Publications

Even though extensively documented in acute experiments, ongoing vagal activity has not been characterized longitudinally over days or weeks in mice, a preferred preclinical model. This study presents a chronic recording model to record compound action potentials (CAPs) from the mouse vagus nerve for up to 6 months in both anesthetized and awake animals, with stable signal-to-noise ratios and half-rise times. The approach allows for longitudinal analysis while tracking individual CAPs across multiple days, their firing rates and phase-locking characteristics with other physiological signals, and in the awake case, movement using unsupervised machine learning models. Results reveal diverse CAP populations with varying degrees of physiological coupling, providing a valuable platform to investigate how vagal activity may be modified based on disease severity and develop closed-loop VNS by predicting flare-ups and tracking stimulation efficacy.

A fully-implantable recording and stimulation neuromodulation device measuring 2.2 cm³ and weighing 2.8 g is described, with a bidirectional wireless interface allowing simultaneous readout of multiple physiological signals and complete control over stimulation parameters, along with a wirelessly rechargeable battery providing up to 5 days of lifetime on a single charge. The device was designed using only commercially available electrical components and 3D-printed packaging to facilitate widespread adoption and accelerate discovery and translation of future bioelectronic therapeutics. The device was implanted to deliver vagus nerve stimulation in 12 animals and demonstrated a functional neural interface capable of inducing acute bradycardia with functional lifetimes exceeding three weeks.

A scalable model for long-term vagus nerve stimulation (VNS) in mice was developed and validated in four research laboratories. Significant heart rate responses were observed for at least 4 weeks in 60-90% of animals. Device implantation did not impair vagus-mediated reflexes, including baroreflex, lung stretch reflex, and feeding reflexes. Histological examination of implanted nerves revealed fibrotic encapsulation without axonal pathology. VNS using this implant significantly suppressed TNF levels in endotoxemia. Because the implant does not interfere with physiological vagus nerve-mediated reflexes and successfully inhibits serum TNF levels in acute endotoxemia, this method may be useful in facilitating mechanistic studies of long-term VNS as therapy for chronic diseases modeled in mice.

Stimulus-evoked compound action potentials (eCAPs) directly provide fiber engagement information but are currently not feasible in humans. A method to estimate fiber engagement through common, noninvasive physiological readouts could be used in place of eCAP measurements. In anesthetized rats, eCAPs were recorded while registering acute physiological response markers to VNS: cervical electromyography (EMG), changes in heart rate (ΔHR) and breathing interval (ΔBI). Results showed that EMG correlates with A-fiber, ΔHR with B-fiber and ΔBI with C-fiber activation, in agreement with known physiological functions of the vagus. Multivariate models were compiled for quantitative estimation of fiber engagement from physiological markers and stimulation parameters, and frequency gain models allow estimation of fiber engagement at a wide range of VNS frequencies.

A common-mode interference rejection algorithm based on an impedance matching approach was developed for bipolar cuff electrodes. Two unipolar channels were recorded from the two electrode contacts of a bipolar cuff, and the impedance mismatch was estimated and used to correct one of the two channels. Using the impedance adjustment algorithm, ECG artifacts were significantly suppressed relative to the simple subtraction method by an additional 9.2 dB on average. The algorithm successfully reduced the common-mode interference from ECG artifacts, stimulation artifacts, and evoked EMG interference while retaining neural signals.

We present a novel 3D self-adaptive nerve electrode for high density nerve signal recording and site-specific stimulation. A new pre-shaped flexible spiral structure has been developed in order to achieve tight contact with small nerves without any additional mechanical locking structure or force. This unique structure enables the nerve electrode to adapt and maintain close contact with the nerve without compressing it or restricting its movement. The spiral nerve electrodes (inner diameter = 310 um) with 8 recording channels (electrode diameter = 50 um) were fabricated and successfully applied to the rat vagus nerve (approximate diameter of 350 um) in order to record compound action potentials.