Motion Perception in Schizophrenia

描述（由申请人提供）：识别疾病相关的遗传效应是精神分裂症研究的主要焦点。努力是多方面的，最终目标是描述从特定的遗传变异到神经元功能变化、行为缺陷到功能障碍的因果路径。精神分裂症的诊断可能反映了几个这样的因果路径的异质组合，因此以不同的表型集合为特征，每种表型都与特定的神经认知缺陷相关，反映了少数基因的影响。非特异性遗传和环境修饰因子也可能在病因学上起作用。基于这种复杂的病因学模型，精神分裂症研究人员提倡使用更多的元素表型。值得注意的例子包括COMT和前额叶功能障碍、尼古丁受体和感觉门控缺陷。研究表明，平滑追求眼动（SPEM）异常也标志着精神分裂症相关的表型。然而，与前额叶和感觉门控缺陷相比，我们对这些异常背后的特定认知过程和相关神经基质知之甚少。近年来，我们一直致力于解决这一关键问题。迄今为止的进展得益于我们在人类和非人类灵长类动物运动感知和动眼肌功能研究中的神经生理学发现，这些研究表明，SPEM反应可以被解析为具有不同神经元基质的组成过程。SPEM广泛涉及：(a)视网膜运动信息的处理（即目标图像在视网膜上的运动）；(b)主要基于视网膜信息的动眼肌反应的启动；(c)处理和整合由眼睛运动产生的视网膜外运动信号；(d)基于由视网膜外信号引导的预测性眼动和由视网膜速度和位置误差信号引导的纠正性眼动相结合的追求维持。精神分裂症患者的SPEM缺陷可能是这些成分中的一个或多个出现问题的结果。我们建议使用一些最近开发的实验技术来表征30名精神分裂症患者、30名表现出精神分裂症谱系人格（SSP）症状的生物学亲属和60名社区受试者（其中30名在没有精神疾病家族史的情况下表现出SSP症状）的运动感知和动眼肌功能的特定方面。结果将通过提供反映特定加工缺陷的措施，加强SPEM表型在精神分裂症研究中的应用。通过这种方式，表型可以更有效地用于成像和药物探针研究，以识别感兴趣的大脑区域和受体系统。精炼的表型也可能更接近基因的影响，因此更适合于分子遗传分析中的替代表型方法。最后，了解SPEM表型背后的生物学机制将加强对已确定的任何候选基因功能意义的研究。拟议中的项目是一个合作项目，包括研究精神分裂症病理生理学的临床科学家和研究运动感知和眼球运动的基础科学家。

DESCRIPTION (provided by applicant): Identifying disease-related genetic effects is a major focus in schizophrenia research. Efforts have been multifaceted with the ultimate goal being to describe a causal path from specific genetic variants to changes in neuronal functioning to behavioral deficits to functional impairments. The schizophrenia diagnosis likely reflects a heterogeneous combination of several such causal paths, and is therefore characterized by a varying collection of phenotypes each associated with specific neurocognitive deficits reflecting the effects of a small number of gene(s). Nonspecific genetic and environmental modifiers also likely play an etiologic role. Based on this complex etiologic model, schizophrenia researchers have advocated the use of more elemental phenotypes. Notable examples include COMT and prefrontal dysfunction and nicotinic receptors and sensory gating deficits. Studies suggest that smooth pursuit eye movement (SPEM) abnormalities also mark a schizophrenia-related phenotype. However, in contrast to prefrontal and sensory gating deficits, we know little about the specific cognitive processes and associated neural substrates underlying these abnormalities. We have been focused in recent years on addressing this critical issue. Progress to date has been aided by our efforts to incorporate neurophysiological findings in human and non-human primate studies of motion perception and oculomotor functioning, which have shown that SPEM response can be parsed into component processes with distinct neuronal substrates. SPEM broadly involves: (a) the processing of retinal motion information (i.e., the movement of a target image on the retina); (b) the initiation of an oculomotor response based primarily on this retinal information; (c) the processing and integration of extraretinal motion signals generated by movement of the eyes; and (d) the maintenance of pursuit based on a combination of predictive eye movements guided by extraretinal signals and corrective eye movements guided by retinal velocity and position error signals. SPEM deficits in schizophrenia could be the result of a problem with one or more of these components. We propose to use a number of recently developed experimental techniques to characterize specific aspects of motion perception and oculomotor functionoing in 30 schizophrenia patients, 30 biological relatives who exhibit schizophrenia spectrum personality (SSP) symptoms, and 60 community subjects (30 of who exhibit SSP symptoms in the absence of family history for psychotic illness). Results will enhance the application of the SPEM phenotype in studies of schizophrenia by providing measures that reflect specific processing deficit(s). In this way, the phenotype can be used more effectively in imaging and drug probe studies to identify brain regions and receptor systems of interest. A refined phenotype is also likely to be more proximal to the effects of genes, and therefore better suited for alternative phenotype approaches in molecular genetic analyses. Finally, knowledge of the biological mechanisms underlying the SPEM phenotype will enhance studies of the functional significance of any candidate genes that are identified. The proposed project is a collaborative effort--involving clinical scientists studying schizophrenia pathophysiology and basic scientists studying motion perception and eye movements.