A Mega-analytic Study of White Matter Microstructural Differences Across 5 Cohorts of Youths With Attention-Deficit/Hyperactivity Disorder

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: While present across cohorts, ADHD-associated microstructural differences had small effects, underscoring the limited clinical utility of this imaging modality used in isolation.

Trial registration: ClinicalTrials.gov NCT01721720.

Keywords: ADHD; Big data; Diffusion tensor imaging; Fractional anisotropy; Mega-analysis; White matter tracts.

Figure 1.

Association between fractional anisotropy of white matter tracts and ADHD diagnosis, and scores on the empirical subscales from the Child Behavior Checklist. Colors indicate t-statistic, single black stars are nominally significant p < .05, double black stars at p < .01, and double red stars mark associations significant at FDR adjusted p < .05. Results for AD and RD metrics are exploratory only, and displayed for comparison to the main FA results.

Figure 2.

Forest plots showing the effect sizes for associations between fractional anisotropy and (A) the diagnosis of ADHD; and (B) CBCL attention problems scale. The individual cohorts are given, followed by the mega-analytic effect size, then results for the population and clinic-based cohorts. Effect sizes are estimated using Cohen’s d in (A) and partial-r in (B). The association between the FA in the right inferior longitudinal fasciculus and attention problems (lower, right plot) only reached nominal significance p < 0.01 in the main analysis, but it is displayed here for completeness.