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

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.

Intermittent KHz-frequency electrical stimulation selectively engages small unmyelinated vagal afferents

“…In our study, we measured physiological responses and eCAPs to understand fiber recruitment caused by KES. We find that nerve conduction block with KES starts with A-fibers, then happens to B-fibers and finally to C-fibers, consistent with previous studies in rats 36,65 . Slowing in conduction velocity, more prominent in slow fibers, was also observed in our results (Fig.…”

“…In our study, we have combined both measurements of physiological states and eCAPs with one stimulating electrode design to assess the effect caused by KES. In terms of eCAPs and KES blocking amplitude, our findings, which show the nerve conduction block starts from large myelinated fiber (A-fiber), to small myelinated (B-fiber) and unmyelinated fiber (C-fiber), is consistent with previous study in the same animal model 35,60 . Similar slowing in the conduction velocity, which is more prominent in slow fiber, was also observed in our results ( Fig.…”

“…eCAPs in response to probing stimuli before, during and after KES are consistent with sequential conduction block as stimulus intensity increases (Figure 2D and Suppl. Figure S5), which starts with A-fibers, then encompasses B-fibers and finally affects C-fibers (Figure 2D-E), as described before (38,55). This "intensity window", within which excitability of A-and B-fibers is almost completely blocked with C-fiber excitability only partially suppressed, provides the basis for the C-afferent selectivity of KES (Figure 2E).…”

“…Though the onset response might lead to side effects for clinical applications, the time window is relatively short that patients might be able to tolerate. Recent optimization method used to eliminate onset response in KES through modulating the intensity at the onset of stimuli might potentially be able to minimize the noncontrollable phase 60 .…”

Quantitative comparisons of block thresholds and onset responses for charge-balanced kilohertz frequency waveforms

“…Our data are the first to quantify onset response profiles across waveforms shapes, highlighting the potential of waveform shape to reduce onset response (Yi and Grill 2020). Since square waveforms had the lowest threshold among those tested, our results indicate that applying square waveforms for block may help reduce onset response simply because amplitudes can be increased well above block threshold while using lower current amplitudes than required of other waveforms.…”