fMRI of Eye Movement Phenotype in Schizophrenia

描述(申请人提供)：精神分裂症的病因生理学尚不完全清楚。有证据支持精神分裂症的遗传易感性与顺畅追踪眼动(SPEM)异常之间的关联，并已提出SPEM可作为分子遗传学研究的一种表型。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。了解SPEM异常的生物学机制及其与精神分裂症表型的关系可能为该病的病因学提供重要的见解。这项拟议研究的目标是将功能磁共振成像(FMRI)和SPEM测量相结合，以研究1)精神分裂症相关SPEM损害的潜在神经机制；2)追求相关成像变化在家庭中聚集的程度。我们已经对视网膜运动和视网膜外运动信号对健康受试者和精神分裂症患者亲属顺利追踪维持的相对贡献进行了行为建模。结果表明，健康受试者的表现主要取决于预测性或视网膜外运动输入，而精神分裂症患者的亲属在追踪反应的这一部分表现出缺陷。这种缺陷可能会导致更多地依赖即时的视网膜运动感官输入来维持顺畅的追赶。我们假设，这种行为异常模式具有神经生理学基础，在fMRI成像信号中可以检测到，视网膜外运动处理路径中的激活减少，同时负责视网膜运动处理的区域的激活代偿性增加。我们进一步假设，这种神经活动模式将出现在受影响的先证者的临床未受影响的兄弟姐妹中，支持对控制精神分裂症预测性平滑追踪缺陷的神经回路的遗传影响。

DESCRIPTION (provided by applicant): The etiopathophysiology of schizophrenia is incompletely understood. Evidence supports an association between genetic liability for schizophrenia and smooth pursuit eye movement (SPEM) abnormalities, and it has been suggested that SPEM can serve as a phenotype in molecular genetic studies. 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. Knowledge of the biological mechanisms underlying SPEM abnormalities and their relationship to the schizophrenia phenotype may provide critical insights into the etiology of this disease. The goal of the proposed research is to combine functional magnetic resonance imaging (fMRI) and SPEM measures to study 1) the underlying neural mechanism of schizophrenia-related SPEM impairments; and 2) the degree to which pursuit-related imaging changes aggregate in families. We have behaviorally modeled the relative contributions of retinal motion and extraretinal motion signals to smooth pursuit maintenance in healthy subjects and in relatives of schizophrenia patients. The results indicate that performance in healthy subjects depends primarily on the predictive, or extraretinal motion input, while relatives of schizophrenia patients show deficits in this component of the pursuit response. This deficit may lead to an increased reliance on the immediate, retinal motion sensory input to maintain smooth pursuit. We hypothesize that this pattern of behavioral abnormality has a neurophysiological basis that will be detectable in fMRI imaging signal as reduced activation in the extraretinal motion processing pathway accompanied by a compensatory increase in activation in regions responsible for retinal motion processing. We further hypothesize that this pattern of neural activity will be present in the clinically unaffected siblings of affected probands, supporting a genetic influence on the neural circuit controlling predictive smooth pursuit deficit in schizophrenia.