Imaging of Neuropsychiatric Disorders with Developmental and Genetic Mechanisms

具有发育和遗传机制的神经精神疾病的影像学

• 批准号: 7969316
• 负责人: Karen FAITH Berman
• 金额: $ 62.36万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7969316
• 关键词: Affect; Affective; Alleles; Antipsychotic Agents; Anxiety; Architecture; Autopsy; Back; Brain; Brain Diseases; Brain region; Catechol O-Methyltransferase; Cerebrovascular Circulation; Clinical; Clinical Research; Cognition; Cognition Disorders; Cognitive; Complex; Control Groups; Corpus striatum structure; Data; Data Set; Databases; Disease; Dopamine; Functional Magnetic Resonance Imaging; Functional disorder; Genes; Genetic; Genetic Polymorphism; Genotype; Hippocampus (Brain); Image; Impairment; Individual; Inpatients; Intramural Research Program; Link; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measurement; Measures; Methods; Methyltransferase Gene; N-acetylaspartate; National Institute of Mental Health; Nature; Neurobehavioral Manifestations; Neurobiology; Neurons; Neurotransmitters; Noise; Oxygen; Pain; Parkinson Disease; Patients; Pattern; Performance; Pharmaceutical Preparations; Phenotype; Physiological; Play; Positron-Emission Tomography; Prefrontal Cortex; Process; Protocols documentation; Psychotic Disorders; Recruitment Activity; Regulation; Research; Rest; Rewards; Risk; Role; Scanning; Schizophrenia; Short-Term Memory; Signal Pathway; Signal Transduction; Sorting - Cell Movement; Structure; Susceptibility Gene; System; Testing; Time; Water; Wisconsin; Work; abstracting; base; cohort; developmental genetics; dopaminergic neuron; drug withdrawal; genetic risk factor; imaging modality; meetings; neural circuit; neurochemistry; neuroimaging; neuropsychiatry; neurotransmission; presynaptic; programs; radioligand; receptor; relating to nervous system; research facility; response; theories; trait; uptake; ward

Our group used functional neuroimaging to determine local neuronal activity in patients with schizophrenia and other neuropsychiatric disorders during performance of working memory and abstract reasoning tasks as well as during performance of matched sensorimotor control tests and other contrast tasks. By using a 2-back version of an N-back continuous working memory task, we have re-confirmed previous findings derived from the Wisconsin Card Sorting Test (WCST) of dysfunction of prefrontal cortex. As in previous studies, the aberrant activation pattern appears to occur even in patients who perform relatively well on the task. We also examined changes in cognitive activation across several time points during a medication-free period in individual patients. This determined the relationship between the physiological changes and concomitant changes in symptoms and cognitive performance. Further analyses of the time course of these changes are ongoing. We have also explored the functional connectivity among various nodes of the working memory system. This has shown that more than half the intergroup variance (across controls and patients) was explained by a single pattern showing inferotemporal-hippocampal-cereballar loading for patients versus dorsolateral-prefrontal-cingulate activity for controls. Expression of this pattern perfectly separated all patient scans from the control group, a finding prospectively validated in two new data sets, suggesting that it may be a trait marker. We have further demonstrated that an important component of this pattern lies in specific abnormality in the functional relationship between the dorsolateral prefrontal cortex (DLPFC) and the hippocampus. We have also shown that even when patients with schizophrenia are compared with young normal subjects with equally poor performance, they still have diminished prefrontal cortical response while performing tasks with a strong working memory component. We have now initiated a number of cross-modal neuroimaging studies in schizophrenia. We previously found that prefrontal N-acetylaspartate (NAA) magnetic resonance spectroscopy signal predicts impaired WCST regional cerebral blood flow (rCBF) activation not only in the prefrontal cortices of our patients, but also in other nodes in the working memory system. This relationship was found in patients, but not in control subjects, and not with NAA in other brain regions. Additionally, we used PET to determine whether and how abnormal striatal presynaptic dopaminergic neurotransmission and disturbed prefrontal cortical function interact in schizophrenia. We determined both prefrontal activity (measured with rCBF) during the WCST and presynaptic dopaminergic function (measured with 18F-DOPA) in patients withdrawn from medication and matched normal controls. Striatal FDOPA uptake in patients was significantly higher than in normal controls, while WCST-related activity in prefrontal cortex was decreased. Most importantly, in patients there was a highly significant negative correlation between task-related prefrontal and striatal dopamine uptake which was absent in controls. This study provided a mechanistic explanation for the coexistence of two key pathophysiological hallmarks of schizophrenia. This year we reviewed the psychopathological manifestations impacting real-world functioning of affected individuals, most arguably, executive impairment, for which there are numerous disrupted component processes, and a very complex dysfunctional neural architecture. Postmortem and neuroimaging studies continue to show alterations in many interacting signaling pathways. There is also an evolving understanding that genetic risk factors give multiple entry points to illness liability. Given all this, we take a systems-level approach to executive dysfunction in schizophrenia by identifying 1) key brain regions that show changes in schizophrenia patients and are also important in cognitive neural circuitry, 2) relevant functional interactions and 3) examined links between risk genes and executive circuit abnormalities observed with neuroimaging. We studied the effect of the COMT (catechol-O-methyltransferase) val158met genotype with relation to resting regional cerebral blood flow (rCBF). The COMT gene, with the high-activity val allele, is weakly associated with risk for schizophrenia, which results in deficits in prefrontal functioning and poor working memory performance in healthy controls and patients with schizophrenia. The low-activity met allele is associated with anxiety and pain and with increased limbic reactivity while viewing aversive images. The effect of the COMT polymorphism is consistent with schizophrenia, during engagement of cognitive tasks. However, task-independent (resting) effects of this polymorphism in schizophrenia have not been characterized. There is mounting evidence for aberrant prefrontal and limbic brain function in schizophrenia during rest, and a lack of data regarding COMT effects on schizophrenia patients at rest. In medication-free patients, we identified the relationship between COMT genotype and resting rCBF in brain structures associated with schizophrenia pathophysiology and where COMT effects have been shown during executive and affective tasks. Our data suggests in schizophrenia at rest, brain structures important for executive and affective processing show activity that is differentially predicted by COMT val or met allele in an opposing manner. Thus, providing evidence that in schizophrenia, COMT genotype shows effects even in the resting state.

我们小组使用功能神经成像技术，在工作记忆和抽象推理任务的执行过程中，以及在匹配的感觉运动控制测试和其他对比任务的执行过程中，确定精神分裂症和其他神经精神障碍患者的局部神经元活动。通过使用2-back版本的N-back连续工作记忆任务，我们再次证实了威斯康星卡片分类测试(WCST)对前额叶皮质功能障碍的先前发现。与以前的研究一样，异常激活模式似乎甚至发生在执行任务相对较好的患者身上。我们还检查了个体患者在停药期间几个时间点认知激活的变化。这决定了生理变化和伴随的症状变化和认知表现之间的关系。对这些变化的时间进程的进一步分析正在进行中。我们还探索了工作记忆系统各节点之间的功能连接。这表明，超过一半的组间差异(跨越对照组和患者)可以用单一模式来解释，即患者的下颞叶-海马体-小脑负荷与对照组的背外侧-前额叶-扣带回活动。这种模式的表达完美地将所有患者的扫描从对照组中分离出来，这一发现在两个新的数据集中得到了前瞻性的验证，表明它可能是一个特征标记。我们进一步证明，这种模式的一个重要组成部分在于背外侧前额叶皮质(DLPFC)和海马体之间的功能关系的特殊异常。我们还表明，即使将精神分裂症患者与表现同样差的年轻正常受试者进行比较，他们在执行具有强大工作记忆成分的任务时，前额叶皮质反应仍然减弱。 我们现在已经启动了一些精神分裂症的跨模式神经成像研究。我们先前发现，前额叶N-乙酰天冬氨酸(NAA)磁共振波谱信号预测WCST局部脑血流(RCBF)激活受损，不仅在我们的患者的前额叶皮质，而且在工作记忆系统的其他节点。这种关系在患者身上发现，但在对照组中没有，而且与其他大脑区域的NAA也没有关系。此外，我们使用PET来确定精神分裂症患者纹状体突触前多巴胺能神经传递异常和前额叶皮质功能障碍是否以及如何相互作用。我们测定了WCST期间的前额叶活动(用rCBF测量)和停药患者和匹配的正常对照组的突触前多巴胺能功能(用18F-DOPA测量)。患者纹状体FDOPA摄取显著高于正常对照组，而前额叶皮质WCST相关活性降低。最重要的是，在患者中，与任务相关的前额叶和纹状体多巴胺摄取之间存在高度显著的负相关，而对照组中没有这种相关性。这项研究为精神分裂症的两个关键病理生理特征的共存提供了一个机制解释。 今年，我们回顾了影响受影响个体真实世界功能的精神病理表现，最有争议的是执行障碍，其有许多中断的组成部分过程，以及非常复杂的功能失调的神经架构。尸检和神经成像研究继续显示，许多相互作用的信号通路发生了变化。还有一种不断发展的理解，即遗传风险因素为疾病责任提供了多个切入点。有鉴于此，我们对精神分裂症的执行功能障碍采取了一种系统水平的方法，确定了1)显示精神分裂症患者的变化且在认知神经回路中也很重要的关键大脑区域，2)相关的功能相互作用，以及3)通过神经成像观察到的风险基因和执行回路异常之间的联系。 我们研究了儿茶酚氧位甲基转移酶(COMT)val158met基因与静息局部脑血流量(RCBF)的关系。带有高活性Val等位基因的COMT基因与精神分裂症的风险相关性较弱，精神分裂症会导致健康对照组和精神分裂症患者的前额叶功能缺陷和工作记忆表现不良。低活性的MET等位基因与焦虑和疼痛有关，并与观看令人厌恶的图像时边缘反应性增加有关。COMT多态与精神分裂症在认知任务中的作用是一致的。然而，这种多态在精神分裂症中的任务无关(静息)效应还没有被表征。越来越多的证据表明，精神分裂症患者在休息时前额叶和边缘脑功能异常，而关于COMT对休息时精神分裂症患者的影响的数据缺乏。在不服用药物的患者中，我们确定了COMT基因型与与精神分裂症病理生理相关的大脑结构中静息rCBF的关系，并在执行和情感任务中显示了COMT效应。我们的数据表明，在静息精神分裂症中，对执行和情感处理重要的大脑结构显示出活动，这种活动是由COMT Val或MET等位基因以相反的方式差异预测的。因此，提供了证据表明，即使在休息状态下，COMT基因也在精神分裂症中发挥作用。