NEUROIMAGING STUDIES OF NEUROPHYSIOLOGICAL PHENOTYPES IN SCHIZOPHRENIA

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 精神分裂症的病因生理学还不完全清楚。遗传流行病学数据表明，这种疾病的病因学中有很强的遗传成分。一些神经生理指标，包括平滑追踪眼球运动(SPEM)、诱发电位(ERP)和功能成像异常，被证明与精神分裂症的遗传易感性有关。例如，SPEM异常是与疾病相关的一些最具重复性的生物学发现。有趣的是，这些令人瞠目结舌的异常不仅在精神分裂症患者身上观察到，而且在没有精神病症状的患者的一级亲属中也发现了，这表明SPEM异常标志着疾病的遗传易感性。已有研究表明，SPEM异常可作为精神分裂症的表型标志。然而，已报道的SPEM异常的神经基础还不是很清楚，对于遗传效应如何转化为控制SPEM的异常神经回路更是知之甚少。另一个例子是诱发电位脑波异常，它也被确定为疾病遗传易感性的潜在生物标记。了解这些神经生理表型背后的心理、物理和生物机制以及它们与精神分裂症表型的关系可能会为这种疾病的病因学提供重要的见解。在这项研究中，我们设计了功能磁共振成像和事件相关电位(ERP)实验，以检验知觉和认知对控制眼动输出的皮质机制的贡献。三组受试者将被测试：精神分裂症患者(~n=60)，患者的完全同胞(~60)，以及没有精神病家族史的健康对照组(~60)，总目标登记约180名受试者。我们期望在这个多年的项目中，fMRI和ERP将提供一种安全的、非侵入性的方法来仔细检查导致精神分裂症患者追踪眼动和诱发电位功能障碍的神经生理过程。我们纳入了完整的兄弟姐妹来检查这些神经生理异常的家族聚集性。由于大多数兄弟姐妹没有服用抗精神病药物，他们的纳入允许检查不受抗精神病药物影响的个人中与精神分裂症有关的一些功能障碍。血液DNA样本将被收集并存储在GCRC基因组核心中。我们将研究候选基因及其对神经成像表型的影响。综上所述，在本项目中，我们建议使用功能磁共振成像和事件相关电位成像技术，获得控制精神分裂症候选神经生理表型的异常回路的直接证据。在识别精神分裂症的遗传病因方面，这种方法可能比行为方法有更高的收益，因为成像技术应该是一种更好的衡量由假定的疾病相关基因控制的核心生物缺陷的方法。使用基于成像的表型，我们应该期待更强大的基因-表型关联。该方案中包括的程序，例如，事件相关电位记录、功能磁共振成像，或对听觉声音或视觉运动呈现的反应，都是非侵入性的，应该对研究对象构成最小的风险。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The etiopathophysiology of schizophrenia is not completely understood. Genetic epidemiological data indicate a strong genetic component in the etiology of the illness. Several neurophysiological measures, including smooth pursuit eye movement (SPEM), evoked potentials (ERP), and functional imaging abnormalities, are shown to be related to the genetic liability of schizophrenia. For example, SPEM abnormalities are some of the most reproducible biological findings associated with the illness. Interestingly, these eyetracking abnormalities are not only observed in patients with schizophrenia, but are also found in first degree relatives of patients who do not have psychotic symptoms, suggesting that SPEM abnormalities mark a genetic liability of the illness. It has been suggested that SPEM abnormalities can serve as a phenotypic marker of schizophrenia. However, the neural basis of reported abnormalities in SPEM is not well understood, and even less is known about how genetic effects are translated into aberrant neural circuit controlling SPEM. Another example is evoked potential brain wave abnormalities, which also have been identified as potential biological markers for the genetic liability of the illness. Knowledge of the psychophysical and biological mechanisms underlying these neurophysiological phenotypes and their relationship to the schizophrenia phenotype may provide critical insight into the etiology of this disease. For this investigation we designed fMRI and event-related potential (ERP) experiments to examine the perceptual and cognitive contributions to cortical mechanisms controlling eye movement outputs. Three groups of subjects will be tested: schizophrenic patients (~ n=60), full siblings of patients (~60), and healthy controls without family history of psychosis (~60), for a total target enrollment of about 180 subjects. We expect that fMRI and ERP will provide a safe, non-invasive approach to carefully examine the neurophysiological process leading to pursuit eye movement and evoked potential dysfunction in schizophrenia in this multi-year project. We have included full siblings to examine the familial aggregation of these neurophysiological abnormalities. Since most of the siblings are not on antipsychotic medications, their inclusion allows an examination of some of the dysfunctions associated with schizophrenia in individuals not affected by antipsychotic medications. Blood DNA sample will be collected and stored in GCRC Genomic Core. We will examine candidate genes and their effects on neural imaging phenotypes. In summary, using fMRI and ERP imaging technology, we propose in this project to gain direct evidence of the abnormal circuitry controlling the candidate neurophysiological phenotypes in schizophrenia. This approach could potentially have a higher yield than behavioral measures in identifying the genetic etiology of schizophrenia because imaging techniques should be a better measure of the core biological deficits controlled by the putative disease-related genes. We should expect more robust genotype-phenotype association using imaging based phenotypes. The procedures included in this protocol, e.g., ERP recording, fMRI, or response to auditory sounds or visual motion presentations are not invasive and should pose minimal risk to research subjects.