Abstract
Introduction: Direct electrical stimulation of the vagus nerve in the neck using surgically implanted electrodes reduces infarct volume in rats. But the invasive nature of the direct stimulation makes it impractical in acute human stroke. We tested the effect of various non-invasive or minimally invasive vagus nerve stimulation (VNS) techniques on infarct size, physiological parameters, and clinical outcome after transient middle cerebral artery (MCA) occlusion in rats. Methods: We induced cerebral ischemia by filament occlusion of the right MCA for 2h, followed by reperfusion in adult male spontaneously hypertensive rats (n=52). We performed: (1) auricular transcutaneous VNS (atVNS) via application of a microelectrode array to the auricular concha, (2) cervical transcutaneous VNS via application of HNS12 transcutaneous nerve stimulator (ctVNS-1) and Gammacore non-invasive cervical vagus nerve stimulator (ctVNS-2) put on to the skin overlying the vagus nerve in the neck. We applied tVNS for 1h starting 30 min after the induction of ischemia. We measured neurological deficit daily; at the end of 1 week we euthanized the animals to determine cerebral infarct volume. In an additional group of animals, we performed c-Fos immunohistochemistry to verify the activation of brainstem vagal centers after tVNS. Results: There was no difference in physiological parameters between control and tVNS-treated animals. c-Fos immunohistochemistry showed activation of nucleus tractus solitarius indicating that tVNS was able to activate the same brain stem nuclei activated by direct VNS. The effect of different tVNS techniques on infarct volume was comparable; infarct volume was 28% smaller with atVNS, 30% with ctVNS-1, and 33% with ctVNS-2 as compared with control animals (p<0.05 for all 3 techniques; n=6 per group). The effect of tVNS on tissue outcome was associated with better neurological scores and grip strength measurements (p<0.05 for all 3 techniques). Conclusion: Non-invasive stimulation of the vagus nerve for a brief period of time provides significant protection against ischemic injury in rats. Given its simplicity and feasibility at the setting of acute ischemic stroke, tVNS holds promise for treatment of human stroke.
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