Neural mechanisms for antisaccade errors among schizophrenia families

描述(申请人提供)：精神病学中的诊断系统有局限性，导致分类不同，缺乏明确的边界，不能与生物学结构充分匹配。临床表型，如精神分裂症(SZ)谱诊断，当应用于基因分析时，尽管有一些有趣的线索，但结果不一致。内表型是介于显性临床疾病和异常基因之间的大脑解剖和/或功能的特定缺陷。这些措施比临床综合征提供了更直接的遗传基础线索，因为它们在病因链上更接近导致疾病的主要体质偏差。目前的应用在两个重要方面响应了对内表型的需求。首先，我们将确定SZ在大脑功能水平上的关键偏差，说明他们的反眼跳异常，这是一种有希望的和可复制的这种疾病的行为内表型。其次，我们将确定SZ的亲缘关系(SZREL)是否表现出与SZ相同的大脑功能偏差。这个项目将解决关于SZ的一个主要问题，并对病理生理学、临床诊断病因学和遗传学的模型产生影响。SZ的一个常见的脑功能异常是前额叶皮质(PFC)的中断。无法抑制行为反应是PFC病理的重要表现，这种异常可以通过在反眼跳任务中抑制对周围目标的反射性扫视的能力来量化。SZ和SZREL有很高的抗眼跳错误率，这表明抗表现指标是这种疾病的责任的体质异常。证明SZ和抗表现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。要弄清SZ相关的神经病理如何导致抗错误能力的增强，需要研究制定这一行为所必需的子过程的神经相关性。本项目将解决这一具体问题，结果将产生神经控制失败的准确衡量标准，说明SZ和SZREL的抗性能较差。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。SZ和SZREL在反任务中的行为调节困难是否与感觉或运动区的准备活动减少或不典型有关尚不确定。因此，这项拟议的工作将解决深圳临床神经科学中的一个根本重要问题。这项研究需要使用一种新的范式，使用高时间分辨率的脑测量技术(多通道脑电)，获取大量的SZ和SZREL样本，以及在这一研究领域的互补知识的研究人员之间进行合作。本项目符合这些要求。与公共健康相关的精神分裂症患者存在抑制问题，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活动增加和支持竞争过程的区域活动减少之间的明显平衡，将通过脑电测量大脑活动和一种新的反眼跳范式来探索一种模式。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.