Artifactual hyperpolarization during extracellular electrical stimulation: Proposed mechanism of high-rate neuromodulation disproved

Publication date: Available online 15 December 2017
Source:Brain Stimulation
Author(s): L. Stephen Lesperance, Milad Lankarany, Tianhe Zhang, Rosana Esteller, Stéphanie Ratté, Steven A. Prescott
BackgroundKilohertz-frequency electric field stimulation (kEFS) applied to the spinal cord can reduce chronic pain without causing the buzzing sensation (paresthesia) associated with activation of dorsal column fibers. This suggests that high-rate spinal cord stimulation (SCS) has a mode of action distinct from conventional, parasthesia-based SCS. A recent study reported that kEFS hyperpolarizes spinal neurons, yet this potentially transformative mode of action contradicts previous evidence that kEFS induces depolarization and was based on patch clamp recordings whose accuracy in the presence of kEFS has not been verified.ObjectivesWe sought to elucidate the basis for kEFS-induced hyperpolarization and to validate the effects of kEFS observed in patch clamp recordings by comparing with independent optical methods.MethodsUsing patch clamp electrophysiology and voltage-sensitive dye (VSD) imaging, we measured the response to kEFS applied in vitro to hippocampal and spinal neurons.ResultsThe kEFS-induced hyperpolarization observed with current clamp recordings was corroborated by VSD imaging and rheobase measurements in patched neurons. However, no hyperpolarization was observed when imaging unpatched neurons or when recording with a voltage-follower amplifier rather than with a patch clamp amplifier (PCA). We found that EFS induced an artifactual current in PCAs that was injected back into current clamped neurons. The artifactual current induced by single, charge-balanced EFS pulse caused modest hyperpolarization, but these unitary hyperpolarizations accumulated when EFS pulses were repeated at kilohertz frequencies.ConclusionOur results rule out hyperpolarization as the mechanism underlying kEFS-mediated analgesia and highlight the risk of recording artifacts caused by extracellular electrical stimulation.



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