Kilohertz Frequency Alternating Current Research Articles

High frequency alternating current neurostimulation decreases nocifensive behavior in a disc herniation model of lumbar radiculopathy

BackgroundThe purpose of this study was to evaluate if kilohertz frequency alternating current (KHFAC) stimulation of peripheral nerve could serve as a treatment for lumbar radiculopathy. Prior work shows that KHFAC stimulation can treat sciatica resulting from chronic sciatic nerve constriction. Here, we evaluate if KHFAC stimulation is also beneficial in a more physiologic model of low back pain which mimics nucleus pulposus (NP) impingement of a lumbar dorsal root ganglion (DRG).MethodsTo mimic a lumbar radiculopathy, autologous tail NP was harvested and placed upon the right L5 nerve root and DRG. During the same surgery, a cuff electrode was implanted around the sciatic nerve with wires routed to a headcap for delivery of KHFAC stimulation. Male Lewis rats (3 mo., n = 18) were separated into 3 groups: NP injury + KHFAC stimulation (n = 7), NP injury + sham cuff (n = 6), and sham injury + sham cuff (n = 5). Prior to surgery and for 2 weeks following surgery, animal tactile sensitivity, gait, and static weight bearing were evaluated.ResultsKHFAC stimulation of the sciatic nerve decreased behavioral evidence of pain and disability. Without KHFAC stimulation, injured animals had heightened tactile sensitivity compared to baseline (p < 0.05), with tactile allodynia reversed during KHFAC stimulation (p < 0.01). Midfoot flexion during locomotion was decreased after injury but improved with KHFAC stimulation (p < 0.05). Animals also placed more weight on their injured limb when KHFAC stimulation was applied (p < 0.05). Electrophysiology measurements at end point showed decreased, but not blocked, compound nerve action potentials with KHFAC stimulation (p < 0.05).ConclusionsKHFAC stimulation decreases hypersensitivity but does not cause additional gait compensations. This supports the idea that KHFAC stimulation applied to a peripheral nerve may be able to treat chronic pain resulting from sciatic nerve root inflammation.

Kilohertz alternating current neuromodulation of the pudendal nerves: effects on the anal canal and anal sphincter in rats.

The first two objectives were to establish which stimulation parameters of kilohertz frequency alternating current (KHFAC) neuromodulation influence the effectiveness of pudendal nerve block and its safety. The third aim was to determine whether KHFAC neuromodulation of the pudendal nerve can relax the pelvic musculature, including the anal sphincter. Simulation experiments were conducted to establish which parameters can be adjusted to improve the effectiveness and safety of the nerve block. The outcome measures were block threshold (measure of effectiveness) and block threshold charge per phase (measure of safety). In vivo, the pudendal nerves in 11 male and 2 female anesthetized Sprague Dawley rats were stimulated in the range of 10 Hz to 40 kHz, and the effect on anal pressure was measured. The simulations showed that block threshold and block threshold charge per phase depend on waveform, interphase delay, electrode-to-axon distance, interpolar distance, and electrode array orientation. In vivo, the average anal pressure during unilateral KHFAC stimulation was significantly lower than the average peak anal pressure during low-frequency stimulation (p < 0.001). Stimulation with 20 kHz and 40 kHz (square wave, 10 V amplitude, 50% duty cycle, no interphase delay) induced the largest anal pressure decrease during both unilateral and bilateral stimulation. However, no statistically significant differences were detected between the different frequencies. This study showed that waveform, interphase delay and the alignment of the electrode along the nerve affect the effectiveness and safety of KHFAC stimulation. Additionally, we showed that KHFAC neuromodulation of the pudendal nerves with an electrode array effectively reduces anal pressure in rats.

Combining direct current and kilohertz frequency alternating current to mitigate onset activity during electrical nerve block

Objective. Electrical nerve block offers the ability to immediately and reversibly block peripheral nerve conduction and would have applications in the emerging field of bioelectronics. Two modalities of electrical nerve block have been investigated—kilohertz frequency alternating current (KHFAC) and direct current (DC). KHFAC can be safely delivered with conventional electrodes, but has the disadvantage of having an onset response, which is a period of increased neural activation before block is established and currently limits clinical translation. DC has long been known to block neural conduction without an onset response but creates damaging reactive species. Typical electrodes can safely deliver DC for less than one second, but advances in high capacitance electrodes allow DC delivery up to 10 s without damage. The present work aimed to combine DC and KHFAC into a single waveform, named the combined reduced onset waveform (CROW), which can initiate block without an onset response while also maintaining safe block for long durations. This waveform consists of a short, DC pre-pulse before initiating KHFAC. Approach. Simulations of this novel waveform were carried out in the axonal simulation environment NEURON to test feasibility and gain insight into the mechanisms of action. Two sets of acute experiments were then conducted in adult Sprague–Dawley rats to determine the effectiveness of the waveform in mitigating the onset response. Main results. The CROW reduced the onset response both in silico and in vivo. The onset area was reduced by over 90% with the tested parameters in the acute experiments. The amplitude of the DC pulse was shown to be particularly important for effective onset mitigation, requiring amplitudes 6–8 times the DC block threshold. Significance. This waveform can reliably reduce the onset response due to KHFAC and could allow for wider clinical implementation of electrical nerve block.

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.

Feasibility of kilohertz frequency alternating current neuromodulation of carotid sinus nerve activity in the pig

Recent research supports that over-activation of the carotid body plays a key role in metabolic diseases like type 2 diabetes. Supressing carotid body signalling through carotid sinus nerve (CSN) modulation may offer a therapeutic approach for treating such diseases. Here we anatomically and histologically characterised the CSN in the farm pig as a recommended path to translational medicine. We developed an acute in vivo porcine model to assess the application of kilohertz frequency alternating current (KHFAC) to the CSN of evoked chemo-afferent CSN responses. Our results demonstrate the feasibility of this approach in an acute setting, as KHFAC modulation was able to successfully, yet variably, block evoked chemo-afferent responses. The observed variability in blocking response is believed to reflect the complex and diverse anatomy of the porcine CSN, which closely resembles human anatomy, as well as the need for optimisation of electrodes and parameters for a human-sized nerve. Overall, these results demonstrate the feasibility of neuromodulation of the CSN in an anesthetised large animal model, and represent the first steps in driving KHFAC modulation towards clinical translation. Chronic recovery disease models will be required to assess safety and efficacy of this potential therapeutic modality for application in diabetes treatment.

Neuromuscular Electrical Stimulation with Kilohertz Frequency Alternating Current to Enhance Sensorimotor Cortical Excitability.

Enhancement of cortical excitability has been demonstrated to be beneficial for neural recovery of motor dysfunction, such as stroke and spinal cord injury. Neuromuscular electrical stimulation (NMES) has been widely used to evoke limb movements, resulting in the increasing cortical excitability. Due to the advantages of low skin impedance and less discomfort, an alternative NMES of kilohertz frequency alternating current (KFAC) has been proposed, and the effects of current parameters on evoked torque has been studied. However, few studies concerned cortical excitability effects during KFAC-evoked limb movement. In this paper, we utilized the event-related spectral estimation (ERSP) to calculate the beta ERD values to investigate the effects of KFAC-evoked elbow flexion movement on cortical excitability and compared them with that of passive movement. Firstly, averaged ERSP values were extracted in beta band during elbow flexion movements by sliding a 2Hz wide window for all trails of each subject. And then the minimal value was chosen as the representative value of beta ERD. Finally, the absolute ERD values and the descending slopes of all subjects were both calculated for statistical analysis by one-way repeated measures ANOVA. The results showed KFAC can increase cortical excitability, especially with long pulse duration. Moreover, beta cortical activities during KFAC500-evoked movement are significantly activated than those during passive movement. Therefore, our study may provide a new NMES rehabilitation method to enhance cortical excitability for motor dysfunction patients.

High-Frequency Electrical Modulation of the Superior Ovarian Nerve as a Treatment of Polycystic Ovary Syndrome in the Rat.

The polycystic ovary syndrome (PCOS) is the most prevalent ovarian pathology in women, with excessive sympathetic activity in the superior ovarian nerve (SON) playing an important role in inducing the PCOS symptoms in the rats and humans. Our previous studies have shown that surgical transection of the SON can reverse the disease progression, prompting us to explore the effect of the kilohertz frequency alternating current (KHFAC) modulation as a method of reversible non-surgical suppression of the nerve activity in the rodent model of PCOS. 56 animals were randomly allocated to three groups: the Control group (n = 18), the PCOS group (n = 15), and the PCOS + KHFAC group (n = 23). The physiological, anatomical, and biochemical parameters of ovarian function were evaluated during the progression of the experimentally-induced PCOS and during long-term KHFAC modulation applied for 2–3 weeks. The KHFAC modulation has been able to reverse the pathological changes in assessed PCOS parameters, namely the irregular or absent estrous cycling, formation of ovarian cysts, reduction in the number of corpora lutea, and ovarian norepinephrine concentration. The fertility capacity was similar in the PCOS and the PCOS + KHFAC groups, indicating the safety of KHFAC modulation approach. In summary, these results suggest that the KHFAC modulation approach of suppressing the SON activity could become a useful treatment modality for PCOS and potentially other pathological ovarian conditions.

Ulnar Nerve Conduction Block Using Surface Kilohertz Frequency Alternating Current: A Feasibility Study.

The aim of this study was to test the effects of kilohertz frequency alternating current (KHFAC) surface stimulation applied to the ulnar nerve on force and myoelectrical activity of the abductor digiti minimi (ADM) muscle. Eighteen healthy volunteers (age: 27.6 ± 7.9 years; 10 males, 8 females) were included in the study. Each subject participated in one session during which a biphasic 7 kHz rectangular pulse was delivered above the medial epicondyle of the humerus to induce ulnar nerve blocking. ADM electromyographic (EMG) activity and contraction force were measured before (Pre), immediately after, and following 5 and 10 min post stimulation (post 1, post 2). The results showed that EMG activity decreased immediately after stimulation compared to prestimulation, it returned to the level of prestimulation at 5 min (post 1), and decreased again at 10 min (post 2). Furthermore, analysis of compound adjusted z-score indicated significant decrease of force and myoelectrical activity immediately, and 10 min post stimulation. The findings, which demonstrate that KHFAC surface stimulation of the ulnar nerve may decrease the motor activity of intrinsic hand muscle, can help to develop future methods of neuromodulation to treat hand spasticity.

Bioelectronic modulation of carotid sinus nerve activity in the rat: a potential therapeutic approach for type 2 diabetes

Aims/hypothesisA new class of treatments termed bioelectronic medicines are now emerging that aim to target individual nerve fibres or specific brain circuits in pathological conditions to repair lost function and reinstate a healthy balance. Carotid sinus nerve (CSN) denervation has been shown to improve glucose homeostasis in insulin-resistant and glucose-intolerant rats; however, these positive effects from surgery appear to diminish over time and are heavily caveated by the severe adverse effects associated with permanent loss of chemosensory function. Herein we characterise the ability of a novel bioelectronic application, classified as kilohertz frequency alternating current (KHFAC) modulation, to suppress neural signals within the CSN of rodents.MethodsRats were fed either a chow or high-fat/high-sucrose (HFHSu) diet (60% lipid-rich diet plus 35% sucrose drinking water) over 14 weeks. Neural interfaces were bilaterally implanted in the CSNs and attached to an external pulse generator. The rats were then randomised to KHFAC or sham modulation groups. KHFAC modulation variables were defined acutely by respiratory and cardiac responses to hypoxia (10% O2 + 90% N2). Insulin sensitivity was evaluated periodically through an ITT and glucose tolerance by an OGTT.ResultsKHFAC modulation of the CSN, applied over 9 weeks, restored insulin sensitivity (constant of the insulin tolerance test [KITT] HFHSu sham, 2.56 ± 0.41% glucose/min; KITT HFHSu KHFAC, 5.01 ± 0.52% glucose/min) and glucose tolerance (AUC HFHSu sham, 1278 ± 20.36 mmol/l × min; AUC HFHSu KHFAC, 1054.15 ± 62.64 mmol/l × min) in rat models of type 2 diabetes. Upon cessation of KHFAC, insulin resistance and glucose intolerance returned to normal values within 5 weeks.Conclusions/interpretationKHFAC modulation of the CSN improves metabolic control in rat models of type 2 diabetes. These positive outcomes have significant translational potential as a novel therapeutic modality for the purpose of treating metabolic diseases in humans.

Temporary persistence of conduction block after prolonged kilohertz frequency alternating current on rat sciatic nerve

Objective. Application of kilohertz frequency alternating current (KHFAC) waveforms can result in nerve conduction block that is induced in less than a second. Conduction recovers within seconds when KHFAC is applied for about 5–10 min. This study investigated the effect of repeated and prolonged application of KHFAC on rat sciatic nerve with bipolar platinum electrodes. Approach. Varying durations of KHFAC at signal amplitudes for conduction block with intervals of no stimulus were studied. Nerve conduction was monitored by recording peak Gastrocnemius muscle force utilizing stimulation electrodes proximal (PS) and distal (DS) to a blocking electrode. The PS signal traveled through the block zone on the nerve, while the DS went directly to the motor end-plate junction. The PS/DS force ratio provided a measure of conduction patency of the nerve in the block zone. Main results. Conduction recovery times were found to be significantly affected by the cumulative duration of KHFAC application. Peak stimulated muscle force returned to pre-block levels immediately after cessation of KHFAC delivery when it was applied for less than about 15 min. They fell significantly but recovered to near pre-block levels for cumulative stimulus of 50 ± 20 min, for the tested On/Off times and frequencies. Conduction recovered in two phases, an initial fast one (60–80% recovery), followed by a slower phase. No permanent conduction block was seen at the end of the observation period during any experiment. Significance. This carry-over block effect may be exploited to provide continuous conduction block in peripheral nerves without continuous application of KHFAC.

Bioelectronic neuromodulation of the paravertebral cardiac efferent sympathetic outflow and its effect on ventricular electrical indices

Neuromodulation of the paravertebral ganglia by using symmetric voltage controlled kilohertz frequency alternating current (KHFAC) has the potential to be a reversible alternative to surgical intervention in patients with refractory ventricular arrhythmias. KHFAC creates scalable focal inhibition of action potential conduction. The purpose of this article was to evaluate the efficacy of KHFAC when applied to the T1-T2 paravertebral chain to mitigate sympathetic outflow to the heart. In anesthetized, vagotomized, porcine subjects, the heart was exposed via a midline sternotomy along with paravertebral chain ganglia. The T3 paravertebral ganglion was electrically stimulated, and activation recovery intervals (ARIs) were obtained from a 56-electrode sock placed over both ventricles. A bipolar Ag electrode was wrapped around the paravertebral chain between T1 and T2 and connected to a symmetric voltage controlled KHFAC generator. A comparison of cardiac indices during T3 stimulation conditions, with and without KHFAC, provided a measure of block efficacy. Right-sided T3 stimulation (at 4 Hz) was titrated to produce reproducible ARI changes from baseline (52 ± 30 ms). KHFAC resulted in a 67% mitigation of T3 electrical stimulation effects on ARI (18.5 ± 22 ms; P < .005). T3 stimulation repeated after KHFAC produced equivalent ARI changes as control. KHFAC evoked a transient functional sympathoexcitation at onset that was inversely related to frequency and directly related to intensity. The optimum block threshold was 15 kHz and 15 V. KHFAC applied to nexus (convergence) points of the cardiac nervous system produces a graded and reversible block of underlying axons. As such, KHFAC has the therapeutic potential for on-demand and reversible mitigation of sympathoexcitation.

Combined KHFAC + DC nerve block without onset or reduced nerve conductivity after block

Objective. Kilohertz frequency alternating current (KHFAC) waveforms have been shown to provide peripheral nerve conductivity block in many acute and chronic animal models. KHFAC nerve block could be used to address multiple disorders caused by neural over-activity, including blocking pain and spasticity. However, one drawback of KHFAC block is a transient activation of nerve fibers during the initiation of the nerve block, called the onset response. The objective of this study is to evaluate the feasibility of using charge balanced direct current (CBDC) waveforms to temporarily block motor nerve conductivity distally to the KHFAC electrodes to mitigate the block onset-response. Approach. A total of eight animals were used in this study. A set of four animals were used to assess feasibility and reproducibility of a combined KHFAC + CBDC block. A following randomized study, conducted on a second set of four animals, compared the onset response resulting from KHFAC alone and combined KHFAC + CBDC waveforms. To quantify the onset, peak forces and the force-time integral were measured during KHFAC block initiation. Nerve conductivity was monitored throughout the study by comparing muscle twitch forces evoked by supra-maximal stimulation proximal and distal to the block electrodes. Each animal of the randomized study received at least 300 s (range: 318–1563 s) of cumulative dc to investigate the impact of combined KHFAC + CBDC on nerve viability. Main results. The peak onset force was reduced significantly from 20.73 N (range: 18.6–26.5 N) with KHFAC alone to 0.45 N (range: 0.2–0.7 N) with the combined CBDC and KHFAC block waveform (p < 0.001). The area under the force curve was reduced from 6.8 Ns (range: 3.5–21.9 Ns) to 0.54 Ns (range: 0.18–0.86 Ns) (p < 0.01). No change in nerve conductivity was observed after application of the combined KHFAC + CBDC block relative to KHFAC waveforms. Significance. The distal application of CBDC can significantly reduce or even completely prevent the KHFAC onset response without a change in nerve conductivity.

Alternating current and infrared produce an onset-free reversible nerve block.

Nerve block can eliminate spasms and chronic pain. Kilohertz frequency alternating current (KHFAC) produces a safe and reversible nerve block. However, KHFAC-induced nerve block is associated with an undesirable onset response. Optical inhibition using infrared (IR) laser light can produce nerve block without an onset response, but heats nerves. Combining KHFAC with IR inhibition [alternating current and infrared (ACIR)] produces a rapidly reversible nerve block without an onset response. ACIR can be used to rapidly and reversibly provide onset-free nerve block in the unmyelinated nerves of the marine mollusk Aplysia californica and may have significant advantages over either modality alone. ACIR may be of great clinical utility in the future.

Direct current contamination of kilohertz frequency alternating current waveforms.

Kilohertz frequency alternating current (KHFAC) waveforms are being evaluated in a variety of physiological settings because of their potential to modulate neural activity uniquely when compared to frequencies in the sub-kilohertz range. However, the use of waveforms in this frequency range presents some unique challenges regarding the generator output. In this study we explored the possibility of undesirable contamination of the KHFAC waveforms by direct current (DC). We evaluated current- and voltage-controlled KHFAC waveform generators in configurations that included a capacitive coupling between generator and electrode, a resistive coupling and combinations of capacitive with inductive coupling. Our results demonstrate that both voltage- and current-controlled signal generators can unintentionally add DC-contamination to a KHFAC signal, and that capacitive coupling is not always sufficient to eliminate this contamination. We furthermore demonstrated that high value inductors, placed in parallel with the electrode, can be effective in eliminating DC-contamination irrespective of the type of stimulator, reducing the DC contamination to less than 1 μA. This study highlights the importance of carefully designing the electronic setup used in KHFAC studies and suggests specific testing that should be performed and reported in all studies that assess the neural response to KHFAC waveforms.

Lowering of Sensory, Motor, and Pain-Tolerance Thresholds With Burst Duration Using Kilohertz-Frequency Alternating Current Electric Stimulation: Part II

Ward AR, Lee Hung Chuen WL. Lowering of sensory, motor, and pain-tolerance thresholds with burst duration using kilohertz-frequency alternating current electric stimulation: part II. Objective To determine the optimum burst duration for discrimination between sensory, motor, and pain tolerance thresholds using 20-Hz bursts of kilohertz-frequency sinusoidal alternating current (AC) applied transcutaneously to human participants. Design A within-subject, repeated-measures trial. Setting A research laboratory. Participants Healthy young adults (N=20). Interventions Bursts of AC electric stimulation at frequencies of 1 and 4kHz. The burst frequency was 20Hz. Burst durations ranged from 250 microseconds (for 1 cycle of 4-kHz AC) and 1 millisecond (for 1 cycle of 1-kHz AC) to 50 milliseconds (continuous AC). Main Outcome Measures Measurement of sensory, motor, and pain-tolerance thresholds. Results Thresholds decreased to a minimum with increasing burst duration. The minimum threshold identified the utilization time over which summation of subthreshold stimuli occurs. Utilization times were different for sensory (∼20ms), motor (∼30ms), and pain (>50ms) and were much higher than found in a previous study that used a higher burst frequency (50Hz). As with the previous study, relative thresholds were found to vary with burst duration. Despite the very different utilization times, maximum separation between sensory, motor, and pain thresholds was found to occur with bursts in the range of 1 to 4 milliseconds, the same range found in the previous study. Conclusions Our conclusions concur with those reported previously and support the contention that short-duration kilohertz-frequency AC bursts (1–4ms) have a more useful role in rehabilitation than the long-duration kilohertz-frequency bursts that characterize Russian and interferential currents.

Electrical Stimulation Using Kilohertz-Frequency Alternating Current

Transcutaneous electrical stimulation using kilohertz-frequency alternating current (AC) became popular in the 1950s with the introduction of "interferential currents," promoted as a means of producing depth-efficient stimulation of nerve and muscle. Later, "Russian current" was adopted as a means of muscle strengthening. This article reviews some clinically relevant, laboratory-based studies that offer an insight into the mechanism of action of kilohertz-frequency AC. It provides some answers to the question: "What are the optimal stimulus parameters for eliciting forceful, yet comfortable, electrically induced muscle contractions?" It is concluded that the stimulation parameters commonly used clinically (Russian and interferential currents) are suboptimal for achieving their stated goals and that greater benefit would be obtained using short-duration (2-4 millisecond), rectangular bursts of kilohertz-frequency AC with a frequency chosen to maximize the desired outcome.

Lowering of Sensory, Motor, and Pain-Tolerance Thresholds With Burst Duration Using Kilohertz-Frequency Alternating Current Electric Stimulation

Ward AR, Lucas-Toumbourou S. Lowering of sensory, motor, and pain-tolerance thresholds with burst duration using kilohertz-frequency alternating current electric stimulation. Objective To determine the optimum burst duration for discrimination between sensory, motor, and pain-tolerance thresholds using 50-Hz bursts of kilohertz-frequency sinusoidal alternating current (AC) applied transcutaneously to human subjects. Design A repeated-measures randomized controlled trial. Setting A research laboratory. Participants Twenty-six healthy young adults. Interventions Bursts of AC electric stimulation at frequencies of 1 and 4kHz. Burst durations ranged from 250μs (for 1 cycle of 4kHz AC, ie, a single biphasic pulse) to 20ms (continuous AC). Main Outcome Measures We measured sensory, motor, and pain-tolerance thresholds at frequencies of 1 and 4kHz. Results We found that threshold voltages decreased to a minimum with increasing burst duration. The minimum threshold identified the “utilization time” over which summation of subthreshold stimuli occurs. Above the utilization time, thresholds increased. Estimated utilization times differed for sensory (≈7ms), motor (>10ms), and pain-tolerance (≥20ms). As a consequence, relative thresholds varied with burst duration. A maximum separation between sensory, motor, and pain-tolerance thresholds was found to occur with bursts in the range 1 to 4ms. Conclusions Short-duration kilohertz-frequency AC bursts might have a more useful role in rehabilitation than either pulsed current or the long duration bursts that characterize Russian and interferential currents. Further clinical studies are needed.