Efficacy profile of noninvasive vagus nerve stimulation on cortical spreading depression susceptibility and the tissue response in a rat model

Title: Efficacy profile of noninvasive vagus nerve stimulation on cortical spreading depression susceptibility and the tissue response in a rat model

Journal: The Journal of Headache and Pain 23, 12 (2022).

Link: [https://thejournalofheadacheandpain.biomedcentral.com/articles/10.1186/s10194-022-01384-1#citeas)

Comments:

Recently, noninvasive vagus nerve stimulation (nVNS) has emerged as a promising therapy for migraine. The authors previously demonstrated that vagus nerve stimulation inhibits cortical spreading depression (CSD), the electrophysiological event underlying migraine aura and triggering headache. The purpose of this study is to highlight the VNS parameters towards efficacy optimization.

Based on their results, nVNS suppressed susceptibility to CSD in an intensity-dependent manner. VNS suppressed KCl-induced CSD frequency by 30% at medium intensity (11.4 V) had efficacy comparable to 34.4% at high intensity (24.4 V) VNS. Two 2-minute nVNS 5 min apart afforded the highest efficacy. Daily nVNS for four weeks did not further enhance efficacy over a single nVNS 20 min prior to CSD. The optimal nVNS also attenuated CSD-induced upregulation of cortical cyclooxygenase-2, calcitonin gene-related peptide in trigeminal ganglia, and c-Fos expression in trigeminal nucleus caudalis.

Vagus nerve contains A-, B- and C-fibers. Activation of different fiber groups require different stimulation parameters, which may influence VNS efficacy. Low to medium intensity VNS may activate A- and B- fibers, and unmyelinated C-fibers have a higher stimulation threshold above 2 mA. They previously suggest that the CSD suppressive effect of VNS is independent of C-fiber activation. Vagal afferents primarily relay in the nucleus tractus solitarius (NTS), which in turn projects to locus coeruleus (LC) and dorsal raphe nuclei (DRN). Their recent studies already demonstrated that VNS inhibits CSD through activation of these nuclei. In addition, elevated glutamate level is a critical mechanism involved in CSD initiation and propagation. In an ischemia model, acute VNS has been reported to inhibit glutamate release. VNS-induced rapid activation of subcortical nuclei or cortical glutamate release may contribute to CSD suppression.

Collectively, these results provide insight on optimal VNS parameters to suppress CSD, depending on adequate combination of intensity and dose. Acute single VNS treatment is efficacious enough for CSD suppression. With the optimal VNS paradigm, their results suggest benefit on CSD induced neuroinflammation and trigeminovascular activation in migraine treatment.