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Medial-prefrontal Enhancement During Schizophrenia Systems Imaging (MESSI)

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ClinicalTrials.gov Identifier: NCT04807530
Recruitment Status : Recruiting
First Posted : March 19, 2021
Last Update Posted : March 25, 2021
Sponsor:
Collaborator:
National Institute of Mental Health (NIMH)
Information provided by (Responsible Party):
University of California, San Francisco

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 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.

Condition or disease Intervention/treatment Phase
Schizophrenia Device: TMS Not Applicable

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 5 daily sessions of either active 10Hz nrTMS targeting mPFC (40HC and 40SZ) or nrTMS targeting a control posterior superior temporal site (pSTS) (40HC and 40SZ). For the pSTS 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 pSTS 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).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 160 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
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 mPFC or a control posterior Superior Temporal Sulcus (pSTS) 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 pSTS site and baseline.
Masking: Triple (Participant, Care Provider, Outcomes Assessor)
Masking Description: Participants and care providers and all outcomes assessors will be blinded as to whether participants will receive the active nrTMS or control nrTMS.
Primary Purpose: Treatment
Official Title: Causal Role of Medial Prefrontal Neural Activity in Self-Agency in Schizophrenia
Actual Study Start Date : November 12, 2020
Estimated Primary Completion Date : December 30, 2025
Estimated Study Completion Date : April 30, 2026

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Schizophrenia

Arm Intervention/treatment
Active Comparator: Medial Prefrontal TMS
10 Hz High frequency TMS applied to the mPFC
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)

Placebo Comparator: Posterior Superior Temporal TMS
10 Hz high frequency TMS applied to the pSTS
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)




Primary Outcome Measures :
  1. 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.

  2. 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.

  3. 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 pSTS as our region-of-interest (ROI)), measured in beta weights neural signal change from baseline to post-TMS. No scales used.

  4. 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 pSTS for ROI analyses) measured in beta weights neural signal change from baseline to post-TMS. No scales used.


Secondary Outcome Measures :
  1. Cognition Change after TMS vs Baseline (metrics units of accuracy and speed of processing) [ Time Frame: From baseline to immediate and distal time points after TMS, up to 4 weeks ]
    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).

  2. Clinical Symptom Change after TMS vs Baseline (metrics units of severity) [ Time Frame: From baseline to immediate and distal time points after TMS, up to 4 weeks ]
    Clinical Symptom Change will be measured by the validated CAINS and HAM-D Integrated Clinical Interview (CHICI) over the past week after TMS compared to baseline. Possible scores depending on the sub scale can range from 0(Absent) to 7 (Extreme).

  3. Daily Functioning Change after TMS vs. Baseline (metrics of functioning) [ Time Frame: From baseline to immediate and distal time points after TMS, up to 4 weeks ]
    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)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04807530


Contacts
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Contact: Yingxin Jia, PhD 4152486534 yingxin.jia@ucsf.edu
Contact: Karuna Subramaniam, PhD karuna.subramaniam@ucsf.edu

Locations
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United States, California
UCSF Recruiting
San Francisco, California, United States, 94143
Contact: Yingxin Jia, PhD       yingxin.jia@ucsf.edu   
Contact: Yingxin Jia         
Sponsors and Collaborators
University of California, San Francisco
National Institute of Mental Health (NIMH)
Investigators
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Principal Investigator: Karuna Subramaniam, PhD University of California, San Francisco
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Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT04807530    
Other Study ID Numbers: 122897
1R01MH122897-01 ( U.S. NIH Grant/Contract )
First Posted: March 19, 2021    Key Record Dates
Last Update Posted: March 25, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: 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.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Analytic Code
Time Frame: 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

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: Yes
Keywords provided by University of California, San Francisco:
Schizophrenia
Transcranial Magnetic Stimulation
Prefrontal Cortex
Self-Agency
Reality Monitoring
Additional relevant MeSH terms:
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Schizophrenia
Schizophrenia Spectrum and Other Psychotic Disorders
Mental Disorders