Efficacy and Safety of Transcranial Temporal Interference Stimulation for Improving Negative Symptoms and Cognition in Schizophrenia: A Pilot Study

Importance Schizophrenia (SCZ) is a severe psychiatric disorder with limited treatment options for negative symptoms and cognitive impairment. Temporal interference stimulation (TIS) is a non-invasive neuromodulation technique that enables targeted deep brain modulation. However, its therapeutic effects on SCZ remain unexplored. Objective To evaluate the safety, efficacy, and tolerability of TIS targeting the right nucleus accumbens (NAc) in improving negative symptoms and cognitive function in patients with SCZ. Design An open-label, single-arm exploratory trial conducted from July 20 to October 30, 2024. Setting Single-center study conducted at a tertiary psychiatric referral hospital (Tianjin Anding Hospital, China). Participants 8 SCZ inpatients (mean age 48.3 ± 12.1 years; 6 males) with persistent negative symptoms (PANSS negative subscale ≥20) were enrolled. Intervention Five consecutive daily sessions of 20-minute individualized MRI-guided 130 Hz TIS targeting the right NAc. Main Outcomes and Measures Primary outcomes: changes in PANSS negative subscale and SANS scores from baseline to two-week follow-up. Secondary outcomes: changes in MATRICS Consensus Cognitive Battery (MCCB) scores across assessment phases. Assessments occurred at baseline, post-intervention, and two-week follow-up. Results All 8 participants completed treatment. PANSS total scores decreased by 8.1% (baseline: 64.5 ± 14.8 vs follow-up: 59.3 ± 15.7; p adj = 0.007), driven by reductions in negative (baseline: 25.4 ± 6.7 vs follow-up: 23.0 ± 6.7; p adj = 0.045) and general subscales. SANS scores declined by 12.5% (baseline: 57.8 ± 9.4 vs follow-up: 50.6 ± 12.9; p adj = 0.045). MCCB total scores improved by 41.8% (baseline: 23.7 ± 10.4 vs follow-up: 33.6 ± 9.7, p adj < 0.001), with significant gains in visual and verbal learning (p adj ≤ 0.02). Adverse events included electrode contact site pressure sensation (n = 4), transient current sensations (n = 4) and fatigue (n = 1). Tolerability was good. Conclusion This pilot study suggests that TIS is a safe and feasible noninvasive deep brain stimulation technology that may alleviate negative symptoms and improve cognitive function in SCZ. Larger randomized controlled trials with extended follow-up periods are warranted to further validate these preliminary results. Trial Registration Chinese Clinical Trial Registry; ChiCTR2400094200.