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

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.Author summary: Many neurological disorders, including pain and spasticity, are characterized by undesirable increases in sensory, motor, or autonomic nerve activity. Local application of kilohertz frequency alternating currents (KHFAC) can effectively and completely block the conduction of undesired hyperactivity through peripheral nerves and could be a therapeutic approach for alleviating disease symptoms. However, 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. We present a novel engineering optimization approach for designing a blocking waveform that completely eliminated the onset firing in peripheral axons by moving voltage-gated Na+ channels to closed-state inactivation. Our results suggest that the resulting KHFAC waveform can generate electric nerve block without an onset response. Our approach for optimizing blocking waveforms represents a novel engineering design methodology with myriad potential applications and has relevance for the conduction block of peripheral nerve hyperactivity.