Human applications of transcranial temporal interference stimulation: A systematic review

BACKGROUND: Many neurological and psychiatric disorders involve dysregulation of subcortical structures. Transcranial temporal interference stimulation (tTIS) is a novel, non-invasive method developed to selectively modulate deep brain regions and associated neural circuits. METHODS: A systematic review was conducted to evaluate human applications of tTIS (PROSPERO ID: CRD42024559678). MEDLINE, Embase, APA PsycINFO, CENTRAL, ClinicalTrials.gov, and WHO ICTRP were searched up to December 12, 2024. Studies involving human applications of tTIS were eligible. Methodological quality was appraised using the National Institutes of Health and modified Oxford Centre for Evidence-Based Medicine tools. RESULTS: Forty-eight records were reviewed (20 published studies, 28 ongoing trials). Of published studies, 16 single-session and 4 multi-session studies assessed safety, mechanistic outcomes, or therapeutic effects of tTIS in 820 participants. Stimulation was most commonly delivered at beta (20 Hz) or gamma (30-130 Hz) envelope frequencies. Neuroimaging studies support target engagement of the motor cortex, basal ganglia, and hippocampus in humans, particularly when stimulation is paired with behavioural tasks. Preliminary clinical findings in small samples demonstrated acute symptom improvements in bradykinesia and tremor within 60 min following a single tTIS session in Parkinson's disease and essential tremor. Reported adverse events across studies were mild (e.g., tingling, itching). Emerging trials increasingly utilize multi-session protocols (2-40 sessions) and are extending tTIS to patients with neurological and psychiatric disorders, particularly epilepsy and depression. CONCLUSIONS: Phase 1 studies demonstrate that tTIS is safe, well-tolerated, and capable of engaging deep brain targets in humans. Well-controlled Phase 2 trials are needed to assess its therapeutic potential in patient populations.