Causal Role of Medial Prefrontal Neural Activity in Self-Agency in Schizophrenia
Overview
- Phase
- Not Applicable
- Intervention
- Not specified
- Conditions
- Schizophrenia
- Sponsor
- University of California, San Francisco
- Enrollment
- 160
- Locations
- 1
- Primary Endpoint
- Self-Agency Behavioral Change during Speech Monitoring after TMS vs Baseline (metrics of speech perturbation units)
- Status
- Recruiting
- Last Updated
- 8 months ago
Overview
Brief Summary
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.
Detailed Description
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).
Investigators
Eligibility Criteria
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
Outcomes
Primary Outcomes
Self-Agency Behavioral Change during Speech Monitoring after TMS vs Baseline (metrics of speech perturbation units)
Time Frame: From baseline, to immediately after TMS, up to 1 week
Change in speech corrective responses during altered vs. unaltered auditory feedback, measured in units of speech perturbation (cents) from baseline to post-TMS. No scales used.
Self-Agency Behavioral Change during Reality Monitoring after TMS vs Baseline (metrics of accuracy)
Time Frame: From baseline, to immediately after TMS, up to 1 week
Change in retrieval accuracy of self-generated information during reality monitoring task from baseline to post-TMS. No scales used.
MEGI Neural Activity Change related to Self-Agency during Speech Monitoring after TMS vs Baseline (metrics of neural beta activation units)
Time Frame: From baseline, to immediately after TMS, up to 1 week
Whole-brain neural activity related to self-agency by contrasting oscillatory activity related to speech onset during altered auditory feedback with activity related to speech onset during unaltered auditory feedback (with focus on mPFC and parietal cortices for ROI analyses) measured in beta weights neural signal change from baseline to post-TMS. No scales used.
MEGI Neural Activity Change related to Self-Agency during Reality Monitoring after TMS vs Baseline (metrics of neural beta activation units)
Time Frame: From baseline, to immediately after TMS, up to 1 week
Whole-brain neural activity change related to self-agency by contrasting oscillatory activity during encoding and retrieval of self-generated information with encoding and retrieval of externally-derived information (with focus on mPFC and parietal cortices as our region-of-interest (ROI)), measured in beta weights neural signal change from baseline to post-TMS. No scales used.
Secondary Outcomes
- Cognition Change after TMS vs Baseline (metrics units of accuracy and speed of processing)(From baseline to immediate and distal time points after TMS, up to 4 weeks)
- Daily Functioning Change after TMS vs. Baseline (metrics of functioning)(From baseline to immediate and distal time points after TMS, up to 4 weeks)
- Clinical Symptom Change after TMS vs Baseline (metrics units of severity)(From baseline to immediate and distal time points after TMS, up to 4 weeks)