Identifying neural mechanisms of aberrant inhibitory processing and salience in patients with schizophrenia

项目摘要 精神分裂症(SZ)患者表现出过滤无关或冗余信息的能力缺陷 并可能将突显错误地归因于思想和事件。反过来，这些损伤可能导致更高的- 与SZ相关的水平认知功能障碍和临床症状。在脑电研究中，抑制性加工 在听觉配对点击范式中，在SZ可靠地观察到缺陷；在健康比较中(HC) 受试者，事件相关电位(ERP)的P50成分被可靠地降低到第二相同 而SZ患者表现出对冗余信息的P50抑制程度降低。在……里面 同样的范式，SZ患者对初始刺激相对的N100事件相关电位反应降低 对于HC参与者，这可能反映了听觉显著加工的减少。一个单独的研究机构 使用功能磁共振成像将SZ的抑制和显著监测缺陷与默认抑制不足联系在一起 模式网络(DMN)，支持内部聚焦认知和自我参照加工。突出之处 网络(SN)是负责监控显著的更高级别的系统，它根据任务的需要调整DMN 需要注意外部刺激的。给定与P50抑制相关的共享构造，N100 注意反应，以及DMN和SN的连接性，我们假设这些测量捕捉到 在相同的机制中，SZ功能障碍的各个方面。使用静息状态fMRI、静息状态EEG和 在SZ患者(N=84)和HCS患者(N=42)的配对点击范式中记录的脑电，建议 研究采用多模式方法来识别和表征异常抑制和显著 在深圳加工。这项研究的主要目的是：1)确定DMN抑制是否代表 抑制性滤过的机制，并评估这种功能障碍在深圳；2)确定是否向下- SN对DMN的调节代表了一种支持抑制加工和显著监控的机制 并评估这些过程对SZ患者功能障碍的贡献。通过整合调查结果 以完善我们对异常抑制加工所涉及的神经回路的理解 和在深圳的突出，这个项目的发现将有助于为未来的研究开发 有针对性的治疗。除了概述的研究目标外，申请者还将继续进行课程学习， 临床科学培训活动和指导，以发展为独立的研究人员与 应用临床神经科学方法阐明认知障碍机制的专业知识 以及精神病理学的临床症状。

Project Summary Individuals with schizophrenia (SZ) demonstrate deficits in the ability to filter irrelevant or redundant information and may misattribute salience to thoughts and events. In turn, these impairments may contribute to higher- level cognitive dysfunction and clinical symptoms associated with SZ. In EEG studies, inhibitory processing deficits are reliably observed in SZ during an auditory paired-click paradigm; in healthy comparison (HC) participants, the P50 component of the event-related potential (ERP) is reliably reduced to the second identical stimulus in a pair whereas individuals with SZ show reduced inhibition of the P50 to redundant information. In the same paradigm, individuals with SZ exhibit a decreased N100 ERP response to the initial stimulus relative to HC participants, which may reflect decreased auditory salience processing. A separate body of research using fMRI has linked inhibitory and salience monitoring deficits in SZ to insufficient suppression of the default mode network (DMN), which supports internally-focused cognition and self-referential processing. The salience network (SN), a higher-order system responsible for monitoring salience, regulates DMN as needed for tasks requiring attention to external stimuli. Given the shared constructs associated with P50 suppression, N100 attentional response, and the connectivity of DMN and SN, we hypothesize that these measures capture aspects of dysfunction in SZ within the same mechanism. Using resting-state fMRI, resting-state EEG, and EEG recorded during the paired-click paradigm from SZ patients (N = 84) and HCs (N = 42), the proposed research employs a multimodal approach to identify and characterize abnormal inhibitory and salience processing in SZ. Primary aims of the study are to 1) determine whether DMN suppression represents a mechanism of inhibitory filtering and evaluate this dysfunction in SZ; and 2) determine whether down- regulation of DMN by SN represents a mechanism supporting inhibitory processing and salience monitoring and evaluate the contribution of these processes to dysfunction in patients with SZ. By integrating findings across modalities to refine our understanding of the neural circuitry involved in aberrant inhibitory processing and salience in SZ, findings from this project will serve to inform future research into the development of targeted treatments. In addition to the outlined research objectives, the applicant will pursue coursework, clinical science training activities, and mentorship in order to develop as an independent researcher with expertise in the application of clinical neuroscience methods to elucidate mechanisms of cognitive impairment and clinical symptoms in psychopathology.