Causal Role of Medial Prefrontal Neural Activity in Self-Agency in Schizophrenia

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Project Summary Patients with schizophrenia (SZ) show severe deficits in self-agency (i.e., the experience of being the agent of one's own thoughts and actions), that directly contribute to debilitating psychotic symptoms and distort reality monitoring (i.e., defined as distinguishing self-generated information from externally-derived information). Current medications are inadequate with up to 40% of SZ remaining symptomatic, thus compelling the need to understand the neurobiology underlying self-agency deficits which we believe drives psychotic experiences in SZ. Here, we test for the first time a novel causal cognitive and neurobiological model underlying self-agency with the aim of developing new effective treatments in SZ. In particular, we examine whether the resulting experience of self-agency is driven by the fundamental ability to make reliable predictions about the outcomes of one's own self-generated actions. This self-prediction ability is critical for the successful encoding and memory retrieval of one's own thoughts and actions during reality monitoring to enable accurate self-agency judgments (i.e., accurate identification of self-generated information). This self-prediction ability is also critical for speech monitoring where we continually compare what we hear while we speak with what we expect to hear. Prior studies have shown that the medial prefrontal cortex (mPFC) is a potential neural substrate that mediates both lower-level self-predictions during speech monitoring, and higher-level self-agency judgments during reality monitoring in healthy controls (HC). Here, we now test whether mPFC activity can causally modulate this self- prediction ability to impact self-agency on two different tasks of reality and speech monitoring. We propose a longitudinal randomized controlled trial in which HC and SZ are assigned to 5 daily sessions of either active high- frequency 10Hz transcranial magnetic stimulation (TMS) to increase mPFC activity or to sham TMS. We use repeated measures of magnetoencephalography imaging (MEGI) to assay neural activity underlying self-agency on reality and speech monitoring tasks from pre-to-post TMS at time-points: (i) baseline, (ii) proximal post-TMS (i.e., right after TMS intervention), and (iii) distal post-TMS (i.e., 1 week after TMS intervention). The specific aims are to delineate with MEGI, proximal and distal mechanisms of how active 10Hz TMS modulates mPFC activity in HC and SZ to induce neural network and behavioral changes in self-agency in reality and speech monitoring tasks, compared to baseline and sham. The overall hypothesis is that high frequency TMS will increase mPFC excitability and enhance self-predictions to improve self-agency on distinct tasks of speech and reality monitoring. If successful, this project will establish mPFC as a new biological target for TMS therapies in SZ, and will show that mPFC provides a unitary basis for self-agency driven by reliance on self-predictions. The long-term objective is to delineate mechanisms of durability and generalizability of how improvements in critical self-agency abilities after TMS of mPFC, can generalize to improvements in cognition, symptoms and life quality in SZ for future TMS treatment development.