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Anatomical studies in lobotomy Smythies, John Raymond 1955

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i  ANATOMICAL STUDIES IN LOBOTOMY  by JOHN. RAYMOND SMITHIES  A"THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF  MASTER OF  i n the Department of Neurological Research  We accept t h i s thesis as conforming to the standard required from candidates f o r the degree o f MASTER OF  SCIENCE  Members of the Department o f  THE UNIVERSITY OF BRITISH COLUMBIA March, 1955  AfeuW<^««/ &4£4#etd  ABSTRACT This thesis contains a report o f an i n v e s t i g a t i o n that has been c a r r i e d out over the l a s t year and a h a l f i n t o the t r a c i n g o f f i b r e t r a c t s i n the human brain by the method of terminal degeneration. Four brains have been used and the extent o f the degeneration (where present) i n each has been traced i n d e t a i l .  P a r t i c u l a r attention has  been paid to improving the method of terminal degeneration by s e t t i n g up and using objective and quantitative c r i t e r i a of degeneration i n place of the subjective and q u a l i t a t i v e c r i t e r i a that have been used i n the past.  Descriptions o f the d i f f e r e n t appearance o f degeneration  i n d i f f e r e n t parts' of the nervous system are also given. Thus an accurate  account can be given o f the f i b r e s cut i n  these cases o f p r e f r o n t a l lobotomy and o f the efferent projections of that part o f the f r o n t a l lobe undercut by the l e s i o n . These accounts help i n placing the operation on a r a t i o n a l basis and give  information  on the anatomy o f the connexions i n the human brain that cannot be obtained i n any other manner.  ACKNOVJLEDGEMENTS I am most grateful to Professor W. C. Gibson for his direction and advice during this work supervised by him.  I should  also like to record my gratitude to Mrs* Nan Purkis and Hrs. Linnea Lowes for their technical assistance i n preparing some of the sections and photographs and for examining some of the cortical sections; to Mrs. Nan Cheney who prepared the artist's drawings from originals prepared by myself; to Miss Susan Calthrop who typed the thesis and to Professor Paul Yakovlev and Brigadier Elbert DaCoursey for the presentation of the pathological specimens.  iii TABLE OF CONTENTS  CHAPTER I. II.  PAGE  INTRODUCTION AND SURVEY OF PREVIOUS LITERATURE  , 1  MATERIAL AND METHODS . . .•  13  III.  RESULTS  19  :-TV.  DISCUSSION  V.  SUMMARY  BIBLIOGRAPHY  .'  24 27 28  iv DESCRIPTION OF FIGURES  MAPS 1-3  Maps of lobotomy wound: brain L-2 (R)  4-6  The same:  brain L-2 (L)  7 - 9  The same.:  brain L-3 (R)  10 - 13  The same:  brain L-4 •....)  14-19  Extent of the degeneration i n the dorso-medial nucleus of the thalamus of brain L-2 (R)  20 - 23  The same : brain L-2 (L)  24 - 30  The same : brain L-3 (R) (Note figure 26 i s from a section as shown i n figure 25 i n which the presence of any bouton or terminal was marked on the map with a dot.)  31-34  The same : brain L-4 (R)  35-41  Extent of degeneration i n the prefronto-pontine tract and pons of brain L-3 (R)  42 - 46  The same : brain L-4 (R) In figures 42 - 43 one stroke stands for 2 f i e l d s .  47 - 49  Extent of the degeneration i n the medial mamillary nucleus of brain L-4 (R)  50  Extent of 'degeneration i n the normal pons (NC2) mapped by 1  'dorso-medial' c r i t e r i a .  Mapped by 'pons' c r i t e r i a this map.  would be blank. 51  The same for the nucleus parafascicularis  CAMERA LUCIDA DRAWINGS 52 - 55  Drawings of degenerating terminals i n the dorso-medial nucleusUnits of degeneration are numbered.  REPRODUCTIONS 56  From Hoff ('32 a)  57  From Hoff ('35)  58  From Brodal ('49)  59  From Brodal, Walberg and Blackstad ('50)  60  From Getz (»52)  61  From Meyer ('49)  PHOTOMICROGRAPHS 62 - 63  Degeneration immediately around the l e s i o n i n b r a i n L-2. x 1,400  64  Degeneration i n the dorso-medial nucleus i n brain L-2. x 1,700  65  The same i n brain L - 4 . x 900  66  Normal boutons termineaux i n nucleus p a r a f a s c i c u l a r i s (NCl). x 1,600  67  The same. x 1,400  68  Degenerating f i b r e s i n the prefronto-pontine t r a c t i n b r a i n  L-3.  x 1,800  69  The f i b r e plexus i n the normal pons (NC2).  x 1,100  70  Degeneration i n the pons i n brain L-4« x 1,000  71  70 enlarged,  72 - 73  The f i b r e plexus i n the normal medial mamillary nucleus (NCl)  x 1,800  x 1,100 74  Degeneration i n the medial mamillary nucleus o f b r a i n L-4» x 1,100  vi ABBREVIATIONS USED IN FIGURES FIGURE 1-13  14-49  a  agranular  e . eulaminate  d  dys granular  m  mesocortex  A.C.  anterior commissure  A.D. ,  antero-dorsal nucleus  A.H.  anterior hypothalamus  A.L.  ansa l e n t i c u l a r i s  A.M.  antero-medial nucleus  ATR.  anterior thalamic r a d i a t i o n  CM.  nucleus c e n t r a l i s medialis  C. N.  caudate nucleus  CE.N.  nucleus centranum medianum  D. H.  dorsal hypothalamus  D.L.  dorso-lateral nucleus  D.M.  dorso-medial nucleus  F.  fornix  F. L.  fasciculus lenticularis  G.P.  globus p a l l i d u s  I.C.  i n t e r n a l capsule  I.T.P.  i n f e r i o r thalamic peduncle  L.H.  l a t e r a l hypothalamus  L.M.  l a t e r a l mamillary nucleus  L.T.(Tu)  l a t e r a l tuberal nucleus  mc  l a r g e - c e l l e d portion  M.B.(M)  mamillary body  M.L.  medial leminiscus  vii FIGURE  52-55  M.T.  mamillary-thalamic t r a c t  N.A.  anterior nucleus  N.S.M.  supra-mamillary nucleus  N.V.  v e n t r a l nucleus  pc  small-celled portion  P.  pyramidal t r a c t  P.F.  parafascicular nucleus  F.H.  posterior hypothalamus  P.T.  parataenial nucleus  PU.  pulvinar  PUT.  putamen  E.V.  paraventricular nucleus  Pa.Cd.  dorsal part of paracentral nucleus  Pa.Cv.  ventral part of paracentral nucleus  R.  red nucleus  R.E#  nucleus reuniens  S.N.  substantia  S.T.  subthalamus  SUM.  nucleus submedius  Th.  thalamus  V.A.  anterior v e n t r a l nucleus  V.L.  l a t e r a l ventral nucleus  V.P.  posterior v e n t r a l nucleus  Z.I.  zona i n c e r t a  g.  nigra  glial cell  N. c•  capillary  nerve  cell  viii SIGNS USED IN FIGURES  THALAMUS  •  2 - 1 4 units o f degeneration.  4-  more than 14 units o f degeneration.  •  2 or more units o f degeneration plus  HYPOTHALAMUS  obvious fragmentation o f the fine, plexus of unmyelinated  PONS (except 41, 50)  •  fibres.  more than 50 boutons and terminals plus obvious fragmentation o f the fine plexus of myelinated f i b r e s .  more than 15 boutons.  FIGURES 41, 50 c  2 u n i t s of degeneration.  •  both.  In a l l cases the sign ^ shows the presence and approximate d i r e c t i o n of degenerated f i b r e s i f more than 1 present.  CHAPTER I INTRODUCTION'AND SURVEY OF PREVIOUS LITERATURE  The method of terminal degeneration used to trace neuronal connexions i n the nervous system depends on the f a c t that, following the cutting of an axon, the axon, i t s preterminal branches and the terminals themselves undergo a series of c h a r a c t e r i s t i c changes that can be detected by the use of s i l v e r s t a i n s *  The f i r s t account of  terminal degeneration i n the axon was given by Nikolajew (1893)•  He'  used the methylene blue method to show the degenerating boutons on the ganglion'cells of the frog's heart ten to f i f t e e n days a f t e r cutting the vagus nerve.  The normally delicate r i n g endings became fragmented  and hypertrophied.  Tuckett (1895) used the same technique to demonstrate  degenerating pre-ganglionic f i b r e s i n the r a b b i t . Cajal ( * l l ) makes the important point ( i n addition to others) that where an axon i s interrupted i n the white matter i t s c e n t r a l segment forms a l a t e 'boute de r e t r a c t i o n ' , having passed through a complex and slow hypertrophy with fusiform swellings, v a r i c o s i t i e s and 'boute en s e r i e s ' .  The peripheral, or severed part of the axon passes  through active phases of n e u r o f i b r i l l a r swelling, formation o f i s o l a t e d spheres, and complicated clusters of n e u r o f i b r i l s showing that l o c a l r e a c t i o n i s possible even i n the i s o l a t e d p o r t i o n . Ranson and B i l l i n g s l e y ('18) using a pyridine s i l v e r method were unable to demonstrate the normally dense plexus o f f i b r e s i n the superior c e r v i c a l ganglion following the section and subsequent degeneration of the pre-ganglionic trunk.  The History of the Method* (a)  The e a r l y years*  De Castro ('30) c a r r i e d out an intensive  i n v e s t i g a t i o n i n t o the degeneration i n the superior c e r v i c a l ganglion i n over 100 cats ( c h i e f l y young).  He used block s i l v e r impregnation methods  with f i x a t i o n i n somnifene or c h l o r a l hydrate and showed that terminal degeneration appears a t the end o f seventeen hours although the axons to which they were attached were often i n t a c t .  This work was confirmed  by Lawrentjew (*34) who used the method of terminal degeneration to determine the method o f ending o f f i b r e s i n the superior sympathetic ganglion.  At about the same time L e v i ('32) studied degeneration i n  nerve processes separated from t h e i r c e l l bodies i n tissue c u l t u r e . Twelve hours following section the d i s t a l segment resembled a 'string o f pearls', the swellings of which were i n the process of fragmentary degeneration.  Sereni and Young ('32) detected bouton changes i n  cephalopods f i f t e e n hours a f t e r the mantle connective and s t e l l a r nerves had been sectioned and the process was complete i n 7 days with gradual disappearance of fragments. (b)  Recent work.  The recent use o f the method dates from  Hoff*s series of i n v e s t i g a t i o n s .  In these he examined the degeneration  produced i n the cat s p i n a l cord ( 32a) a f t e r cutting the afferent roots r  of post-thoracic nerves.  He then used the method (*32b, '35) to study  the termination i n the cord of f i b r e s from the motor and  premotor  cortex i n the cat and monkey. Gibson ('37) described the changes i n the terminals I n the s p i n a l cord following i t s transection i n the c a t . Schimert ('38) used the method to trace the endings of the vestibulo-  3 s p i n a l t r a c t i n the c a t .  This was followed by a number o f communications  from Glees and Le Gros Clark ('41) and Glees  (*41, '42) i n which the  mode o f temmination o f the o p t i c nerve i n the l a t e r a l geniculate body i n various animals was studied* connexions i n cats*  Glees  ('44) studied c o r t i c o - s t r i a t e  Glees, Meyer,and Meyer ('46) used the method to  trace the terminal degeneration i n the f r o n t a l cortex o f the r a b b i t following i n t e r r u p t i o n o f afferent f i b r e s , and Le Gros Clark and Meyer ('47) used i t t o t r a c e the terminal connexions" o f the o l f a c t o r y t r a c t i n -  the r a b b i t .  Brodal ('49) and Brodal, Walberg and Blackstad ('50)  investigated the termination o f the s p i n a l afferents In the l a t e r a l r e t i c u l a r nucleus o f the cat and the termination of the spino-olivary f i b r e s r e s p e c t i v e l y . Adey ('51) and Getz ('52) used the method to trace the hippocampal connexions o f the cingulate cortex o f the rabbit, and the termination o f spino-thalamic f i b r e s i n the cat r e s p e c t i v e l y . I t has been applied to human lobotomy material by Meyer ('49), Beck, Meyer and Le Beau ('51) and Martinez ( 55)* f  We w i l l now consider, the question - How can t h i s method be used so as to give as accurate and consistent r e s u l t s as possible? Three elements i n the answer to t h i s question can be i s o l a t e d * (1)  A method o f s i l v e r s t a i n i n g that w i l l give reasonably consistent  r e s u l t s must be used* (2)  The c r i t e r i a which are used to decide i f a given region contains  degeneration should be made as objective as possible* (3)  The method of presenting the r e s u l t s should be as accurate as these  c r i t e r i a allow.  To take these i n turns (1)  We have found that Gibson's modification of Rio-^Hortega's  impregnation technique gives the c e r t a i n precautions are taken. elsewhere  double-  consistent r e s u l t s providing that We have described the method i n d e t a i l  ( 55)• The main points are that the m a t e r i a l must be 1  properly f i x e d and that the pH and temperature o f the s i l v e r solutions must be kept within narrow l i m i t s . (2)  In a l l previous investigations the c r i t e r i a of deggaaeration have  been q u a l i t a t i v e and subjective.  Decisions as to whether degneration  i s , or i s not, present have been made on the basis of subjective comparisons with sections taken from the same region of a normal b r a i n . These subjective c r i t e r i a of degeneration are s i m i l a r f o r most workers. The f i e l d must contain large argentophile masses, e i t h e r s o l i d or thick-ringed, u s u a l l y of i r r e g u l a r shape and ( i n l a t e r cases) fragmenting.  The more regular of these are regarded as being  degenerating boutons termineaux and the more i r r e g u l a r , p a r t i c u l a r l y i f i n v i s i b l e continuity with a degenerating f i b r e , are regarded as being degenerating pre-terminal f i b r e s .  The two are subsumed under one  term - degenerating 'terminals'. The presence of degenerating f i b r e s i n the f i e l d has been regarded as more r e l i a b l e evidence that degeneration has taken place i n that f i e l d . As degeneration proceeds a progression from normal looped boutons to thickened, s o l i d , and l a s t l y fragmented boutons has been described (Hoff «32 a and b, Gibson '37, and others).  Hoff ('32a)  recognized a thickening (or f i l l i n g in) of the r i n g form of the bouton, swelling, granularity, i r r e g u l a r i t y of shape (often pear-shaped or  great elongation) and a darkness of s t a i n i n g as evidence of degeneration* Hoff ( 35) mentions only 'Progressive swelling and granulation followed f  1  by 'an e a r l y d i s i n t e g r a t i o n ' as signs of degenerating bouton  termineaux*  Gibson ('37) summarised the process of degeneration as f o l l o w s :  an  average degenerating bouton passes through the processes o f hypertrophy, elongation, fragmentation and granulation, and from the c i r c u l a r to the .•' e l l i p s o i d and back to the c i r c u l a r again.' Fedorow and Matwejewa ('35) described the following succession o f changes i n the degeneration of terminals i n the f r o g : Stage 1.  Increased argentophilia of f i b r e s and boutons*  Stage 2.  Swelling of f i b r e s and boutons.  Stage 3*.  V a r i c o s i t i e s appear on the f i b r e s .  Stage 4-*  Vacuolation appears i n the boutons* i n the autumn i n 11-12  This stage i s reached  days and i n the winter not u n t i l  25-30 days. Stage 5*  Disintegration* Glees and Le Gros Clark ('41) recognised swelling, thickening  or a f i l l i n g i n of the r i n g (often with a dense, opaque mass composed of a very fine n e u r o f i b r i l l a r ruetwork) and increased argentophilia as evidence of degeneration.  They noted that there was considerable  v a r i a t i o n i n the extent of degeneration, some terminal remaining quite small.  Swollen, argentophilic f i b r e s ( p a r t i c u l a r l y at t h e i r s i t e s of  branching i n t o the terminal d i v i s i o n s ) with ' c y l i n d r i c a l ' swellings i n t h e i r course were regarded as being degenerating*  Glees ('4-1) noted  that the normal terminal rings (present i n great numbers i n the l a t e r a l geniculate body of the cat) had mostly been transformed into thicker  rings or into s o l i d black bulbs which l a t e r disintegrated into small granules.  'In addition there are also to be seen oval or elongated  end-formations i n the substance o f which a strongly s t a i n i n g n e u r o f i b r i l l a r network i s v i s i b l e . '  Glees ('42) described s i m i l a r  changes i n the r a b b i t and i n the caudate nucleus of the c a t ('44) the degenerating  f i n e terminal f i b r e s were swollen ( p a r t i c u l a r l y where the  main f i b r e broke up into i t s terminal branches) and fragmented. Terminal  arborisations had a f i n e beaded appearance.  Meyer ('46) noted the following signs of degeneration  Glees, Meyer and a t the  termination o f i n j u r e d axons/ a thickening (or f i l l i n g i n ) o f the rings and the presence o f f i b r i l l a t e d r i n g structures.and a beading and granular d i s i n t e g r a t i o n o f f i n e f i b r e s followed by a d i s t i n c t r a r e f a c t i o n o f f i n e f i b r e plexus i n the cortex.  In the course o f the f i b r e s they  recognised a progressive swelling, ballooning and fragmentation o f thicker f i b r e s .  Le Gros Clark and Meyer ('47) used rigorous but s t i l l  subjective c r i t e r i a o f degneration.  They compared the region under  examination f i r s t with the unoperated side o f the same animal and also with the same region o f an e n t i r e l y normal rabbit's brain 'which had been f i x e d and stained under exactly the same conditions as the operated cases'.  Their c r i t e r i a o f s i g n i f i c a n t degeneration were 'a massive  degeneration  o f terminals, preterminals or unmyelinated f i b r e s ' followed  i n other experiments a f t e r a longer time i n t e r v a l by an a c t u a l l o s s o f f i b r e s i n the same r e g i o n .  They considered that the massive  degeneration,  when found, provided conclusive evidence o f terminal connexions but that i t s absence d i d not mean that no interrupted f i b r e s terminated i n the region.  7 Brodal ( 4-9) described degenerating boutons as 'more or less f  spherical, ovoid or more i r r e g u l a r , sometimes almost t r i a n g u l a r and argentophilic, sometimes with a l i g h t e r center*  11  enlarged  The degenerating  f i n e f i b r e s appeared as 'threads varying extremely i n c a l i b e r along t h e i r course, swollen globular,' spindle-shaped or ovoid parts being i n t e r connected with attenuated fragments of the o r i g i n a l f i b e r ' • showed vacuolisation and l a t e r fragmentation*  These  Brodal notes that Phalen  and Davenport ( ' 3 7 ) , Barnard ( ' 4 0 ) , Minckler (*U0) and others had claimed that the appearance o f normal terminal boutons may vary considerably and that 'pictures c l o s e l y resembling degenerated boutons may quite frequently be s e e n • 1  He therefore took no. account of  'Scattered structures with the morphological c h a r a c t e r i s t i c s of degenerating boutons,' but only of 'larger q u a n t i t i e s  1  of them*  He  l a i d more emphasis on 'the occurrence of f i n e degenerated terminal and preterminal f i b e r s than on degenerated boutons' and (as 'additional evidence') the 'very c l e a r cut loss of the f i n e f i b e r s which can be seen a f t e r 7 days or more • • •'.  Blackstad, Brodal and Walberg ('51) make a  further analysis of the method pointing out that 'The vagaries of the s i l v e r techniques are well-known' and that ' A l l authors studying normal terminal boutons agree that they are frequently d i f f i c u l t to i d e n t i f y . ' They also note that there i s not general agreement as to what i s , and what i s not, a degenerating bouton.  They bring t o notice one very  important f a c t , namely that the picture of terminal degeneration i s not the same everywhere.  A p a r t i c u l a r feature of t h e i r findings was, i n  some areas of the o l i v e , a great increase i n the number of stained boutons (from an average of 3 to as many as 25 per f i e l d ) and an increase i n the  8 proportion of large and s o l i d boutons and those of i r r e g u l a r shape* Whereas i n other regions of the o l i v e 'where pronounced a l t e r a t i o n s of f i n e nerve f i b r e s are evidence of marked terminal degeneration the number of boutons appears not to be r a i s e d * '  They conclude 'Only when the  increase of boutons i s exceptionally high i n experimental animals can an area of degeneration be determined on t h i s basis exclusively*  jfhis  i s the f i r s t time that we have come across the suggestion that the mere increase i n the number of boutons v i s i b l e may be used as an exclusive c r i t e r i o n of degenerationjj  In most instances the concomitant  degeneration of the f i n e s t f i b r e s i s a more r e l i a b l e sign*  An increased  number of s o l i d , degenerating boutons i s , however, s i g n i f i c a n t enough of terminal degeneration to be of p r a c t i c a l value•*  The  difficulties  here are ( i ) how large must the increase i n numbers be before i t can be considered s i g n i f i c a n t , and ( i i ) even within one nucleus there may be great differences of bouton concentration and morphology and so i t i s not s u f f i c i e n t to compare the degenerated with the normal unless both the extent of the v a r i a t i o n of the boutons i n d i f f e r e n t parts of one nucleus and i n the same parts of the same nucleus i n d i f f e r e n t brains i s known i n much more d e t a i l than i t i s at .present*  However, i t  must be noted that these same authors ('50) had previously only accepted the presence of degenerated fine f i b e r s as c r i t e r i a of degeneration* Wall, Glees and Pulton ('51) stated that i n view of 'the d i f f i c u l t i e s involved i n the f i n e - f i b r e s t a i n i n g technique, we have recognised degeneration as occurring only i n the following circumstancess f i r s t , when there was clear contrast between the operated and control sides stained simultaneously; second, when the section showed a clear  agranular background with discrete p a r a l l e l - s i d e d f i b r e s ; t h i r d , only gross d i s t o r t i o n s of f i b r e shape and termination were accepted as evidence of degeneration*  1  Adey ( 5 l ) does not give h i s c r i t e r i a of degeneration except f  to say that degenerating terminals are 'swollen * 1  Getz ('52)  states that 'provided that a comparison with  normal material i s c a r e f u l l y carried out and that also  degenerated  terminal f i b r e s are found - the differences between the normal and the degenerating structures are s u f f i c i e n t l y clearcut to allow an exact mapping out of the termination of transected f i b r e t r a c t s • '  His  c r i t e r i a f o r the degeneration of boutons are - an increase i n number of a l l types, e s p e c i a l l y of s o l i d black boutons, 'the shape of s e v e r a l boutons being oval and i r r e g u l a r * '  He states, however, that the.finding  of degenerated boutons alone i s not s u f f i c i e n t to allow the diagnosis of terminal degeneration '*•• t h i s diagnosis can only be made when degenerating terminal f i b r e s are also present'•  His c r i t e r i a of the  degeneration of terminal f i b r e s are a 'drop-like appearance ••• "beading v a c u o l i s a t i o n and an increased a f f i n i t y f o r s i l v e r . '  He would not  include f i b r e s distinguished only by'irregular contours and diameters'* Notice that Getz would only recognise degenerating f i b r e s as providing c e r t a i n evidence of degeneration whereas Brodal, Walberg and Blackstad would also recognise an 'exceptional' increase i n the number of boutons or 'an increased number of s o l i d , degenerating boutons and Le Gros Clark ('41) quote Schimert ('38)*  1  as w e l l *  Glees  '.JHe] considers that the  appearance of the end-bulb i t s e l f i s not always a safe c r i t e r i o n of degeneration, unless i t i s accompanied by degenerative changes a f f e c t i n g  10 the t e r m i n a l f i b r e which c a r r i e s i t . '  However, i t i s n o t always obvious  whether a g i v e n s t r u c t u r e i s a d e g e n e r a t i n g bouton o r t e r m i n a l f i b r e * Meyer  ('4-9),  u s i n g human lobotomy m a t e r i a l , f o l l o w e d t h e s e  c r i t e r i a o f degeneration  'gross changes o f axons and t e r m i n a l s ' ; i n  the case o f boutons the r i n g form had t o be c o m p l e t e l y f i l l e d i n and r e p l a c e d by ' l a r g e homogeneous o r d i s i n t e g r a t i n g s w e l l i n g s ' } , i n the  case  o f p r e t e r m i n a l f i b r e s t h e s e had t o be 'broken up i n t o f i n e d r o p l e t s ' } f i b r e s had t o show ' f r a g m e n t a t i o n and v a c u o l i s a t i o n t o g e t h e r w i t h a marked s w e l l i n g •*• i n t h e i r c o u r s e . '  Beck, Meyer and LeBeau  (*5l)  r e c o g n i s e d o n l y 'an a c c u m u l a t i o n o f g r o s s l y degenerated  f i b r e s and/or  terminals  furthermore  that  'as s i g n i f i c a n t o f d e g e n e r a t i o n .  They s t a t e d  'Negative f i n d i n g s i n a g i v e n a r e a c o u l d s a f e l y be r e g a r d e d a s  p r o o f o f the absence o f any f i b r e connexion w i t h the a b l a t e d o r i s o l a t e d region.'  (our i t a l i c s } ; see a l s o Le Gros C l a r k and Meyer  point).  Martinez  (*55)  ('4-7)  on-this  r e c o g n i s e s ' h y p e r a r g y r o p h i l i c ' f i b r e s and  ' h y p e r t r o p h i c ' boutons o r 'club-shaped'  t e r m i n a l s as b e i n g  degenerated.  (Note however t h a t i n our o p i n i o n the boutons shown i n h i s f i g u r e s 6 and 8 c o u l d w e l l be normal f o r the globus p a l l i d u s and the pons.) I t w i l l be n o t i c e d t h a t i n a l l the accounts g i v e n above the criteria  o f d e g e n e r a t i o n have been q u a l i t a t i v e and s u b j e c t i v e and  moreover have d i f f e r e d somewhat from worker t o worker (owing, to  probably  some e x t e n t , t o the d i f f e r e n t r e g i o n s and d i f f e r e n t s p e c i e s examined  and t o t h e d i f f e r e n t s t a i n s u s e d ) .  I t w i l l be c l e a r t h a t  consistent  and comparable r e s u l t s may n o t be o b t a i n e d i f d i f f e r e n t c r i t e r i a  are  used by d i f f e r e n t p e o p l e . (3)  The method o f p r e s e n t a t i o n o f the r e s u l t s .  I n the case o f n e a r l y  a l l workers the e v a l u a t i o n o f the extent o f the degeneration has been presented ( i ) by w r i t t e n r e p o r t s ; ( i i ) by means o f freehand drawings, or drawings made by some k i n d o f p r o j e c t i o n apparatus, on which the extent o f the degeneration i s marked by dots, cross-hatching, e t c * i n s e r t e d by freehand ( f o r examples see f i g u r e s 58-61); photomicrographs*  and ( i i i ) by  I n Hoff's f i r s t p r e s e n t a t i o n (>32a), however, dots  were used on a camera l u c i d a drawing o f the cord t o show the l o c a t i o n of a c e l l supporting degenerating boutons ( f i g . 56).  I n h i s next  presentation ('32b) round black dots were used t o show the p o s i t i o n . o f each c e l l supporting degenerating boutons, and b l a c k t r i a n g l e s showed the p o s i t i o n o f dendrites supporting degenerating boutons•  Crosses  were used t o show the p o s i t i o n o f p e r i d e n d r i t i c degenerated boutons o c c u r r i n g very close t o the c e l l body.  I n h i s 1935 paper the method  was the same but no crosses were used ( f i g . 5 7 ) . I t therefore seemed t o us t h a t , i n order t o make t h i s method more r i g o r o u s , more o b j e c t i v e c r i t e r i a o f degeneration should be attempted and more p r e c i s e methods o f presenting the extent o f degeneration hasevolved.  The s u b j e c t i v e and q u a l i t a t i v e e v a l u a t i o n o f  degeneration has given reasonably accurate r e s u l t s i n the hands o f experienced workers but there i s always the danger t h a t not a l l the p o t e n t i a l l y a v a i l a b l e information w i l l be gained from the i n v e s t i g a t i o n . That i s t o say t h a t f i n e r d e t a i l s o f d i s t r i b u t i o n o f severed f i b r e s may be l o s t t h a t might have been revealed by o b j e c t i v e and q u a n t i t a t i v e scanning methods*  Furthermore, u s i n g the l a t t e r methods, the r e s u l t s  of d i f f e r e n t workers could be compared w i t h more p r e c i s o n than could be a t t a i n e d when the c r i t e r i a t h a t each worker uses d i f f e r from those  used by other workers to a greater or l e s s e r extent.  However, to be of  much use, these c r i t e r i a would have to obtain general acceptance as i t would be o f l i t t l e advantage i f every worker s e t up h i s own objective c r i t e r i a of degeneration.  CHAPTER I I  MATERIAL AND METHODS  Four lobotomised human brains were available f o r t h i s study. L-l.  This b r a i n came from a case with a s u r v i v a l time of only f i v e  days and no signs of degeneration were found (except immediately around the wound) i n spite o f intensive search. L-2.  This brain was obtained from a case of bronchogenic carcinoma  who died aged 4-9 a t the time o f death.  A b i l a t e r a l p r e f r o n t a l lobotomy  was performed f o r i n t r a c t a b l e pain on A p r i l 11th, 1950.  The day  following the operation the patient was a l e r t but had nausea and was incontinent.  Four days a f t e r the operation he became dyspneic and  i r r a t i o n a l and he died on the seventh post-operative day. On examining the r i g h t side o f the b r a i n a leucotome entry mark could be seen on the extreme l a t e r a l edge of the o r b i t a l surface of the f r o n t a l lobe at the posterior end of the i n f e r i o r f r o n t a l gyrus. of the f r o n t a l lobe are shown i n f i g u r e s 1-3*  Coronal sections  The l e s i o n extended  upwards and forwards undercutting the eulaminate cortex o f the l a t e r a l surface of the f r o n t a l l o b e .  N i s s l stained sections showed that the  region of entry l a y j u s t anterior and l a t e r a l t o dysgranular  cortex.  On the l e f t the leucotome had entered a l i t t l e f a r t h e r forward i n the posterio-intermediate part o f the middle f r o n t a l gyrus.' . N i s s l stained sections showed that t h i s was a n t e r i o r t o dysgranular cortex.  The  l e s i o n extended forwards and upwards as on the r i g h t side (figs • 4.-6) • L-3.  This brain was obtained from a case of schizophrenia  type) 25 years o l d a t the time of death.  (paranoid  On November 6th, 194-7  b i l a t e r a l p r e f r o n t a l lobotomy was performed.  Four days l a t e r he  developed a temperature and a wound i n f e c t i o n was noticed. developed.  Meningitis  Seven days a f t e r the operation the patient died following  four generalised e p i l e p t i f o r m convulsions.  On examination o f the r i g h t  side o f the brain the entry o f the leucotome was v i s i b l e i n the middle o f the middle f r o n t a l gyrus i n Brodmann's area 9*  N i s s l sections  showed t h i s to be anterior to dysgranular cortex.  The l e s i o n extended  downward and backwards to enter the a n t e r i o r pole o f the corpus striatum ( f i g s • 7-9) •  The l e s i o n on the l e f t side was e s s e n t i a l l y  similar. L-4.  1  This b r a i n was obtained from a case o f schizophrenia  type) aged 43 a t the time o f death.  (hebephrenic  B i l a t e r a l p r e f r o n t a l lobotomy was  performed on August 17th, 1948 described as ' c o r t i c a l undercutting of areas 9 and 10.'  Twelve days a f t e r the operation the patient suddenly  collapsed and a s p i n a l puncture revealed a pressure of 500 mm. o f water.  An exploratory operation revealed extreme oedema o f the b r a i n .  On each side of the b r a i n the entry mark o f the leucotome was v i s i b l e i n the middle of the superior f r o n t a l gyrus on the dorsal convexity i n f r o n t o f the dysgranular cortex (confirmed by N i s s l s t a i n i n g ) .  The  l e s i o n extended downward and forward to the extreme f r o n t a l p o l e .  On  the r i g h t side the leucotome had penetrated the cortex again to emerge from the brain through the f r o n t a l p o l e .  On both sides the upper h a l f  of the p r e f r o n t a l region had been undercut including some damage to the cortex of the cingulate region.  There were also signs of recent  haemorrhage i n the anterior part of the corpus callosum.  Although the  leucotome entered eulaminate cortex and i t s path had extended  forwards,  15 there vas also brain damage (haemorrhage, softening and  discolouration)  extending backwards so as to cut into the r o s t r a l t i p of agranular cortex ( f i g s . 10-13). Each brain a r r i v e d f i x e d i n formalin and sectioned by the pathologist conducting the post-mortem examination.  Drawings of each  brain and each s l i c e of brain were made from d i f f e r e n t aspects. Sections from the f r o n t a l lobe cortex were cut on a f r e e z i n g microtome a t 20 u followed by sections taken to include the thalamus, hypothalamus and r e l a t e d structures; the red nucleus, substantia nigra and r e l a t e d structures; the basal ganglia and i n t e r n a l capsule; the hippocampus and amygdala; and the pons.  These sections were stained by Gibson's  modification of Rio-Hortega's double impregnation method. 10.6  At a pH  of  t h i s s t a i n also provides a good method o f determing cytoarchitectonic  features since, at t h i s pH,  the c e l l bodies are stained d i f f e r e n t i a l l y  with respect to the background. as well as Cresyl v i o l e t .  We have used t h i s as a ' N i s s l ' s t a i n  In the locations where degeneration  was  found accurate maps were prepared by p l o t t i n g the outline of the n u c l e i on graph paper from readings taken from the micrometer scale of the moving stage of the microscope.  The presence and extent of  degeneration were inserted as follows : (l)  Objective c r i t e r i a of degeneration were set up.  These c r i t e r i a  were chosen a f t e r studying a large number of sections from these brains (not L-4 which we did not receive u n t i l much l a t e r than the other three) together with sections of the same part taken from each of our three normal control brains and Purkis '55).  (NCI, NC2,  and NC3;  see Smythies, Gibson  In the case of the dorsomedial nucleus of the thalamus  the following c r i t e r i a were decided upon? (i)  One u n i t of degeneration was defined as a dark purple"* object i n -  the f i e l d l a r g e r than 2.5 u i n average diameter;  e i t h e r s o l i d or, i f  perforated, the diameter of the hole (or holes) was not to exceed l / 3 of the t o t a l diameter of the object; and possessing an homogeneous i n t e r n a l structure (studies of brains with longer s u r v i v a l times than ours would presumably have to allow f o r the f i n a l stage of fragmentation)* I f there were two units of degeneration i n a f i e l d  (using a x 100  objective and a x 8 ocular) that f i e l d was marked on the map as a black dot i n i t s p o s i t i o n obtained from the co-ordinates given by the micrometer scale on the moving stage of the microscope*  Traverses  were taken across the section at i n t e r v a l s that varied depending the size of the s e c t i o n . examined.  on  Every consecutive f i e l d on each traverse was  In most cases the f a c t that the degenerated terminal was  l a r g e r than 2.5 u could be judged by eye; i n case o f doubt i t was measured by means of a micrometer eye-piece.  Typical u n i t s of  degeneration are shown i n figures 52-55 and 64-65• We examined a t o t a l of approximately 6,00Q f i e l d s i n the dorso-medial nucleus i n our three control brains without f i n d i n g 2 units of degeneration i n a single field. (ii)  Maps of the c o n t r o l brains would therefore merely be blank. In the pontine n u c l e i these same c r i t e r i a proved to be quite  unsuitable as this region normally contains a large number of bouton  Dark purple using t h i s stains t h i s c r i t e r i o n excludes p a r t i c l e s of m e t a l l i c p r e c i p i t a t e which are j e t black and c o l l o i d globules which are l i g h t purple and have moreover a l e s s clearcut outline than have terminals. x  tera&neaux per f i e l d with a f a i r number f u l f i l l i n g the c r i t e r i a given above*  Figure 50 shows a section from a normal pons mapped according  to these c r i t e r i a .  After examining sections from L-4, which alone o f  our brains appeared to show some degeneration i n the pontine n u c l e i , the following c r i t e r i a were chosen.  On the map a f i e l d was shown as  containing degeneration i f there were more than 50 boutons termineaux and 'degenerating terminals' o f a l l kinds i n the f i e l d together with an obvious thinning o f the normal plexus o f f i n e unmyelinated ( f i g s . 70-71).  fibres  Although f i e l d s with more than 25 boutons per f i e l d  are frequent i n the normal pons as figure 50 shows we d i d not see any f i e l d s i n the normal with as many as 50 boutons per f i e l d .  But as we  do not y e t know the extent o f i n d i v i d u a l v a r i a t i o n i n t h i s respect we introduced the second c r i t e r i o n - the thinning o f the f i b r e plexus although t h i s re-introduces a subjective element i n t o the c r i t e r i a . We were unable however to construct a workable objective c r i t e r i o n f o r the 'thinning' o f a f i b r e plexus. (iii)  In the medial nmamillary nucleus the c r i t e r i a were f i x e d a t two  u n i t s o f degeneration per f i e l d as i n ( i ) together with an obvious thinning and fragmentation o f the normal plexus o f f i n e unmyelinated f i b r e s as i n ( i i ) ( f i g . 74-) •  I t was noticable that the products o f  degeneration i n t h i s region were not as large, nor d i d they s t a i n so darkly as those seen i n ( i ) and ( i i ) . (iv)  We were unable to reach s a t i s f a c t o r y objective c r i t e r i a f o r  degenerating f i b r e s .  The mere size o f the swellings along the course  of the f i b r e would presumably depend to some extent on the i n i t i a l size of the f i b r e .  Fragmentation, vacuolisation and heightened a r g y r o p h i l i a  18  do not lend themselves readily to recordable quantitative treatment which would not at the same time be unworkably clumsy. In our figures the presence of degenerating fibres was shown where there was more than one fibre i n the f i e l d which appeared to be grossly degenerated (showing increased argyrophilia, gross fusiform or more irregular swellings i n their course, vacuolisation and fragmentation)• (2) A method of presenting the information was developed so as to show, as nearly as possible, the actual position of each area of degeneration i n the part concerned.  This was done by preparing accurate maps of  the part by means of readings taken on the micrometer stage of the microscope transferred to graph paper and the exact position of each f i e l d showing degeneration could then be inserted on the map after taking similar readings.  19 CHAPTER i n RESULTS  L-l.  As we mentioned above no degeneration was found anywhere i n t h i s  brain, except immediately around the wound where the appearance was the same as has been described previously i n the l i t e r a t u r e .  Meyer ('4.9)  found no evidence o f degeneration i n a human case with a s u r v i v a l period o f s i x days. L-2 and L-3. In each side of both these brains the extent of the degeneration was very s i m i l a r s (i)  Thalamus.  On each side of L-2 twelve coronal sections a t  approximately equal spacing through the dorso-medial nucleus were examined and maps were prepared from nineof these on each side, s i x of which are shown i n figures  14-19 (R) and four i n figures 20-23 ( L ) .  On the r i g h t side o f L-3 twelve such sections were examined and maps prepared from eight o f these, seven of which are shown i n figures 24-30. On the l e f t side of L-3 and L-4 (extreme posterior part) two such sections were examined and were found to be e s s e n t i a l l y s i m i l a r to those taken from the same p o s i t i o n on the r i g h t side o f these brains.  In  L-2 (R and L) and L-3 R two additonal sections anterior to the r o s t r a l l i m i t of the dorso-medial nucleus and one section posterior to i t s caudal l i m i t were examined. Each of these sections included the f u l l extent o f the thalamus, a l l n u c l e i o f which were included i n the regular scanning.  Maps were only prepared o f regions showing degeneration.  Figures 14-30 show representative examples o f these maps and these show that there was degeneration i n the middle s t r i p o f the dorso-medial  nucleus along almost i t s whole length ( f i g . 64)*  This degeneration  was more marked i n the dorsal part of t h i s s t r i p than i n the v e n t r a l part p a r t i c u l a r l y r o s t r a l l y . L-2  (R) than i n the others.  but was not confined to i t .  I t extended a l i t t l e farther forward i n I t was mostly i n the small-celled part In any case the boundary between the two  portions of the nucleus i s not always c l e a r cut and so we have described the region of degeneration r e l a t i v e to the extent of the whole nucleus. The most medial and the most l a t e r a l portions of the nucleus have escaped the degeneration. submedius.  The apparent  No degeneration was seen i n the nucleus 'degeneration  1  marked i n the nucleus  p a r a f a s c i c u l a r i s i s not true degeneration as a comparison with the normal nucleus shows ( f i g s .  51 and 66-67). This merely  demonstrates,  as has been previously reported (Smythies, Gibson and Purkis '55). that the nucleus p a r a f a s c i c u l a r i s i s unique amongst the thalamic n u c l e i i n having a r e l a t i v e l y large number of large dark boutons termineaux and i s thus not a suitable l o c a t i o n i n which to apply c r i t e r i a of degeneration appropriate to the other thalamic n u c l e i . (ii)  Pre f r on to-pontine tract:.  In L-2 a few f i b r e s were seen  degenerating i n the course of the fronto-pontine t r a c t (as; described by Beck '50).  In L-3 many such f i b r e s were seen degenerating  below the i n f e r i o r l i m i t of the l e s i o n ( f i g s . 35 and 68).  immediately The number  of degenerating f i b r e s seen r a p i d l y decreased the further caudal to the l e s i o n the section was taken ( f i g s .  35-4-0). No d e f i n i t e signs of  degeneration were seen i n the pons (compare f i g . 41 with f i g . 50). (iii)  Elsewhere.  No degeneration was seen i n s i x sections through  the hypothalamus i n each b r a i n nor was there any to be seen i n numerous  sections through the other n u c l e i l i s t e d above i n e i t h e r b r a i n .  L-4. (i)  Thalamus.  Twelve sections spaced through the dorso-medial nucleus  were examined and maps were prepared from seven of these, four of which are shown i n figures 31-34-• figure 65.  The type of degeneration i s shown i n  I t w i l l be seen that the extent and type of degeneration i s  e s s e n t i a l l y s i m i l a r to that seen i n the other two b r a i n s . One point of i n t e r e s t i s the heavy degeneration seen i n the extreme posterior end of the nucleus i n the region of the p u l v i n a r . As no such heavy degeneration was seen i n this region i n brains L-2 and L-3 t h i s provides some evidence that the medial aspect of the f r o n t a l eulaminate cortex (undercut only i n L-4) projects p a r t i c u l a r l y to the posterior end of the dorso-medial nucleus.  On the other hand the place of o r i g i n of  these f i b r e s might be i n the most posterior part of the eulaminate cortex i n the dorsal convexity, also affected only i n L-4..  No degeneration was  seen elsewhere i n the thalamus. (ii)  Prefronto-pontine t r a c t .  Figures 42-4.6 and 69-71  show that the  extent and nature of degeneration of the prefronto-pontine t r a c t and i n the pons i s not s i g n i f i c a n t l y d i f f e r e n t from that reported by other workers.  One possibly s i g n i f i c a n t point i s the heavier degeneration  i n the upper l / 3 of the pons than i n the r e s t of the pons.  I t should  be noted that the sections made by the pathologist i n t h i s brain were not true coronal sections but were very oblique being p a r a l l e l to that part of the f o r n i x that runs through the hypothalamus. (iii)  Hypothalamus and elsewhere.  Four sections through the mamillary  body were examined three of which are shown i n figures 47-49.  The type  and extent of the degeneration (figs.~ that reported by Meyer ('49) antero-posterior difference*  72-74)  was e s s e n t i a l l y s i m i l a r to  except that there was a l e s s cleareut A small bundle of degenerating f i b r e s  was found running down beside the f o r n i x i n the i n f e r i o r thalamic r a d i a t i o n ( f i g * 47)  possibly on i t s way to the mamillary body.  No  degeneration was seen i n four other sections examined through the . hypothalamus and septal n u c l e i *  There was no degeneration seen i n the  caudate nucleus, putamen, globus p a l l i d u s , substantia nigra, subthalamus, zona i n c e r t a or Forel's f i e l d s nor i n four sections taken a t equal i n t e r v a l s along the whole length of the hippocampus*  In the red  nucleus there were more (normal looking) boutons than we had seen i n our normal controls but i n the absence of any other signs of degeneration a mere increase i n the number of boutons can not be regarded as evidence o f degeneration u n t i l much more i s known about the extent of normal v a r i a t i o n between d i f f e r e n t parts of the same nucleus i n one brain and the same parts of the same nucleus i n d i f f e r e n t brains* Cortex j An examination was also made of the extent of degeneration i n the cortex*  In L - l and L-2,  a l l parts o f the cortex and i n L-2 were examined*  68 sections ( i n each) from  40 sections from the f r o n t a l cortex  No signs of degeneration were found except  around the wound ( f i g s *  62-63)*  immediately  I t was noticed that the same general  features of bouton d i s t r i b u t i o n and morphology that we have reported previously were present i n these brains*  In L-4  20 sections of the  f r o n t a l lobe and 7 sections of the o c c i p i t a l and adjoining portions o f the p a r i e t a l and temporal lobes were examined*  In the former  degenerating terminals were seen as has been described by previous  authors, progressively decreasing i n number from layer 6 outwards, the l a t t e r no degeneration was seen.  CHAPTER TV' DISCUSSION These r e s u l t s confirm previous reports that the  eulaminate  cortex of the p r e f r o n t a l region projects to the dorso-medial nucleus of the thalamus*  The extent o f t h i s degeneration i s shown i n our f i g u r e s *  The minor variations i n the d i s t r i b u t i o n of degeneration i n these three brains may prove to have significance i f compared with the r e s u l t s of many more such i n v e s t i g a t i o n s .  The most marked of the variations l i e s  i n the heavy degeneration i n the extreme posterior part of the nucleus i n the only case where the l e s i o n undercut the cortex on the medial aspect of the hemisphere and extended to the most p o s t e r i o r part of the eulaminate  cortex on the dorsal convexity.  We were unable to  confirm previous reports (Meyer'49, Martinez '55) that the nucleus submedius i s also involved*  The morphology of the boutons i f l the  normal nucleus p a r a f a s c i c u l a r i s ( f i g s . 65-66) should be taken into account i n evaluating the presence of degeneration i n this.nucleus and i n the rather i l l - d e f i n e d region between i t and the nucleus submedius* Our r e s u l t s also confirm Meyer's observation ('4-9) that a l e s i o n encroaching upon the granular cortex on the dorsal convexity of the f r o n t a l lobe projects to the medial mamillary body, p a r t i c u l a r l y i t s ventral part. hypothalamic  Our r e s u l t s also confirm that there are no s i g n i f i c a n t  connexions from purely eulaminate regions of the f r o n t a l  lobe outside the o r b i t a l regions (which were not affected i n any of our specimens)•  The prefronto-pontine t r a c t i s also involved i n a l l  oxer brains showing degeneration.  The heavier involvement i n L-4  may  25 merely be an i n d i c a t i o n of the noci-fugal spread of degeneration i n f i b r e tracts shown c l e a r l y i n t h i s t r a c t i n L-3 and described i n the r a b b i t by Glees, Meyer and Meyer (*4-7). We have also attempted to s e t up objective quantitative c r i t e r i a of degeneration and have u t i l i s e d a mapping method of p l o t t i n g the l o c a t i o n of degeneration.  However, these c r i t e r i a are not yet  completely objective as we could not f i n d s a t i s f a c t o r y quantitative c r i t e r i a f o r f i b r e degeneration nor f o r the d i s i n t e g r a t i o n of a f i n e unmyelinated f i b r e plexus. The l o c a l differences i n the picture of degeneration seen are also i n t e r e s t i n g .  In the dorso-medial nucleus of the thalamus the  tendency was to produce large (often 3-5 u) s o l i d , or nearly s o l i d , masses without much sign of any fragmentation of the f i n e unmyelinated plexus ( f i g s . 52-55).  I t was also noteworthy that the picture seen a t  12 days hardly d i f f e r e d from that seen a t 7 days.  In the medial  mamillary body the picture of degeneration was a marked d i s i n t e g r a t i o n of the fine unmyelinated f i b r e plexus i n t o a large number of argentophil masses, mainly s o l i d , but on the average considerably smaller (and less argyrophilic) than those seen i n the dorso-medial nucleus and often not much more than beads ( f i g . 1U) •  In the pons  there was an increase i n the number of boutons seen (with a high proportion of larger terminals) together with a fragmentation and disappearance of the f i n e unmyelinated f i b r e plexus ( f i g s . 70-71). This account only describes what may be seen at c e r t a i n periods a f t e r the i n j u r y .  Examinations a t other post-operative periods might be  expected to give d i f f e r e n t microscopic p i c t u r e s .  /  26 F i n a l l y , f r o m our s t u d y o f t h e n o r m a l d i s t r i b u t i o n and morphology o f boutons t e r m i n e a u x we c a n t e n t a t i v e l y s u g g e s t t h a t o u r • d o r s o - m e d i a l * c r i t e r i a a r e s u i t a b l e f o r a l l p a r t s o f the f o r e b r a i n e x c e p t t h e n u c l e u s p a r a f a s c i c u l a r i s o f the t h a l a m u s , t h e  mesocortex,  s u b s t a n t i a n i g r a and globus p a l l i d u s , and p a r t s o f the a m y g d a l o i d complex*  A r e a U o f t h e n e o c o r t e x and the s u b i c u l u m m i g h t g i v e r i s e  some d i f f i c u l t i e s o f i n t e r p r e t a t i o n *  to  I n the m e d i a l m a m i l l a r y body the  s i z e and d e p t h o f s t a i n i n g o f the p r o d u c t s o f d e g e n e r a t i o n were n o t so marked as t o r e n d e r t h e c r i t e r i a o f d e g e n e r a t i o n based s o l e l y on t h i s f e a t u r e as c e r t a i n as one w o u l d w i s h t h u s n e c e s s i t a t i n g the i n c l u s i o n o f fragmentation o f the f i n e f i b r e p l e x u s .  T h i s disadvantage  might  a l s o be e n c o u n t e r e d i n o t h e r n u c l e i i n w h i c h we d i d n o t have the o p p o r t u n i t y of examining degeneration.  S p e c i f i c c r i t e r i a c a n o n l y be  s e t up f o r e a c h n u c l e u s and c o r t i c a l a r e a a f t e r a t h o r o u g h s t u d y o f t h e f o r m o f d e g e n e r a t i o n i n e a c h p a r t - a n d o f the f o r m o f t h e n o r m a l s y n a p t i c morphology i n each p a r t .  27 CHAPTER V SUMMARY  A study has been made of the extent of terminal i n four lobotomised brains using a s i l v e r method.  degeneration  We have confirmed  previous reports that the eulaminate cortex of the f r o n t a l lobe outside the o r b i t a l region projects e x c l u s i v e l y to ( i ) the dorso-medial nucleus of the thalamus and vre have l o c a l i s e d t h i s p r o j e c t i o n to a s t r i p along the median part of the nucleus i n the greater part of i t s length, and ( i i ) to the pontine n u c l e i .  In one brain the l e s i o n  encroached upon agranular cortex and here degeneration was also found i n the medial mamillary body but not elsewhere.  Differences i n the  microscopic appearance o f terminal degeneration i n the various regions has also been described.  We have also paid p a r t i c u l a r attention to  the method o f terminal degeneration i t s e l f and have endeavoured to place this on a more objective basis, using quantitative c r i t e r i a of degeneration wherever p o s s i b l e .  28 BIBLIOGRAPHY  ADEY, W. R. " 1951 An experimental study o f the hippocampal connexions of the cingulate cortex i n the r a b b i t .  Brain, 24•* 233-247.  BARNARD, R. I . 1940 Experimental changes i n end-feet o f Held-Auerbach i n the s p i n a l cord o f the c a t .  J . Comp. Neur., 23.: 235-266.  BECK, E . 1950 The o r i g i n , course and termination o f the prefrontopontine t r a c t i n the human b r a i n . BECK, E., A. METER AND J . LE BEAU  Brain, 22: 368-391.  1951 E f f e r e n t connexions o f the  human p r e f r o n t a l region, with reference t o fronto-hypothalamic pathways.  J . Neurol. Neurosurg. Psychiat., 14: 295-302.  BLACKS TAD, T., A. BRODAL AND F. WALBERG  1951 Some observations on  normal and degenerating terminal boutons i n the i n f e r i o r o l i v e  of the c a t . Acta Anat., 11: 461-477. BRODAL, A.  1949 S p i n a l afferents to the l a t e r a l r e t i c u l a r nucleus o f  the medulla oblongata i n the c a t .  An experimental study.  J . Comp. Neur., °1: 259-295. BRODAL, A., T. BLACKSTAD AND F. WALBERG  1950  Termination o f s p i n a l  afferents to i n f e r i o r o l i v e i n c a t .  J . Neurophysiol., 13:  431-454. CAJAL, S. RAMON Y  1911 Los fenomenos precoces de l a degeneracion  traumatica de l o s c i l i n d r o s - e j e s d e l cerebro. d i i n v e s t , b i o l . Madrid, 2  s  39-95.  ^ Papers not a c t u a l l y consulted are marked with a s t a r .  Trab. d e l Lab.  29 CLARK, W. E . LE GROS, AND M. MEYER  194-7 The terminal connexions o f the  o l f a c t o r y t r a c t i n the r a b b i t .  Brain, 70: 304.-328.  DE CASTRO, F. 1930 Recherches sur l a degeneration e t l a regeneration du systeme nerveux sympathetique•  Quelques observations sur  l a constitution des synapses dans l e s ganglions.  Trab. d e l  Lab. d i i n v e s t , b i o l . Madrid, 26 : 357-4-56. FEDOROW, B. G., AND S. J . MATWEJEWA  1935 La structure des connexions  interneuronales dans l e systeme nerveux autonome de l a grenouille.  Trav. Lab. Resherches B i o l . Univ. Madrid, _{0:  378-4-01. GETZ, B. 1952 The termination o f spinothalamic f i b r e s i n the cat as studied by the method o f terminal degeneration.  Acta Anat.,  16: 271-290. GIBSON, W. C. 1937 Degeneration o f the boutons terminaux i n the spinal cord.  An experimental study.  Arch. Neurol, and Psychiat.,  28: 1L45-1157. 194-0  Degeneration and regeneration o f sympathetic synapses.  J . Neurophysiol.,  2i 237-247.  GLEES, P. 1941 The termination o f o p t i c f i b r e s i n the l a t e r a l geniculate  body of the c a t . J . Anat., 7j_: 4-34-44-0. 1942  The termination o f o p t i c f i b r e s i n the l a t e r a l geniculate  body of the r a b b i t . .1944  J . Anat.,  76: 313-318.  The anatomical basis o f c o r t i c o - s t r i a t e  connections.  J . Anat., 7J_: 47-51. GLEES, P. AND W. E . LE GROS CLARK  1941 The termination of o p t i c f i b r e s  i n the l a t e r a l geniculate body o f the monkey.  295-308.  J . Anat., 75:  30 GLEES, P., A. MEIER AND M. MEYER  194-6  Terminal degeneration i n the  f r o n t a l cortex o f the r a b b i t following the i n t e r r u p t i o n o f afferent f i b r e s . HOFF, E . C.  1932 a  J . Anat., 80: 101-106.  Central nerve terminals i n the mammalian s p i n a l  cord and t h e i r examination by experimental degeneration. Proc. Roy. Soc. Lond. B., J^i 1932 b  175-188.  The d i s t r i b u t i o n o f the s p i n a l terminals  (boutons)  of the pyramidal t r a c t , determined by experimental degeneration. Proc. Roy. Soc. Lond. B.,  226-237. i  1935  C o r t i c o s p i n a l f i b r e s a r i s i n g i n the premotor area o f  the monkey.  D i s t r i b u t i o n o f bouton terminations. Arch. Neurol.  and Psychia't., 22.'- 689*697. LAWEENTJEW, B. J . 1934- Experimentell-morphologische Studien tlber den feineren Bau des autonomen Nervensystems weitere Unter suchungen fiber die Degeneration und Regeneration der Synapsen. Zrschr. f . mikr. anat. Forsch., 25_: LEVI, G.  1932  71-118.  Uber das mutmassliche Bestehen von sympathischen  i n den k r a n i a l e n und spinalen ganglien. Arbeit von F. Kiss, Anat. Anz., 22: MARTINEZ, A.  1955  194.9  Bernerkungen zu einer  187-190.  Some e f f e r e n t connexions of the human f r o n t a l l o b e .  J . Neurosurg., MEYER, M.  Zellen  12,: 18-25.  Study o f efferent connexions o f the f r o n t a l lobe i n the  human brain a f t e r leucotomy. MINCKLER, J . 194.0  Brain, 22:  265-296.  The morphology of the nerve terminals o f the human  s p i n a l cord as seen i n block s i l v e r preparations, with estimates of the t o t a l number per c e l l .  Anat. R e c , 22*  9-25.  31 NIKOLA JEW, W.  1893 Zur Frage die innervation des Froschherzens. Arch.  f . P h y s i o l . Suppl., 67-73. PHALEN, G. S., AND H. %.. DAVENPORT  1937 P e r i c e l l u l a r end-bulbs i n the  central nervous system o f vertebrates.  J . Comp. Neur., 68:  67-81. RANSON, S. W., AND P. R. BILLINGSLEY  1918 The superior c e r v i c a l  ganglion and the c e r v i c a l portion o f the sympathetic t r a c t .  J . Comp. Neur., .22: 313-358. SCHIMERT, J . 1938 Die Endigungsweise des Tractus Ztschr. f . Anat. u . Entwicklungsgesch., SERENI, E., AND J . Z. YOUNG i n cephalopods.  vestlbulospinalis.  108: 761-767.  1932 Nervous degeneration and regeneration  Pubbl. d. stazione Z o o l . d i Napoli, 12*  173-208. SMYTH EES, J . R., W. C. GIBSON AND V. A. PUREES  1955 The d i s t r i b u t i o n  and morphology o f boutons termineaux i n the human cerebrum. J . Comp. Neur!., i n press. TUCKETT, I . L . 1896 On the structure and degeneration o f non-myelinated nerve f i b r e s .  J . Physiol.,  12* 267-311.  WALL, P. D., P. GLEES AND J . F. FULTON  1951 Corticofugal connexions o f  posterior o r b i t a l surface i n Rhesus monkey.  Brain", 24 66-71. s  i  Fig.  1  Fig.  2  Fig. k  Fig. l_.  5  Fig. 6  Fig. 7  I I  1  e  i  Fig.  8 !  I  Fig. 9  e  Fig. 10  Fig.  ir  r  ! Fig.  j  12  1  !  F i  e° ^  ;  : Fig. 15  ]  1  F i g . 17  Fig. 18  Fig. 20 i  I  i F i g . 21  F i g . 22  ! Fig. I  23  )  I Fig i  r I Fig.  i  26  1  F i g . 27  A.M.  M.T.  Pa Cv  M  I I F i g . 33  )  F i g . 34.  :  F i g . 35  F i g . 36  F i g . 39  F i g . A3  Fig.  U  I Fig. i  Ul  F i g . 48'  Fig. 49  i  1  F i g . 51  t I  F I G . 4A.  F I G . 4B.  F I G . 4 A . — A n outline of the right half of the spinal cord at the seventh post-thoracic segment, from a cat completely de-afferented on the right side of the lumbar enlargement. The drawing was made from six sections, and each dot represents a cell upon which degenerating boutons were found. Cat 2, operation 2. (Camera lucida drawing.) F I G . 4 B . — A diagram showing the manner of termination of afferent nerves in the grey matter of the cord suggested by the location of degenerated boutons in the grey matter of de-afferented cords. The way i n which cells in the mid-region connect w i t h ventral horn cells is not suggested, as implied by the broken line.  ram. Fig. 4 (experiment 2).—Sections of the spinal cord at the seventh cervical and sixth postthoracic segments, showing the distribution of bouton degeneration in the spinal gray matter of a macaque killed four days after ablation of the right premotor area. The black circles and triangles have the same significance as in figure 2. (The diagram was drawn with a projector.)  rn.c.  ventral ii't titr  dorsal forelimb hindlimb  F i g . 7 T o tin- left :i composite d i a g r a m of the findings in this study. The t e r m i n a l iiroii of fillers f r o m tlic cervical segments is indicated by rings, the area for fibers f r o m below mid-thoracic by dots ( f o r tlie sake of s i m p l i c i t y termed f o r e l i m l i a n d h i n d l i m b a r e a s ) . T o tlie r i g h t ;i series of transverse sections through the latci'iil reticnliir nucleus showing the d i s t r i b u t i o n of retrograde cell changes f o l l o w i n g :i p a i a v c r m i a n incision of tlie cerebellum ( " 4 3 ) . B l a c k denotes areas m a x i m a l l y changed, cross hatchings intermediate, a n d simple hatchings s l i g h t l y changed areas. T h e figures of the sections to the right refer to their order in the complete d i a g r a m in the previous paper, and the heavy horizontal lines indicate the level of each section with reference to tlie l o n g i t u d i n a l sections to the left. A b b r e v i a t i o n s , as in figure  Via. A. Diagram of findings in cat .Sp. C . L . 12. Lesion of cord at C_. . Above, series of horizontal sections through inferior olive. Its different parts are indicated (abbreviations as in Kig. 1). Dotted areas show parts in which terminal degeneration of fibers and boutons is present, density of dots giving an approximate impression of intensity of degeneration. Wavy vertical lines indicate coarse ascending degenerated fibers. Below, two sections through spinal cord; left, drawing of superimposed cell-stained sections from Cj_ , showing total extent of lesion (hatchings); right, diagram of ascending degenerated fibers seen in Marchi sections from C , . L: left. H: right. N.r.l.: Lateral reticular nucleus. ;  ;i  F i g . 59  Fig. 2. Diagram of the findings in oat Sp. C. L . 21. Lesion nf the cord at C|. Above, series of frontal sections through the thalamus. The main nuclei are indicated as in figure 1. The dotted areas show where terminal degeneration is present, and the density of the dots give an approximate impression of the intensity of the degeneration. Below, a section through the spinal cord at C • showing the lesion. The area totally damaged is indicated black, areas partly damaged are hatched. v  Sp.CL21 Ci'  ) F i g . 60 |  r  i  I  FIG. 16 {Case 4).  i i  i F i g . 61 '•  F i g . 62  F i g . 63  F i g . 64.  I  F i g . 65  F i g . 66  F i g . 67  F i g . 68  F i g . 69  F i g . 71  

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