title: 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: OBJECTIVE
  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.
  
  
  METHODS
  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).
  
  
  METHODS
  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 < .001) and putamen (P = .01) volumes (both corrected for total brain volume) in control individuals, whereas age was unrelated to these volumes in participants with ADHD and their unaffected siblings. Attention-deficit/hyperactivity disorder was not significantly related to the other subcortical volumes.
  
  
  CONCLUSIONS
  Global differences in gray matter volume may be due to alterations in the general mechanisms underlying normal brain development in ADHD. The age-by-diagnosis interaction in the caudate and putamen supports the relevance of different brain developmental trajectories in participants with ADHD vs control individuals and supports the role of subcortical basal ganglia alterations in the pathophysiology of ADHD. Alterations in total gray matter and caudate and putamen volumes in unaffected siblings suggest that these volumes are linked to familial risk for ADHD.
authors.affiliation: Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands2Karakter Child and Adolescent Psychiatry University Center, Nijmegen, the Netherlands3Social, Genetic.
authors.forename: Corina U
authors.initials: CU
authors.lastname: Greven
authors.affiliation: Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands4Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Janita
authors.initials: J
authors.lastname: Bralten
authors.affiliation: Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Maarten
authors.initials: M
authors.lastname: Mennes
authors.affiliation: Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Laurence
authors.initials: L
authors.lastname: O'Dwyer
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Kimm J E
authors.initials: KJ
authors.lastname: van Hulzen
authors.affiliation: Karakter Child and Adolescent Psychiatry University Center, Nijmegen, the Netherlands5Department of Psychiatry, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Nanda
authors.initials: N
authors.lastname: Rommelse
authors.affiliation: Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Lizanne J S
authors.initials: LJ
authors.lastname: Schweren
authors.affiliation: Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Pieter J
authors.initials: PJ
authors.lastname: Hoekstra
authors.affiliation: Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Catharina A
authors.initials: CA
authors.lastname: Hartman
authors.affiliation: Department of Clinical Neuropsychology, VU University Amsterdam, Amsterdam, the Netherlands.
authors.forename: Dirk
authors.initials: D
authors.lastname: Heslenfeld
authors.affiliation: Department of Clinical Neuropsychology, VU University Amsterdam, Amsterdam, the Netherlands.
authors.forename: Jaap
authors.initials: J
authors.lastname: Oosterlaan
authors.affiliation: Department of Psychiatry, State University of New York Upstate Medical University, Syracuse.
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Faraone
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands5Department of Psychiatry, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Barbara
authors.initials: B
authors.lastname: Franke
authors.affiliation: Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands10Donders Institute for Brain, Cognition, and Behaviour, Radboud University, Nijmegen, the Netherlands.
authors.forename: Marcel P
authors.initials: MP
authors.lastname: Zwiers
authors.affiliation: Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands4Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands5Department.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Arias-Vasquez
authors.affiliation: Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands2Karakter Child and Adolescent Psychiatry University Center, Nijmegen, the Netherlands.
authors.forename: Jan K
authors.initials: JK
authors.lastname: Buitelaar
mesh_terms: D000293:Adolescent; D041923:Adolescent Development; D000328:Adult; D000367:Age Factors; D000679:Amygdala / Q000473:pathology; D001289:Attention Deficit Disorder with Hyperactivity / Q000473:pathology* / Q000503:physiopathology / Q000523:psychology; D001921:Brain / Q000033:anatomy & histology / Q000473:pathology* / Q000503:physiopathology; D001933:Brain Stem / Q000473:pathology; D002421:Caudate Nucleus / Q000033:anatomy & histology / Q000473:pathology* / Q000503:physiopathology; D002648:Child; D002657:Child Development; D003430:Cross-Sectional Studies; D005260:Female; D005917:Globus Pallidus / Q000473:pathology; D066128:Gray Matter / Q000473:pathology; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D009714:Nucleus Accumbens / Q000473:pathology; D009929:Organ Size; D011699:Putamen / Q000033:anatomy & histology / Q000473:pathology* / Q000503:physiopathology; D012307:Risk Factors; D035781:Siblings; D013788:Thalamus / Q000473:pathology; D066127:White Matter / Q000473:pathology; D055815:Young Adult