Electrical Stimulation of the Vagus Nerve Dermatome in the External Ear is Protective in Rat Cerebral Ischemia

Abstract

Background Although cervical vagus nerve stimulation is effective for reducing infarct volume in rats, it is not feasible for acute human stroke as it requires surgical incision of the neck. We hypothesized that stimulation of the dermatome in the external ear innervated by the vagus nerve (auricular vagus nerve stimulation; aVNS) reduces infarct volume after transient focal ischemia in rats. Methods Animals were randomized to active aVNS or sham stimulation. For aVNS, electrical stimulation of the left cavum concha (1 hour duration) using percutaneous needles was initiated 30 min after induction of ischemia. Behavioral and tissue outcome were measured 24 hours after induction of ischemia. In a separate experimental dataset, c-Fos immunohistochemistry was performed to identify the brain regions activated after the stimulation. Results Stimulation of the left cavum concha resulted in bilateral c-Fos staining in the nuclei tractus solitarii and the loci coerulei in all animals. There was no c-Fos staining in any part of the brainstem in sham control animals. The mean infarct volume (SD) as calculated by indirect method was 44.20 ± 7.58% in controls and 31.65 ± 9.67% in treated animals (p<0.0001). The effect of aVNS on tissue outcome was associated with better neurological scores at 24 hours after ischemia (p<0.0001). Conclusions Electric stimulation of the vagus nerve dermatome in the external ear activates brainstem afferent vagal nuclei and reduces infarct volume in rats. This finding has potential to facilitate the development of treatments that leverage the brain’s endogenous neuroprotective pathways at the setting of acute ischemic stroke.

Transcutaneous Cervical Vagus Nerve Stimulation Ameliorates Acute Ischemic Injury in Rats

“…We have previously shown that electrical stimulation of the dermatome corresponding to the auricular branch of the vagus nerve in the external ear using needle electrodes reduces ischemic injury after transient MCAO in healthy adult rats and could be a practical alternative to the invasive cVNS. [22] The present study extends our prior report by showing an infarct reducing effect of another novel transcutaneous stimulation method. We have used a non-invasive stimulator that requires placement of a pair of surface electrodes to the skin overlying the vagus nerve in the neck.…”

“…Number of positive cells in these regions per microscopic field were counted from three consecutive sections and averaged for each animal blindly to the treatment groups. [22]…”

The strange case of the ear and the heart: The auricular vagus nerve and its influence on cardiac control

“…As mentioned, anatomical tracing studies in the cat (Nomura et al, 1984) and rat (He et al, 2013a) have shown that the ABVN projects to the NTS. Evidence that NTS neurones are activated following ABVN stimulation is derived from studies in which electrical stimulation of the concha in rats with transient focal ischemia elicits c-fos staining in the bilateral NTS and locus coeruleus (Ay et al, 2015a).…”

Vagus nerve stimulation inhibits cortical spreading depression

“…Previous work in animal models has shown that VNS activates nucleus tractus solitarius (NTS), locus ceruleus (LC) and dorsal raphe nuclei (DRN) [4; 21; 22; 32], all of which can suppress CSD susceptibility by enhancing serotonergic or β-adrenergic activity [29; 42; 46; 56]. VNS has been effective for the treatment of seizures and depression which show a strong clinical association with migraine [27], and many migraine prophylactic drugs are antiepileptics or antidepressants, and suppress CSD [5].…”