Partial high frequency nerve block decreases neuropathic signaling following chronic sciatic nerve constriction injury.

Objective.High frequency (HF) block can quickly and reversibly stop nerve conduction. We hypothesized HF block at the sciatic nerve would minimize nociception by preventing neuropathic signals from reaching the central nervous system.Approach.Lewis rats were implanted with a constriction cuff and a distal cuff electrode around their right sciatic nerve. Tactile sensitivity was evaluated using the 50% paw withdrawal threshold (PWT) determined using Chaplan's method for von Frey monofilaments. Over the course of 49 d, the 50% PWT was measured (1) before HF block, (2) during HF block (50 kHz, 3Vpp), and (3) after HF block. Gait was observed and scored before and during block. At end point, HF block efficacy was directly evaluated using additional cuff electrodes to elicit and record compound neural action potentials across the HF blocking cuff.Main results.At days 7 and 14 d post-operation, tactile sensitivity was significantly lower during HF block compared to before and after block (p< 0.005). Additionally, an increase in gait disability was not visually observed during HF block.Significance.HF block can reduce tactile sensitivity in a limb with a neuropthic injury in a rapidly reversible fashion.

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

AIMS/HYPOTHESIS: A 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. METHODS: Rats 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. RESULTS: KHFAC 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/INTERPRETATION: KHFAC 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.

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

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

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.