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Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by age-inappropriate levels of inattention and/or hyperactivity-impulsivity. ADHD has been related to differences in white matter microstructure, measured by diffusion-weighted imaging (DWI) and quantified by fractional anisotropy (FA). In the largest DWI analysis of ADHD to date, we systematically investigated if FA is associated with: current and lifetime diagnosis, categorical diagnosis and continuous symptom measures, and impairment in daily life. DWI data were obtained from 654 participants (322 unaffected, 258 affected, 74 subthreshold; 7-29 years of age). For each subject, we applied automated global probabilistic tractography with TRACULA on 18 major white matter pathways and linear mixed effects regression models to examine associations with overall brain and tract-specific FA. There was no significant association of FA with current diagnosis or history of ADHD diagnosis, or impairment. Lower FA was significantly associated with higher ADHD symptom severity in the right cingulum's angular bundle (rCAB; P=0.051), and this was mainly driven by hyperactivity-impulsivity symptoms (P=0.033). This is the first time global probabilistic tractography has been applied to an ADHD DWI dataset of this size. Our findings suggest that continuous symptom measures may be more sensitive to FA differences in association with ADHD than diagnostic categories. The rCAB may play an important role in hyperactivity and impulsivity in ADHD.

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