Temporal Interference Stimulation: Mechanisms, Optimization, Validation, and Clinical Prospects—A Comprehensive Review

ABSTRACT Temporal interference stimulation (TIS) is a novel non‐invasive neuromodulation technique enabling targeted stimulation of deep brain structures with enhanced focality. By applying multiple high‐frequency (≥ 1 kHz) electric fields with a small frequency difference (Δ f ), TIS generates a low‐frequency amplitude‐modulated envelope at the interference focus, modulating neural activity while minimizing superficial stimulation. Since its introduction, research has rapidly explored TIS's computational foundations, biophysical mechanisms, experimental validation, and therapeutic potential. This review synthesizes advancements, detailing computational optimization strategies for personalized targeting and dynamical modeling insights into neuronal mechanisms like nonlinear ion channel rectification, which underpin TIS efficacy. Preclinical and human studies validating functional outcomes (e.g., memory, motor) and assessing the safety profile are evaluated, confirming TIS's ability to modulate deep targets like the hippocampus and striatum. TIS is compared with conventional tES and invasive DBS, highlighting its unique advantages (non‐invasive depth access) and limitations (lower focal intensity, modeling complexity). Emerging clinical applications in disorders like Alzheimer's, Parkinson's, epilepsy, and depression are discussed. Future directions focus on refining protocols, enhancing personalization (e.g., multi‐channel, closed‐loop), and establishing long‐term safety/efficacy. This review consolidates multidisciplinary findings to advance TIS translation from experimental concepts toward clinical reality as a potentially transformative neuromodulation tool.