▪ Abstract The prefrontal cortex has long been suspected to play an important role in cognitive control, in the ability to orchestrate thought and action in accordance with internal goals. Its neural basis, however, has remained a mystery. Here, we propose that cognitive control stems from the active maintenance of patterns of activity in the prefrontal cortex that represent goals and the means to achieve them. They provide bias signals to other brain structures whose net effect is to guide the flow of activity along neural pathways that establish the proper mappings between inputs, internal states, and outputs needed to perform a given task. We review neurophysiological, neurobiological, neuroimaging, and computational studies that support this theory and discuss its implications as well as further issues to be addressed

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An integrative theory of prefrontal cortex function

Publisher Summary This chapter focuses on the modern notion of short-term memory, called working memory. Working memory refers to the temporary maintenance of information that was just experienced or just retrieved from long-term memory but no longer exists in the external environment. These internal representations are short-lived, but can be maintained for longer periods of time through active rehearsal strategies, and can be subjected to various operations that manipulate the information in such a way that makes it useful for goal-directed behavior. Working memory is a system that is critically important in cognition and seems necessary in the course of performing many other cognitive functions, such as reasoning, language comprehension, planning, and spatial processing. This chapter demonstrates the functional importance of dopamine to working memory function in several ways. Elucidation of the cognitive and neural mechanisms underlying human working memory is an important focus of cognitive neuroscience and neurology for much of the past decade. One conclusion that arises from research is that working memory, a faculty that enables temporary storage and manipulation of information in the service of behavioral goals, can be viewed as neither a unitary, nor a dedicated system. Data from numerous neuropsychological and neurophysiological studies in animals and humans demonstrates that a network of brain regions, including the prefrontal cortex, is critical for the active maintenance of internal representations.

Chapter 11 Working memory

Information about the basal ganglia has accumulated at a prodigious pace over the past decade, necessitating major revisions in our concepts of the structural and functional organization of these nuclei. From earlier data it had appeared that the basal ganglia served primarily to integrate diverse inputs from the entire cerebral cortex and to "funnel" these influences, via the ventrolateral thalamus, to the motor cortex (Allen & Tsukahara 1974, Evarts & Thach 1969, Kemp & Powell 1971). In particular, the basal

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Parallel Organization of Functionally Segregated Circuits Linking Basal Ganglia and Cortex

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.

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Distributed Hierarchical Processing in the Primate Cerebral Cortex

Information processing in the cerebral cortex involves interactions among distributed areas. Anatomical connectivity suggests that certain areas form local hierarchical relations such as within the visual system. Other connectivity patterns, particularly among association areas, suggest the presence of large-scale circuits without clear hierarchical relations. In this study the organization of networks in the human cerebrum was explored using resting-state functional connectivity MRI. Data from 1,000 subjects were registered using surface-based alignment. A clustering approach was employed to identify and replicate networks of functionally coupled regions across the cerebral cortex. The results revealed local networks confined to sensory and motor cortices as well as distributed networks of association regions. Within the sensory and motor cortices, functional connectivity followed topographic representations across adjacent areas. In association cortex, the connectivity patterns often showed abrupt transitions between network boundaries. Focused analyses were performed to better understand properties of network connectivity. A canonical sensory-motor pathway involving primary visual area, putative middle temporal area complex (MT+), lateral intraparietal area, and frontal eye field was analyzed to explore how interactions might arise within and between networks. Results showed that adjacent regions of the MT+ complex demonstrate differential connectivity consistent with a hierarchical pathway that spans networks. The functional connectivity of parietal and prefrontal association cortices was next explored. Distinct connectivity profiles of neighboring regions suggest they participate in distributed networks that, while showing evidence for interactions, are embedded within largely parallel, interdigitated circuits. We conclude by discussing the organization of these large-scale cerebral networks in relation to monkey anatomy and their potential evolutionary expansion in humans to support cognition.

The organization of the human cerebral cortex estimated by intrinsic functional connectivity

Anterograde tracing methods were used to examine the topographic organization and interrelationship of projections to the neostriatum arising from various areas of association cortex. In contrast to the currently accepted topographic schema, all cortical areas examined project to longitudinal territories that occupy restricted medial-lateral domains of the neostriatum. The posterior parietal and superior arcuate cortices project to dorsolateral portions of the neostriatum; the dorsolateral and dorsomedial frontal cortices project centrally; and the orbitofrontal, anterior cingulate, and superior temporal projections are distributed to ventromedial regions of the caudate nucleus and putamen. In coronal section, cortical terminal fields form a diagonal strip, extending from the dorsal, ventricular border of the caudate nucleus, through the fiber bundles of the internal capsule, to the ventral margin of the putamen. Double labeling studies, in which two cortical areas were injected in the same animal, indicated that convergence of input within neostriatal domains is not governed by reciprocity of corticocortical connectivity. Thus, the interrelationship of projections arising from connectionally linked cortical areas ranged from nearly complete segregation of terminal fields (e.g., from dorsolateral prefrontal and orbital cortices) to extensive overlap of terminal domains (e.g., from frontal and temporal cortices). In the latter case, detailed analysis revealed that frontal and temporal terminals actually were interdigitated rather than intermixed within the zone of overlap. The present findings suggest a new conceptualization of corticostriatal topography in the primate which emphasizes the longitudinal arrangement of cortical terminal domains. Additionally, these findings provide a map for functional parcellation of the neostriatum on the basis of its cortical innervation which may prove useful to understanding normal striatal function, as well as the symptomatology associated with neostriatal injury and disease.

https://www.jneurosci.org/content/jneuro/5/3/776.full.pdf

Longitudinal topography and interdigitation of corticostriatal projections in the rhesus monkey

The reduced neuropil hypothesis: a circuit based model of schizophrenia

Background: In the past two decades, gross morphologic changes have been uncovered in the schizophrenic brain, eg, increased ventricular width and decreased cortical volume; however, relatively little is known about the area-specific and laminar density of cells in the schizophrenic cortex, particularly in prefrontal areas. Method: A direct, three-dimensional counting method was used to determine cell density in 16 brains from patients with schizophrenia, 19 from normal subjects, six from patients with schizoaffective disorder, and nine from patients with advanced-stage Huntington's disease. Results: Increased neuronal density was found in prefrontal area 9 (17%) and occipital area 17 (10%) in the schizophrenic brains. In area 9, neuronal density was increased in layers III to VI; cell packing of pyramidal and nonpyramidal neurons was elevated. Cortical thickness in the schizophrenic brains was slightly but not significantly reduced in both areas, with a disproportionate reduction in layer V in area 9. In contrast, brains with Huntington's disease exhibited markedly higher glial density Abnormally high density in the cerebral cortices of schizophrenics suggests that neuronal atrophy is the anatomic substrate for deficient information processing in schizophrenia. Conclusion: Abnormally high density in the cerebral cortices of schizophrenics suggests that neuronal atrophy is the anatomic substrate for deficient information processing in schizophrenia.

Abnormally high neuronal density in the schizophrenic cortex. A morphometric analysis of prefrontal area 9 and occipital area 17.

Common efferent projections of the dorsolateral prefrontal cortex and posterior parietal cortex were examined in 3 rhesus monkeys by placing injections of tritiated amino acids and HRP in frontal and parietal cortices, respectively, of the same hemisphere. Terminal labeling originating from both frontal and parietal injection sites was found to be in apposition in 15 ipsilateral cortical areas: the supplementary motor cortex, the dorsal premotor cortex, the ventral premotor cortex, the anterior arcuate cortex (including the frontal eye fields), the orbitofrontal cortex, the anterior and posterior cingulate cortices, the frontoparietal operculum, the insular cortex, the medial parietal cortex, the superior temporal cortex, the parahippocampal gyrus, the presubiculum, the caudomedial lobule, and the medial prestriate cortex. Convergent terminal labeling was observed in the contralateral hemisphere as well, most prominently in the principal sulcal cortex, the superior arcuate cortex, and the superior temporal cortex. In certain common target areas, as for example the cingulate cortices, frontal and parietal efferents terminate in an array of interdigitating columns, an arrangement much like that observed for callosal and associational projections to the principal sulcus (Goldman-Rakic and Schwartz, 1982). In other areas, frontal and parietal terminals exhibit a laminar complementarity: in the depths of the superior temporal sulcus, prefrontal terminals are densely distributed within laminae I, III, and V, whereas parietal terminals occupy mainly laminae IV and VI directly below the prefrontal bands. Subcortical structures also receive apposing or overlapping projections from both prefrontal and parietal cortices. The dorsolateral prefrontal and posterior parietal cortices project to adjacent, longitudinal domains of the neostriatum, as has been described previously (Selemon and Goldman-Rakic, 1985); these projections are also found in close apposition in the claustrum, the amygdala, the caudomedial lobule, and throughout the anterior medial, medial dorsal, lateral dorsal, and medial pulvinar nuclei of the thalamus. In the brain stem, both areas of association cortex project to the intermediate layers of the superior colliculus and to the midline reticular formation of the pons.(ABSTRACT TRUNCATED AT 400 WORDS)

https://www.jneurosci.org/content/jneuro/8/11/4049.full.pdf

Common cortical and subcortical targets of the dorsolateral prefrontal and posterior parietal cortices in the rhesus monkey: evidence for a distributed neural network subserving spatially guided behavior

Lynn D. Selemon

Papers

Longitudinal topography and interdigitation of corticostriatal projections in the rhesus monkey

The reduced neuropil hypothesis: a circuit based model of schizophrenia

Abnormally high neuronal density in the schizophrenic cortex. A morphometric analysis of prefrontal area 9 and occipital area 17.

Common cortical and subcortical targets of the dorsolateral prefrontal and posterior parietal cortices in the rhesus monkey: evidence for a distributed neural network subserving spatially guided behavior

Dual pathways connecting the dorsolateral prefrontal cortex with the hippocampal formation and parahippocampal cortex in the rhesus monkey