Neural mechanisms for antisaccade errors among schizophrenia families

描述（由申请人提供）：精神病学的诊断系统存在局限性，导致分类异构，缺乏明确的界限，并且不能充分匹配生物学结构。临床表型，如精神分裂症（SZ）谱系诊断，当应用于基因分析时，结果不一致，尽管有一些有趣的线索。内表型是脑解剖和/或功能上的特殊缺陷，介于显性临床疾病和异常基因之间。与临床综合症相比，这些措施为遗传基础提供了更直接的线索，因为它们在病因链中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回应了对内表型的需求。首先，我们将在SZ中确定脑功能水平上的临界偏差，这是他们抗眼跳异常的原因，这是该疾病的一种有希望和可复制的行为内表型。其次，我们将确定SZ的生物亲属（SZREL）是否在大脑功能上表现出与SZ相同的偏差。本项目将探讨关于SZ的一个主要问题，并对病理生理学、临床诊断分类学和遗传学的模型产生影响。SZ常见的脑功能异常是前额皮质（PFC）的破坏。无法抑制行为反应是PFC病理的一个重要表现，这种异常可以通过在抗扫视任务中无法抑制对周围目标的反射性扫视来量化。SZ和SZREL有较高的反扫视错误率，提示反表现指标是本病责任的体质异常。证明SZ和反表现之间的关系是理解这种疾病的基本神经病理学和遗传学的重要一步。阐明与sz相关的神经病理如何导致抗错误增加，需要研究制定这种行为所必需的子过程的神经相关。本项目将解决这一具体问题，结果将产生一个精确的测量失败的神经控制，说明SZ和SZREL之间的不良反性能。动物研究表明，神经偏倚信号对于成功抑制抗试验至关重要。在反任务过程中，感觉区或运动区准备活动的减少或不典型是否导致了SZ和SZREL行为调节困难尚不确定。因此，所提出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，使用高时间分辨率脑测量技术（多通道脑电图），获得大的SZ和SZREL样本，以及具有该研究领域互补知识的研究人员之间的合作。目前的项目符合这些要求。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，这一模式将通过脑电图和一种新的反扫视范式来测量大脑活动。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.