Neuromodulation using ultra low frequency current waveform reversibly blocks axonal conduction and chronic pain.

Chronic pain remains a leading cause of disability worldwide, and there is still a clinical reliance on opioids despite the medical side effects associated with their use and societal impacts associated with their abuse. An alternative approach is the use of electrical neuromodulation to produce analgesia. Direct current can block action potential propagation but leads to tissue damage if maintained. We have developed a form of ultra low frequency (ULF) biphasic current and studied its effects. In anesthetized rats, this waveform produced a rapidly developing and completely reversible conduction block in >85% of spinal sensory nerve fibers excited by peripheral stimulation. Sustained ULF currents at lower amplitudes led to a slower onset but reversible conduction block. Similar changes were seen in an animal model of neuropathic pain, where ULF waveforms blocked sensory neuron ectopic activity, known to be an important driver of clinical neuropathic pain. Using a computational model, we showed that prolonged ULF currents could induce accumulation of extracellular potassium, accounting for the slowly developing block observed in rats. Last, we tested the analgesic effects of epidural ULF currents in 20 subjects with chronic leg and back pain. Pain ratings improved by 90% after 2 weeks. One week after explanting the electrodes, pain ratings reverted to 72% of pretreatment screening value. We conclude that epidural spinal ULF neuromodulation represents a promising therapy for treating chronic pain.

Energy efficient neural stimulation: coupling circuit design and membrane biophysics.

The delivery of therapeutic levels of electrical current to neural tissue is a well-established treatment for numerous indications such as Parkinson's disease and chronic pain. While the neuromodulation medical device industry has experienced steady clinical growth over the last two decades, much of the core technology underlying implanted pulse generators remain unchanged. In this study we propose some new methods for achieving increased energy-efficiency during neural stimulation. The first method exploits the biophysical features of excitable tissue through the use of a centered-triangular stimulation waveform. Neural activation with this waveform is achieved with a statistically significant reduction in energy compared to traditional rectangular waveforms. The second method demonstrates energy savings that could be achieved by advanced circuitry design. We show that the traditional practice of using a fixed compliance voltage for constant-current stimulation results in substantial energy loss. A portion of this energy can be recuperated by adjusting the compliance voltage to real-time requirements. Lastly, we demonstrate the potential impact of axon fiber diameter on defining the energy-optimal pulse-width for stimulation. When designing implantable pulse generators for energy efficiency, we propose that the future combination of a variable compliance system, a centered-triangular stimulus waveform, and an axon diameter specific stimulation pulse-width has great potential to reduce energy consumption and prolong battery life in neuromodulation devices.

Dynamics and sensitivity analysis of high-frequency conduction block.

The local delivery of extracellular high-frequency stimulation (HFS) has been shown to be a fast acting and quickly reversible method of blocking neural conduction and is currently being pursued for several clinical indications. However, the mechanism for this type of nerve block remains unclear. In this study, we investigate two hypotheses: (1) depolarizing currents promote conduction block via inactivation of sodium channels and (2) the gating dynamics of the fast sodium channel are the primary determinate of minimal blocking frequency. Hypothesis 1 was investigated using a combined modeling and experimental study to investigate the effect of depolarizing and hyperpolarizing currents on high-frequency block. The results of the modeling study show that both depolarizing and hyperpolarizing currents play an important role in conduction block and that the conductance to each of three ionic currents increases relative to resting values during HFS. However, depolarizing currents were found to promote the blocking effect, and hyperpolarizing currents were found to diminish the blocking effect. Inward sodium currents were larger than the sum of the outward currents, resulting in a net depolarization of the nodal membrane. Our experimental results support these findings and closely match results from the equivalent modeling scenario: intra-peritoneal administration of the persistent sodium channel blocker ranolazine resulted in an increase in the amplitude of HFS required to produce conduction block in rats, confirming that depolarizing currents promote the conduction block phenomenon. Hypothesis 2 was investigated using a spectral analysis of the channel gating variables in a single-fiber axon model. The results of this study suggested a relationship between the dynamical properties of specific ion channel gating elements and the contributions of corresponding conductances to block onset. Specifically, we show that the dynamics of the fast sodium inactivation gate are too slow to track the high-frequency changes in membrane potential during HFS, and that the behavior of the fast sodium current was dominated by the low-frequency depolarization of the membrane. As a result, in the blocked state, only 5.4% of nodal sodium channels were found to be in the activatable state in the node closest to the blocking electrode, resulting in conduction block. Moreover, we find that the corner frequency for the persistent sodium channel activation gate corresponds to the frequency below which high-frequency stimuli of arbitrary amplitude are incapable of inducing conduction block.

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.

Separated interface nerve electrode prevents direct current induced nerve damage.

Direct current, DC, can be used to quickly and reversibly block activity in excitable tissue, or to quickly and reversibly increase or decrease the natural excitability of a neuronal population. However, the practical use of DC to control neuronal activity has been extremely limited due to the rapid tissue damage caused by its use. We show that a separated interface nerve electrode, SINE, is a much safer method to deliver DC to excitable tissue and may be valuable as a laboratory research tool or potentially for clinical treatment of disease.

Design, fabrication and evaluation of a conforming circumpolar peripheral nerve cuff electrode for acute experimental use.

Nerve cuff electrodes are a principle tool of basic and applied electro-neurophysiology studies and are championed for their ability to achieve good nerve recruitment with low thresholds. We describe the design and method of fabrication for a novel circumpolar peripheral nerve electrode for acute experimental use. This cylindrical cuff-style electrode provides approximately 270° of radial electrode contact with a nerve for each of an arbitrary number of contacts, has a profile that allows for simple placement and removal in an acute nerve preparation, and is designed for adjustment of the cylindrical diameter to ensure a close fit on the nerve. For each electrode, the electrical contacts were cut from 25 µm platinum foil as an array so as to maintain their positions relative to each other within the cuff. Lead wires were welded to each intended contact. The structure was then molded in silicone elastomer, after which the individual contacts were electrically isolated. The final electrode was curved into a cylindrical shape with an inner diameter corresponding to that of the intended target nerve. The positions of these contacts were well maintained during the molding and shaping process and failure rates during fabrication due to contact displacements were very low. Established electrochemical measurements were made on one electrode to confirm expected behavior for a platinum electrode and to measure the electrode impedance to applied voltages at different frequencies. These electrodes have been successfully used for nerve stimulation, recording, and conduction block in a number of different acute animal experiments by several investigators.

Conduction block of whole nerve without onset firing using combined high frequency and direct current.

This study investigates a novel technique for blocking a nerve using a combination of direct and high frequency alternating currents (HFAC). HFAC can produce a fast acting and reversible conduction block, but cause intense firing at the onset of current delivery. We hypothesized that a direct current (DC) block could be used for a very brief period in combination with HFAC to block the onset firing, and thus establish a nerve conduction block which does not transmit onset response firing to an end organ. Experiments were performed in rats to evaluate (1) nerve response to anodic and cathodic DC of various amplitudes, (2) degree of nerve activation to ramped DC, (3) a method of blocking onset firing generated by high frequency block with DC, and (4) prolonged non-electrical conduction failure caused by DC delivery. The results showed that cathodic currents produced complete block of the sciatic nerve with a mean block threshold amplitude of 1.73 mA. Ramped DC waveforms allowed for conduction block without nerve activation; however, down ramps were more reliable than up ramps. The degree of nerve activity was found to have a non-monotonic relationship with up ramp time. Block of the onset response resulting from 40 kHz current using DC was achieved in each of the six animals in which it was attempted; however, DC was found to produce a prolonged conduction failure that likely resulted from nerve damage.

Frequency- and amplitude-transitioned waveforms mitigate the onset response in high-frequency nerve block.

High-frequency alternating currents (HFAC) have proven to be a reversible and rapid method of blocking peripheral nerve conduction, holding promise for treatment of disorders associated with undesirable neuronal activity. The delivery of HFAC is characterized by a transient period of neural firing at its inception, termed the 'onset response'. The onset response is minimized for higher frequencies and higher amplitudes, but requires larger currents. However, the complete block can be maintained at lower frequencies and amplitudes, using lower currents. In this in vivo study on whole mammalian peripheral nerves, we demonstrate a method to minimize the onset response by initiating the block using a stimulation paradigm with a high frequency and large amplitude, and then transitioning to a low-frequency and low-amplitude waveform, reducing the currents required to maintain the conduction block. In five of six animals, it was possible to transition from a 30 kHz to a 10 kHz waveform without inducing any transient neural firing. The minimum transition time was 0.03 s. Transition activity was minimized or eliminated with longer transition times. The results of this study show that this method is feasible for achieving a nerve block with minimal onset responses and current amplitude requirements.

Effect of nerve cuff electrode geometry on onset response firing in high-frequency nerve conduction block.

The delivery of high-frequency alternating currents has been shown to produce a focal and reversible conduction block in whole nerve and is a potential therapeutic option for various diseases and disorders involving pathological or undesired neurological activity. However, delivery of high-frequency alternating current to a nerve produces a finite burst of neuronal firing, called the onset response, before the nerve is blocked. Reduction or elimination of the onset response is very important to moving this type of nerve block into clinical applications since the onset response is likely to result in undesired muscle contraction and pain. This paper describes a study of the effect of nerve cuff electrode geometry (specifically, bipolar contact separation distance), and waveform amplitude on the magnitude and duration of the onset response. Electrode geometry and waveform amplitude were both found to affect these measures. The magnitude and duration of the onset response showed a monotonic relationship with bipolar separation distance and amplitude. The duration of the onset response varied by as much as 820% on average for combinations of different electrode geometries and waveform amplitudes. Bipolar electrodes with a contact separation distance of 0.5 mm resulted in the briefest onset response on average. Furthermore, the data presented in this study provide some insight into a biophysical explanation for the onset response. These data suggest that the onset response consists of two different phases: one phase which is responsive to experimental variables such as electrode geometry and waveform amplitude, and one which is not and appears to be inherent to the transition to the blocked state. This study has implications for nerve block electrode and stimulation parameter selection for clinical therapy systems and basic neurophysiology studies.

Nerve conduction block using combined thermoelectric cooling and high frequency electrical stimulation.

Conduction block of peripheral nerves is an important technique for many basic and applied neurophysiology studies. To date, there has not been a technique which provides a quickly initiated and reversible "on-demand" conduction block which is both sustainable for long periods of time and does not generate activity in the nerve at the onset of the conduction block. In this study we evaluated the feasibility of a combined method of nerve block which utilizes two well established nerve blocking techniques in a rat and cat model: nerve cooling and electrical block using high frequency alternating currents (HFAC). This combined method effectively makes use of the contrasting features of both nerve cooling and electrical block using HFAC. The conduction block was initiated using nerve cooling, a technique which does not produce nerve "onset response" firing, a prohibitive drawback of HFAC electrical block. The conduction block was then readily transitioned into an electrical block. A long-term electrical block is likely preferential to a long-term nerve cooling block because nerve cooling block generates large amounts of exhaust heat, does not allow for fiber diameter selectivity and is known to be unsafe for prolonged delivery.

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.

Combined direct current and high frequency nerve block for elimination of the onset response.

Nerve conduction in peripheral mammalian nerves can be blocked by high frequency alternating current (HFAC) waveforms. However, one of the disadvantages of HFAC block is that it produces an intense burst of firing in the nerve when the HFAC is first turned on. This is a significant obstacle to the clinical implementation of HFAC block. In this paper we present a method to produce HFAC block without the onset response, using a combination of direct current (DC) and HFAC block. This method was experimentally evaluated in an in-vivo mammalian model. Successful no-onset HFAC block was obtained using a DC block of 200 microA and an HFAC block of 30 kHz at 10 Vp-p. This may allow HFAC block to be used in clinical applications for pain relief.

Effect of bipolar cuff electrode design on block thresholds in high-frequency electrical neural conduction block.

Many medical conditions are characterized by undesired or pathological peripheral neurological activity. The local delivery of high-frequency alternating currents (HFAC) has been shown to be a fast acting and quickly reversible method of blocking neural conduction and may provide a treatment alternative for eliminating pathological neural activity in these conditions. This work represents the first formal study of electrode design for high-frequency nerve block, and demonstrates that the interpolar separation distance for a bipolar electrode influences the current amplitudes required to achieve conduction block in both computer simulations and mammalian whole nerve experiments. The minimal current required to achieve block is also dependent on the diameter of the fibers being blocked and the electrode-fiber distance. Single fiber simulations suggest that minimizing the block threshold can be achieved by maximizing both the bipolar activating function (by adjusting the bipolar electrode contact separation distance) and a synergistic addition of membrane sodium currents generated by each of the two bipolar electrode contacts. For a rat sciatic nerve, 1.0-2.0 mm represented the optimal interpolar distance for minimizing current delivery.

Designing the optical interface of a transcutaneous optical telemetry link.

Optical telemetry has long been an option for transcutaneous data transfer and has been used in various types of implanted systems. This telemetry modality and the efficiency of these optical links are becoming ever more important as higher bandwidth sources such as cortical recording arrays are being implemented in implanted systems. The design of the transmitter-skin-receiver interface (the "optical interface") is paramount to the operation of a transcutaneous optical telemetry link. This interface functions to achieve sufficient receiver signal power for data communication. This paper describes a mathematical analysis and supporting data that quantitatively describes the relationship between the primary interface design parameters. These parameters include the thickness of the skin through which the light is transmitted, the size of the integration area of the optics, the degree of transmitter-receiver misalignment, the efficiency of the optics system, and the emitter power. The particular combination of these parameters chosen for the hardware device will determine the receiver signal power and, therefore, the data quality for the link. This paper demonstrates some of the tradeoffs involved in the selection of these design parameters and provides suggestions for link design. This analysis may also be useful for transcutaneous optical powering systems.

Design of a high speed transcutaneous optical telemetry link.

In some neural prosthetic applications there is a need for high bandwidth communication between an implanted device and an external device. For example, transmitting 100 channels of neural waveform data for a cortical prosthetic control system may require up to 40 Mbps for a 100 channel array. Due to the high bandwidth required and its relative immunity from interference, optical telemetry is the most realistic method for achieving a clinically robust transcutaneous communication system capable of achieving these data rates. It is proposed that a transcutaneous optical telemetry link design can be optimized to system level design parameters (power consumption, implant location, etc.) by having a quantified understanding of the different link level design parameters (optical power, lens size, tissue effects, transmitter-receiver alignment, etc.) and an understanding as to how those parameters interact, and will allow for a design guided by an a priori assessment of these parameters. Some of these design factors and their interactions are identified and described. One of these parameters, the tissue optical spatial impulse response is measured empirically for several porcine dermal tissue configurations, and it's implications for device design tradeoffs are discussed.