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

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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.