Developmental deviations of structural connectivity in youths with ADHD predict symptom and treatment outcomes

Xu, X.; Fu, Z.; Xu, H.; Zhang, K.; Yang, H.; Li, Y.; Zhao, Y.; Zheng, X.; Keller, A.; Xu, T.; Chen, R.; Cai, W.; Cao, Q.; Yang, L.; Cui, Z.

doi:10.1101/2025.11.20.689391

bioRxiv · 10.1101/2025.11.20.689391

Developmental deviations of structural connectivity in youths with ADHD predict symptom and treatment outcomes

Xu, X.·Fu, Z.·Xu, H.·Zhang, K.·Yang, H.·Li, Y.·Zhao, Y.·Zheng, X.·Keller, A.·Xu, T.·Chen, R.·Cai, W.·Cao, Q.·Yang, L.·Cui, Z.

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Abstract

Attention-deficit/hyperactivity disorder (ADHD) lacks validated biomarkers to track symptom development or guide treatment selection in youth. We quantified individual deviations from normative age-related trajectories of white-matter structural connectivity (SC) across two independent cohorts: 6,687 typically developing and 1,114 ADHD scans from the ABCD study, and 292 typically developing and 482 ADHD participants from a Chinese cohort. Youth with ADHD showed pronounced SC deviations, especially in higher-order association pathways. A subset of connections showed ADHD-specific developmental reductions in deviations beyond typical developmental patterns, and these changes mediated the age-related decline in ADHD symptoms. Longitudinal within-individual analyses demonstrated that decreases in deviation over two years tracked symptom improvement. Baseline deviations also predicted 12-week treatment response to atomoxetine, but not methylphenidate, and follow-up imaging revealed treatment-related reductions in deviation. Together, these findings identify SC deviation as a robust developmental biomarker with prognostic and theragnostic relevance for ADHD, supporting precision care through risk stratification, individualized pharmacotherapy selection, and objective monitoring of treatment effects.

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Xu, X., Fu, Z., Xu, H., Zhang, K., Yang, H., Li, Y., Zhao, Y., Zheng, X., Keller, A., Xu, T., Chen, R., Cai, W., Cao, Q., Yang, L., Cui, Z.. 2025-11-20. Developmental deviations of structural connectivity in youths with ADHD predict symptom and treatment outcomes. https://doi.org/10.1101/2025.11.20.689391

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