Fundamentals of Kilohertz Frequency Alternating Current Nerve Conduction Block of the Peripheral Nervous System

Introduction

The activation of neurons using electrical stimulation is a well-recognized phenomenon and has multiple clinical applications. However, the use of electrical currents to block the conduction of action potentials in peripheral nerves is a more recent discovery and has been the subject of increased interest in the past decade. Inactivation or downregulation of the nervous system has relied on indirect methods, such as neuromodulation, that presumably activate natural inhibitory mechanisms ( ). This chapter focuses on the ability of electrical currents to directly inhibit the conduction of action potentials. This can be achieved both with charge-balanced kilohertz frequency alternating current (KHFAC) (with zero net charge delivery) and with direct current (DC). We focus on KHFAC nerve block in this discussion. Historically, KHFAC electrical nerve block has been poorly understood by the scientific and medical community. The past decade has experienced considerable increase in scientific interest in KHFAC block, with significantly improved analysis of this type of nerve block in both experimental and simulation conditions, as well as in early clinical applications.

It is important to distinguish the parameters used for KHFAC block because the effects on the nerve vary considerably as a function of frequency, amplitude, and electrode design. It is also important to distinguish between neurotransmitter depletion or fatigue block and true nerve conduction block ( ). In true nerve conduction block, such as produced by KHFAC block or DC block, action potentials are arrested as they pass under the blocking electrode. In neurotransmitter depletion, action potentials are generated in the nerve at such a fast rate that the neurotransmitter is transiently depleted at the synaptic or neuromuscular junction. Typically, KHFAC true conduction block occurs at or above 1 kHz and has been tested to as high as 50 kHz. Frequencies below that usually result in a fatigue type of nerve block.

In addition to defining the frequency range for electrical nerve block, it is also important to distinguish between alternating current (AC), DC, and monophasic high-frequency current blocks. As generally applied in the field of electrical stimulation, charge-balanced AC implies a zero net charge. DC generally implies the delivery of a single polarity of current for a prolonged period of time, typically tens of seconds or longer ( ). Monophasic high-frequency stimulation describes the repeated delivery of short electrical pulses that are of the same polarity with interim periods of no delivery. This distinction is important in the field of electrical nerve block, as it has been demonstrated that monophasic stimulation at frequencies above approximately 300 Hz has an effect on the nerve that is similar to DC block ( ). Further, monophasic stimulation, like DC, is damaging to both nerve and electrode and thus is not practical clinically ( ). Thus, the work of , who explored monophasic stimulation for the purpose of nerve block, is not included in this chapter. Unfortunately, this research using monophasic currents rather than charge-balanced currents has resulted in some confusion in the literature regarding the optimal frequencies for nerve block ( ).

We will briefly discuss the historical exploration of the inhibitory effects of electrical current on nerve conduction. The chapter then summarizes the characteristics of KHFAC and related nerve block methods that have been described in the literature, reviewing the methods used to evaluate KHFAC block and the electrical parameters and electrode designs needed to achieve successful block. We describe the “onset response,” which is the initial, transitory volley of activity produced in the nerve each time KHFAC is delivered, and we discuss the various approaches to reduction or elimination of the onset response. We summarize the current use of KHFAC in clinical applications and conclude with a discussion of future areas of research related to KHFAC.

History

In , Bugnard and Hill and Cattel and Gerard published their observations on the diminished nerve responses of the frog sciatic nerve to frequencies up to 2500 Hz. showed inhibition using KHFAC up to 40 kHz in the popliteal nerve of the cat. was the first to show a gradable KHFAC block of nerve conduction in the frog sciatic nerve, using the nerve compound action potential (CAP). confirmed the findings of Tanner in the frog sciatic and cat tibial nerves, using the CAP or single fiber recordings (SFRs) with 20-kHz KHFAC. They showed evidence of the onset response and local complete conduction block.

A comprehensive study on KHFAC nerve block was conducted by Bowman and McNeal in . Responses to voltage-controlled biphasic rectangular pulses over the range of 100–10,000 Hz in the cat sciatic nerve were evaluated by measuring the firing frequencies of spinal ventral roots with SFRs. The waveform used in these studies consisted of a balanced rectangular pulse of 50-μs duration for each phase. They found that a nerve conduction block could be achieved at 4 kHz with an amplitude of 7 V. The KHFAC produced an initial increase in firing (onset response) that lasted 1–2 s, followed by a period of a few seconds where pulses could pass uninhibited through the electrode region, before a true conduction block was established. Once established, this block could be maintained at least 80 s, and conduction could be restored within 1 s after the cessation of block.

Beginning in 2004, a number of research groups began publishing research on KHFAC block ( ). These reports represented a much more systematic analysis of the parameters necessary for KHFAC block, the key characteristics of KHFAC block, and the mechanisms underlying KHFAC block and established early exploration of potential clinical applications using this block. The remainder of this chapter summarizes what is known to date. Despite the recent explosion of interest, there remain many unknown aspects of KHFAC on nerve conduction and there is significant room for additional investigation and refinement of the nerve block strategy.

Characteristics of KHFAC Block

The application of KHFAC to a peripheral nerve produces conduction block in a longitudinal region of the underlying axons ( ). This characteristic was established experimentally utilizing the three electrode configuration shown in Fig. 10.1 . The use of a distal stimulating electrode placed as close as 1 mm from the KHFAC electrode can successfully activate the entire motor nerve, producing the same magnitude of muscle twitch as the proximal electrode and demonstrating that the conduction block is proximal to the distal stimulating electrode ( ).

KHFAC nerve block has been demonstrated in multiple species and over a wide range of peripheral nerve diameters. Animal models used have been the sea slug ( ), frog ( ), rat ( ), cat ( ), dog ( ), goat ( ), pig ( ), and nonhuman primates ( ). Nerve diameters have ranged from around 1 mm to approximately 6 mm (canine radial nerve) ( ). Three separate human clinical studies are using KHFAC on different components of the nervous system; vagus nerve ( ); sciatic, tibial, and common peroneal nerves ( ); and the dorsal region of the thoracic spinal cord ( ). There has been a recent interest (unpublished) in the exploration of KHFAC block of multiple autonomic nerves.

It is possible to use KHFAC to block all sizes of nerve fibers, from the largest motor ( ) and sensory fibers ( ) to the smallest unmyelinated fibers ( ). was the first to describe fiber size selectivity using KHFAC. He reported that larger fibers were blocked at lower amplitudes using a 20-kHz waveform. This result has been confirmed for sensory nerves ( ). have demonstrated that larger motor fibers have lower thresholds for block than C-fibers at frequencies below 30 kHz. This relationship appears to be reversed at frequencies above 30 kHz, but it is not clear if this inversion relates to unmyelinated fibers only or to all fibers sizes in general.

One limitation of KHFAC nerve block is that it produces a short burst of neural activity when turned on, an effect termed the “onset response” ( ). As shown in Fig. 10.2 , the onset response can take the form of a large “twitch” response, or it can be a prolonged period of strong activity that takes many seconds to diminish and cease. This initial response has been observed in computer simulations ( ; ) and in animal experiments using SFR ( ), muscle force ( ), and urethral sphincter pressure ( ). The motor onset response has been shown to consist of two sequential phases, as identified through the motor response to KHFAC block ( ). The first phase consists of a single summated muscle twitch with a peak force equal to or larger than that of a normal supramaximally elicited muscle twitch. This was defined as the “phase I onset,” and it is always present when the KHFAC block is initiated. “Phase II onset” was defined as the variable period of repetitive firing (and the resulting summated tetanic muscle force) that follows immediately after Phase I and ends with complete or partial block ( ). Phase II onsets are amenable to mitigation by the correct selection of frequency, amplitude, and electrode geometry.

The onset response is an impediment to generalized clinical uses of KHFAC block. Therefore, research has been conducted to reduce or eliminate the onset response. demonstrated that slowly ramping the KHFAC from zero to block threshold could not be used to reduce the onset response and, in fact, generally enhanced the onset response. However, several methods for shortening the onset response have been identified, and they include the use of large KHFAC amplitudes ( ), higher frequencies (>20 kHz) ( ), and optimal electrode geometry ( ). However, the phase I portion of the onset response, lasting less than 2 s, is a fundamental component of KHFAC block that cannot be eliminated through modification of the waveform or electrode design alone ( ). Efforts to further eliminate the onset response have centered on the use of charge-imbalanced waveforms.