A major line of evidence that supports the hypothesis of dopamine overactivity in schizophrenia is the psychomimetic potential of agents such as amphetamine that stimulate dopamine outf low. A novel brain imaging method provides an indirect measure of in vivo synaptic dopamine concentration by quantifying the change in dopamine receptor radiotracer binding produced by agents that alter dopamine release but do not themselves bind to dopamine receptors. The purpose of this investigation is (i) to determine the sensitivity (i.e., amount of dopamine ref lected in radiotracer binding changes) of this method by examining the relationship between amphetamine-induced changes in simultaneously derived striatal extracellular dopamine levels with in vivo microdialysis and striatal binding levels with the dopamine D 2 ͞D 3 positron-emission tomography radioligand [ 11 C]raclopride in nonhuman primates, and (ii) to test the hypothesis of elevated amphetamine-induced synaptic dopamine levels in schizophrenia. In the nonhuman primate study (n ‫؍‬ 4), doubling the amphetamine dose produced a doubling in [ 11 C]raclopride specific binding reductions. In addition, the ratio of percent mean dopamine increase to percent mean striatal binding reduction for amphetamine (0.2 mg͞kg) was 44:1, demonstrating that relatively small binding changes ref lect large changes in dopamine outf low. In the clinical study, patients with schizophrenia (n ‫؍‬ 11) compared with healthy volunteers (n ‫؍‬ 12) had significantly greater amphetamine-related reductions in [ 11 C]raclopride specific binding (mean ؎ SEM): ؊22.3% (؎2.7) vs. ؊15.5% (؎1.8), P ‫؍‬ 0.04, respectively. Inferences from the preclinical study suggest that the patients' elevation in synaptic dopamine concentrations was substantially greater than controls. These data provide direct evidence for the hypothesis of elevated amphetamineinduced synaptic dopamine concentrations in schizophrenia.

In vivo tractography based on diffusion magnetic resonance imaging (dMRI) has opened new doors to study structure-function relationships in the human brain. Initially developed to map the trajectory of major white matter tracts, dMRI is used increasingly to infer long-range anatomical connections of the cortex. Because axonal projections originate and terminate in the gray matter but travel mainly through the deep white matter, the success of tractography hinges on the capacity to follow fibers across this transition. Here we demonstrate that the complex arrangement of white matter fibers residing just under the cortical sheet poses severe challenges for long-range tractography over roughly half of the brain. We investigate this issue by comparing dMRI from very-high-resolution ex vivo macaque brain specimens with histological analysis of the same tissue. Using probabilistic tracking from pure gray and white matter seeds, we found that ∼50% of the cortical surface was effectively inaccessible for long-range diffusion tracking because of dense white matter zones just beneath the infragranular layers of the cortex. Analysis of the corresponding myelin-stained sections revealed that these zones colocalized with dense and uniform sheets of axons running mostly parallel to the cortical surface, most often in sulcal regions but also in many gyral crowns. Tracer injection into the sulcal cortex demonstrated that at least some axonal fibers pass directly through these fiber systems. Current and future high-resolution dMRI studies of the human brain will need to develop methods to overcome the challenges posed by superficial white matter systems to determine long-range anatomical connections accurately. diffusion MRI | tractography | neuroanatomy | white matter | connectome T he primate cerebral cortex consists of dozens of areas distinguished by their cytoarchitectonic profiles (1), sensory maps (2), functional specialization (3), and spontaneous activity covariation (4). Attention within neuroscience has increasingly focused on understanding how connectivity among these regions underpins brain function in health and in disease (5). The macaque monkey (Macaca mulatta) has been a fruitful neuroscientific model because the functional organization of its brain is similar in many ways to that of the human (6-8). Tracer injections in the macaque have revealed that virtually all cortical areas give rise to long-range connections, many of which project to other cortical areas, potentially to form processing hierarchies (9). This understanding continues to shape views of functional organization in the human brain. However, studying long-range connections through tracer injections is time consuming, inefficient, and prone to sampling biases, because a given experiment can measure connectivity to only one or a small number of cortical sites. Moreover, although in many respects the macaque brain is a good approximation of the human brain, both species have undergone profound evolutionary changes since the time of their most recent...

Two ideas have dominated the neuropsychology of the orbitofrontal cortex (OFC). One holds that OFC regulates emotion and enhances behavioral flexibility through inhibitory control. The other ascribes to OFC a role in updating valuations based on current motivational states. Neuroimaging, neurophysiological and clinical observations are consistent with either or both hypotheses. Although these hypotheses are compatible in principle, the present results support the latter view of OFC function and argue against the former. We show that excitotoxic, fibersparing lesions confined to OFC in monkeys do not alter either behavioral flexibility, as measured by object reversal learning, or emotion regulation, as assessed by snake fear. A follow-up experiment indicates that previous reports of a loss of inhibitory control resulted from damage to nearby fiber tracts and not from OFC dysfunction. Thus, OFC plays a more specialized role in reward-guided behavior and emotion than currently thought, a function that includes value updating.

Injury to the primary visual cortex (V1) leads to the loss of visual experience. Nonetheless, careful testing shows that certain visually guided behaviors can persist even in the absence of visual awareness1–5. The neural circuits supporting this phenomenon, often termed blindsight, remain uncertain5. Here we demonstrate a causal role of the thalamic lateral geniculate nucleus (LGN) in V1-independent processing of visual information. By comparing fMRI and behavioral measures with and without temporary LGN inactivation, we assessed the contribution of the LGN to visual functions of macaque monkeys with chronic V1 lesions. Prior to LGN inactivation, high contrast stimuli presented to the lesion-affected visual field (scotoma) produced significant V1 independent fMRI activation in extrastriate cortical areas V2, V3, V4, V5/MT, FST, and LIP, and were correctly located by the animals in a detection task. However, following reversible inactivation of the LGN in the V1-lesioned hemisphere both fMRI responses and behavioral detection were abolished. Taken together, these results demonstrate a critical functional contribution of the direct LGN projections to extrastriate cortex in blindsight, and suggest a viable pathway mediating fast detection during normal vision.

Monkeys trained preoperatively on a task designed to assess auditory recognition memory were impaired after removal of either the rostral superior temporal gyrus or the medial temporal lobe but were unaffected by lesions of the rhinal cortex. Behavioral analysis indicated that this result occurred because the monkeys did not or could not use long-term auditory recognition, and so depended instead on short-term working memory, which is unaffected by rhinal lesions. The findings suggest that monkeys may be unable to place representations of auditory stimuli into a longterm store and thus question whether the monkey's cerebral memory mechanisms in audition are intrinsically different from those in other sensory modalities. Furthermore, it raises the possibility that language is unique to humans not only because it depends on speech but also because it requires long-term auditory memory.medial temporal lobe ͉ perirhinal cortex ͉ recognition memory B oth visual and tactile recognition memory in the monkey are severely impaired after bilateral ablation of the medial temporal lobe (1, 2), particularly if the damage is to the perirhinal͞entorhinal, or rhinal, cortices (3)(4)(5)(6)(7)(8). Similarly severe impairment after lesions or inactivation of the rhinal cortices has been demonstrated in olfactory, visual, and gustatory recognition memory in rats (9-11). The results thus suggest that the rhinal cortices are essential multimodal processing areas linking each of the cortical sensory streams to those deeper limbic and diencephalic structures that are also critical for the formation of stimulus memories (e.g., see refs. 12 and 13). The present study was aimed at extending this model of memory formation to the monkey's auditory modality, and for this purpose we examined the effects in monkeys of rostral superior temporal, complete medial temporal, and selective rhinal lesions on delayed matching-to-sample (DMS) with trial-unique sounds, a putative test of one-trial auditory recognition. Unexpectedly, although each of the first two types of lesion produced significant impairment, the rhinal lesions did not (see also ref. 14). A tentative explanation for this lack of impairment is provided by a comparison of the preoperative data gathered here in audition with those commonly obtained in other modalities. The comparison suggests the surprising possibility that, unlike other sensory stimuli, the auditory stimuli failed to engage the rhinal cortices (or their functional analogues in audition) and so were not stored as lasting stimulus representations. If so, then the auditory deficits observed after the rostral superior temporal and complete medial temporal ablations reflect impairments not in long-term auditory recognition but only in auditory working memory. Together, the results imply that the monkey's cerebral mechanisms for memory in audition are fundamentally different from those in other sensory modalities. MethodsSubjects. The subjects were nine experimentally naive rhesus monkeys (Macaca mulatta), five males and four...

It has often been proposed that the vocal calls of monkeys are precursors of human speech, in part because they provide critical information to other members of the species who rely on them for survival and social interactions. Both behavioural and lesion studies suggest that monkeys, like humans, use the auditory system of the left hemisphere preferentially to process vocalizations. To investigate the pattern of neural activity that might underlie this particular form of functional asymmetry in monkeys, we measured local cerebral metabolic activity while the animals listened passively to species-specific calls compared with a variety of other classes of sound. Within the superior temporal gyrus, significantly greater metabolic activity occurred on the left side than on the right, only in the region of the temporal pole and only in response to monkey calls. This functional asymmetry was absent when these regions were separated by forebrain commissurotomy, suggesting that the perception of vocalizations elicits concurrent interhemispheric interactions that focus the auditory processing within a specialized area of one hemisphere.

A combination of anterograde and retrograde tracing techniques was used to study the projections to the nucleus accumbens from the amygdala, the hippocampal formation (including the entorhinal cortex), and the perirhinal cortex in two species of macaque monkey. To help identify possible subregions within the nucleus accumbens, the distribution of calbindin was examined in two additional monkeys. Although this revealed evidence of "core"- and "shell"-like regions within the accumbens, these different regions could not consistently be related to cytoarchitectonic features. The rostral amygdala sent nearly equivalent projections to both the medial and the lateral portions of nucleus accumbens, whereas projections arising from the middle and caudal amygdala terminated preferentially in the medial division of nucleus accumbens. The basal nucleus was the major source of these amygdala efferents, and there was a crude topography as parts of the basal and accessory basal nuclei terminated in different parts of nucleus accumbens. The subiculum was the major source of hippocampal projections to the nucleus accumbens, but some hippocampal efferents also originated in the parasubiculum, the prosubiculum, the adjacent portion of CA1, and the uncal portion of CA3. These hippocampal projections, which coursed through the fornix, showed a rostrocaudal gradient as more arose in the rostral hippocampus. Hippocampal efferents terminated most densely in the medial and ventral portions of nucleus accumbens, along with light label in the adjacent olfactory tubercle. The entorhinal projections were more evenly distributed between the medial nucleus accumbens and the olfactory tubercle, whereas the perirhinal projections were primarily to the olfactory tubercle. These cortical inputs were less reliant on the fornix. Amygdala and subicular (hippocampal) projections overlapped most completely in the medial division of nucleus accumbens.

SUMMARY Advantageous foraging choices benefit from an estimation of two aspects of a resource’s value: its current desirability and availability. Both orbitofrontal (OFC) and ventrolateral (VLPFC) prefrontal areas contribute to updating these valuations, but their precise roles remain unclear. To explore their specializations, we trained macaque monkeys on two tasks: one required updating representations of a predicted outcome’s desirability, as adjusted by selective satiation; the other required updating representations of an outcome’s availability, as indexed by its probability. We evaluated performance on both tasks in three groups of monkeys: unoperated controls and those with selective, fiber-sparing lesions of either OFC or VLPFC. Representations that depend on VLPFC—but not OFC—play a necessary role in choices based on outcome availability; in contrast, representations that depend on OFC—but not VLPFC—play a necessary role in choices based on outcome desirability.