Transcutaneous Auricular Vagus Nerve Stimulation Reduces Inflammatory Biomarkers and Improves Outcomes After Large Vessel Occlusion Stroke: 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. This study investigated whether taVNS could mitigate post-AIS inflammation and improve clinical outcomes.

Methods: In this randomized, sham-controlled trial with blinded outcomes assessment, patients with anterior circulation large vessel occlusion (LVO) AIS were assigned to receive twice-daily taVNS or sham stimulation for 5 days or until discharge. Key inclusion criteria included age ≥18 years, National Institutes of Health Stroke Scale (NIHSS) ≥6, and treatment within 36 hours of last known normal. Primary endpoints were changes in inflammatory biomarkers (white blood cells and cytokines including interleukins-1β, 6, 10, 17α, and tumor necrosis factor alpha) measured at baseline and days 1, 3, 5, and 7. Secondary endpoints included NIHSS changes, 90 day mRS, and safety outcomes.

Results: Thirty-five patients (17 taVNS, 18 sham) were enrolled. The taVNS group showed a significant reduction in normalized aggregated inflammatory cytokines and interleukin-6 levels compared to sham (P=0.03 and P<0.001, respectively). Each 1 pg/mL reduction in interleukin-6 correlated with a 0.872-point improvement in NIHSS in the taVNS group (95% CI [0.101, 1.642], P=0.026), with no significant correlation in the sham group. This effect was most pronounced in patients without successful recanalization. Despite higher initial stroke severity, the taVNS group experienced 58% fewer stroke complications and poor outcomes compared to the sham (incidence rate ratio = 0.42, 95% CI: [0.19, 0.94], z = −2.097, p = 0.036, z-test). A significant dose-dependent relationship was observed between the number of stimulations and clinical improvement, with greater taVNS exposure associated with better modified Rankin Scale scores at 90 days (P=0.023).

Conclusions: taVNS safely reduces post-AIS inflammation in LVO stroke patients, demonstrating both biological and clinical effects, resulting in fewer complications, and demonstrating dose-dependent improvements in functional outcomes. These findings warrant further investigation in larger trials.