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沉重的医疗疾病之一。SCZ 到目前为止，研究已经成功地描述了患者的大脑异常，但未能澄清 幻觉和这种疾病的其他核心精神症状的潜在机制。一项基本原则 大脑的功能是学习环境中的规律，并预测即将发生的事件及其 偶然性(例如，预期在接听电话时听到声音)。预测性中断 大脑的机制，特别是在预测错误信号方面，与妄想倾向相关，并具有 最近被认为是产生幻觉的原因。然而，预测机制之间的因果联系 而精神病症状尚未确定。因此，这项提议的目的是定义神经 听觉-言语预测的相关性(即，听觉语音的期望依赖于变化 在一项新的语音辨别任务中出现语音刺激的概率) (n=20；每个人将接受一次基线功能磁共振扫描)和临床精神疾病高危个体(chr； N=50；每个受试者将在基线和一年后或在转化为精神病时接受fMRI扫描， 无论哪个先出现)，并在这些听觉语言预测和听觉语言预测之间建立直接联系- 言语知觉异常以及转化为精神错乱。CHR阶段对以下方面特别感兴趣 对病理生理过程的研究，因为这样的过程可以与疾病的影响分开， 慢性病、治疗和住院情况。在早期阶段发现的异常更有可能是 特定于疾病，因为它们可能代表更多特定于精神病的上游事件，而不是 普通精神病理学的下游标志物，可以作为共同的最终途径共享，由 不同的障碍。我们假设在听觉皮质中会有预测误差信号的缺陷 在基线时，CHR个体与对照受试者相比，更大的预测误差缺陷 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 在后续行动中发挥作用。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，预测误差赤字比不转换的人更严重。这款R21的贡献很大 因为它将填补SCZ文献中关于症状产生机制的空白，并具有 帮助定义服从于治疗性修改的新目标(感觉预测)的可能性(例如， 以学习为基础的非侵入性方法)。通过纳入有一系列知觉异常的患者 在不同的感觉领域，这个项目还将建立感觉预测缺陷对AVH的特异性 以及一般的精神错乱。听觉系统中的预测性缺陷可能会依赖于国家，并可能 从而为预测精神病的发展和/或监测治疗提供了客观的衡量标准 回应。

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.