Chapter 32 Role of the cerebral cortex and striatum in emotional motor response

G. Holstege, R. Bandler and C.B. Saper (Eds.)

Progress in Brain Research, Vol. 107 0 1996 Elsevier Science B.V. All rights reserved

CHAPTER 32

Role of the cerebral cortex and striatum in emotional motor response Clifford B. Saper Department of Neurology und Program in Neuroscience, Harvard Medical School, Beth Israel Hospital, 330 Brookline Avenue, Boston, MA 02215, USA

Introduction A US Supreme Court justice once remarked, in a case involving the rights of individuals to publish sexually offensive materials, that he could not define pornography, but that he knew it when he saw it. The problem of defining emotion is similar, and perhaps for the same reason: sexual arousal, which is the sine qua non of pornography, is an emotional state, and it is difficult if not impossible to define emotional states in terms of rational cognitive processes. Rather, emotion seems to have its own independent existence in the individual’s cognitive state, with a momentum that outlasts any triggers it may have in rational thought. As a result of this unique status of emotion, as an internal and quintessentially personal state, it is only possible for us to understand emotion as humans, and there are inherent difficulties in evaluating or studying the emotional states of individuals of other species. We may recognize, or believe we recognize, certain aspects of emotion in rats, cats or monkeys, but this is because we are identifying the motor responses associated with emotion, and which can be dissociated from it. To the extent that we impute an internal state to the animal, in which we can only observe the external concomitants associated with emotion, we are necessarily making inferences based upon our own experience, seen through the lens of the higher order processing capabilities of the human brain. Hence, in

coming to terms with the concept of emotion, we necessarily anthropomorphize the experience. For this reason, in the current chapter which aims at understanding the contributions of cortical and striatal systems to emotional expression, we will focus on the mechanism by which the human cerebral cortex and striatum may become involved in emotional response. As much of the data on connectivity are necessarily derived from other species, this review will attempt to integrate these observations into a framework that can provide a coherent view of emotional response, from the perspective of the human brain. In structuring this discussion, we will omit (but not overlook) the prospect that substantial aspects of emotional expression may occur entirely at subcortical levels. Certainly, the “sham rage” phenomenon described by Cannon and Britton (1927) occurs in cats with transections leaving only the diencephalon in continuity with the brainstem (Bard, 1928). However, even these early workers hesitated to label this somatomotor, endocrine and autonomic response, which resembles a rage attack, as true rage, in the absence of the cognitive components of emotion. It is also interesting that “sham rage” occurs with trivial, non-noxious stimulation, suggesting that the cognitive systems of the telencephalon are a necessary component of behaviorally appropriate emotional motor responses in mammals. In light of these constraints, we will attempt, at

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least for this chapter, to define emotion operationally as the process of assessing the personal importance of sensory stimuli for the specific individual. Emotional responses thus become the set of cognitive and motor (including autonomic, endocrine and somatic motor) reactions that are engendered by that emotional state. At first blush this may seem too broad a definition, as it includes such states as hunger, thirst, feeling hot or cold or sexual arousal, within the framework of emotion. Nevertheless, we will endeavor to make the case that these rather elementary emotions color cognitive and motor responses as effectively as the more traditional emotional states of fear, love, hate, jealousy or anger. Furthermore, they may give us some important clues as to how the emotional state of the individual is derived and expressed. Because emotion in humans therefore requires substantial cognitive assessment of incoming stimuli, we will make the case for emotion arising as an emergent property from the forebrain connections that support higher order cognitive processing (see Fig. 1). We will review the mechanisms by which sensory stimuli, both internal (visceral) and external, are processed by the forebrain and converge in the limbic cortex. We will then consider the ways in which output from the

visceral - sensation

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response Endocrlne Autonomlc Somatic automatism

Fig. I . A schematic drawing to illustrate the major determinants of emotion (cognitive state and visceral sensation) and the major components of an emotional response (coloring perception and cognition; visceral response; and the quality of behavioral momentum) which are defined further in the text. The concept of emotion, as defining those aspects of experience that are of greatest personal significance, is equated with the function of the limbic cortex, and the determinants and consequences of the emotional state are identified with the connections of the limbic lobe.

limbic cortex, which weighs the personal significance of external events, can feed back to color cortical processing; feed forward to regulate hypothalamic and brainstem autonomic, endocrine and behavioral integration; and feed forward via the ventral striatum to achieve a psychological momentum that is a common feature of emotional states. Furthermore, to make this discussion relevant to human emotions (which we will argue are by their nature the only ones that we can truly understand), we will attempt to deal wherever possible predominantly with data about functional organization of the primate, and where such data exist the human brain. However, at certain key points we will need to supplement this information with data and concepts that are derived from experimental animals of other species.

Visceral afferents to cerebral cortex In an early theory of emotion, William James ( 1 884) proposed that “bodily changes follow directly the perception of the exciting fact and our feelings of the same changes as they occur is the emotion.” Lange (1 885), the Danish physiologist, further posited that emotional sensation derived solely from afferent impulses from the circulatory system. This theory was widely criticized as insufficient to explain emotions, because spinal cord transection or complete sympathectomy did not prevent emotional display in experimental animals or humans. Nevertheless, it is equally clear that visceral sensations such as pain, hunger, or air hunger (in a hypercarbic or hypoxic state) can have a profound influence over emotional state and behavior. Hence, the ability of visceral sensation to influence emotional state indicates a rather direct access to the forebrain levels at which emotion is organized, and may provide a convenient entrypoint for examining the cortical networks involved in emotional control. Most work on this system has been done in the rat, some in the cat; we shall review this information first, and then consider how much of it may apply to primates including humans. Visceral sensory information reaches the brain via two main

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systems. The sympathetic afferent system originates from visceral sensory fibers that travel in the spinal nerves. These afferents synapse in the superficial layers of the dorsal horn (Cervero and Connell, 1984; Cervero and Tattersall, 1987), where they converge with (mainly nociceptive) afferents from cutaneous fields (Foreman and Blair, 1988). Secondary afferent neurons send ascending axons in the spinothalamic tract to the intralaminar thalamic nuclei as well as to the ventroposterior lateral nucleus of the thalamus, and to the associated posterior intralaminar nuclear complex (see also Chapter 11, this volume). The specific sites of termination of afferents carrying sympathetic visceral sensory information have not been mapped. However, the nociceptive afferents with which they travel appear to terminate in the peripheral shell of the ventroposterior lateral nucleus, in a region that is just lateral to the ventroposterior parvicellular nucleus (Yokota et al., 1988; Lenz et al., 1993; see below). Other branches of the ascending spinothalamic tract innervate a variety of visceral regulatory cell groups, ranging from the ventrolateral medulla and nucleus of the solitary tract to the parabrachial nucleus, the periaqueductal gray matter, and the hypothalamus and the basal forebrain (see Chapters 14 and 15, this volume), providing alternative ascending pathways to the forebrain. The other main visceral sensory system arises from the parasympathetic afferents. These enter the brain via cranial nerves V, VII, IX and X, but all of the visceral afferent fibers terminate in the nucleus of the solitary tract (NTS). The NTS contains a topographically organized representation of the internal body surface, with the tongue most rostral (taste), gastrointestinal afferents in an intermediate position, and cardiorespiratory afferents most caudal (Gwyn et al., 1985; Altschuler et al., 1989; Finley and Katz, 1992). This organization is maintained through a relay in the parabrachial nucleus, and from there to the contralateral parvicellular part of the ventroposterior thalamus (VPpc) (see Cechetto and Saper, 1987; Yasui et al., 1989.) VPpc is also topographically organized, with the taste representation most medial, underlying the

ventroposterior medial nucleus (face and tongue somatosensory representation), and the gastrointestinal and cardiorespiratory representations progressively more lateral, underlying the ventroposterior lateral nucleus (trunk representation). The sympathetic sensory afferents probably overlap with the lateral margin of VPpc, and continue laterally in the outer shell of the ventroposterior nucleus (Foreman and Blair, 1988). The visceral sensory cortex is also topographically organized, with the taste representation rostrally in the dysgranular insular cortex, the gastrointestinal area more caudally in the granular insular region, and the cardiorespiratory area even further caudally in the granular insular cortex (Norgren, 1984; Yamamoto, 1984; Cechetto and Saper, 1987). These regions are just rostral to the perirhinal cortex, an area that receives afferents from the posterior intralaminar complex (Yasui et al, 1989, 1991b). The perirhinal cortex of the rat may be homologous with the primate posterior insular cortex, which receives nociceptive afferents (Robinson and Burton, 1980; Burton et al., 1993). The visceral sensory cortex, in turn, has extensive connections with the adjacent agranular insular cortex, the infralimbic cortex on the medial bank of the hemisphere, and the perirhinal cortex (Saper, 1982; Yasui et al., 1991a). There is only sketchy evidence in monkeys for the organization of the visceral sensory pathways. Beckstead and colleagues (1 980) found that, unlike the rat, the rostral part of the NTS in monkeys directly projects to the medial part of VPpc. However, the gustatory part of the NTS also projects to the parabrachial nucleus, and the other visceral sensory modalities represented more caudally in the NTS appear to be relayed to the thalamus exclusively by the parabrachial nucleus, as in the rat. Only sketchy data are available on the organization of visceral sensation within the thalamus or cortex in primates, although a gustatory representation is preserved in the medial part of VPpc and in the granular insular cortex (Pritchard et al., 1986; Scott et al., 1994) and vagal sensory responses can be obtained more caudally in the insular cortex (Radna and MacLean, 1981; Augustine, 1985).

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Fig. 2. A schematic drawing illustrating the major pathways in the visceral sensory system that contain the neuropeptide, CGRP. CGRP is found in predominantly crossed pathway from the external medial part of the parabrachial nucleus (em) to the thalamic visceral sensory relay nucleus, the VPpc, as well as in a projection from the external lateral parabrachial subnucleus (el) to the central nucleus of the amygdala (CeA) and from the ventral lateral parabrachial subnucleus (vl) to the insular visceral sensory cortex (Ins). CGRP-immunoreactive neurons in the posterior thalamic intralaminar complex (POI) innervate the caudate-putamen (CPu), the central nucleus of the amygdala, and the perirhinal cortex (PR, probably equivalent to the posterior insular cortex of primates). Virtually identical CGRP-immunoreactive cell groups and terminal fields are found in the human brain, suggesting preservation of this set of pathways across the mammalian line.

Similarly, lesions of the anterior insular region and overlying operculum bilaterally can produce a state of ageusia or inability to appreciate taste (see Norgren, 1984), and electrical stimulation of the anterior insular area in humans produces intra-abdominal sensations (Penfield and Rasmussen, 1950).

Given the paucity of information on the organization of the visceral sensory system in primates and humans, and the problems inherent with obtaining such information, we have recently taken a different approach, exploiting the presence of the peptide neuromodulator calcitonin gene-related peptide (CGRP) as a marker for this system across the mammalian line (Fig. 2). In the rat, we found that neurons in the visceral sensory part of the parabrachial nucleus (the external medial subnucleus) stain immunocytochemically with antisera against CGRP, and that their terminals in the VPpc are also CGRP-immunoreactive (Yasui et al., 1989). In addition, we could demonstrate a CGRPimmunoreactive projection from the ventral lateral parabrachial subnucleus directly to the visceral sensory insular cortex, and another CGRPimmunoreactive projection from the posterior intralaminar complex of the thalamus to the perirhinal cortex, just caudal to the insular area (see Yasui et al., 1991b). We have recently found a very similar CGRPimmunoreactive system of neurons in the monkey as well as the human brain (de Lacalle and Saper, 1992). Hence, in the human parabrachial nucleus, we have identified CGRP-immunoreactive neurons in the external medial (visceral sensory relay) subnucleus, and we have found CGRPimmunoreactive terminals in the VPpc. These observations suggest that the parabrachial nucleus remains an important relay to the visceral sensory thalamus in primates, including humans. We have also found CGRP-immunoreactive fibers innervating the insular region that is thought to contain the visceral sensory cortex in humans, and extending into the adjacent posterior insular association area as well. In summary, there is now substantial evidence that visceral sensation is conveyed to the highest levels of the neuraxis, as a topographic sensory representation, similar to other lemniscal sensory systems. In addition, like other sensory cortices, the visceral sensory cortex provides afferents to association areas, which may thereby influence the ongoing cognitive and emotional state of the individual. Although most of these data have been

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gathered in rats and cats, the homology of the CGRP-immunoreactive system in humans and rats makes it likely that the remainder of these systems is similarly organized in the human brain.

Limbic cortex as a site of convergence of highly processed sensory afferents The limbic cortex has been identified with emotional expression since the classic, if inaccurate predictions of Papez (1937) that the recurrent nature of hippocampal circuitry could account for the momentum of emotion. He proposed a four neuron recurrent circuit, from the cingulate cortex, to the hippocampus, then the mammillary body, the anterior thalamic nuclei, and finally back to the cingulate cortex. This model, based upon the mass connectivity of large areas of the brain, is clearly overly simplistic, in that each of these structures contains subregions, with complex topographically organized connectivity (see below). Hence, while parts of the cingulate cortex project to parts of the hippocampal formation, no direct lines of communication to the neurons that give rise to the fornix have been identified. Given the welldocumented complexity of these connections, it is not likely that a neuronal impulse beginning in the cingulate cortex could be transmitted faithfully through a chain of neurons of any number of synapses through the hippocampal formation, mammillary body, and anterior thalamus, and ultimately influence the same cingulate neuron from which the chain originated. Certainly there is no evidence, to this day, that such a phenomenon occurs. Despite these problems, MacLean (1949, 1954) enlarged on Papez’s conceptualization, constructing a much larger limbic “system”, which he charged with the responsibility for emotional expression. The problem with this view is that by enlarging the limbic system conceptually to include all of the structures receiving secondary and tertiary inputs from the amygdala and hippocampus, the limbic system subsumes such a large portion of the mammalian brain that it is difficult to identify its functional properties. At the same time,

the concept of emotion was blurred, and became in MacLean’s “visceral brain” progressively more closely associated with the autonomic outflow associated with emotion, almost an inverse of the James-Lange theory. A consideration of the patterns of connectivity that would be necessary for emotional expression produces a somewhat different conceptualization, and one that is more consistent with the original use of the term limbic lobe by Broca (1878), to describe the cortex forming a “limbus” or border around the medial edge of the cerebral hemisphere: the amygdala, the hippocampal formation, including the parahippocampal gyrus, and the cingulate cortex. In general, it has become apparent over the last two decades that the limbic cortex occupies a unique position in the cortical information processing network, with each of the classic limbic cortices receiving convergence of highly processed sensory information from a broad expanse of cerebral cortex. Positioned in this way, the limbic cortex is ideally placed to make decisions about the personal significance of environmental and cognitive events, and hence to drive the emotional response system. In the discussion that follows, we will focus principally upon studies of the primate cerebral cortex, as its richness and complexity far exceeds that of other experimental animals. A more detailed consideration of cortico-limbic connections, especially in other species, may be found in a recent review by Lopes da Silva et al. ( 1990). The cingulate cortex receives afferents directly from a variety of higher order association areas, organized in a roughly topographic pattern (Baleydier and Maugiere, 1982; Vogt and Pandya, 1987). Although the lateral and orbital prefrontal cortex project widely among the cingulate fields, the prefrontal cortex dominates the anterior cingulate, prelimbic, and infralimbic fields. The posterior cingulate and retrosplenial areas, by contrast, receive more parietal and occipital inputs. Another point of convergence of afferents from higher order association areas is the entorhinal cortex. The entorhinal cortex receives afferents from higher order association areas in the frontal,

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parietal, and temporal lobes (van Hoesen et al., 1972; van Hoesen, 1982; Insausti et al., 1987). In addition it is reciprocally connected both with the basal and lateral amygdaloid nuclei as well as the cingulate cortex. The entorhinal cortex in turn provides a major source of afferents to the hippocampal formation. Entorhinal axons travel through the perforant pathway to the outer portion of the molecular layer of both the dentate gyrus and the CA fields of the hippocampus (van Hoesen, 1982; Rosene and van Hoesen, 1977). In the amygdala, the entorhinal cortex innervates mainly the basal and the lateral nuclei (van Hoesen, 1982). The amygdala also receives afferents more directly from the higher order association areas as well as the hippocampal formation itself, in a topographic manner (Herzog and van Hoesen, 1976; Rosene and van Hoesen, 1977; Turner et al., 1980). Thus the visceral sensory cortex projects to the central nucleus, the olfactory cortex to the medial and cortical nuclei, and the visual, auditory and somatosensory association areas to the basal and lateral nuclei. The limbic cortex is thus at the apex of a pyramid that focuses and concentrates the highest order abstractions from sensory impressions. No other region of the cortical mantle is as well placed to sample the entire stream of experience, detecting the stimuli that are most important for personal needs, and directing behavior toward them. The distinct roles of the different limbic cortices in directing emotional behavior are still incompletely understood. For example, humans or monkeys with bilateral damage to the amygdala are remarkably placid and disinterested in their environment (Kluver and Bucy, 1937; Terzian and Dalle Ore, 1955; Marlowe et al., 1975; Shraberg and Weisberg, 1978; Tranel and Hyman, 1990; Aggleton, 1993). Monkeys with bilateral lesions of the amygdala similarly demonstrate an absence of emotional responses, such as fear (Aggleton, 1993). Experiments in rats suggest that the lateral and central nuclei of the amygdala are critical for acquiring conditioned fear responses (see Chapter 26, this volume). Humans with bilateral lesions of the cingulate cortex tend to become 'abulic, falling into a state of

complete emotional unresponsiveness (Talairach et al., 1973; Vogt et al., 1992; Degos et al., 1993). Such patients sit and stare all day, responding only when vigorously stimulated, but clearly do understand events in their environment. When pressed, they admit that they simply do not care about them. This dense ennui extends even to intemal sensory stimuli, such as pain. Bilateral cingulate lesions have therefore been used as a last-ditch attempt to treat chronic disabling pain. Such patients confirm that they feel the pain, but that it does not bother them. The role of the hippocampus in emotion is controversial. The Papez and MacLean model placed it in a central role, but modern studies of patients with hippocampal lesions disclose a deficit primarily in the consolidation of memory from the short to long term stores (Zola-Morgan et al., 1986; Zola-Morgan and Squire, 1993). While this deficit may not seem at first blush to be related to emotion, and such individuals still display a normal range of emotional responses to stimuli that are immediately in evidence, the relationship between memory and emotion is actually quite strong. Emotional weighting is a key component of memory. Humans do not store recollections like a video camera. Rather, only fragments of memories are retained, and the completeness of retention is closely related to the emotional impact of the events (Halgren et al., 1978; Cahill et al., 1994). Conversely, the amnesic state of the individual who has a hippocampal deficit results in the inability to maintain an emotional response after the individual's attention has been shifted in a different direction. Hence, the ongoing interaction between memory and the emotional state of the individual is consistent with the overall view of the role of the limbic cortex in emotional expression.

Cortico-corticaloutputs from limbic cortex The limbic cortex is able to feed back upon the ongoing processing of sensory and motor responses by means of an extensive series of reciprocal connections with higher order association areas. The efferent outflow from the cingulate

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cortex, like its afferents, is roughly topographically organized (Pandya et al., 1981). The prelimbic cortex projects primarily to the lateral and orbital frontal cortex, as well as to the most rostra1 part of the superior temporal gyrus. The remaining cingulate areas also project to the frontal lobe, but the anterior cingulate area also innervates the premotor, anterior insular, perirhinal and inferior parietal regions. The posterior cingulate cortex projects more extensively to the association cortex in the posterior parts of the parietal and temporal lobes. The hippocampal formation influences cortical function predominantly by means of its projections from the CAI field back to the subiculum and the entorhinal cortex (Rosene and van Hoesen, 1977; van Hoesen, 1982). The subiculum feeds back upon areas in the parahippocampal gyrus and the frontal and cingulate cortex that provide entorhinal inputs. By contrast, the entorhinal cortex projects widely upon higher order unimodal and polymodal association areas in the frontal, parietal, and temporal lobes. The lateral portion of the amygdala, including the lateral and basal nuclear complexes, likewise feed back upon the higher order association areas of the frontal and temporal lobes (Amaral and Price, 1984), which provide amygdaloid inputs. The heaviest projections are to the medial and orbitofrontal cortex, as well as the agranular insular cortex, the temporopolar and the perirhinal areas. Less intense projections include the lateral frontal cortex, most of the remaining temporal association cortex, the parietal cortex in the depths of the intraparietal sulcus, and the prestriate occipital cortex. There are also substantial interconnections between the limbic areas, including major connections between the hippocampus and amygdala (Saunders et al., 1988) and the hippocampus and prelimbic and infralimbic areas (Rosene and van Hoesen, 1977). In summary, the limbic cortex maintains an extensive array of projections back to virtually the entirety of the association cortex, from which it may exercise influence over essentially every aspect of perception and cognition.

Descending outputs from limbic cortex: hypothalamus and brainstem Each of the limbic cortical areas, and only the limbic areas of the cortical mantle, provides extensive projections to areas of the hypothalamus and brainstem involved in the autonomic, endocrine and somatomotor aspects of emotional expression. These systems have been studied most extensively in the rat, and to a lesser extent in the cat, but the similarities are so great that it is likely that this output system is similarly organized in primates, including humans. The descending outflow from the cingulate cortex originates predominantly in the infralimbic area (Room et al., 1985; Hurley et al., 1991). The infralimbic cortex provides a major descending projection through the lateral hypothalamus. Some of these fibers continue caudally into the brainstem and innervate the key sites for autonomic control, including the periaqueductal gray matter, parabrachial nucleus, ventrolateral medulla, and nucleus of the solitary tract. In addition, smaller numbers of fibers from the infralimbic cortex directly innervate parasympathetic preganglionic cell groups in the medulla, as well as the sympathetic preganglionic intermediolateral column of the thoracic spinal cord. In this respect the infralimbic cortex can be regarded as a true visceral motor cortex (Neafsey et al., 1986). As might be expected from this designation, it is reciprocally connected with the visceral sensory cortex in the insular area (Saper, 1982; Room et al., 1985; Hurley et al., 1991). The agranular insular field, an association area closely related to the visceral sensory cortex in the granular and dysgranular insular fields, also provides some descending outflow of its own, primarily to the lateral hypothalamus, parabrachial nucleus, nucleus of the solitary tract, and ventrolateral medulla (Saper, 1982; Allen et al., 1991; Yasui et al., 1991a). It does not appear to innervate preganglionic cell groups directly. Likewise, the prelimbic cortex in the rat also provides some descending outflow from the cingulate cortex, but is more limited in scope than the infralimbic projection, predominantly innervating

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the lateral hypothalamus (Hurley et al., 1991). However, the prelimbic cortex, like other cingulate areas and the CA1 field of the hippocampal formation, provides major inputs to the infralimbic cortex (Rosene and van Hoesen, 1977; Tucker and Saper, 1984). In addition, both the prelimbic and infralimbic areas project heavily into the central nucleus of the amygdala (Hurley et al., 1991), and hence participate in directing its descending output as well. Comparable studies on primates have not been reported, but would be of great interest as the cingulate cortex and its connections are likely to be considerably more complex. The hippocampal formation provides its own massive descending output to the hypothalamus through the fornix, originating predominantly in the ventral subiculum (Swanson and Cowan, 1975). Although the projection through the fornix is most commonly associated with the input to the mammillary body, more than half of the fibers in the post-commissural fornix are distributed more rostrally in the medial and lateral hypothalamus (Valenstein and Nauta, 1956; Powell et al., 1957). The function of the hippocampal projection to the hypothalamus in primates, especially that to the mammillary body, is surprisingly poorly understood (Woolsey and Nelson, 1975; but see Gaffan et al., 1984; Gaffan and Gaffan, 1991). Likewise, no function has been identified for the dense projection via the medial corticohypothalamic tract to the shell of the ventromedial nucleus. The descending output from the amygdala, by contrast, is much better understood. It arises predominantly from the central nucleus (Price and Amaral, 1981) in monkeys, although the lateral, basolateral, medial and cortical nuclei also project as far as the hypothalamus (Krettek and Price, 1978), at least in rats. The central nucleus of the amygdala, which itself receives afferents from the insular and infralimbic areas (see above), provides extensive projections to the lateral hypothalamus, parabrachial nucleus, and nucleus of the solitary tract. Lesions of the central nucleus in the rat prevent both autonomic and behavioral components of a conditioned fear response (see LeDoux, 1995 and Chapter 26, this volume). Similarly, monkeys

with large lesions of the amygdala also appear to lack normal fear responses (Aggleton, 1993). The amygdala, which receives direct sensory afferents from the posterior intralaminar complex of the thalamus and from the visceral sensory system (Yasui et al., 1991b), may play a particularly important role in conditioned emotional responses. Many of the details concerning the relay of the descending outflow from the limbic cortical structures to autonomic, endocrine and somatomotor control systems remain to be worked out, particularly in primates. Nevertheless, studies in the rat indicate that the limbic cortices have direct access to all of these systems, and they are unique among the cortical fields in this regard. In understanding emotion from a human point of view, it is necessary to determine the mechanisms by which cognitive processes may influence emotional response. The limbic cortex is uniquely situated to serve this role.

Descending outputs from limbic cortex: striatum There is one additional component of emotion that separates it from more rational cognitive processes, and that is its momentum: the ability of an emotional state to continue far beyond its inciting sensory stimulus, and perhaps to color behavior for weeks or months, or even for a lifetime. It was this phenomenon that Papez was trying to account for in proposing a reverberating circuit, involving the hippocampus, mammillary body, anterior thalamic nuclei, and cingulate cortex. As discussed above, there is no evidence to support this view. Furthermore, transection of the fornix, which plays a key role in the Papez model, does not disrupt emotional response in monkeys or humans (Woolsey, 1974; Gaffan et al., 1984; Gaffan and Gaffan, 1991). On the other hand, this common view of the momentum of emotion does require a substrate, and it will be the thesis of this chapter that this aspect of emotion may be based upon the projections from the limbic cortices to the ventral striatum. As the connections of the limbic striatum is

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the topic of a separate chapter by Groenewegen in this volume, we will not attempt a full review here, but rather will confine ourselves to a brief recounting of the relationship of the ventral striatum to the limbic cortex, and how these might be particularly important in the human brain. The entire cortical mantle projects topographically onto the striatum, with the classical limbic cortices projecting primarily into the ventral striatum in both rats (Gerfen, 1989, 1992; Voorn et al., 1989; Ragsdale and Graybiel, 1990) and monkeys (Yeterian and Pandya, 1991, 1993; Flaherty and Graybiel, 1993; Kunishio and Haber, 1994). In the rat or cat, the dorsal striatum is predominantly related to sensory and motor areas of the cortex, and the ventral striatum is a limited component, predominantly including the nucleus accumbens and olfactory tubercle (see Chapter 29, this volume). The dorsal striatum participates in the classic extrapyramidal circuit, projecting to the globus pallidus and the entopeduncular nucleus/pars reticulata of the substantia nigra (equivalent to the external and internal segments of the globus pallidus in primates) (Alexander et al., 1990; Gerfen, 1992). The internal pallidal segment projects downstream to the midbrain extrapyramidal area (associated with, but probably not identical to the pedunculopontine tegmental nucleus; see Chapter 25, this volume) and upstream to the motor thalamus. The latter projection, which provides inhibitory GABAergic input to the thalamus, is thought to play a key role in the appropriate inhibition and initiation of motor responses (Alexander et al., 1990; Gerfen, 1992). The ventral striatum, by contrast, projects to the ventral pallidum, both in rats (Groenewegen and Russchen, 1984; Zahm and Heimer, 1990; Groenewegen et al., 1993) and monkeys (Haber et al., 1993). The latter region, in turn, innervates the mediodorsal nucleus of the thalamus, which is reciprocally related to the prefrontal cortex (Young et al., 1984; Haber et al., 1985, 1993; Alheid et al., 1990). Hence, the ventral striatal outflow can be conceived as directed more at regulation of behaviors and thought processes than the initiation or inhibition of specific motor acts.

Recent advances in our understanding of the organization of the striatum have added several additional levels of complexity to this simplified picture. First, it is now clear that the striatum is far from homogeneous, rather consisting of compartments with distinct afferent and efferent connections as well as their associated neurotransmitters and related chemical markers (Gerfen, 1989, 1992;

Fig. 3. A photomicrograph of a section through the anterior part of the striatum in the human brain, stained with an immunoperoxidase technique for choline acetyltransferase, the enzyme that synthesizes acetylcholine. The head of the caudate nucleus (CD) abuts the lateral ventricle (LV), the putamen (PU) is to the left of the internal capsule, and the lower third of the striatum is occupied by the nucleus accumbens (NA) at this level. Note the variegated appearance of the cholinergic innervation. Dark areas (thick black arrow pointing to head of caudate nucleus), signifying intense cholinergic innervation, constitute the traditional matrix compartment of the striatum. Areas of intermediate density of cholinergic innervation (thin black arrows) are present as small striosomes within the head of the caudate nucleus, but occupy most of the putamen. Regions with this density of cholinergic innervation are among the darkest in the nucleus accumbens, where they are interspersed with regions of still lower intensity of cholinergic innervation (large white arrows). Scale bar = 5 mrn (courtesy of D.J.Holt).

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Graybiel, 1990). In some of the earliest work in this field, Graybiel and Ragsdale (1978) demonstrated that the cholinergic innervation of the striatum of the cat consists of a dense background or “matrix” innervation, punctuated by small, round or oval regions with much lower densities of cholinergic input. Similar inhomogeneities were found in the distribution of peptides such as enkephalin, somatostatin, and substance P, and in calcium binding proteins, such as calbindin (see Graybiel, 1990 for review). However, the relatively neat division into striosomes and matrix, which dominates the organization of the dorsal striatum in rats and cats, is not found in the ventral striatum, where a more complex compartmentalization, not quite consistent with either striosomes or matrix, is found (Voorn et al., 1989; Alheid et al., 1990; Zahm and Brog, 1992). Attempts to divide this region into “core” and “shell” compartments in the rat nucleus acumbens have met with some success, but similar divisions have been difficult to identify in other species. We have recently performed a quantitative examination of the compartmental organization of the human striatum. To our surprise, we found not the two compartments that are classically described, but rather three distinct levels of cholinergic innervation in the human striatum (Holt et al., 1992, 1996). Within the dorsal striatum, which in humans appears to correspond only to the head and body of the caudate nucleus and the dorsomedial third of the putamen, the background is predominantly heavily innervated by cholinergic fibers. Clearcut striosomes are also seen in this region, with an intermediate level of cholinergic innervation. However, the ventral part of the putamen and even the most ventral portion of the caudate nucleus, as well as the entirety of the nucleus accumbens, are dominated by the intermediate level of cholinergic innervation. Against this background, small patches of dense cholinergic innervation (equivalent to the matrix areas of the dorsal striatum) are seen, as well as regions of even less intense cholinergic innervation. These cholinergicpoor zones form a third level of innervation, which in the human brain occupies nearly a quarter of the

entire striatum. The intermediate level of innervation accounts for approximately half of the striatum, and the dense level of cholinergic innervation only for about one quarter (compared to an estimated 85-90% of the caudate-putariien in rats and cats). These compartments are confirmed in sections stained for acetylcholinesterase (Holt et al., 1996) and for other markers, including calbindin, enkephalin, and tyrosine hydroxylase (Holt et al., 1993), although the relationships of the staining intensity with the different markers can be complex. These distinctions ar;. important because, in the rat, the classic dorsal striatal output to the globus pallidus and pars reticulata of the substantia nigra arises predominantly from the matrix (Gerfen, 1992). The striosomes, by contrast, project to the pars compacta of the substantia nigra, from which they influence the dopaminergic tone and hence the motor output of the entire striatum. The input to the striosomes is also different from that of the matrix. Whereas the latter receives its afferents from the sensory and motor areas, limbic areas project predominantly to the striosomes in the dorsal striatum. If more than half of the striatum in the human brain is of the striosome/limbic type, then the predominant business of the human striatum may be setting the tone for motor responses and behaviors, and perhaps even thought processes, rather than simply releasing or inhibiting specific movements. This theory is consistent with the observation of the impressive range of behavioral impairment that is seen as a part of diseases of the striatum. Huntington’s and Wilson’s diseases may present in a young individual as a psychotic behavioral disorder that may be very difficult to distinguish from severe depression or schizophrenia (Caine and Shoulson, 1983; Dening, 1985; Akil et al., 1991; Schwartz et al., 1993). In this regard, we have recently examined the striatums from a series of schizophrenic individuals, and explored the chemical compartmentalization of this region, compared to normal subjects. We found that there were large areas of the striatum in the schizophrenic brains in which far fewer than the normal

541

numbers of large cholinergic interneurons were found (Holt et al., 1994). Whether this difference is of etiologic importance, or whether it represents a long term effect of drug treatment, is not yet clear. But our observations are consistent with the striatum playing a major role both in the normal regulation of emotional state, and in the pathology of emotional disorders. Finally, these observations bring up a second important recent advance in the understanding of striatal function that must loom very large in understanding the neural mechanisms of emotion. Although the compartments of the striatum have been identified in large part on the basis of their chemical characteristics, it is now clear that the expression of different neurotransmitters is highly plastic and is influenced by physiological and pharmacological stimuli. For example, chronic administration of dopaminergic antagonists such as haloperidol produce a wide variety of changes in the expression of neurotransmitters in the different striatal compartments (see Graybiel, 1990 for review). In seeking out the substrates for long term changes in mood and emotional state, the remarkably long-lived alterations in striatal expression of neurotransmitters and their receptors (which may last for weeks beyond the initial stimulus) may provide an important insight. In particular, the well-known delays in the full effects of both neuroleptic and antidepressant drugs may reflect the need for the drug to produce a long-term change in gene expression and hence the actual chemical composition of the brain itself. In searching for a substrate for the momentum of emotion, the ability of neuronal activity to produce long-term alterations of the chemical compartmentalization of the ventral striatum may provide an important insight into a potential mechanism. Conclusions Because of its brevity, this review has only touched upon the evidence that provides the underpinnings for the limbic cortex theory of emotion. However, it seems clear from a consideration of the types of inputs that shape emotional re-

sponse, and the wide range of efferent systems involved in its expression, that the limbic cortex occupies a uniquely appropriate position in the mammalian brain to undertake this task. Furthermore, the relationship of the limbic cortex with the ventral striatum may provide an explanation for the momentum of emotion. Given the enormous expansion of the ventral striatum in the human brain, consistent with the evolutionary development of much larger regions of higher order association cortex, it is likely that the striatum plays a role in directing human emotion and behavior that goes far beyond the traditional concepts of extrapyramidal circuitry and function. By understanding the chemical composition of the human striatum, and its changes in behavioral disorders as well as in various drug states, we may gain important insights into the mechanisms of emotional response and dysfunction, and their tendency toward long-term impact upon behavior.

References Aggleton, J.P. (1993) The contribution of the amygdala to normal and abnormal emotional states. Trends Neurosci., 16: 328-333. Akil, M., Schwartz, J.A., Dutchak, D., Yuzbasiyan-Gurkan, V. and Brewer, G.J. (1991) The psychiatric presentations of Wilson’s disease. J. Neuropsychiarry Clin. Neurosci., 3: 317-382. Alexander, G.E., Crutcher, M.D. and DeLong, M.R. (1990) Basal ganglia-thalamocortical circuits: parallel substrates for motor, oculomotor, “prefrontal” and “limbic” functions. Prog. Brain Res., 85: 119-146. Alheid, G.F., Heimer, L. and Switzer, 111, R.C. (1990) Basal ganglia. In G. Paxinos (ed.), The Human Nervous System, Academic Press, San Diego, CA, pp. 483-582. Allen, G.V., Saper, C.B., Hurley, K.M. and Cechetto, D.F. (1991) Organization of visceral and limbic connections in the insular cortex of the rat. J. Comp. Neurol., 3 11: 1-16. Altschuler, S.M., Bao, X., Bieger, D., Hopkins, D.A. and Miselis, R.R. (1989) Viscerotopic representation of the upper alimentary tract in the rat: sensory ganglia and nuclei of the solitary and spinal trigeminal tracts. J. Comp. Neurol., 283: 248--268. Amaral, D.G. and Price, J.L. (1984) Amygdalo-cortical projections in the monkey (Macaca fascicularis). J. Comp. Neurol., 230: 465496. Augustine, J.R. (1985) The insular lobe in primates including humans. Neurol. Res., 7: 2-10.

548 Baleydier, C. and Maugiere, F. (1980) The duality of the cingulate gyrus in monkey. Neuroanatomical study and functional hypothesis. Brain, 103: 525-554. Bard, P. (1928) A diencephalic mechanism for the expression of rage with special reference to the sympathetic nervous system. Am. J . Physiol., 84: 490-5 15. Beckstead, R.M., Morse, J.R. and Norgren, R. (1980) The nucleus of the solitary tract in the monkey: projections to the thalamus and brain stem nuclei. J . Comp. Neurol., 190: 259-282. Broca, P. ( 1 878) Anatomie comparee des circonvolutions cerebrales. Le grand lobe limbique et la scissure limbique dans la serie des mammiferes. Rev. Anthropol., I : 385398. Burton, H., Videen, T.O. and Raichle, M.E. (1993) Tactilevibration-activated foci in insular and parietal-opercular cortex studied with positron emission tomography: mapping the second somatosensory area in humans. Somatosens. Motor Res., 10: 297-308. Cahill, L., Prins, B., Weber, M. and McGaugh, J.L. (1994) Beta-adrenergic activation and memory for emotional events. Nature, 371: 702-704. Caine, E.D. and Shoulson, I. (1983) Psychiatric syndromes in Huntington’s disease. Am. J. Psychiatry, 140: 728-733. Cannon, W.B. and Britton, S.W. (1927) Pseudoaffective medulloadrenal secretion. Am. J. Physiol., 79: 433465. Cechetto, D.F. and Saper, C.B. (1987) Evidence for a viscerotopic sensory representation in the cortex and thalamus in the rat. J . Comp. Neurol., 262: 27-45. Cervero, F. and Connell, L.A. (1984) Distribution of somatic and visceral primary afferent fibres within the thoracic spinal cord of the cat. J. Comp. Neurol., 230: 88-98. Cervero, F. and Tattersall, J.E.H. (1987) Somatic and visceral inputs to the thoracic spinal cord of the cat: marginal zone (lamina 1) of the dorsal horn. J. Physiol. (London), 388: 383-395. de Lacalle, S. and Saper, C.B. (1992) Calcitonin gene-related peptide immunoreactivity in visceral sensory pathways in the human brain. SOC.Neurosci. Abstr., 18: 805. Degos, J.D., da Fonseca, N., Gray, F. and Cesaro, P. (1993) Severe frontal syndrome associated with infarcts of the left anterior cingulate gyrus and the head of the right caudate nucleus: a clinico-pathological case. Brain, 116: 15411548. Dening, T.R. (1985) Psychiatric aspects of Wilson’s disease. Br. J. Psychiatry, 147: 677682. Finley, J.C.W. and Katz, D.M. (1992) The central organization of carotid body afferent projections to the brainstem of the rat. Bruin Res., 572: 108-1 16. Flaherty, A.W. and Graybiel, A.M. (1993) Two input systems for body representation in the primate striatal matrix: experimental evidence in the squirrel monkey. J. Neurosci., 13: 1120-1137. Foreman, R.D. and Blair, R.W. (1988) Central organization of

sympathetic cardiovascular response to pain. Annu. Rev. Physiol., 50: 607-622. Gaffan, D. and Gaffan, E.A. (1991) Amnesia in man following transection of the fornix: a review. Brain, 114, 261 12618. Gaffan, D., Saunders, R.C., Gaffan, E.A., Harrison, S . , Shields, C. and Owen, M.J. (1984) Effects of fornix transection upon associative memory in monkeys: role of the hippocampus in learned action. Q. J. Exp. Psychol., 36: 173-22 I. Gerfen, C.R. (1989) The neostriatal mosaic: striatal patchmatrix organization is related to cortical lamination. Science, 246: 385-388. Gerfen, C.R. (1992) The neostriatal mosaic: multiple levels of compartmental organization in the basal ganglia. Annu. Rev. Neurosci., 15: 285-320. Graybiel, A.M. (1990) Neurotransmitters and neuromodulators in the basal ganglia. Trends Neurosci., 13: 244254. Graybiel, A.M. and Ragsdale, C.W. (1978) Histochemically distinct compartments in the striatum of human, monkey, and cat demonstrated by acetylthiocholinesterase staining. Proc. Natl. Acad. Sci. USA, 75: 5723-5726. Groenewegen, H.J. and Russchen, F.T. (1984) Organization of the efferent projections of the nucleus accumbens to pallidal, hypothalamic, and mesencephalic structures: a tracing and immunohistochemical study in the cat. J. Comp. Neurol., 223: 347-367. Groenewegen, H.J., Berendse, H.W. and Haber, S.N. (1993) Organization of the output of the ventral striatopallidal system in the rat: ventral pallidal efferents. Neuroscience, 57: 113-142. Gwyn, D.G., Leslie, R.A. and Hopkins, D.A. (1985) Observations on the afferent and efferent organization of the vagus nerve and the innervation of the stomach in the squirrel monkey. J. Comp. Neurol., 239: 163-175. Haber, S.N., Groenewegen, H.J., Grove, E.A. and Nauta, W.J.H. (1985) Efferent connections of the ventral pallidum: evidence of a dual striato pallidofugal pathway. J. Comp. Neurol., 235: 322-335. Haber, S.N., Lyndbalta, E. and Mitchell, S.J. (1993) The organization of the descending ventral pallidal projections in the monkey. J. Comp. Neurol., 329: 11 1-128. Halgren, E., Walter, R.D., Cherlow, D.G. and Crandall, P.H. ( 1978) Mental phenomena evoked by electrical stimulation of the human hippocampal formation and amygdala. Brain, 101: 83-1 17. Herzog, A.G. and van Hoesen, G.W. (1976) Temporal neocortical afferent connections to the amygdala in the rhesus monkey. Brain Res., 115: 57-69. Holt, D.J., de Lacalle, S. and Saper, C.B. (1992) Compartmentalization of cholinergic innervation of the human striatum. SOC.Neurosci. Abstr., 18: 307. Holt, D.J., Graybiel, A.M. and Saper, C.B. (1993) Organiza-

549 tion of chemical compartmentalization of the human striatum. SOC.Neurosci. Abstr., 19: 1435. Holt, D.J., Graybiel, A.M., Hyde, T.M., Herman, M.M., Kleinman, J.E., German, D.C. and Saper, C.B. (1994) Decreased density of cholinergic interneurons in the striatum of schizophrenics. SOC.Neurosci. Abstr., 20: 784. Holt, D.J., Hersh, L.B. and Saper, C.B. (1996) Cholinergic innervation of the human striatum: a three compartment model. Neuroscience, in press. Hurley, K.M., Herbert, H., Moga, M.M. and Saper, C.B. (1991) Efferent projections of the infralimbic cortex of the rat. J. Comp. Neurol., 308: 249-276. Insausti, R., Amaral, D.G. and Cowan, W.M. (1987) The entorhinal cortex of the monkey: 11. Cortical afferents. J. Comp. Neurol., 264: 356-395. James, W. (1884) What is emotion? Mind, 19: 188-205. Kliiver, H. and Bucy, P.C. (1937) Psychic blindness and other symptoms following bilateral temporal lobectomy in rhesus monkeys. Am. J. Physiol., 119: 352-353. Krettek, J.E. and Price, J.L. (1978) Amygdaloid projections to subcortical structures within the basal forebrain and brainstem in the rat and cat. J. Comp. Neurol., 178: 225-254. Kunishio, K. and Haber, S.N. (1994) Primate cingulostriatal projection: limbic striatal versus sensorimotor striatal input. J. Comp. Neurol., 350: 337-356. Lange, K. ( 1 885) Om Sindsbevugelser. Copenhagen. LeDoux, J.E. (1995) Emotion: clues from the brain. Annu. Rev. Psychol., 46: 209-235. Lenz, F.A., Seike, M., Lin, Y.C., Baker, F.H., Rowland, L.H., Gracely, R.H. and Richardson, R.T. (1993) Neurons in the area of human thalamic nucleus ventralis caudalis respond to painful heat stimuli. Brain Res., 623: 235-240. Lopes da Silva, F.H., Witter, M.P., Boeijinga, P.H. and Lohman, A.H.M. (1990) Anatomic organization and physiology of the limbic cortex. Physiol. Rev., 70: 453-5 11. MacLean, P.D. (1 949) Psychosomatic disease and the “visceral brain”: recent developments bearing on the Papez theory of emotion. Psychosom. Med., 11: 338-353. MacLean, P.D. (1954) The limbic system and its hippocampal formation: studies in animals and their possible applications in man. J. Neurosurg., 11: 2 9 4 . Marlowe, W.B., Mancall, E.L. and Thomas, J.J. (1975) Complete Kluver-Bucy syndrome in man. Cortex, 11: 53-59. Neafsey, E.J., Bold, E.L., Haas, G.,Hurley-Gius, K.M., Quirk, G.,Sievert, C.F. and Terreberry, R.R. (1986) The organization of the rat motor cortex: a microstimulation mapping study. Bruin Res., 11: 77-96. Norgren, R. (1984) Central neural mechanisms of taste. In: I. Darien-Smith, Handbook of Physiology, Section I: The Nervous System, Vol. I l l , Sensory Processes, American Physiological Society, Bethesda, MD, pp. 1087-1 128. Pandya, D.N., van Hoesen, G.W. and Mesulam, M.M. (1981) Efferent connections of the cingulate gyms in the rhesus monkey. Exp. Bruin Res., 42: 319-330.

Papez, J.W. (1937) A proposed mechanism of emotion. Arch. Neurol. Psychiutr., 38: 725-743. Penfield, W. and Rasmussen, T. (1950) The Cerebral Cortex ofMun, Macmillan, New York. Powell, T.P.S., Guillery, R.W. and Cowan, W.M. (1957) A quantitative study of the fornix-mamillo-thalamic system. J. Anur., 91: 419. Price, J.L. and Amaral, D.G. (1981) An autoradiographic study of the projections of the central nucleus of the monkey amygdala. J. Neurosci., 1: 1242-1259. Pritchard, T.C., Hamilton, R.B., Morse, J.R. and Norgren, R. (1986) Projections of thalamic gustatory and lingual areas in the monkey, Macaca fascicularis. J. Comp. Neurol., 244: 213-228. Radna, R.J. and MacLean, P.D. (1981) Vagal elicitation of respiratory-type and other unit responses in basal limbic structures of squirrel monkeys. Bruin Res., 213: 45-61. Ragsdale, C.W. and Graybiel, A.M. (1990) A simple ordering of neocortical areas established by the compartmental organization of their striatal projections. Proc. Narl. Acad. Sci. USA, 87: 6196-6199. Robinson, C.J. and Burton, H. (1980) Somatic submodality distribution within the second somatosensory (SII), 7b, retroinsular, postauditory, and granular insular cortical areas of M. fascicularis. J. Comp. Neurol., 192: 93-108. Room, P., Russchen, F.T., Groenewegen, H.J. and Lohman, A.H.M. (1985) Efferent connections of the prelimbic (Area 32) and the infralimbic (Area 25) cortices: an anterograde tracing study in the cat. J. Comp. Neurol., 242: 4055. Rosene, D.L. and van Hoesen, G.W. (1977) Hippocampal efferents reach widespread areas of cerebral cortex and amygdala in the rhesus monkey. Science, 198: 315-317. Saper, C.B. (1982) Convergence of autonomic and limbic connections in the insular cortex of the rat. J. Comp. Neurol., 210: 163-173. Saunders, R.C., Rosene, D.L. and van Hoesen, G.W. (1988) Comparison of the efferents of the amygdala and the hippocampal formation in the rhesus monkey, 11: reciprocal and non-reciprocal connections. J. Comp. Neurol., 271 : 185-207. Schwartz, M., Fuchs, S., Polak, H. and Scharf, B. (1993) Psychiatric manifestations of Wilson’s disease. Hurefuah, 124: 75-77. Scott, T.R., Platasalaman, C.R. and Smithswintosky, V.L. (1994) Gustatory neural coding in the monkey cortex: the quality of saltiness. J. Neurophysiol., 7 1: 1692-1701, Shraberg, D. and Weisberg, L. (1978) The Kluver-Bucy syndrome in man. J. New. Ment. Dis., 166: 130-134. Swanson, L.W. and Cowan, W.M. (1975) Hippocampohypothalamic connections: origins in subicular cortex, not Ammon’s horn. Science, 189: 303-304. Talairach, J., Bancaud, J., Geier, S., Bordas-Ferrer, M., Bonis, A., Szikla, G. and Rusu, M. (1973) The cingulate gyrus and

550 human behavior. Electroencephalogr. Clin. Neurophysiol., 34: 45-52. Terzian, H.and Dalle Ore, G. (1955) Syndrome of Kluver and Bucy: reproduced in man by bilateral removal of the temporal lobs. Neurology, 5: 372-380. Tranel, D.and Hyman, B.T. (1990) Neuropsychological correlates of bilateral amygdala damage. Arch. Neurol., 47: 349355. Tucker, D.C. and Saper, C.B. (1984) Neural connections of an infralimbic cortical pressor area. SOC.Neurosci. Abstr., 10: 606. Turner, B.H., Mishkin, M. and Knapp, M. (1980) Organization of the amygdalopetal projections from modalityspecific cortical association areas in the monkey. J. Comp. Neurol., 191: 515-543. Valenstein, E.S. and Nauta, W.J.H. (1956) A comparison of the distribution of the fornix system in the rat, guinea pig, cat, and monkey. J . Comp. Neurol., 106: 183. van Hoesen, G.W. (1982) The parahippocampal gyms: new observations regarding its cortical connections in the monkey. Trends Neurosci., 5: 345-350. van Hoesen, G.W., Pandya, D.N. and Butters, N. (1972) Cortical afferents to the entorhinal cortex of the rhesus monkey. Science, 175: 1471-1473. Vogt, B.A. and Pandya, D.N. (1987) Cingulate cortex of the rhesus monkey, 11: cortical afferents. J. Comp. Neurol., 262: 27 1-289. Vogt, B.A., Finch, D.M. and Olson, C.R. (1992) Functional heterogeneity in cingulate cortex: the anterior executive and posterior evaluative regions. Cerebral Cortex, 2: 435-443. Voorn, P., Gerfen, C.R. and Groenewegen, H.J. (1989) Compartmental organization of the ventral striatum of the rat: immunohistochemical distribution of enkephalin, substance P, dopamine, and calcium-binding protein. J. Comp. Neurol., 289: 189-201. Woolsey, R.M. and Nelson, J.S. (1975) Asymptomatic destruction of the fornix in man. Arch. Neurol., 33: 566-568. Yamamoto, T. (1984) Taste responses of cortical neurons. Prog. Neurobiol., 23: 273-315.

Yasui, Y., Saper, C.B. and Cechetto, D.F. (1989) Calcitonin gene-related peptide immunoreactivity in the visceral sensory cortex, thalamus, and related pathways in the rat. J . Comp. Neurol., 290: 487-501. Yasui, Y., Breder, C.D., Saper, C.B. and Cechetto, D.F. ( 1 991 a) Autonomic responses and efferent pathways from the insular cortex in the rat. J . Comp. Neurol., 303: 355374. Yasui, Y., Saper, C.B. and Cechetto, D.F. (1991b) Calcitonin gene-related peptide (CGRP) immunoreactive projections from the thalamus to the striatum and amygdala in the rat. J. Comp. Neurol., 308: 293-310. Yeterian, E.H. and Pandya, D.N. (1991) Prefrontostriatal connections in relation to cortical architectonic organization in rhesus monkeys. J. Comp. Neurol., 312: 43-67. Yeterian, E.H.and Pandya, D.N. (1993) Striatal connections of the parietal association cortices in rhesus monkeys. J. Comp. Neurol., 332: 175-197. Yokota, T., Asato, F., Koyama, N., Masuda, T. and Taguchi, H. (1988) Nociceptive body representation in nucleus ventralis posterolateralis of cat thalamus. J. Neurophysiol., 60: 1714-1727. Young, W.S., Alheid, G.F. and Heimer, L. (1984) The ventral pallidal projection to the mediodorsal thalamus: a study with fluorescent retrograde tracers and immunohistofluorescence. J. Neurosci., 4: 1626-1638. Zahm, D.S. and Brog, J.S. (1992) On the significance of subterritories in the “accumbens” part of the rat ventral striatum. Neuroscience, 50: 751-767. Zahm, D.S. and Heimer, L. (1990) Transpallidal pathways originating in the rat nucleus accumbens. J. Comp. Neurol., 302: 437-446. %la-Morgan, S. and Squire, L.R. (1993) Neuroanatomy of memory. Annu. Rev. Neurosci., 16547-563: 563. %la-Morgan, S., Squire, L.R. and Amaral, D.G. (1986) Human amnesia and the medial temporal region: enduring memory impairment following a bilateral lesion limited to field CAI of the hippocampus. J. Neurosci., 6: 2950-2967.