ADRA2B genetic polymorphism modulates vagus nerve stimulation response
- 1Cornell University
Abstract
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 {Delta}301-303 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 ({rho} = .45, p = .023). Conclusions. ADRA2B {Delta}301-303 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.
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BibTeX
@misc{riley2026adra2b,
title = {{ADRA2B genetic polymorphism modulates vagus nerve stimulation response}},
author = {E. Riley and S. A. Mabry and M. K. MacMillan and L. Ko and F. A. Middleton and E. De Rosa and A. K. Anderson},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.03.763718},
url = {https://www.biorxiv.org/content/10.64898/2026.11.03.763718v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - ADRA2B genetic polymorphism modulates vagus nerve stimulation response
AU - E. Riley
AU - S. A. Mabry
AU - M. K. MacMillan
AU - L. Ko
AU - F. A. Middleton
AU - E. De Rosa
AU - A. K. Anderson
PY - 2026
DA - 2026/11/03
PB - bioRxiv
DO - 10.64898/2026.11.03.763718
UR - https://www.biorxiv.org/content/10.64898/2026.11.03.763718v1
AB - 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 {Delta}301-303 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 ({rho} = .45, p = .023). Conclusions. ADRA2B {Delta}301-303 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.
ER -