The same biophysical mechanism is involved in both temporal interference and direct kHz stimulation of peripheral nerves

Abstract

Abstract Temporal interference stimulation (TIS) is a promising noninvasive method for neurostimulation, yet its mechanism remains debated. TIS is often described as delivering low-frequency stimulation via the amplitude modulation (beat frequency) of interfering kHz carriers. However, this view overlooks known biophysical responses to kHz stimuli. Here, we test modulated (TIS) and unmodulated kHz waveforms on peripheral nerves in Locusta migratoria and in human sensory and motor pathways. We find that stimulation thresholds and strength-frequency relationships are governed by the kHz carrier itself, with minimal dependence on amplitude modulation. Across 0.5–12.5 kHz in humans and up to 100 kHz in locusts, all waveforms show overlapping excitation behavior, indicating a shared underlying mechanism. Our results support the hypothesis that suprathreshold TIS acts through kHz rectification, rather than envelope-specific effects. We further explore modulation frequency resonance, tonic vs. phasic effects, and suggest that two-electrode premodulated kHz may offer advantages over multielectrode TIS approaches.