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Functional MR imaging of the prefrontal cortex: specific activation in a working memory task.

Functional magnetic resonance imaging was used to identify cortical regions activated by a working memory task involving letter detection. Twenty four normal subjects were scanned with a conventional 1.5-T magnet while performing one of two tasks: In the activation task, subjects responded by pressing a button whenever any presented letter was the same as the second last in the sequence. In the control condition, subjects had to respond to a single predefined letter without memory update requirements. The activation task and the control condition were identical with regard to perceptual input and motor output. They were different only regarding the task demand. Movement artifacts were minimized in a two way strategy and eight subjects were excluded from further analysis. Functional MR data from the remaining 16 subjects were analyzed on the basis of anatomical regions-of-interest which were manually defined in each subject. The engagement of working memory produced significant activation in the dorsolateral prefrontal cortex (Brodmann's areas 9, 10, 46, and 47) in both hemispheres. Results demonstrate the applicability of the paradigm within a clinical MRI setup and corroborate previous findings of non-lateralized dorsolateral prefrontal activation during continuous context updating and active maintenance.

Adult↗

The use of repetitive transcranial magnetic stimulation (rTMS) in chronic neuropathic pain.

Chronic motor cortex stimulation using implanted epidural stimulation was proposed to treat chronic, drug-resistant neuropathic pain. Various studies showed that repetitive transcranial magnetic stimulation (rTMS) applied over the motor cortex could also relieve neuropathic pain, at least partially and transiently. Controlled rTMS studies with other cortical targets, such as the dorsolateral prefrontal cortex, are in waiting. The mechanisms of action of rTMS on chronic pain are mostly unknown. The changes induced by rTMS in neural activities may occur at the stimulated cortical site as well as in remote structures along functional anatomical connections. Compared to chronic implanted procedure, the main limitation of rTMS application is the short duration of clinical effects. Repeated daily rTMS sessions have proved some efficacy to induce long-lasting pain relief that could have therapeutic potential. However, rTMS-induced analgesia varies with the site and parameters of stimulation, in particular the stimulus rate. The efficacious rTMS parameters could differ from those used in chronic epidural stimulation. Differences in the pattern of the current fields respectively induced in the brain by these two techniques might explain this finding. Actually, stimulation parameters remain to be optimised and clinical efficacy to be confirmed by multicentre randomised trials, before considering rTMS as therapeutic tool for patients with chronic pain in neurological practice.

Chronic Disease↗

Expression of Catenin family members CTNNA1, CTNNA2, CTNNB1 and JUP in the primate prefrontal cortex and hippocampus.

Members of the catenin family of proteins are thought to play a major role in the folding and lamination of the cerebral cortex. We have used in situ hybridization to determine the cellular expression patterns of four members of this family, Alpha-E-, Alpha-N-, Beta-, and Gamma-catenins (CTNNA1, CTNNA2, CTNNB1, and JUP respectively) in the adult primate dorsolateral prefrontal cortex (DLPFC) and hippocampus. CTNNA2, CTNNB1, and JUP mRNAs were detected in all layers of the DLPFC and in all neuronal subregions of the hippocampal formation, however CTNNA1 mRNA, coding for an 'epithelial' specific catenin, was not detected in any region of the cortex or hippocampus. CTNNA2, a 'neuronal-specific' catenin, and CTNNB1 mRNAs were abundant in both DLPFC and hippocampus, with a distinct neuronal localization. CTNNA2 mRNA was concentrated in both granular/stellate cells and large pyramidal cell bodies, while CTNNB1 expression was more strongly associated with granular cell bodies throughout the DLPFC, with expression in pyramidal cells confined mainly to cortical Layers III and VI. CTNNA2 and CTNNB1 mRNAs were also abundant in the granule cells of the dentate gyrus and pyramidal cells of Ammon's horn, apparently co-expressed in the same neurons. JUP mRNA was rather diffusely localized in the DLPFC without the distinct laminar patterns seen for CTNNA2 and CTNNB1 but was distinctly localized in the granule cells of the dentate gyrus and pyramidal cells of Ammon's horn. These studies demonstrate a distinct neuronal pattern of gene expression for catenin family members in primate brain structures characterized by high degrees of folding and strong lamination. The high level expression of these transcripts supports the notion of a major role for catenins even in the adult brain. Such an understanding is also important in view of the multiple interactions that catenins have with many other proteins in the adult and ageing brain. This may also have implications for understanding the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, as well as emerging neuronal stem cell therapies.

Animals↗

High-level expression of Dok-1 in neurons of the primate prefrontal cortex and hippocampus.

The docking protein p62Dok-1 (Dok-1) has a central role in cell signaling mediated by a wide range of protein tyrosine kinases, including intrinsic membrane kinases, such as the insulin-like growth factor-1 (IGF-1) receptor. To elucidate potential IGF signaling mechanisms, we used DNA array technology to investigate novel kinase targets expressed in the primate dorsolateral prefrontal cortex (DLPFC). Dok-1 transcripts were among the most abundant found in this structure. Because Dok-1 expression has not been characterized in brain, we evaluated its expression pattern using immunoblotting, in situ hybridization, and immunohistochemistry in the rhesus monkey prefrontal cortex and hippocampal formation. Dok-1 antibodies identified a 62-kDa band in lysates from the DLPFC, consistent with the known size for Dok-1. In situ hybridization showed that Dok-1 mRNA was expressed in all layers of the DLPFC and in all neuronal subregions of the hippocampal formation. Immunohistochemical analysis showed Dok-1 immunoreactivity concentrated in pyramidal neurons of cortical layers IV-V and throughout Ammon's horn and in granule neurons of the dentate gyrus. Dok-1 expression was also identified in endothelial cells of cerebral blood vessels. These expression patterns are very similar to those of the IGF-1 receptor and suggest that Dok-1 could be among the downstream targets of IGF signaling in areas of the primate brain involved in learning and memory.

Animals↗

Antisaccade deficit after anterior cingulate cortex resection.

Suppression of unwanted reflexive saccades is a crucial process allowing to sustain voluntary fixation, when required. This inhibition process, which is mainly controlled by the dorsolateral prefrontal cortex, may also involve other cortical and subcortical structures. We prospectively studied the effect of frontal cortical resections involving adjacent regions to the anterior cingulate cortex on the ability to inhibit reflexive saccades. This lesion study included six patients undergoing resection of frontal low grade gliomas, studied prior and after surgery with electro-oculography, using the antisaccade paradigm. Lesions were normalized and mapped in Talairach space allowing to detail the structures whose lesions were associated with antisaccade deficits. In three of the six patients significant early post-operative antisaccade errors were associated with resection of a common critical region, mainly involving the posterior part of the anterior cingulate cortex. This same region was spared in the three remaining patients with no antisaccade deficit, suggesting that the anterior cingulate cortex, known as the cingulate eye field, could play a role in suppression of unwanted saccades.

Adult↗

Reduced glial and neuronal packing density in the orbitofrontal cortex in alcohol dependence and its relationship with suicide and duration of alcohol dependence.

BACKGROUND: Reduced metabolism, blood flow, and tissue volume have been detected in the dorsolateral prefrontal cortex (dlPFC) of neurologically intact alcoholic subjects and these deficits are accompanied by lower density of neurons and glial cells. Another prefrontal region, the orbitofrontal cortex (ORB), functionally and structurally differentiated from the dlPFC, and heavily involved in decision-making processes, also shows functional alterations in alcoholic subjects. However, it is unknown whether changes in the packing density of neurons or glial cells also occur in the ORB and whether that density may be related to the increased suicide probability of alcoholic subjects or to the duration of alcohol dependence. METHODS: The present study used a 3-dimensional cell-counting method in postmortem brain tissue to determine the packing density of neurons and glial cells in the ORB (area 47) of 15 subjects with alcohol dependence (8 suicides, 7 nonsuicides) and 8 normal controls and to determine whether cell density is correlated with suicide and duration of alcohol dependence. RESULTS: There was a significantly lower density of both neurons (by 27%) and glial cells (by 25%) in the ORB of alcoholic subjects compared with controls. Packing density of either neurons or glial cells was not significantly different in alcoholic suicides compared with alcoholic nonsuicides. Age was not correlated with neuronal or glial density in either group. However, the duration of alcohol dependence and the ratio of that duration to the length of life span were significantly and negatively correlated to the overall density of neurons. CONCLUSION: The present results indicate that alcohol dependence is associated with a decrease in the packing density of neurons and glia in the ORB and that the reduction in neuronal but not glial density progresses with the duration of alcohol dependence.

Adult↗

Genes and memory: the neuroanatomical correlates of emotional memory in monozygotic twin discordant for schizophrenia.

BACKGROUND: Brain morphology and physiological measures in schizophrenia have yielded inconsistent results. This may be due in part to difficulties in ascertaining precisely to what degree each measure deviates from its genetically and environmentally determined potential level. We attempted to surmount this problem in a paradigm involving monozygotic twin pair discordant for schizophrenia. In this paradigm, the difference score and reaction time between the unaffected member and affected member of a twin pair should represent the degree of pathologic involvement irrespective of actual level. METHOD: We investigated, using fMRI, the neural substrate underlying encoding and retrieval of aversive and neutral IAPS pictures. RESULTS: An ANOVA on reaction time (RT) between schizophrenia patient (J) and normal sister (D) significant difference, (F = 5.2, p < or = .02) for J had less RT than D. Conversely, the ANOVA for the correct pictures retrieved was insignificant (F = 1.8, p < or = .2). When the brain activity associated with the encoding and retrieval of the aversive pictures was subtracted (J-D and D-J) from that associated with the neutral ones, significant loci of activation were found. During encoding: for J-D the right fusiform gyrus was significantly activated (p < .0001) and for D-J the orbitofrontal cortex was significantly activated (p < .05). During retrieval: for J-D the right anterior cingulate (p < .0001) was activated and the dorsolateral prefrontal cortex (p < .002). For D-J only the cerebellum showed activation (p < .0001). CONCLUSION: Results indicated subtle attenuations in some aspects of memory, thus providing another evidence for cognitive markers of a genetic component in schizophrenia. New approaches in neuropsychiatry-based on genetic methodologies should further define the cerebral physiology responsible for schizophrenia.

Adult↗

Increased prefrontal and hippocampal glutamate concentration in schizophrenia: evidence from a magnetic resonance spectroscopy study.

BACKGROUND: Glutamatergic dysfunction has been implicated in the pathophysiology of schizophrenia. However, so far there is limited direct evidence of altered in vivo glutamate concentrations in the brains of patients with schizophrenia. To test the hypothesis that altered glutamatergic neurotransmission might play a role in the pathogenesis of schizophrenia, we measured glutamate and glutamine concentrations in the prefrontal cortex and the hippocampus of patients with chronic schizophrenia using high-field magnetic resonance spectroscopy. METHODS: Twenty-one patients with schizophrenia and 32 healthy volunteers were examined clinically and by means of short echo time single voxel magnetic resonance spectroscopy of the dorsolateral prefrontal cortex and the hippocampus. Absolute concentrations of neurometabolites were calculated. RESULTS: Absolute concentrations of glutamate were significantly higher in the prefrontal cortex and the hippocampus in the patient group. Factorial analysis of variance (ANOVA) revealed no significant interactions between duration of schizophrenia, number of hospitalizations, or type of antipsychotic medication and glutamate concentrations. Increased prefrontal glutamate concentrations were associated with poorer global mental functioning. CONCLUSIONS: This is the first study that reports increased levels of glutamate in prefrontal and limbic areas in patients with schizophrenia. Our data support the hypothesis of glutamatergic dysfunction in schizophrenia.

Adult↗

The appreciation of wine by sommeliers: a functional magnetic resonance study of sensory integration.

We set out to investigate how the expertise of a sommelier is embodied in neural circuitry by comparing brain activity elicited by wine tasting with that found in naive drinkers of wine. We used fMRI to study 7 sommeliers and 7 age- and sex-matched control subjects to test the hypothesis that any difference in brain activity would reflect a learned ability to integrate information from gustatory and olfactory senses with past experience. A group analysis showed activation of a cerebral network involving the left insula and adjoining orbito-frontal cortex in sommeliers. Both these areas have been implicated in gustatory/olfactory integration in primates. In addition, activation was found bilaterally in the dorsolateral prefrontal cortex, which is implicated in high-level cognitive processes such as working memory and selection of behavioral strategies. Naive individuals activated the primary gustatory cortex and brain areas, including the amygdala, implicated in emotional processing.

Adult↗

Glial fibrillary acidic protein immunoreactivity in the prefrontal cortex distinguishes younger from older adults in major depressive disorder.

BACKGROUND: Recent postmortem studies in major depressive disorder (MDD) provide evidence for a reduction in the packing density and number of glial cells in different regions of the prefrontal cortex; however, the specific types of glia involved in those morphologic changes are unknown. METHODS: The territory occupied by the astroglial marker glial fibrillary acidic protein (GFAP) was measured as an areal fraction in cortical layers III, IV, and V in sections from the dorsolateral prefrontal cortex (dlPFC) of MDD and control subjects. In addition, the packing density of GFAP-immunoreactive somata was measured by a direct three-dimensional cell counting method. RESULTS: The mean areal fraction and packing density of GFAP-immunoreactive astrocytes in the dlPFC of MDD subjects were not significantly different from those in control subjects; however, in MDD there was a significant strong positive correlation between age and GFAP immunoreactivity. When the MDD group was divided into younger (30-45 years old) and older (46-86) adults, in the five younger MDD adults, areal fraction and packing density were smaller than the smallest values of the control subjects. In contrast, among older MDD subjects these parameters tended to be greater than in the older control subjects. CONCLUSIONS: The present results suggest that the GFAP-immunoreactive astroglia is differentially involved in the pathology of MDD in younger compared with older adults.

Adult↗

Contributions from brain imaging to the elucidation of pathophysiology of bipolar disorder.

Over the past two decades, brain-imaging studies have examined the mechanisms possibly involved in the pathophysiology of bipolar and unipolar mood disorders. The available findings suggest subtle anatomical changes in sub-regions of the prefrontal cortex, medial temporal lobe and cerebellum, and functional abnormalities in brain circuits inter-connecting these same brain regions and the striatum in patients suffering from bipolar disorder. 1H magnetic resonance spectroscopy (MRS) studies reported decreased N-acetyl aspartate (NAA) levels in the dorsolateral prefrontal cortex, and 31P-MRS studies found abnormalities in membrane phospholipids in frontal and temporal regions in bipolar individuals. Few studies have utilized in-vivo receptor imaging to study bipolar patients. Even though preliminary findings from cross-sectional studies indicate anatomical, neurochemical, and functional brain abnormalities in bipolar patients in key regions involved in mood regulation, the relationship of such abnormalities with illness phase and their clinical relevance needs further investigation. The potential for utilization of brain-imaging tools to elucidate the pathophysiology of bipolar disorder is still largely unrealized, and it is anticipated that important new developments in this area will come about over the next years and beyond.

Bipolar Disorder↗

Do we still believe in the dopamine hypothesis? New data bring new evidence.

Schizophrenia is characterized by positive symptoms, negative symptoms and cognitive impairment. The dopamine hypothesis of schizophrenia postulates that an excess of dopamine subcortically is associated with the positive symptoms. At the same time, the negative and cognitive symptoms of schizophrenia are thought to arise from a deficit of dopamine in the cortex. Evidence for the co-existence of subcortical dopamine excess and cortical dopamine deficit in the schizophrenic brain is presented. Neuroreceptor-imaging techniques, such as SPECT and PET, have been used to provide that evidence. After amphetamine challenge (to stimulate dopamine release), dopamine transmission was substantially increased in the brains of schizophrenic subjects compared with healthy controls. In addition, amphetamine challenge was associated with an increase in positive symptoms of schizophrenia. Furthermore, acute dopamine depletion studies indicated that there was an increased occupancy of D2 receptors by dopamine at baseline in schizophrenia in comparison with healthy controls. This is consistent with the notion of hyperstimulation of D2 receptors in schizophrenia. In the cortex, dopamine type-1 (D1) receptors were found to be up-regulated in patients with schizophrenia compared to controls; in the dorsolateral prefrontal cortex, a brain region involved in working memory, this increase correlated with a poor performance on the n-back task. The up-regulation of D1 receptors may represent a compensatory effect of the dopamine deficit in the cortex. These findings provide evidence for a corticalsubcortical imbalance in the schizophrenic brain.

Brain↗

Prediction of immediate and future rewards differentially recruits cortico-basal ganglia loops.

Evaluation of both immediate and future outcomes of one's actions is a critical requirement for intelligent behavior. Using functional magnetic resonance imaging (fMRI), we investigated brain mechanisms for reward prediction at different time scales in a Markov decision task. When human subjects learned actions on the basis of immediate rewards, significant activity was seen in the lateral orbitofrontal cortex and the striatum. When subjects learned to act in order to obtain large future rewards while incurring small immediate losses, the dorsolateral prefrontal cortex, inferior parietal cortex, dorsal raphe nucleus and cerebellum were also activated. Computational model-based regression analysis using the predicted future rewards and prediction errors estimated from subjects' performance data revealed graded maps of time scale within the insula and the striatum: ventroanterior regions were involved in predicting immediate rewards and dorsoposterior regions were involved in predicting future rewards. These results suggest differential involvement of the cortico-basal ganglia loops in reward prediction at different time scales.

Adult↗

Modulation of prefrontal cortex activity by information toward a decision rule.

We used fMRI to investigate how the information content of a stimulus influences activity in brain systems that support decision making. Subjects learned decision rules that were based upon the color, shape, or fill pattern of a series of stimuli. Each stimulus was classified by its information content, defined formally by the decision rules it excluded. While activity in dorsolateral prefrontal cortex (dlPFC) increased with increasing stimulus information, activity in the striatum did not. In contrast, within both the striatum and dlPFC, stimuli consistent with the rule evoked greater activity than stimuli inconsistent with the rule. This dissociation indicates that dlPFC supports modification of sets of stimulus-response contingencies while the striatum supports stimulus-specific learning.

Adult↗

PET study of the human foveal fixation system.

Positron emission tomography (PET) was used to investigate the functional anatomy of the foveal fixation system in 10 subjects scanned under three different conditions: at rest (REST), during the fixation of a central point (FIX), and while fixating the same foveal target during the presentation of peripheral visual distractors (DIS). Compared with the REST condition, both FIX and DIS tasks activated a common set of cortical areas. First, in addition to the involvement of the occipital visual cortex, both the frontal eye field (FEF) and the intraparietal sulcus (IPS) were bilaterally activated. Right frontal activation was also found in the dorsolateral prefrontal cortex, the inferior part of the precentral gyrus, and the inferior frontal gyrus. These results suggest that both FEF and IPS may constitute the main cortical regions subserving bilaterally the foveal fixation system in humans. The remaining right frontal activations may be considered as part of the anterior attentional network, supporting a role for the right frontal lobe in the allocation of the attentional mechanisms. Compared with the FIX condition, the DIS task also revealed the perceptual and cognitive processes related to the presence of peripheral visual distractors during foveal fixation. In addition to a bilateral activation of the V5/MT motion-sensitive area, a right FEF-IPS network was activated which may correspond to the engagement of the visuospatial attention. Finally, normalized regional cerebral blood flow (NrCBF) decreases were also observed during both DIS and FIX condition performance. Such NrCBF decreases were centered in the superior and middle temporal gyri, the prefrontal cortex, and the precuneus and the posterior retrosplenial part of the cingulate gyrus.

Adult↗

Behavioral conflict, anterior cingulate cortex, and experiment duration: implications of diverging data.

We investigated the relationship between behavioral measures of conflict and the degree of activity in the anterior cingulate cortex (ACC). We reanalyzed an existing data set that employed the Stroop task using functional magnetic resonance imaging [Milham et al., Brain Cogn 2002;49:277-296]. Although we found no changes in the behavioral measures of conflict from the first to the second half of task performance, we found a reliable reduction in the activity of the anterior cingulate cortex. This result suggests the lack of a strong relationship between behavioral measurements of conflict and anterior cingulate activity. A concomitant increase in dorsolateral prefrontal cortex activity was also found, which may reflect a tradeoff in the neural substrates involved in supporting conflict resolution, detection, or monitoring processes. A second analysis of the data revealed that the duration of an experiment can dramatically affect interpretations of the results, including the roles in which particular regions are thought to play in cognition. These results are discussed in relation to current conceptions of ACC's role in attentional control. In addition, we discuss the implication of our results with current conceptions of conflict and of its instantiation in the brain. Hum. Brain Mapping 21:96-105, 2004.

Adult↗

Functional neuroanatomy of human rapid-eye-movement sleep and dreaming.

Rapid-eye-movement (REM) sleep is associated with intense neuronal activity, ocular saccades, muscular atonia and dreaming. The function of REM sleep remains elusive and its neural correlates have not been characterized precisely in man. Here we use positron emission tomography and statistical parametric mapping to study the brain state associated with REM sleep in humans. We report a group study of seven subjects who maintained steady REM sleep during brain scanning and recalled dreams upon awakening. The results show that regional cerebral blood flow is positively correlated with REM sleep in pontine tegmentum, left thalamus, both amygdaloid complexes, anterior cingulate cortex and right parietal operculum. Negative correlations between regional cerebral blood flow and REM sleep are observed bilaterally, in a vast area of dorsolateral prefrontal cortex, in parietal cortex (supramarginal gyrus) as well as in posterior cingulate cortex and precuneus. Given the role of the amygdaloid complexes in the acquisition of emotionally influenced memories, the pattern of activation in the amygdala and the cortical areas provides a biological basis for the processing of some types of memory during REM sleep.

Adult↗

Dynamics of oscillatory activity during auditory decision making.

Perceptual decision making requires the comparison and integration of sensory evidence to generate a behavioral response. We used magnetoencephalography to investigate the temporal dynamics of decision making during an auditory task that required forced-choice decisions about whether a pair of syllables S1 and S2 differed either in their acoustic patterns or in the perceived position of their sound sources. Conditions with easy and difficult decisions were created by varying the similarity of S1 and S2. Statistical probability mapping showed enhanced gamma-band activity (GBA) over posterior parietal cortex for spatial and over left inferior frontal cortex for pattern changes (at approximately 120 to 220 ms after S2 onset). Activations were stronger for easy than difficult decisions. GBA over dorsolateral prefrontal cortex was more pronounced at approximately 280 to 430 ms for easy than difficult decisions regardless of type of change, possibly reflecting decision-relevant networks that integrate information from higher sensory areas representing the perceptual alternatives. Sensorimotor beta desynchronization as a measure of motor preparation peaked at approximately 460 ms for easy and at approximately 520 ms for difficult decisions, thus reflecting the reaction time difference between both conditions. In summary, the analysis of oscillatory activity in magnetoencephalogram served to elucidate the temporal dynamics of perceptual decision making in humans.

Adult↗