Clinical trial NCT04807530: Medial-prefrontal Enhancement During Schizophrenia Systems Imaging
Official title: Causal Role of Medial Prefrontal Neural Activity in Self-Agency in Schizophrenia
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Schizophrenia
Keywords: Schizophrenia
Transcranial Magnetic Stimulation
Prefrontal Cortex
Self-Agency
Reality Monitoring
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: National Institute of Mental Health (NIMH)
First posted: 2021-03-19
Enrollment: 160
Sex: ALL
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The investigators propose a longitudinal randomized controlled trial (RCT) in which 80 SZ and 80 HC are randomly assigned to either active high-frequency 10Hz nrTMS to increase activity in medial/superior prefrontal cortex (mPFC) or a control posterior parietal site. The investigators assess durability and generalizability of how active 10Hz nrTMS modulation of mPFC activity in HC and SZ causally induces neural network changes that mediate behavioral changes in self-agency to impact overall cognition, clinical and daily functioning, compared to the control parietal site and baseline.
Primary purpose: TREATMENT

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).

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

Primary outcomes:
measure: Self-Agency Behavioral Change during Reality Monitoring after TMS vs Baseline (metrics of accuracy)
timeFrame: From baseline, to immediately after TMS, up to 1 week
measure: Self-Agency Behavioral Change during Speech Monitoring after TMS vs Baseline (metrics of speech perturbation units)
timeFrame: From baseline, to immediately after TMS, up to 1 week
measure: MEGI Neural Activity Change related to Self-Agency during Reality Monitoring after TMS vs Baseline (metrics of neural beta activation units)
timeFrame: From baseline, to immediately after TMS, up to 1 week
measure: MEGI Neural Activity Change related to Self-Agency during Speech Monitoring after TMS vs Baseline (metrics of neural beta activation units)
timeFrame: From baseline, to immediately after TMS, up to 1 week
Secondary outcomes:
measure: Cognition Change after TMS vs Baseline (metrics units of accuracy and speed of processing)
timeFrame: From baseline to immediate and distal time points after TMS, up to 4 weeks
measure: Clinical Symptom Change after TMS vs Baseline (metrics units of severity)
timeFrame: From baseline to immediate and distal time points after TMS, up to 4 weeks
measure: Daily Functioning Change after TMS vs. Baseline (metrics of functioning)
timeFrame: From baseline to immediate and distal time points after TMS, up to 4 weeks
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: UCSF
state: California
Study officials:
affiliation: University of California, San Francisco
name: Karuna Subramaniam, PhD
role: PRINCIPAL_INVESTIGATOR
References: