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

Attention-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 the ABCD Study® cohort (N=10,526; baseline MRI: 9.92±0.63 years, 12.2% with ADHD; MRI Wave 2: 11.95±0.65 years; 11.3% with ADHD, MRI Wave 3: 14.07±0.69 years, 11.8% with ADHD). Twenty-seven white matter tracts were delineated using multi-shell diffusion-weighted imaging and tractography, with intracellular isotropic (RNI) and directional (RND) diffusion 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 RNI and RND across three biennial MRI waves.

ADHD was associated with decreased RNI in 20 tracts at age 9, with evidence of developmental trajectory differences suggesting attenuation over early adolescence. Enduring ADHD-associated decreases in RND were observed spanning ages 9 to 14 years in 16 tracts, with methylphenidate effects on 2 tracts. RNI but not RND findings were robust in low-motion sensitivity analyses. Exploratory analyses of ADHD severity suggest attenuation of RNI differences were paralleled by reductions in ADHD symptoms.

Altogether, ADHD was robustly associated with reductions in isotropic diffusion in white matter tracts, suggestive of atypical glial cellularity during late childhood. Complementary reductions in directional diffusion of select tracts may suggest atypical axonal organization enduring across early adolescence.