Abstract
Many psychiatric disorders begin during adolescence, coinciding with the rapid development of brain white matter (WM). However, it remains unclear whether deviations from normal WM development during this period contribute to psychopathology. In this study, we developed normative models of brain age based on specific WM tracts using three large-scale developmental datasets ( ~ 10,000 subjects). We found that tract-specific deviations in WM development of association and limbic/subcortical systems were linked to concurrent and future cognition and psychopathology. The spatial pattern of the association system aligned closely with high-order brain networks and mitochondrial maps. Importantly, delayed brain-age especially in dorsal association tracts predicted psychiatric disorders across diagnoses and disorder onset over a 2-year follow-up. By identifying tract-specific WM development during preadolescence as a predictor of cognitive capacity and psychiatric risks, this study provides a framework for tracking individualized brain development and understanding the neurobiological underpinnings of cognition and transdiagnostic psychopathology.
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Data availability
The HCP-D data used in this study are available at (https://www.humanconnectome.org/study/hcp-lifespan-development/) with data access. Preprocessed SRC files for the HCP-D dataset can be downloaded from the Fiber Data Hub (https://brain.labsolver.org/hcp_d.html) with HCP-D data access. The ABCD data used in this study are available through the National Institute of Mental Health Data Archive (NDA; https://abcdstudy.org) upon formal application and approval by the ABCD consortium. preprocessed dMRI data from the HBN study are available at: s3://fcp-indi/data/Projects/HBN/BIDS_curated/derivatives/qsiprep/75. The Population-Probability Atlas of 25 tracts used in this study is available at (https://brain.labsolver.org/hcp_trk_atlas.html). Task-related brain activation maps used in this study were obtained from the NeuroSynth database (version 7; https://github.com/neurosynth/neurosynth-data). Whole-brain mitochondrial property maps are available through NeuroVault (https://neurovault.org/collections/16418/)27. Source data are provided with this paper.
Code availability
This study used openly available codes and software, specifically DSI studio (Chen-2022-12-22; (https://hub.docker.com/r/dsistudio/dsistudio/), R (4.5.1), MATLAB (R2024a), Python (3.10.10) and Connectome Workbench (v2.1.0). The pipeline for data harmonization is available at (https://github.com/Jfortin1/ComBatHarmonization/tree/master/Matlab/). The pipeline for building brain-age models is available on GitHub (https://github.com/garedaba/brainAges). The GM voxel-wise spin-based spatial permutation procedure is available at (https://github.com/murraylab/brainsmash/tree/master/). The WM tract-wise spin-based spatial permutation pipeline is available at (https://github.com/frantisekvasa/rotate_parcellation/).
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Acknowledgements
This work was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health (NIH) and utilized the computational resources of the NIH HPC Biowulf cluster (https://hpc.nih.gov). The contributions of the NIH authors were made as part of their official duties as NIH federal employees, are in compliance with agency policy requirements, and are considered Works of the United States Government. However, the findings and conclusions presented in this paper are those of the author(s) and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services. The authors used data from the Adolescent Brain Cognitive Development Study (ABCD, abcdstudy.org), the Healthy Brain Networks (HBN, data.healthybrainnetwork.org) and the Lifespan Human Connectome Project Development Study (HCP-D, https://www.humanconnectome.org/study/hcp-lifespan-development). The ABCD Study, held in the National Institute of Mental Health (NIMH) Data Archive (NDA), is a multisite, longitudinal study designed to recruit more than 10,000 children aged 9-10 and follow them over 10 years into early adulthood. The ABCD Study is supported by the NIH and additional federal partners under award numbers U01DA041048, U01DA050989, U01DA051016, U01DA041022, U01DA051018, U01DA051037, U01DA050987, U01DA04 1174, U01DA041106, U01DA041117, U01DA041028, U01DA041134, U01DA050988, U01DA051039, U01DA041156, U01DA041025, U01DA 041120, U01DA051038, U01DA041148, U01DA041093, U01DA041089, U24DA041123, and U24DA041147. A full list of supporters is available at https://abcdstudy.org/federal-partners.html. A listing of participating sites and a complete listing of the study investigators can be found at https://abcdstudy.org/consortium_members/. HCP-D was supported by the NIMH of the NIH under Award Number U01MH109589 and by funds provided by the McDonnell Center for Systems Neuroscience at Washington University in St. Louis. HCP-D, HBN and ABCD consortium investigators designed and implemented the study and/or provided data but did not necessarily participate in analysis or the writing of this report. This manuscript reflects the views of the authors and may not reflect the opinions or views of any other agency, organization, employer or company.
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D.W., Y.Y., C.J.H., B.J.S., A.J. and T.J.R. concepted and designed the study. D.W. analyzed the data under the guidance of X.X., T.J.R. and Y.Y. D.W., C.J.H., B.J.S., X.X., A.J., L.M., T.J.R. and Y.Y. drafted the manuscript. D.W., C.J.H., B.J.S., X.X., L.M., H.G., T.Z., A.Q., J.H., H.N., H.L., A.J., T.J.R. and Y.Y. contributed to the interpretation of the results. All authors provided analytical support and contributed to the final manuscript. Y.Y. supervised the overall work.
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Wang, D., Hammond, C.J., Salmeron, B.J. et al. Deviation in development of dorsal association tracts during preadolescence links to concurrent and future cognitive performance and transdiagnostic psychopathology. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69774-6
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DOI: https://doi.org/10.1038/s41467-026-69774-6
