• Martine Hoogman, Janita Bralten, Derrek P Hibar, Maarten Mennes, Marcel P Zwiers, Lizanne S J Schweren, van Hulzen Kimm J E KJE Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands; Donders Institute for Brain, Cognition and Behaviour, Nijm, Sarah E Medland, Elena Shumskaya, Neda Jahanshad, Patrick de Zeeuw, Eszter Szekely, Gustavo Sudre, Thomas Wolfers, Alberdingk M H Onnink, Janneke T Dammers, Jeanette C Mostert, Yolanda Vives-Gilabert, Gregor Kohls, Eileen Oberwelland, Jochen Seitz, Martin Schulte-Rüther, Sara Ambrosino, Alysa E Doyle, Marie F Høvik, Margaretha Dramsdahl, Leanne Tamm, van Erp Theo G M TGM Department of Psychiatry and Human Behavior, University of California, Irvine, CA, USA., Anders Dale, Andrew Schork, Annette Conzelmann, Kathrin Zierhut, Ramona Baur, Hazel McCarthy, Yuliya N Yoncheva, Ana Cubillo, Kaylita Chantiluke, Mitul A Mehta, Yannis Paloyelis, Sarah Hohmann, Sarah Baumeister, Ivanei Bramati, Paulo Mattos, Fernanda Tovar-Moll, Pamela Douglas, Tobias Banaschewski, Daniel Brandeis, Jonna Kuntsi, Philip Asherson, Katya Rubia, Clare Kelly, Martino Adriana Di AD The Child Study Center at NYU Langone Medical Center, New York, NY, USA., Michael P Milham, Francisco X Castellanos, Thomas Frodl, Mariam Zentis, Klaus-Peter Lesch, Andreas Reif, Paul Pauli, Terry L Jernigan, Jan Haavik, Kerstin J Plessen, Astri J Lundervold, Kenneth Hugdahl, Larry J Seidman, Joseph Biederman, Nanda Rommelse, Dirk J Heslenfeld, Catharina A Hartman, Pieter J Hoekstra, Jaap Oosterlaan, Polier Georg von GV Child Neuropsychology Section, University Hospital Aachen, Aachen, Germany., Kerstin Konrad, Oscar Vilarroya, Josep Antoni Ramos-Quiroga, Joan Carles Soliva, Sarah Durston, Jan K Buitelaar, Stephen V Faraone, Philip Shaw, Paul M Thompson, and Barbara Franke.
• 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.
• Lancet Psychiatry. 2017 Apr 1; 4 (4): 310-319.

BackgroundNeuroimaging 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.MethodsIn 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.FindingsOur 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).InterpretationWith 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.FundingNational Institutes of Health.Copyright © 2017 Elsevier Ltd. All rights reserved.

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