Mechanisms of Response to Therapeutic Intervention in Clinical High Risk (CHR) for Psychosis

NCT06542640 | Recruiting DMC

• 2 other identifiers: 2023P0010892R01MH111448
• Study Type: interventional
• Target: 300
• Locations: 1 country
• Sites: 1

Brief Summary

This study, "Psychobiological Follow-up Study of Transition from Prodrome to Early Psychosis", will be conducted in collaboration with the Shanghai Mental Health Center (SMHC) and several data processing sites in the United States. The current study builds on findings from the investigator's previous work that identified several biomarkers in participants at clinical high risk (CHR) for psychosis that may be related to clinical outcomes such as the development of psychosis. This study responds to the critical need to understand links between biomarkers (could be clinical, cognitive, biological or other abnormalities) and later clinical outcomes. Participants will receive either one of two real interventions or one of two sham (a procedure that looks like the real treatment but is not) interventions, involving either: 1. repetitive transcranial magnetic stimulation (rTMS)1; or 2. mindfulness-based real time fMRI neurofeedback (mb-rt-fMRI-NFB). Both procedures will measure brain capacity for change in CHR individuals, thus paving the way forward for future therapeutic interventions. The main hypotheses to be addressed by this study are:

1. 1.\- Following real interventions, novel biomarkers will be more effective predictors of clinical outcome than standard biomarkers in participants at CHR for psychosis
2. 2.\- Following real interventions, novel biomarkers will be more effective predictors of clinical outcomes in participants who received the real intervention than in participants who received sham treatments
3. 3.\- The novel interventions will reduce biomarker abnormalities in individuals with CHR relative to their own baselines and relative to healthy controls (HC)
4. 4.\- The sham interventions will will not reduce biomarker abnormalities in individuals with CHR relative to their own baselines or relative to HC

Conditions

Psychosis; Schizophrenia-Like; Healthy Controls

Keywords

real-time fMRI neurofeedback (rt-fMRI-NFB); mindfulness-based (mb); mb rt-fMRI-NFB (mb-rt-fMRI-NFB); repet. transcran mag stim (rTMS); neuropsycho (NP); diffusion tensor imaging (DTI); clinical high risk (CHR); healthy control (HC); MATRICS Consenus Cog Batt (MCCB)

Outcome Measures

Primary Outcomes (2)

• mb-rt-fMRI-NFB intervention: functional connectivity

  Context-dependent changes in functional connectivity (i.e., coupling) between brain regions will be measured by statistical software programs as Pearson correlation coefficients between brain regions whose activity depends on an interaction between psychological context (the task) and physiological state (the time course of brain activity)

  1 month, 1 year, 2 years

• rTMS intervention: functional connectivity

  Context-dependent changes in functional connectivity (i.e., coupling) between brain regions will be measured by statistical software programs as Pearson correlation coefficients between brain regions whose activity depends on an interaction between psychological context (the task) and physiological state (the time course of brain activity)

  1 month, 1 year, 2 years

Secondary Outcomes (14)

• Clinical

  1 month, 1 year, 2 years

• Neuropsychological function: verbal learning

  1 month, 1 year, 2 years

• Neuropsychological function: visual learning

  1 month, 1 year, 2 years

• Neuropsychological function: visual-spatial / speed of processing

  1 month, 1 year, 2 years

• Neuropsychological function: verbal fluency / speed of processing

  1 month, 1 year, 2 years

Study Arms (5)

CHR with mb-rt-fMRI-NFB Group

EXPERIMENTAL

This CHR group will receive experimental treatment via mb-rt-fMRI-NFB, in a targeted frontal lobe region including the dorsolateral prefrontal cortex (DLPFC).

Device: Mb-rt-fMRI-NFB

CHR with sham mb-rt-fMRI-NFB Group

SHAM COMPARATOR

This CHR group will receive treatment via mb-rt-fMRI-NFB, but in a different, uninvolved brain region

Device: Sham mb-rt-fMRI-NFB

CHR with rTMS Group

EXPERIMENTAL

This CHR group will receive experimental treatment via rTMS, along a targeted neural pathway extending from the cerebellum to the midbrain to the dorsolateral prefrontal cortex (DLPFC)

Device: rTMS

CHR with sham rTMS Group

SHAM COMPARATOR

This CHR group will receive treatment via rTMS, but in a different, uninvolved brain region

Device: Sham rTMS

Healthy Control Group

NO INTERVENTION

The healthy control group will not receive any treatment, but will be used as a comparison for the 2 experimental and 2 sham groups.

Interventions

Mb-rt-fMRI-NFB DEVICE

The MRI and TMS interventions described below will yield measures of change in the targeted brain regions in post- relative to pre- intervention comparisons. These change measures will be compared relative to changes in the sham/control group and the HC group. Furthermore, they will be compared to HC to assess improvement or normalization of brain function in the targeted brain regions. In addition, the investigators will examine treatment effects on traditional biomarkers that are likely to be impacted by such interventions: ERP, NP and NLP measures. Here, mindfulness meditation practiced during a real-time fMRI NFB session will be used to bring connectivity changes to brain structures involved in positive psychiatric symptoms (e.g. attenuated psychotic symptoms) in order to to reduce them.

CHR with mb-rt-fMRI-NFB Group

Sham mb-rt-fMRI-NFB DEVICE

Individuals with CHR who are randomly assigned to this arm will receive mb-rt-fMRI-NFB, as do the experimental group, but it will be aimed at a motor cortex location that is not part of the prefrontal neural networks targeted in the experimental group.

CHR with sham mb-rt-fMRI-NFB Group

rTMS DEVICE

In previous work, the investigators used a multivariate pattern analysis to identify functional connectivity correlates of negative symptom severity in a schizophrenia (SZ) group. DLPFC-cerebellum hypo-connectivity was strongly correlated with negative symptoms. In a separate SZ cohort, the investigators used rTMS targeting the cerebellum to manipulate this circuit. The rTMS-induced increase in functional connectivity in a cerebellar-midbrain-DLPFC circuit was strongly linked to negative symptom severity reduction. Furthermore, individuals varied in the degree of change in functional connectivity in response to rTMS. This variation strongly predicted variation in post-rTMS symptom severity. The investigators predict that rTMS based intervention, but not sham rTMS, will similarly impact the cerebellar-midbrain-dorsolateral prefrontal cortex (DLPFC) network in the CHR group receiving real but not sham rTMS.

CHR with rTMS Group

Sham rTMS DEVICE

Individuals with CHR who are randomly assigned to this arm will receive rTMS, as do the experimental group, but it will be aimed at a motor cortex location that is not part of the prefrontal neural networks targeted in the experimental group.

CHR with sham rTMS Group

Eligibility Criteria

• Age: 15 Years - 35 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Clinical High Risk (CHR):
• Male or female between 15 and 35 years old.
• Can understand and sign an informed consent (or assent for minors) document.
• Must meet the substance use criteria:
• No Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DSM-5) Alcohol or Drug Dependence in the past 3 months;
• No use on the day of assessment, clearly not intoxicated or hung-over.
• Must meet diagnostic criteria for a prodromal syndrome. If under the age of 19 and meet diagnostic criteria for Schizotypal Personality Disorder or meet the diagnostic criteria called the Criteria for Prodromal Syndromes (COPS), which are operationalized as follows (a-c below):
• Genetic Risk and Deterioration Syndrome (GRDS): First degree biological relative with psychosis or subject with Schizotypal Personality Disorder and a 30% drop in Global Assessment of Functioning (GAF) score compared to one year ago, sustained over the past month.
• Attenuated Positive Symptoms Syndrome (APSS): Severity rating of moderate (rating of 3), moderately severe (4) or severe but not psychotic (5) on any one of the five Symptoms of Psychotic Disorders (SOPS) positive symptoms; symptom occurs at or above moderate severity level at an average frequency of at least once per week in the past month; symptom must have begun in the past year or currently rates at least one scale point higher than rated 12 months previously.
• Brief Intermittent Psychotic Syndrome (BIPS): Severity rating of psychotic intensity (6) on any of the 5 SOPS positive symptoms; symptom is present at least several minutes per day at a frequency of at least once per month; symptom(s) must have reached a psychotic intensity in the past 3 months; symptom is not seriously disorganizing or dangerous; symptom(s) do not last for more than 1 hour/day at an average frequency of 4 days/week over 1 month.
• Participant may be remitted from the CHR syndrome or may have converted to a full psychotic disorder since study entry and either is acceptable - they remain eligible to participate in follow-up procedures.

You may not qualify if:

• Meet criteria for current or lifetime Axis I psychotic disorder, including affective psychoses and psychosis Not Otherwise Specified (NOS) at the baseline assessment
• Impaired intellectual functioning (i.e., Intelligence Quotient (IQ)\<70) at baseline.
• Past history of or current clinically significant central nervous system disorder that may contribute to prodromal symptoms or confound their assessment.
• Traumatic Brain Injury that is rated as 7 or above on the Traumatic Brain Injury screening instrument (signifying a significant brain injury with persistent sequelae) or current concussion that interferes with any assessment measures.
• Healthy Controls (HC):
• Must not have a family history (in first-degree relatives) of schizophrenia, schizoaffective disorder, schizotypal personality disorder, or any other disorder involving psychotic symptoms.

Sponsors & Collaborators

• Beth Israel Deaconess Medical Center: lead
• Shanghai Jiao Tong University School of Medicine: collaborator
• Florida A&M University: collaborator
• Brigham and Women's Hospital: collaborator
• Massachusetts General Hospital: collaborator
• VA Boston Healthcare System: collaborator
• National Institute of Mental Health (NIMH): collaborator

Study Sites (1)

Shanghai Mental Health Center

Shanghai, Shanghai Municipality, China

RECRUITING

Related Publications (4)

• Brady RO Jr, Gonsalvez I, Lee I, Ongur D, Seidman LJ, Schmahmann JD, Eack SM, Keshavan MS, Pascual-Leone A, Halko MA. Cerebellar-Prefrontal Network Connectivity and Negative Symptoms in Schizophrenia. Am J Psychiatry. 2019 Jul 1;176(7):512-520. doi: 10.1176/appi.ajp.2018.18040429. Epub 2019 Jan 30.

  PMID: 30696271 BACKGROUND

• Okano K, Bauer CCC, Ghosh SS, Lee YJ, Melero H, de Los Angeles C, Nestor PG, Del Re EC, Northoff G, Whitfield-Gabrieli S, Niznikiewicz MA. Real-time fMRI feedback impacts brain activation, results in auditory hallucinations reduction: Part 1: Superior temporal gyrus -Preliminary evidence. Psychiatry Res. 2020 Apr;286:112862. doi: 10.1016/j.psychres.2020.112862. Epub 2020 Feb 10.

  PMID: 32113035 BACKGROUND

• Bauer CCC, Okano K, Ghosh SS, Lee YJ, Melero H, Angeles CL, Nestor PG, Del Re EC, Northoff G, Niznikiewicz MA, Whitfield-Gabrieli S. Real-time fMRI neurofeedback reduces auditory hallucinations and modulates resting state connectivity of involved brain regions: Part 2: Default mode network -preliminary evidence. Psychiatry Res. 2020 Feb;284:112770. doi: 10.1016/j.psychres.2020.112770. Epub 2020 Jan 14.

  PMID: 32004893 BACKGROUND

• Niznikiewicz MA, Brady RO, Whitfield-Gabrieli S, Keshavan MS, Zhang T, Li H, Pasternak O, Shenton ME, Wang J, Stone WS. Dynamic intervention-based biomarkers may reduce heterogeneity and motivate targeted interventions in clinical high risk for psychosis. Schizophr Res. 2022 Aug;246:60-62. doi: 10.1016/j.schres.2022.05.004. Epub 2022 Jun 13. No abstract available.

  PMID: 35709648 RESULT

MeSH Terms

Conditions

Psychotic Disorders

Condition Hierarchy (Ancestors)

Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders

Study Officials

• William S Stone, Ph.D.

  Beth Israel Deaconess Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

William S Stone, Ph.D.

CONTACT

5087402050; wstone@bidmc.harvard.edu

Margaret A Niznikiewicz, Ph.D.

CONTACT

6176534627; margaret_niznikiewicz@hms.harvard.edu

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Participants and investigators will be blinded to whether participants at CHR for psychosis are randomized to either the real treatment or to the sham conditions for either of the mb-rt-fMRI-NFB or the rTMS conditions. Similarly, outcomes assessors and clinical care providers will be blinded as well.
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Psychology in the Department of Psychiatry

Model Details: The study will consist of two interventions and 2 full assessments, (pre- and post-intervention) (year 1) followed by two clinical/NP/NLP/ERP assessments in years 2 and 3 relative to a CHR's entry to the study. To minimize the time lag between HC's assessment and the last follow-up assessment of the CHR, 50 HC participants will be recruited at the study onset and 50 additional HC will be recruited at years 3 and 4 of the grant. Baseline assessments will be followed by random assignment of CHR subjects to either an intervention group (100 CHR) or sham group (100 CHR). The intervention group will receive either the TMS (50 CHR) or rt-fMRI NFB (50 CHR), with the random CHR assignment to the arm of the study. The sham groups will also be counterbalanced across subjects, with 50 CHR in the TMS-sham and 50 CHR in the rt-fMRI NFB-first group. The two interventions will be delivered over two-week period, followed by post-intervention assessments.

Study Record Dates

• First Submitted: July 8, 2024
• First Posted: August 7, 2024
• Study Start: January 1, 2024
• Primary Completion (Estimated): June 30, 2027
• Study Completion (Estimated): June 30, 2027
• Last Updated: April 20, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will share
• Time Frame: Data will be submitted to NDCT on a semi-annual basis (on or before January 15 and July 15, beginning six months after the award budget period has begun). Raw neuroimaging data will be submitted incrementally as new data are acquired. Descriptive/raw research data are held until the finding is communicated or published. Analyzed data are expected at the time a manuscript is accepted for publication. These data will then be shared when the publication is released, along with the associated descriptive data. Data that remain unpublished are expected prior to project completion and will be shared within one year after the original project completion date, allowing the Principal Investigator and his/her team sufficient time to complete appropriate quality assurance/quality control procedures.
• Access Criteria: All submitted data (both descriptive/raw and analyzed data) will be made available for access by qualified members of the research community according to the provisions defined in the National Institute of Mental Health (NIMH) Data Repositories Data Access Agreement and Use Certification. These procedures are intended to allow investigators sufficient time for data verification, and for submission of primary publications based on the collected data.

Locations

CN (1)