Pulsatile electrical stimulation creates predictable, correctable disruptions in neural firing.

Electrical stimulation is a key tool in neuroscience, both in brain mapping studies and in many therapeutic applications such as cochlear, vestibular, and retinal neural implants. Due to safety considerations, stimulation is restricted to short biphasic pulses. Despite decades of research and development, neural implants lead to varying restoration of function in patients. In this study, we use computational modeling to provide an explanation for how pulsatile stimulation affects axonal channels and therefore leads to variability in restoration of neural responses. The phenomenological explanation is transformed into equations that predict induced firing rate as a function of pulse rate, pulse amplitude, and spontaneous firing rate. We show that these equations predict simulated responses to pulsatile stimulation with a variety of parameters as well as several features of experimentally recorded primate vestibular afferent responses to pulsatile stimulation. We then discuss the implications of these effects for improving clinical stimulation paradigms and electrical stimulation-based experiments.

Peripheral direct current reduces naturally evoked nociceptive activity at the spinal cord in rodent models of pain.

Objective.Electrical neuromodulation is an established non-pharmacological treatment for chronic pain. However, existing devices using pulsatile stimulation typically inhibit pain pathways indirectly and are not suitable for all types of chronic pain. Direct current (DC) stimulation is a recently developed technology which affects small-diameter fibres more strongly than pulsatile stimulation. Since nociceptors are predominantly small-diameter Aδand C fibres, we investigated if this property could be applied to preferentially reduce nociceptive signalling.Approach.We applied a DC waveform to the sciatic nerve in rats of both sexes and recorded multi-unit spinal activity evoked at the hindpaw using various natural stimuli corresponding to different sensory modalities rather than broad-spectrum electrical stimulus. To determine if DC neuromodulation is effective across different types of chronic pain, tests were performed in models of neuropathic and inflammatory pain.Main results.We found that in both pain models tested, DC application reduced responses evoked by noxious stimuli, as well as tactile-evoked responses which we suggest may be involved in allodynia. Different spinal activity of different modalities were reduced in naïve animals compared to the pain models, indicating that physiological changes such as those mediated by disease states could play a larger role than previously thought in determining neuromodulation outcomes.Significance.Our findings support the continued development of DC neuromodulation as a method for reduction of nociceptive signalling, and suggests that it may be effective at treating a broader range of aberrant pain conditions than existing devices.

Galvanic vs. pulsatile effects on decision-making networks: reshaping the neural activation landscape.

Objective. Primarily due to safety concerns, biphasic pulsatile stimulation (PS) is the present standard for electrical excitation of neural tissue with a diverse set of applications. While pulses have been shown to be effective to achieve functional outcomes, they have well-known deficits. Due to recent technical advances, galvanic stimulation (GS), delivery of current for extended periods of time (>1 s), has re-emerged as an alternative to PS.Approach. In this paper, we use a winner-take-all decision-making cortical network model to investigate differences between pulsatile and GS in the context of a perceptual decision-making task.Main results. Based on previous work, we hypothesized that GS would produce more spatiotemporally distributed, network-sensitive neural responses, while PS would produce highly synchronized activation of a limited group of neurons. Our results in-silico support these hypotheses for low-amplitude GS but deviate when galvanic amplitudes are large enough to directly activate or block nearby neurons.Significance. We conclude that with careful parametrization, GS could overcome some limitations of PS to deliver more naturalistic firing patterns in the group of targeted neurons.

Glucose Fuel Cells: Electricity from Blood Sugar.

Harvesting energy from the human body is an area of growing interest. While several techniques have been explored, the focus in the field is converging on using Glucose Fuel Cells (GFCs) that use glucose oxidation reactions at an anode and oxygen reduction reactions (ORRs) at a cathode to create a voltage gradient that can be stored as power. To facilitate these reactions, catalysts are immobilized at an anode and cathode that result in electrochemistry that typically produces two electrons, a water molecule, and gluconic acid. There are two competing classes of these catalysts: enzymes, which use organic proteins, and abiotic options, which use reactive metals. Enzymatic catalysts show better specificity towards glucose, whereas abiotic options show superior operational stability. The most advanced enzymatic test showed a maximum power density of 119 µW/cm2 and an efficiency loss of 4% over 15 hours of operation. The best abiotic experiment resulted in 43 µW/cm2 and exhibited no signs of performance loss after 140 hours. Given the range of existing implantable devices' power budget from 10µW to 100mW and expected operational duration of 10 years or more, GFCs hold promise, but considerable advances need to be made to translate this technology to practical applications.

The Significance of Concentration-dependent Components in Computational Models of C-Fibers.

Computational models of neurons are valuable tools that allow researchers to form and evaluate hypotheses and minimize high-cost animal work. We soon plan to use computational modeling to explore the response of different sensory fiber types to long duration external stimulation to try to selectively block nociceptive C-fibers. In this work, we modified an existing C-fiber-specific axon model to additionally include concentration-dependent conductance changes, the contribution of longitudinal current flow to changes in local concentrations, and longitudinal currents generated by concentration gradients along the axon. Then, we examined the impact of these additional elements on the modeled action potential properties, activity-dependent latency increases, and concentration changes due to external stimulation. We found that these additional model elements did not significantly affect the action potential properties or activity-dependent behavior, but they did have a significant impact on the modeled response to external long duration stimulation.Clinical Relevance- This presents a computational model that can be used to help investigate and develop electrical stimulation therapies for pathological pain.

Cytoelectric coupling: Electric fields sculpt neural activity and "tune" the brain's infrastructure.

We propose and present converging evidence for the Cytoelectric Coupling Hypothesis: Electric fields generated by neurons are causal down to the level of the cytoskeleton. This could be achieved via electrodiffusion and mechanotransduction and exchanges between electrical, potential and chemical energy. Ephaptic coupling organizes neural activity, forming neural ensembles at the macroscale level. This information propagates to the neuron level, affecting spiking, and down to molecular level to stabilize the cytoskeleton, "tuning" it to process information more efficiently.

Low Cost, Ease-of-Access Fabrication of Microfluidic Devices Using Wet Paper Molds.

Rapid prototyping methods enable the widespread adoption of microfluidic technologies by empowering end-users from non-engineering disciplines to make devices using processes that are rapid, simple and inexpensive. In this work, we developed a liquid molding technique to create silicone/PDMS microfluidic devices by replica molding. To construct a liquid mold, we use inexpensive adhesive-backed paper, an acetate backing sheet, and an off-the-shelf digital cutter to create paper molds, which we then wet with predetermined amounts of water. Due to the immiscibility of water and PDMS, mold patterns can be effectively transferred onto PDMS similarly to solid molds. We demonstrate the feasibility of these wet paper molds for the fabrication of PDMS microfluidic devices and assess the influence of various process parameters on device yield and quality. This method possesses some distinct benefits compared to conventional techniques such as photolithography and 3D printing. First, we demonstrate that the shape of a channel's cross-section may be altered from rectangular to semicircular by merely modifying the wetting parameters. Second, we illustrate how electrical impedance can be utilized as a marker for inspecting mold quality and identifying defects in a non-invasive manner without using visual tools such as microscopes or cameras. As a proof-of-concept device, we created a microfluidic T-junction droplet generator to produce water droplets in mineral oil ranging in size from 1.2 µL to 75 µL. We feel that this technology is an excellent addition to the microfluidic rapid prototyping toolbox and will find several applications in biological research.

Difference in Network Effects of Pulsatile and Galvanic Stimulation.

Biphasic pulsatile stimulation is the present standard for neural prosthetic use, and it is used to understand connectivity and functionality of the brain in brain mapping studies. While pulses have been shown to drive behavioral changes, such as biasing decision making, they have deficits. For example, cochlear implants restore hearing but lack the ability to restore pitch perception. Recent work shows that pulses produce artificial synchrony in networks of neurons and non-linear changes in firing rate with pulse amplitude. Studies also show galvanic stimulation, delivery of current for extended periods of time, produces more naturalistic behavioral responses than pulses. In this paper, we use a winner-take-all decision-making network model to investigate differences between pulsatile and galvanic stimulation at the single neuron and network level while accurately modeling the effects of pulses on neurons for the first time. Results show pulses bias spike timing and make neurons more resistive to natural network inputs than galvanic stimulation at an equivalent current amplitude. Clinical Relevance- This establishes that pulsatile stimulation may disrupt natural spike timing and network-level interactions while certain parameterizations of galvanic stimulation avoid these effects and can drive network firing more naturally.

Ionic transistor using ion exchange membranes.

Ionic transistors can be used to modulate ionic current in a way that is analogous to their electronic counterparts. An ionic transistor can reversibly change its ionic conduction to control ionic current by injecting electrical charges. To facilitate its applications in biomedical devices (e.g., controlled drug delivery, rectification of ionic current, and signal processing), an ionic transistor should maintain high performance of ionic current control within physiological solutions (e.g., 0.9% NaCl) for long durations. Here, we introduce an ionic transistor using cation and anion exchange membranes (CEM and AEM). It could impose a 10× impedance change in a channel filled with 0.9% NaCl solution and we observed a stable modulation of ionic current throughout a test of 1000 cycles of on/off switching of the ionic transistor.

A Machine Learning-based Neural Implant Front End for Inducing Naturalistic Firing.

Despite being able to restore speech perception with 99% success rate, cochlear implants cannot successfully restore pitch perception or music appreciation. Studies suggest that if auditory neurons were activated with fine timing closer to that of natural responses pitch would be restored. Predicting the timing of cochlear responses requires detailed biophysical models of sound transmission, inner hair cell responses, and outer hair cell responses. Performing these calculations is computationally costly for real time cochlear implant stimulation. Instead, implants typically modulate pulse amplitude of fixed pulse rate stimulation with the band-limited envelopes of incoming sound. This method is known to produce unrealistic responses, even to simple step inputs. Here we investigate using a machine learning algorithm to optimize the prediction of the desired firing patterns of the auditory afferents in response to sinusoidal and step modulation of pure tones. We conclude that a trained network that consists of 25 GRU nodes can reproduce fine timing with 4.4 percent error on a test set of sines and steps. This trained network can also transfer learn and capture features of natural sounds that are not captured by standard CI algorithms. Additionally, for 0.5 second test inputs, the ML algorithm completed the sound to spike rate conversion in 300x less time than the phenomenological model. This calculation occurs at a real-time compatible rate of 1 ms for 1 second of spike timing prediction on an i9 microprocessor. This suggests that this is a feasible approach to pursue for real-time CI implementation.

A Hydrogel-Based Microfluidic Nerve Cuff for Neuromodulation of Peripheral Nerves.

Implantable neuromodulation devices typically have metal in contact with soft, ion-conducting nerves. These neural interfaces excite neurons using short-duration electrical pulses. While this approach has been extremely successful for multiple clinical applications, it is limited in delivering long-duration pulses or direct current (DC), even for acute term studies. When the charge injection capacity of electrodes is exceeded, irreversible electrochemical processes occur, and toxic byproducts are discharged directly onto the nerve, causing biological damage. Hydrogel coatings on electrodes improve the overall charge injection limit and provide a mechanically pliable interface. To further extend this idea, we developed a silicone-based nerve cuff lead with a hydrogel microfluidic conduit. It serves as a thin, soft and flexible interconnection and provides a greater spatial separation between metal electrodes and the target nerve. In an in vivo rat model, we used this cuff to stimulate and record from sciatic nerves, with performance comparable to that of metal electrodes. Further, we delivered DC through the lead in an acute manner to induce nerve block that is reversible. In contrast to most metallic cuff electrodes, which need microfabrication equipment, we built this cuff using a consumer-grade digital cutter and a simplified molding process. Overall, the device will be beneficial to neuromodulation researchers as a general-purpose nerve cuff electrode for peripheral neuromodulation experiments.

Direct current effects on afferent and hair cell to elicit natural firing patterns.

In contrast to the conventional pulsatile neuromodulation that excites neurons, galvanic or direct current stimulation can excite, inhibit, or sensitize neurons. The vestibular system presents an excellent system for studying galvanic neural interface due to the spontaneously firing afferent activity that needs to be either suppressed or excited to convey head motion sensation. We determine the cellular mechanisms underlying the beneficial properties of galvanic vestibular stimulation (GVS) by creating a computational model of the vestibular end organ that elicits all experimentally observed response characteristics to GVS simultaneously. When GVS was modeled to affect the axon alone, the complete experimental data could not be replicated. We found that if GVS affects hair cell vesicle release and axonal excitability simultaneously, our modeling results matched all experimental observations. We conclude that contrary to the conventional belief that GVS affects only axons, the hair cells are likely also affected by this stimulation paradigm.

On-chip ionic current sensor.

Neural implants that deliver drugs or electrical stimuli via microfluidic ports are promising in providing therapy for various disorders such as epilepsy, chronic pain, and vestibular diseases. To deliver the stimuli to a neural target, these devices incorporate two or more electrodes that apply an electric field to drive charged particles or ions along an aqueous route provided by microfluidic channels. The amount of drug/current delivered is determined by measuring the ionic current flow. When the ionic current can only travel from one electrode to another via a single route or channel, the amount of therapeutic current is stoichiometrically equal to the electronic current applied by the device and therefore can be measured with an electronic current sensor. However, some recently developed devices contain networks of branched channels. In this case, the presence of multiple parallel ionic current paths makes it so that the current through any one individual channel is no longer measurable by observing electronic current alone. Here, we present an on-chip sensor that uses two Pt/Ir electrodes to transduce the ionic current through a target channel into a measurable voltage signal. The size of the metal wires did not impact the measured voltage, the size of the channel between the two sensing electrodes determines sensitivity of the sensor, change in temperature can cause a change in readings, and input impedance of the voltage measuring equipment must be greater than 1 GΩ to maintain measurement stability. The sensor showed stability of reading in a one-week longevity test.

Predicting Response of Spontaneously Firing Afferents to Prosthetic Pulsatile Stimulation.

Pulsatile electrical stimulation is used in neural prostheses such as the vestibular prosthesis. In a healthy vestibular system, head motion is encoded by changes in the firing rates of afferents around their spontaneous baseline rate. For people suffering from bilateral vestibular disorder (BVD), head motion no longer modulates firing rate. Vestibular prostheses use a gyroscope to detect head motion and stimulate neurons directly in a way that mimics natural modulation. Proper restoration of vestibular function relies on the ability of stimulation to evoke the same firing patterns as the healthy system. For this reason, it is necessary to understand what firing rates are produced for different stimulation parameters. Two stimulation parameters commonly controlled in pulsatile neuromodulation are pulse rate and pulse amplitude. Previous neural recording experiments in the vestibular nerve contradict widely held assumptions about the relationship between pulse rates and evoked spike activity, and the relationship between pulse amplitude and neural activity has not been explored. Here we use a well-established computational model of the vestibular afferent to simulate responses to different pulse rates and amplitudes. We confirm that our simulated neural results agree with the existing experimental data. Finally, we developed the "Action Potential Collision" (APC) equation that defines induced firing as a function of spontaneous firing rate, pulse rate, and pulse amplitude. We show that this relationship can successfully predict simulated vestibular activity by accounting for interactions between pulses and spontaneous firing.

Ionic direct current modulation evokes spike-rate adaptation in the vestibular periphery.

Recent studies have shown that ionic direct current (iDC) can modulate the vestibular system in-vivo, with potential benefits over conventional pulsed stimulation. In this study, the effects of iDC stimulation on vestibular nerve fiber firing rate was investigated using loose-patch nerve fiber recordings in the acutely excised mouse crista ampullaris of the semicircular canals. Cathodic and anodic iDC steps instantaneously reduced and increased afferent spike rate, with the polarity of this effect dependent on the position of the stimulating electrode. A sustained constant anodic or cathodic current resulted in an adaptation to the stimulus and a return to spontaneous spike rate. Post-adaptation spike rate responses to iDC steps were similar to pre-adaptation controls. At high intensities spike rate response sensitivities were modified by the presence of an adaptation step. Benefits previously observed in behavioral responses to iDC steps delivered after sustained current may be due to post-adaptation changes in afferent sensitivity. These results contribute to an understanding of peripheral spike rate relationships for iDC vestibular stimulation and validate an ex-vivo model for future investigation of cellular mechanisms. In conjunction with previous in-vivo studies, these data help to characterize iDC stimulation as a potential therapy to restore vestibular function after bilateral vestibulopathy.

Continuous vestibular implant stimulation partially restores eye-stabilizing reflexes.

BACKGROUNDBilateral loss of vestibular (inner ear inertial) sensation causes chronically blurred vision during head movement, postural instability, and increased fall risk. Individuals who fail to compensate despite rehabilitation therapy have no adequate treatment options. Analogous to hearing restoration via cochlear implants, prosthetic electrical stimulation of vestibular nerve branches to encode head motion has garnered interest as a potential treatment, but prior studies in humans have not included continuous long-term stimulation or 3D binocular vestibulo-ocular reflex (VOR) oculography, without which one cannot determine whether an implant selectively stimulates the implanted ear's 3 semicircular canals.METHODSWe report binocular 3D VOR responses of 4 human subjects with ototoxic bilateral vestibular loss unilaterally implanted with a Labyrinth Devices Multichannel Vestibular Implant System vestibular implant, which provides continuous, long-term, motion-modulated prosthetic stimulation via electrodes in 3 semicircular canals.RESULTSInitiation of prosthetic stimulation evoked nystagmus that decayed within 30 minutes. Stimulation targeting 1 canal produced 3D VOR responses approximately aligned with that canal's anatomic axis. Targeting multiple canals yielded responses aligned with a vector sum of individual responses. Over 350-812 days of continuous 24 h/d use, modulated electrical stimulation produced stable VOR responses that grew with stimulus intensity and aligned approximately with any specified 3D head rotation axis.CONCLUSIONThese results demonstrate that a vestibular implant can selectively, continuously, and chronically provide artificial sensory input to all 3 implanted semicircular canals in individuals disabled by bilateral vestibular loss, driving reflexive VOR eye movements that approximately align in 3D with the head motion axis encoded by the implant.TRIAL REGISTRATIONClinicalTrials.gov: NCT02725463.FUNDINGNIH/National Institute on Deafness and Other Communication Disorders: R01DC013536 and 2T32DC000023; Labyrinth Devices, LLC; and Med-El GmbH.

Nerve cuff electrode pressure estimation via electrical impedance measurement.

OBJECTIVE: Implantable neuromodulation devices that have cuff electrodes are known to exert mechanical pressure on the target nerves. The amount of pressure exerted by cuff enclosures is one of the key determinants of physiological safety of these devices since excess pressures can cause neural damage. Because direct measurements of pressure on a nerve are challenging, the current cuff design approaches rely heavily on theoretical models or numerical computations for pressure predictions. An experimental approach to test these devices for pressure can complement existing theoretical models and can also serve as a quality control step to screen cuff electrode designs before implantation. APPROACH: We hypothesize that the pressure exerted on a nerve by a cuff can be estimated by measuring the resulting changes to the nerve's electrical impedance. MAIN RESULTS: We investigated ten 1 cm-long explanted rat sciatic nerves: five that were used within an hour after surgery, and five after 50 h of storage in physiological saline. For each experiment we applied variable pressure on the nerve ex vivo and measured the resulting changes in its impedance. We found a strong correlation between the external pressure on the nerve and its impedance and generated a pressure-impedance calibration curve. At the upper limit of physiologically safe pressure, the nerve impedance increased by ~2 kΩ, whereas, a rise of ~3 kΩ corresponded to pressure value that onsets irreversible nerve damage. SIGNIFICANCE: As a proof-of-concept, we used this protocol to generate a pressure-impedance calibration curve for a monkey tibial nerve and estimated pressure exerted by a commercial silicone cuff electrode on the explanted nerve. This single-point measurement was in an agreement with an independent estimate of the pressure measured using a mechanical pull test within 3 mmHg.

Implantable Direct Current Neural Modulation: Theory, Feasibility, and Efficacy.

Implantable neuroprostheses such as cochlear implants, deep brain stimulators, spinal cord stimulators, and retinal implants use charge-balanced alternating current (AC) pulses to recover delivered charge and thus mitigate toxicity from electrochemical reactions occurring at the metal-tissue interface. At low pulse rates, these short duration pulses have the effect of evoking spikes in neural tissue in a phase-locked fashion. When the therapeutic goal is to suppress neural activity, implants typically work indirectly by delivering excitation to populations of neurons that then inhibit the target neurons, or by delivering very high pulse rates that suffer from a number of undesirable side effects. Direct current (DC) neural modulation is an alternative methodology that can directly modulate extracellular membrane potential. This neuromodulation paradigm can excite or inhibit neurons in a graded fashion while maintaining their stochastic firing patterns. DC can also sensitize or desensitize neurons to input. When applied to a population of neurons, DC can modulate synaptic connectivity. Because DC delivered to metal electrodes inherently violates safe charge injection criteria, its use has not been explored for practical applicability of DC-based neural implants. Recently, several new technologies and strategies have been proposed that address this safety criteria and deliver ionic-based direct current (iDC). This, along with the increased understanding of the mechanisms behind the transcutaneous DC-based modulation of neural targets, has caused a resurgence of interest in the interaction between iDC and neural tissue both in the central and the peripheral nervous system. In this review we assess the feasibility of in-vivo iDC delivery as a form of neural modulation. We present the current understanding of DC/neural interaction. We explore the different design methodologies and technologies that attempt to safely deliver iDC to neural tissue and assess the scope of application for direct current modulation as a form of neuroprosthetic treatment in disease. Finally, we examine the safety implications of long duration iDC delivery. We conclude that DC-based neural implants are a promising new modulation technology that could benefit from further chronic safety assessments and a better understanding of the basic biological and biophysical mechanisms that underpin DC-mediated neural modulation.

Ionic Direct Current Modulation for Combined Inhibition/Excitation of the Vestibular System.

OBJECTIVE: Prosthetic electrical stimulation delivered to the vestibular nerve could provide therapy for people suffering from bilateral vestibular dysfunction. Common encoding methods use pulse-frequency modulation (PFM) to stimulate the semicircular canals of the vestibular system. We previously showed that delivery of ionic direct current (iDC) can also modulate the vestibular system. In this study, we compare the dynamic range of head velocity encoding from iDC modulation to that of PFM controls. METHODS: Gentamicin-treated wild-type chinchillas were implanted with microcatheter tubes that delivered ionic current to the left ear vestibular canals and stimulated with steps of anodic/cathodic iDC or PFM. Evoked vestibulo-ocular reflex eye velocity was used to compare PFM and iDC vestibular modulation. RESULTS: Cathodic iDC steps effectively elicited eye rotations consistent with an increased firing rate of the implanted semicircular canal afferents. Anodic iDC current steps elicited eye rotations in the opposite direction that, when paired with an adapted cathodic offset, increased the dynamic range of eye rotation velocities in comparison to PFM controls. CONCLUSION: Our results suggest that iDC modulation can effectively modulate the vestibular system across a functional range of rotation vectors and velocities, with a potential benefit over a PFM stimulation paradigm. SIGNIFICANCE: In conjunction with a safe dc delivery system, iDC modulation could potentially increase the range of simulated head rotation velocities available to neuroelectric vestibular prostheses.

Normally closed plunger-membrane microvalve self-actuated electrically using a shape memory alloy wire.

Various microfluidic architectures designed for in vivo and point-of-care diagnostic applications require larger channels, autonomous actuation, and portability. In this paper, we present a normally closed microvalve design capable of fully autonomous actuation for wide diameter microchannels (tens to hundreds of µm). We fabricated the multilayer plunger-membrane valve architecture using the silicone elastomer, poly-dimethylsiloxane (PDMS) and optimized it to reduce the force required to open the valve. A 50-µm Nitinol (NiTi) shape memory alloy wire is incorporated into the device and can operate the valve when actuated with 100-mA current delivered from a 3-V supply. We characterized the valve for its actuation kinetics using an electrochemical assay and tested its reliability at 1.5-s cycle duration for 1 million cycles during which we observed no operational degradation.