ADRA2B genetic polymorphism modulates vagus nerve stimulation response

Introduction. Given interest in vagus nerve stimulation (VNS) as a potential therapy for Alzheimer's disease, due to its hypothesized influence on the noradrenergic (NA) system, there is a need to understand the pronounced individual differences in responsiveness to VNS in aging. We tested whether a genetic polymorphism related to NA signaling, the Δ301-303 deletion in the ADRA2B receptor, modulates transcutaneous auricular (taVNS) effects on task-related pupillary responses or pupil-linked cortical activity in noradrenergic projection territory. Methods. Forty-one adults (61% deletion carriers; ages 19-79) performed a visual oddball task during a sham-controlled single-blind crossover taVNS trial. Of these people, 25 (68% deletion carriers) also performed the same task with simultaneous fMRI. Results. ADRA2B genotype predicted the taVNS effect on oddball pupillary responses (t(37) = 3.03, p = .004, d = 0.84). Deletion carrier responses were more likely to increase, while non-carrier responses decreased. Carriers showed stronger spatial alignment between pupil-BOLD coupling and cortical norepinephrine transporter (NET) expression (t(22) = 2.82, p = .010, adjusted d = 1.21). This difference was selective to NET among 19 PET maps (all other p > .11). The individual effect of taVNS predicted NET alignment of pupil-BOLD coupling (ρ = .45, p = .023). Conclusions. ADRA2B Δ301-303 deletion status, which is thought to increase NA availability, predicts the direction of the pupillary response to taVNS and how tightly pupil-linked BOLD activity aligns with cortical noradrenergic projection territory.