Vagus nerve stimulation inhibits cortical spreading depression

Abstract

Vagus nerve stimulation has recently been reported to improve symptoms of migraine. Cortical spreading depression is the electrophysiological event underlying migraine aura and is a trigger for headache. We tested whether vagus nerve stimulation inhibits cortical spreading depression to explain its antimigraine effect. Unilateral vagus nerve stimulation was delivered either noninvasively through the skin or directly by electrodes placed around the nerve. Systemic physiology was monitored throughout the study. Both noninvasive transcutaneous and invasive direct vagus nerve stimulations significantly suppressed spreading depression susceptibility in the occipital cortex in rats. The electrical stimulation threshold to evoke a spreading depression was elevated by more than 2-fold, the frequency of spreading depressions during continuous topical 1 M KCl was reduced by ∼40%, and propagation speed of spreading depression was reduced by ∼15%. This effect developed within 30 minutes after vagus nerve stimulation and persisted for more than 3 hours. Noninvasive transcutaneous vagus nerve stimulation was as efficacious as direct invasive vagus nerve stimulation, and the efficacy did not differ between the ipsilateral and contralateral hemispheres. Our findings provide a potential mechanism by which vagus nerve stimulation may be efficacious in migraine and suggest that susceptibility to spreading depression is a suitable platform to optimize its efficacy.

Conflict of interest statement

Conflict of Interest:

Dr. Bruce Simon is an employee of ElectroCore LLC, and joined the project after completion of the experiments investigating the effect of invasive vagus nerve stimulation. The other authors declare no competing financial interests.

Figures

Fig. 1. Experimental setup and VNS paradigms

A) Left: Surgical exposure of the vagus nerve for iVNS and the vagus nerve segment stimulated using the helical electrode are shown. For nVNS, transcutaneous disc electrodes were placed where indicated by blue circles. Middle and right: Craniotomies were prepared on occipital cortex for electrical or KCl stimulation, and on parietal and frontal cortices for electrophysiological recordings. B) Experimental timeline to test nVNS on electrical CSD threshold. C) Experimental timeline to test nVNS on KCl-induced CSD frequency. D) Experimental timeline to test iVNS on electrical CSD threshold and KCl-induced CSD frequency. All symbols are defined on the right. Details of stimulation parameters are provided in the Methods.

Fig. 2. Effect of nVNS on KCl-induced SD frequency, electrical SD threshold, and SD propagation speed

Representative intracortical microelectrode recordings are provided from the second hemispheres of control and nVNS animals. Graphs show the data from the first and second hemispheres of sham control and nVNS groups (n=6 each), expressed as whisker-box plots (whisker, full range; box interquartile range; line, median, cross, mean). Note that the vertical axis of CSD threshold is in log scale. *p

Fig. 3. Effect of iVNS on KCl-induced SD frequency, electrical SD threshold, and SD propagation speed

A) Graphs show the data from the first and second hemispheres of sham control and iVNS groups (n=8 each), expressed as whisker-box plots (whisker, full range; box interquartile range; line, median, cross, mean). *p

Fig. 4. Systemic physiological, electrophysiological and cerebral blood flow effects

A) The time course of arterial blood pressure (BP) and heart rate (HR) during nVNS (n=12 stimulations) or iVNS (n=98 stimulations). Note that some error bars are too small to be visible. *p