Developmental Differences in White Matter Microarchitecture in Youths With Attention-Deficit/Hyperactivity Disorder:...

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 magnetic resonance imaging (MRI) model in the Adolescent Brain Cognitive Development (ABCD) Study cohort (n = 10,526; baseline MRI: mean ± SD = 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 multishell diffusion-weighted imaging and tractography, with intracellular restricted normalized isotropic (RNI) and restricted normalized directional (RND) diffusion quantified using the restriction spectrum imaging (RSI) model. Longitudinal linear mixed-effects models were used to characterize the effects of ADHD status and medication use on white matter RNI and RND across 3 biennial MRI waves.

ADHD was associated with decreased RNI in 20 tracts at age 9 years, 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 that attenuation of RNI differences was 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.