SPARC: Parameters of Electrical Excitation and Block of the Rat Vagus Nerve

Abstract

There is growing interest in bioelectronic medicines, where diseases are treated through electrical stimulation and block of the peripheral autonomic nervous system. Given the widespread connections of the vagus nerve from the brainstem to most truncal organs, applications include treating epilepsy, depression, obesity, heart failure, and rheumatoid arthritis. However, designing and programming the parameters of bioelectronic medicines require understanding the biophysical responses of small myelinated and unmyelinated autonomic fibers. Using in vivo electrophysiology, we quantified strength‐duration properties, activity‐dependent slowing (ADS), and responses to kilohertz frequency (KHF) signals for rapidly conducting (>2 m/s) and slowly conducting (<2 m/s) fibers in the rat vagus nerve.We stimulated the cervical vagus nerve and recorded compound action potential (CAP) input‐output curves from the abdominal vagus nerve for pulse widths from 20 to 1000 μs. Thresholds were largest for the slowest fibres (0.5 to 1 m/s), especially at shorter pulse widths. Fits to the data using standard strength‐duration equations were qualitatively similar, but the estimates of chronaxie and rheobase varied substantially.ADS describes the slowed conduction in peripheral axons resulting from persistent low frequency activity. Using a novel cross‐correlation CAP‐based analysis method, we measured ADS of ~2.3% after 3 min of 2 Hz stimulation, approximately constant across fiber conduction speeds. This is comparable to that reported for sympathetic efferents in somatic nerves, but much smaller than ADS in cutaneous nociceptors. We found greater ADS with higher stimulation frequency and non‐monotonic changes in conduction speed in select cases.KHF signals can block neural conduction in peripheral axons, and we used CAP recordings to quantify the effects of KHF signals from 10 to 80 kHz on small autonomic fibers. Block thresholds were higher for more slowly conducting fibers, and block thresholds increased monotonically with frequency, in contrast to published findings indicating that block thresholds of unmyelinated axons vary non‐monotonically with frequency. Further, there are varied reports on the time for recovery of neural conduction after KHF block; we found that the carryover effect could last tens of seconds following 25 s of KHF signal.The quantification of mammalian autonomic nerve responses to conventional and kilohertz frequency signals provides essential information for development of bioelectronic medical devices and for understanding mechanisms of action.Support or Funding InformationThis work was supported by Fulbright Canada (15122811), the Natural Sciences and Engineering Research Council of Canada (PGS M‐425353‐2012 and PGS D3‐437918‐2013), and Duke University (University Scholars Program, James B. Duke Fellowship, and Pratt School of Engineering Faculty Discretionary Fund).