There is no Biophysical Distinction between Temporal Interference and Direct kHz Stimulation of Peripheral Nerves

Temporal interference stimulation (TIS) has attracted increasing attention as a promising noninvasive electrical stimulation method. Despite positive results and optimistic expectations, the TIS field has been beset by misunderstandings concerning its mechanism of action and efficacy in safely targeting deep neural structures. Various studies posit that TIS exploits the low-frequency "beat" frequency produced by interference of multiple kHz carriers to essentially deliver low-frequency stimulation at the intersection of the carriers, thereby circumventing limitations associated with tissue impedance and depth penetration. Due to the documented electrophysiological effects of kHz-range stimuli, such a picture is an oversimplification, and at present a critical open question for TIS is how much stimulation thresholds practically differ for amplitude-modulated versus unmodulated kHz stimuli. This paper presents experimental evidence supporting the conclusion that TIS is driven by the kHz carrier itself, and that amplitude modulation frequency has little relatively effect on thresholds. We test TIS and different modulated/unmodulated kHz waveforms on peripheral nerve targets in an invertebrate model (Locusta migratoria), and on sensory and motor stimulation in human subjects. We find that modulated (TIS) and unmodulated sine carrier frequencies in the range 0.5 - 12.5 kHz in humans, and further up to 100 kHz in locusts, demonstrate overlapping strength-frequency (s-f) dependence across all stimulation types. Since all stimulation waveforms are governed by the same s-f curve, this implicates a common underlying biophysical mechanism. This equivalence challenges the notion that the TIS modulated "envelope" frequency can uniquely facilitate neural engagement via other mechanisms. We test amplitude-modulation frequency (AMF) dependence, confirming the resonance effect predicted by kHz rectification theory, and we evaluate the regions of tonic (unmodulated) and phasic (amplitude-modulated) stimulation regions inherent when using TIS. Our results help to resolve the mechanistic debate, at least for suprathreshold TIS. We explain how the findings can be extrapolated to subthreshold stimulation, and further suggest possible advantages of using 2-electrode amplitude-modulated kHz waveforms over the multielectrode TIS configurations.