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

Abstract

AbstractTemporal 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 interference of multiple supraphysiological frequency (kHz range) 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 electric stimuli, such a picture is an oversimplification. Moreover, recent theoretical modelling work has established that the biophysics of TIS is based on kHz stimulation mechanisms. This paper presents experimental evidence supporting this conclusion, by comparing TIS with direct kHz stimulation on peripheral nerve targets in an invertebrate model (Locusta migratoria), and in human subjects. Our findings show that the stimulation effects of TIS are achievable through two-electrode kHz stimulation, without necessitating carrier interference in tissue. By comparing four-electrode TIS with two-electrode stimulation via kHz sine waves for targeting of peripheral nerves, we 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 TIS uniquely facilitates neural engagement via other mechanisms. Furthermore, performing TIS with higher carrier frequencies into the MHz range fails to lead to stimulation. We evaluate the regions of tonic (unmodulated) and phasic (amplitude-modulated) stimulation regions inherent when using TIS, and the associated possibility of off-target effects. Our study further suggests that possible practical advantages of TIS can be achieved in an easier way by simply using amplitude-modulated kHz waveforms.