Literature regarding white matter (WM) abnormalities in attention-deficit/hyperactivity disorder (ADHD) is sparse and inconsistent. In this article, we shed more light on WM microstructure in ADHD, its association with symptom count, and the familiality of WM abnormalities in ADHD. Diffusion tensor imaging (DTI) was performed in a large sample of individuals with ADHD (n = 170), their unaffected siblings (n = 80), and healthy controls (n = 107), aged 8 to 30 years. Extensive categorical as well as dimensional data regarding ADHD status and symptom count were collected. A whole-brain voxelwise approach was used to investigate associations between ADHD status and symptom count and WM microstructure, as measured by fractional anisotropy (FA) and mean diffusivity (MD). Individuals with ADHD showed decreased FA and decreased MD in several widespread, non-overlapping brain regions. In contrast, higher ADHD symptom count was consistently associated with increased FA and decreased MD in the ADHD group. Unaffected siblings resembled individuals in the ADHD group with regard to decreased FA but had MD similar to that in healthy controls. Results were not confounded by socioeconomic status, the presence of comorbidities, or a history of medication use. Our results indicate widespread disturbances in WM microstructure in ADHD, which seem to be driven by 2 different mechanisms. Decreased FA in ADHD may be due to a familial vulnerability to the disorder, whereas a second mechanism may drive the association between ADHD symptom count and both higher FA and lower MD. Such different mechanisms may play an important role in the inconsistencies found in the current literature. Copyright © 2014 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.
