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, 4 (4), 310-319

Subcortical Brain Volume Differences in Participants With Attention Deficit Hyperactivity Disorder in Children and Adults: A Cross-Sectional Mega-Analysis

Martine Hoogman  1 Janita Bralten  2 Derrek P Hibar  3 Maarten Mennes  4 Marcel P Zwiers  4 Lizanne S J Schweren  5 Kimm J E van Hulzen  2 Sarah E Medland  6 Elena Shumskaya  2 Neda Jahanshad  3 Patrick de Zeeuw  7 Eszter Szekely  8 Gustavo Sudre  8 Thomas Wolfers  2 Alberdingk M H Onnink  2 Janneke T Dammers  9 Jeanette C Mostert  2 Yolanda Vives-Gilabert  10 Gregor Kohls  11 Eileen Oberwelland  12 Jochen Seitz  13 Martin Schulte-Rüther  12 Sara Ambrosino  7 Alysa E Doyle  14 Marie F Høvik  15 Margaretha Dramsdahl  16 Leanne Tamm  17 Theo G M van Erp  18 Anders Dale  19 Andrew Schork  20 Annette Conzelmann  21 Kathrin Zierhut  22 Ramona Baur  23 Hazel McCarthy  24 Yuliya N Yoncheva  25 Ana Cubillo  26 Kaylita Chantiluke  26 Mitul A Mehta  27 Yannis Paloyelis  27 Sarah Hohmann  28 Sarah Baumeister  28 Ivanei Bramati  29 Paulo Mattos  30 Fernanda Tovar-Moll  31 Pamela Douglas  32 Tobias Banaschewski  28 Daniel Brandeis  33 Jonna Kuntsi  34 Philip Asherson  34 Katya Rubia  26 Clare Kelly  35 Adriana Di Martino  25 Michael P Milham  36 Francisco X Castellanos  37 Thomas Frodl  38 Mariam Zentis  39 Klaus-Peter Lesch  40 Andreas Reif  41 Paul Pauli  23 Terry L Jernigan  42 Jan Haavik  43 Kerstin J Plessen  44 Astri J Lundervold  45 Kenneth Hugdahl  46 Larry J Seidman  47 Joseph Biederman  48 Nanda Rommelse  49 Dirk J Heslenfeld  50 Catharina A Hartman  5 Pieter J Hoekstra  5 Jaap Oosterlaan  51 Georg von Polier  11 Kerstin Konrad  11 Oscar Vilarroya  52 Josep Antoni Ramos-Quiroga  53 Joan Carles Soliva  54 Sarah Durston  7 Jan K Buitelaar  55 Stephen V Faraone  56 Philip Shaw  57 Paul M Thompson  3 Barbara Franke  58

Subcortical Brain Volume Differences in Participants With Attention Deficit Hyperactivity Disorder in Children and Adults: A Cross-Sectional Mega-Analysis

Martine Hoogman et al. Lancet Psychiatry.


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.


Displayed are the Cohens d effect sizes of differences between patients with ADHD and healthy controlsfor subcortical volumes and ICV, for 4 separate groups:1.) all subjects, 2.) children only (<15years), 3.) adolescents only (15–21 years), and 4.) adults only (>21 years). *significant after false discovery rate (FDR) correction; nominal significant at p<0.05
Displayed are the moving averages, corrected for age, sex, ICV and site for the subcortical volumes.

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