Scalable and reversible axonal neuromodulation of the sympathetic chain for cardiac control.

Maladaptation of the sympathetic nervous system contributes to the progression of cardiovascular disease and risk for sudden cardiac death, the leading cause of mortality worldwide. Axonal modulation therapy (AMT) directed at the paravertebral chain blocks sympathetic efferent outflow to the heart and maybe a promising strategy to mitigate excess disease-associated sympathoexcitation. The present work evaluates AMT, directed at the sympathetic chain, in blocking sympathoexcitation using a porcine model. In anesthetized porcine (n = 14), we applied AMT to the right T1-T2 paravertebral chain and performed electrical stimulation of the distal portion of the right sympathetic chain (RSS). RSS-evoked changes in heart rate, contractility, ventricular activation recovery interval (ARI), and norepinephrine release were examined with and without kilohertz frequency alternating current block (KHFAC). To evaluate efficacy of AMT in the setting of sympathectomy, evaluations were performed in the intact state and repeated after left and bilateral sympathectomy. We found strong correlations between AMT intensity and block of sympathetic stimulation-evoked changes in cardiac electrical and mechanical indices (r = 0.83-0.96, effect size d = 1.9-5.7), as well as evidence of sustainability and memory. AMT significantly reduced RSS-evoked left ventricular interstitial norepinephrine release, as well as coronary sinus norepinephrine levels. Moreover, AMT remained efficacious following removal of the left sympathetic chain, with similar mitigation of evoked cardiac changes and reduction of catecholamine release. With growth of neuromodulation, an on-demand or reactionary system for reversible AMT may have therapeutic potential for cardiovascular disease-associated sympathoexcitation.NEW & NOTEWORTHY Autonomic imbalance and excess sympathetic activity have been implicated in the pathogenesis of cardiovascular disease and are targets for existing medical therapy. Neuromodulation may allow for control of sympathetic projections to the heart in an on-demand and reversible manner. This study provides proof-of-concept evidence that axonal modulation therapy (AMT) blocks sympathoexcitation by defining scalability, sustainability, and memory properties of AMT. Moreover, AMT directly reduces release of myocardial norepinephrine, a mediator of arrhythmias and heart failure.

Evaluation of Activated Carbon and Platinum Black as High-Capacitance Materials for Platinum Electrodes.

The application of direct current (DC) produces a rapid and reversible nerve conduction block. However, prolonged injection of charge through a smooth platinum electrode has been found to cause damage to nervous tissue. This damage can be mitigated by incorporating high-capacitance materials (HCM) (e.g., activated carbon or platinum black) into electrode designs. HCMs increase the storage charge capacity (i.e., "Q value") of capacitive devices. However, consecutive use of these HCM electrodes degrades their surface. This paper evaluates activated carbon and platinum black (PtB) electrode designs in vitro to determine the design parameters which improve surface stability of the HCMs. Electrode designs with activated carbon and PtB concentrations were stressed using soak, bend and vibration testing to simulate destructive in vivo environments. A Q value decrease represented the decreased stability of the electrode-HCM interface. Soak test results supported the long-term Q value stabilization (mean = 44.3 days) of HCM electrodes, and both HCMs displayed unique Q value changes in response to soaking. HCM material choices, Carbon Ink volume, and application of Nafion™ affected an electrode's ability to resist Q value degradation. These results will contribute to future developments of HCM electrodes designed for extended DC application for in vivo nerve conduction block.

Reversible nerve conduction block using kilohertz frequency alternating current.

OBJECTIVES: The features and clinical applications of balanced-charge kilohertz frequency alternating currents (KHFAC) are reviewed. Preclinical studies of KHFAC block have demonstrated that it can produce an extremely rapid and reversible block of nerve conduction. Recent systematic analysis and experimentation utilizing KHFAC block have resulted in a significant increase in interest in KHFAC block, both scientifically and clinically. MATERIALS AND METHODS: We review the history and characteristics of KHFAC block, the methods used to investigate this type of block, the experimental evaluation of block, and the electrical parameters and electrode designs needed to achieve successful block. We then analyze the existing clinical applications of high-frequency currents, comparing the early results with the known features of KHFAC block. RESULTS: Although many features of KHFAC block have been characterized, there is still much that is unknown regarding the response of neural structures to rapidly fluctuating electrical fields. The clinical reports to date do not provide sufficient information to properly evaluate the mechanisms that result in successful or unsuccessful treatment. CONCLUSIONS: KHFAC nerve block has significant potential as a means of controlling nerve activity for the purpose of treating disease. However, early clinical studies in the use of high-frequency currents for the treatment of pain have not been designed to elucidate mechanisms or allow direct comparisons to preclinical data. We strongly encourage the careful reporting of the parameters utilized in these clinical studies, as well as the development of outcome measures that could illuminate the mechanisms of this modality.

First-In-Human Demonstration of High Frequency Electrical Motor Nerve Block: Case Report.

ABSTRACT: This feasibility study tested the capability of high frequency stimulation (HFS) to block muscle contractions elicited by electrical stimulation of the same nerve proximally. During a tendon lengthening surgery in the forearm, the anterior interosseous nerve (AIN) was exposed. A specialized nerve cuff electrode was placed around the nerve, and a stimulating probe held on the nerve 1 cm proximal to the cuff electrode delivered pulses of current causing the pronator quadratus muscle to contract. Through the cuff electrode, 20 kHz HFS was delivered to the nerve for 10 seconds during proximal stimulation. HFS amplitudes between 5 and 10 mA peak-to-peak were tested to determine which produced complete and partial block of the electrically induced contractions. The minimum HFS amplitude that produced complete block was 8 mA, with lower amplitudes producing partial block. In all trials, muscle contractions resumed immediately after HFS was turned off. This demonstration of high frequency electrical nerve block is a milestone in the road to clinical implementation of HFS mediated motor block for spasticity.

Effects on heart rate from direct current block of the stimulated rat vagus nerve.

Objective.Although electrical vagus nerve stimulation has been shown to augment parasympathetic control of the heart, the effects of electrical conduction block have been less rigorously characterized. Previous experiments have demonstrated that direct current (DC) nerve block can be applied safely and effectively in the autonomic system, but additional information about the system dynamics need to be characterized to successfully deploy DC nerve block to clinical practice.Approach.The dynamics of the heart rate (HR) from DC nerve block of the vagus nerve were measured by stimulating the vagus nerve to lower the HR, and then applying DC block to restore normal rate. DC block achieved rapid, complete block, as well as partial block at lower amplitudes.Main Results. Complete block was also achieved using lower amplitudes, but with a slower induction time. The time for DC to induce complete block was significantly predicted by the amplitude; specifically, the amplitude expressed as a percentage of the current required for a rapid, 60 s induction time. Recovery times after the cessation of DC block could occur both instantly, and after a significant delay. Both blocking duration and injected charge were significant in predicting the delay in recovery to normal conduction.Significance. While these data show that broad features such as induction and recovery can be described well by the DC parameters, more precise features of the HR, such as the exact path of the induction and recoveries, are still undefined. These findings show promise for control of the cardiac autonomic nervous system, with potential to expand to the sympathetic inputs as well.

Effects of waveform shape and electrode material on KiloHertz frequency alternating current block of mammalian peripheral nerve.

OBJECTIVES: KiloHertz frequency alternating current waveforms produce conduction block in peripheral nerves. It is not clearly known how the waveform shape affects block outcomes, and if waveform effects are frequency dependent. We determined the effects of waveform shape using two types of electrodes. MATERIALS AND METHODS: Acute in-vivo experiments were performed on 12 rats. Bipolar electrodes were used to electrically block motor nerve impulses in the sciatic nerve, as measured using force output from the gastrocnemius muscle. Three blocking waveforms were delivered (sinusoidal, square and triangular) at 6 frequencies (10-60 kHz). Bare platinum electrodes were compared with carbon black coated electrodes. We determined the minimum amplitude that could completely block motor nerve conduction (block threshold), and measured properties of the onset response, which is a transient period of nerve activation at the start of block. In-vivo results were compared with computational modeling conducted using the NEURON simulation environment using a nerve membrane model modified for stimulation in the kilohertz frequency range. RESULTS: For the majority of parameters, in-vivo testing and simulations showed similar results: Block thresholds increased linearly with frequency for all three waveforms. Block thresholds were significantly different between waveforms; lowest for the square waveform and highest for triangular waveform. When converted to charge per cycle, square waveforms required the maximum charge per phase, and triangular waveforms the least. Onset parameters were affected by blocking frequency but not by waveform shape. Electrode comparisons were performed only in-vivo. Electrodes with carbon black coatings gave significantly lower block thresholds and reduced onset responses across all blocking frequencies. For 10 and 20 kHz, carbon black coating significantly reduced the charge required for nerve block. CONCLUSIONS: We conclude that both sinusoidal and square waveforms at frequencies of 20 kHz or higher would be optimal. Future investigation of carbon black or other high charge capacity electrodes may be useful in achieving block with lower BTs and onsets. These findings will be of importance for designing clinical nerve block systems.

Electrical conduction block in large nerves: high-frequency current delivery in the nonhuman primate.

Recent studies have made significant progress toward the clinical implementation of high-frequency conduction block (HFB) of peripheral nerves. However, these studies were performed in small nerves, and questions remain regarding the nature of HFB in large-diameter nerves. This study in nonhuman primates shows reliable conduction block in large-diameter nerves (up to 4.1 mm) with relatively low-threshold current amplitude and only moderate nerve discharge prior to the onset of block.

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 bothin silicoandin 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.

Fuzzy Logic Control of Heartrate by Electrical Block of Vagus Nerve.

Although vagus nerve stimulation (VNS) can be used to reduce heartrate by enhancing parasympathetic activity, a fully controllable intervention would also require a method for downregulating parasympathetic activity. A direct current (DC) block can be applied to a nerve to block its action potential conduction. This nerve block can be used to downregulate parasympathetic activity by blocking afferent reflexes. The damaging effects of reactions that occur at the electrode-nerve interface using conventional platinum electrodes can be avoided by separating the electrode from the nerve. Using a biocompatible, ionically conducting medium, the electrode and the damaging reactions can be isolated in a vessel away from the nerve. This type of electrode has been called the Separated Interface Nerve Electrode (SINE). Fuzzy logic control (FLC) is a controller approach that is well suited to physiological systems. The SINE, controlled by an FLC, was utilized to block a stimulated vagus nerve and regulate heart rate. The FLC was able to maintain the heartrate at a pre-determined setpoint while still achieving instant recovery when the block was removed.

Conduction block of peripheral nerve using high-frequency alternating currents delivered through an intrafascicular electrode.

Many diseases are characterized by undesired or pathological neural activity. The local delivery of high-frequency currents has been shown to be an effective method for blocking neural conduction in peripheral nerves and may provide a therapy for these conditions. To date, all studies of high-frequency conduction block have utilized extraneural (cuff) electrodes to achieve conduction block. In this study we show that high-frequency conduction block is feasible using intrafascicular electrodes.

Implantable neuroprosthetic technology.

Neuroprostheses electrically stimulate paralyzed muscles to provide functional enhancement for individuals with neurological disorders, especially among persons with spinal cord injuries. Fully implanted neuroprostheses are reliable, require minimal maintenance and are user-friendly. These systems provide a variety of functions, including reaching, hand grasp and release, standing and stepping, bladder and bowel function and respiratory assist. Based on a representative review of the literature, this article presents and evaluates the development, clinical implementation and clinical efficacy and effectiveness of the various implanted neuroprostheses. Directions for future development are also presented.

A Carbon Slurry Separated Interface Nerve Electrode for Electrical Block of Nerve Conduction.

Direct current (DC) nerve block has been shown to provide a complete block of nerve conduction without unwanted neural firing. Previous work shows that high capacitance electrodes can be used to safely deliver a DC block. Another way of delivering DC safely is through a separated interface nerve electrode (SINE), such that any reactive species that are generated by the passage of DC are contained in a vessel away from the nerve. This design has been enhanced by using a high capacitance carbon "slurry" as the electrode in the external vessel to extend the capacity of the electrode (CSINE). With this new design, it was possible to provide 50 min of continuous nerve block without recharge while still maintaining complete recovery of neural signals. Up to 46 C of charge delivery was applied for a total of 4 h of nerve block with complete recovery. Because of the extended delivery time, it was possible to explore several properties of DC block that would not be revealed without the capability of a long-duration continuous block. It was possible to achieve complete block at lower values of DC if the block was applied for a longer period of time. Depending on the amount of charge applied during the block, the recovery was delayed for a period of time before complete force recovery was restored. These new properties provide novel techniques for device development to optimize charge delivery time and device powering concerns.

Measurement of block thresholds in kiloHertz frequency alternating current peripheral nerve block.

BACKGROUND: Kilohertz frequency alternating currents (KHFAC) produce rapid nerve conduction block of mammalian peripheral nerve and have potential clinical applications in reducing peripheral nerve hyperactivity. The experimental investigation of KHFAC nerve block requires a robust output measure and this has proven to be the block threshold (BT), the lowest current or voltage at which the axons of interest are completely blocked. All significant literature in KHFAC nerve block, both simulations and experimental, were reviewed to determine the block threshold method that was used. The two common methods used are the High-Low method experimentally and the Binary search method for simulations. NEW METHOD: Four methods to measure the block threshold (High-Low, High-Low-High, Binary and Random) at three frequencies (10, 20 and 30 kHz) were compared through randomized repeated experiments in the in-vivo rodent sciatic nerve-gastrocnemius model. RESULTS: The literature review showed that more than 50% of publications did not measure the block threshold. The experimental results showed no statistical difference in the BT value between the four methods. COMPARISON WITH EXISTING METHOD(S): However, there were differences in the number of significant onset responses, depending on the method. The run time for the BT determination was the shortest for the High-Low method. CONCLUSIONS: It is recommended that all research in electrical nerve block, including KHFAC, should include measurement of the BT. The High-Low method is recommended for most experimental situations but the Binary method could also be a viable option, especially where onset responses are minimal.

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.

Reversible conduction block in peripheral nerve using electrical waveforms.

INTRODUCTION: Electrical nerve block uses electrical waveforms to block action potential propagation. MATERIALS & METHODS: Two key features that distinguish electrical nerve block from other nonelectrical means of nerve block: block occurs instantly, typically within 1 s; and block is fully and rapidly reversible (within seconds). RESULTS: Approaches for achieving electrical nerve block are reviewed, including kilohertz frequency alternating current and charge-balanced polarizing current. We conclude with a discussion of the future directions of electrical nerve block. CONCLUSION: Electrical nerve block is an emerging technique that has many significant advantages over other methods of nerve block. This field is still in its infancy, but a significant expansion in the clinical application of this technique is expected in the coming years.

Continuous Direct Current Nerve Block Using Multi Contact High Capacitance Electrodes.

Charge-balanced direct current (CBDC) nerve block can be used to block nerve conduction in peripheral nerves. Previous work demonstrated that the CBDC waveform could be used to achieve a 10% duty cycle of block to non-block repeatedly for at least two hours. We demonstrate that the duty cycle of this approach can be significantly increased by utilizing multiple electrode contacts and cycling the CBDC waveform between each contact in a "carousel" configuration. Using this approach, we demonstrated in an acute rat sciatic nerve preparation, that a 30% duty cycle complete block can be achieved with two contacts; and a 100% duty cycle block (>95% complete block) can be achieved with four contacts. This latter configuration utilized a 4-s block plateau, with 3 s between successive plateaus at each contact and a recharge phase amplitude that was 34% of the block amplitude. Further optimization of the carousel approach can be achieved to improve block effectiveness and minimize total electrode length. This approach may have significant clinical use in cases where a partial or complete block of peripheral nerve activity is required. In one example case, we achieved continuous block for 22 min without degradation of nerve conduction. Future study will be required to further optimize this technique and to demonstrate safety for chronic human use.

High frequency electrical conduction block of the pudendal nerve.

A reversible electrical block of the pudendal nerves may provide a valuable method for restoration of urinary voiding in individuals with bladder-sphincter dyssynergia. This study quantified the stimulus parameters and effectiveness of high frequency (HFAC) sinusoidal waveforms on the pudendal nerves to produce block of the external urethral sphincter (EUS). A proximal electrode on the pudendal nerve after its exit from the sciatic notch was used to apply low frequency stimuli to evoke EUS contractions. HFAC at frequencies from 1 to 30 kHz with amplitudes from 1 to 10 V were applied through a conforming tripolar nerve cuff electrode implanted distally. Sphincter responses were recorded with a catheter mounted micro-transducer. A fast onset and reversible motor block was obtained over this range of frequencies. The HFAC block showed three phases: a high onset response, often a period of repetitive firing and usually a steady state of complete or partial block. A complete EUS block was obtained in all animals. The block thresholds showed a linear relationship with frequency. HFAC pudendal nerve stimulation effectively produced a quickly reversible block of evoked urethral sphincter contractions. The HFAC pudendal block could be a valuable tool in the rehabilitation of bladder-sphincter dyssynergia.

Characterization of high capacitance electrodes for the application of direct current electrical nerve block.

Direct current (DC) can briefly produce a reversible nerve conduction block in acute experiments. However, irreversible reactions at the electrode-tissue interface have prevented its use in both acute and chronic settings. A high capacitance material (platinum black) using a charge-balanced waveform was evaluated to determine whether brief DC block (13 s) could be achieved repeatedly (>100 cycles) without causing acute irreversible reduction in nerve conduction. Electrochemical techniques were used to characterize the electrodes to determine appropriate waveform parameters. In vivo experiments on DC motor conduction block of the rat sciatic nerve were performed to characterize the acute neural response to this novel nerve block system. Complete nerve motor conduction block of the rat sciatic nerve was possible in all experiments, with the block threshold ranging from -0.15 to -3.0 mA. DC pulses were applied for 100 cycles with no nerve conduction reduction in four of the six platinum black electrodes tested. However, two of the six electrodes exhibited irreversible conduction degradation despite charge delivery that was within the initial Q (capacitance) value of the electrode. Degradation of material properties occurred in all experiments, pointing to a possible cause of the reduction in nerve conduction in some platinum black experiments .

Direct current electrical conduction block of peripheral nerve.

Electrical currents can be used to produce a block of action potential conduction in whole nerves. This block has a rapid onset and reversal. The mechanism of electrical nerve conduction block has not been conclusively determined, and inconsistencies appear in the literature regarding whether the block is produced by membrane hyperpolarization, depolarization, or through some other means. We have used simulations in a nerve membrane model, coupled with in vivo experiments, to identify the mechanism and principles of electrical conduction block. A nerve simulation package (Neuron) was used to model direct current (dc) block in squid, frog, and mammalian neuron models. A frog sciatic nerve/gastrocnemius preparation was used to examine nerve conduction block in vivo. Both simulations and experiments confirm that depolarization block requires less current than hyperpolarization block. Dynamic simulations suggest that block can occur under both the real physical electrode as well as adjacent virtual electrode sites. A hypothesis is presented which formulates the likely types of dc block and the possible block current requirements. The results indicate that electrical currents generally produce a conduction block due to depolarization of the nerve membrane, resulting in an inactivation of the sodium channels.

Implementation of an implantable joint-angle transducer.

An implantable joint-angle transducer (IJAT) was implemented to provide command-control information from the wrist for functional neuromuscular stimulation (FNS) neuroprostheses. The IJAT uses the Hall effect to sense joint angle. The objectives of this study were to evaluate (1) chronic functionality, (2) safety and biocompatibility, (3) repeatability of the implantation procedure, and (4) clinical feasibility. Accelerated bench testing projected an operating period of over 50 years. In chronic animal experiments, stable output was obtained from three of four IJATs for periods of 10 to 19 months. Histology revealed acceptable osseointegration of the implant. The device has been implanted in human subjects for over 2 years and provides an excellent control signal for hand grasp. We conclude that this device is safe and effective for chronic human use as a control input for an implanted hand neuroprosthesis.