corticothalamic connections of paralimbic regions in the rhesus monkey

THE JOURNAL OF COMPARATIVE NEUROLOGY 269:130-146 (1988)

Corticothalamic Connections of Paralimbic Regions in the Rhesus Monkey

EDWARD H. YETERIAN AND DEEPAK N. PANDYA Department of Psychology, Colby College, Waterville, Maine 04901 (E.H.Y.); Edith Nourse Rogers Memorial Veterans Hospital, Bedford, Massachusetts 01730 (E.H.Y.,

D.N.P.); Departments of Anatomy and Neurology, Boston University School of Medicine, Boston, Massachusetts 02118 (D.N.P.); Harvard Neurological Unit, Beth Israel Hospital,

Boston, Massachusetts 02215 (D.N.P.)

ABSTRACT This study addressed the issue of whether paralimbic regions of the

cerebral cortex share common thalamic projections. The corticothalamic connections of the paralimbic regions of the orbital frontal, medial prefrontal, cingulate, parahippocampal, and temporal polar cortices were studied with the autoradiographic method in the rhesus monkey. The results revealed that the orbital frontal, medial prefrontal, and temporal polar proisocortices have substantial projections to both the dorsomedial and medial pulvinar nuclei, whereas the anterior cingulate proisocortex (area 24) projects exclusively to the dorsomedial nucleus. These proisocortical areas also have thalamic connections with the intralaminar and midline nuclei. The cortical areas between the proisocortical regions on the one hand and the isocortical areas on the other, that is, the posterior cingulate region (area 23) and the posterior parahippocampal gyrus (areas TF and TH), project predominantly to the dorsal portion of the medial pulvinar nucleus, the anterior nuclear group (AV, AM), and the lateral dorsal (LD) nucleus. Addi- tionally, the posterior cingulate and medial parahippocampal gyri (area TH) have projections to the lateral posterior (LP) nucleus.

Thus, it appears that the proisocortical areas, which are characterized by a predominance of infragranular layers and an absence of layer IV, have common thalamic relationships. Likewise, the intermediate paralimbic areas between the proisocortex and isocortical regions, which also have a predominance of infragranular layers but in addition have evidence of a fourth layer, project to the medial pulvinar and to the so-called limbic nuclei, AV, AM, LD, as well as a modality-specific nucleus, LP.

Key words: thalamus, proisocortical, cortex, pulvinar, dorsomedial nucleus

Cortical areas are differentiated on the basis of both architecture and connections. It has long been known that certain cortical regions have preferential relationships with particular thalamic nuclei. For example, the posterior parietal cortex projects heavily to the pulvinar and lateral posterior nuclei (Petras, '71; Weber and Yin, '84; Yeterian and Pandya, '851, whereas the prefrontal cortex projects predominantly to the dorsomedial nucleus (Akert, '64; Nauta, '64; Tanaka, '76; Kunzle and Akert, '77; Kunzle, '78; Jacobson et al., '78; Akert and Hartmann-von Mona- kow, '80; Siwek and Pandya, '84). Moreover, in recent years it has become apparent that cortical areas with certain cytoarchitectonic features have specific thalamic relationships. For example, within the posterior parietal cortex, the

0 1988 ALAN R. LISS, INC.

rostra1 portions of both the superior and inferior parietal lobules (SPL and IPL, respectively; a list of abbreviations used and their meanings adjoins Fig. 1) tend to project mainly to modality-specific nuclei, that is, to the ventral posterolateral, ventral posteromedial, lateral posterior, and oral pulvinar nuclei (Jones et al., '79; Weber and Yin, '84; Yeterian and Pandya, '85). In contrast, more caudal regions of the SPL and IPL tend to project more heavily to non-

Accepted October 9, 1987.

A preliminary report of these findings was presented at the meeting of the Society for Neuroscience, Boston, Massachusetts, November 1983 (Yet- erian, '83).

CORTICOTHALAMIC CONNECTIONS 131

modality-specific nuclei such as the medial pulvinar, lateral dorsal, dorsomedial, and intralaminar nuclei (Jones et al., '79; Weber and Yin, '84; Yeterian and Pandya, '85). Thus, areas at similar architectonic stages, that is, areas with comparable architectonic features, in SPL and IPL, are related to similar types of thalamic nuclei (Yeterian and Pandya, '85).

The medial and ventral paralimbic areas-e.g., the orbital frontal, cingulate, parahippocampal and temporal polar cortices-have diverse locations in the cerebral hemisphere yet share some common architectonic features. These areas have a predominance of infragranular layers and relatively less developed supragranular layers and are often discussed as belonging to a common group within the cortex (Yakov- lev et al., '66; Sanides, '69, '72; Braak, '80; Armstrong et al., '86; Zilles et al., '86). These paralimbic areas have been treated as having an intermediate architectural pattern as well as an integrative functional role, emphasizing on the one hand their limbic ties and on the other their relations with iso- or neocortical regions (MacLean, '49; Nauta, '64; Yakovlev et al., '66; Powell, '73, '78; Diamond, '79; Baley- dier and Mauguiere, '80; Van Hoesen, '82; Isaacson, '82). Classically, in terms of thalamic connectivity, some of these regions, in particular the cingulate gyrus, have been de- scribed as being intimately connected with the so-called limbic nuclei of the thalamus, that is, the anterior nuclear group and the lateral dorsal nucleus (Akert, '64; Yakovlev et al., '66; Vogt et al., '79; Baleydier and Mauguiere, '80).l Other regions, such as the orbital frontal and ventromedial temporal cortices, as well as the cingulate gyrus, have been shown to be connected with the dorsomedial and pulvinar nuclei (Clark and Boggon, '35; Clark, '36; Whitlock and Nauta, '56; Nauta, '64; Bos and Benevento, '75; Tobias, '75; Trojanowski and Jacobson, '76; Kievit and Kuypers, '77; Gower, '81; Siwek and Pandya, '84; Goldman-Rakic and Porrino, '85; Baleydier and Mauguiere, '85; Markowitsch et al., '85). It is not known whether the paralimbic cortices as a group have a common thalamic projection zone which both ties them together and distinguishes them from other isocortical regions. In this investigation, we addressed this issue by tracing thalamic projections of selected orbital frontal, medial prefrontal, cingulate, parahippocampal, and temporal polar regions, using the autoradiographic method. Briefly, the findings show that among the paralimbic regions, the proisocortical areas project predominantly to the dorsomedial and medial pulvinar nuclei as well as to the midline and intralaminar nuclei. In contrast, the paralimbic regions of the caudal cingulate and the lateral parahippocampal gyri project mainly to the medial pulvinar nucleus, the anterior nuclear group, and the lateral dorsal nucleus.

MATERIALS AND METHODS The corticothalamic connections of the paralimbic weas

were traced in 13 rhesus monkeys (Macaca mulatta) with radioactively labeled amino acids. Following a craniotomy performed under sodium pentobarbital anesthesia, the animals received cortical injections (3H-proline and 3H-leucine, and a mixture of amino acids: volume range 0.4-1.0 pl; specific activity 40-80 pci) in different parts of the orbital frontal, medial prefrontal, cingulate, parahippocampal, and temporal polar regions. After a survival period of4-7 days, the animals were deeply anesthetized with sodium pentobarbital and perfused transcardially with isotonic saline followed by 10% formalin. The brains were removed and

processed for autoradiography according to the method of Cowan et al. ('72). The exposure times ranged from 3 to 6 months.

Each hemisphere was divided coronally into two blocks in the stereotaxic plane. The blocks were embedded in paraffin and cut into 10-pm-thick sections in the coronal plane. Every tenth section was processed for autoradiography and stained with thionin. This stain permitted the analysis of cortical cytoarchitecture, localization of the injection site, and identification of the boundaries of thalamic nuclei. The precise location of each injection site was determined by observing the cortical architecture around the labeled area in the cortex and comparing this with the architecture of the corresponding nonlabeled area of the opposite hemisphere. The distribution of terminal label as revealed in each section was charted onto coronal tracings of the thalamus under darkfield illumination. The boundaries of various thalamic nuclei were determined from the thionin-stained sections under brightfield illumination. The atlas of Olszewski ('52) was used as a reference for deline- ating thalamic boundaries and for nomenclature.

RESULTS The term paralimbic cortex as used in this report refers

to cortical regions which are characterized by a predominance of infragranular layers and which are located medially and ventrally in the cerebral hemisphere (Fig. 1). These paralimbic regions may be divided into two categories: proisocortical areas and immediately adjacent paralimbic regions. Proisocortical areas are those which have an ill- defined fourth layer, and they include the orbital frontal, medial prefrontal, anterior cingulate, perirhinal and temporal polar regions, whereas the adjoining paralimbic regions, such as the posterior cingulate and posterior parahippocampal gyri, have a discernible fourth layer. Both the posterior cingulate and the posterior parahippocampal gyri have characteristically proisocortical (predominance of infragranular layers) and isocortical (six layers with a discernible fourth layer) features and can be considered as transitional between limbic and more lateral isocortical regions. Figure 2 shows the architectonic features of various paralimbic areas. We have adopted the architectonic nomenclature of von Bonin and Bailey ('47) to describe the parahippocampal and temporal polar cortices because of its widespread use. All other paralimbic regions are discussed in terms of the architectonic nomenclature of Brodmann ('09).

Orbital frontal and medial prefrontal proisocortices In two cases, separate injections were made into the cau-

dal orbital frontal and rostra1 medial prefrontal regions (Fig. 3). In case 1, the injection involved the caudal portion of area 13 in the orbital frontal cortex, whereas in case 2, the injection occupied area 32 and extended slightly into adjoining area 25 of the medial prefrontal cortex. The resulting silver grains indicating terminal labeling in case 1 were found predominantly over two thalamic nuclei- namely, the dorsomedial (MD) and the medial pulvinar

'The term limbic nuclei refers to the anterior nuclear group (AV, AM, AD) and the lateral dorsal (LD) nucleus, which are known to be connected with cortical limbic areas (Powell et al., '57; Yakov- lev et al., '66; Amaral and Cowan, '80; Baleydier and Mauguiere, '80; Pandya et al., '81; Mufson and Pandya, '84; Aggleton et al., '86).

132

A bbreuiations

AM anterior medial nucleus AS arcuate sulcus AV anterior ventral nucleus BSC CC corpus callosum Cd caudate nucleus Cdc nucleus centralis densocellularis CF calcarine fissure Cif nucleus centralis inferior Cim nucleus centralis intermedialis CING S cingulate sulcus CL nucleus centralis lateralis Clc nucleus centralis latocellularis CM centromedian nucleus CS central superior nucleus CSL nucleus centralis lateralis superior GLd dorsal lateral geniculate nucleus GM medial geniculate nucleus H habenula 10s inferior occipital sulcus IPS intraparietal sulcus ITP inferior thalamic peduncle LD lateral dorsal nucleus LF lateral fissure Li nucleus limitans LOS lateral orbital sulcus LP lateral posterior nucleus LS lunate sulcus MD dorsomedial nucleus MDmc dorsomedial nucleus, magnocellular portion MDpc dorsomedial nucleus, parvicellular portion MOS medial orbital sulcus Pcn nucleus paracentralis P1 inferior pulvinar nucleus

brachium of the superior colliculus

PL PM PO POMS PS Pa Pac Pf R R Re Rh F Rspl SG Sm SN STN STS TF TH THI VA VAmc VL VLC VLm VLO VLps VPL VPM VPMpc X 21

Tempora l

E.H. YETEKIAN AND D.N. PANDYA

lateral pulvinar nucleus medial pulvinar nucleus oral pulvinar nucleus medial parieto-occipital sulcus principal sulcus paratenial nucleus nucleus paraventricularis caudalis parafascicular nucleus parataenial nucleus reticular nucleus nucleus reuniens rhinal fissure retrosplenial cortex suprageniculate nucleus stria medullaris substantia nigra suhthalamic nucleus superior temporal sulcus lateral parahippocampal cortex medial parahippocampal cortex habenulo-interpeduncular tract ventral anterior nucleus ventral anterior nucleus, magnocellular portion ventrolateral nucleus ventrolateral nucleus, caudal portion ventrolateral nucleus, medial portion ventrolateral nucleus, oral portion ventrolateral nucleus, posteriormost portion ventroposterolateral nucleus ventroposteromedial nucleus ventroposteromedial nucleus, parvicellular portion area X zona incerta

Fig. 1. Diagram showing the various paralimbic areas in the medial and orbitofrontal cortices of the cerebral hemisphere in the rhesus monkey. Note the distribution of paralimbic areas on the orbital surface and the paleo-olfactory region (area 13); in the medial prefrontal cortex (areas 25

and 32); in the cingulate gyrus (areas 24, 23, and the retrosplenial area, Rspl); in the parahippocampal gyrus (areas TH and TF); in the perirhinal cortex (area 35); and in the temporal pole (area TG or 38).


Fig. 2. Photomicrographs showing laminar distributions within various proisocortical areas f x 40) indicated in Figure 1. Note that in each of these regions, the laminar pattern is rudimentary in nature, that is, there is a preponderance of infragranular neurons and a lack of layer IV nerve cells, with the exception of areas 23, TH, and TF, which show a pattern resembling incipient isocortex.

(Fig. 8A,D). In both nuclei, the projections were located in the most medial sectors. In the dorsomedial nucleus, the grains were observed in the caudal two-thirds of the nucleus, mainly with the magnocellular division (MDmc). The grains were observed in the caudal two-thirds of the nucleus, mainly within the magnocellular division (MDmc). The grains in the medial pulvinar were confined to the most medial sector of the nucleus throughout almost its entire rostral-caudal extent. In case 2, with an injection in the medial prefrontal proisocortical region, the distribution

of terminal label was also predominantly over the dorsomedial and medial pulvinar nuclei. The silver grains over the dorsomedial nucleus were located in the dorsal and medial portions, within the magnocellular division (Fig. 8E). In the medial pulvinar nucleus, the label was observed over medial and ventral portions, with some grains also found over the lateral pulvinar (PL) and suprageniculate (SG) nuclei. In both of these cases, additional label was noted over midline and intralaminar thalamic nuclei. Thus, in case 1 small clusters of grain were seen over the paraven-

E.H. YETERIAN AND D.N. P m Y A 134

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I D B C Figure 3


tricular (Pa), reuniens (Re), centralis intermedialis (Cim), centralis superior (CS), and the medial portion of the ventral lateral (VLm) nuclei (Fig. 3, upper diagrams). Other thalamic nuclei which showed evidence of terminal label, but which are not illustrated, are the centralis densocellularis (Cdc) and parataenial (Pt) nuclei. In case 2, label was observed over the paracentral (Pcn) and Cdc nuclei of the intralaminar group as well as the magnocellular portion of the ventral anterior (VAmc) nucleus (Fig. 3, lower diagrams). Additionally, sparse grains were noted over the nucleus limitans (Li, not shown).

Cingulate gyrus In five cases, injections were made in various subdivisions

of the cingulate gyrus throughout its rostral-caudal extent. Cases 3 and 4 both involved injections into area 24 of the anterior cingulate gyrus. The overall pattern of projections was similar in both of these cases; the distribution of terminal label for Case 3 is shown in Figure 4. The main bulk of grains was observed in the dorsomedial (MD) nucleus (Fig. 8B), throughout almost its entire rostral-caudal extent, within both the magnocellular and parvicellular (MDpc) divisions. Unlike the preceding cases, however, the grains tended to shift in location, from lateral at rostral levels, to medial at more caudal levels. As shown in Figure 4 (upper diagrams), terminal label also was observed over the anterior medial (AM) nucleus; midline nuclei (centralis latocellularis, Clc; Cim; Pa); intralaminar nuclei (centralis superior lateralis, CSL; centromedian-parafascicular, CM- PD; as well as the ventral anterior (VA), Li, and reticular (R) nuclei. Some grains were noted over other thalamic nuclei (not illustrated): midline nuclei (Cdc; centralis inferior, Cif; Pt; Re), intralaminar nuclei (Pcn; CS), and the ventral lateral (VL) nucleus. However, unlike the preceding cases, virtually no grains were observed over the pulvinar in either case 3 or case 4. Case 5 received an injection in the middle portion of the cingulate gyrus, which involved caudal area 24 and rostral area 23. As shown in Figure 4 (lower diagrams), the main bulk of label in case 5 appeared over the medial pulvinar and dorsomedial nuclei. However, the grains in MD were less extensive than in any of the other cases showing MD projections and were located in a central region of the caudal part of the nucleus (MDpc). The grains over the medial pulvinar occupied its central portion. Terminal label also was observed over the anterior thalamic nuclei (AV, AM) and intralaminar nuclei (CSL) as well as the caudal portion of the ventral lateral (VLc) and the lateral posterior (LP) nuclei. Additionally, some grains were noted over midline nuclei (Re, Cif, Cdc, Cim, Clc-not shown). In cases 6 and 7, injections were placed in the caudal portion of the cingulate gyrus, area 23. In case 7, the injection involved the retrosplenial area as well as the

Fig. 3. Top: Diagrammatic representation of the basal surface of the cerebral hemisphere showing an isotope injection site (dark area) in the caudal orbital frontal cortex, area 13 (case 1, upper left). Also shown are four representative coronal sections through the thalamus from rostral (A) t o caudal (D), depicting the distribution of terminal label (shown as dots) in various nuclei. Bottom: Diagrammatic representation of the medial surface of the cerebral hemisphere showing an isotope injection site in the medial prefrontal cortex, areas 32 and 25 (case 2, upper left). Also shown are four representative sections through the thalamus from rostral (A) to caudal (D), depicting the distribution of terminal label in various nuclei. In this and subsequent figures, the vertical marks on the hemispheric surface indicate the line of cut in the coronal plane for the thalamic sections.

caudal portion of area 23. The basic pattern of terminal labeling in cases 6 and 7 was similar; the distribution of silver grains in case 6 is shown in Figure 5 . Thus, label was found predominantly in the lateral and dorsal portions of the PM nucleus (Fig. 8C,F) and in the dorsal portions of the LP and VLc nuclei. In contrast to the previous cases, both of these cases showed grains over the lateral dorsal (LD) nucleus (Fig. 9A) as well as the AV and AM nuclei. Addi- tionally, case 6 had grains over the VLc nucleus, whereas case 7 had label in the Pcn nucleus (not shown). Only occasional grains were noted over the MD nucleus in these cases (not shown).

Temporal paralimbic cortices: parahippocampal gyrus and temporal pole

In four animals (cases 8-11), injections were placed in the posterior portion of the parahippocampal gyrus (PPG). The injections in cases 8 (Fig. 6, upper diagrams), 9, and 10 were in the lateral parahippocampal gyrus and confined mainly to area TF, whereas in case 11 (Fig. 6, lower diagrams) the injection was situated medially in area TH. The resulting label in these cases was basically similar but with some differential distribution. Thus, all of the PPG cases showed the main bulk of grains in the dorsal portion of the PM nucleus (Fig. 9B,C) and in the LD nucleus (Fig. 9D). The main differences were that in the medial PPG case (case ll), the grains in the LD nucleus were notably more dense, and there were also grains over the AV and LP nuclei (Fig. 6, lower diagrams). In another two animals, injections were placed in the perirhinal cortex, area 35 (case 12) and in the lateral portion of the temporal pole, area TG (case 13). Case 12 (Fig. 7, upper diagrams) showed grains only over the dorsal edge of the medial pulvinar, in the caudal portion of the nucleus. Case 13 (Fig. 7, upper diagrams) showed grains over both the MD (Fig. 9E) and PM (Fig. 9F) nuclei. In the dorsomedial nucleus, the label was located mainly in the caudal sector of MDpc, with some grains in MDmc more rostrally. In the pulvinar, the grains were found in the caudal and medial sectors of the PM nucleus. In case 13, label also was found over the caudalmost portion of the medial geniculate (GM) nucleus (Fig. 7, lower diagrams) as well as in lesser amounts in the Re, CSL, and Pt nuclei (not shown).

DISCUSSION In assessing the role of the cerebral cortex in higher

functions, major emphasis has been placed on corticocortical connections (e.g., Geschwind, '65a,b; Myers, '67; Dama sio, %a). Thalamic connections must also play a significant role in complex functions of the cerebral cortex, since the cerebral cortex and the thalamus are heavily interconnected. A number of investigations have delineated the intricacies of the thalamic relationships of primary and parasensory association areas. It has also been well estab- lished that association areas are closely linked with paralimbic regions (Nauta, '64; Pandya and Kuypers, '69; Jones and Powell, '70; Van Hoesen et al., '72; Mesulam et al., '77; Baleydier and Mauguiere, '80, '87; Pandya et al., '81; Me- sulam and Mufson, '82; Mufson and Mesulam, '82; Markow- itsch et al., '85; Barbas and Pandya, '87; Moran et al., '87). Relatively few studies have addressed the issue of the thalamic connectivity of paralimbic regions (Yakovlev et al., '66; Vogt et al., '79; Baleydier and Mauguiere, '80, '87; Mufson and Mesulam, '84; Markowitsch et al., '85; Gold- man-Rakic and Porrino, '85; Moran et al., '87). In the pres-

E.H. YETERLAN AND D.N. PANDYA

A I CASE 3

B C D

/--.-

CASE 5 A

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CASE 6

I/- il

3 A

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Fig. 5. Diagrams showing an isotope injection site in the caudal part of the cingulate gyrus, area 23 (case 6), as well as four representative thalamic sections depicting the distribution of resulting silver grains.

ent study, we have attempted to delineate the organizational principles of connections from paralimbic regions to the thalamus.

The paralimbic areas are located in the mediobasal regions of the cerebral hemisphere, and have preferential projections to the medial pulvinar and dorsomedial nuclei as well as to intralaminar, midline, and limbic thalamic nuclei. The orbital frontal, medial prefrontal, and temporal polar proisocortical areas project strongly to both the MD and PM nuclei in the medial portions of these nuclei. The rostral cingulate gyrus (area 24), another proisocortical area, in contrast projects mainly to the MD nucleus and not to the PM nucleus. A different pattern of thalamic connectivity is observed for the paralimbic regions which are intermediate to proisocortex on the one hand and isocortex on the other. Thus, the caudal cingulate gyrus (area 23),

Fig. 4. Diagrammatic representations of isotope injection sites in the rostral (case 3, top) and middle (case 5, bottom) portions of the cingulate wrus. as well as remesentative thalamic sections for each case showing the

unlike proisocortical area 24, projects predominantly to the PM nucleus with relatively weak projections to the MD nucleus. Moreover, the caudal cingulate gyrus projects to the LP and LD nuclei. The posterior parahippocampal gyrus, like area 23, has sizable projections to the PM and LD nuclei but none to the MD nucleus. The perirhinal cortex has only a limited projection to the PM nucleus. Overall, our data indicate that the medial pulvinar nucleus is a common target for projections of all paralimbic regions except area 24. Although traditionally the limbic nuclei of the thalamus (AV, AM, AD, and LD) have been considered to have the most intimate relationship with paralimbic areas, it appears that the dorsomedial and medial pulvinar nuclei, as well as the midline and intralaminar nuclei, also have close ties with these regions.

With regard to the anterior group of thalamic nuclei, only certain paralimbic regions appear to project to these nuclei. Thus, the rostral cingulate region projects to the AM nucleus, whereas the caudal cingulate region projects predominantly to the AV nucleus. The midportion of the cingulate gyrus seems to have connections to both the AM and AV thalamic nuclei. Within the posterior parahippocampal gyrus, only the most medial region (area TH) projects to the

I

Zstribution of terminal label. AV nucleus.

CASE 8

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CASE 11 A

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According to their architectonic characteristics, the paralimbic areas occupy an intermediate stage between the limbic system and neocortical structures (e.g., Dart, '34; Abbie, '40; Kaada, '60; Nauta, '64; Sanides, '69, '72). Al- though these regions, like neocortex, have a six-layered organization, they retain limbic features-namely, a predominance of infragranular layers. In proisocortical regions per se, there is a lack of layer IV neurons (Yakovlev et al., '66; Sanides, '72; Braak, '80). The thalamic projections of paralimbic regions as a group appear to reflect their intermediate architectonic position. Thus, on the one hand these regions project to limbic as well as midline and intralaminar thalamic nuclei and on the other to the medial pulvinar and dorsomedial nuclei. This may indicate that the corticothalamic connections of paralimbic areas are organized in a manner consistent with their position intermediate to limbic and neocortical regions. According to Sanides ('69, '72) and others (Galaburda and Pandya, '83; Pandya and Yeterian, '85), paralimbic areas are presumed to differentiate into modality-specific isocortical regions. They themselves, however, remain relatively undifferentiated, and connectionally and functionally they have been shown to be multimodal in nature (Nauta, '64; Pandya and Kuypers, '69; Jones and Powell, '70; Heilman et al., '70; Watson et al., '73; Seltzer and Pandya, '76; Benevento et al., '77; Vogt et al., '79; Desimone and Gross, '79; Baleydier and Mau- guiere, '80, '85; Pandya et al., '81; Van Hoesen, '82). The PM nucleus receives projections from visual, auditory, and somatosensory association cortices as well as from multimodal association areas (Clark, '36; Walker, '38; Whitlock and Nauta, '56; Trojanowski and Jacobson, '75, '77; Benev- ento and Davis, '77; Jones et al., '79; Gower, '81; Weber and Yin, '84; Markowitsch et al., '85; Yeterian and Pandya, '85, '86; Pandya et al., '86) and has been shown to contain neurons responsive to different sensory modalities (e.g., Cooper et al., '74). Likewise, the MD nucleus is shown to receive projections from the prefrontal cortex, which itself is related to the sensory association areas (Nauta, '64; Tan- aka, '76; Kiinzle and Akert, '77; Kiinzle, '78; Akert and Hartmann-von Monakow, '80; Arikuni et al., '83; Siwek and Pandya, '84). The fact that the paralimbic areas are closely related to the MD and PM nuclei, which themselves have diverse cortical connections, is consistent with the undifferentiated nature of the paralimbic regions. It should be pointed out, however, that the paralimbic projections to the PM and MD nuclei have a different distribution than those of the isocortical regions. Whereas the isocortical projections to these nuclei, especially to the medial pulvinar, tend to occupy predominantly central and lateral regions (e.g., Trojanowski and Jacobson, '75; Benevento and Davis, '77; Weber and Yin, '84; Yeterian and Pandya, '851, the paralimbic projections tend to favor medial and dorsal regions (e.g., Clark, '36; Whitlock and Nauta, '56; Yakovlev et al., '66; Fallon and Benevento, '78; Vogt et al., '79; Gower, '81; Baleydier and Mauguiere, '80, '85).

Although, collectively, the paralimbic regions project to both the MD and PM nuclei, there are differences in terms

tle et a1.,-'75; Lynch et al., '77rLynch, '80; Hyvarinen, '82). It should be pointed out that, like the posterior cingulate and the posterior parahippocampal gyri, area Opt has connections with the LD nucleus (Weber and Yin, '84; Yeterian and Pandya, '85; Schmahmann and Pandya, '86; Baleydier and Mauguiere, '87). Thus, this connectivity of paralimbic

Fig. 6. Diagrams showing a n isotope injection site in the parahippocam- and isocortical pal gyrus, area TF (case 8, top), and area TH (case 11, bottom), and represen- in integrating WnsorY and motivational factors during at- tative thalamic sections depicting the distribution of terminal label in these tentional processes.

with the LD may play a

of the connectivity of specific regions with these nuclei. For example, the orbital frontal, medial prefrontal, and temporal polar areas project to both the MD and PM nuclei, albeit differentially in terms of the relative strength of their connections. In contrast, the anterior cingulate gyrus appears to project exclusively to the MD nucleus, whereas the posterior cingulate and posterior parahippocampal gyri project preferentially to PM. This differential pattern may have its basis in the architectonic characteristics of these regions. Thus, area 24, which is truly proisocortical with virtually no granular layer, seems to relate to the medial sector of the MD nucleus, whereas areas TF and 23, which have a definite fourth layer, are connected with the PM nucleus. The caudal orbital frontal (area 131, medial prefrontal (area 32), and temporal polar (area TG) cortices, which have a rudimentary fourth layer, project to both the MD and PM nuclei. Additionally, this connectivity is consistent with the position of paralimbic regions as presumed precursors of different types of isocortical areas. For example, area 24, a proisocortical region which is part of an architectonic trend leading to motor isocortex (Sanides, '69, '72; Barbas and Pandya, '871, projects to the MD nucleus, which is closely linked to the frontal regions involved in the planning and sequencing of motor behavior (Fuster, '80; Milner, '82; Milner and Petrides, '84; Stuss and Benson, '84; Brown, '85). Likewise, the posterior parahippocampal gyrus is part of an architectonic trend which relates to sensory isocortex (Seltzer and Pandya, '76; Van Hoesen, '82; Rosene and Pandya, '83) and is most closely related to the PM nucleus, which is tied to cortical areas involved in sensory functions (Weiskrantz and Mishkin, '58; Wegener, '64; Moffett et al., '67; Cooper et al., '74; Bos and Benevento, '75; Trojanowski and Jacobson, '75, '76, '77; Mountcastle et al., '75; Jones et al., '79; Gower, '81; Hyvarinen, '82; Unger- leider and Mishkin, '82; Weber and Yin, '84; Yeterian and Pandya, '85, '86; Pandya et al., '86).

Another thalamic link of certain paralimbic regions is with the so-called limbic nuclei, the anterior nuclear group and the lateral dorsal nucleus (Yakovlev et al., '66). Thus, the cingulate and parahippocampal gyri project to either the anterior nuclear group or LD or both (Vogt et al., '79; Baleydier and Mauguiere, '80, '85). The preferential projections to the LD nucleus are from the posterior cingulate and the posterior parahippocampal gyri, whereas those to the AV and AM nuclei are from the cingulate gyrus and the medial portion of the posterior parahippocampal gyrus. These projections might be involved in sensory attention, since both the posterior cingulate and the posterior parahippocampal gyri are connected with the posterior parietal cortex, area PG-Opt, and are related via corticocortical connections to multiple sensory modaiities (Seltzer and Pan- dya, '76; Mesulam et al., '77; Hyvarinen, '82; Van Hoesen, '82; Baleydier and Mauguiere, '80, '87). The posterior parietal region, area Opt, has been shown to be involved in attending to motivationally significant stimuli (Mountcas-

CASE 12 A

Fig. 7. Diagrams showing the locations of isotope injections in the perirhinal cortex, area 35 (case 12, top), and the temporal polar region, area TG (case 13, bottom), as well as representative thalamic sections depicting the resulting distribution of silver grains.

142 E.H. YETERIAN AND D.N. PANDYA

Fig. 9. Darkfield photomicrographs ( ~ 3 0 ) showing the distribution of terminal label in various thalamic nuclei. A shows label in the lateral dorsal nucleus following an injection in the caudal cingulate gyrus (area 23), case 6. B shows silver grains in the medial pulvinar nucleus with an injection in the caudal parahippocampal gyms (area TF), case 8. C and D

show terminal label in the medial pulvinar nucleus and the lateral dorsal nucleus, respectively, following a n injection in the medial parahippocampal gyrus (area TH), case 11. E and F show silver grains in the caudal dorsomedial nucleus and the medial pulvinar nucleus, respectively, with an injection in the lateral temporal pole (area TG), case 13.


We have also observed that certain paralimbic regions project to modality-specific thalamic nuclei. Thus, the posterior cingulate (area 23) and the lateral parahippocampal (area TF) cortices have connections to the LP nucleus, which is known to have strong ties to the somatosensory association cortices (Petras, '71; Jones et al., '79; Weber and Yin, '84; Yeterian and Pandya, '85; Schmahmann and Pandya, '86). This connectivity can be correlated with the differential architectonic features of these two regions as compared to proisocortical areas. Although areas 23 and TF both have a predominance of infragranular layers, they also have relatively more developed supragranular layers, especially layer IV (Fig. 2). These latter features are more typical of isocortical regions, which themselves are well known to relate primarily to modality-specific thalamic nuclei.

Support for an interpretation indicating that the paralimbic areas are at a similar architectonic stage (Sanides, '69, '72; Pandya and Yeterian, '85) is provided by evidence of similar thalamic connections. Thus, although the temporal polar and orbital frontal proisocortical regions are located in different lobes, these areas project to markedly similar regions of both the MD and PM nuclei. Likewise, the posterior cingulate and the lateral parahippocampal gyri, both of which are intermediate to proisocortex on the one hand and isocortex on the other, share common thalamic targets-namely, the PM and LD nuclei. It is inter- esting to note that these pairs of paralimbic regions (areas TG and 13; areas 23 and TF) are known to have reciprocal connections at the cortical level (Pandya and Kuypers, '69; Jones and Powell, '70; Chavis and Pandya, '76; Seltzer and Pandya, '76; Baleydier and Mauguiere, '80; Pandya et al., '81; Van Hoesen, '82). Moreover, as has been shown for the caudate nucleus and more recently for the medial pulvinar nucleus, cortically interconnected areas may share common projection zones in subcortical forebrain structures (Yeter- ian and Van Hoesen, '78; Selemon and Goldman-Rakic, '85; Alexander et al., '86; Goldman-Rakic and Selemon, '86; Baleydier and Mauguiere, '87).

Thus, our data imply that the dorsomedial and medial pulvinar nuclei both contain regions which receive significant input from paralimbic cortices. The proisocortical projection zones appear to occupy the medial portions of the MD and the PM nuclei, whereas the adjoining paralimbic regions (areas 23, TF and TH) project to the dorsal portion of the PM nucleus and not to MD. In addition, it seems that proisocortical areas have commonality in terms of projections to the midline and intralaminar nuclei, whereas the adjoining paralimbic regions have common projections to the anterior nuclear group (AV, AM) and the lateral dorsal nucleus. Finally, the differential thalamic connectivity of proisocortical and adjoining paralimbic areas suggests that these cortical groups along with their thalamic connections may compose functional subunits within the forebrain (Vogt et al., '79; Baleydier and Mauguiere, '80).

In regard to the possible functional significance of paralimbic-thalamic connectivity, it is well known that the paralimbic regions have a role in emotional and motivational functions (e.g., Mesulam, '81, '83; Damasio and Van Hoe- sen, '83). As pointed out above, the orbital frontal and temporal polar cortices have common thalamic projection zones and have been shown to have markedly similar functional roles. Thus, cooling of the orbital frontal or temporal polar cortex yields similar deficits on delayed and simulta- neous matching-to-sample tasks in monkeys (Horel et al., '84; Voytko, '85). The common thalamic connectivity of the

orbital frontal and temporal polar regions to the medial portions of both the MD and PM nuclei may play a role in the similar functions of these two regions.

The cingulate gyrus is a major paralimbic area which has been shown to be involved in the regulation of emotional, motivational, visceral, and attentional processes (Papez, '37; MacLean, '49; Kaada, '60; Damasio and Van Hoesen, '83). This region is related to the DM and PM nuclei as well as to the anterior, lateral dorsal, midline, and intralaminar nuclei. However, there is certain specificity in the thalamic projections from the anterior and posterior cingulate regions. Likewise, there is a suggestion of concomitant functional differences with regard to the anterior and the posterior areas. Thus, the anterior cingulate region appears to be more closely related to motor and visceral functions, including the attentional and emotional underpinnings of motor behavior, as compared to the posterior cingulate region (Nielsen and Jacobs, '51; Barris and Schuman, '53; Amyes and Nielsen, '55; Talairach et al., '73; Watson et al., '73; Laplane et al., '81; Damasio and Van Hoesen, '83; Gemba et al., '86). In this regard, it is of interest to note that the thalamic connectivity of the anterior cingulate gyrus is mainly to the MD nucleus, whereas the posterior cingulate region is connected primarily with the medial pulvinar (Vogt et al., '79; Baleydier and Mauguiere, '80, '85, '87). It may be that this differential cingulothalamic connectivity underlies, in part, the functional differentia- tion of these regions. Likewise, the posterior parahippocampal gyrus, which projects predominantly to the PM and LD nuclei, is known to play a role in higher-order sensory functions, such as the recognition of complex forms, e.g., faces (Damasio et al., '82; Damasio, '85b). Moreover, it is also thought, based on experimental studies of Kliiver-Bucy syndrome (Akert et al., '611, that the parahippocampal region has a role in stimulus significance. Thus, the corticothalamic connectivity of this paralimbic region may, in part, be involved in complex perceptual-integrative functions.

In conclusion, although the precise functional role of paralimbic-thalamic connectivity is not known, these connections may be involved in processes which are consistent with the intermediate position of paralimbic areas between limbic and isocortical structures. That is, this connectivity may be involved in integrating limbic influences on the one hand with sensory, motor, and associative processes on the other.

ACKNOWLEDGMENTS We would like to express our sincere thanks to Drs. Gary

W. Van Hoesen and Douglas L. Rosene for providing case material for this study. We are also very grateful to Mr. Brian Butler for technical assistance and to Mrs. Dorothy Evertsen for manuscript processing. This study is sup- ported by the Veterans Administration, Edith Nourse Rog ers Memorial Veterans Hospital, Bedford, Massachusetts, by NIH grant 16841, and by Colby College Social Science grants A22116 and A22157.

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