Functional studies of the dorsolateral prefrontal cortex and the inferior parietal lobe of the rhesus monkey have implicated the former in spatial mnemonic function and the latter in visuospatial processing. We used the 14C-2-deoxyglucose (2DG) method to assess the contribution of these cortical regions to the cognitive performance of monkeys on working memory tasks. In these experiments, one group of monkeys (WORK) was trained to perform tasks (delayed spatial alternation, spatial delayed response, or delayed object alternation) that specifically engaged working memory processing. Local cerebral glucose utilization (LCGU) rates in the WORK group was compared with LCGU rates for a second group of monkeys (CONT) tested on one of two tasks (visual pattern discrimination or sensory-motor) that relied upon associative memory. The results showed that in comparison to the CONT group, working memory performance significantly enhanced LCGU by 19% in the principal sulcus region of prefrontal cortex and by 11–20% in regions of the inferior parietal cortex corresponding to areas 7A, 7B, 7IP, and 7M. By contrast, LCGU in the auditory cortex was similar for both groups. In all areas examined, metabolic activation peaked in lower layer III where the majority of associational and callosal neurons lie. Correlation analyses of LCGU and behavioral task parameters indicated that LCGU in the parietal subdivisions was significantly related either to the accuracy of performance or to the number of trials completed on the 2DG test. In contrast, LCGU in the principal sulcus was positively correlated with task difficulty. These findings suggest that the enhancement of LCGU in the principal sulcus was primarily influenced by the mnemonic components of the tasks whereas LCGU in the inferior parietal cortex was influenced by their sensory-motor demands. These are the first results showing concurrent metabolic activation of the prefrontal and parietal cortex in monkeys performing working memory tasks and they support the suggestion that these cortical regions represent two important nodes in a neural network mediating spatial working memory in the monkey (Goldman-Rakic, 1988). Further, the present report reinforces the power of the 2DG method for functional mapping as these areal and laminar results could not be readily appreciated at this resolution in any other methodological context.

The caudate nucleus is part of an anatomical network subserving functions associated with the dorsolateral prefrontal cortex (DLPFC). The aim of the present study was to investigate whether the metabolic activity in the striatum reflects specific changes in working memory tasks, which are known to be dependent on the DLPFC, and whether these changes reflect the topographic ordering of prefrontal connections within the striatum. Local cerebral glucose utilization (LCGU) rates were assessed in the striatum by the 14 C-2-deoxyglucose method in monkeys that performed a spatial (delayed spatial alternation), a nonspatial (delayed object alternation) visual working memory task, or tasks that did not involve working memory, i.e., a visual pattern discrimination or sensorimotor paradigm.The results show a topographic segregation of activation related to spatial and nonspatial working memory, respectively. The delayed spatial alternation task increases LCGU rates bilaterally by 33-43% in the head of the caudate nucleus, where efferents from the dorsolateral prefrontal cortex project most densely. The delayed object alternation task enhances LCGU rates bilaterally by 32-37% in the body of the caudate nucleus, which is innervated by the temporal cortex. The visual pattern discrimination task similarly activated the body of the caudate, but in a smaller region and only in the right hemisphere.These findings provide the first evidence for metabolic activation of the caudate nuclei in working memory, supporting the role of this nucleus as a node in a neural network mediating DLPFC-dependent working memory processes. The double dissociation of activation observed suggests an anatomical and functional segregation of cortico-striatal circuits subserving spatial and nonspatial cognitive operations.

To evaluate smooth-pursuit (SP) function in the primate frontal eye field (FEF), microinjections of muscimol, a gamma-aminobutyric acid (GABA) agonist, were used to reversibly deactivate physiologically characterized sites in FEF. SP was severely impaired by deactivation at sites in the FEF's smooth eye movement region (FEFsem) located in the fundus and posterior bank of the macaque monkey's arcuate sulcus. These SP deficits were apparent immediately after the muscimol injection and persisted for several hours but recovered by the next day. SP was most drastically and consistently impaired for directions similar to the injected site's elicited smooth eye movement direction or to the optimal SP direction for its neuronal responses. Targets moving in these directions, usually ipsilateral to the injected hemisphere, were tracked primarily with saccades after the muscimol injection, the peak SP velocity being only 10-30% of preinjection velocity. SP in other directions, including contralateral, was less strongly affected. Initial SP acceleration in response to target motion onset was also significantly diminished, generally by approximately the same proportion as peak SP velocity. In contrast, saccades were largely unaffected by muscimol injections in FEFsem; nor was there an immediate effect on SP when control sites in the saccadic region of FEF (FEFsac) were deactivated, although a SP deficit often appeared 30-60 min after FEFsac injections, possibly reflecting diffusion of muscimol into neighboring FEFsem. These reversible SP deficits produced by muscimol inactivation within FEFsem are similar to permanent deficits caused by large aspiration lesions of FEF and indicate that inclusion of FEFsem is the critical factor determining whether FEF lesions impair SP. The severity of the reversible deficits found here indicates how extremely critical FEFsem is for normal highgain SP.

In primates, the frontal eye field (FEF) contains separate representations of saccadic and smooth-pursuit eye movements. The smooth-pursuit region (FEFsem) in macaque monkeys lies principally in the fundus and deep posterior wall of the arcuate sulcus, between the FEF saccade region (FEFsac) in the anterior wall and somatomotor areas on the posterior wall and convexity. In this study, cortical afferents to FEFsem were mapped by injecting retrograde tracers (WGA-HRP and fast blue) into electrophysiologically identified FEFsem sites in two monkeys. In the frontal lobe, labeled neurons were found mostly on the ipsilateral side in the (1) supplementary eye field region and lateral area F7; (2) area F2 along the superior limb of the arcuate sulcus; and (3) in the buried cortex of the arcuate sulcus extending along the superior and inferior limbs and including FEFsac and adjacent areas 8, 45, and PMv. Labeled cells were also found in the caudal periprincipal cortex (area 46) in one monkey. Labeled cells were found bilaterally in the frontal lobe in the deep posterior walls of the arcuate sulcus and postarcuate spurs and in cingulate motor areas 24 and 24c. In postcentral cortical areas all labeling was ipsilateral and there were two major foci of labeled cells: (1) the depths of the intraparietal sulcus including areas VIP, LIP, and PEa, and (2) the anterior wall and fundus of the superior temporal sulcus including areas PP and MST. Smaller numbers of labeled cells were found in superior temporal sulcal areas FST, MT, and STP, posterior cingulate area 23b, area 3a within the central sulcus, areas SII, RI, Tpt in the lateral sulcus, and parietal areas 7a, 7b, PEc, MIP, DP, and V3A. Many of these posterior afferent cortical areas code visual-motion (MT, MST, and FST) or visual-motion and vestibular (PP, VIP) signals, consistent with the responses of neurons in FEFsem and with the overall physiology and anatomy of the smooth-pursuit eye movement system.

The 2-deoxyglucose (2-DG) method was used to study the effect of working memory processing on local cerebral glucose utilization (LCGU) in the diencephalon of the rhesus monkey. Monkeys were given [(14)C]2-DG while performing either one of three tasks that engaged working memory (WORK group) or one of two control tasks (CONT group) that used associative or non associative processes. The tasks of the WORK group-spatial delayed response, spatial delayed alternation, and delayed object alternation-are alike in that the information guiding a correct response changes from trial to trial and only the accurate record of the preceding response (or cue) is relevant for each successive trial. The CONT group, in contrast, performed on either a visual pattern discrimination test, in which the correct stimulus-response association was invariant across all trials and all test sessions, or on a sensorimotor task in which there was no explicit memory requirement. LCGU was examined in five diencephalic regions: the mammillary bodies, the anteroventral and anteromedial thalamus, and the parvocellular and magnocellular components of the mediodorsal thalamic nucleus. Comparisons across the two groups showed that mean LCGU in the anterior and mediodorsal thalamic nuclei was significantly elevated (by 12-16%) in the WORK group relative to the CONT group. Mean LCGU in the mammillary bodies also was higher in the WORK group than in the CONT group, but this difference was not significant. The present findings suggest that the anterior and mediodorsal thalamic nuclei represent diecephalic components of a neural network processing working memory. Together with our previous report on the enhancement of metabolic activity in the hippocampus and dentate gyrus, these results show that working memory has a wide-ranging influence on cerebral metabolism and emphasize the cooperative, rather than dissociable, roles of the hippocampus and medial thalamus in this function.