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

Ultra-thin biocompatible implantable chip for bidirectional communication with peripheral nerves

To realize optimal recording and stimulation of peripheral nerve cells, a CMOS chip is made with a multitude of electrodes which can be individually addressed in order to select after implantation the 16 best positioned electrodes. Since the Foreign Body Reaction should be minimal for optimum electrode-nerve contact, the CMOS chip is thinned down to 35um and fully packaged resulting in a 75um thin encapsulated chip. The chip is embedded in a biocompatible stack consisting of polymers and inorganic diffusion barriers deposited using atomic layer deposition (ALD). A biocompatible metallization is realized using gold and platinum sandwiched between polymers and ALD layers for flexible interconnects, and iridium oxide (IrOx) is selected as electrode material for optimal charge injection during stimulation. After this dedicated packaging based on the FITEP technology platform (Flexible Implantable Thin Electronic Package), the CMOS chip is still fully functional, which was tested dry (in air) as well as during submersion in saline. The form factor of the packaged chip is optimized for intra-fascicular implantation with minimum tissue damage. First acute in vivo stimulation tests proved that the stimulation capabilities of the IrOx electrodes are very good

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 chopper modulated neural recording system

Presented herein is a fully integrated low-noise CMOS multi-channel amplifier for neural recording applications. The circuit employs the chopper modulation technique to reduce the effect of flicker noise and DC offset. A reduced area design implementation is achieved by trading off the increased noise margin performance of the chopper modulator for minimal amplifier area and analog multiplexing of the recording sites. A fully differential topology is used for the signal path to improve noise immunity. The analog amplifier exhibits 56 dB of gain with a 115 kHz bandwidth and a common mode rejection ratio (CNIRR) of 80 dB. Simulation results show a total input referred noise less than 16 nV/rootHz. The system power consumption is approximately 750 muWatts. The fully integrated system was designed in ABN 1.6-um single poly n-well CMOS process

Low-power design methodology for an on-chip bus with adaptive bandwidth capability

This paper describes a low-power design methodology for a bus architecture based on hybrid current/voltage mode signaling for deep sub-micrometer on-chip interconnects that achieves high data transmission rates while minimizing the number of repeaters by nearly 1/3. The technique uses low-impedance current-mode sensing to increase the data throughput and minimizes the static power dissipation inherent to current-mode signaling by adaptively changing the interconnection bandwidth given a change in input signal activity. Since bandwidth is related to power dissipation, the adaptive bus attains energy efficient data transmission by expending minimum power required to support the bus signal activity. The design method is based on statistical analysis of address streams extracted for typical benchmark programs using a microprocessor time-based simulator in combination with circuitlevel power analysis. Simulation results indicate improvements in power dissipation of up to 65 % and 40 % over current and voltage mode signaling schemes, respectively

A wireless power interface for rechargeable battery operated medical implants

Abstract—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 endof-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 0.6μm bulk CMOS technology indicate that ±1.3 % (or ±20μA) end-ofcharge accuracy can be obtained under worst-case conditions for a comparator offset voltage of ±5mV. The circuits occupy 1.735mm 2 with a power dissipation of 8.4mW when delivering a load current of 1.5mA at 4.1V (or 6.15mW) for an efficiency of 73%. I

A 32Gb/s On-chip Bus with Driver Pre-emphasis Signaling

Abstract-A 16-bit on-chip bus with driver pre-emphasi