Sequence of information processing for emotions based on the anatomic dialogue between prefrontal cortex and amygdala

The prefrontal cortex and the amygdala have synergistic roles in regulating purposive behavior, effected through bidirectional pathways. Here we investigated the largely unknown extent and laminar relationship of prefrontal input-output zones linked with the amygdala using neural tracers injected in the amygdala in rhesus monkeys. Prefrontal areas varied vastly in their connections with the amygdala, with the densest connections found in posterior orbitofrontal and posterior medial cortices, and the sparsest in anterior lateral prefrontal areas, especially area 10. Prefrontal projection neurons directed to the amygdala originated in layer 5, but significant numbers were also found in layers 2 and 3 in posterior medial and orbitofrontal cortices. Amygdalar axonal terminations in prefrontal cortex were most frequently distributed in bilaminar bands in the superficial and deep layers, by columns spanning the entire cortical depth, and less frequently as small patches centered in the superficial or deep layers. Heavy terminations in layers 1-2 overlapped with calbindin-positive inhibitory neurons. A comparison of the relationship of input to output projections revealed that among the most heavily connected cortices, cingulate areas 25 and 24 issued comparatively more projections to the amygdala than they received, whereas caudal orbitofrontal areas were more receivers than senders. Further, there was a significant relationship between the proportion of 'feedforward' cortical projections from layers 2-3 to 'feedback' terminations innervating the superficial layers of prefrontal cortices. These findings indicate that the connections between prefrontal cortices and the amygdala follow similar patterns as corticocortical connections, and by analogy suggest pathways underlying the sequence of information processing for emotions.

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title: Changes in Functional Connectivity in Orbitofrontal Cortex and Basolateral Amygdala during Learning and Reversal Training
abstract: Interconnections between orbitofrontal cortex (OFC) and basolateral amygdala (ABL) are critical for encoding and using associative information about the motivational significance of stimuli. Previously, we reported that neurons in OFC and ABL fired selectively to cues during odor discrimination learning and reversal training. Here we conducted an analysis of correlated firing in the cell pairs recorded in the previous study. Correlated firing during the intertrial intervals was compared across task phases during different phases of acquisition and reversal learning. Changes in correlated activity during initial learning and subsequent accurate performance on the discrimination problems closely resembled the changes in odor selectivity in OFC and ABL reported earlier. Increased correlated firing was most pronounced in OFC during accurate go, no-go performance in the postcriterion phase of performance, whereas correlated firing in ABL increased primarily during an earlier phase of learning. In contrast, findings during subsequent reversal training diverged from our earlier report in which odor selectivity diminished in OFC and reversed in ABL. When the reinforcement contingencies of the odors were reversed after the rat had learned the original associations, correlated firing further increased significantly in OFC but remained stable in ABL. This evidence that associative encoding increments with reversal learning in OFC suggests that the original associations, although not expressed as stimulus driven activity, may be maintained within the network as new associations are acquired.

title: Opposing effects of amygdala and orbital prefrontal cortex lesions on the extinction of instrumental responding in macaque monkeys
abstract: Extinction is a well‐known behavioural phenomenon that allows organisms to respond flexibly to a changing environment. Although recent work implicates the amygdala and orbital prefrontal cortex (PFo) in extinction of Pavlovian conditioned fear and aversion, much less is known about the neural bases of instrumental extinction. To explore the contribution of the macaque amygdala to flexible responding in the face of changing reward contingency, we tested the effects of selective, excitotoxic lesions of the amygdala on extinction of an instrumental response. For comparison, we evaluated the effects of ablation of PFo on the same task. Amygdala lesions facilitated the extinction of instrumental responses, whereas lesions of PFo had the opposite effect.

title: Connections underlying the synthesis of cognition, memory, and emotion in primate prefrontal cortices
abstract: Distinct domains of the prefrontal cortex in primates have a set of connections suggesting that they have different roles in cognition, memory, and emotion. Caudal lateral prefrontal areas (areas 8 and 46) receive projections from cortices representing early stages in visual or auditory processing, and from intraparietal and posterior cingulate areas associated with oculomotor guidance and attentional processes. Cortical input to areas 46 and 8 is complemented by projections from the thalamic multiform and parvicellular sectors of the mediodorsal nucleus associated with oculomotor functions and working memory. In contrast, caudal orbitofrontal areas receive diverse input from cortices representing late stages of processing within every unimodal sensory cortical system. In addition, orbitofrontal and caudal medial (limbic) prefrontal cortices receive robust projections from the amygdala, associated with emotional memory, and from medial temporal and thalamic structures associated with long-term memory. Prefrontal cortices are linked with motor control structures related to their specific roles in central executive functions. Caudal lateral prefrontal areas project to brainstem oculomotor structures, and are connected with premotor cortices effecting head, limb and body movements. In contrast, medial prefrontal and orbitofrontal limbic cortices project to hypothalamic visceromotor centers for the expression of emotions. Lateral, orbitofrontal, and medial prefrontal cortices are robustly interconnected, suggesting that they participate in concert in central executive functions. Prefrontal limbic cortices issue widespread projections through their deep layers and terminate in the upper layers of lateral (eulaminate) cortices, suggesting a predominant role in feedback communication. In contrast, when lateral prefrontal cortices communicate with limbic areas they issue projections from their upper layers and their axons terminate in the deep layers, suggesting a role in feedforward communication. Through their widespread connections, prefrontal limbic cortices may exercise a tonic influence on lateral prefrontal cortices, inextricably linking areas associated with cognitive and emotional processes. The integration of cognitive, mnemonic and emotional processes is likely to be disrupted in psychiatric and neurodegenerative diseases which preferentially affect limbic cortices and consequently disconnect major feedback pathways to the neuraxis.

title: Emotion, decision making and the orbitofrontal cortex.
abstract: The somatic marker hypothesis provides a systems-level neuroanatomical and cognitive framework for decision making and the influence on it by emotion. The key idea of this hypothesis is that decision making is a process that is influenced by marker signals that arise in bioregulatory processes, including those that express themselves in emotions and feelings. This influence can occur at multiple levels of operation, some of which occur consciously and some of which occur non-consciously. Here we review studies that confirm various predictions from the hypothesis. The orbitofrontal cortex represents one critical structure in a neural system subserving decision making. Decision making is not mediated by the orbitofrontal cortex alone, but arises from large-scale systems that include other cortical and subcortical components. Such structures include the amygdala, the somatosensory/insular cortices and the peripheral nervous system. Here we focus only on the role of the orbitofrontal cortex in decision making and emotional processing, and the relationship between emotion, decision making and other cognitive functions of the frontal lobe, namely working memory.

title: Inhibitory control and affective processing in the prefrontal cortex: neuropsychological studies in the common marmoset.
abstract: The orbitofrontal cortex has been ascribed a role in the inhibitory control, as well as in the emotional control, of behaviour. While damage to the orbitofrontal cortex in humans and non-human primates can cause inflexibility, impulsiveness and emotional disturbance, the relationship between these effects are unclear. Excitotoxic lesion studies in marmosets comparing the effects of cell loss within specific regions of the prefrontal cortex on performance of a range of behavioural tests reveal that mechanisms of response inhibition are not unique to the orbitofrontal cortex. Instead they are present in distinct cognitive domains for lowerorder as well as higher-order processing throughout the prefrontal cortex. Thus, the lateral prefrontal cortex is involved in the selection and control of action based upon higher-order rules while the orbitofrontal and medial prefrontal cortex may be involved in different but complementary forms of lower-order rule learning, their roles dissociable, as a result of their differential contribution to different types of associative learning.

title: Segregation of working memory functions within the dorsolateral prefrontal cortex
abstract: It is now widely accepted that the prefrontal cortex (PFC) plays a critical role in the neural network subserving working memory (WM). At least three related questions are still under debate: (1) is the PFC critical for all constituent processes of WM (i.e., short-term storage, manipulation, and utilization of mental representations) or only in one or a few of them? (2) Is there segregation of function among different cytoarchitectonic subdivisions of the PFC? (3) If this be the case, is this segregation based on the nature of the information being processed or on the type of cognitive operation performed? The present review article describes findings in the monkey supporting a modular "domain-specific" model of PFC functional organization with respect to WM operations. In this model, the dorsolateral prefrontal cortex (DLPFC) is composed of several subregions, based primarily on the nature of the information being processed in WM. Storage and processing functions are integrally related in each area. Future studies designed to map as yet uncharted areas of prefrontal cortex with refined anatomical and physiological approaches may provide a critical test of the model and evaluate the extent to which it applies generally or, instead, mainly to visual domains or only to dorsolateral convexity areas.

title: Fibre degeneration following lesions of the amygdaloid complex in the monkey.
abstract: Of the amygdaloid projection pathways the stria terminalis has traditionally received strong emphasis in anatomical studies, and less attention has customarily been given other fibre systems originating in the amygdaloid complex. It is, how­ ever, known that the amygdala is connected with other basal telencephalic structures and with the diencephalon by a massive ventral fibre system which spreads forward and medially through the region underneath the lentiform nucleus. This fibre system appears to have been recognized first by Johnston (1923), who considered it to be an amygdalofugal component of his 'longitudinal association bundle '. Johnston limited his account of this projection system to the statement that such fibres beneath the globus pallidus join' the general system of precommissural fibres passing up through the parolfactory area'. Later workers, on the basis of experi­ mental-anatomical observations in the cat, described distributions of the ventral amygdalofugal fibre system to the preoptic region and hypothalamus (Lammers & Lohman, 1957; Hall, 1960), the bed nucleus of the stria terminalis (Fox, 1943), the caudate nucleus and the subcallosal gyrus (Lammers & Lohman, 1951). In Marchi experiments in the monkey, Fox (1949) made the interesting observa­ tion that fibres of apparently the same general category join the inferior thalamic peduncle and terminate in the dorso-medial nucleus of the thalamus. In a recent study by the aid ofthe N auta-Gygax silver technique the existence of a direct amyg­ dalo-thalamic projection in the monkey was confirmed, whereas other components of the ventral amygdalofugal fibre system were traced to the substantia innominata, the lateral preoptic and hypothalamic regions, the basal septal region, olfactory tubercle, and rostral limbic cortex (Nauta & Valenstein, 1958). These findings have hitherto been published only in the form of an abstract. The present paper will serve to present a more detailed account of the pertinent observations.

title: Amygdaloid projections to prefrontal granular cortex in rhesus monkey demonstrated with horseradish peroxidase
abstract: The frontal lobe is divided into an agranular motor and premotor region and a more rostral granular prefrontal region 1. The cortical afferent supply to the motor and premotor areas are the primary and secondary somatosensory regions respectively~, a6, while afferents to the granular cortex arise from more widely distributed sites with several afferent systems converging on this region. These systems originate mainly in the association areas of the visual, auditory and somatosensory corticesS,S,14,16. A recent study of the projections of the amygdala v demonstrated efferent connections from this nucleus to the possible homologue of primate prefrontal cortex in the rat and cat 11. In view of this we have studied the connections of the frontal granular cortex in the rhesus monkey using horseradish peroxidase (HRP) in order to determine whether subcortical projections exist from amygdala to this region in monkey. The brains of 8 adolescent rhesus monkeys were used in this study. All animals received unilateral multiple injections of HRP with each single injection consisting of 0.6 #1 of 10~ aqueous solution of the marker. The injections were carried out over 2-5 min to a depth of 2 mm. The animals survived 65-80 h and the perfusion and processing of the brains for H R P was as previously described z°. Every tenth section through the amygdaloid complex was examined bilaterally under both darkand light-field illumination and the location of the labeled neurons was recorded on a sheet of paper with the aid of an X-ray plotter. In order to determine the exact location of the labeled cells in amygdala, the sections were subsequently stained with cresyl violet and each stained section was projected onto the sheet of paper from the x-y recorder so that the boundaries of the individual nuclei could be drawn in and the HRPpositive neurons located with respect to them. The terminology of Lauer 1° and RusseP 9 is used for the subdivisions of amygdala. HRP-positive neurons were seen in all 8 animals in ipsilateral thalamus and in ipsilateral and contraIateral cortex 4, however, in only 4 of the 8 animals were HRPpositive cells seen in the amygdala and they were always observed ipsilateral to the

title: Cortical and subcortical afferents to the amygdala of the rhesus monkey (Macaca mulatta)
abstract: The afferent projections to the primate amygdala were studied using horseradish peroxidase. The potential advantages of this technique are discussed compared with those previously used to determine amygdaloid afferents. The findings indicate that certain agranular or dysgranular cortical regions may project directly to the amygdala: in particular, the orbital frontal cortex, anterior cingulate gyrus, subcallosal gyrus, temporal pole and anterior insula. These projections probably terminate predominantly in either the lateral or accessory basal nuclei. Other cortical projections from the inferotemporal and superior temporal gyri are described. Evidence was found for a heavy projection from the superior temporal sulcus to the lateral nucleus. Subcortical afferents were found from the hypothalamus, substantia innominata, diagonal band, thalamus, periaqueductal central gray, peripeduncular nucleus and from a band of cells extending medially from the peripeduncular nucleus to the midline, just ventral to the thalamus. In the thalamus, labelled cells were restricted to the non-specific nuclei, and were common in the rostral midline nuclei. No projection was observed from the dorsomedial nucleus of the thalamus. We discuss the implications of these results for interpreting the functions of the amygdala.

title: Direct and indirect pathways from the amygdala to the frontal lobe in rhesus monkeys
abstract: To elucidate the anatomical relationships between the frontal association cortex and the limbic system in primates, projections from the amygdala to frontal cortex were studied in the rhesus monkey using retrograde and anterograde tracing methods. Following injections of horseradish peroxidase (HRP) into the orbital prefrontal cortex, the gyrus rectus, the superior frontal gyrus, and the anterior cingulate gyrus of the frontal lobe, labeled neurons were found in the basolateral, basomedial, or basal accessory nuclei of the amygdala. None of these nuclei contained labeled neurons following HRP injections into the principal sulcus or the lateral inferior convexity of the frontal lobe. This selective distribution of amygdala connections was confirmed by injecting tritiated amino acids into the amygdala. Silver grains were present only over the orbital cortex and gyrus rectus on the ventral surface of the frontal lobe and over the superior prefrontal gyrus and anterior cingulate gyrus on the medial wall of the hemisphere, while the dorsolateral prefrontal cortex was free of radioactivity. The isotope injection of the amygdala also revealed a projection to the magnocellular moeity of the mediodorsal nucleus (MDmc) which is known to innervate the same ventromedial regions of the frontal lobe that receive direct connections from the amygdala. Although MDmc and amygdala project to the same cortical regions, their terminal fields are different. The direct amygdala input terminates in layer 1 in orbital cortex and gyrus rectus and layer 2 in the dorsomedial cortex and cingulate gyrus, while the thalamic input is primarily to layer 3 and, in some areas, also to the superficial half of layer 1.

title: Amygdalo‐cortical projections in the monkey (Macaca fascicularis)
abstract: Amygdalo‐cortical projections were analyzed in the macaque monkey (Macaca fascicularis) in a series of experiments in which 3H‐amino acids were injected into each of the major divisions of the amygdaloid complex and the anterogradely transported label was demonstrated autoradiographically. Projections to widespread regions of frontal, insular, temporal, and occipital cortices have been observed. The heaviest projections to frontal cortex terminated in medial and orbital regions which included areas 24, 25, and 32 on the medial surface and areas 14, 13a, and 12 on the orbital surface. Lighter projections were also seen in areas 45, 46, 6, 9, and 10. The heaviest projection to the insula terminated in the agranular insular cortex with a decreasing gradient of innervation to the more caudally placed dysgranular and granular insular areas. The projection to this region continues around the dorsal limiting sulcus to terminate in the somatosensory fields 3, 1–2, and SII. Essentially all major divisions of the temporal neocortex receive a projection from the amygdaloid complex with the most prominent projections ending in the cortex of the temporal pole (area TG) and the perirhinal cortex. The entire rostrocaudal extent of the inferotemporal cortex (areas TE and TEO) is also in receipt of an amygdaloid projection. While the rostral superior temporal gyrus (area TA) is heavily labeled in several of the experiments (with light labeling continuing into AI and adjacent auditory association regions) there was little indication of labeling in the caudal reaches of area TA. There was a surprisingly strong projection to prestriate regions of the occipital lobe and, in at least one case, clear‐cut labeling in areas OB and 17. Labeling in the parietal cortex was primarily observed in the depths of the intraparietal sulcus. In all cortical fields, label was heaviest at the border between layers I and II and in some regions layers V and VI also had above background levels of silver grains.

title: Projections from the amygdala to basoventral and mediodorsal prefrontal regions in the rhesus monkey
abstract: The sources of ipsilateral projections from the amygdala to basoventral and mediodorsal prefrontal cortices were studied with retrograde tracers (horseradish peroxidase or fluorescent dyes) in 13 rhesus monkeys. The basoventral regions injected with tracers included the orbital periallocortex and proisocortex, orbital areas 13,11, and 12, lateral area 12, and ventral area 46. The mediodorsal regions included portions of medial areas 25, 32, 14, and dorsal area 8. The above sites represent areas within two architectonic series of cortices referred to as basoventral mediodorsal on the basis of their anatomic location. Each series consists of areas that show a gradual increase in the number of layers and their delineation in a direction from the caudal orbital and medial limbic cortices, which have an incipient laminar organization, towards the eulaminated periarcuate cortices (Barbas and Pandya,  286:353‐375, '89).

title: Cytoarchitecture and neural afferents of orbitofrontal cortex in the brain of the monkey
abstract: The orbitofrontal cortex of the monkey can be subdivided into a caudal agranular sector, a transitional dysgranular sector, and an anterior granular sector. The neural input into these sectors was investigated with the help of large horseradish peroxidase injections that covered the different sectors of orbitofrontal cortex. The distribution of retrograde labeling showed that the majority of the cortical projections to orbitofrontal cortex arises from a restricted set of telencephalic sources, which include prefrontal cortex, lateral, and inferomedial temporal cortex, the temporal pole, cingulate gyrus, insula, entorhinal cortex, hippocampus, amygdala, and claustrum. The posterior portion of the orbitofrontal cortex receives additional input from the piriform cortex and the anterolateral portion from gustatory, somatosensory, and premotor areas.

title: Limbic connections of the orbital and medial prefrontal cortex in macaque monkeys
abstract: Previous studies have shown that the orbital and medial prefrontal cortex (OMPFC) is extensively connected with medial temporal and cingulate limbic structures. In this study, the organization of these projections was defined in relation to architectonic areas within the OMPFC. All of the limbic structures were substantially connected with the following posterior and medial orbital areas: the posteromedial, medial, intermediate, and lateral agranular insular areas (Iapm, Iam, Iai, and Ial, respectively) and areas 11m, 13a, 13b, 14c, and 14r. In contrast, lateral orbital areas 12o, 12m, and  and medial wall areas 24a, b and 32 were primarily connected with the amygdala, the temporal pole, and the cingulate cortex. Data were not obtained on the poateroventral medial wall.

title: Deciding Advantageously Before Knowing the Advantageous Strategy
abstract: Deciding advantageously in a complex situation is thought to require overt reasoning on declarative knowledge, namely, on facts pertaining to premises, options for action, and outcomes of actions that embody the pertinent previous experience. An alternative possibility was investigated: that overt reasoning is preceded by a nonconscious biasing step that uses neural systems other than those that support declarative knowledge. Normal participants and patients with prefrontal damage and decision-making defects performed a gambling task in which behavioral, psychophysiological, and self-account measures were obtained in parallel. Normals began to choose advantageously before they realized which strategy worked best, whereas prefrontal patients continued to choose disadvantageously even after they knew the correct strategy. Moreover, normals began to generate anticipatory skin conductance responses (SCRs) whenever they pondered a choice that turned out to be risky, before they knew explicitly that it was a risky choice, whereas patients never developed anticipatory SCRs, although some eventually realized which choices were risky. The results suggest that, in normal individuals, nonconscious biases guide behavior before conscious knowledge does. Without the help of such biases, overt knowledge may be insufficient to ensure advantageous behavior.

title: Orbitofrontal cortex and basolateral amygdala encode expected outcomes during learning
abstract: Reciprocal connections between the orbitofrontal cortex and the basolateral nucleus of the amygdala may provide a critical circuit for the learning that underlies goal-directed behavior. We examined neural activity in rat orbitofrontal cortex and basolateral amygdala during instrumental learning in an olfactory discrimination task. Neurons in both regions fired selectively during the anticipation of rewarding or aversive outcomes. This selective activity emerged early in training, before the rats had learned reliably to avoid the aversive outcome. The results support the concept that the basolateral amygdala and orbitofrontal cortex cooperate to encode information that may be used to guide goal-directed behavior.

title: Connections of the amygdala of the rat. IV: Corticoamygdaloid and intraamygdaloid connections as studied with axonal transport of horseradish peroxidase
abstract: The corticoamygdaloid and intraamygdaloid projections of the rat were studied by the use of retrograde transport of horseradish peroxidase (HRP). Observations based on anterograde transport of the enzyme were exploited to determine the course of the intrinsic connections. The HRP was injected stereotactically by means of iontophoresis. Most of the amygdaloid nuclei were selectively injected, and all but a few were reached by more than one approach.

title: Amygdalopetal projections in the cat. I. Cortical afferent connections. A study with retrograde and anterograde tracing techniques
abstract: The cortical afferent connections of the amygdaloid complex of the cat have been studied by means of retrograde tracing of horseradish peroxidase and the fluorescent substances bisbenzimid and nuclear yellow. Subsequently, anterograde tracing experiments were carried out in order to define more precisely the termination areas of the corticoamygdaloid fibers.

title: Collateralization of the amygdaloid projections of the rat prelimbic and infralimbic cortices
abstract: Previous studies indicate that the distribution of corticoamygdaloid neurons in the rat prelimbic (PL) and infralimbic (IL) cortices overlaps with the distribution of neurons projecting to the contralateral medial prefrontal cortex (MPC), insular cortex, mediodorsal thalamus, and dorsal medulla. In view of the poorly differentiated cytoarchitecture of PL and IL, and their designation as cortical regions transitional between the allocortex and isocortex, the present study sought to determine whether several cortical and subcortical projections from these areas arise as collaterals of corticoamygdaloid neurons. Injections of the fluorescent dyes Fast Blue (FB) or bisbenzimide (BB) were made into the amygdaloid complex and the following areas: agranular and granular insular cortices; mediodorsal thalamic nucleus (MD); nucleus tractus solitarii/dorsal medulla (NTS); contralateral amygdaloid complex; and ipsilateral and contralateral MPC. Neurons projecting to the ipsilateral amygdaloid complex were located mainly in layers II and V with fewer cells in layer III. Concomitant injections into the insular cortex, MD, and NTS labeled populations of neurons arranged in laminae that partially overlapped with, but were essentially separate from, corticoamygdaloid neurons. Projections to the insular cortex arose from layers II and V; those to MD arose from layers V and VI. Corticobulbar projections from IL originated from neurons arranged in a thin lamina in the deep part of layer V. Very few neurons projecting to both the amygdaloid complex and any of these areas were observed. Bilateral injections of FB and BB into the amygdaloid complex producted very few double‐labeled cells in PL and IL. Further, in layer V, ipsilaterally projecting corticoamygdaloid neurons tended to be located more deeply than contralaterally projecting neurons. Combined injections of BB and FB into the amygdaloid complex and the contralateral (but not ipsilateral) MPC resulted in significant numbers of double‐labeled neurons in layers II, III, and V of PL and IL. Control injections of fluorescent dyes into the cerebrospinal fluid labeled few neurons in the superficial layers of PL and IL and a combined injection into the amygdaloid complex (FB) and subarachnoid space (BB) resulted in a very small number of double‐labeled cells in layer II only. The results suggest that a significant proportion of neurons in PL and IL projecting to the amygdaloid complex issue collaterals innervating the contralateral MPC. Evidence is discussed that suggests that the interhemispheric collaterals of MPC corticoamygdaloid neurons may serve to correlate the amygdaloid outputs of the MPC bilaterally.

title: Organization of connections between the amygdaloid complex and the perirhinal and parahippocampal cortices in macaque monkeys
abstract: Neuroanatomical studies in macaque monkeys have demonstrated that the perirhinal and parahippocampal (PRPH) cortices are strongly interconnected with the hippocampal formation. Recent behavioral evidence indicates that these cortical regions are importantly involved in normal recognition memory function. The PRPH cortices are also interconnected with the amygdaloid complex, although comparatively little is known about the precise topography of these connections. We investigated the topographic organization of reciprocal connections between the amygdala and the PRPH cortices by placing anterograde and retrograde tracers throughout these three regions. We found that there was an organized arrangement of connections between the amygdala and the PRPH cortices and that the deep (lateral, basal, and accessory basal) nuclei of the amygdaloid complex were the source of most connections between the amygdala and the PRPH cortices. The temporal polar regions of the perirhinal cortex had the strongest and most widespread interconnections with the amygdala. Connections from more caudal levels of the perirhinal cortex had a more discrete pattern of termination. Perirhinal inputs to the amygdala terminated primarily in the lateral nucleus, the magnocellular and parvicellular divisions of the basal nucleus, and the magnocellular division of the accessory basal nucleus. Return projections originated predominately in the lateral nucleus, the intermediate and parvicellular divisions of the basal nucleus, and the magnocellular division of the accessory basal nucleus. The interconnections between the amygdala and the parahippocampal cortex were substantially less robust than those with the perirhinal cortex and mainly involved the basal nucleus. Area TF was more strongly interconnected with the amygdala than was area TH. Input from the parahippocampal cortex terminated predominantly in the lateral half of the parvicellular division of the basal nucleus but also to a lesser extent in the magnocellular division of the basal nucleus and the lateral nucleus. Return projections originated predominantly in the magnocellular division of the basal nucleus and were directed almost exclusively to area TF.

title: Relationship of prefrontal connections to inhibitory systems in superior temporal areas in the rhesus monkey.
abstract: The prefrontal cortex selects relevant signals and suppresses irrelevant signals in behavior, as exemplified by its functional interaction with superior temporal cortices. We addressed the structural basis of this process by investigating quantitatively the relationship of prefrontal pathways to inhibitory interneurons in superior temporal cortices. Pathways were labeled with neural tracers, and two neurochemical classes of inhibitory interneurons were labeled with parvalbumin (PV) and calbindin (CB), which differ in mode of inhibitory control. Both markers varied significantly and systematically across superior temporal areas. Calbindin neurons were more prevalent than PV neurons, with the highest densities found in posterior high-order auditory association cortices. Axons from anterior lateral, medial prefrontal and orbitofrontal areas terminated in the anterior half of the superior temporal gyrus, targeting mostly the superficial layers (I to upper III), where CB neurons predominated. Reciprocal projection neurons were intermingled with PV neurons, and emanated mostly from the deep part of layer III and to a lesser extent from layers V-VI, in proportions matching the laminar density of inhibitory interneurons. In marked contrast, prefrontal connections in temporal polar cortex were found mostly in the deep layers, showing mismatch with the predominant upper laminar distribution of interneurons. Differences in the relationship of connections to inhibitory neurons probably affect the dynamics in distinct superior temporal cortices. These findings may help explain the reduced efficacy of inhibitory control in superior temporal areas after prefrontal cortical damage.

title: Synaptic distinction of laminar-specific prefrontal-temporal pathways in primates.
abstract: Prefrontal pathways exert diverse effects in widespread cortical areas, issuing projections both to the middle layers and to layer I, which are anatomically and functionally distinct. Here we addressed the still unanswered question of whether cortical pathways that terminate in different layers are distinct at the synaptic level. We addressed this issue using as a model system the robust and functionally significant pathways from prefrontal areas 10 and 32 to superior temporal areas in rhesus monkeys. Boutons from prefrontal axons synapsing in the middle layers of superior temporal cortex were significantly larger than boutons synapsing in layer I. Most synapses were on spines in both layers, which are found on dendrites of excitatory neurons. The less prevalent synapses on smooth dendrites, characteristic of inhibitory interneurons, were more common in the middle cortical layers than in layer I. Bouton volume was linearly related to vesicular and mitochondrial content in both layers, though a subset of small boutons, found mostly in layer I, contained no mitochondria. The systematic laminar-specific presynaptic differences in stable cortical synapses in adult primates were independent of their origin in the functionally distinct prefrontal areas 10 and 32, or their destination in architectonically distinct superior temporal areas. This synaptic distinction suggests differences in efficacy of synaptic transmission and metabolic demands in laminar-specific pathways that may be selectively recruited in behavior.

title: Distributed hierarchical processing in the primate cerebral cortex.
abstract: In recent years, many new cortical areas have been identified in the macaque monkey. The number of identified connections between areas has increased even more dramatically. We report here on (1) a summary of the layout of cortical areas associated with vision and with other modalities, (2) a computerized database for storing and representing large amounts of information on connectivity patterns, and (3) the application of these data to the analysis of hierarchical organization of the cerebral cortex. Our analysis concentrates on the visual system, which includes 25 neocortical areas that are predominantly or exclusively visual in function, plus an additional 7 areas that we regard as visual-association areas on the basis of their extensive visual inputs. A total of 305 connections among these 32 visual and visual-association areas have been reported. This represents 31% of the possible number of pathways if each area were connected with all others. The actual degree of connectivity is likely to be closer to 40%. The great majority of pathways involve reciprocal connections between areas. There are also extensive connections with cortical areas outside the visual system proper, including the somatosensory cortex, as well as neocortical, transitional, and archicortical regions in the temporal and frontal lobes. In the somatosensory/motor system, there are 62 identified pathways linking 13 cortical areas, suggesting an overall connectivity of about 40%. Based on the laminar patterns of connections between areas, we propose a hierarchy of visual areas and of somatosensory/motor areas that is more comprehensive than those suggested in other recent studies. The current version of the visual hierarchy includes 10 levels of cortical processing. Altogether, it contains 14 levels if one includes the retina and lateral geniculate nucleus at the bottom as well as the entorhinal cortex and hippocampus at the top. Within this hierarchy, there are multiple, intertwined processing streams, which, at a low level, are related to the compartmental organization of areas V1 and V2 and, at a high level, are related to the distinction between processing centers in the temporal and parietal lobes. However, there are some pathways and relationships (about 10% of the total) whose descriptions do not fit cleanly into this hierarchical scheme for one reason or another. In most instances, though, it is unclear whether these represent genuine exceptions to a strict hierarchy rather than inaccuracies or uncertainities in the reported assignment.

title: Cortical structure predicts the pattern of corticocortical connections.
abstract: Cortical areas are linked through pathways which originate and terminate in specific layers. The factors underlying which layers are involved in specific connections are not well understood. Here we tested whether cortical structure can predict the pattern as well as the relative distribution of projection neurons and axonal terminals in cortical layers, studied with retrograde and anterograde tracers. We used the prefrontal cortices in the rhesus monkey as a model system because their laminar organization varies systematically, ranging from areas that have only three identifiable layers, to those that have six layers. We rated each prefrontal area based on the number and definition of its cortical layers (level 1, lowest; level 5, highest). The structural model accurately predicted the laminar pattern of connections in approximately 80% of the cases. Thus, projection neurons from a higher-level cortex originated mostly in the upper layers and their axons terminated predominantly in the deep layers (4-6) of a lower-level cortex. Conversely, most projection neurons from a lower-level area originated in the deep layers and their axons terminated predominantly in the upper layers (1-3) of a higher-level area. In addition, the structural model accurately predicted that the proportion of projection neurons or axonal terminals in the upper to the deep layers would vary as a function of the number of levels between the connected cortices. The power of this structural model lies in its potential to predict patterns of connections in the human cortex, where invasive procedures are precluded.

title: Quantitative architecture distinguishes prefrontal cortical systems in the rhesus monkey.
abstract: The prefrontal cortex encompasses a large and heterogeneous set of areas, whose borders have been variously mapped in different architectonic studies. Differences in cortical maps present a formidable problem in comparing data across studies and in constructing databanks on the connections and functional attributes of cortical areas. Here we used quantitative approaches to cortical mapping to investigate (i) if architectonic areas of the prefrontal cortex in adult rhesus monkeys have unique profiles and (ii) if groups of architectonic areas belonging to distinct cortical types, ranging from agranular to eulaminate, have similar features. In addition, we used multidimensional analyses to see if, and how, prefrontal areas form clusters when multiple features are considered simultaneously. We used quantitative unbiased sampling procedures to estimate the areal and laminar density of neurons, glia and neurons positive for the calcium binding proteins parvalbumin (PV), calbindin (CB) and calretinin (CR) among 21 prefrontal areas or subdivisions of areas. Neuronal density varied among the prefrontal cortices (range: 38 569 +/- 4078 to 58 708 +/- 2327 neurons/mm(3)); it was lowest in caudal orbitofrontal and medial areas (OPAll, OPro, 13, 24a, 32, M25) and highest in lateral prefrontal areas (subdivisions of areas 46 and 8). Neurons positive for PV were most prevalent in lateral prefrontal areas and least prevalent in caudal orbitofrontal and medial pre-frontal areas, whereas the opposite trend was noted for neurons that expressed CB. Neurons positive for CR did not show regional differences, and the density of glia showed small variations among prefrontal cortices. The differences among areas, along with differences in the thickness of individual areas and layers, were used to establish a quantitative profile for each area. The results showed that differences in the density of neurons, and the preponderance of neurons positive for PV and CB, were related to different architectonic types of areas found within the prefrontal cortex. Conventional as well as multiparameter statistical analyses distinguished at one extreme the agranular and dysgranular (limbic) cortices, which were characterized by prominent deep layers (V-VI), the lowest neuronal density, the highest ratio of glia/neurons, and the lowest density of PV and the highest for CB. At the other extreme, lateral eulaminate cortices were characterized by the highest density of neurons, a prominent granular layer IV, denser supragranular (II-III) than infragranular (V-VI) layers, and a balanced distribution of neurons positive for PV and CB. The results provide insights into potentially different rates of development or maturation of limbic and eulaminate prefrontal areas, and their differential vulnerability in neurological and psychiatric diseases. The quantitative methods used provide an objective approach to construct maps, address differences in nomenclature across studies, establish homologies in different species and provide a baseline to identify changes in pathologic conditions.

title: Diversity of laminar connections linking periarcuate and lateral intraparietal areas depends on cortical structure
abstract: Lateral prefrontal and intraparietal cortices have strong connectional and functional associations but it is unclear how their common visuomotor, perceptual and working memory functions arise. The hierarchical scheme of cortical processing assumes that prefrontal cortex issues ‘feedback’ projections to parietal cortex. However, the architectonic heterogeneity of these cortices raises the question of whether distinct areas have laminar‐specific interconnections underlying their complex functional relationship. Using quantitative procedures, we showed that laminar‐specific connections between distinct prefrontal (areas 46 and 8) and lateral intraparietal (LIPv, LIPd and 7a) areas in Macaca mulatta, studied with neural tracers, varied systematically according to rules determined by the laminar architecture of the linked areas. We found that axons from areas 46 and rostral 8 terminated heavily in layers I–III of all intraparietal areas, as did caudal area 8 to area LIPv, suggesting ‘feedback’ communication. However, contrary to previous assumptions, axons from caudal area 8 terminated mostly in layers IV–V of LIPd and 7a, suggesting ‘feedforward’ communication. These laminar patterns of connections were highly correlated with consistent differences in neuronal density between linked areas. When neuronal density in a prefrontal origin was lower than in the intraparietal destination, most terminations were found in layer I with a concomitant decrease in layer IV. The opposite occurred when the prefrontal origin had a higher neuronal density than the target. These findings indicate that the neuronal density of linked areas can reliably predict their laminar connections and may form the basis of understanding the functional complexity of prefrontal–intraparietal interactions in cognition.

title: Biotinylated dextran amine as an anterograde tracer for single- and double-labeling studies
abstract: Fluorescent dextran amines have recently been reported to be useful for anterograde pathway tracing. However, fluorescent markers are not always ideal for detailed mapping studies. We therefore evaluated the efficacy of a biotinylated dextran amine (BDA) for anterograde labeling in several different preparations. BDA was visualized with an avidin-biotinylated HRP (ABC) procedure followed by a standard or metal-enhanced diaminobenzidine (DAB) reaction. After iontophoretic injections of BDA into neocortex-like telencephalic regions in pigeons or into visual or somatosensory cortex in rats, there was excellent and abundant labeling of axons and terminals in forebrain, midbrain and hindbrain target areas with 1-week survival times. Large pressure injections of BDA into the avian telencephalon were also found to result in extensive anterograde labeling. We then carried out a series of studies using 2-color DAB double-labeling to determine effective approaches for combining BDA labeling with other labeling methods. Using an isolated embryonic chick spinal cord-hindlimb preparation, we combined BDA labeling with another anterograde labeling method to differentially label two sets of projections. In these studies, sensory neuron and motoneuron projections into the limb from the same segmental level, or motoneuron projections into the limb from two separate segments were differentially labeled by using HRP (visualized first with a blue/black metal-DAB reaction) and BDA (visualized second with a brown DAB reaction). In other double-labeling studies, we combined BDA labeling of axons and terminals with immunohistochemical labeling of neurons. In these experiments, telencephalic neurons in pigeons or rats were labeled immunohistochemically for parvalbumin or substance P (using a brown DAB reaction) and BDA-labeled axons were labeled blue/black (using a metal-intensified DAB reaction). Double-labeling was successful regardless of whether the entire immunohistochemical labeling procedure preceded or followed the BDA labeling procedure. Together, these studies show that BDA is effective for anterograde pathway tracing and can be used in double-label studies with other labeling methods.

title: Pathway tracing using biotinylated dextran amines
abstract: Biotinylated dextran amines (BDA) are highly sensitive tools for anterograde and retrograde pathway tracing studies of the nervous system. BDA can be reliably delivered into the nervous system by iontophoretic or pressure injection and visualized with an avidin-biotinylated HRP (ABC) procedure, followed by a standard or metal-enhanced diaminobenzidine (DAB) reaction. High molecular weight BDA (10 k) yields sensitive and exquisitely detailed labeling of axons and terminals, while low molecular weight BDA (3 k) yields sensitive and detailed retrograde labeling of neuronal cell bodies. The detail of neuronal cell body labeling can be Golgi-like. BDA tolerates EM fixation and processing well and can, therefore, be readily used in ultrastructural studies. Additionally, BDA can be combined with other anterograde or retrograde tracers (e.g. PHA-L or cholera toxin B fragment) and visualized either by multi-color DAB multiple-labeling - if permanent labels are desired, or by using multiple simultaneous immunofluorescence - if fluorescence viewing is desired. In the same manner, BDA pathway tracing and neurotransmitter immunolabeling can be combined. Note that BDA pathway tracing can also be combined with anterograde or retrograde labeling with fluorescent dextran amines, if one wishes to exclusively use tracers with the favorable transport properties and sensitivities of dextran amines. In this case, the BDA can be visualized together with the fluorescent dextran amines using fluorescence labeling for the BDA, or the fluorescent dextran amines can be visualized together with the BDA by multicolor DAB labeling via immunolabeling of the fluorescent dextran amines using anti-fluorophore antisera. BDA is, thus, a flexible and valuable pathway tracing tool that has gained widespread popularity in recent years.

title: Prefrontal Projections to the Thalamic Reticular Nucleus form a Unique Circuit for Attentional Mechanisms
abstract: The inhibitory thalamic reticular nucleus (TRN) intercepts and modulates all corticothalamic and thalamocortical communications. Previous studies showed that projections from sensory and motor cortices originate in layer VI and terminate as small boutons in central and caudal TRN. Here we show that prefrontal projections to TRN in rhesus monkeys have a different topographic organization and mode of termination. Prefrontal cortices projected mainly to the anterior TRN, at sites connected with the mediodorsal, ventral anterior, and anterior medial thalamic nuclei. However, projections from areas 46, 13, and 9 terminated widely in TRN and colocalized caudally with projections from temporal auditory, visual, and polymodal association cortices. Population analysis and serial EM reconstruction revealed two distinct classes of corticoreticular terminals synapsing with GABA/parvalbumin-positive dendritic shafts of TRN neurons. Most labeled boutons from prefrontal axons were small, but a second class of large boutons was also prominent. This is in contrast to the homogeneous small TRN terminations from sensory cortices noted previously and in the present study, which are thought to arise exclusively from layer VI. The two bouton types were often observed on the same axon, suggesting that both prefrontal layers V and VI could project to TRN. The dual mode of termination suggests a more complex role of prefrontal input in the functional regulation of TRN and gating of thalamic output back to the cortex. The targeting of sensory tiers of TRN by specific prefrontal areas may underlie attentional regulation for the selection of relevant sensory signals and suppression of distractors.

title: Architecture and intrinsic connections of the prefrontal cortex in the rhesus monkey
abstract: An investigation of the architectonic organization and intrinsic connections of the prefrontal cortex was conducted in rhesus monkeys. Cytoarchitectonic analysis indicates that in the prefrontal cortex there are two trends of gradual change in laminar characteristics that can be traced from limbic periallocortex towards isocortical areas. The stepwise change in laminar features is characterized by the emergence and gradual increase in the width of granular layer IV, by an increase in the size of pyramidal cells in layers III and V, and by a higher cell‐packing density in the supragranular layers. Myeloarchitectonic analysis reveals that the limbic areas are poorly myelinated, adjacent areas have a diffuse myelin content confined to the deep layers, and in isocortices the myelinated fibers are distributed in organized horizontal bands (of Baillarger) and a vertical plexus. Using the above architectonic criteria, we observed that one of the architectonic trends takes a radial basoventral course from the periallocortex in the caudal orbitofrontal region to the adjacent proisocortex and then to area 13. The next stage of architectonic regions includes orbital areas 12, 11, and 14, which is followed by area 10, lateral area 12, and the rostral part of ventral area 46. The last group includes the caudal part of ventral area 46 and ventral area 8. The other trend takes a mediodorsal course from the periallocortex around the rostral portion of the corpus callosum to the adjacent proisocortical areas 24, 25, and 32 and then to the medially situated isocortical areas 9, 10, and 14. The next stage includes lateral areas 10 and 9 and the rostral part of dorsal area 46. The last group includes the caudal part of dorsal area 46 and dorsal area 8.

title: The new stereological tools: Disector, fractionator, nucleator and point sampled intercepts and their use in pathological research and diagnosis
abstract: The new stereological methods for correct and efficient sampling and sizing of cells and other particles are reviewed. There is a hierarchy of methods starting from the simplest where even the microscopic magnification may be unknown to the most complex where typically both section thickness and the magnification must be known. Opticalsections in suitably modified microscopes can be used to improve the ease and speed with which even the most demanding of these methods are performed. The methods are illustrated by practical examples of applications to a wide range of histological entities including synapses, neurons and cancer cells, glomerular corpuscles and ovarian follicles.

title: Unbiased stereological estimation of the number of neurons in the human hippocampus
abstract: The total numbers of neurons in five subdivisions of human hippocampi were estimated using unbiased Stereological principles and systematic sampling techniques. The method addresses the problems associated with the results and conclusions of previous quantitative studies, virtually all of which have been based on biased estimates of neuron densities. For each subdivision, the total number of neurons was calculated as the product of the estimate of the volume of the neuron‐containing layers and the estimate of the numerical density of neurons in the layers.

title: Three‐dimensional counting: An accurate and direct method to estimate numbers of cells in sectioned material
abstract: We introduce a way to count and measure cells in an optically defined volume of tissue called a counting box. This method—direct three‐dimensional counting (3DC)—eliminates the need for correction factors, such as that introduced by Abercrombie (, to determine the number of cells per unit volume (Nv). Problems caused by irregular cell shape and cell size, nonrandom orientation, and splitting of cells by the knife during sectioning are overcome. Furthermore, 3DC is insensitive to large variations in section thickness.

title: The medial prefrontal cortex in the rat: evidence for a dorso-ventral distinction based upon functional and anatomical characteristics
abstract: The prefrontal cortex in rats can be distinguished anatomically from other frontal cortical areas both in terms of cytoarchitectonic characteristics and neural connectivity, and it can be further subdivided into subterritories on the basis of such criteria. Functionally, the prefrontal cortex of rats has been implicated in working memory, attention, response initiation and management of autonomic control and emotion. In humans, dysfunction of prefrontal cortical areas with which the medial prefrontal cortex of the rat is most likely comparable is related to psychopathology including schizophrenia, sociopathy, obsessive-compulsive disorder, depression, and drug abuse. Recent literature points to the relevance of conducting a functional analysis of prefrontal subregions and supports the idea that the area of the medial prefrontal cortex in rats is characterized by its own functional heterogeneity, which may be related to neuroanatomical and neurochemical dissociations. The present review covers recent findings with the intent of correlating these distinct functional differences in the dorso-ventral axis of the rat medial prefrontal cortex with anatomical and neurochemical patterns.

title: Pattern in the laminar origin of corticocortical connections
abstract: The laminar origin of cortical projections to the frontal cortex was studied in 17 adult rhesus monkeys with the use of the retrograde transport of horseradish peroxidase (HRP). The frontal regions injected with HRP extended from the posterior periarcuate region to the frontal pole. The architectonic boundaries of areas containing HRP‐labeled neurons were determined from matched sections stained for the visualization of cell bodies, myelin, or acetylcholinesterase. The results showed that the laminar origin of both nearby and distant corticocortical projections was correlated with the architectonic differentiation of the regions giving rise to the projecting afferent fibers. Frontally directed projections from limbic cortices, which show a redimentary laminar organization, emanated mainly from deep layers. On the other hand, projections from increasingly more differentiated cortices arose progressively from the upper (or superagranular) layers. This pattern was observed for projections originating along the axis of architectonic differentiation of the visual, somatosensory, auditory, motor, and preforntal cortical systems. Thus, as the cortical architecture within each system changes from limbic areas toward the primary cortices, the origin of frontally directed projections shifts from predominantly infragranular to predominantly superagranular layers.

title: Medial Prefrontal Cortices Are Unified by Common Connections With Superior Temporal Cortices and Distinguished by Input From Memory‐Related Areas in the Rhesus Monkey
abstract: Medial prefrontal cortices in primates have been associated with emotion, memory, and complex cognitive processes. Here we investigated whether the pattern of cortical connections could indicate whether the medial prefrontal cortex constitutes a homogeneous region, or if it can be parceled into distinct sectors. Projections from medial temporal memory‐related cortices subdivided medial cortices into different sectors, by targeting preferentially caudal medial areas (area 24, caudal 32 and 25), to a lesser extent rostral medial areas (rostral area 32, areas 14 and 10), and sparsely area 9. Area 9 was distinguished by its strong connections with premotor cortices. Projections from unimodal sensory cortices reached preferentially specific medial cortices, including a projection from visual cortices to area 32/24, from somatosensory cortices to area 9, and from olfactory cortices to area 14. Medial cortices were robustly interconnected, suggesting that local circuits are important in the neural processing in this region. Medial prefrontal cortices were unified by bidirectional connections with superior temporal cortices, including auditory areas. Auditory pathways may have a role in the specialization of medial prefrontal cortices in species‐specific communication in non‐human primates and language functions in humans.  1999.

title: The laminar pattern of connections between prefrontal and anterior temporal cortices in the Rhesus monkey is related to cortical structure and function.
abstract: The laminar pattern of axonal termination from prefrontal (caudal orbitofrontal, rostral orbitofrontal and lateral areas) to anterior temporal areas (entorhinal cortex, perirhinal cortex and area TE) and from temporal to prefrontal areas was investigated with the aid of anterograde tracers. Both regions are characterized by structural heterogeneity, and include agranular, dysgranular and granular cortical types, denoting, respectively, the absence, incipience and presence of granular layer 4. In addition, both the prefrontal and anterior temporal cortices are composed of areas that have related though specialized functions. The pattern of cortical axonal termination was associated with both the structural type of the cortex of origin and the structure of the destination cortex. Thus, efferent fibers from a single origin in either prefrontal or anterior temporal cortex terminated in different patterns depending on their target area. Conversely, axons terminated in different patterns in a single target area, prefrontal or anterior temporal, depending on their area of origin. Projections from agranular or dysgranular type cortices (e.g. medial temporal areas and caudal orbitofrontal areas) terminated mostly in the upper layers of granular cortices (e.g. area TE and lateral prefrontal areas), and projections from granular cortices terminated mostly in the deep layers of agranular or dys- granular cortices. A robust projection from dysgranular orbitofrontal areas terminated in the deep layers of the agranular entorhinal cortex. Projections from prefrontal areas to area TE terminated in the upper layers, and may facilitate focused attention on behaviorally relevant stimuli processed through reciprocal pathways between prefrontal and temporal cortices.

title: Parallel organization of contralateral and ipsilateral prefrontal cortical projections in the rhesus monkey
abstract: BackgroundThe neocortical commissures have a fundamental role in functional integration across the cerebral hemispheres. We investigated whether commissural projections in prefrontal cortices are organized according to the same or different rules as those within the same hemisphere, by quantitatively comparing density, topography, and laminar origin of contralateral and ipsilateral projections, labeled after unilateral injection of retrograde tracers in prefrontal areas.ResultsCommissural projection neurons constituted less than one third of the ipsilateral. Nevertheless, projections from the two hemispheres were strongly correlated in topography and relative density. We investigated to what extent the distribution of contralateral projections depended on: (a) geographic proximity of projection areas to the area homotopic to the injection site; (b) the structural type of the linked areas, based on the number and neuronal density of their layers. Although both measures were good predictors, structural type was a comparatively stronger determinant of the relative distribution and density of projections. Ipsilateral projection neurons were distributed in the superficial (II-III) and deep (V-VI) layers, in proportions that varied across areas. In contrast, contralateral projection neurons were found mostly in the superficial layers, but still showed a gradient in their distribution within cortical layers that correlated significantly with cortical type, but not with geographic proximity to the homotopic area.ConclusionThe organization of ipsilateral and contralateral prefrontal projections is similar in topography and relative density, differing only by higher overall density and more widespread laminar origin of ipsilateral than contralateral projections. The projections on both sides are highly correlated with the structural architecture of the linked areas, and their remarkable organization is likely established by punctuated development of distinct cortical types. The preponderance of contralateral projections from layer III may be traced to the late development of the callosal system, whose function may be compromised in diseases that have their root late in ontogeny.

title: The organization of prefrontocaudate projections and their laminar origin in the macaque monkey: A retrograde study using HRP‐gel
abstract: The organization of the prefrontocaudate connection in the macaque monkey was studied with a polyacrylamide gel of horseradish peroxidase that was injected, after callosotomy, into the head of the caudate nucleus. Tissues were processed for peroxidase activity with tetramethylbenzidine. Retrogradely labeled cells appeared bilaterally in the prefrontal cortex, and ipsilaterally in the premotor area, frontal operculum, insula, and rostral region of the temporal cortex. In the prefrontal cortex, labeled cells were located in cortical layers 2–6. In layer 2, labeled cells were occasionally seen. In layer 3, a considerable number of labeled cells were seen and were mainly distributed in its lower part. They were pyramidal cells. Layer 4 contained a considerable number of labeled cells that were pyramidal or round. Somal sizes of these labeled cells were from 5 to 15 μm, but none of the cells less than 5 μm were labeled. Layer 5 was densely packed with labeled cells, though at a higher density in its upper part (5a). They were pyramidal cells. In layer 6, pyramidal or fusiform cells were labeled at a lower density than in layer 5. The laminar pattern and density of labeled cells were different among various regions of the prefrontal cortex, but, in general, the supragranular labeling tended to frequently occur in the regions containing the numerous labeled cells. There was a topographical relationship between the prefrontal regions containing the majority of labeled cells and the injection sites in the head of the caudate nucleus: the medial orbitofrontal cortex and the medial surface extending downward from the rostral sulcus project ipsilaterally to the medialmost portion of the ventromedial part of the head of the nucleus, the lateral orbitofrontal cortex projects to the ventromedial part of the head of the nucleus, and the dorsolateral prefrontal cortex ventral to the principal sulcus projects to the central part of the head of the nucleus. Our findings in the macaque monkey indicate that the corticocaudate connection is similar in laminar organization of efferent neurons to the corticocortical connections.

title: Circuits through prefrontal cortex, basal ganglia, and ventral anterior nucleus map pathways beyond motor control
abstract: The ventral anterior (VA) nucleus of the thalamus is connected with prefrontal and premotor cortices and with the basal ganglia. Although classically associated with motor functions, recent evidence implicates the basal ganglia in cognition and emotion as well. Here, we used two complementary approaches to investigate whether the VA is a key link for pathways underlying cognitive and emotional processes through prefrontal cortices and the basal ganglia. After application of bidirectional tracers in functionally distinct lateral, medial, and orbitofrontal cortices, we found that projection neurons were embedded in much larger patches of axonal terminations found in the magnocellular part of VA (VAmc), and in the principal part of VA. Connections from medial prefrontal cortices occupied the dorsomedial and ventromedial VA, and orbitofrontal connections were found in ventrolateral VAmc. Moreover, about half of all projection neurons in orbitofrontal areas directed to the VA or VAmc were positive for calbindin but not parvalbumin, even though comparable populations of neurons were positive for each marker in the VA. We then applied tracers in VA and investigated simultaneously projections from all prefrontal areas, the internal segment of the globus pallidus (GPi), the substantia nigra reticulata (SNr), and the thalamic reticular nucleus. Projection neurons were most densely distributed in anterior cingulate areas 24 and 32, and dorsolateral areas 9 and 8, innervating the same VA sites that received projections from a large part of GPi and dorsal SNr. Nearly as many projection neurons originated from cortical layer V as from layer VI. There is evidence that cortical layer VI neurons innervate thalamic neurons that project focally to the middle cortical layers, whereas layer V neurons synapse with thalamic neurons projecting widely to cortical layer I. Projections from layer V to the VA may facilitate cortical recruitment for executive functions within a cognitive context through lateral prefrontal areas, and autonomic responses within an emotional context through anterior cingulate areas.

title: Dynamic depolarization fields in the cerebral cortex
abstract: Recent physiological evidence shows that in response to stimuli and preceding motor activity, large fields of the upper layers of the cerebral cortex depolarize. It is argued that this finding is a general one and that these dynamic depolarization fields represent the computational elements of the cerebral cortex. Each depolarization field engages many more neurons than do columns and hyper-columns. These fields can be explained by cooperative neuronal computing in layers I-III of the cortex. In these layers, the computing modes might be general for all parts of the cerebral cortex and be sufficiently flexible to handle all sorts of cortical computations, including perception, memory storage, memory retrieval, thought and the production of behavior.

title: Division of labor among distinct subtypes of inhibitory neurons in a cortical microcircuit of working memory.
abstract: A conspicuous feature of cortical organization is the wide diversity of inhibitory interneurons; their differential computational functions remain unclear. Here we propose a local cortical circuit in which three major subtypes of interneurons play distinct roles. In a model designed for spatial working memory, stimulus tuning of persistent activity arises from the concerted action of widespread inhibition mediated by perisoma-targeting (parvalbumin-containing) interneurons and localized disinhibition of pyramidal cells via interneuron-targeting (calretinin-containing) interneurons. Moreover, resistance against distracting stimuli (a fundamental property of working memory) is dynamically controlled by dendrite-targeting (calbindin-containing) interneurons. The experimental observation of inverted tuning curves of monkey prefrontal neurons recorded during working memory supports a key model prediction. This work suggests a framework for understanding the division of labor and cooperation among different inhibitory cell types in a recurrent cortical circuit.

title: The amygdala complex: multiple roles in associative learning and attention.
abstract: Although certain neurophysiological functions of the amygdala complex in learning seem well established, the purpose of this review is to propose that an additional conceptualization of amygdala function is now needed. The research we review provides evidence that a subsystem within the amygdala provides a coordinated regulation of attentional processes. An important aspect of this additional neuropsychology of the amygdala is that it may aid in understanding the importance of connections between the amygdala and other neural systems in information processing.

title: Emotion Circuits in the Brain
abstract: The field of neuroscience has, after a long period of looking the other way, again embraced emotion as an important research area. Much of the progress has come from studies of fear, and especially fear conditioning. This work has pin- pointed the amygdala as an important component of the system involved in the acqui- sition, storage, and expression of fear memory and has elucidated in detail how stimuli enter, travel through, and exit the amygdala. Some progress has also been made in understanding the cellular and molecular mechanisms that underlie fear conditioning, and recent studies have also shown that the findings from experimental animals apply to the human brain. It is important to remember why this work on emotion succeeded where past efforts failed. It focused on a psychologically well-defined aspect of emo- tion, avoided vague and poorly defined concepts such as "affect," "hedonic tone," or "emotional feelings," and used a simple and straightforward experimental approach. With so much research being done in this area today, it is important that the mistakes of the past not be made again. It is also time to expand from this foundation into broader aspects of mind and behavior

title: The amygdala: vigilance and emotion
abstract: Here we provide a review of the animal and human literature concerning the role of the amygdala in fear conditioning, considering its potential influence over autonomic and hormonal changes, motor behavior and attentional processes. A stimulus that predicts an aversive outcome will change neural transmission in the amygdala to produce the somatic, autonomic and endocrine signs of fear, as well as increased attention to that stimulus. It is now clear that the amygdala is also involved in learning about positively valenced stimuli as well as spatial and motor learning and this review strives to integrate this additional information. A review of available studies examining the human amygdala covers both lesion and electrical stimulation studies as well as the most recent functional neuroimaging studies. Where appropriate, we attempt to integrate basic information on normal amygdala function with our current understanding of psychiatric disorders, including pathological anxiety.

title: The human amygdala and the emotional evaluation of sensory stimuli
abstract: A wealth of animal data implicates the amygdala in aspects of emotional processing. In recent years, functional neuroimaging and neuropsychological studies have begun to refine our understanding of the functions of the amygdala in humans. This literature offers insights into the types of stimuli that engage the amygdala and the functional consequences that result from this engagement. Specific conclusions and hypotheses include: (1) the amygdala activates during exposure to aversive stimuli from multiple sensory modalities; (2) the amygdala responds to positively valenced stimuli, but these responses are less consistent than those induced by aversive stimuli; (3) amygdala responses are modulated by the arousal level, hedonic strength or current motivational value of stimuli; (4) amygdala responses are subject to rapid habituation; (5) the temporal characteristics of amygdala responses vary across stimulus categories and subject populations; (6) emotionally valenced stimuli need not reach conscious awareness to engage amygdala processing; (7) conscious hedonic appraisals do not require amygdala activation; (8) activation of the amygdala is associated with modulation of motor readiness, autonomic functions, and cognitive processes including attention and memory; (9) amygdala activations do not conform to traditional models of the lateralization of emotion; and (10) the extent and laterality of amygdala activations are related to factors including psychiatric status, gender and personality. The strengths and weakness of these hypotheses and conclusions are discussed with reference to the animal literature.

title: Pathways for emotion: interactions of prefrontal and anterior temporal pathways in the amygdala of the rhesus monkey
abstract: The amygdala has been implicated in processing information about the emotional significance of the environment and in the expression of emotions, through robust pathways with prefrontal, anterior temporal areas, and central autonomic structures. We investigated the anatomic organization and intersection of these pathways in the amygdala in rhesus monkeys with the aid of bidirectional, retrograde and anterograde tracers. Connections of the amygdala with orbitofrontal and medial prefrontal areas were robust and bidirectional, whereas connections with lateral prefrontal areas were sparse, unidirectional and ascending. Orbitofrontal axons terminated densely in a narrow band around the borders of the magnocellular basolateral nucleus, surrounded by projection neurons along a continuum through the nuclei of the basal complex. In contrast, the input and output zones of medial prefrontal areas were intermingled in the amygdala. Moreover, medial prefrontal axonal terminations were expansive, spreading into the parvicellular basolateral nucleus, which is robustly connected with hypothalamic autonomic structures, suggesting that they may influence the expressive emotional system of the amygdala. On the other hand, orbitofrontal axons heavily targeted the intercalated masses, which issue inhibitory projections to the central nucleus, at least in rats and cats. The central nucleus, in turn, issues a significant inhibitory projection to hypothalamic and brainstem autonomic structures. This evidence suggests that orbitofrontal areas exercise control on the internal processing of the amygdala. In addition, the results provided direct evidence that the connections of anterior temporal visual and auditory association cortices occupy overlapping territories with the orbitofrontal cortices particularly in the posterior half of the amygdala, and specifically within the intermediate sector of the basolateral nucleus and in the magnocellular part of the basomedial nucleus (also known as accessory basal), suggesting a closely linked triadic network. This intricate network may be recruited in cognitive tasks that are inextricably linked with emotional associations.

title: The orbitofrontal cortex.
abstract: The orbitofrontal cortex contains the secondary taste cortex, in which the reward value of taste is represented. It also contains the secondary and tertiary olfactory cortical areas, in which information about the identity and also about the reward value of odours is represented. The orbitofrontal cortex also receives information about the sight of objects from the temporal lobe cortical visual areas, and is involved in learning and in reversing stimulus-reinforcement associations. The stimulus might be a visual or olfactory stimulus, and the primary (unlearned) reinforcer a taste or touch. Damage to the orbitofrontal cortex impairs the learning and reversal of stimulus-reinforcement associations, and thus the correction of behavioural responses when these are no longer appropriate because previous reinforcement contingencies change. The information which reaches the orbitofrontal cortex for these functions includes information about faces, and damage to the orbitofrontal cortex can impair face expression identification. This evidence thus shows that the orbitofrontal cortex is involved in decoding some primary reinforcers such as taste; in learning and reversing associations of visual and other stimuli to these primary reinforcers; and plays an executive function in controlling and correcting reward-related and punishment-related behaviour, and thus in emotion.

title: Relative reward preference in primate orbitofrontal cortex
abstract: The orbital part of prefrontal cortex appears to be crucially involved in the motivational control of goal-directed behaviour. Patients with lesions of orbitofrontal cortex show impairments in making decisions about the expected outcome of actions. Monkeys with orbitofrontal lesions respond abnormally to changes in reward expectations and show altered reward preferences. As rewards constitute basic goals of behaviour, we investigated here how neurons in the orbitofrontal cortex of monkeys process information about liquid and food rewards in a typical frontal task, spatial delayed responding. The activity of orbitofrontal neurons increases in response to reward-predicting signals, during the expectation of rewards, and after the receipt of rewards. Neurons discriminate between different rewards, mainly irrespective of the spatial and visual features of reward-predicting stimuli and behavioural reactions. Most reward discriminations reflect the animals' relative preference among the available rewards, as expressed by their choice behaviour, rather than physical reward properties. Thus, neurons in the orbitofrontal cortex appear to process the motivational value of rewarding outcomes of voluntary action.

title: Top-down facilitation of visual recognition.
abstract: Cortical analysis related to visual object recognition is traditionally thought to propagate serially along a bottom-up hierarchy of ventral areas. Recent proposals gradually promote the role of top-down processing in recognition, but how such facilitation is triggered remains a puzzle. We tested a specific model, proposing that low spatial frequencies facilitate visual object recognition by initiating top-down processes projected from orbitofrontal to visual cortex. The present study combined magnetoencephalography, which has superior temporal resolution, functional magnetic resonance imaging, and a behavioral task that yields successful recognition with stimulus repetitions. Object recognition elicited differential activity that developed in the left orbitofrontal cortex 50 ms earlier than it did in recognition-related areas in the temporal cortex. This early orbitofrontal activity was directly modulated by the presence of low spatial frequencies in the image. Taken together, the dynamics we revealed provide strong support for the proposal of how top-down facilitation of object recognition is initiated, and our observations are used to derive predictions for future research.

title: Prefrontal cortical control of the autonomic nervous system: anatomical and physiological observations.
abstract: Publisher Summary This chapter focuses on the prefrontal autonomic control of the viscera. It also describes the significance of prefrontal cortical control of the autonomic nervous system. Lesion experiments show that the medial, anterior cingulate prefrontal region is necessary for the expression of the normal, sympathetically mediated increase in heart rate during stress. It is necessary for the production of gastric ulcers that develop in rats under restraint stress. The cortex is needed to maintain the normal, resting level of the gain of the cardiac component of the baroreflex response. The identity between the cortex and the organism implies that there is no region of cortex, not even those concerned with the highest processes, which is not also a representation of some part of the organism. Because visceral function and emotion are closely associated, the relationship of the prefrontal cortex to emotion is also reviewed in the chapter. The visceral regions of prefrontal cortex are likely to be brain areas whose activity contributes to psychosomatic disease.

title: Theories of basal forebrain organization and the "emotional motor system".
abstract: Publisher Summary This chapter focuses on the neuroanatomy of the heterogenous structures that comprise the basal forebrain, insofar as this territory, together with its most closely associated cortical areas, is likely to provide important projections activating emotionally related motor areas of the brainstem. Special consideration is given to the ventral striatopallidal system and the extended amygdala and areas of transition between these two systems. Many of the structures in the basal forebrain have been included within the various conceptualizations of the limbic system, and the majority of behavioral observations following the early formulations of this concept by Papez and MacLean have generally reinforced the notion that the basal forebrain is systematically involved in the experience and expression of emotions. To some extent, the description of a “descending limbic motor control system” can face difficulties similar to the definition of the “limbic system” at large. The chapter also summarizes the multiple output channels from the basal forebrain to the motor areas of the brainstem.

title: Serial pathways from primate prefrontal cortex to autonomic areas may influence emotional expression
abstract: BackgroundExperiencing emotions engages high-order orbitofrontal and medial prefrontal areas, and expressing emotions involves low-level autonomic structures and peripheral organs. How is information from the cortex transmitted to the periphery? We used two parallel approaches to map simultaneously multiple pathways to determine if hypothalamic autonomic centres are a key link for orbitofrontal areas and medial prefrontal areas, which have been associated with emotional processes, as well as low-level spinal and brainstem autonomic structures. The latter innervate peripheral autonomic organs, whose activity is markedly increased during emotional arousal.ResultsWe first determined if pathways linking the orbitofrontal cortex with the hypothalamus overlapped with projection neurons directed to the intermediolateral column of the spinal cord, with the aid of neural tracers injected in these disparate structures. We found that axons from orbitofrontal and medial prefrontal cortices converged in the hypothalamus with neurons projecting to brainstem and spinal autonomic centers, linking the highest with the lowest levels of the neuraxis. Using a parallel approach, we injected bidirectional tracers in the lateral hypothalamic area, an autonomic center, to label simultaneously cortical pathways leading to the hypothalamus, as well as hypothalamic axons projecting to low-level brainstem and spinal autonomic centers. We found densely distributed projection neurons in medial prefrontal and orbitofrontal cortices leading to the hypothalamus, as well as hypothalamic axonal terminations in several brainstem structures and the intermediolateral column of the spinal cord, which innervate peripheral autonomic organs. We then provided direct evidence that axons from medial prefrontal cortex synapse with hypothalamic neurons, terminating as large boutons, comparable in size to the highly efficient thalamocortical system. The interlinked orbitofrontal, medial prefrontal areas and hypothalamic autonomic centers were also connected with the amygdala.ConclusionsDescending pathways from orbitofrontal and medial prefrontal cortices, which are also linked with the amygdala, provide the means for speedy influence of the prefrontal cortex on the autonomic system, in processes underlying appreciation and expression of emotions.

title: Differential projections of the infralimbic and prelimbic cortex in the rat
abstract: The medial prefrontal cortex has been associated with diverse functions including attentional processes, visceromotor activity, decision‐making, goal‐directed behavior, and working memory. The present report compares and contrasts projections from the infralimbic (IL) and prelimbic (PL) cortices in the rat by using the anterograde anatomical tracer, Phaseolus vulgaris‐leucoagglutinin. With the exception of common projections to parts of the orbitomedial prefrontal cortex, olfactory forebrain, and midline thalamus, PL and IL distribute very differently throughout the brain. Main projection sites of IL are: 1) the lateral septum, bed nucleus of stria terminalis, medial and lateral preoptic nuclei, substantia innominata, and endopiriform nuclei of the basal forebrain; 2) the medial, basomedial, central, and cortical nuclei of amygdala; 3) the dorsomedial, lateral, perifornical, posterior, and supramammillary nuclei of hypothalamus; and 4) the parabrachial and solitary nuclei of the brainstem. By contrast, PL projects at best sparingly to each of these structures. Main projection sites of PL are: the agranular insular cortex, claustrum, nucleus accumbens, olfactory tubercle, the paraventricular, mediodorsal, and reuniens nuclei of thalamus, the capsular part of the central nucleus and the basolateral nucleus of amygdala, and the dorsal and median raphe nuclei of the brainstem. As discussed herein, the pattern of IL projections is consistent with a role for IL in the control of visceral/autonomic activity homologous to the orbitomedial prefrontal cortex of primates, whereas those of PL are consistent with a role for PL in limbic‐cognitive functions homologous to the dorsolateral prefrontal cortex of primates. Synapse 51:32–58, 2004.

title: Structure and Connections of the Cingulate Vocalization Region in the Rhesus Monkey
abstract: Many primate utterances are simple vocalizations that may be associated with brainstem activity and contain limited information about the internal state of the animal. Sequences of tone and amplitude modulated vocalizations which have associative content form the basis for more complex communication within a species. These complex vocalizations are organized at suprabulbar levels, including the cerebral cortex.

title: Contributions of anterior cingulate cortex to behaviour.
abstract: Assessments of anterior cingulate cortex in experimental animals and humans have led to unifying theories of its structural organization and contributions to mammalian behaviour. The anterior cingulate cortex forms a large region around the rostrum of the corpus callosum that is termed the anterior executive region. This region has numerous projections into motor systems, however, since these projections originate from different parts of anterior cingulate cortex and because functional studies have shown that it does not have a uniform contribution to brain functions, the anterior executive region is further subdivided into 'affect' and 'cognition' components. The affect division includes areas 25, 33 and rostral area 24, and has extensive connections with the amygdala and periaqueductal grey, and parts of it project to autonomic brainstem motor nuclei. In addition to regulating autonomic and endocrine functions, it is involved in conditioned emotional learning, vocalizations associated with expressing internal states, assessments of motivational content and assigning emotional valence to internal and external stimuli, and maternal-infant interactions. The cognition division includes caudal areas 24' and 32', the cingulate motor areas in the cingulate sulcus and nociceptive cortex. The cingulate motor areas project to the spinal cord and red nucleus and have premotor functions, while the nociceptive area is engaged in both response selection and cognitively demanding information processing. The cingulate epilepsy syndrome provides important support of experimental animal and human functional imaging studies for the role of anterior cingulate cortex in movement, affect and social behaviours. Excessive cingulate activity in cases with seizures confirmed in anterior cingulate cortex with subdural electrode recordings, can impair consciousness, alter affective state and expression, and influence skeletomotor and autonomic activity. Interictally, patients with anterior cingulate cortex epilepsy often display psychopathic or sociopathic behaviours. In other clinical examples of elevated anterior cingulate cortex activity it may contribute to tics, obsessive-compulsive behaviours, and aberrent social behaviour. Conversely, reduced cingulate activity following infarcts or surgery can contribute to behavioural disorders including akinetic mutism, diminished self-awareness and depression, motor neglect and impaired motor initiation, reduced responses to pain, and aberrent social behaviour. The role of anterior cingulate cortex in pain responsiveness is suggested by cingulumotomy results and functional imaging studies during noxious somatic stimulation. The affect division of anterior cingulate cortex modulates autonomic activity and internal emotional responses, while the cognition division is engaged in response selection associated with skeletomotor activity and responses to noxious stimuli. Overall, anterior cingulate cortex appears to play a crucial role in initiation, motivation, and goal-directed behaviours.(ABSTRACT TRUNCATED AT 400

title: Amygdala and bed nucleus of the stria terminalis: differential roles in fear and anxiety measured with the acoustic startle reflex.
abstract: Neural stimuli associated with traumatic events can readily become conditioned so as to reinstate the memory of the original trauma. These conditioned fear responses can last a lifetime and may be especially resistant to extinction. A large amount of data from many different laboratories indicate that the amygdala plays a crucial role in conditioned fear. The amygdala receives information from all sensory modalities and projects to a variety of hypothalamic and brainstem target areas known to be critically involved in specific signs that are used to define fear and anxiety. Electrical stimulation of the amygdala elicits a pattern of behaviours that mimic natural or conditioned states of fear. Lesions of the amygdala block innate or conditioned fear and local infusion of drugs into the amygdala have anxiolytic effects in several behavioural tests. Excitatory amino acid receptors in the amygdala are critical for the acquisition, expression and extinction of conditioned fear.

title: Dissociable Contributions of the Human Amygdala and Orbitofrontal Cortex to Incentive Motivation and Goal Selection
abstract: Theories of incentive motivation attempt to capture the way in which objects and events in the world can acquire high motivational value and drive behavior, even in the absence of a clear biological need. In addition, for an individual to select the most appropriate goal, the incentive values of competing desirable objects need to be defined and compared. The present study examined the neural substrates by which appetitive incentive value influences prospective goal selection, using positron emission tomographic neuroimaging in humans. Sated subjects were shown a series of restaurant menus that varied in incentive value, specifically tailored for each individual, and in half the trials, were asked to make a selection from the menu. The amygdala was activated by high-incentive menus regardless of whether a choice was required. Indeed, activity in this region varied as a function of individual subjective ratings of incentive value. In contrast, distinct regions of the orbitofrontal cortex were recruited both during incentive judgments and goal selection. Activity in the medial orbital cortex showed a greater response to high-incentive menus and when making a choice, with the latter activity also correlating with subjective ratings of difficulty. Lateral orbitofrontal activity was observed selectively when participants had to suppress responses to alternative desirable items to select their most preferred. Taken together, these data highlight the differential contribution of the amygdala and regions within the orbitofrontal cortex in a neural system underlying the selection of goals based on the prospective incentive value of stimuli, over and above homeostatic influences.

title: The primate amygdala represents the positive and negative value of visual stimuli during learning
abstract: Visual stimuli can acquire positive or negative value through their association with rewards and punishments, a process called reinforcement learning. Although we now know a great deal about how the brain analyses visual information, we know little about how visual representations become linked with values. To study this process, we turned to the amygdala, a brain structure implicated in reinforcement learning. We recorded the activity of individual amygdala neurons in monkeys while abstract images acquired either positive or negative value through conditioning. After monkeys had learned the initial associations, we reversed image value assignments. We examined neural responses in relation to these reversals in order to estimate the relative contribution to neural activity of the sensory properties of images and their conditioned values. Here we show that changes in the values of images modulate neural activity, and that this modulation occurs rapidly enough to account for, and correlates with, monkeys' learning. Furthermore, distinct populations of neurons encode the positive and negative values of visual stimuli. Behavioural and physiological responses to visual stimuli may therefore be based in part on the plastic representation of value provided by the amygdala.

title: Neocortical modulation of the amygdala response to fearful stimuli
abstract: The cortical circuitry involved in conscious cognitive processes and the subcortical circuitry involved in fear responses have been extensively studied with neuroimaging, but their interactions remain largely unexplored. A recent functional magnetic resonance imaging (fMRI) study demonstrated that the engagement of the right prefrontal cortex during the cognitive evaluation of angry and fearful facial expressions is associated with an attenuation of the response of the amygdala to these same stimuli, providing evidence for a functional neural network for emotional regulation.



In the current study, we have explored the generalizability of this functional network by using threatening and fearful non-face stimuli derived from the International Affective Picture System (IAPS), as well as the influence of this network on peripheral autonomic responses.



Similar to the earlier findings with facial expressions, blood oxygen level dependent fMRI revealed that whereas perceptual processing of IAPS stimuli was associated with a bilateral amygdala response, cognitive evaluation of these same stimuli was associated with attenuation of this amygdala response and a correlated increase in response of the right prefrontal cortex and the anterior cingulate cortex. Moreover, this pattern was reflected in changes in skin conductance.



The current results further implicate the importance of neocortical regions, including the prefrontal and anterior cingulate cortices, in regulating emotional responses mediated by the amygdala through conscious evaluation and appraisal.

title: Modulating dysfunctional limbic-cortical circuits in depression: towards development of brain-based algorithms for diagnosis and optimised treatment.
abstract: While characterization of pathogenetic mechanisms underlying major depression is a fundamental aim of neuroscience research, an equally critical clinical goal is to identify biomarkers that might improve diagnostic accuracy and guide treatment selection for individual patients. To this end, a synthesis of functional neuroimaging studies examining regional metabolic and blood flow changes in depression is presented in the context of a testable limbic-cortical network model. 'Network' dysfunction combined with active intrinsic compensatory processes is seen to explain the heterogeneity of depressive symptoms observed clinically, as well as variations in pretreatment scan patterns described experimentally. Furthermore, the synchronized modulation of these dysfunctional limbic-cortical pathways is considered critical for illness remission, regardless of treatment modality. Testing of response-specific functional relationships among regional 'nodes' within this network using multivariate approaches is discussed, with a perspective aimed at identifying biomarkers of treatment non-response, relapse risk and disease vulnerability. Characterization of adaptive and maladaptive functional interactions among these pathways is seen as a critical step towards future development of evidenced-based algorithms that will optimize the diagnosis and treatment of individual depressed patients.

title: Neuroimaging Abnormalities in the Amygdala in Mood Disorders
abstract: Neuroimaging technology has been applied to investigate the pathophysiology of mood disorders in studies aimed at characterizing the anatomical correlates of depressive symptoms, the neurophysiological effects of antidepressant treatments, and the trait‐like abnormalities that persist despite symptom remission. These studies have identified cerebral blood flow and metabolic differences between depressives and controls in the amygdala and anatomically related areas of the prefrontal cortex, striatum, and thalamus. Taken together with converging evidence from neuroendocrine, lesion analysis, and postmortem studies of clinically depressed subjects, these data suggest that emotional/stress‐response systems that include the amygdala are pathologically activated in major depression and that this activity is associated with dysfunction of the prefrontal cortex and monoamine neurotransmitter systems that normally modulate such responses.

title: Prediction of panic response to a respiratory stimulant by reduced orbitofrontal cerebral blood flow in panic disorder.
abstract: Lack of appropriate top-down governance by frontal cortical regions over a hypersensitive amygdala-centered fear neurocircuitry has been hypothesized to be central in the pathophysiology of panic disorder. The aim of this study was to examine regional cerebral blood flow changes in response to anxiety/panic provocation in subjects with panic disorder and healthy comparison subjects.



Quantitative water method positron emission tomography was used to obtain brain images of five untreated subjects with panic disorder and five healthy comparison subjects before and during anxiogenic challenge with intravenous doxapram, an acute respiratory stimulant.



Baseline perfusion of the orbitofrontal cortex predicted panic attacks: lower perfusion was associated with heightened anxiety in response to doxapram challenge.



The orbitofrontal cortex may be important in the regulation of responding to fear and is a potential area of aberrant functioning in panic disorder.

title: The orbitofrontal–amygdala circuit and self-regulation of social–emotional behavior in autism
abstract: Individuals with an autistic spectrum disorder are impaired not only in understanding others' mental states, but also in self-regulation of social-emotional behavior. Therefore, a model of the brain in autism must encompass not only those brain systems that subserve social-cognitive and emotional functioning, but also those that subserve the self-regulation of behavior in response to a changing social environment. We present evidence to support the hypothesis that developmental dysfunction of the orbitofrontal-amygdala circuit of the brain is a critical factor in the development of autism and that some of the characteristic deficits of persons with autism in socio-emotional cognition and behavioral self-regulation are related to early dysfunction of different components of this circuit. A secondary hypothesis posits that the degree of intellectual impairment present in individuals with autism is directly related to the integrity of the dorsolateral prefrontal-hippocampal circuit of the brain. Together, these hypotheses have the potential to help explain the neurodevelopmental basis of some of the primary manifestations of autism as well as the heterogeneity of outcomes.

title: Trauma modulates amygdala and medial prefrontal responses to consciously attended fear
abstract: Effective fear processing relies on the amygdala and medial prefrontal cortex (MPFC). Post-trauma reactions provide a compelling model for examining how the heightened experience of fear impacts these systems. Post-traumatic stress disorder (PTSD) has been associated with excessive amygdala and a lack of MPFC activity in response to nonconscious facial signals of fear, but responses to consciously processed facial fear stimuli have not been examined. We used functional MRI to elucidate the effect of trauma reactions on amygdala-MPFC function during an overt fear perception task. Subjects with PTSD (n = 13) and matched non-traumatized healthy subjects (n = 13) viewed 15 blocks of eight fearful face stimuli alternating pseudorandomly with 15 blocks of neutral faces (stimulus duration 500 ms; ISI 767 ms). We used random effects analyses in SPM2 to examine within- and between-group differences in the MPFC and amygdala search regions of interest. Time series data were used to examine amygdala-MPFC associations and changes across the first (Early) versus second (Late) phases of the experiment. Relative to non-traumatized subjects, PTSD subjects showed a marked bilateral reduction in MPFC activity (in particular, right anterior cingulate cortex, ACC), which showed a different Early-Late pattern to non-traumatized subjects and was more pronounced with greater trauma impact and symptomatology. PTSD subjects also showed a small but significant enhancement in left amygdala activity, most apparent during the Late phase, but reduction in Early right amygdala response. Over the time course, trauma was related to a distinct pattern of ACC and amygdala connections. The findings suggest that major life trauma may disrupt the normal pattern of medial prefrontal and amygdala regulation.