• Tzu-Ting Liu, Andreia Morais, Tsubasa Takizawa, Inge Mulder, Bruce J Simon, Shih-Pin Chen, Shuu-Jiun Wang, Cenk Ayata, and Jiin-Cherng Yen.
• Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, 5th floor, Shouren Building, No. 155, Sec. 2, Linong St., Beitou District, 112, Taipei, Taiwan.
• J Headache Pain. 2022 Jan 21; 23 (1): 12.

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.© 2022. The Author(s).

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