Validated computational models predict vagus nerve stimulation thresholds in preclinical animals and humans.

We demonstrated how automated simulations to characterize electrical nerve thresholds, a recently published open-source software for modeling stimulation of peripheral nerves, can be applied to simulate accurately nerve responses to electrical stimulation.We simulated vagus nerve stimulation (VNS) for humans, pigs, and rats. We informed our models using histology from sample-specific or representative nerves, device design features (i.

Fibers in smaller fascicles have lower activation thresholds with cuff electrodes due to thinner perineurium and smaller cross-sectional area.

. In nerve stimulation therapies, fibers in larger fascicles generally have higher activation thresholds, but the mechanisms are not well understood. We implemented and analyzed computational models to uncover the effects of morphological parameters on activation thresholds.

Asynchronous axonal firing patterns evoked via continuous subthreshold kilohertz stimulation.

Transcutaneous electrical stimulation of peripheral nerves is a common technique to assist or rehabilitate impaired muscle activation. However, conventional stimulation paradigms activate nerve fibers synchronously with action potentials time-locked with stimulation pulses. Such synchronous activation limits fine control of muscle force due to synchronized force twitches.

Measuring and modeling the effects of vagus nerve stimulation on heart rate and laryngeal muscles.

Background: Reduced heart rate (HR) during vagus nerve stimulation (VNS) is associated with therapy for heart failure, but stimulation frequency and amplitude are limited by patient tolerance. An understanding of physiological responses to parameter adjustments would allow differential control of therapeutic and side effects. To investigate selective modulation of the physiological responses to VNS, we quantified the effects and interactions of parameter selection on two physiological outcomes: one related to therapy (reduced HR) and one related to side effects (laryngeal muscle EMG).

Spatially selective stimulation of the pig vagus nerve to modulate target effect versus side effect.

Electrical stimulation of the cervical vagus nerve using implanted electrodes (VNS) is FDA-approved for the treatment of drug-resistant epilepsy, treatment-resistant depression, and most recently, chronic ischemic stroke rehabilitation. However, VNS is critically limited by the unwanted stimulation of nearby neck muscles-a result of non-specific stimulation activating motor nerve fibers within the vagus. Prior studies suggested that precise placement of small epineural electrodes can modify VNS therapeutic effects, such as cardiac responses.

ASCENT (Automated Simulations to Characterize Electrical Nerve Thresholds): A pipeline for sample-specific computational modeling of electrical stimulation of peripheral nerves.

Electrical stimulation and block of peripheral nerves hold great promise for treatment of a range of disease and disorders, but promising results from preclinical studies often fail to translate to successful clinical therapies. Differences in neural anatomy across species require different electrodes and stimulation parameters to achieve equivalent nerve responses, and accounting for the consequences of these factors is difficult. We describe the implementation, validation, and application of a standardized, modular, and scalable computational modeling pipeline for biophysical simulations of electrical activation and block of nerve fibers within peripheral nerves.

Quantified Morphology of the Cervical and Subdiaphragmatic Vagus Nerves of Human, Pig, and Rat.

It is necessary to understand the morphology of the vagus nerve (VN) to design and deliver effective and selective vagus nerve stimulation (VNS) because nerve morphology influences fiber responses to electrical stimulation. Specifically, nerve diameter (and thus, electrode-fiber distance), fascicle diameter, fascicular organization, and perineurium thickness all significantly affect the responses of nerve fibers to electrical signals delivered through a cuff electrode. We quantified the morphology of cervical and subdiaphragmatic VNs in humans, pigs, and rats: effective nerve diameter, number of fascicles, effective fascicle diameters, proportions of endoneurial, perineurial, and epineurial tissues, and perineurium thickness.

Empirically Based Guidelines for Selecting Vagus Nerve Stimulation Parameters in Epilepsy and Heart Failure.

Vagus nerve stimulation (VNS) is a promising therapy to treat patients with epilepsy and heart failure. Outcomes of preclinical studies and clinical trials indicate that the selection of stimulation parameters has a direct impact on therapeutic efficacy and patient tolerability, suggesting that both the efficacy and tolerability of VNS could potentially be improved with a change in stimulation parameters. In this review, the success of translating stimulation parameters for epilepsy and heart failure from preclinical studies in animal models to human use in the clinic is evaluated on the basis of patient outcomes and stimulation-induced side effects.