Uncovering pathophysiological mechanisms of psychosis using the oculomotor system.

项目总结 自我意识障碍是精神分裂症的一个特征。这些骚乱可能是 以扭曲的代理感为特征的--我导致我产生的行为的主观感觉。代理处 扭曲在精神分裂症的许多精神病症状中都很明显，例如，一个人的妄想 被外星人控制。这些机构干扰的生理机制一直很难确定 辨认身份。对代理扭曲最令人信服的生物学解释是推论中的干扰 放电(Cd)。CD指的是电机信号的“副本”。CD信号不是被发送到肌肉，而是 被发送到感觉区，并允许有机体预测即将发生的行动的感官后果。 动作之后的预期感官事件和实际感官事件之间的匹配会产生一种代理感， 而不匹配则会导致主观体验，即感觉是由外部因素引起的。 动眼系统为研究CD提供了一个理想的框架。最健壮的 研究Cd的行为范式以及Cd信号的唯一神经生理学证据 灵长类动物来自眼动研究。这部作品提供了前所未有的翻译 理解以精神病为特征的机构扰乱的框架，并允许我们翻译 从动物的单细胞发现到以精神病为特征的自我相关症状机制的研究。 最近，我们发现患者的眼球运动系统中存在CD障碍的证据。 患有慢性精神分裂症。在神经生理学研究的启发下，这些行为发现产生了可测试的 关于可能导致精神分裂症CD异常的网络功能障碍的假说。这 4年提案有三个主要目标。第一个是确定慢性CD障碍的神经相关因素 精神分裂症患者使用结构和功能神经成像和最先进的连接性分析。 第二个是检查新近发病的精神分裂症患者是否也存在CD障碍，如 该标本检测相关病理生理机制的条件较好。三是 调查CD损伤是否是精神分裂症特有的，还是代表了一种跨诊断机制 包括有精神病病史的双相情感障碍患者。第四个探索性目标 探讨这种CD异常对精神病患者认知功能受损的影响。 这些发现有可能将精神分裂症的核心现象学经验与活动联系起来。 并了解精神障碍的共同和不同的生物学基础 综合症。此外，在已知传递CD信号的特定神经通路中发现异常 承诺为药物治疗提供信息。最后，我们的行为范例可以提供一个 对治疗目标和早期疾病检测的有用的转换和量化措施。

PROJECT SUMMARY Disturbances in a sense of self are a hallmark of schizophrenia. These disturbances can be characterized by a distorted sense of agency—the subjective sense that I cause the actions I produce. Agency distortions are manifest in many psychotic symptoms of schizophrenia, for example, the delusion that one is being controlled by aliens. The physiological mechanisms of these agency disturbances have been difficult to identify. The most convincing biological explanation for agency distortions is a disturbance in corollary discharge (CD). CD refers to “copies” of motor signals. Rather than being sent to the muscles, CD signals are sent to sensory areas and allow the organism to anticipate the sensory consequences of the impending action. A match between the anticipated and actual sensory events following an action engenders a sense of agency, whereas a mismatch results in the subjective experience that sensations are caused by an external agent. The oculomotor system provides an ideal framework in which to investigate CD. The most robust behavioral paradigms for studying CD as well as the only neurophysiological evidence for CD signals in primates has come from eye movement research. This body of work provides an unprecedented translational framework for understanding the agency disturbances that characterize psychosis and allows us to translate single-cell findings in animals to studies of the mechanisms of self-related symptoms characterizing psychosis. Recently, we have shown evidence for disturbed CD in the saccadic eye movement system in patients with chronic schizophrenia. Informed by neurophysiology studies, these behavioral findings generate testable hypotheses about dysfunctional networks that might be giving rise to CD abnormalities in schizophrenia. This 4-year proposal has three major aims. The first is to identify the neural correlates of disrupted CD in chronic schizophrenia patients using structural and functional neuroimaging and state-of-the-art connectivity analyses. The second is to examine whether CD impairments are also present in recent-onset schizophrenia patients, as the conditions for detecting relevant pathophysiological mechanisms are better in this sample. The third is to investigate whether CD impairments are specific to schizophrenia or represent a trans-diagnostic mechanism of psychosis by including patients with bipolar disorder with a history of psychosis. A fourth exploratory aim explores the implications of this CD abnormality for impaired cognition in psychosis. These findings have the potential to link core phenomenological experiences in schizophrenia to activity of single neurons and to understand shared and distinct biological substrates of psychosis across a range of syndromes. In addition, finding abnormalities in specific neural pathways that are known to convey CD signals holds the promise to inform pharmacological treatments. Finally, our behavioral paradigms can provide a useful translational and quantitative measure of treatment targets and aid in early illness detection.