The functional Magnetic Resonance Imaging (fMRI) group of the Clinical Brain Disorders Branch consists of multidisciplinary specialists with expertise in neurology, psychiatry, physics, biology, and MRI techniques. This group pursues a variety of research agendas involving study of brain function and metabolism in normal healthy controls and patients with neuropsychiatric disorders. Over the last year the group has continued to make more strides in the field of ?Imaging Genomics?, a paradigm in brain research using clinical genetics and neuroimaging, to explore the basic molecular biology and genetics of human information processing in normal health and as related to major psychiatric illnesses. Interesting findings have emerged from these studies: 1) In a study aimed at tackling the problem of ill-defined phenotypes, we examined the contribution of several potentially functional variants in a gene (COMT) and haplotypes to the risk of schizophrenia. Imaging genetics allowed us to evaluate the functional impact of these haplotypes on a neural system-level intermediate phenotype in healthy controls during a working memory task. Our data shows that complex genetic variation can be validated functionally in humans and linked to prefrontal inefficiency. In a recent review looking at subtle gene effects which may be invisible through traditional clinical and psychometric measures, imaging-genetics has elucidated the contribution of COMT, GRM3, G72, DISC1, and BDNF to cognitive deficits in schizophrenia. These data suggest that there are common mechanisms underlying susceptibility for schizophrenia associated with complex genetic variations. Our study which explored the effects a genetic variation in the brain-derived necrotrophic factor (BDNF) gene on hippocampal gray matter volume found bilateral reductions of hippocampal gray matter volumes in methionine carriers (met) compared with valine carriers (val) subjects. The met-BDNF carriers exhibited additional reduced gray matter volumes predominately in the lateral portion of the frontal lobes. These findings are consistent with the cellular and clinical effects of the BDNF val to met polymorphism and suggest that this change of an amino acid also affects the anatomy of the hippocampus and prefrontal cortex (PFC), identifying a genetic mechanism of variation in brain form and structure related to learning and memory. 2) In another study, which explored the effects of a functional polymorphism in a regulatory region of the human serotonin transporter gene (SLC6A4), we found that s-carriers (serotonin short protein-carriers), had significantly reduced bilateral gray matter volumes in both the amygdala and the subgenual anterior cingulate. We also found that the serotonin s-allele effect on subgenual cingulate volume is dramatically reduced in met-BDNF allele carriers in comparison to val/val-BDNF carriers. Together, these results suggest that the val to met BDNF polymorphism may be a modifying genetic factor for depression, because it affects development and plasticity of critical brain systems involving serotonin related to the experience of negative mood and may lead, together with abnormal serotonin function (s-allele), to an anatomical substrate reflecting an increased vulnerability for depression. The group also performed studies in patients with schizophrenia to explore the integrity of brain structures underlying cognitive function and affective behavior. A study explored the phenomenon of low activity and hyperactivity of the dorsolateral prefrontal cortex in schizophrenia. The groups were subdivided on the basis of performance on the working memory task into high or low performing subgroups. Results show that in high-performing schizophrenic patients there were locales of greater prefrontal cortex activation as well as locales of less activation. While only locales of low prefrontal cortex activation were found in the low performing patients. These findings suggest that patients with schizophrenia whose performance on the N-back working memory task is similar to that of healthy comparison subjects, but they use greater prefrontal cortex resources and achieve lower accuracy (i.e., inefficiency). Other patients with schizophrenia fail to sustain the prefrontal cortex network that processes the information, achieving even lower accuracy as a result. These findings add to other evidence that abnormalities of prefrontal cortical function in schizophrenia are not reducible to simply too much or too little activity but, rather, reflect a compromised neural strategy for handling information mediated by the dorsolateral prefrontal cortex. The group examined the effects of genetic variations on cognitive performance. One study found that healthy subjects with the COMT met/met and the DAT 10 repeat alleles had more focused working memory response than those with COMT val and DAT 9 repeat alleles. This suggests, for the first time, an additive genetic effect of two dopamine regulating genes. As previously described, genetic variations of COMT impacts the level of PF dopamine (DA). Dopamine plays a critical role in determining the level of PF signal to noise during information processing. In our study, we found that genetic variation in the COMT gene may affect the efficiency by which DA is inactivated resulting in diminished BOLD FMRI response and increased noise in Val carriers. We also studied the impact of a genetic variation in MAOA and found that the low level variant increased risk for violent behavior and predicted structural and functional changes in the PF-amygdala-hippocampal system for emotional regulation. The group has also been exploring the effects of neuropharmacological manipulation on brain information processing. Evidence suggests that catechol-O-methyl transferase (COMT) may play a unique role in regulating dopamine (DA) flux in the PFC, the group explored if Tolcapone (TOL), a COMT inhibitor can improve efficiency in PFC function. Preliminary results from this study suggest that TOL does enhance the efficiency of PF cortical information processing, and add evidence that COMT plays a significant role in modulating DA tone in the PFC. In another study, using event-related fMRI, we examined the effects of oral dextroamphetamine treatment on brain activity and during active mental processing. We found that by enhancing tonic over phasic activation, dextroamphetamine treatment ?equalized? levels of ventral striatal activity and positive arousal during anticipation of both gain and loss. These findings suggest that therapeutic effects of dextroamphetamine on incentive processing may involve reducing the difference between anticipation of gains and losses. The group also pursued studies to explore the neurophysiological correlates of altered brain function associated with senescence. In a study aimed at exploring the neurophysiological correlates of reduced working memory capacity with age we found that within working memory capacity (as in 1-Back) when the elderly performed as well as the younger subjects, they showed greater prefrontal cortical (BA 9) activity bilaterally. At higher working memory loads (as in 2-Back and 3-Back), however, when they performed worse then the younger subjects, the elderly showed relatively reduced activity in these prefrontal regions. These data suggest that within capacity, compensatory mechanisms such as additional prefrontal cortical activity are called upon to maintain proficiency in task performance. As cognitive demand increases, however, they are pushed beyond a threshold beyond which any compensation can be made probably from a failure to engage such compensatory mechanisms. This leads to a decline in performance. Studies are being pursued to explore the effect of aging on other brain systems, and the role of genetics on these changes.
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