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

摘要

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.