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

识别精神分裂症患者异常抑制处理和显着性的神经机制

• 批准号: 10156079
• 负责人: Anika Maya Guha
• 金额: $ 2.5万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2021-08-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10156079
• 关键词: Attention; Auditory; Brain; Brain region; Clinical; Clinical Sciences; Cognition; Cognitive deficits; Communication; Data; Development; Disease; Down-Regulation; Electroencephalography; Event; Event-Related Potentials; Exhibits; Functional Magnetic Resonance Imaging; Functional disorder; Goals; Impaired cognition; Impairment; Individual; Investigation; Link; Maintenance; Measures; Mentorship; Methods; Modality; Monitor; Neurocognitive; Neurosciences; Participant; Pathway Analysis; Patients; Play; Prevention; Process; Property; Psychopathology; Psychoses; Research; Research Personnel; Resolution; Rest; Role; Schizophrenia; Sensitivity and Specificity; Sensory; Siblings; Stimulus; Symptoms; System; Thinking; Training Activity; associated symptom; auditory stimulus; clinical application; cognitive function; cognitive process; functional magnetic resonance imaging/electroencephalography; functional outcomes; high risk; improved; interest; multimodality; neural circuit; neural network; neuroimaging; neuromechanism; programs; psychotic symptoms; relating to nervous system; response; skills; support network; temporal measurement; therapy development

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.

项目摘要 精神分裂症（SZ）的个体表现出过滤无关或冗余信息的能力的缺陷 并可能错误地将显着性归因于思想和事件。反过来，这些障碍可能有助于更高 与SZ相关的水平认知功能障碍和临床症状。在脑电图研究中，抑制处理 在听觉配对单击范式中，在SZ中可靠地观察到缺陷；在健康比较（HC）中 参与者，与事件相关电位（ERP）的P50组件可靠地降低到第二个相同 一对刺激，而SZ的个体显示P50对冗余信息的抑制作用降低。在 相同的范式，具有SZ的个体表现出对初始刺激相对的N100 ERP响应的降低 对于HC参与者来说，这可能反映了听觉显着性处理的减少。单独的研究机构 使用fMRI已将SZ中的抑制性和显着性监测缺陷链接到不足的默认值 模式网络（DMN），该网络支持内部以内部为中心的认知和自我参照处理。显着性 网络（SN）是一种负责监视显着性的高阶系统，根据需要调节DMN 需要注意外部刺激。鉴于与P50抑制相关的共享构造，N100 注意响应以及DMN和SN的连通性，我们假设这些措施捕获了 同一机制中SZ功能障碍的各个方面。使用静止状态fMRI，静止状态脑电图和 在SZ患者（n = 84）和HCS（n = 42）的配对单击范式中记录的脑电图（n = 42） 研究采用多模式的方法来识别和表征异常的抑制和显着性 在SZ中处理。该研究的主要目的是1）确定DMN抑制是否代表 抑制过滤的机制并评估SZ中这种功能障碍的机制； 2）确定是否向下 - SN对DMN的调节表示支持抑制性处理和显着性监测的机制 并评估这些过程对SZ患者功能障碍的贡献。通过整合发现 跨越模式，以完善我们对涉及异常抑制处理的神经回路的理解 和SZ中的显着性，该项目的发现将为未来的研究提供有关开发的研究 有针对性的治疗。除了概述的研究目标外，申请人还将追求课程工作， 临床科学培训活动和指导，以发展为独立研究人员 在临床神经科学方法应用方面的专业知识来阐明认知障碍机制 和心理病理学的临床症状。