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Neuronal activity representing temporal prediction of reward in the primate prefrontal cortex.

Temporal prediction of future events, especially regarding reward delivery, is critical for controlling/learning purposeful behavior. The dorsolateral prefrontal cortex (DLPFC) has been considered to be involved in behavioral control based on prospective coding for future events, including reward. Thus this area is likely to have a neuronal mechanism responsible for temporal prediction of forthcoming reward. To address this hypothesis, we recorded the neuronal activity from the DLPFC of macaque monkeys while they performed an oculomotor delayed-response task under two conditions regarding the time of reward delivery. In this task, when the subjects made a correct response, the reward was delivered after a reward-delay period of 0.5 or 2 s. At the behavioral level, the onset latency for saccades was significantly faster in the shorter reward-delay trials (0.5 s) than in longer reward-delay trials (2 s), indicating that our subjects actually predicted the time of reward delivery. At the neuronal level, we found that many DLPFC neurons showed differential activity depending on the predicted time of reward delivery during the cue and/or delay periods. These results suggest that a fraction of neurons in the DLPFC represent the temporal prediction of reward and probably a variety of other future events.

Action Potentials↗

Implication of SSAT by gene expression and genetic variation in suicide and major depression.

CONTEXT: A large body of evidence suggests that predisposition to suicide, an important public health problem, is mediated to a certain extent by neurobiological factors. OBJECTIVE: To investigate patterns of expression in suicide with and without major depression and to identify new molecular targets that may play a role in the neurobiology of these conditions. DESIGN: Brain gene expression analysis was performed using the Affymetrix HG-U133 chipset in the orbital cortex (Brodmann area [BA] 11), the dorsolateral prefrontal cortex (BA8/9), and motor cortex (BA4). Subsequent studies were carried out in independent samples from adjacent areas to validate positive findings, confirm their relevance at the protein level, and investigate possible effects of genetic variation. SUBJECTS: We investigated 12 psychiatrically normal control subjects and 24 suicide victims, including 16 with and 8 without major depression, in the brain gene expression analysis, validation, and protein studies. The genetic studies included 181 suicide completers and 80 psychiatrically normal controls. All subjects investigated were male and of French Canadian origin. MAIN OUTCOME MEASURES: Gene expression measures from microarray, semiquantitative reverse transcription-polymerase chain reaction, immunohistochemistry, and Western blot analyses. RESULTS: Twenty-six genes were selected because of the consistency of their expression pattern (fold change, >1.3 in either direction [P<or=.01] in at least 2 regions). The spermine/spermidine N(1)-acetyltransferase gene (SSAT) was successfully validated by reverse transcription-polymerase chain reaction, immunohistochemistry, and Western blot analyses. A variant located in the SSAT polyamine-responsive element regulatory region (SSAT342A/C) demonstrated a significant effect of genotype on SSAT brain expression levels (F(1) = 5.34; P = .02). Further investigation of this variant in an independent sample of 181 male suicide completers and 80 male controls showed a higher frequency of the SSAT342C allele among suicide cases (odds ratio, 2.7; 95% confidence interval, 1.4-5.3; P = .005), suggesting that this allele may increase predisposition to suicide. CONCLUSIONS: These data suggest a role for SSAT, the rate-limiting enzyme in the catabolism of polyamines, in suicide and depression and a role for the SSAT342 locus in the regulation of SSAT gene expression.

Acetyltransferases↗

Brain activations during motor imagery of locomotor-related tasks: a PET study.

Positron emission tomography (PET) was used to study the involvement of supraspinal structures in human locomotion. Six right-handed adults were scanned in four conditions while imagining locomotor-related tasks in the first person perspective: Standing (S), Initiating gait (IG), Walking (W) and Walking with obstacles (WO). When these conditions were compared to a rest (control) condition to identify the neural structures involved in the imagination of locomotor-related tasks, the results revealed a common pattern of activations, which included the dorsal premotor cortex and precuneus bilaterally, the left dorsolateral prefrontal cortex, the left inferior parietal lobule, and the right posterior cingulate cortex. Additional areas involving the pre-supplementary motor area (pre-SMA), the precentral gyrus, were activated during conditions that required the imagery of locomotor movements. Further subtractions between the different locomotor conditions were then carried out to determine the cerebral regions associated with the simulation of increasingly complex locomotor functions. These analyses revealed increases in rCBF activity in the left cuneus and left caudate when the W condition was compared to the IG condition, suggesting that the basal ganglia plays a role in locomotor movements that are automatic in nature. Finally, subtraction of the W from the WO condition yielded increases in activity in the precuneus bilaterally, the left SMA, the right parietal inferior cortex and the left parahippocampal gyrus. Altogether, the present findings suggest that higher brain centers become progressively engaged when demands of locomotor tasks require increasing cognitive and sensory information processing.

Adult↗

Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study.

Microglial activation is implicated in the pathogenesis of ALS and can be detected in animal models of the disease that demonstrate increased survival when treated with anti-inflammatory drugs. PK11195 is a ligand for the "peripheral benzodiazepine binding site" expressed by activated microglia. Ten ALS patients and 14 healthy controls underwent [(11)C](R)-PK11195 PET of the brain. Volumes of interest were defined to obtain [(11)C](R)-PK11195 regional binding potential values for motor and "extra-motor" regions. Significantly increased binding was found in motor cortex (P = 0.003), pons (P = 0.004), dorsolateral prefrontal cortex (P = 0.010) and thalamus (P = 0.005) in the ALS patients, with significant correlation between binding in the motor cortex and the burden of upper motor neuron signs clinically (r = 0.73, P = 0.009). These findings indicate that cerebral microglial activation can be detected in vivo during the evolution of ALS, and support the previous observations that cerebral pathology is widespread. They also argue for the development of therapeutic strategies aimed at inflammatory pathways.

Adult↗

The functional anatomy of visual-tactile integration in man: a study using positron emission tomography.

The integration of neural signals from different sensory modalities is a prerequisite for many cognitive and behavioural functions. In this study, we have mapped the functional anatomy of the integration of sensory signals across the tactile and visual modalities. Using the PET radiotracer H2(15)O, regional cerebral blood flow (rCBF) changes were measured in eight normal volunteers performing crossmodal recognition of simultaneously presented visual and tactile stimuli using a modified version of the 'arc-circle test'. Whilst intramodal matching within the visual modality led to relative rCBF increases in the visual association cortex, crossmodal matching (visual-tactile), when compared to intramodal matching, was accompanied by relative rCBF increases in the anterior cingulate cortex, inferior parietal lobules, the left dorsolateral prefrontal cortex (DLPFC) and the left claustrum/insular cortex. The pattern of brain activation is congruent with areas of heteromodal and supramodal cortex and indicates that activation of multimodal areas is required to solve the crossmodal problem.

Adult↗

Neural systems and cue-induced cocaine craving.

We have extended our previous work investigating the neural correlates of cue-induced cocaine craving through the use of positron emission tomography with greater spatial resolution (<4.6 mm), an evocative script, and a pixel-by-pixel analysis. Craving and cerebral glucose metabolism were measured after presentation of cocaine-related or neutral cues to 11 cocaine abusers. Cocaine cues elicited a higher degree of craving than has been previously reported and resulted in left hemispheric activation of lateral amygdala, lateral orbitofrontal cortex, and rhinal cortex and right hemispheric activation of dorsolateral prefrontal cortex and cerebellum. The intensity of activation in these areas (except cerebellum), as well as left insula, was also correlated with craving. Deactivation occurred in left ventral pole and left medial prefrontal cortex. The results suggest that induction of drug craving involves a neural network that assigns incentive motivational value to environmental stimuli through the coactivation of brain regions that process information about memories and emotions.

Adult↗

Cortical and limbic activation during viewing of high- versus low-calorie foods.

Despite the high prevalence of obesity, eating disorders, and weight-related health problems in modernized cultures, the neural systems regulating human feeding remain poorly understood. Therefore, we applied functional magnetic resonance imaging (fMRI) to study the cerebral responses of 13 healthy normal-weight adult women as they viewed color photographs of food. The motivational salience of the stimuli was manipulated by presenting images from three categories: high-calorie foods, low-calorie foods, and nonedible dining-related utensils. Both food categories were associated with bilateral activation of the amygdala and ventromedial prefrontal cortex. High-calorie foods yielded significant activation within the medial and dorsolateral prefrontal cortex, thalamus, hypothalamus, corpus callosum, and cerebellum. Low-calorie foods yielded smaller regions of focal activation within medial orbitofrontal cortex; primary gustatory/somatosensory cortex; and superior, middle, and medial temporal regions. Findings suggest that the amygdala may be responsive to a general category of biologically relevant stimuli such as food, whereas separate ventromedial prefrontal systems may be activated depending on the perceived reward value or motivational salience of food stimuli.

Adult↗

Functional brain networks in Parkinson's disease.

With the advent of new methods of network analysis, we have utilized metabolic data acquired through positron emission tomography (PET) to identify disease-related patterns of functional pathology in the movement disorders. In Parkinson's disease (PD), we have used [(18)F]-fluorodeoxyglucose (FDG)/PET to identify a disease-related regional metabolic covariance pattern characterized by lentiform and thalamic hypermetabolism associated with regional metabolic decrements in the lateral premotor cortex, the supplementary motor area, the dorsolateral prefrontal cortex, and the parieto-occipital association regions. The expression of this network is modulated in a predictable fashion by levodopa therapy and by stereotaxic interventions for PD.We have extended this network analytical approach from studies of glucose metabolism in the resting state to dynamic studies of brain activation during motor performance. These PET studies utilized [(15)O]-water (H(2) (15)O) to measure cerebral blood flow activation responses during the execution of simple and complex motor tasks. In addition to the modulation of abnormal resting metabolic networks, effective PD therapy can enhance brain activation responses during motor execution, with specific regional associations with improvements in timing and spatial accuracy.This approach is also useful in identifying specific brain networks mediating the learning of sequential information. We have found that the normal relationship between brain networks and learning performance are altered in the earliest stages of PD with a functional shift from striatal to cortical processing. Brain activation PET studies during therapeutic interventions for PD demonstrate how normal brain-behavior relationships can be restored with successful therapy. Thus, functional brain imaging with network analysis can provide insights into the mechanistic basis of basal ganglia disorders and their treatment.

Antiparkinson Agents↗

Motor system activation after subcortical stroke depends on corticospinal system integrity.

Movement-related brain activation patterns after subcortical stroke are characterized by relative overactivations in cortical motor areas compared with controls. In patients able to perform a motor task, overactivations are greater in those with more motor impairment. We hypothesized that recruitment of motor regions would shift from primary to secondary motor networks in response to impaired functional integrity of the corticospinal system (CSS). We measured the magnitude of brain activation using functional MRI during a motor task in eight chronic subcortical stroke patients. CSS functional integrity was assessed using transcranial magnetic stimulation to obtain stimulus/response curves for the affected first dorsal interosseus muscle, with a shallower gradient representing increasing disruption of CSS functional integrity. A negative correlation between the gradient of stimulus/response curve and magnitude of task-related brain activation was found in several motor-related regions, including ipsilesional posterior primary motor cortex [Brodmann area (BA) 4p], contralesional anterior primary motor cortex (BA 4a), bilateral premotor cortex, supplementary motor area, intraparietal sulcus, dorsolateral prefrontal cortex and contralesional superior cingulate sulcus. There were no significant positive correlations in any brain region. These results suggest that impaired functional integrity of the CSS is associated with recruitment of secondary motor networks in both hemispheres in an attempt to generate motor output to spinal cord motoneurons. Secondary motor regions are less efficient at generating motor output so this reorganization can only be considered partially successful in reducing motor impairment after stroke.

Adult↗

Functional connectivity of the fusiform gyrus during a face-matching task in subjects with mild cognitive impairment.

Cognitive function requires a high level of functional interaction between regions of a network supporting cognition. Assuming that brain activation changes denote an advanced state of disease progression, changes in functional connectivity may precede changes in brain activation. The objective of this study was to investigate changes in functional connectivity of the right middle fusiform gyrus (FG) in subjects with mild cognitive impairment (MCI) during performance of a face-matching task. The right middle FG is a key area for processing face stimuli. Brain activity was measured using functional MRI. There were 16 MCI subjects and 19 age-matched healthy controls. The linear correlation coefficient was utilized as a measure of functional connectivity between the right middle FG and all other voxels in the brain. There were no statistical differences found in task performance or activation between groups. The right middle FG of the healthy control and MCI groups showed strong bilateral positive linear correlation with the visual cortex, inferior and superior parietal lobules, dorsolateral prefrontal cortex (DLPFC) and anterior cingulate. The healthy controls showed higher positive linear correlation of the right middle FG to the visual cortex, parietal lobes and right DLPFC than the MCI group, whereas the latter had higher positive linear correlation in the left cuneus. In the healthy controls, the right middle FG had negative linear correlation with right medial frontal gyrus and superior temporal gyrus and with left inferior parietal lobule (IPL), angular gyrus, superior frontal gyrus and anterior cingulate gyrus, but the MCI group had negative linear correlation with the left IPL, angular gyrus, precuneus, anterior cingulate, and to right middle temporal gyrus and posterior cingulate gyrus. In the negatively linearly correlated regions, the MCI group had reduced functional connectivity to the frontal areas, right superior temporal gyrus and left IPL. Different regions of the cuneus and IPL had increased functional connectivity in either group. The putative presence of Alzheimer's disease neuropathology in MCI affects functional connectivity from the right middle FG to the visual areas and medial frontal areas. In addition, higher linear correlation in the MCI group in the parietal lobe may indicate the initial appearance of compensatory processes. The results demonstrate that functional connectivity can be an effective marker for the detection of changes in brain function in MCI subjects.

Aged↗

[Time perception in functional brain imaging].

BACKGROUND: Knowledge of physiological mechanisms underlying time perception is still rather limited. The aim of our study was to search for a 'time accumulator', i.e. the part of the brain where information on the duration of time is stored. METHODS AND RESULTS: Nine healthy volunteers were given a time reproduction task during event-related fMRI. Subjects were instructed to retain the duration of the stimulus presented (presentation phase) and then to reproduce it by pressing a button (reproduction phase). Two different analyses were made: event-related (P < 0.05, FWR corrected) and parametric (BOLD signal increase/decrease during the presentation/reproduction phases correlated with the time intervals; P < 0.01, FDR corrected). When the event-related approach was employed, activation was noted bilaterally in the inferior prefrontal cortex (IPFC), supplementary motor area (SMA), precuneus and secondary visual cortex. On the right, there was activation in the dorsolateral prefrontal cortex (DLPFC), gyrus cinguli and inferior parietal lobule. On the left, the primary sensory-motor cortex was activated. While during the presentation phase the left DLPFC activity inversely correlated with the presented duration, a nearly identical area showed positive correlation in the reproduction phase. CONCLUSIONS: The event-related analysis did not allow distinguishing the process of time perception from many cognitive processes running simultaneously. In turn, the parametric analysis was based on visualizing regions, in which the signal correlated with the varying duration of the time interval provided the level of attention, decision-making and the processes of behavioral response planning and execution were constant. Moreover, the right and left DLPFC seem to play different roles in time perception. While the left one is functioning as a "time accumulator", the right one is rather involved in the recognition of previously perceived intervals.

Adult↗

Consciousness.

Consciousness offers a major challenge to the neurosciences. Even though consciousness is by definition subjective and private to the organism concerned, we consider it to be an intrinsic feature of biological processes in the brain. As such, it should be viewed in the Darwinian perspective of natural selection which implies that the conscious brain function does have survival value and cannot be a mere epiphenomenon. We attempted a neurophysiological approach by assessing perceptual processing of simple somatic sensory inputs in humans. We found that short-latency cortical potentials evoked by a target finger stimulus attended by the subject are strongly enhanced, thus manifesting a remarkable potentiation of the cognitive representations in primary parietal cortex. About 80 msec later, the dorsolateral prefrontal cortex discloses enhanced electrogeneses which we believe to reflect activation of somatic representations in 'working memory'. A functional 'binding' between these critical areas has been revealed by the transient and selective synchrony of 40 Hz oscillations recorded in the cortical areas of the parietal and prefrontal cortices. We consider these re-entrant interactions at 40 Hz to be an essential part of the conscious brain mechanisms that achieve the identification of an object (in this example, a finger) and the decision to release a motor behavioral response.

Brain↗

A pen-and-paper human analogue of a monkey prefrontal cortex activation task: spatial working memory in patients with schizophrenia.

In order to pursue the hypothesis that the dorsolateral prefrontal cortex is a source of cognitive deficit in schizophrenia, we developed an easily administered pen-and-paper human analogue of a visuospatial working memory task that in non-human primates activates the neurons of Walker area 46 (Goldman-Rakic, 1987). Compared to normal controls, schizophrenic patients made significantly greater errors in identifying where a visuospatial stimulus had been presented to them 30 and 60 seconds earlier, and these differences were significantly greater than in an immediate recall condition. These data suggest that schizophrenic patients have visuospatial working memory deficits that are sensitive to pen-and-paper versions of the tasks that activate the Walker area 46 in non-human primates. The availability of an easily administered test that may be associated with the functioning of the prefrontal cortex may enable more specific assessment of this brain region in humans.

Adolescent↗

Morphometric analysis of the prefrontal cortex in Huntington's disease.

We performed a morphometric analysis of cresyl violet-stained sections from the dorsolateral prefrontal cortex of 81 patients with Huntington's disease (HD) (grades 2, 3, and 4) and 23 age-matched normal controls. We counted large pyramidal neurons, small neurons, astrocytes, oligodendroglia, and microglia under the guidance of a specifically predefined set of morphologic criteria for each cell type and recorded the thickness of each cortical layer. Our results demonstrate a selective and progressive loss of a subset of the large pyramidal neurons in cortical layers III, V, and VI of HD patients, and a decrease in the thickness of the respective cortical laminae. A genetically determined, cell-autonomous degeneration of cortical neurons could constitute the primary pathologic process. However, the loss of only a fraction of pyramidal cells suggest a parallel, or an alternative, possibility of a retrograde degeneration of cortical neurons that project solely, or principally, to the site of primary degeneration in caudate nuclei.

Adult↗

Neuronal activity in primate dorsolateral and orbital prefrontal cortex during performance of a reward preference task.

An important function of the prefrontal cortex (PFC) is the control of goal-directed behaviour. This requires information as to whether actions were successful in obtaining desired outcomes such as rewards. While lesion studies implicate a particular PFC region, the orbitofrontal cortex (OFC), in reward processing, neurons encoding reward have been reported in both the OFC and the dorsolateral prefrontal cortex (DLPFC). To compare and contrast their roles, we recorded simultaneously from both areas while two rhesus monkeys (Macaca mulatta) performed a reward preference task. The monkeys had to choose between pictures associated with different amounts of a juice reward. Neuronal activity in both areas reflected the reward amount. However, neurons in the DLPFC encoded both the reward amount and the monkeys' forthcoming response, while neurons in the OFC more often encoded the reward amount alone. Further, reward selectivity arose more rapidly in the OFC than the DLPFC. These results are consistent with reward information entering the PFC via the OFC, where it is passed to the DLPFC and used to control behaviour.

Action Potentials↗

Coactivation of prefrontal cortex and inferior parietal cortex in working memory tasks revealed by 2DG functional mapping in the rhesus monkey.

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.

Animals↗

A distributed cortical network for auditory sensory memory in humans.

Auditory sensory memory is a critical first stage in auditory perception that permits listeners to integrate incoming acoustic information with stored representations of preceding auditory events. Here, we investigated the neural circuits of sensory memory using behavioral and electrophysiological measures of auditory processing in patients with unilateral brain damage to dorsolateral prefrontal cortex, posterior association cortex, or the hippocampus. We used a neurophysiological marker of an automatic component of sensory memory, the mismatch negativity (MMN), which can be recorded without overt attention. In comparison with control subjects, temporal-parietal patients had impaired auditory discrimination and reduced MMN amplitudes with both effects evident only following stimuli presented in the ear contralateral to the lesioned hemisphere. This suggests that auditory sensory memories are predominantly stored in auditory cortex contralateral to the ear of presentation. Dorsolateral prefrontal damage impaired performance and reduced MMNs elicited by deviant stimuli presented in either ear, implying that dorsolateral prefrontal cortices have a bilateral facilitatory effect on sensory memory storage. Hippocampal lesions did not affect either performance or electrophysiological measures. The results provide evidence of a temporal-prefrontal neocortical network critical for the transient storage of auditory stimuli.

Acoustic Stimulation↗

Neuronal representation of response-outcome in the primate prefrontal cortex.

For flexible control of behaviour, it is important to associate preceding behavioural response with its outcome. Since the dorsolateral prefrontal cortex (dlPFC) plays a major role in such control, it is likely that this area has a neuronal mechanism of coding response-outcome, such as reward/non-reward, based on the nature of the behavioural response made immediately before. To test this hypothesis, we examined neuronal activity in the dlPFC while monkeys performed a variant of the oculomotor delayed-response (ODR) task that had two reward conditions. In this task, the correct response was rewarded in half of the trials only and the subject could not expect the outcome (reward/non-reward). The response was followed by a fixation of 2 s (F2-period). We also employed a fixation (FIX) task that required monkeys to fixate on the peripheral target only, with two reward conditions that were similar to those in the ODR task. Post-response activity of a subset of dlPFC neurons was modulated by both the direction of the preceding response and its outcome. None of these neurons showed directional F2-period activity in the FIX task. These results suggest that a subset of dlPFC neurons represent response-outcome (i.e. reward/non-reward associated with directional saccade made immediately before).

Algorithms↗