The Suprathreshold Mechanisms of Khz and Temporal Interference Stimulation

Introduction: Temporal interference stimulation (TIS) uses interference of kilohertz (kHz) carrier waveforms to generate low-frequency amplitude modulation (AM) at depth, proposed for targeted neuromodulation. A common assumption is that the carriers are electrophysiologically inert and that stimulation arises from selective demodulation of the AM frequency. We critically tested this assumption and also evaluated the broader potential of modulated kHz stimulation—using both AM and frequency modulation (FM)—for functional electrical stimulation (FES) of mixed motor–sensory nerves, assessing muscle activation efficacy and subjective comfort relative to conventional biphasic pulsed current stimulation.

Methods: We compared stimulation thresholds and strength–frequency (s–f) relationships for TIS, pre‐AM sine, FM sine, sine burst, and unmodulated sine waveforms in Locusta migratoria N5 nerves and in human mixed nerves (median, ulnar, common peroneal). Carriers ranged from 0.5–12.5 kHz (humans and insects) to 100 kHz (insects). AM frequency (AMF) was varied from 0.03–50 Hz. Functional endpoints included phasic motor activation (e.g., finger flexion, ankle dorsiflexion) and sensory perception thresholds. Comfort was compared between kHz waveforms and biphasic pulsed stimulation of matched motor effect. Finite element modeling visualized tonic versus phasic stimulation regions in TIS versus two-electrode AM/FM delivery.

Results: Across all models, modulated (AM, FM) and unmodulated kHz waveforms exhibited overlapping s–f curves, indicating a common carrier‐driven rectification mechanism. Optimal AMF yielded ≤20% lower thresholds but did not alter the fundamental equivalence between TIS and direct kHz stimulation. In FES trials, both AM and FM kHz waveforms produced strong, phasic muscle contractions with substantially reduced unpleasant sensory perception which accompanied matched pulsed current stimulation. Modeling showed that TIS inherently creates bimodal stimulation—phasic in interference “hotspots” and tonic near electrodes—while two-electrode AM/FM delivery is monomodal and uses lower total current for equivalent target fields.

Conclusion: Suprathreshold TIS acts through the same kHz rectification mechanism as direct kHz stimulation, not through carrier‐independent demodulation. Modulated kHz waveforms—AM or FM—are promising for FES, offering robust muscle activation with improved comfort versus conventional pulsed current. These findings have implications for designing neuromodulation protocols that balance efficacy, comfort, and spatial selectivity.