Tzu-Ting Liu1, Andreia Morais2,3, Cenk Ayata2, Jiin-Cherng Yen4, Tsubasa Takizawa2, Inge Mulder2, Bruce J Simon5, Shih-Pin Chen6,7,8,9,10, Shuu-Jiun Wang6,9,10. 1. 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. 2. Neurovascular Research Lab, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA. 3. National Institute of Translational Neuroscience, Biomedical Science Institute, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil. 4. 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. jcyen@ym.edu.tw. 5. electroCore, Inc, Basking Ridge, NJ, USA. 6. Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan. 7. Institute of Clinical Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan. 8. Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan. 9. Faculty of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan. 10. Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan.
Abstract
BACKGROUND: Noninvasive 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. METHODS: Various 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. RESULTS: nVNS 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. CONCLUSIONS: Our study provides insight on optimal nVNS parameters to suppress CSD and suggests its benefit on CSD-induced neuroinflammation and trigeminovascular activation in migraine treatment.
BACKGROUND: Noninvasive 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. METHODS: Various 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. RESULTS: nVNS 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. CONCLUSIONS: Our study provides insight on optimal nVNS parameters to suppress CSD and suggests its benefit on CSD-induced neuroinflammation and trigeminovascular activation in migraine treatment.
Authors: Michael S Borland; Crystal T Engineer; William A Vrana; Nicole A Moreno; Navzer D Engineer; Sven Vanneste; Pryanka Sharma; Meghan C Pantalia; Mark C Lane; Robert L Rennaker; Michael P Kilgard Journal: Neuroscience Date: 2017-11-10 Impact factor: 3.590
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