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bioRxiv · 10.64898/2026.02.20.707054

Developmental Differences in White Matter Microarchitecture in Youth with ADHD: Longitudinal Findings from the ABCD Study

Overholtzer, L. N.·Bottenhorn, K. L.·Ahmadi, H.·Karalunas, S. L.·Peterson, B. S.·Herting, M.
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Abstract

BackgroundAttention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder and is a risk factor for later brain disorders. Here, we characterize the relationship between ADHD status and white matter cellularity across development and examine associations with medication, using a novel biophysical diffusion MRI model in youth aged 9 to 14 years. Methods: The ABCD Study(R) is a longitudinal cohort study with three biennial waves of brain MRI collection. Twenty-seven white matter tracts were delineated using multi-shell diffusion-weighted imaging (DWI) and tractography. Intracellular isotropic (RNI) and directional (RND) diffusion were quantified using the Restriction Spectrum Imaging (RSI) model. Longitudinal linear mixed-effect models characterize the effects of ADHD status and medication use on white matter cellularity across three waves. Results: By wave: 9,426 participants at baseline (mean [SD] age: 9.92 [0.63] years; 48.7% Female; 12.2% with ADHD), 6745 participants at 2-year (11.95 [0.65] years; 46.8% Female; 11.3% with ADHD), and 2,483 participants at 4-year (14.07 [0.69] years; 46.0% Female; 11.8% with ADHD). ADHD was associated with decreased RNI in 20 tracts at age 9, with evidence of developmental trajectory differences suggesting attenuation over early adolescence. We found enduring ADHD-associated decreases in RND of 16 tracts spanning ages 9 to 14 years, with methylphenidate effects on 2 tracts. Low-motion sensitivity analyses confirmed robust RNI findings, but not RND findings. ConclusionsADHD was associated with reductions in isotropic diffusion in white matter tracts, and possibly with complementary reductions in directional diffusion of select tracts. Isotropic diffusion findings suggest atypical glial cellularity in white matter during late childhood.

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Overholtzer, L. N., Bottenhorn, K. L., Ahmadi, H., Karalunas, S. L., Peterson, B. S., Herting, M.. 2026-02-21. Developmental Differences in White Matter Microarchitecture in Youth with ADHD: Longitudinal Findings from the ABCD Study. https://doi.org/10.64898/2026.02.20.707054

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