Martine Hoogman1, Janita Bralten2, Derrek P Hibar3, Maarten Mennes4, Marcel P Zwiers4, Lizanne S J Schweren5, Kimm J E van Hulzen2, Sarah E Medland6, Elena Shumskaya2, Neda Jahanshad3, Patrick de Zeeuw7, Eszter Szekely8, Gustavo Sudre8, Thomas Wolfers2, Alberdingk M H Onnink2, Janneke T Dammers9, Jeanette C Mostert2, Yolanda Vives-Gilabert10, Gregor Kohls11, Eileen Oberwelland12, Jochen Seitz13, Martin Schulte-Rüther12, Sara Ambrosino7, Alysa E Doyle14, Marie F Høvik15, Margaretha Dramsdahl16, Leanne Tamm17, Theo G M van Erp18, Anders Dale19, Andrew Schork20, Annette Conzelmann21, Kathrin Zierhut22, Ramona Baur23, Hazel McCarthy24, Yuliya N Yoncheva25, Ana Cubillo26, Kaylita Chantiluke26, Mitul A Mehta27, Yannis Paloyelis27, Sarah Hohmann28, Sarah Baumeister28, Ivanei Bramati29, Paulo Mattos30, Fernanda Tovar-Moll31, Pamela Douglas32, Tobias Banaschewski28, Daniel Brandeis33, Jonna Kuntsi34, Philip Asherson34, Katya Rubia26, Clare Kelly35, Adriana Di Martino25, Michael P Milham36, Francisco X Castellanos37, Thomas Frodl38, Mariam Zentis39, Klaus-Peter Lesch40, Andreas Reif41, Paul Pauli23, Terry L Jernigan42, Jan Haavik43, Kerstin J Plessen44, Astri J Lundervold45, Kenneth Hugdahl46, Larry J Seidman47, Joseph Biederman48, Nanda Rommelse49, Dirk J Heslenfeld50, Catharina A Hartman5, Pieter J Hoekstra5, Jaap Oosterlaan51, Georg von Polier11, Kerstin Konrad11, Oscar Vilarroya52, Josep Antoni Ramos-Quiroga53, Joan Carles Soliva54, Sarah Durston7, Jan K Buitelaar55, Stephen V Faraone56, Philip Shaw57, Paul M Thompson3, Barbara Franke58. 1. 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. 2. Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands; Donders Institute for Brain, Cognition and Behaviour, Nijmegen, Netherlands. 3. 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. 4. Donders Institute for Brain, Cognition and Behaviour, Nijmegen, Netherlands. 5. Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, Netherlands. 6. QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. 7. NICHE-lab, Brain Center Rudolf Magnus, Department of Psychiatry, University Medical Center Utrecht, Utrecht, Netherlands. 8. Neurobehavioral Clinical Research Section, National Human Genome Research Institute, Bethesda, MD, USA. 9. Department of Psychiatry, Radboud University Medical Center, Nijmegen, Netherlands; Donders Institute for Brain, Cognition and Behaviour, Nijmegen, Netherlands. 10. Asociación para la Innovación en Análisis, Gestión y Procesamiento de Datos Científicos y Tecnológicos, Barcelona, Spain. 11. Child Neuropsychology Section, University Hospital Aachen, Aachen, Germany. 12. Child Neuropsychology Section, University Hospital Aachen, Aachen, Germany; JARA Translational Brain Medicine, Research Center Juelich, Aachen, Germany. 13. Department of Child and Adolescent Psychiatry, University Hospital Aachen, Aachen, Germany. 14. 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. 15. Department of Clinical Medicine, University of Bergen, Bergen, Norway. 16. Psychiatry, Region Zealand, Denmark. 17. Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. 18. Department of Psychiatry and Human Behavior, University of California, Irvine, CA, USA. 19. 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. 20. Department of Cognitive Science, UC San Diego, La Jolla, CA, USA. 21. Department of Child and Adolescent Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany; Department of Psychology, University of Würzburg, Würzburg, Germany. 22. Department of Medical Psychology and Psychotherapy, Medical Sociology and Rehabilitation Sciences, University of Würzburg, Würzburg, Germany; Department of Psychology, University of Würzburg, Würzburg, Germany. 23. Department of Psychology, University of Würzburg, Würzburg, Germany. 24. Department of Psychiatry, University of Dublin, Trinity College Dublin, Dublin, Ireland. 25. The Child Study Center at NYU Langone Medical Center, New York, NY, USA. 26. Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. 27. Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. 28. Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. 29. D'Or Institute for Research and Education, Rio de Janeiro, Brazil. 30. D'Or Institute for Research and Education, Rio de Janeiro, Brazil; Institute of Psychiatry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. 31. D'Or Institute for Research and Education, Rio de Janeiro, Brazil; Morphological Sciences Program, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. 32. Department of Psychiatry, University of California, Los Angeles, CA, USA. 33. 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. 34. Social Genetic and Developmental Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. 35. 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. 36. 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. 37. 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. 38. Department of Psychiatry, University of Dublin, Trinity College Dublin, Dublin, Ireland; Department of Psychiatry and Psychotherapy, University Hospital, Otto-von-Guericke-University, Magdeburg, Germany. 39. Department of Psychiatry and Psychotherapy, University Hospital, Otto-von-Guericke-University, Magdeburg, Germany. 40. 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. 41. Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany. 42. Departments of Cognitive Science, Psychiatry, Radiology, and Center for Human Development, University of California, San Diego, CA, USA. 43. KG Jebsen Centre for Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, Bergen, Norway; Department of Psychiatry, Haukeland University Hospital, Bergen, Norway. 44. Child and Adolescent Mental Health Center, Capital Region, Denmark. 45. Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway. 46. 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. 47. Department of Psychiatry, Harvard Medical School, Boston, MA, USA; Beth Israel Deaconess Medical Center, Boston, MA, USA. 48. 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. 49. Department of Psychiatry, Radboud University Medical Center, Nijmegen, Netherlands; Karakter Child and Adolescent Psychiatry, Nijmegen, Netherlands. 50. Department of Cognitive Psychology, VU University Amsterdam, Amsterdam, Netherlands; Department of Clinical Neuropsychology, VU University Amsterdam, Amsterdam, Netherlands. 51. Department of Clinical Neuropsychology, VU University Amsterdam, Amsterdam, Netherlands. 52. Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; Fundació IMIM, Barcelona, Spain. 53. Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; Department of Psychiatry, Hospital Universitari Vall d'Hebron, CIBERSAM, Barcelona, Spain. 54. Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain. 55. 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. 56. KG Jebsen Centre for Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, Bergen, Norway; Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY, USA. 57. Neurobehavioral Clinical Research Section, National Human Genome Research Institute, Bethesda, MD, USA; National Institute of Mental Health, Bethesda, MD, USA. 58. 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.
Abstract
BACKGROUND: 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. METHODS: 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. FINDINGS: 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). INTERPRETATION: 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. FUNDING: National Institutes of Health.
BACKGROUND: 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. METHODS: 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. FINDINGS: 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). INTERPRETATION: 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. FUNDING: National Institutes of Health.
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