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

Tzu-Ting Liu,Shih-Pin Chen,Inge Mulder,Shuu-Jiun Wang,Cenk Ayata,Andreia Morais,Tsubasa Takizawa,Bruce J Simon,Jiin-Cherng Yen

doi:10.1186/s10194-022-01384-1

Abstract

BackgroundNoninvasive vagus nerve stimulation (nVNS) has recently emerged as a promising therapy for migraine. We previously demonstrated that vagus nerve stimulation inhibits cortical spreading depression (CSD), the electrophysiological event underlying migraine aura and triggering headache; however, the optimal nVNS paradigm has not been defined.MethodsVarious intensities and doses of nVNS were tested to improve efficacy on KCl-evoked CSD frequency and electrical threshold of CSD in a validated rat model. Chronic efficacy was evaluated by daily nVNS delivery for four weeks. We also examined the effects of nVNS on neuroinflammation and trigeminovascular activation by western blot and immunohistochemistry.ResultsnVNS suppressed susceptibility to CSD in an intensity-dependent manner. Two 2-minute nVNS 5 min apart afforded the highest efficacy on electrical CSD threshold and frequency of KCl-evoked CSD. 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.ConclusionsOur study provides insight on optimal nVNS parameters to suppress CSD and suggests its benefit on CSD-induced neuroinflammation and trigeminovascular activation in migraine treatment.

Highlights

Noninvasive vagus nerve stimulation has recently emerged as a promising therapy for migraine
We have previously shown that vagus nerve stimulation (VNS) acutely inhibits susceptibility to cortical spreading depression (CSD) [15], a neuronal and glial depolarization wave propagating across the cerebral gray matter, as one mechanism that might explain its efficacy in migraine
Noninvasive Noninvasive vagus nerve stimulation (nVNS) had a quasi-dose effect on CSD VNS suppressed KCl-induced CSD frequency by 30% at medium (11.4 V) and 34.4% at high (24.4 V); low intensity VNS (1 V) was ineffective, suggesting a threshold effect (Fig. 1)

Summary

Introduction

Noninvasive vagus nerve stimulation (nVNS) has recently emerged as a promising therapy for migraine. Only 18-50% of patients receiving triptans, one of the most effective abortive drugs for migraine, had a 2-hour pain-free response [2] Nonpharmacologic approaches, such as vagus nerve stimulation (VNS), have recently emerged as promising alternatives to existing standard treatments [3]. A doubleblind, randomized sham-controlled trial has established the efficacy of acute nVNS therapy in episodic migraine comparable to standard treatments, with the added benefit of being well-tolerated [3]. The diversity of VNS paradigms used in different studies, such as variable intensity, duration, repetition intervals [6, 7, 13, 14], highlighted the need to examine VNS parameters towards optimization

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