MRI Studies Of Brain Function And Metabolism

临床脑疾患科的功能磁共振成像（fMRI）小组由神经病学、精神病学、物理学、生物学和MRI技术的多学科专家组成。该组从事各种研究议程，包括正常健康对照和神经精神疾病患者的脑功能和代谢研究。在过去的一年里，该集团继续在？成像基因组学?运用临床遗传学和神经影像学的脑研究范式，探索正常健康和与主要精神疾病相关的人类信息处理的基本分子生物学和遗传学。在一项旨在探索脑源性坏死因子（BDNF）基因遗传变异对海马灰质体积影响的研究中，我们发现蛋氨酸携带者（met-BDNF）与缬氨酸携带者（val/val-BDNF）受试者相比，双侧海马灰质体积减少。met-BDNF携带者也表现出额外的灰质体积减少，主要是在额叶的外侧部分。这些发现与BDNF缬氨酸对蛋氨酸多态性的细胞和临床影响一致，并表明这种氨基酸的变化也影响海马和前额叶皮质（PFC）的解剖结构，从而确定了与学习和记忆相关的大脑形态和结构变异的遗传机制。2)在另一项研究中，我们探索了人类5 -羟色胺转运基因（SLC6A4）调控区域功能多态性的影响，我们发现s-载体（5 -羟色胺短蛋白载体）显著减少了杏仁核和亚属前扣带的双侧灰质体积。我们还发现，在met-BDNF等位基因携带者中，与val/val- bdnf携带者相比，5 -羟色胺s等位基因对亚属扣带体积的影响显著降低。总之，这些结果表明，缬氨酸对蛋氨酸BDNF多态性可能是抑郁症的一个修饰性遗传因素，因为它影响涉及与消极情绪体验相关的血清素的关键大脑系统的发育和可塑性，并可能与血清素功能异常（s等位基因）一起导致解剖学基础反映出抑郁症易感性的增加。

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 exploring the effects a genetic variation in the brain-derived necrotrophic factor (BDNF) gene on hippocampal gray matter volume we found bilateral reductions of hippocampal gray matter volumes in methionine carriers (met-BDNF) compared with valine carriers (val/val-BDNF) subjects. The met-BDNF carriers also 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 valine to methionine 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, exploring 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 valine to methionine 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. In one study aimed at exploring 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 schizophrenic 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 has also been exploring the effects of neuropharmacological manipulation on brain information pproocessing. Based on recent evidence which suggests that catechol-O-methyl transferase (COMT) may play a unique role in regulating dopamine (DA) flux in the PFC, the group has explored if Tolcapone (TOL), a COMT inhibitor which penetrates the blood brain barrier can improve efficiency in PFC function. Preliminary results from this study suggest that TOL does enhance the efficiency of prefrontal cortical information processing, and add to evidence that COMT plays a significant role in modulating DA tone in the PFC. The impact of COMT genotype on these effects is also being explored. 2) In another study, using event-related fMRI, we examined at the effects of oral dextroamphetamine treatment on brain activity and during active mental processing. We found that presumably 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.