Temporal Interference Stimulation (TI) for Schizophrenia (SCZ)

This multicenter, randomized, double-blind, parallel-group, sham-controlled trial will evaluate individualized temporal interference (TI) stimulation targeting the left insula as an adjunct to usual clinical treatment for schizophrenia. Randomization will be stratified by study center with a 1:1 allocation ratio. An independent statistician will generate the randomization sequence, which will be implemented through a central randomization system after eligibility confirmation and baseline assessment. Access to treatment allocation codes will be restricted to authorized unblinded personnel who are not involved in outcome assessment or data analysis. Baseline high-resolution three-dimensional T1-weighted magnetic resonance imaging (MRI) will be used to construct an individualized finite-element head model. The positions and channel configuration of two pairs of scalp electrodes will be optimized to enhance the modeled modulation field within the predefined left-insula target while reducing electric-field exposure in superficial cortical and other nontarget regions. Active TI will use carrier frequencies of 2000 Hz and 2005 Hz to produce a 5-Hz modulation frequency. Sham TI will use the same electrode setup, session duration, and device interface and simulate brief scalp sensations, without sustained treatment current during the middle of each session. Both groups will continue usual clinical treatment. Clinically necessary adjustments to antipsychotic medication will be permitted and documented, including medication names, doses, timing and reasons for adjustments, and concomitant medication use. Other neuromodulation interventions that could affect study outcomes will be prohibited during participation. The primary efficacy analysis will use a mixed model for repeated measures in the modified intention-to-treat population. The model will include treatment group, visit, treatment-by-visit interaction, study center, and prespecified baseline covariates. The primary treatment comparison will be the between-group difference in change from baseline to Day 15 in Positive and Negative Syndrome Scale (PANSS) total score. Per-protocol analyses and analyses addressing missing data and medication adjustments will serve as sensitivity analyses to support interpretation of the primary results. Exploratory analyses of structural and resting-state functional MRI will examine treatment-related imaging changes, their associations with symptom improvement, and the potential predictive value of baseline imaging and individualized electric-field measures. An independent data and safety monitoring board will oversee participant safety and study conduct.