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）患者表现出过滤无关或冗余信息的能力缺陷 并且可能将显著性错误地归因于思想和事件。反过来，这些损伤可能会导致更高的- 水平认知功能障碍和临床症状与SZ相关。在脑电图研究中， 在听觉成对点击范例中，在SZ中可靠地观察到缺陷;在健康对照中（HC） 事件相关电位（ERP）的P50成分可靠地减少到第二个相同的水平。 而SZ个体对冗余信息的P50抑制降低。在 同样的范式，SZ个体表现出对初始刺激的N100 ERP反应降低， HC参与者，这可能反映了降低听觉显着性处理。一个独立的研究机构 使用功能磁共振成像已经将SZ中的抑制性和显著性监测缺陷与默认抑制不足联系起来 模式网络（DMN），支持内部关注的认知和自我参照处理。的突出地位 网络（SN）是一个负责监控显著性的高阶系统，根据任务需要调节DMN 需要注意外部刺激。考虑到与P50抑制相关的共享结构，N100 注意反应，以及DMN和SN的连接，我们假设这些措施捕获 在相同的机制内SZ功能障碍的方面。使用静息态功能磁共振成像，静息态脑电图， SZ患者（N = 84）和HC患者（N = 42）在配对点击范例期间记录的EEG， 研究采用多模态方法来识别和表征异常的抑制性和显著性 在SZ加工。该研究的主要目的是1）确定DMN抑制是否代表 抑制性过滤的机制，并评估这种功能障碍在SZ;和2）确定是否下降- SN对DMN的调节代表了一种支持抑制加工和显著性监测的机制 并评估这些过程对SZ患者功能障碍的贡献。通过整合调查结果 以完善我们对异常抑制处理中涉及的神经回路的理解 和突出的深圳，从这个项目的结果将有助于通知未来的研究发展， 有针对性的治疗除了概述的研究目标，申请人将追求课程， 临床科学培训活动，并指导，以发展为一个独立的研究人员， 应用临床神经科学方法阐明认知障碍机制的专业知识 和精神病理学中的临床症状