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.

我们的小组使用功能神经影像学来确定精神分裂症和其他神经精神疾病患者在执行工作记忆和抽象推理任务期间以及执行匹配的感觉运动控制测试和其他对比任务期间的局部神经元活动。通过使用 N-back 连续工作记忆任务的 2-back 版本，我们重新证实了之前从威斯康星州卡片分类测试 (WCST) 中得出的关于前额皮质功能障碍的发现。与之前的研究一样，即使在任务表现相对较好的患者中也会出现异常激活模式。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。这确定了生理变化与伴随的症状和认知表现变化之间的关系。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个节点之间的功能连接。这表明，超过一半的组间差异（对照组和患者之间）可以用单一模式来解释，该模式显示患者的颞下-海马-小脑负荷与对照组的背外侧-前额叶-扣带回活动。这种模式的表达将所有患者扫描与对照组完美分开，这一发现在两个新数据集中得到前瞻性验证，表明它可能是一种性状标记。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层（DLPFC）和海马之间的功能关系的特定异常。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影像学研究。我们之前发现，前额叶 N-乙酰天冬氨酸 (NAA) 磁共振波谱信号不仅可以预测患者前额皮质的 WCST 区域脑血流 (rCBF) 激活受损，还可以预测工作记忆系统中其他节点的受损。在患者中发现了这种关系，但在对照组中没有发现这种关系，在其他大脑区域也没有发现 NAA 的关系。此外，我们使用 PET 来确定异常纹状体突触前多巴胺能神经传递和紊乱的前额皮质功能是否以及如何在精神分裂症中相互​​作用。我们测定了停药患者和匹配的正常对照患者在 WCST 期间的前额叶活动（用 rCBF 测量）和突触前多巴胺能功能（用 18F-DOPA 测量）。患者纹状体 FDOPA 摄取量显着高于正常对照，而前额叶皮层 WCST 相关活性下降。最重要的是，在患者中，任务相关的前额叶和纹状体多巴胺摄取之间存在高度显着的负相关性，而对照组则不存在这种相关性。这项研究为精神分裂症的两个关键病理生理学特征的共存提供了机制解释。 今年，我们回顾了影响受影响个体现实世界功能的精神病理学表现，最有争议的是执行障碍，其中有许多被破坏的组成过程和非常复杂的功能失调的神经结构。尸检和神经影像学研究继续表明许多相互作用的信号通路发生了变化。人们也逐渐认识到，遗传风险因素为疾病责任提供了多个切入点。 鉴于这一切，我们采用系统级方法来治疗精神分裂症的执行功能障碍，方法是确定 1) 显示精神分裂症患者变化且在认知神经回路中也很重要的关键大脑区域，2) 相关功能相互作用，以及 3) 检查风险基因与神经影像学观察到的执行回路异常之间的联系。 我们研究了 COMT（儿茶酚-O-甲基转移酶）val158met 基因型对静息局部脑血流量 (rCBF) 的影响。 COMT 基因具有高活性 val 等位基因，与精神分裂症风险微弱相关，这会导致健康对照者和精神分裂症患者前额功能缺陷和工作记忆表现不佳。低活性met等位基因与焦虑和疼痛以及观看厌恶图像时边缘系统反应性增加有关。在参与认知任务期间，COMT 多态性的影响与精神分裂症一致。 然而，这种多态性对精神分裂症的独立于任务（静息）的影响尚未得到表征。 越来越多的证据表明精神分裂症患者休息时前额叶和边缘脑功能异常，但缺乏有关 COMT 对休息时精神分裂症患者影响的数据。 在未接受药物治疗的患者中，我们确定了与精神分裂症病理生理学相关的大脑结构中 COMT 基因型和静息 rCBF 之间的关系，以及在执行和情感任务中 COMT 效应的表现。我们的数据表明，在休息时的精神分裂症中，对于执行和情感处理很重要的大脑结构显示出 COMT val 或 met 等位基因以相反方式差异预测的活动。因此，提供证据表明，COMT 基因型即使在静息状态下也能对精神分裂症产生影响。