High-Frequency Stimulation Selectively Blocks Different Types of Fibers in Frog Sciatic Nerve

Abstract

Conduction block using high frequency alternating current (HFAC) stimulation has been shown to reversibly block conduction through various nerves. However, unlike simulations and experiments on myelinated fibers, prior experimental work in our lab on the sea-slug, Aplysia, found a nonmonotonic relationship between frequency and blocking thresholds in the unmyelinated fibers. To resolve this discrepancy, we investigated the effect of HFAC waveforms on the compound action potential of the sciatic nerve of frogs. Maximal stimulation of the nerve produces a compound action potential consisting of the A-fiber and C-fiber components corresponding to the myelinated and unmyelinated fibers’ response. In our study, HFAC waveforms were found to induce reversible block in the A-fibers and C-fibers for frequencies in the range of 5–50 kHz and for amplitudes from 0.1–1 mA. Although the A-fibers demonstrated the monotonically increasing threshold behavior observed in published literature, the C-fibers displayed a nonmonotonic relationship, analogous to that observed in the unmyelinated fibers of Aplysia. This differential blocking behavior observed in myelinated and unmyelinated fibers during application of HFAC waveforms has diverse implications for the fields of selective stimulation and pain management.

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“…The monotonic decrease of block threshold for frequencies above 20 kHz (Fig.3) is mainly determined by the passive axonal membrane properties (Fig.7) since the high-frequency stimulation completely closes both sodium and potassium channels. Therefore, the non-monotonic relationship between the block threshold and stimulation frequency, which was discovered recently in unmyelinated axons of sea-slugs [12] and frogs [13] and reproduced in this stimulation study, can be fully explained by the kinetics of potassium and sodium channels during high-frequency biphasic electrical stimulation.…”

“…This nerve blocking mechanism has the potential to eliminate the action potentials elicited at the beginning of blocking stimulation at relatively higher frequencies (>30 kHz) ). This study and our previous studies [7] [18] using an unmyelinated axonal model (Hodgkin-Huxley model) have successfully predicted not only the minimal blocking frequency (5 kHz) [12][13] [19]- [21] but also the frequencies (13)(14)(15)(16) where the block threshold starts decreasing [12] [13]. These results indicate that the kinetics of ion channel gating plays a major role in the conduction block induced by high-frequency biphasic electrical current.…”

“…This study employed the Hodgkin-Huxley axonal model to simulate nerve conduction block in unmyelinated axons during high-frequency (up to 100 kHz) biphasic electrical stimulation ( Fig.2) and reproduced the non-monotonic relationship between block threshold and stimulation frequency ( Fig.3), which was recently discovered in unmyelinated axons of sea-slugs [12] and frogs [13]. In addition, our study revealed that deactivation of sodium channels by the high-frequency stimulation is the mechanism underlying the decrease in block threshold at frequencies above 20 kHz (Figs.4-7).…”

“…This potassium channel mechanism governs the monotonic increase in block threshold as the stimulation frequency is increased up to 10 kHz (Fig.3). As the frequency increases further, it saturates the faster kinetics of the sodium channel at about [13][14][15][16] (Fig.3) causing the sodium channel to lose its ability to follow the high-frequency stimulation and becomes completely deactivated [ Fig.4 (d) and Fig.5 (a)]. This sodium channel mechanism is responsible for the conduction block ].…”

“…15 Our results show that high-frequency blocking stimulation actually induces a hyperpolarization rather than a depolarization under the block electrode [ Fig.2, Fig.4 (a Based on our hypothesis about the role of different ion channel kinetics in conduction block, it would be logical to predict that a non-monotonic relationship between the block threshold and the stimulation frequency should also exist in myelinated axons. However, currently the results obtain from animal studies [10][11] [13] only show that the block threshold monotonically increases as the frequency increases up to 50 kHz. Since the sodium channel in myelinated axons [22] has a much faster kinetics than in unmyelinated axons [14], it is possible that a frequency greater than 50 kHz might be needed in order to drive the sodium channels in myelinated axons to a completely deactivated state.…”