sensory and premotor connections of the orbital and medial prefrontal cortex of macaque monkeys

THE JOURNAL OF COMPARATIVE NEUROLOGY 363:642-664 ( 1995)

Sensory and Premotor Connections of the Orbital and Medial Prefrontal

Cortex of Macaque Monkeys

S.T. CARMICHAEL AND J.L. PRICE Department of Anatomy and Neurobiology, Washington University School of Medicine,

St. Louis. Missouri 63110

ABSTRACT Sensory and premotor inputs to the orbital and medial prefrontal cortex (OMPFC) were

studied with retrograde axonal tracers. Restricted areas of the lateral and posterior orbital cortex had specific connections with visual-, somatosensory-, olfactory-, gustatory-, and visceral-related structures. More medial areas received few direct sensory inputs.

Within the lateral and posterior orbital cortex, area 121 received a substantial projection from visual areas in the inferior temporal cortex (TE). Area 12m received somatosensory input from face, digit, or forelimb regions in the opercular part of area 1-2, in area 7b, in the second somatosensory area (SII), and in the anterior infraparietal area (AIP). Areas 13m and 131 also received a projection from the opercular part of areas 1-2 and 3b. The posteromedial and lateral agranular insular areas (Iapm and Ial, respectively) received fibers from the ventral part of the parvicellular division of the ventroposterior medial nucleus of the thalamus (VPMpc) that may represent a visceral afferent system. The dorsal part of VPMpc projected to the adjacent gustatory cortex. These restricted inputs from several sensory modalities and the convergent corticocortical connections to orbital areas 131 and 13m suggest a network related to feeding.

The OMPFC was also connected to premotor cortex in ventral area 6 (areas 6va and 6vb), in cingulate area 24c, and probably in the supplementary eye field. Area 6va projected to area 12m, whereas a region of area 6vb projected to area 131. The region of the supplementary eye field projected to areas 121, 120, and 12r. Area Ial received fibers from area 24c.

Lighter and more diffuse projections also reached wider areas of the OMPFC. For example, injections in several orbital areas labeled a few cells scattered through the anterior part of area TE and the superior temporal gyrus. There was also a projection to the intermediate agranular insular area (Iai) and to areas 13a and 120 from the apparently multimodal areas in the superior temporal sulcus and gyrus. I 1995 Wiley-Liss, Inc.

Indexing terms: frontal lobe, somatosensory cortex, visual pathways, olfaction, viscera

The prefrontal cortex has been implicated in the use of sensory or motor cues to guide behavior, with different functions localized in different prefrontal regions. Lesions of the lateral orbital cortex and ventrolateral convexity disrupt the ability to alter goal-directed responses based on changing reward contingencies (Mishkin et al., 1969; But- ter, 1969; Iversen and Mishkin, 1970; Passingham, 1972a,b; Passingham and Ettlinger, 1972; Mishkin and Manning, 1978). Lesions of the medial orbital cortex interfere with the extinction of unreinforced responses and have a profound effect on the level of emotional responsivity to environmental stimuli (Butter, 1969; Butter and Snyder, 1972). These deficits differ from those observed with dorsolateral prefrontal lesions, particularly those that involve area 46, that specifically disrupt the use of visuospatial cues

over a time delay (Mishkin et al., 1969; Goldman and Rosvold, 1970; Mishkin and Manning, 1978).

An understanding of the sensory and premotor connections of the dorsolateral prefrontal cortex has provided a framework for the interpretation of its visuospatial function. Area 46 is reciprocally connected with posterior parietal areas implicated in the processing of visuospatial cues (Chavis and Pandya, 1976; Barbas and Mesulam, 1981; Petrides and Pandya, 1984; Cavada and Goldman- Rakic, 1989b) and with premotor areas (Barbas and Mesu-

Accepted J u n e 24, 1995. Address reprint requests to Joseph L. Price, Department of Anatomy and

Neurobiology, Washington University School of Medicine, St. Lows, MO 63110.

SENSORY AND PREMOTOR CONNECTIONS OF OMPFC 643

lam, 1985; Barbas and Pandya, 1987; Huerta et al., 1987; Huerta and Kaas, 1990; Stanton et al., 1993) concerned with and eye and proximal limb movements (Bruce et al., 1985; Schlag and Schlag-Rey, 1987; di Pelligrino and Wise, 1991; Mitz et al., 1991). Anatomical studies of these areas indicate that they form a tightly integrated network (Schwartz and Goldman-Rakic, 1984; Selemon and Gold- man-Rakic, 1988). Inactivation of the different elements of this network alters its overall function and alters the response properties of neurons in subregions (Fuster and Alexander, 1970; Petrides and Iversen, 1979; Lawler and Cowey, 1987; Quintana et al., 1989; Quintana and Fuster, 1993). These data begin to provide information on the actual mechanisms behind the visuospatial delayed response function of the dorsolateral prefrontal cortex and provide a basis for more detailed study of the underlying neuronal properties of such a function (Joseph and Barone, 1987; Barone and Joseph, 1989; Funahashi et al., 1989, 1991).

Far less information is available on the possible sensory and premotor relationships of the orbital and medial prefrontal cortex (OMPFC). Olfactory inputs have been demonstrated to the posterior orbital cortex (Potter and Nauta, 1979; Carmichael et al., 1994). Anterior portions of vision- related areas in the inferior temporal cortex project to several regions within the OMPFC (Pandya and Kuypers, 1969; Jones and Powell, 1970; Chavis and Pandya, 1976; Seltzer and Pandya, 1989; Webster et al., 19941, but the relative strength and distribution of the connections have not been determined. The projections of other sensory modalities into the OMPFC have not been similarly studied in the macaque. There is some evidence that sensory inputs to the OMPFC may be segregated into an area-specific pattern (Barbas, 19881, but a systematic study of the sensory and premotor relationships of individual orbital and medial prefrontal areas has not been performed. An understanding of these connections will provide the basis for further investigation of the perseverative and response- inhibition deficits seen with lesions of these areas.

The present study defines the sensory and premotor connections of individual areas in the OMPFC. The results indicate that these connections define a general organization within the OMPFC, such that lateral orbital areas receive the bulk of the sensory- and premotor-related inputs, and posterior and central orbital areas participate in several stages of convergent olfactory, visceral, and gustatory processing.

MATERIALS AND METHODS Animals

Eighteen Macaca fascicularis monkeys and one Macaca nemestrina monkey were utilized in this study. A previous paper in this series (Carmichael and Price, 1994) noted that no significant qualitative differences were found in the architectonic organization or connections of the OMPFC in different macaque species. All of the animals were adults. The anesthetic and operative procedures have been described in the companion paper (Carmichael and Price, 1995). Briefly, anesthesia was induced with ketamine (10 mg/kg, i.rn.1 and xylazine (0.67 mgikg, i.m.), and surgical anesthesia was continued with a gaseous mixture of oxy- gen, nitrous oxide and halothane.

Injections, perfusion, and tissue processing The procedures for the microinjection of anatomical

tracers, brain perfusion, and tissue processing have been described in the companion paper (Carmichael and Price, 1995). The location and extent of each tracer injection is shown in coronal sections of each figure in this paper as well as in Figures 1 and 2 of the companion paper (Carmichael and Price, 1995a). Of the experiments used in the previous studies, only the retrograde tracer experiments will be described here. Most of the anterograde tracer injections were into medial and posteromedial orbital areas and the medial wall and did not appreciably connect with sensory or

A AIP amts AON AONl AONm as CI Cm

dWMpc

ECo En G lac Iai la1 lam Iapl Iapm Id Ig LA MA MD 0g ots

cs

Abbreviations

amygdala anterior intraparietal area anterior medial temporal sulcus anterior olfactory nucleus lateral division, anterior olfactory nucleus medial division, anterior olfactory nucleus arcuate sulcus central lateral nucleus of thalamus central median nucleus of thalamus cingulate sulcus dorsal segment, parvicellular division, ventroposterior me-

olfactory field, entorhinal cortex endopiriform nucleus gustatory cortex caudal agranular insular field intermediate agranular insular area lateral agranular insular area medial agranular insular area posterolateral agranular insular area posteromedial agranular insular area dysgranular insula granular insula lateral auditory area middle auditory area rnediodorsal nucleus opercular gyrus (on frontal operculum) occipitotemporal sulcus

dial nucleus of thalamus

PAC0 PC Pf PI PrCO PS RA Re SEF STGa

STGp

TE TEO TF THI TPag TPdgd TPdgv

WI W L W M WMpc

vWMpc

TPg

olfactory field, periamygdaloid cortex piriform cortex parafascicular nucleus of thalamus parainsular area precentral opercular cortex principal sulcus rostra1 auditory area reuniens nucleus of thalamus supplementary eye field anterior division of the cortex of the superior temporal gyrus

posterior division of the cortex of the superior temporal gy-

architectonic area TE architectonic area TEO architectonic area T F thalamointerpeduncular tract agranular area of temporal polar cortex dorsal dysgranular area of temporal polar cortex ventral dysgranular area of temporal polar cortex granular area of temporal polar cortex ventroposterior inferior nucleus of thalamus ventroposterior lateral nucleus of thalamus ventroposterior medial nucleus of thalamus parvicellular division, ventroposterior medial nucleus of

ventral segment, parvicellular division, ventroposterior me-

and sulcus

rus and sulcus

thalamus

dial nucleus of thalamus

644 S.T. CARMICHAEL AND J.L. PRICE

TABLE 1. Sensory Projections to the OMPFC’

Area TE 1-2 3bl SII 7b G Olf Olfneo Viscthal Viscctx STGa STGp PI

120 + + + + + + + + + + + + + + + 12r + + + 121 + + + + + + + 12m + + + + + +++ + + + + + + + + 131 + + + + + + + + + + + + + + + + 13m + + + + + ++ + + + + + + + 1 :ia + + + + + + + + + + + + + + + 13h + + + + la1 + + + + + + + + + + + + + + lam + + + + + + + + + + + + + + la1 + + + + + + ++ + + + + + + + + + + 14r + + + + + 14c + + + + + + I00 + + + + + I l m + + + 111 + + + + + + + + + + 32 + + 24a.h + + ‘G. Lwstatov cortex: Olf, primary olfactory cortex: Olf neo, olfactory neocortex larea laml; STGa,p; cortex in the superior temporal gyrus and sulcus, anterior and posterior; 3 1 , second somatosensory area: TE. Inferior temporal visual association cortex; Visc thal, ventral part of ventral posterior medial nucleus of thalamus parvicellular division; Visc ctx. viscpral cortex iareas lapm. I d , Iapl, Id]; 1-2, opercular part of areas 1 and 2; ++ +. suhstant id projection, large numbpr of rrtrogradley labelled cells; + +, moderate projectim: +. light projection. ‘Labeled cells are in the most anterior and ventral part uf Bb.

lapm + + + + + + + + + + + + +

premotor areas (see below), although they are robustly connected with limbic areas (Carmichael and Price, 1995a).

Data analysis The distribution of labeled cells was analyzed as de-

scribed in the companion paper (Carmichael and Price, 1995). Briefly, the locations and extent of the injections and the positions of labeled cells were plotted from coronal sections with a computerized digital plotting system (Min- nesota Datametrics). This system allowed accurate plots of every labeled cell within the section, with a resolution of about 5 km. Structural features and cortical boundaries were then determined from adjacent sections stained for Nissl, myelin, acetylcholinesterase (AChE), and several immunohistochemical markers (Carmichael and Price, 1994).

In order to describe the relative strength of the labeled projections, estimates were made of the numbers of labeled cells within each cortical area (Table 1). These were in- tended to give an indication of the relative size of a projection and were not strictly quantitative. In general, a projection was considered “heavy” if the densest region of labeling within an area had more than ten labeled cells within a 1-mm-wide traverse through the cortex. A “moderate” projection had less than ten and more than one labeled cell within a 1-mm-wide traverse. A “light” projection either had no more than one cell within such a traverse or had only one small patch of labeled cells within a large cortical area.

RESULTS Sensory connections of the OMPFC

Oueruiew. The sensory inputs to the OMPFC were defined with 29 retrograde tracer injections into single cortical areas (the same experiments were also used in the companion paper; see Figs. 1 and 2 in Carmichael and Price, 1995). These indicate that the OMPFC receives input from many primary sensory and sensory association areas. Most of these inputs are directed to posterior and lateral orbital areas. Few sensory-related inputs reach the medial orbital areas or the medial wall (Table 1). Thus, within the OMPFC, sensory-related inputs define a lateral orbital

sensory-related region, a posterior orbital sensory-related region, and a medial, relatively nonsensory region.

Within the lateral sensory-related orbital region, vision and somatic sensory-related structures project to specific cortical areas. Substantial visual projections are directed to area 121. Area 12m receives somatosensory input from several parietal and insular areas. The posterior orbital sensory-related region receives visceral and olfactory- related inputs. The posteromedial and lateral agranular insular areas (Iapm and Ial, respectively) receive a putative visceral projection from the ventral edge of the VPMpc, whereas the medial agranular insular area (Iam) is most closely related to the primary olfactory cortex (Carmichael et al., 1994). The primary olfactory cortex also projects to areas Iapm and Ial, and areas Iapm, Ial, and Iam are all strongly interconnected.

In addition to these dense, area-specific sensory inputs, there are more widespread and diffuse sensory projections to the OMPFC. That is, retrograde tracer injections into restricted prefrontal areas not only label a large number of cells concentrated in specific sensory-related areas but also label a smaller number of cells scattered through other sensory areas. Thus, the sensory input to the OMPFC takes two forms: substantial projections from particular sensory modalities that have concentrated terminations in specific cortical areas and lighter, divergent projections that reach several different areas.

Visual association cortex. Within the cortical areas that are directly related to the visual system, only the inferior temporal cortex contained labeled cells following retrograde tracer injections into the OMPFC. Especially from the lateral orbital areas, cells were labeled throughout the rostrocaudal extent of Bonin and Bailey’s field TE (Bonin and Bailey, 19471, which, as used here, extends along the inferior temporal gyrus from the granular temporal polar area (TPg; Carmichael and Price, 1995) rostrally to the boundary with architectonic area TEO near the anterior tip of the posterior medial temporal sulcus caudally (Boussaoud et al., 1991). This definition includes the anterior and central inferior temporal fields of Van Essen et al. (1990).

Within the OMPFC, area 121 receives the most substantial projection from TE. A retrograde tracer injection into

SENSORY AND PREMOTOR CONNECTIONS OF OMPFC

A

OM9 D Y 4 2 1

Fig. 1. Projections to area 121 demonstrated by a diamidino yellow (DYI injection in case OM9. A-D: The distribution of retrogradely labeled cells are represented on coronal sections. Each dot represents one labeled cell. The levels of the coronal sections that illustrate the injection and retrogradely labeled cells are illustrated on the lateral view of the macaque brain in the lower left corner. Note that most of the

area 121 (case OM9, Fig. 1) labeled clusters of cells in layers I11 and V of the rostrocaudal extent of TE. Throughout much of TE, cells were clustered in the ventral bank of the superior temporal sulcus (Fig. 1C,D). In the intermediate part of TE, cell clusters were located in the ventral surface of the hemisphere, near the anterior medial temporal sulcus (Fig. 1C). In the caudal part of TE, labeled cells were scattered over both ventral and dorsal parts of the field but appeared to be concentrated in the ventral part, lateral to the occipitotemporal sulcus (Fig. 1D).

cells that project to area 121 are in the inferior temporal cortex, area TE. A small number of cells are present in the dorsal bank of the superior temporal sulcus and in area TEO. Rostrally, a dense cluster of cells is labeled in area 45 rostra1 to the frontal eye fields, and there is a column of labeled cells in area 6d corresponding to the supplementary eye field (SEF). See list ofAbbreviations.

In addition, there is an apparently lighter projection from TE to several other orbital areas. Retrograde tracer injections into areas of the OMPFC other than area 121 label scattered cells in TE, mostly in its anterior part. Thus, small clusters of retrogradely labeled cells were found in anterior TE following injections into areas 12r (case OM20, not shown), 12m (case OM14, Fig. 2), and 120 (case OM14, Fig. 3; case OM7, not shown). A few scattered cells are located in the anterior part of TE following injections into areas 13m (case OM21, Fig. 71, 131 (case OM12, Fig. 61, 13b


- B 2.50mm A

OM14 DY- 12m C

D

Fig. 2 . A-D: Projections to area 12m demonstrated by a DY injection in case OM14. Conventions as in Figure 1. Note that, unlike the projection to area 121, most of the cells labeled from the injection into area 12m are in somatosensory areas of the parietal cortex and

parietal operculum. Only very few labeled cells are present in the inferior temporal cortex. Rostrally, there are many cells in area 6va and in the precentral operculum. See list of Abbreviations.

:case OMS, not shown), 111 (case OM21, not shown), the intermediate agranular insular area (Iai; case OM15, Fig. 4; :ase MN12, Fig. 7), and Iapm (case OMlS, not shown; Ta- d e 1).

The most substantial somatosensory projection to the OMPFC is directed to area 12m,

although several other orbital areas also receive lighter projections. A retrograde tracer injection into area 12m (case OM14, Fig. 2) labeled a large number of cells in the second somatosensory area 6111, in area 7b, and in neighboring areas in the inferior parietal lobule, the opercular part of area 1-2, and the posterior granular insula (Ig; Fig.

Somatosensory areas.


OM14 FB -1 20 -

2.50mm

\

B A B W

Fig. 3. A,B: Projections to area 120 demonstrated by a fast blue (FBI injection in case OM14. Conventions as in Figure 1. Note that most of the labeled cells in the temporal and parietal lobes are present in the dorsal bank and crest of the superior temporal cortex and in the

2B-D). A few cells were also labeled at the most anterior and ventral edge of area 3b where it borders on the precentral opercular cortex (PrCO; not shown). I t is striking that, although area 12m borders 121 (compare Figs. 1 and 2 ) , this somatosensory input to area 12m is distinct from the visual related input to area 121.

A somatosensory projection has also recently been reported to a second area within the prefrontal cortex, area 46vr in the ventral lip of the principle sulcus, dorsal to area 12m (Preuss and Goldman-Rakic, 1989). The injection into area 12m was small (100 71) and was centered in this cortical area, but a small amount of injectate leaked up the pipette track into the region of 46vr (Fig. 2 ) . The leakage appeared to be too small to constitute an effective injection in 46vr, however, and this is confirmed by the pattern of label in the thalamus. Area 46 receives a prominent input from the lateral part of the mediodorsal nucleus of the thalamus (Goldman-Rakic and Porrino, 1985), but, in a parallel analysis of the thalamic label from this injection into area 12m, labeled cells were not found in this part of the mediodorsal nucleus (Ray and Price, 1993).

-9 'Y J

parainsular cortex. Relatively few labeled cells are present in the parietal somatosensory areas and the inferior temporal cortex. In the agranular insula, there is a dense concentration of labeled cells in the intermediate agranular insular area (Iai). See list of Abbreviations.

In the opercular part of area 1-2, the cells labeled from area 12m were located near the border with the gustatory cortex (defined according to Pritchard et al., 1986, and by parvalbumin immunoreactivity; Carmichael and Price, 1994). There is a slightly greater density of labeled cells in layer I11 than in layer V. Although some authors have distinguished areas 1 and 2 in this regon (Preuss and Goldman-Rakic, 19891, it appears sufficiently uniform in myelin and Nissl stains that we have retained the terminol- ogy of Roberts and Akert (19631, in which the two fields were not separated.

Two foci within SII project to area 12m. The largest concentration of labeled cells occupies the middle extent of SII anteriorly, although the cells extend laterally to the border with area 1-2 (Fig. 2C). In particular, the labeled cells are clustered in the vicinity of a small opercular gyrus (og; Fig. 2C) and avoid the most medial portion of SII near the fundus of the superior limiting sulcus. This corresponds to the position of the digit representation in the anterior body map of SII (Friedman et al., 1980; Robinson and Burton, 1980a; Burton, personal communication; see Dis-


OM15

D Y 4 3a labelled cells '.-5.

F B A a i labelled cells .:.':

Fig. 4. Projections to areas 13a and Iai demonstrated by two different retrograde tracer injections of DY and FB in case OM15. Conventions as in Figure 1. Like area 120, the cells that project to areas Iai and 13a are4 located in the dorsal bank and crest of the superior

temporal sulcus and in the parainsular cortex. A few cells that project to area 13a are also found in the rostra1 part of area TE and in area TF. See list of Abbreviations.

cussion). The second projection arises from a smaller number of cells in the posterior part of SII caudal to the posterior end of the insula. Labeled cells in this region lie ventromedial to the border of SII with area 7b just below the inferior lip of the inferior parietal lobule (Fig. 2D). The cells in both foci are equally dense in layers I11 and V.

Three more posterior regions of the parietal cortex (areas 7a, 7b, and AIP) also project to area 12m. Several cell clusters are labeled in the lateral part of area 7b (Fig. 2D) throughout the full rostrocaudal length of this area. La- beled cells are also present in area 7a, in the tip of the ventral lip of the intraparietal sulcus (not shown). A third, much smaller group of cells is found in the rostral part of the ventral bank of the intraparietal sulcus, dorsally adjacent to area 7b (Fig. 2D). This region appears to correspond to AIP (Preuss and Goldman-Rakic, 1991), which has connections with both the first somatosensory area (SI; H. Burton, personal communication) and the motor cortex (Godshalk et a]., 1984). In all three parietal areas, most of the labeled cells are located in layer I11 (Fig. 2D).

Another somatosensory projection to area 12m originates from the posterior Ig. A patch of cells was labeled from area

12m in the middle of area Ig, midway between the superior and inferior limiting sulci and extending rostrally from the level of the anterior tip of the central sulcus approximately 3 mm. The labeled cells are located in both layers I11 and V, but they predominate in layer V. This region of the Ig receives direct input from SI (H. Burton, personal communication) and from SII (Friedman et a]., 1986) and projects to the motor cortex (Godshalk et al., 1984).

Areas 13m, 131, and Ial also receive somatosensory inputs. Retrograde tracer injections into these areas (area 13m, cases OM5 and OM21; area 131, cases OM12 and OM21; Ial, case OM22) labeled cells in area 1-2 (Figs. 6B, 7A) and in the most anterior and ventral part of area 3b, mostly in layer 111 (Fig. 6B). The position of the cells that project to all of the orbital areas partially overlaps in the rostral part of area 1-2, up to and extending into area PrCO (Figs. 2A,B, 6A,B, 7B). In contrast, there are differences in the caudal part of area 1-2. The cells that project to Ial are all situated rostral to the point where the two limbs of the arcuate sulcus meet. The cells that project to areas 13m and 131 extend farther caudally to the level of the anterior tip of

SENSOKY AND PREMOTOR CONNECTIONS OF OMPFC 649

OM18 FB __G

labelled cells -'{.

DY-Iapm labelled cells ':i:

double labelled cells \;,

1.25mm

: .u A

Ventral Thalamus: Area of Detail

OM22 FB -1al

Fig. 5. Projections to the gustatory cortex, posterior orbital cortex, and rostra1 insula from the ventroposterior medial thalamic nucleus. FB and DY were injected into the gustatory cortex and into the posteromedial agranular insular area (Iapm) in case OM18 (A) , and FB was injected into the lateral agranular insular area (Ial) in case OM22

(B). The coronal section tinset, center) shows the location of the cell plots in the ventral thalamus. Note that all injections labeled cells in the parvicellular part of VPM, and the cells labeled from the agranular insular areas are ventral to those labeled from the gustatory cortex. See list ofAbbreviations.

the central sulcus (Figs. 6B, 7A). The cells that project to area 12m extend approximately 1 mm caudal to this point.

Like all of the sensory-related prefrontal projections, there are smaller somatosensory projections to widespread parts of the OMPFC. Retrograde tracer injections into areas 111 (case OM211, 120 (cases OM7 and OM14, Fig. 3), and Iapm (case OM18) labeled a small number of cells in SII, 1-2, 3b, or 7b (Table 1).

In addition to the visual-related input from inferior temporal cortex,

Superior temporal and parainsular cortex.

several areas of the OMPFC receive projections from the superior temporal cortex. This region appears to be polysensory or multimodal in nature (Desimone and Gross, 1979; Bruce et al., 1981; Hikosaka et a]., 1988). I t encompasses the superior temporal gyrus and the dorsal bank of the superior temporal sulcus.

At least three subdivisions can be recognized within the superior temporal cortex. Rostra1 to the amygdala, near the temporal pole, the cortex has a relatively thin layer IV, little sublamination in layers I11 and V, and a poor separation


OM12 DY-131

A 'B

B

Fig. 6. A,B: Projections to area 131 demonstrated by an injection of DY in case OM12. Conventions as in Figure 1. There are dense populations of labeled cells in Iapm, in the medial agranular insular area (Iam), in the dysgranular insula, and in the gustatory cortex. Projections are also labeled from the premotor area 6vb, the precentral

opercular area, and area Iam. Note that, unlike the projections to area 120 (Fig. 31, there are few labeled cells in area Iai (or in area 120) and very few labeled cells in the superior temporal cortex. See list of Abbreviations.

between layers V and VI, whereas, farther caudally, layer IV is more granular, layers 111 and V are sublaminated, and all layers are distinct. In keeping with previous classifica- tions (Moran et al., 1987; Carmichael and Price, 1995), the anterior region is termed the TPg. This area has widespread connections with the OMPFC that have been previously described (Carmichael and Price, 1995).

Caudal to the temporal pole, different projections are found from more anterior and posterior parts of the superior temporal cortex. Rostra1 to the level of the anterior

tip of the central sulcus, the superior temporal cortex sends a light but widespread projection to many areas of the OMPFC (Table 1). The superior temporal cortex posterior to this level (extending to the caudal edge of the insula) has a more restricted prefrontal projection. These two regions will be referred to as anterior and posterior parts of the superior temporal gyral cortex (STGa and STGp, respectively).

Only three areas of the OMPFC receive a substantial projection from both STGa and STGp. Injections into areas


OM2 1 F B 4 3 m (131)

MN12 DY-Iai

Fig. 7. A,B: Projections to areas 13m and Iai demonstrated by injections of FB and DY in cases OM21 and MN12. Conventions as in Figure 1. The injection into area 13m encroached slightly into area 131. Area 13m receives a substantial projection from rostral insular areas Ilapm, the posterolateral agranular insular area (lapl), and the dysgranular insula ( Id ) ] , whereas there are very few cells in the rostral insula

120 (cases OM7 and OM14), Iai (cases OM15 and MN12), and 13a (case OM151 labeled a large number of cells in the fundus and dorsal bank of the superior temporal sulcus and on the crest of the superior temporal gyms (Figs. 3,4). The labeled cells were aggregated into patches 1-3 mm across. In case OM15, two different retrograde tracers were injected into areas 13a and Iai (Fig. 4). The cells labeled from each area formed interdigitating columns in STGa and STGp.

In addition, STGa sent less substantial projections to virtually every area of the OMPFC (Table 1). In every experiment, retrograde tracer injections into the OMPFC labeled at least a small number of cells in STGa. Most of these were scattered single cells (Figs. lA, 5B), but isolated columns of labeled cells were also present (Figs. 2C, 7A).

The orbital injections that labeled the most cells in STGa and STGp also labeled a substantial number of cells in the parainsular cortex (PI) in the inferior limiting sulcus. This area receives a projection from auditory-related cortical areas in the superior temporal plane (Galaburda and Pan-

that project to area Iai. Thus, although Iai is in closer proximity to the rostral insula than area 13m, it is less connected with this region. Unlike the laterally adjacent area 131 (Fig. 61, area 13m receives input from relatively few cells in the gustatory cortex. See list of Abbrevia- tions.

dya, 1983), and preliminary evidence suggests that it may receive a direct projection from the primary auditory cortex (Morel and Kaas, 1992). There has not been an electrophysiological study of this area, however, and other areas in the temporal lobe that receive auditory projections have multimodal response properties (Desimone and Gross, 1979; Bruce et al., 1981; Baylis et al., 1987; Hikosaka et al., 1988). Tracer injections into areas 120 (cases OM7 and OM14), 13a (case OM151, and Iai (cases OM15 and MN12) labeled a substantial number of cells in PI (Figs. 4, 5). The labeled cells were situated in a large region of PI that stretches from a level near the middle portion of the amygdala to a point near the caudal end of the uncus of the hippocampus. This stretch of P I appears to include areas para1 and proA of Galaburda and Pandya (1983). The labeled cells were present in layers I11 and V, with slightly more in layer I11 than in layer V.

Visceral input: Paruicellular division of ventroposterior medial nucleus. In addition to the sensory inputs that reach the orbital cortex via corticocortical connections. the


experiments have also provided evidence for a thalamic sensory relay through the VPMpc. This nucleus receives gustatory input from a brainstem relay for cranial nerves V, VII, and IX in the rostral part of the nucleus of the solitary tract (NTS; for review, see Norgren, 1984). Previous studies have shown that VPMpc projects to the gustatory cortex in the fundus of the superior limiting sulcus and to the mouth representation in area 3b (Pritchard et al., 1986). The present experiments also demonstrate another projection from the ventral part of VPMpc to Iapm and Ial in the posterior orbital cortex and the rostral insula (cases OM18 and OM22, Fig. 5). The cells that give rise to this second projection are largely segregated from more dorsal cells that project to the gustatory cortex (case OM18, Fig. 5 ) .

In case OM18, an injection of fast blue was placed into the gustatory cortex in the fundus of the superior limiting sulcus, and an injection of diamidino yellow was placed in area Iapm in the ventral edge of the insula (Fig. 5A). The position of the gustatory cortex was based on anatomical and electrophysiological studies (Pritchard et al., 1986; Scott et al., 1986; Yaxley et al., 1990) and was confirmed by the presence of a parvalbumin-immunoreactive plexus in layers 111 and IV (Carmichael and Price, 1994).

A large number of cells were labeled in VPMpc from both injections. The cells labeled from the gustatory cortex are clustered in a row, which is located dorsally and somewhat medially in the nucleus. The cells labeled from Iapm are located ventral to the gustatory cells and extend farther laterally (Fig. 5A). At rostral levels, the two cell populations partially mix in the medial portion of the nucleus. There were few double-labeled cells in this experiment; those present were located within the row of cells that projects to Iapm (Fig. 5A).

In case OM22, an injection of fast blue into Ial also labeled a row of cells in the ventral part of VPMpc (Fig. 5B). At middle and caudal parts of the nucleus, this row stretches laterally to the lateral border of VPMpc (Fig. 5B). In the rostral part of the nucleus, the labeled cells are concentrated dorsomedially.

Within the OMPFC, the projection from VPMpc is specific to Iapm and Ial, No other tracer injection produced label in this nucleus, including retrograde tracer injections into the surrounding areas Iam (case OMS), Iai (cases OM15 and MN12), and 120 (cases OM7 and OM14) and an anterograde tracer injection into PrCO (case OM22; see Fig. 2 of Carmichael and Price, 1995). Interestingly, an anterograde tracer injection into the portion of Iapm rostral to the limen insula (case OM8) did not label axons within VPMpc. The connection with VPMpc may be limited to the caudal part of Iapm.

The different cortical connections of the dorsal and ventral parts of VPMpc may correspond to gustatory vs. visceral relays from NTS. The rostral gustatory-related part of NTS appears to project principally to the dorsal and medial part of VPMpc, whereas the caudal vagal-related part of NTS projects principally to the ventral and lateral part of VPMpc (Beckstead et al., 1980). Physi- ological data from primates and rats (Blomquist et al., 1962; Rogers et al., 1979) also suggest that cranial nerves V, VII, and IX are represented dorsally and medially within VPMpc, whereas cranial nerve X is represented ventrally and laterally. Thus, it is likely that the ventral VPMpc is a general visceral relay in parallel with the dorsal VPMpc gustatory relay and that Iapm and Ial constitute a t least part of a visceral cortex.

Visceral cortex.

Areas Iapm and Ial project substantially to posterior and central orbital areas and to one lateral orbital area (Figs. 6-8). Within the posterior orbital cortex, the heaviest projection is directed to Iam, as shown by the retrograde tracer injection into this area in case OM18 (Fig. 8A) that labeled a large number of cells in Iapm and Ial. This projection is reciprocal, because an anterograde tracer injection into Iam (case OM20, not shown) labeled axons in Iapm and Ial, and retrograde tracer injections into Iapm and Ial labeled a substantial number of cells in Iam (Fig. 8C; see also Carmichael and Price, 1996). In contrast to this robust connection with Iam, the neighboring area Iai has much lighter connections with Iapm and Ial. That is, retrograde (case OM15, Fig. 4; case MN12, Fig. 7) and anterograde (case MN12, not shown) tracer injections into Iai labeled only a small number of cells and fibers in Iapm.

Two central orbital areas, 13m and 131, received a heavy projection from the putative visceral cortical areas. Retro- grade tracer injections into areas 13m (case OM5, not shown) and 131 (case OM12, Fig. 6) or into both areas (case OM21, Fig. 7) labeled a large number of cells in Iapm, Ial, and neighboring areas Iapl and Id. This connection is reciprocal, because retrograde tracer injections into Iapm (case OM18, Fig. SC) and Ial also labeled cells in area 13m.

In the lateral orbital cortex, the retrograde tracer injection in area 12m (case OM14, Fig. 2) labeled a substantial cluster of cells in Ial. This projection is specific to area 12m, because tracer injections into surrounding areas 121 (Fig. I), 120 (Fig. 31, and 12r (Carmichael and Price, 1995; Fig. 10) labeled very few cells in Ial.

The projections from these putative visceral areas in the posterior orbital cortex, and rostral insula to the OMPFC are selective and do not simply reflect nearest-neighbor connections. For example, tracer injections into Iai, which borders Iapm and Ial, labeled only scattered cells in these areas (case OM15, Fig. 4; case MN12, Fig. 7B), whereas tracer injections into the more rostral areas 13m and 131 produced substantial numbers of labeled cells in Iapm and Ial (Figs. 6, 7A, 8A). Similarly, a tracer injection into area 13a (case O M E ) , which is caudal to area 13m, labeled a substantial number of cells only in Iapm and not in Ial.

The gustatory cortex projects to area 131 and, to a lesser extent, to area Ial. A tracer injection into area 131 (case OM12, Fig. 6) labeled a large number of cells in the middle portion of the gustatory cortex, extending from approximately 300 pm rostral to the limen insula to the level of the spur of the arcuate sulcus. An injection into Ial (case OM22) labeled fewer cells in a more caudal part of the gustatory cortex, from the level of the caudal tip of the principle sulcus to the caudal border of the gustatory cortex. The cells that project to both Ial and area 13m were equally distributed in layers 111 and V. Retrograde tracer injections into areas surrounding area 131 (area 13m, case OM5; area 120, cases OM7 and OM14; Iam, case OMS) labeled a only a small number of cells in the gustatory cortex (Figs. 3, 7 , s ) .

Compared to the strength of the gustatory cortex projection to areas 131 and Ial, the return projection from both of these areas appears weak. An injection into the gustatory cortex (case OM18) labeled only scattered cells in areas 131 and Ial, mostly in layer 111.

Nine olfactory-related neocortical areas have been identified in the posterior orbital cortex of the macaque (Carmichael et al., 1994). Based on the density and distribution of the projection from primary olfactory

Gustatorg input.

0Zfuctory input.


OM8 D Y 4 a r n

A

Iapm

P

OM2 1 F B 4 3 m (131)

2.50mm

B OM18

4 a p m

Fig. 8. Connections between the rostral insula and orbital cortex demonstrated in cases OM8,OM21, and OM18. The coronal sections on the left are through the center of the retrograde tracer injections sites. A,B: Coronal sections through the rostral insula from the limen insula to approximately 1.5 mm caudal to the h e n . C: Section through the posterior orbital cortex a t the level of the coronal sections with the

injection sites in A and B. Note that most of the cells in Iapm that project rostrally to areas 13m and lam are located in the deep cortical layers. Conversely, most of the cells in areas 13m and Iam that project caudally to Iapm are located in the superficial cortical layers. See list of Abbreviations.

cortex and its electrophysiological response properties, one area, Iam, appears to be the most closely related to the primary olfactory cortex.

The projections of the Iam resemble those of the Iapm and Ial. Area Iam is labeled most heavily following tracer injections into posterior orbital areas Iapm (case OM18, Fig. 8C1, Ial (case OM221, 13a (case OM15, Fig. 41, 13m (case OM5, Fig. 7A), and 131 (case OM12, Fig. 6).

Premotor connections of the OMPFC Recent evidence indicates that the frontal lobe of the

macaque contains several cytoarchitectonically distinct areas that possess reciprocal connections with the motor cortex, spinal cord, or superior colliculus and, thereby, have been defined as premotor areas (Mukkassa and Strick, 1979; Godshalk et al., 1984; Matelli et al., 1986; Dum and Strick, 1990; Huerta and Kaas, 1990; Morecraft and Van Hoesen, 1992). Four of these premotor areas project to the OMPFC. These include area 24c (in the rostral part of the

cingulate sulcus), two divisions of ventral area 6 (6va and 6vb, in and immediately ventral to the ventral part of the arcuate sulcus; Barbas and Pandya, 19871, and the supplementary eye field (SEF; in the dorsal part of area 6; Schlag and Schlag-Rey, 1987; Huerta and Kaas, 1990).

Area 24c projects to two areas in the OMPFC. An injection into Ial (case OM22) labeled cells in layer 111 of 24c, in the fundus and ventral bank of the cingulate gyrus (Fig. 9Bj. A retrograde tracer injection into area 24b, which also involved area 32 (case OM31, labeled cells in layer 111 at the same site within area 24c. This projection is most likely directed to area 24b, because other retrograde tracer injections that involved ventral parts of area 32 (cases OM4 and OM7j did not label cells in area 24c.

Area 6va projects substantially to area 12m. A retrograde tracer injection into area 12m labeled cells in area 6va throughout the entire length of the inferior bank and ventral lip of the ventral arcuate sulcus (Fig. 2A). Only a small number of labeled cells are found caudal to the point


OM3 6d

OM9

Fig. 9. Projections from area 24c and the dorsal part of area 6 (corresponding to SEF) to the orbital and medial prefrontal cortex (OMPFC) demonstrated by injections of DY or FB in cases OM3,OM22, and OM9. Conventions as in previous figures. Area 24c has a substan-

tial projection to the rostra1 part of area 24b and a lighter projection to area 121. The SEF in the dorsal part of area 6 projects to area 121. The inset over the section in the bottom right is the region shown at higher magnification in Figure 10. See list OfAbbreviations.

at which the two limbs of the arcuate sulcus meet. The labeled cells are located predominantly in layer V (Fig. ZA), but this may reflect the fact that the tracer injection into area 12m was mostly confined to layers V and VI (Carmi- chael and Price, 1995). In addition, a tracer injection into area 111 labeled a small number of cells in area 6va, although these did not extend as far caudally as those labeled from area 12m.

In contrast to the projection pattern of area 6va, area 6vb projects heavily to area 131. Labeled cells from the injection into area 131 (case OM121 are scattered throughout area 6vb, predominantly in layer I11 (Fig. 6). A smaller number of labeled cells are present in area 6vb following tracer injections into areas 13m (case OM21, Fig. 7A; case OM5, not shown) and 120 (case OM14, Fig. 3; case OM7, not shown).

Although the SEF is difficult to identify on anatomical grounds alone, cells in the region of dorsal area 6 that has been identified as the SEF (Schlag and Schlag-Rey, 1987; Huerta and Kaas, 1990) project to areas 121, 120, and 12r. (Figs. 9, 10). Injections into all three areas labeled a patch of cells 0 9-1 2 m m in diameter. In case OM20. two different

retrograde tracers were placed in area 12r and in area 121 (with some involvement of areas 12m and 120), and an anterograde tracer was placed into the posterior part of area 8 (Fig. 10). The resultant labeled axons and cells formed overlapping patches in the supplementary eye field (Fig. 10). The projections arise from ceIIs in layers I11 and V (Figs. 9, 10). Cells labeled from injections into areas 121 and 120 (Figs. 9, 10) are located in layers I11 and V, whereas those that project to area 12r are located predominantly in layer V.

DISCUSSION The major finding of the present study is that the lateral

and posterior orbital areas have substantial and specific connections with other cortical areas that are involved in sensory and premotor functions. Vision-related inputs from much of the inferior temporal cortex (area TE) reach area 121. Somatosensory projections from areas SII, 7b, 3b, AIP, and Ig are directed to area 12m and, to a lesser extent, to area 131. A transthalamic visceral sensory relay has been identified through VPMDC to IaDm and Ial. In terms of


OM20

DY - 12r FB 421/120/12m 3HL -8- labelled cells @$’ labelled cells $& labelled axons

Fig. 10. Connections between the region of the SEF and the OMPFC. Two different retrograde tracers (DY and FBI and one anterograde tracer (Wleucine) were placed in the lateral orbital cortex of case OM20. The FB injection was confined to layers 1-111 and

premotor inputs, the SEF projects to area 121, ventral area 6 projects to areas 12m and 131, and the cingulate premotor area 24c projects to Ial. The organization of these inputs complements the pattern of limbic connections, which are primarily directed to medial and posterior orbital areas (Carmichael and Price, 1995). In particular, the medial orbital areas that are related to the hippocampus are segregated from the lateral and posterior orbital areas that are related to the sensory and premotor areas.

The sensory and premotor inputs to the OMPFC take two anatomical patterns. In the first pattern, a substantial projection from a limited and characteristic set of sensory or premotor areas converges on individual areas in the lateral and posterior orbital cortex. These inputs are area specific: The predominant sensory or premotor input directed to one area is not directed to its neighbors. For example, a large number of cells in visual association area TE in the inferior temporal cortex send a restricted projection to area 121, which does not extend into the adjacent area 12m. The second type of projection pattern is much lighter and more diffuse, arising from fewer cells but with fibers terminating a wide region of lateral, posterior, and rostral orbital cortex. For example, in addition to the substantial projection from area TE to area 121, scattered cells in the rostral part of area TE send fibers to several orbital areas. The existence of two different types of sensory and premotor projections to the prefrontal cortex may have complicated the interpretation of previous stud-

involved areas 121, 120, and 12m. The labeled axons and cells form overlapping patches in the dorsal part of area 6 in the region identified as the SEF. See list of Abbreviations.

ies (Pandya and Kuypers, 1969; Jones and Powell, 1970; Chavis and Pandya, 1976; Petrides and Pandya, 1984, 1988; Seltzer and Pandya, 1989). Large lesions or injections of retrograde or anterograde tracers into sensory-related regions of the parietal and temporal lobes would involve not only the substantial number of cells that give rise to area specific projections but also the clusters or isolated columns of cells that send diffuse projections to many areas.

Pattern of sensory input to the OMPFC Visual input. Area 121 in the lateral orbital cortex and

ventrolateral convexity receives a projection from the entire rostralicaudal extent of area TE. This projection arises from sites in both the ventral bank of the superior temporal sulcus and the ventral surface of the temporal lobe.

Anatomical evidence in both owl monkeys (Weller and Kaas, 1987) and macaques (Seltzer and Pandya, 1978; Umitsu and Iwai, 1980; Van Essen et al., 1990) suggests that TE is not a homogeneous cortical field. Electrophysi- ological (Desimone and Gross, 1979) and behavioral (Horel et al., 1987) studies support a rostrocaudal subdivision of TE, and it appears that the caudal portion of TE is earlier in the pathway for visual processing of form and color (Weller and Kaas, 1987; Van Essen et a]., 1990). The caudal part of TE receives visual input from area V4 (Umitsu and Iwai, 1980; Weller and Kaas, 1987; Van Essen et al., 1990), whereas the rostral part receives visual input primarily

656

from caudal TE (Weller and Kaas, 1987; Umitsu and Iwai, 1980). In concert with this organization, the present findings show rostral vs. caudal differences in the projection from TE to the OMPFC. Only area 121 receives a projection from both rostral and caudal regions of TE, but rostral TE also projects lightly to several other orbital regions.

Webster et al. (1994) have recently reported that the inferior temporal cortex projects to area 12 as well as to area 45 and to the ventral part of area 8 in the dorsolateral prefrontal cortex. Although they did not subdivide area 12, the projection is concentrated in the lateral part of this area, corresponding to area 121, as defined here. The projection arises both in area TE and in the more caudal area TEO. Much more variable projections were also identified from rostral area TE to areas 13 and 11. These projections closely resemble the convergent projection to area 121, and they also resemble the more scattered projections to other areas described here.

A similar projection from TE to the OMPFC is also seen in owl monkeys. In this New World monkey, both parts of TE project to a restricted portion of the frontal lobe that includes the cortex on the ventrolateral convexity and lateral orbital surface (Weller and Kaas, 1987). The position of this frontal region is very similar to area 121 in macaques. Rostra1 TE in owl monkeys also sends a few fibers to other regions of the orbital cortex (Weller and Kaas, 1987). Thus, in owl monkeys, both the difference in the projections of rostral vs. caudal TE and the termination of the caudal TE projection within the prefrontal cortex correlate with the present findings in macaques.

In other reports, Barbas (1988) has identified a predominantly visual projection to a lateral region of area 12 and a predominantly somatosensory projection to a medial region of area 12. These results are consistent with the segrega- tion of visual input to area 121 and somatosensory input to 12m. Other studies in macaques have been complicated by methodological problems. Within the temporal lobe, large tracer injections or lesions have been placed in inferior temporal cortex that, in many cases, involve both rostral and caudal parts of TE (Pandya and Kuypers, 1969; Jones and Powell, 1970; Chavis and Pandya, 1976; Seltzer and Pandya, 1989). In other experiments (Chavis and Pandya, 1976; Seltzer and Pandya, 1989), the lesion or tracer injection site involved both TE and the temporal polar area TPg (Moran et al., 1987). Because TPg and the anterior part of TE project widely to the orbital cortex (Carmichael and Price, 1995; present study), the involvement of these areas would obscure the projection pattern of posterior TE. However, three findings emerge from these studies that are consistent with the projections reported in the present study: Large tracer injections into, or lesions of, TE consis- tently demonstrated axons in the lateral orbital cortex and the ventrolateral convexity. Injections or lesions confined to the middle region of TE labeled axons within the OMPFC that were restricted to the lateral orbital cortex or to the ventrolateral convexity. And, when injections involved the rostral part of TE, the label was again concentrated in the lateral orbital cortex and the ventrolateral convexity but was also found in other orbital areas.

Somatosensor-y input. The predominant somatosensory input to the OMPFC is directed to an area in the rostral part of the lateral orbital sulcus, area 12m. The most substantial part of this projection originates from portions of the parietal operculum. This includes part of area 1-2 rostrally and two more caudal foci within SII. An additional projection arises in the posterior Ig area. In the

S.T. CARMICHAEL AND J.L. PRICE

inferior parietal lobule, areas 7a, 7b, and AIP project to area 12m.

The somatosensory input to area 12 is also supported by previous studies. Several studies have shown a projection from area 7b to the region of area 12, although the distribution within area 12 was not determined (Pandya and Kuypers, 1969; Andersen et al., 1990). Jones and Powell (1970) also described a projection to this region from inferior parietal cortex, including area 7 . Cavada and Goldman-Rakic ( 1989b) illustrated anterograde and retrograde label from a horseradish peroxidase injection into area 7b in the cortex at the rostral end of the lateral orbital sulcus, a position consistent with area 12m. Barbas (1988) reported that a retrograde tracer injection into the medial part of area 12, overlapping area 12m as defined here (Carmichael and Price, 1994), labeled cells in areas 1-2, SII, and 7b.

The location of the cells that project to area 12m suggests that this area receives a projection from the face, digit, or forelimb representations in areas SII and 7b and, to a lesser extent, area 3b. Both of the projections from SII originate from regions that have receptive fields on the face or digits or that are connected to face and digit areas of SI (Robinson and Burton, 1980a; Burton and Fabri, 1994). An approxi- mate landmark for the digit representation in anterior SII of macaques is the small opercular gyrus in the parietal operculum (Fig. 2; see Friedman et al., 1980; Robinson and Burton, 1980a). The second, more posterior SII projection to area 12m also originates from a face and digit representation. The posterior face and digit representations lie in a second somatotopic body map that is situated caudally in SII (Robinson and Burton, 1980a; Burton et al., 1994).

The somatotopic organization of area 7b is less well defined than that in SII, but a gross somatotopy has been reported. Neurons with hand and mouth receptive fields tend to be located on the anterior and lateral surface of the inferior parietal lobule (Hyvarinen and Shelepin, 1979; Leionen and Nyman, 1979; Robinson and Burton, 1980bj. This position is coextensive with the cells that project to area 12m. Unlike SII, the organization of area 7b is probably not purely somatotopic, because ophthalmic, perioral, forelimb, hand, and whole body receptive fields have also been recorded in the same region (Robinson and Burton, 1980b). Hand and mouth representation is also found in other areas related to area 12m. In area 3b, the relatively small number of cells that project to area 12m are located in the region that contains a representation of the mouth (Pritchard et al., 1986). The premotor projection to area 12m, as discussed below, arises from a portion of area 6 that has been reported to represent mouth and forelimb movements (Rizzolatti et al., 1981a,b, 1988).

In addition to areas SII and 7b, area 12m receives projections from the Ig, from area AIP, and from the opercular portion of areas 1-2. Although the connections and physiological responses of areas SII and 7b have been described (Robinson and Burton 1980b; Friedman and Murray, 1986; Neal et al., 1987; Cavada and Goldman- Rakic, 1989a; Andersen et al., 1990; Burton and Fabri, 1994), only anatomical evidence places AIP, the opercular part of areas 1-2, and the Ig within the somatosensory system. The region of the Ig that projects to area 12m receives input from SI (Burton et al., 1994) and SII (Friedman and Murray, 1986). Area AIP is also connected with SI (Burton and Fabri, 1994) and with the motor cortex (Godshalk et al., 1984). Roberts and Akert (1963) defined the region rostral to SII as an opercular extension of areas 1


and 2 on the basis of cytoarchitecture, and Burton and Jones (1976) demonstrated that this region receives a projection from the ventroposterior inferior nucleus in the macaque and in squirrel monkeys.

Altogether, these projections provide convergent inputs to area 12m from several areas that represent different hierarchical levels within the somatosensory system (i.e., areas SII, 7b, Ig, and AIP; Friedman et al., 1980, 1986; Robinson and Burton, 1980a,b; Neal et al., 1987; Andersen et al., 1990; Felleman and Van Essen, 1991). This relationship is similar to that discussed above for area TE and appears to be a general principle in the sensory connections of the prefrontal cortex.

In a previous paper, it was shown that the primary olfactory cortex projects to several areas in the posterior orbital cortex, including areas Iam, Ial, Iapm, and 13m (Carmichael et al., 1994). On the basis of its connections and electrophysiological responses, Iam has been identified as the area most closely related to the olfactory system (Carmichael et al., 1994). In turn, this area is connected with other areas in the posterior orbital cortex that receive gustatory and, probably, visceral inputs (see below). This represents the earli- est stage at which the olfactory and gustatory systems converge, and it may provide the substrate for conjoint appreciation of olfactory and gustatory aspects of food as flavor. In addition, the convergence of other sensory modalities on the same orbital areas suggests that they are concerned with other aspects of food as well and, possibly, with wider motivational factors (see below).

One of the striking findings of the present study is that complementary regions within the parvicellular division of VPMpc project differentially either to the gustatory cortex or to the posterior orbital areas Iapm and Ial. The cells that project to Iapm and Ial are clustered ventrally and laterally in VPMpc, whereas cells that project to the gustatory cortex lie in the dorsal and medial parts of the nucleus. A connection between ventral VPMpc and the rostral insula has also been reported in other tract-tracing studies in the macaque (Mufson and Mesulam, 1984; Friedman et al., 1986).

Evidence from several mammalian species indicates that the ventrolateral part of VPMpc functions as a general visceral relay that is segregated from the relay of gustatory afferents. In primates, the projection from the caudal vagal-recipient part of the nucleus of the solitary tract appears to terminate principally in the ventral and lateral part of VPMpc, whereas the rostral gustatory-related part of nucleus of the solitary tract projects principally to the dorsal and medial part of VPMpc (Beckstead et al., 1980). Similarly, multiunit activity evoked by stimulation of the glossopharyngeal, chorda tympani, and trigeminal nerves is confined to the dorsal and medial parts of VPMpc; the most ventral and lateral parts of VPMpc are unresponsive to stimulation of these nerves (Blomquist et al., 1962). Also, single units in the macaque that respond to sapid stimulation of the tongue are concentrated in the medial part of VPMpc (Pritchard et al., 1986). These results fit with the early observation in the cat that stimulation of the vagus nerve evokes activity in the ventral and lateral parts of the ventral thalamus (Dell and Olson, 1951).

In the rat, there is also evidence for a visceral relay that is segregated from the gustatory relay. Cells at the ventrolat- era1 edge of the ventroposterior nucleus, lateral to the gustatory relay cells, project to visceral and autonomic responsive areas in the insula (Cechetto and Saper, 1987;

Olfactorg, gustatory, and visceral inputs.

Allen et a]., 1991). Similar to the monkey, the areas of the insula that receive this thalamic projection border the gustatory cortex (Cechetto and Saper, 1987; Allen et al., 1991). Also, single units in the ventral and lateral part of the ventroposterior nucleus respond to peripheral autonomic stimulation (Rogers et al., 1979).

The suggestion that visceral afferent information is represented in the posterior orbital cortex and rostral insula receives support from almost a century’s worth of studies. Stimulation of the posterior orbital cortex and rostral insula in experimental animals evokes profound alterations in respiratory, hemodynamic, and visceral function (Spencer, 1896; Bailey and Sweet, 1940; Delgado and Livingston, 1948; Livingston eta]., 1948; Sugar et a]., 1948; Kaada et al., 1949; Penfield and Rasmussen, 1950; Wall and Davis, 1951; Hoffman and Rasmussen, 1953) and even myocardial infarction (Hall and Cornish, 1977). Although electrical stimulation of other cortical sites also evokes autonomic alterations, the rostral insula is the site that gives the most consistent autonomic responses (Hoffman and Rasmussen, 1953). Furthermore, there is evidence from cortical stimulation in humans that both sensory and motor aspects of visceral function are represented in the rostral insula (Penfield and Rasmussen, 1950; Penfield and Faulk, 1955).

Although olfactory, visceral, and gustatory inputs reach the cortex through different routes, there is substantial convergence of these sensory modalities at the cortical level. Projections from the primary olfactory cortex and from ventral VPMpc converge on Iapm and Ial. Thus, olfactory- and visceral-related inputs converge on single areas at the first neocortical processing stage for these senses. Also, Iapm and Ial are reciprocally connected with Iam, providing a neocortical link between olfactory and visceral inputs. Area Ial also connects with the gustatory cortex. Thus, Ial receives convergent olfactory, visceral, and gustatory inputs. Rolls and Bayliss (1994) have recently reported that individual cells in the posterior orbital cortex can be driven by gustatory, olfactory, or visual stimuli, either separately or in combination.

Many of the multimodal cells recorded by Rolls and Bayliss (1994) were located rostral to Iam, Iapm, and Ial, in the region of areas 13m and 131; and, indeed, the olfactory-, gustatory-, and visceral-related areas in the posterior orbital cortex project rostrally to these central orbital areas (Fig. 11; see also Carmichael and Price, 1996). However, there are important differences in the connections of areas 13m and 131. Area 13m receives a light but direct projection from the primary olfactory cortex; area 131 does not (Carmi- chael et al., 1994). Conversely, area 131 receives a substantial projection from the gustatory cortex that is not directed to area 13m. Both area 13m and area 131 also receive a projection from the opercular part of area 1-2 and from the most anterior and ventral part of area 3b. This appears to be the region of area 3h with a perioral and tongue representation (Pritchard et al., 1986); it receives afferents from the VPMpc and is also closely connected with the gustatory cortex (Pritchard et al., 1986; Carmichael and Price, unpublished observations). Area 13m receives a much lighter projection from area 3b than from area 131. In total, the anatomical connections of the central orbital areas provide for complex chemical and somatic sensory convergence.


SII Ig

cortex

Chemical Sensory and Visceral Inputs

12m Network

Polymodal Inputs 121 Network

131 Network

olfactory Cortex

13m Network

Fig. 11. Summary of the major, most substantial sensory and premotor connections of the OMPFC. Olfactory, gustatory, and visceral inputs reach the posterior orbital cortex from the primary olfactory cortex and from the thalamic nucleus VPMpc. Somatic sensory and premotor inputs converge on area 12m, and visual-related inputs converge on area 121. Areas 120, 13a, and Iai form a different system

What are the properties of a general visceral cortex?

Several previous studies have suggested that the chemical and visceral senses are represented within a single

that receives apparently polymodal inputs from the superior temporal gyrus. Areas 131 and 13m receive convergent sensory inputs from the olfactory-, gustatoryivisceral-, and somatosensory-related orbital areas, In addition, as described in the text, there are lighter, although widespread, sensory inputs to other areas of the OMPFC. See list of Abbreviations.

region or type of cortex, which is usually referred to as the periallocortex or the proisocortex (Mesulam and Mufson, 1982a,b; Mesulam, 1986; Morecraft et al., 1992). These cortical regions are considered to be situated in the lower part of a hierarchy of cortical types that extends from limbic


or allocortical areas at the bottom to the granular association isocortex and primary sensory or motor cortex at the top (Mesulam and Mufson, 1982a,b; Mesulam, 1986; Bar- bas and Pandya, 1989; Morecraft et al., 1992). This hierarchy has been thought to have both developmental and functional significance, such that areas within each type of cortex have a generally similar structure and have similar connections and functions.

Against this concept, the substantial structural and connectional differences between the olfactory, visceral, and gustatory areas shown in the current study argue that these areas should not be considered as a single regional unit or type of cortex. Although the posterior orbital areas are similar, in that they are all agranular or dysgranular, they differ substantially in other architectural features, including staining for myelin, AChE, presynaptic zinc, parvalbumin and calbindin immunoreactivity (Carmichael and Price, 1994), and muscarinic acetylcholine receptors (Mash et al., 1988). The connections of adjacent areas also differ significantly. For example, area Iai receives a substantial projection from the superior temporal cortex that does not extend into the adjacent area Iam, whereas Iam receives an input from the primary olfactory cortex that does not extend to Iai (Carmichael et al., 1994). The connections of these areas within the prefrontal cortex are also very different (Carmichael and Price, 1996).

Such structural and connectional differences between the areas of the posterior orbital cortex, rostral insula, and frontal operculum suggest a modular arrangement in the processing and analysis of olfactory, gustatory, and visceral sensory information. The unique structure and connections of each area, or module, allow for differential processing of the sensory inputs to that area. A similar structure- function correlation is emerging from the studies of other regions of cortex, particularly the posterior parietal cortex (Newsome and Pare, 1988; Newsome et al., 1989; Andersen et al., 1990; Barash et al., 1991; Duffy and Wurtz, 1991).

Sensory prefrontal-premotor connections Each of the sensory-related areas in the posterolateral

part of the OMPFC also receives a specific input from a premotor area. A good example of this is found in the visual-related areas of the prefrontal cortex. Area TE projects strongly to area 121, which, in turn, is connected with the SEF (Huerta and Kaas, 1990; this study). TE also projects to areas 45 and 8v (Webster et al., 19941, and these areas are connected with area 121. Areas 45 and 8v contain saccadic premotor neurons (Bruce et al., 1985), although it is not clear whether these are in the same parts of these areas that are connected with area 121. Thus, the SEF/ frontal eye field, areas 121 and 45, and the inferior temporal cortex all possess specific interconnections with each other. Recent electrophysiological recordings from area 45 in response to a delayed recognition task suggest that this system may be involved in working memory for objects or patterns (Wilson et al., 1993). Area 121 may contribute an affective component to this network. Although area 45 receives little direct limbic input, area 121 is strongly connected with the amygdala and with posterior orbital areas.

Several other areas of the OMPFC also possess premotor connections. Two different regions within the ventral part of area 6 are connected with areas 131 and 12m. Area 12m receives a substantial projection from area 6va, whereas area 131 receives a projection from area 6vb. Projections

from the ventral part of area 6 to area 12 have been demonstrated previously (Barbas and Pandya, 1987), although the organization of this projection was not defined. Similarly, degenerating axons in the region of areas 12m and 131 were reported after large lesions that included ventral area 6 (Pandya and Kuypers, 1969; Jones and Powell, 1970). The electrophysiological response properties of ventral area 6 indicate that it contains a representation of face and forelimb movements (Gentilucci et al., 1988; Rizzolatti et al., 1988). Together with the pattern of face and forelimb somatosensory projections to areas 12m and 131, this suggests the presence of a network dedicated to face and forelimb involvement in feeding behaviors (see below).

Area Ial is the only posterior orbital area to receive a premotor input (from the rostral part of area 24c) in the fundus and ventral bank of the cingulate sulcus. Based on the somatotopic organization within area 24c (Mukkassa and Strick, 1979; Hutchins et al., 1988; Dum and Strick, 1990; Morecraft and Van Hoesen, 1992), the projection appears to arise from a face area.

A network involved in feeding behavior The connections between the orbital areas also form a

pattern or a network that appears to subserve sensory and premotor convergence (Fig. 11). Although such a network would involve several areas, the connections of area 131 are an especially clear example of the convergence of inputs from olfactory-, gustatory-, and putative visceral-related areas on the one hand, with inputs from face and forelimb portions of somatosensory and premotor areas on the other hand. In this section, the connections of area 131 will be discussed together with psychophysical data that provide evidence for a close association of taste, smell, texture, and satiety signals in ingestive behaviors. Together, these data suggest that the network related to area 131 is involved in feeding behavior and, particularly, in the perception of flavor and palatability and the alteration of sensory-to- motor transformations based on hedonic or motivational cues.

Flauor. Area 131 is one of the first sites within the central nervous system for convergence of olfactory- and gustatory-related activity, which occurs through substantial projections from the primary neocortical representations of gustation and olfaction: Iam and the gustatory cortex. There are other possible gustatory and olfactory convergence sites in the brain, but the inputs to those areas are either less direct or less substantial. For example, the lateral nucleus of the amygdala receives a projection from Iam and the gustatory cortex (Yasui et al., 1987; Carmi- chael and Price, 1995). This projection is less dense than the projection to area 131. Also, the output of the lateral nucleus is either back to the gustatory and olfactory areas or to the other nuclei of the amygdala (Amaral et al., 1992; see Carmichael and Price, 1995). In either case, these connections would be unlikely to have a large influence on the perceptual integration of these senses or on the motor planning of feeding behavior. Another very indirect route for olfactory and gustatory convergence might occur through the hypothalamic connections from the primary olfactory cortex and the nucleus of the solitary tract. However, these pathways are polysynaptic and involve only a few cells within a small region of the hypothalamus (Norgren, 1984; Price et al., 1991).

In sensory terms, the convergence of olfactory and gustatory pathways in area 131 presumably provides a substrate


for flavor. Flavor, which is often described as “smell in the mouth,” is a simultaneous combination of olfactory and gustatory perceptions (Tichener, 1909; Mozell et al., 1969; Rozin, 1982). In psychophysical tests, the combined perception of smell and taste into flavor is so robust that a pure odor can produce a taste illusion (Murphy et al., 1977; Murphy and Cain, 19801, and flavor perception can be disrupted by interfering with olfactory reception (Mozell et al., 1969).

The psychophysics of taste perception also indicates a close relationship between flavor and oral tactile information. Tactile inputs provide the textural and temperature cues that form an important part of palatability and food choice (Tichener, 1909; Rozin, 1982). Tactile information also helps to localize gustatory and olfactory stimuli within the mouth and to specific components of food items (Rozin, 1982: Bartoshuk, 1989; Todrank and Bartoshuk, 1991). Indeed, the tactile localization of the sense of flavor within the mouth can be manipulated to form “taste illusions” (Todrank and Bartoshuk, 1991). Even the perception of an olfactory stimulus differs if the stimulus is presented in the environment vs. within the mouth (Rozin, 1982). This has even lead to the proposal that olfactory information is processed in a dual mode in the brain through a nasal or “extraoral” path and through an oral taste-smell-tactile path (Rozin, 1982). Although there is no clear anatomical evidence for such a dual path, the several olfactory related areas in the posterior orbital cortex (areas Iam, Iapm, 131, 13m, and 13a; Carmichael et al., 1994) presumably provide a mechanism for differential processing of specific aspects of olfactory stimuli.

Visceral inputs. A general role for visceral input in feeding behavior is suggested by a number of psychophysical observations. Postconsumptive, presumably visceral signals alter the perception of satiety and influence the palatability or hedonic value of food. In humans, the previous consumption of a food item immediately decreases the palatability or “pleasantness” of that item, while leaving the simple discrimination of its gustatory and olfactory intensity intact (Rolls et al., 1981, 1983). The palatability of simple olfactory and gustatory stimuli is also specifically decreased by the ingestion of food associated with the stimuli but not by the ingestion of unrelated foods (Cabanac, 1971). An extensive body of evidence has also established a link between the palatability of simple salt and sugar solutions and prior sugar or salt loading or deprivation (Wilkens and Richter, 1940; Mayer-Gross and Walker, 1946; Henkin et al., 1963; Cabanac et al., 1969; Booth et al., 1976: Essers and Herman, 1983; Zellner et al., 1983; Pangborn and Giovanni, 1984; Shepherd et al., 1984; Rodin et al., 1985). All of these effects are present in the palatability or self-reported “pleasantness” of a food item, whereas the sensory properties of the food are unchanged (LeMagnen, 1971; Rolls et al., 1981, 1983). This alteration in food palatability is in part related to gastric stretch, but it is also clearly dependent on other general visceral inputs (as well as remembered information; for review, see Cabanac, 1989). The sensory-specific modulation of the hedonic response to food produced by the internal state of the animal has been termed alliesthesia (literally, changing sensation; Cabanac and Duclaux, 1970). The presence of visceral inputs to the same orbital areas that receive smell, taste, and somatosensory information may provide an anatomical substrate for alliesthesia.

Indeed, neurons exhibiting the property of alliesthesia have been recorded in the posterior orbital cortex. Rolls et al. (1989) reported that the responses of some neurons in the posterior orbital cortex to specific gustatory stimuli decreased as the animals were fed to satiety on solutions containing these stimuli. The decrease in neuronal responsiveness was correlated with the monkey’s behavioral responses: from avid acceptance to rejection. Moreover, this response profile was stimulus specific. For example, an animal fed to satiety on a glucose solution showed decreased neuronal responsiveness to the taste of glucose but not to the taste of berry juice (Rolls et al., 1989). This satiety-based modulation of neuronal responsiveness was not observed in lower gustatory areas such as the nucleus of the solitary tract or the gustatory cortex (Yaxley et al., 1985, 1988; Rolls et al., 1988).

However, the total percentage of neurons that exhibited the property of alliesthesia in the posterior orbital cortex was very low (Rolls et al., 1989). This may be because the region sampled appears to have included area 120 and not area 131. Areas 120 and 131 are substantially interconnected (Carmichael and Price, 1996), but, given the specific visceral input to area 131, it might be expected that alliesthesic responses would be more prevalent in area 131.

In addition to its unique combination of sensory inputs, area 131 is also connected with the premotor area 6va. Anatomical and physiological evidence indicates that this area contains a representation of the mouth and hand. Area 6va is connected with the perioral regions of the motor cortex (Godshalk et al., 1984; Matelli et al., 1986). Neurons in this region of area 6 have somatosensory receptive fields on the mouth, tongue, digits, and hands as well as on combinations of these body regions (Rizzolatti et al., 1981a). Many of these neurons also have bimodal visual and somatosensory responses. The visual receptive fields of such neurons are in register with the somatosensory receptive fields and are confined to the space immediately surrounding the mouth and hand region (Rizzolatti et al., 1981a,b).

In the awake behaving animal, neurons in ventral area 6 fire in relation to specific movements, the majority of which can be described as “grasping with the hand and the mouth” and “grasping with the hand” (Rizzolatti et al., 1988). However, these movements must be directed towards food. These neurons do not fire in relation to the same sequence of joint movements and muscle activation when they are not directed towards a food item (Rizzolatti et al., 1988).

Rizzolatti and colleagues suggest that the region that includes area 6va is involved in the motor programming of sensory-guided movements (Rizzolatti et al., 1988). In particular, they have hypothesized that neuronal responsiveness in this area is modulated by tactile stimuli on the hand, digits, and mouth and by visual stimuli in the space immediately surrounding them. They propose that neurons in ventral area 6 are activated by these visual and somatosensory stimuli but that the output from ventral area 6 to motor cortex (to initiate a movement) is triggered only if these stimuli are in some way rewarding. In most cases, this reward is a food item presented to a food-deprived animal (Rizzolatti et al., 1988).

Given the constellation of sensory inputs to area 131 and the psychophysical evidence for their combination into the perceptions of flavor and palatability, it may be hypothesized that the connection between areas 131 and 6va

Premotor inputs.

Hypothesis.

SENSWKY AND YKEMO'L'OK CONNECTIONS OF OMPFC 66 1

provides the motivational input that triggers the initiation from area 6va of motor programs that underlie feeding. Conversely, if a lesion or an injury removed the contribu- tion of area 131, then only a system of sensory and premotor connections would be left in place. Following the normal synaptic reorganization that occurs after cerebral injury, this might lead to strengthened and unregulated sensory-to- motor transformations that would be devoid of motivational influences.

Lesions in the lateral orbital cortex and the ventrolateral convexity in the human also produce direct sensory-to- motor transformations that are no longer informed by motivational or affective inputs. Patients with lesions that include these areas display what has been termed imitation or utilization behaviors (Lhermite, 1983; Lhermite et al., 1986). These patients automatically imitate the gestures or movements of another person or the normal functions of common objects when the actions or objects are presented in isolation and in close proximity (Lhermite, 1983; Lher- mite et al., 1986). For example, these patients will often mimic military-style salutes or the use of food utensils if they are performed or placed in front of them. These patients will imitate, even if they are expressly told not to, immediately prior to the test. They have a direct, unalter- able motor response to a sensory stimulus.

The similarities in the connections of areas 12m, 131, and 121 with visceral or limbic regions, on the one hand, and premotor and sensory areas, on the other hand, suggest that the principles elaborated for area 131 may generally apply to the other lateral orbital areas. These lateral orbital areas provide for the correlation of visceral or limbic input with somatosensory, visual, and premotor activity. A lesion that removes or disconnects the lateral orbital cortex would be expected to leave the sensory-premotor system intact and to provide the basis for stimulus-response behaviors that are no longer altered by the changing needs of the animal.

ACKNOWLEDGMENTS We thank Dr. Harold Burton for his help in defining the

somatosensory projections to the prefrontal cortex and Mr. Hieu Luu and Mrs. Van Nguyen for their excellent techni- cal assistance. This research was supported by NIH grant DC00093. S.T.C. was supported by traininggrant NS07057.

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