Cerebral Cortex, Vol. 10, No. 3, 220-242,
March 2000
© 2000 Oxford University Press
The Anatomical Connections of the Macaque Monkey Orbitofrontal Cortex. A Review
Departamento de Morfología, Facultad de Medicina, Universidad Autónoma de Madrid, 28029 Madrid, Spain
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Abstract |
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The orbitofrontal cortex (OfC) is a heterogeneous prefrontal sector selectively connected with a wide constellation of other prefrontal, limbic, sensory and premotor areas. Among the limbic cortical connections, the ones with the hippocampus and parahippocampal cortex are particularly salient. Sensory cortices connected with the OfC include areas involved in olfactory, gustatory, somatosensory, auditory and visual processing. Subcortical structures with prominent OfC connections include the amygdala, numerous thalamic nuclei, the striatum, hypothalamus, periaqueductal gray matter, and biochemically specific cell groups in the basal forebrain and brainstem. Architectonic and connectional evidence supports parcellation of the OfC. The rostrally placed isocortical sector is mainly connected with isocortical areas, including sensory areas of the auditory, somatic and visual modalities, whereas the caudal non-isocortical sector is principally connected with non-isocortical areas, and, in the sensory domain, with olfactory and gustatory areas. The connections of the isocortical and non-isocortical orbital sectors with the amygdala, thalamus, striatum, hypothalamus and periaqueductal gray matter are also specific. The medial sector of the OfC is selectively connected with the hippocampus, posterior parahippocampal cortex, posterior cingulate and retrosplenial areas, and area prostriata, while the lateral orbitofrontal sector is the most heavily connected with sensory areas of the gustatory, somatic and visual modalities, with premotor regions, and with the amygdala.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsOverview of the Connections...Architectonic Parcellation of...Specific Connections of the...Comments on FunctionNotesReferences |
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The orbital sector of the primate frontal lobe, or orbitofrontal cortex (OfC), forms the base of the lobe that leans on the upper wall of the orbit. Perhaps in part because of this relatively unapproachable location it has been notably less explored than other prefrontal sectors, notably the lateral prefrontal cortex. Recent work in humans and in non-human primates has highlighted the functional importance of the OfC in affective and motivational behavior, prompting an unprecedented interest in this prefrontal sector (Dias et al., 1996
; Nakamura et al., 1998; Tremblay and Schultz, 1999). Lesions of the OfC in humans are accompanied by disorders in personality, mood and social behavior (Eslinger and Damasio, 1985; Stuss and Benson, 1986; Fuster, 1989; Malloy et al., 1993). Recently, abnormal neuronal and glial cytoarchitecture in orbitofrontal areas, as well as in the dorsolateral prefrontal cortex, has been detected in the brains of patients suffering from major depression (Rajkowska et al., 1999).
As knowledge of the connectional links of the OfC is necessary to advance our understanding of its participation in brain function and dysfunction, we review its major afferent and efferent connections with the cortex and with subcortical structures. This review is based on our own work (Cavada and Reinoso-Suárez, 1989, 1990; Cavada et al., 1991, 1992; Compañy et al., 1993; Cruz-Rizzolo et al., 1993; Cavada, 1995, 1998) and on data from literature concerning the brains of adult macaque monkeys. The authoritative contributions by H. Barbas, R.J. Morecraft and J.L. Price, and their colleagues, over the last decade deserve special mention (Barbas, 1988; Barbas and Pandya, 1989; Barbas and De Olmos, 1990; Barbas et al., 1991; Morecraft et al., 1992; Barbas, 1993; Morecraft and Van Hoesen, 1993, 1998; Ray and Price, 1993; Carmichael et al., 1994; Carmichael and Price, 1994, 1995a,b, 1996; Barbas and Blatt, 1995; An et al., 1998; Öngür et al., 1998; Rempel-Clower and Barbas, 1998).
Following a brief description of the experimental procedures employed, we present first an overview of the cortical and subcortical connections of the OfC as a whole, emphasizing the structures the OfC is connected with. After presenting the evidence for parcellation of the OfC, we focus on the main differential connections of its subdivisions. We finally discuss the selective connections of the OfC with diverse brain regions with a perspective on memory and other integrative functions attributed to the OfC.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsOverview of the Connections...Architectonic Parcellation of...Specific Connections of the...Comments on FunctionNotesReferences |
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Ten adult Macaca nemestrina of both sexes, weighing 3.3–7.8 kg, were used. We followed European and Spanish guidelines for the use of animals in research (86/609/EEC: European Communities Council Directive of 24 November 1986; and BOE of 18 March 1988). Four animals (M1–M4) received unilateral injections of a horseradish peroxidase cocktail (HRP + HRP–wheatgerm agglutinin [WGA]) in different sectors of the prefrontal cortex, including the OfC in one case (Fig. 1
), and the remaining animals (M5–M10) received unilateral or bilateral injections of various tracers in specific areas of the OfC. See Table 1 for details of the experimental procedures in each case.
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The monkeys were adequately anesthetized with sodium pento-barbital, monitored, and operated under strict asepsis and antibiotic prophylaxis. The tracer deposits were made with a 1 µl Hamilton syringe by means of multiple penetrations. Monkeys with orbital injections were enucleated in order to gain direct access to the OfC through the upper wall of the orbit, thus preventing any spread of the tracers over the lateral or medial prefrontal cortex through the needle penetrations. After appropriate survival times, the animals were deeply anesthetized and perfused with saline, aldehydes and sucrose solutions in phosphate buffer. The aldehydes employed for fixation varied depending on the tracers injected. In cases M1–M4, which received injections of an HRP cocktail, a mixture of 1% paraformaldehyde and 1.25% glutaraldehyde was used. In the remaining cases, all of which were injected with fluorescent tracers, either no or only low concentrations of glutaraldehyde were used to fix the brains (Cavada et al., 1984
): 1.5% paraformaldehyde + 0.5% glutaraldehyde in cases M5 and M6; 4% paraformaldehyde + 0.2% glutaraldehyde in M7 and M8; and 4% paraformaldehyde in M9 and M10. The brains were sectioned frozen at 40 or 50 µm, and several adjacent series of sections were collected to be processed variously. In all cases one series was stained with cresyl violet and another was processed for acetylcholinesterase (AChE) histochemistry as described earlier (Cavada et al., 1995). These two series were used to examine areal boundaries. HRP activity was revealed following the tetramethylbenzidine procedure of Mesulam et al. (Mesulam et al., 1982). The series employed to visualize the fluorescent tracers were simply dehydrated, defatted and cover-slipped. These procedures help visualize and preserve the fluorescence present in the tissue. Fluorescent labeling can also be satisfactorily observed in the sections processed to reveal HRP (Cavada et al., 1984).
Sections were studied with a Zeiss Axiophot microscope using appropriate bright-field, dark-field or fluorescent illumination. Labeled neurons or terminals were plotted onto photographs or drawings of the sections using color codes and taking references from the boundaries of the section, blood vessels and other tissue elements. The labeling located in the cortex was subsequently transferred onto lateral, medial and orbital surface views of the hemispheres (Figs 1, 7
). With the exception of Figures 1B' and 2F, only labeling present in the hemispheres ipsilateral to the injections is illustrated.
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The labeled neurons located in the hippocampus of five hemispheres were counted [cases M1 (left hemisphere), M5 and M6 (left and right hemispheres); see also Fig. 3
]. Counts were performed in a rostrocaudal series of sections, spaced 400 µm from each other; i.e. one out of eight consecutive sections was counted, with a total of 34–38 sections counted in each hemisphere. The total number of labeled neurons in each hippocampus was estimated by multiplying the sum of the counted labeled cells by eight. Subsequently, the percentages of labeled neurons present in the rostral, middle and caudal thirds of the hippocampus were calculated (Fig. 3). In M5 and M6, the percentages of double-labeled neurons ranged from 4.15% to 7.1%. These double-labeled neurons were considered to project to both injected regions, and were included in the calculations made for each target area in Figure 3.
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The areal parcellation of the macaque cerebral cortex used here is shown in Figure 1A
and in Table 2, where the appropriate references are given. The subdivisions of the hippocampus and subicular complex follow Rosene and Van Hoesen (Rosene and Van Hoesen, 1987), while amygdaloid nuclei are named according to Price et al. (Price et al., 1987) [see also Amaral and Bassett (Amaral and Bassett, 1989)]. For the thalamic nuclei we use Olszewski's nomenclature, with some modifications (Olszewski, 1952; Cavada et al., 1995). The reader is referred to Table 3 for definitions of the abbreviations used in the text, figures and tables.
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Overview of the Connections of the OfC |
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TopAbstractIntroductionMaterials and MethodsOverview of the Connections...Architectonic Parcellation of...Specific Connections of the...Comments on FunctionNotesReferences |
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Corticocortical Connections
The OfC is reciprocally connected with extensive cortical territories of prefrontal, motor, limbic and sensory affiliation. These connections will be discussed in some detail in the following paragraphs. Figure 1 illustrates them and compares the overall pattern of OfC corticocortical connections (M1, Fig. 1B) with those of other prefrontal sectors (M2–M4, Fig. 1C–E). The OfC is the prefrontal sector that has the strongest links with the temporal cortex, notably with medial areas, the temporal pole, the superior temporal gyrus and with the cortex buried in the Sylvian sulcus. With minor exceptions, most OfC corticocortical connections are reciprocal, because retrogradely labeled neurons were consistently observed overlapping anterogradely labeled terminals. For this reason, generally no attempt to distinguish between afferent and efferent cortical connections will be made. Figure 7 illustrates the patterns of retrograde labeling in the ipsilateral hemispheres after injections of fluorescent tracers in specific territories of the OfC.
Connections with Prefrontal and Motor Areas
As depicted in Figures 1A,B and 7, intraprefrontal connections are heavy and include both lateral and medial prefrontal areas: 9, 46, 8A, 8B, 45, 12, 10 and 32. In the motor domain, anterior premotor area F7 (the supplementary eye field) and cingulate area 24c are the most distinctly connected with the OfC. Thus, areas involved in eye [8A, 8B, 45, F7 (Schlag and Schlag-Rey, 1987; Mitz and Godschalk, 1989)], face and forelimb movement control [24c (Luppino et al., 1991, 1994; He et al., 1995; Picard and Strick, 1996; Morecraft et al., 1996, 1997)] are linked to the OfC. Recent anatomical evidence suggests that area 24c mostly controls distal arm muscles (Morecraft et al., 1997).
Connections of the OfC with other prefrontal regions have been studied in detail by Barbas and Pandya (Barbas and Pandya, 1989), and Carmichael and Price (Carmichael and Price, 1996). The former proposed organized patterns of connections within and between areas belonging to the two prefrontal cyto-architectonic trends they distinguished, the basoventral and the mediodorsal. The basoventral trend includes the caudal non-isocortical regions of the OfC, orbital areas 13, 12, 11, 14, 10, lateral area 12 and the rostral part of ventral area 46. The mediodorsal trend includes the periallocortex next to the rostral corpus callosum, medial areas 24, 25, 32, 9, 10 and 14, lateral areas 10 and 9, and dorsal areas 46 and 8 (Barbas and Pandya, 1989). Carmichael and Price distinguished two corticocortical networks, one linking caudal and lateral parts of the OfC, and the other involving medial prefrontal, and medial and rostral orbital areas (Carmichael and Price, 1996); the two networks communicate through specific subareas. Regardless of whether the interconnections of prefrontal territories are interpreted within the frameworks adopted by either Barbas and Pandya (Barbas and Pandya, 1989), or Carmichael and Price (Carmichael and Price, 1996), it is obvious that complex intrinsic interconnections heavily tie orbital, lateral and medial prefrontal territories (Figs 1B–E, 7).
The OfC connections with the periarcuate areas 8A, 8B, and with the supplementary eye field have been reported by a number of researchers (Barbas and Mesulam, 1981; Huerta and Kaas, 1990; Morecraft et al., 1992; Carmichael and Price, 1995b), and they seem to be rather meager. It should be noted that Huerta et al. (Huerta et al., 1987) and Stanton et al. (Stanton et al., 1993) did not trace a connection between the cortex of the frontal eye field buried in the rostral bank of the arcuate sulcus, as defined by microstimulation, and the OfC. Nevertheless, even though labeling was never heavy in the rostral bank of the arcuate sulcus following tracer injections in the OfC, we have consistently observed it, and also after restricted OfC injections (Figs 1B, 7).
The cortical connections of medial motor areas have been studied in recent years, but different studies do not agree on the links with the OfC. Our findings, pointing to motor cingulate area 24c as the one most heavily connected with the OfC, agree with those reported by Carmichael and Price (Carmichael and Price, 1995b). Morecraft and Van Hoesen (Morecraft and Van Hoesen, 1993, 1998) also observed OfC connections with 24c (which they name M3), but they, like Bates and Goldman-Rakic (Bates and Goldman-Rakic, 1993), also described orbital connections with the supplementary [also called M2 (Morecraft and Van Hoesen 1993), F3 (Matelli et al., 1985, 1991) and 6M (Preuss and Goldman-Rakic, 1991)] and the pre-supplementary [F6 (Matelli et al., 1991)] motor areas, and with posterior cingulate area 23c [M4 (Morecraft et al., 1996, 1997)]. However, Luppino et al. (Luppino et al., 1993) did not find direct connections by F3 or F6 with the OfC, although both areas, in particular F6, were connected with 24c, which therefore appears to be a main gateway for the OfC, as well as for other prefrontal sectors, to the skeletomotor system (Fig. 1B–E). Regarding OfC connections with more posterior cingulate motor areas, we agree with Bates and Goldman-Rakic (Bates and Goldman-Rakic, 1993), and Morecraft and Van Hoesen (Morecraft and Van Hoesen, 1998) that such a connection may exist, since we observed weak labeling in 24d and 23c in several experimental cases (Figs 1B, 7).
There is another connection between the ventral portion of premotor area F5 [or ventral area 6 (Barbas and Pandya, 1987)] and precentral operculum (PrCO) with the nearby lateral and caudal OfC (Barbas and Pandya, 1987; Morecraft et al., 1992; Carmichael and Price, 1995b) (Figs 1B, 7C). Interestingly, distal arm movements are represented in F5 and its neurons fire in response to motivationally meaningful visual stimuli and goal-related motor acts (Gentilucci et al., 1988; Rizzolatti et al., 1988).
Connections with Limbic Areas
The limbic cortical areas connected with the OfC are multiple and diverse, and include the insular cortex (areas Iag, Idg and Ig), temporopolar cortex (areas Tpag, Tpdg and Tpg), cingulate areas 25, 24a, 24b, 23a, 23b, 23v [area 23v is the isocortical component of the caudomedial lobule of Goldman-Rakic et al. (Goldman-Rakic et al., 1984)], retrosplenial areas 29 and 30, and medial temporal areas, including the entorhinal and perirhinal cortices (areas 28, 35 and 36), parahippocampal areas TF and TH, and the hippocampus (Figs 1A,B, 7, 11) (Morecraft et al., 1992; Barbas, 1993; Barbas and Blatt, 1995; Carmichael and Price, 1995a).
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The connections of the insular and temporopolar cortices with the OfC and other cortical areas were studied in detail by Mesulam and colleagues, who proposed that the lateral orbital, temporopolar and insular regions form an integrated unit on the basis of similarities in cytoarchitectonic trends and connections (Mesulam and Mufson, 1982a
,b; Mufson and Mesulam, 1982; Morán et al., 1987). An interesting functional conclusion from their connectional analysis, and other studies, is that various types of sensory modalities are represented in the insular cortex: olfaction, visceral sensation and taste anteriorly, and somatic sensation posteriorly, in granular field Ig (Yaxley et al., 1990; Schneider et al., 1993) [reviewed by Mesulam and Mufson (Mesulam and Mufson, 1985) and Augustine (Augustine, 1996)]. Thus, the insular cortex is in a position to convey diverse sensory information to the OfC.
There are several parallel channels that link the OfC with the hippocampal formation (Figs 1A,B, 2A,B, 3, 7, 11): first, the connections with the entorhinal cortex, which engage mainly rostral, intermediate and lateral entorhinal subdivisions (Van Hoesen and Pandya, 1975b; Van Hoesen et al., 1975; Insausti et al., 1987; Morecraft et al., 1992; Carmichael and Price, 1995a); second, the connections with the perirhinal cortex and posterior parahippocampal areas TF and TH (Van Hoesen and Pandya, 1975b; Van Hoesen et al., 1975; Morecraft et al., 1992; Suzuki and Amaral, 1994; Carmichael and Price, 1995a), all of which are reciprocal; and third, direct connections from the hippocampus. The hippocampal–OfC projection is ipsilateral and arises principally from fields CA1 and CA1'. The prosubiculum, adjacent to CA1, also projects to the OfC (Figs 2A,B, A',B', 3). The existence of a reciprocal OfC–hippocampal projection is unclear: Carmichael and Price mentioned a ‘very weak return projection’ (Carmichael and Price, 1995a), and we observed fine punctate labeling in the regions holding the retrogradely labeled neurons, but definite demonstration of an OfC–hippocampal projection requires further study.
Morecraft and co-workers traced projections from CA1 and the prosubiculum to the OfC (Morecraft et al., 1992), and later others (Barbas and Blatt, 1995; Carmichael and Price, 1995a) reported more extensively on the projections from the hippocampus and subicular complex to the medial and orbital sectors of the prefrontal cortex. Their conclusions do not concur: while Barbas and Blatt asserted that the main sources of the projection are the rostral part of field CA1 and field CA1', Carmichael and Price concluded that the rostral subiculum is the main origin of the projection, with the prosubiculum also holding projecting neurons, and hippocampal fields CA1 and CA3 would only hold scattered projecting neurons. A main reason for these discrepancies is presumably the different field assignments the authors gave to the labeling located in the dorsomedial part of the genu of the hippocampus: Barbas and Blatt ascribed this labeling to CA1' and Carmichael and Price ascribed it to the rostral subiculum.
We concur with Barbas and Blatt (Barbas and Blatt, 1995) in that CA1 and CA1' are the main sources of the hippocampal–OfC projection. Our delineation of the hippocampal and subicular fields mostly relies on AChE staining, also used by Barbas and Blatt, which gives nearly unequivocal information for most of the anteroposterior extent of the hippocampal formation (Fig. 2B'). The CA1 hippocampal field has moderate cholinesterase activity, is more lightly stained than fields CA2 and CA3, and has a paler band of staining in the middle of the pyramidal cell layer; the prosubiculum (P in Figs 2A',B' and 3), which is at the border between CA1 and the subiculum, shows a high uniform cholinesterase activity; finally, the subiculum (Sb in Figs 2A',B') is virtually unstained, and only has two thin positive bands located superficial and deep to the pyramidal cell layer (Bakst and Amaral, 1984; Rosene and Van Hoesen, 1987). Identification of the hippocampal fields at the genu is more difficult. Based on the AChE staining patterns at more posterior levels, we identified the subiculum, the prosubiculum, CA1, and field CA1' dorsomedially (Rosene and Van Hoesen, 1987) (Fig. 2A'), and subsequently concluded that virtually all the neurons labeled after the large injection in case M1 are in fields CA1' and CA1. Most of the neurons have a pyramidal shape and in CA1 occupy the deepest part of the pyramidal cell layer (Fig. 2B, inset). Neuronal labeling in the prosubiculum often extended more superficially and stopped abruptly at the oblique border of this field with the subiculum. The various subicular fields, where we found hardly any labeling after OfC injections, appear to project mostly to lateral and medial prefrontal sectors (Rosene and Van Hoesen, 1977; Goldman-Rakic et al., 1984; Barbas and Blatt, 1995).
A marked rostrocaudal gradient is present in the projections from CA1, CA1' and the prosubiculum to the OfC: ~70% of all the labeled neurons were located in the rostral third of the hippocampal formation [n = 20 600 in M1; 23 584 in M5 (left hippocampus); 24 464 and 27 640 in M6 (right and left hippocampus respectively)], with 20% and 10% located in the middle and caudal thirds respectively (Fig. 3). More precisely, the rostral 2 mm of the hippocampus holds about half (50–56%) of the total population of hippocampal neurons that project to the OfC (the rostrocaudal length of the hippocampus in M. nemestrina is ~14 mm). Topographic specificity is also maintained within the OfC surface, with the medial areas as the specific targets of the hippocampal projection (Fig. 3, and further discussion below). The axons of the projecting neurons run through the fimbria– fornix, where we observed HRP-labeled axons in case M1 (not illustrated). However, we cannot discard the possibility of an additional temporofrontal route followed by the hippocampal– OfC axons.
The hippocampal–OfC projection is remarkable for its origin, magnitude and precise topographic organization. The hippocampus is a critical structure in declarative memory consolidation (Squire and Zola, 1996). Field CA1, in particular, has been shown to be selectively damaged in cases of human anterograde amnesia (Zola-Morgan et al., 1986; Rempel-Clower et al., 1996); also, CA1 is the hippocampal sector that is affected the soonest and most severely by neurodegenerative lesions in Alzheimer's disease (Price, 1986; Braak and Braak, 1993). In monkeys, selective hippocampal damage also results in memory impairment (Zola-Morgan et al., 1992; Alvarez et al., 1995), and field CA1 exhibits marked functional activation in macaques engaged on working-memory tests (Friedman and Goldman-Rakic, 1988). The robust projection from the hippocampus, as well as from the other hippocampal formation structures described above, which also contribute significantly to memory function (Zola-Morgan et al., 1989; 1993; Rempel-Clower et al., 1996), strongly suggests that the OfC is a pivotal cortical link within the neural networks that are active in learning and memory.
The striking rostrocaudal topographic organization of the hippocampal projecting neurons is enigmatic. Recent functional studies in humans give an interesting clue which suggests that the rostral hippocampal region is mainly active during episodic memory encoding, while the caudal regions are associated with memory retrieval (Lepage et al., 1998; Dolan and Fletcher, 1999). Extrapolating between species, and on the assumption that connections and function are related, one would expect the OfC to be engaged in encoding operations. Interestingly, Haxby and co-workers have reported activation of the human left OfC, as measured by regional cerebral blood flow with positron emission tomography, during face encoding (Haxby et al., 1996).
Connections with Sensory Areas
The OfC is connected with a constellation of areas affiliated to various sensory modalities: olfactory, gustatory, visceral, somatic, auditory and visual. The olfactory areas include both primary and secondary areas. The anterior olfactory nucleus, olfactory tubercle and piriform cortex receive connections from the olfactory bulb, so they are considered primary olfactory cortices, and project to the OfC (Morecraft et al., 1992; Barbas, 1993; Carmichael et al., 1994). In addition, the OfC is connected with the anterior insular area Iag, and with the olfactory field of the entorhinal cortex, both of which receive input from primary olfactory areas (Insausti et al., 1987; Morecraft et al., 1992; Barbas, 1993; Carmichael et al., 1994). The primary gustatory areas of the orbitofrontal operculum (OFO), adjacent insular field Idg and ventral area 3 are connected with the OfC (Figs 1A,B, 7) (Morecraft et al., 1992; Barbas, 1993; Baylis et al., 1995; Carmichael and Price, 1995b; Cipolloni and Pandya, 1999). These three areas receive projections from the thalamic relay nucleus for taste, i.e. the parvicellular subdivision of the ventral posteromedial nucleus (Pritchard et al., 1986). Carmichael and Price (Carmichael and Price, 1995b) have called attention to an additional type of sensory input reaching this thalamic nucleus: the vagal visceral, which would be relayed to subfields within the agranular insular field Iag. Since these subfields project to the OfC, visceral information could reach the OfC through this route.
The somatic sensory areas connected with the OfC principally include the ventral part of primary areas 1–2, secondary area S2, insular area Ig and parietal area 7b (Figs 1A,B, 7) (Morecraft et al., 1992; Barbas, 1993; Carmichael and Price, 1995b). Trigeminal and hand representations predominate in these areas (Cavada and Goldman-Rakic, 1989a; Carmichael and Price, 1995b). With regard to the auditory modality, a constellation of recently identified belt and parabelt areas are connected to the OfC. Of the seven belt areas which surround, and are connected with, the three core primary auditory areas A1, R and RT (Hackett et al., 1998), mainly the rostral areas are connected with the OfC: RM, RTM, RTL and AL (Fig. 1A,B) (Romanski et al., 1999). The parabelt auditory areas in the superior temporal gyrus RPB and CPB, which are connected to belt areas (Hackett et al., 1998), are more heavily connected with the OfC than the belt areas, in particular the rostral RPB area (Figs 1A,B, 7) (Hackett et al., 1999; Romanski et al., 1999). In addition, auditory association areas TS1 and TS2 are connected to the OfC, as well as the superior temporal polysensory area STP (Figs 1A,B, 7) (Petrides and Pandya, 1988; Seltzer and Pandya, 1989; Morecraft et al., 1992; Barbas, 1993; Romanski et al., 1999). In view of the rostrocaudal topography of the connections of the OfC and lateral prefrontal cortex with rostral and caudal belt and parabelt auditory areas, Romanski and co-workers have suggested that functionally distinct streams of auditory processing reach different prefrontal regions (Romanski et al., 1999). The rostral stream, which preferentially targets the OfC, appears to be primarily engaged in phonetic processing, while the caudal stream, associated preferentially to the periarcuate prefrontal cortex, is mostly involved in auditory–spatial processing. It should be noted, however, that this dichotomy is not strict, and some convergent input from both streams may reach either prefrontal region (Fig. 1A,B) (Romanski et al., 1999).
With regard to vision, areas of the ventral processing stream are the most heavily connected with the OfC, although there are connections with dorsal stream areas (Figs 1A,B, 7) (Barbas, 1988, 1993; Martin-Elkins and Horel, 1992; Morecraft et al., 1992; Webster et al., 1994; Carmichael and Price, 1995b). Among the former, the inferior temporal areas TEa and TEp, in particular their portions within the lower bank of the superior temporal sulcus, are prominently connected with the OfC. These inferior temporal areas receive visual input principally from ventral stream prestriate areas containing central field representations (Baizer et al., 1991) and are involved in object vision (Mishkin et al., 1983; Van Essen and Maunsell, 1983). In addition, area TEv, located medial to the anteromedial temporal sulcus and identified by Horel as an additional inferior temporal area (Horel, 1996), sustains a particularly heavy connection with the OfC. TEv appears to belong to a parallel ventral visual stream that includes ventral prestriate areas and area TF (Martin-Elkins and Horel, 1992), and, unlike areas TEa and TEp, is critical for performing delayed match-to-sample tasks (Horel, 1996). Within the dorsal stream areas, 7a and 7ip (in particular its posterior part 7ip[p]) are connected to the OfC (Fig. 1A,B) (Cavada and Goldman-Rakic, 1989b; Morecraft et al., 1992). These parietal areas are connected to visual areas where the periphery of the visual field is represented, and are involved in spatial vision and eye movement control (Mishkin et al., 1983; Van Essen and Maunsell, 1983; Shibutani et al., 1984; Cavada and Goldman-Rakic, 1989a; Andersen et al., 1992).
In addition to the connections with areas of the ventral and dorsal visual streams, the OfC is heavily linked with area STP, located in the upper bank of the superior temporal sulcus (Figs 1A,B, 7) (Barbas, 1988; Seltzer and Pandya, 1989; Morecraft et al., 1992; Barbas, 1993). As its name indicates, STP is a polysensory region, but visual responses predominate there (Bruce et al., 1981; Baylis et al., 1987), and it has been proposed as a site of integration for spatial and object information (Morel and Bullier, 1990; Baizer et al., 1991).
Finally, the OfC is also connected with a poorly understood area, called the prostriata (ProS; Figs 1A,B, 7A,B) (Barbas, 1993). ProS is located in the upper bank of the rostral calcarine sulcus, at the junction of the medial visual cortex and the retrosplenial region (Fig. 1A), and has been thought to have a visual function (Sousa et al., 1991; Rosa et al., 1997).
Connections with Contralateral Areas
As illustrated in Figure 1B', the OfC is notably connected with the cortex of the opposite hemisphere, to both homotopic and to heterotopic regions. The latter principally include the loci sustaining the heaviest intrahemispheric connections. The extensive contralateral connections of the OfC suggest that it may participate in interhemispheric integration on a broad scale. The axons of the contralaterally projecting neurons course through the anterior portion of the genu and the rostrum of the corpus callosum (Barbas and Pandya, 1984).
Subcortical Connections
Cholinergic and Aminergic Subcortical Nuclei
The OfC, like other cortical regions, is innervated by cholinergic and aminergic subcortical fibers. The cholinergic innervation is similar in distribution and density to that of the medial and lateral prefrontal sectors (Lewis, 1991), and principally comes from the nucleus basalis of Meynert (Nb in Fig. 2D), in particular from the intermediate and anterior subdivisions Ch4id, Ch4iv, Ch4am and Ch4al (Mesulam et al., 1983; Morecraft et al., 1992). It is also possible that some of the cholinergic innervation of the OfC may arise from cholinergic neurons in the septal area, the diagonal band and brainstem (Morecraft et al., 1992). It is interesting that the OfC is one of the few structures that project into the nucleus basalis, and therefore is in a position to control the cholinergic innervation of the entire cerebral cortex (Mesulam and Mufson, 1984; Öngür et al., 1998) (note the anterograde labeling in Fig. 2D). The other regions sending axons to the nucleus basalis are limbic cortices interconnected with the OfC (piriform cortex, anterior insula, temporal pole, entorhinal and posterior parahippocampal cortex), the septal nuclei, the nucleus accumbens-ventral pallidum complex and the hypothalamus (Mesulam and Mufson, 1984).
Unlike the cholinergic innervation, the catecholaminergic innervation of the macaque prefrontal cortex is heterogeneous. The density of dopaminergic and noradrenergic axons in the OfC is intermediate to that of the medial and lateral prefrontal sectors (Lewis et al., 1987, 1988; Lewis and Morrison, 1989). The dopaminergic axons originate in mesencephalic neurons, most of which are presumably in the ventral tegmental area and the retrorubral area, while the noradrenergic axons originate bilaterally in the locus coeruleus (LC in Fig. 2E) (Porrino and Goldman-Rakic, 1982; Morecraft et al., 1992; Williams and Goldman-Rakic, 1998).
Serotoninergic innervation of the OfC, which appears similar in distribution and density throughout the prefrontal cortex (Lewis, 1990), is thought to originate bilaterally in the dorsal raphe (DR in Fig. 2F) and central superior raphe nuclei (Porrino and Goldman-Rakic, 1982; Morecraft et al., 1992).
Amygdala
The OfC, together with the medial prefrontal sector, is heavily connected with the amygdala. The following amygdaloid nuclei project to the OfC: basal (principally from the magnocellular and intermediate subdivisions), accessory basal (principally from the magnocellular and ventromedial subdivisions), lateral, anterior cortical, medial and periamygdaloid cortex (Porrino and Goldman-Rakic, 1981; Amaral and Price, 1984; Barbas and De Olmos, 1990; Morecraft et al., 1992; Baylis et al., 1995; Carmichael and Price, 1995a). The basal and accessory basal nuclei hold the densest concentrations of neurons projecting to the OfC (Figs 2C,C', 8). In turn, the OfC projects to the following amygdaloid nuclei: basal, accessory basal, lateral, central, paralaminar, anterior cortical, periamygdaloid cortex and amygdalo-hippocampal area (Fig. 2C,C') (Van Hoesen, 1981). Our observations from M1 indicate that the incoming axons from the OfC cover a wider amygdalar surface than the territories occupied by the amygdalo-OfC projecting neurons, and include nuclei, like the paralaminar and central, that are devoid of neurons projecting to the OfC (Fig. 2C,C', and additional non-illustrated observations).
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The lateral amygdaloid nucleus is the main recipient for the sensory input reaching the amygdala (Van Hoesen, 1981
; Iwai and Yukie, 1987; Price et al., 1987), but this nucleus sends meager projections to the OfC compared to those sent by the basal and accessory basal nuclei, which receive mostly intraamygdaloid input from the lateral and basal nuclei (Aggleton, 1985; Pikänen and Amaral, 1991). Therefore, most of the amygdaloid input received by the OfC has been processed within that structure before being transferred to the OfC. Thalamus
The organization of the thalamic connections of the OfC is quite complex. The following nuclei or group of nuclei of the ipsilateral hemithalamus are connected with the OfC: midline, anteromedial (AM), anteroventral (AV), ventral anterior (VA), area X, paracentral (Pcn), central medial (CeM), centromedian-parafascicular (CnMd-Pf), mediodorsal (MD) [particularly the medial and posterior sectors (MDm and MDp), but also medial parts of the lateral and ventral sectors (MDl, MDv)], medial pulvinar (Pul M), limitans (Li) and suprageniculate (SG; Figs 4, 5, 9) (Goldman-Rakic and Porrino, 1985; Giguere and Goldman-Rakic, 1988; Barbas et al., 1991; Siwek and Pandya, 1991; Morecraft et al., 1992; Ray and Price, 1993; Romanski et al., 1997). In addition, the following contralateral hemithalamus nuclei are connected with the OfC: paratenial (Pt), AM, MDm, ventromedial sector of VA (VAvm) and CeM (Figs 4, 5) (Dermon and Barbas, 1994) (the neurons assigned to the contralateral Pcn nucleus by Dermon and Barbas are probably analogous to those we assigned to the CeM). For the most part the thalamic territories receiving the OfC axons overlap the territories containing the neurons projecting to the OfC in the ipsilateral thalamus. Admittedly, the corticothalamic projection often seems to extend beyond the territories occupied by the thalamocortical neurons, but overall the ipsilateral thalamo-OfC connection may be considered reciprocal (Figs 4A, 5–C). In the contralateral hemithalamus the cortical-recipient territory is clearly larger than the sites occupied by the contralaterally projecting neurons (Figs 4A,B, 5), an observation that is in keeping with earlier observations regarding other prefrontal territories (Preuss and Goldman-Rakic, 1987). It has been suggested that the crossed corticothalamic and thalamocortical connections may subserve integrative functions, that might be related to memory (Preuss and Goldman-Rakic, 1987).
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The ipsilateral connection of the MD nucleus with the prefrontal cortex is the most studied. It is generally emphasized that the magnocellular portion of the nucleus is selectively connected with the OfC, as well as with the medial prefrontal cortex (Goldman-Rakic and Porrino, 1985
; Giguere and Goldman-Rakic, 1988; Barbas et al., 1991; Siwek and Pandya, 1991; Ray and Price, 1993). Ray and Price have subdivided the magnocellular MD into a medial pars paramediana and a lateral pars fibrosa on the basis of their myelination patterns (Ray and Price, 1993). In addition, they defined a pars caudodorsalis within MD, and proposed that all these MD subdivisions sustain differential connections with specific OfC and medial prefrontal areas (to be discussed below). We have examined the chemical architecture of the macaque monkey thalamus with reference to patterns of AChE activity and proposed AChE staining as a reference or template marker for the thalamus since this technique can reveal its nuclei and relevant subdivisions within the nuclei (Cavada et al., 1995). Thus, we defined several chemoarchitectonic sectors within MD: medial (MDm), lateral (MDl) and ventral (MDv; Fig. 5B,B'), which are present through most of the rostral three-quarters of MD, and a posterior sector, MDp, which extends parallel to the anteroposterior dimension of the habenular complex. MDm, characterized by poor AChE activity, is selectively connected with the OfC, and is largely coextensive with the magnocellular MD territory. MDp has an overall higher AChE activity than more anterior parts of MD; rostrally, the most medial MDp is connected with the OfC, whereas the area connected with the OfC at the posterior pole is wider and occupies most of the MDp surface (Fig. 4, sections #5 and #6).
The reason for analyzing connectional territories in parallel with chemoarchitectonic ones is the possibility of gaining functional insight. Thus, the poor cholinergic innervation of the large MDm territory connected with the OfC, when compared to the rich cholinergic innervation of the MDl territory connected with the lateral prefrontal cortex (Schwartz and Mrzljak, 1993, Cavada et al., 1995), indicates that the OfC, unlike the lateral prefrontal cortex, is largely free of acetylcholine influence acting on MD. If one considers the complex chemical architecture of the many thalamic nuclei connected with the OfC, the emerging picture is extremely complex. For instance, VAvm is a subdivision of VA defined by its particular AChE staining pattern, which is intense and uniformly distributed; VAvm is heavily connected with the OfC (Fig. 4, sections #1 and #2, Fig. 5A,A'). An additional salient example of correspondence between connectional and chemoarchitectonic territories is in the dorsomedial part of Pul M, where a patch of high AChE activity appears to be selectively linked with the OfC (Fig. 5C,C') (Cavada et al., 1995). Finally, following recent and ongoing studies on the catecholaminergic innervation of the thalamus, we have concluded that the OfC may be subject to specific modulation by dopamine, noradrenaline and adrenaline acting on several thalamic nuclei that project to the OfC, in particular midline nuclei, Pf, and medial MD regions (Rico and Cavada, 1998) (also B. Rico and C. Cavada, submitted, and additional unpublished observations).
Other Subcortical Connections
In the telencephalon, the claustrum and the striatum are linked with the OfC. The claustrum pro