Enhancing selectivity of minimally invasive peripheral nerve interfaces using combined stimulation and high frequency block: from design to application

The discovery of the excitable property of nerves was a fundamental step forward in our knowledge of the nervous system and our ability to interact with it. As the injection of charge into tissue can drive its artificial activation, devices have been conceived that can serve healthcare by substituting the input or output of the peripheral nervous system when damage or disease has rendered it inaccessible or its action pathological. Applications are far-ranging and transformational as can be attested by the success of neuroprosthetics such as the cochlear implant. However, the body’s immune response to invasive implants have prevented the use of more selective interfaces, leading to therapy side-effects and off-target activation. The inherent tradeoff between the selectivity and invasiveness of neural interfaces, and the consequences thereof, is still a defining problem for the field. More recently, continued research into how nervous tissue responds to stimulation has led to the discovery of High Frequency Alternating Current (HFAC) block as a stimulation method with inhibitory effects for nerve conduction. While leveraging the structure of the peripheral nervous system, this neuromodulation technique could be a key component in efforts to improve the selectivity-invasiveness tradeoff and provide more effective neuroprosthetic therapy while retaining the safety and reliability of minimally invasive neural interfaces. This thesis describes work investigating the use of HFAC block to improve the selectivity of peripheral nerve interfaces, towards applications such as bladder control or vagus nerve stimulation where selective peripheral nerve interfaces cannot be used, and yet there is an unmet need for more selectivity from stimulation-based therapy. An overview of the underlying neuroanatomy and electrophysiology of the peripheral nervous system combined with a review of existing electrode interfaces and electrochemistry will serve to inform the problem space. Original contributions are the design of a custom multi-channel stimulator able to combine conventional and high frequency stimulation, establishing a suitable experimental platform for ex-vivo electrophysiology of the rat sciatic nerve model for HFAC block, and exploratory experiments to determine the feasibility of using HFAC block in combination with conventional stimulation to enhance the selectivity of minimally-invasive peripheral nerve interfaces.Open Acces

Design and Implementation of a Passive Neurostimulator with Wireless Resonance-Coupled Power Delivery and Demonstration on Frog Sciatic Nerve and Gastrocnemius Muscle

The thesis presented has four goals: to perform a comprehensive literature review on current neurostimulator technology; to outline the current issues with the state-of-the-art; to provide a neurostimulator design that solves these issues, and to characterize the design and demonstrate its neurostimulation features. The literature review describes the physiology of a neuron, and then proceeds to outline neural interfaces and neurostimulators. The neurostimulator design process is then outlined and current requirements in the field are described. The novel neurostimulator circuit that implements a solution that has wireless capability, passive control, and small size is outlined and characterized. The circuit is demonstrated to operate wirelessly with a resonance-coupled multi-channel implementation, and is shown powering LEDs. The circuit was then fabricated in a miniature implementation which utilized a 10 x 20 x 3 mm&179 antenna, and occupied a volume approximating 1 cm&179. This miniature circuit is used to stimulate frog sciatic nerve and gastrocnemius muscle in vitro. These demonstrations and characterization show the device is capable of neurostimulation, can operate wirelessly, is controlled passively, and can be implemented in a small size, thus solving the aforementioned neurostimulator requirements. Further work in this area is focused on developing an extensive characterization of the device and the wireless power delivery system, optimizing the circuit design, and performing in vivo experiments with restoration of motor control in injured animals. This device shows promise to provide a comprehensive solution to many application-specific problems in neurostimulation, and be a modular addition to larger neural interface systems

Feasibility of kilohertz frequency alternating current neuromodulation of carotid sinus nerve activity in the pig

Recent research supports that over-activation of the carotid body plays a key role in metabolic diseases like type 2 diabetes. Supressing carotid body signalling through carotid sinus nerve (CSN) modulation may offer a therapeutic approach for treating such diseases. Here we anatomically and histologically characterised the CSN in the farm pig as a recommended path to translational medicine. We developed an acute in vivo porcine model to assess the application of kilohertz frequency alternating current (KHFAC) to the CSN of evoked chemo-afferent CSN responses. Our results demonstrate the feasibility of this approach in an acute setting, as KHFAC modulation was able to successfully, yet variably, block evoked chemo-afferent responses. The observed variability in blocking response is believed to reflect the complex and diverse anatomy of the porcine CSN, which closely resembles human anatomy, as well as the need for optimisation of electrodes and parameters for a human-sized nerve. Overall, these results demonstrate the feasibility of neuromodulation of the CSN in an anesthetised large animal model, and represent the first steps in driving KHFAC modulation towards clinical translation. Chronic recovery disease models will be required to assess safety and efficacy of this potential therapeutic modality for application in diabetes treatment

A Novel Approach to Peripheral Nerve Activation Using Low Frequency Alternating Currents

Indiana University-Purdue University Indianapolis (IUPUI)The standard electrical stimulation waveform used for electrical activation of nerve is a rectangular pulse or a charge balanced rectangular pulse, where the pulse width is typically in the range of ∼100 µsec through ∼1000 µsec. In this work, we explore the effects of a continuous sinusoidal waveform with a frequency ranging from 5 through 20 Hz, which was named the Low Frequency Alternating Current (LFAC) waveform. The LFAC waveform was explored in the Bioelectronics Laboratory as a novel means to evoke nerve block. However, in an attempt to evoke complete nerve block on a somatic motor nerve, increasing the amplitude of the LFAC waveform unexpectedly produced nerve activation, and elicited a strong non-fatiguing muscle contraction in the anesthetized rabbit model (unpublished observation). The present thesis aimed to further explore the phenomenon to measure the effect of LFAC waveform frequency and amplitude on nerve activation. In freshly excised canine cervical vagus nerve (n=3), it was found that the LFAC waveform at 5, 10, and 20 Hz produced burst modulated activity. Compound action potentials (CAP) synchronous to the stimuli was absent from the electroneurogram (ENG) recordings. When applied in-vivo, LFAC was capable of activating the cervical vagus nerve fibers in anaesthetized swine (n=5) and induced the Hering-Breuer reflex. Additionally, when applied in-vivo to anesthetized Sprague Dawley rats (n=4), the LFAC waveform was able to activate the left sciatic nerve fibers and induced muscle contractions. The results demonstrate that LFAC activation was stochastic, and asynchronous to the stimuli unlike conventional pulse stimulation where nerve and muscle response simultaneously and synchronously to stimulus. The activation thresholds were found to be frequency dependent. As the waveform frequency increases the required current amplitude decreases. These experiments also implied that the LFAC phenomenon was most likely to be fiber type-size dependent but that more sophisticated exploration should be addressed before reaching clinical applications. In all settings, the LFAC amplitude was within the water window preventing irreversible electrochemical reactions and damages to the cuff electrodes or nerve tissues. This thesis also reconfirms the preliminary LFAC activation discovery and explores multiple methods to evaluate the experimental observations, which suggest the feasibility of the LFAC waveform at 5, 10, and 20 Hz to activate autonomic and somatic nerve fibers. LFAC appears to be a promising new technique to activate peripheral nerve fibers

Offset prediction for charge-balanced stimulus waveforms

Functional electrical stimulation with cuff electrodes involves the controlled injection of current into an electrically excitable tissue for sensory or motor rehabilitation. Some charge injected during stimulation is 'lost' at the electrode-electrolyte interface when the charge carrier is translated from an electron to an ion in the solution. The process of charge injection through chemical reactions can reduce electrode longevity and implant biocompatibility. Conventionally, the excess charge is minimized by complex hardware solutions, which are often not appropriate for robust long-term implantable solutions. Here, we present a method of waveform design that minimizes irrecoverable charge during continuous pulsing through the use of biphasic waveforms with unequally charged phases. We developed an equivalent electrical model of the electrode-electrolyte impedance based on the electrode's surface chemistry during psuedo-bipolar stimulation conditions. Simulations with the equivalent circuit determined the uncompensated charge to be a function of stimulus parameters. In vitro stimulation experiments in saline confirmed that we could preemptively compensate for the excess charge following biphasic stimulus waveforms. As a result, there was a 92% reduction in the pre-pulse potential after a pulse train with this new waveform design when compared to stimulation with conventional biphasic waveforms

Electrical stimulation of renal nerves for modulating urine glucose excretion in rats

Abstract Background The role of the kidney in glucose homeostasis has gained global interest. Kidneys are innervated by renal nerves, and renal denervation animal models have shown improved glucose regulation. We hypothesized that stimulation of renal nerves at kilohertz frequencies, which can block propagation of action potentials, would increase urine glucose excretion. Conversely, we hypothesized that low frequency stimulation, which has been shown to increase renal nerve activity, would decrease urine glucose excretion. Methods We performed non-survival experiments on male rats under thiobutabarbital anesthesia. A cuff electrode was placed around the left renal artery, encircling the renal nerves. Ureters were cannulated bilaterally to obtain urine samples from each kidney independently for comparison. Renal nerves were stimulated at kilohertz frequencies (1–50 kHz) or low frequencies (2–5 Hz), with intravenous administration of a glucose bolus shortly into the 25–40-min stimulation period. Urine samples were collected at 5–10-min intervals, and colorimetric assays were used to quantify glucose excretion and concentration between stimulated and non-stimulated kidneys. A Kruskal-Wallis test was performed across all stimulation frequencies (α = 0.05), followed by a post-hoc Wilcoxon rank sum test with Bonferroni correction (α = 0.005). Results For kilohertz frequency trials, the stimulated kidney yielded a higher average total urine glucose excretion at 33 kHz (+ 24.5%; n = 9) than 1 kHz (− 5.9%; n = 6) and 50 kHz (+ 2.3%; n = 14). In low frequency stimulation trials, 5 Hz stimulation led to a lower average total urine glucose excretion (− 40.4%; n = 6) than 2 Hz (− 27.2%; n = 5). The average total urine glucose excretion between 33 kHz and 5 Hz was statistically significant (p < 0.005). Similar outcomes were observed for urine flow rate, which may suggest an associated response. No trends or statistical significance were observed for urine glucose concentrations. Conclusion To our knowledge, this is the first study to investigate electrical stimulation of renal nerves to modulate urine glucose excretion. Our experimental results show that stimulation of renal nerves may modulate urine glucose excretion, however, this response may be associated with urine flow rate. Future work is needed to examine the underlying mechanisms and identify approaches for enhancing regulation of glucose excretion.https://deepblue.lib.umich.edu/bitstream/2027.42/143868/1/42234_2018_Article_8.pd

Biophysical Determinants of the Behaviour of Human Myelinated Axons

This thesis investigates the role of the hyperpolarization-activated current, Ih, on the excitability of human axons. It exploits the unique characteristics of the underlying hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels to improve existing and create new techniques for studying Ih. An isolated amplifier with low-noise and high common-mode rejection was developed, and threshold tracking techniques were modified to allow the measurement of the excitability of low-threshold sensory axons and of cutaneous afferents close to their receptors. These developments open up the possibility of studying changes in polyneuropathies, where symptoms and possibly the underlying pathology are more apparent distally in the limbs. Strong and long-lasting hyperpolarization was used to open more HCN channels and to examine their contribution to the excitability of motor and sensory axons. A mathematical model of myelinated motor axons was adapted to account for the response to strong and long-lasting hyperpolarization. Without structural changes the model was then modified to fit the observed excitability of sensory axons. Changes in the excitability and safety margin during focal hyperthermia were studied in both motor and sensory axons of the median nerve, and the underlying mechanisms were explored using the new mathematical model. Finally, the involvement of Ih in the frequency preference of oscillation in human axons was investigated by developing resonance techniques that have hitherto never been used to study axonal function