21 Evidence for the role of a frontostriatal system in cognition and behavior was first suggested by a series of experimental observations.22 Specifically, lesions of electrical stimulation of the dorsolateral prefrontal cortex or of the anterodorsal head of the caudate nucleus, to

which this region projects, were found to produce deficits in the same behavioral domain- namely, delayed-response and delayed-alternation tasks.23 Similarly, lesions or electrical stimulation, either of the orbitofrontal cortex or of the Raf activity ventrolateral head of the caudate, resulted in comparable deficits in object alternation or response Inhibitors,research,lifescience,medical inhibition paradigms.14 Accordingly, disruption to cognitive processes following striatal injury was interpreted as the ”downstream“ interruption of anatomically Inhibitors,research,lifescience,medical congruent outflow from the frontal cortex.24,25 Basic circuit structure The five major frontal-subcortical circuits suggested by Alexander et al5,7-9 are now generally accepted. These include a motor circuit that originates in the supplementary motor area, and an oculomotor circuit originating in the frontal eye field. The motor circuit originates from neurons in the supplementary motor area, premotor Inhibitors,research,lifescience,medical cortex, motor

cortex, and somatosensory cortex, recently confirmed by fMRI findings.26 These areas project principally to the putamen in a somatotopic distribution. The putamen in turn projects to ventrolateral globus pallidus interna (GPi), globus Inhibitors,research,lifescience,medical pallidus externa (GPe), and caudolateral SN. The globus pallidus (GP) connects to the ventrolateral, ventral anterior, and centromedianum nuclei of the thalamus, whose major efferents Inhibitors,research,lifescience,medical are to the supplementary motor area, premotor cortex, and motor

cortex, completing the circuit. Thalamic nuclei have reciprocal connections with the putamen and cerebral cortex, in addition to the connections contained within the circuit. Throughout the circuit, all the discrete somatotopic organization of movement-related neurons is maintained. Information processing in the circuits is not strictly sequential; neurophysiological investigations of movement demonstrate preparatory premovement activity, serial processing of movements initiated in the cortex, and concurrent parallel processing in the structures of the circuit.8,27,28 The oculomotor circuit originates in the frontal eye field (Brodmann’s area 8) as well as prefrontal and posterior parietal cortex, and connects sequentially to the central body of the caudate nucleus, dorsomedial GP and ventrolateral SN, ventral anterior and mediodorsal thalamic nuclei, and frontal eye field.