Transcutaneous auricular vagus nerve stimulation in drug‐resistant epilepsy: A randomized, sham‐controlled crossover trial with exploratory EEG and MRI response phenotyping

OBJECTIVE: Transcutaneous auricular vagus nerve stimulation (taVNS) is a noninvasive neuromodulation strategy for drug-resistant epilepsy, but clinical response is heterogeneous. We examined whether electroencephalographic (EEG) and structural magnetic resonance imaging (MRI) phenotypes were associated with active-specific clinical benefit from taVNS. METHODS: In this single-center, randomized, double-blind, sham-controlled crossover exploratory pilot trial, 14 patients with drug-resistant focal epilepsy received 8 weeks of active taVNS and 8 weeks of sham stimulation, separated by a 4-week washout, in randomized sequence. The primary clinical outcome was seizure reduction ratio (SRR) during active versus sham stimulation. Active-specific clinical benefit was defined as ΔSRR = SRR_active - SRR_sham. Resting-state EEG was obtained at baseline and at the end of the protocol. Changes in regional relative band power were correlated with ΔSRR, with a focus on the β band based on prior evidence of vagal stimulation-related desynchronization. Baseline structural MRI findings were explored by active-phase responder status. RESULTS: Active taVNS did not significantly outperform sham stimulation. Mean SRR was 46.26 ± 40.96% during active stimulation and 48.62 ± 37.27% during sham stimulation, with a mean within-subject difference of -2.37 ± 16.64% (p = 0.604). Greater β-band attenuation was associated with larger active-specific clinical benefit in the occipital (ρ = -0.723, p = 0.003, q = 0.017) and frontal regions (ρ = -0.657, p = 0.011, q = 0.027). Parietal β-band attenuation showed a nominal association (ρ = -0.552, p = 0.041, q = 0.068). Bilateral structural abnormalities and limbic involvement were more frequent among nonresponders (both p = 0.021, uncorrected). SIGNIFICANCE: Although primary clinical efficacy was not demonstrated, EEG β-band modulation and limbic structural network burden may help explain interindividual variability in taVNS benefit. The substantial sham response underscores the need for rigorous sham-controlled taVNS trials. PLAIN LANGUAGE SUMMARY: About one-third of people with epilepsy keep having seizures despite medication. taVNS is a noninvasive treatment that stimulates a nerve at the outer ear. In this small, carefully blinded trial, active taVNS did not reduce seizures more than an inactive (sham) treatment, and the sham response was large. However, people whose EEG β brain waves decreased during the study tended to benefit more, and those with more widespread limbic or structural brain changes tended to benefit less. If confirmed in larger studies, these EEG and MRI markers might help identify who is most likely to respond to taVNS.