Dorsal anterior cingulate cortex-targeted transcranial temporal interference stimulation for negative symptoms and cognitive impairment in schizophrenia: a participant- and assessor-blinded, sham-controlled randomized controlled trial protocol.

Background: Persistent negative symptoms and cognitive deficits remain major obstacles to functional recovery in schizophrenia. These impairments are often only partially responsive to antipsychotic treatment and may persist even when other symptoms are clinically stable. Psychosocial interventions show inconsistent efficacy, and commonly used non-invasive brain stimulation techniques have limited ability to target deeper cortical regions. Transcranial temporal interference stimulation (tTIS) has recently emerged as a promising approach for modulating neural activity in such regions. This trial aims to evaluate the clinical efficacy of tTIS targeting the dorsal anterior cingulate cortex (dACC) in individuals with schizophrenia. Methods: Seventy-four participants with schizophrenia will be enrolled in a parallel-group, sham-controlled trial. After random allocation, half of the participants will receive active stimulation and the remainder will receive sham stimulation. Group assignment will be blinded from participants and clinical evaluators. Each participant will complete 10 sessions over 2 weeks, with one 30-minute session scheduled on each weekday. Assessments will be completed before the first session, after the treatment course, and 4 weeks after treatment completion. Evaluation will include symptom ratings, neuropsychological testing, behavioral tasks, and multimodal neuroimaging. The primary endpoint is the baseline-adjusted between-group difference in the Positive and Negative Syndrome Scale negative symptom subscale (PANSS-NS) score at T1. The PANSS-NS score at T2 will be analyzed as a secondary outcome to evaluate the durability of the treatment effect. The Brief Assessment of Cognition in Schizophrenia composite z-score and the Scale for the Assessment of Negative Symptoms total score are prespecified as key secondary outcomes. Participants will be included in the primary analysis according to their original treatment assignment. Discussion: This study aims to determine whether dACC-targeted tTIS is feasible and clinically promising in schizophrenia. By combining symptom evaluation with cognitive, behavioral, and imaging measures, the trial may also generate preliminary evidence about treatment-related neural changes. The results will help guide the design of future studies evaluating deep-targeted non-invasive stimulation in psychiatric populations. Clinical trial registration: https://clinicaltrials.gov/, identifier NCT07658898.