title: Transcutaneous Cervical Vagus Nerve Stimulation Ameliorates Acute Ischemic Injury in Rats.
abstract: BACKGROUND
  Direct stimulation of the vagus nerve in the neck via surgically implanted electrodes is protective in animal models of stroke. We sought to determine the safety and efficacy of a non-invasive cervical VNS (nVNS) method using surface electrodes applied to the skin overlying the vagus nerve in the neck in a model of middle cerebral artery occlusion (MCAO).
  
  
  METHODS
  nVNS was initiated variable times after MCAO in rats (n = 33). Control animals received sham stimulation (n = 33). Infarct volume and functional outcome were assessed on day 7. Brains were processed by immunohistochemistry for microglial activation and cytokine levels. The ability of nVNS to activate the nucleus tractus solitarius (NTS) was assessed using c-Fos immunohistochemistry.
  
  
  RESULTS
  Infarct volume was 43.15 ± 3.36 percent of the contralateral hemisphere (PCH) in control and 28.75 ± 4.22 PCH in nVNS-treated animals (p < 0.05). The effect of nVNS on infarct size was consistent when stimulation was initiated up to 4 hours after MCAO. There was no difference in heart rate and blood pressure between control and nVNS-treated animals. The number of c-Fos positive cells was 32.4 ± 10.6 and 6.2 ± 6.3 in the ipsilateral NTS (p < 0.05) and 30.4 ± 11.2 and 5.8 ± 4.3 in the contralateral NTS (p < 0.05) in nVNS-treated and control animals, respectively. nVNS reduced the number of Iba-1, CD68, and TNF-α positive cells and increased the number of HMGB1 positive cells.
  
  
  CONCLUSIONS
  nVNS inhibits ischemia-induced immune activation and reduces the extent of tissue injury and functional deficit in rats without causing cardiac or hemodynamic adverse effects when initiated up to 4 hours after MCAO.
authors.affiliation: MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA. Electronic address: iay@mgh.harvard.edu.
authors.forename: Ilknur
authors.initials: I
authors.lastname: Ay
authors.affiliation: MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
authors.forename: Rena
authors.initials: R
authors.lastname: Nasser
authors.affiliation: electroCore LLC, Basking Ridge, NJ, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Simon
authors.affiliation: MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA; Stroke Service, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Hakan
authors.initials: H
authors.lastname: Ay
mesh_terms: D000818:Animals; D001794:Blood Pressure; D002545:Brain Ischemia / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D004567:Electrodes, Implanted; D006339:Heart Rate; D008297:Male; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017552:Solitary Nucleus / Q000502:physiology; D004561:Transcutaneous Electric Nerve Stimulation; D014630:Vagus Nerve / Q000502:physiology; D055536:Vagus Nerve Stimulation
chemical_list: D016760:Proto-Oncogene Proteins c-fos
keywords: Cerebral ischemia; Electrical stimulation; Inflammation; Neuroprotection; Vagus nerve