New paper: Limited sensitivity of Hippocampal synaptic function or network oscillations to unmodulated kilohertz electric fields
New publication in eNeuro
Zeinab Esmaeilpour, Mark Jackson, Greg Kronberg, Rosana Esteller, Brad Hershey, and Marom Bikson
eNeuro 16th December 2020, ENEURO. 0368-20.2020;
Abstract
Understanding the cellular mechanisms of kHz electrical stimulation is of a broad interest in neuromodulation including forms of transcranial electrical stimulation (tES), interferential stimulation, and high-rate spinal cord stimulation (SCS). Yet, the well-established low-pass filtering by neuronal membranes suggests minimal neuronal polarization in response to charge-balanced kHz stimulation. The hippocampal brain slice model is among the most studied systems in neuroscience and exhaustively characterized in screening the effects of electrical stimulation. High-frequency electric fields of varied amplitudes (1-150 V/m), waveforms (sinusoidal, symmetrical pule, asymmetrical pulse), and frequencies (1 and10 kHz) were tested. Changes in single or paired-pulse field excitatory postsynaptic potentials (fEPSP) in CA1 were measured in response to radial- and tangential-directed electric fields, with a brief (30 s) or long (30 min) application times. The effects of kHz stimulation on ongoing endogenous network activity were tested in carbachol-induced gamma oscillation of CA3a and CA3c. Across 23 conditions evaluated, no significant changes in fEPSP were resolved, while responses were detected for within-slice control DC fields. 1 kHz sinusoidal and pulse stimulation (≥60 V/m), but not 10 kHz induced changes in an oscillating neuronal network. We thus report no responses to low-amplitude 1 kHz or any 10 kHz fields, suggesting that any brain sensitivity to these fields is via yet-to-be-determined mechanism(s) of action which was not identified in our experimental preparation.
SIGNIFICANCE STATEMENT There a large mismatch between enthusiasm for clinical treatments using kHz frequency electrical stimulation and the understanding of kHz mechanisms of action. Indeed, the well-established low-pass properties of cell membranes should attenuate any response to kHz stimulation. This study presents the largest and broadest characterization of the cellular effects of kHz stimulation using the most established animal model to detect CNS sensitivity to electric fields: Our work systematically evaluated sensitivity of hippocampal synaptic function and oscillatory network activity in response to kHz. Only at low kHz (1 kHz but not 10 kHz) with high intensity and during oscillations responses were detected. These systematic and largely negative experimental series suggest kHz neuromodulation operates via yet to be determined mechanisms.
