Medial-prefrontal Enhancement During Schizophrenia Systems Imaging

Schizophrenia Clinical Trial

— MESSI  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04807530
• Other study ID #: 122897
• Secondary ID: 1R01MH122897-01
• Status: Recruiting
• Phase: N/A
• Start date: November 12, 2020
• Est. completion date: December 30, 2026

Study information

• Verified date: May 2024
• Source: University of California, San Francisco
• Contact: Yingxin Jia, PhD
• Phone: 4152486534
• Email: yingxin.jia[@]ucsf.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 160
• Est. completion date: December 30, 2026
• Est. primary completion date: December 30, 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 64 Years

Eligibility

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

Related Conditions & MeSH terms

• Schizophrenia

Intervention

Device:
• TMS
The investigators will use the NEXSTIM NAVIGATED BRAIN STIMULATION (NBS) SYSTEM to apply 10 Hz nrTMS to healthy controls (HC) and schizophrenia patients (SZ)

Locations

Country	Name	City	State
United States	UCSF	San Francisco	California

Sponsors (2)

Lead Sponsor	Collaborator
University of California, San Francisco	National Institute of Mental Health (NIMH)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Self-Agency Behavioral Change during Reality Monitoring after TMS vs Baseline (metrics of accuracy)	Change in retrieval accuracy of self-generated information during reality monitoring task from baseline to post-TMS. No scales used.	From baseline, to immediately after TMS, up to 1 week
Primary	Self-Agency Behavioral Change during Speech Monitoring after TMS vs Baseline (metrics of speech perturbation units)	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.	From baseline, to immediately after TMS, up to 1 week
Primary	MEGI Neural Activity Change related to Self-Agency during Reality Monitoring after TMS vs Baseline (metrics of neural beta activation units)	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.	From baseline, to immediately after TMS, up to 1 week
Primary	MEGI Neural Activity Change related to Self-Agency during Speech Monitoring after TMS vs Baseline (metrics of neural beta activation units)	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.	From baseline, to immediately after TMS, up to 1 week
Secondary	Cognition Change after TMS vs Baseline (metrics units of accuracy and speed of processing)	The PENN Cognitive battery is a validated assessment of cognition in which accuracy scores and reaction times will computed after TMS compared to baseline.The PENN Cognitive battery includes 10 brief cognitive tests, and the score ranges between 0 (worst possible performance) and 1000 (best possible performance).	From baseline to immediate and distal time points after TMS, up to 4 weeks
Secondary	Clinical Symptom Change after TMS vs Baseline (metrics units of severity)	Clinical Symptom Change will be measured by the validated SAPS and SANS over the past week after TMS compared to baseline. Possible scores depending on the sub scale can range from 0(Absent) to 7 (Extreme).	From baseline to immediate and distal time points after TMS, up to 4 weeks
Secondary	Daily Functioning Change after TMS vs. Baseline (metrics of functioning)	Daily functioning will be measured with the Global Assessment of Functioning (GAF) scale over the past week, after TMS compared to baseline. Possible score range from 0 (inadequate information or in persistent danger of severely hurting self or others) to 100 (superior functioning in a wide range of activities)	From baseline to immediate and distal time points after TMS, up to 4 weeks