Kilohertz waveforms optimized to produce closed-state Na+channel inactivation eliminate onset response in nerve conduction block.

Guosheng Yi,Warren M Grill,Jonathan Rubin

doi:10.1371/journal.pcbi.1007766

Guosheng Yi, Warren M Grill + Show 1 more

Open Access

https://doi.org/10.1371/journal.pcbi.1007766

Copy DOI

Abstract

The delivery of kilohertz frequency alternating current (KHFAC) generates rapid, controlled, and reversible conduction block in motor, sensory, and autonomic nerves, but causes transient activation of action potentials at the onset of the blocking current. We implemented a novel engineering optimization approach to design blocking waveforms that eliminated the onset response by moving voltage-gated Na+ channels (VGSCs) to closed-state inactivation (CSI) without first opening. We used computational models and particle swarm optimization (PSO) to design a charge-balanced 10 kHz biphasic current waveform that produced conduction block without onset firing in peripheral axons at specific locations and with specific diameters. The results indicate that it is possible to achieve onset-free KHFAC nerve block by causing CSI of VGSCs. Our novel approach for designing blocking waveforms and the resulting waveform may have utility in clinical applications of conduction block of peripheral nerve hyperactivity, for example in pain and spasticity.

Highlights

Multiple neurological disorders are characterized by undesirable increases in sensory, motor, or autonomic nerve activity, for example pain and spasticity
Kilohertz frequency alternating current (KHFAC) nerve block produces an undesirable initial burst of action potentials prior to achieving block. This onset firing may result in muscle contraction and pain and is a significant impediment to potential clinical applications of KHFAC nerve block
Our results suggest that the resulting KHFAC waveform can generate electric nerve block without an onset response

Summary

Introduction

Multiple neurological disorders are characterized by undesirable increases in sensory, motor, or autonomic nerve activity, for example pain and spasticity. Several approaches are proposed to reduce or eliminate the onset response, including transitioning KHFAC waveform from a high amplitude and high frequency to a low amplitude and low frequency [13], slowly increasing the amplitude of the KHFAC waveform [14, 15], introducing direct current (DC) nerve block [12, 16], and modifying electrode geometries [17] These approaches are either unable to eliminate completely the onset firing or are challenging for clinical implementation [12,13,14,15,16,17]. We employed engineering optimization to design a stimulus waveform to achieve conduction block while preventing the onset responses

Objectives

Methods

Results

Discussion

Conclusion