Using Compound Neural Action Potentials for Functional Validation of a High-Density Intraneural Interface: A Preliminary Study.

Compound nerve action potentials (CNAPs) were used as a metric to assess the stimulation performance of a novel high-density, transverse, intrafascicular electrode in rat models. We show characteristic CNAPs recorded from distally implanted cuff electrodes. Evaluation of the CNAPs as a function of stimulus current and calculation of recruitment plots were used to obtain a qualitative approximation of the neural interface's placement and orientation inside the nerve. This method avoids elaborate surgeries required for the implantation of EMG electrodes and thus minimizes surgical complications and may accelerate the healing process of the implanted subject.

Characterization of the electrical properties of mammalian peripheral nerve laminae.

BACKGROUND AND OBJECTIVE: The intrinsic electrical material properties of the laminar components of the mammalian peripheral nerve bundle are important parameters necessary for the accurate simulation of the electrical interaction between nerve fibers and neural interfaces. Improvements in the accuracy of these parameters improve the realism of the simulation and enables realistic screening of novel devices used for extracellular recording and stimulation of mammalian peripheral nerves. This work aims to characterize these properties for mammalian peripheral nerves to build upon the resistive parameter set established by Weerasuriya et al. in 1984 for amphibian somatic peripheral nerves (frog sciatic nerve) that is currently used ubiquitously in the in-silico peripheral nerve modeling community. METHODS: A custom designed characterization chamber was implemented and used to measure the radial and longitudinal impedance between 10 mHz and 50 kHz of freshly excised canine vagus nerves using four-point impedance spectroscopy. The impedance spectra were parametrically fitted to an equivalent circuit model to decompose and estimate the components of the various laminae. Histological sections of the electrically characterized nerves were then made to quantify the geometry and laminae thicknesses of the perineurium and epineurium. These measured values were then used to calculate the estimated intrinsic electrical properties, resistivity and permittivity, from the decomposed resistances and reactances. Finally, the estimated intrinsic electrical properties were used in a finite element method (FEM) model of the nerve characterization setup to evaluate the realism of the model. RESULTS: The geometric measurements were as follows: nerve bundle (1.6 ± 0.6 mm), major nerve fascicle diameter (1.3 ± 0.23 mm), and perineurium thickness (13.8 ± 2.1 µm). The longitudinal resistivity of the endoneurium was estimated to be 0.97 ± 0.05 Ωm. The relative permittivity and resistivity of the perineurium were estimated to be 2018 ± 391 and 3.75 kΩm ± 981 Ωm, respectively. The relative permittivity and resistivity of the epineurium were found to be 9.4 × 106 ± 8.2 × 106 and 55.0 ± 24.4 Ωm, respectively. The root mean squared (RMS) error of the experimentally obtained values when used in the equivalent circuit model to determine goodness of fit against the measured impedance spectra was found to be 13.0 ± 10.7 Ω, 2.4° ± 1.3°. The corner frequency of the perineurium and epineurium were found to be 2.6 ± 1.0 kHz and 368.5 ± 761.9 Hz, respectively. A comparison between the FEM model in-silico impedance experiment against the ex-vivo methods had a RMS error of 159.0 ± 95.4 Ω, 20.7° ± 9.8°. CONCLUSION: Although the resistive values measured in the mammalian nerve are similar to those of the amphibian model, the relative permittivity of the laminae bring new information about the reactance and the corner frequency (frequency at peak reactance) of the peripheral nerve. The measured and estimated corner frequency are well within the range of most bioelectric signals, and are important to take into account when modeling the nerve and neural interfaces.

A Reversible Low Frequency Alternating Current Nerve Conduction Block Applied to Mammalian Autonomic Nerves.

Electrical stimulation can be used to modulate activity within the nervous system in one of two modes: (1) Activation, where activity is added to the neural signalling pathways, or (2) Block, where activity in the nerve is reduced or eliminated. In principle, electrical nerve conduction block has many attractive properties compared to pharmaceutical or surgical interventions. These include reversibility, localization, and tunability for nerve caliber and type. However, methods to effect electrical nerve block are relatively new. Some methods can have associated drawbacks, such as the need for large currents, the production of irreversible chemical byproducts, and onset responses. These can lead to irreversible nerve damage or undesirable neural responses. In the present study we describe a novel low frequency alternating current blocking waveform (LFACb) and measure its efficacy to reversibly block the bradycardic effect elicited by vagal stimulation in anaesthetised rat model. The waveform is a sinusoidal, zero mean(charge balanced), current waveform presented at 1 Hz to bipolar electrodes. Standard pulse stimulation was delivered through Pt-Black coated PtIr bipolar hook electrodes to evoke bradycardia. The conditioning LFAC waveform was presented either through a set of CorTec® bipolar cuff electrodes with Amplicoat® coated Pt contacts, or a second set of Pt Black coated PtIr hook electrodes. The conditioning electrodes were placed caudal to the pulse stimulation hook electrodes. Block of bradycardic effect was assessed by quantifying changes in heart rate during the stimulation stages of LFAC alone, LFAC-and-vagal, and vagal alone. The LFAC achieved 86.2±11.1% and 84.3±4.6% block using hook (N = 7) and cuff (N = 5) electrodes, respectively, at current levels less than 110 µAp (current to peak). The potential across the LFAC delivering electrodes were continuously monitored to verify that the blocking effect was immediately reversed upon discontinuing the LFAC. Thus, LFACb produced a high degree of nerve block at current levels comparable to pulse stimulation amplitudes to activate nerves, resulting in a measurable functional change of a biomarker in the mammalian nervous system.

In-vivo application of low frequency alternating currents on porcine cervical vagus nerve evokes reversible nerve conduction block.

BACKGROUND: This paper describes a method to reversibly block nerve conduction through direct application of a 1 Hz sinusoidal current waveform delivered through a bipolar nerve cuff electrode. This low frequency alternating current (LFAC) waveform was previously shown to reversibly block the effects of vagal pulse stimulation evoked bradycardia in-vivo in the anaesthetised rat model (Mintch et al. 2019). The present work measured the effectiveness of LFAC block on larger caliber myelinated vagal afferent fibers in human sized nerve bundles projecting to changes in breathing rate mediated by the Hering-Breuer (HB) reflex in anaesthetized domestic swine (n=5). METHODS: Two bipolar cuff electrodes were implanted unilaterally to the left cervical vagus nerve, which was crushed caudal to the electrodes to eliminate cardiac effects. A tripolar recording cuff electrode was placed rostral to the bipolar stimulating electrodes on the same nerve to measure changes in the compound nerve action potentials (CNAP) elicited by the vagal pulse stimulation and conditioned by the LFAC waveform. Standard pulse stimulation was applied at a sufficient level to induce a reduction in breathing rate through the HB reflex. If unblocked, the HB reflex would cause breathing to slow down and potentially halt completely. Block was quantified by the ability of LFAC to reduce the effect of the HB reflex by monitoring the respiration rate during LFAC alone, LFAC and vagal stimulation, and vagal stimulation alone. RESULTS: LFAC achieved 87.2 ±8.8% block (n=5) at current levels of 1.1 ±0.3 mAp (current to peak), which was well within the water window of the working electrode. CNAP showed changes that directly correlated to the effectiveness of LFAC block, which manifested itself as the slowing and amplitude reduction of components of the CNAP. CONCLUSION: These novel findings suggest that LFAC is a potential alternative or complementary method to other electrical blocking techniques in clinical applications.

Splenic Nerve Neuromodulation Reduces Inflammation and Promotes Resolution in Chronically Implanted Pigs.

Neuromodulation of the immune system has been proposed as a novel therapeutic strategy for the treatment of inflammatory conditions. We recently demonstrated that stimulation of near-organ autonomic nerves to the spleen can be harnessed to modulate the inflammatory response in an anesthetized pig model. The development of neuromodulation therapy for the clinic requires chronic efficacy and safety testing in a large animal model. This manuscript describes the effects of longitudinal conscious splenic nerve neuromodulation in chronically-implanted pigs. Firstly, clinically-relevant stimulation parameters were refined to efficiently activate the splenic nerve while reducing changes in cardiovascular parameters. Subsequently, pigs were implanted with a circumferential cuff electrode around the splenic neurovascular bundle connected to an implantable pulse generator, using a minimally-invasive laparoscopic procedure. Tolerability of stimulation was demonstrated in freely-behaving pigs using the refined stimulation parameters. Longitudinal stimulation significantly reduced circulating tumor necrosis factor alpha levels induced by systemic endotoxemia. This effect was accompanied by reduced peripheral monocytopenia as well as a lower systemic accumulation of CD16+CD14high pro-inflammatory monocytes. Further, lipid mediator profiling analysis demonstrated an increased concentration of specialized pro-resolving mediators in peripheral plasma of stimulated animals, with a concomitant reduction of pro-inflammatory eicosanoids including prostaglandins. Terminal electrophysiological and physiological measurements and histopathological assessment demonstrated integrity of the splenic nerves up to 70 days post implantation. These chronic translational experiments demonstrate that daily splenic nerve neuromodulation, via implanted electronics and clinically-relevant stimulation parameters, is well tolerated and is able to prime the immune system toward a less inflammatory, pro-resolving phenotype.

A multi-channel peripheral nerve stimulator with integrate-and-fire encoding.

Activation of peripheral nervous system (PNS) fibres to produce variable tactile and proprioceptive sensations in advanced bidirectional prosthetic limbs relies on neural stimulators with high spatial selectivity, dynamic range and resolution. A multi-channel application-specific integrated circuit (ASIC) is developed for PNS fibre activation using a wide dynamic range (10 nA-5 mA), high-resolution (30 nA step, 100 ns pulse accuracy) current stimulator, dissipating 0.73-2.75 mW at 3 V. The ASIC also enables encoding of external pressure signals via an integrate-and-fire methodology. Electrophysiological data of compound nerve action potentials were recorded for a range of stimulus amplitudes and pulse widths. This data was used to benchmark the performance of the ASIC with a known neural stimulator.

Toward energy efficient neural interfaces.

This letter presents progress toward an energy efficient neural data acquisition transponder for brain-computer interfaces. The transponder utilizes a four-channel time-multiplexed analog front-end and an energy efficient short-range backscattering RF link to transmit digitized wireless data. In addition, a low-complexity autonomous and adaptive digital neural signal processor is proposed to minimize wireless bandwidth and overall power dissipation.

Neural cache: a low-power online digital spike-sorting architecture.

Transmitting large amounts of data sensed by multi-electrode array devices is widely considered to be a challenging problem in designing implantable neural recording systems. Spike sorting is an important step to reducing the data bandwidth before wireless data transmission. The feasibility of spike sorting algorithms in scaled CMOS technologies, which typically operate on low frequency neural spikes, is determined largely by its power consumption, a dominant portion of which is leakage power. Our goal is to explore energy saving architectures for online spike sorting without sacrificing performance. In the face of non-stationary neural data, training is not always a feasible option. We present a low-power architecture for real-time online spike sorting that does not require any training period and has the capability to quickly respond to the changing spike shapes.

A multi-channel instrumentation system for biosignal recording.

This paper reports a highly integrated battery operated multi-channel instrumentation system intended for physiological signal recording. The mixed signal IC has been fabricated in standard 0.5microm 5V 3M-2P CMOS process and features 32 instrumentation amplifiers, four 8b SAR ADCs, a wireless power interface with Li-ion battery charger, low power bidirectional telemetry and FSM controller with power gating control for improved energy efficiency. The chip measures 3.2mm by 4.8mm and dissipates approximately 2.1mW when fully operational.

A wireless power interface for rechargeable battery operated neural recording implants.

This paper describes an integrated analog front-end for wireless powering and recharging of miniature Li-ion batteries used in implantable neural recording microsystems. DC signal extraction from a wireless carrier is accomplished using Schottky barrier contact diodes with lower forward voltage drop for improved efficiency. The battery charger employs a new control loop that relaxes comparator resolution requirements, provides simultaneous operation of constant-current and constant-voltage loops, and eliminates the external current sense resistor from the charging path. The accuracy of the end-of-charge detection is primarily determined by the voltage drop across matched resistors and current-sources and the offset voltage of the sense comparator. Experimental results in 0.6 mum bulk CMOS technology indicate that +/- 1.3% (or +/-20 microA) end-of-charge accuracy can be obtained under worst-case conditions for a comparator offset voltage of +/-5mV. The circuits occupy 1.735 mm(2) with a power dissipation of 8.4 mW when delivering a load current of 1.5 mA at 4.1 V (or 6.15 mW) for an efficiency of 73%

Electronic visual prosthesis.

Retinitis pigmentosa (RP) and age-related macular degeneration (AMD) are incurable diseases that result in profound vision loss due to degeneration of the light sensing photoreceptors. However, the discovery that direct electrical stimulation of the retinal neurons creates visual sensation has inspired prosthetic devices aimed to restore useful vision in RP/AMD patients. The approach to one such electronic visual prosthesis is described in this article. The prosthesis consists of an external unit and an internal unit. The communication link has three components--power and data transfer from the external to the internal unit, and data transfer from the internal to the external unit. A novel method of integrating power transfer and back telemetry is described here. The goal is to design a stimulator chip with a small area with low power consumption. This chip, capable of stimulating 60 dedicated electrodes, is fabricated using AMI 1.2 microm process technology and the results are presented. Improvements in the design to increase the number of outputs to 1,000 have been discussed. The new circuit is aimed at increasing the circuit density, reducing power per stimulus, and meeting the requirements more closely than the previous designs. The results of the designed chip are presented.