Abstract

Vagus nerve stimulation has recently been reported to improve symptoms of migraine. Cortical spreading depression is the electrophysiological event underlying migraine aura, and a trigger for headache. We tested whether vagus nerve stimulation inhibits cortical spreading depression to explain its anti-migraine effect. Vagus nerve stimulation was delivered either non-invasively through the skin or directly by electrodes placed around the vagus nerve unilaterally. Systemic physiology was monitored throughout the study. Both non-invasive transcutaneous and invasive direct vagus nerve stimulation 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 two-fold, the frequency of spreading depressions during continuous topical 1M 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. Non-invasive 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.