Association between attention-deficit/hyperactivity disorder symptom severity and white matter integrity moderated by...

Attention-deficit/hyperactivity disorder (ADHD) is a common and debilitating neurodevelopmental disorder associated with various negative life impacts. The manifestation of ADHD is very heterogeneous, and previous investigations on neuroanatomical alterations in ADHD have yielded inconsistent results. We investigated the mediating effect of in-scanner head motion and ADHD hyperactivity severity on motion-corrected fractional anisotropy (FA) using diffusion tensor imaging in the currently largest sample (n = 739) of medication-naïve children and adolescents (age range 5-22 years). We used automated tractography to examine whole-brain and mean FA of the tracts most frequently reported in ADHD; corpus callosum forceps major and forceps minor, left and right superior-longitudinal fasciculus, and left and right corticospinal tract (CST). Associations between FA and hyperactivity severity appeared when in-scanner head motion was not accounted for as mediator. However, causal mediation analysis revealed that these effects are fully mediated through in-scanner head motion for whole-brain FA, the corpus callosum forceps minor, and left superior-longitudinal fasciculus. Direct effect of hyperactivity severity on FA was only found for the left CST. This study illustrates the crucial role of in-scanner head motion in the identification of white matter integrity alterations in ADHD and shows how neglecting irremediable motion artifacts causes spurious findings. When the mediating effect of in-scanner head motion on FA is accounted for, an association between hyperactivity severity and FA is only present for the left CST; this may play a crucial role in the manifestation of hyperactivity and impulsivity symptoms in ADHD.