Brain-age defines a structural signature of outcomes after vagus nerve stimulation in children

INTRODUCTION: Outcomes following vagus nerve stimulation (VNS) are difficult to predict prior to surgery in pediatric drug-resistant epilepsy (DRE). We investigated whether structural brain differences among children may explain variability in VNS response. METHODS: A pediatric-specific brain-age model was developed using structural MRI from 2,623 healthy individuals aged 1.9 to 90 years, capturing nonlinear neurodevelopmental trajectories. Model accuracy was evaluated using cross-validation and independent validation in a pediatric cohort. The model was then applied to a multicenter cohort of 126 children with DRE treated with VNS. RESULTS: = 0.93; mean absolute error = 3.5 years) and generalized well to an independent pediatric cohort (mean absolute error = 2.16 years). Applied to the VNS cohort, it revealed significantly elevated brain-age gaps (BrainAGEgap) compared to age- and sex-matched controls (t = 6.27, p < 0.0001), indicating cumulative structural divergence from age-referenced norms. BrainAGEgap correlated with baseline seizure burden and postoperative changes in seizure frequency. Lower pre-surgical BrainAGEgap predicted a significantly higher likelihood of becoming a clinical responder to VNS (p = 0.01). Local age within the cingulate cortex, thalamus, nucleus accumbens, and prefrontal cortex contributed disproportionately to BrainAGEgap differences, aligning with VNS-related circuitry. CONCLUSION: Developmental structural differences can be summarized using a robust, single-metric biomarker that reflects both disease burden and treatment responsiveness. BrainAGEgap may support individualized prognostic assessment and improve clinical decision-making in pediatric DRE undergoing neuromodulation.

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Publication Details

Journal
Brain stimulation
Published
2026-05-01
DOI
https://doi.org/10.1016/j.brs.2026.103117
Primary Topic
Vagus Nerve Stimulation Research
Type
article
Field-Weighted Citation Impact
0.00

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article

Brain-age defines a structural signature of outcomes after vagus nerve stimulation in children

Timur H. Latypov, Alexandre Berger, Elizabeth N. Kerr, Melissa A. LoPresti et al.
Brain stimulation
Vagus Nerve Stimulation Research
article

Brain-age defines a structural signature of outcomes after vagus nerve stimulation in children

Timur H. Latypov, Alexandre Berger, Elizabeth N. Kerr, Melissa A. LoPresti, Karim Mithani, Nisha Gadgil, Sebastian C. Coleman, Howard L. Weiner, Gregory W. Albert, Emefa Akwayena, Shelly Wang, Hrishikesh Suresh, Simeon M. Wong, Flavia Venetucci Gouveia, Philippe Major, Diane Aum, Elizabeth Donner, Shelly Weiss, Dewi Schrader, Sean Lew, Toba Niazi, Jeffrey S. Raskin, Matthew D. Smyth, Aristides Hadjinicolaou, Madison Remick, Eisha Christian, Robert J. Bollo, Aria Fallah, Puneet Jain, Alexander G. Weil, James T. Rutka, Lauren Sham, George M. Ibrahim, Jignesh Tailor, Taylor J. Abel, Elysa Widjaja, Vann Chau
article en

Abstract

INTRODUCTION: Outcomes following vagus nerve stimulation (VNS) are difficult to predict prior to surgery in pediatric drug-resistant epilepsy (DRE). We investigated whether structural brain differences among children may explain variability in VNS response. METHODS: A pediatric-specific brain-age model was developed using structural MRI from 2,623 healthy individuals aged 1.9 to 90 years, capturing nonlinear neurodevelopmental trajectories. Model accuracy was evaluated using cross-validation and independent validation in a pediatric cohort. The model was then applied to a multicenter cohort of 126 children with DRE treated with VNS. RESULTS: = 0.93; mean absolute error = 3.5 years) and generalized well to an independent pediatric cohort (mean absolute error = 2.16 years). Applied to the VNS cohort, it revealed significantly elevated brain-age gaps (BrainAGEgap) compared to age- and sex-matched controls (t = 6.27, p < 0.0001), indicating cumulative structural divergence from age-referenced norms. BrainAGEgap correlated with baseline seizure burden and postoperative changes in seizure frequency. Lower pre-surgical BrainAGEgap predicted a significantly higher likelihood of becoming a clinical responder to VNS (p = 0.01). Local age within the cingulate cortex, thalamus, nucleus accumbens, and prefrontal cortex contributed disproportionately to BrainAGEgap differences, aligning with VNS-related circuitry. CONCLUSION: Developmental structural differences can be summarized using a robust, single-metric biomarker that reflects both disease burden and treatment responsiveness. BrainAGEgap may support individualized prognostic assessment and improve clinical decision-making in pediatric DRE undergoing neuromodulation.

Brain stimulation
Arkansas Children's Hospital (US), Johns Hopkins University (US), University of California, Los Angeles (US), University of Pittsburgh (US), Medical College of Wisconsin (US), Washington University in St. Louis (US), University of Utah (US), Hospital for Sick Children (CA), Centre Hospitalier Universitaire Sainte-Justine (CA), University of Rochester Medical Center (US), Mental Health Research Canada (CA), Johns Hopkins All Children's Hospital (US), Lurie Children's Hospital (US), SickKids Foundation (CA), Miami Children's Hospital (US), Texas Children's Hospital (US), BC Children's Hospital (CA), Indiana University (US)
LivaNova, Hospital for Sick Children
Gender equality
Openalex Percentile: Top 6%
Vagus Nerve Stimulation Research
DOIOpen Access PDFOpenAlex
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