Sensory-learning deficits and conversion to psychosis among individuals at clinical high-risk: a longitudinal model-based fMRI study

精神分裂症（SCZ）是世界上最严重和最繁重的医疗条件之一。SCZ 迄今为止的研究已经成功地描述了患者的大脑异常，但未能阐明 幻觉和其他核心精神病症状的潜在机制。一项基本 大脑的功能是学习环境中的行为，预测即将发生的事件及其后果。 突发事件（例如，在接听电话时期望听到声音）。预测性中断 大脑的机制，特别是预测错误信号，与妄想倾向相关， 最近被认为是幻觉的基础然而，预测机制之间的因果关系 和精神病症状尚未确定因此，本建议的目的是定义神经 语义-语言预测的相关性（即，对听到声音的期望取决于 在新的言语辨别任务期间言语刺激出现的概率 （N=20;每个人将接受一次基线fMRI扫描）和精神病临床高风险个体（10; N=50;每名受试者将在基线和一年后或转换为精神病时接受fMRI扫描， 以先到者为准），并在这些口头预测和听觉预测之间建立直接联系。 言语知觉异常以及转化为精神病。特别令人感兴趣的是， 病理生理过程的研究，因为这些过程可以从疾病的影响中分离出来， 慢性病、治疗和住院。在这个早期阶段确定的绑架者更有可能是 具体到疾病，因为它们可能代表更多的精神病特异性上游事件，而不是 一般精神病理学的下游标志物，可以共享，作为一个共同的最终途径， 不同的疾病我们假设听觉皮层中的预测错误信号会有缺陷 在基线时，与对照组相比， 基线将预测转化为精神病，以及更严重的症状和更差的神经认知 功能，在后续。我们还假设，转化为精神病的个体将有更大的 随着时间的推移，预测误差赤字比非转换器恶化。R21的贡献是巨大的 因为它将填补SCZ文献中关于症状产生机制的空白， 有助于定义适合治疗修改的新靶点（感觉预测）的潜力（例如， 基于学习的非侵入性方法）。通过包括一系列知觉异常的患者 在不同的感觉领域，该项目还将建立AVH感觉预测缺陷的特异性 和一般的精神病。听觉系统的预测缺陷可能是状态依赖的， 从而提供了预测精神病发展和/或监测治疗的客观量度 反应

Schizophrenia (SCZ) is among the most severe and burdensome of medical conditions worldwide. SCZ research to date has succeeded in describing brain abnormalities in patients but has failed to clarify the mechanisms underlying hallucinations and other core psychotic symptoms of this disorder. A fundamental function of the brain is to learn regularities in the environment and predict upcoming events and their contingencies (e.g., anticipating hearing a voice when answering the phone). Disruptions in predictive mechanisms of the brain, specifically in prediction-error signaling, correlate with delusion propensity and have recently been hypothesized to underlie hallucinations. However, a causal link between predictive mechanisms and psychotic symptoms has yet to be established. Thus, the aim of this proposal is to define the neural correlates of auditory-verbal predictions (i.e., the expectation of hearing voices depending on varying probabilities of the occurrence of speech stimuli during a novel speech discrimination task) in healthy controls (N=20; each will receive one baseline fMRI scan) and individuals at clinical high risk for psychosis (CHR; N=50; each subject will receive an fMRI scan at baseline and after one year or at conversion to psychosis, whichever comes first), and to establish a direct link between these auditory-verbal predictions and auditory- verbal perceptual abnormalities as well as conversion to psychosis. The CHR phase is of particular interest in the study of pathophysiological processes because such processes can be separated from effects of illness, chronicity, treatment and hospitalizations. Abnormalities identified in this early phase are more likely to be specific to the illness, because they may represent more psychosis-specific upstream events rather than downstream markers of general psychopathology that could be shared, as a common final pathway, by different disorders. We hypothesize that there will be deficits in prediction-error signaling in the auditory cortex at baseline in CHR individuals compared to control subjects, and that greater prediction-error deficits at baseline will predict conversion to psychosis, as well as greater symptoms and worse neurocognitive functioning, at follow up. We also hypothesize that individuals who convert to psychosis will have greater worsening of prediction error deficits over time than non-converters. The contribution of this R21 is significant because it will fill a gap in the SCZ literature regarding the mechanisms of symptom generation and has the potential to help define a novel target (sensory predictions) that is amenable to therapeutic modification (e.g., with learning-based, noninvasive approaches). By including patients with a range of perceptual abnormalities in different sensory domains, this project will also establish the specificity of sensory predictive deficits to AVH and psychosis in general. The predictive deficits in the auditory system will likely be state-dependent and may thus provide an objective measure for predicting the development of psychosis and/or monitoring treatment response.