title: Subcortical brain volume differences in participants with attention deficit hyperactivity disorder in children and adults: a cross-sectional mega-analysis.
abstract: Neuroimaging studies have shown structural alterations in several brain regions in children and adults with attention deficit hyperactivity disorder (ADHD). Through the formation of the international ENIGMA ADHD Working Group, we aimed to address weaknesses of previous imaging studies and meta-analyses, namely inadequate sample size and methodological heterogeneity. We aimed to investigate whether there are structural differences in children and adults with ADHD compared with those without this diagnosis.
  
  
  
  In this cross-sectional mega-analysis, we used the data from the international ENIGMA Working Group collaboration, which in the present analysis was frozen at Feb 8, 2015. Individual sites analysed structural T1-weighted MRI brain scans with harmonised protocols of individuals with ADHD compared with those who do not have this diagnosis. Our primary outcome was to assess case-control differences in subcortical structures and intracranial volume through pooling of all individual data from all cohorts in this collaboration. For this analysis, p values were significant at the false discovery rate corrected threshold of p=0·0156.
  
  
  
  Our sample comprised 1713 participants with ADHD and 1529 controls from 23 sites with a median age of 14 years (range 4-63 years). The volumes of the accumbens (Cohen's d=-0·15), amygdala (d=-0·19), caudate (d=-0·11), hippocampus (d=-0·11), putamen (d=-0·14), and intracranial volume (d=-0·10) were smaller in individuals with ADHD compared with controls in the mega-analysis. There was no difference in volume size in the pallidum (p=0·95) and thalamus (p=0·39) between people with ADHD and controls. Exploratory lifespan modelling suggested a delay of maturation and a delay of degeneration, as effect sizes were highest in most subgroups of children (<15 years) versus adults (>21 years): in the accumbens (Cohen's d=-0·19 vs -0·10), amygdala (d=-0·18 vs -0·14), caudate (d=-0·13 vs -0·07), hippocampus (d=-0·12 vs -0·06), putamen (d=-0·18 vs -0·08), and intracranial volume (d=-0·14 vs 0·01). There was no difference between children and adults for the pallidum (p=0·79) or thalamus (p=0·89). Case-control differences in adults were non-significant (all p>0·03). Psychostimulant medication use (all p>0·15) or symptom scores (all p>0·02) did not influence results, nor did the presence of comorbid psychiatric disorders (all p>0·5).
  
  
  
  With the largest dataset to date, we add new knowledge about bilateral amygdala, accumbens, and hippocampus reductions in ADHD. We extend the brain maturation delay theory for ADHD to include subcortical structures and refute medication effects on brain volume suggested by earlier meta-analyses. Lifespan analyses suggest that, in the absence of well powered longitudinal studies, the ENIGMA cross-sectional sample across six decades of ages provides a means to generate hypotheses about lifespan trajectories in brain phenotypes.
  
  
  
  National Institutes of Health.
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands; Donders Institute for Brain, Cognition and Behaviour, Nijmegen, Netherlands. Electronic address: martine.hoogman@radboudumc.nl.
authors.forename: Martine
authors.initials: M
authors.lastname: Hoogman
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands; Donders Institute for Brain, Cognition and Behaviour, Nijmegen, Netherlands.
authors.forename: Janita
authors.initials: J
authors.lastname: Bralten
authors.affiliation: Imaging Genetics Center, Mark and Mary Stevens Institute for Neuroimaging and Informatics, Keck School of Medicine of USC, University of Southern California, Marina del Rey, CA, USA.
authors.forename: Derrek P
authors.initials: DP
authors.lastname: Hibar
authors.affiliation: Donders Institute for Brain, Cognition and Behaviour, Nijmegen, Netherlands.
authors.forename: Maarten
authors.initials: M
authors.lastname: Mennes
authors.affiliation: Donders Institute for Brain, Cognition and Behaviour, Nijmegen, Netherlands.
authors.forename: Marcel P
authors.initials: MP
authors.lastname: Zwiers
authors.affiliation: Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
authors.forename: Lizanne S J
authors.initials: LSJ
authors.lastname: Schweren
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands; Donders Institute for Brain, Cognition and Behaviour, Nijmegen, Netherlands.
authors.forename: Kimm J E
authors.initials: KJE
authors.lastname: van Hulzen
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Medland
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands; Donders Institute for Brain, Cognition and Behaviour, Nijmegen, Netherlands.
authors.forename: Elena
authors.initials: E
authors.lastname: Shumskaya
authors.affiliation: Imaging Genetics Center, Mark and Mary Stevens Institute for Neuroimaging and Informatics, Keck School of Medicine of USC, University of Southern California, Marina del Rey, CA, USA.
authors.forename: Neda
authors.initials: N
authors.lastname: Jahanshad
authors.affiliation: NICHE-lab, Brain Center Rudolf Magnus, Department of Psychiatry, University Medical Center Utrecht, Utrecht, Netherlands.
authors.forename: Patrick de
authors.initials: P
authors.lastname: Zeeuw
authors.affiliation: Neurobehavioral Clinical Research Section, National Human Genome Research Institute, Bethesda, MD, USA.
authors.forename: Eszter
authors.initials: E
authors.lastname: Szekely
authors.affiliation: Neurobehavioral Clinical Research Section, National Human Genome Research Institute, Bethesda, MD, USA.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Sudre
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands; Donders Institute for Brain, Cognition and Behaviour, Nijmegen, Netherlands.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wolfers
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands; Donders Institute for Brain, Cognition and Behaviour, Nijmegen, Netherlands.
authors.forename: Alberdingk M H
authors.initials: AMH
authors.lastname: Onnink
authors.affiliation: Department of Psychiatry, Radboud University Medical Center, Nijmegen, Netherlands; Donders Institute for Brain, Cognition and Behaviour, Nijmegen, Netherlands.
authors.forename: Janneke T
authors.initials: JT
authors.lastname: Dammers
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands; Donders Institute for Brain, Cognition and Behaviour, Nijmegen, Netherlands.
authors.forename: Jeanette C
authors.initials: JC
authors.lastname: Mostert
authors.affiliation: Asociación para la Innovación en Análisis, Gestión y Procesamiento de Datos Científicos y Tecnológicos, Barcelona, Spain.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Vives-Gilabert
authors.affiliation: Child Neuropsychology Section, University Hospital Aachen, Aachen, Germany.
authors.forename: Gregor
authors.initials: G
authors.lastname: Kohls
authors.affiliation: Child Neuropsychology Section, University Hospital Aachen, Aachen, Germany; JARA Translational Brain Medicine, Research Center Juelich, Aachen, Germany.
authors.forename: Eileen
authors.initials: E
authors.lastname: Oberwelland
authors.affiliation: Department of Child and Adolescent Psychiatry, University Hospital Aachen, Aachen, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Seitz
authors.affiliation: Child Neuropsychology Section, University Hospital Aachen, Aachen, Germany; JARA Translational Brain Medicine, Research Center Juelich, Aachen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schulte-Rüther
authors.affiliation: NICHE-lab, Brain Center Rudolf Magnus, Department of Psychiatry, University Medical Center Utrecht, Utrecht, Netherlands.
authors.forename: Sara
authors.initials: S
authors.lastname: Ambrosino
authors.affiliation: Department of Psychiatry and Center for Human Genetics Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Stanley Center for Psychiatric Research at the Broad Institute, Cambridge, MA, USA.
authors.forename: Alysa E
authors.initials: AE
authors.lastname: Doyle
authors.affiliation: Department of Clinical Medicine, University of Bergen, Bergen, Norway.
authors.forename: Marie F
authors.initials: MF
authors.lastname: Høvik
authors.affiliation: Psychiatry, Region Zealand, Denmark.
authors.forename: Margaretha
authors.initials: M
authors.lastname: Dramsdahl
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Leanne
authors.initials: L
authors.lastname: Tamm
authors.affiliation: Department of Psychiatry and Human Behavior, University of California, Irvine, CA, USA.
authors.forename: Theo G M
authors.initials: TGM
authors.lastname: van Erp
authors.affiliation: Departments of Neurosciences and Radiology, University of California, San Diego, San Diego, CA, USA; UCSD Center for Translational Imaging and Precision Medicine, San Diego, CA, USA.
authors.forename: Anders
authors.initials: A
authors.lastname: Dale
authors.affiliation: Department of Cognitive Science, UC San Diego, La Jolla, CA, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Schork
authors.affiliation: Department of Child and Adolescent Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany; Department of Psychology, University of Würzburg, Würzburg, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Conzelmann
authors.affiliation: Department of Medical Psychology and Psychotherapy, Medical Sociology and Rehabilitation Sciences, University of Würzburg, Würzburg, Germany; Department of Psychology, University of Würzburg, Würzburg, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Zierhut
authors.affiliation: Department of Psychology, University of Würzburg, Würzburg, Germany.
authors.forename: Ramona
authors.initials: R
authors.lastname: Baur
authors.affiliation: Department of Psychiatry, University of Dublin, Trinity College Dublin, Dublin, Ireland.
authors.forename: Hazel
authors.initials: H
authors.lastname: McCarthy
authors.affiliation: The Child Study Center at NYU Langone Medical Center, New York, NY, USA.
authors.forename: Yuliya N
authors.initials: YN
authors.lastname: Yoncheva
authors.affiliation: Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Ana
authors.initials: A
authors.lastname: Cubillo
authors.affiliation: Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Kaylita
authors.initials: K
authors.lastname: Chantiluke
authors.affiliation: Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Mitul A
authors.initials: MA
authors.lastname: Mehta
authors.affiliation: Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Yannis
authors.initials: Y
authors.lastname: Paloyelis
authors.affiliation: Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hohmann
authors.affiliation: Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Baumeister
authors.affiliation: D'Or Institute for Research and Education, Rio de Janeiro, Brazil.
authors.forename: Ivanei
authors.initials: I
authors.lastname: Bramati
authors.affiliation: D'Or Institute for Research and Education, Rio de Janeiro, Brazil; Institute of Psychiatry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Paulo
authors.initials: P
authors.lastname: Mattos
authors.affiliation: D'Or Institute for Research and Education, Rio de Janeiro, Brazil; Morphological Sciences Program, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Tovar-Moll
authors.affiliation: Department of Psychiatry, University of California, Los Angeles, CA, USA.
authors.forename: Pamela
authors.initials: P
authors.lastname: Douglas
authors.affiliation: Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Banaschewski
authors.affiliation: Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Department of Child and Adolescent Psychiatry, Psychiatric Hospital, University of Zurich, Zurich, Switzerland; Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland; Neuroscience Centre Zurich, University of Zurich, Zurich, Switzerland; ETH Zurich, Zurich, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Brandeis
authors.affiliation: Social Genetic and Developmental Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Jonna
authors.initials: J
authors.lastname: Kuntsi
authors.affiliation: Social Genetic and Developmental Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Asherson
authors.affiliation: Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Katya
authors.initials: K
authors.lastname: Rubia
authors.affiliation: Department of Psychiatry, University of Dublin, Trinity College Dublin, Dublin, Ireland; The Child Study Center at NYU Langone Medical Center, New York, NY, USA; Trinity College Institute of Neuroscience, Dublin, Ireland.
authors.forename: Clare
authors.initials: C
authors.lastname: Kelly
authors.affiliation: The Child Study Center at NYU Langone Medical Center, New York, NY, USA.
authors.forename: Adriana Di
authors.initials: AD
authors.lastname: Martino
authors.affiliation: Center for the Developing Brain, Child Mind Institute, New York, NY, USA; Center for Biomedical Imaging and Neuromodulation, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Milham
authors.affiliation: The Child Study Center at NYU Langone Medical Center, New York, NY, USA; Division of Child and Adolescent Psychiatric Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
authors.forename: Francisco X
authors.initials: FX
authors.lastname: Castellanos
authors.affiliation: Department of Psychiatry, University of Dublin, Trinity College Dublin, Dublin, Ireland; Department of Psychiatry and Psychotherapy, University Hospital, Otto-von-Guericke-University, Magdeburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Frodl
authors.affiliation: Department of Psychiatry and Psychotherapy, University Hospital, Otto-von-Guericke-University, Magdeburg, Germany.
authors.forename: Mariam
authors.initials: M
authors.lastname: Zentis
authors.affiliation: Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, Germany; Department of Translational Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands.
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Lesch
authors.affiliation: Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Reif
authors.affiliation: Department of Psychology, University of Würzburg, Würzburg, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Pauli
authors.affiliation: Departments of Cognitive Science, Psychiatry, Radiology, and Center for Human Development, University of California, San Diego, CA, USA.
authors.forename: Terry L
authors.initials: TL
authors.lastname: Jernigan
authors.affiliation: KG Jebsen Centre for Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, Bergen, Norway; Department of Psychiatry, Haukeland University Hospital, Bergen, Norway.
authors.forename: Jan
authors.initials: J
authors.lastname: Haavik
authors.affiliation: Child and Adolescent Mental Health Center, Capital Region, Denmark.
authors.forename: Kerstin J
authors.initials: KJ
authors.lastname: Plessen
authors.affiliation: Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway.
authors.forename: Astri J
authors.initials: AJ
authors.lastname: Lundervold
authors.affiliation: Department of Psychiatry, Haukeland University Hospital, Bergen, Norway; Department of Radiology, Haukeland University Hospital, Bergen, Norway; Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Hugdahl
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, MA, USA; Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Seidman
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, MA, USA; Clinical and Research Programs in Pediatric Psychopharmacology and Adult ADHD, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Biederman
authors.affiliation: Department of Psychiatry, Radboud University Medical Center, Nijmegen, Netherlands; Karakter Child and Adolescent Psychiatry, Nijmegen, Netherlands.
authors.forename: Nanda
authors.initials: N
authors.lastname: Rommelse
authors.affiliation: Department of Cognitive Psychology, VU University Amsterdam, Amsterdam, Netherlands; Department of Clinical Neuropsychology, VU University Amsterdam, Amsterdam, Netherlands.
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Heslenfeld
authors.affiliation: Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
authors.forename: Catharina A
authors.initials: CA
authors.lastname: Hartman
authors.affiliation: Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
authors.forename: Pieter J
authors.initials: PJ
authors.lastname: Hoekstra
authors.affiliation: Department of Clinical Neuropsychology, VU University Amsterdam, Amsterdam, Netherlands.
authors.forename: Jaap
authors.initials: J
authors.lastname: Oosterlaan
authors.affiliation: Child Neuropsychology Section, University Hospital Aachen, Aachen, Germany.
authors.forename: Georg von
authors.initials: GV
authors.lastname: Polier
authors.affiliation: Child Neuropsychology Section, University Hospital Aachen, Aachen, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Konrad
authors.affiliation: Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; Fundació IMIM, Barcelona, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Vilarroya
authors.affiliation: Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; Department of Psychiatry, Hospital Universitari Vall d'Hebron, CIBERSAM, Barcelona, Spain.
authors.forename: Josep Antoni
authors.initials: JA
authors.lastname: Ramos-Quiroga
authors.affiliation: Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Joan Carles
authors.initials: JC
authors.lastname: Soliva
authors.affiliation: NICHE-lab, Brain Center Rudolf Magnus, Department of Psychiatry, University Medical Center Utrecht, Utrecht, Netherlands.
authors.forename: Sarah
authors.initials: S
authors.lastname: Durston
authors.affiliation: Department of Cognitive Neuroscience, Radboud University Medical Center, Nijmegen, Netherlands; Donders Institute for Brain, Cognition and Behaviour, Nijmegen, Netherlands; Karakter Child and Adolescent Psychiatry, Nijmegen, Netherlands.
authors.forename: Jan K
authors.initials: JK
authors.lastname: Buitelaar
authors.affiliation: KG Jebsen Centre for Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, Bergen, Norway; Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY, USA.
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Faraone
authors.affiliation: Neurobehavioral Clinical Research Section, National Human Genome Research Institute, Bethesda, MD, USA; National Institute of Mental Health, Bethesda, MD, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Shaw
authors.affiliation: Imaging Genetics Center, Mark and Mary Stevens Institute for Neuroimaging and Informatics, Keck School of Medicine of USC, University of Southern California, Marina del Rey, CA, USA.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Thompson
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands; Department of Psychiatry, Radboud University Medical Center, Nijmegen, Netherlands; Donders Institute for Brain, Cognition and Behaviour, Nijmegen, Netherlands.
authors.forename: Barbara
authors.initials: B
authors.lastname: Franke
mesh_terms: D000293:Adolescent; D000328:Adult; D001289:Attention Deficit Disorder with Hyperactivity / Q000473:pathology* / Q000503:physiopathology; D001921:Brain / Q000473:pathology* / Q000503:physiopathology; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D016014:Linear Models; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D059906:Neuroimaging; D055815:Young Adult