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

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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BibTeX RIS

BibTeX

@misc{bu2026pediatric,
  title = {{Pediatric brain charts reveal ADHD biotypes with distinct developmental, molecular, and therapeutic profiles}},
  author = {X. Bu and L. Sun and Z. Fu and Y. Zhao and X. Zheng and K. Zhang and X. Liang and Z. Cui and J.-H. Gao and G. Gong and R. Huang and S. Li and L. Luo and W. Men and Y. Peng and L. Sun and X. Sun and X. Wang and M. Xia and T. Zhao and L. Zhu and X. Zuo and Y. Wang and Q. Dong and Q. Cao and L. Yang and Y. He},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.22.760978},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.22.760978v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - Pediatric brain charts reveal ADHD biotypes with distinct developmental, molecular, and therapeutic profiles
AU  - X. Bu
AU  - L. Sun
AU  - Z. Fu
AU  - Y. Zhao
AU  - X. Zheng
AU  - K. Zhang
AU  - X. Liang
AU  - Z. Cui
AU  - J.-H. Gao
AU  - G. Gong
AU  - R. Huang
AU  - S. Li
AU  - L. Luo
AU  - W. Men
AU  - Y. Peng
AU  - L. Sun
AU  - X. Sun
AU  - X. Wang
AU  - M. Xia
AU  - T. Zhao
AU  - L. Zhu
AU  - X. Zuo
AU  - Y. Wang
AU  - Q. Dong
AU  - Q. Cao
AU  - L. Yang
AU  - Y. He
PY  - 2026
DA  - 2026/10/22
PB  - bioRxiv
DO  - 10.64898/2026.10.22.760978
UR  - https://www.biorxiv.org/content/10.64898/2026.10.22.760978v1
AB  - 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.
SN  - 2692-8205
ER  -

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