Limited sensitivity of hippocampal synaptic function or network oscillations to unmodulated kilohertz electric fields

Understanding the cellular mechanisms of kilohertz (kHz) electrical stimulation is of broad interest in neuromodulation including forms of transcranial electrical stimulation, interferential stimulation, and high-rate spinal cord stimulation (SCS). Yet, the well-established low-pass filtering by neuronal membranes suggests minimal neuronal polarization in respond 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 EPSPs (fEPSP) in CA1 were measured in response to radial-directed and tangential-directed electric fields, with brief (30 s) or long (30 min) application times. The effects of kHz stimulation on ongoing endogenous network activity were tested in carbachol-induced g oscillation of CA3a and CA3c. Across 23 conditions evaluated, no significant changes in fEPSP were resolved, while responses were detected for withinslice control direct current (DC) fields; 1-kHz sinusoidal and pulse stimulation (60 V/m), but not 10 kHz, induced changes in 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 were not identified in our experimental preparation.