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

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. \- Following real interventions, novel biomarkers will be more effective predictors of clinical outcome than standard biomarkers in participants at CHR for psychosis
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. \- The novel interventions will reduce biomarker abnormalities in individuals with CHR relative to their own baselines and relative to healthy controls (HC)
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

Interventions

DEVICE

Mb-rt-fMRI-NFB

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.

DEVICE

Sham mb-rt-fMRI-NFB

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.

DEVICE

rTMS

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.

DEVICE

Sham rTMS

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.

Sponsors & Collaborators

• Shanghai Jiao Tong University School of Medicine

  collaborator OTHER

• Florida A&M University

  collaborator OTHER

• Brigham and Women's Hospital

  collaborator OTHER

• Massachusetts General Hospital

  collaborator OTHER

• VA Boston Healthcare System

  collaborator FED

• National Institute of Mental Health (NIMH)

  collaborator NIH

• Beth Israel Deaconess Medical Center

  lead OTHER

Principal Investigators

• William S Stone, Ph.D. · Beth Israel Deaconess Medical Center

Study Design

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

QUADRUPLE

Model

PARALLEL

Eligibility

Min Age

15 Years

Max Age

35 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2024-01-01

Primary Completion

2027-06-30

Completion

2027-06-30

Countries

• China

Study Locations