Neural mechanisms for antisaccade errors among schizophrenia families

描述（由申请人提供）：精神病学中的诊断系统具有局限性，导致分类是异质的，缺乏明确的边界，并且不充分匹配生物结构。临床表型，如精神分裂症（SZ）谱诊断，当应用于遗传分析，导致不一致的结果，尽管有一些有趣的线索。内表型是介于明显的临床疾病和异常基因之间的脑解剖和/或功能的特异性缺陷。这些措施提供了更直接的线索，遗传基础比临床综合征，因为他们更接近的病因链的主要体质偏差导致的疾病。本申请以两种重要方式响应对内表型的需要。首先，我们将确定在SZ的关键偏差，在脑功能水平占他们的antisaccade异常，一个有前途的和复制的行为内表型，这种疾病。其次，我们将确定是否SZ（SZREL）的生物亲属表现出相同的偏差，在脑功能的SZ。这个项目将解决一个主要的问题，SZ的病理生理学，临床诊断疾病分类学和遗传学模型的影响。SZ患者脑功能的一个常见异常是前额叶皮质（PFC）的破坏。无法抑制行为反应是PFC病理学的一个重要表现，这种异常可以通过在反跳跃任务中无法抑制对周边目标的反射性扫视来量化。SZ和SZREL有较高的反跳错误率，这表明反跳指标是这种疾病的体质异常。证明SZ和反性能之间的关系是了解这种疾病的基本神经病理学和遗传学的重要一步。澄清SZ相关的神经病理学如何导致增加的抗错误需要研究制定这种行为所需的子过程的神经相关性。本项目将解决这个具体问题，其结果将产生一个精确的措施失败的神经控制占SZ和SZREL之间的反性能差。动物研究表明，神经偏向信号对于成功抑制反试验至关重要。无论是减少或非典型的准备活动，在感觉或运动领域占SZ和SZREL行为调节困难，在反任务是不确定的。因此，拟议的工作将解决深圳临床神经科学中一个根本性的重要问题。这项研究需要使用一种新的范式，使用高时间分辨率的大脑测量技术（多通道脑电图），获得大SZ和SZREL样本，并与该研究领域的互补知识的研究人员之间的合作。本项目符合这些要求。精神分裂症患者有抑制问题，这可以通过大脑活动的变化来预测。健康受试者的活动模式涉及帮助准备正确反应的区域中的活动增加与支持竞争过程的区域中的活动减少之间的明显平衡，将使用通过EEG和新的反跳范式测量大脑活动来探索模式。预计这种模式将在精神分裂症患者及其亲属中被打破。

DESCRIPTION (provided by applicant): Diagnostic systems in psychiatry have limitations resulting in classifications that are heterogeneous, lack clear boundaries, and inadequately match biological constructs. Clinical phenotypes such as schizophrenia (SZ)-spectrum diagnoses, when applied in genetic analyses, result in inconsistent findings, despite some interesting leads. Endophenotypes are specific deficits in brain anatomy and/or function interposed between overt clinical disease and aberrant genes. Such measures provide more direct clues to genetic underpinnings than do clinical syndromes because they are closer in the etiological chain to the primary constitutional deviations resulting in disease. The current application responds to the need for endophenotypes in two important ways. First, we will identify in SZ the critical deviation at the level of brain function accounting for their antisaccade abnormalities, a promising and replicated behavioral endophenotype for this illness. Second, we will determine whether biological relatives of SZ (SZREL) manifest the same deviations in brain functioning as the SZ. This project will address a major question about SZ with implications for models of pathophysiology, clinical diagnostic nosology, and genetics. A common anomaly in brain function in SZ is disruption of prefrontal cortex (PFC). An inability to inhibit behavioral responses is an important manifestation of PFC pathology, an abnormality that can be quantified by the inability to inhibit reflexive glances to peripheral targets during antisaccade tasks. SZ and SZREL have high antisaccade error rates suggesting that anti-performance indexes a constitutional abnormality of liability for this illness. Demonstrating a relationship between SZ and anti-performance is an important step toward understanding the essential neuropathology and genetics of this illness. Clarifying how SZ-related neuropathology causes increased anti-errors requires studying the neural correlates of sub- processes necessary to enact this behavior. The present project will address this specific issue, and the results will yield a precise measure of failed neural control accounting for poor anti-performance among SZ and SZREL. Animal research indicates that neural bias signals are crucial for enabling successful inhibition on an anti-trial. Whether reduced or atypical preparatory activities in sensory or motor areas account for SZ and SZREL behavioral regulation difficulties during anti-tasks is uncertain. The proposed work, therefore, will address a fundamentally important question in the clinical neuroscience of SZ. This research requires the use of a novel paradigm, the use of high temporal resolution brain measurement technology (multichannel EEG), access to large SZ and SZREL samples, and collaboration between investigators with complimentary knowledge of this research area. The present project meets these requirements. PUBLIC HEALTH RELEVANCE People with schizophrenia have problems with inhibition which can be predicted by changes in brain activity. The patterns of activity in healthy subjects involve a distinct balance between increased activity in regions that help prepare a correct response and decreased activity in regions supporting competing processes, a pattern will be probed using measurement of brain activity via EEG and a novel antisaccade paradigm. It is expected this pattern will be disrupted in people with schizophrenia and their relatives.