Pediatric brain charts reveal ADHD biotypes with distinct developmental, molecular, and therapeutic profiles

Bu, X.; Sun, L.; Fu, Z.; Zhao, Y.; Zheng, X.; Zhang, K.; Liang, X.; Cui, Z.; Gao, J.-H.; Gong, G.; Huang, R.; Li, S.; Luo, L.; Men, W.; Peng, Y.; Sun, X.; Wang, X.; Xia, M.; Zhao, T.; Zhu, L.; Zuo, X.; Wang, Y.; Dong, Q.; Cao, Q.; Yang, L.; He, Y.

doi:10.64898/2026.10.22.760978

bioRxiv · 10.64898/2026.10.22.760978

Pediatric brain charts reveal ADHD biotypes with distinct developmental, molecular, and therapeutic profiles

Bu, X.·Sun, L.·Fu, Z.·Zhao, Y.·Zheng, X.·Zhang, K.·Liang, X.·Cui, Z.·Gao, J.-H.·Gong, G.·Huang, R.·Li, S.·Luo, L.·Men, W.·Peng, Y.·Sun, X.·Wang, X.·Xia, M.·Zhao, T.·Zhu, L.·Zuo, X.·Wang, Y.·Dong, Q.·Cao, Q.·Yang, L.·He, Y.

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Abstract

Attention-deficit/hyperactivity disorder (ADHD) exhibits profound clinical heterogeneity; however, its underlying neurobiological substrates remain unclear. Here, leveraging large - scale structural magnetic resonance imaging data from 12,663 typically developing children and 1,699 children with ADHD across Chinese and United States cohorts, we construct population specific pediatric brain charts via hierarchical Bayesian normative modeling to quantify individual deviations in cortical morphology. Data-driven clustering identifies two robust, cross - ethnically replicable ADHD biotypes: an infra - normal biotype characterized by widespread cortical thinning and a supra - normal biotype marked by cortical thickening. Multivariate analyses reveal distinct brain-behavior architectures: cortical deviations correlate preferentially with symptom severity in the infra-normal biotype but with both symptom severity and cognitive performance in the supranormal biotype. Clinically, the infra-normal biotype demonstrates a superior response to methylphenidate over atomoxetine, whereas the supra-normal biotype responds comparably to both. Transcriptomic analyses identify biotype-specific molecular signatures converging with ADHD genome-wide association study (GWAS) risk loci but exhibiting distinct expression patterns in the brain. These findings classify ADHD heterogeneity into neurobiologically distinct, clinically informed biotypes, providing a mechanistic framework for precision psychiatry in pediatric ADHD.

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Bu, X., Sun, L., Fu, Z., Zhao, Y., Zheng, X., Zhang, K., Liang, X., Cui, Z., Gao, J.-H., Gong, G., Huang, R., Li, S., Luo, L., Men, W., Peng, Y., Sun, X., Wang, X., Xia, M., Zhao, T., Zhu, L., Zuo, X., Wang, Y., Dong, Q., Cao, Q., Yang, L., He, Y.. 2026-10-23. Pediatric brain charts reveal ADHD biotypes with distinct developmental, molecular, and therapeutic profiles. https://doi.org/10.64898/2026.10.22.760978

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