Temporal interference stimulation: A new paradigm for non-invasive deep brain stimulation—mechanistic insights, clinical advances, and future directions

Neurological and psychiatric disorders frequently arise from dysfunctional deep-brain circuits, yet targeting these subcortical structures with conventional non-invasive neuromodulation remains a significant challenge due to the lack of focal precision at depth. Temporal Interference (TI) stimulation has emerged as a transformative paradigm, leveraging the intersection of multiple high-frequency electric fields to generate a low-frequency amplitude-modulated envelope within deep-seated targets. This biophysical strategy enables the modulation of subcortical dynamics while minimizing the activation of overlying cortical tissues. Emerging preclinical evidence demonstrates that TI can robustly orchestrate neurotransmitter release, facilitate synaptic plasticity, and ameliorate deficits in both motor and cognitive domains. Preliminary clinical translations further underscore its potential in enhancing memory precision, accelerating motor skill acquisition, and suppressing epileptic biomarkers. The mechanistic understanding of TI has evolved from passive low-pass filtering to include nonlinear ion-channel rectification and, more recently, network-mediated inhibition-particularly the recruitment of parvalbumin-positive interneurons in superficial layers-as a critical determinant of spatial selectivity. Human intracranial studies have further refined this framework, revealing that TI operates in a subthreshold regime, produces carrier-independent deep modulation, and elicits a sustained carry-over effect absent from unmodulated kilohertz stimulation. The efficacy of TI is fundamentally governed by a complex interplay of controllable parameters-including carrier frequency offset (Δf), current intensity, electrode geometry, and timing-alongside uncontrollable factors such as individual anatomical heterogeneity and endogenous brain states. Furthermore, advanced computational modeling, particularly finite element simulations incorporating personalized head models, has become indispensable for characterizing electric field distributions and achieving individualized, high-precision targeting. This review provides a comprehensive synthesis of TI's mechanistic foundations, safety profiles, and therapeutic trajectory, while critically discussing the integration of closed-loop systems, multi-target paradigms, and patient-specific optimization as the next frontiers in non-invasive deep brain stimulation.