Btam Research, 95 (1975) 25-38 c(~ Else',ler Scientific Pubhshmg Company, Amsterdam - Printed m The Netherlands
25
S O M E C O N N E C T I O N S O F T H E E N T O R H I N A L ( A R E A 28) A N D P E R I R H I N A L ( A R E A 35) C O R T I C E S O F T H E R H E S U S M O N K E Y 11 F R O N T A L L O B E A F F E R E N T S *
GARY W VAN HOESEN**, DEEPAK N PANDYA** AND NELSON BUTTERS Hat yard Neurological Umt, Boston City Hospital Boston, Mass 02118 attd Aphasia Research Centel, Department of Neurology, Boston UntveratO, Medical Sckool, Boston, Ma~s 02130 ( U S A )
(Accepted March 10th, 1975)
SUMMARY
I n this m v e s t l g a h o n , the efferent c o r t l c o - c o r t l c a l p r o j e c t i o n s o f the o r b l t o f r o n t a l cortex in the rhesus m o n k e y have been investigated using silver i m p r e g n a t i o n m e t h o d s P r o j e c t i o n s f r o m this a r e a were o b s e r v e d to t e r m i n a t e m the rostral p o r t i o n s o f the t e m p o r a l lobe (areas T A , T E a n d T G ) a n d c m g u l a t e gyrus (area 24), the insular cortex, a n d some d o r s o l a t e r a l p r e f r o n t a l areas A l t h o u g h these c o n n e c t i o n s characterlzed all areas, with the exception o f W a l k e r ' s area 14 a n d Bonln a n d Bailey's a r e a F L , the c a u d a l levels o f the o r b l t o f r o n t a l area were f o u n d to give rise to an a d d i t i o n a l p r o j e c t i o n which t e r m i n a t e d in the e n t o r h l n a l cortex a n d the t r a n s i t i o n a l cortices b o r d e r i n g the rhlnal sulcus The source o f this p r o j e c t i o n c o r r e l a t e d closely wIth an a r e a l a b e l e d F F by Bonln a n d Bailey This c o n n e c t i o n m a y p r o v i d e a m u c h m o r e direct m e a n s for the frontal lobe to Influence the h~ppocampus t h a n those l n v o l w n g the c m g u l a t e gyrus
INTRODUCTION
In a previous r e p o r t z4 the origin o f some sources o f afferent i n p u t to the entorhlnal (area 28) a n d p e r l r h l n a l (area 35) cortices o f the rhesus m o n k e y were described The focus o f that investigation centered on n e o c o r t l c a l a n d l lmblc cortical regions o f the ventral t e m p o r a l lobe as p o t e n t i a l afferent sources for these areas It was p o i n t e d out t h a t o n l y B r o d m a n n ' s areas 51, 35, 49, 27, a n d B o n l n a n d Bailey's 3 area T F - T H were f o u n d to project directly to the classical subareas o f e n t o r h m a l cortex (areas 28a a n d 28b) A l l areas, however, o f the ventral t e m p o r a l neocortex were f o u n d to con* A prehmmary report regardmg some of the findings described here has been previously pubhshed z5 ** Present address Harvard Neurological Unit, Beth Israel Hospital, Boston, Mass 02215, U S A
26 tribute at least some afferents to the perlrhmal and prorhlnal tranb~tlonal cortices bordering the rhlnal sulcus These connections were characterized as possible hnal relays m mult~synapttc pathways hnkmg the entorhmal cortex and, ultimately, the hlppocampus to the association areas of the frontal, parietal, occipital and temporal lobes In view of these findings it ~s also essential to enqmre whether the frontal lobe, and in particular its prefrontal subdwlSlOn, might also be directly linked anatomically to the perlrhlnal and entorhlnal cortices Since previous mvesttgatlons 1 16,~7 have found httle evidence for such direct connections from frontal dorsolateral granular and agranular regions, this report deals with the efferent cort~co-cortlcal connections of the orb~tofrontal portton of the frontal cortex in the rhesus monkey METHODS
Surgtcal procedure The histological material was from the brains of 10 young-adult rhesus monkeys After a frontal cranlotomy and the administration of 40 ml of 25 ~ manmtol (OsmItrol), each monkey recewed a undateral cortical ablation by subptal aspwatlon while under Nembutal anesthesm To expose the area, the monkey was placed on its side w~th its head elevated Gutta percha was then inserted between the dura mater overlying the orbit and the cortex After the overall volume of the brain decreased following the mannItol, small pieces of sahne-soaked cottonold were inserted beneath the gutta percha to elevate the orbltofrontal area. When the area to be ablated was visuahzed, the remaining areas of the orbitofrontal cortex were protected wtth gutta percha and the ablation was made
Htstologtcal procedures The histological processing and subsequent hght microscopic analysis were ldenhcal to that described previously 24 Briefly, after a 6-12-day survwal period and a month's fixation in 10~o formahn, the brains were embedded in an albumin and gelatin matrix and sliced on a freezing m~crotome Sections were stained according to the Nauta 15, Flnk and Helmer 7, and N~ssl methods (cresyl violet) The topography of the ablation and evidence of degenerahon were charted with the use of an X-Y recorder Th~s reformation was reconstructed onto tracings from photographs of the dorsal, lateral, ventral and medial views of each brain
At chttectural orgamzatton of the orbttofrontal area Walker 26 parcellated the orbltofrontal area of the rhesus monkey into 5 cytoarch~tectonlcally distinguishable subareas (see Fig 1A), and his map provides a useful starting point for the analysis of efferent connections from this area Walker's area 10 ~s located on the ventral aspect of the frontal pole and extends onto both the dorsolateral and me&al portions of the hemisphere Area 11 is located along the lateral aspect of the orbltofrontal area caudal to area 10. Its medial limit is defined by the rostral portion of the medml orbital sulcus and its caudal limit by the fronto-orbital
27 A r e a 13
A
/ 14
CASE I
ORBITOFRONTAL AREA
CASE 2
o,--',, J CASE .3
~......_]~
-
rs
Fig 1 A this Illustration depicts the conventional ventral view of orbltofrontal area and the rostral temporal lobe in the rhesus monkey It has been redrawn from Walker's23 map, and the approximate locahzatlon of his various cytoarchltectomc subareas xs indicated by half tones and hatching B, this illustration shows the topography of the regional ablatmns m cases 1-4 on the orbltofrontal surface of the frontal lobe The general pattern of terminal degeneratmn observed for a case is depicted by dots
sulcus A r e a 12 is located c a u d a l to a r e a 11, however, u n h k e the latter extends o n t o the d o r s o l a t e r a l surface o f the h e m i s p h e r e This a r e a Is b o u n d e d m e d i a l l y by the fronto-orb~tal sulcus, whereas c a u d a l l y it merges w~th the l n s u l o t e m p o r a l cortex A r e a 13 ~s p o s i t i o n e d m e d i a l l y a n d c a u d a l l y w~thln the o r b i t o f r o n t a l area Its m e d m l h m l t is u s u a l l y well-defined b y the m e d i a l o r b i t a l sulcus a n d its lateral hm~t b y the c a u d a l p o m o n o f the f r o n t o - o r b ] t a l sulcus L i k e a r e a 12 it merges with the msulot e m p o r a l cortex Lastly, W a l k e r ' s a r e a 14 ~s a n a r r o w strip o f cortex confined to the extreme m e d m l a n d c a u d a l p o r t i o n s o f the a r e a It hes b e n e a t h the o l f a c t o r y tract and b o r d e r s the o l f a c t o r y tubercle at c a u d a l levels L a t e r a l l y , it Js b o u n d e d by the c a u d a l o n e - h a l f o f the m e d i a l o r b i t a l sulcus, while r o s t r a l l y it a d j o i n s a r e a 10 T h e efferent s u b c o r t i c a l a n d c o r t i c o - c o m c a l c o n n e c t i o n s o f some p o m o n s o f the orb~tofrontal a r e a m the rhesus m o n k e y have been r e p o r t e d p r e w o u s l y x6 A d d i t i o n a l l y , a n o t h e r Investigation dealing with the efferent c o n n e c t m n s o f b e h a v i o r a l l y defined sectors o f th~s a r e a has also been r e p o r t e d 1° A l t h o u g h these investigations shed h g h t
28 on the subcortlcal connections of the orbltofrontal area, they do not allow a dehnm~e evaluatmn of the archltectomc parcellanon proposed by Walker -'f' from the poml ol view of c o m c o - c o m c a l connections Therefore, m this report attentmn will be locu~ed on the dlfferentml cortlco-comcal connectmns of the orbltofrontal area, and especmll? the relationship that th~s area has w~th the entorhmal and penrhmal areas of the temporal lobe RESULTS
Regional ablation of the orbttoft ontal area As indicated above, the topographical boundaries between the orbltofrontal subareas in Walker's scheme are closely related to the sulcal pattern of the three majol sulcl of this area (Fig 1A) Although the pattern depicted in his map is no doubt applicable to a population of rhesus monkeys, considerable variation was encountered during surgery when an Individual monkey was considered To obviate this difficulty, the first 4 cases received large regional ablations which involved two or more of Walker's subareas The results from these cases are summarized in Fig 1B Case 1 had a large ablation confined to areas 10 and 11 It was p n m a r d y localized to the ventral aspect of the frontal lobe, however, did extend onto the dorsolateral surface of the hemisphere where the lower bank of the rostral one third of the principal sulcus was damaged Considerable white matter damage was assocmted with this ablation Case 2 received a superficial ablation largely medial to the medial orbital sulcus The caudal portions of area 10 as well as a sizable portion of area 14 were damaged Superficlal damage was also observed on the lateral bank of the medial orbital sulcus ind,caring that areas 11 and 13 were hkewlse partially revolved Caudally, the ablation encroached into the olfactory tubercle but spared the olfactory tract and the more laterally located frontal p r e p m f o r m cortex As depicted in Fig 1B, case 3 had a caudally placed ablation in the medial portion of the orbltofrontal area Area 13 was heavily damaged as well as the caudal aspects of area 12 and the medial portions of area 14 Case 4 had a large ablatmn which damaged the medial and caudal aspects of areas 10, ! 2, 13 and 14 Area 11 was not damaged, and although the ablation bordered paraolfactory areas, no damage was observed The white matter underlying area 14 was heawly revolved, undercutting the ventral portmns of area 24 and 25 located on the medml wall of the hemisphere The general dlstrlbutmn of degeneratmn elicited from these ablatmns was remarkably similar, and portions of the overall patterns observed are summarized m Fig IB on ventral wews of the hemispheres In terms of local connections, all unablated regions of the orbltofrontat, and to some extent the dorsolateral prefrontal cortex contained moderate to heavy fiber and terminal degeneration The latter was predominantly assocmted w~th layer IV and decreased as it was followed dorsally within the prefrontal area With the exception of case 1, where the ablatmn was confined to areas 10 and 11, the superior prefrontal lobule, and especmlly its caudal regions, contained little evidence of degeneration. The cortex of the arcuate concavity contained terminal degeneratmn in only those cases involving areas 12 No degenera-
29 tlon was observed caudal to the arcuate sulcus m the frontal agranular cortex (areas 4 and 6) in any of the cases On the medial wall of the hemisphere heavy degeneration was observed in the ventral portions of area 24, and m area 25 in cases 2, 3 and 4 Terminal degeneration here was associated w~th a dense band of degenerating fibers which ascended vertically rostral to the genu of the corpus callosum A few fibers from this pathway continued dorsally and joined the cmgulum bundle where they took a dorsal posMon These were dlstNbuted to area 24 dorsal to the corpus callosum No degenerating fibers or terminals were observed caudal to this area within the clngulate gyrus In case 1, a similar d~strlbutlon of degeneration was observed, although it was hghter than that of the caudally and medially placed ablations Evidence for distal connections from these ablations could be localized m the rostral portions of the insular cortex and temporal lobe areas TA, TG, TE, 28 and Pr2 in cases 2, 3 and 4 Terminal degeneration in the insular cortex was more moderate and diffuse m all cases except case 4 where a heavy quantity was observed This was correlated with the fact that the ablation extended caudally into the rostral msulotemporal cortex while the other ablations did not Ewdence of heavy terminal degeneration was always conspicuous m area TG and the rostral portions of area TE The degeneration in area TE was largely confined to the middle temporal gyrus, or that cortex forming the lower bank and depths of the superior temporal sulcus Th~s was continuous with terminal degeneration in area TA along the upper bank of the same sulcus This degeneration extended laterally into the superior temporal gyrus at only rostral levels The inferior temporal gyrus contained only hght evidence of termination m these cases The laminar distribution of degeneration observed m area TA was particularly notable In all other projection fields of the orbltofrontal area, with the exception of area 24, the insular cortex, and to some extent area TG, evidence of terminal degeneration was always assocmted with layer IV In area TA, howe~er, an additional band of terminal degeneration was observed m layer I This pattern disappeared in the depths of the superior temporal sulcus where areas TA and TE merge Surprisingly, the cort~co-cortlcal projections were remarkably slmdar for all cases depicted in Fig 1B, although the primary locus of the ablations differed relative to Walker's parcellatlon of the orb~tofrontal area A major exception was that m cases 2, 3 and 4 conspicuous terminal degeneration (see Fig 5c) was observed m area 28b of entorhmal cortex and m the prorhmal cortex along the medial bank of the rhlnal sulcus (Fig 5e) Area 35 (perlrhlnal cortex) along the lateral bank of the rhmal sulcus contained only light termination In all 3 cases the terminal degeneration in area 28b was confined to only layer III In the prorhlnal and perlrhmal cortex, it was d~ffuse and spread across all laminae In the former, however, the deeper layers contained a greater quantity of terminals These observations suggest that whde the cortlco-cortlcal connections of the orbltofrontal areas as a whole are quite similar, some regional parcellatlon of this cortex can be drawn on the basis of d~rect connections to the perlallocortex of the uncus Since case l, the only regional ablation not observed to have connections to areas 28 and 35, had extensive damage to orbltofrontal areas 10 and I l, these areas
30 CASE
5
II I_....-I..~_
CASE 6
DE
~II
_Y[ /
/~[
C. --
I
~
\\
~i , . i_ q - ~ l ''-~
I:
123
Amg
4 Zo
s
A.
2
CASE 7
CASE 8 ~ [
0A
'
;~1~,,,
.
/
oh,-" oA
Fig 2 A this dlustratlon depicts the topography of the restricted ablations m cases 5-8 on the orbttofrontal surface of the frontal lobe The two series of transverse sections (1-3) were taken from cases 5 and 6, and their approximate levels correspond to the numerals shown on the orb~tofrontal views of the frontal lobe for these cases The general pattern of terminal degeneration obserced for a case is depicted by dots B this dlustratlon summarizes the observed projections to the entorhmal, prorhinal, and pertrhmal cortices after the various orbltofrontal ablations Specific dots and arrows are not meant to ~mply pathways or point to pomt projections, but only the general s~te of o n g m for a projection and the cytoarchltectomcally defined region w~thm which ~t terminates,
31 may be ruled out as the o n g m of these projections The precise origin of these connections, however, cannot be ascertained in cases 2, 3 and 4, since all had ablation damage m areas 12, 13 and 14, and obwously one or all of these areas could have given rise to the observed projections Re~tt lcted ablations o f the ot bttof~ ontal at ea Cases 5-8 (Fig 2A) received smaller ablations of the orbitofrontal area m an effort to restrict the damage to a single cytoarchltectonlcally defined area In case 5, the ablation was localized in area 12 caudal to the fronto-orbltal sulcus Medially the ablation extended into the superficial lamina of area 13, but this region was largely spared Case 6 received a superficial ablation primarily in the caudal portions of area 13 Laterally, the medial and caudal portions of area 12 were damaged Additionally, this ablation extended caudally for a few millimeters into the lnsulotemporal cortex In case 7, a narrow ablation was made which was locahzed m area 14 and the caudal levels of area 10 Unlike the larger regional ablation of these areas there was little accompanying white matter involvement Case 8 received a centrally located ablation within the orbltofrontal area primarily confined to the caudal portions of area 11 and the rostral levels of area 13 As illustrated in Fig 2A, the distribution of degeneration elicited from these ablations was similar to that observed following the larger regional ablations The major exception observed occurred in case 7 where only sparse evidence of terminal degeneration was found in the rostral portions of areas TA and TE As with the regional ablations, only the medially and caudally located restricted ablations had terminal degeneration in the entorhlnal, prorhlnal, and perlrhlnal cortlces The localization of termination was also identical m these cases, occurring d~ffusely m the perlrhmal and prorhmal cortex, but discretely m layer llI of area 28b (Fig 5d) In case 8, where the caudal portions of area 11 and rostral portions of area 13 were damaged, no evidence of degeneration was observed m these areas These results (Fig 2B) suggest that the caudal levels of areas 12, 13 and 14 give rise to d~rect projections to the entorhmal, prorhlnal, and per~rhmal cortices of the temporal lobe In wew of the rarity, however, of d~rect connections from neocortex to entorhlnal cortex, ~t ~s essential to rule out potential confounding factors that could have contributed to this result As indicated above, white matter involvement was observed along the medial border of some ablations This could disrupt efferent fibers oNgmatlng from the medial surface of the hemisphere and coursing to the temporal lobe via an orbltofrontal-unclnate fasclculus route Additionally, for some ablations, the olfactory tract was mechanically manipulated e~ther in an effort to protect it, or to ablate area 14 beneath ~t Although this was not consistently correlated w~th terminal degeneration In area 28b, ~t ~s nonetheless essential to define the extent to which this may have affected the results Ablations o f areas 24 and 25 and olfactory tt act pt ojectlons As Illustrated in Fig 3, case 9 received a large ablation of the medial portion of the frontal lobe dorsal and ventral to the subcallosal sulcus Ventrally, Walker's area 10 was damaged and the olfactory tract partially transected N o evidence of degenera-
32
OASE,Ofl
ill "
I
" ~ , ~
('~---'~ ~--' II I
/-~>
. I ~
/'-\
"o
"~ "~,'b( \ ] "-J---" " - ' "
Fig 3 This illustration depicts the locahzatlon of the ablations m cases 9 and 10 on medml and ventral views of the hemisphere The general pattern of terminal degeneration observed for a case is depicted by dots Note the partial transection of the olfactory tract in case 9, and its total transection in case 10 tlon was observed m areas 28b, Pr2, or 35 In case t0 (Fig 3) the olfactory tract was totally transected caudal to the olfactory bulb and rostral to its attachment to the orbitofrontal area In this case, as well as case 9, degenerating fibers or terminals were readily identified m the olfactory tubercle, frontal and temporal prepmform cortex, and the periamygdalold cortex dorsal and ventral to the amygdaloid sulcus, but no degeneration was observed in area 28b, Pr2, and 35
Tl ajectory of orbltoentorhmal J~bers In all cases except case 10, the uncmate fasclculus contamed fiber degeneration that was traceable caudally into the temporal lobe Our results indicate that the orbltoentorhmal projections travel for a short distance in the uncmate fasciculus Following a caudal orbttofrontal ablation (Fig 4D and E) a diffuse stream of degenerating fibers could be observed leaving the medial portion of the uncmate bundle dorsal to the amygdala These fibers formed small bundles and could be traced ventrally lateral to the amygdala (Fig 5a) and into the white matter of area 28b dorsal to the depths of the rhmal sulcus (Fig 5b) From this p o s m o n they ascended into the entorhmal cortex and terminated in layer Ill (Fig 5c-d) This trajectory was noted in all orbltofrontal cases having terminal degeneration m area 28b What this pathway should be labeled after leaving the uncmate fasciculus would appear open to conjecture Clearly, at rostral levels these fibers are located medial to the temporal extension of the claustrum (Fig 4D) and, by analogy to more dorsal levels of the brain, could be considered a ventral but diffuse component of the external capsule At more caudal levels, however, they would also appear to travel m the ventral and lateral p o m o n s of the anterior commissure (Fig 4E)
33 A
B
C
)' olf tr
olf tr
If
D
E
\ If
ylf
rs~sts F~g 4 A - E m this allustratlon 5 transverse sections taken from case 6 depict the fiber trajectory of some orbatofrontal projectaons The levels of these sections correspond to those denoted by letters for case 6 m Fag 2 In each sectaon the arrow mdacates the most compact portion of the uncmate fa.scacu]us at that level Terminal degenerataon as depicted by dots and fiber degenerataon by short hnes Note m sectaon D, that fibers destined for the entorhanal cortex appear to leave the compact port~on of the unclnate fasc~culus dorsal and lateral to the amygdala
DISCUSSION
The orbJtofrontal area is a u m q u e region of cerebral cortex for several anatomical reasons Fibers originating here are dlstrlbuted to widespread regions of brain including the brain stem 12,14, mldbraln la, dlencephalon and strlatum 1°,13,16 Additionally, the orbltofrontal area is rectprocally connected with the magnocellular portion o f the dorsomedlal thalamlc nucleus 2,16, and is one of the few regions o f ricocortex that sends fiber projections directly to the h y p o t h a l a m u s l°,16 Our results appear to contribute another unique anatomical feature, m that the orbltofrontal area has been found, as suggested by Cragg's 6 results m cats, to contribute direct afferents to one of the classical subareas o f entorhlnal cortex Thus, it is one o f only two neocortical regions we have f o u n d having such connections By virtue o f the heavy con-
34
Fig 5 a fiber degeneration dorsal and lateral to the amygdala following an orbltofrontal (case 4) ablation 120 b fiber degeneration ascending out of the white matter beneath the entorhmat and prorhlnal cortices (case 4) 620 c and d depict terminal degeneration m layer II[ of the entorhmal cortex (28b) m cases 4 and 6 e depicts terminal degeneration m layers V and VI of the prorhlnal cortex m case 4 400 (Fmk and Hezmer stare )
nectlons between this area of the entorhmal cortex and the hlppocampus 8, these findings imply that potentially the orbltofrontai area might exert conszderable influence on this allocortlcal area Although there is disagreement among investigators regarding the cytoarchltectonic orgamzatlon of the orbltofrontal areas, Walker's 26 more discrete parcellatlon was chosen for this investigation since it more fully afforded the opportumty to assess possible differential cortlco-cortlcal connections He dtvlded the orbltofrontal area of the rhesus monkey into 5 subareas and labeled them area 10, 1 1, 12, 13 and 14 in a later report, Bonm and Barley 3 rejected th~s scheme and instead dw~ded the area into only two portions w~th one, area FD, subsuming Walker's areas 10, 1 1, 12 and the rostral portion o f h l s area 13, and the other, area FF, corresponding to the caudal portions of area 13 The orb~tofrontal portion of area F D was deemed continuous with the neocortex of the inferior prefrontal lobule Area FF was set aside as a separate subarea, since according to Bonm and Barley 3, the tuner granular layer (lamina IV) is
35 poorly developed and occupied in part by pyramidal cells The caudal and medial portion of the orbltofrontal area in the rhesus monkey (Walker's area 14) was not acknowledged by Bonln and Bailey either, since it was felt to be continuous with and identical in architecture, to an area they labeled FL on the medial surface of the hemisphere ventral to the subcallosal sulcus The results described here indicate that in terms of local connections, the orbltofrontal area sends projections to the cortex forming the medial wall of the hemisphere as well as to the cortex forming the inferior prefrontal lobule, ventral to the principal sulcus None of the various subareas except areas 10 and 11 were observed to contribute afferents to the caudal portions of the superior prefrontal lobule, but all ablations led to terminal degeneration in the cortex of the frontal pole Distal connections from the various ablations were always observed in the rostral lnsula, area 24 (the rostral clngulate gyrus), and areas TE and T G of the temporal lobe The extreme rostral portions of area TA contained evidence of terminal degeneration in all cases except those in which the ablation was largely confined to the medial portion of areas 10 and 14 These areas also appear to project only minimally to area TE as well In so far as cortlco-cortlcal connections are concerned, most of Walker's various subareas of the orbltofrontal area were found not to give rise to widely divergent differential projections The topographical distribution of degeneration from all areas, with the exception of area 14, was remarkably similar It IS significant that virtually the same conclusion was reached by Johnson et al to, in regard to differential subcortlcal connections from the orbltofrontal area in the rhesus monkey We cannot, however, confirm these author's observations of orbltofrontal projections to the caudal clngulate gyrus or directly into the hlppocampus None of our cases contained any evidence of either fiber or terminal degeneration in these areas The most conspicuous aspect of the results was that medially and caudally placed orb~tofrontal ablations consistently led to terminal degeneration in the lateral portion of the entorhlnal cortex (area 28b) and the transitional prorhlnal and perlrhlnal (area 35) cortices forming the walls of the rhlnal sulcus The focus for this projection would seem to be the caudal levels of Walker's area 13, or specifically Bonln and Bailey's area FF We cannot, however, rule out the fact that the caudal levels in areas 12 and 14 may also contribute some projections to these areas This general region has long been recognized as having so-called hmblc cytoarchltectual characteristics 8 11 2o 2z,2v and our observations regarding its connections would be concordant with such views However, like the clngulate gyrusl, 19, and the parahlppocampal area T F - T H 24,25, which also give rise to perlallocortlcal projections, these areas and area FF also give rise to projections to other neocortlcal areas Certainly this anatomical feature of their organization should not be overlooked because of their unique relationship with the llmblc system Curiously the hmblc nature of area F F ' s connection IS not dlstlngmshed by projections to the nearby insular cortex, since all regions of the orb~tofrontal area appear to project there, instead, it is distinguished by direct projections to the entorhlnal cortex, a classical penallocortlcal area There is a distinct correlation between the orbltofrontal projections described
36 here and the c y t o a r c h a e c t o m c parcellatlon ot this area proposed by Bonm and Bafle) Their orbltofrontal p o m o n of area F D corresponds to an area from whJch we did not observe &fferential projectmns Slmdarly, their area FL corresponds to an area whose connectmns appear d~fferent from those of area F D And finally, their area F F ~orresponds to that orb~tofrontal area from which we have observed projections &rectly to the entorhmal cortex It as s~gmficant that the posterome&al orb~tofrontal area appears to be the anatomical focus for a behavioral change characterized by enhanced averswe reactions and reduced aggressive responses m threatening s~tuat~ons 5 A d & tlonally, ablations of thB area y~eld &fferentlal behavioral changes relanve to ablations confined to other areas of the orbltofrontal 4 9 and dorsolateral prefrontal areas a Nauta ~ emphasized that the orb~tofrontal area, by wrtue of heavy connections with the temporal neocortex, could exert considerable influence on the amygdala in contrast, the dorsolateral prefrontal cortex, wa connections w~th the cmgulate gyrus and presublculum, was thought to be more associated with the hlppocampal system The results described here extend these observations, however, they do dlmmBh thB &stmctmn by demonstrating a direct connection from the orNtofrontal area to the entorhmal cortex, an area heawly connected to the hlppocampus s A d d m o n a l l y , our observations of orbltofrontal projections to area 24, and projections from thB area to the lateral basal amygdalold nucleus ~s also m&cate that the orb]tofrontal area can potentially affect the amygdala wa two quite separate routes Since the cortex of both the supermr and inferior prefrontal lobule projects to area 24 as well ~, a slgmficant p o r t m n of the output of the dorsolateral and orb~tofrontal prefrontal cortex ~s &rected toward cortical afferent sources of both the amygdala and h~ppocampus A less &rect avenue of input to the h~ppocampus ~s achieved by &rect projectmns from the orb]to-
NeocorhcaI-Dmb~cCorticalConnechons
~
DmblcCort~caI-DmblcCorticalConnechons
25
S O M E C O N N E C T I O N S O F T H E E N T O R H I N A L ( A R E A 28) A N D P E R I R H I N A L ( A R E A 35) C O R T I C E S O F T H E R H E S U S M O N K E Y 11 F R O N T A L L O B E A F F E R E N T S *
GARY W VAN HOESEN**, DEEPAK N PANDYA** AND NELSON BUTTERS Hat yard Neurological Umt, Boston City Hospital Boston, Mass 02118 attd Aphasia Research Centel, Department of Neurology, Boston UntveratO, Medical Sckool, Boston, Ma~s 02130 ( U S A )
(Accepted March 10th, 1975)
SUMMARY
I n this m v e s t l g a h o n , the efferent c o r t l c o - c o r t l c a l p r o j e c t i o n s o f the o r b l t o f r o n t a l cortex in the rhesus m o n k e y have been investigated using silver i m p r e g n a t i o n m e t h o d s P r o j e c t i o n s f r o m this a r e a were o b s e r v e d to t e r m i n a t e m the rostral p o r t i o n s o f the t e m p o r a l lobe (areas T A , T E a n d T G ) a n d c m g u l a t e gyrus (area 24), the insular cortex, a n d some d o r s o l a t e r a l p r e f r o n t a l areas A l t h o u g h these c o n n e c t i o n s characterlzed all areas, with the exception o f W a l k e r ' s area 14 a n d Bonln a n d Bailey's a r e a F L , the c a u d a l levels o f the o r b l t o f r o n t a l area were f o u n d to give rise to an a d d i t i o n a l p r o j e c t i o n which t e r m i n a t e d in the e n t o r h l n a l cortex a n d the t r a n s i t i o n a l cortices b o r d e r i n g the rhlnal sulcus The source o f this p r o j e c t i o n c o r r e l a t e d closely wIth an a r e a l a b e l e d F F by Bonln a n d Bailey This c o n n e c t i o n m a y p r o v i d e a m u c h m o r e direct m e a n s for the frontal lobe to Influence the h~ppocampus t h a n those l n v o l w n g the c m g u l a t e gyrus
INTRODUCTION
In a previous r e p o r t z4 the origin o f some sources o f afferent i n p u t to the entorhlnal (area 28) a n d p e r l r h l n a l (area 35) cortices o f the rhesus m o n k e y were described The focus o f that investigation centered on n e o c o r t l c a l a n d l lmblc cortical regions o f the ventral t e m p o r a l lobe as p o t e n t i a l afferent sources for these areas It was p o i n t e d out t h a t o n l y B r o d m a n n ' s areas 51, 35, 49, 27, a n d B o n l n a n d Bailey's 3 area T F - T H were f o u n d to project directly to the classical subareas o f e n t o r h m a l cortex (areas 28a a n d 28b) A l l areas, however, o f the ventral t e m p o r a l neocortex were f o u n d to con* A prehmmary report regardmg some of the findings described here has been previously pubhshed z5 ** Present address Harvard Neurological Unit, Beth Israel Hospital, Boston, Mass 02215, U S A
26 tribute at least some afferents to the perlrhmal and prorhlnal tranb~tlonal cortices bordering the rhlnal sulcus These connections were characterized as possible hnal relays m mult~synapttc pathways hnkmg the entorhmal cortex and, ultimately, the hlppocampus to the association areas of the frontal, parietal, occipital and temporal lobes In view of these findings it ~s also essential to enqmre whether the frontal lobe, and in particular its prefrontal subdwlSlOn, might also be directly linked anatomically to the perlrhlnal and entorhlnal cortices Since previous mvesttgatlons 1 16,~7 have found httle evidence for such direct connections from frontal dorsolateral granular and agranular regions, this report deals with the efferent cort~co-cortlcal connections of the orb~tofrontal portton of the frontal cortex in the rhesus monkey METHODS
Surgtcal procedure The histological material was from the brains of 10 young-adult rhesus monkeys After a frontal cranlotomy and the administration of 40 ml of 25 ~ manmtol (OsmItrol), each monkey recewed a undateral cortical ablation by subptal aspwatlon while under Nembutal anesthesm To expose the area, the monkey was placed on its side w~th its head elevated Gutta percha was then inserted between the dura mater overlying the orbit and the cortex After the overall volume of the brain decreased following the mannItol, small pieces of sahne-soaked cottonold were inserted beneath the gutta percha to elevate the orbltofrontal area. When the area to be ablated was visuahzed, the remaining areas of the orbitofrontal cortex were protected wtth gutta percha and the ablation was made
Htstologtcal procedures The histological processing and subsequent hght microscopic analysis were ldenhcal to that described previously 24 Briefly, after a 6-12-day survwal period and a month's fixation in 10~o formahn, the brains were embedded in an albumin and gelatin matrix and sliced on a freezing m~crotome Sections were stained according to the Nauta 15, Flnk and Helmer 7, and N~ssl methods (cresyl violet) The topography of the ablation and evidence of degenerahon were charted with the use of an X-Y recorder Th~s reformation was reconstructed onto tracings from photographs of the dorsal, lateral, ventral and medial views of each brain
At chttectural orgamzatton of the orbttofrontal area Walker 26 parcellated the orbltofrontal area of the rhesus monkey into 5 cytoarch~tectonlcally distinguishable subareas (see Fig 1A), and his map provides a useful starting point for the analysis of efferent connections from this area Walker's area 10 ~s located on the ventral aspect of the frontal pole and extends onto both the dorsolateral and me&al portions of the hemisphere Area 11 is located along the lateral aspect of the orbltofrontal area caudal to area 10. Its medial limit is defined by the rostral portion of the medml orbital sulcus and its caudal limit by the fronto-orbital
27 A r e a 13
A
/ 14
CASE I
ORBITOFRONTAL AREA
CASE 2
o,--',, J CASE .3
~......_]~
-
rs
Fig 1 A this Illustration depicts the conventional ventral view of orbltofrontal area and the rostral temporal lobe in the rhesus monkey It has been redrawn from Walker's23 map, and the approximate locahzatlon of his various cytoarchltectomc subareas xs indicated by half tones and hatching B, this illustration shows the topography of the regional ablatmns m cases 1-4 on the orbltofrontal surface of the frontal lobe The general pattern of terminal degeneratmn observed for a case is depicted by dots
sulcus A r e a 12 is located c a u d a l to a r e a 11, however, u n h k e the latter extends o n t o the d o r s o l a t e r a l surface o f the h e m i s p h e r e This a r e a Is b o u n d e d m e d i a l l y by the fronto-orb~tal sulcus, whereas c a u d a l l y it merges w~th the l n s u l o t e m p o r a l cortex A r e a 13 ~s p o s i t i o n e d m e d i a l l y a n d c a u d a l l y w~thln the o r b i t o f r o n t a l area Its m e d m l h m l t is u s u a l l y well-defined b y the m e d i a l o r b i t a l sulcus a n d its lateral hm~t b y the c a u d a l p o m o n o f the f r o n t o - o r b ] t a l sulcus L i k e a r e a 12 it merges with the msulot e m p o r a l cortex Lastly, W a l k e r ' s a r e a 14 ~s a n a r r o w strip o f cortex confined to the extreme m e d m l a n d c a u d a l p o r t i o n s o f the a r e a It hes b e n e a t h the o l f a c t o r y tract and b o r d e r s the o l f a c t o r y tubercle at c a u d a l levels L a t e r a l l y , it Js b o u n d e d by the c a u d a l o n e - h a l f o f the m e d i a l o r b i t a l sulcus, while r o s t r a l l y it a d j o i n s a r e a 10 T h e efferent s u b c o r t i c a l a n d c o r t i c o - c o m c a l c o n n e c t i o n s o f some p o m o n s o f the orb~tofrontal a r e a m the rhesus m o n k e y have been r e p o r t e d p r e w o u s l y x6 A d d i t i o n a l l y , a n o t h e r Investigation dealing with the efferent c o n n e c t m n s o f b e h a v i o r a l l y defined sectors o f th~s a r e a has also been r e p o r t e d 1° A l t h o u g h these investigations shed h g h t
28 on the subcortlcal connections of the orbltofrontal area, they do not allow a dehnm~e evaluatmn of the archltectomc parcellanon proposed by Walker -'f' from the poml ol view of c o m c o - c o m c a l connections Therefore, m this report attentmn will be locu~ed on the dlfferentml cortlco-comcal connectmns of the orbltofrontal area, and especmll? the relationship that th~s area has w~th the entorhmal and penrhmal areas of the temporal lobe RESULTS
Regional ablation of the orbttoft ontal area As indicated above, the topographical boundaries between the orbltofrontal subareas in Walker's scheme are closely related to the sulcal pattern of the three majol sulcl of this area (Fig 1A) Although the pattern depicted in his map is no doubt applicable to a population of rhesus monkeys, considerable variation was encountered during surgery when an Individual monkey was considered To obviate this difficulty, the first 4 cases received large regional ablations which involved two or more of Walker's subareas The results from these cases are summarized in Fig 1B Case 1 had a large ablation confined to areas 10 and 11 It was p n m a r d y localized to the ventral aspect of the frontal lobe, however, did extend onto the dorsolateral surface of the hemisphere where the lower bank of the rostral one third of the principal sulcus was damaged Considerable white matter damage was assocmted with this ablation Case 2 received a superficial ablation largely medial to the medial orbital sulcus The caudal portions of area 10 as well as a sizable portion of area 14 were damaged Superficlal damage was also observed on the lateral bank of the medial orbital sulcus ind,caring that areas 11 and 13 were hkewlse partially revolved Caudally, the ablation encroached into the olfactory tubercle but spared the olfactory tract and the more laterally located frontal p r e p m f o r m cortex As depicted in Fig 1B, case 3 had a caudally placed ablation in the medial portion of the orbltofrontal area Area 13 was heavily damaged as well as the caudal aspects of area 12 and the medial portions of area 14 Case 4 had a large ablatmn which damaged the medial and caudal aspects of areas 10, ! 2, 13 and 14 Area 11 was not damaged, and although the ablation bordered paraolfactory areas, no damage was observed The white matter underlying area 14 was heawly revolved, undercutting the ventral portmns of area 24 and 25 located on the medml wall of the hemisphere The general dlstrlbutmn of degeneratmn elicited from these ablatmns was remarkably similar, and portions of the overall patterns observed are summarized m Fig IB on ventral wews of the hemispheres In terms of local connections, all unablated regions of the orbltofrontat, and to some extent the dorsolateral prefrontal cortex contained moderate to heavy fiber and terminal degeneration The latter was predominantly assocmted w~th layer IV and decreased as it was followed dorsally within the prefrontal area With the exception of case 1, where the ablatmn was confined to areas 10 and 11, the superior prefrontal lobule, and especmlly its caudal regions, contained little evidence of degeneration. The cortex of the arcuate concavity contained terminal degeneratmn in only those cases involving areas 12 No degenera-
29 tlon was observed caudal to the arcuate sulcus m the frontal agranular cortex (areas 4 and 6) in any of the cases On the medial wall of the hemisphere heavy degeneration was observed in the ventral portions of area 24, and m area 25 in cases 2, 3 and 4 Terminal degeneration here was associated w~th a dense band of degenerating fibers which ascended vertically rostral to the genu of the corpus callosum A few fibers from this pathway continued dorsally and joined the cmgulum bundle where they took a dorsal posMon These were dlstNbuted to area 24 dorsal to the corpus callosum No degenerating fibers or terminals were observed caudal to this area within the clngulate gyrus In case 1, a similar d~strlbutlon of degeneration was observed, although it was hghter than that of the caudally and medially placed ablations Evidence for distal connections from these ablations could be localized m the rostral portions of the insular cortex and temporal lobe areas TA, TG, TE, 28 and Pr2 in cases 2, 3 and 4 Terminal degeneration in the insular cortex was more moderate and diffuse m all cases except case 4 where a heavy quantity was observed This was correlated with the fact that the ablation extended caudally into the rostral msulotemporal cortex while the other ablations did not Ewdence of heavy terminal degeneration was always conspicuous m area TG and the rostral portions of area TE The degeneration in area TE was largely confined to the middle temporal gyrus, or that cortex forming the lower bank and depths of the superior temporal sulcus Th~s was continuous with terminal degeneration in area TA along the upper bank of the same sulcus This degeneration extended laterally into the superior temporal gyrus at only rostral levels The inferior temporal gyrus contained only hght evidence of termination m these cases The laminar distribution of degeneration observed m area TA was particularly notable In all other projection fields of the orbltofrontal area, with the exception of area 24, the insular cortex, and to some extent area TG, evidence of terminal degeneration was always assocmted with layer IV In area TA, howe~er, an additional band of terminal degeneration was observed m layer I This pattern disappeared in the depths of the superior temporal sulcus where areas TA and TE merge Surprisingly, the cort~co-cortlcal projections were remarkably slmdar for all cases depicted in Fig 1B, although the primary locus of the ablations differed relative to Walker's parcellatlon of the orb~tofrontal area A major exception was that m cases 2, 3 and 4 conspicuous terminal degeneration (see Fig 5c) was observed m area 28b of entorhmal cortex and m the prorhmal cortex along the medial bank of the rhlnal sulcus (Fig 5e) Area 35 (perlrhlnal cortex) along the lateral bank of the rhmal sulcus contained only light termination In all 3 cases the terminal degeneration in area 28b was confined to only layer III In the prorhlnal and perlrhmal cortex, it was d~ffuse and spread across all laminae In the former, however, the deeper layers contained a greater quantity of terminals These observations suggest that whde the cortlco-cortlcal connections of the orbltofrontal areas as a whole are quite similar, some regional parcellatlon of this cortex can be drawn on the basis of d~rect connections to the perlallocortex of the uncus Since case l, the only regional ablation not observed to have connections to areas 28 and 35, had extensive damage to orbltofrontal areas 10 and I l, these areas
30 CASE
5
II I_....-I..~_
CASE 6
DE
~II
_Y[ /
/~[
C. --
I
~
\\
~i , . i_ q - ~ l ''-~
I:
123
Amg
4 Zo
s
A.
2
CASE 7
CASE 8 ~ [
0A
'
;~1~,,,
.
/
oh,-" oA
Fig 2 A this dlustratlon depicts the topography of the restricted ablations m cases 5-8 on the orbttofrontal surface of the frontal lobe The two series of transverse sections (1-3) were taken from cases 5 and 6, and their approximate levels correspond to the numerals shown on the orb~tofrontal views of the frontal lobe for these cases The general pattern of terminal degeneration obserced for a case is depicted by dots B this dlustratlon summarizes the observed projections to the entorhmal, prorhinal, and pertrhmal cortices after the various orbltofrontal ablations Specific dots and arrows are not meant to ~mply pathways or point to pomt projections, but only the general s~te of o n g m for a projection and the cytoarchltectomcally defined region w~thm which ~t terminates,
31 may be ruled out as the o n g m of these projections The precise origin of these connections, however, cannot be ascertained in cases 2, 3 and 4, since all had ablation damage m areas 12, 13 and 14, and obwously one or all of these areas could have given rise to the observed projections Re~tt lcted ablations o f the ot bttof~ ontal at ea Cases 5-8 (Fig 2A) received smaller ablations of the orbitofrontal area m an effort to restrict the damage to a single cytoarchltectonlcally defined area In case 5, the ablation was localized in area 12 caudal to the fronto-orbltal sulcus Medially the ablation extended into the superficial lamina of area 13, but this region was largely spared Case 6 received a superficial ablation primarily in the caudal portions of area 13 Laterally, the medial and caudal portions of area 12 were damaged Additionally, this ablation extended caudally for a few millimeters into the lnsulotemporal cortex In case 7, a narrow ablation was made which was locahzed m area 14 and the caudal levels of area 10 Unlike the larger regional ablation of these areas there was little accompanying white matter involvement Case 8 received a centrally located ablation within the orbltofrontal area primarily confined to the caudal portions of area 11 and the rostral levels of area 13 As illustrated in Fig 2A, the distribution of degeneration elicited from these ablations was similar to that observed following the larger regional ablations The major exception observed occurred in case 7 where only sparse evidence of terminal degeneration was found in the rostral portions of areas TA and TE As with the regional ablations, only the medially and caudally located restricted ablations had terminal degeneration in the entorhlnal, prorhlnal, and perlrhlnal cortlces The localization of termination was also identical m these cases, occurring d~ffusely m the perlrhmal and prorhmal cortex, but discretely m layer llI of area 28b (Fig 5d) In case 8, where the caudal portions of area 11 and rostral portions of area 13 were damaged, no evidence of degeneration was observed m these areas These results (Fig 2B) suggest that the caudal levels of areas 12, 13 and 14 give rise to d~rect projections to the entorhmal, prorhlnal, and per~rhmal cortices of the temporal lobe In wew of the rarity, however, of d~rect connections from neocortex to entorhlnal cortex, ~t ~s essential to rule out potential confounding factors that could have contributed to this result As indicated above, white matter involvement was observed along the medial border of some ablations This could disrupt efferent fibers oNgmatlng from the medial surface of the hemisphere and coursing to the temporal lobe via an orbltofrontal-unclnate fasclculus route Additionally, for some ablations, the olfactory tract was mechanically manipulated e~ther in an effort to protect it, or to ablate area 14 beneath ~t Although this was not consistently correlated w~th terminal degeneration In area 28b, ~t ~s nonetheless essential to define the extent to which this may have affected the results Ablations o f areas 24 and 25 and olfactory tt act pt ojectlons As Illustrated in Fig 3, case 9 received a large ablation of the medial portion of the frontal lobe dorsal and ventral to the subcallosal sulcus Ventrally, Walker's area 10 was damaged and the olfactory tract partially transected N o evidence of degenera-
32
OASE,Ofl
ill "
I
" ~ , ~
('~---'~ ~--' II I
/-~>
. I ~
/'-\
"o
"~ "~,'b( \ ] "-J---" " - ' "
Fig 3 This illustration depicts the locahzatlon of the ablations m cases 9 and 10 on medml and ventral views of the hemisphere The general pattern of terminal degeneration observed for a case is depicted by dots Note the partial transection of the olfactory tract in case 9, and its total transection in case 10 tlon was observed m areas 28b, Pr2, or 35 In case t0 (Fig 3) the olfactory tract was totally transected caudal to the olfactory bulb and rostral to its attachment to the orbitofrontal area In this case, as well as case 9, degenerating fibers or terminals were readily identified m the olfactory tubercle, frontal and temporal prepmform cortex, and the periamygdalold cortex dorsal and ventral to the amygdaloid sulcus, but no degeneration was observed in area 28b, Pr2, and 35
Tl ajectory of orbltoentorhmal J~bers In all cases except case 10, the uncmate fasclculus contamed fiber degeneration that was traceable caudally into the temporal lobe Our results indicate that the orbltoentorhmal projections travel for a short distance in the uncmate fasciculus Following a caudal orbttofrontal ablation (Fig 4D and E) a diffuse stream of degenerating fibers could be observed leaving the medial portion of the uncmate bundle dorsal to the amygdala These fibers formed small bundles and could be traced ventrally lateral to the amygdala (Fig 5a) and into the white matter of area 28b dorsal to the depths of the rhmal sulcus (Fig 5b) From this p o s m o n they ascended into the entorhmal cortex and terminated in layer Ill (Fig 5c-d) This trajectory was noted in all orbltofrontal cases having terminal degeneration m area 28b What this pathway should be labeled after leaving the uncmate fasciculus would appear open to conjecture Clearly, at rostral levels these fibers are located medial to the temporal extension of the claustrum (Fig 4D) and, by analogy to more dorsal levels of the brain, could be considered a ventral but diffuse component of the external capsule At more caudal levels, however, they would also appear to travel m the ventral and lateral p o m o n s of the anterior commissure (Fig 4E)
33 A
B
C
)' olf tr
olf tr
If
D
E
\ If
ylf
rs~sts F~g 4 A - E m this allustratlon 5 transverse sections taken from case 6 depict the fiber trajectory of some orbatofrontal projectaons The levels of these sections correspond to those denoted by letters for case 6 m Fag 2 In each sectaon the arrow mdacates the most compact portion of the uncmate fa.scacu]us at that level Terminal degenerataon as depicted by dots and fiber degenerataon by short hnes Note m sectaon D, that fibers destined for the entorhanal cortex appear to leave the compact port~on of the unclnate fasc~culus dorsal and lateral to the amygdala
DISCUSSION
The orbJtofrontal area is a u m q u e region of cerebral cortex for several anatomical reasons Fibers originating here are dlstrlbuted to widespread regions of brain including the brain stem 12,14, mldbraln la, dlencephalon and strlatum 1°,13,16 Additionally, the orbltofrontal area is rectprocally connected with the magnocellular portion o f the dorsomedlal thalamlc nucleus 2,16, and is one of the few regions o f ricocortex that sends fiber projections directly to the h y p o t h a l a m u s l°,16 Our results appear to contribute another unique anatomical feature, m that the orbltofrontal area has been found, as suggested by Cragg's 6 results m cats, to contribute direct afferents to one of the classical subareas o f entorhlnal cortex Thus, it is one o f only two neocortical regions we have f o u n d having such connections By virtue o f the heavy con-
34
Fig 5 a fiber degeneration dorsal and lateral to the amygdala following an orbltofrontal (case 4) ablation 120 b fiber degeneration ascending out of the white matter beneath the entorhmat and prorhlnal cortices (case 4) 620 c and d depict terminal degeneration m layer II[ of the entorhmal cortex (28b) m cases 4 and 6 e depicts terminal degeneration m layers V and VI of the prorhlnal cortex m case 4 400 (Fmk and Hezmer stare )
nectlons between this area of the entorhmal cortex and the hlppocampus 8, these findings imply that potentially the orbltofrontai area might exert conszderable influence on this allocortlcal area Although there is disagreement among investigators regarding the cytoarchltectonic orgamzatlon of the orbltofrontal areas, Walker's 26 more discrete parcellatlon was chosen for this investigation since it more fully afforded the opportumty to assess possible differential cortlco-cortlcal connections He dtvlded the orbltofrontal area of the rhesus monkey into 5 subareas and labeled them area 10, 1 1, 12, 13 and 14 in a later report, Bonm and Barley 3 rejected th~s scheme and instead dw~ded the area into only two portions w~th one, area FD, subsuming Walker's areas 10, 1 1, 12 and the rostral portion o f h l s area 13, and the other, area FF, corresponding to the caudal portions of area 13 The orb~tofrontal portion of area F D was deemed continuous with the neocortex of the inferior prefrontal lobule Area FF was set aside as a separate subarea, since according to Bonm and Barley 3, the tuner granular layer (lamina IV) is
35 poorly developed and occupied in part by pyramidal cells The caudal and medial portion of the orbltofrontal area in the rhesus monkey (Walker's area 14) was not acknowledged by Bonln and Bailey either, since it was felt to be continuous with and identical in architecture, to an area they labeled FL on the medial surface of the hemisphere ventral to the subcallosal sulcus The results described here indicate that in terms of local connections, the orbltofrontal area sends projections to the cortex forming the medial wall of the hemisphere as well as to the cortex forming the inferior prefrontal lobule, ventral to the principal sulcus None of the various subareas except areas 10 and 11 were observed to contribute afferents to the caudal portions of the superior prefrontal lobule, but all ablations led to terminal degeneration in the cortex of the frontal pole Distal connections from the various ablations were always observed in the rostral lnsula, area 24 (the rostral clngulate gyrus), and areas TE and T G of the temporal lobe The extreme rostral portions of area TA contained evidence of terminal degeneration in all cases except those in which the ablation was largely confined to the medial portion of areas 10 and 14 These areas also appear to project only minimally to area TE as well In so far as cortlco-cortlcal connections are concerned, most of Walker's various subareas of the orbltofrontal area were found not to give rise to widely divergent differential projections The topographical distribution of degeneration from all areas, with the exception of area 14, was remarkably similar It IS significant that virtually the same conclusion was reached by Johnson et al to, in regard to differential subcortlcal connections from the orbltofrontal area in the rhesus monkey We cannot, however, confirm these author's observations of orbltofrontal projections to the caudal clngulate gyrus or directly into the hlppocampus None of our cases contained any evidence of either fiber or terminal degeneration in these areas The most conspicuous aspect of the results was that medially and caudally placed orb~tofrontal ablations consistently led to terminal degeneration in the lateral portion of the entorhlnal cortex (area 28b) and the transitional prorhlnal and perlrhlnal (area 35) cortices forming the walls of the rhlnal sulcus The focus for this projection would seem to be the caudal levels of Walker's area 13, or specifically Bonln and Bailey's area FF We cannot, however, rule out the fact that the caudal levels in areas 12 and 14 may also contribute some projections to these areas This general region has long been recognized as having so-called hmblc cytoarchltectual characteristics 8 11 2o 2z,2v and our observations regarding its connections would be concordant with such views However, like the clngulate gyrusl, 19, and the parahlppocampal area T F - T H 24,25, which also give rise to perlallocortlcal projections, these areas and area FF also give rise to projections to other neocortlcal areas Certainly this anatomical feature of their organization should not be overlooked because of their unique relationship with the llmblc system Curiously the hmblc nature of area F F ' s connection IS not dlstlngmshed by projections to the nearby insular cortex, since all regions of the orb~tofrontal area appear to project there, instead, it is distinguished by direct projections to the entorhlnal cortex, a classical penallocortlcal area There is a distinct correlation between the orbltofrontal projections described
36 here and the c y t o a r c h a e c t o m c parcellatlon ot this area proposed by Bonm and Bafle) Their orbltofrontal p o m o n of area F D corresponds to an area from whJch we did not observe &fferential projectmns Slmdarly, their area FL corresponds to an area whose connectmns appear d~fferent from those of area F D And finally, their area F F ~orresponds to that orb~tofrontal area from which we have observed projections &rectly to the entorhmal cortex It as s~gmficant that the posterome&al orb~tofrontal area appears to be the anatomical focus for a behavioral change characterized by enhanced averswe reactions and reduced aggressive responses m threatening s~tuat~ons 5 A d & tlonally, ablations of thB area y~eld &fferentlal behavioral changes relanve to ablations confined to other areas of the orbltofrontal 4 9 and dorsolateral prefrontal areas a Nauta ~ emphasized that the orb~tofrontal area, by wrtue of heavy connections with the temporal neocortex, could exert considerable influence on the amygdala in contrast, the dorsolateral prefrontal cortex, wa connections w~th the cmgulate gyrus and presublculum, was thought to be more associated with the hlppocampal system The results described here extend these observations, however, they do dlmmBh thB &stmctmn by demonstrating a direct connection from the orNtofrontal area to the entorhmal cortex, an area heawly connected to the hlppocampus s A d d m o n a l l y , our observations of orbltofrontal projections to area 24, and projections from thB area to the lateral basal amygdalold nucleus ~s also m&cate that the orb]tofrontal area can potentially affect the amygdala wa two quite separate routes Since the cortex of both the supermr and inferior prefrontal lobule projects to area 24 as well ~, a slgmficant p o r t m n of the output of the dorsolateral and orb~tofrontal prefrontal cortex ~s &rected toward cortical afferent sources of both the amygdala and h~ppocampus A less &rect avenue of input to the h~ppocampus ~s achieved by &rect projectmns from the orb]to-
NeocorhcaI-Dmb~cCorticalConnechons
~
DmblcCort~caI-DmblcCorticalConnechons
