Developmentally stable whole-brain volume reductions and developmentally sensitive caudate and putamen volume alterations in those with attention-deficit/hyperactivity disorder and their unaffected siblings

Abstract

IMPORTANCE: Attention-deficit/hyperactivity disorder (ADHD) is a heritable neurodevelopmental disorder. It has been linked to reductions in total brain volume and subcortical abnormalities. However, owing to heterogeneity within and between studies and limited sample sizes, findings on the neuroanatomical substrates of ADHD have shown considerable variability. Moreover, it remains unclear whether neuroanatomical alterations linked to ADHD are also present in the unaffected siblings of those with ADHD. OBJECTIVE: To examine whether ADHD is linked to alterations in whole-brain and subcortical volumes and to study familial underpinnings of brain volumetric alterations in ADHD. DESIGN, SETTING, AND PARTICIPANTS: In this cross-sectional study, we included participants from the large and carefully phenotyped Dutch NeuroIMAGE sample (collected from September 2009-December 2012) consisting of 307 participants with ADHD, 169 of their unaffected siblings, and 196 typically developing control individuals (mean age, 17.21 years; age range, 8-30 years). MAIN OUTCOMES AND MEASURES: Whole-brain volumes (total brain and gray and white matter volumes) and volumes of subcortical regions (nucleus accumbens, amygdala, caudate nucleus, globus pallidus, hippocampus, putamen, thalamus, and brainstem) were derived from structural magnetic resonance imaging scans using automated tissue segmentation. RESULTS: Regression analyses revealed that relative to control individuals, participants with ADHD had a 2.5% smaller total brain (β = -31.92; 95% CI, -52.69 to -11.16; P = .0027) and a 3% smaller total gray matter volume (β = -22.51; 95% CI, -35.07 to -9.96; P = .0005), while total white matter volume was unaltered (β = -10.10; 95% CI, -20.73 to 0.53; P = .06). Unaffected siblings had total brain and total gray matter volumes intermediate to participants with ADHD and control individuals. Significant age-by-diagnosis interactions showed that older age was linked to smaller caudate (P