Advances in transcranial alternating current stimulation and temporal interference stimulation for neuropsychiatric disorders: mechanisms, technical developments, and preclinical evidence

Abstract

Transcranial alternating current stimulation (tACS) is a non-invasive neuromodulation technique that modulates neural activity through frequency- and phase-dependent electrical currents and has shown potential for enhancing cognition and alleviating symptoms in neurological and psychiatric disorders. Temporal interference (TI) stimulation applies two or more kilohertz-frequency electric fields with slightly different frequencies to generate a low-frequency amplitude-modulated field within neural tissue, offering a potential strategy for preferentially engaging deeper neural targets with improved spatial steering. Foundational studies in this field have used diverse methodologies, including multiscale computational modeling, cellular experiments, intact-animal studies, and disease-specific animal models, to elucidate stimulation principles, parameter dependencies, neuromodulatory mechanisms, safety, and functional efficacy. This review synthesizes recent advances in the basic and preclinical research of tACS and TI, with an emphasis on biophysical and physiological mechanisms, safety evaluation, parameter optimization, technological developments, peripheral nerve applications, and therapeutic effects and associated mechanisms in animal disease models. Current evidence indicates that both approaches can influence neural function across membrane, cellular, circuit, network, synaptic, and behavioral levels. Although tACS has undergone extensive human and clinical investigation, transcranial temporal interference stimulation (tTIS) remains at an earlier stage of mechanistic and translational development. Further systematic studies are required to clarify direct and indirect stimulation mechanisms, long-term safety, dose-response relationships, target engagement, and protocol optimization, thereby facilitating the clinical translation of these techniques, particularly for individualized and precision neuromodulation of brain disorders.