Kilohertz-frequency stimulation of the nervous system: A review of underlying mechanisms

Abstract

Background: Electrical stimulation in the kilohertz-frequency range has gained interest in the field of neuroscience. The mechanisms underlying stimulation in this frequency range, however, are poorly characterized to date. Objective/hypothesis: To summarize the manifold biological effects elicited by kilohertz-frequency stimulation in the context of the currently existing literature and provide a mechanistic framework for the neural responses observed in this frequency range. Methods: A comprehensive search of the peer-reviewed literature was conducted across electronic databases. Relevant computational, clinical, and mechanistic studies were selected for review. Results: The effects of kilohertz-frequency stimulation on neural tissue are diverse and yield effects that are distinct from conventional stimulation. Broadly, these can be divided into 1) subthreshold, 2) suprathreshold, 3) synaptic and 4) thermal effects. While facilitation is the dominating mechanism at the subthreshold level, desynchronization, spike-rate adaptation, conduction block, and non-monotonic activation can be observed during suprathreshold kilohertz-frequency stimulation. At the synaptic level, kilohertz-frequency stimulation has been associated with the transient depletion of the available neurotransmitter pool e also known as synaptic fatigue. Finally, thermal effects associated with extrinsic (environmental) and intrinsic (associated with kilohertz-frequency stimulation) temperature changes have been suggested to alter the neural response to stimulation paradigms. Conclusion:The diverse spectrum of neural responses to stimulation in the kilohertz-frequency range is distinct from that associated with conventional stimulation. This offers the potential for new therapeutic avenues across stimulation modalities. However, stimulation in the kilohertz-frequency range is associated with distinct challenges and caveats that need to be considered in experimental paradigms.

Multiscale Computational Model Reveals Nerve Response in a Mouse Model for Temporal Interference Brain Stimulation

“…Several studies have been conducted for multiscale modeling, particularly for TMS ( De Geeter et al, 2015 ; Goodwin and Butson, 2015 ; Gomez-Tames et al, 2019c ), where the pulse frequency is of the order of kHz that have been able to predict experimental thresholds ( Gomez-Tames et al, 2018 , 2020b ; Aberra et al, 2020 ). If the stimulation of the mouse cortex can be explained in terms of multiscale modeling, the abovementioned hypothesis can be clarified, except for the possible synaptic effect ( Gomez-Tames et al, 2019b ; Neudorfer et al, 2021 ).…”

Kilohertz Transcranial Magnetic Perturbation (kTMP): A New Non-invasive Method to Modulate Cortical Excitability

“…subthreshold kilohertz stimulation 13 . Although we did not observe significant differences between the three carrier frequencies, the effect was most pronounced in the condition in which the carrier frequency was set to 3.5 kHz.…”

Intermittent KHz-frequency electrical stimulation selectively engages small unmyelinated vagal afferents

“…Previous nerve stimulation studies explored the possibility of selective block in peripheral nerves using KES of 5 ~ 50 kHz frequency 69 : However, the full range of KES effects, from subthreshold facilitation to suprathreshold block, have not been demonstrated in the vagus, which comprises different fiber types 70 . We used anatomically-accurate, biophysically-plausible computational models of vagal axons to explain the observed selective nerve activation under different KES conditions.…”

“…The frequency-dependency and fiber-selectivity of KES activation and block could further be explained by the kinetics of ion channels that determine the refractory period and the passive membrane properties of axons that determine the time constant 70,76 . An axon’s refractory period, ranging from 1 to 2 ms 77,78 , imposes a frequency limit of 0.5-1kHz for stimuli to trigger action potentials (APs) in a one-to-one manner, with one stimulus leading to one AP 70 . For single stimuli, whether those are pulses or sinusoidal cycles, at intensities below the AP generation threshold for a given fiber type, activation can result from temporal summation of subthreshold membrane voltage fluctuations.…”