Whither the ADHD Brain? Waning Structural Brain Differences in a Sample of Thousands

Background: Structural neuroimaging studies, including meta-analyses, have identified a variety of differences across cortical and subcortical structures associated with Attention deficit hyperactivity disorder (ADHD) among children. However, studies to date have not employed large, representative samples, complete with data on potential confounders. Here, we compared brain measures among 9- and 10-year-old children with and without ADHD using data from the Adolescent Brain and Cognitive Development (ABCD) Study, the largest longitudinal study of brain development in the United States. Methods: We used baseline demographic, clinical, and neuroimaging data from the ABCD Study. Neuroimaging data underwent centralized quality control, harmonization, and processing by the ABCD Team. Mixed effects models were used to estimate effect sizes (Cohen’s d) associated with ADHD. We used a novel simulation strategy to assess our ability to detect significant effects despite misclassification. Outcomes: Our sample included 949 participants with ADHD and 9,787 without. In the full model, which included a priori selected potential confounders, we found only 11 significant differences across 79 brain regions using a false discovery rate correction. Significant effect sizes ranged from -0.07 to -0.05. Effect sizes remained essentially unchanged using alternative diagnostic instruments. Simulations indicated that we were well powered to detect differences even if there was substantial misclassification in the sample. Interpretation: We found fewer and smaller differences than previous studies, consistent with the trend towards smaller effects in larger samples. Our results suggest that there are few meaningful and specific structural differences associated with ADHD among children in the general population. Funding: We thank the Adolescent Brain and Cognitive Development Study Team. JB was supported by Grant No. T32 MH016434-41, by the AACAP Pilot Research Award for Attention Disorders, and by the Bender-Fishbein Award in Child Psychiatry Research. JP was supported by the Edwin S Webster Foundation, Suzanne Crosby Murphy Endowment and by NIH (UH3 OD023328). Declaration of Interest: JP has received research support from Takeda (formerly Shire) and Aevi Genomics, and consultancy fees from Innovative Science Solutions. JB, AL, LC, EB, and JD declare no competing interests. Ethical Approval: Institutional review boards at each site approved the study procedures. Written consent was obtained from all parents, and children gave verbal assent.