Systematic review of experimental studies in humans on transcranial temporal interference stimulation

Transcranial temporal interference stimulation (tTIS) has recently emerged as a non-invasive neuromodulation method aimed at reaching deeper brain regions than conventional techniques. However, many questions about its effects remain, requiring further experimental studies. This review consolidates the experimental literature on tTIS's effects in the human brain, clarifies existing evidence, identifies knowledge gaps, and proposes future research directions to evaluate its potential. A systematic literature search was performed in PubMed, Web of Science, and Scopus for studies published up to 27 January 2025. Eligible studies applied tTIS to the human brain and examined its effects on neural, behavioral, and clinical outcomes. Of 127 publications screened, 18 met the inclusion criteria. Studies were analyzed for design, stimulation target, parameters, control conditions, and outcome measures. Included studies exhibited low bias or minor concerns using the Cochrane RoB2 and ROBINS-I tools. Ten studies targeted cortical regions (motor, occipito-parietal, fronto-parietal), and eight probed subcortical sites (striatum, hippocampus, globus pallidus, caudate). Motor-cortex tTIS enhanced motor-network connectivity, though the effect was similar to that of transcranial direct current stimulation. Beta-band stimulation envelopes (20 Hz) promoted learning-related plasticity, while gamma-band envelopes (70 Hz) yielded immediate performance improvements. Occipito-parietal tTIS did not modulate alpha power. Preliminary deep-target findings are promising: 5 Hz hippocampal tTIS improved episodic recall, 100 Hz striatal tTIS enhanced motor learning in older adults, and 100 Hz hippocampal-entorhinal tTIS aided spatial navigation. Two fMRI studies confirmed network-specific modulation, although one raised concerns about using a fixed montage between individuals. Clinical evidence remains limited, with two Parkinson's pilots and one epilepsy study showing short-term benefits. Overall, tTIS shows potential to modulate human brain activity and behavior. However, current evidence is preliminary and predominantly focused on cortical rather than deep targets. Larger, well-controlled studies are needed to reliably determine whether tTIS can effectively engage subcortical structures and provide meaningful clinical benefits.