Destruction of Peripheral C‐Fibers Does Not Alter Subsequent Vagus Nerve Stimulation‐Induced Seizure Suppression in Rats

Abstract

Summary:Purpose: Early animal studies of the therapeutic mechanisms of vagus nerve stimulation (VNS) suggested that seizure suppression requires maximal activation of small, unmyelinated vagal C fibers. However, effective therapeutic stimulation parameters appear to be subthreshold for these fibers in humans, and there are no clinical reports of the autonomic side effects that would be expected if these fibers were maximally activated. We report here that selective destruction of C fibers with capsaicin does not affect VNS-induced seizure suppression in rats.Methods: Rats were pretreated with capsaicin or vehicle in three injections over a 2-day period. A cuff electrode was later implanted on the left cervical vagus nerve. Two days after surgery, VNS was given to half of the capsaicin-and vehicletreated rats. The remaining rats were connected to the stimulator but did not receive VNS. Thirty seconds after VNS onset, seizures were induced by pentylenetetrazol (PTZ), and seizure severity was measured. Two days later, the reciprocal VNS treatment was given, and PTZ-induced seizure severity was again measured.Results: VNS effectively reduced seizure severity in both capsaicin-and vehicle-treated rats as compared with their non-VNS baselines.Conclusions: These results indicate that activation of vagal C fibers is not necessary for VNS-induced seizure suppression. Key Words: VNS-Capsaicin-Fibers-Pentylenetetrazol-Anticonvulsant-Epilepsy.Vagus nerve stimulation (VNS) is a novel anticonvulsant therapy now gaining prominence for the treatment of refractory epilepsy. Compared with conventional epilepsy neurosurgery, this technique involves a lower-risk surgery and results in fewer complications (1). The surgery in humans involves the placement of spiral electrodes on the left cervical vagus nerve, with intermittent stimulation provided by a neurocybernetic prosthesis (NCP) (Cyberonics, Inc., Houston, TX, U.S.A.) implanted subcutaneously in the upper chest. Clinical trials have found the device to reduce the incidence of complex partial seizures in the majority of patients tested, with 20-40% of patients achieving a >50% reduction in seizure frequency (2). Stimulation parameters are adjusted to produce a minimum of side effects. Some side effects, such as a tingling sensation in the neck and temporary hoarseness during stimulation, do persist; however, significant gastrointestinal, cardiac, or respiratory effects are not apparent (2).At the cervical level, the afferent component of the vagus nerve is a composite of myelinated A and B fibers, and unmyelinated C fibers, conveying sensory information from a number of organs, including the heart, lungs, liver, stomach, and intestines. The afferent C fibers are the most numerous, accounting for ∼65-80% of the fibers in the cervical vagal trunk (3). Early animal studies on the therapeutic mechanisms of VNS suggested that seizure suppression requires the activation of vagal C fibers (4). However, effective therapeutic stimulation parameters appear to be subthreshold for vagal C f...

Vagus Nerve Stimulation Applied with a Rapid Cycle Has More Profound Influence on Hippocampal Electrophysiology Than a Standard Cycle

“…This observation aligns with a previous observation from our laboratory that VNS at 250 μA was sufficient to reduce cortical excitability [20], while further increases did not yield additional effects. The observation that further increases in stimulation intensity produces no further effects supports the involvement of thick myelinated vagal type A afferents, which generally exhibit a more homogeneous threshold for activation than slowly conducting and less densely myelinated fiber types [34,35]. Thick myelinated vagal afferents additionally exhibit a threshold for electrical activation similar to that of efferent motor fibers innervating the laryngeal muscle, and laryngeal muscle-evoked potentials have thus been proposed as a marker for effective recruitment of vagal afferents during VNS [36].…”

Enhancing Rehabilitative Therapies with Vagus Nerve Stimulation

“…The cervical level of the vagus nerve is comprised of myelinated A and B fibers, as well as unmyelinated C fibers [127,128]. There is considerabe diversity in morphological and functional parameters of the nerve from individual to individual, suggesting that optimal stimulation parameters may also vary [129,130].…”

Vagus Nerve Stimulation for Epilepsy and Depression

“…27 A more recent study observed no effect on VNS-induced seizure suppression in response to selective destruction of C fibers with capsaicin. 28 Certainly, further investigation in this area is necessary to better assess the role of C fibers in VNS.…”