized  deficit  in 
autonomic  reactivity  in  schizophrenia,  but  that  such  deficits  occur  speci- 
fically to  meaningful  or  demanding  stimuli  such  as  those  involved  in  task 
performance.  It  is  also  apparent  from  the  literature  that  a  simple  inverted- 
U  relation  between  autonomic  arousal  and  performance  is  not  well  confirmed, 
and  that  what  we  have  called  specific  and  non-specific  arousal  might  have 
different  relationships  to  behavior  in  schizophrenia. 

Significance  to  Biomedical  Research  and  the  Program  of  the  Institute;  The 
role  of  autonomic  arousal  and  responsivity  in  schizophrenic  deficits  in 
behavior  remains  obscure,  but  it  is  clear  from  our  own  research  and  that  of 
other  investigators  that  a  low  arousal  level  is  not  the  critical  factor  as 
has  sometimes  been  postulated.  Oiir  evidence  suggests  that  a  high  arousal 
level  that  is  non-task-related  (non-specific  arousal)  and  low  task-related 
increments  in  arousal  or  the  relationship  between  these  may  be  related  to 
such  performance  deficits.  Further  elucidation  of  the  autonomic  concomitants 
of  symptoms  and  behavior  deficits  in  schizophrenia  may  give  us  an  increased 
understanding  of  the  biological  aspects  of  this  condition  and  therefore  may 
lead  to  more  specific  therapeutic  procedures . 

In  view  of  the  abundant  evidence  that  genetic  factors  are  of  importance 
in  the  etiology  of  schizophrenia,  it  is  reasonable  to  ask  if  a  "schizophrenic 
genotype"  is  manifested  in  the  autonomic  nervous  system.  Some  suggestions  of 
autonomic  hyperactivity  in  our  co-twins  indicate  that  if  there  is  a  genetic- 
ally determined  autonomic  pattern  that  predisposes  individuals  to 
schizophrenia  it  is  of  a  markedly  different  nature  than  that  shown  by 
individuals  who  are,  in  fact,  schizophrenic. 


I 


2iiT 


M-P-C-(C)-  #17,  page  k. 

Proposed  Course  of  Project:   1.  Further  analysis  of  the  data  from  the  twins 
and  their  families  wili  include  (a)  examining  more  autonomic  variables  such 
as  vasomotor  changes,  and  other  aspects  of  electrodermal  functioning 
based  on  new  findings  in  the  literature;  (b)  multivariate  statistical 
analysis  of  group  differences;  and  (c)  partial  correlations  on  selected 
subsets  of  the  large  set  of  variables  from  different  investigators. 
2,   The  development  of  techniques  to  manipulate  general  arousal  levels  and 
specific  alerting  systems  independently.  The  use  of  shock  to  reinforce 
slow  reaction  times  and  in  a  non-contingent  fashion  may  be  a  promising 
start  on  "chis  problem.  3-  More  precise  measurement  of  cardiac  responsivity 
will  be  attempted  by  means  of  estimation  techniques  based  on  auto-regressive 
and  cross-regressive  models  of  heart  rate  variation,  h.     Continued  data 
collection  on  acute  subjects. 

Honors  and  Awards :  None . 

Publications:  None. 


2k8 


Serial  No.  M-P-C-(c)  -  36 

1.  Laboratory  of  Psychology 

2.  Section  of  the  Chief 

3.  Bethesda 

PHS-IiSMHA-MMH 
Indi-vidual  Project  Report 
Julj  1,  1971  through  June  30,  1972 

Project  Title:  Psychological  Correlates  of  Cortical  Evoked  Responses 

Previous  Serial  Number:  Same 

Principal  Investigator:  Monte  Buchsbaum 


Other  Investigators ; 


Cooperating  Units : 


Man  Years: 

Total:  / 

Professional: 

Other: 

Project  Description: 


Lyman  C.  Wynne,  Stephen  Landau,  Thomas  Bittker, 
Paul  Fedio,  Dennis  Murphy,  Frederick  Goodwin, 
Paul  H.  Wender  and  Robert  I.  Henkin. 

Adult  Psychiatiy  Branch,  NIMH 
S\irgical  Neurology  Branch,  NINDS,  NIH 
Laboratory  of  Clinical  Science,  NIMH 
Clinical  Endocrinology,  NHI,  NIH 


2.2 
1.2 
1.0 


Objectives :  Exploration  of  relationships  between  perceptual  response 
patterns,  psychiatric  clinical  dimensions  and  neurophysiological  measures; 
the  development  of  improved  techniques  for  collecting  and  analyzing  neuro- 
physiological data  collected  from  intact  human  subjects;  detailed  study  of 
the  interaction  between  attention,  cortical  area  and  individual  differences 
in  neurophysiological  response. 

Methods  Employed:   Central  nervous  system  function  has  been  difficult  to 
study  in  psychiatric  patients  by  either  conventional  neuroanatomic  or 
implanted  electrode  techniques,  as  the  former  requires  a  dead  patient 
(or  an  animal  model  of  the  disease)  and  the  latter  requires  a  hazardous 
surgical  procedure.  Obviously,  neither  method  permits  long-term  study 
of  psychiatric  episodes.  With  the  development  of  average  evoked  response 
techniques,  which  allow  recovery  of  relatively  specific  CNS  signals  from 
scalp  EEG,  neurophysiological  attempts  to  study  psychiatric  disorders 
received  new  impetus.  The  average  evoked  response  (AER)  is  a  particularly 
promising  tool  for  studying  perception  in  the  psychiatric  patient  because, 
unlike  traditional  psychophysical  techniques,  it  does  not  depend  upon  the 
patient's  report  or  overt  performance.  Thus,  the  importance  of  motivation 
or  motor  activity  is  minimized  and  a  clearer  separation  of  perceptual  (input) 
and  performance  (output)  factors  may  be  achieved. 


2^+9 


Serial  Wo.  M-P-C-(C)  -  36,  page  2 

Cortical  average  evoked  responses  (AER's)  are  patterns  of  electrical 
response  to  sensory  input  which  are  recorded  from  the  electroencephalogram. 
Because  evoked  responses  are  usually  of  extremely  small  amplitude  (less  than 
10  millionths  of  a  volt),  these  patterns  are  completely  lost  in  the  apparently 
random  fluctuation  of  the  EEG.  But  we  can  overcome  this  obstacle  by  taking 
advantage  of  the  fact  that  an  evoked  response  is  always  related  in  time,  or 
"time -locked,"  to  a  sensory  stimulus,  whereas  the  background  EEG  activity 
varies  and  bears  no  fixed  relationship  to  the  stimulus.  By  presenting  the 
subject  with  a  long  series  of  stimuli,  such  as  flashes  of  light,  and  summing 
the  EEG  for  a  brief  time  interval  after  each  flash,  an  AER  is  produced. 

The  development  of  computer  technology  has  been  an  essential  step  in 
the  application  of  AER  measures  to  large-scale  patient  testing.  During  the 
past  year  a  system  for  the  collection  and  processing  of  evoked  response  data 
has  been  put  into  operation  on  the  SEL  8lO  B.  This  is  a  modular,  multi- 
purpose system,  allowing  the  investigator  maximum  flexibility  in  running  and 
in  implementing  new  experiments.  The  system  is  comprised  of  three  parts. 
The  first  phase,  EXPMAS ,  controls  the  actual  running  of  the  experiment.   It 
is  table  driven  and  allows  for  easy   implementation  of  new  paradigms.  The 
second  phase,  AERMAS ,  provides  for  scoring  of  evoked  response  records.  The 
third  phase  is  a  package  of  statistical  routines  to  perform  the  final 
statistical  analysis.  The  major  utility  of  the  system  is  the  short  amount 
of  time  between  the  conception  of  a  new  experiment,  its  actual  implementation, 
and  final  data  analysis.  Since  all  aspects  of  the  experimental  situation  are 
under  the  system's  control,  the  investigator  may  proceed  with  his  design 
without  a  delay  for  experiment  changes . 

Major  Findings:  Coping  with  sensory  overload  is  perhaps  the  major  percep- 
tual problem  of  20th  century  urban  man;  individuals  differ  widely  both  in 
their  relative  success  in  meeting  the  challenge  and  in  their  styles  of 
coping.  Evoked  responses  to  loud,  repetitious,  meaningless  and  meaningful 
stimuli  have  been  studied  in  subjects  attending  to  or  trying  to  ignore  the 
stimuli.  The  early  discovery  that  some  subjects  paradoxically  showed  actual 
decreases  in  AER  amplitude  with  increasing  stimulus  intensity  led  to  the 
development  of  a  perceptual  style  concept  known  as  "stimulus  intensity 
control",  and  to  a  variety  of  clinical  and  more  basic  investigations. 

1.  Methodologic  Issues.  The  apparent  ability  of  these  subjects  to 
"turn  down"  or  "turn  off"  is  evidenced  most  strongly  over  nonspecific 
cortical  areas  (vertex  vs.  occipital  cortex)  and  is  unrelated  to  changes  in 
pupillary  diameter.  When  the  subject's  attention  is  directed  toward  the 
stimuli,  the  rate  of  increase  in  AER  amplitude  with  stimulus  intensity  is 
correlated  across  visual  and  auditory  modalities,  thus  supporting  the  concept 
of  a  central  stimulus  intensity  modulating  mechanism. 


2.  Biochemical  and  Clinical  Studies.  AER  amplitude  has  been  found  to 
increase,  especially  at  high  intensities,  after  infusion  of  L-dopa  in 
patients  with  affective  disorders  in  late  (200  msec)  components,  but  not  in 
earlier  ones  (l40  msec).  Amphetamine  in  hyperactive  children  has  a  similar 
effect.  This  is  in  contrast  to  phenothiazine  and  lithium  results  where  the 


250 


1 


Serial  No.  M-P-C-(c)  -  36,  page  3 

earlier  peak  was  affected.   Individual  differences  in  drug  response  were 
important  in  toth  cases;  patients  categorized  as  unipolar  depressive 
illnesa  and  children  who  showed  worsening  of  hyperactivity  on  amphetamine 
both  showed  the  AER  augmentation;  other  patients  and  children  who  showed 
clinical  improvement  (decreasing  hyperactivity)  showed  AER  reduction. 

3.  Arousal  and  Attention;  The  effects  of  muscle  tension,  pain,  and 
shifts  in  attention  on  the  AER  to  varying  intensities  of  light  were  studied 
in  a  series  of  experiments.  In  subjects  actively  discriminating  light  inten- 
sities, low  intensity  stimulus  AER  were  as  large  as  high  intensity  AER. 
This  perhaps  makes  possible  an  independent  neurophysiological  assessment  of 
attention.  Muscle  tension  significantly  decreased  mean  AER  amplitude  but 
did  not  alter  the  mean  rate  of  change  of  AER  amplitude  with  stimulus  inten- 
sity. In  contrast,  the  painful  or  sensory  overload  condition  caused  the 
high  intensity  response  to  diminish  and  the  low  intensity  response  to 
increase  without  altering  the  mean  across  intensities .  Direction  of  attention 
toward  the  subject's  body  or  to  a  diffuse  task,  such  as  searching  for  an 
intensity  sequence,  had  no  effect  either  on  amplitude  or  amplitude-intensity 
relationships .  ! 

h.  Twin  Studies.  Data  on  AER,  perceptual  tasks,  autonomic  psychophysio-  Ji 
logy,  blood  type  and  interview  material  have  been  collected  on  60  normal  twin  ||, 
pairs.  Data  analysis  will  begin  shortly  (see  Project  M-AP(c)  -  21-4).  « 

5.  Contrast,  Congruence  and  Habituation.  Anchoring  or  contrast  effects 
were  further  explored  using  groups  of  individuals  which  either  increased 
(augmenters)  or  decreased  (reducers)  their  AER  amplitude  with  increasing 
stimulus  intensity.  The  augmenter  group  showed  evoked  responses  which  were 
diminished  by  having  an  intense  preceding  stimulus  and  increased  by  having 
a  dim  preceding  stimulus.  The  reducer  group,  as  might  be  expected,  showed 
the  reverse.  They  showed  evoked  responses  which  were  larger  when  preceded 
by  an  intense  stimulus  and  smaller  when  preceded  by  a  dim  stimulus .   Thus 
in  both  cases  an  intense  preceding  stimulus  moved  the  perceived  intensity 
of  the  stimulus  to  a  lower  level  and  a  preceding  dim  stimulus  moved  the 
perception  of  intensity  to  a  higher  level.  This  further  demonstrated  the 
tendency  of  the  AER  to  reflect  the  perceived  intensity  of  stimulation. 
This  contrast  effect  may  be  closely  linked  to  the  phenomena  of  habitua- 
tion, and  the  failure  to  contrast  to  dishabituation — again  both  mechanisms 
for  dealing  with  sensoiy  overload.  In  a  series  of  studies  using  complex 
stimulus  sequences,  pronounced  individual  differences  were  found  in  a 
subject's  tendency  to  ignore  minor  differences  as  reflected  in  the  AER. 
This  tendency  to  ignore  stimulus  complexity  —  the  "congruence  illusion" — 
can  be  reversed  by  providing  them  with  sufficient  information  to  permit 
them  to  build  more  sophisticated  and  accurate  interval  constructs  for 
their  perceptual  experience. 


251 


Serial  No.  M-P-C-(c)  -  36,  page  k 

Significance  to  Bio-Medical  Research  and  the  Program  of  the  Institute; 
This  project,  in  helping  to  give  a  neurophysiological  basis  to  psycho- 
logical tests,  contributes  to  the  effort  to  understand  mechanisms  of 
variation  in  human  personality.   Further,  the  techniques  may  yield 
psychological  information  from  subjects  without  the  need  for  language  or 
more  than  passive  cooperation. 

Proposed  Course  of  Project;  This  year's  work  has  suggested  potential  ways 
of  giving  relatively  specific  biochemical,  psychological  and  perhaps  even 
anatomic  meaning  to  certain  AER  components.  Emphasis  in  the  next  two 
years  will  go  on  exploiting  these  new  leads  and  developing  new  mathematical 
techniques.  Eventually  these  new  refinements  will  be  applied  in  clinical 
directions  suggested  by  our  twin  studies. 

1.  Biochemical  and  clinical  studies  will  continue  with  study  of  MBD 
children,  patients  with  affective  disorders  and  normal  volunteers  given 

d-  and  1- amphetamine.  Analysis  of  current  data  on  a  sample  of  83  patients 
and  a  large  group  of  age  and  sex  matched  normals  is  currently  underway. 

2.  Twin  studies  will  enter  a  data  analysis  phase  with  emphasis  both 
on  determining  Mz  -  Dz  differences  and  using  physiological  and  psychologi- 
cal data  to  predict  perceptual  differences  in  Mz  pairs. 

3.  Habituation.  Parallels  between  our  human  AER  habituation  results 
and  Thompson's  dual  process  theory  of  habituation  (based  on  acute  spinal 
cat  data)  are  intriguing  and  will  be  further  explored  in  parametric  studies, 

h.     Studies  of  the  interaction  of  attention,  habituation,  and  stimulus 
intensity  in  normal  subjects  are  planned.  These  studies  will  yield  a  more 
detailed  understanding  of  the  AER  variation  seen  with  shifts  of  attention 
and  aid  in  the  development  of  clinical  tools  for  testing  attentional 
deficits.   Further,  they  will  expand  our  battery  of  AER  measures  defining 
mechanisms  for  coping  with  sensory  overload. 

5«  New  mathematical  approaches.  A  package  of  basic  mathematical 
routines  required  for  the  analysis  of  time  series  data  has  been  completed. 
This  will  allow  spectral,  cross-spectral  and  covariance  analysis  for 
data  collected  on  the  SEL  system.  A  group  of  users  interested  in  time 
series  analysis  of  EEG  and  EEG  frequency  conditioning  will  collaborate. 
It  is  planned  to  contract  for  additional  programming  necessary  to  utilize 
these  routines  in  specific  experimental  designs. 

The  combination  of  these  techniques  with  beam-forming  may  enable 
localization  and  detection  of  individual  components  of  the  AER.  The 
analysis  of  a  subject's  signal  detection  processes  on  a  neurophysiological 
basis  will  then  be  investigated. 

Honors  and  Awards:  None. 


252 


Serial  No.  M-P-C(c)  -  36,  page  5 
Publications : 

Buchsbaum,  M.:   Average  evoked  response  techniques  and.  applications, 
Schiz.  Bull.  Winter,  I97O.  pp.  IO-I8. 

Buchsbaum,  M.,  Silvennan,  J.,  and  Henkin,  R.:  Contrast  effects  on  the 
auditory  evoked  rec;ponse  and  its  relation  to  psychophysical  judg- 
ments. Percep.  Psychophys .   9:   379-385,  I97I. 

Buchsbaiun,  M.,  King,  C.  and  Henkin,  R.  I.:  Average  evoked  responses  and 

psychophysical  performance  in  patients  with  pseudohypoparathyroidism, 
J.  Neurol.  Neurosurg.  Psychol.  In  press. 

Buchsba\im,  M.:  Cybernetics  and  the  cortical  evoked  potential.   Trans. 
Amer,  Cybernetic  Soc.   In  press. 

Buchsbaum,  M.:  Neural  events  and  psychophysical  law.  Science.  172:  502, 
1971. 

Buchsbaum,  M.  and  Pfefferbaum,  A.:  Individual  differences  in  stimulus  inten- 
sity response.  Psychophys iol.  8  (5):   6OO-61I,  I97I. 

Buchsbaum,  M.,  Goodwin,  F. ,  Murphy,  D.,  axid  Borge,  G.  AER  in  affective  dis- 
orders. Amer.  J.  Psychiat.  128:   19-25,  I97I. 

Borge,  G.,  Buchsbaum,  M.,  Goodwin,  F.,  Murphy,  D.,  and  Silverman,  J.: 

Neuropsychological  correlates  of  affective  disorders.  Arch.  Gen.. Psychiat. 
2k:      501-504,  1971. 

Fedio,  P.,  and  Buchsbaum,  M.:  Unilateral  temporal  lobectomy  and  changes 
in  evoked  responses  during  recognition  of  verbal  and  non-verbal 
material  in  the  left  and  right  visual  fields.  Neuropsychologia 
9:  261-271,  1971. 

Gips,  J.,  Pfefferbaum,  A.,  and  Buchsbaum,  M. :   Use  of  a  small  process  control 
computer  in  a  psychophysiological  laboratory.  Psychophysiol .   8  (h): 
538-5^2,  1971. 

Gips,  J.,  Pfefferbaum,  A.  and  Buchsbaum,  M. :   ERL  -  A  language  for  implement- 
ing evoked  response  and  psychophysiological  experiments.  Behav.  Res . 
Meth.  Instrument.  3  (4):   199-201,  1971. 

Gillin,  J.  C,  Jacobs,  L.S.,  Fram,  D.H.,  Williams,  R.,  Buchsbaum,  M.  and 

Snyder,  F.  Partial  REM  phase  deprivation  and  schizophrenia:  An  experi- 
mental reappraisal.  Arch.  Gen.  Psychiat.  In  press. 

Pfefferba-um,  A.,  Buchsbaum,  M.,  and  Gips,  J.  :  Enhancement  of  the  AER  to 
tone  onset  and  cessation.  Psychophysiol.  8  (3):  332-339?  1971. 

Silverman,  J.,  Buchsbaum,  M.  and  Stierlin,  H.  Sex  differences  in  perceptual 
differentiation  and  stimulus  intensity  control.  J.  Pers.  Soc.  Psychol. 
In  press. 

253 


Serial  Wo.   M-P-C(C)    -   36,   page  6 
5.      237-2i4-0,   1971. 


25^ 


serial  No.  M-P-C-(c)-39 

1.  Laboratory  of  Psychology 

2.  Section  of  the  Chief 

3 .  Bethesda 

PHS-HSMEIA-WIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   Study  of  heredity  and  environmental  factors  in  schizophrenia. 

Previous  Serial  Number:   Same 

Principal  Investigator:   Paul  H.  Wender 

Other  Investigators:   David  Rosenthal,  John  Rainer  (New  York), 
Laurence  Greenhill 

Cooperating  Units:   Research  Foundation  for  Mental  Hygiene,  Inc., 
722  West  168th  Street,  New  York,  N.Y.   10032 

Man  Years: 

Total:  3.1 
Professional:  2.3 
Other:         .8 

Project  Description: 

Objectives:   To  assess  the  role  of  environmental  factors  in  the  etiology  of 
schizophrenia. 

Methods  Employed:   The  strategy  involves  the  use  of  adopted  subjects  to 
separate  the  roles  of  genetic  and  experiential  factors.   Since  the  biologi- 
cal parents  are  not  the  parents  who  rear  their  children,  the  transmitters 
of  genetic  factors  and  social  experience  are  separated.   In  this  study  we 
evaluate  the  psychiatric  status  and  cognitive  function  of  three  groups  of 
parents:   those  who  have  adopted  children  who  subsequently  became  schizophre- 
nic; those  who  reared  their  own  schizophrenic  children;  and  those  who  reared 
their  own  organically  impaired  offspring. 

Psychiatric  pathology  is  assessed  by  means  of  structured  interviews  ad- 
ministered by  interviewers  who  are  blind  as  to  the  status  of  the  parents 
interviewed.   Cognitive  function  is  assessed  by  means  of  a  battery  of  psy- 
chological tests. 

The  design  permits  a  test  of  three  hypotheses:   (l)  if  psychopathology 
among  the  parents  of  schizophrenics  is  a  cause  of  the  disturbance  in  the 
offspring  it  should  be  present  in  both  the  adopting  and  biological  parents 
of  schizophrenics;  (2)  if  psychopathology  in  the  parents  of  schizophrenics 
is  largely  a  manifestation  of  a  genetically  transmitted  disorder,  it  should 
be  present  in  the  biological  and  not  the  adopting  parents  of  schizophrenics; 

255 


Serial  No.  M-P-C-(c)-39,  page  2. 

(3)  if  psychopathology  among  the  parents  of  schizophrenics  is  largely  re- 
active to  pathology  in  the  child,  it  should  be  present  equally  in  the  parents 
of  schizophrenics  and  of  organically  impaired  children. 

The  present  study,  -which  replicates  an  earlier  study  of  the  adopted  par- 
ents of  schizophrenics,  has  three  methodological  improvements:   (l)  it  employs 
systematic  sampling;  (2)  it  employs  raters  who  are  kept  blind  as  to  the  status 
of  the  parents  interviewed;  (3)  it  employs  a  comparison  group  of  parents  of 
organically  impaired  children  (controlling  for  the  effect  of  the^  child  on  the 
parent) . 

Ma.ior  Findings:   Case  findings  and  evaluation  have  been  completed.   Fifty- 
eight  couples  (of  the  sixty  proposed)  have  been  interviewed  and  tested. 

Significance  to  Bio-medical  Research  and  the  Program  of  the  Institute:   ¥e 
are  attempting  to  validate  our  earlier  finding  which  indicated  that  parental 
psychopa-chology  did  net  seem  strongly  related  to  the  etiology  of  schizo- 
phrenia. 

Proposed  Course  of  Project:   Transcription  of  the  Interview  and  test  material 
should  be  completed  by  July  1972.   Data  analysis  will  begin  at  that  time  and 
should  be  complete  --  except  for  the  Rorschach  evaluations  --by  the  spring 
of  1973. 


256 


Serial  No.  M-P-C-(c)-to 

1.  Laboratory  of  Psychology 

2.  Section  of  the  Chief 

3.  Bethesda 

'■'■'■■■  PHS-HSMHA-NIMH 

Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   Changes  in  neurological  and  psychological  functioning  in 

children  with  minimal  brain  dysfunction  receiving  d-ampheta- 
mine    •  ,     . 

Previous  Serial  Number:   Same 

Principal  Investigator:   Paul  H.  Wender 

Other  Investigators:   Monte  Buchsbaum 


Cooperating  Units: 

None 

Man  Years: 

Total: 

Professional: 

Other: 

.1 
.1 
.0 

Project  Description: 

Objectives:   To  compare  neurological  and  psychological  functioning  of 
children  with  minimal  brain  dysfunction  and  normal  children  and  to  eval- 
uate the  changes  produced  in  the  former  group  following  treatment  with 
d -amphetamine. 

Methods  Employed:   The  study  population  consists  of  a  group  of  normal 
children  and  a  group  of  children  with  minimal  brain  dysfunction  who  have 
manifested  a  clear-cut  clinical  improvement  following  treatment  with 
d-amphetamine. 

Both  groups  will  be  evaluated  to  assess  positions  and  changes  along 
the  following  dimensions:   (l)  average  cortical  evoked  response,  and 
(2)  field  dependence. 

Children  with  minimal  brain  dysfunction  are  characterized  by  inat- 
tentiveness  and  stimulus  boundedness,  both  of  which  appear  to  change  fol- 
lowing successful  treatment  with  d-amphetamine.   These  characteristics  (and 
change  in  them)  may  be  associated  with  performance  on  certain  tasks;  par- 
ticularly the  Rod  and  Frame  test,  and  the  Petrie  task,  and  in  average  cor- 
tical evoked  response  to  sensory  stimuli.   It  is  the  purpose  of  this  pro- 
ject to  determine  if  correlates  exist  between  the  clinical  condition,  re- 
sponse to  treatment,  and  test  performance. 


257 


Serial  No.  M-P-C-(c)-40,  page  2. 

Ma.ior  Findings:  None.   Data  analysis  has  "begun. 

Significance  to  Bio-medical  Research  and  the  Program,  of  the  Institute: 
Minimal  brain  dysfunction  is  an  extremely  common  syndrome  in  the  pre-adoles- 
cent  population,  occurring  in  perhaps  57°  of   that  population.   Its  neuro- 
physiological  basis  is  not  understood  and  its  diagnosis  cannot  be  made  with 
accuracy.  This  project  may  contribute  to  an  understanding  of  its  etiology 
and  to  more  accurate  diagnostic  technique. 

Proposed  Course  of  Project:  To  date,  l6  children  with  minimal  brain  dysfunc- 
tion and  12  controls  have  been  tested.  Data  analysis  should  be  completed  by 
the  summer  of  1972. 

Honors  and  Awards:  None. 

Publications:  None. 


258 


Serial  No.  M-P-C-(c)-ii3 

1.  Laboratory  of  Psychology 

2.  Section  of  the  Chief 
3-   Bethesda 


PHS-HSMHA-HIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:   Lithium  as  a  therapeutic  agent  in  hyperkinetic  behavior 
disorders  of  childhood. 

Previous  Serial  Number:   Same 

Principal  Investigator:   Paul  H.  Wender 

Other  Investigators:   Ronald  0.  Rieder,  James  Weiss,  Monte  Buchsbaum, 
Theodore  Zahn 

Cooperating  Units:   Office  of  the  Chief,  Laboratory  of  Clinical  Science 

Man  Years: 

Total:  1.2 
Professional:  1.2 
Other:        0 

Project  Description: 

Objectives:   To  compare  the  physiological,  neurological,  and  behavioral 
effects  of  lithium  carbonate  and  dextro -amphetamine  sulfate  in  single  blind 
trials  on  a  hospitalized  population  of  children  with  the  hyperkinetic  syn- 
drome who  have  been  unresponsive  to  amphetamines  and  phenothiazines. 

Methods  Employed:   Subjects  ages  6  to  1^+  diagnosed  as  hyperkinetic  who  have 
failed  to  respond  to  conventional  drugs.   The  subjects  are  admitted  to  the 
NIH.   During  their  first  week  in  the  hospital,  the  children  are  screened  for 
cardiac  and  thyroid  abnormalities,  have  routine  urinary  17-hydroxy  steroid 
levels  taken,  and  have  baseline  evoked  potentials  and  autonomic  reactivity 
studies  completed.   They  are  placed  on  a  placebo  at  this  time  and  baseline 
nurses'  behavioral  ratings  and  teachers'  ratings  at  NIH  are  obtained. 
During  the  second  week,  the  children  are  given  dextro -amphetamine  sulfate 
(not  to  exceed  30  mg.  q.o.d.,  p.o.)  and  again,  2k   hour  urines,  physiological 
measures,  and  teachers'  and  nurses'  behavioral  check  lists  are  obtained. 
During  the  third  and  final  week,  the  children  are  given  lithium  carbonate 
(not  to  exceed  1200  mg.  p-o.,  q.o.d.),  daily  lithium  blood  levels  are  drawn, 
and  the  urines  are  obtained.  As  the  child  reaches  the  therapeutic  dose 
level  of  between  0.8  mEq.  per  liter  and  1.2  mEq.  per  liter,  he  is  discharged 
to  home  and  is  followed  on  a  weekly  basis  in  the  NIH  Outpatient  Clinic.   Two 
weeks  following  the  child's  first  blood  level  of  at  least  or  more  than 


259 


Serial  Uo.  M-P-C-(c)-i+3,  page  2. 

0.8  mEq.  per  liter,  the  third  set  of  physiological  studies  are  done  on  an 
outpatient  basis. 

Because  of  the  favorable  effects  of  the  small  WLE   classroom,  frequent 
one  to  one  nursing,  and  the  strict  structured  environment  of  the  ward,  it 
is  difficult  to  completely  evaluate  any  possible  improvement  seen  in  the 
hospital.   The  post-hospitalization  period  is  then  used  as  a  true  single 
blind  study  and  behavioral  check  lists  are  distributed  to  the  child's 
teacher  and  the  child's  own  parents.   It  is  one  of  the  major  objectives  of 
this  project  to  establish  both  the  safety  and  efficacy  of  lithium  carbonate 
treatment  in  children  outside  the  hospital. 

Major  Findings:  None.   To  date  ten  children  have  been  treated.   It  appears 
that  these  children  handle  lithium  very  well  and  that  safe  blood  levels  can 
be  reached  and  stably  maintained  without  difficulty.   Data  on  the  effective- 
ness of  lithium  will  not  be  available  until  a  large  sample  has  been  obtained. 

Significance  to  Bio-medical  Research  and  the  Program  of  the  Institute:   The 
hyperkinetic  syndrome  of  childhood  is  an  extremely  common  syndrome  in  the 
preadolescent  population,  but  only  one-half  to  two-thirds  of  these  children 
respond  well  to  current  medication.   Recent  reports  by  Annell  and  Dyson  have 
suggested  that  lithium  carbonate  may  assist  some  of  these  formerly  unrespon- 
sive children.   Both  reports  tend  to  stress  subgroups  of  the  hyperkinetic 
population,  i.e.,  Dyson  has  worked  with  offspring  of  manic  depressives  and 
Annell 's  success  is  limited  to  borderline  psychotic  adolescents.   Furthermore, 
lithium  carbonate  treatment  may  be  a  less  toxic  drug  than  dextro-amphetamine 
sulfate  when  given  over  several  years'  time. 

Proposed  Course  of  Project:   Data  collection  has  been  completed.   Data  analy- 
sis should  be  completed  by  the  spring  of  1972. 

Honors  and  Awards:   None. 

Publications:  None. 


260 


Serial  No.  M-P-C-(c)-  hk 

1.  Laboratory  of  Psychology 

2.  Section  of  the  Chief 
3^     Bethesda 


PHS-HSMHA-NIMH 


Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   Individual  Differences  in  Eye  Movement  Search  Patterns. 

Previous  Serial , Number:  Same 

Principal  Investigator:  Monte  Buchsbaum 


Other  Investigators : 
Cooperating  Units: 


Richard  Coppola,  Richard  Stillman,  James  Bryan 
and  Lyman  C .  Wynne . 

Adult  Psychiatry  Branch,  NIMH 

Section  on  Technical  Development,  MHERP 


Man  Years:  ,  ' 

Total:. 

2.0 

Professional: 

1.6 

Other: 

.k 

h 


Project  Description: 

Objectives;  ^  Development  of  a  computer  controlled,  interactive,  real  time 
eye  movement'  detector;  study  of  individual  differences  in  eye  movement  with 
rega,rd  to  search  patterns,  information  input  and  feedback;  exploration  of 
eye  movement  characteristics  in  normal  and  various  psychopathologic  groups . 

Methods  Employed:  The  apparatus  recently  developed  by  this  project  utilizes 
a  MacWorth  eye  movement  camera  stand  and  a  television  camera.  The  corneal 
reflection  of  a  visible  light  source  is  transmitted  through  an  optical 
system  into  a  television  camera.  The  cartesian  coordinates  are  determined 
from  the  video  signal  by  analog  devices,  thus  yielding  the  eye's  point  of 
regard  at  any  given  time.  A  process  control  computer  (lINC)  is  used  to 
generate  visual  displays  and  record  the  analog  record  data.  A  data  editing 
system  allows  calibration  of  the  analog  inputs  and  conversion  of  the  data  to 
the  screen  coordinates .  The  program  then  outputs  the  duration  and  location 
of  each  successive  eye  fixation. 

The  resultant  system  provides  for  the  first  time  an  on  line  process 
control  eye  movement  recorder  and  display  system.  Prior  to  this  development 
individual  difference  studies  have  been  prohibitively  costly  in  terms  of  time 
required  for  data  analysis.   For  instance,  hand  analysis  of  10  seconds  of  eye 
movements  recorded  on  motion  picture  film  would  require  four  hours  to  prepare 
before  it  could  be  used  as  computer  input.  This  stage  of  data  analysis  is 
now  completely  eliminated  and  the  average  subject  is  run  on  20  such  10-second 


261 


Serial  No.  M.  P-C-(c)  -  kk,   page  2 

trials.  The  system  has  been  dramatically  upgraded  this  year  with  the  in- 
troduction of  a  silicon  matrix  vision  tube  with  low  noise  levels  which 
permits  cleaner  records  and  easier  adjustment  of  subjects.  In  addition 
the  LINC  computer  has  been  interfaced  wi*-h  our  medium  sized  SEL  system, 
allowing  rapid  statistical  analysis  of  the  eye  movements.  A  group  of 
Markov  analysis  programs  were  written  and  utilized  in  describing  the  data. 

Experimental  Methods:   Fifteen  normal  subjects  have  been  tested  on  two 
separate  occasions.  Each  subject  viewed  a  computer  display  of  the  outline 
of  two  squares;  one  of  which  was  always  the  same  size  and  the  other  a  vari- 
able size  from  one  presentation  to  the  next.  He  was  given  the  task  of 
ascertaining  whether  the  variable  square  was  larger  or  smaller  than  the 
standard.  Sixty  twin  pairs  (Mz  and  Dz)  and  10  schizophrenic  subjects  have 
also  been  tested. 

Results :   The  reliability  of  individual  differences  in  patterns  of  eye 
fixation  during  a  size  estimation  task  were  studied  in  normal  adults, 
each  tested  twice.  The  most  stable  measures  not  specifically  related  to 
the  stimulus  configuration  appeared  to  be  the  number  of  fixations  per  unit 
time;  measures  related  to  dispersal  of  looking  were  unreliable.  Data  on 
where  the  subject  looked,  the  duration  of  each  fixation  and  the  distance 
between  fixation  points  appeared  to  follow  1st  order  Markov  processes  and 
the  transitional  probabilities  appeared  to  be  individual  characteristics 
stable  over  time. 

Significance  to  Biomedical  Research  and  the  Program  of  the  Institute; 

Eye  movements  are  important  indicators  of  information  input  strategies  and 

may  therefore  reflect  psychophysiological  styles  of  information  search. 

The  possibility  of  using  this  and  other  objective,  physiological  measures 

to  better  distinguish  psychiatric  patients  is  central  to  psychophysiological 

research. 

Proposed  Course  of  Project:   Characterization  of  eye  movement  parameters 
as  1st  and  2nd  order  Markov  chains  has  suggested  a  conceptual  model  of  a 
possible  psychophysiological  information  search  strategies--individuals 
with  independent  eye  movements  (o  order  Markov  process,  transitional 
probabilities  independent  of  current  state)  lack  any  overall  information 
gathering  strategy  or  fail  to  change  strategies  after  inputing  relevant 
information.  Further  research  is  planned  exploiting  the  Markov  analysis 
fully.  These  data  analysis  techniques  will  be  applied  to  the  twin  and 
schizophrenic  data  sample. 

Honors  and  Awards:  None. 

Publications : 


262 


Serial  No.  U-F-C-{c)-h^ 

1.  Laboratory  of  Psychology 

2.  Section  of  the  Chief 

3.  Bethesda 

PHS-HSMEA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   The  offspring  of  schizophrenics:   markers  of  a  schizophrenic 
disposition. 

Previous  Serial  Number:   None 

Principal  Investigator:   Ronald  0.  Rieder 

Other  Investigators:   David  Rosenthal,  Paul  Wender 

Cooperating  Units:   PHS-NIH-NINDS-PRB 

Man  Years: 

Total:  1.2 
Professional:  .9 
Other:         .3 

Project  Description: 

Objectives:  To  discover  differences  between  the  offspring  of  schizophrenics 
and  controls,  at  an  early  stage  in  life,  which  may  represent  a  predisposition 
to  develop  schizophrenia  later  in  life. 

Methods  Employed:   This  study  has  utilized  the  data  previously  collected  by 
the  National  Institute  of  Neurological  Diseases  and  Stroke,  Perinatal  Re- 
search Branch,  in  their  "Collaborative  Study  on  Cerebral  Palsy,  Mental  Re- 
tardation and  Other  Neurological  and  Sensory  Disorders  of  Infancy  and  Child- 
hood." In  that  project,  some  55,000  pregnancies  and  the  offspring  were 
studied,  with  the  7  year  follow-up  now  being  completed.   About  900  of  the 
mothers  or  fathers  had  had  a  psychiatric  hospitalization,  and  of  this  group, 
we  have  taken  220  who  were  studied  in  the  Boston  area  to  use  for  our  study. 
Since  we  are  primarily  interested  in  the  offspring  of  schizophrenics,  the 
past  year  has  been  used  to  gather  the  records  of  psychiatric  hospitaliza- 
tions, so  that  we  could  diagnose  the  parents  according  to  a  set  of  uniform 
criteria.   Since  records  on  the  children  are  already  complete,  when  the 
work  of  diagnosis  is  completed,  we  will  match  a  control  group  and  compare 
the  groups  on  such  measures  as  the  neurological  examination  and  the  Bayley 
Scale  of  infant  behavior. 

Major  Findings:   None  to  date 


k 


263 


Serial  Wo.  M-P-C-(c)-i+5,  page  2. 

Significance  to  Bio-medical  Research  and  the  Program  of  the  Institute:   This 
work  follows  the  work  of  this  Laboratory  on  the  genetics  of  schizophrenia. 
We  need  to  find  a  clinical  or  hehavioral  marker  of  the  predisposition  to 
schizophrenia  if  we  are  to  effectively  intervene  or  do  biochemical  or  physio- 
logical investigations  of  the  developm.ent  of  schizophrenia. 

Proposed  Course  of  the  Pro.iect:   Record  collection  and  diagnosis  should  be 
completed  by  July  1972.  Data  analysis  on  the  offspring  will  begin  in  the 
next  year,  and  will  probably  be  completed  by  July  1973- 

Honors  and  Awards:   None 

Publications:   None 


^ 


261+ 


Serial  No.  M-P-C-(C)  -  #^6 

1.  Laboratory  of  Psychology 

2.  Office  of  the  Chief 
•  .                   '     3.  Bethesda 

PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   Psychophysiological  Changes  During  the  Menstrual  Cycle. 

Previous  Serial  Number :  M-P-C-(c)  -  17 

Principal  Investigator:   Theodore  P.  Zahn,  Ph.D. 

Other  Investigator:      Betsy  Little  (Guest  Worker) 

Cooperating  Units:       None 

Man  Years : 

Total:  .6 
Professional: .1 
Other:       .5 

Project  Description: 

Objectives:  To  study  autonomic  changes  through  the  menstral  cycle.   To 
study  the  relationships  between  autonomic  changes  and  changes  in  time 
estimation,  reaction  time,  and  mood  throughout  the  menstrual  cycle. 

Methods :  A  short  experimental  procedure  is  used  every  day  for  each  subject 
for  a  complete  cycle.   Five  autonomic  measures  are  used  (finger-pulse 
volume,  heart-rate,  respiration,  skin  temperature  and  skin  resistance,)  in 
three  situations :- 

(i)  giving  the  subject  moderate  intensity  tones  to  listen  to 
(ii)   asking  the  subject  to  estimate  5-sec  intervals 
(iii)  giving  the  subject  a  simple  reaction-time  situation  where 
she  has  to  life  a  key  as  quickly  as  possible  on  hearing  a 
tone. 

Both  subjects  and  experimenter  fill  out  a  mood  scale  daily.  A  few  males 
are  being  tested  as  controls. 

Major  Findings:   It  appears  that  there  are  very  striking  baseline  shifts 
through  the  cycle;  tentatively  it  can  be  said  that  there  is  a  much  higher 
skin  resistance  during  the  premenstrual  week  than  at  other  times  in  the 
cycle.   The  results  with  regard  to  other  measures  are  still  ambiguous. 

Significance  to  Biomedical  Research  and  the  Program  of  the  Institute; 
It  is  hoped  to  relate  changes  in  autonomic  fimctioning  during  the  cycle  in 
order  to  help  elucidate  the  mechanisms  responsible  for  mood  fluctuations 
during  the  cycle,  particularly  "premenstrual  tension". 

265 


Serial  No.  M-P-C-(c)  #kG 

Proposed  Course  of  Project;   Further  collection  of  data  on  normals  and 
possitly  in  depressive  and  schizophrenic  patients  as  well. 

Honors  and  Awards:  None. 

Publications:  None. 


266 


Serial  No.  M-P-C-(C)  -  #k'J 

1.  Laboratory  of  Psychology 

2.  Section  of  the  Chief 

3.  Bethesda 

PHS-HSMHA-NIMfi 

Individual  Project  Report 

July  1,  1971  through  June  30,  I972 

Project  Title:  Psychophysiological  Concomitants  of  Minimal  Brain 
Dysfunction  in  Children, 

Previous  Serial  Number:  M-P-C-(c)-#17 

Principal  Investigator:  Theodore  P.  Zahn 

Other  Investigators:  Paul  H.  Wender,  Betsy  Little  (Guest  Worker) 

Cooperating  Units:  None 

Man  Years: 

Total:  1.1 

Professional:  .8 

Other:  1.1 

Project  Description: 

Objectives;   To  compare  MBD  children  with  normal  children  in  autonomic 
functioning.   To  assess  the  effects  of  drug  therapy.   To  predict  MBD 
children's  response  to  drug  therapy. 

Methods  Employed;  Peripheral  measures  of  autonomic  functioning,  namely  skin 
resistance,  heart  rate,  respiration,  skin  temperature,  and  pupil  size  are 
recorded  during  two  sessions  in  which  children  are  exposed  to  mild  auditory 
and  visual  stimuli,  perform  reaction  time  tests  and  perform  a  cold  pressor 
procedure.  Parents  are  given  questionnaires  relating  to  child  rearing  atti- 
tudes and  practices,  and  their  child's  behavior. 

Subjects  are  children  from  the  Washington  area  with  a  diagnosis  of  MBD 
under  treatment  by  a  psychiatrist.  Controls  are  from  a  nearby  elementary 
school  and  have  been  chosen  by  their  teachers  as  not  having  significant 
behavior  problems.   The  patients  are  tested  both  on  and  off  amphetamine 
therapy . 

Comparison  of  autonomic  base  levels,  responsivity  to  meaningless  and 
meaningful  stimuli  and  variability  will  be  made  for  normal  vs.  MBD  children 
for  MBD  children  on  and  off  amphetamines,  and  between  MBD  children  who     ' 
respond  successfully  to  the  drugs  (as  Judged  by  their  psychiatrist)  and 
those  who  do  not. 

A  small  number  of  MBD  patients  who  did  not  respond  to  amphetamines  were 
given  a  clinical  trial  of  lithium.   Those  subjects  have  been  tested  on  both 
diTigs  and  off  drugs . 

267 


Serial  No.  M-P-C-(c)  -  #14-7, page  2 

Major  Findings:   None,  as  yet. 

Significance;   Reports  in  the  literature  suggest  that  MBD  children  may  be 
hypoaroused.  It  is  of  great  importance  to  test  this,  since,  if  true,  it 
would  help  explain  the  "paradoxical"  effect  of  amphetamines.  This  study 
should  suggest  the  extent  of  autonomic  involvement  in  MBD,  and  hopefully 
will  have  some  predictive  value  in  determining  which  children  will  respond 
successfully  to  amphetamines . 

Proposed  Course  of  Project:   Continued  data  collection  and  analysis. 

Honors  and  Awards:  None. 

Publications:  None. 


268 


Serial  No.  M-P-C-(c)-#i+8 

1.  Laboratory  of  Psychology 

2.  Section  of  the  Chief 

3.  Bethesda  _:.....•: 


PHS -HSMHA-NIMH  a  ■ 

Individual  Project  Report 
July  1,  1971  through  June  30,  1972      •  :'   : 

Project  Title:   Autonomic  Functioning  in  MZ  and  DZ  Twins. 

Previous  Serial  Number:  M-P-C-(c)-  #17 

Principal  Investigator:  Theodore  P.  Zahn 

Other  Investigators:  Monte  Buchsbaum,  Lyman  C.  Wynne. 

Cooperating  Units:    Adult  Psychiatry  Branch,  NIMH 

Man  Years : 

Total:  .6 
Professional:  .3 
Other:        .3 

Project  Description: 

Objectives;   To  determine  the  relative  importance  of  genetic  vs .  environ- 
mental factors  in  various  aspects  of  autonomic  functioning.  To  determine 
the  relationships  of  autonomic  nervous  system  activity  to  personality, 
task  performance  and  electrocortical  functioning. 

Methods  Employed;  Peripheral  measures  of  autonomic  functioning,  namely  skin 
resistance,  heart  rate,  finger  pulse  volume,  respiration,  and  skin  temper- 
ature are  recorded  during  two  sessions  which  include  rest  periods,  a  series 
of  mild  tones,  a  reaction  time  task  and  mental  arithmetic.  The  subjects  are 
30  MZ  and  30  DZ  twin  pairs  equally  male  and  female.  Some  opposite  sex  DZ 
pairs  have  also  been  tested. 

Intraclass  correlation  will  be  the  primary  method  of  analysis.  It  \<rill 
be  based  on  base  levels,  responsivity  to  non-demanding  and  demanding 
stimuli,  variability  and  response  specificity. 

Major  Findings:  None,  as  yet. 

Significance  to  Biomedical  Research  and  the  Program  of  the  Institute: 
Aside  from  the  inherent  interest  in  the  basic  question  of  the  heritability 
of  autonomic  indices  and  patterns,  the  data  from  this  project  will  be  used 
to  help  interpret  the  earlier  findings  from  a  similar  study  on  schizo- 
phrenic MZ  twins  (M-P-C-(C)-#17). 


269 


Serial  No.  M-P-C-(c)-  #i+8,page  2 

Further  Course  of  Project;  Continued  data  collection  and  analysis. 
Correlation  of  autonomic  data  with  personality,  behavioral  and  electro- 
cortical  data  on  the  same  subjects. 

Honors  and  Awards :  None . 

Publications :  None . 


270 


Serial  No.  M-P-D-(C)-30 

1.  Laboratory  of  Psychology 

2.  Section  on  Early  Learning 

and  Development 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:   Stimulus  Conditions,  Infant  Behaviors,  Caretaker-Child 

Interaction,  and  Social  Learning  in  Diverse  Child-Rearing 
Environments 

Previous  Serial  Number:   Same 

Principle  Investigator:   Jacob  L.  Gewirtz,  Ph.D. 

Cooperating  Units:   Department  of  Psychology,  Hebrew  University  of  Jerusalem; 
Computer  Science  Center  at  the  University  of  Maryland 

Man  Years : 

Total:  2.00 

Professional:  1.60 

Other:  .40 

Project  Description: 

Objectives ;   In  this  continuing  project,  diverse  behaviors  which  connote  the 
quality  of  adaptation  and  social  responsiveness  of  infants  to  their  environ- 
ments are  being  related  to  stimulus  conditions  which  represent  opportunities 
for  adaptive  and  social  learning  in  early  life.  Within  each  of  four  child- 
rearing  environments,  our  aims  have  been:   (a)  to  describe  the  typical  day 
for  the  infant,  including  a  catalogue  of  caretaking  schedules,  the  types  of 
stimuli  provided  (primarily  those  provided  through  interaction  with  care- 
takers) ,  and  the  types  and  frequencies  of  behaviors  of  the  infant;  (b)  to 
determine  the  sequential  contingencies  between  environmental  stimuli  and 
infant  responses  insofar  as  they  represent  opportunities  for  learning;  and 
(c)  to  consider  specific  performance  issues,  such  as  the  infant's  response  to 
short-term  separation  from  a  caretaker  to  whom  he  has  become  "attached" 
(e.g.,  his  mother),  and  her  responses  to  his  subsequent  initiations.   It  is 
thought  such  data  can  provide  a  fruitful  basis  for  examining  the  utility  of 
the  concepts  available  for  conceptualizing  the  filiild's  early  experience  with 
his  envi  r  onmen  t . 

Methods  Employed:   Subjects  (Ss)  :   Samples  of  S^s  were  drawn  from  the  infant 
population  of  Israel.   One  sample  consists  of  108  S^s  in  four  age  groups  (8, 
16,  24,  and  32  weeks)  from  four  child-rearing  environments  [the  Residential 
Institution,  the  Kibbutz,  the  Only-child  and  the  (Youngest-child  of)  Multiple- 
child  Middle-class  Town  family] .   Each  S^  was  observed  in  his  natural  setting 
by  a  trained  woman  observer  for  two  half-days,  providing  data  to  represent  one 
complete  day  of  his  life.   A  second  sample  included  some  700  infants  in  the 

271 


Serial  No.  M-P-D-(C)-30,  Page  2 

Methods  Employed  (Continued) :   first  18  months  of  life  from  the  listed 
environments  and'  a  day-care  environment  as  well.   Each  S_  was  observed  once. 
His  smiles,  vocal,  and  other  social  responses  to  a  woman's  face  presented  in 
a  standard  way  were  recorded. 

A  codified  observation  procedure  was  developed  and  used.   Reliable  observation 
categories  and  codes  were  devised  for:   (a)  background  events  (e.g.,  mother 
enters,  caretaker  talks  to  visitor,  caretaker  attends  to  neighboring  child); 
(b)  setting  (e.g.,  feeding,  sleeping,  bathing);  (c)  S^' s  behaviors  (e.g., 
smiles,  vocalizes,  follows,  manipulates);  (d)  the  various  stimuli  provided  by 
(behavior  of)  the  environment,  particularly  those  of  caretakers  toward  S^ 
(e.g.,  mother  approaches,  caretaker  picks  up  S^,  father  tickles  S^,  caretaker 
smiles);  (e)  the  sequential  contingencies  comprising  interactions  between  the 
infant  and  his  environment;  (f)  S^'s  gross  activity  level  (e.g.,  changes 
position  off  and  on,  mouths).   Behaviors  (but  not  their  durations)  were 
scored  as  they  occurred  during  the  observation  period. 

Each  infant's  record,  in  successive  30-second  time  units,  has  been  mounted  on 
tape-reels,  as  have  a  number  of  the  computer  programs  required  for  analyses 
of  event  frequencies  and  rates,  and  of  selected  contingencies.   Programs  for 
analyzing  sequential  details  of  the  interaction  process  have  recently  been 
completed.   These  have  been  devised  to  index  various  aspects  of  interaction 
sequences  that  will  serve  as  dependent  variables  in  group  comparisons  between 
Ss,  as  well  as  to  characterize  patterns  within  a  S^.   Setting  and  background 
data  have  been  summarized,  as  have  behavior  frequencies  and  rates  and  sequences 
of  occurrence  of  the  environmental  stimuli  provided  and  of  the  infants' 
behaviors.   Comparisons  within  and  between  the  different  environmental  and 
age  groups  are  being  made  via  multivariate  analyses  of  variance  employing  the 
dependent  variables  so  developed.   In  this  process,  after  adjusting  for  time 
spent  by  caretakers  with  their  infants,  comparisons  among  environmental  groups 
are  being  made  on:   (a)  the  types  and  frequencies  of  stimuli  provided  infants 
by  caretaker-adults  (through  gross  physical  contact  like  lifting,  fine 
physical  contact  like  tickling  or  nuzzling,  as  well  as  talking,  smiling); 
(b)  the  types  and  frequencies  of  infant  responses  to  or  in  the  presence  of 
the  adults  (e^g.,  looking,  smiling,  vocalizing,  crying,  motor  responding); 
and  (c)  the  incidence  and  details  of  patterns  of  interaction  between 
caretaker-adults  and  the  infant. 

Major  Findings:   During  the  past  year,  we  have  concentrated  on  defining 
conditions  prevailing  in  the  kibbutz  environment,  a  topic  that  has  been  of 
considerable  interest  in  the  professional  literature  during  recent  decades. 
One  research  tack  has  been  to  compare  the  kibbutz  to  the  residential 
institution,  in  the  time  spent  by  caretakers  with  their  infants  and  in 
behaviors  by  caretakers  to  infants  and  by  infants  to  their  caretakers.   The 
analysis  was  performed  separately  for  periods  spent  in  ministering  to  their 
infants'  physical  needs — "caregiving"  (feeding,  diapering,  dressing,  bathing) 
and  for  periods  when  caretakers  were  in  their  infants'  vicinity  when  not 
ministering  to  their  infants'  physical  needs — "pure-social  time". 

Analyses  of  the  periods  caretakers  spent  in  their  infants'  vicinity  showed 
that,  compared  to  kibbutz  caretakers,  institution  caretakers  spend  about 

272 


Serial  No.  M-P-D-(C)-30,  Page  3 

Major  Findings  (Continued);   twice  as  much  time  in  caregi  \ing,  and  about 
three  times  as  much  time  in  pure-social  time.   This  difference  appears  to 
reflect  the  facts  that  kibbutz  mothers  do  much  of  the  caregiving  during  the 
first  8  months  of  their  infants'  lives — the  period  investigated;   and  that 
institution  caretakers  are  scored  as  being  near  an  infant  when  they  minister 
to  nearby  children.   E  en  so,  caretaker  time  spent  with  or  near  infants 
represents  no  more  than  opportunities  for  interchanges  with  them.   Therefore, 
differences  in  actual  behaviors  exhibited  by  caretakers  to  their  infants,  and 
by  their  infants  to  them,  were  next  considered. 

An  overall  difference  in  caretaker  behaviors  during  caregiving  was  found 
between  kibbutz  and  institution  caretakers.   Specifically,  compared  to  kibbutz 
caretakers,  institution  caretakers  showed  more  Smiles  and  Fine-contact  responses. 
However,  in  the  Institution,  the  caretakers  were  the  only  ones  who  ministered 
to  their  charges  while,  in  the  kibbutz,  caretakers  shared  this  role  with  mothers. 
(In  fact,  kibbutz  caretakers  spent  relatively  little  time  caring  for  the 
physical  needs  of  their  infants  in  the  early  months,  but  took  increasing 
responsibility  for  that  care  as  their  infants  grew  older.)   This  difference 
between  caretaker  behavior  patterns  disappeared  when  scores  were  adjusted  for 
the  fact  that  caretakers  in  the  institution  spent  twice  as  much  time  ministering 
to  charges  than  did  kibbutz  caretakers  during  this  infancy  period  and  thus  had 
much  more  opportunity  for  interaction  with  their  infants.   A  similar  result 
pattern  was  found  for  infant  behaviors  _to  their  caretakers,  while  those  infants 
were  receiving  physical  care.   Institution  infants  showed  more  looking  at, 
smiling,  and  vocalizing  to  their  caretakers.   However,  these  differences 
between  caretaker  behaviors  during  caregiving  dropped  out  when  adjustment  was 
made  for  differences  in  caregiving  time  (and  in  the  differences  in  opportunity 
for  interaction  that  time  implies). 

Our  next  examination  was  of  pure-social  time  caretaker  behavior  differences 
between  institution  and  kibbutz,  when  they  were  not  ministering  to  their 
infants'  physical  needs.   The  difference  pattern  found,  which  decreased  with 
age,  was  the  institution  caretakers  showed  more  Fine-contact,  Talk,  and 
Gross-contact  behaviors  than  did  kibbutz  caretakers.   However,  when  scores 
were  adjusted  for  the  fact  that  institution  caretakers  are  in  the  vicinity  of 
their  children  thrice  as  much  as  kibbutz  caretakers  (who  share  responsibilities 
with  mothers) ,  the  caretakers  were  found  to  differ  only  in  the  incidence  of 
Gross-contact:   compared  to  the  kibbutz  caretakers,  institution  caretakers 
showed  more  of  this  behavior  at  2  months,  the  same  amount  at  6  months,  and  less 
at  8  months.   No  differences  were  found  between  infant  group  behaviors  _to 
those  caretakers  during  "pure-social"  settings  when  caretakers  were  not 
ministering  to  their  charges.   This  was  the  case  whether  or  not  account  was 
taken  of  the  fact  that  institution  caretakers  spent  three  times  as  much  time 
near  their  infants  as  did  kibbutz  caretakers. 

An  intriguing  difference  pattern  was  found  when  (holding  age  constant)  we 
compared  kibbutz  and  institution  on  the  pattern  of  correlation  between 
caretaker  and  infant  behaviors  within  and  between  the  caregiving  and  pure-social 
settings.   Within  those  settings,  the  correlations  between  caretaker  and 
infant  behaviors  were,  overall,  higher  for  the  kibbutz  than  for  the  institution 

273 


Serial  No.  M-P-D-(C)-30 ,  Page  4 

environment.   Moreover,  the  within-setting  correlations  were  higher  than  the 
between-setting  correlations  for  kibbutz  infants,  while  they  were  not  at  all 
different  for  institution  infants.   Thus,  kibbutz  infant-caretaker  pairs 
behaved  differently,  as  a  unit,  in  pure-social  than  in  caregiving  periods,  but 
institution  caretaker-infant  pairs  did  not  behave  differently.   That  is,  a  dis- 
crimination between  those  two  interaction  settings  was  found  in  the  kibbutz 
environment  but  not  in  the  institution  environment.   This  same  overall  pattern 
holds  as  well  for  infant  behavior  intercorrelations  and  for  caretaker  behavior 
intercorrelations.   Hence,  this  pattern  is  a  general  one.   Relative  to  the 
institution,  it  suggests  a  greater  organization  by  interaction-setting  in  the 
kibbutz  between  infant  and  caretaker  behaviors,  within  infant  behaviors,  and 
within  caretaker  behaviors.   The  possible  determinants  of  these  patterns  are 
being  explored  further. 

Kibbutz  caretakers  and  mothers  were  compared  next  in  terms  of:  a)  time  they 
spend  in  the  settings,  b)  their  behaviors  to  th^ir  infants;  c)  behaviors  shown 
by  their  infants  to  them;  and  d)  the  correlations  of  their  behaviors  to  their 
infants'.   These  analyses  provided  more  direct  leverage  upon  the  role  differ- 
ences between  kibbutz  mother  and  caretaker.   In  terms  of  the  time  spent  with 
their  charges,  both  in  caregiving  and  pure-social  settings,  mothers  spent  more 
time  than  did  caretakers  with  their  infants  during  the  first  8  months  of  life: 
in  caregiving  settings,  where  caretaker  time  remains  constant  through  the 
eight  months,  mothers  spend  50  times  as  much  time  at  two  months,  and  twice  as 
much  time  at  eight  months;  in  pure-social  settings,  where  both  mothers  and 
caretakers  spend  increasing  time  with  their  infants  with  age,  mothers  spend 
about  twice  as  much  time  with  their  infants  as  do  caretakers. 

When  differences  in  mother  and  caretaker  behaviors  were  examined  in  caregiving 
settings,  mothers  showed  more  Fine-contact  and  Gross-contact  responses  to 
their  infants  than  did  the  caretakers  (when  adjustment  was  made  for  the  greater 
amounts  of  time  mothers  spent  with  the  infants) .   During  pure-social  periods 
(regardless  of  time  adjustments),  mothers  displayed  more  Smile,  Fine-contact, 
Talk,  and  Gross-contact  behaviors  than  did  caretakers.   When  differences  in 
infant  behaviors  to  mothers  and  caretakers  were  examined  during  caregiving 
periods,  infants  showed  more  Watch,  Smile,  Vocal  sound.  Cry,  and  Motor  act 
responses  in  the  presence  of  their  mothers  than  in  the  presence  of  caretakers. 
However,  these  differences  tended  to  drop  out  when  infant  behavior  scores  were 
adjusted  for  the  fact  that  mothers  spent  greater  amounts  of  time  in  caregiving 
than  did  caretakers.   A  similar  configuration  of  results  was  found  for  the 
difference  in  infant  behaviors  to  mothers  and  caretakers  during  pure-social 
periods,  excepting  that  after  behavior  scores  were  adjusted  for  greater  pure- 
social  time  spent  with  the  mother  than  with  the  caretaker,  it  was  found  that 
more  Vocal  sounds  and  Motor  acts  were  exhibited  by  infants  to  their  mothers 
than  to  their  caretakers. 

An  examination  of  the  correlations  between  adult  and  infant  behaviors  within 
and  between  the  caregiving  and  pure-social  periods  was  next  attempted.  Holding 
age  constant,  the  correlations  within  and  between  caregiving  and  pure-social 
periods  were  invariably  of  higher  magnitudes  between  mother  and  infant  behaviors 
than  they  were  between  caretaker  and  infant  behaviors.   This  result  suggests  a 
better  organization  between  the  behaviors  of  a  mother  and  her  infant  than 
between  a  caretaker 

27^ 


Serial  No.  M-P-U-(C)-30,  Page  5 

and  the  same  Infant.   This  Interpretation  Is  supported  by  our  having  found: 
a)  lilgher  intercorrelatlons  within  child  behaviors  in  interaction  with  the 
mother  han  In  those  same  behaviors  when  in  interaction  with  the  caretaker; 
and  b)  higher  caretaker-Infant  and  mother-infant  behavior  intercorrelatlons  at 
8-months  than  at  2-months  of  age.   The  possible  determinants  of  these 
patterns  are  being  explored  further. 

In  this  context,  we  also  compared  the  correlations  between  the  behaviors  of 
mothers  and  their  Infants  (within  and  between  the  caregivlng  and  pure-social 
periods)  in  the  kibbutz  with  two  other  environments,  that  of  the  youngest- 
child  and  that  of  the  only-child  family  (both  urban  middle-class) .   The 
correlational  pattern  between  the  behaviors  of  a  mother  and  her  Infant  was 
found  to  be  reliably  higher  in  magnitude  In  the  kibbutz  than  in  either  the 
youngest-  or  the  only-child  environments.  However,  because  Intercorrelatlons 
within  infant  behaviors  and  within  mother  behaviors  were  found  to  follow 
parallel  patterns  in  this  three-environment  comparison,  some  other  possible 
determinants  of  these  patterns  are  being  explored.   In  particular,  contingent 
relations  between  the  various  adult  and  infant  behaviors  are  being  examined 
with  the  aim  of  pinpointing  at  a  more  detailed  level  of  analysis  the  nature 
of  the  adult-infant  dependencies  involved. 

Finally,  the  three  tntercorrelational  analyses  were  examined  In  terms  of  age 
of  Infant.   It  was  found  that  the  correlational  patterns  between  adult  and 
infant  behaviors  were  reliably  higher  for  older  (8  months)  Infants  than  for 
younger  (2  months)  Infants.   Thus,  the  behavior  organization  between  Infant 
and  adult  behaviors,  and  within  each  of  those  behavior  sets,  appears  to 
Increase  within  the  age  range  studied. 

In  this  frame  of  intercorrelatlons  and  mean  differences,  we  have  attained 
considerable  empirical  leverage  on  the  difference  In  role  between  mother  and 
caretaker  in  the  kibbutz  environment,  between  caretakers  in  the  kibbutz  and 
Institution,  as  well  as  between  kibbutz  and  urban  family  mothers. 

Scientific  Significance  to  the  Program  of  Mental  Health  Research;  Watchlng- 
scanning,  smiling,  vocal,  and  similar  adaptive  behaviors  constitute  key 
human  response  systems,  for  they  mediate  (and  hence  can  also  index)  much  of 
initial  adaptive  and  social  learning  and  development  of  the  Infant  as  well  as 
his  subsequent  patterns  of  social- Interaction.   A  developmental  picture  of 
the  early  course  of  these  behavior  systems  can  be  of  considerable  use  In 
Itself,  but  can  also  provide  a  context  for  understanding  the  nature  of  the 
outcomes  of  different  conditions  of  child-rearing.   These  conditions  can  be 
assumed  to  provide  differential  varieties  and  amounts  of  stimulation,  and  hence 
varying  opportunities  for  social  learning.   At  the  same  time,  this  investigation 
can  provide  data  on  an  issue  that  has  become  increasingly  salient  in  parent- 
child  relations:   how  the  child's  behaviors  can  affect  the  parent's  or 
caretaker's  behaviors  in  relation  to  him. 

Proposed  Course  of  the  Project:   It  is  expected  that  most  reports  for 
publication  from  this  project  will  be  completed  during  the  coming  year. 

Honors  and  Awards :   None 

Publications:   None  ^'^ 


Serial  No.  M-P-D-(C)-34 

1.  Laboratory  of  Psychology 

2.  Section  on  Early  Learning 

and  Development 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH   ■. 
Individual  Project  Report 
July  1,  1971  through  June '30,  1972 

Project  Title:   Contextual  Determinants  of  Stimulus  Power* 

Previous  Serial  Number:   Same 

Principal  Investigator:   Jacob  L.  Gewirtz,  Ph.D. 

Other  Investigators:   None 

Cooperating  Units :  None 

Man  Years : 

Total:  .30 

Professional:  .20 

Other:   .  .10     * 

Project  Description: 

Objectives:   A  great  variety  of  preceding  or  concurrent  contextual  conditions 
potentially  exist  which  could  determine  the  power  of  a  focal  stimulus  in 
evoking,  cueing,  or  reinforcing  behavior.   Their  effects  often  cumulate.   Our 
aim  has  been  to  survey  the  range  of  contextual  factors  that  can  q^ualify 
stimulus  efficacy,  to  make  a  preliminary  categorization  of  them,  and  to 
consider  some  underlying  issues  in  their  operation. 

Methods  Employed:   In  the  empirical  portion  of  this  program,  some  key 
contextual  factors  have  been  manipulated.   For  instance,  deprivation  and 
satiation  conditions  for  a  social  stimulus  class  were  effected  by  varying  the 
availability  of  a  social  stimulus  to  subjects  in  a  period  immediately 
preceding  a  test  for  the  effectiveness  of  that  stimulus.   A  further  aim  has 
been  to  implement  different  maintenance  patterns  of  prior  stimulus  availability. 

Major  Findings:   Data  from  diverse  sources  are  being  surveyed  to  identify 
classes  of  contextual  factors.   In  this  frame  and  on  the  basis  of  our  earlier 
empirical  studies,  it  was  concluded  that  the  function  of  a  stimulus  on  a 
particular  occasion,  in  evoking,  cueing,  or  reinforcing  behavior,  may  be 
enhanced  or  decreased  by  the  manipulation  of  the  context  of  stimulus 
provision.   Moreover,  even  the  direction  of  the  effects  of  a  stimulus  on 
behavior  may  be  determined  by  the  stimulus  context.   That  is,  whether  a  given 

*Former  title  of  project:   Deprivation  and  Satiation  of  Social  Stimuli  as 

Determinants  of  their  Reinforcing  Efficacy 


277 


Serial  No.  M-P-D-CC)-34,  Page  2 

Major  Findings  (Continued) :  stimulus  evokes  an  approach  or  an  avoidance 
response  will  often  depend  entirely  on  the  context  of  its  provision. 

Scientific  Significance  to  the  Program  of  Mental  Health  Research:   The 
efficiency  of  human  learning  and  performance  depends  on  the  effectiveness  of 
the  available  stimuli  in  each  of  their  roles.   Hence,  the  identities-  of 
contextual  setting  conditions  can  provide  an  important  key  for  understanding 
the  acquisition  and  performance  of  child  behavior  systems,  particularly  in 
natural  settings.   The  principles  identified  should  also  bear  on  such 
conceptions  as  childhood  "privation"  as  they  suggest  that  effective  stimulation 
depends  not  only  on  the  type  and  number  of  stimuli  available  but  also  on  the 
contexts  of  their  provision  as  well. 

Proposed  Course  of  the  Project;   Our  plan  is  to  carry  out  experiments  in  this 
problem  area  when  new  laboratory  facilities  become  available  in  1972. 

Honors  and  Awards :   None 

Publications: 

Gewirtz,  J.  L.   Some  contextual  determinants  of  stimulus  potency.   In  R.  D. 
Parke  (Ed.),  Recent  Trends  in  Social  Learning  Theory.   New  York: 
Academic  Press,  1972.   Pp.  7-33. 


278 


Serial  No.  M-P-I>-CC)-42 

1.  Laboratory  of  Psychology 

2.  Section  on  Early  Learning  and 

Development 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:   Evaluation  of  Concepts  Employed  for  Early  Learning  and 
Development 

Previous  Serial  Number:   None 

Principle  Investigator:   Jacob  L.  Gewirtz,  Ph.D. 

Other  Investigators:   None 

Cooperating  Units :   None 

Man  Years : 

Total:  .30 
Professional: .20 
Other:       .10 

Project  Description: 

Objectives:   To  analyze  the  roles  in  theory  and  research  of  focal  concepts 
employed  in  the  area  of  early  adaptive  and  social  learning  and  behavioral 
development,  and  thereby  to  provide  a  basis  for  evaluating  and  facilitating 
researches  in  those  sectors.   Included  are  such  concepts  as  development, 
critical  period,  environmental  stimulation,  drives  and  motivation,  stimulus 
privation,  deprivation,  and  separation,  attachment  and  dependence,  imitation 
and  identification,  and  vicarious-reinforcement  and  observational  learning. 

Methods  Employed;  While  the  moment-to-moment  details  of  the  interchange 
between  stimuli  and  responses  are  relevant  to  many  process  theories  of 
learning  and  development,  researches  done  under  the  aegis  of  such  theories 
have  almost  routinely  employed  global  concepts  for  environment  and  behavior 
(e.g.,  traits)  that  only  summarize  through  lengthy  time  spans  the  occurrence 
of  either  stimuli  or  responses  but  not  both  facets  of  the  (S-R)  interchange. 
These  research  variables  are  therefore  often  remote  from  the  level  of  analysis 
required  by  the  process  theories  that  have  spawned  them.   Our  approach  to 
human  social  learning  has  proceeded  as  a  detailed  functional  analysis  of 
stimuli  and  responses,  their  interchange  at  a  particular  moment,  and  the 
sequences  of  interaction  across  successive  moments  (i.e.,  the  stimulus-response 
chain).   Thus,  the  conditioning  concepts  we  have  employed  order  environmental 
operations  that  effect  systematic  and  (usually)  reversible  changes  in 
observable  behaviors.   The  approach  employed  is  open  to  the  addition  of  new 
concepts  as  required,  and  to  the  differentiation  and  refinement  of  the 
concepts  in  current  use. 

279 


Serial  No.  M-P-D-(C)-42,  Page  2 

Major  Findings: .  We  moved  forward  during  the  year  in  the  evaluation  of  the 
efficacy  of  key  concepts  of  attachment  and  dependence  in  ordering  the 
behavioral  phenomena  for  which  they  were  devised,  and  in  relating  them  to 
what  we  observed  in  child-rearing  settings.   In  particular,  we  have 
surveyed  possible  indices  for  those  concepts  from  the  viewpoint  of  some  of 
the  models  advanced  for  their  acquisition  and  maintenance.   We  considered 
indices  for  cases  where  these  terms  were  conceived  as  abstractions  for 
classes  of  functional  relationships  involving  the  positive  stimulus  control 
over  a  wide  \ariety  of  an  individual's  responses  by  stimuli  provided  either 
by  a  class  of  persons  (dependence)  or  by  a  particular  person  (attachment) . 
We  surveyed  indices  for  other  cases  as  well,  such  as  a)  for  different 
approaches  to  the  origins  of  attachment  and  dependence,  b)  for  different 
bases  of  distinctions  between  the  concepts,  and  c)  for  diverse  assumptions 
underlying  cognitive-ethological  and  learning  approaches  to  human  attachment 
and  the  mother- infant  relationship.   As  we  conceive  dependence  and 
attachment  to  be  gross  abstractions,  in  different  contexts  many  types  of 
behaviors  (e.g.,  approach,  preference,  approach  in  the  context  of  avoidance, 
disorganization  behaviors)  could  be  used  to  index  each  concept.   Considerations 
were  outlined  for  index  selection  under  different  research  strategies  and 
tactics . 

Scientific  Significance  to  the  Program  of  Mental  Health  Research:  Clarification 
of  the  purpose  and  utility  of  concepts  such  as  those  examined  should  lead  to 
more  efficient  mental  health  research  and  application.   Also,  the  role  of 
response  acquisition  in  various  complex  personality  processes  that  underlie  such 
concepts,  and  distinctions  between  motivation  and  learning  concepts,  can  be 
delineated  more  explicitly  and  parsimoniously.   On  this  basis,  research  and  its 
applications  in  the  area  of  the  psychological  development  of  the  normal  child 
should  be  facilitated. 

Proposed  Course  of  the  Project:   The  need  for  this  project  is  a  continuing 
one,  as  concepts  like  the  ones  being  analyzed  are  in  common  use  in  the  field  at 
large  and  serve  important  functions  in  our  research  program. 

Honors  and  Awards :   None 

Publications : 

Gewirtz,  J.  L.   Attachment  and  dependence:   Some  strategies  and  tactics  in 

the  selection  and  use  of  indices  for  those  concepts.   In  T.  M.  Alloway, 
L.  Krames,  and  P.  Pliner  (Eds.),  Communication  and  Affect.   New  York: 
Academic  Press,  1972,  in  press. 


280 


Serial  No.   M-P-P-(c)-6 

1.  Latoratoiy  of  Psychology 

2.  Section  on  Personality 

3.  Bethesda,  Maryland 


PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 


Project  Title:   The  Investigation  of  Some  Formal  Characteristics  of  Speech 

Previous  Serial  Number:   Same 

Principal  Investigator:   Donald  S.  Boomer,  Ph.D. 

Other  Investigators:   Allen  T.  Dittmann,  Ph.D. 

Cooperating  Units:  None 
Man  Years 


Total: 

2.20 

Professional: 

2.00 

Other: 

.20 

Project  Description: 

Objectives: 

General:   To  elaborate  and  test  a  psycholinguistic  theory  of  speech 
performance. 

Specific:   To  explore  the  psychological  properties  of  some  functional 
speech  units  specified  by  the  theory. 

Methods  Employed: 

1.  Linguistic  and  phonetic  analysis  of  natural  speech  utterances. 

2.  Controlled  experimental  situations  which  systematically  vary 
parameters  of  speech  production  and  perception,  and  their  correlates. 

Major  Findings: 

An  extended  research  program,  summarized  in  previous  annual  reports  has 
been  incorporated  into  a  developing  theory  of  speech  production.   In  bare 
outline,  the  theory  posits  a  central  speech  planning  mechanism  which 
assembles  motor  production  programs  which,  in  turn,  control  the  external 
articulators  during  actual  speech  production.   The  pre-planning  aspect  of 


281 


Serial  No.   M-P-P-(C)-6,  Page  2 

this  theory  distinguishes  it  from  more  conventional  associative  theories 
which  explain  speech  production  in  terms  of  associative  bonds  between 
elements:   i.e.,  words  and/or  sounds.   Major  findings  from  this  project, 
previously  reported,  include  demonstrations  that  speech  non-fluencies  such  as 
hesitations,  repetitions,  and  tongue-slips  are  not  random  "noise"  but  occur 
lawfully  with  respect  to  the  functional  speech  units  posited  in  the  theory. 

During  the  past  year  this  research  has  focussed  on  speech  perception. 
The  guiding  hypothesis  has  been  that  listeners,  like  speakers,  process 
"chunks"  of  speech  which  are  defined  by  intonational  patterns.   In  perception 
these  units,  phonemic  clauses,  are  held  in  short-term  memory  and  processed  as 
patterns  of  sound,  syntax,  and  sense. 

The  pupillographic  work  begun  last  year  has  continued.   This  work  has 
been  an  attempt  to  extend  Kahneman  and  Beatty's  finding  that  pupillary  dia- 
meter seems  to  be  directly  associated  with  intercurrent  load  on  short-term 
memory.   We  have  hypothesized  that  as  a  subject  listens  to  speech  a  gradient 
of  pupillary  dilatation  would  occur  over  the  co\jrse  of  a  phonemic  clause, 
while  it  is  being  loaded  into  short-term  memory. 

Since  the  pupil  is  richly  and  complexly  innervated  and  a  variety  of 
processes  are  affecting  its  moment-to-moment  diameter,  signal  averaging 
techniques  are  required  in  order  to  separate  out  the  hypothesized  psycho- 
linguistic  effect  from  "noise," 

The  course  of  the  project  this  year  has  involved  repeated  attempts  to 
match  a  set  of  experimental  stimuli  to  a  Line  computer  program  in  such  a 
fashion  as  to  be  able  to  test  the  pupil  diameter  hypothesis.   A  number  of 
difficult  problems  have  been  solved;  some  still  remain.   These  attempts 
will  continue  during  the  next  year. 

Scientific  Significance  to  Mental  Health  Research  Program: 

Behavioral  and  medical  research  involving  speech  fvmction,  studies  of 
psychotherapy  and  aphasia,  for  example,  are  hampered  by  the  lack  of  appro- 
priate psychological  theories  of  speech  production.   Most  current  linguistic 
theories  are  inappropriate  in  that  they  aim  to  describe  abstract  language 
structures  without  reference  to  the  live  users  of  the  language,  thus  failing 
to  link  with  theories  and  data  in  psychology  and  neurophysiology.   The  theory 
underlying  the  present  program  is  broadly  psycholinguistic  in  scope  and  can 
thus  accommodate  data  and  observations  from  other  relevant  disciplines.   Of 
more  direct  benefit  to  the  field  of  neurophysiology  is  the  fact  that  this 
work  provides  a  detailed,  structured  analysis  of  the  output  of  an  important 
motoric  system.   Such  analysis  will  be  necessary  as  neurophysiology  increas- 
ingly attempts  to  deal  with  complex  sequential  behavior. 


282 


Serial  No.   M-P-P-(c)-6,  Page  3 
Proposed  Course  of  Project: 

A  number  of  lines  of  investigation  will  be  pursued  in  the  coming  year. 

1.  A  continued  attempt  to  separate  the  processes  of  word- finding 

and  syntactic  framing  —  the  so-called  paradigmatic-syntagmatic  distinction 
proposed  by  Jakob son. 

2.  The  pupillographic  work  will  continue.   The  LINC  signal  averaging 
program  for  pupil  data  has  been  rewritten  and  tried  3  times  in  the  past  year, 
and  is  still  unsatisfactory.   These  electronic  and  data  handling  difficulties 
are  being  worked  on  with  assistance  from  James  Bryan  and  his  staff. 

Honors  and  Awards :   None 

Publications: 

Boomer,  D.  S. :   Review  of  Rhythms  of  Speech  by  Jaffe  and  Feldstein. 
Contemporaiy  Psychology.   l6: 530-531,  1971- 

Boomer,  D.  S.  and  Laver,  J.   Slips  of  the  tongue.   Brit.  Jour.  Disord. 
Commun.   3:   2-11,  1968.   Reprinted  in  V.  A.  Frofflkin   (Ed.):  Speech 
Errors  as  Linguistic  Evidence.  Mouton  (in  press). 


283 


Serial  No.   M-P-P-(c)-22 

1.  Laboratory  of  Psychology 

2 .  Section  on  Personality 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   Development  of  Potentially  Creative  Scientists:  Personality 
Characteristics  Associated  with  Creative  Performances 

Previous  Serial  Ninnber:   Same 

Principal  Investigator:   Kenneth  Burgdorf,  Ph.D. 

Other  Investigators:   Morris  B.  Parloff,  Ph.D. 

Cooperating  Units:   None 

Man  Years 

Total:  _  .20 
Professional:  .10 
Other:  .       .10  . 

Project  Description: 

Objectives:  " 

To  conduct  a  longitudinal  study  to  assess  the  nature,  degree  and  cor- 
relates of  personality  change  evidenced  by  highly  selected  samples  of  male 
subjects  judgedto  be  highly  creative,  as  well  as  those  judged  to  be  less 
creative.   This  aspect  of  the  study  covers  a  five  year  period  following  high 
school  graduation. 

Methods  Employed: 

In  accordance  with  the  plans  for  this  longitudinal  study,  a  battery  of 
tests  was  readministered  in  1970-1971  to  a  sample  of  approximately  itOO  sub- 
jects (Beta  Sample)  who  had  been  previously  identified  and  tested  in  I965 
and  1966.   The  Personality,  Social  Adjustment  and  Performance  measures 
employed  are  identical  to  those  administered  to  another  sample  of  approxi- 
mately 500  students  (Alpha  Sample)  who  had  been  studied  by  these  investi- 
gators in  1963,  196^1  and  I969.   The  Battery  included  the  California  Psycho- 
logical Inventory,  four  scales  from  the  MMPI,  a  specially  devised  Social 
History  Questionnaire,  and  other  instruments  related  to  achievement, 
recognition,  and  creativity. 


285 


Serial  No.   M-P-P-{C)-22,  Page  2 
Major  Findings: 

1.  Followup  personality  data  from  the  Beta  sample  were  found  comparatle 
to  the  data  from  the  Alpha  sample, 

2.  Individual  differences  in  personality  changes  over  time  were  found 
strongly  related  to  individual  differences  in  psychiatric  help  seeking  be- 
havior.  These  relationships  have  been  described  elsewhere  (see  project 

Wo.  M-P-P-(c)-it2). 

3.  Followup  personality  variables  differentiated  high  and  low  creativity 
subjects  much  less  strongly  than  high  school  personality  variables  had  been 
found  to  do. 

k.     This  finding  (No.  3)  was  found  to  be  largely  an  artifact  resulting 
from  sample  attrition.   The  nature  of  this  artifact  was  rather  interesting. 
No  differences  were  found  on  high  school  personality  measures  between  the 
total  group  of  subjects  who  returned  followup  data  and  the  overall  group  of 
non-respondents.   A  number  of  interactions  were  found,  however,  between 
creativity  and  foUowup  response  status  on  high  school  personality  measures. 
Specifically,  low  creative  non-respondents  were  much  lower  than  low  creative 
respondents  on  measures  of  ego-strength,  adjustment,  sense  of  well-being, 
responsibility,  and  similar  traits,  while  the  differences  on  these  measures 
between  high  creative  respondents  and  high  creative  non-respondents  were 
also  large  but  in  the  opposite  direction. 

5.   It  appears  that  those  members  of  the  high  creativity  group  who  were 
especially  well-functioning  during  high  school  and  those  members  of  the  low 
creativity  group  who  were  least  integrated  during  high  school  were  the  ones 
who  did  not  return  followup  data  five  years  later.   This  explains  the  attenu- 
ation of  creativity  group  differences  in  the  followup  sample.   It  also  sug- 
gests that  two  rather  different  kinds  of  people  may  fail  to  return  question- 
naires dealing  with  achievements,  accomplishments,  etc.:  those  who  have  few 
accomplishments  to  report  and  those  who  feel  too  busy  to  waste'  their  time 
responding  to  questionnaires  which  have  no  direct  bearing  on  their  lives. 

Scientific  Significance  to  Mental  Health  Research  Programs: 

Factors  which  influence  personality  development  and  motivation  are 
known  to  facilitate  or  impede  the  full  use  of  one's  capacities.   While  this 
issue  is  of  significance  in  affecting  the  development  of  all  individuals,  it 
is  of  particular  iuportance  in  aiding  us  to  understand  the  impact  of  social 
and  cultural  influences  on  uniquely  gifted  individuals  who  demonstrated 
"creative"  abilities  at  an  early  age. 


286 


Serial  No.   M-P-P-(c)-22,  Page  3 

Proposed  Course  of  Project: 

These  findings  -will  be  prepared  for  publication. 

Honors  and  Awards :   None 

Publications: 

Parloff ,  M.  B.  :   Creativity  research  program:  A  review.   In 
Taylor,  C.  W.  (Ed.):   Climate  for  Creativity.  Elmsford,  New  York, 
Pergamon  Press.   In  press. 


287 


Serial  No.   M-P-P-(c)-i+0 


1.  Laboratory  of  Psychology 

2.  Section  on  Personality 

3.  Bethesda,  Maryland 


PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 


Project  Title:   Body  Movement  as  Expression  of  Change  in  Psychological 
Tension  States 

Previous  Serial  Number:   Same 

Principal  Investigator:   Allen  T.  Dittmann,  Ph.D. 

Other  Investigators:   Donald  S.  Boomer,  Ph.D. 

Cooperating  Units :  None 

DISCONTINUED. 


289 


Serial  No.  M-P-P-(C)-Ul 

1.  Laboratoiy  of  Psychology 

2.  Section  on  Personality 

3.  Bethesda,  Maryland 


PHS-HSMHA-NIMH 

Individual  Project  Report 

July   1,  1971  through  June  30,  1972 


Project  Title:   Survey  of  Literature  on  Emotional  Communication 

Previous  Serial  Number:   Same 

Principal  Investigator:   Allen  T.  Dittmann,  Ph.D. 

Other  Investigators:   None 

Cooperating  Units :   None 

Man  Years 


Total: 

.k6 

Professional: 

.25 

Other: 

.21 

Project  Description: 

Objectives :   To  provide  a  conceptual  framework  within  which  existing 
research  on  emotional  communication  may  he  evaluated  and  new  research 
designed;  and  to  test  the  concepts  of  that  theory  in  the  context  of  various 
specific  research  areas. 

Methods  Employed:   Standard  library  research  methods  for  the  development 

of  the  theory  and  for  some  of  its  applications;  research  methods  appropriate 

to  the  study  for  other  applications. 

Ma j or  Findings :   The  monograph ,  Interpersonal  Messages  of  Emotion,  the 
general  theoretical  statement,  is  now  in  press.   Two  studies  of  specific 
applications  are  published. 

Scientific  Significance  to  Mental  Health  Research  Program:   The  sort  of 
general  theorizing  with  which  this  project  began  has  turned  out  to  be 
useful  in  examining  two  quite  disparate  problems  in  language  behavior, 
a  topic  related  to,  but  in  certain  respects  not  central  to  the  original 
theory  itself.   The  theory  thus  appears  to  have  useful  generality,  and 
will  no  doubt  find  application  in  other  research  areas. 


291 


Serial  Wo.  M-P-P-(C)-l4l,  Page  2 


Proposed  Course  of  Project:   Project  completed. 

Honors  and  Awards :   None 

Publications : 

Dittmann,  A.  T. :   The  body  and  movement-speech  rhythm  relationship 
as  a  cue  to  speech  encoding.   In  Siegman,  A.  W.  and  Pope,  B.  (Eds.): 
Studies  in  Dyadic  Communication.   Elmsford,  New  York:  Pergamon  Press, 
1972,  pp.  135-151. 

Dittmann,  A.  T. :   Review  article  on  Kinesics  and  Context  by  Ray  L. 
Birdwhistell.   Psychiati-y,   3^:   33^-3^2,  1971. 

Dittmann,  A.  T. :   Interpersonal  Messages  of  Emotion.   New  York, 
Springer  Publishing  Co.   In  press. 


Serial  No.  M-P-P-(C)-U2 

1.  Laboratoiy  of  Psychology 

2.  Section  on  Personality 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:   Precocious  Science  Students  in  Psychiatric  Treatment: 
A  Longitudinal  Study 

Previous  Serial  Number:   Same 

Principal  Investigator:   Kenneth  Burgdorf,  Ph.D. 

Other  Investigators:   Morris  B.  Parloff,  Ph.D. 

Cooperating  Units :   None 

Man  Years 

Total:  2.08 

Professional:     -70 
Other:         1>38 

Project  Description: 

Objectives : 

1.  To  describe  the  pre-college,  college,  and  post-college  characteristics 
and  experiences  of  a  group  of  precocious  science  students  who  enter  psychiatric 
treatment  during  college. 

2.  To  describe  the  type  and  magnitude  of  treatment-related  change  ex- 
hibited by  the  patient  group. 

3.  To  examine  relations  between  treatment-related  change  and  (a)  para- 
meters of  treatment;  (b)  pre-college  characteristics;  and  (c)  college 
experiences . 

Methods  Employed: 

1.   A  wide  variety  of  measures,  including  indices  of  personality  traits, 
parent-child  relationships,  interests,  activities,  achievements,  etc.,  were 
collected  on  a  nationwide  sample  of  756  precocious  science  students  at  each 
of  three  points  in  time:  (a)  senior  year  of  high  school;  (b)  freshman  year 
of  college;  and  (3)  first  year  of  graduate  school  (i.e.  ,  5  years  after  high 
school) . 


293 


Serial  No.   M-P-P-(cLl|2,  Page  2 

2.   The  post-college  followup  contained  a  series  of  items  in  which  sub- 
jects were  asked  whether'  or  not  they  had  sought  professional  assistance  for 
emotional  problems  while  at  college  and,  if  so,  to  describe  the  assistance 
which  they  had  received.   Initial  analyses  involved  comparisons  between 
students  who  reported  receiving  5  or  more  sessions  of  individual  or  group 
therapy  (W  =  95)  and  students  who  reported  that  they  had  neither  entered  nor 
ever  seriously  considered  entering  treatment  (N  =  k26) . 

Major  Findings: 

1.  In  this  sample,  the  number  of  students  who  expressed  concern  about 
emotional  well-being  at  college  was  remarkably  high.   Nearly  half  of  the 
sample  reported  that  they  had  seriously  considered  entering  treatment  at 
some  time  during  college,  and  23^  of  the  sample  (i.e.,  half  of  those  who 
considered  entering  treatment)  actually  did  so.   The  prevalence  of  psychiatric 
help-seeking  among  college  students  in  general  is  about  6%. 

2.  Specific  problems  of  adjustment  at  college  appeared  to  be  the  primary 
source  of  motivation  for  help-seeking.   Students  who  reported  feeling  "out 

of  place"  at  college  or  who  received  low  grades,  for  example,  were  much  more 
likely  to  seek  assistance  than  those  who  did  not  experience  such  problems. 

3.  Treatment-related  change  tended  to  be  negative  in  direction  and  non- 
specific in  type.   That  is,  a  decline  in  quality  of  functioning  was  evident 
for  students  who  had  received  psychiatric  treatment  on  measures  of  change 
(post-college  data  being  compared  to  pre-college  data)  in  personality,  self- 
esteem,  family  relations,  academic  and  extracurricular  achievement,  social 
and  career  development,  etc.   The  extent  of  change  was  strongly  related  both 
to  Intensiveness '  and  to  duration  of  treatment.   Thus,  students  who  received 
more  than  20  sessions  of  individual  psychotherapy  exhibited  the  greatest 
negative  change,  while  those  who  received  fewer  than  five  sessions  of  voca- 
tional counseling  changed  in  a  positive  direction  on  most  measures.   The 
quality  of  functioning  of  untreated  students  tended  to  improve  over  time. 

k.      In  attempting  to  explain  help-seeking  (and  the  decline  in  fionctioning 
associated  with  it)  in  terms  of  pre-college  characteristics  and  college  ex- 
periences, it  was  found  useful  to  distinguish  help-seekers  who  gave  evidence 
of  psychiatric  problems  during  high  school  from  those  who  did  not  give  such 
evidence.  Approximately  two  thirds  of  the  help-seekers  were  of  the  latter 
type:  their  emotional  problems  did  not  antedate  college.   The  basic  relation- 
ships were:  (a)  students  who  evidenced  psychiatric  problems  during  high  school 
and  attended  extremely  selective,  competitive  colleges  were  very  likely  to 
experience  adjustment  problems,  to  enter  treatment,  and  to  become  increasingly 
impaired;  (b)  impaired  students  who  attended  less  selective  colleges  tended 
not  to  experience  adjustment  problems,  not  to  enter  treatment,  and  to  improve 
over  time;  and  (c)  among  students  who  appeared  psychiatrically  unimpaired 
during  high  school,  those  who  were  most  talented,  forceful,  and  autonomous 
were  the  ones  most  likely  to  feel  frustrated  at  college,  to  enter  treatment, 
and  to  become  psychiatrically  impaired. 


29^^ 


Serial  No.   M-P-P-(C)-U2,  Page  3 

5.   It  appears  that  a  substantial  number  of  students  who  enter  college 
with  highly  developed  sliills  and  interests  in  science  react  to  college  by- 
developing  adjustment  problems  and  by  entering  psychiatric  treatment.   It 
is  also  apparent  that  the  assistance  which  such  students  receive  is  typically 
ineffective  either  at  producing  an  amelioration  of  problems  or  at  preventing 
a  continued  deterioration  of  functioning. 

Scientific  Significance  to  Mental  Health  Research  Programs: 

Recognizing  that  some  students  react  adversely  to  stresses  in  the  college 
environment  and  that  others  possess  long-standing  emotional  problems  which 
limit  their  ability  to  function  productively,  many  colleges  and  universities 
have  instituted  programs  to  meet  the  mental  health  needs  of  their  students. 
Very  little  is  known  at  present  about  the  kinds  of  students  who  seek  help 
at  college  mental  health  facilities  or  about  the  effectiveness  of  the  assist- 
ance which  they  receive.   At  the  very  least,  the  results  of  this  study 
demonstrate  that  current  methods  of  psychiatric  intervention  are  not  adeq^uate 
to  meet  the  mental  health  needs  of  all  college  students .   Distinguishing 
students  who  are  likely  to  respond  well  to  current  methods  of  intervention 
from  those  who  are  not,  and  devising  more  effective  modes  of  treatment  for 
the  latter  group  should  become  high  priority  topics  for  future  research  in 
this  area. 

Proposed  Course  of  the  Project: 

Data  analyses  have  been  completed.   A  monograph  length  report  of 
this  research  is  being  prepared  for  publication. 

Honors  and  Awards :   None 

Publications :   None 


295 


Serial  No.   M-P-P(c)-ii3 


1.  Laboratory  of  Psychology 

2.  Section  on  Personality 

3.  Bethesda,  Maryland 


PHS-HSMHA-NIMH 
Individual  Project  Eeport 
July  1,  1971  through  June  30,  1972 


Project  Title:   Test  and  Performance  Measures  of  Creativity  in  Science 

Previous  Serial  Niiunber:   Same 

Principal  Investigator:   Kenneth  Burgdorf,  Ph.D. 

Other  Investigators:   Morris  B.  Parloff,  Ph.D. 

Cooperating  Units :  None 

Man  Years 

Total:        .   .58  '■ 
Professional:    .20 
Other:  .38 

Project  Description: 

Objectives: 

1.  To  examine  the  construct  validities  (meaningfulness )  of  two  per- 
formance meas\ares  of  individual  differences  in  scientific  creativity  in  a 
highly  select  group  of  adolescents. 

2.  To  examine  the  construct  validities  of  six  -well-known  paper-and- 
pencil  tests  alleged  to  measure  creative  ability  in  science. 

3.  To  examine  the  construct  validity  of  a  paper-and-pencil  test  of 
creativity  developed  by  the  senior  investigator  from  theories  which  conceptu- 
alize creativity  as  a  personality  trait  rather  than  as  an  ability  trait. 

k.      To  assess  the  relative  advantages  of  the  approaches  to  test  and 
performance  measurement  represented  in  the  study. 

Methods  Employed: 

1.   Subjects  were  131  male  high  school  seniors  who:   (a)  had  indicated  a 
strong  desire  to  pursue  careers  in  science;  (b)  had  demonstrated  an  exception- 
ally high  degree  of  familarity  with  basic  facts,  principles,  and  methods  in 
science;  and  (c)  had  produced  at  least  one  major  independent  research  project 
in  a  field  of  science.   High  levels  of  scientific  knowledge,  motivation  for 


297 


Serial  Wo.   M-P-P-(C)-l+3,  Page  2 

research,  and  effort  to  actually  do  research  are  regarded  as  necessary  pre- 
conditions for  the  demonstration  of  creativity  in  science. 

2.  Subjects'  research  projects  were  classified  by  field  of  science 
(mathematics,  biochemistry,  etc.)  and  were  rated  for  creativity  by  two 
eminent  scientists  whose  expertise  was  in  that  field.   Reasoning  that  sci- 
entific research  is  an  intrinsically  creative  activity  and  that  any  indication 
of  research  quality  might  be  a  useful  index  of  extent  of  creativity  in  this 
sample,  a  second  performance  measure  was  formed  by  determining  the  level  of 
recognition  in  science  which  each  subject  had  attained  (national  vs.  less 
than  national). 

3.  The  construct  validities  of  the  test  and  performance  measures  were 
assessed  by  examining  the  pattern  of  correlates  which  each  produced  with  a 
set  of  reference  variables.   In  addition,  it  was  predicted  that  each  of  the 
tests  (if  valid)  would  be  found  associated  with  at  least  one  of  the  two  per- 
formance measures. 

Ma j  or  Findings : 

1.  Of  the  two  performance  measures,  recognition  was  found  to  possess  the 
superior  construct  validity.   As  compared  to  the  project  evaluation  measure, 
it  was  more  strongly  related  to  indices  of  achievement  in  science  and  in 
other  creative  fields,  to  self-ratings  of  creativity,  to  personality  traits 
theoretically  allied  to  the  concept  of  creativity,  etc.   As  hypothesized, 
both  performance  measures  were  found  unrelated  to  indices  of  academic  aptitude 
and  achievement. 

2.  The  evidence  of  construct  validity  for  the  creative  ability  tests  was 
nil.   None  was  associated  in  the  expected  manner  with  other  ability  tests, 
with  either  of  the  performance  measures,  with  the  test  developed  by  the  in- 
vestigators, or  with  any  of  the  reference  variables.   The  personality  test, 
on  the  other  hajid,  was  found  to  possess  a  remarkably  high  degree  of  construct 
validity. "  It  was  associated  with  the  recognition  measure  of  performance  and 
its  pattern  of  correlates  with  reference  variables  was  completely  in  accord 
with  expectation  (i.e.,  nearly  identical  to  that  produced  by  the  recognition 
measure) . 

3.  The  conclusions  are:  (a)  When  major  creativity-irrelevant  determinants 
of  behavior  are  controlled,  recognition  measiires  provide  useful  and  meaningful 
indices  of  individual  differences  in  creative  performance;  (b )  All  of  the 
ability  tests  investigated  are  invalid  measures  of  scientific  creativity  and 
should  not  be  used  as  operational  definitions  of  the  constnict  in  future 
research;  and  (c)  For  purposes  of  theory  development,  it  may  prove  more  use- 
ful to  conceptualize  creativity  as  a  personality  trait  than  as  an  ability 
trait . 


Serial  No.   M-P-P-(C)-i+3,  Page  3 

Scientific  Significance  to  Mental  Health  Research  Programs: 

Creativity  has  become  the  topic  of  a  great  deal  of  speciolation  in 
recent  years,  much  of  which  involves  mental  health  matters.   It  has  been 
claimed,  for  example,  that  certain  forms  of  psychotherapy  enhance  creativity, 
that  mental  illness  impairs  creativity,  and  that  creative  individuals  develop 
psychiatric  problems  when  exposed  to  certain  kinds  of  educational  environ- 
ments.  Before  such  speciilations  can  be  verified  or  disproven,  an  understand- 
ing of  the  nature  of  creativity  must  be  attained  and  valid  measures  of  the 
trait  must  be  found.   This  project  is  felt  to  contribute  to  this  end  by 
demonstrating  that  several  popular  tests  of  creativity  are  not  valid  and  by 
suggesting  an  approach  which  may  prove  more  fruitful. 

Proposed  Course   of  Project: 

The  findings  are  currently  being  prepared  for  publication. 

Honors  and  Awards:   None 

Publications :   None 


299 


Serial  No.   M-P-P-(C)-ltlt 

1.  Laboratory  of  Psychology 

2.  Section  on  Personality 

3.  Bethesda,  Maryland 


PHS-HSMHA-NIMH 

Individual  Project  Report 

Jiily  1,  1971  through  June  30,  1972 


Project  Title:   Psychodynamic  and  Instrimiental  Learning  Models: 

Implications  for  Personality  Theory  and  Psychotherapy. 

Previous  Serial  Number :   Same 

Principal  Investigator:   Stanley  I.  Greenspaji,  M.D. 

Other  Investigator:   None 

Cooperating  Units:   School  and  Residence — Hillcrest  Children's  Center 
Children's  Hospital,  Washington,  D.  C. 


Man  Years 

Total: 

1.20 

Professional: 

1.00 

Other : 

.20 

Project  Description: 
Objectives: 

1.  To  develop  an  internally  consistent  model  of  personality  (development 
and  organization)  based  on  instrumental  learning  theory  and  psychodynamic 
theories. 

2.  To  develop  a  psychoanalytic  learning  model. 

3.  To  test  the  utility  of  the  integrated  model  as  an  aid  to:   (a)  pro- 
viding a  conceptual  basis  for  examining  change  in  psychotherapy;  (b) 
facilitating  differential  diagnosis  and  treatment  of  children  and  adoles- 
cents ;  (c)  designing  an  effective  classroom  milieu  in  a  traditional  school 
setting;  (d)  aiding  psychotherapy  in  a  residential  child  treatment  setting; 
(e)  aiding  psychoanalytic  conceptualizations  of  the  role  of  external  reality 
in  personality  development  and  in  treatment;  and  (f)  aiding  behavioral 
approaches  in  using  psychoanalytic  concepts  to  enrich  -cheir  techniques. 


301 


Serial  No.   M-P-P-(C  )-Ui+,  Page  2 

Methods  Employed:   Formulation  of  an  integrated  model  representing  critical 
variables  affecting  human  behavior.   Utilizing  these  concepts  in  establish- 
ing a  therapeutic  milieu  in  the  treatment  center,  and  an  environment  con- 
ducive to  learning  in  a  classroom.   Formulation  of  a  psychoanalytic  learning 
model  as  an  addition  to  current  psychoanalytic  theory.   Pilot  studies  of  the 
clinical  and  educational  effectiveness  of  this  approach  were  conducted  with 
the  aid  of  a  psychotherapy  team  and  of '  educators . 

Major  Findings:   Ho  firm  conclusions  are  warranted  in  this  time  regarding 
the  effectiveness  of  the  derived  techniques;  however,  the  applicability  of 
the  model  to  the  educational  and  treatment  setting  has  been  demonstrated. 
The  model  was  translatable  into  operational  terms  and  was  successfully  com- 
municated to  the  staffs  of  the  two  centers.   The  treatment  plan,  derived 
from  the  integrated  model,  appeared  to  be  effective  in  aiding  the  treatment 
of  a  child  and  an  adult  who  had  previously  been  described  as  "resistant  to 
treatment." 

The  consideration  of  this  model  together  with  educators  suggests  that  it  is 
useful  in  the  joint  conceptualization  of  educational  and  mental  health  aspects 
of  the  school  setting.   Specific  recommendations  for  research  projects  on 
classroom  structure  to  test  this  and  other  models  are  being  considered. 
A  monograph  integrating  learning  variables  into  psychoanalytic  theory  has 
been  completed.   It  provides  a  framework  for  studying  the  effect  of  environ- 
mental variables  in  early  personality  development  and  analytic  therapy. 

Scientific  Significance  to  Mental  Health  Research  Program:   Theories  which 
focus  on  intrapsychic  determinants  of  behavior  have  each  made  important 
contributions  to  our  understanding  of  personality  development,  organization, 
psychopathology,  and  treatment.   A  more  unified  model  allows  conceptualiza- 
tion of  both  these  sets  of  variables  within  one  model  and  thereby  affords  a 
fuller  understanding  of  these  important  areas. 

Proposed  Course  of  Project:   Further  development  of  the  more  lonified  model 
with  special  emphasis  on  its  practical  applications. 

Honors  and  Awards :   None 

Publications:   None 


302 


Serial  No.   M-P-P-(C)-lt5 

1.  Laboratory  of  Psychology 

2.  Section  on  Personality 

3.  Bethesda,  Maryland 


PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 


Project  Title:   Developmental  Factors  in  Conversational  Behavior 

Previous  Serial  Number:  M-P-C-(c)-35 

Principal  Investigator:   Allen  T.  Dittmann,  Ph.D. 

Other  Investigator:   Donald  S.  Boomer,  Ph.D. 

Cooperating  Units:   Green  Acres  School,  Bethesda,  Maryland. 

Man  Years: 

Total:  l.i+li 
Professional:  .75 
Other:  .69 

Project  Description: 

Objectives:   To  compare  language-like  listener  responses  ("M-hmm,"  head 
nods,  and  the  like)  in  children  of  different  ages  with  those  of  adolescents 
and  adults,  with  special  reference  to  the  situations  in  which  they  occur, 
the  events  which  stimulate  them,  and  their  functions,  both  for  the  listener 
as  a  direct  consequence  of  his  speech  decoding  efforts,  and  for  the  speaker 
as  social  feedback. 

Methods  Employed:   Systematic  observations  of  children  in  a  school  (but  not 
an  instructional)  situation,  and  more  controlled  observational  sessions  in 
the  laboratory.   School  observations  were  taken  at  Green  Acres  School  of 
kindergarten,  1st,  2nd,  3rd,  and  5th  grades,  with  the  most  complete  obser- 
vations in  1st,  3rd,  and  5th  grade  classes.   The  situation  was  a  free-time 
period  of  30  minutes  in  each  class ,  when  pupils  chose  their  own  activities , 
including  reading  and  studying,  drawing,  playing  games,  talking  quietly. 
Most  of  the  time  included  conversation,  but  its  importance  to  the  rest  of 
the  activity  varied  widely.   Three  observers  watched  small  groups  of 
children  in  interactions  ranging  from  brief  exchanges  to  periods  lasting 
10  minutes.   Notes  were  later  judged  for  the  degree  to  which  the  social 
situation  "pulled"  listener  responses  (structured  games  had  low  piill,  inter- 
current conversation  while  drawing  had  medium  pull,  while  straight  conversa- 
tion and  instructing  another  in  a  game  had  high  pull). 


303 


Serial  Wo.   M-P-P-(C)-^5,  Page  2 

The  situations  in,  the  laboratory  have  been  exploratory.   Since  this  area  of 
research  is  new,  there  is  no  body  of  knowledge  to  draw  upon  in  designing  an 
experiment.   We  have  learned  from  the  school  observations  and  from  initial 
laboratory  observations  that  we  must  systematically  vary  the  situation  by  a 
number  of  factors:   (l)  differences  between  conversational  partners  along 
variables  of  age,  sex,  acquaintance,  status,  and  the  like;  (2)  the  purpose 
of  the  interaction,  such  as  instruction  compared  with  social  conversation; 
(3)  the  content  of  the  conversation,  such  as  emotional,  personal,  focused, 
"weather  talk,"  and  others;  {h)   the  physical  structure  of  the  conversational 
environment,  such  as  spatial  arrangements  between  the  conversationalists. 
All  sessions  are  recorded  on  video  tape  and  audio  tape,  and  a  few  have  also 
used  the  head,  movement  transducers  from  earlier  studies  to  record  precise 
timing  of  the  responses. 

Analysis  of  the  laboratory  observations  begins  with  segmenting  the  type- 
script of  the  speaker's  speech  into  what  are  called  phonemic  sentences,  a 
unit  derived  from  the  Trager-Smith  phonemic  clause.   Then  the  visible  and 
audible  responses  are  entered  into  the  typescript.   Rates  of  listener 
response  per  phonemic  sentence  are  then  computed  for  comparisons. 

Ma j or  Findings :   In  the  school  situation  h'J   children  were  observed  for  a 
total  of  111  minutes.   Twenty-nine  listener  responses  were  observed  and 
these  were  all  contributed  by  8  of  the  children.   The  responses  came  almost 
exclusively  in  high  pull  conditions.   The  exceptions  came  in  medium  pull 
conditions ,  but  there  was  some  question  as  to  whether  they  should  be  classi- 
fied as  listener  responses;  their  function  appeared  to  be  not  so  much  letting 
the  speaker  know  that  he  was  being  understood  as  to  initiate  a  turn  in  the 
conversation.   The  striking  occurrences  were  those  where  the  observers  judged 
the  situation  to  be  high  pull  conditions  and  yet  where  no  responses  were 
emitted.  And  of  course  29  responses  in  111  minutes  (.26  responses /minute)  of 
conversational  time  is  a  very  low  rate  in  comparison  with  results  from  the 
previous  project  conducted  here  with  college  students:   in  a  total  of  ko 
minutes,  these  subjects  produced  538  responses  (l3.^5  responses /minute ) .   The 
two  studies  are  not  directly  comparable,  because  the  college-age  subjects 
were  observed  under  more  controlled  conditions,  but  that  difference  can 
probably  not  account  for  the  50-1  difference  in  rates. 

In  the  laboratory  observations  we  have  closer  comparisons,  despite  the  fact 
that  the  experimental  situation  is  still  being  developed.   Four  subjects 
younger  than  adolescent,  and  h   adolescent  and  young  adults  have  been  recorded, 
half  of  each  sex  in  both  groups.   The  rate  of  response  per  phonemic  sentence 
differs  significantly  on  both  the  age  and  sex,  with  no  interaction  between 
the  two.   The  fact  that  large  individual  differences  occur  for  both  groups 
(earlier  research  on  other  aspects  of  conversational  behavior  led  us  to  ex- 
pect this)  did  not  obscure  these  group  differences.   These  results  must  of 
course  be  regarded  as  most  preliminary. 


304 


Serial  No.   M-P-P-(C)-li5,  Page  3 

Some  qualitative  observations  of  the  responses  of  the  children  are  of  con- 
siderable interest:   (l)  many  of  the  responses  are  very  slight  (a  head 
movement  of  such  small  extent  that  it  is  visible  only  on  repeated  viewings 
of  video  tape,  for  example)  and  seem  not  to  function  as  communications  to 
the  speaker;  (2)  many  responses  of  the  yoiinger  children  are  late  in  compar- 
ison to  those  of  adults,  so  that  they  overlap  the  speaker's  next  words. 

Scientific  Significance  to  Mental  Health  Research  Program:   Finding  a 
lajiguage-like  response  to  be  learned  late  (or  used  late  if  it  is  learned 
earlier)  opens  a  number  of  research  and  practical  possibilities  ranging 
from  basic  research  about  language  learning  to  educational  and  diagnostic 
applications.   From  the  standpoint  of  language  learning,  the  responses  seem 
to  fimction  partly  as  an  offshoot  of  the  person's  mastery  of  the  decoding 
process,  as  has  been  studied  here  before.   One  hypothesis  from  the  first 
results  of  the  present  research  is  that  few  responses  mean  meager  under- 
standing, and  that  study  of  these  responses  may  provide  a  new  research  tool 
for  problems  in  language  learning  —  and  the  acquisition,  or  reliable  use, 
of  these  responses  appears  to  come  at  a  stage  in  life  far  later  than  that 
which  most  language-learning  research  these  days  is  concentrating  on.   It 
is,  in  fact,  the  age  when  reading  is  being  learned,  and  some  recent  theorizing 
relates  reading  readiness  to  listening  skills.   Hence  the  educational  possi- 
bilities in  this  research. 

The  other  aspect  of  the  listening  response  is  the  more  obvious  one:  it  is  a 
social  response,  one  which  provides  the  speaker  with  feedback  on  his  progress 
—  the  cue  to  whether  he  is  getting  his  points  across  successfully.   Seen  in 
this  light  the  development  of  the  response  corresponds  to  social  development, 
to  how  well  the  child  is  becoming  aware  of  how  the  other  person  (the  speaker) 
feels  about  his  own  progress,  or  how  much  the  young  child  is  really  listening 
to  the  speaker,  as  Piaget  questioned  many  years  ago.   From  this  standpoint, 
the  listener  response  may  have  possibilities  for  the  study  of  social  develop- 
ment, and  eventually  for  developmental  diagnosis. 

Proposed  Course  of  Project:   To  pursue  the  parameters  of  this  finding  in 
depth,  developing  more  precise  methods  for  observation.   This  will  require 
cooperative  work  with  schools,  since  the  individual  differences  are  so  large 
that  many  subjects  must  be  used.   In  addition,  new  conceptualizations  must  be 
developed  to  account  for  these  differences  so  that  they  can  be  examined  in 
fvirther  studies . 

Honors  and  Awards :   None 

Publications :   None 


305 


I 


Serial  No.  M-P-P-(C)-it6 

1.  Laboratory  of  Psychology 

2.  Section  on  Personality 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   Stimulus  Intensity  Modification:  Ueurophysiologic  and 
Psychoanalytic  Relationships. 

Previous  Serial  Number:   None 

Principal  Investigator:   Stanley  I.  Greenspan,  M.D. 

Other  Investigators:  Monte  Buchshaum,  M.D. 

Cooperating  Units:  Unit  on  Psychophysiology,  Laboratory  of  Psychology, 
NIMH. 

Man  Years 

Total:  .68 
Professional:  .50 
Other;        .18 

Project  Description: 

Objectives : 

1)  To  develop  a  psychoanalytic  model  of  defense  organization  based  on 
defense  patterns  established  early  in  life  which  would  provide  a  psycholo- 
gical parallel  to  the  augmenting  vs.  reducing  average  evoked  response  measure. 

2)  To  test  first  the  possibility  of  a  relationship  between  this  model 
and  the  augmenting  and  reducing  measures  by  using  it  to  make  blind  predictions 
of  the  rank  order  distribution  of  augmenting  and  reducing  in  a  small  group  of 
normal  young  adults  who  were  previously  measured  along  the  augmenting-reducing 
dimens  ion . 

3)  To  refine  the  model  and  to  develop  a  replicable  scoring  system  and 
test  it  on  a  large  sample  of  young  adults. 

3)  To  do  the  same  for  a  group  of  young  children. 

Methods  Employed: 

Groups  of  normal  volunteers ,  ages   18-30 ,  were  studied  on  whom  both 
Rorschach  and  neurophysiological  data  were  already  available.   The  augment- 
ing-reducing average  evoked  response  procedures  is  described  elsewhere 


307 


Serial  No.   M-P-P-(C)-1|6,  Page  2 

(see  M-P-P-(C)-36,  19Tl).   The  Rorschach  records  were  rated  according  to  the 
appearance  of  predefined  defense  patterns  and  from  these  ratings  with  rank 
order  distribution  of  augmenting  and  reducing  was  predicted. 

Ma,i  or  Findings  : 

Part  one  of  this  project  has  heen  accomplished.   A  model  of  defense 
organization  hypothesizing  two  defense  patterns  was  developed.   One  pattern 
was  the  internalization  of  stimuli  or  stimulus  deprivation  which  is  related 
to  the  development ally  early  defenses  incorporation  withdrawal  and  identifi- 
cation of  stimuli  or  stimulus  deprivation  which  is  related  to  the  develop- 
mentally  early  defenses  incorporation  withdrawal  and  identification.   The 
second  defense  pattern  was  the  externalization  of  stimuli  or  stimulus  enrich- 
ment related  to  the  developmentally  early  defenses  projection  acting  out  and 
active  avoidance.   Rank  order  predictions  of  augmenting  and  reducing  were 
made  on  two  groups  of  eight  subjects.   The  model  and  scoring  procedure  was 
refined  between  the  first  and  second  group.   The  predictions  for  the  second 
group  were  significant  (rho  =  .97,  -.01).   This  finding  supports  the  pro- 
posed model  of  defense  organization  as  a  parallel  to  augmenting  and  reducing. 
It  supports  the  further  development  of  the  model  and  scoring  procedures  for 
the  next  steps  in  the  project. 

Scientific  Significance  to  Mental  Health  Research  Programs : 

There  are  a  number  of  implications  from  this  project.   The  suggested 
relationship  between  constructs  from  two  separate  disciplines  can  aid  in 
cross-validating  each  construct  and  in  giving  each  construct  added  meaning. 
If  our  proposal  model  is  correct,  the  neurophysiologic  constructs  of  augment- 
ing and  reducing  can  be  related  to  both  individual  and  groups  of  defenses. 
The  psychoanalytic  meaning  of  defense  mechanism  can  be  expanded  to  include 
basic  neurophysiologic  mechanisms.   An  easily  replicable  way  to  measure 
complex  psychological  processes  can  be  developed. 

In  addition,  identifying  neurophysiologic  and  concomitant  psychological 
differences  in  homogeneous  diagnostic  groups  would  further  the  development 
of  an  effective  nosology  with  implications  for  prevention  and  treatment. 

Further  documentation  of  the  relationship  of  augmenting  and  reducing  to 
specific  psychological  mechanisms  may  provide  a  model  and  a  technology  to 
observe  the  early  predisposition  toward  specific  character  styles  as  well 
as  pathologic  formations. 

Proposed  Course  of  Project: 

Further  development  of  this  model,  as  mentioned,  and  a  study  of  its 
implications  for  models  of  psychopathology  and  personality  development. 

Honors  and  Awards :   None 

Publications:   None 


Serial  No.  M-F-A-I6 

1.  Laboratory  of  Psychology 

2.  Section  on  Higher  Thought 

Processes 

3.  Bethesda 


PHS-BBMHA-NIMH 

Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:  A  Study  of  the  Means-end  Thought  Processes  in  Hiiman  Subjects. 

Previous  Serial  Number:  Same 

Prlnci^l  Investigator:  ildward  A.  Jerome 

Other  Investigators:  None 

Cooperating  Units:  Technical  Development  Section,  NIMH,  Computer  Systems 
Laboratory,  DCRT 


-Man  Years: 

!E6tal:'' 

4.00 

Proifefisioilal: 

1.00 

Other-:  -     "' 

3.00 

Project  Description:   ■   •         ^ 

Objectives;  It  is  the  purpose  of  this  project  to  investigate  the  mental 
activities  that  are  responsible  for  resolving  problematic  situations  that 
occur  in  the  course  of  the  individual's  interaction  with  his  environment. 
Problems  often  resxilt  from  imperfect  knowledge  of  the  operational  regular- 
ities' of  the  escternal  systems,  and  resolution  of  the  difficulty  is  achieved 
by  cdBipetent  inquiry  into  these  regularities.  In  order  to  be  effective,  the 
inquiries  must  be  guj.ded  or  controlled  by  a  set  of  cognitive  principles 
collectively  called  heuristic  processes.'  This  project  has  the  following 
objectives:  to  describe  the  distribution  of  heuristic  capabilities  in 
various  cross- sections  of  the  population,  to  discover  meajis  of  facilitating 
the  acquisition  of  heuristic  principles,  to  find  ways  of  improving  the 
ability  to  apply  such  principles,  and  to  participate  in  the  development  of 
a  hormative  thepry  of  effective  heuristic  structures. 

Methods  Employed;   Standard  tests  of  mental  ability  are  administered  for  com- 
parison with  performances  on  a  variety  of  computer- controlled  system  analysis 
problems  developed  for  this  project.  A  set  of  ik   related  classes  of  prob- 
lems called  HEPP  has  been  described  in  previous  reports.  Two  sets  of  new 
problems  were  developed  last  year  for  the  new  SEL  81OB  real-time  computer 


309 


Serial  No.  M-P-A-I6,  Page  2 

configuration.  The  new  problems ^  called  ATSEL  and  ATREC,  monitor  improved 
procedures  for  the  selection  and  reception  paradigms  of  experiments  on 
concept  formation.  All  of  these  programs  implement  special  controls  that 
were  impossible  (prohibitively  expensive  and/or  cumbersome)  without  the 
support  of  a  high  speed  process- control  computer. 

An  investigation  designed  to  evaluate  the  difficulty  of  two  types 
of  means-end  thinking  is  in  progress.  It  is  concerned  with  those  numerous 
situations  in  which  uncertainty  results  from  not  knowing  which  subset  of  a 
given  set  of  factors  is  relevant  to  a  desired  outcome.  When  the  given  set 
is  known  to  include  all  possibly  relevant  factors,  two  types  of  Information 
about  any  particiilar  factor  is  possible:   one  implies  that  the  factor  is 
relevant,  the  other  implies  that  it  is  irrelevant.   Sufficient  information 
to  control  outcomes  may  be  a  mixture,  in  various  proportions,  of  these  two 
types  of  implications,  i.e.,  the  set  of  factors  implied  to  be  relevant  may 
not,  in  itself,  be  sufficient,  and  the  set  of  factors  implied. to  be 
irrelevant  may  not,  in  itself,  be  sufficient,  but  the  sum  of  these  two 
sets  of  implications  may  suffice  to  yield  the  desired  control. 

The  experiment  in  progress  provides  data  on  the  relative  efficiency 
with  which  people  use  information  (a)  that  implies  relevance  for  a  sufficient 
set  of  factors,  (b)  that  implies  irrelevance  for  a  sufficient  set  of  factors, 
or  (c)  that  implies  the  relevance  of  some  factors  and  the  irrelevance  of 
others  so  that  the  simi  of  information  is  just  sufficient  to  support  a 
solution.  The  evaluations  will  be  derived  from  a  factorial  design  in  which 
comparisons  will  be  made  within  individuals  (i.e.,  each  S  will  serve  as  his 
own  control) . 

Major  Findings: 

Acquisition  and  Interpretation  of  Information.  From  an  analysis  of  data 
obtained  in  an  experiment  described  in  last  year's  report,  new  perspectives 
on  the  analysis  of  data  obtained  from  attribute  identification  paradigms 
have  been  formulated.  It  was  foiond  advantageous  to  replace  the  traditional 
analysis  of  "total  trials  (errors,  time)  to  solve"  by  separate  analyses  of 
trials  that  occur  before  and  after  the  trial  on  which  sufficient  infor- 
mation (tSI)  for  a  solution  becomes  available.  Most  of  the  earlier  trials 
are  necessary  to  elicit  information  that  has  not  been  disclosed,  whereas 
all  of  the  later  trials  are  redundant,  but  apparently  required  to  assist 
in  the  process  of  interpretation.  Moreoever,  the  number  of  pre-TSI  trials 
is  largely  determined  by  objective  characteristics  of  the  problem  space  and 
it  shows  little  within-  or  between- subject  variability,  whereas  post-TSI 
trials,  being  associated  with  the  difficulty  of  interpreting  information," 
reflect  the  psychologically  interesting  components  of  performance  and  ac- 
count for  most  of  the  within-  and  between- subject  variability. 


310 


Serial  No.  M-P-A-I6,  Page  3 

It  is,  of  course,  possible  for  the  processes  of  acquisition  and 
interpretation  to  function  concurrently;  in  this  case  the  problem  is  solved 
on  the  TSI.  The  present  analyses  demonstrate — and  all  prior  data  suggest — 
that  the  two  processes  usually  proceed  in  a  serial,  or  possibly  overlapping 
sequence.  Some  people  learn — for  a  particular  problem  area,  at  least — to 
interpret  information  as  it  is  acquired,  but  this  appears  to  be  a  somewhat 
special  cognitive  skill  that  other  people  do  not  manifest  during  practice 
sessions  that  are  not  arbitrarily  long.  In  any  case,  it  is  important  to 
study  acquisition  and  interpretation  of  information  as  conceptually  separable 
processes. 

Attribute  Identification  System.  A  computer  program  that  " solves"  attribute 
identification  problems  by  heuristics  specified  in  a  variety  of  current 
theories  has  been  developed  as  sm  experimental  device  for  performing  suf- 
ficiency tests  on  any  explicit  and  reasonably  concise  hypothesis  about  the 
heuristics  used  by  human  subjects  in  their  efforts  to  solve  this  type  of 
problem. 

Thus  far  the  simple  "hypothesis"  theory  and  the  "local  consistency" 
theory  with  memories  of  length  1,  2  and  3j  with  and  without  a  heuristic 
that  concentrates  on  the  more  informative  type  of  instance  (positive  in- 
stances are  more  informative  then  negative  instances  in  conjunction  problems, 
and  the  reverse  is  the  case  in  disjvmction  problems)  have  been  implemented. 
A  device  that  is  driven  by  a  random  mechanism  under  "local  consistency" 
constraints  with  a  memory  for  two  events  and  a  knowledge  of  the  more  in- 
formative type  of  instance  does  as  well  as  a  human  subject  on  all  classes 
of  problems  in  a  binary  valued  universe  of  four  dimensions  regardless  of 
the  logical  connective  that  governs  the  classification  rule .  Systems  with 
progressively  fewer  constraints  on  the  random  driver  perform  progressively 
less  efficiently. 

Although  simulators  are,  of  course,  important  instruments  for 
checking  and  developing  theories,  their  greatest  value  may  be  found  to 
derive  from  the  care  and  attention  to  detail  that  they  force  upon  their 
designers.  The  present  effort  has  directed  attention  to  several  formal 
characteristics  of  the  traditional  attribute  Identification  paradigm  that 
have  important  technical  implications  suggesting  that  a  new  type  of  problem, 
having  a  less  constrained  uncertainty  structure,  is  needed  in  the  current 
stage  of  development  of  this  research  area. 


h 


311 


Serial  No.  M-P-A-I6,  Page  k 

Scientific  Significance  to  the  Program  of  Mental  Health  Research:  On  the 
hypothesis  that  one  of  the  most  important  determiners  of  mental  health  in 
a  normal  person  is  his  ability  to  think  effectively  in  the  variety  of 
puzzling  situations  that  challenge  him  daily,  the  primary  goal  selected  for 
this  project  is  the  development  of  theory  and  the  acquisition  of  data  on  the 
quality  of  means-end  thinking  in  the  population  as  a  whole  and  in  selected 
sub- samples  thereof.  More  specifically  it  is  directed  toward  the  detection 
of  heuristic  or  thinking  deficits  and  toward  the  development  of  methods  for 
avoiding  or  repairing  such  deficits  in  otherwise  normal  people.   To  acquire 
the  understanding  necessary  to  achieve  this  goal  present  theory  and  knowledge 
of  the  processes  that  support  this  mental  activity  need  to  be  extended  by 
intensive  research. 

Proposed  Course  of  the  Project:  Experiments  will  be  developed  to  evaluate 
the  ability  of  people  to  discover  what  kinds  of  regularity  exist  in  events 
(rule  identification),  and  a  study  of  how  this  ability  can  be  improved  will 
be  undertaken.   In  the  direction  of  training,  an  effort  will  be  made  to 
design  a  computer  implemented  version  of  the  WFF  'N  PROOF  games,  which 
purport  to  be  enjoyable  lessons  in  logic. 

The  work  on  simulators  will  be  extended  in  the  direction  of  discovering 
what  kinds  of  amendments  to  existing  theories  seem  to  be  required  in  order 
to  increase  their  ability  to  predict  problem  solving  behavior. 

Honors  and  Awards:  None 

Publications:  Jerome,  E.  A.,  and  Young,  M.  L.:  Means-end  thinking  of 

schizophrenics.  Psych.  Reports  29:  855-862,  I97I. 

Young,  M.  L.:  Age  and  sex  differences  in  problem  solving. 

J.  Geront .  26:  330-336,  1971. 


^ 


312 


Serial  No.  M-P-B-2 

1.  Laboratory  of  Psychology 

2.  Section  on  Neuropsychology 
•?  -                               3.  Bethesda 

PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   Analysis  of  the  relationship  between  problem-solving  behavior 
and  certain  cortical  and  subcortical  structures  in  the  sub- 
human primate  brain. 

Previous  Serial  Number:   Same. 

Principal  Investigators:   H.  Enger  Rosvold,  Mortimer  Mishkin,  Patricia 

Goldman 

Other  Investigators:   Lajos  Vereczkei  (International  Research  and  Exchanges 
Board,  Foreign  Exchange  Scholar,  University  Medical 
School,  Pecs,  Hungary) 
,,  ,        Roger  Buddington  (NIMH  Postdoctoral  Fellow) 

Cooperating  Units:   None 

Man  Years: 

i. Total:  5  3/5 
.^Professional:  3 
.-  Other:  2  3/5 

Project  Description: 

Project:  To  identify  the  brain  structures  that  are  essential  for  problem- 
solving  behavior. 

Objectives:   To  determine  the  neural  system  or  systems  serving  problem-solving 
behavior  as  exemplified  in  delayed-response,  discrimination,  learning  set, 
etc.,  and  to  describe  the  nature  of  the  behavioral  deficits  which  follow 
damage,  to  the  structures  comprising  these  systems. 

Methods:   (1)  A  variety  of  behavioral  tests  are  used  to  define  the  functions 
which  are  specific  to  the  prefrontal  lobes  as  a  whole,  or  to  various  of  its 
parts.   The  current  emphasis  is  to  analyze  the  frontal-lobe  deficit  in  terms 
of  its  participation  in  spatially  directed  responses  and  the  utilization  of 
interoceptive  and  exteroceptive  cues.   (2)  Lesions  are  placed  in  subcortical 
structures  (caudate  nucleus,  centrum  medlanum,  medialis  dorsalis  hypothalamus) 
and  the  effects  compared  with  those  following  selective  frontal  lesions. 


313 


Serial  No.  M-P-B-2,  Page  2 

Major  Findings:   (1)  Earlier  work  had  suggested  that  the  deficit  in  monkeys 
following  dorsolateral  prefrontal  lesions  is  due  to  a  disturbance  in  the 
utilization  of  response-produced  cues  elicited  by  spatial  responses  in  a  test. 
To  assess  this  view,  monkeys  with  dorsolateral  prefrontal  lesions  and  normal 
controls  were  trained  to  run  to  one  side  of  a  T-Maze  under  two  conditions  of 
illumination  -  dimly  lit  and  well  lit.   When  the  maze  is  dimly  lit,  learning 
the  spatial  response  should  rely  heavily  on  response-induced  or  proprio- 
ceptive cues  and  frontal  monkeys  should  be  impaired.   In  fact,  the  results 
did  not  confirm  the  prediction.   While  the  data  from  "critical"  trials  inter- 
polated between  regular  training  trials  indicated  that  the  monkeys  did  indeed 
learn  the  task  on  the  basis  of  proprioception,  the  frontal  monkeys  neverthe- 
less performed  as  well,  if  not  better,  than  the  controls.   In  the  well  lit 
condition,  by  contrast,  frontal  monkeys  were  impaired  and  there  was  evidence 
to  indicate  that  they  attended  to  and  were  perhaps  confused  by  the  visual- 
spatial  cues  available  in  that  situation.   This  study  is  the  first  of  its 
kind  to  dissociate  between  sensory  (response-produced  or  proprioceptive)  and 
"gnostic"  modes  of  spatial  learning  in  frontal  monkeys  and  to  call  into 
question  the  proprioceptive  basis  of  the  frontal  disorder.   (2)  Earlier  work 
had  demonstrated  that  those  functions  which  are  differentially  affected  by 
dorsolateral  and  orbital  cortical  lesions  are  also  differentially  affected  by 
lesions  in  subcortical  structures  which  receive  anatomical  projections  selec- 
tively from  the  dorsolateral  or  orbital  frontal  cortex.   One  of  these  sub- 
cortical structures  is  the  medial  dorsal  thalamic  nucleus.   It  has  been  a 
long-standing  puzzle  in  neuropsychology  that  lesions  in  this  nucleus  do  not 
result  in  "frontal"  deficits  despite  the  intimacy  of  its  anatomical  connec- 
tions with  the  frontal  cortex.  Nevertheless,  since  the  anatomical  relation- 
ships are  so  compelling,  we  undertook  to  investigate  this  problem  again  with 
slightly  different  procedures.   The  results  clearly  indicate  that  lesions  in 
this  nucleus  can  result  in  profound  deficits  on  these  tasks.   Current  efforts 
are  being  directed  toward  determining  which  of  the  factors  introduced  into 
the  new  study  is  critical  in  producing  these  deficits ,   Another  of  these  sub- 
cortical structures  having  close  anatomical  relationships  with  the  prefrontal 
cortex,  is  the  hypothalamus.   While  many  studies  have  demonstrated  similari- 
ties between  the  frontal  cortex  and  the  hypothalamus  in  the  emotional  and 
motivational  functions  which  they  subserve,  none  has  considered  whether  or 
not  there  are  also  similarities  in  cognitive  functions .   Our  recent  work  has 
shown  >;hat  large  lesions  involving  different  divisions  of  the  hypothalamus 
result  in  a  pattern  of  deficits  on  cognitive  problems  which  are  characteristic 
of  damage  to  the  orbital  frontal  cortex.   Smaller,  selectively  placed  lesions, 
though  resulting  in  impairments,  did  not  yield  a  pattern  of  deficits  unequi- 
vocally characteristic  of  one  or  the  other  of  the  frontal-lobe  systems. 

Scientific  Significance  to  Mental  Health:   The  results  of  this  project  have 
revealed  that  the  prefrontal  cortex  in  monkeys  is  functionally  heterogeneous 
with  dorsal  and  ventral  areas  participating  in  problem-solving  behavior  in  two 
quite  different  ways;  even  within  these  areas  there  is  evidence  of  further 
specialization  of  function.   Furthermore,  each  of  these  frontal  areas  appears 
to  be  but  one  component  of  a  larger  cortical-subcortical  system.   Specifica- 


314 


Serial  No.  M-P-B-2,  Page  3 

tion  of  the  types  of  cortical  contributions  to  problem-solving,  and  delineation 
of  the  two  cortical-subcortical  systems,  should  help  to  resolve  the  long- 
standing puzzle  regarding  the  functions  of  the  frontal  lobes. 

Proposed  Course  of  Project:   No  major  shift  in  emphasis  is  anticipated. 

Honors  and  Awards:   None 

Publications: 

Goldman,  P.  S.,  Rosvold,  H.  E. ,  Vest,  B.  and  Galkin,  T.  W.   Analysis  of  the 
delayed-alternation  deficit  produced  by  dorsolateral  prefrontal  lesions  in 
the  Rhesus  monkey.   J.  Comp.  Physiol.  Psychol.,  77:   212-220,  1971. 

In  Press: 

Rosvold,  H.  E.   The  frontal  lobe  system:   cortical-subcortical  interrelation- 
ships.  Acta  Neurobiologiae  Experimentalis  (In  Press). 


315 


Serial  No.  M-P-B-5 
1.  Laboratory  of  Psychology 
■  -  2 .  Section  on  Neuropsychology 

3.  Bethesda 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:   Neural  mechanisms  in  vision. 

Previous  Serial  Number:  Same 

Principal  Investigator:  Mortimer  Mishkin 

Other  Investigators:  Lillian  Blake  (Consultant  Part-time) 
Charlene  Jarvis  (NIMH  Staff  Fellow) 

Jean  Delacour  (NIMH  Guest  Worker  from  College  de  France, 
Paris) 

Cooperating  Units:  Charles  Gross,  Princeton  University,  Cambridge 
Frederick  J.  Manning,  WRAIR,  Washington,  D.  C. 
Marvin  Sr5"'^=er  (NEI,  Research  Psychology) 

Man  Years: 
Total:  4  3/5 
Professional:  1  3/5 
'  Other:  3   , 

Project  Description: 

Project:  Behavioral,  anatomical,  and  electrophysiological  analysis  of  neural 
mechanisms  in  vision. 

Objectives:  To  define  the  role  in  vision  of  neural  structures  outside  the 
primary  visual  projection  system. 

Methods:  (1)  Monkeys  are  prepared  at  NIMH  with  various  lesions  to  the  visual 
system,  and  they  are  then  studied  electrophysiologically  at  Princeton  Univer- 
sity by  Gross  and  his  colleagues  to  determine  whether  or  not  the  receptive 
field  properties  of  inferotemporal  units  have  been  altered  in  a  manner  pre- 
dicted by  our  theory  of  cortico-cortical  transmission.   (2)  Monkeys  are 
trained  before  and  after  tectal  or  pulvinar  lesions  on  a  spatial  or  a  diffi- 
cult non-spatial  visual  discrimination  task  as  a  step  toward  determining 
whether  the  tecto  -  pulvinar  -  extrastriate  cortical  projection  might  be 
concerned  with  spatial  as  opposed  to  object  or  pattern  vision.   (3)  Monkeys 
are  trained  after  various  lesions  of  the  limbic  system  on  visual  associative 
learning  tasks  as  a  step  toward  determining  whether  direct  interaction  between 
the  visual  and  limbic  systems  might  be  the  mechanism  whereby  visual  stimuli 
gain  emotional/motivational  significance  for  the  animal. 


317 


Serial  No.  M-P-B-5,  Page  2 

Major  Findings:  (1)  In  accord  with  predictions,  left  striate  cortex  ablation 
restricts  the  receptive  zones  of  inf erotemporal  units  in  both  hemispheres  to 
the  left  visual  field,  while  forebrain  commisurotomy  limits  the  receptive 
zones  of  inf erotemporal  units  to  the  visual  field  contralateral  to  the 
hemisphere  being  recorded  from  (i.e.,  the  left  field  for  right  inf erotemporal 
units,  and  the  right  field  for  left).   Pulvinar  lesions  do  not  eliminate 
any  visual  inputs.   (2)  Tectal  lesions  impair  performance  on  visual  spatial 
but  not  on  nonspatial  discriminations,  supporting  the  conception  that  the 
"second"  visual  system  is  concerned  with  spatial  rather  than  object  vision. 
(3)  Both  orbital  frontal  and  temporal  pole  plus  amygdala  lesions  (but  not 
hlppocampal  lesions)  impaired  object  reversal  learning,  suggesting  that 
anatomical  interconnections  between  the  visual  system  and  these  two  parts  of 
the  limbic  system  may  indeed  participate  critically  in  the  formation  of 
stimulus-reward  associations. 

Scientific  Significance  to  Mental  Health  Research:  Vision  is  perhaps  the  best 
understood  of  the  sensory  modalities  in  relation  to  the  functioning  of  the 
nervous  system.  Yet  a  major  problem  remains  unsolved  in  vision  as  it  does 
in  all  sensory  modalities:  Delineation  of  the  events  which  intervene  between 
stimulus  reception  at  the  cortex  and  the  observed  response.   The  demonstration 
that  damage  to  the  inferior  convexity  of  the  temporal  lobes  in  monkeys  produces 
impairment  in  visually-guided  behavior  has  opened  up  the  hitherto  inaccessible 
area  of  the  intracerebral  processes  in  vision,  i.e.,  neural  activity  related 
to  vision  hut  beyond  the  level  of  the  striate  cortex.   Unravelling  these 
mechanisms  in  vision  should  aid  greatly  in  the  solution  of  a  general  problem 
for  psychology,  viz.,  accounting  for  the  intervening  neural  processes  (thought 
and  its  breakdown)  in  normal  and  abnormal  behavior. 

Proposed  Course  of  Project:  (1)  Monkeys  with  bimacular  striate  and  prestriate 
lesions  are  currently  being  added  to  the  electrophysiological  study  in  order 
to  test  the  theoretical  neural  model  in  greater  detail.   (2)  Animals  are 
being  trained  on  the  visual  spatial  tasks  preliminary  to  electrocoagulation  of 
the  pulvinar.   (3)  Animals  with  temporal  pole  plus  amygdala  lesions  and  animals 
with  anterior  inf erotemporal  lesions  will  be  compared  on  associative  learning 
and  on  visual  memory  tasks . 

Honors  and  Awards:  None 

Publications : 

Mishkin,  M.   Cortical  visual  areas  and  their  interactions.   In  A.  G.  Karczmar 
&  J.  C.  Eccles  (eds) :  The  Brain  and  Human  Behavior,  Springer-Verlag,  1972, 
pp.  187-208. 

Snyder,  M.   The  evolution  of  mammalian  visual  mechanisms.   In  R.  Jung  (ed)  : 
A  Handbook  of  Sensory  Physiology,  Springer-Verlag.   In  Press. 


318 


Serial  No.  M-P-B-5,  Page  3 

Jones,  B.  and  Mishkin,  M.   Limbic  lesions  and  the  problem  of  stimulus-rein- 
forcement associations.   Experimental  Neurology .   In  Press. 


319 


Serial  No.  M-P-B-7 

1.  Laboratory  of  Psychology 

2 .  Section  on  Neuropsychology 

3.  Bethesda 

PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:  Histological  analysis  of  cerebral  lesions  and  Intracerebral 
connections  in  primates . 

Previous  Serial  Number:  Same 

Principal  Investigator:  H.  E.  Rosvold,  M.  Mishkin,  Patricia  S.  Goldman 

Other  Investigators:  T.  N.  Johnson  (Consultant  Part-time) 

Marvin  Snyder  (NEI  Research  Psychologist) 

Cooperating  Units:  None 

Man  Years: 
Total:  2  2/5 
Professional:  4/5 
Other:  2  2/5 

Project  Description: 

Project:  Verification  of  lesions  in  chronic  experimental  animals,  and 
analysis  of  intracerebral  connections  in  acute  preparations . 

Objectives:   The  objective  of  the  first  part  of  this  project  is  to  delineate 
the  loci  of  the  lesions  which  produce  specific  behavioral  effects,  and  of 
the  second,  to  determine  whether  or  not  loci  yielding  similar  effects  are 
anatomically  interconnected. 

Methods :  When  the  behavioral  testing  of  chronic  experimental  animals  is 
completed,  their  brains  are  embedded  in  either  celloidin  (large  specimens) 
or  paraffin  (smaller  specimens),  sectioned,  stained  for  cells  and  fibers, 
examined  microscopically,  and  the  lesions  reconstructed.   In  the  second 
part  of  the  project,  animals  are  prepared  with  selective  lesions  purely 
for  anatomical  investigation.   The  animals  are  sacrificed  within  a  few  days 
after  surgery  and  their  brains  examined  microscopically  to  determine  the 
locus,  extent  and  course  of  degenerating  fibers.   Special  staining  procedures 
and  fiber-size  determinations  are  used  to  study  stage  of  myelinization. 

Major  Findings:  Specimens  completely  processed  and  examined  include  70  monkey 
brains.   This  material  has  been  examined  for  the  purpose  of  verifying  the 
loci  of  the  cortical  and  subcortical  lesions  in  animals  used  for  behavioral 
studies.   Twenty  others  have  been  studied  to  determine  intracerebral 


321 


Serial  No.  M-P-B-7,  Page  2 

interconnections . 

In  previous  studies  it  had  been  demonstrated  that  there  is  a  topographic 
projection  of  fibers  from  various  parts  of  the  prefrontal  cortex  to  the  head 
of  the  caudate  nucleus  and  putamen.   We  have  now  completed  a  study  demon- 
strating that  this  topographic  arrangement  is  maintained  in  the  efferent 
projections  of  the  caudate  to  the  globus  pallidus,  fibers  from  the  dorso- 
lateral caudate  taking  a  lateral  position  in  the  pallidum,  and  fibers  from 
the  ventrolateral  caudate  taking  a  medial  position  in  the  pallidum.   Current 
work  is  intended  to  show  that,  in  turn,  the  efferents  from  the  lateral  palli- 
dum and  from  the  medial  pallidum  are  dissociable,  each  taking  separate 
trajectories  into  the  thalamus  and  subthalamus.   Another  study  concerned  with 
the  connections  between  frontal  cortex  and  caudate  nucleus  deals  with  the 
question  of  when  in  ontogeny  these  connections  are  established.   So  far, 
infant  animals  at  various  stages  of  development  have  been  prepared  with 
lesions  in  different  parts  of  the  cortex  and  their  brains  have  been  processed 
for  study  of  degenerating  fibers. 

lu  an  anatomical  study  concerned  with  interrelationships  in  the  visual 
system,  lesions  were  placed  in  the  superior  colliculus  of  monkeys  to  deter- 
mine whether  the  secondary  visual  pathway  present  in  the  rat,  cat,  tree 
shrew,  and  squirrel  is  also  present  in  higher  primates.   Utilizing  both  the 
Fink-Heimer  and  Voneida  silver-impregnation  techniques  we  have  demonstrated 
that  the  superior  colliculus  sends  a  heavy  projection  to  the  inferior 
portion  of  the  pulvinar,  a  connection  which  appears  to  be  homologous  to  that 
reported  in  non-primate  animals.   In  addition  the  colliculus  sends  a  rela- 
tively heavy  projection  to  the  nucleus  centralis  lateralis.  Animals  have 
now  been  prepared  with  lesions  placed  either  superficially  or  deep  in  the 
superior  colliculus  to  determine  if  these  two  pathways  can  be  dissociated. 
Preliminary  results  from  another  study  indicate  that  the  pretectim,  also 
involved  in  vision,  projects  to  the  parietal  cortex  through  the  lateral 
posterior  nucleus,  suggesting  still  another  visual  pathway. 

Scientific  Significance  to  Mental  Health  Research:  Sufficient  evidence  has 
been  accumulated  in  behavioral  studies  with  brain  damaged  animals  to  suggest 
that  widely  separated  cell  aggregates  in  cortex  and  subcortex  may  be  combined 
into  a  complex  system;  and  it  is  the  functioning  of  such  neural  systems,  rather 
than  the  functioning  of  the  particular  elements  of  which  they  are  composed, 
that  seems  most  directly  relevant  to  an  understanding  of  the  organization 
and  disorganization  of  behavior.   The  significance  of  this  project  lies  in 
the  fact  that  it  can  provide  detailed  information  on  the  composition  of  these 
neural  systems;  systems  which  through  electric  and  chemical  manipulation 
have  been  related  to  mental  health  and  disease. 

Proposed  Course  of  Project:  The  studies  involving  localization  of  function, 
anatomical  substrate  of  the  frontal  systems,  and  anatomical  substrate  of  the 
visual  systems  will  continue.   Their  will  be  an  increased  emphasis  on  the 


322 


Serial  No.  M-P-B-7,  Page  3 

ontogeny  of  the  development  of  the  connections  in  the  frontal  system  and, 
as  well,  the  anatomical  basis  of  the  potential  for  cerebral  reorganization 
in  the  infant  brain.   Electronmicroscopic  and  autoradiographic  techniques 
as  well  as  traditional  techniques  will  be  used  for  this  purpose. 

Honors  and  Awards:  None 

Publications : 

Johnson,  T.  N. ,  and  Rosvold,  H.  E.:  Topographic  projections  on  the  globus 
pallidus  and  the  substantia  nigra  of  selectively  placed  lesions  in  the 
precommissural  caudate  nucleus  and  putamen  in  the  monkey.   Experimental 
Neurology,  33:  584-596,  1971 


323 


Serial  No.  M-P-B-14 

1.  Laboratory  of  Psychology 

2.  Section  on  Neuropsychology 

3.  Bethesda 

PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  title:   The  neural  regulation  of  appetitive  behavior. 

Previous  Serial  Number:   Same 

Principal  Investigator:   H.  Enger  Rosvold 

Other  Investigator:   Douglas  Bowden  (University  of  Washington,  Seattle) 

Cooperating  Units:   None 

Man  Years: 

Total:   0  of  NIMH;  only  of  other  investigator 
Professional:   0 
Other:   0 

Project  Description: 

Project:   To  identify  the  brain  structures  which  are  involved  in  food-oriented 
social  behavior. 

Objectives:   The  objective  is  first  to  identify  structures  in  the  brain  which 
are  related  to  food  and  water  oriented  behavior,  then  to  obtain  an  under- 
standing of  how  food  regulating  mechanisms  in  the  brain  function. 

Methods:   The  brain  is  first  explored  with  roving  electrodes  for  sites  which 
regulate  drinking  behavior  when  stimulated  while  the  animal  is  restrained. 
When  such  structures  are  located,  the  effect  of  stimulation  in  these  areas 
was  examined  with  respect  to  various  degrees  of  thirst  motivation  and  the 
reliability  of  the  effects  over  length  of  time  of  stimulation.   Four  monkeys 
were  implanted  with  a  total  of  80  chronic  electrodes  in  brain  areas  where 
electrical  stimulation  elicits  drinking.  All  of  the  histological  analysis  has 
been  completed  and  the  behavioral  data  has  been  analyzed.   The  material  is  now 
being  prepared  for  publication. 

Major  Findings:   The  effect  of  stimulation  in  areas  which  elicit  drinking  was 
examined  with  respect  to  the  various  degrees  of  thirst  motivation  and  the 
reliability  of  the  effects  over  length  of  time  of  stimulation.   It  was  found 
that  some  animals  drink  to  brain  stimulation,  others  do  not,  even  though  the 
same  brain  areas  are  stimulated.   In  those  animals  that  drink  to  stimulation, 
the  volume  of  the  brain  system  mediating  the  response  increased  during  the 
six  weeks  of  stimulation  for  drinking  points;  i.e.,  a  greater  proportion  of 
sites  gave  rise  to  the  response  as  the  exploration  for  sites  proceeded.   In 

325 


Serial  No.  M-P-B-14,  Page  2 

non-drinkers,  the  anatomical  system  from  which  drinking  could  be  elicited 
became  smaller.   Within  animals,  the  relationship  between  self-stimulation 
and  drinking  elicited  from  selected  points  was  consistent  from  point-to-point, 
but  the  kind  of  relationship  differed  for  the  two  animals  which  were  studied 
in  this  regard.   The  interpretation  being  placed  on  these  data  is  that  activi- 
ty in  at  least  some  cells  of  the  hypothalamus  motivates  behavior  only  in  a 
general  sense  until  physiological  and/or  environmental  conditions  are  such  as 
to  shape  specific  behavior  patterns.   Furthermore,  these  cells  can  be  com- 
mitted to  other  functions  should  the  conditions  change. 

Scientific  Significance  to  Mental  Health  Research:   Understanding  the  motiva- 
tion of  behavior  is  fundamental  to  an  understanding  of  both  normal  and  ab- 
normal behavior.   It  is  anticipated  that  this  study  will  contribute  to  an 
understanding  of  the  brain's  participation  in  motivation. 

Proposed  Course  of  Project:  Project  will  terminate  with  publication  of  re- 
sults. No  further  research  on  this  project  is  possible  due  to  reduction  in 
staff. 

Honors  and  Awards:   None 

Publications:   None 


326 


Serial  No.  M-P-B-16 

1.  Laboratory  of  Psychology 

2.  Section  on  Neuropsychology 

3.  Bethesda 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:  Cerebral  mechanisms  underlying  functional  plasticity  in  the 
developing  organism. 

Previous  Serial  No.:  Part  of  M-P-B-2 

Principal  Investigator:  Patricia  S.  Goldman 

Other  Investigators:  H.  Enger  Rosvpld 

Epp  Milder  (NIMH  Postdoctoral  Fellow) 

Cooperating  Units :  None       _,  . 

Man  Years:  . 

Total:  4  2/5  ' 

Professional:  1  4/5 
Other:  2  3/5 

Project  Description: 

Project:  To  determine  the  cerebral  mechanisms  underlying  functional  plasti- 
city in  the  developing  organism. 

Objectives:  Behavioral  deficits  following  cortical  injury  are  commonly  less 
severe  the  earlier  in  life  the  injury  is  sustained.   The  major  purpose  of 
this  research  is  to  understand  the  mechanisms  by  which  recovery  is  accom- 
plished following  brain  damage  in  infancy  and  to  determine  whether  or  not 
similar  mechanisms  could  be  enhanced  or  induced  when  such  damage  is  sustained 
later  in  life 

Methods:  The  studies  involve  the  comparison  of  identical  lesions  in  infants 
and  juveniles.   The  infants  are  usually  operated  when  they  are  2-months  of 
age;  the  juveniles  between  11/2  and  2  years  old.   Both  groups  are  allowed 
a  10-month  postoperative  recovery.   Thus,  the  infants  are  1-year  of  age  and 
the  juveniles  28-34  months  old  when  formal  testing  of  their  cognitive 
abilities  is  begun.   Unoperated  monkeys  of  the  same  ages  (that  have  also 
resided  in  the  laboratory  for  ten  preceding  months)  are  tested  as  well.   The 
studies  have  involved  the  following  lesions:  prefrontal  lobectomies;  dorso- 
lateral prefrontal  and  orbital  prefrontal  resections;  caudate  nucleus 
lesions;  combined  prefrontal  lobectomies  and  caudate  lesions;  and  ablation 
of  the  dorsomedial  nucleus  of  the  thalamus.   The  behavioral  tests  utilized 


327 


Serial  No.  M-P-B-16,  Page  2 

are  designed  to  measure  specific  and  dissociable  functions  of  the  prefrontal 
cortex.   The  same  tests  are  given  in  the  same  order  to  infants  and  juveniles 
alike.   Upon  completion  of  the  testing,  which  may  require  a  year  or  longer, 
the  monkeys  are  sacrificed  and  their  brains  processed  for  histological 
examination. 

Major  Findings;  (1)  Recovery  of  function  is  not  an  immutable  consequence  of 
early  brain  damage  as  the  literature  would  imply.   Lesions  of  the  orbital 
cortex  in  infants,  unlike  those  in  other  regions  of  the  cortical  mantle, 
produce  impairments  in  behavior  comparable  to  those  produced  by  identical 
lesions  in  adults.   (2)  These  impairments  are  equally  severe  whether  the 
lesions  are  induced  at  3  days,  1  week,  4  weeks,  8  weeks,  or  130  weeks  of  age. 
(3)  The  capacity  for  recovery  is  directly  related  to  the  age  of  the  animal 
at  surgery  but  the  relationship  is  almost  the  opposite  of  what  might  be  ex- 
pected.  It  might  be  supposed  that  the  less  mature  the  cortical  area  is  when 
damaged,  the  greater  the  chance  of  recovery.  Actually,  if  a  lesion  is  made 
in  an  area  such  as  the  orbital  cortex  that  develops  early  in  ontogeny,  there 
will  ultimately  be  greater  recovery  than  if  a  lesion  is  made  in  the  dorso- 
lateral cortex  which  develops  later  in  ontogeny.  We  have  proposed  a  theo- 
retical frame  work  for  interpreting  these  somewhat  paradoxical  phenomena, 
stressing  the  relative  maturity  of  functionally  related  areas  which  are 
spared  by  the  early  injury.   (4)  Both  the  expression  of  deficits  attributable 
to  early  brain  damage  as  well  as  compensatory  readjustments  to  such  injury 
may  be  delayed  until  the  brain  approaches  full  maturity.   Thus,  monkeys  given 
dorsolateral  lesions  in  infancy  appear  to  behave  as  well  as  normal  controls 
at  early  stages  in  development  but  later  in  ontogeny  there  emerges  a  picture 
of  retarded  development.   In  the  case  of  monkeys  given  orbital  lesions  in 
infancy,  the  adultlike  deficits  which  are  evident  when  testing  is  conducted 
in  the  first  year  and  a  half  of  life,  tend  to  disappear  when  the  monkeys 
reach  two  years  of  age.   (5)  Recovery  mechanisms  are  not  necessarily  reci- 
procal.  Our  evidence  suggests  that  the  dorsolateral  cortex  may  compensate 
for  the  loss  of  orbital  cortex  since  monkeys  given  orbital  lesions  as  infants 
recover  at  about  the  time  the  dorsolateral  cortex  approaches  functional 
maturity.  Monkeys  given  dorsolateral  lesions,  on  the  other  hand,  do  not 
recover  despite  the  integrity  of  the  orbital  cortex.   (6)  Subcortical  functions 
may  be  more  vulnerable  to  early  injury  than  are  cortical  mechanisms.   Lesions 
of  the  caudate  nucleus  and  the  dorsomedial  nucleus  of  the  thalamus  in  infants 
result  in  severe  impairments  irrespective  of  age  at  surgery.   (7)  Monkeys 
given  caudate  lesions  as  infants  are  impaired  on  just  those  tasks  and  at  just 
those  ages  that  the  monkeys  with  dorsolateral  lesions  are  not.   This  finding 
suggests  that  in  the  course  of  normal  development,  subcortical  structures 
may  be  primarily  responsible  for  mediating  many  of  the  functions  that  the 
cortex  will  ultimately  assume. 

Scientific  Significance  to  Mental  Health  Research:  By  understanding  mechanisms 
for  recovery  of  function  following  neonatal  injury,  we  may  be  in  a  better 
position  to  correct  errors  of  normal  development  as  well  as  approach  the 
problem  of  recovery  in  the  adult-brain  injured. 


328 


Serial  No.  M-P-B-16,  Page  3 

Proposed  Course  of  Project;  So  far  our  studies  have  been  neuropsychological 
in  emphasis.  Many  questions  remain  concerning  the  behavioral  effects  of 
early  lesions  within  the  frontal-lobe  system  and  our  current  efforts  are 
designed  to  confront  these  questions  in  neurobehavioral  terms .  At  the  same 
time,  our  accumulated  knowledge  about  the  functions  of  the  frontal  lobes 
justifies  directing  our  efforts  to  another  level  of  analysis,  namely  the 
neuroanatomical.   Two  types  of  neuroanatomical  questions  arise  within  the 
context  of  developmental  research.   The  first  has  to  do  with  the  normal 
development  of  the  nervous  system.   We  are  seeking  to  determine  when  in 
ontogeny  the  dorsolateral  cortex  establishes  connections  with  the  caudate 
nucleus.  Monkeys  will  receive  selective  cortical  lesions  at  various  stages 
of  developm.ent  and  silver  impregnation  techniques  will  be  used  to  determine 
the  status  of  cortical-subcortical  pathways .   The  information  from  such 
studies  will  be  valuable  in  their  own  right  since  little  is  known  about  the 
structural  development  of  the  nervous  system  but  they  will  also  bear  directly 
on  the  theoretical  analysis  of  our  behavioral  findings.   The  second  major 
question  which  we  wish  to  approach  anatomically  concerns  the  presumptive  re- 
organization of  the  nervous  system  upon  early  injury.   To  this  end,  monkeys 
who  have  been  given  orbital  prefrontal  lesions  as  infants,  for  example,  will 
be  allowed  to  mature  and  behavioral  data  will  be  collected  at  maturity  to  in- 
sure that  functional  recovery  has  been  realized.  At  this  time,  unilateral 
cortical  lesions  will  be  placed  in  the  area  suspected  of  mediating  the  re- 
covery and  silver  impregnation  techniques  will  be  used  to  determine  if  there 
has  been  any  alteration  or  elaboration  of  normally  existing  pathways  which 
could  mediate  the  behavioral  recovery.   Ultimately  we  would  like  to  combine 
the  neuroanatomical,  behavioral,  and  neurochemical  approaches  to  obtain  as 
complete  a  picture  as  possible  of  the  normal  development  of  the  brain  and  its 
decreasing  potential  for  plasticity  with  age. 

Honors  and  Awards:   None 

Publications: 

Bowden,  D.  M. ,  Goldman,  Patricia  S.,  Rosvold,  H.  E.  and  Greenstreet,  R.  L. 
Free  behavior  of  Rhesus  monkeys  following  lesions  of  the  dorsolateral  and 
orbital  prefrontal  cortex  in  infancy.   Experimental  Brain  Research,  12: 
265-274,  (1971). 

Goldman,  Patricia  S.   Functional  development  of  the  prefrontal  cortex  in  early 
life  and  the  problem  of  neuronal  plasticity.   Experimental  Neurology,  32: 
366-387,  (1971). 

Goldman,  Patricia  S.   Developmental  determinants  of  cortical  plasticity.  Acta 
Neurobiologiae  Experimentalis  (In  Press). 


329 


Serial  No.  M-P-B-16,  Page  4 

Goldman,  Patricia  S.  and  Rosvold,  H.  E.   The  effects  of  selective  caudate 
lesions  in  infant  and  juvenile  Rhesus  monkeys.   Brain  Research.   (In  Press), 


330 


Serial  Wo.  M-P-L-5 

1.  Laboratory  of  Psychology 

2.  Section  on  Perception 

3.  Bathe sda 


PHS-HSMHA-imffl 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:   Individual  Differences  in  Normal  Perceptual  Processes 

Previous  Serial  Number:   Same 

Principal  Investigator:  V.  R.  Carlson 

Other  Investigators:   Harry  Blum,  Francine  Frome 

Cooperating  Units:   DCRT;  University  of  Maryland 

Man  Years 

Total: 

Professional: 
Others : 

Project  Description: 

Objectives:   (l)  To  obtain  normal  control  data  for  standardizing  procedures 
and  apparatus  in  the  measurement  of  perceptual  variables ,  and  to  obtain 
comparison  data  for  evaluating  the  effects  of  abnormal  and  other  special 
conditions.   (2)  To  develop  a  general  specification  of  perceptual  response 
in  terms  of  the  parameters  of  the  immediate  stimulus-situation,  past 
experience,  generalized  perceptual- cognitive  attitudes,  and  the  subject's 
motivational  reaction  to  the  situation. 

A  general  difficulty  hampering  the  investigation  of  form  perception  has 
been  the  lack  of  a  psychologically  adequate  method  for  specifying  form. 
Concepts  based  on  the  Euclidean  geometry  of  contours  have  so  fax  not  resulted 
in  a  coherent  set  of  parameters  in  terms  of  which  perceptual  responses  to 
shapes  and  patterns  can  be  ordered.  A  biologically-oriented  geometry  of 
form  has  recently  been  developed  by  Harry  Blum,  DCRT,  -which  provides  a  more 
efficient  set  of  principles  for  generating  the  kinds  of  shapes  occurring  in 
the  natural  environments  of  organisms.  The  initial  objective  of  the  present 
research  was  to  see  whether  differential  response  could  be  demonstrated  to 
variation  in  a  parameter,  the  symmetric  axis,  postulated  to  be  a  primary 
aspect  of  form  generation. 

Methods  Employed:  It  is  well-established  that  the  perception  of  the 
orientation  of  oblique  lines  is  less  accurate  than  the  perception  of 
horizontal  and  vertical  lines.   Accuracy  is  also  dependent  upon  line 


k 


331 


Serial  No.  M-P-L-5,  Page  2 

length.   Subjects  judged  the  orientations  of  a  series  of  ellipses  with 
varying  lengths  of  major  diameter,  focal  axis,  and  symmetric  axis.  The 
relationship  between  length  and  orientation  accuracy  was  determined  for 
each  of  these  parameters. 

Major  Findings:  Judged  orientation  of  the  ellipses  followed  a  function 
similar  to  that  for  straight  lines,  and  the  precision  of  perceived 
orientation  was  significantly  related  to  the  length  of  the  symmetric  axis 
but  not  to  the  lengths  of  the  conventional  geometrical  properties  of  the 
ellipse,  major  diameter  and  focal  axis.   The  theoretical  Implication  is 
that  the  perceptual  information  presented  by  the  ellipse  is  contained  in 
the  symmetric  axis. 

Scientific  Significance  to  Mental  Health  Research  Program:   The  geometry 
tested  may  prove  to  be  an  invaluable  tool  in  dealing  with  biological  shape 
and  growth  processes  in  general.  The  present  test  indicates  that  it  may 
have  important  specific  application  to  developmental  and  physiological 
processes  underlying  visual  perception. 

Proposed  Course  of  Project:  The  present  experiment  was  a  preliminary  test 
in  one  particular  area.  Tests  in  other  aspects  of  form  perception  are 
planned.  If  these  indicate  that  the  principles  involved  have  sufficient 
generality,  application  to  development  ally  related  problems  will  be  explored. 

Honors  and  Awards:  Appointment  to  Board  of  Editors,  Perception  & 
Psychophysics . 

Publications:  None 


332 


Serial  No.  M-P-L-7 

1.  Laboratory  of  Psychology 

2.  Section  on  Perception 

3.  Bethesda  ■ 


PHS-HSMHA-m]y[H 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 


Project  Title:   Perceptual  Adaptation 

Previous  Serial  Number:   Same 

Principal  Investigator:   V.  R.  Carlson 

Other  Investigators:   Irwin  Feinherg,  Eugene  Tassone 

Cooperating  Units:  VA  Hospital,  S^  Francisco 

Man  Years  •   ■  ■^      . 

Total: 

Professional: 

Others: 

Project  Description: 

Objectives:  To  investigate,, the  characteristics  of  perceptual  adaptation,.  -.. 
both  when  the  adaptation  occurs  in  a  single  limited  period  of  persistent 
stimulation  and  when  it  is  cumulative  in  a  series  of  stimulations  over 
relatively  long  periods  of  time. 

A  basic  problem  in  the  investigation  of  perceptual  adaptation  is  the 
role  of  the  perception  of  time  itself,  whether  changes  in  time  sense  are  a 
cause  or  an  effect  of  adaptational  change.   The  predominant  view  is  that  the 
subjective  rate  of  the  passage  of  time  is  dependent  upon  the  events  and 
factors  determining  the  state  of  the  organism  at  any  given  time.   Changes  in 
such  factors  as  body  temperature,  metabolic  rate,  and  neural  activity  of  the 
brain  associated  with  the  circadian  cycle  have  figured  most  prominently  in 
theories  of  the  basis  of  the  time  sense.   The  eAridence  upon  which  the  apparent 
lability  of  time  perception  rests,  however,  has  depended  upon  time  judgments 
which  may  be  affected  by  motivational,  emotional,  and  attitudinal  factors 
whether  or  not  the  fundamental  ability  to  discriminate  time  is  also  affected. 
We  have  sought  to  develop  a  method  of  measurement  less  susceptible  to  the 
influence  of  extraneous  factors  and  to  apply  this  method  to  conditions 
purported  to  produce  changes  in  time  perception. 

Methods  Employed:   The  essential  difference  between  the  method  and 
conventional  methods  is  that  we  obtain  a  measure  of  the  slopes  of  the 
response  x  time  functions  generated  by  three  different  procedures  and 
determine  whether  variations  in  these  slopes  are  mutually  consistent  among 

333 


Serial  BTo.  M-P-L-7,  Page  2 

the  procedures.  Data  to  date  have  heen  obtained  -under  conditions  of  extended 
repeated  testing  over  periods  of  waking  activity  and  over  periods  of  normal 
nighttime  sleep  during  which  EEG  activity  was  continuously  monitored. 

Major  Findings:  Unlike  the  inconsistencies  generally  found  with  conventional 
measures,  changes  in  the  slopes  of  the  response  functions  were  highly 
consistent  for  the  different  procedures  and  indicate  a  moderate  slowing  in 
the  subjective  rate  of  the  passage  of  time  at  reduced  levels  of  arousal. 
Interpretation  in  terms  of  variation  in  the  rates  of  body  processes  is  not 
justified,  however,  because  a  similar  slowing  occurred  over  periods  of 
testing  during  normal  waking  activity.  The  effect  appears  rather  to  be  in 
the  nature  of  an  habituative  or  adaptational  shift  with  repeated  exposure 
to  constant  external  stimulus  conditions. 

Scientific  Significance  to  Mental  Health  Research  Program:  Abnormal  behavior 
is  often  accompanied  by  disorientation  with  respect  to  time,  and  even  normally 
one  may  be  disoriented  for  awhile  when  aroused  out  of  deep  sleep.  A 
perplexing  question  is  whether  such  disorientation  depends  upon  a  disordered 
capacity  to  discriminate  time  or  whether  aberrant  time  judgments  are  the 
result  of  generally  confused  thought  processes.  The  present  research 
indicates  that  the  perception  of  time  is  a  stable  psychological  capacity 
in  spite  of  gross  variations  in  physiological  activity  and  state  of  arousal. 
If  time  perception  is  involved  in  a  behavior  disorder,  however,  it  may  well 
be  as  a  basic  causal  factor  rather  than  as  a  symptomatic  aspect  of  the 
disorder. 

Proposed  Course  of  Project:  An  evaluation  of  the  effect  of  more  purely 
psychological  alterations  on  time  perception  is  planned  utilizing  THC 
intoxication  as  a  means  of  altering  psychological  state. 

Honors  and  Awards:  None 

Publications:  None 


33^ 


Serial  No.  M-P-L-9 

1.  Laboratory  of  Psychology 

2.  Section  on  Perception 

3.  Bethesda 


PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 


Project  Title:  Discriminative  and  Conceptual  Behavior  in  Preschool  Children 

Previous  Serial  Number:   Same 

Principal  Investigator:  Albert  J.  Caron 

Other  Investigators:  None 

Cooperating  Units:  Private  and  Cooperative  Nursery  Schools  in  Montgomery 
County  and  the  District  of  Columbia 

Man  Years:  None 

This  project  was  temporarily  suspended  and  is  being  held  in  abeyance 

Honors  and  Awards:  None 
Publications:  None 


335 


Serial  Wo.  M-P-L-10 

1.  Laboratory  of  Psychology 

2.  Section  on  Perception 

3.  Bethesda 


PHS-HSMHA-KIMH 

Individual  Project  Report 

Jioly  1,   1971  through  June  30,   1972 


Project  Title:      Discriminative  and  Conceptual  Behavior  in  Infancy 

Previous   Serial  Number:      Same 

Principal  Investigator:      Albert  J.    Caron 

Other  Investigators:      Rose  F.    Caron 

Cooperating  Unit:      Eye  Research  Foundation 

Man  Years: 


Total: 

1.50 

Professional: 

1.00 

Others 

.50 

Project  Description: 

Objectives:   To  assess  the  perceptual- cognitive  capacities  of  human  infants 
during  the  first  year  of  life  and  to  investigate  the  antecedent  environmental 
conditions  promoting  early  perceptual  and  intellective  development. 

Study  I:   The  specific  aim  of  a  study  just  completed  was  to  determine 
which  features  (eyes,  nose/mouth,  contour)  predominate  in  the  four-month-old's 
perception  of  the  human  face  and  to  what  extent  these  are  seen  as  isolated 
elements  or  as  structured  configurations. 

Methods  Employed:   Fixation  time  to  a  regular  schematic  face  was  compared  for 
sixteen  groups  of  infants  (7  boys  and  7  girls  per  group)  following  prolonged 
exposure  to  a  distorted  version  of  the  schematic  face,  under  the  assumption 
that  the  greater  the  perceived  difference  between  the  regular  face  and  the 
previously  exposed  distortion,  the  longer  the  looking  time  to  the  former. 
The  groups  differed  only  in  terms  of  the  facial  distortion  presented  for 
prior  exposure.   The  distortions  were  applied  independently  to  four  facial 
areas — eyes,  nose/mouth,  contour,  and  all  features  combined — and  were  of  four 
general  types:   (a)  elimination  of  feature,  (b)  scrambling,  (c)  positional 
displacement,  and  (d)  orientation  change.   A  control  group  was  given  prior 
exposure  to  the  regular  face. 

Major  Findings:   The  data  are  now  being  analyzed  but  preliminary  indications 
are  that  in  the  four-month-old's  perception  of  the  human  face  (l)  the  eyes  are 

337 


Serial  No.  M-P-L-10,  Pa^e  2 

more  salient  than  the  nose/mouth,  (2)  the  orientation  of  the  contour  is  more 
critical  than  the  orientation  of  the  features,  and  (3)  the  horizontal 
arrangement  of  the  eyes  is  more  important  than  their  precise  orientation. 

Study  II:  The  purpose  of  a  study  now  in  progress  is  to  determine  whether 
the  three-month-old  has  already  achieved  perceptual  object  constancy,  i.e., 
whether  objects  retain  their  identity  despite  shifts  in  perspective. 

Methods  Employed:  A  number  of  three-month-old  infants  are  being  given 
discriminative  operant  training  to  the  point  where  they  will  emit  responses 
(l8°  head-turns  to  the  left  or  right)  in  the  presence  of  a  rectangle  and  not 
emit  responses  in  the  presence  of  a  trapezoid.  Following  conditioning,  the 
infants  will  be  shown,  together  with  the  original  stimuli,  two  critical  test 
stimuli:   (l)  a  backward  tilted  rectangle  (which  projects  retinally  as  a 
trapezoid)  and  a  forward  tilted  trapezoid  (which  projects  retinally  as  a 
rectangle) .  The  extent  of  responding  in  the  presence  of  these  stimuli  will 
provide  an  indication  of  whether  the  infant  perceives  retinally  or  objectively, 
and  hence  whether  he  has  learned  to  use  visual  distance  cues  such  as  binocular 
parallax  and  motion  parallax  to  preserve  object  constancy. 

Major  Findings:  This  study  actually  involves  two  phases:   (l)  bringing  yovmg 
infants  under  precise  discriminative  control  (not  yet  successfully  accomplished 
in  any  infant  laboratory)  and  (2)  testing  for  generalization  to  the  critical 
transfer  stimuli.  The  first  phase  has  involved  a  number  of  knotty  technical 
problems  such  as  (a)  putting  together  an  optimal  reinforcement  package  to 
prevent  satiation  and  loss  of  interest  prior  to  the  establishment  of 
discriminative  control,  (b)  preventing  infants  from  becoming  emotionally 
upset  during  extinction  periods,  (c)  insuring  attention  to  the  discriminative 
stimuli,  and  (d)  establishing  precise  control  by  the  form  dimension.  During 
the  past  year  we  have  successfully  negotiated  the  first  two  of  these  problems 
and  are  currently  on  the  threshold  of  solving  the  third  and  fourth.  We  expect 
within  the  next  two  months  to  bring  a  number  of  infants  under  rectangle- 
trapezoid  control,  which  in  itself  will  constitute  a  contribution  to  the 
infant  experimental  literature.  Once  this  is  achieved  we  should  be  able  to 
answer  our  primary  question  concerning  object  constancy. 

Study  III:  The  purpose  of  a  third  study  for  which  equipment  is  now  under 
construction  is  to  determine  whether  differential  responding  and/or  differen- 
tial consequences  are  necessary  for  infants  to  learn  to  discriminate  between 
stimuli  (or  whether  they  can  learn  by  simple  exposure  to  the  stimuli  and 
without  the  occurrence  of  correlated  consequences) . 

Methods  Employed:   Groups  of  infants  will  receive  different  types  of 
discriminative  training  over  a  four  week  period  in  the  home.  One  group  will 
be  required  to  make  differential  responses  (e.g.,  head  turn  vs.  no  head  turn) 
to  two  stimuli  (e.g.,  circle  and  triangle)  which  in  turn  lead,  to  differential 
rewards  (visual  and  auditory  events  vs.  no  consequence).   A  second  group  will 
not  be  required  to  emit  differential  responses  but  will  receive  visual  and 
auditory  events  in  the  presence  of  the  circle  and  no  such  event  in  the  presence 

338 


Serial  No.  M-P-L-10,  Page  3 

of  the  triangle.   A  third  group  (a  simple  exposure  group)  will  not  he 
required  to  emit  differential  responses  nor  will  it  experience  differential 
consequences  in  the  presence  of  the  circle  and  triangle.   Appropriate  control 
groups  to  assess  the  independent  contributions  of  responding,  reinforcement, 
and  operant  training  will  be  employed.   Apparatus  is  currently  being 
constructed  which  will  allow  for  automatic  presentation  and  recording  of 
these  various  types  of  contingencies. 

Major  Findings;   There  are  no  findings  at  this  time. 

Scientific  Significance  to  Mental  Health  Research  Program:   The  three  studies, 
taken  together,  will  give  us  some  insight  into  the  yoiing  infant's  perceptual 
capabilities  and,  what  is  more  important,  into  the  environmental  arrangements 
which  helped  foster  these  attainments.  Once  we  have  learned  how  the  environ- 
ment impresses  itself  on  the  maturing  organism  to  produce  a  stable  perceptual 
world,  then  we  are  in  a  position  to  manipulate  the  sensory  input  to  infants 
to  promote  optimal  perceptual  and  intellective  development. 

Proposed  Course  of  Project:   This  project  is  an  indefinitely  continuing  one 
in  pursuance  of  the  general  objectives  stated  above. 

Honors  and  Awards:  Elected  Fellow,  American  Psychological  Association  (Div.  7). 

Publicatioias: 

Caron,  R.  F.,  Caron,  A.  J.,  and  Caldwell,  R. :   Satiation  of  visual 
reinforcement  in  young  infants.  Developmental  Psychology,  _5(2): 
279-289,  1971. 


339 


Serial  No.  M-P-L-12 

1.  Laboratory  of  Psychology 

2.  Section  on  Perception 

3 .  Bethesda 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  Juae  30,  1972 

Project  Title:   Cortical  Mechanisms  in  Somesthesis 

Previous  Serial  Number:   M-P-B-12 

Principal  Investigator:   Josephine  Serames 

Other  Investigators:  Mary  Randolph  (NIMH  Special  Fellow) 

Louis  Porter  (NIMH  Predoctoral  Fellow) 

Cooperating  Units:   None 

Man  Years 

Total:  k 

Professional:  2 

Other :  2 

Project  Description: 

Objectives:   The  general  aim  is  to  identify  in  monkeys  the  neural  mechanisms 
crucially  concerned  in  various  forms  of  somesthetic  perception.   Our  recent 
experimentation  has  focus sed  on  the  sensorimotor  cortex  contralateral  to  the 
hand  trained  on  a  series  of  manual  discrimination  tasks.   The  immediate  pur- 
pose is  to  define  more  precisely  the  contributions  made  by  the  various  sub- 
divisions of  this  general  region.   Behavioral  tests  are  needed  in  order  to 
confirm  or  deny  hypotheses  derived  from  electrophysiological  and  anatomical 
studies  concerning  the  functional  organization  of  the  region  and  its  relation 
to  other  parts  of  the  cortex. 

Methods:  Rhesus  monkeys  are  trained  to  make  somesthetic  discriminations  in 
a  situation  requiring  them  to  reach  with  one  hand  into  an  opaque  box  and 
select  one  of  two  stimulus  objects,  indicating  his  choice  by  pulling  it 
toward  him.   Discrimination  tasks  involving  consistency,  shape,  size,  rough- 
ness, and  temperature  have  been  employed,  and  for  the  last  three,  repeated 
determinations  of  thresholds  are  made.  In  these  tasks,  the  monkey  subject 
has  to  discover  the  differential  cue  by  active  palpation.  A  passive  testing 
situation  has  also  been  used:  the  monkey  is  restrained  in  an  opaque  box  with 
the  hand  to  be  tested  extending  through  an  aperture  and  held  flat  on  a  plat- 
form by  straps.  An  instrumental  response,  pushing  open  a  hinged  door  when 
the  animal  detects  the  positive  stimulus,  is  performed  with  the  free  hand. 
The  threshold  of  sensitivity  to  light  touch,  as  determined  by  a  series  of 
graded  nylon  filaments ,  is  determined  in  this  manner . 


3iH 


Serial  No.  M-P-L-12  p.  2. 

Ablations  of  cortical  areas  are  made  by  aspiration  of  grey  matter,  with 
aseptic  technique  and  barbiturate  anesthesia.  The  postoperative  recovery 
period  is  usually  four  weeks,  after  which  training  or  retraining  is  begun. 
Following  completion  of  the  behavioral  observations  and  the  formal  diserimin- 
ination  tests,  the  monkeys  are  given  a  lethal  dose  of  barbiturate,  and  their 
brains  are  prepared  for  histological  examination.  The  actual  limits  of  the 
cortical  lesion  and  the  consequent  thalamic  degeneration  are  then  determined. 
Special  attention  is  given -to  unintended  sparing  of  tissue  within  the  limits 
of  the  planned  ablation  and  to  unintended  damage  outside  these  limits . 

Major  Findings:  Previous  research  in  this  unit  has  established  that  either 
anterior  or  posterior  lesions  of  the  precentral  gyrus  (the  classical  motor 
cortex)  have  no  adverse  effects  whatever  on  performance  of  any  of  the  soma- 
tosensory discrimination  tasks,  despite  a  substantial  projection  to  this 
gyrus  from  the  main  thalamic  somatosensory  nucleus  (ventralis  posterolatera- 
lis).   In  contrast  to  these  negative  findings,  lesions  of  the  immediately 
adjacent  postcentral  gyrus  (the  classical  somatosensory  cortex),  which  also 
receives  input  from  this  nucleus,  produce  marked  decrements  in  performance, 
an  effect  which  was  much  more  severe  in  our  experiments  than  in  those  reported 
in  the  literature.  The  anterior  postcentral  lesion  we  made  was  followed  by 
severe  deficit  on  all  tests,  which  amounted  in  many  instances  to  complete 
inability  to  learn  to  discriminate  grossly  different  stimulus  objects.  The 
posterior  postcentral  removal  produced  a  selective  deficit  on  difficult 
shape  discriminations.  These  two  impairments  (the  general  after  the  anterior,- 
and  the  selective  after  the  posterior  postcentral  lesion)  provided  the 
starting-point  for  investigations  designed  to  discover  the  most  important 
parts  of  the  original  lesions  in  the  production  of  the  deficits,  and  to 
illuminate  the  nature  of  each  of  them. 

With  respect  to  the  anterior  postcentral  lesion,  we  have  found  that  the 
part  in  the  posterior  bank  of  the  central  sulcus  is  far  more  crucial  than 
the  part  on  the  crown  of  the  gyrus.  Since  it  has  been  discovered  by  others 
that  the  more  crucial  area  is  characterized  by  slowly-adapting  neurons  repre- 
senting the  entire  hand,  whereas  the  less  crucial  one  is  characterized  by 
quickly-adapting  units  likewise  representing  the  entire  hand,  our  behavioral 
findings  provide  an  important  tie-in  to  electrophysiological  data.  Turning 
now  to  the  nature  of  the  deficit,  we  have  found  that  monkeys,  following  the 
anterior  postcentral  lesion,  either  retain  or  quickly  recover  normal  sensi- 
tivity to  simple  punctate  tactile  stimuli,  thus  showing  that  their  severe 
deficits  on  other  tasks  cannot  be  ascribed  to  cutaneous  hypesthesia.   This 
finding  led  us  to  look  more  closely  at  our  testing  procedures  that  had 
revealed  the  deficits.  We  investigated  the  possible  ameliorative  effects 
of  intensive  preoperative  training  on  all  tasks,  or  of  a  postoperative  re- 
covery period  of  six  months  (the  latter  in  order  to  allow  the  ataxia  commonly 
found  after  postcentral  removals  ample  time  to  disappear).  Neither  of  these 
procedural  modifications  proved  to  ameliorate  the  deficit,  however.   Thus, 
although  we  have  ruled  out  certain  hypotheses  as  to  the  nature  of  the  anterior 
postcentral  deficit,  we  have  yet  to  establish  in  positive  terms  how  it 
should  be  interpreted. 


3^2 


Serial  No.  M-P-L-12  p.  3- 

With  respect  to  the  posterior  postcentral  lesions,  we  have  \mdertaken 
analogous  experiments  with  the  aims  of  more  precisely  localizing  the  subarea 
responsible  for  the  deficit  and  of  exploring  further  the  nature  of  the 
selective  impairment  in  difficult  shape  discriminations.  The  former  objec- 
tive is  being  pursued  by  comparing  the  effects  of  lesions  of  the  posterior 
crown  of  the  postcentral  gyrus  with  those  of  the  anterior  bank  of  the  intra- 
parietal  sulcus,  since  both  these  subareas  were  included  in  the  original 
lesion.  As  to  the  second  objective,  we  have  already  shown  that  animals  with 
this  lesion,  like  those  with  the  more  anterior  removal,  exhibit  normal  sensi- 
tivity to  simple  light  tactile  stimuli.  Procedural  modifications  such  as 
those  described  above  will  also  be  tried  in  order  to  see  if  the  severity  of 
the  deficit  can  be  influenced  by  these  means.  A  further  question  of  interest 
is  how  the  postcentral  deficit  is  shape  discrimination  compares  in  severity 
and  quality  with  that  described  by  others  as  following  lesions  of  the  parietal 
"association"  area  behind  the  postcentral  gyrus. 

A  kind  of  somesthetic  discrimination  not  previously  studied  in  this 
laboratory,  namely,  temperature,  is  being  explored  by  Mr.  Porter  for  his 
doctoral  dissertation.  A  new  way  of  teaching  monkey  to  discriminate  tempera- 
tures, which  results  in  far  more  rapid  learning  than  do  the  procedures  pre- 
viously employed  by  other  investigators,  has  been  worked  out.  The  major 
finding  of  Mr.  Porter's  experiment  is  that  manual  temperature  discrimination, 
like  simple  touch,  is  extremely  resistant  to  disturbance  by  cortical  lesions, 
even  those  which  include  the  entire  somatosensory  cortex  of  both  hemispheres. 
It  is  true  that  learning  times  may  be  prolonged,  both  with  regard  to  gross 
and  to  fine  temperature  discriminations,  but  eventually  all  animals  are  able 
to  respond  consistently  and  appropriately  to  differences  of  2°  C  or  less. 
With  regard  to  the  most  important  part  of  the  somatosensory  cortex  for  such 
discrimination,  he  has  shown  that  bilateral  destruction  of  the  postcentral 
gyrus  is  necessary,  but  not  sufficient,  to  produce  the  prolonged  learning 
times  mentioned  above. 

Scientific  Significance  to  Bio-Medical  Research:  The  finding  of  a  difference 
in  the  degree  of  the  cortical  contribution  to  light  touch  and  temperature,  on 
the  one  hand,  and  to  the  appreciation  of  consistency,  shape,  size,  and  rough- 
ness, on  the  other,  is  not  wholly  unexpected  but  has  never  before  been 
clearly  established  by  objective  tests  on  animals  with  verified  cortical 
lesions.   The  finding  may  be  related  to  the  classical  distinction  between  the 
kinds  of  sensation  mediated  by  the  lemniscal  vs.  the  anterolateral  ("spino- 
thalamic") tracts  in  the  spinal  cord,  but  it  has  not  heretofore  been  suggested 
that  this  particular  kind  of  distinction  might  also  apply  to  the  cortical 
level.  Our  experiments  are  also  the  first  to  demonstrate  a  sharp  functional 
distinction  between  the  precentral  and  postcentral  gyri,  and  to  relate  the 
deficit  found  after  postcentral  lesions  to  the  slowly-adapting  rather  than 
the  quickly-adapting  population  of  postcentral  neurons.   It  is  further 
expected  that  the  outcome  of  our  study  of  the  postcentral  vs.  the  posterior 
parietal  deficits  in  shape  discrimination  may  clarify  the  functions  of  the 
parasensory  "association"  cortex.   These  contributions  to  basic  knowledge  of 
cortical  organization  in  somesthesis  will,  it  is  hoped,  lead  to  rational  re- 
habjlitative  procedures  for  patients  with  losses  in  sensation  occasioned  by 
cerebral  disease  or  injury. 

3^3 


Serial  Wo.  M-P-L-12  p.  h. 

Proposed  Course  of  Project:   Studies  designed  to  localize  more  precisely  the 
lesions  within  the  sensory  cortex  which  are  responsible  for  deficits,  and  to 
examine  the  nature  of  those  deficits,  will  be  pursued.   The  first  of  these 
objectives  leads  to  further  investigations  designed  to  determine  what  connect- 
ions of  the  crucial  area  give  it  its  special  function.  The  second  leads  to 
experiments  with  additional  tests  and  modified  procedures  which  attempt  to 
resolve  ambiguities  in  interpretation  of  deficits  obtained. 

Honors  and  Awards:   1.  Membership,  Experimental  Psychology  Study  Section, 
DRG,  1969-1973. 


2.   Editorship,  CORTEX,  I968- 


Publications; 


Schwartzman,  R.  J.  and  Semmes,  J.:  The  sensory  cortex  and  tactile  sensitivity. 
Exptl.  Neurol.,  1971,  33:  1^7  -  158. 

Semmes,  J.:  Soraesthetic  effects  of  damage  to  the  central  nervous  system.   In 
Jung,  R.  (Ed.):  Handbook  of  Sensory  Physiology.  New  York,  Springer- 
Verlag,  in  press. 

Semmes,  J.  and  Porter,  L. :  A  Comparison  of  Precentral  and  Postcentral  Cortical 
Lesions  on  Somatosensory  Discrimination  in  the  Monkey.  Cortex,  1972,  in 
press . 

Semmes,  J.,  Porter,  L. ,  and  Randolph,  M.  C:   Further  Studies  of  Anterior 
Postcentral  Lesions  in  the  Monkey.  Cortex,  1972,  in  press. 


3hk 


Serial  No.   M-S-C-11 


1.  Socio- environmental  Studies 

2.  Office  of  the  Chief 

3.  Bethesda,  Maryland 


PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 


Project  Title:   Social  Psychological  Correlates  of  Occupational  Position 

Previous  Serial  Number:   Same 

Principal  Investigators:  Melvin  L.  Kohn  and  Carmi  Schooler 

Other  Investigators:   Lindsley  Williams  (guest  worker,  on  assignment  from 
the  Career  Development  Program  in  Global  Community 
Health,  HSMHA) 

Cooperating  Units:   None 

Person  Years 

Total:  4  5/6 
Professional:  1  1/3 
Other:         3  1/2 

Project  Description: 

Objectives:   To  ascertain  the  relationship  of  some  principal  dimensions  of 
job,  occupation,  and  career  to  relevant  aspects  of  men's  values, 
social  orientation,  self-conception,  and  off-the-job  behavior. 

Methods  Employed:   Structured  interviews  with  a  sample  of  3100  men,  represent- 
ative of  all  men  employed  in  civilian  occupations  in  the  United 
States. 

Major  Findings:   A.   Occupational  Experience  and  Psychological  Functioning. 
The  issue  of  principal  concern  in  this  year's  analyses  is  whether 
occupation  affects  or  only  reflects  personality.   Our  key  to  dealing 
with  this  problem  is  to  focus  on  dimensions  of  occupation,  in  con- 
trast to  the  traditional  approach  of  studying  some  one  occupation. 
We  attempt  to  disentangle  the  many  intercorrelated  dimensions  of 
occupation  by  securing  a  large  sample  of  men  who  work  in  many  occu- 
pations, inventorying  their  job  conditions,  and  differentiating  the 
psychological  concomitants  of  each  facet  of  occupation  by  statistical 
analysis.   There  are  serious  limitations  to  securing  occupational 
data  by  interviewing  a  representative  sample  of  men.   For  example, 
many  men  have  only  limited  inforraation  about  some  facets  of  their 


3^5 


Serial  No.   M-S-C-11,  page  2 

jobs;  moreover,  a  sample  of  men  scattered  across  many  occupations 
and  many  work  places  does  not  contain  enough  people  in  any  occupation 
or  any  workplace  to  trace  out  interpersonal  networks  and  belief 
systems.   But  the  method  is  highly  satisfactory  for  studying  the 
immediate  conditions  of  the  man's  own  job--what  he  does,  who  deter- 
mines how  he  does  it,  in  what  physical  and  social  circumstances, 
and  subject  to  what  risks  and  rewards. 

As  noted  in  last  year's  report,  virtually  all  of  the  many 
occupational  conditions  we  have  examined  are  significantly  related 
to  one  or  another  of  the  facets  of  psychological  functioning  included 
in  our  study.   But  relatively  few  occupational  conditions- -thirteen 
in  all--are  significantly  related  to  more  than  one  facet  of 
psychological  functioning,  independently  of  education  and  of  all  the 
other  pertinent  dimensions  of  occupation.   Although  few  in  number, 
these  occupational  conditions  are  sufficient  to  define  the  structural 
imperatives  of  the  job.   The  thirteen  occupational ^conditions  can  be 
grouped  into  four  clusters--( 1)  organizational  locus  [ownership, 
bureaucracy,  position  in  the  supervisory  hierarchy];  (2)  occupational 
self -direction  [closeness  of  supervision,  routinization,  substantive 
complexity];  (3)  job  pressures  [time  pressure,  overtime,  heaviness 
of  the  work,  dirtiness];  and  (4)  uncertainties  [the  likelihood  of  a 
dramatic  change  in  the  man's  situation,  the  frequency  with  which  men 
in  his  position  are  held  responsible  for  things  outside  of  their 
control,  the  risk  of  loss  of  job  or  business]. 

Our  preferred  explanation  of  the  linkages  between  these 
occupational  conditions  and  psychological  functioning  is  that  job 
conditions  affect  men's  orientations  to,  and  behavior  in,  both  occu- 
pational and  nonoccupational  realms  of  life.   But  there  are  other 
possible  interpretations.   The  two  most  important  are  that  our  findings 
reflect  a  tendency  for  men  to  mold  their  conditions  of  work  to  meet 
their  needs  and  values,  and  that  men  are  selectively  recruited  and 
retained  in  jobs  to  which  they  are  well  suited. 

Job  molding.   Several  lines  of  evidence  suggest  that  job- 
molding  processes  take  place  within  rather  narrow  structural  limita- 
tions--too  narrow  to  provide  an  adequate  explanation  of  the  relation- 
ships between  occupational  conditions  and  psychological  functioning. 

In  particular,  occupational  conditions  are  structurally 
interrelated.   Thus,  a  man  who  does  substantively  complex  work  stands 
a  greater  risk  of  being  held  responsible  for  things  outside  of  his 
control  than  does  a  man  who  works  at  simpler  tasks:  the  correlation 
of  substantive  complexity  with  such  a  risk  is  0.32.   The  risk  in- 
creases if  the  job  is  not  only  substantively  complex  but  also  time- 
pressured  (the  multiple  correlation  being  0.36),  and  increases  further 
if  the  man  stands  high  on  the  supervisory  ladder  or  is  an  owner 
(r  =  0.40).   From  this  perspective,  an  increased  risk  of  being  held 


3h6 


Serial  No.   M-S-C-11,  page  3 

responsible  for  things  outside  of  one's  control  is  the  price  one 
pays  for  holding  an  interesting  and  responsible  job.   Each  of  the 
other  occupational  conditions  cem  also  be  seen  as  part  of  an  inter- 
locking network.   It  is  not  as  if  one  could  make  a  series  of  independent 
decisions--to  be  self-directed,  not  to  be  under  great  time-pressure, 
to  work  in  a  non-bureaucratic  firm;  their  structural  interrelatedness 
means  that  one  has  to  accept  some  occupational  conditions  as  the 
price  for  securing  others. 

Other  findings- -from  analyses  of  men's  job  preferences,  from 
comparisons  of  men  who  do  and  who  do  not  have  much  control  over 
their  occupational  conditions,  and  from  analyses  of  those  occupational 
conditions  that  may  be  especially  subject  to  workers'  control --buttress 
our  conclusion.   The  evidence  consistently  suggests  that,  although  men 
undoubtedly  do  mold  their  jobs  to  fit  their  personal  requirements, 
these  processes  do  not  provide  anything  like  a  complete  explanation 
of  the  relationships  between  occupational  conditions  and  psychological 
functioning. 

Occupational  self-selection.   The  issue  here  is  whether  occu- 
pation is  related  to  personality  mainly  because  employers  hire  men 
they  think  are  qualified,  because  men  search  out  jobs  that  meet 
their  needs  and  desires,  and  because  men  drop  out  of  jobs  for  which 
thoy  are  ill-suited  or  which  they  find  intolerable.  Our  method  of 
analysis  is  based  on  a  reconstruction  of  each  man's  job  history,  with 
emphasis  on  one  pivotal  facet  of  occupation,  the  substantive  complexity 
of  men's  jobs  been  affected  by  their  psychological  characteristics, 
and  to  what  extent  have  their  psychological  characteristics  been 
affected  by  the  substantive  complexity  of  their  jobs? 

Since  we  do  not  have  measures  of  psychological  functioning 
from  times  before  the  men  entered  their  present,  and  each  of  their 
previous  jobs,  we  must  estimate.   To  do  this,  we  provisionally  make 
an  assumption  directly  contrary  to  our  major  thesis:  we  assume  that 
men's  levels  of  psychological  functioning  are  essentially  established 
before  their  occupational  careers  begin.   If  so,  indices  based  on 
performance  at  the  present  time  would  provide  reasonably  accurate 
estimates  of  what  the  men's  level  of  functioning  had  been  at  earlier 
times.   Such  indices  enable  us  to  assess  the  maximum  possible  effect 
of  psycholgical  functioning  on  occupational  recruitment  and  retention. 

Our  analyses  show  that  psychological  functioning  plays,  at 
most,  a  small  part  in  determining  the  substantive  complexity  of  men's 
past  and  present  jobs.   Moreover,  no  matter  which  aspect  of  psycholog- 
ical functioning  we  examine,  it  is  more  affected  by,  than  a  determinant 
of,  the  substantive  complexity  of  the  job.   Occupational  self- 
selection  undoubtedly  does  take  place,  but  it  does  not  provide  the 
major  explanation  of  our  findings.   There  must  be  some  continuing 
interplay,  throughout  men's  careers,  between  man  affecting  job  and 
job  affecting  man. 

3^7 


Serial  No.  M-S-C-11,  page  4 

There  are  several  implications  of  these  findings.   First 
and  most  generally,  these  findings  contribute  to  the  growing  sense, 
in  social  science  as  in  society  at  large,  that  we  have  for  too  long 
fixated  on  the  importance  of  early,  especially  childhood,  experience 
in  the  shaping  of  personality.   The  potentiality  for  change  exists 
well  into  adulthood;  our  findings  suggest  that  this  potentiality 
persists  throughout  men's  occupational  careers. 

Second,  these  findings  should  help  reshape  sociological  con- 
ceptions about  what  is  important  in  occupational  experience.   The 
variables  that  have  been  at  the  center  of  interest  in  the  study  of 
occupations--status,  interpersonal  relationships,  organizational 
structure- -prove  to  be  less  pertinent  for  psychological  functioning 
than  do  the  immediate  realities  of  men's  jobs. 

Third,  these  findings  bear  directly  on  the  issue  of  whether 
men  similarly  located  in  the  structure  of  society  come  to  share 
beliefs  and  values  because  of  their  similar  experiences  or  because  of 
some  process  of  value-transmission.  Marx  and  the  structuralists 
would  have  us  believe  that  the  former  is  basic,  theorists  as  diverse 
as  the  "human  relations  in  industry"  and  "culture  of  poverty"  schools 
stress  the  latter.   Our  data  come  down  solidly  on  the  side  of  the 
structuralists.  Men  come  to  value  self -direction,  for  example,  not 
because  they  live  in  an  atmosphere  where  others  value  it,  but  because 
they  work  under  conditions  where  they  can  and  must  exercise  it.  Men 
learn  from  their  own  experience.   Social  structure  matters  because 
it  shapes  this  experience. 

Fourth,  our  findings  provide  some  insight  into  the  processes 
by  which  occupational  experience  affects  psychological  functioning. 
These  findings  argue  for  a  learning- generalization  model,  as  opposed 
to  a  reaction-formation  or  compensatory  model.   That  is,  the  specific 
linkages  between  particular  facets  of  occupational  experience  and 
particular  facets  of  psychological  functioning  suggest  that  men  learn 
to  cope  with  the  realities  of  their  job  and  they  generalize  these 
lessons  to  non-occupational  realities.  Men  whose  jobs  require  intel- 
lectual flexibility,  for  example,  come  not  only  to  exercise  their 
intellectual  prowess  on  the  job  but  also  to  engage  in  intellectually 
demanding  leisure-time  activities.   Nowhere  in  these  data  is  there 
evidence  that  men  turn  their  occupational  f  rustrations  loose  on  the 
nonoccupational  world  or  try  to  find  compensation  in  nonoccupational 
realities  for  occupational  lacks  and  grievances. 

B.   Community  and  Psychological  Functioning.   Lindsley 
Williams  has  pursued  his  interest  in  a  topic  that  links  three  domains: 
the  psychological  functioning  of  individuals,  their  social  charac- 
teristics, and  the  social  characteristics  of  the  communities  in  which 
they  reside.   In  this  work  he  is  utilizing  1600  respondents  to  the 
national  survey,  melding  these  data  with  data  which  characterize  the 
41  urbanized  areas  in  which  the  sample  was  drawn. 

3U8 


Serial  No.   M-S-C-11,  page  5 

This  research  is  directed  at  several  objectives.   The  first 
is  to  demonstrate  that  human  values  and  orientations  differ  from 
one  urban  setting  to  another.   The  second  objective  is  to  interpret 
these  variations  in  terms  of  the  social  dimensions  that  underlie 
the  communities  in  which  they  reside  and  in  which  these  values  operate. 
The  third  objective  is  to  explore  variations  in  individual  orienta- 
tion to  self  and  others  in  terms  of  the  social  consonnance  (or 
dissonance)  of  the  individual's  characteristics  with  those  of  the 
community  in  which  he  lives,  that  is,  an  analysis  of  the  social 
context  in  which  the  individual  finds  himself. 

All  of  the  data  excepting  those  which  characterize  communities 
were  drawn  from  the  Occupations  Study;  they  represent  a  subset  of  the 
original  3100  obseirvations,  namely  those  persons  living  within  the 
perimeter  for  urbanized  areas  as  defined  by  the  U.  S.  Bureau  of  the 
Census.   The  social  characteristics  of  the  communities  themselves  were 
drawn  from  data  published  by  the  Census  for  "Urbanized  Areas."  These 
include  the  size  of  the  population;  density  per  square  mile;  rate  of 
growth;  the  composition  of  the  community  in  terms  of  marital  status, 
housing  stock,  ethnicity,  racial  groups;  age  distribution;  and 
indicators  of  collective  social  status  including  education,  family 
income,  occupation  and  a  composite  index. 

The  overall  inquiry  is  being  carried  out  in  several  steps.   The 
first  is  a  confirmation  that  human  values  and  social  orientations  do 
vary  from  one  community  to  the  next.   The  second  step  is  an  exajnination 
of  the  social  characteristics  of  the  communities  themselves,  this 
being  in  preparation  to  the  second  analysis  in  which  variation  from 
community  to  community  is  considered  from  the  vantage  point  of  the 
underlying  dimensions  of  urban  social  structure  (a  logic  which 
parallels  that  of  the  analysis  of  occupations).   The  third  step  con- 
siders the  juxtaposition  of  the  social  characteristics  of  the  individ- 
ual and  his  community  where  dimensional  counterparts  exist;  it 
addresses  questions  such  as  the  following:  Does  an  individual's  own 
education  make  more  or  less  of  a  difference  to,  say,  his  level  of 
anxiety,  depending  upon  the  general  level  of  education  in  the  community? 

Work  has  proceeded  to  the  point  where  some  findings  may  be 
reported.   First,  variation  exists  in  the  psychological  functioning 
of  residents  of  different  urbanized  areas.   These  variations  exist 
both  in  the  outlook  a  person  has  to  others  as  well  as  to  himself. 

Second,  there  are  a  number  of  social  dimensions  or  "factors" 
that  underlie  community.   These  social  factors  include  urbanicity, 
the  distribution  of  households  and  housing,  the  composition  of  the 
population  with  respect  to  social  minorities,  and  a  factor  of  socio- 
economic status.   Each  of  these  factors,  as  reflected  in  its  constituent 
elements,  apparently  influences,  though  hardly  determines,  the 
psychological  functioning  of  community  residents.   It  was  expected 
that  many  dimensions  would  operate  at  the  level  of  the  community  in 

3^9 


Serial  No.   M-S-C-11.  page  6 

the  same  direction  as  did  their  "counterpart"  at  the  level  of  the 
individual.   For  example,  persons  of  more  education  are  generally 
more  composed,  less  anxious.   It  was  expected  that  anxiety  would 
operate  in  the  same  way  for  communities  as  a  whole,  i.e.,  residents  of 
more  highly  educated  communities  would  reveal  less  anxiety.   In  this 
case  the  hypothesis  was  supported.   In  other  instances  the  community 
characteristic  was  of  significance,  but  in  an  opposing  direction-- 
suggesting  an  provocative  conflict  in  individual  versus  collective 
characteristics:  while  more  highly  educated  persons  are  less  self- 
deprecating  (more  self -approving) ,  residents  of  more  highly  educated 
communities,  controlling  on  their  own  education,  are  more  self- 
deprecating.   Finally,  a  number  of  instances  of  a  second  order  rela- 
tionship appear  in  which  residents  of  urbanized  areas  at  the  extremes 
differ  from  residents  of  more  typical  communities.   Residents  of  the 
more  highly  educated  communities  together  with  those  from  less  highly 
educated  ones  are  less  willing  to  accept  change  than  those  who  are 
resident  in  communities  in  the  midst  of  the  collective  distribution. 

Scientific  Significance:   In  industrial  society,  occupational  role  is  of 

central  importance  in  shaping  men's  conceptions  of  self  and  of  social 
reality.   This  research  is  addressed  to  a  systematic  appraisal  of 
precisely  which  aspects  of  occupation  affect  which  facets  of  man's 
social  psychological  functioning. 

Proposed  Course  of  Project:   The  analyses  on  which  we  are  embarked  will 

continue  for  some  time:  the  data  are  rich  and  the  scientific  payoff 
has  thus  far  been  considerable,  but  the  analytic  problems  are 
exceedingly  difficult  and  it  would  be  foolhardy  to  expect  them  to  be 
solved  quickly. 

Honors  and  Awards:   None 

Publications: 

Kohn,  M.  L. :  Bureaucratic  man:  a  portrait  and  an  interpretation. 
American  Sociological  Review  36:  461-474,  1971. 

Kohn,  M.  L. :  Class,  family,  and  schizophrenia:  a  reformulation. 
Social  Forces,  in  press. 

Schooler,  C. :  Childhood  family  structure  and  adult  characteristics. 
Sociometry,  in  press. 

Schooler,  C. :  Psychological  antecedents  of  the  modem  adult. 
American  Journal  of  Sociology,  in  press. 

Schooler,  C. :  Birth  order  effects:  not  here,  not  nowl   Psychological 
Bulletin,  in  press.  — 


350 


Serial  No.   M-S-D-10 


1.  Socio- environmental  Studies 

2.  Developmental  Psychology 

3.  Bethesda,  Maryland 


PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 


Project  Title:   Research  on  the  Processes  of  Internalization  of  Rules, 
Standards,  and  Values 

Previous  Serial  Number:   Same 

Principal  Investigator:   Roger  V.  Burton 

Other  Investigators:   None 

Cooperating  Units:   None 

Person  Years 

Total :  2 

Professional:   1 
Other:  1 

Project  Description: 

Objectives:   This  project  entails  research  on  conditions  leading  to  self- 
control  during  temptation.   The  primary  study  of  focus  this  year 
was  designed  to  investigate  how  a  mother's  presence  and  her  specific 
childraaring  practices  are  related  to  her  child's  behavior  in  a 
cheating  test.   The  issue  of  generality  of  the  child's  behavior  and 
of  the  effects  of  the  mother's  actions  on  the  child  were  also  analyzed. 
The  two  aspects  of  consistency  in  the  child  that  could  be  explored 
were  (1)  a  comparison  of  the  same  measures  of  his  honesty  under  two 
different  conditions,  and  (2)  how  related  were  the  two  facets  of 
conscience  of  observing  rules  in  a  game  and  of  telling  the  truth. 
The  mother's  behavior  was  assessed  both  for  its  immediate  Impact  on 
the  child  and  for  its  more  long-term  effect  on  the  inculcation  of 
honesty  when  the  child  performed  alone. 

It  is  felt  that  in  our  society  an  especially  worthwhile 
temptation  to  investigate  is  one  in  which  the  values  of  honesty  and 
successful  achievement  are  in  conflict.   Research  on  conscience 
development  and  achievement  motivation,  and  the  social  learning 
theory  of  the  Investigator  indicated  that  the  rearing  areas  of  warmth, 
rejection,  dominance,  harmony,   and  achievement  orientation  would  be 
most  likely  to  demonstrate  the  kinds  of  interactions  leading  o  honesty 
or  cheating  in  an  achievement  arousing  temptation  test. 

351 


Serial  No.   M-S-D-10.  page  2 

Methods  Employed:   To  analyze  the  relations  between  the  mother's  rearing 
and  the  child's  self-control  requires  a  measure  of  the  child's 
resistance  to  temptation  when  by  himself.   For  the  rearing  measures 
to  be  immediately  relevant  for  assessing  how  honesty  is  trained, 
mother-child  interactions  obtained  in  a  temptation  test  setting  are 
needed.   Therefore,  the  child's  honesty  was  measured  twice:  when 
alone  and  when  the  mother  was  present,  with  all  other  condi tiors  held 
constant.   The  rearing  measures  were  based  on  the  interactions  during 
this  second  test. 

The  child's  performance  on  a  bean  bag  game  provided  the 
measures  of  his  behavior  during  temptation.   Deviation  from  the  simple 
rules  were  necessary  to  achieve  a  good  score.   All  children  were 
first  tested  alone.   A  week  later,  their  mothers  were  asked  to  be 
with  them  while  they  were  retested.   The  interactions  were  scored  by 
direct  observation  from  behind  one-way  mirrors.   An  interview  with 
the  mother  immediately  following  the  test  explained  the  purposes  of 
the  study  and  obtained  information  on  what  she  thought  the  study  was 
about  and  what  we  were  measuring,  and  on  her  judgments  of  how  "normal" 
her  behavior  was  during  the  test  compared  to  her  behavior  at  home, 
especially  on  the  major  dimensions  of  child  rearing  that  were  scored. 

Major  Findings:   The  analysis  of  consistency  of  the  children's  behavior 

showed  that  the  control  group  of  children  retested  alone  under  identi- 
cal conditions  were  very  stable  in  either  cheating  or  being  honest. 
By  comparison,  a  significant  number  of  the  children  changed  in  their 
observance  of  the  rules  with  their  mothers  present,  the  tendency  being 
stronger  in  changing  from  having  been  honest  to  cheating.   The  mother's 
presence  influenced  some  of  the  children,  who  had  demonstrated  inter- 
nalized self-control  in  the  first  test,  to  cheat,  and  in  some  cases 
this  influence  was  shown  quite  directly  in  that  the  mother  told  the 
child  to  ignore  the  rules.   The  reluctance  of  these  children  to  cheat 
was  reflected  in  their  cheating  later  and  less  extensively  than 
either  ihe  experimental  or  control  groups  of  consistent  cheaters. 
The  effect  of  the  mother's  presence,  however,  is  more  complex  in 
that,  besides  tending  to  increase  the  number  of  cheaters,  it  also 
inhibited  cheating  among  those  who  had  already  cheated  by  themselves 
even  though  they  again  cheated  with  the  mother.   The  inhibitory 
effect  in  these  consistent  cheaters  was  shown  in  their  cheating  later 
and  to  a  lesser  extent  than  they  had  when  alone.   This  contrasts 
significantly  with  the  behavior  of  the  consistent  cheaters  in  the 
control  group  who  cheated  earlier  and  more  extensively  in  the  second 
test.   There  is  no  support  here  for  what  has  been  described  as 
"externalization  of  conscience"  or  "transfer  of  the  superego"  which 
has  been  hypothesized  to  occur  when  the  presence  of  an  adult  (espec- 
ially the  parent)  permits  the  child  to  shift  responsibility  for  con- 
trol from  himself  to  the  adult.   On  the  contrary,  the  evidence 
indicates  the  presence  of  the  mother  inhibited  cheating  even  more 
than  when  the  child  was  alone  and  yet  her  actions  kept  him  engaged  in 
the  g£ime  and  eventually  elicited  some  deviation, 

352 


Serial  No.   M-S-D-10,  page  3 

The  child's  portrayal  of  the  rules  were  scored  for  truth- 
fulness (or  lying).   This  lying  score  was  significantly  correlated 
with  cheating  when  alone,  with  the  mother,  and  most  strongly  with 
consistency  of  cheating.   The  magnitudes  of  the  correlations  (.35  to 
.50)  are  larger  than  has  generally  been  reported  and  is  likely  due 
to  the  commonness  of  the  situation  for  the  scores.   Nevertheless, 
these  findings  provide  rather  substantial  evidence  that  under  such 
conditions  there  is  more  generality  across  these  response  dimensions 
of  honesty  than  would  be  expected  from  a  strictly  specificity  position. 

It  is  often  concluded  from  reviews  of  research  on  conscience 
development  that  parental  warmth  is  positively  associated  with  early 
and  high  conscience  development.   The  finding  for  this  study  was  the 
opposite:  A  measure  of  overall  warmth  was  related  to  cheating  in  the 
mother's  presence  and  to  cheating  consistently.   Further  analyses  that 
separated  the  expressions  of  warmth  contingent  on  the  child's  behavior 
in  the  game  from  noncontingent  warmth  provided  a  clearer  understanding 
of  the  processes  involved.   The  noncontingent  warmth,  a  measure 
similar  to  "general  warmth"  as  usually  used,  was  unrelated  to  any  of 
the  measures  of  the  child's  behavior,  whereas  the  measure  of  contingent 
warmth  showed  significant  relations  to  cheating  with  the  mother 
present,  to  consistent  cheating  across  both  conditions,  and  to  cheat- 
ing alone,  though  in  this  last  case  for  girls  only.   These  findings 
challenge  the  interpretation  that  "warmth"  is  related  to  high  conscience 
and  suggest  that  the  broad  notion  of  warmth  that  has  served  as  the 
basis  for  assessing  the  nurturant  relationship  provided  the  child 
is  misleading.   These  findings  indicate  that  warmth  may  be  more 
adequately  conceptualized  as  a  specific  resource  that  is  manipulated 
rather  than  as  a  general  quality  of  a  relationship.   These  data  do 
fit  predictions  from  social  learning  principles  that  requiring 
successful  achievement  for  showing  warmth  or  reacting  to  poor  per- 
formance by  withholding  or  withdrawing  emotional  support  by  the 
mother  would  lead  to  cheating  rather  than  to  honesty, 

A  measure  of  the  mother's  relationship  to  the  child  during 
the  test  period  compared  to  her  usual  expressions  of  warmth  was 
obtained  in  the  post-test  interview.   This  interview  measure  of 
warmth  was  unrelated  to  the  child's  cheating.   It  was  also  unrelated 
to  the  observed  measures  of  the  mother's  warmth.   Even  though 
obtained  in  the  same  setting,  this  self-report  measure  and  the 
observed  measures  of  expressed  warmth  were  certainly  not  equivalent 
nor  even  seemed  to  assess  the  same  underlying  dimension.   In  a  factor 
analysis  of  the  mothers'  scores,  this  self -report  measure  of  warmth 
loaded  highest  on  a  factor  that  combined  the  self -reports  of  more 
warmth,  less  tension,  and  less  directing  with  the  behavioral  measures 
of  noncompliance,  and  depriving-ignoring-rejecting.   Thus  the  mothers 
seem  to  perceive  their  nonintrusive  though  calmly  (cooly)  controlling 
behavior  during  the  test  period  as  a  reflection  of  warmth  rather  than 
as  more  like  what  would  be  rated  from  the  observations  as  rejection. 


353 


Serial  No.   M-S-D-10,  page  4 

For  those  observed  measures  of  rejection  that  loaded  on 
this  factor  with  self -reported  warmth,  noncompliance  and  depriving- 
ignoring-rejecting  were  associated  with  honesty  for  girls  (unrelated 
for  boys).   These  findings  suggest  that  the  lack  of  overt  and  direct 
attempts  to  control  the  child's  behavior  (such  as  scolding  or 
physically  restraining  or  punishing  the  child)  is  perceived  by  the 
mother  as  warmth,  and  there  is  the  further  possibility  that  some  of 
the  association  between  the  self -reported  warmth  and  the  child's 
conscience  development  found  in  previous  studies  is  based  on  inter- 
actions that  would  be  scored  toward  the  cold  end  of  the  warmth 
continuum. 

In  addition  to  warmth  and  rejection,  the  other  domains  of 
childrearlng  assessed  were  dominance,  harmony,  and  achievement 
orientation.   The  specific  findings  from  each  of  these  sets  of 
observational  measures  rather  consistently  fit  the  interpretation 
that  the  more  the  mother  focused  her  own  attention  on  the  child's 
successful  achievement  and  attempted  to  direct  and  restrict  the 
child's  behavior  to  performance  of  the  game,  the  more  likely  the 
child  was  to  violate  the  rules.   Findings  from  the  self -report 
measures  generally  were  not  consistent  with  their  observational 
counterparts.   For  example,  the  observational  measure  of  directing 
and  restricting  related  to  cheating  whereas  the  self-report  measure 
of  directing  related  to  honesty.   The  implication  is  that  the  mothers 
reacted  to  quite  different  aspects  of  the  situation  than  were  scored 
by  observing  her  behavior.   Rather  than  indicate  that  only  one  type 
of  measure  is  worthwhile,  the  evidence  indicates  the  value  of  obtain- 
ing both  kinds  of  information  for  providing  a  fuller  understanding 
of  the  processes  involved  in  personality  development. 

To  achieve  a  parsimonious  picture  of  the  underlying  dimensions 
in  the  mothers'  behavior,  a  factor  analysis  was  done  and  the  factor 
scores  correlated  with  the  child  measures.   The  first  rotated  factor 
accounted  for  most  of  the  common  variance  and  correlated  strongly 
with  the  consistency  score  (cheating  in  both  sessions)  and  especially 
with  cheating  in  the  mother's  presence.   The  rearing  measures  that 
defined  this  factor  were  initiations,  game  related  statements,  con- 
tingent warmth,  negative  evaluations,  pushing,  directions  and 
restrictions,  and  the  self-report  measure  of  tension.   This  factor, 
labelled  "Intrusive,  Dominant  Achievement  Orientation,"  is  composed 
of  measures  from  all  five  of  the  domains  of  childrearlng  hypothesized 
as  determinants  of  moral  conduct.   It  is  unlikely  that  this  factor 
is  a  basic  dimension  of  childrearlng  but  rather  represents  those 
various  techniques  commonly  brought  to  bear  in  a  mother's  Immediate 
attempts  to  produce  successful  achievement  in  her  child.   A  different 
pattern  was  primarily  related  to  the  measures  representing  the  child's 
internalization  of  moral  standards.   Though  no  factor  related 
significantly  for  boys'  self-control,  two  independent  factors  related 
to  the  performance  of  girls  when  alone.   The  first  factor,  "Interest 


35^ 


Serial  No.  M-S-D-10.  page  5 

with  Indirect  Control,"  indicated  that  a  blend  of  active  interest  in 
the  child's  activity  with  noncompliance  and  unresponsiveness  to 
unwanted  behavior  as  the  means  of  setting  limits  related  to  the 
inculcation  of  honesty.   The  mother's  conscious  avoidance  of  directing 
the  child's  behavior  toward  achievement  and  behaviorally  not  exerting 
direct  control  was  related  to  her  daughter's  low  self-control. 

These  findings  indicate  the  dilemma  confronting  parents  in 
their  attempts  to  inculcate  a  balance  in  their  children  of  standards 
of  moral  conduct  and  of  excellence  in  achievement.   The  indications 
are  that  some  rearing  techniques  develop  achievement  at  the  expense 
of  honesty,  and  conversely.   An  awareness  of  the  possibility  of  over- 
emphasizing one  value  seems  desirable  for  the  parent  to  achieve  a 
desired  balance. 

Scientific  Significance:  These  studies  will  contribute  to  an  understanding 
of  socialization  process,  particularly  to  the  inculcation  of  moral 
standards  involved  during  temptation  to  cheat  in  an  achievement 
situation.   This  information  will  add  important  empirical  data 
necessary  to  the  building  of  a  comprehensive  theory  of  socialization 
and  of  the  development  of  conscience. 

Proposed  Course  of  Project:   A  paper  is  being  prepared  for  submission  to 
scientific  publications. 

Honors  and  Awards :   None 

Publications: 

Burton,  R.  V. :   Cross-sex  identity  in  Barbados.   Developmental 
Psychology  6,  1972,  365-374. 


i 


355 


Serial  No.   M-S-D-L6 


1.  Socio- environmental  Studies 

2.  Developmental  Psychology 

3.  Bethesda,  Maryland 


I 


PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 


Project  Title:   Occupational  Experiences  of  Muscians 

Previous  Serial  Number:   Same 

Principal  Investigator:   Roger  V.  Burton 

Other  Investigators:   None 

Cooperating  Units:   None 

Person  Years 

Total:  0 
Professional :  0 
Other:         0 

Project  Description: 

Objectives :   This  study  explores  how  adult  coping  mechanisms  and  personality 
measures  determine  and,  in  turn,  are  modified  by  reactions  to 
naturally  occurring  stress  in  the  occupational  sphere  of  a  group  of 
highly  competent,  intensively  trained  persons  who  were  strongly 
dedicated  and  committed  to  their  professions.   The  sample  is  a  select 
group  of  professional  musicians,  most  of  whom  had  been  under  contract 
to  a  motion  picture  studio.   These  men,  whom  this  investigator  had 
previously  studied  while  under  contract  and  when  there  was  no  indica- 
tion of  the  future  stress,  suddenly  became  part  of  the  large  number 
of  "free-lance"  musicians  competing  for  the  diminishing  demands  for 
their  skills.   The  precipitating  event  was  the  termination  of  all 
musicians'  contracts  in  all  studios. 

Methods  Employed:   The  main  instrument  in  the  earlier  study  had  been  the 
Guilf ord-Zimmerman  Temperament  Scale,  a  standardized,  objective 
personality  inventory.   This  test  is  again  being  used  in  order  to 
have  objective  measures  of  changes  which  might  have  occurred  since 
the  loss  of  definite  steady  employment.   Two  other  objective  instru- 
ments are  used- -Rosenberg ' s  Self -Esteem  and  Faith-in-People  Scales-- 
together  with  a  semi -structured  interview  for  information  on  the 
musician's  background,  musical  training,  reactions  to  the  loss  of  a 
contract,  and  his  current  overall  circumstances. 


357 


Serial  No.   M-S-D-16,  page  2 

Major  Findings:   This  project  has  continued  to  be  inactive  this  year 
because  of  other" commitments.   Broadly  speaking,  the  findings 
already  cited  for  previous  reports  indicate  that  the  large  majority 
of  these  successful  musicians  have  stable  and  desirable  personalities. 
Furthermore,  the  increased  pressure  from  decreasing  work  appears  to 
have  eliminated  those  with  unstable  characteristics  and  to  have 
changed  those  who  coped  well  toward  being  more  competitive  and 
indifferent  about  the  plight  of  their  colleagues. 

Scientific  Significance:   Capitalizing  on  a  previous  study  of  these 

musicians,  this  project  uses  an  unfortunate  but  naturally  occurring 
event  (contract  termination)  to  investigate  reactions  to  occupational 
stress.   Stability  of  personality,  predictability  of  individual 
ability  to  cope  with  occupational  stress,  and  modification  of  per- 
sonality through  adaptation  to  major  problems  in  life  are  some  of 
the  issues  considered  in  this  investigation. 

Proposed  Course  of  Project:   Some  analyses  have  already  been  performed 
though  many  still  need  to  be  done. 

Honors  and  Awards :   None 

Publications:   None 


358 


Serial  No.   M-S-D-23 


1.  Socio-environmental  Studies 

2.  Developmental  Psychology 

3.  Bethesda,  Maryland 


PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 


Project  Title:   Observational  Learning  from  Nurturant  and  Nonnurturant 
Models 

Previous  Serial  Number:   Same 

Principal  Investigators:   Marian  Radke  Yarrow,  Carolyn  Zahn  Waxier,  and 

Phyllis  M.  Scott 

Other  Investigators:   None 

Cooperating  Units:   None 

Person  Years 

Total:         1  1/2 
Professional :   1 
Other:  1/2 

Project  Description: 

Objectives:   To  investigate  the  effects  of  nurturant  and  nonnurturant 

adult  models  on  children's  behavior,  with  particular  interest  in 
(a)  observing  influences  over  a  wide  range  of  behaviors,  and  (b) 
examining  the  impact  of  varying  kinds  of  modeling  input:  symbolic 
and  live  modeling,  didactic  and  incidental  modeling. 

Methods  Employed:   Experimental  socialization  environments  were  created 
in  which  the  models  had  caretaker  roles,  either  nurturant  or  non- 
nurturant.  As  meaningful  persons  in  the  children's  experience, 
the  experimenters  modeled  a  diversity  of  behaviors:  (a)  a  variety 
of  isolated  responses,  including  neutral  acts  and  acts  of  positive 
and  negative  affect;  and  (b)  behaviors  that  represented  more  inherent 
qualities  of  the  adult--her  preferences,  her  motivations,  a  self- 
involved  response,  namely  altruism. 

The  children  were  130  nursery  school  children.   The  details 
of  procedure  have  been  described  in  previous  reports.   The  experi- 
ment was  replicated;  also,  the  intactness  of  the  experimental  effects 
were  examined  six  months  later. 


359 


Serial  No.   M-S-D-23.  page  2 

Major  Findings:   Selected  parts  of  the  analyses  have  been  described  in 

previous  annual  reports.   As  a  final  report  of  the  completed  project, 
the  major  conclusions  are  summarized. 

These  conclusions  regarding  modeling  effects  on  child  behavior 
should  be  interpreted  within  the  following  conditions:  (a)  The 
models  are  women  who  have  meaningful  caretaker  functions  in  the 
children's  experiences,   (b)  The  children  are  of  preschool  age, 
(c)  The  model's  nurturance  is  a  high  schedule  of  reinforcement,  not 
for  imitation.   The  model's  nonnurturance  is  not  of  high  intensity; 
it  is  nonreinforcement  and  mild  reproof, 

1,  When  easy-to-perform  actions  are  modeled  repeatedly  by  the 
adult,  and  relatively  obtrusively,  the  majority  of  children  match 
some  of  the  adult's  behavior.   Although  the  majority  adopt  some  of 
the  adult's  behaviors,  at  least  on  a  temporary  basis,  the  amount  of 
imitation  is  very  often  small.   The  frequency  of  matching  is  in- 
creased when  the  child's  imitation  of  the  adult  receives  approval  by 
the  adult. 

2,  When  matching  occurs  in  the  presence  of  the  model,  or  in 
close  proximity  in  time  to  the  adult's  modeling,  it  is  likely  to  be 
equally  frequent  whether  the  model-child  relationship  has  involved 
nurturance  or  nonnurturance, 

3,  When  the  adult's  modeling  has  been  relatively  didactic,  as 
in  a  demonstration  to  which  the  child's  attention  has  been  directed, 
variables  of  nurturance  again  do  not  affect  the  children's  performance. 

4,  The  social  responses  by  the  adult  when  modeled  in 
symbolic  or  play  form  were  imitated  and  generalized  in  a  similar 
play  form,  but  there  was  no  generalization  of  these  responses  into 
real  behavior. 

5,  Children  are  selective  in  what  they  imitate.   Regardless 
of  the  model-child  relationship,  specific  aggressive  acts  are  more 
readily  selected  out  of  the  adults'  repertoires  than  are  specific 

acts  of  positive,  friendly  affect.   (The  models'  friendly  and  aggressive 
actions  were  observed  in  dramatic  play. )   However,  when  themes  of 
aggression  and  of  friendliness  are  considered  in  relation  to  each 
other,  and  the  individual  child  is  his  own  control,  there  is  signifi- 
cant over- emphasis  on  aggressive  themes  when  the  model  has  been 
nonnurturant  to  the  children;  whereas  the  emphasis  is  reversed,  toward 
imitation  of  friendly  themes,  when  the  models  have  been  nurturant  to 
the  children. 

6,  Nurturant  adults  are  significantly  more  effective  as 
models  than  are  nonnurturant  adults  under  the  following  circumstances: 


360 


Serial  No.   M-StD-23,  page  3 

(a)  when  the  adult's  modeling  is  incidental,  her  behaviors  occurring 
in  natural  and  meaningful  social  interactions,  as  opposed  to  test 
situations  with  demand-characteristics;  (b)  when  the  learning  of  the 
child  is  measured  after  a  passage  of  time;  (c)  when  the  child's 
imitations  involve  his  own  idiosyncratic  adaptations  of  the  adult's 
responses;  and  (d)  when  the  child  is  confronted  later  with  situations 
in  which  his  newly- learned  behaviors  are  appropriate.   Under  these 
circumstances,  meaningful  patterns  of  adult  behavior- -hobby  prefer- 
ences and  sympathetic  helping  of  others  in  circumstances  of  distress- - 
were  adopted  significantly  more  frequently  by  children  of  nurturant 
models  than  by  children  of  nonnurturant  models. 

Scientific  Significance:   The  focus  in  these  projects  on  the  dimensions  of 

nurturance  and  nonnurturance  in  the  rearing  agent  was  prompted  by  the 
considerable  inconsistency  in  existing  research  evidence  regarding 
the  effects  of  these  variables  on  learning,  particularly  learning 
through  observing  the  adult.   Research  on  nurturance  is  hampered  by 
conceptual  ambiguities,  and  by  inadequate  manipulations  of  nurturance 
in  experimental  work.   These  studies  have  been  directed  to  these 
issues.   Further,  one  set  of  experiments  in  this  series  contributes 
data  to  the  understanding  of  the  origins  and  development  of  a 
socially  valued  behavior,  namely  the  development  of  altruism  or 
concern  for  the  welfare  of  others. 

Proposed  Course  of  Project:   The  project  has  been  completed,  with  the 
findings  published  or  in  press. 

Honors  and  Awards:   Invited  symposium  on  The  Development  of  Altruism: 

Theory,  Research,  and  Social  Import.   Divisions  7  and  8,  American 
Psychological  Association,  Honolulu,  Hawaii,  August,  1972. 

Publications: 

Yarrow,  M.  R,  and  Scott,  P.  M. :  Imitation  of  nurturant  and  non- 
nurturant models.   Journal  of  Personality  and  Social  Psychology, 
in  press. 

Yarrow,  M.  R. ,  Waxier,  C.  Z. ,  and  Scott,  P.  M. :  Child  effects  on 
adult  behavior.   Developmental  Psychology  5:  300-311,  1971. 


361 


Serial  No.   M-S-D-26 

1.  Socio- environmental  Studies 

2.  Developmental  Psychology 

3.  Bethesda,  Maryland 


PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 


Project  Title:   An  Observational  Study  of  Maternal  Models 

Previous  Serial  Number:   Same 

Principal  Investigators:   Carolyn  Zahn  Waxier  and  Marian  Radke  Yarrow 

Other  Investigators:   None 

Cooperating  Units:   National  Institute  of  Child  Health  and  Human 
Development 

Person  Years 

Total:  3/4 
Prof  es  s  ional :  1/2 
Other:         1/4 

Project  Description: 

Objectives:   To  examine  interactions  between  mothers  and  their  20-month- 
old  children  in  relation  to  patterns  of  maternal  behavior  that 
influence  imitative  responding,  and  in  relation  to  theoretical  form- 
ulations regarding  the  origins  of  imitation.   In  particular,  to 
examine  sequences  of  behavior  in  terms  of  a  reinforcement  theory 
of  generalized  imitation,  and  to  identify  characteristics  of 
parental  models  associated  with  imitative  responding  in  their  chil- 
dren.  This  study  extends  investigation  to  a  much  younger  age  than 
that  of  the  usual  subjects  in  experimental  work  on  imitation. 

Methods  Employed:   Thirty-five  black  mothers  from  middle  and  low  economic 
classes  were  observed  with  their  children  in  a  planned  series  of 
settings  which  permitted  natural  and  semi-natural  interaction. 
Mother  and  child  were  observed  in  a  laboratory  trailer  during  a 
brief  waiting  period,  in  play,  in  teaching  situations,  and  in  a 
planned  modeling  session.   Later,  an  experimenter  repeated  the 
mother's  modeling.   On  another  occasion,  the  children  were  given 
the  Bayley  Developmental  Test.   Interactions  were  observed,  with  the 
mothers'  knowledge,  from  behind  a  one-way  screen.   Observer  re- 
liabilities on  exact  matching  of  sequential  behavior  units  range 
from  68%  to  87%. 


363 


Serial  No.  M-S-D-26.  page  2 

Major  Findings:  Analyses  to  date  have  dealt  only  with  the  settings  that 
preceded  the  planned  modeling  session;  in  other  words,  the  mother 
was  not  aware  of  the  research  intent.   Every  child  imitated  at  least 
a  few  of  the  mother's  manipulations  of  the  teaching  and  play 
materials;  however,  there  was  an  appreciable  range  of  matching  be- 
haviors.  What  might  account  for  differing  frequencies?  Prominent 
in  theory  and  experimental  research  is  the  theme  that  consistent 
rewards  for  imitating,  early  in  the  child's  developmental  history, 
are  the  important  determinants.   In  the  ongoing  interactions  ob- 
served, consistent  schedules  of  reward  were  not  common.   Over  one- 
fourth  of  the  children  were  never  rewarded  for  imitation,  and  less 
than  one-fourth  received  over  50%  reinforcement  (average  rate  of 
reward  was  28%).   These  relatively  "lean"  schedules  occurred  in 
settings  when  the  mothers  are  most  free  to  be  sensitive  and  responsive 
to  children's  actions. 

Within  the  range  of  reinforcement  observed,  is  there  evidence 
of  an  association  between  maternal  rewards  and  child  imitations? 
Children  who  received  a  relatively  high  rate  of  reinforcement  for 
imitation  did  not  imitate  more  frequently  than  did  children  who 
had  received  little  reinforcement.   Children  were  no  more  likely 
to  respond  readily  with  another  imitation  after  reward  than  after 
nonreward.   Both  analyses  lead  to  the  same  conclusion:  that  imitation 
is  not  under  the  control  of  specific  reinforcements  for  such  actions. 
Further,  neither  mothers'  general  rewardingness  nor  their  level  of 
punitiveness  was  related  to  children's  imitation.   Characteristics 
of  the  mother's  rewardingness,  other  than  frequency,  are  being 
explored--e.g, ,  explicitness,  appropriateness,  and  timing  in  a 
given  situation.   Similarly,  maternal  behaviors  relating  specifically 
to  modeling  have  yet  to  be  analyzed- -enthusiasm  and  enjoyment, 
clarity  of  manipulations,  verbal  accompaniments  that  highlight  actions, 
manner  of  encouraging  child  participation,  etc. 

Imitation  was  related  to  the  children's  affective  states. 
Children  who  expressed  a  great  deal  of  enjoyment,  who  laughed  and 
smiled  frequently,  were  the  same  children  who  were  highly  imitative. 
Conversely,  in  a  separate  measure  of  negative  affect  (crying, 
sulking,  whining),  the  children  who  were  unhappy  showed  infrequent 
imitation.   Child  dependency  was  not  predictive  of  imitation, 
contrary  to  theories  in  which  imitation  is  associated  with  attention- 
seeking. 

Scientific  Significance:   Observed  interactions  of  mothers  and  children 
under  field  conditions  can  (a)  test  principles  formulated  from 
laboratory  research,  (b)  raise  questions  about  these  formulations, 
and  (c)  provide  new  evidence  that  will  further  understanding  of 
the  processes  involved. 


36k 


Serial  No.  M-S-D-26,  page  3 

Proposed  Course  of  Project:   A  small  amount  of  staff  time  has  been 

assigned  to  this  project.   Work  will  continue  on  it  through  this 
year. 

Honors  and  Awards:   None 

Publications:   None 


365 


Serial  No.   M-S-D-28 


1,  Socio- environmental  Studies 

2,  Developmental  Psychology 

3,  Bethesda,  Maryland 


PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 


Project  Title:   A  Comparison  of  Methods  of  Obtaining  Data  on  Parent  and 
Child  Behavior 

Previous  Serial  Number:   None 

Principal  Investigators:  Marian  Radke  Yarrow  and  Carolyn  Zahn  Waxier 

Other  Investigators:   Thomas  A.  Padrick 

Cooperating  Units:   None 

Person  Years 

Total;         2  7/12 
Professional:    1/2 
Other:         2  1/12 

Project  Description: 

Objectives:   To  compare  information  concerning  child  rearing  and  child 

behavior  obtained  by  different  and  accepted  methods  of  assessment, 
and  to  examine  particular  problems  associated  with  different  data- 
gathering  procedures. 

Methods  Employed:   Sixty  preschool  children  and  sixty  families  were  the 

subjects.   From  an  interview  with  the  mother,  summary  assessments  of 
her  rearing  practices  and  her  child's  behavior  were  obtained.   In 
the  following  two  weeks,  there  were  four  hours  of  observations  in 
the  home.   Observations  were  in  the  form  of  sequential  accounts  of 
mother  and  child  behavior.   Ratings  of  mother  and  child  behavior  in 
the  home  were  also  made,  based  on  the  same  periods  of  observation. 
At  the  close  of  the  second  session  in  the  home,  the  mother  was  inter- 
viewed about  the  behavior  that  had  occurred  during  that  session. 

Behaviors  were  assessed  in  the  following  dimensions:  mother's 
warmth,  coldness,  demonstrativeness,  rewarding,  and  punishing  of 
the  child's  dependency;  child's  compliance  or  dependaicy,  "conscience," 
and  aggression.   In  coding  the  interviews  and  in  making  the  observa- 
tional ratings,  the  same  categories  and  scales  were  used.   In  coding 
the  observations,  the  indicators  for  each  variable  were  as  similar  as 

367 


Serial  No.   M-S-D-28,  page  2 

possible  to  those  used  in  the  interviews.   The  observational  records 
were  time-marked  in  30-second  intervals.   Based  on  the  proportion  of 
time  units  in  which  the  variaU  e  occurred,  subjects  were  assigned 
decile  scores  on  each  variable. 

The  interviewer  and  the  observer  of  a  given  subject  were 
never  the  same  person.   All  interviews  were  coded  independently  by  two 
coders;  intercoder  reliabilities  ranged  from  r' s  of  .51  to  .93.   Dual 
observations  carried  out  in  the  nursery  school  were  the  basis  of  an 
estimate  of  observer  reliability  in  the  home.   Correlations  ranged 
from  r's  of  .50  to  .89.   Variable  observer  agreement  on  different 
behavioral  dimensions  was  one  of  the  interests  in  the  analysis. 

Analyses  are  directed  to  examining  the  congruence  of  assess- 
ments (a)  of  the  same  variable  across  methods,  and  (b)  of  relation- 
ships between  variables--both  within  the  same  method  and  across 
methods.   There  are  eight  maternal  variables  and  six  child  variables 
in  four  within-method  comparisons,  and  in  six  across-methods  com- 
parisons. 

Associations  between  variables  across  data  sets  and  within 
data  sets  were  analyzed  using  Pearson  correlations  and  Kendall's 
Tau  coefficients. 

Major  Findings:   1.   One  should  expect  in  assessing  the  same  parents  and 

children,  on  the  same  dimensions,  at  very  nearly  the  same  time,  that 
the  levels  of  association  (i.e.,  the  similarity  of  scores  on  the 
four  instruments)  would  be  statistically  significant  and  high.   This 
is  not  generally  the  case,  however. 

(a)  Four  hours  of  observation  in  the  home  and  the  typical 
child  rearing  interview  do  not,  by  and  large,  result  in  similar  ratings 
of  mother  and  child.   Tau  coefficients  range  from  -.16  to  +.48; 
correlations  from  -.17  to  +.57.  Most  associations  do  not  reach  the 

5%  level  of  significance, 

(b)  Of  considerable  methodological  significance  is  the  com- 
parison of  two  sets  of  observational  assessments.   These  were  made 
by  the  same  observers,  and  with  reference  to  the  same  four  hours  of 
observed  interaction  in  the  home.   One  set  is  in  the  form  of  5-point 
ratings  made  shortly  after  the  observations;  the  other  set  is  sequential 
accounts  of  interaction,  from  subsequent  coding  of  which  the  fre- 
quencies of  specific  behaviors  could  be  ascertained.   Associations 
between  these  two  data  sets  range  from  a  tau  of  -.16  on  measures  of 
warmth  to  a  tau  of  +.29  on  reward  and  praise. 

(c)  Closest  agreement  was  obtained  between  observer's  ratings 
and  ratings  by  mother  when  both  were  referring  to  the  specific  period 
of  home  observation.   Associations  were  significant  (r's  from  .25  to 


368 


I 


Serial  No,   M-S-D-28,  page  3 

.53)  on  all  but  one  variable  (use  of  praise  and  reward,  r  =  .13). 
When  the  sequential  observation  records  (rather  than  the  observer's 
ratings)  and  the  mother's  ratings  of  the  same  period  in  the  home  are 
compared,  all  associations  are  nonsignificant  (Taus  -.08  to  +.13). 

(d)  Directional  differences  between  observers  and  mothers 
occur  on  four  child  variables;  each  time  the  mothers  are  "harder"  in 
their  judgments  of  the  child.   Directional  differences  occur  on  four 
mother  variables;  each  time  the  mothers  are  "easier"  in  their  judg- 
ments of  themselves  than  are  the  observers, 

2.   Relations  between  maternal  and  child  behaviors  based  on 
one  method  of  assessment  are  not  identical  to  the  relations  based  on 
another  assessment.   For  example,  based  on  interview  data,  maternal 
warmth  is  associated  with  the  child's  ability  to  abide  by  the  mother's 
rules  (Tau  =  +.31,  p  <  .08);  whereas,  based  on  observational  data, 
the  tau  is  -.02. 

Scientific  Significance:   Preceding  work  in  this  program  of  research  has  been 
concerned  with  methods  of  investigating  child  and  parent  behaviors 
through  the  use  of  verbal  reports.   In  those  studies,  major  and  dis- 
tressing inconsistencies  were  frequently  found  in  the  empirical  data 
deriving  from  different  measuring  techniques.   The  present  project 
extends  the  investigation  to  methods  using  direct  observations.   An 
appraisal  of  observational  data,  along  with  verbal  report  information, 
is  important  to  the  understanding  of  the  methods  upon  which  research 
and  theory  rely. 

Proposed  Course  of  Project:   The  data  have  been  analyzed  and  the  writing  of 
a  scientific  report  is  in  progress. 

Honors  and  Awards :   None 

Publications: 

Yarrow,  M.  R. :   Research  on  child  rearing  as  a  basis  for  practice. 
Journal  of  Child  Welfare,  in  press. 


369 


Serial  No.   M-S-P(C)-23 


1.  Socio- environmental  Studies 

2.  Personality  and  Environment 

3.  Bethesda,  Maryland 


PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 


Project  Title:  Cultural  and  Psychodynamic  Factors  in  the  Occurrence  and 
Treatment  of  Psychiatric  Illnesses  in  Japan,  Taiwan,  and 
the  United  States 

Previous  Serial  Number:   Same 

Principal  Investigator:   Carmi  Schooler 

Other  Investigators:   William  Caudill,  Hsien  Rin 

Cooperating  Units:   Department  of  Psychiatry,  National  Taiwan  University, 
Taipei ,  Taiwan 


Person  Years 

Total: 

1  1/12 

Professional: 

1/3 

Other: 

3/4 

Project  Description: 

Objectives:   (1)  To  identify  and  describe  the  types  and  symptom  patterns 

of  psychiatric  illnesses  in  Japan  and  Taiwan.   (2)  To  determine  the 
relationship  of  these  types  of  illnesses  to  social,  cultural,  £Uid 
psychological  variables  in  Japanese  and  Chinese  cultures,   (3)  To 
compare  the  results  obtained  with  results  from  similar  data  on 
psychiatric  patients  in  the  United  States, 

Methods  Employed:  Methods  have  been  described  in  detail  in  previous  annual 
reports.   Currently  we  are  working  with  two  samples  obtained  by  use 
of  the  same  schedule  in  interviews  with  patients  and  their  families: 
(1)  all  admissions  to  five  psychiatric  hospitals  in  Tokyo  during  a 
twelve-month  period  in  1963-64  for  a  total  of  994  patients;  (2)  all 
admissions  to  three  psychiatric  hospitals  in  Taipei  during  a  two- 
year  period,  1967-68,  for  a  total  of  1,009  patients. 

Major  Findings:   This  year  saw  the  completion  of  the  data  coding  and  of  the 
first  stage  of  the  data  analysis--the  factor  analysis  of  patient 
symptomatology.   Factor  analyses  were  carried  out  for  the  cross- 
cultural  sample  as  a  whole,  and  separately  for  each  culture,  and  also 


371 


Serial  No.   M-S-P(C)-23,  page  2 

within  each  culture  separately  by  sex.   Although  there  were  minor 
differences,  a  fairly  similar  factor  structure  emerged  in  each  of  the 
different  samples  so  that  factor  scores  based  on  the  factor  analyses 
of  the  total  population  seem  to  accurately  index  the  pathology  of 
individuals  of  both  races  and  sexes. 

The  eight  factors  which  emerged  from  the  analysis  of  the 
total  population  are  (1)  hostility,  (2)  apathy  and  retardation, 
(3)  depression,  (4)  reality  break  (delusions,  hallucinations),  (5) 
bizarre  hebephrenic  behavior,  (6)  headaches  and  bodily  concerns, 
(7)  physical  somatization  (sleeping,  eating,  and  gastrointestinal 
problems),  and  shinkeishitsu  (a  combination  of  phobia,  obsessiveness, 
and  tense  interpersonal  relations  which  was  found  and  described 
in  our  earlier  work  on  Japan). 

We  have  also  been  able  to  do  some  preliminary  analysis  of 
cultural  differences.   These  analyses  were  done  through  the  use  of 
multiple  regression  techniques  which  permit  the  control  of  the  back- 
ground variables  of  the  patient's  age,  sex,  rurality,  and  his  father's 
social  class  and  size  of  place  of  work.   These  analyses  reveal  that 
the  Taiwanese  are  generally  more  inclined  than  the  Japanese  to  show 
hostility,  breaks  with  reality,  and  bodily  concerns  and  headaches. 
The  Japanese  of  both  sexes  are  more  likely  to  show  shinkeishitsu  and 
depression,  and  Japanese  women  exhibit  more  apathy,  bizarre  hebe- 
phrenic behavior,  and  somatization  than  do  Taiwanese  women. 

Scientific  Significance:  Our  preliminary  findings  suggest  that  Japan  and 

Taiwan  are  quite  similar  in  their  pattern  of  psychiatric  symptomatology 
and  that  this  pattern,  in  all  likelihood,  is  not  very  dissimilar  from 
that  of  the  United  States.   Some  of  the  details  of  the  above  analyses 
may  well  be  modified  as  more  sophisticated  methods  are  undertaken. 
However,  very  meaningful  differences  between  the  two  cultures  do 
exist.   The  magnitude  of  some  of  these  differences  strongly  suggests 
that  a  central  finding  which  will  almost  certainly  persist  is  the 
difference  between  the  two  cultures  in  the  direction  in  which 
psychiatric  patients  express  negative  affect:  inwardly  in  Japan 
through  shinkeishitsu  and  depression,  and  outwardly  in  Taiwan  through 
hostile  aggressive  behavior. 

groposed  Course  of  Project:   Analysis  of  the  data  will  continue,  both  in 

terms  of  cross-cultural  comparisons  and  in  the  investigation  of  the 
relation  between  social  structural  variables,  likelihood  of  hospital- 
ization, and  symptom  patterns  within  cultures. 

Since  the  symptomatology  of  the  Taiwanese  patients  has  also 
been  rated  on  a  rating  form  (IMPS)  which  is  in  standard  use  in  the 
United  States,  it  is  hoped  that  it  will  be  possible  to  make  com- 
parisons between  these  two  cultures,  as  well. 


372 


Serial  No.  M-S-P(C)-23.,  page  3 

Honors  and  Awards:   Dr.  Carmi  Schooler  was  awarded  a  Japanese  Government 
Research  Award  for  Foreign  Specialists.   This  award  was  sponsored 
by  the  Japanese  National  Institute  of  Mental  Health,  and  permitted 
Dr.  Schooler  to  carry  out  research  in  Japan  during  the  period  May  1. 
1971  to  November  30,  1971. 

Publications:   None 


373 


Serial  No.   M-S-P(C)-27 


1.  Socio -environmental  Studies 

2.  Personality  and  Environment 

3.  Bethesda,  Maryland 


PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 


Project  Title:   Parental  Care  and  Child  Behavior  in  Japan  and  the  United 
States 

Previous  Serial  Number:   Same 

Principal  Investigator:   William  Caudill 

Other  Investigators:   Carmi  Schooler 

Cooperating  Units:   None 

Person  Years 


Total : 

4 

Professional: 

1  1/6 

Other: 

2  5/6 

Project  Description: 

Objectives:   (1)  To  identify  and  describe  patterns  of  parental  care  and 

child  behavior  in  Japanese  and  American  families.   (2)  To  determine 
the  relationship  of  these  patterns  of  behavior  to  personality 
development,  psychopathology,  culture,  and  social  structure  in  the 
two  countries. 

Methods  Employed:   The  basic  design  of  the  study  and  methods  used  have  been 
described  in  detail  in  previous  reports.   Briefly,  this  is  a  longi- 
tudinal observational  study  of  the  behavior  of  parents  and  children 
in  the  home  over  the  first  six  years  of  life  in  Japan  and  the  United 
States.   During  1961-64,  30  Japanese  and  30  American  middle-class 
mother-infant  pairs  were  selected  for  observation.   The  infants  were 
first-born,  normal  babies,  and  were  three-to-four  months  of  age  at 
the  time  of  observation.   The  first  20  Japanese  and  the  first  20 
American  cases  were  selected  for  follow-up  study  at  2^  years  of  age, 
and  observations  in  the  home  were  completed  during  1963-1967.   These 
same  children  were  studied  for  a  third  and  final  time  at  6  years  of 
age  during  1967-70,  and  all  observations  have  been  completed. 

Major  Findings:   The  great  bulk  of  the  time  during  the  current  year  has  been 
spent  in  the  detailed  task  of  coding  the  data  from  the  observations 


375 


Serial  No.  M-S-P(C)-27,  page  2 

at  6  years  of  age.   Preliminary  data  analyses  were  also  performed 
on  the  data  gathered  when  the  subjects  were  2%  years  of  age.   The 
preliminary  analysis  of  the  data  gathered  when  the  subjects  were 
2%  years  old  gives  a  striking  indication  of  the  general  continuity 
of  the  cultural  differences  in  the  behavior  of  both  the  children 
and  their  caretakers.   Just  as  they  were  at  three  months,  both 
American  children  and  parents  were  more  vocal  than  were  Japanese 
children  and  parents.   Furthermore,  a  higher  proportion  of  the 
American  vocal  behavior  was  aimed  at  cognitive  communication, 
whereas  Japanese  mothers  were  more  likely  to  make  lulling,  or 
cognitively  noncommunicative,  and  emotionally  expressive  sounds 
than  were  American  mothers. 

The  earlier  greater  level  of  physical  activity  of  both  American 
children  and  their  caretakers  also  continues  at  this  later  date. 
Additionally,  this  greater  activity  on  the  part  of  the  American 
children  is  linked  to  signs  of  increased  independence.   The  Japanese 
caretaker  is  likely  to  assist  the  children  in  performing  these 
functions  over  80%  of  the  time,  while  in  America  this  occurs  only 
about  50%  of  the  time.   Another  continuity  in  cultural  differences 
is  in  the  emotional  sphere.   Japanese  children  at  3  months  were  more 
likely  to  vocalize  unhappily  than  were  American  children.   This 
same  tendency  continues  at  3  years  of  age. 

Scientific  Significance:   This  research  permits  us  to  empirically  examine 
some  of  the  most  important  processes  through  which  culture  affects 
personality.   It  does  this  by  providing  precise  measures  of  parental 
care  and  of  infant  and  child  behavior  in  two  cultures.   The  longitudinal 
nature  of  the  design  maikes  it  possible  to  study  both  cultural  differ- 
ences in  childrearing  practices,  and  children's  reactions  to  such 
differences  from  birth  to  six  years  of  age.   Furthermore,  the  exis- 
tence of  such  data  permits  us  to  examine  cross-culturally  the  con- 
sistency of  an  individual's  behavior  patterns  from  infancy  through 
young  childhood.   The  similar  behaviors  of  both  caretaker  and  child, 
(e.g.,  the  greater  level  of  physical  and  verbal  behavior  and  the  more 
open  expression  of  hostility  on  the  part  of  the  Americans)  strongly 
suggest  that  the  differences  between  the  behavior  of  the  children  in 
the  two  cultures  can  be  explained  on  the  bases  of  learning  and 
modeling.   Such  an  explanation  seems  especially  likely  since  the 
work  reported  last  year  showing  essential  similarities  in  the 
behavior  of  2%  month  old  Japanese-American  and  Caucasian-American 
babies  would  make  a  genetic  explanation  of  the  cross-cultural 
differences  unlikely.   The  preliminary  results  we  now  have  clearly 
indicate  that  the  differences  in  both  the  pattern  of  childrearing 
and  children's  behavior  in  the  two  cultures,  particularly  the  greater 
stress  on  independence  among  the  Americans,  are  congruent  with  fre- 
quently reported  differences  between  the  two  cultures. 

Proposed  Course  of  Project:   To  the  great  shock  of  those  of  us  who  knew 
him,  Dr.  William  Caudill  died  on  March  24,  1972.   Since  that  time 

376 


Sen.  al  No.  M-S-P(C)-27.  page  3 

we  have  been  able  to  ascertain  that  his  data  were  in  such  good 
condition  that  it  should  be  possible  to  carry  out  the  main  thrust 
of  his  investigation:  the  longitudinal  cross-cultural  examination 
of  continuities  and  discontinuities  in  childrearing  practices  and 
child  behavior.  Of  course,  the  final  product,  whatever  its  level 
of  statistical  sophistication,  will  lack  the  clinical  and  anthro- 
pological insights  which  only  Dr.  Caudill  could  have  provided. 

Honors  and  Awards:   None 

Publications: 

Caudill,  W. :  Tiny  dramas:  vocal  communication  between  mother  and 
infant  in  Japanese  and  American  families.   In  Lebra,  W.  P.  (Ed.): 
Mental  Health  Research  in  Asia  and  the  Pacific,  Volume  Two. 
Honolulu,  East-West  Center  Press,  in  press, 

Caudill,  W. :  A  comparison  of  maternal  care  and  infant  behavior  in 
Japanese-American,  American,  and  Japanese  families.   In  Lebra, 
W.  P.  (Ed.):  Mental  Health  Research  in  Asia  and  the  Pacific, 
Volume  Three.   Honolulu,  East-West  Center  Press,  in  press. 


I 


377 


Serial  No.   M-S-P(C)-38 


1.  Socio- environmental  Studies 

2.  Personality  and  Environment 

3.  Bethesda,  Maryland 


PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 


Project  Title:   The  Interrelationships  between  Social  Interaction, 

Psychological  Functions,  Perceptual  Style,  Physiological 
Arousal  and  Personal  History  Factors  Among  Schizophrenics 

Previous  Serial  Number:   Same 

Principal  Investigator:   Carmi  Schooler 

Other  Investigators:  Monte  S.  Buchsbaum 

Cooperating  Units:   Laboratory  of  Psychology,  NIMH;  Saint  Elizabeths 
Hospital;  DCRT 

Person  Years 

Total:         11/12 
Professional:    1/6 
Other:  3/4 

Project  Description: 

Objectives:   The  objective  of  this  series  of  studies  remains  the  attempt  to 
explain  the  variance  found  in  earlier  experiments  with  schizophrenics 
by  discovering  the  interrelationships  among  those  variables  which 
these  earlier  studies  indicate  are  central  to  an  understanding  of 
schizophrenia:  task  performance,  physiological  arousal,  perceptual 
style,  social  behavior,  symptomatology  and  psychiatric  history, 

^ethods  Employed:   Several  approaches  are  presently  being  followed.   (1) 

The  level  of  physiological  arousal  and  task  performance  under  different 
social  conditions  of  both  schizophrenics  and  nonschizophrenics  have 
been  measured  and  related  to  variations  in  perceptual  style  and 
personal  history.   (2)  A  major  study  has  been  initiated  which  involves 
the  interrelating  of  measures  of  evoked  response,  perceptual  style, 
skin  temperature  (a  measure  of  physiological  arousal)  and  symptom- 
atology.  (3)  In  order  to  facilitate  the  continuance  of  both  of  the 
above  types  of  study,  an  attempt  is  being  made  to  develop  a  generalized 
computer  program  to  simplify  the  analysis  of  measure  of  physiological 
arousal  and  to  relate  these  measures  to  each  other  and  to  other 
aspects  of  the  experimental  situations. 


379 


Serial  No.   M-S-P(C)-38.  page  2 

Major  Findings:   This  year  there  are  no  new  findings;  the  year  has  been 

devoted  primarily  to  the  collection  of  data  both  at  Saint  Elizabeths 
Hospital  and  at  the  National  Institutes  of  Health  for  the  above- 
mentioned  study  of  the  interrelationships  between  evoked  response, 
perceptual  style,  skin  temperature,  and  symptomatology,  and  to  the 
continued  development  of  the  general  computer  program  to  analyze 
physiological  measures  of  arousal. 

Scientific  Significance:   Since  clinicians  had  long  noted  that  social  with- 
drawal appeared  to  be  a  marked  feature  of  schizophrenia,  and  exper- 
iments by  Schooler  and  others  had  demonstrated  that  the  greater  the 
degree  of  social  contact  the  greater  the  decrement  in  the  schizo- 
phrenic's functioning,  it  seemed  reasonable  to  initiate  a  series  of 
studies  seeking  the  key  to  the  schizophrenic's  malfunctioning  in 
his  reactions  to  his  social  environment.   In  one  of  these  studies. 
Schooler  and  his  co-workers  were  able  to  establish  through  direct 
observation  of  ward  behavior  that  lack  of  social  interaction  is, 
indeed,  one  of  the  characteristics  which  differentiates  schizophrenics 
from  other  hospitalized  mental  patients.   Furthermore,  the  results  of 
another  study  indicate  that  this  lack  of  interaction  is  mirrored  by 
an  expressed  preference  for  avoiding  entanglements  with  others. 
Additional  studies  in  the  series  have  shown  how  the  schizophrenic's 
performance  in  standard  psychological  experiments  is  affected  by 
orientations  which  are  at  least  partially  the  results  of  his  past 
social  experiences.   Thus,  one  study  indicates  that  the  effect  of 
positive  or  negative  evaluation  on  verbal -paired  associate  learning 
is  a  function  of  the  subject's  self-esteem;  subjects  with  low  self- 
esteem  doing  especially  poorly  on  tasks  requiring  novel  associations 
after  being  given  positive  evaluations  of  their  performance  which 
are  dissonant  with  their  negative  self-image. 

Several  other  studies  point  to  the  possibility  that  society's 
general  norms  as  to  sex  roles  have  differentially  affected  male  and 
female  schizophrenics'  willingness  to  show  or  receive  signs  of  positive 
or  negative  feelings.   Their  findings  are  congruent  with  the  supposi- 
tion that  in  our  culture  the  expression  of  emotion,  and  particularly 
of  affection,  is  an  area  of  conflict  for  men,  while  for  women  a  major 
area  of  concern  is  fear  of  evoking  the  hostility  of  others.   The 
possibility  that  social  psychological  factors  can  even  affect 
psychophysiological  relationships  is  indicated  by  the  findings  of 
another  study  which  show  that  the  social  nature  of  the  situation 
can  affect  the  direction  of  the  relationship  between  physiological 
arousal  and  task  performance. 

The  interaction  between  the  social  situation,  the  schizo- 
phrenic's functioning,  and  his  physiological  reactivity  pointed  to  a 
general  weakness  in  the  way  this  series  of  studies  had  been  carried 
out.   It  had  been  conducted  primarily  from  one  research  perspective 
and  was  concerned  with  only  a  liitited  area  of  the  individual's 


Serial  No,   M-S-P(C)-38,  page  3 


functioning.   Although  the  findings  were  significant  they  had  not  been 
very  powerful,  possibly  because  differences  in  the  nature  of  physio- 
logical reactivity  of  different  subgroups  of  schizophrenics  may 
have  produced  contrasting,  or  at  least  differing,  results. 

A. review  of  the  literature  revealed  that  the  general  concentra- 
tion on  one  aspect  of  the  individual  which  had  marked  these  social 
■psychologically  oriented  studies  was  at  least  as  pronounced  in 

,  studies  in  other  areas.   It  was  therefore  not  at  all  surprising  that 
the  weak  results  which  marked  the  series  of  social  psychological 
studies  were  at  least  as  powerful  as  the  results  of  studies  approaching 
the  problem  of  schizophrenia  from  other  directions.   Thus,  for  example 
.years  of  search  for  biochemical  differences  between  schizophrenics 

-  and  others  have  resulted  in  no  reliably  replicable  findings.   The 
effects  of  genetics  appear  to  be  less  and  less  powerful,  the  better 
controlled  the  study.   Putative  social  class  differences  between 
schizophrenics  and  others  do  not  seem  to  exist  under  all  conditions 
and  where  they  do  exist  it  is  far  from  clear  whether  such  differences 
are  related  to  the  cause  of  the  disease  or  its  effects.   Those  theor- 
etically based  systems  of  classifying  patients  into  subgroups  which 
have  been  investigated  have  not  produced  consistent  findings  and, 
in  fact,  the  most  highly  touted  mode  of  classification- -pre-morbid 
adjustment-.proved  totally  unable  to  pass  the  test  of  controlled 
replication. 

The  lack  of  findings  has  certainly  not  been  due  to  any  lack 
of  theories  or  hypotheses.   Hypotheses  have  been  brought  forth  with 
the  ease  of  the  proverbial  blind  men  describing  the  elephant,  e  g 
those  studying  tails  describing  the  elephant  as  long,  thin  and  " 
floppy;  those  studying  problem- solving  seeing  the  essence  of  schizo- 
phrenia in  thought  disorder. 

Two  courses  seem  to  be  presently  open.   One  can  keep  on  making 
hypotheses  from  limited  bodies  of  data,  hoping  to  achieve  the  flash 
of  insight  which  will  permit  us  to  see  from  our  limited  point  of  view 
what  the  elephant  is  really  like,  or  one  can  go  ahead  with  the  duller 
task  of  trying  to  do  studies  which  attempt  to  coordinate  data  from 
many  vantage  points  in  order  to  get  enough  information  to  make  meaning- 
ful hypotheses  possible.   The  present  series  of  studies  represents 
an  attempt  to  follow  the  second  of  these  courses  with  the  aid  of  modern 
multivariate  techniques  and  computer  technology.   It  thus  involves 
the  interrelation  of  five  different  types  of  variables  which  seem  to 
be  the  most  promising  in  terms  of  their  possible  etiological  significance, 
their  consistency  in  predicting  schizophrenic  responses,  and  their 
amenability  to  experimental  manipulation.   These  five  classes  of  data 
are  (1)  perceptual  functioning,  (2)  central  and  autonomic  nervous 
system  arousal,  (3)  task  performance,  (4)  social  interaction,  (5) 
psychiatric  symptomatology  and  history. 


381 


Serial  No.   M-S-P(C)-38,  page  4 

Studies  were  undertaken  which  involved  the  replication  and 
evaluation  of  earlier  studies  of  schizophrenia  in  these  five  areas 
in  a  way  which  would  permit  the  examination  of  their  interrelation- 
ships among  different  schizophrenic  subgroups.   These  studies  of  the 
investigator  and  his  collaborators  are  now  starting  to  show  that  many 
of  the  previously  contradictory  findings  in  the  area  of  schizophrenia 
research  have  been  due  to  an  incomplete  comprehension  of  the  com- 
plexity of  the  interrelationships  between  psychiatric  sjmiptomatology, 
patterns  of  physiological  arousal,  and  perceptual  and  social  function- 
ing among  different  types  of  patients. 

Proposed  Course  of  Project:  Data  collection  will  be  continued  and  analyses 
of  already  collected  data  will  be  continued  and  the  results  prepared 
for  publication  in  a  scientific  journal. 

Honors  and  Awards:   None 

Publications:   None 


382 


Serial  No.   M-S-PS-1 


1,  Soclo-environinental  Studies 

2,  Personality  and  Stress 

3,  Bethesda,  Maryland 


PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 


Project  Title:   Health  Orientations  of  Parents  and  Children 

Previous  Serial  Number:   Same 

Principal  Investigator:  John  D.  Campbell 

Other  Investigators:   Iris  Posner,  Margaret  F.  Luther 

Cooperating  Units:   Children's  Hospital,  Washington,  D.  C. 

Person  Years 

Total:  2  1/4 

Professional:    1 
Other:  1  1/4 

Project  Description: 

Objectives:   To  study  health  orientations  of  family  members.   Specifically, 
the  goals  of  the  study  are,  first,  to  describe  systematically  the 
patterns  of  variation  in  family  members'  attitudes,  values,  beliefs, 
perceptions,  and  behavior  concerning  phenomena  of  illness  and  health; 
and  second,  to  examine  ways  in  which  selected  personal  and  situational 
factors  relate  to  health  orientations.   Relev£int  to  the  attainment 
of  these  objectives  are  the  following  three  assumptions  basic  to  the 
study:   (a)  an  individual's  orientation  to  health  and  illness  is 
embedded  in  interactive  processes;  (b)  such  orientations  are  at 
least  in  part  learned;  and  (c)  to  a  considerable  extent  such  learning 
takes  place  as  an  aspect  of  routine  family  relationships. 

Methods  Employed:   Information  on  264  hospitalized  children  and  their 

mothers  was  obtained  by  use  of  focused  interviews,  questionnaires, 
and  rating  scales.   Interviews  with  children  and  mothers,  and 
questionnaires  completed  by  the  mothers  provide  data  on  (a)  aspects 
of  their  definitions  of  illness,  (b)  reports  of  their  own  and  other 
family  members'  feelings  and  actions  when  ill,  (c)  their  attitudes 
and  beliefs  about  illness  prevention  and  treatment,  (d)  their  values 
in  selected  areas  not  directly  relevant  to  health,  and  (e)  views 
about  appropriate  standards  of  behavior:  what  should  or  should  not 
be  done  in  circumstances  pertaining  to  illness  and  health.   Ratings, 


383 


Serial  No.   M-S-PS-1,  page  2 

made  by  .nurses  in  the  hospital  setting,  appraise  children's  emotional 
dependence  and  anxiety. 

Major  Findings :   During  the  past  year  data  analyses  have  dealt  primarily 
with  three  different  facets  of  mothers'  and  children's  views  of 
illness:  (a)  variations  in  definitional  sophistication  of  illness 
concepts,  (b)  variations  in  circumstances  perceived  as  pivotal  in 
labeling  a  person  as  sick,  and  (c)  variations  in  the  extent  to  which 
a  series  of  specific  signs  and  sjmiptoms  is  viewed  as  indicative  of 
illness. 

Comparison  of  mothers'  and  children's  thematic  emphases  in 
their  definitions  of  illness  has  shown  that  as  social  development 
progresses  persons  typically  adopt  a  broader,  more  psychosocial ly 
oriented,  more  precise,  and  more  subtle  configuration  of  themes  in 
their  illness  concepts.   These  appraisals  have  led  to  a  composite 
measure  of  definitional  sophistication,  an  index  permitting  further 
exploration  of  the  development  and  intergenerational  transmission  of 
illness  concepts.   As  expected,  sophistication  of  children's  illness 
definitions  was  clearly  related  to  age.   Yet  with  age  statistically 
controlled,  the  negligible  correlation  between  mothers'  and  children's 
sophistication  scores  provided  little  support  for  the  logical  possi- 
bility that,  in  defining  illness,  the  child  adopts  a  conceptual 
style  similar  to  that  of  his  mother.  Moreover,  parent-child  corre- 
spondence on  this  dimension  of  qualitative  variation  was  not  enhanced 
by  certain  favorable  mother-child  relationships.   To  a  considerable 
extent,  then,  children's  illness  concepts  may  be  acquired,  not  by 
adoption,  but  by  independent  formulation  growing  out  of  their  own 
experiences.   In  addition  to  and  independent  of  the  effect  of  the 
child's  age,  several  aspects  of  family  composition  showed  a  cumulative 
impact  on  sophistication  of  definition:  If  a  child's  mother  was  older 
than  the  average,  if  he  had  a  relatively  large  number  of  younger 
siblings,  and  if  his  mother  was  not  employed  outside  the  home,  that 
child  was  more  likely  than  others  to  define  illness  in  a  conceptually 
sophisticated  fashion. 

There  is  a  difference  between  knowing  what  illness  is  and 
knowing  when  one  is  ill- -the  difference  between  the  definition  of  a 
state  and  the  specification  of  pivotal  circumstances  labeling  the 
onset  of  that  state.   This  is  evident  when  one  considers  critical 
illness-defining  circumstances:  For  children  the  relevant  circumstances 
are  in  some  respects  markedly  different  from  those  of  adults.   Parents 
serve  as  gatekeepers  for  the  child,  legitimizing  his  illness  or 
imposing  a  label  of  illness  on  him.   Children  were  nearly  ten  times 
more  likely  than  mothers  to  state  that  a  pivotal  circumstance  in 
defining  illness  was  the  intervention  of  some  other  family  member, 
and  younger  children  were  more  than  one  and  one-half  times  more 
likely  than  older.   Moreover,  after  age  differences  were  eliminated, 
the  child's  likelihood  of  viewing  behavior  of  other  family  members 


38k 


Serial  No.  M-S-PS-1,  page  3 

as  critical  in  defining  illness  was  clearly  linked  to  his  past 
health  history  and  the  extent  to  which  the  mother  saw  the  child  as 
inclined  to  reject  the  sick  role. 

Another  approach  to  the  illness  concept  is  through  an  exam- 
ination of  the  frequency  with  which  children,  given  particular 
symptoms,  view  themselves  or  their  mothers  as  sick.   As  was  indicated 
in  a  previous  report,  people  see  themselves  as  being  less  vulnerable 
to  illness  than  are  others.   This  tendency  is  enhanced  with  age, 
largely  through  a  decline  in  attributing  illness  to  oneself.   Moreover, 
above  and  beyond  the  effects  of  age,  the  child's  own  perception  of 
reward  for  being  sick,  his  assessment  of  his  mother's  own  approach  to 
the  sick  role,  and  certain  of  his  own  standards  for  functioning  in 
the  sick  role  have  a  cumulative  effect  on  the  child's  viewing  signs 
and  symptoms  as  indicative  of  illness  in  himself.   If  he  (a)  sees  his 
mother  as  more  attentive,  affectionate  and  indulgent  when  he  is  sick, 
(b)  reports  that  she  herself  readily  accepts  the  sick  role,  and  (c) 
thinks  that  it  is  acceptable  to  express  one's  emotions  openly  when 
sick,  he  is  then,  given  specified  signs  and  symptoms,  more  likely  to 
see  himself  as  ill.   In  short,  to  the  degree  that  a  child  perceives 
the  general  milieu  as  providing  support  for  his  adopting  the  sick 
role,  to  that  extent  will  he  readily  attribute  illness  to  himself. 

Scientific  Significance:   This  research  provides  information  about  a  specific 
area  that  is  currently  only  inadequately  covered;  it  should  lead  to 
a  more  systematic  picture  of  health  orientations  and  factors  acsociated 
with  such  orientations  than  is  now  available.   The  potential  value 
of  the  research  is  not,  however,  restricted  solely  to  the  confines  of 
sickness  and  health.   Within  the  framework  of  the  study,  such  general 
social  psychological  issues  as  role  learning,  developmental  changes 
in  family  relationships,  and  role  behavior  in  stressful  conditions 
can  be  treated.   The  phenomena  of  illness  and  health  can  be  viewed 
as  representing  aspects  of  these  general  issues. 

Proposed  Course  of  Project:   Data  analysis  is  in  process.   One  paper  on  the 
development  of  illness  concepts  has  been  completed  and  will  be  sub- 
mitted for  publication.   Other  research  reports  will  be  written  after 
subsequent  stages  of  data  analysis  have  been  completed. 

Honors  and  Awards :   None 
Publications:   None 


385 


Serial  No.   M-S-S-12 


1.  Socio- environmental  Studies 

2.  Section  on  Social  Structure 

3.  Bethesda,  Maryland 


PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 


Project  Title:   Developmental  Study  of  the  Self-image 

Previous  Serial  Number:   Same 

Principel  Investigators:  Morris  Rosenberg  and  Roberta  G.  Simmons 

Other  Investigators:   None 

Cooperating  Units :   None 

Person  Years 

Total:  2 
Professional:  1 
Other:         1 

Project  Description: 

Objectives:   To  learn  how  children's  self-images  change  as  they  grow  older 
and  to  gain  increased  understanding  of  the  social  factors  that 
influence  self-image  formation.   While  most  previous  systematic 
research  has  focused  on  self-esteem,  the  present  investigation  con- 
siders a  number  of  other  aspects  of  the  self-image  as  well:  degree 
of  self -consciousness;  preoccupation  with  the  self;  the  quality  of 
sel f -detachment ;  stability  of  self -concept ;  "front"  or  "presenting 
self";  committed  and  idealized  images;  development  of  ego- 
extensions;  and  other  aspects  of  the  self-image.   The  aim  is  to  under- 
stand how  these  aspects  of  the  self-image  develop;  to  examine  their 
relationships  to  a  range  of  social  conditions  and  experiences;  and 
to  learn  how  they  are  associated  with  other  psychological  states, 
such  as  anxiety,  vulnerability  and  depression. 

Methods  Employed:   Structured  and  open-ended  interviews.   A  stratified 

random  sample  of  1910  children  from  the  third  through  the  twelfth 
grades  in  a  large  urban  school  system  was  interviewed.   Additional 
brief  interviews  were  conducted  with  400  parents  to  obtain  certain 
essential  background  information. 

Major  Findings:   In  agreement  with  other  recent  systematic  research,  the 

data  from  this  study  indicate  that  black  children  do  not  have  lower 
self-esteem  than  white  children.   The  central  objective  of  our 

387 


Serial  No.    M-S-S-12,  page  2 

analysis  has  been  to  elucidate  the  social  psychological  factors 
contributing  to  this  surprising  result.   Three  general  factors 
appear  to  be  implicated. 

The  first  is  the  consonant  or  dissonant  social  context,  i.e., 
the  concordance  or  discordance  of  the  individual's  social  character- 
istics with  those  of  the  environment  by  which  he  is  surrounded.   The 
consequences  of  contextual  consonance  or  dissonance  turn  out  to  be 
varied;  some  are  beneficial  to  the  individual,  others  injurious. 
In  this  study  we  have  found  that,  at  the  secondary  school  level, 
black  children  attending  schools  in  which  they  are  in  a  racial  minority 
are  more  likely  than  those  in  predominantly  black  schools:  (1)  to 
have  lower  self-esteem;  (2)  to  report  that  they  have  experienced 
direct  race  prejudice;  (3)  to  be  fully  cognizant  of  the  status 
assigned  their  group  by  society;  (4)  if  they  come  from  separated- 
never  married  families,  to  have  lower  self-esteem  and  to  be  more 
likely  to  report  being  teased  about  their  families  than  other  black 
children  from  separated-never  married  families;  (5)  to  obtain  higher 
marks  in  school;  and  (6)  to  have  more  white  friends. 

The  consonant  social  context  thus  appears  to  protect  the 
self-esteem  of  the  black  child  in  a  variety  of  ways.   First  of  all, 
a  child  in  such  a  context  has  little  direct  exposure  to  white 
children,  and  is  thus  unlikely  to  experience  direct  prejudice. 
Second,  he  is  exposed  to  a  set  of  experiences  and  a  communications 
environment  which  is  less  likely  to  make  him  fully  aware  of  the  rank 
of  his  group  in  the  total  society.   Third,  if  he  comes  from  a 
separated-never  married  family,  he  is  less  likely  to  feel  deep  per- 
sonal shame  at  the  fact  since  the  stigma  attached  to  this  family 
type  is  probably  less  strong  in  this  environment.   Fourth,  although 
his  school  performance  tends  to  be  considerably  poorer  than  that 
of  whites,  he  usually  compares  himself  with  others  of  his  race. 
Finally,  he  finds  himself  in  an  environment  which  is  more  hospitable 
to  the  use  of  certain  psychological  mechanisms  for  protecting  self- 
esteem. 

The  last  point  merits  elaboration.   In  this  study,  four  pro- 
tective mechanisms  have  been  observed:  (1)  the  "inflation  mechanism" 
(e.g.,  the  tendency  for  children  to  believe  that  society  ranks 
their  race,  religion,  or  father's  occupation  higher  than  it  actually 
does);  (2)  "selective  interpretation"  (e.g.,  the  child  who  does       M 
poorly  in  school  is  less  likely  to  believe  that  low  marks  signify     9 
low  intelligence);  (3)  "selective  perception"  (e.g.,  the  child  who 
does  poorly  in  school  perceives  his  parents  as  considering  him 
intelligent,  and  the  child  with  dark  skin  believes  that  his  parents 
care  little  about  good  looks);  and  (4)  "value  selectivity"  (e.g., 
the  academically  unsuccessful  child  is  less  likely  to  stake  his 
feeling  of  self -worth  on  the  quality  of  intelligence).   These 
mechanisms  are  calculated  to  protect  the  self-esteem  of  the  child. 


Serial  No,   M-S-S-12,  page  3 

The  point. is,  however,  that  they  are  not  employed  equally;  it 
appears  that  they  are  chiefly  employed  in  environments,  particularly 
consonant  social  contexts,  which  are  especially  hospitable  to  their 
use,  and  that  the  individual's  self -picture  may  benefit  accordingly. 

The  concept  of  "comparison  reference  groups"  has  also  helped 
to  explain  the  findings  of  this  study.   It  is  widely  recognized 
that  an  individual's  self -evaluation  will  be  influenced  by  the  group 
with  which  he  compares  himself.   For  example,  white  children  who  are 
poor,  come  from  separated-never  married  families,  and  are  poor  school 
performers  do  have  lower  self-esteem  than  other  white  children. 
Since  black  children,  compared  to  whites,  tend  to  be  poor,  to  come 
from  separated-never  married  families,  and  to  do  poorly  in  school, 
it  has  been  assumed  by  many  social  scientists  that  their  self-esteem 
would  be  low.   What  is  overlooked,  however,  is  the  question:  Do 
black  children  tend  to  compare  themselves  with  whites  or  with  other 
blacks?  There  are  six  points  in  this  investigation  where  it  has 
been  possible  to  examine  this  issue.   In  every  case,  the  data  suggest 
that  the  black  child  compares  himself  with  those  children  with  whom 
he  is  in  sustained  social  interaction,  whether  black  or  white.   The 
fact  that  currently  such  interaction  tends  to  go  on  within  racial 
groups  appears  to  be  protective  of  the  deprived  child's  self-esteem. 

Finally,  the  theory  of  reflected  appraisals  suggests  that  the 
individual's  self -attitude  will  be  strongly  influenced  by  his  percep- 
tion of  the  attitudes  of  others  toward  him;  this  will  be  especially 
true  of  "significant  others,"  i.e.,  those  in  his  immediate  environ- 
ment who  play  an  important  role  in  his  life.   In  this  respect,  our 
data  indicate,  the  black  child  appears  to  fare  as  well  as  the  white. 
Black  children  are  just  as  likely  as  whites  to  believe  that  their 
mothers,  friends,  and  teachers  hold  favorable  opinions  of  them 
Furthermore,  these  perceptions  are  at  least  as  strongly  related  to 
the  self-esteem  of  black  as  of  white  children.   This  factor  thus 
serves  to  protect  the  self-esteem  of  the  black  child  against  the 
other  deprivations  to  which  he  is  subjected. 

In  sura,  our  data  suggest  that  it  is  the  immediate  environment 
of  the  child  which  chiefly  constitutes  the  crucible  within  which  his 
self-image  is  formed.   This  environment,  to  be  sure,  is  structured 
by  the  operation  of  broader  social  forces,  many  of  which  are  of  a 
hostile  nature.   But  this  immediate  environment,  as  constituted 
appears  to  be  such  that  it  is  generally  protective  of  the  self-esteem 
of  the  black  child. 

Scientific  Significance:  Problems  of  the  self-image  are  often  involved  in 
mental  health  and  illness.  Yet  little  is  currently  known  about  how 
position  in  the  social  structure,  and  the  characteristic  experiences 
associated  with  this  position,  influence  the  formation  of  the  self- 
image.  This  study  is  designed  to  contribute  knowledge  to  this  area 
and  to  learn  how  the  self-image  changes  with  age.  ' 


Serial  No.   M-S-S-12,  page  4 

Proposed  Course  of  Proiect:   Data  analysis  will  continue  through  the  coming 

year.   Work  on  the  study  of  developmental  changes  in  various  dimensions 
of  the  self-image,  such  as  self-esteem,  self-consciousness,  stability 
of  self,  content  of  self,  and  internal-external  locus  of  self- 
judgment,  will  continue. 

Honors  and  Awards :   None 

Publications: 

Simmons,  R,  G.  and  Rosenberg,  M. :  Functions  of  children's  perceptions 
of  the  stratification  system.   American  Sociological  Review  36; 
233-249,  1971. 

Rosenberg,  M.  and  Simmons,  R.  G. :  Black  and  White  Self -Esteem: 
The  Urban  School  Child.   Arnold  and  Carolyn  Rose  Monograph  Series. 
Washington,  D.  C.  :  American  Sociological  Association,  1972, 


390 


Serial  No.   M-S-SP-3 


1,  Socio-environmental  Studies 

2,  Section  on  Social  Process 

3,  Bethesda,  Maryland 


PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  197  2 


Project  Title:   Variables  Affecting  Twin  Birth  Frequencies 

Previous  Serial  Nvimber:   Same 

Principal  Investigator:   Gordon  Allen 

Other  Investigators:   None 

Cooperating  Units:   In  prior  years  data  have  been  supplied  by  the  National 
Center  for  Health  Statistics,  Public  Health  Service. 
New  data  will  be  obtained  if  possible  from  the  Perinatal 
Research  Branch,  NINDS. 

Person  Years 

Total:  0 
Professional:  0 
Other:         0 

Project  Description: 

Objectives:   To  develop  hypotheses  to  explain  temporal  and  geographic 

variations  in  plural  birth  frequencies  and  to  test  any  hypothesis 
for  which  appropriate  data  can  be  obtained. 

Methods  Employed:   Birth  intervals  preceding  same-sex  and  opposite-sex  twin 
births  and  singleton  births  will  be  adjusted  for  age  and  parity.   Use 
will  also  be  made  of  information  on  contraception  and  on  intervening 
abortions.   Significant  differences  among  the  adjusted  birth  inter- 
vals will  rule  various  hypotheses  in  or  out. 

Major  Findings:   None  this  year. 

Scientific  Significance:   The  growing  evidence  for  a  relation  between 

twinning  and  ease  of  conception  indicates  that  epidemiological  study 
of  twinning  may  provide  some  general  parameters  of  female  reproduction 
and  fertility. 

Proposed  Course  of  Project:   Access  through  the  NINDS  to  birth  data  of  the 

Collaborative  Study  of  Cerebral  Palsy  is  still  under  negotiation.   If 


391 


Serial  No.  M-S-SP-3,  page  2 

the  data  can  be  secured  before  the  summer,  analysis  should  be 
completed  during  fiscal  year  1973. 

Honors  and  Awards :   None 

Publications: 

Allen,  G.  and  Schachter,  J. :   Ease  of  conception  in  mothers  of 
twins.   Social  Biology  18:  18-27,  1971. 


392 


Serial  No.   M-S-SP-4 


1.  Socio -environmental  Studies 

2.  Section  on  Social  Process 

3.  Bethesda,  Maryland 


PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 


Project  Title:   Individual  Differences  in  Survival  and  Reproduction  Among 
Old  Colony  Mennonites  in  Mexico 

Previous  Serial  Number:   Same 

Principal  Investigators:   Gordon  Allen  and  Calvin  Redekop  (non-PHS) 

Other  Investigators:   None 

Cooperating  Units:   Goshen  College,  Goshen,  Indiana 

Person  Years 

Total:  1  7/8 
Professional:  7/8 
Other:         1 

Project  Description: 

Objectives:   To  demonstrate  the  presence  or  apparent  absence  of  selective 
survival  and  reproduction  with  respect  to  individual  behavioral 
characteristics.   Also  to  study  natural  patterns  of  marriage  and.  .,  ,. 
reproduction  in  a  relatively  simple  agricultural  society  of  tradi-  ~ 
tional  European  type. 

Methods  Employed:   The  population  under  study  consists  of  about  13,000 

German- speaking  Mennonites  in  a  politically  integrated  cluster  of 
villages  in  northern  Mexico.   These  people  were  selected  because  of 
their  simple  and  uniform  culture  insulated  from  mass  communication 
media  and  because  of  their  apparently  unrestricted  fertility.   Also 
important  was  the  fact  that,  unlike  some  similar  religious  isolates, 
this  society  supports  a  considerable  degree  of  economic  competition. 

Information  was  gathered  by  means  of  a  combined  census  and 
questionnaire  that  reached  a  third  of  the  population.   This  has  been 
supplemented  with  photographs  of  all  vital  records  kept  by  the  church, 
a  public  list  of  farmers  and  their  holdings,  a  list  of  all  village 
and  church  leaders  in  the  40-year  history  of  the  population,  and 
records  of  Mennonite  births  in  local  hospitals.   Interviews  were 
conducted  by  the  investigators  end  by  a  Canadian  Mennonite  with  the 


393 


Serial  No.   M-S-SP-4,  page  2 

aid  of  cooperative  local  men.   This  material  defines  the  background 
of  attitudes  toward  community  problems,  overpopulation,  and  birth 
control. 

The  largest  body  of  data,  church  records  of  vital  events, 
has  been  edited  and  is  now  being  studied  by  cross- tabluation.   After 
the  census  and  other  data  sets  have  been  edited,  all  will  be  collated. 
Final  analysis  will  include  multivariate  methods. 

Major  Findings:   Preliminary  tabulation  of  the  church  records  reveals  rapid 
transformation  of  the  population  structure  over  the  40  years  of 
residence  in  Mexico.   The  population  doubled  its  numbers  in  the  first 
20  years,  but  increased  by  only  54%  in  the  subsequent  20  years, 
presumably  because  the  initially  young  adult  immigrant  population  has 
stopped  reproducing  and  begun  to  die.   This  emphasizes  the  fact  that 
nearly  all  analysis  of  the  data  will  have  to  take  account  of  the  time 
dimension. 

Scientific  Significance:   Natural  selection  is  apparently  the  sole  agent 
responsible  for  the  progressive  evolution  and  maintenance  of  human 
mental  capacities.   The  study  of  selection  in  a  pre-industrial 
European  society  may  indicate  some  of  the  influences  that  have  pro- 
duced present  genetic  tendencies  and  draw  a  base  line  for  future 
studies  of  selection  under  modern  conditions. 

Proposed  Course  of  Project:   Analysis  of  the  data  is  expected  to  occupy 
between  two  and  four  years. 

Honors  and  Awards :   None 

Publications:   None 


39it 


Serial  No.   M-S-SP-5 


1.  Socio- environmental  Studies 

2.  Section  on  Social  Process 

3.  Bethesda,  Maryland 


PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 


Project  Title:   Social  Origins  of  Stress 

Previous  Serial  Number:   None 

Principal  Investigator:   Leonard  I.  Pearlin 

Other  Investigators:   Frederic  W.  Ilfeld,  Jr.,  Albert  J.  McQueen, 
Marilyn  T.  Oliver,  and  Clarice  W.  Radabaugh 

Cooperating  Units:   None 

Person  Years 

Total:  4  1/3 
Professional:  2  1/6 
Other:         2  1/6 

Project  Description: 

Obiectiyes:   This  study  examines  the  positions  and  statuses  of  people  in 
the  social  structure  in  relationship  to  the  inner  stresses  that 
they  experience.   It  will  ask,  first,  how  economic,  occupational, 
tt''''^^lt        '    ^^'''   ^^^'    ^^   ^^^i^l  differences  are  associated  with 
cn^/i   y^""^  u"  ""^Z   problems  that  people  confront  in  their  daily 
social  roles  as  breadwinners,  parents,  husbands  and  wives,  and  occu- 
pationally  engaged.   Second,  it  will  inquire  into  the  social  and 
material  resources  that  groups  have  available  to  them  for  the  manaee- 
ment  of  their  problems.   Third,  it  will  examine  how  the  different  ^ 
structural  groups  compare  in  their  use  of  these  resources  In  dealing 
with  daily  problems.   And,  last,  it  will  seek  to  learn  how  the 
stresses  that  people  feel  are  related  to  the  foregoing  issues   Th^ 
attentions  and  theoretical  interests  of  the  investigation  th;n 
are  focused  on  experiences  and  on  patterns  of  response  to  these' 

soclirT  '''^'   ?'°P''  ""^^^  ""^  ^^  1^^^"  from^thers  of  the  same 
social  and  economic  positions. 

Methods  Emploved:   The  data  will  be  gathered  through  interviews  with  a 

probability  sample  of  2,000  urban  residents'in  a  major  citj   Mother 
300  interviews  will  be  conducted  among  purposefully  selected  ^TuT. 
such  as  unemployed  white-collar  workers,  upper-class  blacks  Unit' 
groups  that  are  of  theoretical  importance  but  who'n^'r  In  th^ 

395 


Serial  No.   M-S-SP-5,  page  2 

general  population  are  limited.   The  interviews  will  be  conducted 
by  using  a  standardized  schedule  that  has  been  developed  and  tested 

over  the  past  year. 

Major  Findings :   A  systematic  pretest  of  a  preliminary  interview  schedule 
was  conducted  by  a  professional  survey  organization.   They  inter- 
viewed 100  randomly  drawn  residents  of  Chicago,  Illinois.   The  re- 
sults are  crucial  to  the  future  course  of  this  survey.   In  particular, 
the  pretest  has  provided  an  opportunity  for  a  critical  examination 
of  the  adequacy  of  our  indicators  of  major  conceptual  areas;  namely, 
of  social  experiences  that  are  potentially  productive  of  stress,  of 
the  mediating  reactions  that  might  regulate  and  deflect  the  impact 
of  these  experiences,  of  the  subjective  condition  of  stress  itself, 
and,  finally,  of  sjrmptoms  indicative  of  psychiatric  syndromes  that 
are  part  of  personality.   While  it  is  possible  to  distinguish  concep- 
tually between  these  areas,  there  is  some  question  of  whether  informa- 
tion that  people  give  in  response  to  interview  questions  can  provide 
empirical  distinctions  between  such  interlocked  conceptual  areas. 
One  may  ask,  for  example,  whether  the  problematic  experiences  a  person 
reveals  and  the  stress  he  reports  don't  both  indicate  a  single  aspect 
of  personality  rather  than  independent  (although  possibly  related) 
phenomena.   The  pretest,  then,  permitted  us  to  see  if  the  problems 
and  stresses  that  people  told  us  about  reflect  more  on  general 
personality  predispositions  than  on  specific  stresses  attached  to 
specific  experiences  within  specific  role  areas.   The  issue  was 
approached  by  asking  three  questions  of  the  data:  are  problematic 
experiences  in  one  role  area  likely  to  be  part  of  a  more  general 
perception  of  problems  in  other  areas;  are  reports  of  problematic 
experiences  likely  to  be  associated  with  reports  of  stress;  and  are 
reports  of  stress  in  one  area  likely  to  be  part  of  a  more  general 
reporting  of  stress  across  the  several  areas  we  are  investigating. 

The  answers  we  found  to  these  questions  suggest  that  our 
indicators  are  catching  the  differentiations  and  distinctions 
respondents  were  being  asked  to  make,  and  are  not  simply  tapping 
the  same  basic  personality  dimensions.   Thus,  a  majority  of  people 
who  report  problematic  experiences  in  one  area  are  not  likely  to 
report  them  in  others;  of  those  who  do  say  they  have  problems  in  a 
role,  most  are  likely  to  indicate  no  stress;  and  of  those  reporting 
stress  in  one  area,  most  are  likely  to  report  none  in  other  role 
areas.   This  kind  of  independence  of  responses  to  different  parts 
of  the  interview  is  necessary  before  statistical  relationships  between 
responses  can  be  meaningful. 

Scientific  Significance:   The  significance  of  this  study  derives  from  several 
of  its  features.   First,  no  other  inquiry  has  brought  together  as 
large  an  array  of  variables  under  the  umbrella  of  a  single  study. 
Hopefully,  this  will  enable  us  to  begin  to  unfold  a  process  by  which 
basic  features  of  social  organization  are  united  with  basic  features 


396 


Serial  No.  M-S-SP-5,  page  3 

of  the  i,nner  life  of  people.   Secondly,  it  emphasizes  ordinary, 
recurrent  experiences  of  daily  life  rather  than  eruptive  issues  or 
transitional  events.   Third,  by  attending  to  a  range  of  coping  and 
management  devices,  it  should  help  to  inform  us  how  people  living 
under  extremely  challenging  conditions  nevertheless  manage  to  per- 
severe and  even  flourish. 

The  study  is  also  clearly  relevant  to  prevailing  mental  health 
issues.   The  importance  of  such  social  phenomena  as  class,  roles, 
family,  and  community  to  a  wide  variety  of  pathologies  is  coming  into 
recognition.   Yet,  there  is  a  striking  absence  of  studies  that 
empirically  deal  with  the  intricate  relationships  among  the  tradi- 
tionally clinical  and  the  more  social  variables.   This  study  will  be 
addressed  to  a  large  number  of  such  relationships. 

Proposed  Course  of  Project:   It  is  expected  that  the  schedule  will  be  placed 
in  the  field  in  June  1972.   The  collection  of  the  data  should  be 
completed  in  early  fall,  1972,  after  which  the  data  will  be  coded 
and  readied  for  analysis.   It  is  anticipated  that  analysis  will 
commence  early  in  1973. 

Honors  and  Awards :   None 

Publications:   None 


397 


Serial  No.   M-S-SP-6 


1.  Socio- environmental  Studies 

2.  Section  on  Social  Process 

3.  Bethesda,  Maryland 


PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 


Project  Title:   Studies  of  Evolution  of  Reacting  Chemical  Mixtures  Under 
Nearly  Steady-State  Conditions 

Previous  Serial  Number:  M-S-C-8 

Principal  Investigator:   Gordon  Allen 

Other  Investigators :   None 

Cooperating  Units:   None 

Person  Years 

Total:  1/8 
Professional :  1/8 
Other :         0 

Project  Description: 

Objectives:   To  explore  the  possible  relevance  of  simple  orgemic  catalysts 
to  the  origin  of  life. 

Methods  Employed:   Laboratory  work  was  concluded  in  1964.   This  year  a 

mathematical  model  of  the  1964  experiments  was  constructed  and  tested 
by  computer  methods. 

Major  Findings:   Computer  runs  of  the  model  experiment  revealed  that  one 
feature  of  the  experimental  design  was  very  unfavorable  for  the 
success  of  the  work. 

In  the  primitive  ocean,  reactants  and  reaction  products  could 
accvmiulate  with  no  limit  but  that  set  by  their  solubility  or  their 
stability.   In  my  experiments  high  concentrations  of  reactants  were 
achieved  at  the  very  start  and  a  portion  of  the  solution  was  replaced 
each  time  fresh  reactants  were  added,  but  this  kept  the  concentration 
of  products  low.   The  computer  model  revealed  that  this  removal  of 
products  would  be  much  more  effective  in  preventing  reflexive 
catalysis  than  I  suspected  in  1964. 


399 


Serial  No.   M-S-SP-6.  page  2 

Scientific  SjRnificance:  It  now  appears  that  the  experiments  done  in  1964, 
which  never  quite  ruled  out  reflexive  catalysis,  were  in  fact  only 
a  feeble  test  of  the  hypothesis.   Future  experiments  should  be  designed 
so  as  to  permit  indefinite  accumulation  of  rare  secondary  and  tertiary 
products.   At  least  one  other  scientist  is  engaged  in  experiments 
that  ought  to  be  modified  in  this  direction. 

Proposed  Course  of  Project:   No  further  work  is  planned. 

Honors  and  Awards :   None 

Publications: 

Allen,  G. :  Chemical  evolution  under  the  bion  hypothesis.   Theory 
and  Experiment  in  Exobiology,  in  press. 


1 


ifOO 


Serial  No.  M-OD-BBR-2 

1.  Division  of  Biological  and 
Biochemical  Research 

2.  Office  of  the  Director 

3.  Bethesda.  Maryland 


PHS-HSMHA-NIMH 
Individual  Project  Reports 
July  1,  1971  through  June  30,  1972 


Project  Title:   Characteristics  of  Membranes  in  Muscle 

Previous  Serial  Number:   Same 

Principal  Investigator:   W.  H.  Freygang 

Other  Investigators:   D.  A.  Goldstein,  R.  Gunn,  B.  Mobley 

Cooperating  Units:   Department  of  Radiation 

Biology  and  Atomic  Energy  Project 
University  of  Rochester 

Man  Years: 

Total:  3.2 

Professional:  3.2 

Other:  0,0 

Project  Description: 

Objectives :   It  seems  most  likely  that  the  initiation  of  contraction  in 
striated  muscle  is  a  consequence  of  the  release  of  free  calcium  ions  in  the 
interior  of  the  cell.   The  signal  for  this  release  is  an  electrical  one  that 
spreads  into  the  interior  of  the  muscle  fiber  through  an  array  of  tubules. 
It  is  not  clear  if  an  action  potential  is  propagated  in  the  tubules  or  not. 
In  any  case,  it  seems  reasonable  to  suppose  that  the  release  of  calcium 
arises  from  an  electrically  induced  breakdown  of  an  intracellular  barrier 
to  the  movement  of  calcium  that  may  be  the  tubules  or  another  intracellular 
structure.   Our  objective  is  to  locate  the  barrier  and  describe  the  condi- 
tions that  lead  to  its  breakdown. 

Methods  Employed:   Myoplasmic  impedance  is  measured  by  two  methods. 

(1)  A  bundle  of  fibers  from  the  frog's  semitendinosus  muscle  is  suspended 
.vertically  in  oil  between  two  pools  of  Ringer's  solution.   The  impedance 

is  measured  by  means  of  a  Wheatstone  bridge  that  is  connected  to  the  pools. 

(2)  Myoplasmic  impedance  is  calculated  from  the  transfer  impedance  between 
two  intracellular  electrodes. 


401 


Serial  No.  M-OD-BBR-2 


Other  methods  are  routine  ones  that  employ  micropipettes. 

Major  Findings:   (1)   There  is  a  capacitive  reactance  in  myoplasm.   (2)  The 
late  after-potential  that  follows  a  train  of  impulses  can  still  be  explained 
by  an  accumulation  of  potassium  ions  in  the  tubules  that  indicates  a  change 
in  the  permeability  of  the  tubules  with  a  change  in  the  electric  potential 
across  them.   This  view  has  recently  been  questioned  by  Adrian,  Chandler, 
and  Hodgkin  who  interpreted  their  data  as  being  in  conflict  with  potassium 
accumulation.  We,  however,  can  reproduce  their  data  with  our  old  model  that 
is  based  upon  potassium  accumulation. 

Significance  to  Biomedical  Research  and  the  Program  of  the  Institute: 
(1)  The  description  of  the  membrane  parameters  of  frog  muscle  are  made  more 
exact  by  the  recognition  of  the  error  that  has  been  introduced  in  ignoring 
the  myoplasmic  capacitive  reactance.   (2)  The  role  of  the  tubular  system  in 
coupling  the  electrical  impulse  to  the  mechanical  twitch  is  implied  by 
changes  in  its  permeability  to  potassium  during  the  electrical  event. 

Proposed  Course;   The  results  of  this  project  since  1969  have  not  been 
published  because  it  is  thought  that  it  is  best  to  exhaust  the  methods 
employed  before  adding  to  the  already  too  massive  literature  on  this  subject. 
The  results  have  been  very  carefully  checked  and  will  be  prepared  for 
publication. 

Honors  and  Awards :   None 

Publications:   None 


lj-02 


serial  No.  M-LBEB^CN-l 

1.  Laboratory  of  Brain 

Evolution  and  Behavior 

2 .  Section  on  Comparative 

Neurophysiology  and  Behavior 

3.  Poolesville,  Maryland 

PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   Neural  substrate  of  mirror  display  in  squirrel 
monkey  (Saimiri  sciureus) . 

Previous  Serial  No.:   M-NP-LI-23 

Principal  Investigators:   Paul  D.  MacLean 

Other  Investigators:   Robert  E.  Gelhard 

Cooperating  Units :   None 

Man  Years 


Total: 

1 

1 

Professional : 

0 

3 

Other: 

0 

8 

Project  Description: 

Objectives :   This  long-term  study  seeks  (1)  to  utilize  the  innate 
display  behavior  of  the  squirrel  monkey  for  obtaining  information 
about  the  cerebral  representation  of  unlearned  patterns  of  be- 
havior and  associated  imitative  factors  and  (2)  to  identify 
structures  involved  in  the  integration  of  autonomic  and  somatic 
functions  in  visually  guided  sociosexual  behavior.   The  present 
experiments  focus  on  the  effects  of  bilateral  lesions  of  the 
globus  pallidus. 

Methods  Employed:   The  mirror  display  test  for  male  gothic  type 
squirrel  monkeys  has  been  described  in  previous  project  reports 
(M-NP-LI-17,  1963  and  1964).   After  the  monkey  reaches  criterion 
in  30  or  more  trials  it  is  subjected  to  bilateral  coagulation 
of  the  target  structures.   The  voliome  of  the  target  structures 
and  the  size  of  the  lesions  are  determined  by  planimetry. 

Major  Findings: 

Pallidal  lesions.   Five  additional  animals  (F-4 ;G-4 ;H-4 ; 1-4 ; 
J-4)  have  been  subjected  to  bilateral  lesions  of  the  globus 
pallidus,  making  a  total  of  twelve  monkeys  that  have  sustained 
lesions  of  various  parts  of  this  structure.   Although  there  is  no 


Seria,!  No.  M-LBEB-CN-l,  page  2 

apparent  motor  incapacity,  moderately  large  lesions  eliminate  or 
practically  eliminate  all  aspects  of  the  display,  with  the 
somatic  manifestations  being  initially  more  affected  than  the 
genital  response.   The  decline  in  performance  of  the  display  may 
take  place  over  a  period  of  two  and  a  half  months,  suggesting 
the  possibility  of  progressive  neural  degeneration  that  may  in 
part  be  transneuronal .   It  was  therefore  significant  to  learn 
whether  or  not  animals  with  smaller  lesions  would  show  deteriora- 
tion of  performance  if  followed  for  a  longer  time.   Two  animals 
CF-4;G-4)  with  bilateral  small  lesions  in  the  posterior  part  of 
the  globus  pallidus  displayed  consistently  at  the  hundred  percent 
level  for  more  than  six  months.   When  additional  lesions  were 
placed  more  anteriorly,  there  was  only  an  occasional  partial  dis- 
play, in  one  animal  ceasing  altogether. 

Additional  findings.   One  animal  sacrificed  since  last  year's 
progress  report   continued  to  display  consistently  in  spite  of 
bilateral  section  of  the  fornix  and  stria  medullaris,  and  the 
left  mammillothalamic  tract.   Subsequent  to  gonadectomy  this 
animal  continued  to  display  but  by  the  second  set  of  30  trials 
there  was  a  marked  reduction  in  the  incidence  of  the  somatic 
aspects  of  the  display  Cp  <  0.0001).   At  the  end  of  150  trials 
there  was  also  a  significant  reduction  in  the  genital  response 
(p  <  0.0001)  Ccf.  findings  described  above). 

Significance  to  Biomedical  Research  and  Program  of  the 
Institute.   The  present  findings  suggest  that  the  striatal 
complex  may  be  part  of  a  neural  repository  requisite  for  species- 
specific  forms  of  behavior  and  associated  imitative  factors,  and 
that  gonadal  hormones  may  be  an  adjuvant  of  striatal  function. 
There  has  existed  a  dearth  of  information  about  neural  mechanisms 
of  imitation--an  indispensable  form  of  behavior  that  works  in 
myriad  ways  to  maintain  group  identity  and  promote  group  survival. 
A  cardinal  feature  of  childhood  autism  is  an  inability  for  natural 
imitation.   Since  the  early  part  of  the  19th  Century  emphasis  has 
been  given  to  the  use  of  imitation  in  the  training  of  mentally 
retarded  children. 

Proposed  Course  of  the  Project:   To  be  continued,  with  a  focus 
on  the  effects  of  diffuse  chemical  lesions  of  the  caudate  nucleus 
and  putamen . 

Honors  and  Awards:   Items  pertaining  to  Dr.  MacLean  are  as 
follows : 

1)  Lecture:  "Cerebral  Evolution  and  Emotional  Processes", 
The  New  York  Academy  of  Sciences,  Barbizon-Plaza  Hotel, 
New  York,  N.Y.,  May  4,  1971. 

2)  Member:  Ad  Hoc  Committee  on  the  Proposed  Congo  Primate 


Serial  No.  M-LBEB-CN-1,  page  3 


Center,  National  Academy  of  Sciences,  Joseph  Henry 
Building,  21st  &  Pennsylvania  Ave.,  N.W. ,  Washington, 
D.C.,  November  2,  1971. 

3)  Lecture:  "An  Evolutionary  Approach  to  Brain  Studies  on 
Aggression",  The  Medical  College  of  Pennsylvania, 
Philadelphia,  Pennsylvania,  November  15,  1971. 

4)  Invited  Illustrated  Lecture:  "The  Brain's  Generation 
Gap:  Some  Human  Implications",  The  American  Association 
for  the  Advancement  of  Science,  Bellevue-Stratford 
Hotel,  Philadelphia,  Pennsylvania,  December  27,  1971. 

5)  The  G.  Burroughs  Mider  Lecture  Award:  "Survival 
Mechanisms  of  the  Triune  Brain:  Some  Hopeful  Aspects," 
Clinical  Center,  National  Institutes  of  Health, 
Bethesda,  Maryland,  February  9,  1972. 

6)  Lecture:  "A  Search  for  Neural  Mechanisms  of  Natural 
Imitation",  Department  of  Neurology,  The  New  York 
Hospital-Cornell  Medical  Center,  New  York,  New  York, 
April  6,  1972. 

7)  The  Karl  Spencer  Lashley  Award  of  the  American 
Philosophical  Society  "in  recognition  of  his  useful 
and  significant  work  in  the  field  of  neurobiology," 
presented  on  April  21,  1972. 

8)  Lecture:  "Evolutionary  Trends  of  the  Triune  Brain: 
From  Imitation  to  Creativity",  Scientific  Symposium 
for  the  Sesquicentennial  Celebration  of  The  Institute 
of  Living,  Hartford,  Connecticut,  May  23,  1972. 


Publications : 


MacLean,  P.D.:  Cerebral  evolution  and  emotional  processes 
Transactions  of  the  New  York  Academy  of  Sciences,  (in 
press) . 

MacLean,  P.O.:  New  findings  on  brain  function  and  socio- 
sexual  behavior.  Transactions  of  the  American  Psycho- 
pathological  Association,  (in  press) . 

MacLean,  P.D.:  An  evolutionary  approach  to  the  investiga- 
tion of  psychoneuroendocrine  functions.   Proceedings  of 
The  Second  Congress  of  the  International  Society  of 
Psychoneuroendocrinology ,  (in  press) . 


to5 


Serial  No.  M-LBEB-CN-1,  page  4 

MacLean,  P.D.:  Implications  of  microelectrode  findings  on 
exteroceptive  inputs  to  the  limbic  cortex.   In:  Hockman, 
C.H.  (Ed.),  Limbic  System  Mechanisms  and  Autonomic  Function. 
Springfield,  Charles  C  Thomas,  1972,  pp.  115-136. 

Bachman,  D.S.  and  MacLean,  P.D.:  Unit  analysis  of  inputs 
to  cingulate  cortex  in  awake,  sitting  squirrel  monkeys 
I.  Exteroceptive  systems.   Intern.  J.  Neuroscience,  2: 
109-112,  1971. 

MacLean,  P.D.:  The  limbic  galaxy:  Honoring  a  brain 
astronomer  at  Graz.   Graz  Symposium,  (in  press). 


i^06 


Serial  No.  M-LBEB-CN-2 

1 .  Laboratory  ot  Brain 

Evolution  and  Behavior 

2 .  Section  on  Comparative 

Neurophysiology  and  Behavior 

3.  Poolesville,  Maryland 


PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   Unit  study  of  interoceptive  inputs  to  the 
cingulate  cortex  of  squirrel  monkey. 

Previous  Serial  Number :M-NP-LI-4 8 

Principal  Investigators:   David  S.  Bachman  and  Paul  D.  MacLean 

Other  Investigators:   None 

Cooperating  Units :   None 

Man  Years 

Total :  1.5 
Professional:  0.6 
Other :         0.9 

Project  Description: 

Objectives:   There  is  a  paucity  of  information  about  the 
important  question  of  visceral  influences  on  the  three  main 
evolutionary  formations  of  the  forebrain.   The  present  study 
tests  the  effects  of  vagal  stimulation  on  unit  activity  of  the 
cingulate  and  supracingulate  cortex.   The  cingulate  gyrus, 
which  is  a  major  part  of  the  limbic  system,  is  known  to  affect 
viscerosomatic  functions. 

Methods  Employed:   Extracellular  unit  activity  is  recorded 
with  platinum  microelectrodes  in  squirrel  monkeys  prepared 
with  a  chronically  fixed  stereotaxic  platform.   A  new  method 
has  been  devised  for  the  implantation  of  electrodes  around 
the  vagus  nerve.   A  multistranded  silver  wire  is  placed  around 
the  vagus  nerve  near  its  entrance  into  the  jugular  foramen. 
This  permits  free  movement  of  the  monkey's  head  without 
tension  on  the  nerve. 


1*07 


Serial  No.  M-LBEB-CN-2,  page  2 

Major  Findings;   To  date,  485  units  have  been  tested  in  seven 
squirrel  monkeys  (Nos .  802,833,  621,623,751,817,742)  between 
frontal  planes  F4  and  F20.   Vagal  volleys  evoked  discharges  of 
units  in  the  middle  part  of  the  cingulate  gyrus.   Response 
latencies  ranged  from  10-40  msec.   Following  the  initial 
discharge  there  was  commonly  a  period  of  inhibition  lasting 
up  to  300  msec. 

Responsive  units  elsewhere  in  the  cingulate  gyrus  usually 
showed  only  inhibitory  effects.   A  number  of  units  in  the 
supracingulate  cortex  were  also  affected  by  vagal  stimulation, 
but  the  response  pattern  was  an  increased  firing  pattern  like 
that  seen  with  somatic  stimulation  (see  Project  M-NP-LI-47) . 

Significance  to  Biomedical  Research  and  Program  of  the  Institute : 
Stimulation  of  the  anterior  cingulate  gyrus  is  known  to  elicit 
autonomic  changes,  including  cardiovascular,  respiratory, 
gastrointestinal,  and  genital  effects.   It  has  been  claimed  on 
the  basis  of  experimental  and  clinical  findings  that  cingulumo- 
tomy  prevents  the  autonomic  symptoms  of  addicted  si±ijects 
deprived  of  narcotic  drugs.   The  present  study  contributes  to 
the  knowledge  of  sensory  mechanisms  involved  in  the  cortical 
regulation  of  visceral  functions. 

Proposed  Course  of  the  Project;   To  be  continued.   Interim 
report  presented  at  meeting  of  Eastern  Association  of 
Electroencephalographers ,  December  1,  1971  (abstract  to  be 
published  in  Electroencephalography  and  Clinical  Neurophysiology) 

Honors  and  Awards:   Invitation  to  Dr.  Bachman  to  present  a 
paper  "Microelectrode  study  of  visceral  projections  to  cingulate 
cortex  in  awake,  sitting  squirrel  monkeys"  at  a  Symposium  on 
Cingulotomy  Treatment  of  Psychiatric  Disorders  and  Pain; 
Hahnemann  Hospital,  Philadelphia,  June  16-17. 

Publications;   None 


408 


Serial  No,  M-LBEB-CN-3 

1.  Laboratory  of  Brain 

Evolution  and  Behavior 

2.  Section  on  Comparative 

Neurophysiology  and  Behavior 

3.  Poolesville,  Maryland 

PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   Effect  of  intravenous  injections  of 

5 -hydroxy try pt amine  (serotonin)  on  unit  activity 
of  cingulate  cortex  of  awake  squirrel  monkeys 
CSaimiri  sciureus) . 

Previous  Serial  Number:   None 

Principal  Investigators:   David  S.  Bachman,  Howard  Katz,  and 

Paul  D.  MacLean 

Other  Investigators:   None 

Cooperating  Units :   None 

Man  Years 

Total:  0.9 
Professional:  0.5 
Other:        0.4 

Project  Description: 

Objectives:   This  study  is  related  to  the  Project  M-LBEB-CN-2, 
dealing  with  the  question  of  interoceptive  inputs  to  the  cingu- 
late cortex.   Serotonin,  which  ostensibly  does  not  cross  the 
blood-brain  barrier,  is  known  to  excite  visceral  receptors. 
The  present  experiments  test  the  effects  of  intravenous  injections 
of  microamounts  of  serotonin  on  unit  activity  of  the  cingulate 
and  supracingulate  cortex. 

Methods  Employed;   The  method  for  recording  unit  activity  was 
the  same  as  in  the  preceding  project  (M-LBEB-CN-2) .   Microamounts 
(200  ug)  of  serotonin  were  injected  through  an  indwelling 
catheter  in  the  jugular  vein.   Saline  injections  served  as 
controls. 

Major  Findings:   During  exploration  of  seven  tracks  between 
frontal  planes  F18  and  F9  (Monkey  No.  813B)  209  units  were 
tested  in  the  supracallosal  cingulate,  subcallosal  cingulate. 


k09 


Serial  No.  M-LBEB-CN-3,  page  2 

and  supracingulate  cortex.   In  the  supracallosal  cingulate 
cortex,  serotonin  altered  the  firing  rate  of  15  of  82  (18.3%) 
units,  with  two- thirds  showing  an  increased  firing  rate  and 
one-third  a  decrease.   Only  one  (3.2%)  of  31  subcallosal  units 
was  affected.   Four  (4.2%)  of  96  supracingulate  units  were 
responsive,  all  being  located  in  the  superior  bank  of  the  cingu- 
late sulcus.   Mean  response  latencies  based  on  repeated  trials 
varied  from  1.5  seconds  to  8.1  seconds. 

Significance  to  Biomedical  Research  and  Program  of  the  Institute; 
Because  of  the  positive  findings  obtained  by  a  different  approach, 
the  present  study  gives  added  significance  to  the  results 
described  in  the  preceding  project  (M-LBEB-CN-2) . 

Proposed  Course  of  the  Project;   Concluded  with  the  presentation 
of  the  findings  at  the  Federation  Proceedings  [Abstract;  Bachitian, 
D.S.,  Katz ,  H.M. ,  and  MacLean,  P.D.   Effect  of  intravenous 
injections  of  5-hydroxytryptamine  (serotonin)  on  unit  activity 
of  cingulate  cortex  of  awake  squirrel  monkeys.   Fed.  Proc.  , 
31:  303,  1972],  and  publication  of  the  results  as  part  of  the 
preceding  study  (M-LBEB-CN-2) . 

Honors  and  Awards;   None 

Publications:   None 


ino 


Serial  No.  M-LBEB-CN-4 

1.  Laboratory  of  Brain 

Evolution  and  Behavior 

2.  Section  on  Comparative 

Neurophysiology  and  Behavior 

3.  Poolesville,  Maryland 

PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   Physiological  effects  of  intravenous 

administration  of  serotonin  (5-hydroxytryptamine) 
in  awake   squirrel  monkey  (Saimiri  sciureus) . 

Previous  Serial  Number:   None 

Principal  Investigators:   David  S.  Bachman,  Howard  Katz, 

and  Paul  D.  MacLean 

Other  Investigators:   None 

Cooperating  Units:   None 

Man  Years 

Total:  0.6 

Professional:   0.3 
Other:         0.3 

Project  Description: 

Objectives :   Information  is  not  available  regarding  the 
physiological  effects  of  intravenous  injections  of  serotonin 
in  the  monkey.   Preliminary  to  using  serotonin  for  activating 
visceral  receptors  in  the  preceding  microelectrode  study 
(M-LBEB-CN-3)  it  was  necessary  to  learn  the  dose-response 
parameters  in  the  squirrel  monkey. 

Methods  Employed:   Six  squirrel  monkeys  (Nos.  802 ,812 , 813B, 
814, 816B, 819)  were  prepared  with  chronically  fixed  stereotaxic 
platforms.   Intravenous  serotonin  was  injected  percutaneous ly 
into  the  tail  vein  or  into  the  superior  vena  cava  through  a 
chronically  implanted  catheter  with  a  stopcock  fixed  to  the 
stereotaxic  platform. 

Major  findings:   Injections  of  200  yg  of  serotonin  were 
required  to  elicit  the  cardiopulmonary  effects  described  in 
other  species.   Apnea  or  shallow  respiration  occurred  at 
2.5-4  sec  and  cardiac  arrhythmias  at  3.5-5  sec.   In  addition 

Ifll 


Serial  No.  M-LBEB-CN-4 ,  page  2 

penile  erection  was  consistently  elicited  in  three  monkeys  at 
a  latency  of  about  7  sec,  a  finding  that  has  not  been  previously 
reported.   Bilateral  vagotomy  had  no  effect  on  this  manifestation. 
Tachyphylaxis  did  not  develop.   Injections  of  5-hydroxyindole 
acetic  acid  Cserotonin  precursor) ,  5-hydroxytryptophane  (serotonin 
metabolite),  or  tryptamine  (which,  like  serotonin,  excites 
visceral  receptors)  did  not  result  in  erection. 

Significance  to  Biomedical  Research  and  Program  of  the  Institute; 
This  study  has  shown  that  serotonin  produces  cardiopulmonary 
effects  in  the  monkey  that  are  similar  to  those  described  for 
other  species.   It  also  appears  to  be  the  first  time  that  penile 
erection  has  been  observed  following  the  administration  of 
serotonin,  a  finding  that  invites  further  investigation  in 
regard  to  the  disputed  role  of  parachlorophenylalanine  (a 
serotonin  depletor)  in  sexual  arousal  of  animals  and  man. 

Proposed  Course  of  the  Project:   To  be  concluded  with  the 
publication  of  a  short  report. 

Honors  and  Awards :   None 

Publications:   None 


iH2 


Serial  No.  M-LBEB-CN-5 

1.  Laboratory  of  Brain 

Evolution  and  Behavior 

2.  Section  on  Comparative 

Neurophysiology  and  Behavior 

3.  Poolesville,  Maryland 


PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   ECG  changes  and  myocardial  myocytolysis 
following  vagal  stimulation  in  awake, 
sitting   squirrel  monkey  (Saimiri  sciureus) . 

Previous  Serial  Number:   None 

Principal  Investigators:   David  S.  Bachman,  Anton  M.  Allen, 

and  Paul  D.  MacLean 

Other  Investigators:   None 

Cooperating  Units:   Veterinary  Resources  Branch 

Man  Years 

Total:  0.3 

Professional:   0.2 
Other:  0.1 

Project  Description: 

Objectives:   To  call  attention  to  a  case  that  implicates  the 
parasympathetic  nervous  system  in  the  pathogenesis  of  myocardial 
arrhythmias  and  necrosis. 

Methods  Employed:   The  observations  to  be  described  were  made 
during  the  course  of  a  microelectrode  study  of  the  influence 
of  vagal  volleys  on  unit  activity  of  the  cingulate  gyrus  (see 
M-LBEB-CN-2) . 

Major  Findings:   In  one  monkey  (No. 742)  the  left  vagus  nerve 
was  unintentionally  stimulated  for  4  minutes  with  0.3  msec 
negative  constant-current  pulses  of  1  ma  at  10  per  sec.   Pre- 
mature ventricular  contractions  and  episodes  of  bigeminy  began 
during  stimulation  and  continued  for  one  and  one-half  hours. 
The  ECG  showed  changes  characteristic  of  myocardial  infarction. 
Death  occurred  15  days  later.   The  coronary  arteries  and 
myocardium  appeared  grossly  normal,  but  the  histological 
examination  revealed  a  focal  myocytolysis  in  the  region  of  the 
apex. 

hl3 


Serial  No.  M-LBEB-CN-S ,  page  2 


Significance  to  Biomedical  Research  and  Program  of  the  Institute; 
The  significance  of  the  present  findings  is  to  be  considered  in 
the  light  of  increasing  clinical  evidence  that  in  a  sizeable 
percentage  of  patients  dying  from  acute  ischemic  heart  disease 
(Roberts  and  Buja)  there  may  be  no  coronary  arterial  thrombosis 
or  infarction.   It  has  been  shown  in  cats  that  vagal  stimulation 
after  the  exclusion  of  sympathetic  factors  may  result  in 
myocytolysis .   These  considerations  also  raise  the  question  of 
the  role  of  vagally  induced  arrhythmias  in  other  conditions  of 
unknown  etiology  such  as  sudden  death  in  infancy  ("crib  death") 
and  S-T  and  T-wave  changes  in  young  healthy  adults  with  normal 
coronary  arteries  demonstrated  by  arteriography.   Pending 
further  research,  it  would  be  worth  considering  the  advisability 
of  prophylactic  atropinization  in  individuals  subject  to  risk 
from  vagal  activation. 

Proposed  Course  of  the  Project:   To  be  concluded  with  the 
publication  of  a  short  case  report. 

Honors  and  Awards:   None 

Publications:   None 


i^l^ 


Serial  No.    M-LBEB-CN-6 

1.  Laboratory  of   Brain 

Evolution  and  Behavior 

2.  Section  on  Comparative 

Neurophysiology   and  Behavior 

3.  Poolesville,  Maryland 

PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   Transsynaptic  cellular  degeneration  following 
vagal  nerve  section  in  the  newborn  rabbit. 

Previous  Serial  Number:   None 

Principal  Investigators:   David  S.  Bachman 

Other  Investigators :   None 

Cooperating  Units :   None 

Man  Years 

Total:  0.4 
Professional:  0.1 
Other:        0.3 

Project  Description: 

Objectives :   This  anatomical  study  is  undertaken  in  conjunction 
with  the  microelectrode  investigation  of  the  central  projections 
of  the  vagus  nerve.   It  uses  Gudden's  method  in  an  attempt  to 
reveal  supramedullary  structures  belonging  to  an  ascending  vagal 
system. 

Methods  Employed :   Twenty-seven  newborn  rabbits  from  four 
litters  were  operated  at  less  than  24  hours  of  age.   Eleven 
received  unilateral  cervical  vagotomies,  3  were  sham  operated 
controls ,  and  the  remainder  had  bilateral  vagotomies  in  one 
or  in  two  stages.   Surviving  animals  were  sacrificed  at  60  days 
of  age  by  perfusion  through  the  heart. 

Major  Findings;  Section  of  one  vagus  nerve  results  in  total 
unilateral  disappearance  of  the  dorsal  vagal  nucleus  and  the 
nucleus  solitarius.  Preliminary  findings  suggest  an  ipsilateral 
decrease  of  the  cells  in  the  tegmental  nucleus  of  Gudden  and 
the  mammillary  nucleus,  but  no  apparent  changes  in  the  locus 
caeruleus. 


iH5 


Serial  No.  M-LBEB-CN-6,  page  2 

Bilateral  vagotomy  proved  to  be  incompatible  with  prolonged 
life;  the  longest  survivor  died  ten  days  after  section  of  the 
second  vagus  nerve.   The  histological  picture  in  this  case  added 
no  new  information. 

Significance  to  Biomedical  Research  and  Program  of  the  Institute: 
There  are  no  previous  reports  in  which  Gudden's  method  was  used 
in  an  attempt  to  reveal  supramedullary  connections  of  the  vagus 
nerve . 

Proposed  Course  of  the  Project:   To  be  concluded. 

Honors  and  Awards :   None 

Publications:   None 


kl6 


Serial  No.  M-LBEB-CN-7 

1 .  Laboratory  of  Brain 

Evolution  and  Behavior 

2.  Section  on  Comparative 

Neurophysiology  and  Behavior 

3.  Poolesville,  Maryland 


PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   Exploratory  study  on  actions  of  biogenic  amines 
in  squirrel  monkeys . 

Previous  Serial  Number:   M-NP-LI-49 

Principal  Investigators:   Paul  D.  MacLean  and  Robert  E.  Gelhard 

Other  Investigators:   Lorenz  K.-Y.  Ng  and  David  M.  Jacobowitz 

Cooperating  Units:   Laboratory  of  Clinical  Science 

National  Institute  of  Mental  Health 

Man  Years 

Total:  0.5 
Professional:  0.1 
Other:         0.4 

Project  Description: 

Objectives :   In  connection  with  this  Section's  investigation  of 
the  functions  of  the  corpus  striatum,  two  questions  are  of 
primary  interest  in  regard  to  dopaminergic  mechanisms  of  the 
corpus  striatum:  CD  Is  it  possible  to  induce  dyskinesias  in 
the  monkey  by  depositing  6-hydroxydopamine  (6-OHDA)  in 
respective  parts  of  the  corpus  striatum  and  then  challenging 
with  L-dopa  or  apomorphine?   (2)  Is  it  possible  by  this  method 
to  produce  damage  of  the  dopaminergic  terminals  throughout  the 
striatum? 

Methods  Employed:   Stereotaxic  deposition  of  solid  substances 
m  the  brain  is  accomplished  by  MacLean's  method  (1957).   This 
method  avoids  the  complication  of  reflux  of  chemicals  into  the 
entricular  system  that  occurs  with  injections  of  solutions. 
"itrol  observations  are  provided  by  depositing  the  substance 
ally  sucrose)  used  to  seal  the  tip  of  the  cannula. 


kll 


Serial  No.  M-LBEB-CN-7,  page  2 

Major  Findings;   Last  year's  report  (M-NP-LI-49)  described  four 
animals  that  received  cerebral  injections  of  6-OHDA  but  developed 
no  dyskinesias  unless  they  v/ere  challenged  by  intraperitoneal 
doses  of  L-dopa  or  by  a  single  subcutaneous  dose  of  apomorphine. 
It  has  since  been  shown  in  two  animals  (No.  811  and  No.  815)  in 
which  6-OHDA  was  applied  to  the  caudate  or  putamen  that  the  same 
kind  of  dyskinesias  could  be  elicited  by  the  challenging  with 
apomorphine  one  year  later. 

One  animal  (No. 8  39)  was  especially  prepared  for  fluorescent 
study  of  the  volume  of  striatal  tissue  affected  by  the  deposit 
of  6-OHDA  at  two  central  sites  in  the  right  putamen  and  caudate. 
The  unoperated  left  side  served  as  the  control.   Immediately 
surrounding  the  site  of  deposit  of  6 -hydroxy dopamine  powder  there 
is  a  marked  vascular  hyperplasia  and  infiltration  of  glia  cells. 
In  frontal  sections  there  was  a  loss  of  fluorescence  extending 
to  the  margins  of  each  structure.   The  anterior-posterior  loss 
of  fluorescence  extended  about  4  mm  on  the  experimental  side. 
Brightly  fluorescent,  beaded  fibers  were  seen  fanning  out  through 
the  globus  pallidus  while  others  formed  small  fasciculi  in  the 
ventromedial  part  of  the  internal  capsule  running  in  the  direc- 
tion of  the  caudate  nucleus.   These  fibers  appeared  to  stem  from 
the  ansa  lenticularis  and  were  inferred  to  be  part  of  the 
ascending  dopaminergic  system  from  the  substantia  nigra.   Another 
division  of  this  system  appeared  to  course  above  the  siibthalamic 
nucleus  before  fanning  out  in  the  globus  pallidus,  presumably 
terminating  in  the  putamen  and  corresponding  in  part  to  the 
projections  recently  described  by  Carpenter  and  Peter  by  means 
of  a  new  silver  technique. 

Significance  to  Biomedical  Research  and  Program  of  the 
Institute;   The  findings  would  be  compatible  with  the  clinical 
hypothesis  that  the  dyskinesias  seen  in  the  treatment  of 
Parkinsonism  with  L-dopa  may  be  the  result  of  a  hypersensitivity 
of  striatal  dopamine  receptors.   In  addition,  it  appears  to  be 
the  first  time  that  details  about  the  course  of  ascending  nigro- 
striatal  fibers  in  the  monkey  have  been  demonstrated  by  the 
fluorescent  technique  of  Falk  and  Hilarp.   The  course  is  somewhat 
different  from  that  described  for  the  rat. 

Proposed  Course  of  the  Project;   To  be  continued. 

Honors  and  Awards: 

Invitation  to  present  a  paper  at  the  Centennial  Symposium 
on  Huntington's  Chorea,  Columbus,  Ohio,  March  26-28,  1972, 
Ng,  L.K.Y.,  Gelhard,  R.E.,  Chase,  T.N. ,  andMacLean,  P.D.: 
"Drug-Induced  Dyskinesia  in  Monkeys;  A  Pharmacologic  Model 
Employing  6-Hydroxydopamine . " 


1H8 


Serial  No.  M-LBEB-CN-7,  page  3 


Publications; 


Ng,  L.K.Y.,  Gelhard,  R.E.,  Chase,  T.N. ,  and  MacLean,  P.D.; 
Drug-induced  dyskinesia  in  monkeys:  A  pharmacologic  model 
employing  6-hydroxydopamine .   In:  Barbeau,  A.,  Chase,  T.N. 
and  Paulson,  G.W.  (Eds.),  Huntington's  Chorea,  New  York, 
Raven  Press,  (in  press). 


I 


1»-19 


Serial  No.  M-LBEB-CN-8 

1.  Laboratory  of  Brain 

Evolution  and  Behavior 

2.  Section  on  Comparative 

Neurophysiology  and  Behavior 

3.  Poolesville,  Maryland 

PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   Neural  substrate  of  olfaction  in  the  rat 

Previous  Serial  Number:  M-NP-LI-50 

Principal  Investigators:   Burton  M.  Slotnick 

Other  Investigators:   Robert  Gelhard 

Cooperating  Units:   None 

Man  Years 

Total:  1.7 

Professional:   0.6 
Other:         1.1 

Project  Description: 

Objectives :  Olfactory  cues  are  of  critical  importance  for  a 
variety  of  species-specific  behaviors  but  knowledge  of  the  under- 
lying neural  mechanisms  has  advanced  slowly  because  of  special 
technical  problems.   The  present  project  takes  advantage  of  an 
improved  technique  described  in  last  year's  report  (M-NP-LI-50), 
to  test  the  effect  of  bilateral  section  of  the  lateral  olfactory 
tract  on  the  retention  and  acquisition  of  an  olfactory  discrim- 
ination task. 

Methods  Employed:   Rats  were  trained  in  a  wind-tunnel  olfactometer 
to  detect  the  presence  of  a  1  sec  odor  sample  of  dilute  amyl 
acetate.   The  stimulus  strength  was  calculated  to  be  2.5  -  3.5 
orders  of  magnitude  above  the  olfactory  detection  threshold  and 
1  order  of  magnitude  below  the  trigeminal  threshold.   Following 
extensive  overtraining  and  determination  of  detection  threshold, 
the  lateral  olfactory  tract  was  exposed  bilaterally  and  sectioned 
in  six  rats  at  the  level  of  the  olfactory  peduncle.   A  small 
segment  of  cortex  dorsal  to  the  olfactory  tract  was  ablated 
bilaterally  in  3  controls.   Following  postoperative  recovery 
animals  were  retested  for  retention  and  then  given  further  train- 
ing on  2-odor  discrimination  problems.   Postoperative  testing  was 

ij-21 


Serial  No.  M-LBEB-CN-8,  page  2 

terminated  if  an  animal  showed  no  evidence  of  acquisition  in 
500  trials. 

Major  Findings:   Postoperatively,  controls  showed  perfect  or 
near  perfect  retention  and  no  change  in  detection  threshold. 
Experimental  rats  had  no  retention  of  the  detection  problem  but 
were  able  to  acquire  the  discrimination  following  extensive 
retraining.   Little  or  no  change  in  detection  threshold  was 
observed.   In  subsequent  2-odor  discrimination  tasks  controls 
showed  rapid  learning;  experimental  animals  failed  to  learn 
or  showed  marked  retardation  in  acquisition. 

Significance  to  Biomedical  Research  and  Program  of  the 
Institute:   The  present  study  is  the  first  to  provide  behavioral 
observations  on  the  functional  role  of  the  lateral  olfactory 
tract  in  olfactory  detection  and  discrimination.   On  the  basis 
of  the  preliminary  histological  analysis  it  appears  that  bilateral 
transaction  of  this  tract  eliminates  the  retention  of  a  highly 
over learned  and  simple  odor  detection  problem,  but  that  relearning 
is  eventually  possible.    The  findings  on  the  2-odor  discrimination 
problem  suggest  that  remaining  olfactory  function  may  be  limited 
to  detection  of  odors . 

Proposed  Course  of  the  Project:   To  be  continued. 

Honors  and  Awards : 

Invited  Lecture;  "Olfactory  Reversal  Learning  Sets  in 
Rats."  Annual  Meeting  of  the  Pavlovian  Society  of  North 
America,  Charlottesville,  Va. ,  October  8,  1971. 

Invited  Lecture:  "The  Limbic  System. "  Fourth  Summer 
Workshop  in  Neuropharmacology,  Vanderbilt  University, 
Nashville,  Tenn. ,  June  14,  1972. 

Publications:   None 


ij-22 


Serial  No.    M-LBEB-CN-9 

1.  Laboratory  of   Brain 

Evolution  and  Behavior 

2.  Section  on  Comparative 

Neurophysiology  and  Behavior 

3.  Poolesville,  Maryland 


PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   Taste  and  location  aversion  in  bait  shyness. 

Previous  Serial  Number:   None 

Principal  Investigators:   Burton  M.  Slotnick 

Other  Investigators :   None 

Cooperating  Units:   Section  on  Behavioral  Systems,  LBEB 

Man  Years 

Total:  0.2 
Professional:  0.1 
Other:         0.1  \ 

Project  Description: 

Objectives:   Reports  on  "bait  shyness"  suggest  that  taste,  and 
possibly  olfactory  cues  are  the  sole  conditioning  factors.   Before 
further  investigation  of  the  role  of  olfaction  (see  M-NP-LI-50) 
in  bait  shyness,,,  it  is  desirable  to  learn  whether  or  not  rats  will 
avoid  a  place  where  illness  was  precipitated  following  sampling 
of  a  novel  taste  solution.   In  other  words,  does  "location"  also 
serve  as  a  conditional  stimulus? 

Methods  Employed:   Nine  adult  albino  rats  were  maintained  in  a 
9'x9'  Calhoun  environment.   Three  one-liter  water  bottles 
(designated  as  A,  B,  and  C)  were  placed  in  distinctive  locations. 
Bottles  A  and  B  were  adjacent  to  one  another  at  one  end  of  the 
room.   Bottle  C  was  located  8  feet  away  at  the  opposite  end  of 
the  room.   Water  intake  was  recorded  for  10  days  prior  to  a 
saccharine-apomorphine  conditioning  trial.   Twenty-four  hours 
prior  to  treatment  all  bottles  were  removed.   On  the  treatment 
day  the  preferred  water  bottle  (bottle  A)  was  filled  with  a  0.1% 
sodium  saccharine  solution  and  replaced  in  the  room  for  20  minutes, 
After  all  animals  had  tasted  the  solution,  they  were  given  a 


Serial  No.  M-LBEB-CN-9 ,  page  2 

10  mg/kg  intraperitoneal  injection  of  apomorphine  hydrochloride. 
Bottles  filled  with  water  were  replaced  in  the  three  locations 
and  intake  was  recorded  for  the  next  four  days.   On  the  fifth 
day,  bottle  A  was  filled  with  a  0.1%  sodiiim  saccharine  solution. 

Major  Findings:   if  rats  avoid  a  place  where  illness  was 
precipitated  by  apomorphine,  there  should  be  a  change  in  preference 
among  the  3  bottles  following  the  treatment  session.   As  shown  in 
Table  1,  however,  both  prior  to  and  following  treatment  the 
colony  showed  a  consistent  preference  for  water  in  bottle  A. 
That  apomorphine  treatment  was  an  effective  conditioning  agent 
in  producing  the  bait-shyness  effect  is  evident  from  the  dramatic 
shift  in  preference  for  bottle  B  when  the  saccharine  solution  was 
offered  in  bottle  A  on  the  last  test  day. 


Table 

J^. 

Percent  of 

Total  Intake 

Bottle  A 

Bottle  B 

Bottle  C 

Pre- treatment 
(10  days) 

Median 

53 

33 

14.5 

Post- treatment 

Range 

48-72 

20-47 

05-16 

"location  aversion' 

test 

Median 

70 

17 

15 

C4  days) 

Range 

63-77 

15-18 

6-19 

Post- treatment 

"taste  aversion"test  7         86 

(1  day) 


Significance  to  Biomedical  Research  and  Program  of  the 
Institute;   Studies  by  Garcia  suggest  that  "bait  shyness" 
represents  a  unique  form  of  learning  in  which  tastes  (and 
possibly  odors),  but  not  other  sensory  cues,  acquire  aversive 
properties  as  the  result  of  an  illness  following  ingestion  of 
a  novel  substance.   The  present  results  show,  in  addition,  the 
location  where  a  substance  is  ingested  does  not  play  a  role  in 
the  development  of  bait  shyness. 

Proposed  Course  of  the  Project:   Terminated. 

Honors  and  Awards :   None 

Publications:   None 


k2k 


Serial  No.  M-LBEB-CN-10 

1.  Laboratory  of  Brain 

Evolution  and  Behavior 

2.  Section  on  Comparative 

Neurophysiology  and  Behavior 

3.  Poolesville,  Maryland 


PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 


Project  Title:   Aggression  and  defense  in  rats  with  septal 
lesions. 

Previous  Serial  Number:   None 

Principal  Investigator:   Burton  M.  Slotnick 

Other  Investigators:   None 

Cooperating  Units :   None 

Man  Years 


Total: 

0.2 

Professional: 

0.1 

Other: 

0.1 

Project  Description: 

Objectives:   Docile  white  rats  show  a  syndrome  of  irritability 
following  septal  lesions.   This  finding,  together  with  assess- 
ments based  on  emotional  rating  scales  and  artificially  induced 
fighting,  has  led  to  the  hypothesis  that  the  septtim  is  implicated 
in  the  control  of  aggressive  behavior.   In  an  attempt  to  obtain 
a  more  adequate  test  of  this  hypothesis,  the  present  study 
investigates  the  effects  of  septal  lesions  on  intraspecific 
aggression  in  animals  living  in  a  seminatural  environment. 

Methods  Employed:  Nine  60-day-old  rats  were  introduced  into  a 
9'x9'  Calhoun  rat  universe.   Individual  rats  were  identified  by 
pellage  markings .   Observations  were  made  from  a  ceiling  window 
and  specific  behaviors  were  systematically  scored.   After  social 
organization  in  the  colony  stabilized,  a  control  or  experimental 
animal  was  introduced,  and  the  social  interactions  were  observed 
for  a  period  of  30  minutes.   No  more  than  one  session  was 
conducted  in  one  week.   , 

Major  Findings:   To  date,  2  normal  controls,  1  sham-lesioned 
control,  and  4  septal-lesioned  rats  have  been  tested.   Two  to 

k2^ 


Serial  No.  M-LBEB-CN-10 ,  page  2 

five  minutes  after  introduction  each  of  the  controls  was  attacked 
by  one  of  the  colony  animals ,  with  further  attacks  following  at 
frequent  intervals.   In  response,  the  attacked  animal  either  ran 
away  or  adopted  a  submissive  posture.   Submissiveness  usually 
inhibited  further  aggression,  whereas  running  away  appeared  to 
invite  further  attack.'  In  the  latter  half  of  the  test  period, 
each  control  remained  in  an  upright,  submissive  posture  for  many 
consecutive  minutes.   After  removal  from  the  colony  controls  were 
found  to  have  deep  lacerations  of  the  skin  about  the  head  and 
rump. 

In  contrast  to  the  controls,  the  septal-lesioned  animals 
explored  freely  and  seemed  uninhibited  when  introduced  into  the 
colony.   They  reciprocated  any  investigatory  approaches  and  if 
treated  too  roughly,  would  adopt  an  upright  aggressive  posture. 
If  attacked,  they  vigorously  defended  themselves  and  thereafter 
turned  back  any  approaches  by  assuming  an  upright  threatening 
posture. 

Significance  to  Biomedical  Research  and  Program  of  the 
Institute;   An  understanding  of  the  functional  role  of  the  limbic 
system  in  the  social  organizatbn  and  natural  history  of  a  species 
requires  experiments  employing  natural  or  semi-natural  environ- 
ments that  allow  full  expression  of  species-specific  modes  of 
behavior.   By  combining  approaches  used  in  ecology,  ethology,  and 
neuropsychology  the  present  study  has,  in  its  initial  phase, 
given  strength  to  the  hypothesis  that  the  septum  is  part  of  a 
system  involved  in  the  control  of  aggressive  behavior. 

Proposed  Course  of  the  Project:   To  be  continued. 

Honors  and  Awards:   None 

Publications;   None 


^26 


Serial  No.  M-LBEB-CN-10 


1.  Laboratory  of  Brain 

Evolution  and  Behavior 

2 .  Section  on  Comparative 

Neurophysiology  and  Behavior 

3.  Poolesville,  Maryland 


PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   Aggression  and  defense  in  rats  with  septal 
lesions . 

Previous  Serial  Number:   None 

Principal  Investigator:   Burton  M.  Slotnick 

Other  Investigators:   None 

Cooperating  Units :   None 

Man  Years 

Total:  0.2 

Professional:   0.1 
Other:  0.1 

Project  Description: 

Objectives :   Docile  white  rats  show  a  syndrome  of  irritability 
following  septal  lesions.   This  finding,  together  with  assess- 
ments based  on  emotional  rating  scales  and  artificially  induced 
fighting,  has  led  to  the  hypothesis  that  the  septum  is  implicated 
in  the  control  of  aggressive  behavior.   In  an  attempt  to  obtain 
a  more  adequate  test  of  this  hypothesis,  the  present  study 
investigates  the  effects  of  septal  lesions  on  intraspecific 
aggression  in  animals  living  in  a  seminatural  environment. 

Methods  Employed:  Nine  60-day-old  rats  were  introduced  into  a 
9'x9'  Calhoun  rat  universe.   Individual  rats  were  identified  by 
pellage  markings .   Observations  were  made  from  a  ceiling  window 
and  specific  behaviors  were  systematically  scored.   After  social 
organization  in  the  colony  stabilized,  a  control  or  experimental 
animal  was  introduced,  and  the  social  interactions  were  observed 
for  a  period  of  30  minutes.   No  more  than  one  session  was 
conducted  in  one  week.   , 

Major  Findings:   To  date,  2  normal  controls,  1  sham-lesioned 
control,  and  4  septal-lesioned  rats  have  been  tested.   Two  to 

J+25 


Serial  No.  M-LBEB-CN-10,  page  2 

five  minutes  after  introduction  each  of  the  controls  was  attacked 
by  one  of  the  colony  animals,  with  further  attacks  following  at 
frequent  intervals.   In  response,  the  attacked  animal  either  ran 
away  or  adopted  a  submissive  posture.   Submissiveness  usually 
inhibited  further  aggression,  whereas  running  away  appeared  to 
invite  further  attack.'  In  the  latter  half  of  the  test  period, 
each  control  remained  in  an  upright,  submissive  posture  for  many 
consecutive  minutes.   After  removal  from  the  colony  controls  were 
found  to  have  deep  lacerations  of  the  skin  about  the  head  and 
rump. 

In  contrast  to  the  controls,  the  septal-lesioned  animals 
explored  freely  and  seemed  uninhibited  when  introduced  into  the 
colony.   They  reciprocated  any  investigatory  approaches  and  if 
treated  too  roughly,  would  adopt  an  upright  aggressive  posture. 
If  attacked,  they  vigorously  defended  themselves  and  thereafter 
turned  back  any  approaches  by  assuming  an  upright  threatening 
posture. 

Significance  to  Biomedical  Research  and  Program  of  the 
Institute:   An  understanding  of  the  functional  role  of  the  limbic 
system  in  the  social  organizatbn  and  natural  history  of  a  species 
requires  experiments  employing  natural  or  semi-natural  environ- 
ments that  allow  full  expression  of  species-specific  modes  of 
behavior.   By  combining  approaches  used  in  ecology,  ethology,  and 
neuropsychology  the  present  study  has,  in  its  initial  phase, 
given  strength  to  the  hypothesis  that  the  septum  is  part  of  a 
system  involved  in  the  control  of  aggressive  behavior. 

Proposed  Course  of  the  Project:   To  be  continued. 

Honors  and  Awards:   None 

Publications :   None 


k2G 


Serial  No.  M-LBEB-CN-11 

1.  Laboratory  of  Brain  Evolution 

and  Behavior 

2 .  Section  on  Comparative 

Neurophysiology  and  Behavior 

3.  Poolesville,  Maryland 

PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   Sensory  control  of  fighting  in  mice 

Previous  Serial  Niomber:   None 

Principal  Investigators:   Burton  M.  Slotnick  and  Burr  Eichelman 

Other  Investigators:   None 

Cooperating  Units:   Laboratory  of  Chemical  Psychobiology 
National  Institute  of  Mental  Health 

Man  Years 

Total:  0.2 
Professional:  0.1 
Other:         0.1 

Project  Description: 

Objectives :   According  to  previous  reports  mice  rendered  anosmic 
by  bilateral  bulbectomy  do  not  fight.   In  rats,  on  the  contrary, 
it  has  been  shown  by  Eichelman  that  bulbectomy  has  little  or  no 
effect  on  shock-induced  attack  behavior,  whereas  removal  of  the 
vibrissae  dramatically  decreases  the  incidence  of  fighting.   The 
present  project  plans  first  to  test  the  effects  of  removing  the 
vibrissae  in  mice  and  then  examine  the  influence  of  other  sensory 
inputs  on  fighting  behavior. 

Methods  Employed:   Twenty  male  albino  mice  were  isolated  following 
weaning.   Three  months  later  they  were  paired  according  to  weight 
and  placed  in  a  small  plastic  cage  in  which  their  time  spent 
fighting  during  a  6-minute  period  was  scored  by  two  observers 
using  an  event  recorder.   The  ten  pairs  of  animals  were  then 
divided  into  2  equal  groups  matched  on  the  basis  of  fighting 
scores.   Members  of  the  experimental  group  were  anesthetized  with 
ether  and  the  vibrissae  shaved  off.   Animals  in  the  control  group 
were  similarly  treated  except  that  part  of  the  lumbar,  rather 
than  the  facial,  region  was  shaved.   Four  days  later  each  pair 
was  given  a  second  fighting  match. 


L 


it-2T 


Serial  No.  M-LBEB-CN-11 ,  page  2 

Major  Findings;   As  shown  in  Table  1,  removal  of  the  vibrissae 
was  without  effect  on  fighting  behavior. 

Table  1 

Time  spent  fighting  (in  seconds) 

First  Fight   Second  Fight 
Median  55  46 

Range  33-104         31-61 


Controls 


Experimental 


Median 
Range 


62 
44-112 


42 
31-60 


Proposed  Course  of  the  Project:  Additional  experiments  are 
planned  to  investigate  the  role  of  vision  and  olfaction  on 
fighting  behavior. 

Significance  to  Biomedical  Research  and  Program  of  the 
Institute;   Recent  studies  have  indicated  that  the  behavioral 
effects  of  destroying  comparable  brain  structures  are  species- 
dependent.   The  present  investigation  extends  these  observations 
by  demonstrating  that  the  same  principle  may  apply  with  respect 
to  receptor  mechanisms.   Findings  of  this  kind  emphasize  the 
need  for  a  comparative  approach  in  the  study  of  the  neural  basis 
of  similar  forms  of  unlearned  behaviors  in  different  species. 

Honors  and  Awards; 

Invited  Lecturer;   "Murine  Isolation-induced  Aggression: 
Parameters  and  Sequential  Analysis."   Seminars  on  Animal 
Aggression,  sponsored  by  the  Laboratory  of  Clinical 
Psychobiology,  NIMH,  February  23,  1972. 

Pxoblications: 

Slotnick,  B.M.  and  McMullen,  M. :  Intraspecif ic  fighting 
in  albino  mice  with  septal  forebrain  lesions.   Physiology 
and  Behavior,  1972,  8^:  333-344. 

Slotnick,  B.M.:  Stereotaxic  surgical  techniques  for  the 
mouse.   Physiology  and  Behavior,  1972,  8^:  139-142. 

Slotnick,  B.M.  and  Lidsky,  A.:  Effects  of  posttrial  limbic 
stimulation  on  retention  of  a  one-trial  passive  avoidance 
response.   J . Comp . Physiol . Psychol .  ,  1971,  76^:  337-348. 


k2Q 


Serial  No.  M-LBEB-CN-12 

1.  Laboratory  of  Brain 

Evolution  and  Behavior 

2 .  Section  on  Comparative 

Neurophysiology  and  Behavior 

3.  Poolesville,  Maryland 


PHS-HSMHA-Nir4H 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   Reinforcing  properties  of  nesting  material 
during  gestation  in  rats 

Previous  Serial  Number:   None 

Principal  Investigators:   Burton  M.  Slotnick 

Other  Investigators :  None 

Cooperating  Units :   None 

Man  Years 

Total :  0.2 

Professional:   0.1 
Other:         0.1 

Project  Description: 

Objectives :   The  present  experiment  obtains  a  measure  of  the 
reinforcing  value  of  nesting  material  during  gestation  in  rats. 

Methods :   Adult  pregnant  rats  are  individually  housed  in  cages 
equipped  with  a  bar  and  a  device  to  dispense  50  cm  long  strips 
of  1  cm  wide  paper  tape.   Both  progressive  and  fixed  ratio 
reinforcement  schedules  are  used.   Nesting  material  is  removed 
and  total  responses  recorded  each  day. 

Major  Findings:   On  each  of  the  first  20  days  of  gestation  the 
three  animals  tested  thus  far  earned  approximately  50  paper 
strips  which  were  used  to  build  a  flat  sleeping  nest. 

Twelve  to  48  hours  prior  to  parturition  each  animal  showed 
a  200-400%  increase  in  responding  and  built  a  compact  maternal- 
type  nest  with  walls  and  a  floor.   Working  for  nesting  material 
continued  at  high  levels  for  the  first  3-4  days  postpartum  after 
which  responding  decreased  gradually  to  early  prepartum  levels. 


it29 


Serial  No.  M-LBEB-CN-12 ,  page  2 

Significance  to  Biomedical  Research  and  Program  of  the  Institute; 
The  sudden  increase  in  nesting  behavior  prior  to  parturition 
suggests  that  the  operant  technique  employed  is  sensitive  to, 
and  probably  reflects,  physiological  changes  determining  motiva- 
tional level  for  nesting  behavior  during  the  course  of  pregnancy 
in  the  rat.   The  results  suggest  that  operant  techniques  would 
be  useful  in  obtaining  a  measure  of  motivation  in  other  forms  of 
species- typical  behavior. 

Proposed  Course  of  the  Project:   To  be  continued. 

Honors  and  Awards : 

Invited  Lecture; "On  the  Onset  of  Nesting  and  Other  Maternal 
Behaviors  in  Rats  Prior  to  Parturition."   Eastern  Regional 
Conference  on  Reproductive  Behavior.   Tulane  University, 
June  7-10,  1972. 

Publications :   None 


^30 


Serial  No.  M-LBEB-CN-13 

1.  Laboratory  of  Brain 

Evolution  and  Behavior 

2.  Section  on  Comparative 

Neurophysiology  and  Behavior 

3.  Poolesville,  Maryland 

PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   Functions  of  avian  paleostriatal  complex. 

I.  Question  of  its  role  in  imitative  behavior. 

Previous  Serial  Number:   None 

Principal  Investigators:   Paul  D.  MacLean 

Other  Investigators:   Robert  Gelhard 

Cooperating  Units :   None 

Man  Years 

Total:  0.4 
Professional:  0.1 
Other:         0.3 

Project  Description: 

Objectives:   In  evolution  a  major  part  of  the  forebrain  in  birds 
and  in  mammals  retains  the  features  of  the  reptilian  paleo- 
striatum.  Despite  extensive  investigation,  there  is  little 
definite  knowledge  about  the  functions  of  this  large  evolutionary 
development.   In  birds,  the  paleostriatal  complex  lies  ventral 
to  the  dorsal  medullary  lamina  and  includes  the  Paleostriatum 
augmentatum  et  primitivum.   The  selective  staining  of  P. 
augmentatiim  for  cholinesterase  and  its  fluorescence  because  of 
the  presence  of  dopamine,  support  the  inference  that  it 
corresponds  to  the  corpus  striatum  of  mammals .   Because  of  the 
detailed  information  about  innate  behavior  in  birds,  avian  forms 
will  be  used  to  investigate  the  role  of  the  paleostriatal 
complex  in  species-specific  and  propendent  forms  of  behavior, 
and  in  endocrine  functions. 

Methods  Employed:   Because  of  the  necessity    to  avoid  injury 
to  overlying  and  surrounding  structures,  a  method  is  required 
for  selectively  destroying  the  paleostriatal  complex.   The 
first  series  of  experiments  has  involved  an  attempt  to  interfere 
with  the  special  blood  supply  to  these  structures  by  surgical 
cauterization  of  the  lateral  striate  vessels.   A  second  approach 
has  attempted  to  produce  selective  damage  by  carbon  monoxide 

J^31 


Serial  No.  M-LBEB-CN-13,  page  2 

poisoning.   Tom  turkeys  are  used  in  the  pilot  studies  because 
the  group  gobbling  response  (G.G.R.)  provides  a  paradigm  for 
investigations  on  imitative  behavior. 

Major  Findings; 

1.  Carbon  monoxide  poisoning.   The  production  of  a  comatose 
state  by  a  series  of  five  treatments  with  carbon  monoxide 
resulted  no  lasting  change  in  the  G.G.R.  or  in  detectable 
damage  of  cerebral  neurons. 

2.  Occlusion  of  lateral  striate  vessels.   In  three  torn 
turkeys  the  vessels  in  the  region  of  the  perforating  lateral 
striate  arteries  were  cauterized  on  one  side.   Unexpectedly, 
this  one-sided  operation  resulted  in  a  deterioration  of  the 
G.G.R.  and  in  other  behavioral  changes  characterized  by  the 
tendency  of  the  animal  to  linger  on  the  fringe  of  the  flock 

and  to  separate  inappropriately  from  the  flock  under  threatening 
conditions . 

The  histological  examination  of  the  brains  has  not  yet  been 
completed.   In  one  case  the  operation  successfully  destroyed 
the  paleostriatal  complex,  but  the  adjacent  ectostriatum  was 
also  involved. 

Significance  to  Biomedical  Research  and  Program  of  the  Institute; 
No  definitive  information  exists  regarding  neural  mechanisms 
of  imitative  behavior,  which  serves  to  maintain  group  identi- 
fication and  promote  group  survival.   The  incapacity  for 
natural  imitation  is  a  cardinal  feature  of  autistic  children. 
The  use  of  imitative  techniques  in  training  mentally  retarded 
children  has  long  been  recognized.   The  present  study  on  the 
imitative  gobbling  response  in  tom  turkeys  is  of  comparative 
interest  in  connection  with  the  investigation  of  neural 
mechanisms  of  imitative  behavior  in  the  monkey  (M-LBEB-CN-1) . 

Proposed  Course  of  the  Project;   To  be  continued. 

Honors  and  Awards ;   None 

Publications:   None 


J+32 


Serial  No.  M-LBEB-CN-14 

1.  Laboratory  of  Brain 

Evolution  and  Behavior 

2 .  Section  on  Comparative 

Neurophysiology  and  Behavior 

3.  Poolesville,  Maryland 


PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   Behavioral  effects  of  hippocampal  destruction 

in  the  Virginia  opossum  (Didelphis  virginiana) . 

Previous  Serial  Number:   None 

Principal  Investigators:   Paul  D.  MacLean 

Other  Investigators :   Robert  Gelhard 

Cooperating  Units : 

Man  Years 

Total:  0.2 
Professional:  0.1 
Other :        0.1 

Project  Description 

Objectives :   Although  the  hippocampus  (archicortical  component 
of  the  limbic  system)  has  been  implicated  in  emotional,  memory, 
visceromotor,  and  endocrine  functions,  no  definite  evidence 
exists  about  the  global  functions  of  this  structure.   The  present 
project  attempts  to  assess  the  effects  of  diffuse  hippocampal 
damage  in  the  opossum  on  behavior  requisite  for  survival  in  a 
quasi-natural  habitat.   The  opossum,  sometimes  referred  to  as  a 
living  fossil,  is  of  particular  behavioral  interest  because  it 
represents  a  primitive  mammalian  form  that  retains  certain 
behaviors  characteristic  of  reptiles. 

Methods  Employed:   Preliminary  to  the  proposed  studies,  it  is 
desirable  to  devise  a  non-surgical  method  that  will  diffusely 
damage  the  hippocampus  without  causing  injury  to  other  cerebral 
structures.   Scharrer  originally  reported  that  carbon  monoxide 
(CO)  poisoning  selectively  damages  the  hippocampus  in  opossums. 
Accordingly,  the  first  experiments  attempt  to  repeat  his 
findings. 


i+33 


Serial  No.  M~LBEB-CN-14 ,  page  2 

Major  Findings;   A  six  to  seven  minute  exposure  of  CO  typically 
resulted  in  a  seizure  characterized  by  tonic  extension  of  the 
extremities  and  loss  of  responsiveness,  following  which  artifi- 
cial respiration  was  usually  required  to  restore  breathing. 
Tonic-clonic  generalized  seizures  did  not  develop.   Regaining 
of  posture  and  locomotion  occurred  in  about  14  to  20  minutes. 
A  series  of  six  administrations  of  CO  at  intervals  of  three  to 
four  days  resulted  in  no  evident  lesions  in  the  hippocampus  or 
other  parts  of  the  brain. 

Significance  to  Biomedical  Research  and  Program  of  the  Institute; 
Some  pathological  studies  have  shown  that  sclerosis  of  the 
hippocampus  is  the  common  denominator  of  pathological  findings 
in  cases  of  psychomotor  epilepsy.   The  aura  experienced  in 
psychomotor  epilepsy  is  characterized  by  a  broad  spectrum  of 
vivid  emotional  feelings.   The  aura,  as  well  as  the  interictal 
symptomatology,  in  some  patients  may  have  psychotic  attributes. 
The  hippocampus  has  several  distinctive  chemical  features  that 
make  it  susceptible  to  the  action  of  neuropharmacological  agents. 
In  the  present  experiments  on  a  primitive  mammal  it  is  hoped  that 
basic  information  will  be  obtained  about  the  function  of  the 
hippocampus . 

Proposed  Course  of  the  Project;   As  a  next  step  in  attempting  to 
produce  diffuse  non-surgical  hippocampal  lesions,  opossums  will 
be  treated  with  3-acetylpyridine,  an  analogue  of  nicotinic  acid, 
which  was  previously  shown  in  this  Section  to  result  in  selective 
destruction  of  areas  CA3  and  CA4  of  the  hippocampus  in  mice 
(see  M-NP-LI-1,  1959). 

Honors  and  Awards ;   None 

Publications:   None 


ksk 


Serial  No.   M-LBEB-CB-1 

1.  Laboratory  of  Brain  Evolution 

and  Behavior 

2.  Section  on  Comparative  Biopsychology 

3.  Poole sville,  Md. 

PHS-HSMHA-IO]yH 

Individual  Project  Report 

July  1,  1971  through  Jime  30,  1972 

Project  Title:  Temporal  Organization  of  Feeding  Sequences  and  Sucking 
Behavior  in  Infant  Dogs 

Previous  Serial  Number:  Part  of  M-P-CB-(C)-1 

Principal  Investigator:  Walter  C.  Stanley 

Other  Investigators:  E.  Faye  Bacon  and  Leslie  Heiple 

Cooperating  Units:  None 

Man  Years 

Total:  1.63 
Professional:  .Ul 
Other:         1.22 

Project  Description: 

Objectives :  The  aim  of  this  project  is  to  increase  understanding  of  the 
temporal  organization  of  neonatal  behavior  by  studying  the  effects  of  envi- 
ronmental stimulation  and  internal  bodily  states  on  the  component  responses 
of  feeding  sequences  in  neonatal  dogs.   Prior  research  in  this  project  has 
demonstrated  the  powerful  effects  on  sucking  of  stimulus  parameters,  as 
nipple  resiliency  and  length,  stomach  fullness,  and  repeated  periods  of  daily 
food  deprivations.   This  year  we  resumed  analysis  of  operant  milk  reinforce- 
ment, using  computer-controlled  sucking-contingent  DRL  (Differential 
Reinforcement  of  Low  rate  of  sucking)  schedules  of  milk  delivery.   Five  years 
ago  we  demonstrated  that  DRL  schedules  of  milk  reinforcement  could  produce 
spaced  sucking,  but  the  effects,  except  for  one  subject,  were  typically  of 
brief  duration.   Since  I'esuming  the  I'esearch,  we  have  focussed  on  variables 
that  might  aid  neonatal  dogs  to  space  their  sucking  for  longer  periods  of 
time.   In  general,  we  introduced  variable.^  that  might  suppress  sucking,  at 
least  temporally,  and  thereby  set  additional  occasions  for  the  puppies  to 
receive  milk  contingent  on  spaced  sucking. 

Methc)ds  Employed:   Beafjle  dogs  ai'e  ti'ained  in  one  unit  of  the  compute r- 

cunti'Cjlled,  multiple-unit  automated  appai'atus  for  study  of  animal  infant 
behavior  (project  re])ort  M-P-CB-(c)-l4,  1971 )  •   In  Experiment  1,  four  7-17 

'lay  old  beagles  ;r'r>ceive(3  HO  training  sessions  and  one   subject,  iH  session::'.. 


ii35 


Serial  No.  M-LBEB-CB-1 
Page  2 

We  explored  the  sucking-suppressing  effects  of  omitting  milk  entirely  (extinc- 
tion procedure),  rendering  sucks  undetectable  (time-out  procedure),  and  delivering 
of  multiple  .1-ml.  sq.uirts  of  milk  (interference  procedure).   In  Experiment  2, 
four  7-12  day  old  beagles  were  run  for  36  sessions.  Two  started  training  on  a 
decreasing-amount,  multiple-milk  delivery  DEL  schedule,  such  that  three  squirts 
of  milk  were  contingent  on  a  suck  with  an  interresponse  time  of  .5  to  1.0 
seconds,  two  squirts,  were  contingent  on  sucks  with  times  of  1.0  to  1,5  seconds 
and  one  squirt  was  contingent  on  sucks  with  times  greater  than  1.5  seconds. 
In  contrast,  two  subjects  started  training  with  increasing-amount  multiple 
milk  deliveries.  Sucks  with  shorter  interresponse  times  (.5  to  1.0  second) 
being  followed  by  one  squirt,  intermediate  times  by  two  squirts  (l.O  to  1.5 
seconds),  and  longer  times  by  three  squirts  (greater  than  1.5  seconds).   In 
Experiment  3,  two  8-15  day  old  beagles  were  run  on  a  decreasing-amount  DRL 
schedule . 

Major  Findings:  Of  the  three  procedures  introduced  in  Experiment  1,  the  inter- 
ference procedure  based  on  multiple  squirts  of  milk  was  most  successful.  Indeed, 
one  of  the  five  subjects  spaced  its  sucks  on  two  successive  sessions  (28  and  29), 
on  the  average,  more  than  2  seconds  apart  and  obtained  milk  on  51'^  and  57'^  of 
its  sucks.   In  Exjjeriment  2,  markedly  spaced  sucking  was  acquired  by  one  subject, 
a  decreasing-amount  DRL  animal.  Its  peak  session  performance  came  on  the  third 
day  of  training.  Session  l8,  when  it  received  milk  on  99^  of  its  sucks  and  re- 
sponded at  a  rate  of  about  one  suck  per  6  seconds.  In  Experiment  3,  one  of  the 
two  subjects  run  on  the  decreasing-amount  DRL  schedule  also  acquired  highly 
spaced  sucking,  the  peak  session  performance  being  85^  reinforced  sucks,  about 
1  suck  per  5  seconds  on  Session  7-   In  Experiments  2  and  3 5  changed  reinforce- 
ment conditions  led  to  somewhat  faster  sucking,  but  not  to  true  high  rate 
sucking,  indicating  partial,  but  not  complete,  reversibility  of  the  learned 
spaced  sucking. 

Significance  to  Biomedical  Research  and  the  Program  of  the  Institute:  First, 
the  findings  demonstrate  the  powerful  effect  that  appropriate  scheduling  of  a 
reinforcer  can  have  on  such  highly  organized  behavior  as  neonatal  sucking. 
Second,  the  findings  are  theoretically  important  because  they  demonstrate 
that  the  same  commodity,  milk,  can  suppress  ("punish")  or  maintain  ("reinforce") 
behavior  depending  on  how  it  is  scheduled  in  relation  to  the  temporal  prop- 
erties of  ongoing  behavior.  The  demonstration  of  this  phenomenon  in  neonatal 
dogs  indicates  that  it  is  a  process  that  would  repay  careful  study  in  human 
neonates,  children,  and  adults.   It  may  be  one  mechanism  whereby  a  person's 
successes  and  rewards  paradoxically  suppress  rather  than  enhance  the  behavior 
which  leads  to  them. 

Proposed  Course  of  the  Project:  To  continue  to  study  sucking-contingent  DRL 

schedules  until  we  achieve  near  100^  success  in  training  neonatal  beagles  to 

space  their  sucks  or  can  account  for  individual  failures .  Project  will  ter- 
minate with  publication  of  findings. 


k36 


M-LBEB-CB-1 
Page  3 


Honors  and  Awards: 

Dr.  Walter  C.  Stanley: 

Accepted  invitation  to  tecome  member  of  Pavlovian  Society  of  America. 

Accepted  invitation  to  present  paper  on  the  organization  of  sucking 
behavior  at  Fourth  Symposium  on  Sensation  and  Perception. 

Publications : 

Stanley,  W.  C:  Perspectives  in  behavior  organization  and 
development  resulting  from  studies  of  feeding  behavior  in  infant 
dogs.   In  Bosma,  J.  F.  (Ed.):  Third  Symposium  on  Oral  Sensation 
and  Perception:  The  Mouth  of  the  Infant.   Springfield,  Thomas, 
Chapter  8,  in  press. 


437 


Serial  No.  M-LBEB-CB-2 

1.  Laboratory  of  Brain  Evolution 

and  Behavior 

2 .  Section  on  Comparative  Biopsychology 

3.  Poolesville,  Md. 


PHS-HSMHA-inMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 


Project  Title:  Behavioral  Effects  of  Response-Contingent  Intragastric 
Versus  Intraoral  Milk  Injection  in  Infant  Beagle  Dogs 

Previous  Serial  Number:  Part  of  M-P-CB-(C)-1 

Principal  Investigators:  Walter  C.  Stanley 

Other  Investigators:  E.  Faye  Bacon 

Cooperating  Units:  None 

Man  Years 


Total 

.k8 

Professional: 

.16 

Other: 

.32 

Project  Description: 

Objectives :  In  instrumental  and  operant  conditioning,  a  reinforcer  is  an 
event  that  increases  the  frequency  of  behavior  it  has  followed.  For  neonatal 
dogs,  milk  taken  normally  in  the  mouth  is  a  powerful  reinforcer.  Is  this 
reinforcing  effect  due  to  mouth  stimulation,  stomach  stimulation,  or  some 
other  correlated  factor?  Previous  findings  in  the  project  indicated  that 
direct  intragastric  milk  injection  via  nasopharjmgeal  fistula  is  a  moderately 
stable  reinforcer  with  respect  to  sucking,  an  apparently  unstable  reinforcer 
with  respect  to  button  pushing,  and  devoid  of  reinforcing  properties  with 
respect  to  key  lifting.   Such  data  point  to  the  preeminence  of  oral  factors, 
both  stimulus  and  response,  in  milk  reinforcement.   The  project  seeks  direct 
evidence  for  the  preeminence  of  oral  factors  in  milk  reinforcement  by  study 
of  neonatal  dogs  surgically  prepared  for  mouth  stimulation  without  correlated 
gastric  stimulation  and  gastric  stimulation  without  correlated  mouth  stimula- 
tion in  the  same  animal. 

Methods  Employed:  Because  of  its  simplicity,  a  single-stage  dual  esophagostomy 
was  first  tried  on  two  neonatal  beagles  under  sodiimi  pentobarbital  anesthesia, 
but  the  surgery  did  not  yield  a  preparation  sufficiently  stable  for  chronic 
behavioral  study.  Accordingly,  a  two-stage  dual  esophagostomy  was  carried  out. 
In  the  first  stage,  a  temporary  nasopharyngeal  intragastric  cannula  is  inserted 
into  place,  the  esophagus  is  exteriorized,  and  the  skin  closed  under  the 
exterior  esophageal  loop.   Three  days  later,  the  esophagus  is  severed,  and  its 
cut  ends  allowed  to  retract  to  form  "button  hole"  shapes.  The  nasopharyngeal 

^39 


Serial  No.  M-LBEB-CB-2 
Page  2 


intragastric  cannula  is  also  removed.  The  puppy  is  ready  for  feeding  or  test- 
ing after  insertion  of  catheters  with  inflatable  bulbs  into  the  cut  ends  of  the 
esophagus.  A  peristaltic  pump  is  used  to  inject  milk  directly  into  the  stomach 
or  remove  milk  after  it  enters  the  mouth  but  before  it  enters  the  stomach. 

Major  Findings:  The  dual  stage  esophagostomy  was  successfully  carried  out 
in  a  neonatal  beagle  puppy.  Feeding  and  testing  were  without  complications. 
Sucking  was  maintained  when  sucking-contingent  milk  entered  the  mouth  and 
was  pumped  out  of  the  esophagus,  indicating  a  reinforcing  effect.  However, 
sucking  ceased  abruptly  when  sucking-contingent  milk  by-passed  the  mouth  and 
entered  the  stomach  directly,  indicating  suppressive  rather  than  reinforcing 
effects  of  direct  intragastric  milk  injection  in  an  esophagostcmized  preparation. 

Significance  to  Biomedical  Research  and  Program  of  the  Institute;  The  concept 
of  reinforcement  is  one  of  the  most  widely  generalized  and  conceptually 
integrating  concepts  relevant  to  the  psychology,  physiology,  and  biology  of 
behavior.  Knowledge  of  the  anatomical  locus  of  the  action  of  food  reinforce- 
ment in  neonates  should  contribute  to  our  understanding  of  learning  and  its 
relation  to  motivation  and  behavioral  development. 

Proposed  Course  of  the  Project:  To  study  four  to  eight  esophagostcmized 
beagle  puppies  under  varied  conditions  of  stomach  fullness,  then  terminate 
the  project  with  publication  of  findings . 

Honors  and  Awards:    None 

Publications :        None 


kko 


Serial  No.  M-LBEB-CE-3 

1.  Laboratory  of  Brain  Evolution 

and  Behavior 

2.  Section  on  Comparative  Biopsychology 

3.  Poolesville,  Md. 


PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,   1971  through  June  30,   1972 

Project  Title:      Schedule-Induced  Maladaptive  Adjunctive  Behavior   in  Infant 
Beagle  Dogs 

Previous  Serial  Numher:  M-P-CB-(c)-l   (Part   of) 

Principal  Investigators:  Walter  C.   Stanley 

Other  Investigators:  E.   Faye  Bacon 

Cooperating  Units:  Hone 

Man  Years 

Total:  .67 

Professional:    .^5 
Other:  .22 

Project  Description: 

Objectives :   (l)  To  describe  more  accirrately  maladaptive  behavioral  states  which 
occur  in  feeding  situations  and  are  characterized  by  the  following! 

(a)  sustained  tongue  position — pressed  up  against  the  roof  of  the  mouth 
or  pressed  down  on  the  floor  of  the  mouth,  and  designated,  respectively, 
tongue-on-the-roof-of -mouth  (TOR)  and  tongue-on-the-floor-of -mouth  (TOF); 

(b)  generalized  loss  of  normally  directed  and  effective  feeding  movements 
involving  mouth,  head,  trunk,  and  limbs;  and  (c)  rigid  and  stylized  body 
posturings  and  stereotypic  and  repetitive  movements  of  mandible,  head,  trunk;, 
and  limbs.   (2)  To  determine  the  relationships  between  differing  oral  stimula- 
tion and  the  tongue  position  responses  in  U-8  day  old  and  15-17  day  old  infant 
dogs.   (3)  To  determine  the  excitation  correlated  with  tongue  positions  and 
body  postures . 

Methods  Employed:  For  Objective  1,  analysis  of  video  taped  pictures,  photo- 
graphs, and  cumulative  response  records  obtained  in  operant  key  lift  situations 
when  puppies  display  the  maladaptive  adjunctive  behaviors.  For  Objective  2, 
30  younger  and  30  older  infant  beagle  puppies  were  repeatedly  stimulated  by 
placing   in  the  mouth    a  milk-containing  artificial  nipple,    a  finger 
above  the  tongue,  or    a  finger  below  the  tongue.   For  Objective  3?  methods 
are  only  in  the  planning  stage . 


kkl 


Serial  No.  M-IiBEB-CB-3 
Page  2 


Major  Findings:  In  respect  to  Objective  1,  we  have  obtained  improved  video 
tape  pictures  of  the  TOF  variant  of  the  adjunctive  behavioral  state.  This 
variant  is  associated  with  a  characteristic  "buffalo"  stance  in  which  the 
hind  quarters  of  the  puppy  are  low  or  in  a  seated  position,  the  forelegs  are 
extended  and  straight,  the' head  thrust  downward  at  the  neck,  the  mandible 
moving  in  suck-like  fashion,  and  the  tongue  flattened  and  on  the  floor  of 
the  mouth.  In  respect  to  Objective  2,  intermittent  stimulations  to  suck  were 
followed  by  differential  tongue  position  responses  in  both  younger  {k-8   day  old) 
and  older  (l5-17  day  old)  beagle  puppies.  When  stimulation  to  suck  was  by 
finger  placed  below  the  tongue,  the  response  was  primarily  sustained  tongue 
position  against  the  roof  of  the  mouth.  When  stimulation  to  suck  was  by  finger 
or  milk-containing  nipple  placed  normally  above  the  tongue,  the  response  was 
primarily  sustained  tongue  position  on  the  floor  of  the  mouth. 

Significance  to  Biomedical  Research  and  Program  of  the  Institute;  The 
maladaptive  tongue  position  responses  and  related  hypertonic  and  dystonic 
posturings  are  maladaptive  in  that  they  interfere  with  normally  directed 
food- obtaining  behavior  in  operant  conditioning  situations.  They  are  adjunctive 
in  that  they  are  not  required  to  obtain  food,  but  emerge  after  the  necessary 
operant  behavior  is  learned.  The  adjunctive  behavior  is  most  probable  of 
occurrence  immediately  after  milk  reinforcement  (withdrawal  of  milk-containing 
nipple)  when  the  probability  of  milk- obtaining  in  the  key-lift  situation  is 
temporarily  equal  to  zero.  Regardless  of  the  relation  of  tongue  position 
responses  to  adult  adjunctive  behaviors,  such  as  "psychogenic  polydipsia" 
in  adult  rats,  the  tongue  position  responses  are  so  striking  that  they  merit 
study  in  their  own  right  with  pharmacological  and  neurophysiological  techniques. 

Proposed  Comrse  of  the  Project:  A  chapter  is  in  press  describing  the  TOR  and 
TOF  states  and  their  discovery  in  the  operant  key  lift  situation.  A  report 
of  the  mouth  stimulation  study  will  be  presented  in  1972  at  the  Annual  Meetings 
of  the  American  Psychological  Association  and  the  data  published.  Exploratory 
experiments  will  determine  whether  we  shall  focus  during  the  coming  year  on 
myographic  studies  in  infant  dogs  or  on  the  study  of  schedule-induced  adjunctive 
behavior  in  juvenile  and  adult  beagle  dogs.  This  continuing  project  may  provide 
an  animal  model  for  the  study  of  excessively  maladaptive  adjunctive  behavior 
throughout  the  life-span  of  the  subject.  In  view  of  the  rich  emotional  and 
empathic  behavior  of  the  dog  in  interspecific  social  situations  with  man  and 
breed  variations  in  temperament,  the  study  of  life-span  maladaptive  adjunctive 
behavior  in  the  dog  could  be  a  heuristic  source  of  novel  approaches  to 
conceptual  and  empirical  analyses  of  neurological  and  behavioral  disorder  in  man. 

Honors  and  Awards : 

Dr.  Walter  C.  Stanley  was  invited  to  report  material  on  maladaptive 
adjunctive  behavior  at  the  Fourth  Symposium  on  Oral  Sensation  and 
Perception. 


i^i^2 


Serial  No.  M-LBEB-CB-3 
Page  3 


Publications: 


Stanley,  W.  C:  Induction  of  maladaptive  behavior  by  experimental 
manipulation  of  feeding  in  infant  dogs.  In  Bosma,  J.  F.  (Ed.):  Third 
Symposium  on  Oral  Sensation  and  Perception;  The  Mouth  of  the  Infant. 
Springfield,  Thomas,  Chapter  18,  in  press. 


41^-3 


Serial  No.   M-LBEB-CB-U 

1.  Laboratory  of  Brain  Evolution 

and  Behavior 

2.  Section  on  Comparative  Biopsychology 

3.  Poole sville,  Md. 


PHS-HSMHA-inMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 


Project  Title:  Capacity  for  Learning  in  Neonatal  Dogs:  Parametric  Studies 

Previous  Serial  Number:   Part  of  M-P-CB-(C)-1 

Principal  Investigators:  Walter  C.  Stanley  and  ¥.  Edward  Bacon 

Other  Investigators:      None 

Cooperating  Units:       None 

Man  Years 


Total: 

M 

Professional: 

.23 

Other: 

.21 

Project  Description: 

Objectives:  In  the  1950 's  and  early  1960's  many  authorities  believed  that 
learning  in  human,  as  well  as  animal,  neonates  was  either  nonexistent  or 
transient  ajid  unstable  if  it  occurred  at  all.  The  aim  of  this  project  is  to 
provide  evidence  on  the  capacity  for  learning  in' neonatal  (O-l^J-  day  old)  dogs 
in  instrimiental  and  operant  learning  situations.  Earlier  work  by  the  Principal 
Investigator  (Walter  C.  Stanley)  had  established  that  neonatal  Shetland  sheep- 
dogs and  cocker  spaniels  are  capable  of  classical  appetitive  conditioning  of 
sucking  and  classical  aversive  conditioning  of  struggling  when  the  unconditional 
stimuli  are,  respectively,  milk  and  bitter-tasting  solution  in  the  mouth.  This 
year,  operant  learned  performance  is  being  assessed  in  relation  to  age  and 
schedule  of  milk  reinforcement. 

Methods  Employed:  Neonatal  beagle  dogs  are  run  in  the  operant  key  lift  apparatus 
following  procedures  described  in  last  year's  project  report,  M-P-CB-(c)-l. 

Major  Findings:   In  line  with  o\ir  initial  demonstrational  studies,  the  data 
indicate  that  it  is  difficult  for  the  0-1  week-old  beagle,  as  compared  with 
the  1-2  week-old  beagle,  to  acquire  operant  key  lifting  behavior  in  a  stable 
manner,  apparently  because  motor  coordination  has  not  yet  developed  suffi- 
ciently for  performance  of  the  response.   Data  on  a  fixed  interval  schedule 
(nipple  insertion  contingent  on  passage  of  time  plus  key  lift)  and  fixed 
ratio  schedule  (nipple  insertion  contingent  on  a  fixed  number  of  key  lifts) 
are  ctirrently  being  analyzed. 

hk5 


Serial  No.  M-LBEB-CB-if 
Page  2 

Sienificance  to  Biomedical  Research  and  the  Pro-am  of  the  Institute:  Failures 
to  learn  in  the  very  young  appear  more  attributable  to  sensory-motor  incapacity 
than  to  seme  general  inability  to  learn.  Ueurophysiologically,  the  findings 
indicate  central  nervous  system  function  prior  to  myelination  characteristic      ^ 
of  the  transitional  period  which  follows  the  neonatal  period  m  dogs. 

Proposed  Course  of  the  Project ;  To  terminate  the  project  upon  publication  of 
findings  on  age  differences  and  quality  and  schedules  of  reinforcement  m  neonata^ 
beagle  dogs. 

Honors  and  Awards : .  None 

Publications : 

Bacon,  ¥.  E.  and  ¥ong,  I.  G.:  Reinforcement  value  of  electrical  brain 
stimulation  in  neonatal  dogs.  Develop.  Psychobiol.,  in  press. 


l^lj.6 


Serial  No.  M-LBEB-CB-$ 
.  ■_■■:  .  1.   Laboratory  of  Brain  Evolution 

and  Behavior 

2,  Section  on  Comparative  Biopsychology 

3.  Poole s villa,  Md. 

:.  ■  ■  .  "  "    "  "     'FHS-BSMHA-mMH 

Individual  Project  Report 
■   .-    "         July  1,    1971  through  June  30,   1972 

Project  Title:     Excitatory  and  Inhibitory  Processes  in  Discriminated 
Instrumental  Behavior   of  Neonatal  Beagle  Dogs 

Previous  Serial  Number:        Part   of  M-P-CB-(c)-l 

Principal  Investigator:       W.  Edward  Bacon 

Other  Investigators:  '  None 

Cooperating  Units:  None 

Man  Years: 

Total:  Ac 
Professional:  .35 
Other:  .05 

Project  Description: 

Objectives:   (l)  To  determine  whether  infant  dogs  can  master  a  discrimination 
problem  when  cues  are  presented  successively  rather  than  simultaneously. 
(2)  To  compare  discriminated  behavior  based  on  different  sense  modalities 
(tactual  versus  thermal).   (3)  To  assess  the  roles  of  conditional  excitation 
and  inhibition  in  the  discrimination  learning  of  neonatal  dogs. 

Methods  Employed:   Neonatal  beagle  dogs,  2-li^-  days  of  age  are  trained  to 
crawl  for  milk  in  alleyways  of  different  smoothness  or  softness  (tactual 
discrimination)  or  of  different  temperatures  (thermal  discrimination) . 
Excitatory  and  inhibitory  functions  of  cues  are  assessed  by  (a)  stimulus 
generalization  tests,  (b)  reversal  training,  and  (c)  transfer  of  training 
to  new  cues . 

Major  Findings:  Neonatal  dogs  are  capable  of  learning  both  tactual  and 
thermal  discrimination  problems  when  cues  are  presented  successively 
although  the  tactual  discrimination  is  somewhat  more  stable  and  requires 
less  training  than  the  thermal  discrimination.  Assessment  of  the  roles  of 
conditional  excitatory  and  inhibitory  processes  suggests  that  for  infant 
dogs,  unlike  adult  mammals  and  adult  birds,  discrimination  learning  is  based 
primarily  upon  an  excitatory  process.   No  evidence  was  found  implicating  a 
conditional  inhibitory  process. 


ifl+T 


Serial  No.  M-LBEB-CB-5 
Page  2 


Significance  to  Biomedical  Research  and  Program  of  the  Institute:  The  results 
demonstrate  some  remarkable  learning  abilities  in  an  organism  with  limited 
sensory-motor  capacity  and  an  immature  nervous  system.   Some  properties  of 
the  discrimination  process  in  the  very  young  appear  to  be  fundamentally 
different  from  those  in  the  adult . 

Proposed  Course  of  the  Project:  To  be  completed  with  publication'  of  the 
results . 

Honors  and  Awards:  None 

Publications: 

Bacon,  W.  E.,  Stimulus  control  of  discriminated  behavior  in  neonatal 
dogs.  J.  Comp.  Physiol.  Psychol.,  j6:     k2h-h3,3,   1971. 


khS 


Serial  No.  M-LBEB-CB-6 

1.  Laboratory  of  Brain  Evolution 

and  Behavior 

2.  Section  on  Comparative  Biopsychology 

3.  Poolesville,  Md.      -' 

PHS-HSMHA.-NIMH 

Individual  Project  Report 

July  1,   1971  through  June  30,   1972 

Project  Title:      Instrimiental  Escape  and  Avoidance   Learning  in  Neonatal 
Mongrel  Cats  . 

Previous  Serial  Number:  Part   of  M-P-CB-(c)-l 

Principal  Investigator:  W.  Edward  Bacon 

Other  Investigators:  None 

Cooperating  Units:  None 

Man  Years: 

Total:  .ho 

Professional:        .35 
Other:  .05 

Project  Description: 

Objectives:   (l)  To  extend  the  methodology  developed  for  the  study  of  in- 
strumental learning  in  neonatal  dogs  to  another  infant  mammal.   (2)  To 
compare  the  newborn  kitten  with  the  puppy  in  terms  of  stability  and  foim 
of  learning.   (3)  To  determine  whether  motivation-performance  relationships         |; 
obtained  in  adult  mammals  would  also  hold  for  infant  kittens. 

Methods  Employed:  Fourteen  kittens,  3-6  days  old  were  trained  in  a  two- 
compartment  avoidance  box  (one-way  shuttle)  which  provided  distinct 
tactual  cues.   Pressurized  air  served  as  an  aversive  stimulus  and  typical 
instrumental  escape  and  avoidance  learning  paradigms  were  used. 

Major  Findings:   (l)  Kittens  are  capable  of  avoidance  learning  but  the 
avoidance  behavior  is  not  as  stable  or  of  the  same  form  as  that  previously 
observed  with  infant  dogs.   (2)  Escape  performance  is  an  increasing, 
negatively  accelerated  fuaction  of  air  pressure,  similar  to  the  relationship 
obtained  with  electric  shock  in  adult  animals . 


hk9 


Serial  Ko.  M-LBEB-CB-6 
Page  2 


Significance  to  Biamedical  Research  and  the  Program  of  the  Institute:  The 
research  points  out  similarities  in  the  functional  properties  of  learning 
between  infant  and  adult  as  well  as  delineating  differences  in  the  form  of 
early  learning  between  two  carnivores  (Felis  catus  and  Canis  familiar is) 
with  similar  sensory-motor  capacities  and  nervous  systems  at  birth.  The 
project  thus  provides  new  knowledge  concerning  both  the  phylogeny  and 
ontogeny  of  the  learning  process. 

Proposed  Course  of  the  Project:  The  objectives  of  the  project  have  been 
met  and  a  research  report  has  been  submitted  for  publication. 

Honors  and  Awards:     None 

Publications:         None 


k^O 


Serial  No.  M-LBKB-CB-7 

1.  Laboratory  of  Brain  Evolution 

and  Behavior 

2.  Section  on  Comparative  Biopsychology 

3.  Poole sville,  Md. 


PHS-HBMHA.-WIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 


Project  Title:  Attachment  Behavior  in  Beagle  Dogs  as  a  Function  of  Social 
Reinforcement 

Previous  Serial  Number:  M-P-CB-(c)-2 

Principal  Investigators:  Walter  C.  Stanley  and  W.  Edward  Bacon 

Other  Investigators:  Stephen  C.  Barker  and  Holly  Neyman 

Cooperating  Units:  None 

Man  Years 


Total: 

1.62 

Professional: 

.kQ 

Other : 

l.lii 

Project  Description: 

Objectives:  YoiHig  dogs  form  strong  attachments  to  their  handlers.  Experi- 
mental analyses  of  interspecific  (dog-person)  interactions  by  the  Principal 
Investigators  have  shown  that  contact  with  a  passive  person  is  a  reinforcer 
in  dogs  when  made  contingent  on  dogs'  approach  to  person.  The  efficacy  of 
a  passive  person  reinforcer  has  been  demonstrated  in  normally  reared  basenjis 
(African  barkless),  Shetland  sheepdogs,  wirehaired  foxterrier  X  beagle  hybrids, 
and  isolation-reared  beagles,  but  not  in  normally  reared  beagles.  The  aim 
of  the  present  project  is  to  determine  (l)  under  what  conditions  a  passive 
person  is  a  reinforcer  in  normally  reared  beagle  dogs,  and  (2)  how  its 
strength  and  effects  on  behavior  compare  with  the  action  of  homeostatic 
(food)  and  nonhomeostatic  (novel  stimuli)  reinforcers. 

Methods  Employed:  Eighteen  beagles,  51  days  old  at  the  start  of  experimentation 
and  115  days  at  end  of  experimentation,  received  three  pretraining  and  25 
training  trials,  one  per  day.  For  the  continuous  reinforcement  training 
group,  a  passive  person  was  seated  in  the  goal  area  of  an  L-alleyway  on  every 
trial,  for  the  partial  reinforcement  training  group,  a  passive  person  was 
present  on  half  the  training  trials.  There  followed  kO   extinction  trials, 
with  the  goal  person  completely  omitted  for  all  subjects.  The  goal  person 
served  only  that  function,  never  otherwise  handling  the  subjects.   Other 
research  support  personnel  handled  and  fed  the  subjects.  Work  has  begun 
on  a  follow-up  experiment  in  which  the  handling,  caretaking,  and  goal  person 

i^51 


Serial  Wo.  M-LBEB-CB-7 
Page  2 

activities  are  carried  out  by  one  and  the  same  person   Half  the  dogs  are 
being  run  with  goal  person  present  on  every  trial  and  half  with  the  goal 
person  never  present.  After  25  training  trials,  the  goal  person  mil  be 
omitted  for  all  subjects. 

Major  Findings:  When  the  goal  person  is  different  from  the  handlers  and  care- 
taicers,  beagle  dogs  apparently  acquired  attachment  behavior,  but  showed  no 
consistent  tendency  to  stop  running  when  the  person  was  omitted,  i.e.,  they _ 
failed  to  display  extinction  of  the  apparently  conditioned  attachment  behavior. 
There  also  was  no  difference  in  behavior  between  dogs  receiving  partial  versus 
continuous  iDassive  person  reinforcement,  a  finding  consistent  with  that  on 
basenjis.  In  the  second  experiment,  dogs  trained  with  person  present  m  goal 
area  are  ranning  faster  than  dogs  trained  without  person  (goal  area  empty) , 
If  these  data  hold  up  in  additional  subjects  and  extinction  of  the  approach 
behavior  occurs  when  the  person  is  omitted,  the  findings  on  beagles  will  be 
more  consistent  with  those  on  other  breeds  of  dogs.  However,  further  research 
will  be  required  to  ascertain  why  normally  reared  beagles  do  not  stop  or  reduce 
their  running  when  the  passive  person  is  omitted  from  the  goal  area.  Perhaps 
beagles  form  a  stronger  attachment  to  persons  serving  handler-caretaker  functions 
than  to  the  passive  goal  person.  This  possibility  may  also  account  for  the 
lack  of  partial  passive  person  reinforcement  training  leading  to  greater 
resistance  to  extinction  than  continuous  reinforcement  training.  In  any 
event,  variables  affecting  resistance  to  extinction  after  training  with  passive 
person  reinforcement  appear  different  from  those  typically  affecting  resistance 
to  extinction  after  training  with  food  reinforcement. 

Significance  to  Biomedical  Research  and  Program  of  the  Institute:  Study  of 
sources  of  social  reinforcement  inherent  in  the  interspecific  dog-man  inter- 
action provides  a  paradigm  for  experiments  ethically  impossible  in  man  and 
scientifically  impossible  in  animals  without  strong  attachment  behavior  to  man. 

Proposed  Course  of  the  Project:  To  finish  the  second  experiment  described ^ 
above  where  the  passive  goal  person  is  also  the  handler-caretaker  and  publish 
the  findings.  Additional  experiments  are  planned  using  automated  apparatus 
(M-LBEB-CB-9)  to  eliminate  need  for  handlers. 


Honors  and  Awards : 

Dr.  Walter  C.  Stanley  was  a  formal  discussant  of  papers  at  "Symposium 
on  the  Physiological  and  Neurophysiological  Aspects  of  Social  Attach- 
ment and  the  Effect  of  Person ,"  12th  Meeting  of  The  Pavlovian  Society 
of  America,  1971.  He  also  has  been  invited  to  prepare  a  paper  on  the 
passive  person  reinforcement  and  related  studies  in  the  dog  and  to 
relate  it  to  the  biology  of  affiliation. 

Riblications :   None 


k52 


I 


Serial  No,  M-LBEB-CB-8 

1.  Laboratory  of  Brain  Evolution 

and  Behavior 

2.  Section  on  Comparative  Biopsychology 

3.  Poolesville,  Md. 

PHS-HSMHA-WIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:  Behavioral  14athematics  and  the  Logic  of  Measurement 

Previous  Serial  Number:    M-P-CB-(c)-3 

Principal  Investigator:    Walter  C.  Stanley 

Other  Investigators:       None 

Cooperating  Units:        None 

Man  Years 

Total:  .20 
Professional:  .10 
Other:         .10 

Project  Description: 

Objectives:  To  develop  logic  and  mathematics  directly  relevant  to  the  measure- 
ment of  stable  and  changing  behavior  as  it  occurs  in  learning  situations  in 
order  that  amount  of  behavioral  change  may  be  validly  compared  from  one  response 
class  to  another  in  the  same  or  different  organisms. 

Methods  Employed:  Most  applications  of  mathematics  to  behavioral  data  represent 
empirical  curve-fitting,  statistical  analyses,  or  models,  the  terms  of  which 
refer  to  inferred  or  assumed  processes.  The  present  effort  differs  from  tra- 
ditional approaches  by  starting  from  a  theory  of  measurement  rather  than  from 
a  theory  of  behavior  or  learning.   It  also  differs  from  traditional  approaches 
by  assuming  that  the  relevant  mathematics  (n\miber  system  and  functions)  must 
be  abstracted,  rather  than  inferred,  from  directly  recorded  and  reinforced 
behavioral  elements.  Each  behavioral  element  of  a  definable  and  recordable 
behavioral  class  is  regarded  as  uniquely  specifiable  by  the  assignment  of  two 
numbers,  one  symbolizing  order  of  occui-rence  {c)   of  the  behavioral  elements, 
the  other,  time  (t)  of  occurrence. 

Major  Findings:  The  status  of  time  measures  of  behavior  was  further  clarified. 
In  order  to  measure  behavior  in  units  of  time,  periods  of  not  responding  as 
well  as  periods  of  responding  must  be  assigned  time  unit  values.   For  a 
particular  response  class,  the  shortest  interresponse  time  (or  the  shortest 
response  time  from  some  meaningful  reference  point)  may  be  taken  as  a  behavioral 


453 


Serial  No.  M-IxBEB-CB-8 
Page  2 


time  unit  to"lay-end-to_-end"  in  order  to  measure  periods  of  not  responding  as 
well  as  periods  of  responding.  Analysis  suggests  that  numerical  representa- 
tions of  responding  and  not  responding  in  terms  of  such  time  units  require 
real  and  imaginary  number  components.   If  this  is  true,  numerical  struct\ares 
necessary  for  the  measurement  of  "behavior  may  be  mathematically  "complex", 
not  merely  "real",  in  their  properties. 

Significance  to  Biomedical  Research  and  Program  of  the  Institute:  The 
induction  of  a  behavioral  number  system  and  mathematics  from  the  study  of 
behavior  in  experimental  and  naturalistic  settings  is  propaedeutic  to  true 
measurement  in  the  behavioral  sciences. 

Proposed  Course  of  the  Project:  To  continue  working  on  the  mathematics  of 
behavior  occiurring  in  learning  situations  and  to  continue  work  in  the  develop- 
ment of  a  logic  of  behavioral  measurement . 

Honors  and  Awards:    None 

Publications:        Incorporated  into  chapter  entitled:  Perspectives  in 
behavior  organization  and  development  resulting  from 
studies  of  feeding  behavior  in  infant  dogs.  For 
reference,  see  M-LBEB-CB-1 


k5k 


Serial  No.  M-LBEE-CB-9 

1.  Laboratory  of  Brain  Evolution 

and  Behavior 

2.  Section  on  Comparative  Biopsychology 

3.  Poole  sville,  Md. 

EHS-HSMHA.-WIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:  Automated  Apparatus  for  the  Biopsychological  Study  of  Behavior 

Previous  Serial  Number:    M-P-CB-(c)-i+ 

Principal  Investigators:   Walter  C.  Stanley  and  Stephen  ET.  Lee 


Other  Investigators: 

None 

Cooperating  Units: 

None 

Man  Years 

Total: 

1.12 

Professional: 

1.02 

Other : 

.10 

Project  Description: 

Objectives :  To  design,  construct,  modify,  and  evaluate  on-line  computer- 
controlled  apparatus  suitable  for:   (l)  maintaining  at  least  four  mammalian  in- 
fants away  from  their  natural  mothers,  scheduling  of  stimuli  and  the  recording 
and  analysis  of  data  on  sucking,  key  lifting,  vocalization  and  loccmotory  be- 
havior; (2)  studying  attachment  behavior  in  isolated  dogs;  and  (3)  assessing 
the  development  of  adjunctive  behavior  in  operant  conditioning  situations. 

Methods  Employed:  For  Objective  1,  infant  dogs  less  than  two  weeks  of  age 
have  been  maintained  for  over  two  weeks  in  individual  compartments  placed 
on  a  turntable  which  automatically  moved  to  a  feeding  station.  The  feeding 
station  consisted  of  a  nipple  on  a  moving  carriage  and  connections  necessary 
for  the  recording  of  both  negative  press^ure  producing  and  the  nipple  manipula- 
tive components  of  sucking  behavior  and  for  the  delivery  of  milk  contingent  on 
the  suction  component  of  sucking.  The  action  of  the  apparatus  and  the  behavior 
of  the  experimental  subjects  were  observed  around-the-clock  to  determine  ways 
of  improving  the  efficiency  and  consistency  of  operation  of  all  elements  of 
the  apparatus  and  the  ease  with  which  puppies  can  feed  themselves.  A  single- 
animal  (one -compartment)  apparatus  has  been  built  to  pretest  additional  features 
to  be  incorporated  in  the  multiple-unit  carrousel.  For  Objective  2,  photo-cell 
beam  controlled  circuitry  and  doors  were  added  to  two  12-ft.  shuttle-boxes. 
For  Objective  3,  contact  recording  circuitry  was  added  to  a  drinking  tube  in 
a  canine  operant  chamber  built  to  our  design  specifications 


^55 


Serial  No.  M-LBEB-CB-9 
Page  2 

Major  Findings:  Programs  and  subroutines  were  developed  and  found  suitable 
for  iise  with  the  on-line  computer  controlling  two  or  more  classes  of  discrimina- 
tive stimulation,  availability  and  scheduling  of  milk  deliveries,  classification 
of  interresponse  times  for  contingent  milk  delivery,  and  designation  of  number 
and  rate  of  milk  delivery.  Interfacing  of  the  Section's  LINC  computer  to 
BRS  logic  control  systems  permitted  such  uses  as  direct  control  of  relays  and 
sensing  of  switch  closure  and  allowed  two  subjects  to  be  run  simultaneously, 
but  on  different  milk  reinforcement  schedules.  Programs  were  also  worked  out 
for  recording  and  storing  stimulus  and  response  events  occurring  throughout 
sessions  for  off-line  computer  data  analysis. 

Significance  to  Biomedical  Research  and  Program  of  the  Institute:  Improvement 
of  the  highly  specialised  apparatus  will:   (1)  permit  more  than  one  experiment 
to  be  conducted  simultaneously  by  personnel  available;  (2)  allow  more  flexibility 
and  control  in  scheduling  of  feeding  and  reinforcement  of  neonatal,  juvenile, 
and  adult  dogs;  and  (3)  reduce  greatly  the  time  needed  for  data  analysis. 

Pi-'oposed  Course  of  the  Project:  Continuation  of  efforts  until  attainment  of: 
(1)  totally  on-line  computer  control  of  maintenance  and  feeding;  (2)  reliable, 
valid,  and  objective  on-line  recording,  and  on-line  data  analysis  of  sucking, 
nipple  latching,  locomotion,  vocalizing,  and  more  generally,  instrumentally- 
operantly  conditioned  behavior.  Extension  of  these  principles  to  automated 
apparatus  suitable  for  the  biopsychological  study  of  behavior  in  pre- juvenile 
(3-12  week-old) ,  juvenile  (l2  weeks  to  sexual  maturity)  and  adult  dogs  and 
other  mammals. 

Honors  and  Awards:    None 

Publications :        None 


456 


Serial  No.  M-LBEB-BS-1 

1.  Laboratory  of  Brain  Evolution 
and  Behavior 

2.  Section  of  the  Chief 

3 .  Section  on  Behavioral  Systems 

4 .  Poolesville  ,  Maryland 

PHS-?ISMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   Vitamin  A  Induced  Alteration  of  Social  Behavior 

Previous  Serial  Number:   M-P-C-(C)-37  (In  years  prior  to  1970-71) 

Principal  Investigator:   John  B.  Calhoun 

Other  Investigators:   None 

Cooperating  Units:   None 


Man 

Years 

Total : 

0 

3 

Professional : 

0 

2 

Other : 

0 

1 

Project  Description: 

Objectives ;   To  determine  the  impact  of  slightly  elevated 
dietary  intake  of  vitamin  A  on  social  behavior  of  Osborne- 
Mendel  Strain  rats. 

Methods  Employed:   Vitamin  A  was  administered  in  a  highly 
controlled  synthetic  diet,  with  3  i.u.  of  vitamin  A  per  g.  of 
diet  taken  as  the  normal.   6  i.u.  and  12  i.u.  diets  were  also 
employed.   Populations  were  established  in  highly  structured 
environments.   Detailed  observational  histories  were  maintained 
on  all  individuals.   These  included  social  interactions,  general 
health,  and  reproductive  histories.   At  the  end  of  18  months, 
all  survivors  were  sacrificed  and  assays  obtained  of  liver 
storage  levels. 

Major  Findings:    Comment  will  here  be  made  on  only  the  3  i.u. 
and  the  12  i.u.  diet  groups.   Rats  on  the  four-fold  normal  diet 
at  all  ages  have  liver  storage  of  1.3  to  1.45  that  of  those  on 
the  normal  diet.   Rats  on  the  elevated  intake  exhibited  the 
following  aberrations:   (1)   Males  much  more  frequently  mounted 
inappropriate  sex  partners  such  as  other  adult  males,  non- 
receptive  females,  juveniles  of  both  sexes;  (2)   There  was  a 
heightened  prevalence  of  premature  pregnancies  resulting  from 
males  copulating  with  juvenile  females  that  had  not  yet  developed 
the  full  repertoire  of  characteristics  that  normally  represents 
appropriateness  for  sexual  advances;  (3)  Females  were  only  half 

1^57 


Serial  No.  M-LBEB-BS-1  ,  Page  2 

as  successful  at  rearing  young  to  weaning;   (4)   Aggression 
among  males  was  markedly  reduced.   Even  this  reduced  aggression 
is  interpreted  as  pathology  that  reflects  a  reduced  capacity  to 
detect  the  characteristics  in  others  that  would  normally  elicit 
status  interactions  that  in  rats  are  expressed  by  aggressive 
acts.   Similarly  the  distortions  for  reproductive  and  maternal 
behavior  are  interpreted  as  resulting  from  vitamin  A  induced 
impairment  of  ability  to  perceive  the  complex  gestalts  requisite 
for  appropriate  full  behavior.   These  behavioral  distortions 
become  more  accentuated  in  rats  born  after  the  populations 
became  more  crowded.   The  rate  of  storage  of  vitamin  A  in  rats 
born  under  crowded  conditions  doubles  over  that  of  rats  born  in 
uncrowded  conditions. 

Significance  to  Bio-medical  Research  and  the  Program  of  the 
Institute;   It  would  appear  that  evolution  has  established  a 
feedback  loop  that  enhances  vitamin  A  storage  under  conditions 
when  it  is  beneficial  to  individual  survival  to  block  out 
awareness  of  surrounding  social  milieu  which  otherwise  would 
prove  stressful  to  the  organism.   If  man  is  affected  similar  to 
rats  by  slight  elevations  of  vitamin  A  intake  above  those 
regularly  experienced  in  the  evolutionary  history  of  the  species, 
drastic  alterations  of  behavior  in  a  significant  proportion  of 
the  population  may  arise  in  the  relatively  near  future.   A  3  i.u. 
per  gram  of  food  intake  for  rats  compares  to  a  2500  i.u.  intake 
per  day  for  man.   Behaviorally  and  physiologically  these 
represent  completely  adequate  intake  levels.   On  the  human  level 
in  the  United  States  the  adequacy  of  the  diet  and  the  supple- 
mentation of  many  foods  with  vitamin  A  provide  the  opportunity 
of  many  individuals  obtaining  at  least  5000  i.u. /day.   In 
addition,  availability  of  vitamin  pills  can  provide  additional 
daily  intakes  of  500  to  25000  i.u. /day.   Thus,  many  individuals 
may  be  experiencing  prolonged  intakes  equal  to  or  greater  than 
the  relative  intake  levels  producing  distortion  of  social 
behavior  in  rats.   The  above  insights  conflict  with  Professor 
Linus  Pauling's  theories  of  orthomolecular  psychiatry  which 
suggest  the  desirability  of  massive  doses  of  certain  normal 
metabolites,  such  as  vitamin  A. 

Proposed  Course  of  Project;   The  recent  completion  of  the  pilot 
phase  of  development  of  a  "socioenvironometer " ,  an  automated 
methodology  for  monitoring  in-context  behavior  makes  it  now 
possible  to  plan  for  the  larger  scale  studies  necessary  to 
validate  and  expand  insights  about  the  impact  of  vitamin  A  on 
behavior.   Such  planning  is  in  process. 

Honors  and  Awards:   (Principal  Investigator) 

1.   Presented  a  seminar  to  the  Department  of  Psychology, 
University  of  Wisconsin,  Madison,  Wisconsin,  27  March 
1972,  Titled;   "Vitamin  A  Induced  Distortions  of 
Behavior  in  Rats". 


Serial  No.  M-LBEB-BS-1,  Page  3 
Publications:      None 


459 


Serial  No.  M-LBEB-BS-2 

1.  Laboratory  of  Brain  Evolution 
and  Behavior 

2.  Section  on  Behavioral  Systems 

3.  Poolesville,  Maryland 

PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  197  2 

Project  Title:   Social  Velocity 

Previous  Serial  Number:   M-P-C- (C) -37 ,  42 

Principal  Investigator:   John  B.  Calhoun 

Other  Investigators:   Halsey  M.  Marsden,  Gerald  G.  Wheeler 

Cooperating  Units:   None 


Man  Years 

Total: 

0 

.6 

Professional: 

0 

.3 

Others 

0 

.3 

Project  Description: 

Objectives :    To  explore  how  social  velocity  is  modified  by 
group  size,  individual  social  history,  population  history,  and 
structure  of  the  physical  environment.   Social  velocity  is 
defined  as  the  relative  degree  of  activity  in  those  parts  of 
the  environment  where  social  status  interactions  are  more  likely 
to  occur. 

Methods  Employed:   Mice  and  rats  are  housed  in  groups  of  4  to 
2000  in  large  highly  structured  environments.   Individuals  are 
marked  to  permit  visual  or  automated  recording  of  place  and 
degree  of  activity.   Seven  major  studies  are  included.   They 
encompass  four  groups  or  populations  of  rats  and  twenty-one  of 
mice.   All  observations  have  been  formated  on  magnetic  tape  for 
computer  analysis. 

Major  Findings:   Preliminary  analyses  provide  the  following 
major  insights:   (1)   In  an  optimum  sized  group  of  N  individuals 
relative  social  velocity  varies  between  1.0  and  1/N.   (2) 
Behavioral  pathology  varies  inversely  with  social  velocity. 
(3)   As  the  group  size  increases  beyond  the  optimum,  social 
velocity  decreases.   (4)   In  groups  whose  members  have  lost 
the  capacity  for  effective  social  organization  most  individuals 
exhibit  a  reduced  social  velocity  approaching  the  minimum  value 
of  1/N  exhibited  in  optimum  sized  groups. 


U6l 


Serial  No.  M-LBEB-BS-2 ,  Page  2 

Significance  to  Bio-medical  Research  and  the  Program  of  the 
Institutil    The  high  degree  of  association  of  these  measures 
of  social  velocity  with  social  status,  behavioral  deviation, 
and  physiology  promise  to  make  this  concept  a  useful  one  in 
understanding  the  origin  of  social  withdrawal,  and  physiological 
and  behavioral  pathology  arising  from  crowding  and  inadequately 
designed  physical  environments. 

Proposed  Course  of  Project:   Detailed  analysis  of  the  currently 

available  data  pool  has  high  priority  for  FY  73.   The  recently 

developed  "socioenvironometer "  will  be  used  for  rapid  acquisition 
and  analysis  of  social  velocity  data. 

Honors  and  Awards:   None 

Publications:    None 


k62 


Serial  No.  M-LBEB-BS-3 

1.  Laboratory  of  Brain  Evolution 
and  Behavior 

2.  Section  on  Behavioral  Systems 

3.  Poolesville,  Maryland 

PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   The  Overliving  of  a  Mouse  Population 

Previous  Serial  Number:   M-P-C-(C)-37 

Principal  Investigator:   John  B.  Calhoun 

Other  Investigators:   Halsey  M.  Marsden,  Gerald  G.  Wheeler 

Cooperating  Units:   Office  of  the  Director,  IR,  NINDS 

(H.  M.  Marsden  assigned  to  SOBS,  LBEB, 
NIMH  from  NINDS) 


Years 

Total: 

2 

3 

Professional : 

0 

5 

Other : 

1 

8 

Project  Description: 

Objectives :   To  determine  the  consequences  of  reducing  death 
control  factors  to  the  point  that  more  individuals  survive 
than  can  be  incorporated  into  the  social  organization  of  a 
population. 

Methods  Employed:   Experimental  and  environmental  designs  remain 
as  previously  described  (M-P-C- (C) -37  for  FY  '70).   The 
population  increased  to  a  maximum  of  2200  individuals  and  it 
became  impossible  to  maintain  detailed  observations  on  each 
individual  animal.   However  based  on  prior  life  history  data 
and  an  intensive  effort  to  identify  all  mice  which  persistently 
exhibited  certain  quasi-normal  or  pathological  behaviors,  8 
groups  of  males  and  8  groups  of  females  with  12  mice  in  each 
group  were  selected  for  intensive  observation  of  behavior.   Each 
mouse  had  its  fur  color-coded  for  individual  recognition.   8,000 
observations  were  made  of  these  192  selected  mice.   Periodic 
surveys  of  the  entire  population  or  portions  of  it  with  respect 
to  location  of  individuals  or  groups  and  to  physical  condition 
have  continued  throughout  the  year . 


h63 


Serial  No.  M-LBEB-BS-3,  Page  2 

Major  Findings:    The  cessation  of  population  growth  which 
occurred  March'  1,  1970  has  been  followed  by  a  slow  decline  in 
the  number  of  mice  from  a  maximum  of  2200  to  290  as  of  this 
writing  (March  22,  1972).   During  this  decline  no  young  survived 
to  weaning,  and  during  the  past  year  no  mice  were  born.   There 
is  some  evidence  for  an  improvement  in  the  quality  of  nest 
building,  but  the  "behavioral  sinks"  remain  (large  clusters  of 
animals  at  one  resource  location  to  the  exclusion  of  adjacent 
locations) .   During  the  intensive  observations  of  color-coded 
groups  one  mating  was  seen,  and  some  males  retained  fragments 
of  territorial  behavior.   These  observations  also  confirmed  the 
existence  of  groups  of  individual  animals  with  differing 
behavioral  profiles  -  many  pathological.   Males  are  currently 
dying  at  a  faster  rate  than  females  as  the  sex  ratio  has 
increased  from  about  2-1  to  3-1  in  favor  of  females. 

Significance  to  Bio-medical  Research  and  the  Program  of  the 
Institute :    A  more  complete  report  on  the  significance  to  bio- 
medical  research  is  included  in  M-P-C-(C)-37  for  FY  '71. 

To  make  a  broad  generalization:   When  the  adult  members  of  a 
social  system  produce  and  provide  adequate  early  development 
for  more  young  than  can  be  provided  with  meaningful  social  roles 
as  adults  in  the  established  social  order,  then  these  excess 
members  will  be  vigorously  rejected.   The  process  of  rejection 
leads  to  a  disruption  of  capacity  for  normal  social  behavior, 
and  culminates  in  the  rejected  individual  becoming  extremely 
violent,  with  the  violence  having  its  major  repercussions  turned 
inward  toward  other  rejected  individuals.   However,  the  very 
process  of  rejection  leads  to  the  disruption  of  adequate  social 
behavior  by  the  formerly  organized  adults.   Later  young  reared 
by  them  become  autistic-like  with  little  capacity  to  engage  in 
those  complex  behaviors  essential  for  the  survival  of  the 
species.   These  complex  behaviors,  which  in  the  mouse  primarily 
concern  reproductive  and  aggressive  behavior,  on  the  human  level 
concern  the  creation,  acquisition  and  implementation  of  ideas. 
The  United  States  and  the  world  stand  at  a  critical  stage  in 
evolution  having  many  counterparts  to  the  history  of  this  mouse 
population. 

Proposed  Course  of  Project^   High  priority  will  be  placed  on  the 
analysis  and  reporting  of  results  of  this  study.   To  date  a  File 
Outline  for  transferring  all  of  the  multivariable  data  in  a 
logical,  computer  retrievable  format  from  IBM  cards  to  magnetic 
tape  has  been  developed.   Some  programs  have  been  written  and 
tested  to  accomplish  this  task.   Once  this  is  accomplished, 
question  asking  and  answering  can  be  rapid  and  efficient 
predicated  on  the  progress  of  the  programming  effort  for  data 
retrieval.    This  last  of  the  large  mouse  populations  will  be 


k6h 


Serial  No.  M-LBEB-BS-3  ,  Page  3 

permitted  to  continue  until  all  members,  or  at  least  all  males, 
have  died  of  old  age.   Periodic  surveys  and  observations  will 
continue  to  be  made. 

An  increasing  emphasis  will  be  placed  on  varying  the  environmental 
conditions,  both  physical  and  social,  which  form  the  mold  for 
guiding  the  development  and  expression  of  both  individual 
behavior  and  social  organization. 

Honors  and  Awards:   None 

Publications:      None 


k65 


/ 

Serial  No.  M-LBEB-BS-4 

1.  Laboratory  of  Brain  Evolution 
and  Behavior 

2 .  Section  on  Behavioral  Systems 

3.  Poole sville,  Maryland 

PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   Role  of  Prior  Social  Experience  in  Altering 
Adaptive  Behavior 

Previous  Serial  Niamber:   M-P-C(c)-4  2 

Principal  Investigator:   Halsey  M.  Marsden 

Other  Investigators:   John  B.  Calhoun 

Cooperating  Units:  Office  of  the  Director,  IR,  NINDS  (Principal 
Investigator  is  assigned  to  SOBS,  LBEB,  NIMH 
from  NINDS) . 


Man  Years 

Total: 

0 

4 

Professional: 

0 

2 

Other : 

0 

2 

Project  Description: 

Objectives:    To  determine  the  influence  of  prior  experience 
in  crowded  environments  on  the  ability  of  individuals  to 
reconstitute  normal  behavior  and  group  organization  in  new, 
low  density  settings. 

Methods  Employed:   The  subjects  used  to  initiate  the  studies  in 
this  project  are  products  of  studies  included  in  Project  No. 
M-P-C- (C) -37 .   Data  collection,  data  processing,  and  techniques 
of  observations  adhere  closely  to  methods  which  have  evolved  from 
that  Project. 

1.   Study  #122  -  Males  undergo  social  withdrawal  in  mouse 
populations  at  high  density  in  structured  habitats.   In  this 
study  twelve  males  in  each  of  six  groups  were  introduced  to  six 
new,  identically  structured,  habitats.   The  groups  were  as 
follows: 

(1)  Aggressors  -  Dominant,  territorial  males. 

(2)  Pooled  withdrawn  -  Males  living  in  large,  all-male 
groups  on  the  floor  of  the  habitat. 


k6j 


Serial  No.  M-LBEB-BS-4  ,  Page  2 

(3)  Solitary  withdrawn  -  Isolated,  single  males 
living  on  platforms  adjacent  to  food  and  water 
resources . 

(4)  Beautiful  mice  -  Males  living  in  small,  all-male 
groups  in  nest  boxes.   Animals  in  excellent  physical 
condition. 

An  old  and  young  sub-category  for  groups  2  and  4 
completed  the  total  of  six. 

The  density  in  the  new  habitats  was  3  mice/cell  in  a  four-cell 
habitat,  reduced  from  about  137/cell  in  the  former  environment. 

2.   Study  #  124  -  The  4  animals  with  the  highest  social 
velocity  (high  social  status)  from  each  of  the  6  groups  in  Study 
122  were  reassembled  in  two  new  social  groups  of  12.   Conversely 
the  4  animals  with  the  lowest  velocity  from  each  Study  122  group 
were  assembled  in  two  additional  groups.   Two  animals  from  each 
Study  122  group  having  middle  social  velocity  scores  comprised 
a  5th  new  group  of  12.   All  groups  were  placed  in  clean,  4-cell 
habitats . 

Major  Findings: 

1 .  Study  #  122  -  None  of  the  six  groups  formed  a  normal 
social  structure  although  the  basics  of  each  were  similar.   Each 
group  divided  into  two  subgroups:   (1)   three  males  which 
exhibited  territoriality  to  varying  degrees;  (2)   nine  which 
entered,  or  remained  in,  states  of  withdrawal.   The  territorial 
males  were  distributed  one  to  each  of  three  cells.   All  others 
concentrated  in  the  fourth  cell .   One  animal  among  the  nine 
showed  a  degree  of  dominance  over  his  fellows,  but  did  not 
defend  territory.   Defense  of  territory  was  not  uniform  across 
groups.   It  was  strongest  in  the  beautiful  mice  and  the  aggressors, 
weakest  in  the  pooled  withdrawn,  with  the  solitary  withdrawn  being 
intermediate.   The  level  of  general  social  activity  followed  the 
same  ordering.   The  pooled  withdrawn  retained  the  characteristic 
pooling  behavior,  feeding  or  resting  on  platforms  in  aggregates 

of  up  to  eight  animals. 

2.  Study  #  124  -  The  second  attempt  to  socially  organize      , 
was  a  failure  in  all  five  reconstituted  groups.   There  was  no 
evidence  of  consistent  territorial  behavior  by  any  animal.   The 
animals  appeared  totally  unable  to  cope  with  this  second 
socioenvironmental  challenge. 

Significance  to  Bio-Medical  Research  and  the  Program  of  the 
Institute!    It  is  concluded  that  results  of  exposure  to  high- 
density  living,  resulting  in  social  withdrawal  and  maladaptive 
behavior  are,  at  least  in  part,  irreversible  in  new  environments 
devoid  of  the  original  influences  of  crowding.   Persistence  of 

k68 


Serial  No.  M-LBEB-BS-4  >    Page  3 

behavioral  pathology  in  new  "ideal"  settings  when  coupled  with 
an  inability  to  organize  socially  when  challenged  could  have 
profound  implications  for  mental  health  if  the  parallel  is  made 
with  the  human  scene. 

Proposed  Course  of  Project:   Analysis  and  interpretation  of  data 
remained  the  first  priorities  for  the  coming  year.   A  new  and 
potentially  important  aspect  of  this  project  has  emerged.   The 
small,  all  male  groups  in  the  "experimental  mouse  universes" 
provide  a  relatively  simple  but  powerful  methodology,  not  only 
to  test  the  effects  of  social  experiences,  but  also  the  critical 
triune  relationship  between  physical  environment,  social  environ- 
ment, and  brain  as  it  affects  behavior. 

The  social  and  physical  environments  and  their  interaction  can 
be  defined  and  experimentally  manipulated.   A  third  set  of 
variables,  impinging  on  the  organisms  central  nervous  system 
could  be  additional  input.   These  could,  e.g.,  take  the  form 
of  brain  lesions  or  drugs.   Forebrain  septal  lesions  and  physical 
environmental  deprivation  will  be  the  initial  variables  of  choice. 
In  studying  the  interaction  between  these  two  sets  of  variables 
insight  can  be  gained  with  regard  to  brain  function  in  a  changing 
environment.   Such  potential  insight  into  these  critical  deter- 
minants of  social  behavior  has  not  been  possible  heretofore  in 
animal  studies. 

Honors  and  Awards:   (Principal  Investigator) 

1.  Invited  Speaker,  Environmental  Study  Group,  Goddard 
Space  Center,  NASA,  October  1971. 

2.  Invited  Lecturer,  LaGuardia  College,  New  York, 
Colloquium  on  Population  and  the  Environment, 
February,  1972. 

3.  Invited  Speaker,  Seminars  on  Animal  Aggression, 
Sponsored  by  the  Laboratory  of  Clinical  Psychobioloav 
NIMH,  March,  1972. 

Publications: 

1.  Marsden,  H.M.  1972.   Crowding  and  Animal  Behavior. 

In:   Behavioral  Science  and  Problems  of  the  Environment, 
American  Psychological  Association,  Washington  (In 
Press)  . 

2.  Marsden,  H.M.  1972.   The  Effect  of  Food  Deprivation  on 
Intergroup  Relations  in  Rhesus  Monkeys.   In:   Behavioral 
Biology,  Academic  Press,  N.  Y.  (In  Press) . 


469 


r 


Serial  No.  M-LBEB-BS-4  ,  Page  4 

Marsden,  H.M.  1972.   Aggression  within  Social  Groups 
of  Rhesus  Monkeys:   Effect  of  Contact  between  Groups. 
In:   Animal  Behaviour.  (In  Press). 


kjo 


Serial  No.  M-LBEB-BS-5 

1.  Laboratory  of  Brain  Evolution 
and  Behavior 

2.  Section  on  Behavioral  Systems 

3.  Poolesville,  Maryland 

FHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   Modification  of  Catecholamine  Metabolism  in  a 
Crowded  Mouse  Population 

Previous  Serial  Number:   None 

Principal  Investigator:   Halsey  M.  Marsden 

Other  Investigators:   John  B.  Calhoun,  K.Y.  Ng,  Robert  W.  Colburn 

Cooperating  Units:   Office  of  the  Director,  IR,  NINDS,  NIH 

(Principal  Investigator  is  assigned  to  SOBS, 
LBEB,  NIMH);  Section  on  Pharmacology,  CBRS, 
NIMH. 


n  Years 

Total: 

0.8 

Professional : 

0.4 

Other : 

0.4 

Project  Description: 

Objectives:    Because  of  the  possible  role  of  catecholamine- 
containing  neural  systems  in  mediating  a  variety  of  behavioral 
states,  (1)   to  identify  persistent  and  contrasting  behavioral 
states,  both  quasi-normal  and  pathological,  in  mice  which  have 
evolved  to  extreme  densities  in  structured  habitats,  (2)   to 
select  individual  animals  strongly  representative  of  those 
states,  and  (3)   to  compare  the  catecholamine  containing  neural 
systems  across  a  spectrum  of  such  behavioral  types. 

Methods  Employed:    The  subjects  used  to  initiate  the  studies  in 
this  project  are  products  of  studies  included  in  Project  No. 
M-P-C-(C)-37— mice  having  evolved  to  a  state  of  maximum  crowding 
beyond  which  no  successful  reproduction  had  occurred  population 
wide  for  one  year.   Animals  were  captured  in  recognizable 
behavioral  states,  individually  identified,  and  returned  to  the 
population.   Animals  with  the  highest  frequency  of  recaptures, 
on  subsequent  observations,  in  the  same  behavioral  state  were' 
selected  to  represent  contrasting  groups  of  males.   Assays  of 
the  levels  of  the  catecholamine  synthesizing  enzymes  tyrosine 
hydroxylase   (TOH)  and  phenylethanolamine-N-methyl  transferase 
(PNMT)  in  brain  and  adrenal  glands  were  performed,  and,  in 

k-TL 


Serial  No.  M-LBEB-BS-S,  Page  2 

vivo  synthesis  of  catecholamines  was  determined  by  the  injection 

of  radioactively  labelled  tyrosine.   Comparable  groups  were 

color-coded  and  returned  to  the  habitat  for  subsequent  behavioral 
observation. 

Major  Findings:    The  selection  procedure  for  animals  followed  a 
logical  strategy  and  was  successful  in  confirming  the  existence 
of  contrasting  behavioral  states  in  individual  animals.   Two 
primary  states  were  recognized  for  males:   (1)   socially  with- 
drawn, either  singly  or  in  pools,  and  (2)  aggressive,  territorial 
animals.   When  contrasted  on  a  neurochemical  basis  the  socially 
withdrawn  group  showed  a  significantly  higher  TOH  activity  in 
brain  and  a  higher  PNMT  activity  in  adrenals.   Studies  on 
catecholamine  synthesis  in  vivo  suggested  that  the  processes  of 
production  and  utilization  of  catecholamine  may  be  accelerated 
in  socially-withdrawn  mice  when  compared  to  the  territorial 
aggressors.   A  comparable,  previous  selection  and  assay  of 
adrenal  PNMT  by  Calhoun  and  Axelrod  included  a  third  contrasting 
male  group:   mice  not  socially  involved  in  defense  of  territory 
but,  in  contrast  to  the  socially  withdrawn,  in  excellent  pelage 
with  no  wounds  and  not  showing  pathological  episodes  of  violent 
behavior  (biting  and  holding) .   This  intriguing  observation 
suggests  a  history  of  early  non-involvement  in  contrast  to 
probable  competition,  defeat,  and  subsequent  social  withdrawal 
in  the  socially  withdrawn.   These  mice,  termed  the  "beautiful 
ones"  showed  PNMT  levels  no  different  from  the  territorial 
aggressors  and  significantly  below  the  levels  of  the  socially 
withdrawn,  implying  a  different  route  for  coping  with  the  stress 
of  crowding. 

Significance  to  Biomedical  Research  and  the  Program  of  the 
Institute:    Mental  health  is  inseparable  from  the  environment, 
both  physical  and  social.   This  project  has  demonstrated   by 
example,  that  this  approach,  this  conjunction  of  two  worlds, 
is  possible  and  hopefully  can  lead  to  a  more  holistic  approach 
to  animal  research  in  relation  to  mental  health,  specifically 
the  examination  of  the  continuous  interaction  between  environment 
and  organism. 

Proposed  Course  of  Project:    A  manuscript  is  in  preparation 
which  will  describe  this  collaborative  effort  in  some  detail. 

Honors  and  Awards: 

1.   Invited  paper,  AAAS  Symposium  on  Knowledge  Requirements 
for  Peace:   The  Biological  Basis  of  Destructive  Behavior, 
December,  1971. 

Publications:    None 


4T2 


Serial  No .  M-LBEB-BS-6 

1.  Laboratory  of  Brain  Evolution 
and  Behavior 

2 .  Section  on  Behavioral  Systems 

3.  Poolesville,  Maryland 

PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   Socially  Induced  Dissolution  of  Reproductive 
Capacities  in  Mice 

Previous  Serial  Number:   None 

Principal  Investigator:   Halsey  M,  Marsden 

Other  Investigators:   John  B.  Calhoun 

Cooperating  Units:   Office  of  the  Director,  IR,  NINDS,  NIH 

(Principal  investigator  is  assigned  to  SOBS, 
LBEB,  NIMH) 

Man  Years 

Total:  0.5 

Professional:  0.2 

Other:  0.3 

Project  Description: 

Objectives :   To  examine  the  influence  of  prior  experience  in 
crowded  socio-environmental  settings  on  the  ability  to  reproduce 
in  new  settings  devoid  of  the  inhibiting  or  disruptive  aspects 
or  processes  charcateristic  of  the  former  environment. 

Methods  Employed:   The  subjects  used  to  initiate  the  studies  in 
this  project  were  products  of  studies  included  in  Project  Number 
M-P-C(c)-37.   Data  collection,  data  processing,  and  techniques 
of  observations  adhered  closely  to  methods  which  evolved  from 
that  Project.   Experimental  techniques  included  (1)  drastic  and 
sudden  reduction  of  population  density  in  situ  to  near  optimal 
levels,  (2)  formation  of  small  groups  of  selected  animals  in  new 
environments,  (3)  social  isolation,  and  (4)  exposure  to  normal 
animals  of  the  opposite  sex  either  in  a  group  or  paired  situa- 
tion. 

1.   Study  #122.   At  a  later  stage  in  the  study  of  small 
all-male  groups  selected  from  a  crowded  environment  (See  Project 
Number  M-P-C (c) -37) ,  72  normal  female  mice,  which  had  attained 
prime  reproductive  age  in  6  groups  of  12  each,  were  introduced 
to  the  6  all^-male  groups. 


ii-73 


Serial  No.   M-LBEB-BS-6,  Page  2 

2.  Study  #123.   In  this  closely  related  study,  two  groups 
of  males  (4  in  each  group)  and  two  groups  of  females  (8  in  each 
group)  were  selected  from  a  two-celled  habitat  in  which  success- 
ful reproduction  had  ceased.   These  4  groups  remained  in  the 
habitat.   The  former  environment  was  altered  by  removing  all 
other  animals,  a  reduction  in  density  from  about  160  mice/cell 
to  12/cell.   Following  this  phase  of  study  the  animals  were  re- 
moved from  the  habitat  and  placed  in  new  settings  with  normal 
associates  of  the  opposite  sex.   The  8  males  underwent  two  suc- 
cessive, individual  pairings  with  normal  females.   The  16  females 
were  placed  in  a  new,  identical  habitat  with  an  established 
social  group  of  8  normal  males;  and,  later,  individually  paired 
with  normal  stud  males. 

3.  Study  #126.   Late  in  the  slow-decline  phase  of  popula- 
tion history  m  our  one  remaining  crowded  population,  6  groups 

of  8  animals  (4  males  and  4  females)  were  selected  and  introduced 
to  new  habitats  to  test  reproductive  capability  (8  was  the  number 
of  original  colonizers) .   The  selection  was  biased  toward  "nor- 
mality"-those  animals  most  likely  to  achieve  reproductive  success 
including  (1)  animals  having  been  seen  engaged  in  reproductive 
behavior  in  the  crowded  environment,  (2)  females  visibly  pregnant 
within  the  previous  year,  and  (3)  males  having  recently  shown 
some  degree  of  territorial  behavior. 

Major  Findings; 

1.  Study  #122.   Reproductive  performance  of  the  males 
with  the  normal  female  groups  was  abnormal  and  reflected  the 
social  structure  directly.   The  3  or  4  males  in  each  group  which 
had,  to  varying  degrees,  recouped  the  ability  to  express  domin- 
ance or  territoriality  were  responsible  for  96  of  98  observed 
copulations.   Overall  reproductive  performance  was  poor  across 
all  groups.   Only  15  of  the  72  females  became  pregnant  (in  a 
strain  in  which  over  95%  reproductive  success  is  normally  ac- 
hieved) . 

2.  Study  #123.   Intensive  observations  over  two  months 
revealed  no  reproductive  behavior  among  the  24  animals.   In  the 
new  settings  male  reproductive  failure  continued.   Seven  of  the 
16  females  did  become  pregnant  while  living  with  the  social 
group  of  8  normal  males.   However,  13  of  the  16  females  continued 
to  live  in  the  same  nest  site,  and  this  was  where  all  pups  were 
dropped.   The  nest  was  no  more  than  a  sparse  mat  soaked  with 
urine.   Only  5  pups  survived  to  14  days  of  age.   This  was  a 
dramatic  example  of  retention  of  the  "behavioral  sink"  phenomenon 
m  a  new,  potentially  ideal  setting. 

When  paired  in  individual  cages  with  normal  stud  males  the  16 
females  produced  50  pups.   Upon  autopsy  female  tracts  had  a  total 
of  73  fresh  placental  saars.   Thus  isolation  with  normal  studs 


Serial  No.   M-LBEB-BS-6,  Page  3 

produced  a  marked  improvement  in  reproductive  performance, 
although  there  was  still  evidence  of  maternal  neglect,  canni- 
balism, embryo  resorption  and  possibly  spontaneous  abortion. 

Interestingly,  4  spares,  (2  males  and  2  females)  selected  and 
isolated  at  the  time  of  the  reduction  of  the  population  from 
320  to  24,  were  individually  paired  with  normal  partners.   All 
4  were  successful  reproducers.   Thus  pocial  isolation  appears 
to  have  a  curative  effect  over  time. 

3.   Study  #126.   Two  months  of  behavioral  observation  re- 
vealed no  sign  of  reproductive  activity.   The  study  was  termina- 
ted  and  upon  autopsy  no  female  was  pregnant.   Certainly,  at 
this  stage,  age  could  have  been  a  major  factor. 

Significance  to  Bio-medical  Research  and  the  Program  of  the 
Institute:   It  xs  concluded  that  exposure  to  high  density  living 
can  result  in  a  total  loss  of  capacity  to  reproduce  within  a 
population  of  mice.   This  loss  is  largely  irreversible,  at  least 
in  social  groups,  in  new  environments  potentially  devoid  of 
crowding  influences.   Reproduction,  in  the  sense  of  carrying 
viable  offspring  past  the  weaning  stage,  involves  the  most  com- 
plex series  of  behaviors  of  which  a  mouse  is  capable.   If  the 
parallel  is  made  with  the  human  scene  the  focus  must  be  on  the 
most  complex  human  attributes,  particularly  the  capacity  to 
effectively  create  and  mentally  transmit  ideational  information. 

Proposed  Course  of  Project;   The  last  male  mouse  in  the  popula- 
tion should  die  sometime  this  summer.   Extreme  age  now  appears 
to  be  the  major  limiting  factor  and  further  tests  of  reproductive 
capacity  are  not  planned. 

Honors  and  Awards:      None 
Publications:      None 


J+T5 


Serial  No.  M-LBEB-BS-7 

1.  Laboratory  of  Brain  Evolution 
and  Behavior 

2.  Section  on  Behavioral  Systems 

3.  Poolesville,  Maryland 

PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   Rhythms  of  Spontaneous  Behavior 

Previous  Serial  Number:   None 

Principal  Investigator:   John  B.  Calhoun 

Other  Investigators:   Halsey  M.  Marsden 

Cooperating  Units:   Olfice  of  the  Director,  IR,  NINDS,  (Marsden 

assigned  to  SOBS,  LBEB,  NIMH  from  NINDS) 
Man  Years 

Total:         .4 

Professional:  .2 

Others         .2 

Project  Description: 

Objectives:    To  investigate:   (1)   the  variability  of  behaviors 
over  the  24-hour  cycle;  (2)  the  durations  of  behaviors;  and  (3) 
the  sequence  of  behaviors,  with  reference  to  determing  how  these 
three  characteristics  of  behavior  are  influenced  by:  (a)  social 
or  experiential  history;  or  (b)  concurrent  changes  in  the 
environment. 

Methods  Employed:    Two  methods  are  employed:   (1)  observation 
of  distinctively  marked  rats  or  mice  in  complex  social  settings; 
(2)   removal  of  individuals  with  known  social  histories  and 
isolating  each  in  an  RSB  (rhythms  of  spontaneous  behavior) 
apparatus  that  continuously  records  the  start  and  stop  times  of 
the  several  major  behaviors  possible  in  this  restricted  setting. 

Major  Findings;   On  the  basis  of  similarity  of  prior  history  16 
groups  of  12  mice  were  identified.   The  members  of  each  group 
represented  a  distinct  behavioral  type.   These  groups  lived  in 
and  were  representative  of  a  total  population  of  1800.   Each 
group  exhibited  a  distinctive  24-hour  cycle  of  activity.   These 
findings  indicate  the  capacity  of  a  social  system  to  reduce 
conflict  through  differential  usage  of  time  by  contained 
behavioral  types.   From  analysis  of  the  RSB  apparatus  data  it 
has  been  found  that  every  individual  may  be  described  in  terms 
of  four  probability  functions  which  characterize  every  behavioral 
state/  6:(1)  p'  is  the  probability  of  terminating  the  ongoing  6 
in  a  fixed  next  unit  of  time,  t;  '.2)  p"  is  the  probability  that 
the  p'  related  signal  can  function;  (3)  p  is  the  probability 


Serial  No.  M-LBEB-BS-7,  Page  2 

that  a  particular  g  has  of  being  initiated  after  termination  of 
an  ongoing  6  ;  (4)  p   is  the  probability  of  entrainment  of  one 
6  after  another  B.   ^Drive  becomes  equivalent  to  p.   Motivation 
becomes  a  function  of  p'  and  p" .   Mood  is  the  setting  of  these 
four  probabilities  at  any  time.   Emotion  is  a  function  of  the 
change  in  these  probabilities  between  time  t  and  t  +  1;  the 
greater  the  degree  of  change,  the  more  heightened  is  the 
emotional  state.   Emotion,  so  defined,  increases  in  proportion 
to  changes  in  the  physical  and  social  environment,  away  from 
prior  experience. 

Significance  to  Bio-medical  Research  and  the  Program  of  the 
Institute ;   As  population  density  increases  members  of  the 
population  mutually  interfere  with  each  other's  access  to 
resources.   Knowledge  about  the  distribution  of  individuals 
over  time  will  facilitate  the  reduction  of  conflicts  arising 
over  their  distribution  over  space.   These  studies  of  rhythms 
of  spontaneous  behavior  have  resulted  in  operationally  definable 
measures  of  motivation,  drive,  emotion  and  mood  that  may  prove 
useful  in  other  areas  of  animal  and  human  behavior. 

Proposed  Course  of  Project;   The  currently  developed  "socioenviron- 
ometer"  permits  continuous  recording  of  all  major  behavioral  states 
and  their  changes,  in  all  members  of  a  population.   Focus  in  FY  '73 
will  be  placed  on  this  tool  to  determine  the  influence  of  endogenous, 
social,  and  environmental  factors  in  modifying  the  expression  of 
sequential  behaviors  of  individuals. 

Honors  and  Awards: 

1.   Principal  investigator  presented  two  lectures  on  the 
above  topics  at  the  1971-1972  Nebraska  Symposia  on 
Motivation. 

Publications:   None 


i^78 


Serial  No.  M-LBEB-BS- 8 

1.  Laboratory  of  Brain  Evolution 
and  Behavior 

2.  Section  on  Behavioral  Systems 

3.  Poolesville,  Maryland 


PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  19  72 


Project  Title; 


An  Automated   System 
Context  Behavior 


for  Monitoring  In- 


Previous  Serai  Number:   None 

Princip    Investigator:   John  B.  Calhoun 

Other  Investigators:   Gerald  G.  Wheeler,  Leonard  E.  Olson, 

Halsey  M.  Marsden 


Cooperating  Units; 


Office  of  the  Director,  IR,  NINDS  (H.  M. 
Marsden  assigned  to  SOBS,  LBEB,  NIMH  from 
NINDS) 


Man  Years 

Total:  2.1 

Professional:  1.3 

Other:  0.8 

Project  Description: 

Objectives:   To  develop    an  automated  system  for  monitoring 
activities  of  individuals  and  groups  of  domesticated  rats  in 
specially  designed  environments.   Valid  animal  research  of  this 
kind  requires  minimizing  physical  constraint  and  handling  of  the 
animals,  collecting  continuous  data  for  a  long  period  of  time 
(generations) ,  and  structuring  the  physical  environment  to  pro- 
mote expression  of  behaviors  specific  to  the  genetic  template  of 
the  animals.   Therefore,  the  objective  includes  the  capacity  to 
record  subsets  of  behaviors  of  each  member  of  a  group  of  unrestrain- 
ed    animals  (N)  within  a  bounded  environment  (E)  over  a  period 
(T) .   With  a  projected  N  of  500;  E  of  ten,  730  cubic  feet  habi- 
tats; and  T  of  1-3  years. 

Methods  Employed :   In  the  whole-system  test  now  being  conducted, 
the  activities  of  ten  separately  identified  rats  are  being 
monitored  24  hours  a  day  in  one  of  the  designed  environments. 
The  9'  X  9'  X  9'  environment  is  divided  into  physically  separated 

zones  with   different  resources  within  them food,  water,  nest 

boxes,  open  spaces,  etc.   The  animals  are  free  to  move  at  will 
between  these  zones.   To  pass  from  one  to  another,  however,  they 
must  move  through  an  animal  detection  portal.   The  portal  is  a 


1^79 


Serial  No.   M-LBEB-BS-8,  Page  2 

short  (4")  tunnel  whose  wall  is  made  of  concentric  electromag- 
netic drive  and  detector  coils.   Each  animal  is  implanted  (be- 
neath the  abdominal  skin)  with  a  glass-enclosed  resonator  cir- 
cuit which  is  excited  into  oscillation  at  a  unique  frequency  by 
the  pulsed  field  of  the  drive  coil.   Twin  detector  coils  in  the 
portal  measure  this  frequency,  and,  using  the  sequence  of  detec- 
tion, determine  the  direction  of  the  animal  in  passage.   The 
unique  frequency  (the  unique  animal  identification  number)  and 
the  passaged  direction  is  relayed  to  a  small  computer.   The  19 
portals  nov7  installed  are  connected  in  parallel  to  the  computer 
through  a  scanning  device  which  allows  storage  of  passage  data 
from  several  portals  simultaneously.   When  the  central  processor 
is  free,  the  passage  data  is  associated  with  the  particular 
portal  from  which  it  came  and  with  the  time  for  the  event  derived 
from  a  real-time  clock. 

Data  collected  via  this  automated  system  is  coupled  to  data  from 
visual  observations  both  to  provide  systems  reliability  checks 
and  possible  new  insights  into  social  dynamics  not  programmed 
for  automated  collection.   Most  of  the  user's  information 
requirement  regarding  movements  and  social  interactions  can  be 
satisfied  through  this  dual  data  collection  methodology. 

Major  Findings:   The  system  elements  which  sense  and  relay 
portal  passage  have  proved  very  reliable  and  accurate  (.001 
error) .   Contrasting  this  method  with  human  observation  techniques, 
the  automated  system  is  900  times  as  efficient  (measured  in  man 
years) .   Although  other  elements  are  still  undergoing  minor 
modification,  headway  has  been  sufficient  to  provide  data 
adequate  to  program  expanded  application  and  verify  that  such 
an  automated  animal  monitoring  system  holds  great  promise. 

Significance  to  Bio-Medical  Research  and  the  Program  of  the 
Institute :   The  system  is  a  sophisticated  and  sensitive  tool 
for  research.   For  that  part  of  our  research  which  focuses  on 
the  promotion  of  mental  health  through  an  understanding  of  the 
biological  and  physical  determinants  of  social  organization 
it  has  provided  otherwise  unobtainable  data  on  how  animals  "use" 
their  environment  and  are  affected  by  it.   This  tool  provides 
knowledge  about  such  basic  concepts  as  territoriality,  dominance- 
subordinance  hierarchy,  stereotopy  or  fixation  in  movement 
patterns,  and  the  internal  (central)  programming  of  resource 
utilization. 

The  tool  provides  input  to  these  and  other  conceptual  areas 
where  the  significance  and  potential  application  of  findings 
demand  studying  animals  in  a  social  context.   With  this  capacity, 
a  wide  range  of  bio-medical  problems  can  be  addressed  including: 
the  effect  on  mental  health  of  an  inordinant  (to  the  biological 
system)  number  of  social  contacts  (e.g.  overpopulation/crowding), 
and  the  effect  on  both  individual  and  group  of  psycho-physio- 

1+80 


Serial  No.  M-LBEB-BS-8,  Page  3 

logical  stress  (e.g.  drugs). 

To  make  major  decisions  affecting  society's  mental  health,  it  is 
imperative  that  input  from  the  bio-medical  sciences  include 
animal-in-context ,  long-term,  sensitive  information  that  the 
kind  of  tool  being  developed  here  can  provide. 

Proposed  Course  of  Project;   Following  some  minor  systems 
modification  and  testing,  full-scale,  uninterrupted,  operation 
for  three  months  will  be  conducted.   Resulting  data  will  be 
analyzed  and  the  whole  system  evaluated.   Contingent  on 
performance,  economics,  and  human  resources,  the  system  will 
be  expanded . 

Honors  and  Awards:      None 
Publications:         None 


481 


'/- 


Serial  No.  M-LBEB-BS-9 

1 .  Laboratory  of  Brain  Evolution 
and  Behavior 

2 .  Section  on  Behavioj:a,l  Systems 

3.  Poolesville,  Maryland 


PHS-^HSMHAtNIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   Population,  Space  and  Mental  Health 

Previous  Serial  Number:   M-P-C^CC)-38 

Principal  Investigator:   John  B.  Calhoun 

Other  Investigators:   None 

Cooperating  Units:   None 


Man  Years 

Total 

0.3 

Professional : 

0.2 

Others: 

0.1 

Project  Description: 

Objectives:   To  develop  methodologies  for  determining  the  impact 
of  environmental  and  population  changes  on  mental  health. 

Methods  Employed:   Focus  is  here  placed  on  one  specific  aspect  of 
this  broader  problem  area.   Large  bodies  of  published  data  are 
abstracted.   The  abstracts  are  then  indexed  and  generic  concepts 
established  that  encompass  many  contained  index  term  descriptors. 
For  the  present  year  emphasis  has  been  placed  on  developing  the 
network  of  generic  concepts.   The  basic  data  consists  of  2500 
concept  equivalences  permutated  from  A  =  B  to  B  =  A,  thus  forming 
5000  equivalences.   Each  such  equivalence  pair  was  placed  on  a 
punched  card  and  then  sorted  alphabetically  to  indicate  all  the 
equivalences  to  each  concept  descriptor.   Generic  concept  networks 
are  then  developed  as  a  means  of  more  creative  search  of  the 
information  pool  in  a  manner  simulating  brain  function. 

Major  Findings ;So  far  the  network  has  been  traced  seven  steps  from 
the  near-central  concept  of  "loneliness".   This  has  sufficed  to 
show  that  the  network  is  three  dimensional  and  that  ten  steps 
will  suffice  to  encompass  the  entire  domain  of  concern  falling 
under  the  rubric  of  "population  and  mental  health" .   The  effort 
has  involved  three  major  steps  in  the  creative  process, 
selectivity,  condensation  and  appropriateness  of  relationship. 
350  source  documents  were  selected  from  a  much  larger  pool.   These 
were  then  condensed,  in  the  author's  own  words  to  3200  excerpts 

k83 


Serial  No.  M-LBEB-BS-9,  Page  2 

of  20  line  average  length.   A  record  was  kept  of  the  excerpt  of 
origin  of  each'  generic  equivalence  associations.   Then  the 
concept  linkages  between  "awareness"  and  "responsibility"  on  one 
side  of  the  network  through  "loneliness"  to  "blindness"  and 
"violence"  on  the  opposite  were  determined.   With  very  minor 
editing  these  excerpts  were  then  strung  together  in  the  exact 
pattern  dictated  by  the  network  to  form  an  anthology  titled 
"Seven  Steps  from  Loneliness". 

Significance  to  Bio-medical  Research  and  the  Program  of  the 
Institute :    If  the  theoretical  and  empirical  efforts  continue 
to  prove  as  successful  as  they  have  to  date,  they  should  culminate 
in  the  development  of  procedures  for  computer  composition  of 
consensual  or  creative  documents.   Knowledge  of  the  network  of 
generic  concepts  will  permit  the  writing  of  computer  programs 
which  will  simulate  the  manner  in  which  the  individual  human 
brain  utilizes  stored  information  for  reassembly  into  a  written 
document.   This  effort  should  culminate  with  strategies  for 
information  processing  that  will  contribute  to  the  resolution 
of  the  information  overload  now  confronting  intellectual 
endeavors . 

Proposed  Course  of  the  Project;    This  information  processing 
methodology  will  be  refined  during  FY  '73. 

Awards  and  Honors; 

1.  Prepared  an  analysis  and  condensation  of  the  document 

on  subject  area  IV,  Agenda  Item  13  on  the  informational, 
educational,  social  and  cultural  implications  of  the 
environment  that  will  be  discussed  at  the  United  Nations 
Conference  on  the  Human  Environment  June  6-15,  1972. 
This  was  for  transmittal  by  the  Director,  NIMH  to  the 
Secretary,  HEW,  as  background  for  the  U.  S.  position  on 
this  subject. 

2.  Asked  to  represent  NIMH  on  the  HSMHA  ad  hoc  committee  J 
for  establishing  an  Environmental  Impact  Statement  % 
Coordinating  Unit  in  HSMHA  to  assure  conformity  with 

PL  90-190  Sec.  2 (C) . 

3.  Presented  a  seminar  titled  "R  evolutionary  Mental  Health" 
to  the  Community  Mental  Health  Support  Branch,  NIMH,  on 
April  14,  1972. 

4.  Continued  as  special  consultant  to  the  Committee  on 
Preventive  Psychiatry  of  the  Group  for  the  Advancement 
of  Psychiatry,  re  the  preparation  of  their  report 
relative  to  population  and  mental  health. 


k8k 


Serial  No.  M-LBEB-BS-9,  Page  3 

Invited  to  participate  in  the  May  5-8,  1972  NASA 
sponsored  forum,  "Information~Interactions  in  the  Next 
Generation"  to  explore  the  social,  cultural,  political 
and  biomedical  implications  of  current  and  anticipated 
breakthrough  in  communication  systems  and  technologies. 

Presented  a  seminar  to  the  Institute  for  Psychiatry  and 
Foreign  Affairs,  Smithsonian  Institution's  Members  of 
the  Seminar  titled  "Man's  Internal  Environment",  April 
19,  1972. 


Publications : 


Calhoun,  J.B.:   The  positive  animal:   Increased  human 

potentiality  enhances  stability  of  the  total  ecosystem 
and  preserves  evolution.   Man-Environment  Systems .   CI: 
1-5,  1971. 

Calhoun,  J.B.:   The  declaration  of  environment.   J .  Environ . 
Health.  34(4):  357-364,  1972. 

Calhoun,  J.B.:   Control  of  population:  Numbers;   Environment 
&  society  in  transition.   Ann  NY  Acad  Sci.   184:  148-155, 
1971. 


1*85 


Serial  No.  M~CM-DN-1 

1.  Laboratory  of  Cerebral  Metabolism 

2.  Section  on  Developmental 

Neurochemistry 

3.  Bethesda,  Maryland 


PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 


Project  Title:   The  mechanism  of  action  of  thyroxine  and  its 
relation  to  cerebral  metabolism 

Previous  Serial  Number:   Same 

Principal  Investigator:   Louis  Sokoloff,  M.D. 

Other  Investigators:   Patricia  A.  Roberts,  Barbara  A.  Jant , 

Elaine  E,  Kaufman,  Oilman  D.  Grave, 
Glenna  G.  Fitzgerald,  John  E.  Kline  and 
Esther  L.  Lewis 


Cooperating  Units: 

Man  Years; 

Total: 

Professional; 

Other: 

Project  Description; 


None 


6.75 
2.75 
4.00 


Objectives:   The  ultimate  goal  of  this  project  is  the 
elucidation  of  the  role  of  the  thyroid  hormone  in  the  maturation 
and  development  of  the  brain  and  the  influence  of  the  hormone  in 
the  regulation  of  cerebral  metabolic  processes.   A  necessary 
intermediate  objective  is  the  determination  of  the  molecular 
mechanisms  of  the  physiological  and  biochemical  actions  of  the 
thyroid  hormone.   Earlier  work  done  previously  in  this  project 
demonstrated  a  stimulating  action  of  thyroid  hormones  on 
protein  biosynthesis.   The  mechanism  of  action  of  thyroxine 
still  remains  the  primary  focus  of  the  project. 

Methods  Employed:   The  effects  of  thyroid  hormones  on 
radioactive  amino  acid  incorporation  into  protein  are  examined 
in  cell-free  protein  synthesizing  systems  from  various  mammalian 
tissues,  such  as  liver,  brain,  reticulocytes,  etc.   Studies  are 
occasionally  carried  out  in  vivo,  in  which  the  uptake  of  amino 
acids  into  protein  in  various  tissues  is  measured  in  the  intact 
animal  or  the  effects  of  experimentally  induced  thyroid  disease 


k8j 


Serial  No.  M-CM-DN-1,  Page  2 

on  various  metabolic  activities  are  examined.   A  wide  variety 
of  enzyme  purification  and  assay  procedures  are  also  employed. 

Major  Findings:   The  major  accomplishment  of  this  project 
thus  far  is  the  demonstration  for  the  first  time  that  thyroxine 
stimulates  protein  biosynthesis  and  that  this  effect  is  probably 
primary  to  most  of  the  generally  recognized  physiological  actions 
of  the  thyroid  hormones.   Thyroxine,  administered  ^^  vivo  or 
in  vitro,  stimulates  amino  acid  incorporation  into  protein  in 
"cell-free  rat  liver  preparations.   Conversely,  hypothyroidism 
induced  by  surgical  thyroidectomy,  results  in  a  reduction  in 
the  rate  of  amino  acid  incorporation  into  protein  in  similar 
preparations,  indicating  that  the  thyroid  effect  on  protein 
biosynthesis  is  tonically  active  and  physiological. 

The  biochemical  mechanism  of  the  thyroxine  stimulation  of 
protein  biosynthesis  has  been  studied  in  considerable  detail  in 
completely  in  vitro  systems.   Thyroxine  added  in  vitro  to  cell- 
free  liver  Homogenates  stimulates  amino  acid  inc'or por a t i on  into 
protein.   The  in  vitro  thyroxine  effect  is  preceded  by  a  5  to  7 
minute  latent  period  preceding  the  stimulation.   This  lag  can  be 
eliminated  by  preincubation  for  a  similar  amount  of  time, 
provided  thyroxine,  mitochondria,  and  an  oxidizable  substrate 
are  present  during  the  preincubation.   The  thyroxine  effect 
exhibits  an  absolute  requirement  for  mitochondria  and  an 
oxidizable  substrate;  when  these  components  of  the  system  are 
replaced  by  an  alternative  ATP  generating  system,  such  as 
creatine  phosphate  and  creatine  kinase,  there  is  no  thyroxine 
effect  although  the  control  rate  of  amino  acid  incorporation 
into  protein  is  essentially  the  same  as  with  the  mitochondrial 
system.   Although  the  mitochondria  are  essential  for  the  effect, 
the  thyroxine  effect  is  to  stimulate  amino  acid  incorporation 
into  microsomal  protein.   The  thyroxine  effect  on  protein 
synthesis  is  not  direct,  however.   It  has  now  been  established 
that  thyroxine  must  first  react  with  some  mitochondrial 
component  in  an  energy-dependent  reaction  during  the  latent 
period  to  produce  an  as  yet  unidentified  product(s)  which  in 
turn  act(s)  on  the  ribosomal  protein  synthesizing  machinery  to 
enhance  the  rate  of  polypeptide  chain  elongation  and  completion. 
It  has  been  found  possible  to  carry  out  this  preliminary 
reaction  under  controlled  conditions,  then  remove  the  mitochondria, 
add  the  residual  soluble  components  of  the  mixture  to  a  protein 
synthesizing  system  supported  by  a  creatine  phosphate-ATP 
generating  system,  and  observe  the  thyroxine  stimulation.   These 
results  indicate  the  presence  of  the  active  factor(s)  formed  by 
the  interaction  of  thyroxine  and  mitochondria  which  is  (are) 
responsible  for  the  thyroxine  stimulation  of  protein  biosynthesis. 
The  Section  has  been  carrying  out  a  series  of  experiments  aimed 


Serial  No.  M-CM-DN-1,  Page  3 


at  isolating,  purifying,  and  identifying  the  active  agent(s) . 
The  results  thus  far  indicate  that  its  production  by  the 
thyroxine-mitochondrial  system  requires  a  high  energy  compound, 
probably  ATP.   It  can  be  prepared  in  soluble  form  and  stored  at 
-20°C  for  several  months  without  loss  of  activity.   It  is  a 
small,  dialyzable,  heat-stable,  acid-labile,  moderately  base- 
stable,  organic,  anionic  substance.   It  does  not  extract  into 
butanol,  indicating  that  it  is  not  an  iodothyronine  derivative. 
During  the  past  year  studies  have  been  continued  to  be  directed 
at  identifying  this  active  agent  both  by  defining  further  the 
properties  of  the  stimulating  activity  as  well  as  by  examining 
possible  candidates  for  the  putative  agent.   Cyclic  AMP,  which 
is  known  to  regulate  a  number  of  intracellular  metabolic 
processes  in  mammalian  cells,  has  been  examined  as  the  possible 
active  agent.   It  has  been  found  that  it  is  capable  of  stimula- 
ting protein  synthesis  in  the  same  assay  system,  but  its  effect 
is  not  nearly  so  great  as  that  of  the  thyroxine-mitochondrial 
factor.   Furthermore,  the  thyroxine  effect  is  additive  with  the 
cyclic  AMP  effect  over  a  wide  concentration  range,  suggesting 
that  cyclic  AMP  is  not  responsible  for  the  thyroxine-mitochondrial 
protein  synthesis-stimulating  activity.   The  identity  of  the 
active  factor  remains  unknown,  but  significant  progress  has  been 
made  in  its  purification  and  characterization. 

Work  on  the  factor  was  temporarily  interrupted  during  the 
past  year  to  examine  a  couple  of  published  allegations  that 
thyroxine  could  stimulate  protein  synthesis  in  vitro  in  systems 
devoid  of  mitochondria.   Experiments  have  been  carried  out  which 
have  conclusively  demonstrated  that  these  alleged  effects  are 
artifactual,  and  the  nature  of  the  artifacts  has  been  identified. 
One  of  the  reported  mitochondria-independent  effects  was  found 
to  be  not  an  effect  on  protein  synthesis  but  a  preservative 
effect  on  ATP  levels  in  the  presence  of  an  ATP-def icient  system. 
The  preservation  of  ATP  was  found  to  be  due  to  an  inhibition  of 
microsomal  ATPase  activity  by  thyroxine.   The  physiological 
significance  of  this  newly-discovered  effect  of  thyroxine  is 
under  study.   The  other  alleged  mitochondria-independent  effect 
of  thyroxine  on  protein  synthesis  was  found  to  be  an  artifact 
rather  than  an  effect  on  protein  synthesis.   Indeed,  it  was 
found  to  be  obscured  by  protein  synthesis.   Inhibition  of  protein 
synthesis  by  removal  of  microsomes,  addition  of  drugs  which 
inhibit  protein  synthesis,  removal  of  energy  sources,  or  dilution 
of  the  l^C-labeled  amino  acid  precursor  by  unlabeled  amino  acid 
of  the  same  species,  all  enhanced  the  effect.   Very  recently  it 
was  found  that  the  stimulation  of  the  incorporation  of  I'^C  into 
protein  did  not  even  represent  an  effect  on  amino  acid  incorpora- 
tion into  protein  but  rather  an  effect  on  the  incorporation  into 


i+89 


Serial  No.  M-CM-DN-1,  Page  4 


soluble  protein  of  a  radioactive  contaminant  of  the  commercial 
14c-labeled  amino  acid  preparation  used  as  the  precursor  for 
protein  synthesis.   These  studies  are  currently  being  completed 
and  organized  in  preparation  for  publication.   These  studies 
have  restored  the  validity  of  the  thesis  that  mitochondria  are 
fundamentally  involved  in  the  mechanism  of  the  stimulation  of 
protein  synthesis  by  thyroid  hormones. 

The  inhibition  of  microsomal  ATPase  activity  has  also 
been  under  study.   Evidence  has  been  accumulating  that  thyroid 
hormones  may  also  have  important  effects  on  the  transport  of  ions 
into  and  out  of  cells.   Experiments  have  been  carried  out  in  this 
laboratory  on  the  effects  of  thyroxine  on  the  various  microsomal 
ATPases  in  rat  liver  cells.   Among  them  is  a  Na+-K+-stimulated 
ATPase  which  is  intimately  involved  in  the  active  transport  of 
Na+  and  K+  between  cells  and  their  external  environment. 
Thyroxine  has  been  found  to  inhibit  the  overall  microsomal 
ATPase  activity.   Attempts  to  identify  which  of  the  various 
ATPases  are  affected  have  thus  far  shown  no  specificity.   In 
intact,  fresh  rat  liver  microsomes,  the  Mg++-,  the  Ca+"'"-,  and 
the  K+,Na+-stimulated  ATPases  are  all  inhibited  by  thyroxine. 
Experiments  to  determine  whether  these  effects  have  physiological 
significance  in  the  intact  animal  will  be  carried  out  soon  with 
a  recently  acquired  atomic  absorption  spectrophotometer  which 
will  permit  the  analysis  of  tissue  ion  concentration  in  experi- 
mental thyroid  disease.   In  the  meantime  the  effects  on  micro- 
somal ATPase  activity,  which  were  originally  discovered  with 
liver  microsomes,  have  been  reexamined  with  brain  microsomes  and 
found  to  be  even  greater  than  in  liver.   Except  for  the  greater 
magnitude,  the  effects  with  brain  microsomes  are  qualitatively 
similar  in  all  respects  to  those  with  liver  preparations. 

Thyroxine  is  known  to  have  profound  effects  on  mito- 
chondrial energy  metabolism.   It  depresses  the  efficiency  of  the 
conservation  of  energy  derived  from  substrate  oxidation  in  high 
energy  phosphate  bonds  such  as  ATP.   A  number  of  amino  acids, 
including  naturally  occurring  species,  have  been  found  in  this 
laboratory  to  stimulate  mitochondrial  respiration  and  associated 
phosphorylation,  effects  which,  in  general,  are  quite  the 
opposite  of  those  of  thyroxine.   The  mechanism  of  this  effect 
may  involve  processes  like  those  affected  by  thyroid  hormones, 
lodohistidine,  histidine,  and  other  amino  acids  have  been  found 
to  increase  the  rates  of  respiration  and  coupled  phosphorylation 
while  thyroxine  depresses  phosphorylation  and  the  efficiency  of 
oxidative  phosphorylation  in  intact  rat  liver  mitochondria.   The 
mechanism  of  the  effects  of  these  amino  acids  on  mitochondrial 
ATP  generation  has  been  under  study  in  this  laboratory.   The 

ii-90 


Serial  No.  M-CM-DN-1,  Page  5 


results  at  present  suggest  that  these  effects  are  related  to  and 
may  be  a  consequence  of  effects  on  adenine  nucleotide  and, 
perhaps,  also  ion  transport  through  the  mitochondrial  membrane. 
Since  ion  transport  and  energy  metabolism  are  known  to  be  closely 
related  in  mitochondria,  these  studies  may  be  of  interest  and 
significance  in  regard  to  the  intracellular  regulation  of  energy 
metabolism  as  well  as  the  mechanism  of  thyroxine  action. 

The  thyroid  hormones  promote  the  structural,  functional, 
and  biochemical  maturation  of  the  brain.   In  addition  to  the 
studies  of  the  mechanism  of  action  of  the  thyroid  hormones,  the 
Section  has  also  been  studying  the  nature  of  the  biochemical 
changes  which  occur  in  the  brain  with  maturation.   A  prominent 
developmental  change  in  the  brain  is  a  rise  in  the  level  of 
mitochondrial  enzymes  involved  in  oxygen  consumption  and  energy 
metabolism  of  the  brain.   One  of  these,  D-P-hydroxybut3rric 
dehydrogenase  (BDH) ,  was  found  in  this  laboratory  to  rise  with 
brain  development  just  like  other  mitochondrial  enzymes  but, 
unlike  these  others,  such  as  cytochrome  oxidase  and  succinoxidase, 
to  decline  again  gradually  following  weaning.   Evidence  has  been 
obtained  that  the  changes  in  the  level  of  this  enzyme  in  brain 
are,  at  least,  in  part  related  to  nutritional  factors.   It  has 
also  been  found  recently  that  hyperthyroidism  shifts  the 
developmental  pattern  in  this  enzyme  to  an  earlier  age  (e.g., 
it  causes  a  more  rapid  and  earlier  rise  in  the  enzyme  level  in 
the  brain,  an  earlier  achievement  of  its  peak  level,  and  an 
earlier  decline) .   Hypothyroidism  would  be  expected  to  shift  it 
in  the  other  direction,  but  these  studies  have  not  yet  been 
carried  out.   In  the  course  of  these  studies  an  interesting 
observation  was  made  which  might  be  a  valuable  model  for  the 
elucidation  of  the  mechanism  of  action  of  thyroxine  in  mitochondria 
Physiologically  active  thyroid  hormones  and  their  analogues  were 
found  in  vitro  to  inhibit  BDH  activity  at  extremely  low 
concenTrations .   The  inhibition  was  found  to  represent  a 
competitive  inhibition  by  the  hormone  of  the  binding  of  the 
normal  substrates  to  the  enzjTne .   The  enzyme  is  a  membrane-bound 
enzyme  in  mitochondria.   Efforts  have  been  initiated  to 
solubilize  and  purify  the  enzyme  so  that  the  mechanism  of  the 
hormone  effect  can  be  definitively  studied.   Progress  has  been 
encouraging,  and  recently  the  enzyme  has  been  successfully 
solubilized  and  partially  purified.   Studies  directed  at  further 
purification  are  in  progress. 

Significance  to  Bio-medical  Research  and  the  Program  of 
the  Institute:   A  unique  feature  of  the  cerebral  metabolism  is 
its  apparent  lack  of  response  to  high  circulating  levels  of 
thyroid  hormone.   An  understanding  of  the  basis  of  this  unique 


ij-91 


Serial  No.  M-CM-DN-1,  Page  6 


behavior  may  reveal  information  concerning  the  metabolism  of  the 
brain  in  health  and  disease.   Also,  the  mechanism  of  action  of 
thyroxine  has  been  under  investigation  for  many  decades,  but  thus 
far  a  satisfactory  explanation  of  the  mechanism  by  which  it 
increases  metabolic  rate,  stimulates  metamorphosis  and  growth, 
or  causes  the  many  disturbances  in  body  physiology  and  bio- 
chemistry in  thyroid  disease  has  eluded  investigators.   The 
solution  of  this  problem  could  then  lead  to  fundamental  advances 
not  only  in  the  understanding  of  how  this  important  hormone 
regulates  bodily  functions  but  also  of  the  nature  of  bodily 
processes  on  which  it  acts.   The  clarification  of  the  relation- 
ship between  its  mechanism  of  action  and  its  effects  on 
development  of  the  brain  might  also  lead  to  a  better  understanding 
of  the  many  biochemical  processes  underlying  the  maturation  of 
the  brain. 

Proposed  Course  of  Project:   The  project  will  be 
continued  essentially  on  the  course  already  indicated.   The  major 
avenues  to  be  pursued  are:   (1)  the  attempts  to  isolate,  purify, 
and  identify  the  product  of  the  thyroxine-mitochondrial  reaction 
responsible  for  the  stimulation  of  protein  biosynthesis;  (2) 
further  studies  on  the  elucidation  of  the  mechanism  of  the 
stimulation  of  the  protein  biosynthetic  processes;  (3)  the 
further  study  of  the  thyroxine  inhibition  of  microsomal  ATPase; 
(4)  further  studies  of  the  biochemical  differences  between 
mature  and  immature  brain  and  the  role  of  thyroxine  in  the 
biochemical  changes  leading  to  maturation  and  development  of  the 
brain;  (5)  purification  of  brain  p-hydroxybutyric  dehydrogenase; 
and  (6)  studies  of  the  mechanism  of  the  inhibition  of  P- 
hydroxybutyric  dehydrogenase  by  thyroxine. 

Honors  and  Awards;   None 

Publications; 

Sokoloff,  L.:   Action  of  thyroid  hormones.   In  Lajtha,  A. 
(Ed.).   Handbook  of  Neurochemistry ,  Vol.  5.   New  York,  Plenum 
Press,  1971,  pp.  525-549. 

Sokoloff,  L.  and  Roberts,  P.  A.:   Biochemical  mechanisms 
of  the  action  of  thyroid  hormones  in  nervous  and  other  tissues. 
In  Ford,  D.  H.  (Ed.) .   Influence  of  Hormones  on  the  Nervous 
System.   New  York/Basel,  S,  Karger,  1971,  pp.  213-230. 


i+92 


Serial  No,  M-CM-DN-1,  Page  7 


Sokoloff,  L.,  and  Raskin,  N.  H.:   Chapter  96.   Thyroid 
Disorders.   In  Shy,  M.,  Appel,  S.,  and  Goldensohn,  E.  (Eds.). 
The  Cellular  and  Molecular  Basis  of  Neurological  Disease. 
New  York,  Lea  &  Febiger,  1969  C  in  press)  , ' 

Sokoloff,  L.:   The  effects  of  thyroid  hormones  on 
protein  synthesis.   In  Methods  in  Investigative  and  Diagnostic 
Endocrinology .   North-Holland  Publishing  Co.,  Amsterdam, 
The  Netherlands,  1970  (in  press) . 


k93 


Serial  No.  M-CM-DN-2 

1.  Laboratory  of  Cerebral  Metabolism 

2.  Section  on  Developmental 

Neurochemistry 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   Studies  on  regional  cerebral  circulation  and 
metabolism 

Previous  Serial  Number:   Same 

Principal  Investigator:   Charles  Kennedy,  M.D. 

Other  Investigators:      Louis  Sokoloff,  Oilman  D.  Grave, 

Jane  W.  Jehle,  John  E.  Kline  and 
Esther  L.  Lewis 

Cooperating  Units:       Martin  Reivich,  M.D.,  Associate 

Professor,  Department  of  Neurology 
University  of  Pennsylvania 
Philadelphia,  Pennsylvania 

Man  Years: 

Total:  2.25 
Professional:  1.25 
Other:         1.0 

Project  Description: 

Objectives: 

1.  To  elucidate  the  patterns  of  development  of  circulation 
and  energy  metabolism  in  various  structural  components  of 
the  developing  mammalian  brain. 

2.  To  quantify  the  effects  of  hyperoxia  on  nucleic  acid 
synthesis  and  cell  division  in  the  developing  brain. 

3.  To  determine  whether  diphenylhydantoin  affects  the 
regional  circulation  of  the  brain  when  given  in  doses 
known  to  increase  the  seizure  threshhold. 

4  .   To  continue  the  development  of  a  method  for  measurement 
of  regional  glucose  utilization  of  the  brain  in  vivo. 


U95 


Serial  No.  M-CM-DN-2 ,  Page  2 

5.   To  determine  the  effect  of  a-aminobutyric  acid  (GABA) 
on  cerebral  blood  flow. 

Methods  Employed: 

1  Regional  circulation  is  measured  by  the  autoradiographic 
14c_antipyrine  technique  developed  in  this  laboratory. 

2  Nucleic  acid  contents  of  brain  tissue  are  measured  by 
the  Santen  and  Agranoff  modification  of  the  original  Schmidt- 
Tannhauser  procedure. 

3  The  method  for  regional  glucose  utilization  is  one  which 
has  been  under  theoretical  development  in  this  laboratory  for 
several  years.   This  is  an  autoradiographic  procedure  m  which 
the  non-metabolized  analogue  of  glucose,  2-deoxyglucose  is  used 
as  a  radioactive  tracer  (14C)  . 


Major  Findings: 

1   The  study  on  the  maturational  changes  in  local  cerebral 
flow  was  completed;  the  manuscript,  including  figures  and  tables, 
has  been  assembled  and  it  has  been  submitted  to  the  Journal  of 
Neurochemistry  for  publication. 

A  study  on  gestational  changes  up  to  the  newborn  period 
in  the  monkey  has  likewise  been  completed,  and  the  manuscript  is 
now  in  preparation. 

2.  The  study  entitled,  "Impairment  of  growth  and  develop- 
ment of  the  rat  brain  by  hyperoxia  at  atmospheric  pressure," 
has  been  published  in  the  Journal  of  Neurochemistry  19:187-194, 
1972. 

3.  Studies  of  the  effect  of  diphenylhydantoin  on  local 
cerebral  blood  flow  in  the  rat  are  in  progress.   This  agent  which 
is  used  primarily  to  control  seizures  has  also  been  found  to  be 
of  value  in  the  management  of  cardiac  arrhythmia.   There  is 
evidence  that  it  acts  to  stabilize  membranes  by  making  more 
efficient  the  cell's  ability  to  maintain  ion  gradients.   Inasmuch 
as  this  action  may  be  associated  with  some  action  on  cellular 
metabolism  and,  therefore  blood  flow,  the  present  study  was 
initiated  to  determine  whether  this  anti-convulsant  agent  may 
have  a  predominantly  local  action  in  the  brain.   The  method  used 
could  establish  the  site(s)  of  such  local  action. 

In  an  initial  series  of  animals  given  20  mgm/kg  of 
diphenylhydantoin  intravenously  values  for  blood  flow  were  the 

1^96 


Serial  No.  M-CM-DN-2,  Page  3 

same  as  in  matched  controls  which  received  saline.   Plasma  levels 
of  diphenylhydantoin ,  however,  were  found  to  be  lower  than  those 
necessary  to  attain  pharmacologic  effects  in  other  species,  i.e. 
<  10  [xg/ml .   Therefore  a  second  series  of  rats  were  given  five 
times  the  dose  of  diphenylhydantoin  (100  mgm/kg) .   This  induced 
lethargy  and  resulted  in  plasma  levels  30  to  50  \ig/ml .      At  this 
dose  there  was  an  effect  on  blood  flow  in  the  cerebellar  nuclei 
and  hippocampus  which  was  higher  than  the  controls  by  16% 
(p  <  0.05)  and  30%  (p  <  0.01)  respectively.   In  the  same  animals 
there  was  an  opposite  effect  on  blood  flow  to  the  auditory 
cortex  and  inferior  colliculus  where  values  were  22%  and  17%, 
respectively,  lower  than  in  the  controls.   In  the  remaining 
structures  no  differences  in  blood  flow  were  found.   The  work  is 
presently  being  pursued  by  administering  a  dose  of  diphenyl- 
hydantoin sufficient  to  attain  levels  between  10  and  20  M-g/ml  of 
plasma.   This  is  the  range  found  in  man  to  be  non-toxic,  yet  one 
in  which  the  anticonvulsant  effect  is  present. 

4 .   Progress  has  been  made  in  the  development  of  a  method 
to  measure  local  glucose  utilization  in  the  various  component 
structures  of  the  brain.   The  method  is  based  on  a  model  which 
assumes  that  l'*C-deoxyglucose  can  be  used  as  a  tracer  for  glucose 
uptake  by  tissues.   The  fact  that  this  substance  is  transported 
in  a  manner  almost  identical  to  glucose,  yet  is  not  metabolized, 
means  that  the  tracer  accumulates  in  the  tissue  at  a  rate  aqual 
to  glucose  utilization.   If  I'^C-labeled-deoxyglucose  is  infused 
into  an  animal,  and  the  changing  concentration  is  monitored  in 
the  arterial  blood,  a  knowledge  of  tissue  concentration  will 
permit  the  calculation  of  the  rate  of  transport  into  that  tissue. 
This  rate  is  directly  proportional  to  the  glucose  utilization  of 
that  tissue.   Alternate  formulations  of  the  relationship  between 
the  history  of  deoxyglucose  in  arterial  blood  and  its  concentra- 
tion in  tissues  in  a  variety  of  experimental  conditions  have  been 
considered.   Experiments  carried  out  in  rats  and  cats  indicate 
that  1)  a  pool  of  glucose  is  of  sufficient  size  to  cause  an  over- 
estimation  of  values;  2)  that  this  pool  rapidly  exchanges  with 
blood.   These  findings  indicate  the  need  to  saturate  such  a  pool 
early  in  the  course  of  the  experiment  so  that  the  net  uptake  of 
tracer  will  be  large  and  thereby  the  error  of  over-estimation 
reduced  to  a  minimum. 

Values  obtained  to  date  are  close  to  those  expected  from 
measurements  made  of  overall  glucose  utilization  in  the  brain. 
It  remains  now  to  test  the  method  under  conditions  which  are 
known  to  affect  blood  flow  only  to  be  sure  glucose  utilization 
remains  unchanged  under  those  conditions,  and  also  to  carry  out 
measurements  under  conditions  known  to  alter  the  cerebral 
metabolic  rate. 


h91 


Serial  No.  M-CM-DN-2 ,  Page  4 


5.   A  study  has  been  conducted  on  the  effect  of  a-amino- 
butyric  acid  (GABA)  on  the  local  cerebral  circulation  of  the 
rat.   This  substance  is  known  to  be  an  inhibitory  neuro- 
transmitter, but  there  is  little  information  on  its  effect  on 
cerebral  vessels.   That  it  might  have  such  an  effect  was 
considered  with  the  recent  disclosure  of  the  presence  of  the 
enzyme  capable  of  generating  GABA  in  blood  vessels  (a-amino- 
butyric  decarboxylase  II)  .   The  infusion  of  even  very  low  doses 
of  GABA  into  rats  (0.3  (xM/kg)  resulted  in  a  10-15%  fall  in 
blood  pressure.   Higher  doses,  variably,  induced  more  marked 
hypotension.   In  the  absence  of  an  accompanying  tachycardia 
this  hypotensive  action  was  thought  to  reflect  vasodilatation. 
However  this  vasodilator  effect  was  not  found  to  alter 
significantly  blood  flow  to  any  of  18  cerebral  structures.   Even 
when  the  dose  was  increased  to  levels  100  or  1000  times  that 
capable  of  inducing  mild  hypotension,  cerebral  blood  flow  was 
unaltered. 

Significance  to  Biomedical  Research  and  the  Program  of 
the  Institute"   The  vast  majority  of  individuals  with  detective 
mental  development  (mental  retardation,  minimal  cerebral 
dysfunction)  are  considered  to  have  suffered  some  derangement 
of  normal  metabolic  processes  during  the  period  of  most  rapid 
brain  growth,  i.e.,  just  before  and  just  after  birth.   Recent 
studies,  both  experimental  and  those  involving  children, 
confirm  the  evidence  that  there  is  a  short  period  of  brain 
growth  when  the  demand  for  substrate  for  energy  and  growth  is 
such  that  deficiencies  result  in  irreversible  deficit.   The 
studies  carried  out  in  this  laboratory  are  an  effort  to  measure 
aspects  of  normal  energy  metabolism  and  the  interdependence  of 
these  on  the  cerebral  circulation.   Our  earlier  work  has  shown 
that  the  developing  cerebral  vasculature  responds  by  marked 
vasoconstriction  when  oxygen  is  present  in  excess.   With  the 
development  of  a  method  for  measuring  local  glucose  utilization, 
it  is  proposed  to  determine  whether  or  not  increases  in  oxygen 
tension  in  the  blood  may  limit  the  supply  of  glucose,  an 
essential  substrate  for  brain  growth  and  function.   The  outcome 
of  such  studies  may  have  direct  bearing  on  current  medical 
practices  in  the  care  of  the  human  newborn,  especially  the 
prematurely  born,  which  are  prone  to  sub-optimal  mental 
development . 

At  the  other  end  of  the  age  spectrum,  normal  mental 
function  is  also  known  to  be  impaired  by  defective  function  of 
the  cerebral  circulation.   The  study  of  the  effect  of 
diphenylhydantoin  on  cerebral  blood  flow  is  timely  in  the  light 
of  recent  reports  suggesting  its  administration  leads  to  a 


J+98 


Serial  No.  M-CM-DN-2 ,  Page  5 


reduction  of  episodes  of  cerebrovascular  occlusion.   Similarly, 
the  study  of  vasoactive  agents,  as  it  may  elucidate  the  brain's 
normal  control  mechanisms  for  regulating  cerebral  blood  flow, 
may  prove  of  great  importance  in  the  prevention  and  control  of 
cerebral  vascular  disease  and  its  consequences  to  mental 
function . 

Proposed  Course  of  Project:   Major  emphasis  will  be  placed 
on  the  development  of  the  method  for  measuring  local  cerebral 
glucose  utilization  and  on  the  testing  of  the  hypothesis  that 
impairment  of  brain  growth  and  development  by  high  oxygen  in  the 
early  postnatal  period  is  the  result  of  reduced  cerebral  blood 
flow  and  restricted  glucose  availability  for  nucleic  acid 
synthesis . 

Honors  and  Awards;   None 

Publications : 

Sokoloff,  L.:  Neurophysiology  and  neurochemistry  of  coma. 
In  Polli,  E.  (Ed.):  Neurochemistry  of  Hepatic  Coma.  New  York/ 
Basel,  S.  Karger.   Exp.  Biol.  Med.  4;15-c?c{,  iiJVi. 

Kennedy,  C,  Grave,  G.  D.,  and  Jehle,  Jane  W.:   The  effect 
of  hyperoxia  on  the  cerebral  circulation  of  the  newborn  puppy. 
Pediat.  Res.  5:659-667,  1971. 

Grave,  G.  D.,  Kennedy,  C.,  and  Sokoloff,  L.:   Impairment  of 
growth  and  development  of  the  rat  brain  by  hyperoxia  at 
atmospheric  pressure.   J.  Neurochem.  19:187-194,  1972. 

Sokoloff,  L.,  Grave,  G.  D. ,  Jehle,  J.  W.,  and  Kennedy,  C.: 
Postnatal  Development  of  the  Local  Cerebral  Blood  Flow  in  the 
Dog.   International  Symposium  on  Cerebral  Blood  Flow  Regulation, 
Acid-Base  and  Energy  Metabolism  in  Acute  Brain  Injuries,  Rome, 
Italy,  October  27-31,  1971.   New  York/Basel.   S.  Karger  (in  press) 

Kennedy,  C,  Grave,  G.  D.,  Jehle,  J.  W.,  and  Sokoloff,  L.: 
Alterations  of  Local  Cerebral  Blood  Flow  Due  to  Exposure  of 
Newborn  Puppies  to  80-90%  Oxygen.   International  Symposium  on 
Cerebral  Blood  Flow  Regulation,  Acid-Base  and  Energy  Metabolism 
in  Acute  Brain  Injuries,  Rome,  Italy,  October  27-31,  1971. 
New  York/Basel.   S.  Karger  (in  press). 


k99 


Serial  No.  M-CM-DN-3 

1.  Laboratory  of  Cerebral  Metabolism 

2.  Section  on  Developmental 

Neurochemistrjr 

3.  Bethesda,  Maryland 


PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 


Project  Title:   Biochemical  bases  of  alcohol  addiction 

Previous  Serial  Number:   M-CS-CM-11 

Principal  Investigator:   Louis  Sokoloff,  M.D. 

Cooperating  Units:       Neil  H.  Raskin,  M.D.,  Department  of 

Neurology,  University  of  California 
Medical  Center,  San  Francisco,  Calif. 

Other  Investigators:      None 


Man  Years: 

Total: 

Professional: 

Other: 

0.25 
0.25 
0 

Project  Description: 

Objectives:   This  project  is  directed  at  the  acquisition 
of  knowledge  of  the  biochemical  changes  associated  with  chronic 
alcohol  ingestion  and  the  integration  of  such  knowledge  into  a 
framework  which  it  is  hoped  will  provide  a  basis  for  the  under- 
standing of  the  mechanisms  underlying  alcohol  addiction  and  the 
withdrawal  effects. 

Methods  Employed:   The  enzymes  associated  with  ethanol 
metabolism  and  that  of  its  products  are  assayed  in  brain,  liver, 
and  other  tissues  of  normal  rats  and  rats  fed  various  amounts  of 
ethanol  for  various  periods.   Evidence  of  enzyme  inductions  or 
repression  by  alcohol  will  be  sought.   Any  changes  in  tissue 
enzyme  levels  will  be  examined  for  possible  effects  on  the 
metabolism  of  other  important  metabolites  on  which  these  enzymes 
could  conceivably  act.   In  parallel  studies  purified  enzymes  of 
the  alcohol  metabolic  pathway  will  be  studied  for  substrate 
specificity  and  their  effects  on  selected  metabolites  known  to 
be  important  in  the  functional  activity  of  the  nervous  system. 
Classical  methods  of  enzymology  will  be  employed. 


501 


Serial  No.  M-CM-DN-3,  Page  2 


Major  Findings:   This  project  is  being  worked  on  in 
collaboration  with  Dr.  Neil  H.  Raskin,  a  previous  Research 
Associate  in  this  Section,  and  presently  an  Assistant  Professor 
in  the  Department  of  Neurology,  University  of  California  Medical 
Center,  San  Francisco,  California.   This  project  had  previously 
demonstrated  by  means  of  a  new  assay  technique  the  presence  of 
alcohol  dehydrogenase,  the  enzyme  responsible  for  the  metabolism 
of  ethanol,  in  the  brain.   Previous  efforts  by  other  investi- 
gators to  find  the  enzyme  in  brain  had  been  unsuccessful  because 
of  inadequately  sensitive  and  specific  methods.   The  kinetic 
properties  and  the  responsivity  to  specific  inhibitors  of  the 
brain  enzyme  have  been  examined  and  compared  to  those  of  the 
liver  enzyme  and  found  to  be  almost  identical.   A  tissue  survey 
of  the  alcohol  dehydrogenase  has  revealed  its  presence  in  all 
tissues  which  exhibit  pathological  changes  with  chronic 
excessive  alcohol  ingestion.   In  studies  in  rats  it  was  found 
that  the  brain  enzyme  activity  uses  about  50%  with  chronic 
alcohol  ingestion.   This  is  in  contrast  to  the  liver  enzyme  which 
remains  unchanged.   This  is  the  first  evidence  of  a  specific 
enzyme  change  in  the  brain  with  alcohol  intake  and  suggests  a 
possible  relationship  to  the  development  of  tolerance  to  ethanol 
and/or  a  biochemical  basis  for  the  development  of  CNS  symptoms 
following  withdrawal  from  alcohol  after  prolonged  ingestion. 
Current  studies  are  underway  to  determine  if  the  enzyme  change 
in  brain  is  associated  with  behavioral  changes.   Preliminary 
results  suggest  that  the  rise  in  brain  alcohol  dehydrogenase 
activity  is  paralleled  by  an  increased  tolerance  for  alcohol, 
but  no  evidence  of  addiction  or  alcohol-withdrawl  symptoms  has 
been  obtained. 

Significance  to  Bio-medical  Research  and  the  Program  of 
the  Institute":   Numerous  drugs  and  chemical  agents  cause 
addiction  which  results  in  withdrawal  symptoms  when  their  use  is 
discontinued.   Alcohol  is  one  of  the  most  common.   Although  it 
is  clear  that  some  biochemical  change  must  have  occurred,  none 
yet  has  been  found  which  could  satisfactorily  explain  the 
phenomenon.   Elucidation  of  the  biochemical  mechanism  of  alcohol 
addiction  might  not  only  serve  as  a  model  for  other  types  of 
addiction  but  might  also  lead  to  a  more  rational  approach  to 
therapy. 

Proposed  Course  of  Project:   Studies  will  be  continued  to 
determine  whether  the  changes  in  brain  alcohol  dehydrogenase 
activity  with  chronic  alcohol  intake  are  associated  with  patho- 
logical, biochemical  and  behavioral  changes.   The  brain  alcohol 
dehydrogenase  will  also  be  purified  and  its  substrate  specificity 
determined  with  particular  emphasis  on  normally  present  brain 


502 


Serial  No.  M-CM-DN-3 ,  Page  3 


metabolites  which  might  be  critical  for  normal  cerebral 
metabolism  and  function. 

Honors  and  Awards:    None 

Publications; 

Raskin,  N.  H.  and  Sokoloff,  L.:   Enzymes  catalysing 
ethanol  metabolism  in  neural  and  somatic  tissues  of  the  rat 
J.  Neurochem.  19:273-282,  1972. 

Raskin,  N.  H.  and  Sokoloff,  L.:   Ethanol-induced 
adaptation  of  enzymatic  activity  in  rat  brain.   Nature  New 
Biology   236:138-140,  1972.  


503 


Serial  No.  M-CM-DN-4 

1.  Laboratory  of  Cerebral  Metabolism 

2.  Section  on  Developmental 

Neurochemistry 

3.  Bethesda ,  Maryland 

PHS-HSMHA-NIMII 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   Regulation  of  protein  synthesis  in  the  brain 

Previous  Serial  Number:   None 

Principal  Investigator:   Michael  J.  Schmidt,  Ph.D. 

Other  Investigators;      Louis  Sokoloff,  M.D. 

Cooperating  Units:       None 

Man  Years: 

Total:  1.25 

Professional:    1,25 
Other:  0 

Project  Description: 

Objectives:   One  of  the  most  prominent  biochemical  changes 
occurring  in  the  brain  during  maturation  and  development  is  a 
change  in  the  rate  of  protein  synthesis.   Earlier  work  in  this 
and  other  laboratories  has  demonstrated  in  the  rat  that  cerebral 
protein  synthesis  proceeds  rapidly  in  the  early  postnatal  period 
but  declines  markedly  as  maturation  is  achieved.   The  initial 
objective  of  this  project  is  the  elucidation  of  the  control 
mechanisms  responsible  for  this  fundamental  biochemical  change 
with  maturation. 

Methods  Employed:   Protein  synthesis  is  measured  in  cell- 
free  preparations  from  brains  of  rats  of  various  ages  from  birth 
to  maturity.   The  soluble  enzymes  and  the  ribosomes,  which 
comprise  the  cellular  biochemical  machinery  for  protein  bio- 
synthesis, are  separated  and  purified  by  a  variety  of  ultra- 
centrif ugation  techniques  and  by  isolectric  precipitation,  salt- 
fractionation ,  gel  adsorption,  and  ion-exchange  chromatographic 
methods.   These  are  recombined  in  reaction  mixtures  containing 
necessary  energy  sources,  cof actors,  and  radioactive  amino  acids 
to  permit  the  process  of  protein  synthesis  to  proceed  under 
optimal  or  test  conditions.   The  influence  of  cyclic  AMP- 


505 


Serial  No.  M-CM-DN-4 ,  Page  2 


stimulated  protein  kinase  on  the  process  of  protein  synthesis  is 
also  under  investigation.   Protein  components  of  the  protein 
synthesizing  system  are  pre-treated  with  ATP-^-^  and  cyclic  AMP- 
stimulated  purified  protein  kinase  enzyme,  and  the  degree  of 
phosphorylation  of  the  protein  components  measured.   The  effect 
of  phosphorylation  of  the  protein  components  on  their  activity 
in  protein  synthesis  is  being  examined  with  preparations  derived 
from  rats  of  various  ages.   Both  endogenous  protein  kinase 
activity  and  phosphate  acceptor  activity  of  the  various  cellular 
fractions  involved  in  protein  biosynthesis  are  being  examined  as 
a  function  of  age.   Particular  attention  is  being  given  to  the 
ribosomal  components  which  are  suspected  to  be  most  altered 
functionally  during  development  of  the  brain. 

Major  Findings:   Previous  work  in  this  laboratory  demon- 
strated  that  protein  synthesis  in  vitro  in  cell-free  preparations 
from  rat  brain  declined  about  75%'  between  the  ages  of  15  days  and 
45-60  daySo   During  this  interval  the  major  part  of  postnatal 
development  and  maturation  of  the  brain  occurs.   These  in  vitro 
data  are  in  close  agreement  with  the  results  obtained  by  otners 
in  vivo,  but  the  in  vitro  methods  permit  more  definitive  studies 
of  the  mechanism  of  the  change.   Other  laboratories  since  have 
demonstrated  that  there  is  a  progressive  decline  in  protein 
synthesis  in  the  brain  with  maturation  and  have  implicated 
functional  changes  in  the  ribosomes  as  being,  at  least  partly  if 
not  completely,  responsible  for  the  change. 

The  principal  investigator  has  previously  found  an  almost 
inverse  pattern  of  change  of  the  cyclic  AMP  system  in  developing 
rat  brain.   This  system  is  relatively  inactive  at  birth  and  then 
rises  to  the  adult  level  during  maturation  of  the  brain.   Cyclic 
AMP  is  known  to  stimulate  the  activity  of  protein  kinase,  an 
enzyme(s)  which  catalyses  the  phosphorylation  of  many  proteins. 
The  question  has,  therefore,  been  raised  whether  the  cyclic  AMP- 
stimulated  protein  kinase  may  not  cause  phosphorylation  of 
proteins  of  the  protein  synthesizing  system  and  thus  modify 
their  activity  in  protein  synthesis.   In  particular,  the 
hypothesis  being  tested  is  that  the  development  of  the  cyclic 
AMP  system  during  maturation  of  the  brain  leads  to  increased 
phosphorylation  of  ribosomal  structural  or  functional  proteins, 
thus  causing  lower  ribosomal  activity  in  protein  synthesis  with 
maturation . 

The  initial  results  have  demonstrated  that  microsomes 
contain  protein  kinase  activity  which  is  stimulated  by  cyclic 
AMP,  but  no  differences  were  observed  with  age  of  the  animal. 
It  has  also  been  found  that  ribosomal  proteins  are  phosphorylated 


506 


Serial  No.  M-CM-DN-4 ,  Page  3 


by  protein  kinase.   Studies  currently  in  progress  are  directed 
at  determining  whether  the  phosphate-acceptor  activity  of  the 
ribosomal  protein  shows  a  pattern  of  change  with  age  and 
maturation  of  the  brain. 

Significance  to  Bio-medical  Research  and  the  Program  of 
the  Institute:   Protein  synthesis  is  a  key  process  involved  in 
the  development  and  maturation  of  all  tissues,  including  the 
brain,  as  well  as  in  the  renewal  of  their  intracellular 
components  and  in  regulation  of  their  biochemical  processes  in 
response  to  physiological,  pharmacological,  and  pathological 
stresses.   A  number  of  syndromes  of  mental  retardation  are 
clearly  the  result  of  some  disturbance  in  the  process  of  protein 
synthesis  or  its  regulation  in  the  brain  during  its  maturation. 
It  is  hoped  that  these  studies  will  shed  some  light  on  the 
normal  mechanisms  of  regulation  of  protein  synthesis  in  the 
brain  during  maturation  so  that  more  directed  and  relevant 
studies  of  the  biochemical  bases  of  the  abnormalities  in  mental 
retardation  can  be  undertaken. 

Proposed  Course  of  Project;   The  project  is  in  its  early 
stages,  and  there  are  a  number  of  options  about  the  course  to  be 
followed  depending  on  the  nature  of  the  initial  results.   The 
emphasis  at  first  is  on  the  development  and  validation  of  the 
methods  to  be  used.   Much  of  this  has  already  been  done,  and  the 
immediate  goal  for  the  coming  year  is  the  determination  of 
whether  there  are  age-dependent  changes  in  ribosomal  protein- 
phosphate  acceptor  activity.   If  so,  then  the  effects  of 
phosphorylation  of  ribosomal  protein  on  protein  synthesis 
activity  will  be  examined. 

Honors  and  Awards;   None 

Publications:        None 


507 


Serial  No.  M-CM-MyC-1 

1.  Laboratory  of  Cerebral  Metabolism 

2.  Section  on  Myelin  Chemistry 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June' 30,  1972 

Project  Title:   Biochemical  studies  on  myelin  and  myelin  basic 
protein 

Previous  Serial  Number:   Same 

Principal  Investigator:   Russell  E.  Martenson 

Other  Investigators:   Marian  W.  Kies  and  Gladys  E.  Deibler 

Cooperating  Units:   None 

Man  Years : 

Total:  3 
Professional:  2 
Others:        1 

Project  Description: 

Objectives:   To  examine  the  relationships  between  structure 
and  biological  activity  of  the  myelin  basic  proteins  (MyBPs)  of 
several  mammalian  and  nonmammalian  species;  to  elucidate  the 
phenomenon  of  charge  heterogeneity  of  pure  guinea  pig  myelin 
basic  protein. 

Methods  Employed:   (1)  Polyacrylamide  gel  electrophoresis; 

(2)  amino  acid  analysis  of  CNS  proteins  and  their  derivatives; 

(3)  chromatographic  fractionation  of  proteins  and  peptides; 

(4)  liquid  scintillation  techniques  for  detection  of  radioactivity, 
and  (5)  specific  chemical  and  enzymic  cleavage  of  MyBPs. 

Major  Findings;   (A)  Microheterogeneity :   Last  year  we  re- 
ported preliminary  studies  aimed  at  exploring  the  relationship 
between  methylation  of  MyBP  and  the  microheterogeneity  observed 
in  MyBP  upon  electrophoresis  or  ion-exchange  chromatography  at 
alkaline  pH.   Recently  an  improved  procedure  has  been  developed 
in  our  laboratory  by  Mrs.  Deibler  for  the  determination  of  methyl- 
ated basic  amino  acids  which  permits  resolution  of  arginine, 
W-N-monomethylarginine  (MMA)  ,  «b>-N,N  ' -dimethylarginine  (SDMA), 
fc>-NjN-dimethylarginine  (UDMA)  as  well  as  mono-  and  dimethyllysine, 
3-methylhistidine,  and  ammonia.   Individual  components  of  guinea 
pig  MyBP  have  been  isolated  and  purified  chromatographically,  and 
acid  hydrolyzates  of  the  purified  components  have  been  analyzed 

509 


Serial  No.  M-CM-MyC-1,  page  2 

for  methylated  basic  amino  acids.   Only  MMA  and  SDMA  are  present 
in  the  purified  components  and  in  the  total  MyBP.   All  6  compo- 
nents contain  MMA  and  SDMA  in  approximately  4:1  ratio,  with  the 
highest  amounts  of  total  methylated  arginine  in  the  least  basic 
components.   The  analytical  values  are  the  first  obtained  directly 
from  total  acid  hydrolyzates  of  individual  components  as  well  as 
total  protein.   The  results  have  shown  conclusively  that  the 
charge  differences  do  not  arise  from  methylation  of  a  single 
arginine  residue  in  the  protein.   Additional  studies  have  sug- 
gested two  entirely  different  factors  contributing  to  the  micro- 
heterogeneity:   one  is  a  modification  of  amino  acid  residues  (not 
methylation  of  arginine)  leading  to  three  different  molecular 
species  of  MyBP,  and  the  second  is  a  removal  of  one  or  both  argi- 
nine residues  from  the  C-terminal  end  of  the  polypeptide  chain. 
Studies  are  currently  underway  to  check  these  phenomena. 

(B)  Identification  of  probable  contaminants  of  purified  MyBP: 
Last  year  we  reported  that  MyBP  preparations  were  accompanied  by 

a  CNS-specific  protein  similar  to  MyBP  in  charge  but  larger  in 
size.   This  minor  component  together  with  others  of  even  higher 
mol.  wt .  have  been  isolated  from  a  bovine  MyBP  preparation  by  gel 
filtration.   The  amino  acid  composition  and  specific  encephalito- 
genic  activity  in  guinea  pigs  of  the  high  mol.  wt .  fraction  is 
identical  with  those  of  the  18,400  mol.  wt .  MyBP.   A  corresponding 
fraction  isolated  from  a  preparation  of  rat  S  MyBP  was  found  to 
be  identical  in  amino  acid  composition  with  the  14,000  mol.  wt . 
rat  S  protein.   Since  the  high  mol.  wt .  components  are  stable  to 
low  pH  and  8  M  urea,  it  is  likely  that  the  high  mol.  wt .  fraction 
consists  of  MyBP  molecules  cross-linked  covalently.   Lack  of  cys- 
tine and  cysteine  and  a  high  content  of  lysine  and  glutamine  in 
MyBP  suggest  the  possibility  of  isopeptide  bonds.   Studies  to 
examine  this  possibility  are  currently  underway. 

(C)  Relation  of  structure  to  biologic  activity:   MyBPs  of 
various  vertebrates,  mammalian  and  submammalian,  have  been  exam- 
ined for  encephalitogenic  activity  in  guinea  pigs  and  Lewis  rats. 
MyBPs  from  mammalian,  avian  (chicken),  reptilian  (turtle),  and 
amphibian  (frog)  species  are  active  in  rats  at  a  level  of  50  (xg; 
those  of  fish  (carp,  shark)  are  completely  inactive.   None  of  the 
MyBPs  from  the  submammalian  species  is  active  in  guinea  pigs  at 
levels  as  high  as  250  \ig .      Guinea  pigs  respond  equally  well  to 

5  Jig  of  all  mammalian  MyBPs  tested  except  the  smaller  of  the  two 
rat  proteins,  which  is  completely  inactive  at  this  level.   In 
contrast,  rats  respond  well  to  guinea  pig  and  both  the  larger  and 
the  smaller  rat  proteins,  but  not  as  well  to  proteins  of  the  other 
mammals  (bovine,  rabbit,  and  human)  at  a  10  jig  level.   The  dif- 
ferent patterns  of  reactivity  of  guinea  pigs  and  rats  to  mammalian 
and  submammalian  MyBPs  suggest  that  the  two  animals  recognize 
different  amino  acid  sequences  in  the  basic  protein  molecule  as 
being  encephalitogenic  determinants.   Other  workers  have  shown 

510 


Serial  No,  M-CM-MyC-1,  page  3 

that  the  guinea  pig  responds  to  the  sequence  Phe-Ser-Trp-Gly-Ala- 
Glu-Gly-Gln-Lys.   Our  experiments  have  shown  that  this  sequence 
is  not  obligatory  for  induction  of  EAE  in  the  rat. 

Significance  to  Biomedical  Research  and  the  Program  of  the 
Institute:   MyBP  is  one  of  the  best  characterized  proteins  of 
the  CNS^  largely  due  to  our  efforts.   Although  its  role  in  human 
autoimmune  disease  still  remains  to  be  defined,  its  use  as  an 
experimental  tool  is  important  because  of  the  possibility  that  a 
peptide  fragment  or  a  modified  MyBP  might  prove  to  be  a  useful 
protective  antigen  in  the  treatment  of  autoimmune  diseases  in 
humans.   Our  careful  studies  on  protein  purification  along  with 
our  development  of  special  analytical  techniques  have  enabled  us 
to  resolve  some  of  the  conflicting  reports  on  the  encephalito- 
genicity  of  MyBPs  from  various  species.   Guinea  pigs,  rats,  mon- 
keys, and  rabbits  have  been  used  for  bioassay  with  apparently 
inconsistent  results.   It  is  now  evident  that  there  are  multiple 
encephalitogenic  sites  in  these  proteins  which  do  not  have  equiv- 
alent activities  in  all  species.   Slight  variations  in  structure 
have  resulted  in  marked  variations  in  activity.   Aside  from  its 
possible  role  in  human  autoimmune  diseases,  MyBP  appears  to  serve 
a  unique  role  in  contributing  to  (or  making  possible)  the  struc- 
tural stability  of  the  myelin  sheath.   Comparative  studies  on  the 
structure  of  MyBPs  of  widely  differing  species,  in  addition  to 
contributing  to  our  understanding  of  autoimmune  phenomena,  should 
enable  us  to  define  those  properties  of  the  protein  that  are 
essential  for  its  function  in  the  myelin  sheath. 

Proposed  Course  of  Project ;   In  order  for  safe  and  effective 
treatment  schedules  to  be  developed  the  specific  antigenic  site 
which  is  involved  in  human  demyelination  must  be  identified  just 
as  it  has  been  for  different  experimental  animals.   Furthermore, 
the  nature  of  the  biochemical  lesion  which  is  triggered  by  the 
immunologic  event  must  be  understood.   We  are  presently  planning 
experiments  designed  to  define  the  encephalitogenic  and  immuno- 
genic regions  in  the  MyBPs  of  several  mammalian  and  submammalian 
species  by  fragmenting  the  proteins  by  specific  chemical  and 
enzymic  agents.   Special  consideration  will  be  given  to  defining 
the  regions  of  MyBP  which  are  encephalitogenic  in  monkeys .   We 
will  continue  to  investigate  the  nature  and  cause  of  microhetero- 
geneity  since  it  is  possible  that  the  effectiveness  of  the  basic 
protein  in  maintaining  the  normal  structure  of  myelin  is  controlled 
through  a  mechanism  which  manipulates  the  charge  on  the  molecule. 
Failure  of  this  mechanism  may  be  the  initial  biochemical  lesion 
in  demyelination. 

Honors  and  Awards:   None 


511 


Serial  No.  M-CM-MyC-1,  page  4 
Publications: 

Martenson,  R.  E.^  Deibler,  G.  E.^  and  Kies,  M.  W.:   Microhetero- 
geneity  and  species-related  differences  among  myelin  basic  pro- 
teins.  In  Rowland,  L.  P.  (Ed.):   Immunological  Disorders  of  the 
Nervous  System,  Proc .  Assoc.  Res.  Nerv .  Ment .  Dis .   Baltimore, 
Md.,  Williams  and  Wilkins,  1971,  Vol.  XLIX,  pp.  76-94. 

Martenson,  R.  E.,  Deibler,  G.  E.,  and  Kies,  M.  W.:   Electropho- 
retic  characterization  of  basic  proteins  in  acid  extracts  of 
central  nervous  system  tissue.   J.  Neurochem.  18:   2417-2426,  1971. 

Martenson,  R.  E.,  Deibler,  G.  E.,  and  Kies,  M.  W.:   The  occurrence 
of  two  myelin  basic  proteins  in  the  central  nervous  system  of 
rodents  in  the  suborders  Myomorpha  and  Sciuromorpha .   J.  Neurochem. 
18:   2427-2433,  1971. 

Martenson,  R.  E.,  Deibler,  G.  E.,  and  Kies,  M.  W.:   Comparison 
of  amino  acid  sequences  of  hypothalamic  peptide,  brain-specific 
histone  and  myelin  basic  protein.   Nature  New  Biology  234:   87-89, 
1971. 

Martenson,  R.  E.,  Deibler,  G.  E.,  Kies,  M.  W,,  McKneally,  S.  S., 
Shapira,  R.,  and  Kibler,  R.  F.:   Differences  between  the  two 
myelin  basic  proteins  of  the  rat  central  nervous  system.   A 
deletion  in  the  smaller  protein.   Biochim.  Biophys .  Acta   263: 
193-203,  1972, 

Martenson,  R.  E.,  Deibler,  G.  E.,  Kies,  M.  W.,  Levine,  S.,  and 
Alvord,  E.  C,  Jr.:   Myelin  basic  proteins  of  mammalian  and  sub- 
mammalian  vertebrates:   encephalitogenic  activities  in  guinea 
pigs  and  rats.   J.  Immun.   (in  press). 

Deibler,  G.  E.,  Martenson,  R.  E.,  and  Kies,  M.  W.:  Large  scale 
preparation  of  myelin  basic  protein  from  central  nervous  tissue 
of  several  mammalian  species.   Preparative  Biochem.  (in  press). 


512 


Serial  No.  M-CM-MyC-2 

1.  Laboratory  of  Cerebral  Metabolism 

2.  Section  on  Myelin  Chemistry 

3.  Bethesda^  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:   Immunological  studies  on  experimental  allergic 
encephalomyelitis  (EAE) 

Previous  Serial  Number:   Same 

Principal  Investigator:   Marian  W.  Kies 

Other  Investigators:   None 

Cooperating  Units:   None 

Man  Years 

Total:  2 
Professional:  1 
Others:        1 

Project  Description: 

Objectives:   Study  of  structural  relationships  among  myelin 
basic  proteins  by  means  of  their  antigenic  reactivity. 

Methods  Employed:   Induction  of  precipitating  antibody  in 
rabbits.   Detection  of  antibody  by  Immunoelectrophoresis  and  a 
new  micro  precipitin  reaction  developed  for  rapid  survey  of  large 
numbers  of  antisera.   Use  of  a  solid  imraunoadsorbent  to  prepare 
pure  (monospecific)  antibodies. 

Major  Findings:   Last  year  we  reported  on  the  development  of 
a  rapid  qualitative  test  suitable  for  monitoring  large  numbers  of 
sera  for  presence  of  specific  antibody.   This  test  has  been  used 
to  help  us  accumulate  a  stock  of  specific  antibody  which  will  be 
used  in  our  analysis  of  antigenic  (i.e.,  antibody -combining)  sites 
on  the  MyBP  molecule.   In  another  project  (MyC-1)  we  have  reported 
on  the  relationship  of  structure  to  the  encephalitogenic  activity, 
i.e.,  this  concerned  the  encephalitogenic  site  in  the  protein 
molecule  rather  than  the  antibody -combining  sites. 

In  the  present  study  we  have  found  that  all  six  mammalian 
MyBPs  we  have  isolated,  except  for  the  smaller  of  the  two  rat  pro- 
teins, are  equally  encephalitogenic  in  the  guinea  pig  and  all 
appear  to  have  equivalent  antigenic  cross  reactivity.   The  smaller 


513 


Serial  No.  M-CM-MyC-2,  page  2 

of  the  rat  proteins  (which  Dr.  Martenson  found  to  differ  from  the 
larger  by  aS  internal  deletion  of  -40  amino  acxd  residues)  reacts 
with  anti-bovine  MyBP  but  gives  a  reaction  of  only  partial  identity 
to  bovine  MyBP.   This  suggests  that  the  deletion  of  ^40  amino  acid 
residues  which  essentially  bisects  the  encephalitogenic  site  ef- 
fective in  guinea  pigs  also  eliminates  at  least  one  of  the  anti- 
genic sites  which  are  shared  by  all  of  the  mammalian  MyBPs .   Two 
submammalian  MyBPs,  chicken  and  turtle,  which  are  nonencephalito- 
genic  in  guinea  pigs,  cross  react  in  the  same  manner  with  mam- 
malian MyBPs,  giving  a  reaction  of  partial  identity  to  the  latter. 

We  have  obtained  sera  which  contain  antibody  both  to  guinea 
pig  MyBP  and  to  species-specific  impurities  in  the  GP-MyBP  prep- 
arations.  Rabbit  MyBP  adsorbed  on  CM-cellulose  can  be  used  to 
remove  antibody  specific  to  MyBP  from  these  sera  leaving  behind 
the  species-specific  antibodies.   These  sera  can  be  used  as  re- 
agents for  assessing  the  purity  of  other  GP-MyBP  preparations. 

Significance  to  Biomedical  Research  and  the  Program  of  the 
Institute:   Highly  specific  precipitating  antibody  is  a  powerful 
tool  in  the  investigation  of  details  of  protein  structure.   This 
technique  will  detect  minor  but  biologically  significant  differ- 
ences among  the  myelin  basic  proteins  of  various  species. 

Induction  of  precipitating  antibody  is  also  the  most  sensitive 
technique  known  to  biologists  for  the  detection  of  traces  of  con- 
taminating proteins  in  a  purified  protein  preparation. 

Proposed  Course  of  Project:   The  new  micro-technique  can  be 
used  for  surveys  of  human  sera.   The  primary  use  of  the  rabbit 
antisera  will  be  to  assist  us  in  further  structural  studies  of 
MyBP  particularly  with  respect  to  cross-reactivity  among  MyBPs  of 
various  species  and  for  the  identification  of  impurities  in 
various  preparations  of  MyBP. 

Honors  and  Awards: 

Dr.  Kies  received  a  Travel  Award  from  The  Freudenberg  Foun- 
dation to  attend  The  Third  International  Meeting  of  The  Inter- 
national Society  for  Neurochemistry,  Budapest,  Hungary,  1971. 


5lh 


Serial  No.  M-CM-MyC-2,  page  3 

Publications: 

Kies,  M.  W.:   Use  of  myelin  basic  protein  for  immunologic  studies 
In  Field,  E.  J.,  Bell,  T.  M.,  and  Carnegie,  P.  R.  (Eds.): 
Multiple  Sclerosis.   Amsterdam,  North-Holland  Publishing  Co., 
1972,  pp.  80-86. 

Kies,  M.  W.,  Martenson,  R,  E.,  and  Deibler,  G.  E.:   Myelin  basic 
proteins.   In  Davison,  A.  N.,  Morgan,  I.G.,  and  Mandel,  P.  (Eds.); 
Structural  and  Functional  Proteins  of  the  Nervous  System  (in 
press)  . 


515 


Serial  No.  M-CM-MyC-3 

1 .  Laboratory  of  Cerebral  Metabolism 

2.  Section  on  Myelin  Chemistry 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:   Studies  on  delayed  hypersensitivity  in  EAE 

Previous  Serial  Number:   Same 

Principal  Investigator:   Bernard  F.  Driscoll 

Other  Investigators:   Marian  W.  Kies 

Cooperating  Units:   None 

Man  Years 

Total:  3 
Professional:  1 
Others:        2 

Project  Description: 

Objectives:   To  study  the  role  of  delayed  hypersensitivity 
in  the  pathogenesis  of  EAE  at  the  cellular  level. 

Methods  Employed:   Induction  of  EAE  by  adoptive  transfer 
can  be  used  as  a  tool  to  study  mechanisms  of  suppression  or 
treatment  of  EAE.   Donor  animals  are  sensitized  with  massive 
doses  of  homologous  myelin  basic  protein  (MyBP)  and  mycobacteria 
(HsyRy) .   Suspensions  of  lymph  node  cells  made  on  day  12  post 
sensitization  are  injected  intraperitoneally  into  normal,  histo- 
compatible  recipients. 

Major  Findings:   It  was  reported  earlier  by  members  of  this 
Section  that  guinea  pigs  made  tolerant  to  EAE  by  either  pre- 
immunization  with  moderate  amounts  of  MyBP  alone  or  by  myco- 
bacteria alone  fail  to  display  either  clinical  or  histological 
signs  of  EAE  when  subsequently  challenged  with  an  encephalito- 
genic  emulsion  (i.e.,  MyBP  plus  mycobacteria).   In  preliminary 
experiments  several  years  ago  with  outbred  guinea  pigs,  we  were 
unsuccessful  in  attempts  to  reverse  EAE  once  clinical  signs  of 
the  disease  had  become  manifest .   Recent  reports  that  monkeys 
had  been  successfully  treated  suggested  that  we  re-examine  this 
phenomenon. 


517 


Serial  No.  M-CM-MyC-3,  page  2 

We  have  observed  that  Strain  13  guinea  pigs  (a  highly  inbred 
histocompatible  strain  produced  by  t^^NIH  Rodent  and  Rabbxt 
Production  Section)  respond  uniformly  to  treatment.   The  guinea 
pigs  Sere  sensitized  with  a  massive  dose  of  MyBP  +  mycobacteria 
(complete  Freund's  adjuvant,  or  CFA) .   Ordinarily  these  guinea 
pigs  would  become  ill  and  begin  losing  weight  on  day  10  or  11 
post  sensitization.   Treatment  was  begun  within  24  hours  of  the 
first  definite  signs  of  illness.   The  control  group  received 
daily  injections  of  incomplete  Freund's  adjuvant,  or  IFA  which 
contains  no  mycobacteria.   The  MyBP-treated  group  received  1  mg 
homologous  MyBP  in  the  same  IFA;  on  nine  subsequent  days  they 
received  0.2  mg  MyBP  in  IFA.   "Treated"  animals  began  to  gain 
weight  within  a  day  or  two  and  rapidly  regained  their  normal 
healthy  appearance.   All  of  the  control  animals  succumbed  to 
EAE  within  2  or  3  days  after  treatment  injections  were  begun. 
No  relapse  occurred  in  the  MyBP-treated  guinea  pigs  for  3  weeks 
following  the  last  injection,  at  which  time  they  were  sacrificed 
for  histologic  studies.   None  showed  histologic  evidence  of  EAE. 
This  experiment  has  been  repeated  2  or  3  times  with  comparable 
results . 

Recently  our  collaborators,  Drs .  Shaw  and  Alvord,  have 
attempted  to  treat  outbred  Hartley  strain  guinea  pigs  with  little 
success.   We  repeated  our  current  experiments  with  outbred  NIH 
guinea  pigs  and  found  also  that  they  were  less  responsive  to 
treatment.   Only  3  of  9  guinea  pigs  treated  with  MyBP  recovered. 
The  recovery  of  these  3  was  just  as  complete  as  was  the  recovery 
of  the  Strain  13  guinea  pigs.   The  rest  continued  to  lose  weight 
and  succumbed  as  rapidly  as  did  the  IFA-treated  controls. 

The  sera  of  treated  and  control  guinea  pigs  were  tested 
for  the  presence  of  antibodies  to  MyBP  bv  radioimmunoassay . 
Each  serum  bound  from  25  to  100  (ig  of  I"'"'^^  MyBP  per  ml.   Sera 
from  treated  and  control  guinea  pigs  were  indistinguishable. 
We  conclude  from  this  that  production  of  antibody  per  se  is  not 
a  factor  in  treatment , 

Another  question  we  asked  concerned  the  requirement  for 
encephalitogenic  activity  and  the  ability  of  the  molecule  to 
reverse  clinical  signs.   Some  rodents  have  two  MyBPs  instead  of 
the  single  one  found  in  guinea  pigs  and  other  mammals.   In  rat 
myelin  the  smaller  BP,  rat  S,  predominates.   The  larger  BP  of 
rat  myelin  closely  resembles  the  corresponding  protein  isolated 
from  myelin  of  other  mammalian  species  with  respect  to  size, 
electrophoretic  behavior  and  encephalitogenic  activity.   Rat  S 
differs  from  rat  L  by  a  deletion  of  *»40  amino  acid  residues. 
This  deletion  bisects  the  portion  of  the  molecule  considered  to 
be  responsible  for  its  encephalitogenicity  in  guinea  pigs.   Thus, 
it  has  a  structure  that  duplicates  about  80%  of  the  guinea  pig 
MyBP,  yet  is  nonencephalitogenic .   Rat  S  in  CFA  is  essentially 

518 


Serial  No,  M-CM-MyC-3,  page  3 

nonencephalitogenic  in  Strain  13  guinea  pigs  at  100  and  500  meg 
levels.   We  therefore  investigated  its  effectiveness  in  treat- 
ment of  guinea  pigs  in  which  EAE  had  been  induced  with  guinea 
pig  MyBP  and  found  rat  S  to  be  incapable  of  reversing  clinical 
signs  of  EAE,   Disease  onset  and  severity  in  4  of  the  5  guinea 
pigs  treated  with  rat  S  were  indistinguishable  from  IFA-injected 
controls . 

Significance  to  Biomedical  Research  and  the  Program  of  the 
Institute:   Although  several  neurologic  diseases  are  thought  to 
be  autoimmune  in  nature  most  investigators  have  failed  to  obtain 
evidence  of  cytotoxic  antibodies  in  humans  with  these  diseases. 
The  current  hypothesis  is  that  sensitized  cells  rather  than 
antibodies  are  responsible  for  CNS  damage.   We  hope  to  use  the 
study  of  treatment  of  EAE  as  an  experimental  tool  to  obtain 
further  information  regarding  the  participation  of  sensitized 
lymphocytes  in  the  pathogenesis  of  EAE:   for  example,  by  studying 
the  effect  of  treatment  of  donors  with  MyBP  on  the  ability  of 
their  lymph  node  cells  to  confer  EAE  on  naive  recipients. 

We  have  also  instituted  a  study  of  the  outbred  NIH  guinea 
pigs  to  see  if  first  generation  offspring  of  treated  survivors 
are  any  more  uniform  in  their  response  to  treatment.   Although 
the  importance  of  genetic  factors  in  the  susceptibility  of  humans 
to  multiple  sclerosis  (MS)  has  not  been  established,  recent 
studies  have  shown  differences  between  MS  patients  and  normal 
adults  in  the  distribution  of  certain  HLA-antigens  in  their 
lymphocytes . 

Proposed  Course  of  Project :   Knowledge  of  structure  of  the 
encephalitogen  has  far  surpassed  information  on  the  role  of 
cellular  sensitivity  in  pathogenesis  of  EAE.   Although  several 
encephalitogenic  sites  have  been  defined,  this  information  fails 
to  clarify  the  nature  of  the  disease  process.   In  theory,  the 
experimental  disease  results  from  the  production  of  MyBP-sensitized 
cells  which  damage  the  target  organ  because  of  some  specific 
reaction  with  intrinsic  antigen.   The  nature  of  this  reaction  or 
the  mechanism  of  participation  of  normal  cells  in  lesion  formation 
remains  obscure.   We  intend  to  continue  our  search  for  these 
"helper"  cells  in  an  attempt  to  define  the  nature  of  their  inter- 
action with  "effector"  cells.   Continuation  of  our  study  of  the 
nature  of  the  binding  site  on  the  lymphocyte  membrane  of 
"effector"  cells  is  also  part  of  our  current  plans. 

Honors  and  Awards:   None 


519 


Serial  No.  M-CM-MyC-3,  page  4 


Publications; 


Levine,  S.,  Sowinski,  R.,  and  Kies,  M.  W.:   Treatment  of  experi- 
mental allergic  encephalomyelitis  with  encephalitogenic  basic 
proteins.   Proc .  Soc .  Exp.  Biol.  Med.  139:   506-510,  1972. 

Kies,  M.  W,:   The  biological  activity  of  myelin  basic  proteins. 
In  UCLA  Forum  in  Medical  Sciences,  Vol.  16  (in  press). 


520 


Serial  No.  M-CM-MeC-1 

1.  Laboratory  of  Cerebral  Metabolism 

2.  Section  on  Membrane  Chemistry 

3.  Bethesda ,  Maryland 

PHS-HSMHA-NIMH 
Individuial  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   Study  of  the  modulation  of  central  nervous 
system  metabolism  and  function  through 
alterations  in  membrane  permeability  and 
transport 

Previous  Serial  Number:   Same 

Principal  Investigator:   Harry  R.  Steinberg,  M.D. 

Other  Investigators:   Ana  Maria  Lennon,  Ph.D.,  James  D.  Brown, 

Carolyn  S.  Cottingham,  and  Louis 
Sokoloff,  M.D. 

Cooperating  Units:     None 

Man  Years: 

Total:  4.1 
Professional:  2.1 
Other:         2.0 

Project  Description: 

Objectives:   Previous  investigation  in  this  laboratory, 
as  well  as  studies  of  others,  indicates  that  the  alteration  of 
membrane  properties  may  play  a  central  role  in  the  modulation  of 
central  nervous  system  (CNS)  activities.   The  objective  of  this 
study  is  to  define  the  mechanisms  by  which  CNS  membranes  may  be 
altered  and  to  relate  these  changes  to  those  caused  physio- 
logically, by  putative  neurotransmitters. 

Methods  Employed:   This  problem  has  been  approached  at 
three  levels  of  complexity.   At  the  highest  level,  intact  cells 
in  an  isolated  tissue  have  been  studied  while  maintaining  many 
of  their  usual  intercellular  relations.   At  the  next  level, 
tissue  homogenates  have  been  fractionated  so  that  specific 
portions  of  the  cells  may  be  subjected,  in  vitro,  to  the  action 
of  various  hormones  and  pharmacological  agents ,  to  demonstrate 
their  action  on  these  subcellular  components  in  the  absence  of 
the  remainder  of  the  cell.   Finally,  the  action  of  these  agents 


521 


Serial  No.  M-CM-MeC-1,  Page  2 

is  observed  in  simpler  systems  containing  partially  purified 
macromolecules  to  provide  further  insight  into  the  mechanism  of 
action   At  all  levels,  alterations  in  the  membrane  constituents, 
their  interaction  with  active  transmitters  and  changes  in 
permeability  are  of  particular  interest.   High  voltage  electro- 
phoresis, column  and  thin-layer  chromatography,  differential  and 
density  gradient  centrifugation ,  and  studies  of  the  turnover  of 
radioactively  labelled  compounds  represent  a  major  portion  of 
the  methodology. 

Major  Findings:   Previous  workers  in  this  laboratory  have 
suggested  a  mechanism  for  the  enhanced  incorporation  of  radio- 
phosphate  into  phosphatidyl  inositol  and  phosphatidic  acid  which 
occurs  in  the  presence  of  ACh  and  eserine.   According  to  their 
proposal,  ACh  increases  the  rate  of  hydrolysis  of  phosphatidyl 
inositol  by  a  phosphatidyl  inositol  hydrolase.   This  reaction 
liberates  membrane  bound  diglyceride  which  is  presumed  to  be 
rate  limiting  in  the  synthesis  of  phosphatidic  acid,  a  precursor 
of  phosphatidyl  inositol.   Evidence  supporting  this  hypothesis 
was  obtained  in  experiments  in  which  guinea  pig  brains  were 
labelled  in  vivo  with  ^H-inositol  and  then  a  crude  mitochondrial 
fraction  was  incubated  with  ACh  and  eserine.   An  increase  of  -^H 
labelled  inositol  phosphates  was  observed.   During  the  past  year 
further  investigation  of  this  system  was  undertaken.   It  has 
been  found  that  inositol  triphosphate  accumulates  during  the 
incubation  period  as  well  as  inositol  monophosphate  and  inositol 
diphosphate.   Furthermore,  it  has  been  shown  that  Ca"^"*"  stimulates 
the  increase  in  inositol  phosphates  observed  during  the 
incubation,  and  EGTA ,  a  Ca^^-chelating  agent,  inhibits  the 
normally  occurring  increase  and  blocks  the  ACh  effect.   EGTA  has 
also  been  found  to  inhibit  the  ACh  stimulated  incorporation  of 
32p  into  phosphatidic  acid, although  basal  ^^P  incorporation  into 
phosphatidic  acid  was  enhanced, in  a  cell-free  preparation  of 
guinea  pig  cerebral  cortex  by  EGTA.   In  other  experiments  the 
role  of  Ca^"*"  in  phosphoinositide  turnover  in  rat  diaphragm  has 
been  studied  and  these  experiments  also  suggest  that  Ca2+  plays 
a  role  in  phosphoinositide  turnover. 

Significance  to  Bio-medical  Research  and  the  Program  of 
the  Institute:   The  mechanism  by  which  neurotransmitters  exert 
effects  on  post-synaptic  and  effector  cells  is  at  present 
unknown.   Elucidation  of  this  mechanism  would  very  probably 
shed  considerable  light  on  the  mechanism  of  action  of  many 
psychotropic  drugs.   Further,  since  many  hallucinogenic  drugs  are 
related  chemically  to  neurotransmitters,  elucidation  of  the 
mechanism  of  transmitter  effect  would  very  likely  greatly  increase 
understanding  of  induced  hallucinations  and  perhaps  naturally 
occurring  hallucinations  as  well.   There  is,  in  addition,  a  great 


522 


Serial  No.  M-CM-MeC-1,  Page  3 


theoretical  interest  in  the  problem  of  how  transmitters  cause 
post-synaptic  and  effector  cell  membranes  to  alter  in 
permeability . 

Proposed  Course  of  Project:   Further  studies  of  phospho- 
inositide  metabolism  and  the  metabolism  of  other  phospholipids 
in  skeletal  muscle  and  nervous  tissues  are  planned. 

Honors  and  Awards:   None 

Publications:        None 


523 


Serial  No.  M  -  LGCB  16B 

1.  Laboratory  of  General  and 
Comparative  Biochemistry 

2.  Section  on  Proteins 

3.  Bethesda,  Maryland 

PHS-HSHMA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:   Amino  Acid  tRNA  Synthetases.   Their  Role  In 
Protein  Synthesis,  and  Interaction  With  tRNA 

Previous  Serial  Number:   M-LGCB  16  and  16A 

Principal  Investigator:   Giulio  L.  Cantoni 

Other  Investigators:   Elizabeth  A.  Boeker 

Cooperating  Units :   None 

Man  Years : 

Total:   2 
Professional:   1 
Other :   1 

Project  Description: 

Objectives:   Aminoacyl  tRNA  synthetases  catalyze  the  first 
reaction  of  protein  synthesis: 

Amino  acid  +  ATP  +  Synthetase  tt  Aminoacyl-AMP-Synthetase 

+  P~P 

Aminoacyl-AMP-Synthetase  +  tRNA  ^  Aminoacyl- tRNA  +  AMP 

+  Synthetase 

Synthetase 
Amino  acid  +  ATP  +  tRNA     ^  Aminoacyl- tRNA  +  AMP 

+  P~P 

The  specificity  of  the  translation  of  genetic  information 
from  DNA  into  linear  polypeptide  chains  depends  critically 
on  the  recognition  by  aminoacyl  tRNA  synthetases  of  their 
specific  amino  acids  and  cognate  tRNA  molecules.   Although 
each  tRNA  has  a  unique  base  sequence,  the  secondary  and 
tertiary  structures  of  these  nucleic  acids  are  all  rather 
similar,  and  the  mechanism  by  which  a  specific  synthetase 
recognizes  the  correct  tRNA  is  not  known.   The  specificity 


525 


Serial  No,  M  -  LGCB  16B,  page  2 

of  this  recognition  cannot  reside  in  the  anti-codon  unique 
to  each  tRNA  since,  in  several  cases,  a  single  synthetase 
recognizes  multiple  tRNA's,  all  coding  for  the  same  amino 
acid  but  having  different  anti-codons.   The  interaction 
between  tRNA  and  aminoacyl  tRNA  synthetases  thus  provides 
an  ideal  system  for  investigation  of  the  mechanism  by  which 
proteins  recognize  nucleic  acids,  a  mechanism  central  to  a 
variety  of  problems  of  great  biological  importance. 

The  aminoacyl  tRNA  synthetases  also  represent  a  family 
of  enzymes  which  catalyze  formally  similar  reactions  with 
different  substrate  specificities.   A  class  of  enzymes  such 
as  this  might  be  expected  to  show  rather  similar  structural 
parameters,  but  simple  structural  analysis  has  already  shown 
that  this  is  not  the  case.   Based  on  the  available  data  for 
the  molecular  weight  and  subunit  structure  of  less  than  half 
of  the  20  synthetases,  at  least  three  classes  are  distin- 
guishable: monomers  with  a  molecular  weight  of  approximately 
100,000,  dimers  with  a  total  molecular  weight  also  approxi- 
mating 100,000,  and  tetramers  with  a  total  molecular  weight 
around  180,000.   The  data  currently  available  are  not 
sufficient  to  interpret  these  differences  meaningfully,  and 
a  great  deal  of  additional  information  will  be  required  to 
achieve  an  adequate  understanding. 

Methods  Employed:   Amino  acid  activation  can  be  measured 
either  by  the  incorporation  of   Prg  into  ATP  (exchange 
reaction)  or  the  incorporation  of   C-serine  into  tRNA 
(acylation  reaction) .   Classical  methods  of  enzymology  and 
protein  chemistry  are  used  in  the  purification  and  structural 
characterization  of  the  synthetase.   In  a  particularly  useful 
feature  of  this  system,  both  the  aminoacyl-AMP-synthetase 
complex,  formed  in  the  absence  of  tRNA,  and  the  synthetase- 
tRNA  complex,  formed  in  the  absence  of  ATP  and  serine,  can 
be  isolated  by  gel  filtration  or  trapped  on  nitrocellulose 
filters,  allowing  independent  evaluation  of  the  characteristics 
of  each  interaction.   The  information  thus  obtained  using 
substrate  levels  of  enzyme  complements  that  obtained  from 
kinetic  analyses  using  catalytic  quantities  of  the  synthetase. 

Major  Findings:   The  serine  tRNA  synthetase  of  E.  coli  B 
has  been  purified  to  homogeneity;  the  procedure  is  adequate 
for  the  isolation  of  sufficient  enzyme  to  carry  out 
structural  studies.   The  enzyme  is  essentially  homogeneous 
by  the  criteria  of  acrylamide  gel  electrophoresis  and  iso- 
electric focusing. 


526 


Serial  No.  M  -  LGCB  16B,  page  3 

To  investigate  the  enzyme-substrate  complexes  formed  by 
the  seryl  tRNA  synthetase,  we  have  employed  equilibrium 
dialysis  and  have  modified  the  gel  filtration  procedure  so 
that  it  is  carried  out  under  steady-state  conditions,  allowing 
quantitative  treatment  of  the  data.   In  the  absence  of  serine 
and  tRNA,  an  enzyme-ATP  complex  (Ka  =  4  X  10'*  M~l)  is  formed; 
the  corresponding  enzyme-serine  complex  has  not  been  detected 
(Ka  <  5  X  10~3  M-1).   In  the  absence  of  tRNA,  an  enzyme-seryl- 
AMP  complex  is  formed;  the  stoichiometry  of  both  complexes  is 
1  mole  of  substrate (s)  per  53,000  g. 

An  extensive  ultracentrifuge  investigation  of  the  free 
enzyme  and  both  complexes  has  revealed  no  substantial 
differences  in  behavior  among  the  three  species.   All  have  a 
molecular  weight  of  ca.  100,000,  a  sedimentation  coefficient, 
^20, w'  ot   5.4  S,  and  a  tendency  to  dissociate  at  low  protein 
concentrations.   Gel  electrophoresis  in  sodium  dodecyl  sulfate 
and  isoelectric  focusing  in  urea  indicate  that  the  native 
enzyme  is  composed  of  two  apparently  identical  subunits  with 
a  molecular  weight  of  53,000  ±  3000.   We  conclude  that  the 
native  enzyme  is  a  dimer  having  two  identical  subunits  and 
two  independent  active  sites. 

At  least  8  kinetically  distinguishable  mechanisms  can  be 
written  for  the  exchange  of  PPj^^'^  into  ATP;  rate  equations 
expressing  the  explicit  dependence  of  the  initial  exchange 
rates  on  substrate  concentrations  have  been  developed  and 
tested.   The  results  indicate  that  the  exchange  reaction 
proceeds  with  ordered  addition  of  substrates  (ATP  first)  and 
two  detectable  ternary  complexes,  enzyme-serine-ATP  and 
enzyme- seryl-AMP.   Additional  kinetic  measurements  in  the 
presence  of  tRNA  show  that  the  acylation  reaction  proceeds 
by  a  similar  mechanism. 

Scientific  Significance:   Interaction  between  nucleic  acids 
and  proteins  is  an  important  biological  phenomenon.   The 
interaction  of  an  amino  acid  tRNA  synthetase  with  the 
corresponding  tRNA  in  a  highly  purified  system  may  afford 
a  useful  model  for  such  interactions  in  general.   In  addition, 
this  study  should  provide  important  information  about  the 
complex  two-step  reaction  catalyzed  by  the  amino  acid  tRNA 
synthetases. 

Proposed  Course  of  Research:   These  studies  will  be  continued 
as  they  are  part  of  the  Laboratory's  long-range  program  on 
the  nucleic  acid  protein  recognition  and  interactions. 


527 


Serial  No.  M  -  LGCB  16B,  page  4 

Honors  and  Awards:   None 

Publications : 

Cantoni,  G.  L. ,  and  Davies,  D.  R.  (Eds.):   Procedures  in 
Nucleic  Acid  Research.   New  York,  Harper  and  Row,  1971, 
vol.  2,  924  pp. 


528 


Serial  No.  M  -  LGCB  18 

1.  Laboratory  of  General  and 
Comparative  Biochemistry 

2.  Section  on  Proteins 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:   Studies  on  the  Structure  and  Function  of  Thetin- 
Homocysteine  Methylpherase  and  Lactose  Synthetase 

Previous  Serial  Nvimber:   Same 

Principal  Investigator:   Werner  A.  Klee 

Other  Investigators:   K.  Subramonia  Iyer  and  Claude  B.  Klee 

Cooperating  Units:   Laboratory  of  Biochemical  Pharmacology,  NIAMD 

Man  Years : 

Total:   2 

Professional:  1-1/2 
Other :   1/2 

Project  Description: 

Objectives :   Macromolecular  complexes  on  many  levels  are 
a  central  principle  of  biological  organization.   This 
project  is  aimed  at  learning  how  the  properties  of  such 
complexes  can  differ  from  those  of  the  isolated  components 
in  two  enzyme  systems.   One  enzyme,  thetin-homocysteine 
methylpherase,  exhibits  a  number  of  interactions  of  like 
protein  species;  the  other,  lactose  synthetase,  is  an  example 
of  an  enzyme  in  which  two  very  different  protein  species 
interact  to  form  the  whole. 

Methods  Employed:   We  are  using  the  standard  methods  of 
protein  chemistry  including  chromatography,  electrophoresis, 
preparative  and  analytical  ultracentrifugation,  spectro- 
photometry and  spectropolarimetry .   In  addition,  many  of  the 
standard  analytical  techniques  of  enzymology  are  being 
employed.   Band  sedimentation  methods  for  studying  macro- 
molecular  interactions  are  being  developed  as  part  of  this 
proj  ect . 


529 


Serial  No.  M  -  LGCB  18,  page  2 

Major  Findings:   Lactose  synthetase  consists  of  two  protein 
components  both  of  which  are  found  in  lactating  mammary 
glands  and  in  milk.   The  two  proteins  are  the  A- protein  and 
a-lactalbumin.   We  have  isolated  the  A-protein  from  milk 
and  shown  it  to  be  a  mixture  of  closely  related  glycoproteins. 
The  A-protein  alone  can  carry  out  galactose  transfer  reactions 
from  UDP-galactose  to  a  variety  of  glycoproteins,  glycolipids 
and  to  some  simple  sugars  such  as  N-acetylglucosamine. 
Although  it  had  at  first  been  believed  that  the  A-protein _ 
will  not  transfer  galactose  to  glucose  (to  make  lactose)  in 
the  absence  of  a-lactalbumin  we,  and  others,  have  found  that 
at  very  high  glucose  concentrations  a-lactalbumin  is  not 
required.   The  effect  of  ot-lactalbtimin  on  the  system  is  to 
produce  a  dramatic  increase  in  the  affinity  for  sugar 
acceptors  be  they  glucose  or  N-acetylglucosamine.   This 
simple  picture  is  complicated  by  the  existence  of  a  substrate 
inhibition  seen  at  high  concentrations  of  acceptor  sugars, 
a-lactalbumin  enhances  this  effect  as  well  and  so  is  seen  to 
stimulate  or  inhibit  glycosyl  bond  formation  depending  on  the 
acceptor  sugar  concentration. 

These  kinetic  observations  made  it  appear  highly  likely 
that  a-lactalbumin  functions  by  combining  with  the  A-protein 
to  form  a  multisubunit  complex.   We  have  found  that  such 
complexes  are  indeed  formed  but  only  in  the  presence  of  one 
of  the  substrates  of  the  enzyme,  either  UDP-galactose  or  N- 
acetylglucosamine.   The  latter  sugar  is  much  more  effective 
than  glucose  by  virtue  of  its  greater  binding  affinity. 
Complex  formation  was  demonstrated  by  a  number  of  methods 
including  a  newly  developed  modification  of  band  sedimentation 
in  the  analytical  ultracentrifuge.   The  complex  contains  one 
molecule  of  A-protein  and  one  molecule  of  a-lactalbumin  and 
is  quite  easily  dissociated.   Although  a-iactalbvimin  is  the 
only  protein  known  to  function  in  this  system,  it  has  been 
found  that  the  only  modifications  to  its  structure  which  will 
prevent  interaction  with  the  A-protein  are  major  ones  such  as 
disulfide  bond  reduction  or  extensive  proteolysis.   Modifica- 
tion of  amino  acid  residues  such  as  tyrosine,  methionine, 
histidine  and  at  least  some  aspartic  and  glutamic  acids 
results  in  only  a  minor  decrease  in  activity.   Thus,  the 
interaction  of  the  two  proteins  may  involve  the  mutual 
recognition  of  large  areas  of  their  surfaces. 

Dr.  Iyer  has  initiated  a  study  of  the  reaction  of  a- 
lactalbumin  with  the  guanidinating  agent  0-methylisourea. 
This  reagent  is  known  to  convert  the  lysine  residues  of 
proteins  to  homoarginine  with  a  high  degree  of  specificity. 
This  modification  has  usually  been  found  not  to  change  the 
biological  activity  of  proteins  (with  the  sole  exception  of 
pancreatic  ribonuclease)  and  so  should  be  a  useful  general 

530 


b 


Serial  No.  M  -  LGCB  18,  page  3 

way  of  introducing  a  radioactive  label  into  proteins, 
a-lactalbumin  can  be  very  highly  guanidinated  without  loss 
of  activity.   At  very  long  times  of  reaction  however  there 
is  a  loss  of  activity  which  can  be  described  by  a  kinetic 
model  assuming  that  11  of  the  12  lysine  residues  of  the 
protein  react  rapidly  and  without  activity  loss  whereas  the 
remaining  lysine  reacts  slowly  and  with  loss  of  activity. 
Physical  studies  have  shown  that  the  activity  loss  is 
associated  with  a  marked  unfolding  of  the  protein  as  well  as 
a  high  degree  of  aggregation.   The  validity  of  the  kinetic 
model  described  above  is  now  open  to  question  since  Dr.  Iyer 
has  been  able  to  fractionate  the  guanidinated  a-lactalbumin 
into  a  series  of  components  by  gel  filtration  which  differ 
in  size,  structure  and  activity  but  apparently  not  in  the 
degree  of  guanidination.   It  appears  that  the  activity  loss 
may  be  an  indirect  result  of  complete  guanidination. 

An  activity  similar  to  or  identical  with  that  of  the 
A- protein  found  in  milk  has  been  reported  to  be  present  in 
particulate  fractions  of  many  tissues.  We  have  therefore 
initiated  an  examination  of  the  properties  of  this  enzyme 
in  a  number  of  tissues  but  have  concentrated  our  attention 
on  brain.   In  the  rat  brain  we  have  found  appreciable  amounts 
of  A-protein  which  are  associated  primarily  with  the 
synaptosomal  fractions,  as  isolated  by  differential  centrifu- 
gation  techniques.   The  enzyme  activity  associated  with  these 
particles  is  not  sensitive  to  modification  by  a-lactalbumin 
unless  it  is  first  converted  to  a  soluble  protein  with 
detergent  treatment.   This  solubilized  enzyme,  from  either 
rat  or  bovine  brain  is  kinetically  indestinguishable  from  the 
A-protein  in  bovine  milk.   It  may  readily  be  purified  by 
affinity  chromatography  on  columns  of  a-lactalbumin  bound  to 
sepharose. 

Scientific  Significance:   The  lactose  synthetase  system 
represents  a  novel  type  of  evolutionary  adaptation  in  which 
an  enzyme  which  is  normally  used  for  glycoprotein  and  glyco- 
lipid  biosynthesis  (the  A-protein)  is  modified  to  accomplish 
a  new  function,  lactose  biosynthesis,  by  complexing  with 
another,  non-catalytic  protein,  a-lactalbtimin.   Thus,  the 
system  is  a  clear  example  of  how  protein  function  can  be 
modified  in  a  dramatic  way  by  incorporation  into  more  complex 
structures.   Furthermore,  the  A-protein  is  known  to  be 
associated  with  membrane  systems  such  as  synaptosomes  and 
liver  cell  membranes  and  may  have  an  important  role  in 
membrane  synthesis  or  function. 


531 


Serial  No.  M-  LGCB  18,  page  4 

Honors  and  Awards :   None 

Publications : 

Klee,  W.A. ,  and  Klee,  C.B,:  The  interaction  of  a-lactalbumin 
and  the  A-protein  of  lactose  synthetase.  J.  Biol.  Chem.  247: 
2336-2344,  1972. 


532 


Serial  No.  M  -  LGCB  35 

1.  Laboratory  of  General  and 
Comparative  Biochemistry 

2.  Section  on  Proteins 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:   Studies  on  Protein  Conformation  and  Limited 
Proteolysis 

Previous  Serial  Number:   Same 

Principal  Investigator:   Werner  A.  Klee 

Other  Investigators :   None 

Cooperating  Units :   None 

Man  Years : 

Total:   3/4 
Professional:   1/4 
Other :   1/2 

Project  Description: 

Objectives:   Although  it  is  now  a  well  established  principle 
that  the  linear  sequence  of  the  amino  acids  of  a  polypeptide 
chain  determines  the  nature  of  the  characteristic  structure 
(conformation)  of  proteins,  the  process  whereby  this  trans- 
formation of  two  dimensional  information  to  a  three 
dimensional  structure  occurs  is  not  well  understood.   The 
ultimate  goal  of  this  project  is  to  supply  experimental  data 
which  may  lead  to  some  insight  into  this  problem.   A  closely 
related  question  which  we  would  like  to  help  answer  is:   What 
is  the  nature  of  the  conformational  changes  which  take  place 
in  protein  systems  and  what  is  the  role  of  such  structural 
flexibility  in  the  functioning  of  macromolecular  systems? 

Methods  Employed:   One  way  of  finding  out  something  of  the 
nature  of  the  conformational  determinants  of  proteins  is  to 
study  the  properties  of  smaller  fragments  of  the  molecules. 
We  have  prepared  a  number  of  peptides  of  overlapping  sequence 
from  three  proteins  by  a  combination  of  proteolytic  and 
chemical  cleavage,  and  are  studying  the  conformational 
properties  of  these  materials  by  physical  methods  which  include 
spectropolarimetry,  ultraviolet  and  nuclear  magnetic  spectros- 
copy, ultracentrifugation  and  titrimetry.   These  studies  are 


533 


Serial  No.  M  -  LGCB  35,  page  2 

performed  over  a  range  of  solvent  conditions  and  temperatures 
and  provide  information  on  the  conformation  of  these  peptides 
in  solution  which  can  then  be  compared  with  the  known 
structures  of  these  materials  when  they  are  part  of  the 
intact  protein  in  the  crystalline  state.   We  also  study  the 
nature  of  the  conformational  changes  in  which  intact  proteins 
participate  on  variation  of  the  state  of  their  environment 
or  as  a  result  of  interactions  with  other  kinds  of  molecules. 
This  work  uses  the  same  kinds  of  physical  methods  described 
above  in  conjunction  with  some  more  subtle  probes  of  structure 
such  as  limited  proteolytic  cleavage  of  exposed  (and  un- 
structured) regions. 

Major  Findings:   We  have  studied  in  detail  the  conformational 
properties  of  a  nvimber  of  peptide  fragments  of  ribonuc lease, 
of  insulin  and  of  a-lactalbumin.   The  peptides  chosen  for 
study  to  date  are  all  fragments  containing  the  amino  terminus 
of  the  protein  and  vary  simply  in  the  length  of  the  rest  of 
the  polypeptide  chain  which  remains  attached.   In  this  way  a 
comparison  of  the  properties  of  closely  related  peptides  gives 
information  about  the  structure  determining  role  of  successive 
regions  of  the  polypeptide  sequence.   The  results  of  this 
work  to  date  are  consistent  with  the  hypothesis  that  those 
portions  of  the  polypeptide  chain  of  the  proteins  which  are 
found  to  be  in  a  helical  region  of  the  intact  protein 
participate  in  a  helix- like  structure  in  solution  as  well. 
In  isolation,  these  helices  have  rather  different  stability 
properties  from  those  of  the  protein  and  may  be  more 
appropriately  considered  to  be  "nascent"  helices  rather  than 
fully  formed  ones.   Peptide  segments  which  do  not  participate 
in  a  repeating  structure  in  the  intact  protein  appear  to  be 
essentially  disordered  in  solution.   An  analysis  of  the 
published  data  from  other  laboratories  with  peptides  derived 
from  other  proteins  indicates  that  the  phenomenon  of  "nascent 
helix"  formation  by  fragments  of  helical  regions  of  intact 
proteins  may  be  a  general  one. 

Our  work  with  ribonuc lease  fragments  had  shown  that  the 
nascent  helix  near  the  amino- terminus  of  the  molecule  is 
stable  only  at  low  temperatures  when  fragments  of  short 
length  are  studied.   The  behavior  of  the  nascent  helix  of 
the  insulin  B  chain,  (which  corresponds  to  the  amino  terminus 
of  proinsulin)  is  interesting  in  that  it  is  stable  only  at 
high  temperatures  (37°)  and  becomes  disordered  as  the 
temperature  is  lowered.   It  thus  appears  that  there  may  be 
more  than  one  kind  of  nascent  helix  which  is  formed.   It  may 
be  that  the  structure  in  the  case  of  the  insulin  fragment  is 
stabilized  largely  by  hydrophobic  interactions  whereas  that 
of  the  ribonuclease  fragment  is  stabilized  primarily  by 
other  kinds  of  forces. 

53^ 


Serial  No.  M  -  LGCB  35,  page  3 

The  three  dimensional  structure  of  a-lactalbumin 
(see  Project  M-LGCB  18)  has  so  far  eluded  solution  by  x-ray 
crystallographic  methods.   The  amino  acid  sequence  of  this 
protein  is,  however,  known  to  be  very  closely  related  to  that 
of  the  well  characterized  protein  antibiotic,  lysozyme  and 
it  has  been  proposed  that  the  conformation  of  the  two  proteins 
should  therefore  be  similar.   Studies  of  the  physicochemical 
properties  of  the  two  proteins  in  this  and  other  laboratories 
support  this  hypothesis.   We  have  now  succeeded  in  preparing 
mixed  crystals  of  the  two  proteins  which  are  stabilized 
primarily  by  salt  linkages  and  appear  to  be  composed  of  a- 
lactalbumin  and  lysozyme  in  the  molar  ratio  of  1:2.   It  is 
possible  that  the  availability  of  such  a  mixed  crystal  system 
will  facilitate  the  x-ray  analysis  of  a-lactalbumin  structure. 

Scientific  Significance:   These  studies  are  providing  a  stock 
of  techniques  which  may  be  generally  useful  in  studying  the 
nature  of  the  determinants  of  protein  structure.   On  the 
basis  of  our  results  it  would  appear  that  short  range  inter- 
actions, among  near  neighbor  amino  acid  residues,  control 
the  nature  of  the  protein  structure  to  an  important  degree. 
The  specific  types  of  short  range  interactions  involved  are 
yet  to  be  determined  but  it  would  appear  that  there  may  be 
at  least  two  distinct  ways  of  specifying  helical  structures. 

Proposed  Course  of  Research:   We  intend  to  continue  these 
studies  along  the  general  lines  discussed  above. 

Honors  and  Awards:   None 

Publications :   None 


535 


Project  Title; 


Serial  No.  M  -  LGCB  56 

1.  Laboratory  of  General  and 
Comparative  Biochemistry 

2.  Section  on  Proteins 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Determination  of  the  Effect  of  Small  Viruses 
and  Their  Nucleic  Acids  On  the  Biochemistry 
of  Living  Organisms 


Previous  Serial  Number : 


Same 


Principal  Investigator:   Carl  R.  Merril 


Other  Investigators; 


Cooperating  Units : 


:   T,  Friedman,  K.  Krell,  M.  Gottesman, 

J.  Petricciani,  M.  Geier,  I.  Prissovsky, 
R.  Yarkin 

Laboratory  of  Molecular  Biology,  NCI; 
Pathology  Laboratory,  Division  of  Biologies 
Standards,  NIH 


Man  Years 

Total:   4-1/4 
Professional:   1-3/4 
Other:   2-1/2 

Project  Description: 

Objectives :   An  attempt  to  determine  the  genetic  information 
contained  within  the  nucleic  acids  of  small  "viruses"  and 
their  effect  on  various  organisms. 

Methods  Employed:   Biochemical  techniques  for  purification 
and  analysis  of  small  viruses  and  nucleic  acids,  ultraviolet 
spectroscopy,  density  gradient  ultracentrifugation,  bacterio- 
phage genetics,  radioactive  tracer  techniques,  mammalian 
tissue  culture  methods  and  fruit  fly  developmental  genetics. 

Major  Findings:   1.   By  using  a  bacteriophage  carrying 
bacterial  genes  (the  galactose  operon) ,  it  was  possible  to 
infect  human  cells,  with  a  defect  in  galactose  metabolism, 
and  demonstrate  a  change  in  their  galactose  metabolism.   The 
effect  of  the  bacteriophage  on  transcriptional  events  in  the 
human  cells  was  monitored  by  DNA-RNA  hybridization  techniques 
while  translational  events  were  demonstrated  by  an  enzyme 
assay  for  the  bacterial  enzyme  in  the  human  cells.   These 


537 


Serial  No.  M  -  LGiCB  56,  page  2 

virus  induced  trans lational  and  transcriptional  events 
persisted  for  over  40  days  of  culturing  indicating  not  only 
viral  gene  expression,  but  maintenance. 

2.  To  study  the  effect  of  such  viruses  on  a  whole  organism, 
we  have  embarked  on  a  study  of  the  effect  of  these  viruses 
on  the  fruit  fly.   By  using  prematurely  laid  fly  eggs  it 

is  possible  to  infect  these  eggs  with  bacteriophage,  or  DNA. 
Preliminary  experiments  indicate  that  wild  type  flies  are 
lacking  in  the  same  enzyme  as  galactosemic  individuals. 
Infection  of  these  flies  with  the  virus  used  on  human  cells 
has  been  very  encouraging. 

3.  In  viruses  which  are  capable  of  integrating  into  a  host 
chromosome,  such  as  X  bacteriophage,  a  repressor  molecule 
is  produced  which  prevents  expression  of  other  phase 
functions  in  E.  coli.   Repressor  synthesis  is  itself  under 
positive  control.   The  initiation  of  the  expression  of  the 
repressor  gene  requires  CII  and  CIII  gene  products,  or  the 
presence  of  the  repressor  molecule  itself.   The  ability  of 
the  repressor  to  promote  the  initiation  of  repressor 
synthesis  suggested  that  the  repressor  molecule  might 
influence  its  own  rate  of  synthesis.   To  test  this  we 
examined  the  rate  of  repressor  transcription,  the  level  of 
immunity  and  the  amount  of  repressor  in  lysogens  bearing 
one,  two  or  three  viruses.   We  found  that  the  rate  of 
repressor  gene  expression  is  independent  of  repressor 
concentration  and  conclude  that  the  intracellular  concentra- 
tion of  repressor  is  not  a  limiting  factor  in  the  rate  of 
repressor  synthesis.   This  study  was  conducted  in 
collaboration  with  Dr.  Max  Gottesman  and  involved  analytic 
and  preparative  ultracentrifugation  of  virus  and  their 
nucleic  acids,  radioactive  tracer  techniques,  and  genetic 
analysis  of  bacteria  and  viruses. 

Scientific  Significance:   1.   It  is  not  known  at  the  present 
time  whether  the  viral  transferase  production  in  human  cells 
is  the  result  of  integration  of  the  viral  DNA  into  the  host 
genome  or  whether  the  viral  DNA  is  functioning  independently 
in  the  cytoplasm  in  a  plasmid-like  fashion,  or,  in  some 
totally  unknown  manner.   However,  the  results  presented  here 
suggest  that  it  might  be  possible  to  introduce  a  selected 
bacterial  gene  into  human  cells  in  vitro,  using  phage  as  a 
vehicle.   Our  results  are  also  in  agreement  with  recent 
evidence  that  there  are  much  greater  biochemical  similarities 
between  far-ranging  living  species  than  had  been  appreciated 
previously. 


538 


Serial  No,  M  -  LGCB  56,  page  3 

2.  Studies  of  the  effects  of  these  viruses  and  their  DNA 
on  the  fruit  fly  will  allow  us  to  follow  the  results  of 
such  infection  over  generations  in  a  relatively  short  time 
span. 

3.  The  total  amount  of  \   virus  specific  transcription  in 
lysogens  directly  reflects  their  prophage  content.   Thus, 
a  single  lysogen  has  half  as  much  message  as  a  double  and 
one- third  as  much  as  the  triple  lysogen,   A  surprising 
feature  of  this  transcription  is  that  a  large  portion  of 
the  transcription  derives  from  regions  of  the  virus  other 
than  the  repressor  gene,  however,  the  amount  of  repressor 
message  was  shown  to  reflect  the  number  of  prophage  copies. 
The  development  of  techniques  to  follow  specific  genetic 
messages  may  prove  important  in  future  studies  of  genetic 
diseases  and  viral  infections. 

Proposed  Course  of  Research;   To  continue  the  study  of 
these  viruses  and  their  interaction  with  other  life  forms, 
with  emphasis  on  molecular  level  events. 

Honors  and  Awards : 

Dr.  Merril's  invited  activities: 

1.  Lecture:   "Bacterial  Gene  Effects  in  Eukaryotic  Cells," 

Columbia  University,  November  16,  1971. 

2.  Lecture:   "Bacterial  Virus  Gene  Expression  In  Mammalian 

Cells,"  Council  for  the  Advancement  of  Science 
Writing,  Brookhaven  National  Laboratory,  N,Y. , 
November  17,  1971, 

3,  Lecture:   "Bacterial  Virus  Gene  Expression  in  Mammalian 

Cells,"  Georgetown  University,  November  30,  1972. 

4.  Workshop:   "Mechanisms  and  Prospects  of  Genetic  Exchange," 

sponsored  by  the  Max-Planck  Institut  fur 
Biochemie,  Berlin,  Germany,  Dec.  11-13,  1971. 
Presented  paper  on  "Bacterial  Gene  Expression 
in  Mammalian  Cells,"  to  be  published  in 
Advances  in  the  Biosciences. 

5,  Lecture:   "Bacterial  Gene  Expression  in  Eukaryotic  Cells," 

University  of  Rome  and  NRC  Center  for  Nucleic 
Acid  Research,  Rome,  Italy,  December  15,  1971, 

6,  Lecture:   "Bacterial  Genes  in  Higher  Organisms,"  National 

Naval  Research  Center,  Bethesda,  Md, ,  Jan,  26, 
1972, 


539 


Serial  No.  M  -  LGCB  56,  page  4 

Seminar:   Origin  of  Life,  Genetic  Engineering  and 

Evolution,  sponsored  by  the  Consortium  of 
Universities  and  Smithsonian  Institute, 
Washington,  D.  C,  March  9,  1972.   Lecture 
entitled:   "Use  of  Bacterial  Genes  in  Human 
Cells." 

Lecture:   "The  Search  for  Bacteriophage  Effects  on 
Higher  Organisms,"   Jackson  Laboratories, 
E.  I.  DuPont  de  Nemours  and  Company,  Wilmington, 
Delaware,  March  23,  1972, 

Symposium:   Sixth  Annual  Miles  International  Symposium 

on  Molecular  Biology,  Johns  Hopkins  University, 
June  8-9,  1972.   Lecture  entitled:   "Effects 
of  Bacteriophage  on  Eukaryotes." 


Publications : 


Merril,  C.R.,  Geier,  M.R. ,  and  Petricciani,  J.C.:   Bacterial 
gene  expression  in  human  cells.   Nature  233 :   398-400,  1971. 

Petricciani,  J.C.,  Binder,  M.K. ,  Merril,  C.R.,  Geier,  M.R. : 
Galactose  utilization  in  galactosemia.   Science  175: 
1368-1370,  1972, 

Geier,  M.R. ,  and  Merril,  C.R.:   Lambda  phage  transcription 
in  human  fibroblasts.   Virology  47:   638-643,  1972. 

Merril,  C.R.,  Geier,  M.R.  ,  and  Petricciani,  J.C:   Bacterial 
gene  expression  in  mammalian  cells.   Advances  in  the 
Biosciences,  in  press. 


5  to 


Serial  No.  M  -  LGCB  58 

1.  Laboratory  of  General  and 
Comparative  Biochemistry 

2.  Section  on  Proteins 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:   Ribonuclease  Specific  for  RNA-DNA  Hybrids 

Previous  Serial  Number:   Same 

Principal  Investigator:   Giulio  L.  Cantoni 

Other  Investigators:   Roy  C.  Haberkern 

Cooperating  Units:   None 

Man  Years : 

Total:   1 
Professional:   1 
Other :   0 

Project  Description: 

Objectives :   An  enzymatic  activity  from  calf  thymus  extracts 
has  been  reported  to  specifically  hydrolyze  the  RNA  portion 
of  RNA-DNA  hybrids,  with  no  activity  on  RNA  in  other  forms. 
This  activity  has  been  purified  and  further  studied. 

Methods  and  Findings :   Protein  purification  and  nucleic  acid 
isolation  and  characterization  have  been  by  standard  methods. 
The  enzyme  has  been  purified  to  >80%  purity.   The  enzyme 
activity  has  been  shown  to  be  a  property  of  a  single  protein, 
MW  ~  70-75,000,  with  no  subunits.   Substrate  specificity  has 
been  confirmed  using  both  biologic  (viral)  and  synthetic 
nucleic  acid  substrates.   The  enzyme  is  located  in  the  cell 
cytoplasm. 

Similar  enzymatic  activity  has  been  reported  in  adrenal 
tissue,  mouse  tumor  cells  adapted  to  culture,  and  RNA  tumor 
viruses . 

Scientific  Significance:   That  an  enzyme  of  such  specificity 
is  present  in  a  variety  of  tissues  suggests  that  its  substrate, 
RNA-DNA  hybrid  molecules,  exist  and  have  a  function  in  cells. 
Current  notions  regarding  information  transfer  in  cells  do 
not  make  clear  what  function  such  hybrids,  and  their  hydrolysis 


5^1 


Serial  No.  M  -  LGCB  58,  page  2 

by  this  nuclease,  might  serve.   It  is  conceivable  that  study 
of  this  question  might  revise  thinking  about  nucleic  acids 
and  their  function. 

RNA  tumor  viruses  are  believed  to  replicate  via  an  RNA- 
DNA  intermediate.   This  model,  and  the  finding  of  hybrid 
ribonuc lease  activity  in  association  with  these  viruses, 
makes  it  conceivable  that  study  of  the  nuclease  will  be 
instructive  as  to  the  biology  of  these  viruses. 

Proposed  Course  of  Research:   Characterization  of  the  enzyme 
with  regard  to  kinetics  and  chemical  nature  of  the  products 
is  to  be  completed.   Inhibitor  studies  with  rifampicin 
derivatives  are  in  progress . 

A  survey  for  presence  of  the  enzyme  in  mammalian 
tissues  is  planned. 

Honors  and  Awards :   None 

Publications :   None 


5^2 


Serial  No.  M  -  LGCB  59 

1.  Laboratory  of  General  and 
Comparative  Biochemistry 

2.  Section  on  Proteins 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Reprot 

July  1,  1971  through  June  30,  1972 

Project  Title:   Spermidine  Synthesis  in  Rat  Brain 

Previous  Serial  Number :   None 

Principal  Investigator:   Giulio  L.  Cantoni 

Other  Investigators:  Gregory  L.  Schmidt 

Man  Years 

Total:   1 
Professional:   1 
Other :   0 

Project  Description: 

Objectives:   The  polyamine  spermidine  has  been  implicated 
as  a  control  factor  in  several  rapid  growth  processes.   This 
project  is  designed  to  determine  whether  spermidine  is  also 
involved  in  the  control  of  rat  brain  development. 

Methods  Employed:   Two  of  the  three  enzymes  involved  in  the 
synthesis  of  spermidine  from  ornithine  and  S-adenosyl- 
methionine  (AMe) ,  ornithine  decarboxylase  and  AMe 
decarboxylase,  have  been  isolated  from  rat  brain  and 
characterized  to  an  extent  sufficient  to  allow  determination 
of  optimal  assay  parameters  and  assays  applicable  to  small 
amounts  of  brain  tissue  have  been  developed.   The  activities 
of  both  enzymes  are  measured  by  determination  of  ■'•'*C02 
released  from  the  substrates.   These  enzymes  are  measured  in 
rat  brain  homogenates  at  2-3  day  intervals  following  birth 
and  related  to  known  synthetic  and  anatomical  correlates  of 
brain  development. 

Major  Findings  and  Scientific  Significance:   Both  ornithine 
decarboxylase  and  AMe  decarboxylase  have  pH  optima  and 
kinetic  parameters  similar  to  those  reported  in  other  rat 
tissues.   AMe  decarboxylase  is  a  soluble  enzyme  which  requires 
putrescine  for  activity  but  apparently  does  not  require 
pyridoxal  phosphate.   Ornithine  decarboxylase  is  a  nuclear 
enzyme  for  which  pyridoxal  phosphate  is  the  probable  cof actor. 


5^3 


Serial  No.  M  -  LGCB  59,  page  2 

Preliminary  results  indicate  that  the  specific  activities  of 
ornithine  decarboxylase  and  AMe  decarboxylase  increase  to 
plateau  levels  within  several  days  after  birth  of  the  rat 
then,  at  an  age  of  approximately  two  weeks,  increase  to 
levels  4-5  fold  higher  than  the  initial  plateau.   These  two 
phases  approximately  coincide  with  the  time  of  maximal  rates 
of  DNA,  RNA,  and  protein  synthesis  and  the  time  of  maximal 
synapse  formation  and  myelination,  respectively. 

Proposed  Course  of  Research:   The  studies  on  rat  brain 
development  will  be  continued  until  definitive,  reproducible 
trends  have  been  determined.   Further  study  could  involve 
determination  of  spermidine  synthetic  rates  in  the  various 
anatomical  divisions  of  the  brain  and  also  in  the  nerve 
ending  fractions.   Further  purification  of  brain  AMe 
decarboxylase  is  also  contemplated. 

Honors  and  Awards :   None 

Publications :   None 


5hk 


Serial  No.  M  -  LGCB  43 

1 .  Laboratory  of  General  and 
Comparative  Biochemistry 

2.  Section  on  Alkaloid  Biosynthesis 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:  Homocystinuria:  Methionine  Metabolism  in  Mammals. 

Previous  Serial  Number:  Same 

Principal  Investigator:  S.  Harvey  Mudd,  M.D. 

Other  Investigators:  B.  W.  Uhlendorf,  Ph.D. 

Cooperating  Units:  Laboratory  of  Viral  Immunology,  DBS 

Man  Years: 

Total :  2 
Professional:  1 
Other:  1 

Project  Description: 

Objectives:  The  objectives  of  this  project  are  to  obtain  a  detailed 
knowledge  of  the  biochemistry  of  sulfur-containing  compounds  in  the 
mammalian  body,  with  emphasis  on  the  transsulfuration  pathway.  Special 
attention  will  be  focused  on  the  regulatory  devices  which  control  this 
area  of  metabolism. 

Methods  Employed:  Most  of  the  methods  employed  have  been  presented  in 
detail  in  previous  Annual  Reports.  In  general,  standard  methods  of 
enzyme  purification  and  assay  have  been  employed.  Automated  amino  acid 
analysis  has  been  used  extensively.  The  techniques  used  for  growth  of 
cells  in  tissue  culture  are  the  usual  ones.  During  the  past  year  it  has 
been  necessary  to  develop  an  assay  for  methyl enetetrahydrofol ate  reductase 
activity.  This  was  accomplished  by  a  series  of  modifications  of  a 
previously  described  method  (Kutzbach  and  Stokstad,  Biochim.  Biophys. 
Acta  139:  217  (1967)).  In  principle,  the  oxidative  conversion  of 
-^'♦CHg-NS-methyl tetrahydrof ol ate  to  i'*CH20  is  followed.  After  termination 
of  the  reaction,  the  radioactive  formaldehyde  formed  is  converted  to  the 
dimedone  complex  and  measured  after  extraction  into  toluene.  The 
modifications  adopted  led  to  a  considerably  more  sensitive  and  reliable 
assay. 

Major  Findings:  A  number  of  lines  of  investigation  are  being  pursued  in 
this  project.  Only  those  in  a  relatively  advanced  stage  of  development 
will  be  commented  upon. 

5i^5 


Serial  No.  M  -  LGCB  43,  page  2 

(a)  During  the  past  year  we  have  defined  a  hitherto  unrecognized  inborn 
error  of  inetabolisin  which  leads  to  abnormalities  in  the  metabolism  of 
folic  acid  derivatives.  These  studies  were  carried  out  upon  three  patients: 
two  siblings  discovered  by  Dr.  John  Freeman,  Department  of  Pediatric 
Neurology,  Johns  Hopkins  University,  and  a  sixteen-year-old  boy  discovered 
by  Dr„  Vivian  Shih,  Department  of  Neurology,  Massachusetts  General  Hospital. 
These  patients  excrete  elevated  amounts  of  horaocystine  and  have  elevated 
homocystine  concentrations  in  their  plasmas.  In  contrast  to  most 
homocystinurics,  they  do  not  have  elevations  of  plasma  or  urinary 
methionine.  This  was  presumptive  evidence  that  these  subjects  were  not 
cystathionine  synthase  deficient,  the  common  cause  of  homocystinuria.  This 
presumption  was  confirmed  by  demonstration  that  the  patients  converted  the 
sulfur  of  a  large  oral  dose  of  methionine  to  inorganic  sulfate  at  a  normal 
rate  and  that  extracts  from  fibroblasts  of  these  patients  grown  in  tissue 
culture  contained  normal  activities  of  cystathionine  synthase.  These 
fibroblasts  were  unable  to  form  methionine  from  homocystine  as  rapidly  as 
normal  cells  as  shown  by  their  inability  to  grow  upon  media  in  which 
methionine  had  been  replaced  by  homocystine.  However,  the  enzyme  system 
responsible  for  the  conversion  of  homocysteine  to  methionine  in  fibroblasts 
(N^-methyltetrahydrofolate-homocysteine  methyl  transferase)  was  entirely 
normal  in  extracts  of  these  cells  assayed  in  vitro.  It  was  concluded  that 
there  might  be  a  defect  in  the  generation  of  substrate  for  this  enzyme, 

i.e.  N^-methyltetrahydrofolic  acid.  Measurement  of  methylene  tetrahydro- 
folate  reductase  activity  in  extracts  of  normal  fibroblasts  and  fibroblasts 
from  the  patients  in  question  confirmed  this  postulate.  Each  patient  was 
markedly  deficient  in  the  activity  of  this  enzyme. 

Discovery  of  this  new  enzyme  lesion  is  important  for  several  reasons. 
It  confirms  the  quantitative  importance  of  the  remethylation  of  homocysteine 
in  man,  as  originally  suggested  by  our  studies  of  patients  with  defective 
Bi2  metabolism.  It  furnishes  a  new  tool  to  study  normal  and  abnormal 
folate  metabolism  and  its  regulation.  Finally,  it  may  be  significant  that 
one  of  these  patients  has  been  diagnosed  as  having  schizophrenia  and  that 
this  schizophrenia  is  alleviated  by  treatment  with  large  doses  of  folic 
acid  and  pyridoxine.  Further  studies  of  clinical  and  biochemical  aspects 
of  this  disease  may  possibly  throw  some  light  upon  the  relationship 
between  at  least  one  form  of  schizophrenia  and  its  underlying  cause. 

(b)  Last  year  we  alluded  briefly  to  preliminary  results  of  studies  of 
cystathionine  synthase  activity  in  fibroblasts  grown  from  homocystinuric 
patients  deficient  in  this  enzyme.  These  preliminary  results  have  now 
been  extended  and  confirmed.  An  extremely  sensitive  assay  has  been  used 
to  study  cystathionine  synthase  activity  in  39  such  cell  lines.  The 
patients  from  whom  33  of  these  lines  derived  have  been  classified  clinically 
(mostly  in  other  institutions)  as  being  either  responsive  to  large  doses 

of  pyridoxine  (Bj  or  not  responsive.  A  response  in  these  cases  is  charac- 
terized by  a  marked  decrease  in  urinary  and  plasma  homocystine  and  methionine 
clearly  correlated  with  administration  of  Bg.  In  most  cases  it  is  possible 
to  judge  quite  unequivocally  whether  or  not  a  patient  responds.  Among 
those  patients  so  classified,  24  were  judged  to  be  responsive,  9  not 

5h6 


Serial  No.  M  -  LGCB  43,  page  3 

responsive.  The  cells  from  23  of  the  24  responders  contained  detectable 
cystathionine  synthase  activity  (usually  1-2%  of  normal).  One  exceptional 
line  contained  no  detectable  activity.  (It  is  known  this  girl  has  about 
2%  of  normal  activity  in  her  liver.  The  results  with  the  fibroblasts  are 
presumed  to  be  a  "false"  negative).  The  cells  from  8  of  the  9  non- 
responders  had  no  detectable  activity.  One  exceptional  line  contained 
activity  which  was  unique  in  that  it  was  stimulated  about  10-fold  by 
addition  of  pyridoxal  phosphate  in  vitro.  (Cystathionine  synthase  from 
normal  subjects  or  Bg  responsive  patients  is  stimulated  only  about  30% 
by  addition  of  pyridoxal  phosphate).  These  results  supply  very   strong 
support  to  our  working  hypothesis  that  the  basis  for  the  response  to  Bg 
is  an  increase  in  the  residual  activity  of  cystathionine  synthase.  Previous 
studies  suggested  that  the  stimulation  of  liver  enzyme  activity  is  from  a 
basal  1-2%  of  normal  up  to  3-4%  when  the  patient  is  in  response.  The 
relatively  small  magnitude  of  the  increase  has  made  difficult  an 
experimental  approach  to  this  problem.  If  our  current  concept  of  the 
mechanism  of  the  Bg  response  can  be  further  substantiated,  the  foreseeable 
results  include  opening  of  a  new  approach  to  the  therapy  of  many  inborn 
errors  of  metabolism — that  is,  specific  stimulation  of  the  deficient  enzyme 
activity.  Of  further  importance  will  be  the  insight  into  mechanisms  of 
vitamin  responsiveness,  since  there  is  now  increasing  evidence  that  a 
variety  of  diseases  may  be  responsive  to  large  doses  of  one  or  another 
vitamin.  Understanding  of  the  mechanism(s)  of  these  responses  may  be 
expected  to  allow  rational  extension  of  this  approach  to  additional  areas 
not  now  categorized  as  classical  inborn  errors  of  metabolism. 

Scientific  Significance:  Discussed  under  individual  headings  above. 

Proposed  Course  of  Research:  The  different  lines  of  work  will  be  pursued 
as  suggested  above. 

Honors  and  Awards:  Invited  lectures:  "Mechanisms  underlying  Vitamin  Respon- 
siveness" -  Department  of  Biochemistry,  Vanderbilt  University  School  of 
Medicine. 

"Mechanisms  underlying  Vitamin  Responsiveness"  -  Department  of  Pharmacology, 
Johns  Hopkins  University  Medical  School. 

Publications: 

Mahoney,  M.  J.,  Rosenberg,  L.  E. ,  Mudd,  S.  H.,  and  Uhlendorf,  B.  W. : 
Defective  Metabolism  of  Vitamin  Bi2  in  Fibroblasts  from  Children  with 
Methylmalonicaciduria.  Biochem.  Biophys.  Res.  Comm.  44:  375,  1971. 

Mudd,  S.  H.,  Uhlendorf,  B.  W.,  Freeman,  J.  M. ,  Finkelstein,  J.  D. ,  and 
Shih,  V.  E.:  Homocystinuria  Associated  with  Decreased  Methyl enetetrahydro- 
folate  Reductase  Activity.  Biochem.  Biophys.  Res.  Comro.  46:  905,  1972. 


5hl 


Serial  No.  M  -  LGCB  48 

1 .  Laboratory  of  General  and 
Comparative  Biochemistry 

2.  Section  on  Alkaloid  Biosynthesis 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:  Transsulfuration  in  Higher  Plants 

Previous  Serial  Number;  Same 

Principal  Investigators:  John  Giovanelli,  Ph.D.  and  Anne  H.  Datko,  Ph.D. 

Other  Investigators:  S.  Harvey  Mudd,  M.D.  and  Lowell  D.  Owens,  Ph.D. 

Cooperating  Units:  Agricultural  Research  Service,  USDA 

Man  Years 

Total :  2-1 /6 
Professional:  2-1/6 
Other:  0 

Project  Description: 

Objectives:  Previous  work  has  shown  that  extracts  of  spinach  and  other 
higher  plants  catalyze  the  synthesis  of  homocysteine  (and  methionine)  by 
two  main  pathways  -  a  direct  sulfhydration  pathway  and  a  transsulfuration 
pathway.  The  long-range  objective  of  the  project  is  to  determine  the 
relative  physiological  significance  and  the  mechanisms  of  control  of  these 
pathways.  The  problem  is  being  attacked  along  three  main  lines: 

(1)  A  study  of  the  enzymes  involved  in  the  two  pathways. 

(2)  In  vivo  evaluation  of  the  relative  physiological  significance  of  the 
two  pathways  by  use  of  inhibitors  that  specifically  block  one  of  the 
pathways. 

(3)  Physiological  and  biochemical  studies  with  algae  (wild  type),  and 
algal  mutants  in  which  the  biosynthesis  of  homocysteine  and 
methionine  is  affected. 

Methods  Employed:  Most  of  the  methods  employed  have  been  described  in 
previous  reports.  Oxalyl  CoA  was  prepared  by  organic  synthesis.  Endo- 
genous substrate  for  cystathionine  synthesis  was  isolated  and  purified 
from  plant  tissues  by  ion  exchange  chromatography  on  Dowex  1  and  Dowex 
50,  and  by  paper  electrophoresis  and  chromatography.  Preparations  of 
endogenous  substrate  were  assayed  by  incubation  with  spinach  cystathionine 
synthase  in  the  presence  of  either  cysteine-^'^C  (single  labeled  assay) 
or  cysteine-^'*C  and  O-phosphorylhomoserine-^H  (double  labeled  assay). 
The  amount  of  endogenous  substrate  was  quantitated  from  the  amount  of 
cystathionine-^'*C  synthesized  (single  labeled  assay),  or  from  the 

5^9 


Serial  No.  M  -  LGCB  48,  page  2 
depression  of  the  3H/^'*C  ratio  (double  labeled  assay).  The 


effects  of  rhizobitoxine  on  corn  seedlings  were  studied  as  follows. 
Corn  seedlings  were  allowed  to  absorb  rhizobitoxine  through  the  roots, 
and  the  activity  of  g-cystathionase  was  determined  at  various  time 
intervals.  In  parallel  experiments,  ^^S%   was  fed  through  the  roots 
and  the  pattern  of  incorporation  of  radioactivity  into  sulfur  amino  acids 
determined  essentially  by  methods  already  described.  Characterization 
and  quantitation  of  cystathionine-^^s  was  facilitated  by  addition  of  a 
preparation  of  authentic  cystathionine-^H  which  was  synthesized  from 
serine-^H  and  homocysteine  by  rat  liver  cystathionine  synthase. 

Major  Findings:  (1)  Extracts  of  spinach  catalyze  the  biosynthesis  of 
cystathionine  from  a  number  of  activated  homoserine  derivatives  (see 
previous  annual  report).  It  has  now  been  established  that  plants 
representing  a  wide  range  of  evolutionary  lines  have  an  essentially 
similar  spectrum  of  substrate  specificity  for  cystathionine  synthase. 
A  minor  difference  in  the  spectrum  of  substrate  specificity  was  observed 
between  primitive  plants  (e.g.  Chlorella,  Pol ytri chum,  Equisetum, 
Lycopodium  and  Ginkgo)  and  the  Angiosperms  (flowering  plants),  the 
relative  activities  in  the  primitive  group  are  0-malonylhomoserine> 
0-phosphorylhomoserine>0-succinylhomoserine;>0-oxalylhomoserine> 
0-acetyl homoserine.  Angiosperms  show  essentially  the  same  relative 
activities,  except  that  activity  with  0-succinyl homoserine  is  either 
equal  to  or  greater  than  that  with  0-phosphoryl homoserine.  The  signifi- 
cance of  this  minor  difference  between  these  two  groups  is  not  at  present 
clear.  No  significant  activity  with  0-phosphoryl homoserine  could  be 
detected  with  Escherichia  coli  or  with  the  blue-green  algae  Anabaena. 
Green  plants  are  therefore  unique  in  their  ability  to  use  0-phosphoryl- 
homoserine  as  a  substrate  for  cystathionine  synthesis,  and  this  ability 
developed  very  early  in  their  evolution--somewhere  between  the  blue-green 
and  the  green  algae.  These  results  alone  do  not,  however,  permit  one  to 
decide  which  of  the  four  active  homoserine  derivatives  are  of  physiological 
significance  for  cystathionine  synthesis  in  plants. 

Two  independent  lines  of  evidence  are  now  available  which  strongly 
suggest  that  0-phosphoryl homoserine  is  the  physiological  substrate: 

(a)  No  generally  distributed  plant  enzyme  could  be  detected  that 
catalyzed  the  synthesis  of  either  0-malonyl-,  0-succinyl-,  0-oxalyl- 
or  0-acetyl -homoserine.  Synthesis  of  these  0-acyl homoserine 
derivatives  could  be  demonstrated  only  in  extracts  of  plants  in 
which  they  accumulate  naturally,  e.g.,  0-acetyl homoserine  in  young 
pea  pods  and  0-oxalyl -homoserine  in  seedlings  of  Lathyrus  sativus 
(grass  pea).  These  results  suggest  that  none  of  the  0-acyl homoserine 
derivatives  listed  above  are  of  physiological  significance  in 
cystathionine  synthesis  in  plants.  By  contrast,  synthesis  of 
0-phosphoryl -homoserine  could  be  readily  demonstrated  in  plant 
extracts . 

(b)  The  natural  occurrence  of  activated  homoserine  derivatives  was 
examined  in  a  range  of  plant  tissues,  representing  a  broad 
evolutionary  span,  and  including  various  organs  (e.g.  roots  and 

550 


Serial  No.  M  -  LGCB  48,  page  3 

shoots).  Legumes  which  are  known  to  contain  abnormally  high 
concentrations  of  certain  0-acylhomoserine  derivatives  (see  above) 
were  deliberately  excluded  from  the  survey.  Endogenous  substrate 
was  detected  in  all  tissues  examined,  and  has  been  tentatively 
characterized  as  0-phosphorylhomoserine.  0-Malonyl-,  0-succinyl- 
and  O-oxalyl-homoserine  could  not  be  detected  and,  if  present, 
were  at  a  concentration  of  less  than  10%  that  of  0-phosphorylhomo- 
serine. The  endogenous  substrate  is  now  being  fully  characterized 
by  ion  exchange  chromatography,  paper  electrophoresis,  and  by  its 
reaction  to  phosphatase  and  base  treatment. 

Subject  to  full  characterization  of  endogenous  substrate,  these 
combined  results  provide  strong  evidence  that  0-phosphorylhomoserine  is 
the  physiological  substrate  for  cystathionine  synthesis  in  green  plants. 
This  observation  is  of  considerable  interest  since  in  other  taxa  the 
physiological  substrate  is  either  0-succinylhomoserine  (bacteria)  or 
0-acetylhomoserine  (fungi  and  bacteria). 

(2)  Inactivation  of  B-cystathionase  by  rhizobitoxine  proceeds  in  vitro 
by  an  active-site-directed  irreversible  inhibition  (see  previous  annual 
report).  It  was  hoped  that  rhizobitoxine  might  act  as  a  specific  inhib- 
itor of  3-cystathionase  in  vivo,  thereby  providing  a  tool  for  studying 
the  significance  of  the  transsulfuration  pathway  in  plants.  Previous 
experiments  with  spinach  failed  to  demonstrate  such  an  in  vivo  inhibition. 
Research  has  been  pursued  using  improved  experimental  design,  and 
replacing  spinach  with  corn  seedlings,  which  allow  the  effect  of 
rhizobitoxine  to  be  studied  in  various  organs.  These  experiments 
successfully  demonstrated  the  in  vivo  inhibition  of  B-cystathionase  by 
rhizobitoxine.  Administration  of  rhizobitoxine  to  corn  seedlings  resulted 
in  a  reduction  of  B-cystathionase  activity  to  approximately  30%  of  that 
in  the  untreated  controls.  This  relative  activity  in  the  rhizobitoxine- 
treated  and  control  seedlings  was  observed  within  12  hours  after 
administration  of  rhizobitoxine  and  remained  unchanged  up  to  24  hours, 
when  pathologic  symptoms  due  to  rhizobitoxine  began  to  appear. 
Incorporation  of  ^^SCfi^  into  sulfur  amino  acids  was  also  studied  in  the 
rhizobitoxine-treated  and  control  seedlings.  Rhizobitoxine  treatment 
resulted  in  a  dramatic  increase  in  labeled  cystathionine.  Thus,  the 
amount  of  radioactive  cystathionine  in  the  mesocotyls,  roots  and  shoots 
of  the  rhizobitoxine-treated  plants  was  3x,  8x,  and  15x,  respectively, 
that  of  the  control  plants.  No  marked  differences  were  observed  in  the 
relative  amount  of  radioactivity  in  any  of  the  other  sulfur  amino  acids. 
These  results  suggest  that  rhizobitoxine  inhibits  B-cystathionase  in 
vivo,  and  the  physiological  response  to  this  inhibition  is  an  increase 
in  concentration  of  the  substrate  cystathionine.  After  attainment  of  a 
new  steady  state,  the  rate  of  methionine  synthesis  is  not  impaired.  The 
in  vivo  turnover  of  cystathionine  is  unequivocally  demonstrated  for  the 
first  time  in  plants.  Of  further  interest  is  the  indication  that  impair- 
ment of  methionine  formation  is  unlikely  to  be  the  primary  cause  of  the 
pathological  effects  of  rhizobitoxine  on  corn  seedlings.  It  is  planned 
to  use  this  in  vivo  effect  of  rhizobitoxine  in  studying  the  pathway  of 

551 


Serial  No.  M  -  LGCB  48,  page  4 

methionine. biosynthesis  in  plants  (see  below). 

Scientific  Significance:  Discussed  under  individual  headings  above. 

Proposed  Course  of  Research:  (1)  The  studies  described  above  provide 
strong  evidence  for  the  operation  of  a  transsulfuration  pathway  for 
methionine  biosynthesis  in  higher  plants.  However,  the  importance  of 
this  pathway  relative  to  the  direct  sulf hydration  pathway  remains  to  be 
established.  Research  on  this  problem  will  continue  along  the  following 
lines:  (a)  Determination  of  the  substrate  specificity  of  the  enzyme(s) 
that  catalyzes  the  direct  sulfhydration  of  activated  homoserine  derivatives 
to  homocysteine,  (b)  Determination  of  the  kinetics  of  incorporation  of 
^^SOij  into  sulfur  amino  acids  in  the  presence  and  absence  of  rhizobitoxine. 
Chi  Orel  la  will  be  used  in  this  study  to  enable  rapid  and  precise  control 
of  labeling  times,  (c)  Combined  studies  on  the  enzymology,  physiology 
and  genetics  of  the  biosynthesis  of  sulfur  amino  acids  in  Chlorella. 

(2)  The  plant  enzyme(s)  catalyzing  the  synthesis  of  cystathionine  will  be 
purified  and  its  properties  examined. 

Honors  and  Awards:  None 

Publications:  None 


552 


Serial  No.  M-NB-1 

1.   Lai)  of  Neurobiology 
2. 

3.   Bethesda,  Maryland,  and 
Woods  Hole ,  Massachusetts 

PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   Transient  changes  in  extrinsic  fluorescence  of  nerve 
produced  by  electric  stimulation 

Previous  Serial  Number:   Same 

Principal  Investigators:   Ichiji  Tasaki,  M.D. ,  Mark  Hallett,  M.D. 

Allan  S.  Schneider,  Ph.D.,  Emilio  Carbone,  Ph.D. 
and  Ronald  Sandlin 

Cooperating  Units:   Marine  Biological  Laboratory,  Woods  Hole,  Mass. 

Man  Years 

Total:  5.6 

Professional :   H. 0 
Other:         1.6 

Project  Description 

Objective:   One  of  the  main  objectives  of  this  laboratory  has  been  the 
analysis  of  the  macromolecular  structure  of  the  nerve  cell  membrane  and  the 
changes  in  that  structure  during  excitation.   Recently  we  have  utilized  the 
technique  of  extrinsic  fluorescence  with  hopes  of  extending  this  analysis. 
After  several  years  of  work,  and  the  development  of  our  own  instrumentation, 
transient  changes  in  extrinsic  fluorescence  (called  optical  signals)  were 
demonstrated  with  a  variety  of  dyes.   The  objective  now  is  to  study  the 
details  of  these  optical  signals  to  see  what  they  can  reveal  about  membrane 
structure.  , 

Methods  Employed:   Giant  axons  from  the  squid  were  used  in  most  experiments; 
nerve  trunks  from  crab  and  lobster  were  also  employed.   The  dyes  which 
received  most  attention  belong  to  a  class  known  as  the  hydrophobic  probes  and 
include  2-p-toluidinylnaphthalene-6-sulfonate  (2-6  TNS)  and  1-anilinonaph- 
thalene- 8- sulfonate  (1-8  ANS).   External  staining  was  carried  out  by  soaking 
the  nerve  in  a  solution  of  the  dye.   Internal  staining  of  the  squid  axons  was 
usually  accomplished  by  injecting  a  small  volume  of  dye  into  the  axon  interior. 

The  stained  nerve  was  mounted  in  a  black  Lucite  chamber  which  was  specially 
designed  for  simultaneous  electrical  and  optical  measurements.   Electrical 
stimulation  and  recording  could  be  extracellular  via  two  pairs  of  platinum 
wires  or  internal  via  an  electrode  made  of  two  platinum  wires  twisted 


553 


Serial  No.  M-NB-1  (Page  2) 

together  which  was  inserted  longitudinally  into  the  axon.   The  nerve  chamber 
was  placed  inside  a  refrigerator  to  maintain  a  steady  low  temperature. 

The  excitation  light  originated  in  a  200  W  xenon-mercury  source  and  was 
focused  onto  the  nerve  by  means  of  lenses  and  diaphragms  through  one  wall  of 
the  refrigerator.   Interference  filters  were  used  to  select  a  quasi- 
monochromatic  beam  to  excite  the  dye  molecules  at  an  absorption  maximum. 
Fluorescent  light  was  detected  with  a  photomultiplier  at  90°  to  the 
excitation  beam.  A  secondary  filter  was  placed  between  the  nerve  and  the 
phototube  to  select  part  or  all  of  the  fluorescent  light  for  study  and  to 
block  all  of  the  scattered  excitation  light.   In  experiments _ of  fluorescence 
polarization,  a  polarizer  was  inserted  into  the  excitation  light  path  and  an 
analyzer  was  inserted  into  the  emission  light  path. 

In  order  to  reduce  the  effect  of  fluctuations  in  the  intensity  of  the 
light  source,  a  small  part  of  the  exciting  light  was  reflected  to  a  second 
photomultiplier.   The  output  of  the  main  photomultiplier  was  modified  by  the 
output  of  the  second  photomultiplier  through  a  differential  amplifier.   The 
output  of  this  amplifier  was  fed  to  a  CAT  computer  for  signal  averaging. 
Optical  signals  could  be  detected  on  the  computer  after  averaging 
approximately  5000  trials. 

Major  Findings: 

A.   Studies  with  the  hydrophobic  probes. 

Fluorescence  polarization  was  used  to  analyze  the  optical  signals  from 
the  hydrophobic  probes.  2-6  TNS ,  and  analogues  with  a  similar  2-6 
configuration,  gave  highly  polarized  signals.   This  revealed  the  presence  of 
two  classes  of  oriented  molecules ,  one  longitudinal  and  the  other  perpendicular 
to  the  longitudinal  axis  of  the  axon.   1-8  ANS ,  and  analogues  with  a  similar 
1-8  configuration,  gave  unpolarized  signals.   The  mode  of  binding  of  these 
probes  to  the  membrane  must  be  very  different  from  that  of  the  2-6  derivatives. 
It  should  be  noted  in  this  connection  that  the  2-6  derivatives  are  long  (10  A) 
and  planar  while  the  1-8  derivatives  are  short  and  twisted. 

Details  of  the  binding  of  2-6  TNS  to  the  axon  membrane  were  investigated. 
Using  the  technique  of  intracellular  perfusion  of  various  concentrations  of 
the  dye,  some  information  was  obtained  about  the  apparent  binding  constant 
and  the  number  of  molecules  bound.   We  were  also  able  to  find  the  average 
quantim  yield  of  the  dye  molecules  bound  to  the  membrane  and  the  quantum 
yield,  and  the  change  in  that  quantum  yield,  of  those  dye  molecules  which  are 
affected  by  the  excitation  process. 

B.   Studies  with  the  tetracyclines 

The  tetracycline  dyes  are  sensitive  to  membrane  associated  divalent 
diamagnetic  cations  (of  which  Ca-ion  is  the  major  one  of  biological  interest). 
Fluorescent  increases  were  seen  during  the  action  potential  for  internally 
stained  squid  axons  and  externally  stained  lobster  nerves.   In  the  case  of 

55^ 


Serial  No.  M-NB-1  (Page  3) 

lobster  nerve  it  was  clearly  shown  that  the  concentration  of  Ca-ion  in  the 
bathing  fluid  influences  the  size  of  the  signal.   These  and  other 
experiments  suggest  that  the  tetracyclines  are  monitoring  the  Ca- 
concentration  at  the  Stern  Layer  at  the  inner  side  of  the  axon  membrane. 

C.  Studies  with  aequorin 

Aequorin  is  a  Ca-sensitive  auto- luminescent  protein.   It  can  be  used 
to  measure  influx  of  Ca-ion  into  cells.   We  employed  aequorin  to  study  the 
Ca- influx  associated  with  the  action  potential  in  the  squid  giant  axon.   The 
apparatus  was  essentially  the  same  as  for  the  fluorescence  experiments 
except  that  we  did  not  need  light  for  excitation  of  the  probe  molecules.   A 
luminescent  response  was  detected  for  an  individual  action  potential  (by 
signal  averaging)  and  the  kinetics  of  the  response  were  examined  on  a  kinetic 
basis.   Light  responses  to  trains  of  action  potentials  were  also  obtained 
and  compared  to  what  would  be  expected  on  the  basis  of  superposition  of  a 
series  of  single  responses.   With  aequorin,  a  new  phenomenon  was  encountered: 
a  large  Ca- influx  was  associated  with  a  long  pulse  of  inward  current. 

D.  Model  studies 


In  order  to  interpret  the  optical  signals  obtained  with  the  nerves , 
we  must  have  a  good  understanding  of  the  physico-chemical  parameters  which 
influence  the  probe  molecules.   Some  of  this  information  is  obtained  by 
reading  the  literature  and  some  is  obtained  in  this  laboratory  utilizing 
simpler  model  systems.   For  example,  the  directions  of  the  transition 
moments  of  the  hydrophobic  probes  were  investigated  by  incorporating  these 
molecules  into  stretched  polyvinylalcohol  sheets.   Factors,  such  as  polarity, 
pH  and  concentration,  which  influence  the  fluorescence  of  dye  molecules  were 
studied  in  the  test  tube  in  the  presence  of  phospholipids  or  proteins.   One 
of  the  main  systems  utilized  has  been  red  cell  membranes.   A  study  is  in 
progress  of  the  effect  of  hydration  of  these  membranes  on  the  fluorescence  of 
incorporated  hydrophobic  probes. 

Significance:   Based  to  a  large  degree  on  our  growing  knowledge  about  the 
physico-chemical  properties  of  the  probe  molecules  employed,  our  understanding 
of  the  optical  signals  from  the  nerve  is  improving.   With  regard  to  the 
hydrophobic  probes  it  is  now  reasonably  clear  how  these  molecules  bind  to  the 
nerve  membrane  both  inside  and  out.   The  changes  in  their  fluorescence  can 
be  interpreted  as  signaling  changes  in  the  physico-chemical  nature  of  these 
binding  sites.   For  example,  it  seems  that  the  whole  membrane  —  both  inside 
and  outside  surfaces  —  undergoes  a  hydrophobic  to  hydrophilic  transition 
during  the  action  potential.   The  more  detailed  studies  with  2-6  TNS  have 
revealed  that  the  number  of  membrane  sites  which  bind  this  probe  and  which 
change  during  the  excitation  process  is  about  200  per  square  micron  of 
membrane  surface. 

The  most  striking  finding  which  has  led  to  new  understanding  of  the 
membrane  is  that  the  2-6  aminonaphthalene- sulfonate  derivatives  (as  well  as 


555 


Serial  No.  M-NB-1  (Page  4-) 

other  dyes  such  as  pyronin  B)  give  rise  to  highly  polarized  emission  when 
incorporated  in  nerve  membrane.   This  must  mean  that  the  membrane  has  a 
highly  regular,  oriented,  rigid  crystalline  architecture.   In  the  case  of 
2-6  TNS  (and  2-6  ANS)  there  are  two  distinct  classes  of  oriented  molecules: 
one  longitudinal  and  the  other  perpendicular  to  the  membrane  (this  latter 
class  is  now  thought  to  be  radially  oriented  with  respect  to  the  membrane). 
This  result  is  consistent  with  recent  electronmicrographs  from  a  variety  of 
membranes  which  show  the  fine  structure  of  a  regular  hexagonal  lattice. 

Work  with  aequorin  and  the  tetracyclines  has  added  to  the  body  of 
knowledge  about  the  interaction  of  Ca-ion  with  the  excitable  membrane. 
Studies  with  aequorin  have  verified  the  notion  that  the  Ca- influx  associated 
with  the  action  potential  occurs  during  the  time  of  the  loss  of  membrane 
impedance.   Analysis  of  the  signals  associated  with  the  tetracyclines 
suggests  that  these  dyes  reflect  the  Ca-concentration  at  the  Stern  Layer  at 
the  inner  surface  of  the  membrane.   If  this  is  true,  then  we  have  a  new 
understanding  of  the  changes  of  Ca-concentration  at  this  site  during  the 
excitation  process.   For  example,  results  would  suggest  that  the  Ca- 
concentration  decreases  at  the  Stern  Layer  during  a  membrane  hyperpolarization. 

Proposed  Course:   We  will  continue  to  analyze  in  further  detail  the 
characteristics  of  the  fluorescent  light  which  make  up  the  optical  signals. 
In  particular  we  will  emphasize  studies  of  fluorescence  polarization, 
spectral  analysis  and  the  effects  of  changes  in  concentration  of  the  probe 
molecules.   We  also  hope  to  begin  studies  of  the  fluorescence  life-times  of 
these  molecules.   In  addition,  the  phenomenon  of  birefringence  change  will 
be  reexplored  in  some  detail  hoping  to  relate  it  more  to  the  fluorescence 
results  (and  thus  to  membrane  structure).   There  will  be,  as  always, 
considerable  emphasis  on  further  investigations  of  the  physico-chemical 
parameters  which  influence  the  fluorescence  of  probe  molecules.   In  addition, 
a  study  will  be  initiated  on  the  excitability  properties  of  isolated  drops 
of  Nitella  cytoplasm. 

Honors  and  Awards : 

Dr.  Tasaki  was  awarded  an  honorary  Doctor  of  Medicine  degree  by  the 
Medical  Faculty  of  the  University  of  Uppsala,  Sweden. 

Publications : 

Camay,  L.D.:   The  excitable  membrane.   In  Laki,  K.  (Ed..):   Contractile 
Proteins  and  Muscle.   New  York,  Marcel  Dekker,  Inc.,  1971,  pp.  34-1-354. 

Camay,  L.D.  and  Tasaki,  I.:   Ion  exchange  properties  and  excitability  of 
the  squid  giant  axon.   In  Adelman,  W.J. ,  Jr.  (Ed.):   Biophysics  and 
Physiology  of  Excitable  Membranes.   New  York,  Van  Nostrand  Reinhold  Co., 
1971,  pp.  379-422. 


556 


Serial  No.  M-NB-1  (Page  5) 

Conti,  F. ,  Tasaki,  I.  and  Wanke ,  E. :   Fluorescence  signals  in  ANS-stained 
squid  giant  axons  during  voltage- clamp.   Biophyslk,  8:  58-70,  1971. 

Kobatake,  Y. ,  Tasaki,  I.  and  Watanabe,  A.:   Phase  transition  in  membrane 
with  reference  to  nerve  excitation.   In  Kotani,  M.  (Ed.):   Advances  in 
Biophysics.   Tokyo,  University  of  Tokyo  Press,  1971,  pp.  1-31. 

Tasaki,  I.:   Fluorescence  changes  in  dye-treated  nerve  following  electric 
stimulation.   In  Chance,  B. ,  Lee,  C-P.  and  Blasie,  J.K.  (Eds.):   Probes  of 
Structure  and  Function  of  Macromolecules  and  Membranes ,  Vol.  1,  Probes  and 
Membrane  Function.   New  York  and  London,  Academic  Press,  Inc.,  1971, 
pp.  235-237, 

Tasaki,  I.:   Nerve  excitation  and  "phase  transition"  in  membrane 
macromolecules.   In  Biel,  J.H.  and  Abood,  L.G.  (Eds.):   Biogenic  Amines  and 
Physiological  Membranes  in  Drug  Therapy  (Part  A).   New  York,  Marcel  Dekker, 
Inc. ,  1971,  pp.  73-105. 

Tasaki,  I.,  Watanabe,  A.  and  Hallett,  M. :   Properties  of  squid  axon  membrane 
as  revealed  by  hydrophobic  probe,  2-p-toluidinylnaphthalene- 5- sulfonate. 
Proc.  Nat.  Acad.  Sci.  USA,  68:  938-941,  1971. 

Watanabe,  A.  and  Tasaki,  I.:   The  biionic  action  potential  and 
indispensability  of  divalent  cations  in  the  external  medium  for  nerve 
excitation.   In  Nichols,  G.  and  Wasserman,  R.H.  (Eds.):   Cellular  Mechanism 
for  Calcium  Transfer  and  ?Iomeostasis ,  New  York,  Academic  Press,  Inc.,  ,1971, 
pp.  77-100. 


557 


Serial  No.  M-NB-2 

1.   Lab  of  Neurobiology 

2. 

3.   Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:   Sensory-motor  integration  in  the  primate  visual  system 

Previous  Serial  Number:   Same 

Principal  Investigators:   Robert  H.  Wurtz,  Ph.D.,  Michael  E.  Goldberg,  M.D.  , 

David  L.  Robinson,  Ph.D.  and  Charlene  D.  Jarvis,Ph.D. 

Man  Years 

Total :  6.0 
Prof es  s  ional :  3.5 
Other :        2.5 

Project  Description 

Objective:   Our  goal  in  the  past  year  has  been  to  complete  experiments  on 
the  superior  colliculus  of  the  monkey  and  to  formulate  a  view  of  what  the 
contributioi:  of  this  area  might  be  in  the  production  of  behavior. 

Methods  Employed:   Three  general  techniques  were  employed  in  these 
experiments.   First,  monkeys  were  trained  to  look  for  several  seconds  at  a 
spot  of  light  on  a  screen  in  front  of  them,  using  methods  explained  in 
previous  annual  reports.   The  monkeys  did  not  move  their  eyes  even  when  a 
second  spot  of  light  was  flashed  onto  the  screen.   This  permitted  us  to  study 
the  normal  visual  input  to  the  nervous  system  without  the  complications  of 
large  random  eye  movements.   Second,  single  cells  were  recorded  in  the 
superior  colliculus  while  the  monkey  was  awake  and  the  location  of  these  cells 
in  the  brain  was  marked  at  the  recording  sites  and  located  on  histological 
sections  of  the  brain.   This  enabled  us  to  say  how  a  cell  responded  in 
relation  to  the  monkey's  trained  behavior  and  where  that  cell  was  located  in 
the  brain.   Third,  small  lesions  were  made  in  the  brain  with  the  micro- 
electrode  after  the  response  characteristics  of  cells  in  the  area  had  been 
obtained.   By  damaging  the  cells  we  have  studied  we  were  able  to  see  further 
what  the  contribution  of  these  cells  was  to  behavior. 

Major  Findings:   In  the  upper  layers  of  the  superior  colliculus  (optic  and 
superficial  gray  layers)  all  cells  responded  to  light.   The  predominant  cell 
type  responded  to  stationary  spots  of  light  and  to  spots  of  light  moving  in 
any  direction  through  the  receptive  field.   The  cells  were  remarkably 
insensitive  to  many  stimulus  parameters  including  shape,  orientation,  and 
size  of  spot.   The  receptive  field  size  of  the  cells  was  large  relative  to 
that  of  cortical  and  retinal  ganglion  cells,  and,  for  a  given  penetration  in 
the  colliculus,  increased  in  size  with  depth  of  the  cell  in  the  first  two 
layers . 

559 


M-NB-2  (Page  2) 

Half  of  these  cells  in  the  upper  layers  had  the  striking  property  of 
responding  not  only  to  the  physical  parameters  of  the  stimulus ,  but  also  to 
the  behavioral  parameter  of  how  the  monkey  was  going  to  respond  to  it.   The 
response  to  light  of  the  cells  considered  so  far  were  all  determined  while 
the  monkey  looked  at  the  fixation  point.   We  next  determined  what  change 
in  the  response  of  the  cell  occurred  when  the  monkey  was  forced  to  pay 
attention  to  the  spot  of  light  falling  on  the  receptive  field  of  the  cell 
being  studied  by  requiring  the  monkey  to  use  the  receptive  field  stimulus  as 
the  target  for  a  rapid  eye  movement.   In  this  case  the  response  of  cells  to 
the  visual  stimulus  was  more  vigorous  on  most  trials  and  more  regular  on 
successive  trials  during  the  period  when  the  monkey  was  paying  attention  to 
the  stimulus  than  when  he  was  not. 

A  critical  point  in  the  analysis  of  this  enhanced  response  is  whether  it 
was  selectively  related  to  certain  stimuli  which  were  the  target  of  the  eye 
movements  (and  thus  could  be  reasonably  regarded  as  related  to  attention)  or 
whether  it  was  related  to  any  eye  movement  to  any  part  of  the  visual  field 
(and  therefore  might  be  related  to  a  more  general  activation  or  arousal 
level).   To  test  the  selectivity  of  the  enhanced  response,  we  allowed  the 
monkey  to  saccade  to  either  of  two  spots  of  light ,  one  spot  in  the  receptive 
field  of  the  cell  another  outside  the  field.   In  those  trials  when  the 
monkey  saccaded  to  the  control  stimulus  there  was  slight  if  any  enhancement. 
In  those  trials  when  the  monkey  saccaded  to  the  receptive  field  stimulus  the 
enhancement  of  the  response  was  clear.   The  enhancement  effect,  therefore, 
is  selective. 

While  the  monkey  attended  to  the  receptive  field  stimulus  by  saccading  to 
it ,  the  response  of  the  cell  to  the  stimulus  did  not  habituate  with 
successive  stimulus  presentations.   When  the  monkey  stopped  saccading  to  the 
receptive  field  stimulus  at  the  end  of  a  series  of  trials  the  discharge  of 
the  cells  also  frequently  did  not  return  to  the  previous  level  immediately 
but  showed  a  gradual  habituation.  Thus  when  the  monkey  was  not  attending  to 
the  receptive  field  stimulus,  habituation  began  and  the  response  of  the  cell 
to  the  stimulus  was  reduced  to  its  previous  level.   This  strongly  suggests 
that  lack  of  attention  leads  to  habituation  of  the  response  at  least  in 
these  collicular  cells. 

Unlike  the  cells  in  the  upper  layers  of  the  colliculus ,  cells  in  the 
intermediate  gray  and  white  layers  discharged  before  eye  movements  to  a 
particular  area  of  the  visual  field.  The  eye  movement  related  activity  of 
these  cells  was  independent  of  orbital  position  and  depended  only  upon  the 
position  of  the  saccade  target  being  in  one  area  of  the  visual  field.   We 
call  this  area  of  the  visual  field  the  movement  field  of  a  cell,  in  analogy 
to  the  visual  receptive  field  of  a  sensory  cell,  and,  indeed,  the  movement 
field  of  an  intermediate  layer  neuron  lies  in  the  same  area  of  the  visual 
field  as  the  receptive  fields  of  the  cells  in  the  superficial  layers  just 
above  them. 

In  order  to  see  the  contribution  of  ensembles  of  collicular  cells  to  the 

560 


M-NB-2  (Page  3) 

generation  of  accurate  eye  movement,  we  tested  the  effect  of  focal  lesions  in 
the  colliculus  on  visually  guided  eye  movements.   Cells  in  each  area  of  the 
colliculus  are  dedicated  to  a  particular  area  of  the  visual  field,  both  in 
responding  to  visual  stimuli  from  that  area  and  in  discharging  before  eye 
movements  to  that  area.   We  reasoned  that  a  lesion  made  through  a  micro- 
electrode  from  which  we  had  recorded  cells  responsive  to  a  particular  area  of 
the  visual  field  should  affect  eye  movements  to  that  area  of  the  field,  and 
the  nature  of  the  deficit  would  help  us  describe  the  nature  of  the  colliculus ' 
participation,  if  any,  in  the  generation  of  eye  movements.   We  found  that 
following  a  lesion,  the  monkey  saccaded  to  the  area  of  the  visual  field 
related  to  the  damaged  collicular  area  just  as  accurately  as  before  the  lesion. 
What  did  change  was  the  latency  of  the  saccades;  they  are  now  150-300  msec 
later  when  made  to  the  area  of  the  visual  field  related  to  the  lesion. 

Significance:   We  believe  our  experiments  indicate  that  the  superior 
colliculus  probably  is  not  critical  for  eye  movement  guidance.   The  cell 
properties  are  not  those  of  a  precise  guidance  system  and  the  effect  of 
ablating  the  colliculus  is  not  to  alter  the  accuracy  or  speed  of  an  eye  move- 
ment but  only  to  increase  reaction  time  for  the  eye  movement.   Instead,  the 
results  of  our  experiments  suggest  that  the  superior  colliculus  of  the 
primate  may  contribute  to  a  shift  of  visual  attention  and  a  facilitation  of  eye 
movement  toward  important  areas  of  the  visual  field.   The  cells  in  the 
superficial  layers  show  evidence  of  this  shift  in  attention;  they  discharge 
more  vigorously  and  more  regularly  to  a  stimulus  the  monkey  is  required  to 
saccade  to.   The  effect  of  this  selective  enhancement  of  discharge  would  be 
that  stimuli  in  one  part  of  the  visual  field  are  more  effective  than  those 
falling  on  the  rest  of  the  retinal  mosaic.   Cells  participating  in  this  shift 
of  attention  from  one  part  of  the  visual  field  to  another  need  not  be  very 
precise  analyzers  of  stimulus  characteristics.   Indeed,  the  collicular  cells 
can  specify  only  in  a  rough  way  where  the  important  area  of  the  visual  field 
is.   Similarly,  the  output  of  the  movement-related  cells  in  the  intermediate 
layers  could  facilitate  an  eye  movement  to  a  general  area  of  the  field  that 
could  be  translated  into  a  precisely  guided  eye  movement  by  other  systems. 
When  the  collicular  cells  are  destroyed  by  a  lesion,  we  v:ew  the  increased 
latency  for  a  saccade  as  a  delay  in  the  monkey's  noticing  the  target  so  that 
the  monkey  shifts  his  attention  to  it  more  slowly,  and  saccades  to  it  later. 
The  deficit  following  a  collicular  ablation  is  therefore  a  deficit  in  the 
transfer  of  the  effect  of  visual  attention  to  the  oculomotor  system,  not  a 
deficit  in  the  guidance  system  itself. 

Proposed  Course:   Our  line  of  experiments  will  proceed  in  two  directions . 
First,  several  aspects  of  the  superior  colliculus  will  be  investigated  further. 
For  example ,  we  have  seen  a  clear  relation  between  superior  colliculus  cells 
and  eye  movements ;  we  will  next  determine  whether  these  cells  are  related  to 
head  as  well  as  eye  movements.   Second,  we  will  investigate  other  visually 
related  areas  of  the  brain  to  determine  the  effect  of  attention  on  these  other 
areas . 


561 


M-NB-2  (Page  U) 
Honors  and  Awards : 

Dr.  Wurtz  was  an  invited  participant  at  the  United  States-Australian 
Symposiimi  on  Vision,  held  in  Canberra,  Australia,  February  7-11,  1972. 

Dr.  Goldberg  received  the  S.  Weir  Mitchell  Award  given  by  the  American 
Academy  of  Neurology  for  his  essay  on,  "The  role  of  the  primate  superior 
colliculus  in  visually  evoked  eye  movements . " 

Dr.  Wurtz  and  Dr.  Goldberg  were  invited  participants  at  the  symposium  on 
superior  colliculus  at  the  XXV  International  Congress  of  Physiological 
Sciences  held  in  Munich,  Germany,  July  1972,  and  at  the  satellite  symposium 
on,  "Cerebral  control  of  eye  movements,"  held  in  Freiburg,  Germany. 

Pi±ilications : 

Wurtz,  R.H.  and  Goldberg,  M.E. :   The  role  of  the  superior  colliculus  in 
visually-evoked  eye  movements.   Bibl.  Ophthalm.   83:  472-477,  1972. 


562 


Serial  No.  M-NB-3 

1.   Lab  of  Neiorobiology 
2. 

3.   Bethesda,  Maryland 
PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   Metabolic  activity  of  nuclear  proteins  from  rat  brain  cells 

Previous  Serial  No.   Same 

Principal  Investigator:   JosS  A.  Burdman,  M.D. 

Man  Years 

Total:  0.3 
Professional:  0.2 
Other :         0 . 1 

Project  Description 

Objective:   The  objectives  of  the  present  study  were:  (a)  to  investigate 
intranuclear  sites  of  protein  synthesis  in  brain  cells,  (b)  to  explore  the 
possible  relationship  between  rate  of  synthesis  of  nuclear  proteins  and 
physiological  stimulation  of  the  brain,  and  (c)  to  investigate  the  relation- 
ship between  the  rate  of  cell  division  in  the  brain  with  the  metabolic 
activities  of  nuclear  proteins. 

Proposed  Course:   Project  was  terminated. 


563 


Serial  No.  M-NC-1 
1 .   Neurochemistry 
2. 
3.   Bethesda,  Md. 


PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 


Project  Title:   The  Conversion  of  Phenylalanine  to  Tyrosine 

Previous  Serial  Number:   M-NC-1 

Principal  Investigator:   Seymour  Kaufman 

Other  Investigators:   Daniel  Fisher,  Paul  Friedman,  Charles 

Huang,  Jonathan  Craine 


Man  Years: 

Total       : 

4.4 

Professional: 

3.4 

Other       : 

1.0 

Project  Description: 

Objectives:   The  oxidation  of  foodstuffs,  which  ultimately 
supplies  the  energy  for  all  cellular  functions,  can  be 
effected  by  two  completely  different  processes.   Organic 
compounds  can  either  be  oxidized  by  dehydrogenation,  the 
removal  of  hydrogen,  or  by  oxygenation,  the  addition  of 
oxygen  to  the  substrate  molecule.   The  first  type  of  re- 
action predominates  in  carbohydrate  and  fat  metabolism. 
The  mechanism  of  this  kind  of  oxidation  has  been  the  subject 
of  investigation  for  50  years  and  is  now  quite  well  under- 
stood.  Oxygenation  reactions  are  encountered  mainly  in  the 
cellular  catabolism  of  ring  compounds  such  as  aromatic  and 
heterocyclic  amino  acids,  hormones  and  drugs.   In  contrast 
to  hydrogenations,  the  mechanism  of  oxygenation  reactions 
has  remained  obscure.   The  conversion  of  phenylalanine  to 
tyrosine  is  an  oxidation  reaction  of  this  type  and  the  goal 
of  this  study  is  to  gain  insight  into  the  mechanism  of  this 
kind  of  oxidation  reaction . 

Methods  Employed:   Standard  methods  of  protein  purification, 
including  salt  and  ethanol  fractionation,  ion-exchange  chro- 
matography and  sephadex-gel  filtration,  have  been  used.   The 
following  methods  of  protein  analysis  have  been  used  to 
characterize  the  hydroxylase:   Sucrose-density  ultracentri- 
fugation  and  polyacrylamide  gel  electrophoresis. 

565 


Serial  No.  M-NC-1,  page  2 


Ma j or  Findings : 

TT. In  the  presence  of  tetrahydrobiopterin,  the  hydroxylase 

is  stimulated  50-fold  by  phospholipids  such  as  lysolecithin; 
the  related  phospholipid,  lecithin,  is  a  potent  inhibitor 
of  the  enzyme . 

2.  Dihydropteridine  reductase,  the  enzyme  that  normally 
operates  in  conjunction  with  the  hydroxylase  to  maintain  the 
tetrahydropterin  in  the  reduced  form,  has  been  purified  to 
homogeneity  from  sheep  liver.   In  confirmation  of  previous 
findings  made  with  crude  preparations,  the  enzyme  is  more 
active  with  DPNH  than  with  TPNH.   In  liver,  adrenals  and 

in  brain,  the  reductase  is  present  in  vast  excess  over  the 
pterin-dependent  hydroxylases  known  to  be  present  in  these 
tissues . 

3 .  Antibodies  to  the  pure  hydroxylase  have  been  produced  by 
injection  of  the  rat  liver  enzyme  into  sheep.   The  antibodies 
cross-react  with  phenylalanine  hydroxylase  in  human  liver. 

No  cross-reacting  protein  has  been  detected  in  single  liver 
biopsy  samples  from  a  patient  with  phenylketonuria  (PKU) 
and  from  a  patient  with  hyperphenylalaninemia . 

Scientific  Significance:   The  demonstration  that  phenyl- 
alanine hydroxylase  can  be  markedly  stimulated  by  certain 
phospholipids,  and  that  it  can  be  inhibited  by  others  sug- 
gests that  phospholipids  may  play  an  important  role  in  the 
regulation  of  the  activity  of  the  enzyme  in  vivo.   Specifi- 
cally, these  results  suggest  that  another~Tiver  enzyme,  phos- 
pholipase  A,  which  can  catalyze  the  conversion  of  the  inhib- 
itor, lecithin  to  the  activator,  lysolecithin,  could  be  one 
of  the  determining  factors  in  the  expression  of  hydroxylase 
activity  in  vivo. 

The  activation  by  phospholipids  may  also  find  an  impor- 
tant application  in  the  assay  of  the  hydroxylase  in  human 
tissue  biopsy  samples.   Since  the  activation  can  increase 
the  sensitivity  of  the  assay  by  50-fold,  its  use  should  facil- 
itate the  detection  of  the  hydroxylase  in  tissues  other  than 
liver. 

The  more  sensitive  assay  will  also  be  valuable  in  de- 
termining more  precisely  the  extent  of  the  enzymatic  defect 
in  PKU.   Based  on  the  sensitivity  of  the  assays  used  pre- 
viously, it  can  only  be  concluded  that  in  PKU  liver  samples 
there  is  less  than  1  to  2%  of  the  normal  enzyme  activity. 
With  our  new  assay  conditions,  it  will  be  possible  to  detect 
hydroxylase  activity  at  the  level  of  0.02  to  0.05%  of  normal. 

566 


Serial  No.  M-NC-1,  page  3 


There  has  been  a  considerable  amount  of  speculation 
in  recent  years  about  the  possibility  that  dihydropteridine 
reductase  could  be  the  limiting  enzyme  in  the  biosynthesis 
of  the  neurotransmitters,  norepinephrin  and  serotonin. 

The  finding  that  dihydropteridine  reductase  is  present 
in  vast  excess  over  known  pterin-dependent  hydroxylases  in 
liver,  adrenals  and  brain,  makes  it  unlikely  that  the  re- 
ductase could  limit  the  rate  of  hydroxylation  of  phenyl- 
alanine in  liver,  of  tyrosine  in  adrenals  or  of  tyrosine 
or  tryptophan  in  brain  tissue. 

The  preparation  of  antibodies  to  phenylalanine  hydrox- 
ylase, and  their  cross-reactivity  with  the  normal  human 
enzyme,  has  led  to  an  advance  in  our  knowledge  of  the  nature 
of  the  enzyme  defect  in  PKU  and  in  hyperphenylalaninemia. 
Our  results,  which  are  so  far  limited  to  only  a  single  liver 
sample  from  each  disease  type,  demonstrate  that  there  is  no 
detectable  cross-reacting  material  (CRM)  in  either  condition. 
The  immunological  tests  that  were  performed  could  have  de- 
tected CRM  at  the  level  of  5%  of  normal.   With  a  more  sensi- 
tive test,  based  on  the  inhibition  by  the  antibodies  of  the 
small  amount  of  enzyme  activity  in  the  hyperphenylalaninemic 
liver  sample,  CRM  could  be  detected. 

Furthermore,  we  have  found  that  the  hydroxylase  from 
hyperphenylalaninemic  liver  has  a  different  Km  for  phenyl- 
alanine than  does  the  normal  liver  enzyme.   These  results 
indicate  that  hyperphenylalaninemia  is  a  disease  that  is 
caused  by  a  mutation  in  the  structural  gene  for  phenylalanine 
hydroxylase.   The  altered  gene  product  has  the  following 
characteristics:   a)  only  about  5%  of  the  normal  hydroxylase 
activity;   b)  a  significantly  lower  Km  for  phenylalanine; 
c)   it  interacts  with  antibodies  to  the  normal  hydroxylase, 
but  the  antibody-antigen  complex  does  not  precipitate  com- 
pletely nor  does  it  lose  all  of  its  catalytic  activity. 

By  contrast,  classical  PKU  is  either  a  deletion  mutation, 
in  which  no  gene  product  is  made,  or  else  it  is  a  structural 
gene  mutation  that  leads  to  a  product  that  is  so  altered  that 
it  has  no  detectable  hydroxylase  activity  and  no  cross-reac- 
tivity with  antibodies  to  the  normal  enzyme. 

Proposed  Course:   Further  studies  on  the  mechanism  and 
regulatory  properties  of  the  enzyme  will  be  carried  out. 
The  function  of  the  iron  in  the  enzyme  will  be  investigated. 


567 


Serial  No.  M-NC-1,  page  4 


Honors  and  Awards :   None 

Publications : 

Friedman,  P.  A.  and  Kaufman,  S:   A  study  of  the  development 
of  phenylalanine  hydroxylase  in  fetuses  of  several  mammalian 
species.   Arch.  Biochem.  Biophys .  146:   321-326,  1971. 

Storm,  C.  B.,  Shiman,  R. ,  and  Kaufman,  S. :   Preparation  of 
6-substituted  pterins  via  the  Isay  reaction.   J.  Org.  Chem. 
36:   3925-3927,  1971. 

Kaufman,  S.  and  Max,  E.  E.:   Studies  on  the  phenylalanine 
hydroxylating  system  in  human  liver  and  their  relationship 
to  pathogenesis  of  PKU  and  hyperphenylalaninemia.   In 
Bickel,  H.,  Hudson,  F.   .  and  Woolf,  L.  I.  (Eds.):  Phenyl- 
ketonuria and  some  other  inborn  errors  of  amino  acid  metab- 
olism. Stuttgart,  Georg  Thieme  Verlag,  1971,  pp.  13-19 . 

Kaufman,  S. :   Fractionation  of  protein  mixtures  with  organic 
solvents.   In  Jakoby,  W.  B.  (Ed.):   Methods  in  Enzymology, 
Vol.  XXII.   New  York,  N.Y. ,  Academic  Press,  1971,  pp.  233- 
238. 

Kaufman,  S. :   The  phenylalanine  hydroxylating  system  from 
mammalian  liver.   In  Meister,  A.  (Ed.):   Advances  in  Enzym- 
ology, Vol.  35,  New  York,  N.Y.,  John  Wiley,  1971,  pp.  245- 
320. 

Fisher,  D.  B.  and  Kaufman,  S. :   The  stimulation  of  rat  liver 
phenylalanine  hydroxylase  by  phospholipids.   J.  Biol.  Chem. 
247:   2250-2252,  1972. 


568 


Serial  No.  M-NC-2 
1 .   Neurochemistry 
2. 
3.   Bethesda,  Md. 


PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 


Project  Title:   Biosynthesis  of  Catecholamines 
Previous  Serial  Number:   M-NC-2 
Principal  Investigator:   Thomas  A.  Lloyd 
Other  Investigator:   Seymour  Kaufman 
Man  Years 


Total        : 

1 

2 

Professional: 

1 

2 

Other       : 

0 

Project  Description: 

Objectives:   These  investigations  are  a  continuation  of 
previous  work  in  this  laboratory  concerning  the  biosyn- 
thesis of  catecholamines.   Since  tyrosine  hydroxylase  has 
been  demonstrated  to  be  the  rate  limiting  step  in  the  bio- 
synthesis of  catecholamines,  present  goals  include:   a  puri- 
fication of  tyrosine  hydroxylase  from  mammalian  central 
nervous  system  and  a  comparison  of  the  physical  and  bio- 
chemical properties  of  this  enzyme  to  those  of  highly  puri- 
fied adrenal  tyrosine  hydroxylase  and  to  those  of  highly 
purified  liver  phenylalanine  hydroxylase. 

Methods  Employed:  The  role  of  phenylalanine  and  tyrosine  as 
substrates  for  brain  tyrosine  hydroxylase  and  as  precursors 
in  the  biosynthesis  of  catecholamines  have  been  investigated 
through  the  use  of  tissue  slices,  tissue  mincers  and  par- 
tially purified  enzyme  preparations.   The  purification  of 
brain  tyrosine  hydroxylase  per  se,  has  required  investiga- 
tion of  classical  techniques,  e.g.,  gel  filtration,  salt 
and  organic  solvent  fractionatTon,  ion  exchange  chromato- 
graphy and  some  more  novel  approaches,  e.g.,  affinity 
chromatography  and  cross-reactivity  tests~with  sheep  anti- 
body to  rat  liver  phenylalanine  hydroxylase. 


569 


Serial  No.  M-NC-2,  page  2 


Major  Findings: 

T.      Comparative  studies  on  the  role  of  phenylalanine  and 
tyrosine  as  precursors  in  the  biosynthesis  of  catecholamines: 
In  earlier  studies  with  highly  purified  tyrosine  hydroxylase 
from  bovine  adrenal  medulla,  we  observed  that  in  the  presence 
of  the  natural  pterin  cof actor,  phenylalanine  was  hydroxylated 
as  rapidly  as  tyrosine.   Furthermore,  phenylalanine  does  not 
produce  substrate  inhibition,  whereas,  tyrosine  does.   We 
have  subsequently  examined  the  generality  and  possible  phy- 
siological significance  of  these  observations  in  other 
tissues  and  at  higher  levels  of  organization.   When  rat 
brain  minces  were  presented  with  either  phenylalanine  or 
tyrosine  as  the  substrate  for  catecholamine  biosynthesis, 
the  catecholamines  formed  from  phenylalanine  represented 
more  than  40%  as  much  as  from  tyrosine,  with  no  correction 
being  made  for  the  additional  dilution  experienced  by 
phenylalanine  in  the  intracellular  phenylalanine  pool. 
Further  studies  with  rat  brain  minces  demonstrated  that 
phenylalanine  and  tyrosine  appear  to  compete  as  precursors, 
both  in  uptake  and  as  enzymatic  substrates.   Thus,  when  the 
levels  of  these  two  substrates  in  the  incubation  medium  were 
adjusted  to  plasma  levels  (which  happen  to  be  nearly  iden- 
tical to  intracellular  concentration) ,  the  amount  of  cate- 
cholamines formed  from  phenylalanine  represented  17%  of  that 
formed  from  tyrosine.   Again,  no  correction  has  been  made 
for  the  extra  dilution  that  probably  occurs  when  the  pre- 
cursor is  phenylalanine. 

II .   Production  of  antibodies  to  rat  liver  phenylalanine 
hydroxylase :   Cross-reactivity  with  other  pterin-dependent 
hydroxylases :   The  pterin-dependent  aromatic  amino  acid 
hydroxylases  -  phenylalanine  hydroxylase,  tyrosine  hydrox- 
lyase,  and  tryptophan  hydroxylase  -  show  striking  similari- 
ties in  many  of  their  kinetic  and  regulatory  properties. 
Only  rat  liver  phenylalanine  hydroxylase  has  been  purified 
extensively  enough  for  detailed  physical  characterization. 
Since  it  was  of  interest  to  know  if  these  hydroxylases  mani- 
fest physical  similarities,  we  have  compared  the  hydroxylases 
immunochemical ly.   A  potent,  specific  antiserum  to  rat  liver 
phenylalanine  hydroxylase  was  produced  in  sheep.   The  antigen 
was  obtained  in  homogeneous  form  by  electrophoresis  of  857o 
pure  material  and  extraction  of  the  gel  bands  containing 
pure  phenylalanine  hydroxylase .   Agar  double-immunodiffusion 
reactions  and  enzyme  inhibition  studies  revealed  an  exten- 
sive cross-reactivity  between  the  antiserum  and  phenyl- 
alanine hydroxylases  from  guinea  pig,  mouse,  monkey,  and 
human  liver,  as  well  as  from  rat  kidney.   No  cross-reactivity 
with  Pseudomonas  phenylalanine  hydroxylase  could  be 


570 


Serial  No.  M-NC-2,  page  3 

demonstrated.   Further  studies  suggest  cross-reactivity 
with  bovine  adrenal  and  rat  brain  tyrosine  hydroxylases, 
but  not  with  rat  brain  tryptophan  hydroxylase,  rat  kidney 
aromatic  L-amino  acid  decarboxylase,  or  bovine  adrenal 
dopamine-P-hydroxylase . 

Scientific  Significance: 

I .  Although  our  studies  have  shown  that  more  hydroxylated 
products  are  formed  when  phenylalanine  is  used  as  the  pre- 
cursor, we  have  found  it  difficult  to  evaluate  the  physiolo- 
gical significance  of  these  observations  since  at  present, 
we  have  no  way  of  evaluating  the  local  intracellular  pools 
of  phenylalanine  and  tyrosine  associated  with  the  biosyn- 
thesis of  catecholamines.   If  the  intracellular  phenyl- 
alanine pool  diluted  the  specific  activity  of  the  added 
radiophenylalanine  five-fold,  then  we  could  conclude  that 
tyrosine  and  phenylalanine  are  equivalent  precursors. 
Lacking  this  information  we  must  conclude  only  that  phenyl- 
alanine is  responsible  for  at  least  20%  of  central  nervous 
system  catecholamine  biosynthesis. 

II.  We  have  shown  immunochemically  that  there  is  close 
physical  resemblance  between  several  phenylalanine  hydrox- 
ylases, that  two  tyrosine  hydroxylases  bear  some  antigenic 
resemblance  to  phenylalanine  hydroxylase  and  that  tryptophan 
hydroxylase  is  antigenically  distinct. 

Proposed  Course:   Since  the  biosynthesis  of  catecholamines 
is  affected,  and  possibly  regulated,  by  the  nature  and 
proximity  of  the  reduced  pteridine  cof actor,  further  studies 
are  in  progress  on  the  isolation,  characterization,  and  dis- 
tribution of  the  pteridine  cof actor  in  mammalian  brain. 
Studies  are  also  in  progress  on  the  production  of  a  specific 
antibody  to  pure  tyrosine  hydroxylase  from  adrenal  medulla. 

Honors  and  Awards :   None 

Publications : 

Kaufman,  S.:   Dopamine  p -hydroxylase .   In  Tabor,  H.  and 
Tabor,  C.  W.  (Eds.):   Methods  in  Enzymology,  17B.   New  York, 
N.Y.,  Academic  Press,  1971,  pp.  754-761. 

Lloyd,  T.,  Mori,  T.,  and  Kaufman,  S. :   6-Methyltetrahydro- 
pterin.   Isolation  and  identification  as  the  highly  active 
hydroxylase  cof actor  from  tetrahydrofolate .   Biochemistry 
10:   2330-2336,  1971.  


571 


Serial  No.  M-NC-4 
1 .   Neurochemistry 
2. 
3.   Bethesda,  Md. 


PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 


Project  Title:   The  Biochemical  Basis  of  Skeletal  Muscle 
Hypertrophy 

Previous  Serial  Number:   M-NC-4 

Principal  Investigator:   Seymour  Kaufman 

Other  Investigator:   Charles  Jablecki 


Man  Years 

Total        : 

2.1 

Professional: 

1.3 

Other       : 

0.8 

Project  Description: 

Objectives :   The  objective  of  this  project  is  unchanged: 
The  elucidation  of  the  biochemical  correlates  of  muscle 
cell  hypertrophy. 

Methods  Employed:   We  are  using  an  operation  to  produce 
work-induced  hypertrophy  of  skeletal  muscle  in  vivo  as  pre- 
viously described.   The  biochemical  fractions  of  interest 
are  labeled  isotopically .   RNA  is  separated  by  a  modified 
Schmidt -Tannhauser  procedure  and  phospholipids  and  their 
precursors  by  the  Folch  procedure. 

Major  Findings:   RNA  studies .   We  have  completed  an  auto- 
radiographic  study  to  localize  the  changes  in  RNA  synthesis 
that  occur  in  skeletal  muscle  during  work-induced  hypertrophy, 
The  bulk  of  the  increased  net  rate  of  RNA  synthesis,  as 
measured  by  the  incorporation  of  orotic  acid  and  uridine,  is 
localized  to  the  connective  tissue .   No  significant  change 
in  RNA  synthesis  was  found  in  muscle  cells. 

Phospholipids  studies.   An  early  change  in  phospholipid 
synthesis  has  been  documented  in  skeletal  muscle  within  two 
hours  following  tenotomy.   This  change  appears  to  be  specific 
to  hypertrophy;  rats  subjected  to  acute  exercise  and  an  en- 
durance training  program  did  not  show  this  change . 

573 


Serial  No.  M-NC-4,  page  2 

Scientific  Significance:   Many  studies  documenting  early 
biochemical  changes  in  skeletal  and  cardiac  muscle  have 
ignored  connective  tissue  as  a  possible  site  of  these 
changes.   Henceforth  it  must  be  realized  that  the  connective 
tissue  is  very  active  metabolically  during  work-induced 
hypertrophy  of  the  organ,  and  it  must  be  considered  as  a 
site  of  biochemical  events  measured  during  the  course  of 
muscle  hypertrophy. 

Proposed  Course:   An  autoradiographic  study  of  the  early 
changes  in  phospholipid  metabolism  during  work-induced 
hypertrophy  of  skeletal  muscle  is  planned. 

Honors  and  Awards :   None 

Publications:   None 


57i^ 


Serial  No.  M-NC-5 
1 .   Neurochemistry 
2. 
3.   Bethesda,  Md. 


PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   The  Process  of  Lysogeny 

Previous  Serial  Number:   M-NC-5 

Principal  Investigator:   Howard  A.  Nash 

Other  Investigators:   Cecilia  M.  Hidalgo 

Man  Years 

Total  :  3 
Professional:  2 
Other        :   1 

Project  Description: 

Objectives:   The  project  is  a  continuing  study  of  the  pro- 
cesses involved  in  the  insertion  of  viral  DNA  into  the  host 
genome.   An  elucidation,  at  the  level  of  biochemistry  and 
molecular  biology,  of  the  steps  involved  in  DNA-DNA  recom- 
bination is  the  overall  goal. 

Methods  Employed:   Microbiological  techniques  for  isolation, 
growth,  genetic  characterization  of  bacteriophages;  radio- 
active and/or  density  labeling  procedures  for  bacteriophage; 
buoyant  density  and  sedimentation  analysis  using  density 
gradients  in  a  high  speed  preparative  ultracentrifuge ; 
thin  layer  chromatographic  analysis  of  nucleotide  bases; 
polyacrylamide  gel  electrophoresis;  chromatographic  column 
separations,  filter  membrane  binding  analysis  of  protein- 
nucleic  acid  interactions . 

Major  Findings  and  Significance: 

Part  I.   A  gene  in  phage  \,    int,  is  the  only  known  genetic 
element  necessary  for  viral  integration.   In  double  label 
experiments,  using  ultraviolet  damaged  host  cells,  material 
with  a  subunit  molecular  weight  of  45,000  has  been  shown  to 
be  the  product  of  the  int  structural  gene,  rather  than  a 
product  made  under  its  indirect  control.   By  a  combination 
of  streptomycin  precipitation,  ammonium  sulfate  fractionation, 


575 


Serial  No.  M-NC-5,  page  2 


DEAE  cellulose  and  phosphocellulose  chromatography,  the 
protein  has  been  purified  to  radiochemical  homogeneity. 
The  purification  has  permitted  the  establishment  of  several 
facts  concerning  int  protein.   Under  a  variety  of  ionic  con- 
ditions, the  molecule  has  a  sedimentation  value  of  3-4 
svedbergs,  consistent  with  a  monomeric  form  for  the  non- 
denatured  protein.   The  protein  has  been  shown  to  have  a 
high  affinity  for  double  stranded  DNA.   1-5  molecules  of 
int  monomer  are  bound  per  100,000  nucleotides  and  the 
eflective  dissociation  constant  is  around  10-10  M/L .   The 
binding  appears  to  be  similar  for  X    DNA  carrying  0,  1  or  2 
recombination  sites,  and  DNA  from  the  unrelated  phage  T4. 
The  purification  scheme  established  for  int  produced  in 
irradiated  hosts  has  been  extended  to  int  produced  under 
normal  growth  conditions.   The  identical  purification  has 
been  shown  to  be  appropriate  for  int  produced  in  this  way 
and  has  permitted  the  acquisition  of  larger  amounts  of  int 
protein.   In  addition,  the  temporal  and  genetic  control  of 
int  production  has  been  investigated.   Int  has  been  shown 
directly  to  be  repressed  by  a  control  gene,  tof,  and  to  be 
under  some  additional  negative  control  late  after  phage 
induction. 

Part  II.   The  role  that  methylated  nucleotides  play  in  site 
specific  receptor  processes  involving  DNA  has  been  investi- 
gated by  examining  the  distribution  of  methyl  groups  with 
respect  to  known  genetic  elements  in  \    DNA.   Earlier  work 
in  this  laboratory  demonstrated  uniformity  of  distribution 
with  respect  to  single  strands  and  a  small  non-uniformity 
along  the  double  helix.   The  possible  existence  of  non- 
uniformly  distributed  subclasses  of  methylated  nucleotides 
has  been  examined  by  observing  the  methyl  groups  synthesized 
during  deprivation  of  the  major  known  methyl  donor,  S-adeno- 
sylmethionine .   The  reduction  of  the  intercellular  content 
of  S-adenosylmethionine  was  achieved  by  infecting  the 
phage  T3  which  codes  for  an  enzyme  which  splits  this  com- 
pound. X    produced  during  infection  with  phage  T3  was 
shown  to  have  suffered  interference  with  its  host  modifica- 
tion, a  property  known  to  be  dependent  on  DNA  methylation. 
Direct  nucleotide  analysis  revealed  almost  no  residual 
methylation  occurred  in  DNA  made  under  these  conditions. 

Scientific  Significance: 

Part  I .   These  studies  continue  to  elucidate  the  molecular 
nature  of  int  gene  product .   They  indicate  that  this  mole- 
cule probably  works  by  an  attachment  to  DNA  and  precession 
to  the  ultimate  substrate  site.   The  purification  schemes 
for  int  protein  should  continue  to  be  useful  in  studies  of 


576 


Serial  No.  M-NC-5,  page  3 

control  mechanism  since  it  places  int  as  only  the  second 
early  gene  locus  in  phage  x    to  have  a  method  for  quanti- 
tating  the  amount  of  protein  made.   In  this  regard,  the 
studies  of  control  of  int  production  late  after  induction 
may  have  uncovered  a  previously  unrecognized  mode  of  turnoff 
of  early  functions. 

Part  II.   The  results  concerning  methyl  group  distribution 
in  \    DNA  have  been  used  to  rule  out  several  significant 
models  of  the  role  played  by  methylated  nucleotides.   The 
bulk  of  the  methylated  bases  cannot  be  used  as  a  regulation 
element  to  signal  either  of  the  parent  strands  during 
asymmetric  replication.   Nor  can  they  be  used  as  a  signal 
for  early  versus  late  gene  transcription.   These  data  favor 
models  which  involve  nonvital  functions  for  methylated  bases 
The  experiments  with  undermethylated  phage  are  a  detailed 
test  of  the  unique  role  played  in  DNA  methylation  by  SAM 
They  establish  the  hypothesis  that  all  the  in  vivo  methyla- 
tion of  DNA  proceed  from  methionine  via  SAM"! 

Proposed  Course:   We  will  continue  with  our  study  of  the 
interaction  of  int  protein  and  x   DNA.   New  systems  will  be 
developed  to  in'Eroduce  purified  and  crude  int  protein  into 
contact  with  genetic  material  to  further  elucidate  the  steps 
involved  in  int  dependent  recombination.   New  modes  of  con- 
trol of  X    functions  by  fusion  of  x    genes  with  those  of  bac- 
terial operons  will  be  examined  for  their  effect  on  int 
production.   The  methylation  study  is  essentially  complete 
It  has  been  written  up  and  has  been  submitted  for  publication 

Honors  and  Awards:   None 
Publications : 

Nash,  H.  A.  and  Robertson,  C.  A.:   On  the  mechanism  of  Int- 
promoted  recombination.   Virology  44:   446-449   1971.   


577 


Serial  No.  M-NC-6 
1 .   Neurochemistry 
2. 
3.   Bethesda,  Md. 


PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 


Project  Title:   Physicochemical  Investigations  of  Biofunctional 
Structures  of  Glycosaminoglycans  and  Glycolipids 

Previous  Serial  Number:   M-NC-6 

Principal  Investigator:   Audrey  Larack  Stone 

Other  Investigators:   A.  D.  Van  Praag,  S.  Farber 

Cooperating  Units:   Dept .  of  Medicine,  N.Y.U.  Medical  College 

Man  Years 


Total       : 

0.3 

Professional: 

0.3 

Other       : 

0 

Project  Description: 

Physicochemical  measurement  of  optical  conformations  of 
glycosaminoglycans  (GAG,  mucopolysaccharides) ;  and  deter- 
mination of  the  molecular  basis  for  the  formation  and  main- 
tenance of  inter-  and  intra-molecular  structures  known  to  be 
involved  in  the  rapid  transformation  of  simple  cations  (and 
biogenic  amines)  from  the  bound  to  the  active  form. 

Objectives :   To  elucidate  the  particulars  of  the  various 
molecular  conformations  by  means  of  their  recently  dis- 
covered (M-NC-21,  1967)  ultraviolet  amide  transition  bands 
and  the  special  optical  effects  of  their  dye  complexes 
(M-NC-21,  1965)  with  the  view  towards  developing  a  sensitive 
method  of  identification,  and  a  molecular  basis  for  biologi- 
cal activities  associated  with  interstitial  matrices  such  as 
the  greater  neuronal  membrane . 

Major  Findings:   Standard  GAG  exhibit  particular  CD  in  the 
spectral  region  of  the  n-w   and  tt-tt  amide  transitions  (see 
M-NC-6,  1971) .   Heparan  sulfate  (HS)  has  been  found  in  the 
kidney  cortex,  isolated  at  relatively  higher  salt  elution 
than  that  exclusively  found  in  other  tissues.   (This  type  of 
HS  has  significance  in  Hurlers  diseases.)   The  renal  cortex 


5T9 


Serial  No.  M-NC-6,  page  2 


glycosaminoglycans  are  HS  and  dermatan  sulfate  in  sharp  con- 
trast with  those  found  in  the  renal  papillae,  chondroitin 
sulfate  (ChS)  and  hyaluronic  acid  (HA) .   Renal  GAG  are  about 
one-half  the  molecular  weights  found  in  other  tissues. 

Scientific  Significance:   See  M-NC-6,  1971.   Circular 
dichroisra  patterns  correlated  with  salt  elution  fractions 
of  GAG  provide  clear  aid  to  identification  and  characteriza- 
tion of  these  polymers,  especially  where  substances  like 
heparan  sulfate  might  be  overlooked.   These  methods  have 
already  become  important  to  other  investigators  in  the  field 
and  collaborative  efforts  have  led  to  the  finding  of  large 
amounts  of  HS  in  kidney  cortex  and  elucidation  of  a  number 
of  differences  among  various  HS  forms  in  this  poorly  defined 
family  of  GAG  substances. 

The  striking  difference  in  glycosaminoglycan  composition 
in  the  two  anatomical  zones  of  the  kidney  correlate  with 
their  different  physiological  functions  involving  cation  and 
water  transport  into  the  interstitium.   The  great  excess  of 
sulfated  over  non-sulfated  glycosaminoglycans  in  the  cortex 
may  correlate  with  the  functions  of  the  proximal  tubules  in 
the  cortex  which  are  actively  transporting  Na+  and  isosmo- 
tically  resorbing  water.   The  distal  tubules  in  the  cortex 
reabsorb  Na+  and  H"*"  and  K+  without  resorption  of  water. 
These  functions  are  consonant  with  the  finding  of  a  low 
hyaluronic  acid  content  in  the  cortex.   In  the  papillary 
tubules,  H2O  is  resorbed  by  a  process  of  equilibration  of 
tubular  urine  with  a  hypertonic  interstitium.   Antidiuretic 
hormone  control  over  water  resorption  in  the  collecting 
duct  may  be  related  to  the  metabolism  of  hyaluronic  acid 
and/or  chondroitin  sulfate.   One  postulate  relates  water 
resorption  to  the  degradation  or  depolymerization  of 
hyaluronic  acid.   The  finding  of  essentially  different 
glycosaminoglycan  compositions  in  the  cortex  and  papillae 
supports  the  idea  that  these  substances  play  a  direct  role 
in  the  various  tubular  functions.   The  molecular  basis  of 
neuronal  membrane  function  may  involve  similar  molecules. 


I 


Proposed  Course  of  Project:   Specific  optical  measurements 
of  GAG  will  be  undertaken,  with  continued  structural  and 
conformational  studies  on  the  various  kinds  of  HS . 


580 


Serial  No.  M-NC-6,  page  3 


Honors  and  Awards : 


Elected  to  Vice  President  of  the  NIH  Interassembly  Council 
of  Scientists,  March  1972. 


Publications: 


Van  Praag,  D.,  Stone,  A.  L.,  Richter,  A.,  and  Farber,  S.  J. 
Composition  of  glycosaminoglycans  (Mucopolysaccharides)  in 
rabbit  kidney:   II.   Renal  cortex.   Biochim.  Biophys .  Acta, 
in  press. 


I 


581 


Serial  No.  M-NC-7 

1 .  Neurochemistry 

2.  Biophysical  Chemistry 

3.  Bethesda,  Md. 

PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   The  Role  of  the  Cell  Membrane  in  Cellular 
Organization,  A  Molecular  Study 

Previous  Serial  Number:   M-NC-7 

Principal  Investigator:   David  M,  Neville,  Jr. 

Other  Investigators:   Hartmut  Glossmann; 

Ronald  Kahn,  NIAMD 

Man  Years 

Total  3.5 

Professional:   2.5 
Other       :   1 

Project  Description: 

Objectives :   The  aim  of  this  project  is  to  determine  the 
specific  chemical  interactions  which  occur  at  the  surfaces 
of  cells  which  affect  cellular  differentiation  and  cellular 
organization.   Specifically  we  propose  that  the  recognition 
which  cells  have  of  their  solid  environment  and  neighboring 
cells  is  mediated  by  specific  proteins  on  the  surface  mem- 
branes.  In  addition,  the  surface  of  each  cell  has  protein 
or  glycoprotein  receptors  for  a  variety  of  soluble  hormones 
and  transmitter  substances.   Our  aim  is  to  study  the  inter- 
action between  the  receptor  molecules  and  the  soluble  and 
fixed  transmitter  molecules  so  that  the  interaction  which 
leads  to  altered  cell  function  can  be  quantitatively  defined. 
Having  done  this  we  propose  to  examine  these  interactions  in 
pathological  states  in  order  to  determine  if  altered  recep- 
tors or  receptor  concentration  play  a  role  in  disease  states. 


I 

I 


Methods  Employed:   Ultracentrifugation,  disc  electrophoresis, 
gel  filtration,  immuno-dif fusion,  fluorescence  microscopy, 
circular  dichroism,  tissue  and  organ  culture. 

Major  Findings:   1.   The  obese  hyperglycemic  mouse  displays  a 
markedly  altered  metabolic  state  characterized  by  obesity. 


583 


Serial  No.  M-NC-7,  page  2 


hyperglycemia,  and  insulin  resistance.   The  state  is  the 
consequence  of  a  single  recessive  genetic  defect.   We  have 
found  that  the  obese  mouse  exhibits  a  marked  alteration  in 
insulin-insulin  receptor  interaction  when  studied  in  vitro 
using  purified  liver  plasma  membranes.   The  concentration 
of  insulin  receptors  is  reduced  3-6-fold  per  mg  of  membrane 
protein  in  the  obese  mouse  as  compared  to  normal  littar  mate 
controls. 

2 .   The  proximal  convoluted  tubule  of  the  kidney  is  respon- 
sible for  absorbing  most  of  the  glucose  present  in  the 
glomerular  filtrate.   The  glucose  is  first  absorbed  through 
the  specialized  luminal  membrane  of  the  tubular  cell,  the 
brush  border.   We  have  found  that  isolated  purified  brush 
border  membranes  are  enriched  for  a  highly  stereospecif ic 
binding  site  for  phlorizin,  a  glucose  analogue  which  in- 
hibits renal  tubular  reabsorption  of  glucose.   The  stereo- 
specificity  of  the  site,  the  binding  constant  for  phlorizin 
and  the  constant  of  competitive  inhibition  for  glucose  all 
suggest  that  this  site  is  the  binding  site  for  glucose 
during  transport. 


I 


Scientific  Significance:   1.   The  finding  that  the  insulin 
receptor  concentration  of  the  liver  surface  membrane  is 
markedly  decreased  in  the  obese  hyperglycemic  mouse  is  the 
first  demonstration  of  altered  membrane  receptor  concentra- 
tion in  a  disease  state.   We  do  not  yet  know  whether  the 
altered  receptor  concentration  causes  the  abnormal  metabolic 
state  or  whether  it  represents  an  adaption  to  it.   Never- 
theless these  studies  lend  considerable  weight  to  the  idea 
that  there  may  be  a  wide  variety  of  disease  states  which  are 
receptor  diseases.   It  is  quite  plausible  that  this  phenomenon 
extends  beyond  hormone-liver  cell  interaction  and  may  exist 
for  receptors  in  neural  tissue,  thus  altering  the  effect  of 
neurotransmitters . 

2.   It  is  now  possible  having  identified  the  glucose  carrier 
in  kidney  brush  border  membrane  to  isolate  this  material 
and  to  begin  to  determine  the  mechanism  of  action  of  membrane 
carriers.    In  addition  it  becomes  possible, utilizing  the 
knowledge  already  acquired  to  search  for  glucose  receptors 
in  other  tissues  such  as  pancreas  and  hypothalamus  which 
may  be  involved  in  disease  states. 


58^ 


Serial  No.  M-NC-7,  page  3 

Honors  and  Awards:   None 

Publications: 

Neville,  D.  M.,  Jr.:   Molecular  weight  determination  of 
protein-dodecyl  sulfate  complexes  by  gel  electrophoresis 
in  discontinuous  buffer  systems.   J.  Biol.  Chem.  246: 
6328-6334,  1971. 

Neville,  D.  M. ,  Jr.  and  Glossmann,  H. :   Plasma  membrane 
protein  subunit  composition:   A  comparative  study  by  dis- 
continuous electrophoresis  in  sodium  dodecyl  sulfate. 
J.  Biol.  Chem.  246:   6335-6338,  1971. 

Glossmann,  H.  and  Neville,  D.  M. ,  Jr.:   Glycoproteins  of  cell 
surfaces.   A  comparative  study  of  three  different  cell  sur- 
faces of  the  rat.   J.  Biol.  Chem.  246:   6339-6346,  1971. 

Glossmann,  K.  and  Neville,  D.  M. ,  Jr.:   y  glutamyltrans- 
f erase  in  kidney  brush  border  membranes.   FEBS  Letters  19: 
340-344,  1972. 

Neville,  D.  M.,  Jr.:   The  isolation  of  the  kidney  brush 
border.   A  chapter  in  Biomembranes,  a  volume  of  Methods  in 
Enzymology,  in  press . 

Neville,  D.  M. ,  Jr.  and  Glossmann,  H. :   Molecular  weight 
determination  of  membrane  protein  and  glycoprotein  subunits 
by  discontinuous  gel  electrophoresis  in  dodecyl  sulfate. 
A  chapter  in  Biomembranes,  a  volume  of  Methods  in  Enzymology, 
in  press . 

Freychet,  P.,  Kahn,  R.  R.,  Roth,  J.,  and  Neville,  D.  M. ,  Jr.: 
Insulin  interactions  with  liver  plasma  membranes:   Indepen- 
dence of  binding  of  the  hormone  and  its  degradation.   J. 
Biol .  Chem.  ,  in  press.  "~ 


585 


Serial  No.  M-NC-8 
1 .   Neurochemistry 
2. 
3.   Bethesda,  Md. 


Project  Title: 


PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 


Biological  and  Biochemical  Models  for  the 
Genetic  Disease,  Phenylketonuria  (PKU) 


Previous  Serial  Number :  M-NC-8 

Principal  Investigator:  Audrey  L.  Stone 

Other  Investigators:   a)  Seymour  Kaufman,  b)  Harvey  Mudd,  LGCB 

Man  Years 


Total        : 

1 

2 

Professional: 

0 

7 

Other       : 

0 

5 

Project  Description: 

Development  of  a  murine  model  for  PKU  using  X-irradiated 
sires  and  a  screening  test  for  serum  phenylalanine  and 
tyrosine  levels  as  guide  for  heterozygosity  for  the  phenyl- 
alanine hydroxylase  gene;  investigation  of  natural  history 
of  the  enzyme  with  the  use  of  cell  models  using  murine, 
human  and  primate  organs. 

Objectives:   a)  to  produce  and  develop  a  mutant,  murine 
strain  with  the  genetic  defect  of  PKU;  to  examine  organs 
and  cells  of  human,  primate  and  other  species  for  the  ex- 
pression of  phenylalanine  hydroxylase  (PAH)  activity;  to 
compare  in  particular  the  biological  and  biochemical  pro- 
perties of  phenylalanine  hydroxylase  from  human  liver  and 
kidney  cells  or  tissue  transplants  in  the  PKU  infant; 
b)  to  examine  suspect-mutants  for  PAH  cofactor  and  cofactor 
reductase  as  other  possible  modes  of  PAH  deficiency. 

Methods:   1)  See  M-NC-8,  1971;  2)  suspect-mutant  mouse  liver 
samples  (obtained  by  partial  hepatectomy  performed  by  H. 
Mudd)  are  tested  for  biopterin  and  dihydropteridine  reduc- 
tase activities. 


587 


Serial  No.  M-NC-8,  page  2 


Major  Findings:   One  hundred  and  fifty  suspect  mice  have 
been  studied  showing  normal  distributions  for  serum  phenyl- 
alanine and  tyrosine  levels.   Liver  samples  showed  no 
mutants  for  biopterin  levels  or  the  dihydroreductase . 

PAH  activity  in  livers  of  various  known  mouse  strains 
has  shown  unusually  high  values  for  the  C57  L/J  leaden 
strain . 

Scientific  Significance:   A  screening  program  for  a  murine 
model  for  PKU  has  been  shown  to  be  possible.   Time  and 
numbers  will  provide  the  "mutant"  of f springs  for  testing. 

No  mutant  strains  have  been  developed  to  date,  as 
expected  from  the  very  low  statistical  chance  of  success 
with  150  suspect  mice. 

Proposed  Course:   The  screening  program  for  the  murine  model 
for  PKU  will  be  improved  by  the  use  of  screening  of  wild 
mice  when  this  becomes  feasible  here  at  NIH.   Primary  human 
and  primate  cell  cultures  and  fresh  autopsy  human  tissues 
will  be  handled  in  a  special  biohazard  hood  enabling  bio- 
chemical studies  on  model  systems  closer  phylogenetically 
to  PKU  individuals.   The  genetic  search  is  expected  to 
extend  beyond  the  next  fiscal  year. 


Honors  and  Awards :   None 
Publications:   None 


Serial  No.  M-NC-9 
1 .   Neurochemistry 
2. 
3.   Bethesda,  Md. 

PHS-HSMHA-NIMH 
Individual  Project  Report 
July  1,  1971  through  June  30,  1972 

Project  Title:   The  Conversion  of  Tryptophan  to  5-Hydroxy 
Tryptophan 

Previous  Serial  Number :   None 

Principal  Investigator:   Seymour  Kaufman 

Other  Investigators:   Paul  Friedman,  Hanson  Kappelman 

Man  Years 

Total        :  2.1 

Professional:  1.1 

Other        :  1.0 

Project  Description: 

Objectives :   The  conversion  of  tryptophan  to  5-hydroxy- 
tryptophan  is  believed  to  be  the  rate-limiting  step  in  the 
biosynthesis  of  the  neurotransmitter,  serotonin.   The  re- 
action is  catalyzed  by  the  mixed-function  oxidase,  tryptophan 
hydroxylase.   The  goal  of  this  project  is  to  isolate  the 
enzyme  in  order  to  study  its  regulatory  properties . 

Methods  Employed:   Standard  methods  of  protein  purification, 
including  salt  fractionation,  ion-exchange  chromatography, 
and  sephadex-gel  filtration,  have  been  used. 

Major  Findings:   A  new  assay  procedure  has  been  developed  to 
measure  tryptophan  hydroxylase  activity.   The  procedure  is 
based  on  the  fluorescence  of  5-hydroxy  tryptophan.   The 
method  is  sensitive,  specific,  and  relatively  rapid.   In 
contrast  to  all  previous  methods  employed,  this  one  does  not 
use  a  radioactive  substrate . 

We  have  purified  about  10-fold  the  hydroxylase  from 
rabbit  hindbrain.   The  enzyme  utilizes  the  cof actor  that  was 
previously  discovered  in  this  laboratory,  tetrahydrobiopterin. 
We  have  determined  for  the  first  time  that  the  stoichiometry 
of  the  reaction  catalyzed  by  the  enzyme  is  as  shown  in 
equation  1. 


Serial  No.  M-NC-9,  page  2 

L-tryptophan  +  tetrahydrobiopterin  +  Og  -  L-5-hydroxy- 

tryptophan  +  E^O  +   quinonoid  dihydrobiopterin 

We  have  determined  the  Km  for  tryptophan  and  shown  that  it 
is  markedly  lower  in  the  presence  of  tetrahydrobiopterin 
than  it  is  in  the  presence  of  the  commonly  used  cofactor 
analogue,  6, 7-dimethyltetrahydropterin.   In  the  presence  of 
tetrahydrobiopterin,  but  not  in  the  presence  of  the  dxmethyl- 
pterin,  tryptophan  in  excess  of  0.2  mM  inhibits  the  enzyme. 

Just  as  with  tryptophan,  the  Km  for  oxygen  is  also 
much  lower  when  tetrahydrobiopterin,  rather  than  tetra- 
hydrodimethylpterin  is  used  as  the  cofactor. 

Scientific  Significance:   Many  of  the  properties  of  brain 
tryptophan  hydroxylase  are  similar  to  those  of  the  other  two 
pterin-dependent  hydroxylases,  phenylalanine  and  tyrosine 
hydroxylases.   It  is  thus  becoming  clear  that  these  enzymes 
constitute  a  family.   The  important  consequence  of  this 
finding  is  that  it  is  possible,  in  many  cases,  to  predict 
the  properties  of  these  enzymes  from  the  knowledge  of  any 
member  of  the  family. 

One  of  these  common  properties  is  that  the  Km  for  the 
amino  acid  substrate  is  lower  in  the  presence  of  tetrahydro- 
biopterin than  it  is  with  pterin  analogues.   The  previously 
accepted  values  for  the  Km  of  tryptophan  of  about  0.30  mM 
(determined  in  the  presence  of  dimethylpterin)  are  far 
greater  than  the  levels  of  tryptophan  occurring  in  brain 
(about  0.03  mM) .   This  high  Km  value  indicated  that  the 
activity  of  the  enzyme  in  vivo  is  severely  limited  by  sub- 
strate availability.   Our  results  suggest  that  this  limita- 
tion is  not  any  more  severe  with  this  enzyme  than  it  is  with 
most  other  enzymes,  i^.e.,  tryptophan  hydroxylase  probably 
functions  in  the  brain  with  Km  levels  of  its  substrate  . 

Our  finding  that  tryptophan  in  excess  inhibits  its  own 
hydroxylation  is  another  property  that  this  enzyme  shares 
with  the  other  pterin-dependent  hydroxylases .   This  finding 
suggests  the  possibility  that  in  malignant  carcinoid  syn- 
drome, characterized  by  excessive  production  of  serotonin, 
administration  of  high  tryptophan  might  be  of  value  in  par- 
tially inhibiting  serotonin  production. 


590 


Serial  No.  M-NC-9,  page  3 

Proposed  Course:   Further  purification  of  the  enzyme  from 
brain  will  be  attempted.   Such  preparations  will  be  used  to 
examine  other  possible  regulatory  behavior  of  the  enzyme, 
such  as  the  effects  of  phospholipids. 

Honors  and  Awards :   None 

Publications:   None 


591 


Serial  No.  M-NP-3 


1.   Laboratory  of  Neurophysiology 

2. 

3.   Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:   Electrical,  ionic  and  physical  properties  of 
muscle. 

Previous  Serial  Number:   Same 

Principal  Investigators:   S.  I.  Rapoport 

Other  Investigators:   J.  Bidinger,  R.  FitzHugh 

Cooperating  Units :   Section  on  Technical  Development 

National  Institute  of  Mental  Health 
(Mr.  James  Bryan) 

Laboratory  of  Biophysics 

National  Institute  of  Neurological  Diseases 

and  Stroke 

Man  Years : 

Total:  3.00 
Professional:  2.00 
Other:         1.00 

Project  Description: 

Objectives :  a)  To  determine  the  elastic  and  plastic  properties 
of  the  muscle  fiber  membrane  (sarcolemma)  and  relate  them  to  the 
physiological  function  of  the  fiber  under  conditions  of  tension. 

b)   To  study  the  effect  of  isometric  stretch  on  muscle 
metabolism  and  muscle  survival.   To  see  whether  effects  on  metab- 
olism can  be  functionally  related  to  effects  on  muscle  survival. 

Methods  Employed:   a)   Photomicrographic  techniques  are  used  to 
study  a  single  Fiber  under  high  magnification.   The  fiber  is 
held  by  a  transducer  tension  device,  and  measurements  are  made 
with  usual  amplification  and  recording  techniques.   Micromanip- 
ulation of  the  fiber  is  performed.   Various  mathematical  tech- 
niques are  used  and  analysis  of  data  is  made  with  the  use  of  a 
computer.   In  addition,  regions  on  the  fiber  are  sucked  into  a 
pipette  with  controlled  pressure  (elastimeter  method) .   Theoret- 
ical models  for  elasticity  of  parts  of  the  fiber  are  formulated 
and  tested  by  analytic  procedures. 


593 


Serial  No.  M-NP-3,  page  2 

b)   Twitch  and  tetanic  tensions  are  recorded  from  muscles 
with  transducers,  amplifiers  and  pen  recorders.   Muscles  are 
stimulated  periodically  with  standard  neurophysiological  tech- 
niques.  Ionic  determinations  of  Ca,  Mg,  Na  and  K  are  made  after 
measuring  wet  and  dry  v/eights,  ashing  in  a  furnace,  and  using 
emission  and  atomic  absorption  spectrophotometry.   Data  are 
analyzed  with  computer  techniques. 

Major  Findings :   a]   The  elastimeter  method  was  applied  to  the 
single  muscle  fiber  of  the  frog  semitendinosus  to  obtain  the 
elastic  moduli  of  the  sarcolemma  and  myoplasm,  as  well  as  their 
relative  contributions  to  resting  fiber  tension  at  different 
extensions.   A  bleb  which  was  sucked  into  a  flat-mouthed  pipette 
at  the  fiber  surface  separated  into  an  external  sarcoleinmal  mem- 
brane and  a  thick  inner  myoplasmic  region.   Measurements  showed 
that  the  sarcolemma  does  not  contribute  to  intact  fiber  tension 
at  sarcomere  lengths  below  3y.   The  sarcolemma  was  estimated  to 
contribute  in  the  order  of  10%  to  intact  fiber  tension  at 
sarcomere  lengths  between  3  and  3.75y,  and  more  so  with  further 
extension.   The  sarcolemma  can  be  linearly  extended  at  sarcomere 
lengths  between  3  and  3.75|j,  with  an  elastic  modulus  of  5  x  10^ 
dyne/cm'^  (assuming  a.  thickness  of  O.ly).  Its  modulus  increases 
abruptly  at  higher  extensions.   Resistance  to  deformation  of 
the  inner  bleb  region  is  due  to  myoplasmic  elasticity.   The 
elastic  modulus  of  the  myoplasm  was  estimated  to  be  between 
0.5  and  3  x  10^  dyne/cm^,  for  sarcomere  lengths  between  2.5 
and  3. 5y . 

Tension  and  curvature  of  the  sarcolemmal  tube  of  a  damaged 
frog  muscle  fiber  were  measured  at  different  extensions.   The 
tube  could  be  extended  reversibly  by  48%  from  its  rest  length. 
A  linear  model  for  a  cylindrical  elastic  tube  was  derived  and 
was  found  to  apply  to  the  sarcolemmal  tube.   For  13  tubes  which 
were  extended  reversibly,  the  model  was  used  to  calculate  the 
median  longitudinal  elastic  modulus,  Ej^  =  3.3  x  10'  dyne/cm^, 
the  median  circumferential  elastic  modulus,  E^,  =  0.66  x  10' 
dyne/cm2,  and  the  geometric  mean  longitudinal  Poisson's  ratio, 
Ol  =  1.   Sarcolemmal  thickness  was  taken  as  O.ly.   For  reversible 
extensions,  the  geometric  mean  of  the  ratio   El/Eq  =  7.8,  which 
shows  that  the  sarcolemma  is  anisotropically  elastic  and  less 
extensible  in  the  longitudinal  direction.   The  contribution  of 
the  sarcolemma  to  whole  fiber  tension  was  estimated  to  be  =25% 
for  fiber  extensions  to  sarcomere  lengths  less  than  3.75y.   The 
elastic  modulus  of  the  intact  fiber  was  calculated  to  be  1  x  105 
dyne/cm   at  a  rest  sarcomere  length  of  2.33y.   The  fiber  modulus 
is  referred  to  a  reference  sarcomere  length  of  2y.   This  work 
is  in  press.   Rapoport,  S.  I.   with  an  Appendix  by  R.  FitzHugh 
and  S.  I.  Rapoport.   The  anisotropic  elastic  properties  of  the 
sarcolemma  of  the  frog  semitendinosus  muscle  fiber.   Biophys.  J. 
(In  press)  1972. 


59h 


Serial  No.  M-NP-3,  page  3 

b)   Pairs  of  frog  sartorii  were  mounted  in  an  oxygenated 
Ringer  bath  at  room  temperature.   After  stretching  one  muscle 
to  20-30%  rest  length,  both  were  stimulated  extracellularly  by 
a  supramaximal  pulse  or  0 . 5  sec  train.   Stretched  muscles  re- 
tained 201  of  their  initial  twitch  or  tetanic  tensions  4  hrs 
longer  (P<0.05)  than  unstretched  muscles,  confirming  work  of 
Weiss  (Am.  J.  Physiol.  106,  156,  1933).   Prolongation  by  stretch 
of  survival  at  the  20%  level  was  abolished  by  10"^  M  ouabain, 
K-free  Ringer  and  by  low  temperature  (2°C).   Stretched  muscles 
removed  from  Ringer  after  24  hr  and  washed  in  Tris  Ringer  for 
10  min  had  less  Na  fl8  +  5,  S.E.)  and  more  K  (28  +  5,  S.E., 
n=19)  ,  as  ymole/gm  dry  wt,  than  corresponding  unstretched  muscles. 
These  differences  were  abolished  by  2°C  and  ouabain.   In  K-free 
Ringer,  stretch  still  reduced  muscle  Na.   Ouabain  and  K-free 
Ringer  reduced  20%  survival  time  to  18  and  12  hr,  respectively, 
from  the  36  hr  in  Ringer  at  room  temperature  (P<0.05).   Low 
temperature  prolonged  survival  time  (P<0.05).   Prolongation  of 
survival  time  by  stretch  is  correlated  with  decreased  intracel- 
lular Na  and  increased  K.   Stretch  may  act  directly  or  indirectly 
on  the  Na  pump.   This  work  has  been  published  as  an  abstract: 
Rapoport,  S.  I.  and  Bidinger,  J.  M.   Effect  of  stretch  on  survival 
and  ionic  content  of  sartorius  muscle  in  vitro.   Fed.  Proceedings. 
31,  324,  1972. 

Significance  to  Bio-medical  Research  and  Program  of  the  Institute: 

a)  A  knowledge  of  mechanical  properties  of  the  sarcolemma 
myofibrils,  and  of  their  relative  contribution  to  tension  as  a 
function  of  stretch,  is  required  to  understand  the  process  of 
contraction  and  of  the  resistance  of  the  muscle  to  stretch 
under  physiological  conditions.   Correlation  between  electro- 
microscopic  structure  of  the  sarcolemma  and  myofibrils  and  their 
properties  permits  a  better  understanding  of  the  molecular  forces 
regulating  tension. 

b)  Stretch  prolongs  frog  muscle  survival  and  stimulates 
muscle  metabolism.   These  effects  have  not  been  related  up  to 
now,  but  the  present  work  shows  that  they  may  be  related  through 
the  stimulation  of  the  Na  pump  by  stretch.   The  Na  pump  will 
determine  ionic  contents  of  the  muscle,  and  these  in  turn  may 
determine  membrane  potential  and,  therefore,  contraction  thres- 
hold.  The  effect  of  stretch  in  frog  sartorius  is  relevant  to 
the  problem  of  stretch- induced  muscle  hypertrophy. 

Proposed  Course  of  Project:   a)   To  analyze  the  data  on  the 
contribution  of  the  sarcolemma  and  myoplasm  to  muscle  tension 
in  terms  of  the  models  which  have  been  formulated,  and  to 
make  accurate  estimates  of  the  contribution  of  each  to  whole 
fiber  tension.   To  formulate  a  model  which  will  perm.it  the 
estimate  of  the  contribution  of  the  sarcolemma,  based  on  obser- 
vations on  the  sarcolemmal  tube. 


L 


595 


Serial  No.  M-NP-3,  page  4 

b)  To  analyze  the  data  on  the  effect  of  stretch  on  muscle 
survival  and  ionic  contents.  To  see  whether  effects  of  stretch 
are  related  to  muscle  fatigue. 

Honors  and  Awards :   None 

Publications : 

Rapoport,  S.  I.  Mechanical  properties  of  the  sarcolemma  and 
myofibrils  in  frog  muscle  as  a  function  of  sarcomere  length. 
J.  Gen.  Physiol.   May,  19  72. 


596 


Serial  No.  M-NP-8 

1.   Laboratory  of  Neurophysiology 

2. 

3.   Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:   Transport  Mechanisms  Across  Membranes 

Previous  Serial  Number:   Same 

Principal  Investigators:   S.  I.  Rapoport 

Other  Investigators:   J.  Bidinger,  H.  Thompson,  I.  Klatzo, 

M.  Hori,  D.  S.  Bachman,  M.  W.  Brightman, 
T.  S.  Reese  and  M.  Spatz. 

Cooperating  Units:   (a)  Laboratory  of  Neuropathology  and  Neuro- 

anatomical  Sciences,  National  Institute 
of  Neurological  Diseases  and  Stroke, 
N .  I .  H . 
(b)  Laboratory  of  Brain  Evolution  and  Be- 
havior, National  Institute  of  Mental 
Health. 


Man  Years 


Total: 

Professional: 

Other: 

Project  Description; 


1.50 

1.25 

.25 


Objectives :  To  consider  and  amplify  the  theory  of  transport  of 
substances  across  artificial  and  cellular  membranes,  and  to  re- 
late transport  to  membrane  potential  and  function. 

Methods  Employed:  (a)  A  variety  of  mathematical  techniques  are 
used  in  conjunction  with  the  theory  of  transport  and  its  coupling 
to  metabolism,  within  the  formalism  of  irreversible  thermodynamics, 
Theoretical  considerations  are  derived  from  principles  of  physical 
chemistry  and  biochemistry,  and  from  experimental  observations  on 
neuronal  and  other  cellular  membranes. 

(b)  For  the  blood-brain  barrier  project,  surgical  procedures  were 
used  for  opening  the  skull  and  dura  of  the  rabbit  and  monkey,  iso- 
lating and  perfusing  the  internal  carotid  artery.   Neurological 
examinations  were  performed  on  monkeys.   Photographic  and  histo- 
logical procedures  were  used  on  the  brain  and  eye,  as  well  as 
electron  microscopy.   The  theory  cf  irreversible  thermodynamics 


597 


Serial  No.  M-NP-8,  page  2 

was  used  to  formulate  a  model  for  the  osmotic  action  of  substances 
on  the  barrier,  and  to  calculate  thermodynamic  parameters.   Com- 
puters were  used  for  data  analysis. 

Major  Findings:   (a)  The  Na-K  Exchange  Pump.   The  formulation _ 
of  the  Na-K  exchange  pump,  published  earlier,  was  applied  to  in- 
terpret the  electrogenic  and  transport  properties  of  the  pump  in 
frog  sartorius  muscle.   The  following  parameters  were  calculated  - 
hyperpolarization,  passive  fluxes,  net  fluxes,  active  fluxes, 
chemical  reaction  rate,  stoichiometric  ratio  of  pump  K  to  pumped 
Na,  free  energy  change  of  the  pump  reaction,  and  effect  of  active 
transport  on  membrane  resistance.   The  model  was  used  to  demon- 
strate the  feedback  relations  between  a  chemical  pump  and  the 
electrical  properties  of  the  membrane. 

(b)  Osmotic  Breakdown  of  the  Blood-Brain  Barrier.   The  following 
work  was  done  in  collaboration  with  Drs.  Hori  and  Klatzo.   It 
was  hypothesized  that  some  concentrated  solutions  open  the  blood- 
brain  barrier  to  the  Evans  blue-albumin  complex  by  shrinking  bar- 
rier cells  and  opening  up  the  spaces  between  them.   Four  experi- 
mental criteria  are  required  if  the  action  of  those  solutions 
is  consistent  with  this  hypothesis.   The  solute  should  act  re- 
versibly,  it  should  not  act  on  the  barrier  because  of  a  specific 
drug  action,  its  damaging  effect  should  increase  with  increasing 
concentration,  its  effect  should  be  related  inversely  to  its 
ability  to  penetrate  the  cell  membrane.   Concentrated  solutions 
of  electrolytes  and  non-electrolytes  were  applied  to  the  pia- 
arachnoid  surface  of  the  rabbit  cerebral  cortex  to  study  opening 
of  the  barrier  of  the  pia-arachnoid  blood  vessels  to  the  intra- 
vascular Evans  blue-albumin  complex.   The  electrolytes  and  rela- 
tive lipid  insoluble  non-electrolytes  opened  up  the  barrier  re- 
versibly  and  acted  consistently  with  the  four  criteria  of  the 
osmotic  hypothesis.   The  more  lipid  soluble  non-electrolytes 
damaged  the  barrier  irreversibly  and  would  not  be  expected  to  act 
osmotically.   Intracarotid  perfusions  of  solutions  of  concentrated 
urea,  which  is  relatively  lipid  insoluble,  opened  up  the  blood- 
brain  barrier  at  the  brain  capillaries  reversibly,  while  solutions 
of  the  more  lipid  soluble  propylene  glycol  opened  it  irreversibly, 
consistent  with  topical  observations.   On  the  basis  of  these  phys- 
iological studies,  it  was  concluded  that  the  blood-brain  barrier 
acts  like  a  layer  of  cells,  probably  the  endothelial  cells  of  the 
cerebral  vascular  system.   This  work  is  being  published  in  detail: 
Rapoport,  S.  I.,  Hori,  M.  and  Klatzo,  I.   Testing  of  an  hypothesis 
for  osmotic  opening  of  the  blood-brain  barrier.   Amer.  J.  Physiol, 
(in  press),  1972. 

The  following  work  was  done  in  collaboration  with  Dr.  Bachman  and 
Mr.  Thompson.   The  internal  carotid  arteries  of  monkeys  were  per- 
fused with  concentrated  urea  solutions  to  see  the  effect  of  os- 
motic opening  of  the  blood-brain  barrier  in  the  chronic  animal. 


Serial  No.  M-NP-8,  page  3 

Evans  blue  dye  was  injected  intravenously  as  a  barrier  indicator. 
Three  of  12  animals  in  which  the  barrier  had  been  opened  had  no 
neurological  sequelae  or  brain  pathology,  indicating  that  osmotic 
barrier  opening  is  possible  without  complications.   Nine  of  12 
animals  had  some  degree  of  brain  necrosis  and  motor  sequelae. 
Osmotic  opening  of  the  barrier  is  feasible  without  damaging  the 
brain,  and  if  the  technique  is  developed  to  give  better  results, 
it  may  be  of  use  in  brain  pharmacotherapy.   An  abstract  of  this 
work  has  been  published:  Rapoport,  S.  I.,  Bachman,  D.  S.  and 
Thompson,  H.  K.   Chronic  effects  of  osmotic  opening  of  the  blood- 
brain  barrier  in  the  monkey.   Proc.  Eastern  EEG  Society,  Mont. 
Gabriel,  Canada,  February  23-28,  1972.   This  work  is  also  in 
press:  Rapoport,  S.  I.,  Bachman,  D.  S.  and  Thompson,  H.  K.   Chronic 
effects  of  osmotic  opening  of  the  blood-brain  barrier  in  the  mon- 
key.  Science  (in  press)  1972. 

A  summary  of  the  osmotic  model  of  the  blood-brain  barrier,  derived 
from  the  original  observations  on  the  cortical  acidic  response 
(Rapoport,  S.I.  The  effect  of  concentrated  solutions  on  the  blood- 
brain  barrier.  Amer.  J.  Physiol.,  219,  270-274,  1969)  and  later 
observations  are  in  press  (Rapoport,  S.  I.   Evidence  for  reversible 
opening  of  the  blood-brain  barrier  by  osmotic  shrinkage  of  cere- 
brovascular endothelium  and  opening  of  the  tight  junctions.  In: 
Radiology  and  the  Microvascular  System  [publication  of  the  Asso- 
ciation  of  University  Radiologists,  1772]  in  press). 

Significance  to  Bio-medical  Research  and  the  Program  of  the  Insti- 
tute:  Ta)  The  functioning  of  excitable  tissue  (nerve,  muscle) 
depends  on  the  maintenance  of  the  resting  potential  by  active 
mechanisms  which  require  energy  and  may  extrude  Na   and  accumulate 
K"*".   The  theory  relates,  for  the  first  time,  metabolic  rate  and 
stoichiometry  of  the  active  transport  reaction  to  the  neurophysio- 
logical  parameters  of  membrane  potential,  hyperpolarization,  mem- 
brane resistance  and  ionic  currents.   Data  which  previously  were 
incompletely  interpreted  on  the  electrogenic  pump  in  muscle  were 
shown  to  fit  into  the  model.   The  model  should  therefore  be  appli- 
cable to  a  variety  of  nervous  and  muscle  tissues  and  proposes  for 
the  first  time  feedback  relations  between  metabolic  activity  and 
nervous  function. 

(b)  The  model  for  blood-brain  barrier  breakdown  is  new.  It  pro- 
poses that  the  barrier  can  be  broken  down  irreversibly,  as  it  has 
in  the  past,  or  reversibly,  by  shrinkage  of  endothelium  cells, 
because  of  osmotic  action.   The  reversible  breakdown  of  the  bar- 
rier could  be  of  significance  to  the  treatment  of  cerebral  dis- 
eases by  facilitating  drug  passage  into  the  brain. 

Proposed  Course  of  Project:   (a)  The  theory  of  the  Na-K  exchange 
pump  will  be  applied  to  muscle  and  other  excitable  tissue  in  an 
effort  to  interpret  biological  data  as  well  as  to  test  its  ap- 
plicability.  The  linear  theory  will  be  developed  further  to  take 
into  account  non-linearities  in  active  transport. 

599 


Serial  No.  M-NP-8,  page  4 

(b)   Further  evidence  for  demonstrating  that  osmotic  agents 
shrink  barrier  cells  will  be  looked  for.   The  metabolic  effects 
of  urea  treatment  will  be  studied.  Attempts  will  be  made  to  im- 
prove the  technique  for  osmotically  opening  the  blood-brain 
barrier  in  the  monkey,  so  that  fewer  neuroloaical  sequelae  will 
be  produced. 

Honors  and  Awards ;   (1)  Invited  lecturer,  Cornell  University, 
Department  of  Neurology,  November,  1971,  "Reversible  osmotic 
opening  of  the  blood-brain  barrier"  and  (2)  Invited  participant. 
Symposium  on  Radiology  and  Microvascular  System,  sponsored  by 
the  Association  of  University  Radiologists,  Glen  Cove,  Long 
Island,  April  23-26,  1972. 

Publications ; 

Rapoport,  S.  I.   The  cortical  acidic  response  to  intravenous 
NaHC03  and  the  nature  of  blood-brain  barrier  damage.   Int'l.  J. 
Neuroscience  2^:  1-6,  1971. 

Rapoport,  S.  I.   The  sodium-potassium  exchange  pump.   II.  Analysis 
of  Na-loaded  frog  sartorius  muscle.   Biophysical  Journal,  11: 
631-647,  1971. 

Rapoport,  S.  I.,  Hori,  M.  and  Klatzo,  I.   Reversible  osmotic 
opening  of  the  blood-brain  barrier.   Science,  173:  1026-1028, 
1971. 


600 


I 


Serial  No.  M-NP-47 

1.   Laboratory  of  Neurophysiology 

2. 

3.   Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:   The  ionic  and  metabolic  basis  of  neuronal  ther- 
mosensitivity . 

Previous  Serial  Number:   Same 

Principal  Investigators:   David  0.  Carpenter 

Other  Investigators:   H.  Levitan 

Cooperating  Units:   None 

Man  Years 

Total:  2.30 
Professional:  1.45 
Other:  .85 

Project  Description: 

Obj  ectives :   This  project  is  concerned  with  an  investigation  of 
a  variety  of  membrane  properties  of  neurons,  particularly  those 
properties  which  are  temperature  dependent  and  influence  neu- 
ronal excitability.   The  ultimate  aim  is  to  understand  the  ionic 
mechanism  underlying  thermosensitivity  and  thermoregulation  in 
the  mammalian  nervous  system. 

Methods  Employed:   Most  studies  were  carried  out  on  the  isolated 
nervous  systems  of  the  marine  molluses,  Aplysia  and  Navanax,  but 
additional  studies  were  performed  on  peripheral  afferent  fibers, 
spinal  cord  and  sensori-motor  cortex  of  the  cat.   In  the  inver- 
tebrates intracellular  recordings  were  made  from  neurons  isolated 
from  the  animal  where  sea  water  composition  and  temperature  could 
be  manipulated  and  drugs  added.   In  cats  intracellular  recordings 
were  made  from  cortical  and  spinal  cord  neurons.   Activity  of  af- 
ferent fibers  was  monitored  from  dorsal  root  filaments  and  the 
excitability  of  afferent  terminals  was  tested  by  antidromic  activ- 
ation of  the  fibers  while  recording  from  peripheral  nerves.   In 
the  cat  CO-,  was  administered  through  a  respirator. 

Maj  or  Findings :   1)   In  Aplysia  neurons  thermosensitivity  is 
imparted  to  each  cell  by  at  least  two  separate  mechanisms.   The 
first,  an  electrogenic  sodium  pump,  causes  the  cell  membrane 
potential  to  increase  with  temperature.   The  second  mechanism 


601 


Serial  No,  M-NP-47,  page  2 

tends  to  depolarize  and  excite   the  cell  with  warming  as  a  result 
o£  a  greater  temperature  dependence  of  the  passive  permeability 
of  the  membrane  to  sodium  than  to  potassium. 


rons .   The  endogenous  pacemaker  activity  can  be  adequately  ex 
plained  by  a  model  containing  a  voltage  and  time  varying  potas- 
sium conductance  in  the  face  of  a  high  resting  sodium  conductance. 
Metabolic  processes  influence  discharge  dramatically  but  are  not 
directly  responsible  for  discharge.   The  electrogenic  sodium  pump 
does  not  underlie  the  bursting  discharge  characteristic  of  some 
neurons,  as  has  been  suggested  by  others.   A  metabolic  regula- 
tion of  membrane  conductance  is  important,  but  only  in  mainte- 
nance of  a  high  membrane  resistance  which  is  necessary  for  normal 
pacemaker  discharge. 

3)  The  effects  of  CO7  on  nerve  cell  activity.   This  study 
concludes  two  series  of  investigations  carried  out  several  years 
ago  on  CO2  effects  on  neurons  of  sensori-motor  cortex  of  the  cat 
and  on  Aplysia  neurons.   In  addition,  a  new  series  of  experiments 
were  done  investigating  the  effect  of  CO2  on  the  monosynaptic 
reflex  in  the  cat.   From  all  three  preparations  evidence  was 
found  that  CO2  can  cause  some  but  not  all  neurons  to  hyperpolarize 
and  become  less  excitable.   This  effect  does  not  result  from  a 
change  in  pH.   The  hyperpolarizing  effect  of  CO2  is  very  pro- 
nounced in  cortical  neurons  and  in  afferent  fibers,  but  is  small 
or  absent  in  spinal  motoneurons  and  Aplysia  neurons.   CO2  does 

not  affect  glial  cells.   The  depressive  effect  of  CO2  on  the 
monosynaptic  reflex  results  primarily  from  the  hyperpolarization 
of  1  a  afferent  terminals,  presumably  to  such  a  degree  that  in- 
vasion of  the  spike  into  the  terminal  is  blocked. 

4)  Acetlylcholine  sensitivity  of  neurons  of  Navanax.   This 
project  ii  the  conclusion  of  work  done  by  Dr.  Herbert  Levitan 
while  in  this  laboratory  one  year  ago.   The  project  is  concluded 
upon  publication  of  the  results. 

5)  Collaborative  studies  with  the  Department  of  Physiology, 
Centro  de  Investigacion  del  Institute  Polytechnico  Nacional, 
Mexico  City,  D.  F.',  Mexico.   This  study  on  the  organization  of 
primary  afferent  depolarization  in  the  isolated  spinal  cord  of 
the  frog  is  a  continuation  of  the  program  initiated  in  January, 
1971,  when  Dr.  Carpenter  was  a  Visiting  Professor  in  the  Depart- 
ment of  Physiology.   The  results  of  this  study  have  been  written 
and  submitted  as  two  full  papers  to  the  Journal  of  Neurophysiology 
In  addition,  three  short  presentations  of  this  work  were  given 
and  published  at  the  Mexican  Congress  of  Physioligists  at  Oaxte- 
pec,  Morelos,  Mexico  in  December,  1971,  and  also  at  the  FASEB 
meeting  in  Atlantic  City,  April,  1972. 

Significance  to  Bio-medical  Research  and  Program  of  the  Institute: 

ll   An  understanding  of  the  elementary  ionic  and  metabolic 
mechanisms  of  nerve  cells  is  essential  not  only  in  the  develop- 


602 


I 


Serial  No.  M-NP-47,  page  3 

ment  o£  an  understanding  of  how  the  brain  works  but  also  in  pur- 
suit of  rational  approches  to  treatment  of  neuronal  diseases  by- 
drugs.   These  experiments  attempt  to  study  these  elementary  pro- 
cesses in  simple  nervous  systems  and  then  to  test  the  conclusions 
in  mammalian  nervous  systems.   In  the  case  of  neuronal  thermo- 
sensitivity  we  now  have  isolated  several  temperature  dependent 
procesi  j   which  we  will  test  in  mammalian  preparations. 

2)  The  study  of  the  ionic  basis  of  neuronal  pacemaker  dis- 
charge also  has  relevance  to  the  mammal.   The  neuronal  pacemaker 
functions  in  a  manner  very  similar  to  that  of  the  heart.   In 
addition,  there  is  accumulating  a  considerable  body  of  evidence 
suggesting  that  there  may  be  endogenous  activity  of  neurons  in 
vertebrates  as  well  as  invertebrates. 

3)  Carbon  dioxide  is  produced  by  all  cells  in  the  process 
of  metabolism.   Our  demonstration  that  CO^  acts  directly  to  de- 
press the  excitability  of  neurons  may  be  the  mechanism  under- 
lying the  anesthetic  effects  of  CO2  which  have  long  been  known 
clinically.   The  demonstration  that  some  types  of  cells  are  more 
sensitive  than  others  may  provide  a  means  of  separating  out  at 
least  one  common  membrane  property  of  those  neurons  affected  by 
CO2. 

Proposed  Course  of  Project:   1)   A  study  will  be  done  on  Aplysia 
neurons  to  investigate  the  effects  of  preconditioning  animals  at 
various  temperatures  on  the  activity  of  the  electrogenic  sodium 
pump . 

2)  The  study  of  pacemaker  activity  will  be  continued  with 
Capt.  James  Willis,  at  the  Armed  Forces  Radiobiology  Research 
Institute . 

3)  The  CO2  experiments  in  the  spinal  cord  will  be  continued 
and  published. 

4)  A  new  study  will  begin  testing  the  effects  of  drugs  and 
ionic  changes  of  the  medium  on  activity  of  mammalian  thermosen- 
sitive  afferent  fibers,  in  the  hope  of  documenting  which  of  the 
processes  studied  in  the  inverebrates ,  if  any,  underlie  thermo- 
sensitivity  in  the  mammal. 

Honors  and  Awards :   Dr.  Carpenter  was  invited  to  participate  in 
and  present  papers  at  the  following  conferences: 

1)  Symposium  on  CO7  and  Metabolic  Regulation,  July  20-22, 
19  71,  Monte  Carlo,  Monaco. 

2)  Symposium  on  Invertebrates  Neurobiology:   Mechanisms  of 
Rhythm  Regulation,  August  2-5,  1971,  Tihany.  Hungary. 

3)  Symposium  on  Biological  Membrane:   The  role  of  the 
Sodium  Pump,  January  27,  19  72,  Duke  University.  Durh am , 
North  Carolina. 

Publications : 


603 


Serial  No.  M-NP-47,  page  4 

Carpenter,  D.  0.,  Hubbard,  J.  H.,  Humphrey,  D.  R. ,  Thompson, 
H.  K.  and  Marshall,  W.  H.   CO?  effects  on  nerve  cell  function. 
Proc.  Symposium  "CO2  and  Metabolic  Regulation"  held  7/20-22, 
1971,  Monte  Carlo,  Monaco.   Springer-Verlag .   In  Press. 

Levitan,  H.  and  Tauc,  L.   Acetylcholine  Receptors:   Topographic 
Distribution  and  Pharmacological  Properties  of  Two  Receptor 
Types  on  a  Single  Molluscan  Neuron.   Journal  of  Physiology. 
In  Press. 


60k 


Serial  No.  M-NP-48 

1.   Laboratory  of  Neurophysiology 

2. 

3.   Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:   The  State  of  Ions  and  Water  in  Living  Cells. 

Previous  Serial  Number:   Same 

Principal  Investigators:   M.  Hovey ,  D.  0.  Carpenter  and  A.  Bak 

Other  Investigators:   Harry  K.  Thompson 

Cooperating  Units:   None 

Man  Years: 

Total:  2.00 

Professional:   2.00 
Other:  0 

Project  Description: 

Objectives :   In  this  study  v;e  attempt  to  determine  the  state  of 
water  and  ions  in  large  nerve  and  muscle  cells  by  measurements  of 
the  electrical  conductivity  of  the  internal  medium. 

Methods  Employed:   Intracellular  conductivity  was  measured  with  a 
capacitance- conductance  meter  consisting  principally  of  an  opera- 
tional amplifier  and  feedback  resistance  circuit  with  a  high  fre- 
quency source.   Metal  microelectrodes  were  supported  by  a  micro 
positioner  and  electrically  connected  to  the  meter.   Each  elec- 
trode was  calibrated  in  normal  sea  water.   By  diluting  the  sea 
water  in  steps  (1  to  100%  of  normal)  a  calibration  curve  was 
drawn  and  compared  with  the  records  taken  from  the  cells. 

Major  Findings:   We  have  previously  established  that  this  tech- 
nique  measures  conductivity  of  the  solution  at  the  tip  of  the 
microelectrode .   We  have  extended  the  tests  of  the  technique  to 
an  analysis  of  frequency  of  the  applied  current  both  in  solutions 
and  in  neurons.   In  the  neuronal  cell  bodies  of  the  marine  mol- 
luscs, Aplysia,  Navanax  and  Anisodoris ,  the  internal  conductivity 
is  only  5%  that  of  sea  water  or  less.   In  contrast,  in  the  giant 
axon  of  the  squid,  internal  conductivity  is  80-100%  that  of  sea 
water.   In  the  giant  axon  of  the  marine  annelid,  Myxicola,  in- 
ternal conductivity  is  30-50%  that  of  sea  water,  and  in  the 
muscle  fibers  of  the  giant  barnacle ,  internal  conductivity  is 
about  15%  that  of  sea  water. 


605 


Serial  No.  M-NP-4  8,  page  2 

Experiments  have  also  been  done  in  Aplysia  neurons  measuring 
conductivity  by  a  method  completely  independent  of  the  one  de- 
scribed above,  using  a  4-pole  array  of  microelectrodes  and  measur- 
ing the  voltage  drop  across  the  center  two  electrodes  upon  appli- 
cation of  constant  current  pulses.   These  experiments  have  con- 
firmed the  values  of  internal  conductivity  measured  with  the 
technique  utilizing  the  single  electrode. 

Analysis  of  conductivity  has  also  been  made  in  solutions 
containing  a  known  concentration  of  salt  and  a  variety  of  organic 
substances.   Addition  of  albumin,  sugars  and  polysaccrides  depress 
conductivity,  but  do  not  do  so  by  binding  the  ions  since  the  ionic 
activities  are  not  depressed.   Thus,  it  seems  likely  that  these 
substances  depress  conductivity  as  a  result  of  a  structuring  of 
cell  water.   By  analogy  we  attribute  the  low  internal  conductiv- 
ity of  neuronal  cell  bodies  to  the  existence  of  extensive  struc- 
turing of  cell  water.   In  contrast  little  structured  water  ap- 
pears to  exist  in  squid  axon,  while  the  Myxicola  axon  and  bar- 
nacle fibers  show  intermediate  values  of  conductivity  and  thus 
presumably  a  lesser  degree  of  structuring  than  is  characteristic 
of  cell  bodies. 

Significance  to  Bio-medical  Research  and  Program  of  the  Institute; 
Our  results  to  date  suggest  that  ions  in  nerve  cell  bodies  exist 
in  a  very  different  state  from  those  in  axons.   If  this  be  true 
it  is  necessary  to  re-examine  many  of  the  concepts  which  were  de- 
veloped to  explain  electrical  events  in  axons  and  which  have  been 
assumed  to  apply  to  all  excitable  tissues  on  the  assumption  that 
all  ions  are  free.   Moreover,  it  seems  very  possible  that  the 
state  of  ions  in  most  cell  bodies  may  be  more  like  that  in  Aplysia 
neurons  than  that  in  squid  axons  since  the  cell  bodies  contain 
many  more  membraneous  structures  and  a  higher  concentration  of 
organic  molecules  (which  are  probably  the  site  of  the  ion  and 
water  binding).   Our  observations,  therefore,  may  have  relevance 
to  all  types  of  cells. 

Proposed  Course  of  Project;  We  will  extend  the  use  of  this  tech- 
nique  to  a  variety  of  tissues  from  land  animals,  including  verte- 
brates.  Tissues  to  be  used  include  skeletal  muscle,  heart 
muscles,  red  blood  cells  and  neuronal  cell  bodies  of  land  snails, 
frogs  and  mammals.   In  addition,  we  will  attempt  to  study  mam- 
malian neurons  in  tissue  culture.   Further  studies  will  be  made 
on  solutions  of  salts,  macromolecules  and  water  and  will  include 
direct  measurement  of  ionic  activities  with  ion  specific  micro- 
electrodes,  conductivity,  viscosity,  and  electron  spin  resonance 
of  free  radicals  which  will  give  an  independent  measure  of  the 
bound  water. 

Honors  and  Awards;   Dr.  David  Carpenter  was  invited  to  present 
these  results  at  the  International  Conference  on  the  Structure 

606 


I 


Serial  No.  M-NP-48,  page  3 

of  Water  and  Ions  in  Living  Cells  and  Model  Systems,  sponsored 
by  the  New  York  Academy  of  Science,  January  10-12,  1972. 

Publications ;   D.  0.  Carpenter,  M.  M.  Hovey,  and  A.  F.  Bak: 
Measurements  of  intracellular  conductivity  in  Aplysia  neurons: 
Evidence  for  organization  of  water  and  ions.   N.  Y.  Acad.  Sci. 
(in  press) . 


I 


60T 


Serial  No.  M-NP-63 

1.   Laboratory  of  Neurophysiology 

2. 

3.  Bethesda,  Maryland 


L 


PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 


Project  Title:   The  functional  organization  of  the  sensorimotor  cortex  in 
the  initiation  and  control  of  movement 

Previous  Serial  Number:   Same 

Principal  Investigator:   Edv/ard  V.  Evarts 

Other  Investigators:   William  Burriss,  Tom  Stoodley 

Cooperating  Units:   None 

Man  Years:  Total:  4.00 
Professional:  1.70 
Other:         2.30 

Project  Description: 

Objectives :   This  project  is  aimed  at  understanding  how  the  inputs  and 
outputs  of  the  cerebral  sensorimotor  cortex  function  in  control  of  movement 
and  to  discover  what  areas  of  the  cortex  initiate  movement,  what  areas  con- 
trol and  regulate  movement,  and  how  these  areas  for  initiation  and  control 
are  interrelated. 

Methods  Employed:  Microelectrodes  are  used  to  record  the  activity  of 
individual  neurons  during  natural,  voluntary  movement  in  the  monkey.  This 
use  of  single  unit  analysis  in  relation  to  voluntary  movement  is  analogous 
to  the  long-established  use  of  single  unit  analysis  in  determining  how  the 
brain  receives  and  elaborates  its  sensory  input,  but  single  unit  analysis 
has  only  recently  been  carried  out  in  animals  trained  to  perform  skilled 
movements  during  recording. 

Major  Findings: 

1 .   Differences  in  Central  Delay  for  Motor  Output  Initiated  by  Visual 
vs.  Kinesthetic  Input.   Previous  investigations  in  monkeys  have  shown  that 
motor  cortex  PTN  output  prior  to  learned  movement  triggered  by  a  visual 
stimulus  occurs  about  100  msec  following  the  stimulus  and  is  associated  with 
muscular  contraction  beginning  about  50  msec  later.   Reaction  times  in 
monkeys  in  this  situation  correspond  to  reaction  times  observed  in  man  under 
corresponding  circumstances.   However,  when  the  stimulus  given  to  man  is 
kinesthetic  rather  than  visual,  reaction  time  may  be  considerably  shorter. 
Hammond  demonstrated  that  when  subjects  made  responses  to  displacement  of 

609 


Serial  No.  M-NP-63,  page  2. 


1 


the  arm,  reaction  time  was  as  short  as  50  msec.   Results  from  recordings  In 
sensorimotor  cortex  of  the  monkey  when  the  animal  makes  a  movement  in 
response  to  an  input  delivered  to  the  hand  showed  that  under  these  circum- 
stances motor  cortex  pyramidal  tract  neurons  can  discharge  at  much  shorter 
latency  than  is  the  case  for  movements  initiated  by  a  visual  stimulus.   In 
the  experiments  carried  out  by  Hammond,  it  had  been  observed  that  muscular 
responses  dependent  upon  the  voluntary  set  of  the  subject  occur  50  msec      ^ 
following  stimulus.   In  the  experiments  on  monkeys,  changes  in  muscle 
activity  depending  upon  the  set  of  the  animal  occur  at  a  latency  of  approxi-  j 
mately  35  msec  following  the  stimulus.   These  changes  in  muscle  activity  were 
preceded  by  activity  of  neurons  in  motor  cortex.   Recordings  from  the  motor 
cortex  reveal  that  pyramidal  tract  neurons  became  active  at  latencies  as 
short  as  20  msec  following  a  stimulus  to  the  hand.  Non-pyramidal  tract 
neurons  of  motor  cortex  became  active  even  earlier,  and  neurons  of  the  post- 
central gyrus  were  active  at  still  shorter  latencies  of  10-12  msec  following 
the  stimulus  to  the  hand.   In  interpreting  his  observations  on  man,  Hammond 
proposed  that  very  short  reaction  times,  dependent  upon  the  voluntary  set  of 
the  subject,  might  involve  a  setting  of  spinal  reflexes.   The  present  obser- 
vations showing  changes  in  motor  cortex  output  at  very  short  latencies  would 
suggest  that  in  addition  to  a  presetting  of  spinal  reflex  mechanisms,  such 
short  latency  responses  dependent  on  voluntary  set  may  also  involve  pre- 
setting of  cortical  mechanisms. 


2  .   Development  of  Computer  Programs  for  Analysis  of  Cerebral  Activity 
Associated  with  Learned  Movement.   Over  a  period  of  several  years  we  have 
been  working  on  computer  programs  which  can  be  used  to  analyze  the  relation- 
ship between  neuronal  activity  and  behavior.   Development  of  these  programs 
has  progressed  very  well  and  we  now  have  what  is  probably  the  most  effective 
analysis  and  display  system  yet  developed  for  showing  the  relationship 
between  stimulus  and  response  in  learned  behavior  that  depends  upon  the  set 
and  attention  of  the  experimental  animal.   Our  computer  program  separates 
different  trials  by  the  animal  depending  on  the  stimulus  and  response  con- 
ditions and  displays  activity  of  single  cells  in  such  a  way  as  to  allow  a 
photographic  record  of  results  to  be  obtained  with  speed  and  at  low  cost. 
In  addition,  the  program  presents  graphical  data  showing  the  pattern  of 
neuronal  discharge  and  also  computes  the  time  at  which  activity  changes  in 
relation  to  the  stimulus  and  response.   The  program  is  of  sufficiently 
general  nature  so  that  it  can  be  used  in  studies  of  a  variety  of  different 
forms  of  behavior.   Thus,  it  has  been  used  to  study  complex  learning  phe- 
nomena such  as  delayed  alternation  in  the  monkey,  and  at  the  same  time  has 
been  used  to  study  more  elementary  phenomena  such  as  cerebellar  neuronal 
activity  associated  with  startle  responses.   Not  only  can  the  display  system^ 
deal  with  pulse  activity  from  single  cells,  but  it  can  be  used  for  displaying 
and  averaging  analog  waveforms  such  as  electromyographic  activity.  At  the 
present  time  certain  additional  developments  on  the  program  are  being  carried j 
out  by  Mr.  Tom  Stoodley.  | 

The  developmental  work  in  connection  with  the  computer  program  was 
carried  out  using  a  Spear  LINC  computer  under  the  supervision  of  the  Section^ 

610 


Serial  No.  M-NP-63,  page  3. 


on  Technical  Development.   The  program  has  now  been  set  up  to  use  a  PDP-12 
computer.  Because  of  the  success  of  the  computer  program  and  the  wide  appli- 
cation which  it  will  have  within  our  Laboratory,  it  has  been  decided  that  it 
is  justifiable  to  obtain  a  computer  for  the  use  of  the  Laboratory  and  a 
PDP-12  computer  has  now  been  ordered  for  this  purpose. 

Significance  to  Bio-medical  Research  and  the  Program  of  the  Institute: 
The  work  which  has  been  done  showing  a  short -latency  response  in  pyramidal 
tract  neurons  of  motor  cortex  when  the  stimulus  for  movement  comes  via  the 
hand  reveals  that  certain  sorts  of  inputs  can  traverse  the  cerebral  cortex 
more  quickly  than  was  suspected.   From  this  result  it  seems  clear  that  a 
number  of  the  forms  of  reflex  motor  activity  dependent  upon  the  set  and 
expectation  of  the  subject  (and  occurring  at  short  latency)  may  actually 
involve  mediation  by  cerebral  cortex,  rather  than  being  exclusively  spinal 
cord  phenomena . 

Perhaps  the  most  interesting  part  of  the  observation,  however,  is  that 
the  quick  output  from  motor  area  is  not  an  automatic  consequence  of  input 
but  that  it  can  be  modified  or  gated  depending  on  the  volitional  goals  of 
the  subject.   It  seems  possible  that  certain  cells  in  the  motor  area  are 
more  or  less  directly  tied  to  the  input  and  that  neuronal  networks  within 
the  cerebral  cortex  are  able  to  facilitate  or  prevent  the  transmission  of 
these  patterns  of  discharge  to  the  pyramidal  tract  output  from  the  cortex. 
The  time  available  for  this  switching  to  take  place  is  brief  and  this  fact 
means  that  analysis  of  the  mechanisms  underlying  the  gating  on  or  off  of 
motor  output  may  be  approached  more  effectively  than  has  heretofore  been 
possible . 

A  number  of  formulations  concerning  the  nature  of  mental  disorder  in 
patients  have  proposed  a  disturbance  in  the  cerebral  mechanisms  which  under- 
lie the  maintenance  of  "set"  or  "attention."  It  appears  that  the  present 
neurophysiological  experiments  on  monkeys  begin  to  get  at  mechanisms  which 
are  close  to  the  attentional  and  set  determining  mechanisms  of  the  brain. 
If  these  mechanisms  can  be  better  understood,  it  seems  possible  that  they 
will  lead  to  a  sounder  understanding  of  a  variety  of  disturbances  of  psycho- 
logical function. 

Proposed  Course  of  Project: 

1.   Differences  in  Central  Delay  for  Motor  Output  Initiated  by  Visual 
vs.  Kinesthetic  Input.   The  findings  described  concerning  this  part  of  the 
project  will  be  pursued  by  training  animals  to  do  somewhat  different  tasks. 
In  the  work  which  has  already  been  done,  animals  were  trained  to  maintain  a 
fixed  position  of  their  hand  and  then  to  resume  this  fixed  position  follow- 
ing a  perturbation  by  an  external  force.   In  the  coming  experiment,  animals 
will  be  trained  to  have  different  responses  to  the  same  stimulus.   Thus,  as 
was  done  for  man,  monkeys  will  be  trained  to  resist  a  perturbation  of  the 
handle  they  are  holding  under  certain  circumstances,  and  to  let  go  in 
response  to  this  same  perturbation  under  other  circumstances.   Thus,  for  the 

611 


Serial  No.  M-NP-63,  page  4. 


same  input  it  will  be  possible  to  observe  two  different  motor  outputs,  and  to 
localize  the  part  of  the  brain  at  which  there  is  a  gating  of  this  same  input 
into  different  motor  control  neurons  which  determine  the  different  motor  out- 
puts. By  means  of  this  experiment  we  should  learn  more  about  the  location  of 
the  neurons  which  are  preset  either  in  cerebral  cortex  or  in  spinal  cord  in 
association  with  quick,  volitionally  determined  "reflex"  movements. 

I 
2  .   Development  of  Computer  Programs  for  Analysis  of  Cerebral  Activity 
Associated  with  Learned  Movement.   The  availability  of  a  PDP-12  computer 
within  the  Laboratory  will  greatly  facilitate  our  ability  to  add  new  and  more 
thorough  analytic  tools  to  the  ones  we  have  already  developed.   We  will 
develop  programs  which  will  enable  us  to  select  certain  sets  of  trials  on 
the  basis  of  a  variety  of  additional  characteristics  so  that  we  can  discover 
the  relationship  between  neuronal  activity  and  a  range  of  variables  which  we 
have  not  yet  been  able  to  select.  With  the  computer  available  in  the  Labora- 
tory, it  will  be  possible  to  interconnect  more  of  the  experimental  rooms  with 
it  so  that  each  of  the  investigators  will  be  able  to  use  the  computer  more 
readily . 

3 .   Studies  of  Input-Output  Relations  for  the  Sensorimotor  System  in 
Man.   This  new  area  of  investigation  has  been  stimulated  by  our  findings  of 
the  marked  differences  in  central  delay  depending  upon  modality  via  which 
the  input  generates  motor  output.   In  analyzing  our  results  and  considering 
the  literature  on  this  general  problem,  it  seems  clear  that  more  rapid  pro- 
gress in  understanding  control  of  movement  can  be  made  if  we  carry  out  com-   ' 
plimentary  studies  both  on  man  and  animal.   We  have  engaged  in  preliminary 
conversations  with  several  members  of  the  clinical  staff  in  the  Neurology 
and  Mental  Health  Institutes,  and  we  intend  to  set  up  a  laboratory  for  human 
studies  in  Building  36.   This  laboratory  will  be  able  to  utilize  our  new 
computer  facility  together  with  the  technical  help  available  in  the  Labora- 
tory, and  we  will  be  able  to  carry  out  studies  in  both  man  and  animal  and 
interchange  the  knowledge  available  from  both  of  these  types  of  experimenta- 
tion.  The  experiments  in  man  would  involve  recordings  of  motor  performance 
and  in  some  cases  electromyographic  activity.   No  attempt  would  be  made  to 
record  from  the  nervous  system  itself.  ] 

Honors  and  Awards : 

Invited  Lecturer  at: 

1.  International  Congress  of  Physiological  Sciences,  Munich,  Germany, 
July  28,  1971. 

2.  Gyllenberg  Symposium,  Helsinki,  Finland,  August  2-3,  1971. 

3.  International  Congress  of  Physiological  Sciences  Satellite  Symposium, 
Zurich,  Switzerland,  August  7-8,  1971. 


612 


Serial  No.  M-NP-63,  page  5. 

4.  Parkinson's  Disease  Research  Center,  New  York,  New  York,  October  5-6, 

5.  Biological  Sciences  Group,  University  of  Connecticut,  Storrs , 
Connecticut,  October  21,  1971. 

6.  Laboratory  of  Psychology,  Brown  University,  Providence,  Rhode  Island 
November  3,  1971. 

7.  Department  of  Physiology,  Harvard  Medical  School,  Boston,  Massachusetts 
November  17,  1971. 

8.  Department  of  Psychiatry,  University  of  Michigan,  Ann  Arbor,  Michigan 
December  9,  1971. 

9.  Department  of  Physiology  and  Pharmacology,  Duke  University,  Durham, 
North  Carolina,  April  21,  1972. 

10.  American  Academy  of  Neurology,  St.  Louis,  Missouri,  April  25,  1972. 
Serves  on: 

1.  Board  of  Co-editors,  Experimental  Brain  Research 

2.  Advisory  Board,  Journal  of  Neuroscience 

3.  Editorial  Board,  International  Review  of  Neurobiology 

4.  Council,  Society  for  Neuroscience 

5.  Secretary,  Society  for  Neuroscience 
Publications : 

Evarts,  E.V.:   Contrasts  between  activity  of  precentral  and  postcentral 
neurons  of  cerebral  cortex  during  movement  in  the  monkey.  Brain  Res  40' 
25-31,  1972  


613 


Serial  No.  M-NP-65 

1.   Laboratory  of  Neurophysiology 

2. 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:   Functional  role  of  the  basal  ganglia  in  the  control  of 
movement  and  posture 

Previous  Serial  Number:  None 

Principal  Investigator:  Mahlon  R.  DeLong 

Other  Investigators:   William  T.  Burrias 

Cooperating  Units:   None 

Man  Years:  Total:  2.00 
Professional:  1.40 
Other:         .60 

Project  Description: 

Objectives:   This  study  is  directed  towards  learning  how  the  basal 
ganglia  function  in  the  control  of  movement  and  posture.   What  is  the 
functional  organization  of  these  structures?   Do  they  play  a  role  primarily 
in  the  initiation  of  movement  or  in  feedback  control?   What  are  the  specific 
contributions  of  these  nuclei  as  contrasted  with  those  of  other  brain 
structures  involved  in  motor  function,  such  as  the  cerebellum? 

Methods  Employed:   These  studies  utilize  the  techniques  of  single  unit 
recording  in  intact  moving  animals  developed  in  this  Laboratory  over  past 
years.  Animals  are  trained  to  make  movements  of  the  limbs,  and  cell 
activity  is  recorded  during  the  animal's  performance  of  the  task.   Cell 
activity  is  correlated  with  various  aspects  of  the  movements. 

Major  Findings:   Clinico-pathologic  studies  in  man  have  long  indicated 
that  the  corpus  striatum  (i.e.,  caudate -putamen  and  pallidum)  plays  an 
important  role  in  the  control  of  movement  and  posture,  since  when  these 
structures  are  damaged  through  disease,  abnormalities  in  posture,  muscle 
tone,  and  involuntary  movements  frequently  result  (e.g.,  Parkinsonism, 
chorea,  etc.).   These  large  subcortical  nuclei,  forming  a  major  portion  of 
the  so-called  extrapyramidal  motor  system,  are  of  special  interest  from  the 
standpoint  of  motor  control  since  the  major  influences  from  these  nuclei 
appear  to  be  exerted  upon  the  motor  cortex.  The  major  efferents  from  the 
corpus  striatum  arise  from  the  pallidum  and  terminate  in  "motor"  portions 
of  the  thalamus  (i.e.,  the  ventrolateral  and  ventroanterior  nuclei),  which 
in  turn  project  to  the  motor  cortex.   The  corpus  striatum  thus  gives  rise  to 

615 


Serial  No.  M-NP-65,  page  2, 


the  other  major  Input  (also  via  those  same  thalamic  nuclei).   Previous 
experimental  studies  dealing  with  the  functions  of  the  corpus  striatum  have 
been  concerned  largely  with  the  effects  of  ablation  and  stimulation  of  por- 
tions of  these  structures.   These  approaches  have  not  proven  particularly 
revealing,  due  in  part  to  the  "distance"  of  these  structures  from  the  "out- 
put" and  the  difficulties  of  confining  lesions  and  stimulation  to  these 
deeply  located  and  anatomically  complex  regions.   It  was  thus  of  considerable 
importance  to  apply  the  techniques  of  single  unit  recording  In  intact 
animals  in  order  to  learn  more  about  how  these  nuclei  normally  function 
during  movement. 

Studies  described  in  last  year's  report  showed  that  neurons  in  the 
globus  pallidus  which  were  related  to  arm  movements  discharged  prior  to  the 
onset  of  an  arm  movement.   This  demonstrated  that  the  discharge  of  these 
units  was  not  solely  due  to  sensory  feedback  from  the  moving  limb,  and 
indicated  that  these  nuclei  play  a  role  in  the  initiation  of  movement.   In 
these  experiments,  monkeys  were  trained  to  exert  a  steady  pushing  or  pulling 
force  on  a  rigid  rod  positioned  in  front  of  the  hand,  and  then  to  rapidly 
reverse  the  direction  of  the  force  on  presentation  of  a  visual  stimulus. 
Extracellular  recordings  were  then  carried  out  during  the  execution  of  the 
task.   The  globus  pallidus  was  studied  in  greatest  detail  initially.   In 
subsequent  studies  recordings  have  been  made  in  the  putamen  and  caudate  as 
well.   In  these  latter  nuclei,  unit  discharge  was  also  found  to  precede  the 
arm  movements,  expecially  in  the  putamen.  A  functional  organization  was 
observed  in  both  the  pallidum  and  the  caudate-putamen  whereby  the  majority 
of  movement -related  units  are  located  in  those  regions  which  receive  their 
input  from  the  sensorimotor  cortex. 

Significance  to  Bio-medical  Research  and  the  Program  of  the  Institute: 
Studies  on  the  function  of  the  corpus -striatum  are  of  relevance  to  the 
program  of  the  Institute  since  these  regions  of  the  brain  appear  to  have 
important  integrative  as  well  as  purely  motor  functions  which,  when  dis- 
turbed as  in  disease,  produce  disturbances  of  movement,  motivation,  and 
affect.   Current  theories  suggest  that  the  site  of  action  of  L-Dopa,  which 
abolishes  symptoms  in  the  majority  of  Parkinsonian  patients,  is  upon  the 
cells  of  the  caudate  and  putamen  via  a  dopaminergic  nigro-striatal  pathway. 
An  understanding  of  the  normal  functioning  of  the  corpus  striatum  should 
provide  a  firm  basis  for  studies  on  the  effects  of  disease  and  pharmacologic 
agents  on  these  structures . 

Proposed  Course  of  Project:   Experiments  now  in  preparation  will  attempt 
to  determine  the  specific  contribution  of  the  corpus  striatum  to  the  control 
of  movement.   It  has  been  postulated  that  the  major  role  of  the  corpus 
striatum  is  to  generate  smoothly  integrated  "ramp"  movements,  while  the 
cerebellum  functions  primarily  in  the  "timing"  of  onset  and  duration  of 
rapid,  more  ballistic  movements.  Monkeys  are  being  trained  to  carry  out 
both  ballistic  and  graded,  ramp  movements  with  the  same  arm.   Recordings 
will  be  made  from  neurons  in  the  corpus  striatum  during  the  execution  of 
these  two  types  of  movements  to  determine  whether  neurons  there  are  related 


616 


Serial  No.  M-NP-65,  page  2. 


preferentially  to  one  form  of  movement  or  another.   Later,  in  the  same 
animals,  the  effects  of  lesions  in  these  same  nuclei  will  be  made  in  order  to 
determine  whether  a  selective  impairment  of  one  type  or  movement  results. 
Although  previous  investigators  have  studied  the  effects  of  striatal  lesions 
on  movement,  the  observations  have  been  largely  naturalistic  and  the  animals' 
motor  abilities  have  not  been  quantitatively  evaluated. 

Honors  and  Awards :   None 

Publications : 

DeLong,  M.R. :  Activity  of  pallidal  neurons  during  movement.   J.  Neuro- 
physiol.  34:   414-427,  1971 

DeLong,  M.R. :  Activity  of  basal  ganglia  neurons  during  movement. 
Brain  Res.  40: 


617 


Serial  No.  M-NP-66 

1.   Laboratory  of  Neurophysiology 

2. 

3.   Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:   The  role  of  the  cerebellum  in  the  generation  of  saccadic  eye 
movements 

Previous  Serial  Number:   None 

Principal  Investigator:   F.  A.  Miles 

Other  Investigators:   None 

Cooperating  Units :   None 

Man  Years:  Total:  1.70 
Professional:  1.20 
Other:  .50 

Project  Description: 

Objectives :   This  project  is  aimed  at  understanding  the  role  of  the 
cerebellum  in  the  generation  of  saccadic  eye  movements.   Recent  stimulation 
and  ablation  studies  on  monkeys  suggest  that  the  vermis  (especially  lobules 
V,  VI  and  VII)  is  involved  in  the  programming  of  these  eye  movements. 

Methods  Employed:  Microelectrode  recordings  are  made  in  the  cerebellum 
of  conscious  monkeys  and  a  search  is  made  for  individual  units  whose  firing 
patterns  correlate  with  the  animal's  saccadic  eye  movements.   The  animal  is 
trained  to  press  a  bar  which  switches  on  a  small  spot  of  light  on  a  screen 
facing  him,  and  he  must  release  the  bar  when  this  light  dims.   Successful 
performance  is  rewarded  with  a  drop  of  water,  and  all  the  animal's  fluid 
intake  is  earned  by  working  at  this  task.   Using  this  approach,  four  monkeys 
have  been  trained  to  fixate  a  small  spot  of  light  and  maintain  this  fixation 
even  when  the  spot  changes  position.   Thus  it  is  possible  to  induce  the 
animal  to  generate  saccadic  eye  movements  of  known  magnitude  and  direction 
merely  by  changing  the  position  of  the  fixation  target.   The  behavioral  task 
requires  immense  vigilance  from  the  animal  and  cannot  be  performed  with 
peripheral  vision,  so  that  successful  performance  can  only  be  achieved  if 
the  animal  makes  the  required  eye  movements .   Oculograms  recorded  from 
implanted  electrodes  are  used  to  confirm  the  nature  of  the  animal's  eye 
movements  whilst  he  is  performing  the  task.   Correlations  between  eye  move- 
ments and  single  unit  firing  are  made  on-line  using  a  raster  display  in 
which  action  potentials  are  represented  as  dots  on  the  screen  of  a  storage 
oscilloscope.   The  oculogram  generated  during  each  eye  movement  is  used  to 
trigger  a  single  sweep  of  the  oscilloscope  and  the  action  potentials  are 

619 


Serial  No.  M-NP-66,  page  2. 

displayed  after  passing  through  a  delay  line.   In  this  way  unit  firing 
patterns  during  successive  saccade  trials  are  displayed  in  rows  on  the 
storage  oscilloscope.  The  delay  facility  allows  one  to  look  at  the  unit 
firing  before,  as  well  as  during  and  after,  the  eye  movements. 

Major  Findings:   To  date,  single  unit  recordings  have  been  made  from 
the  cerebellar  vermal  cortex  and  sub-cortical  nuclei  in  one  monkey  perform- 
ing the  controlled  eye  movements.   Seventeen  units  were  found  to  relate  to 
saccade  eye  movements.   The  site  of  these  cells  was  marked  with  small  elec- 
trolytic lesions  and  has  yet  to  be  confirmed  with  histology,  but  it  is  felt 
with  reasonable  certainty  that  they  probably  all  lie  within  the  fastigial 
nuclei.   No  Purkinje  cell  firing  was  observed  to  correlate  with  these  eye 
movements.   This  data  is  stored  on  magnetic  tape  and  still  remains  to  be 
analyzed  in  detail,  but  the  main  characteristics  of  this  saccade-related 
firing  which  are  apparent  from  the  on-line  analysis  are: 

a)  It  is  usually  directionally  selective,  showing  a  burst  during  ipsi- 
lateral  saccades  and  either  suppression  or  no  response  during  contralateral 
saccades .   Occasional  units  generate  a  burst  during  all  saccades. 

b)  This  burst  can  start  before  the  saccade,  but  the  exact  time  relation- 
ships remain  to  be  estimated. 

c)  The  magnitude  of  these  bursts  is  related  to  the  magnitude  of  the 
saccades  and  there  seems  to  be  an  optimum  eye  movement  for  which  responses 
are  maximal,  and  larger  or  smaller  saccades  are  associated  with  less  vigor- 
ous activity. 

d)  At  least  in  some  units,  the  saccade-related  burst  is  not  very  sensi- 
tive to  the  initial  start  position  of  the  eye. 

It  is  hoped  that  further  analysis  and  additional  unit  recordings  from  other 
animals  will  furnish  more  extensive  documentation  of  these  preliminary 
findings. 

Significance  to  Bio-medical  Research:   In  recent  years  there  has  been  a 
notable  advance  in  our  knowledge  of  the  microcircuitry  within  the  cerebellum. 
However,  whilst  this  structural  organization  must  clearly  provide  the  sub- 
strate for  models  of  cerebellar  function,  few  of  these  studies  were  done  on 
conscious  animals  performing  meaningful  movements,  and  consequently  little 
is  known  of  the  operational  role  of  the  cerebellum  in  the  control  of  move- 
ment. It  is  felt  that  single  unit  studies  on  conscious  animals  trained  to 
produce  a  precise  repertoire  of  movements  provide  a  powerful  approach  to  this 
problem.   Eye  movements  take  a  very  stereotyped  form  about  which  a  great  deal 
has  been  learned  in  recent  years  and  allow  the  observer  to  make  unusually 
precise  correlations  between  single  unit  firing  patterns  and  motor  output. 
The  saccadic  eye  movements  of  the  trained  animal  are  readily  manipulated  and 
should  provide  a  very  versatile  tool  for  testing  operational  models  of  cere- 
bellar function. 


620 


Serial  No.  M-NP-66,  page  3. 

Proposed  Course  of  Project:   The  project  is  only  at  an  early  stage  and 
it  is  proposed  to  pursue  the  preliminary  findings  outlined  above. 

Honors  and  Awards :   None 

Publications:   None 


621 


Serial  No.  M-NP-67 

1.  Laboratory  of  Neurophysiology 

2. 

3.  Bethesda,  Maryland 

PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 

Project  Title:   Temporal  sequence  of  cerebellar  activity  in  relation  to  the 
initiation  and  control  of  movements 

Previous  Serial  Number:   None 

Principal  Investigator:   James  A.  Mortimer 

Other  Investigators:   None 

Cooperating  Units:   Laboratory  of  Applied  Science,  DCRT,  NIH 

Man  Years:  Total:  1-70 
Professional:  0.70 
Other:         0.45 

Project  Description: 

Objectives :   The  general  objective  of  this  research  is  to  understand  the 
relationship  between  the  cerebellar  cortex  and  the  cerebellar  nuclei  in  the 
control  and  initiation  of  movement.  More  specif icially,  the  aim  is  to  dis- 
cover the  functional  role  of  direct  afferent  inputs  to  the  nuclei.   In  higher 
vertebrates  the  deep  cerebellar  nuclei  provide  the  major  output  from  the 
cerebellum.   The  cells  of  these  nuclei  are  controlled  by  two  major  inputs: 
an  inhibitory  input  from  the  output  Purkinje  neurons  of  the  cerebellar  cortex 
and  an  excitatory  input  from  the  collaterals  of  afferents  to  the  cortex.   Two 
hypotheses  have  been  proposed  for  the  functional  operation  of  the  cerebellum. 
In  the  first  hypothesis,  the  direct  excitatory  input  to  the  nuclei  is  con- 
sidered to  provide  only  a  steady  level  of  background  facilitation;  changes  in 
nuclear  activity  then  reflect  changes  in  the  inhibitory  input  from  Purkinje 
cells.  An  alternative  hypothesis  is  that  the  cerebellar  cortex  output  is 
superimposed  upon  an  ongoing  nuclear  discharge  evoked  by  its  direct  afferent 
input . 

Methods  Employed:   Extracellular  records  of  single  neurons  of  the  cere- 
bellar cortex  and  nuclei  of  the  awake  monkey  are  obtained  in  association  with 
startle  responses  evoked  by  brief  auditory  stimuli.   This  technique  is  par- 
ticularly applicable  to  the  problem  of  determining  the  times  at  which  various 
neurons  become  active  in  relation  to  a  discretely-timed  motor  response. 

Major  Findings:   Recordings  of  cerebellar  Purkinje  and  nuclear  cells 
revealed  a  temporal  sequence  of  neuronal  activity  following  the  stimuli,  in 
which  changes  in  nuclear  cell  discharge  preceded  the  earliest  changes  in 

623 


Serial  No.  M-NP-67,  page  2. 

Purkinje  cell  activity.  Virtually  all  nuclear  cells  responded  with  a  short- 
latency  burst  of  spikes,  which  occurred  several  milliseconds  before  the 
earliest  change  in  EMG  activity  associated  with  the  startle  response.   Shortly 
after  the  onset  of  the  EMG  response,  increases  and  decreases  in  Purkinje  dis- 
charge rate  were  observed.   These  findings  suggest  that  direct  excitatory 
input  to  the  nuclei  is  capable  of  initiating  activity,  which  is  modified 
after  a  delay  by  the  inputs  from  Purkinje  cells.   It  is  possible  that  the 
early  nuclear  discharge  contributes  to  the  initiation  of  motor  activity 
associated  with  the  startle  response.   These  findings  have  been  presented  in 
a  paper  entitled  "Latency  Differences  in  Cerebellar  Purkinje  and  Nuclear  Cell 
Activity  in  Association  with  Startle  Responses,"  an  abstract  for  which 
appeared  in  Fed.  Proc .  31:  378,  1972. 

Significance  to  Bio-medical  Research  and  the  Program  of  the  Institute: 
One  symptom  of  cerebellar  damage  is  slowness  in  the  initiation  of  voluntary 
movement.   Prior  studies  have  shown  that  cerebellar  neurons  are  active  before 
such  movements ,  but  have  not  provided  information  regarding  which  inputs  and 
which  cerebellar  neurons  are  involved  in  generating  the  initial  changes  in 
activity  accompanying  these  movements.   In  particular,  it  is  important  to 
determine  whether  the  cerebellar  cortex  and  nuclei  play  different  roles, 
perhaps  relating  to  the  initiation  vs.  control  of  movement.   The  current  pro- 
ject is  aimed  at  understanding  these  roles,  thereby  permitting  a  more  accurate 
assessment  to  be  made  of  specific  cerebellar  deficiencies. 

Proposed  Course  of  Project:   It  is  proposed  to  continue  this  research, 
focusing  on  the  following  two  questions:   1)  Do  the  cerebellar  cortex  and 
nuclei  receive  the  same  or  different  inputs?  2)  If  they  receive  input  from 
the  same  as  well  as  different  sources,  what  is  the  relation  of  their  shared 
and  non-shared  inputs  to  each  other  and  to  the  associated  motor  activity? 


Honors  and  Awards :   None 
Publications:   None 


d 


62k 


Serial  No.  M-NP^68 

1.  Laboratory  of  Neurophysiology 

2. 

3.  Bethesda,  Maryland 


PHS-HSMHA-NIMH 

Individual  Project  Report 

July  1,  1971  through  June  30,  1972 


Project  Title:   Studies  on  the  neuronal  activity  of  the  prefrontal  cortex 

Previous  Serial  Number:   None 

Principal  Investigator:   Hiroaki  Niki 

Other  Investigators:   Mortimer  Mishkin 

Cooperating  Units:   Laboratory  of  Psychology,  NIMH 

Man  Years:  Total:  1.65 
Professional:  1.20 
Other:         .45 

Project  Description: 

Objectives :   The  portion  of  the  frontal  cortex  lying  rostral  to  the 
premotor  areas  and  frontal  eyefields  has  been  designated  as  "prefrontal 
cortex."   It  is  now  well  established  that  bilateral  ablation  of  the  dorso- 
lateral prefrontal  cortex  produces  a  severe  deficit  in  spatial  delayed 
response  performance.   Little  is  known,  however,  about  the  neuronal  activity 
of  the  prefrontal  cortex.   In  a  previous  study  (which  was  done  in  the  Primate 
Research  Institute,  Kyoto  University,  Japan),  the  single  unit  activity  of  the 
dorsolateral  prefrontal  cortex  was  analyzed  during  delayed  alternation  per- 
formance and  two  types  of  related  units  were  found.   One  type  of  unit 
increased  its  discharge  rate  immediately  before  alternate  lever-pressing  per- 
formance, while  the  other  decreased  its  rate  during  responding.   The  aim  of 
the  present  study  is  to  analyze  further  the  nature  of  the  prefrontal  cortical 
neuronal  activity. 

Methods  Employed:   In  order  to  extend  this  line  of  investigation,  the 
task  situation  was  modified  so  that  the  position  and  movement  of  the  animal's 
hand  during  the  delay  period  can  be  controlled.   First,  an  ablation  experi- 
ment was  conducted  in  collaboration  with  Dr.  Mortimer  Mishkin  in  the  Labora- 
tory of  Psychology,  NIMH,  in  order  to  confirm  a  deficit  in  this  modified 
delayed  alternation  task  in  which  the  animal  must  keep  pressing  a  holding 
button  during  the  delay  period  (5  sec).   In  the  second  series  of  experiments, 
which  are  now  in  progress ,  the  unit  activity  of  the  dorsolateral  prefrontal 
cortex  is  analyzed  during  the  delayed  alternation  performance,  using  a  method 
developed  by  Dr.  E.  V.  Evarts . 


625 


Serial  No.  M-NP-68,  page  2. 

Major  Findings :   IVo  monkeys  with  bilateral  lesions  of  the  dorsolateral 
prefrontal  area  (one  with  total  dorsolateral  removal  and  another  with  total 
lesions  of  the  principal  sulcus)  showed  a  severe  permanent  deficit  in  this 
delayed  alternation  performance,  but  they  could  perform  quite  well  on  a  cue- 
guided  alternation  task.   On  the  delayed  alternation  task  these  prefrontal 
animals  performed  at  chance  levels  even  after  7,000  post -operative  trials. 
So  far,  the  following  results  have  been  obtained  from  unit  recording  experi- 
ments. Most  of  the  related  units  showed  an  increase  in  their  discharge  rate 
immediately  before  responding  and  showed  no  directional  specificity.   In  con- 
trast, some  units  showed  a  decrease  in  discharge  rate  during  responding.   In 
some  units  directional  specificity  was  observed,  i.e.,  changes  (increase  and 
decrease)  in  discharge  rate  were  consistently  greater  when  the  animal  pressed 
the  one-side  button.   Some  units  showed  an  increase  in  rate  when  the  delay 
period  began.  An  abstract  describing  these  findings,  entitled  "Prefrontal 
Cortical  Unit  Activity  during  Delayed  Alternation  (DA)  in  Monkeys,"  has  been 
submitted  for  presentation  at  the  annual  meeting  of  the  Society  for  Neuro- 
science . 

Significance  to  Bio-medical  Research:   The  prefrontal  cortex  has  been 
thought  to  be  concerned  in  higher  mental  processes,  but  the  way  cells  of  this 
area  participate  in  such  processes  has  not  been  well  understood.   Thus,  an 
understanding  of  the  physiology  of  the  prefrontal  cortex  is  essential  for  an 
understanding  of  the  cerebral  basis  of  mental  processes. 

Proposed  Course  of  Project:   In  a  subsequent  study,  units  related  to  the 
delayed  alternation  task  will  be  tested  in  other  tasks  such  as  a  visually- 
guided  movement,  color  alternation,  and  performance  under  a  schedule  of  dif- 
ferential reinforcement  of  low  rate,  in  order  to  make  clear  the  nature  of  the 
relationship  between  unitary  discharge  in  the  prefrontal  cortical  area  and 
these  forms  of  behavior. 

Honors  and  Awards :  None 

Publications:   None 


626 


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