Uncovering pathophysiological mechanisms of psychosis using the oculomotor system.

项目摘要 自我意识的紊乱是精神分裂症的标志。这些干扰可能是 其特征是一种扭曲的能动性--主观的感觉是我导致了我所产生的行为。机构 扭曲表现在精神分裂症的许多精神病症状中，例如，一个人是 被外星人控制。这些机构干扰的生理机制一直难以解释。 确认身份。对代理扭曲的最有说服力的生物学解释是一种推论干扰 放电（CD）。CD指的是运动信号的“副本”。CD信号不是被发送到肌肉， 发送到感觉区域，并允许有机体预测即将发生的动作的感觉结果。 在一个动作之后，预期的和实际的感觉事件之间的匹配产生了一种代理感， 而不匹配导致感觉是由外部因素引起的主观体验。 眼科系统为研究CD提供了一个理想的框架。最稳健的 研究CD的行为范例以及CD信号的唯一神经生理学证据， 灵长类动物的研究都来自于眼动研究。这项工作提供了前所未有的翻译 理解精神病特征的代理障碍的框架，并允许我们翻译 从动物的单细胞发现到精神病自我相关症状的机制研究。 最近，我们发现了患者扫视眼球运动系统中CD紊乱的证据 患有慢性精神分裂症根据神经生理学研究，这些行为发现产生了可检验的 关于功能失调的网络可能导致精神分裂症中CD异常的假说。这 4-该年的建议有三个主要目标。第一个是确定慢性脑梗死患者CD受损的神经相关性。 精神分裂症患者使用结构和功能神经成像和国家的最先进的连接分析。 第二个是检查CD损伤是否也存在于新近发作的精神分裂症患者中，因为 该样品中检测相关病理生理机制的条件更好。三是 研究CD损伤是否是精神分裂症特有的或代表一种跨诊断机制 通过将有精神病史的双相情感障碍患者纳入精神病研究。第四个探索目标 探讨了这种CD异常对精神病认知受损的影响。 这些发现有可能将精神分裂症的核心现象学体验与活动联系起来 的单个神经元，并了解共享和不同的生物基板的精神病在一系列 综合征此外，在已知传递CD信号的特定神经通路中发现异常， 有望为药物治疗提供信息。最后，我们的行为模式可以提供一个 治疗目标的有用的转化和定量测量，并有助于早期疾病检测。

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.