Abstract 155: Vagus Nerve Stimulation Activates the Critical Brain Nuclei Involved in Ischemic Neuroprotection

Objectives: Stimulation of the vagus nerve in the neck provides up to 50% reduction in infarct volume after middle cerebral artery occlusion (MCAO) in rats. The mechanism of neuroprotection by vagus nerve stimulation (VNS) is not known. We sought to investigate the brain circuitry underlying ischemic protection activated by VNS using functional MRI (fMRI). Methods: We performed right vagus nerve stimulation using a pair of implantible electrodes in healthy (n=6) and MCAO (n=8) male and female rats. We used ultrahigh-field fMRI (9.4T) to assess fMRI response to VNS at the nucleus tractus solitarius (NTS) and the cerebellar fastigial nucleus (FN) using 30sec ON (0.5ms, 0.5mA), 270sec OFF block-design (TR=1s, TE=20ms, field of view=2.5cm). We assessed optimal frequency to maximize NTS activation by delivering stimuli that ranged between 1Hz and 50Hz. Results: VNS induced increased BOLD signal in both NTS and FN (Figure). The intensity of activation was dependent on stimulation frequency: 1Hz stimulation failed to produce activation in NTS whereas 25Hz induced the maximum BOLD response. Functional connectivity analysis in healthy rats revealed that VNS provoked broader functional connectivity across the brain. In MCAO rats, basal functional connectivity was enhanced in the intact hemisphere but reduced in the ischemic hemisphere. After VNS, the previously enhanced connectivity in the intact hemisphere was reduced while the functional connectivity in the ischemic hemisphere was enhanced. Conclusion: This study shows that VNS activates NTS and FN, the two key structures that are linked to neurogenic neuroprotection, via a stimulation frequency-dependent effect. Our findings also indicate that VNS restores reduced functional connectivity in the ischemic hemisphere after MCAO.