Transauricular Vagus Nerve Stimulation Reduces Inflammation and Improves Outcomes in Ischemic Strokes: the NUVISTA Trial

Background: Inflammation plays a critical role in brain injury following acute ischemic stroke (AIS). Transcutaneous auricular vagus nerve stimulation (taVNS) has shown anti-inflammatory properties in various conditions, but its efficacy in AIS remains unexplored. We investigated if taVNS could mitigate post-AIS inflammation and its safety. Methods: In this randomized, sham-controlled trial with blinded outcomes assessment, patients with anterior circulation large vessel occlusion (LVO) AIS were assigned to twice-daily taVNS or sham stimulation for five days or until discharge. Key inclusion criteria included age ≥18 years, National Institutes of Health Stroke Scale (NIHSS) ≥6, anterior circulation LVO, and enrollment within 36 hours of last known normal. Primary endpoints were changes in inflammatory biomarkers (white blood cells and cytokines including interleukins (IL)-1beta, 6, 10, 17alpha, and tumor necrosis factor alpha (TNF?) measured at baseline and Days 1, 3, 5, and 7, and taVNS safety. Secondary exploratory endpoints included change in NIHSS, 90 day modified Rankin score (mRS), and safety (bradycardia, hypotension, infection, and death). Results: Thirty-five patients (17 taVNS, 18 sham) were enrolled. The taVNS group showed a significant rate of change in normalized aggregate pro-inflammatory cytokines and interleukin-6 levels compared to sham (p=0.04 and p<0.001, respectively). Each 1 pg/mL reduction in interleukin-6 correlated with a 0.798-point improvement in NIHSS in the taVNS group (95% confidence interval [0.077, 1.518], p = 0.031]), with no significant correlation in the sham group. IL-1beta, 10, 17alpha, and TNFalpha showed reduction in cytokine levels, but did not reach statistical significance. There were no statistically significant differences amongst mRS and safety outcomes between both groups. Conclusions: taVNS safely reduced post-AIS inflammation in anterior circulation LVO stroke patients, demonstrating biological effects. Secondary analyses also found potential effects in NIHSS improvements. These promising findings warrant further investigation in larger trials.