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Am J Psychiatry. 2019 Jul 1;176(7):531-542. doi: 10.1176/appi.ajp.2019.18091033. Epub 2019 Apr 24.

Brain Imaging of the Cortex in ADHD: A Coordinated Analysis of Large-Scale Clinical and Population-Based Samples.

Hoogman M1, Muetzel R1, Guimaraes JP1, Shumskaya E1, Mennes M1, Zwiers MP1, Jahanshad N1, Sudre G1, Wolfers T1, Earl EA1, Soliva Vila JC1, Vives-Gilabert Y1, Khadka S1, Novotny SE1, Hartman CA1, Heslenfeld DJ1, Schweren LJS1, Ambrosino S1, Oranje B1, de Zeeuw P1, Chaim-Avancini TM1, Rosa PGP1, Zanetti MV1, Malpas CB1, Kohls G1, von Polier GG1, Seitz J1, Biederman J1, Doyle AE1, Dale AM1, van Erp TGM1, Epstein JN1, Jernigan TL1, Baur-Streubel R1, Ziegler GC1, Zierhut KC1, Schrantee A1, Høvik MF1, Lundervold AJ1, Kelly C1, McCarthy H1, Skokauskas N1, O'Gorman Tuura RL1, Calvo A1, Lera-Miguel S1, Nicolau R1, Chantiluke KC1, Christakou A1, Vance A1, Cercignani M1, Gabel MC1, Asherson P1, Baumeister S1, Brandeis D1, Hohmann S1, Bramati IE1, Tovar-Moll F1, Fallgatter AJ1, Kardatzki B1, Schwarz L1, Anikin A1, Baranov A1, Gogberashvili T1, Kapilushniy D1, Solovieva A1, El Marroun H1, White T1, Karkashadze G1, Namazova-Baranova L1, Ethofer T1, Mattos P1, Banaschewski T1, Coghill D1, Plessen KJ1, Kuntsi J1, Mehta MA1, Paloyelis Y1, Harrison NA1, Bellgrove MA1, Silk TJ1, Cubillo AI1, Rubia K1, Lazaro L1, Brem S1, Walitza S1, Frodl T1, Zentis M1, Castellanos FX1, Yoncheva YN1, Haavik J1, Reneman L1, Conzelmann A1, Lesch KP1, Pauli P1, Reif A1, Tamm L1, Konrad K1, Oberwelland Weiss E1, Busatto GF1, Louza MR1, Durston S1, Hoekstra PJ1, Oosterlaan J1, Stevens MC1, Ramos-Quiroga JA1, Vilarroya O1, Fair DA1, Nigg JT1, Thompson PM1, Buitelaar JK1, Faraone SV1, Shaw P1, Tiemeier H1, Bralten J1, Franke B1.

Author information

1
The Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands (Hoogman, Guimaraes, Shumskaya, Wolfers, Bralten, Franke); the Donders Institute for Brain, Cognition, and Behavior, Radboud University, Nijmegen, the Netherlands (Hoogman, Shumskaya, Mennes, Wolfers, Buitelaar, Bralten, Franke); the Department of Child and Adolescent Psychiatry, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands (Muetzel, El Marroun, White, Tiemeier); the Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands (Muetzel); the Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behavior, Nijmegen, the Netherlands (Guimaraes, Zwiers, Buitelaar); the Imaging Genetics Center, Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, Marina del Rey, Calif. (Jahanshad, Thompson); National Human Genome Research Institute, Bethesda, Md. (Sudre, Shaw); the Department of Behavioral Neuroscience, Oregon Health and Science University, Portland (Earl, Fair, Nigg); the Department of Psychiatry and Forensic Medicine, Autonomous University of Barcelona, Cerdanyola del Vallès, Spain (Soliva Vila, Ramos-Quiroga, Vilarroya); Instituto ITACA, Polytechnic University of Valencia, Valencia, Spain (Vives-Gilabert); the Olin Neuropsychiatry Research Center, Hartford Hospital, Hartford, Conn. (Khadka, Novotny, Stevens); University of Groningen, University Medical Center Groningen (UMCG), Department of Psychiatry, Interdisciplinary Center Psychopathology and Emotion Regulation (ICPE), Groningen, the Netherlands (Hartman, Schweren); Faculty of Behavioral and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam (Heslenfeld); the Department of Child and Adolescent Psychiatry, University of Groningen, University Medical Center Groningen, the Netherlands (Hoekstra); NICHE Lab, Department of Psychiatry, UMC Utrecht Brain Center, Utrecht, the Netherlands (Ambrosino, Oranje, de Zeeuw, Durston); Laboratory of Psychiatric Neuroimaging (LIM-21), Department and Institute of Psychiatry, Faculty of Medicine, University of São Paulo, São Paulo, Brazil (Chaim-Avancini, Rosa, Zanetti, Busatto); the Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, São Paulo, Brazil (Chaim-Avancini, Rosa, Zanetti, Busatto); the Developmental Imaging Group, Murdoch Children's Research Institute, Melbourne, Australia (Malpas); the Clinical Outcomes Research Unit (CORe), Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne, Australia (Malpas); the Melbourne School of Psychological Sciences, University of Melbourne, Melbourne, Australia (Malpas); the Child Neuropsychology Section, University Hospital RWTH Aachen, Aachen, Germany (Kohls, Konrad; Child and Adolescent Psychiatry, University Hospital RWTH Aachen, Aachen, Germany (Polier, Seitz); Institute of Neuroscience and Medicine-Brain and Behavior (INM-7), Research Center Jülich, Jülich, Germany (Polier); the Clinical and Research Programs in Pediatric Psychopharmacology and Adult ADHD, Department of Psychiatry, Massachusetts General Hospital, Boston (Biederman); the Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston (Biederman, Doyle); the Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston (Doyle); the Departments of Neurosciences, Radiology, and Psychiatry and the Center for Multimodal Imaging and Genetics, University of California San Diego (Dale); the Clinical and Translational Neuroscience Laboratory, Department of Psychiatry and Human Behavior, University of California Irvine, Irvine (van Erp); the Division of Behavioral Medicine and Clinical Psychology, Cincinnati Children's Hospital Medical Center, and the Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati (Epstein, Tamm); the Center for Human Development, University of California San Diego, San Diego (Jernigan); the Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, Germany (Ziegler, Lesch); the Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, Amsterdam (Schrantee, Reneman); the Department of Clinical Medicine, University of Bergen, Bergen, Norway (Høvik); the Division of Psychiatry, Haukeland University Hospital, Bergen, Norway (Høvik, Haavik); the Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway (Lundervold); the K.G. Jebsen Center for Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, Bergen, Norway (Lundervold, Haavik); the School of Psychology and the Department of Psychiatry, School of Medicine, and the Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland (Kelly); the Department of Child and Adolescent Psychiatry, NYU Langone Medical Center, New York (Kelly, Castellanos, Yoncheva); the Department of Psychiatry, Trinity College Dublin, Ireland (McCarthy, Skokauskas, Frodl); the Centre for Advanced Medical Imaging, St. James's Hospital, Dublin, Ireland (McCarthy); the Center for Child and Adolescent Mental Health, NTNU, Norway, Norwegian University of Science and Technology, Norway (Skokauskas); the Center for MR Research, University Children's Hospital, and the Zurich Center for Integrative Human Physiology, Zurich (O'Gorman Tuura); Magnetic Resonance Image Core Facility, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain (Calvo, Lazaro); the Department of Child and Adolescent Psychiatry and Psychology, Institute of Neurosciences, Hospital Clinic, Barcelona, Spain (Lera-Miguel, Nicolau, Lazaro); the Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Chantiluke, Christakou, Cubillo, Rubia); the School of Psychology and Clinical Language Sciences, Centre for Integrative Neuroscience and Neurodynamics, University of Reading, Reading, U.K. (Christakou); the Department of Paediatrics, University of Melbourne, Australia (Vance, Coghill, Silk); the Department of Neuroscience, Brighton and Sussex Medical School, Falmer, Brighton, U.K. (Cercignani, Gabel, Harrison); the Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Asherson, Kuntsi); the Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Mannheim, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany (Baumeister, Brandeis, Hohmann, Banaschewski); the Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric Hospital, University of Zurich, Zurich (Brandeis, Brem, Walitza); the Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich (Brandeis, Brem, Walitza); the D'Or Institute for Research and Education, Rio de Janeiro (Bramati, Tovar-Moll, Mattos); the Morphological Sciences Program, Federal University of Rio de Janeiro, Rio de Janeiro (Tovar-Moll); the Department of Psychiatry and Psychotherapy, University Hospital of Tübingen, Tübingen, Germany (Fallgatter, Schwarz, Ethofer); LEAD Graduate School, University of Tübingen, Germany (Fallgatter); the Department of Biomedical Magnetic Resonance, University of Tübingen, Tübingen, Germany (Kardatzki, Ethofer); the National Medical Research Center for Children's Health, Department of Magnetic Resonance Imaging and Densitometry, Moscow (Anikin); the National Medical Research Center for Children's Health, Moscow (Baranov, Solovieva); Russian National Research Medical University, Ministry of Health and Social Development of the Russian Federation, Central Clinical Hospital MSHE, Moscow (Namazova-Baranova); the National Medical Research Center for Children's Health, Laboratory of Neurology and Cognitive Health, Moscow (Gogberashvili, Karkashadze); the National Medical Research Center for Children's Health, Department of Information Technologies, Moscow (Kapilushniy); the Department of Pediatrics, Erasmus MC-Sophia, Rotterdam, the Netherlands (El Marroun); the Department of Psychology, Education, and Child Studies, Erasmus University Rotterdam, Rotterdam, the Netherlands (El Marroun); the Department of Radiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands (White); Federal University of Rio de Janeiro, Rio de Janeiro (Mattos); the Department of Psychiatry, University of Melbourne, Melbourne, Australia (Coghill); the Murdoch Children's Research Institute, Melbourne, Australia (Coghill, Silk); the Division of Neuroscience, University of Dundee, Dundee, U.K. (Coghill); the Child and Adolescent Mental Health Center, Capital Region Copenhagen (Plessen); the Division of Child and Adolescent Psychiatry, Department of Psychiatry, University Hospital Lausanne, Switzerland (Plessen); the Department of Neuroimaging, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Mehta, Paloyelis); Sussex Partnership NHS Foundation Trust, Swandean, East Sussex, U.K. (Harrison); the Monash Institute for Cognitive and Clinical Neurosciences (MICCN) and the School of Psychological Sciences, Monash University, Melbourne, Australia (Bellgrove); Deakin University, School of Psychology, Geelong, Australia (Silk); the Department of Medicine, University of Barcelona, Barcelona, Spain (Lazaro); the Department of Psychiatry and Psychotherapy, Otto von Guericke University Magdeburg, Germany (Frodl); the German Center for Neurodegenerative Diseases (DZNE), Germany (Frodl); Bezirksklinikum Regensburg, Germany (Zentis); the Nathan Kline Institute for Psychiatric Research, Orangeburg, N.Y. (Castellanos); the Brain Imaging Center, Amsterdam University Medical Centers, Amsterdam (Reneman); the Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, Tübingen, Germany (Conzelmann); the Department of Psychology, Biological Psychology, Clinical Psychology, and Psychotherapy, University of Würzburg, Würzburg, Germany (Conzelmann, Pauli, Baur-Streubel, Zierhut); the Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, Moscow (Lesch); the Department of Neuroscience, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Maastricht, the Netherlands (Lesch); the Department of Psychiatry, Psychosomatic Medicine, and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany (Reif); JARA Institute Molecular Neuroscience and Neuroimaging (INM-11), Institute for Neuroscience and Medicine, Research Center Jülich, Germany (Konrad); Translational Neuroscience, Child and Adolescent Psychiatry, University Hospital RWTH Aachen, Aachen, Germany (Oberwelland Weiss); Cognitive Neuroscience (INM-3), Institute for Neuroscience and Medicine, Research Center Jülich, Germany (Oberwelland Weiss); the Department of Psychiatry, Faculty of Medicine, University of São Paulo, São Paulo, Brazil (Busatto, Louza); the Clinical Neuropsychology Section, Vrije Universiteit Amsterdam, Amsterdam (Oosterlaan); Emma Children's Hospital Amsterdam Medical Center, Amsterdam (Oosterlaan); the Department of Pediatrics, VU Medical Center, Amsterdam (Oosterlaan); the Department of Psychiatry, Yale University School of Medicine, New Haven, Conn. (Stevens); the Department of Psychiatry, Vall d'Hebron University Hospital, Barcelona, Spain (Ramos-Quiroga); Biomedical Network Research Center on Mental Health (CIBERSAM), Barcelona, Spain (Lazaro, Ramos-Quiroga); Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain (Vilarroya); the Department of Psychiatry, Oregon Health and Science University, Portland (Fair, Nigg); Karakter Child and Adolescent Psychiatry University Center, Nijmegen, the Netherlands (Buitelaar); Departments of Psychiatry and of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, New York (Faraone); NIHM, Bethesda, Md. (Shaw); the Department of Social and Behavioral Science, Harvard T.H. Chan School of Public Health, Boston (Tiemeier).

Abstract

OBJECTIVE:

Neuroimaging studies show structural alterations of various brain regions in children and adults with attention deficit hyperactivity disorder (ADHD), although nonreplications are frequent. The authors sought to identify cortical characteristics related to ADHD using large-scale studies.

METHODS:

Cortical thickness and surface area (based on the Desikan-Killiany atlas) were compared between case subjects with ADHD (N=2,246) and control subjects (N=1,934) for children, adolescents, and adults separately in ENIGMA-ADHD, a consortium of 36 centers. To assess familial effects on cortical measures, case subjects, unaffected siblings, and control subjects in the NeuroIMAGE study (N=506) were compared. Associations of the attention scale from the Child Behavior Checklist with cortical measures were determined in a pediatric population sample (Generation-R, N=2,707).

RESULTS:

In the ENIGMA-ADHD sample, lower surface area values were found in children with ADHD, mainly in frontal, cingulate, and temporal regions; the largest significant effect was for total surface area (Cohen's d=-0.21). Fusiform gyrus and temporal pole cortical thickness was also lower in children with ADHD. Neither surface area nor thickness differences were found in the adolescent or adult groups. Familial effects were seen for surface area in several regions. In an overlapping set of regions, surface area, but not thickness, was associated with attention problems in the Generation-R sample.

CONCLUSIONS:

Subtle differences in cortical surface area are widespread in children but not adolescents and adults with ADHD, confirming involvement of the frontal cortex and highlighting regions deserving further attention. Notably, the alterations behave like endophenotypes in families and are linked to ADHD symptoms in the population, extending evidence that ADHD behaves as a continuous trait in the population. Future longitudinal studies should clarify individual lifespan trajectories that lead to nonsignificant findings in adolescent and adult groups despite the presence of an ADHD diagnosis.

KEYWORDS:

Attention Deficit Hyperactivity Disorder; Cortical Surface Area; Cortical Thickness; Imaging; Meta-Analysis; Neuroanatomy

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