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 specializing in neuromodulation therapies (Tianjin Anding Hospital, China). Participants: Eight 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; padj = 0.007), driven by reductions in negative (baseline: 25.4 ± 6.7 vs follow-up: 23.0 ± 6.7; padj = 0.045) and general subscales. SANS scores declined by 12.5% (baseline: 57.8 ± 9.4 vs follow-up: 50.6 ± 12.9; padj = 0.045). MCCB total scores improved by 41.8% (baseline: 23.7 ± 10.4 vs follow-up: 33.6 ± 9.7, padj < 0.001), with significant gains in visual and verbal learning (padj ≤ 0.02). Adverse events included transient electrode-related sensations (n = 8) 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.