MRI Studies Of Brain Function And Metabolism

CBDB的功能MRI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，这个小组的大部分努力都在继续研究神经精神病学任务中的认知激活，以及使用磁共振波谱成像（MRSI）对正常人、精神分裂症患者及其未受影响的兄弟姐妹、精神分裂症动物模型和帕金森病患者的脑代谢物[N乙酰天冬氨酸（NAA）、胆碱和肌酸]进行成像。在一项利用功能性磁共振成像（fMRI）研究精神分裂症患者前额叶皮质（PFC）功能的实验中，一组在n-back工作记忆（WM）任务参数化版本中表现相对较好的精神分裂症患者，在不同的WM负荷下，PFC fMRI激活的“健康”模式出现了三个基本偏差。第一个特征是尽管WM表现轻微受损（即生理效率低下），但PFC fMRI激活的幅度更大。第二，在两组中，行为WM表现与fMRI激活之间的显著相关性是相反的。第三，通过对PFC背侧n-乙酰天冬氨酸浓度（NAA）的测定来预测PFC异常fMRI反应的程度，这是一种使用质子磁共振波谱获得的神经元病理指标。患者PFC背侧NAA显著低于对照组，且PFC背侧NAA与不同WM负荷下PFC背侧（9-10/46区）的fMRI反应呈负相关；支持异常PFC反应是由异常PFC神经元引起的假设。虽然PFC神经元病理学似乎在一定程度上解释了有限的WM能力，但这些数据进一步表明，精神分裂症患者的背侧PFC功能损伤可能比腹侧PFC更大。2)前额叶效率似乎也是健康受试者的普遍特征。我们假设儿茶酚- o -甲基转移酶（COMT）基因型[COMT是多巴胺分解代谢途径中的一种酶，具有功能多态性（Val158Met）]会对工作记忆挑战期间PFC效率产生可测量的影响。一项正在进行的功能磁共振成像（fMRI）研究的初步结果表明，COMT基因型预测前额叶皮层对工作记忆任务的BOLD反应，val/val个体效率最低，其次是val/met和met/met。这些数据强调了最佳多巴胺在前额皮质调节工作记忆表现中的重要性。met等位基因的存在赋予前额皮质更高的效率。3)在一项双盲安慰剂对照研究中，右旋安非他明对各组表现和前额皮质激活的影响存在异质性。它只改善了那些基线工作记忆容量相对较低的受试者的表现，而在基线工作记忆容量相对较高的受试者中，它使他们的表现恶化。在表现恶化的受试者中，信号变化相对大于表现改善的受试者。这些数据揭示了单胺张力、工作记忆和前额叶功能相互作用的方式，此外，表明即使在正常受试者中，右旋安非他明的行为和神经生理效应也不是均匀的。右旋安非他明的这些异质效应可以用与右旋安非他明作用相互作用的遗传变异来解释。进一步的研究正在探索这一假设。4)除了经典的运动症状外，帕金森病患者还会出现认知缺陷，包括工作记忆容量下降。在工作记忆任务的表现没有任何显著差异的情况下，帕金森病患者在工作记忆的皮层区域（特别是背外侧前额叶皮层和顶叶区域）在关闭状态下比在打开状态下表现出更大程度的激活。这些结果表明，帕金森病的低多巴胺能状态与服务于工作记忆的皮层区域效率下降有关。此外，他们证明了多巴胺在提高这些皮质区域的效率方面的神经调节作用。5)一项正在进行的研究的初步分析显示，精神分裂症患者及其兄弟姐妹在感觉运动皮层的功能偏侧方面与正常对照者不同。患者及其兄弟姐妹的运动皮质偏侧性明显低于正常受试者。正在收集一个更大的数据库，以评估这种现象是否代表与精神分裂症相关的中间表型。5)在精神分裂症患者中，背外侧前额叶皮质的NAA测量选择性地预测了安非他明输注后11C氯pride纹状体位移和基底节区更高的D-2结合电位（通过I123IBZM SPECT测量）。相比之下，其他皮质区域和健康受试者的NAA测量没有显示出任何相关性。这些结果支持了精神分裂症中背外侧前额叶皮层神经元病理与皮层下多巴胺功能异常直接相关的假设。6)两组独立的精神分裂症患者在工作记忆任务中，DLPFC的NAA测量值与分布式工作记忆网络（包括背外侧前额叶、颞叶和下顶叶皮层）的激活密切相关。相比之下，其他皮质区域或比较对象的NAA没有显示出这些关系。这些发现直接暗示了DLPFC神经元群选择性地解释了精神分裂症中分布式工作记忆皮层网络的活动，并补充了DLPFC连接是该疾病病理生理学基础的其他证据。7)前额叶NAA测量值与负症状评分存在区域特异性负相关。任何其他区域NAA测量值与阴性症状或任何区域NAA测量值与阳性症状均未发现显著相关性。较低的前额叶NAA——通过推断更大的神经病理学——预示着这些患者更严重的阴性症状。这些数据首次直接证明了DLPFC完整性的神经元内测量与体内阴性症状之间的关系，并进一步证明了DLPFC参与与精神分裂症相关的阴性症状。8)一项评估抗精神病药物是否改变精神分裂症患者大脑NAA测量的研究结果表明，抗精神病药物选择性地增加了背外侧前额叶皮层的NAA测量。这些结果表明，抗精神病药物以特定区域的方式改变皮层神经元的功能。未来几年的研究将继续在神经精神任务中认知激活的大脑研究领域进行，并在有神经精神疾病（如精神分裂症、帕金森病等）风险的家庭成员中绘制脑功能和代谢图。这是可以想象的遗传风险标记，可能用于连锁研究，可以确定。

The functional MRI group of CBDB 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. The lion's share of the effort of this group over the last year has continued to be in studies of cognitive activation during neuropsychiatric tasks and imaging of brain metabolites [N acetyl aspartate (NAA), choline and creatine] using magnetic resonance spectroscopic imaging (MRSI) in normal individuals, patients with schizophrenia and their unaffected siblings, animal models of schizophrenia, and in patients with Parkinson's disease. Several interesting findings have emerged from these studies: 1) In an experiment investigating prefrontal cortex (PFC) function in schizophrenia using functional magnetic resonance imaging (fMRI), a group of patients with schizophrenia who performed relatively well on a parametric version of the n-back working memory (WM) task showed three fundamental deviations from the "healthy"pattern of PFC fMRI activation to varying WM load. The first characteristic was a greater magnitude of PFC fMRI activation in spite of slightly impaired WM performance (i.e., physiological inefficiency). The second was that the significant correlations between behavioral WM performance and fMRI activation was in opposite directions in the two groups. Third, the magnitude of the abnormal PFC fMRI response was predicted by an assay of n-acetyl aspartate concentrations (NAA) in dorsal PFC, a measure of neuronal pathology obtained using proton magnetic resonance spectroscopy. Patients had significantly lower dorsal PFC NAA than controls and dorsal PFC NAA inversely predicted the fMRI response in dorsal PFC (areas 9-10/46) to varying WM load; supporting the assumption that abnormal PFC responses arose from abnormal PFC neurons. While PFC neuronal pathology appears to explain in part limited WM capacity, these data further suggest that there may be greater functional impairment in dorsal than ventral PFC in schizophrenia.2) Prefrontal efficiency appears to be a general characteristic within healthy subjects as well. We hypothesized that Catechol-O-methyltransferanse (COMT) genotype [COMT is an enzyme in the catabolic pathway of dopamine and has a functional polymorphism (Val158Met)] would have a measurable impact on PFC efficiency during working memory challenge. Preliminary results from an ongoing fMRI study suggest that COMT genotypes predict the prefrontal cortical BOLD response to a working memory task with val/val individuals least efficient followed by val/met and met/met. These data emphasize the importance of optimal dopamine tone in prefrontal cortex for modulating working memory performance. The presence of the met allele confers greater prefrontal cortical efficiency. 3) In a double-blinded placebo controlled study, the effect of dextroamphetamine on performance and prefrontal cortical activation was heterogeneous across the group. It improved performance only in those subjects who had relatively low working memory capacity at baseline, whereas in subjects that had relatively high working memory capacity at baseline it worsened performance. In subjects whose performance deteriorated, signal change was relatively greater than in subjects who had an improvement in performance. These data shed light on the manner in which monoaminergic tone, working memory, and prefrontal function interact and, moreover, demonstrate that even in normal subjects the behavioral and neurophysiologic effects of dextroamphetamine are not homogeneous. These heterogeneic effects of dextroamphetamine may be explained by genetic variations that interact with the effects of dextroamphetamine. Further studies are in progress to explore this hypothesis. 4) In addition to the classic motor symptoms, patients with Parkinson's disease also suffer from cognitive deficits including decreased working memory capacity. In the absence of any significant difference in performance of a working memory task, patients with Parkinson's disease show a greater extent of activation in the cortical regions subserving working memory (particularly in the dorsolateral prefrontal cortex and parietal regions) during the off-state than during the on-state. These results suggest that the hypodopaminergic state of Parkinson's disease is associated with decreased efficiency of the cortical regions subserving working memory. Further, they demonstrate the neuromodulatory effects of dopamine in improving the efficiency of these cortical regions. 5) Preliminary analysis from an ongoing study revealed that both patients with schizophrenia and their siblings differed from normal control subjects in the functional lateralization of the sensorimotor cortex. Patients and their siblings had significantly reduced motor cortex laterality than normal subjects. A larger database is being collected to evaluate if this phenomenon represents an intermediate phenotype associated with schizophrenia. 5) In patients with schizophrenia, NAA measures in dorsolateral prefrontal cortex selectively predicted striatal displacement of 11C raclopride after amphetamine infusions and a higher D-2 binding potential in the basal ganglia (as measured by I123IBZM SPECT). In contrast, NAA measures in other cortical regions and in healthy subjects did not show any correlation. These results support the hypothesis that in schizophrenia neuronal pathology of dorsolateral prefrontal cortex is directly related to abnormal subcortical dopamine function.6) Measures of NAA in DLPFC strongly correlated with activation of the distributed working memory network, including dorsolateral prefrontal, temporal, and inferior parietal cortices during working memory tasks in two independent groups of patients with schizophrenia. In contrast, NAA in other cortical regions or in comparison subjects did not show these relationships. These findings directly implicate a population of DLPFC neurons as selectively accounting for the activity of the distributed working memory cortical network in schizophrenia and compliment other evidence that DLPFC connectivity is fundamental to the pathophysiology of the disorder. 7) A regionally specific negative correlation was found between prefrontal NAA measures and negative symptom ratings. No significant correlations were found for any other regional NAA measure and negative symptoms or for any regional NAA measure and positive symptoms. Lower prefrontal NAA -- and by inference greater neuronal pathology -- predicted more severe negative symptoms in these patients. These data represent the first direct demonstration of a relationship between an intraneuronal measure of DLPFC integrity and negative symptoms in vivo and represent further evidence for the involvement of DLPFC in negative symptoms associated with schizophrenia.8) Results from a study performed to assess whether antipsychotics modify brain NAA measures of patients with schizophrenia suggest that antipsychotic drugs increase NAA measures selectively in the dorsolateral prefrontal cortex. These results suggest that antipsychotics modify the function of cortical neurons in a region specific manner. Studies in the upcoming years will continue in the realm of brain studies of cognitive activation during neuropsychiatric tasks with pharmacological manipulations, and mapping brain function and metabolism in family members who are at risk for neuropsychiatric illnesses such as schizophrenia, Parkinson's disease, etc. It is conceivable that a genetic risk marker, possibly of use in linkage studies, could be identified.