This randomized controlled trial in healthy controls (HC) and patients with schizophrenia (SZ) aims to examine 1) the underlying cognitive and neural cause of self-agency deficits in SZ; 2) the responsiveness to a novel navigated repetitive transcranial magnetic stimulation (nrTMS) target in the medial/superior prefrontal cortex (mPFC); and 3) how modulation of mPFC activity impacts the larger self-agency network to mediate changes in self-agency judgments. Our overall hypothesis is that increased mPFC excitability by active high-frequency nrTMS in HC and SZ will induce behavioral improvements in self-agency and neural changes in the larger self-agency network that will generalize to improvements in overall cognition, symptoms and daily functioning, and will likely lead to the development of new effective neuromodulation therapies in patients with schizophrenia.

This longitudinal mechanistic randomized controlled trial in patients with schizophrenia (SZ) and matched healthy controls (HC) examines the underlying cause of self-agency deficits in SZ and their responsiveness to navigated repetitive transcranial magnetic stimulation (nrTMS) of the medial prefrontal cortex. Using a multimodal neuroimaging approach that combines structural MRI with functional magnetoencephalography imaging (MEGI) and nrTMS that is integrated with cognitive and clinical assessments, this research provides an unprecedented rigorous assessment of the neural and cognitive basis of self-agency and its modulation by nrTMS, using two distinct and validated paradigms involving speech monitoring (pitch perturbation) and reality monitoring.

Subjects will first be assessed for 1 week for diagnostic inclusion criteria and eligibility assessment. They will complete baseline assessments (i.e., cognitive, clinical and daily functioning assessments, structural MRI, and MEGI scans while they perform reality and speech monitoring tasks). After baseline assessments, 80 SZ and 80 age, gender, and education-matched HC will be randomly assigned to either active 10Hz nrTMS targeting mPFC (40HC and 40SZ) or nrTMS targeting a control posterior parietal site (40HC and 40SZ). For the parietal site, the investigators will use the same TMS protocol parameters as the active nrTMS condition. Between and within group analyses will utilize repeated measures mixed-effects models to examine durability and generalizability of behavioral, cognitive, clinical and whole-brain neural oscillatory network changes (with focus on mPFC) after neuromodulation by active nrTMS at proximal, and distal post-nrTMS time-points, compared to control nrTMS of parietal site and baseline. Whole-brain correlations will be computed between neural activity (e.g., with focus on mPFC) related to self-agency during reality and speech monitoring tasks and behavior (e.g., self-generated retrieval accuracy and corrective response magnitude), and between neural activity with cognition, clinical symptoms and daily functioning).

Inclusion Criteria:

All Subjects:

• Good general physical health
• English is first language
• No neurological disorder
• Meets MRI criteria
• No current alcohol or substance use disorder

Schizophrenia participants:

• Schizophrenia diagnosis of any illness duration,
• Clinical stability, defined as 12 weeks outpatient status and 4 weeks low to moderate dose of antipsychotic medication (<1000 mg. chlorpromazine equivalents), plus stable doses of all other psychotropic medications

Exclusion Criteria:

All Subjects:

• Implanted metallic parts of implanted electronic devices
• Pregnant or trying to become pregnant
• Any condition that would prevent the subject from giving voluntary informed consent
• Scalp wounds or infections
• Claustrophobia precluding MRI
• Ongoing seizures
• Neurological disorder

De-identified data will include clinical, behavioral and cognitive scores, nrTMS data, and neuroimaging data. Neuroimaging data will include MEGI and structural MRI scans. All de-identified data will also be made available through presentations at scientific conferences, symposia, and seminars, as well as through publications in scientific journals. All University of California employees are committed to an open access policy to make all publications freely available. In compliance with this policy, all publications resulting from this proposal will be submitted for archiving on PubMed Central and BioRxiv.

The investigators aim to complete all data analyses by end of 2025-2026, when the complete, and all deidentified data will be available for sharing

Participants and care providers and all clinical outcomes assessors will be blinded as to whether participants will receive the active nrTMS or control nrTMS.