A mega-analytic study of white matter microstructural differences across five cohorts of youth with attention deficit hyperactivity disorder

Published:September 25, 2022DOI:



      While ADHD has been associated with differences in the structural connections formed by the brain’s white matter tracts, studies of such differences have returned inconsistent findings, likely reflecting small sample sizes. Thus, we conducted a mega-analysis on in vivo measures of white matter microstructure obtained through diffusion tensor imaging of over 6000 participants, from five cohorts.


      In a mega-analysis, linear mixed models tested for associations between the fractional anisotropy of 42 white matter tracts and ADHD traits and diagnosis. Contrasts were made against measures of mood, anxiety, and other externalizing problems.


      Overall, 6993 participants (between ages 6 to 18 years, mean 10.62 [SD 1.99]; 3,368 girls, 3,625 boys; 4146 white, non-Hispanic, 764 African American, 2083 other race/ethnicities) had either measures of ADHD and other emotional/behavioral symptoms (N=6933) and/or enough clinical data to allow a diagnosis of ADHD (N=951) or its absence (N=4884). Both the diagnosis and symptoms of ADHD were associated with lower fractional anisotropy of inferior longitudinal and left uncinate fasciculi (at FDR adjusted p<0.05). Associated effect sizes were small (the strongest association with ADHD traits had an effect size of partial-r=-0.14, while the largest case control difference was associated with an effect size of d=-0.3). Similar microstructural anomalies were not present for anxiety, mood, or externalizing problems. Findings held when ADHD cases and controls were matched on in-scanner motion.


      While present across cohorts, ADHD-associated microstructural differences had small effects, underscoring the limited clinical utility of this imaging modality in isolation.


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