Brain-age defines a structural signature of outcomes after vagus nerve stimulation in children.
Authors
Affiliations (22)
Affiliations (22)
- Neurosciences and Mental Health, SickKids Research Institute, Toronto, Canada.
- Neurosciences and Mental Health, SickKids Research Institute, Toronto, Canada; Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada; Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada.
- Division of Neurology, The Hospital for Sick Children, Toronto, ON, Canada.
- Division of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC, Canada.
- Division of Neurosurgery, Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC, Canada.
- Department of Neurological Surgery, Indiana University School of Medicine, IN, United States of America.
- Department of Neurological Surgery and Bioengineering, University of Pittsburgh, Pittsburgh, PA, United States of America.
- Department of Pediatrics, British Columbia Children's Hospital, Vancouver, BC, Canada.
- Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, UT, United States of America.
- Department of Neurological Surgery, Johns Hopkins All Children's Hospital, St. Petersburg, FL, United States of America.
- Department of Neurology, Washington University School of Medicine, St. Louis, Missouri.
- Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, WI, United States of America.
- Department of Neurosurgery, Nicklaus Children's Hospital, Miami, FL, United States of America.
- Division of Pediatric Neurosurgery, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, United States of America.
- Department of Medical Imaging, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, United States of America.
- Division of Neurosurgery, Arkansas Children's Hospital, University of Arkansas for Medical Sciences, Little Rock, AR, United State of America.
- Division of Pediatric Neurosurgery, Department of Surgery, Texas Children's Hospital, Houston, TX, United States of America.
- Department of Neurosurgery, University of Rochester Medical Center, New York, United States of America.
- Department of Neurosurgery, David Geffen School of Medicine at the University of California, Los Angeles, CA, United States of America.
- Department of Psychology, Hospital for Sick Children, Toronto, ON, Canada.
- Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada.
- Neurosciences and Mental Health, SickKids Research Institute, Toronto, Canada; Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada; Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada. Electronic address: [email protected].
Abstract
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. 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. The brain-age model demonstrated high accuracy (R<sup>2</sup> = 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. 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.