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Background Twin studies show that age-related change in symptoms of attention-deficit/hyperactivity disorder (ADHD) is heritable. However, we do not know the heritability of the development of the neural substrates underlying the disorder. Here, we estimated the heritability of developmental change in white matter tracts and the brain’s intrinsic functional connectivity using longitudinal data. We further determined associations with change in ADHD symptoms. Methods The study reports on 288 children, which included 127 siblings, 19 cousins, and 142 singletons; 150 (52%) had a diagnosis of ADHD (determined by clinician interview with parent); 188 were male. All had two clinical assessments (overall baseline mean age: 9.4 ± 2.4 years; follow-up: 12.5 ± 2.6 years). Diffusion tensor imaging estimated microstructural properties of white matter tracts on 252 participants. Resting-state functional magnetic resonance imaging estimated intrinsic connectivity within and between major brain networks on 226 participants. Total additive genetic heritability (h2) of the annual rate of change in these neural phenotypes was calculated using SOLAR (Sequential Oligogenic Linkage Analysis Routines). Results Significant heritability was found for the rates of change of 6 white matter tract microstructural properties and for change in the connectivity between the ventral attention network and both the cognitive control and dorsal attention networks. Change in hyperactivity-impulsivity was associated with heritable change in white matter tracts metrics and change in the connectivity between the ventral attention and cognitive networks. Conclusions The relatively small number of heritable, ADHD-associated developmental neural phenotypes can serve as phenotypes for future gene discovery and understanding.

While attention-deficit/hyperactivity disorder (ADHD) has been associated with differences in the structural connections formed by the brain's white matter tracts, studies of such differences have yielded inconsistent findings, likely reflecting small sample sizes. Thus, we conducted a mega-analysis on in vivo measures of white matter microstructure obtained through diffusion tensor imaging of more than 6000 participants from 5 cohorts.In a mega-analysis, linear mixed models were used to test for associations between the fractional anisotropy of 42 white matter tracts and ADHD traits and diagnosis. Contrasts were made against measures of mood, anxiety, and other externalizing problems.Overall, 6993 participants (ages 6-18 years, mean age 10.62 years [SD 1.99]; 3368 girls, 3625 boys; 764 African American, 4146 non-Hispanic White, and 2083 other race/ethnicities) had measures of ADHD and other emotional/behavioral symptoms (N = 6933) and/or enough clinical data to allow a diagnosis of ADHD (n = 951) or its absence (n = 4884). Both the diagnosis and symptoms of ADHD were associated with lower fractional anisotropy of the inferior longitudinal and left uncinate fasciculi (at a false discovery rate-adjusted p.05). Associated effect sizes were small (the strongest association with ADHD traits had an effect size of partial r = -0.14, while the largest case-control difference was associated with an effect size of d = -0.3). Similar microstructural anomalies were not present for anxiety, mood, or externalizing problems. Findings held when ADHD cases and control subjects were matched on in-scanner motion.While present across cohorts, ADHD-associated microstructural differences had small effects, underscoring the limited clinical utility of this imaging modality used in isolation.

Symptoms of attention-deficit/hyperactivity disorder (ADHD) run a variable course through adolescence. While most affected individuals show some improvement, particularly of hyperactivity-impulsivity, symptoms of inattention are more persistent, and some individuals may meet diagnostic criteria for the first time during adolescence. Genetic factors affect adolescent symptom trajectories; those showing persistence likely carry a greater burden of common risk alleles. Rare structural genomic variants, such as copy number variants and point mutations, might also play a role. Although psychostimulant medication is associated with better functional outcomes, an impact on underlying adolescent symptom trajectories has been hard to demonstrate. At a neural level, several studies report that adolescents whose childhood ADHD symptoms have remitted are indistinguishable from neurotypical individuals. This finding could reflect the "carrying forward" of relatively typical childhood neural features among those destined for adolescent remission or the correction of early childhood anomalies with a convergence toward typical dimensions. Other studies have noted unique, possibly compensatory patterns of neural activity among adolescents whose ADHD has improved. Finally, different neural processes might occur in different brain regions. Thus, some functional imaging studies find that subcortical anomalies reflect the onset of ADHD and remain throughout life regardless of symptom change, whereas the variable clinical course of adolescent ADHD is determined by plasticity of the cerebral cortex. Integrating an understanding of the neural processes with genomic risk could elucidate the mechanisms underlying the complex course of adolescent ADHD.

Background It was recently found that the development of typical patterns of prefrontal, but not posterior, cortical asymmetry is disrupted in right-handed youth with attention-deficit/hyperactivity disorder (ADHD). Using longitudinal data, we tested the hypothesis that there would be a congruent disruption in the growth of the anterior corpus callosum, which contains white matter tracts connecting prefrontal cortical regions. Methods Areas of five subregions of the corpus callosum were quantified using a semiautomated method from 828 neuroanatomic magnetic resonance scans acquired from 236 children and adolescents with ADHD (429 scans) and 230 typically developing youth (399 scans), most of whom had repeated neuroimaging. Growth rates of each diagnostic group were defined using mixed-model linear regression. Results Right-handed participants with ADHD showed a significantly higher rate of growth in the anterior-most region of the corpus callosum (estimated annual increase in area of .97%, SEM .12%) than their typically developing peers (annual increase in area of .32% SEM .13%; t = 3.64, p = .0003). No significant diagnostic differences in growth rates were found in any other regions in right-handed participants, and no significant diagnostic differences were found in non-right-handed participants. Conclusions As hypothesized, we found anomalous growth trajectories in the anterior corpus callosum in ADHD. This disrupted anterior callosal growth may reflect, or even drive, the previously reported disruption in the development of prefrontal cortex asymmetry. The finding documents the dynamic, age-dependent nature of callosal and congruent prefrontal cortical abnormalities characterizing ADHD.

Childhood attention-deficit/hyperactivity disorder (ADHD) persists into adulthood in around half of those affected, constituting a major public health challenge. No known demographic, clinical, or neuropsychological factors robustly explain the clinical course, directing our focus to the brain. Herein, we link the trajectories of cerebral cortical development during childhood and adolescence with the severity of adult ADHD.Using a longitudinal study design, 92 participants with ADHD had childhood (mean 10.7 years, SD 3.3) and adult clinical assessments (mean 23.8 years, SD 4.3) with repeated neuroanatomic magnetic resonance imaging. Contrast was made against 184 matched typically developing volunteers.Attention-deficit/hyperactivity disorder persisted in 37 (40%) subjects and adult symptom severity was linked to cortical trajectories. Specifically, as the number of adult symptoms increased, particularly inattentive symptoms, so did the rate of cortical thinning in the medial and dorsolateral prefrontal cortex. For each increase of one symptom of adult ADHD, the rate of cortical thinning increased by .0018 mm (SE = .0004, t = 4.2, p.0001), representing a 5.6% change over the mean rate of thinning for the entire group. These differing trajectories resulted in a convergence toward typical dimensions among those who remitted and a fixed, nonprogressive deficit in persistent ADHD. Notably, cortical thickening or minimal thinning (greater than -.007 mm/year) was found exclusively among individuals who remitted.Adult ADHD status is linked with the developmental trajectories of cortical components of networks supporting attention, cognitive control, and the default mode network. This informs our understanding of the developmental pathways to adult ADHD.