Accelerated Neuromodulation Therapy and Neurocomputational Biomarkers in Individuals at Clinical High Risk for Psychosis

There is currently no clinically validated treatment that reduces the risk of psychosisonset or mitigates the severity of a first psychotic episode in individuals at clinicalhigh risk for psychosis (CHR‐P). CHR‐P is associated with attenuated psychotic symptoms,functional decline, and high rates of affective symptoms, including a comorbid mooddisorder prevalence of 40% or higher. Repetitive transcranial magnetic stimulation (rTMS)targeting the left dorsolateral prefrontal cortex (LDLPFC) is an established treatmentfor depression and is increasingly supported for negative symptoms in psychoticdisorders, making it a promising low‐burden candidate for early intervention in CHR‐P.This pilot study evaluates an accelerated intermittent theta burst stimulation (iTBS)protocol, delivered over five consecutive days, in individuals at CHR‐P (SIPS‐confirmed,aged 18‐34). Forty participants will be randomized 1:1 to active accelerated iTBS or shamstimulation to the LDLPFC, using standard scalp‐based (BEAM‐F3) targeting rather thanMRI‐guided neuronavigation, reflecting the pilot nature and funding constraints of thisearly‐phase study.Given the variable incidence of and long latency to psychosis onset in the CHR‐Ppopulation, this study also incorporates a battery of neurocomputational tasks (analyzedusing Hierarchical Gaussian Filter modeling) and a multimodal digital phenotypingframework (wearables, smartphone‐based passive sensing, facial/vocal affect analysis, andstructured speech analysis) to assess candidate biomarkers of treatment response.Primary outcomes are the safety, feasibility, and tolerability of the acceleratedprotocol in this population. Secondary outcomes include the sensitivity ofneurocomputational biomarkers to treatment and change in depressive symptoms. Exploratoryoutcomes include treatment‐related change across multiple domains of real‐worldfunctioning captured through digital phenotyping. This study is not designed to establishdefinitive treatment efficacy but to inform the design of future, adequately poweredtrials.