Subcortical brain volume differences in participants with attention deficit hyperactivity disorder in children and adults: a cross-sectional mega-analysis

Martine Hoogman, Janita Bralten, Derrek P. Hibar, Maarten Mennes, Marcel P. Zwiers, Lizanne S.J. Schweren, Kimm J.E. van Hulzen, 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 & 62 others Jochen Seitz, Martin Schulte-Rüther, Sara Ambrosino, Alysa E. Doyle, Marie F. Høvik, Margaretha Dramsdahl, Leanne Tamm, Theo G.M. van Erp, 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, Adriana Di Martino, 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, Georg von Polier, Kerstin Konrad, Oscar Vilarroya, Josep Antoni Ramos-Quiroga, Joan Carles Soliva, Sarah Durston, Jan K. Buitelaar, Stephen V. Faraone, Philip Shaw, Paul M. Thompson, Barbara Franke

Research output: Contribution to JournalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)310-319
Number of pages10
JournalThe Lancet Psychiatry
Volume4
Issue number4
DOIs
Publication statusPublished - 2017

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Attention Deficit Disorder with Hyperactivity
Cross-Sectional Studies
Brain
Amygdala
Hippocampus
Globus Pallidus
Putamen
Thalamus
Meta-Analysis
National Institutes of Health (U.S.)
Neuroimaging
Sample Size
Psychiatry
Longitudinal Studies
Magnetic Resonance Imaging
Phenotype

Cite this

Hoogman, Martine ; Bralten, Janita ; Hibar, Derrek P. ; Mennes, Maarten ; Zwiers, Marcel P. ; Schweren, Lizanne S.J. ; van Hulzen, Kimm J.E. ; Medland, Sarah E. ; Shumskaya, Elena ; Jahanshad, Neda ; Zeeuw, Patrick de ; Szekely, Eszter ; Sudre, Gustavo ; Wolfers, Thomas ; Onnink, Alberdingk M.H. ; Dammers, Janneke T. ; Mostert, Jeanette C. ; Vives-Gilabert, Yolanda ; Kohls, Gregor ; Oberwelland, Eileen ; Seitz, Jochen ; Schulte-Rüther, Martin ; Ambrosino, Sara ; Doyle, Alysa E. ; Høvik, Marie F. ; Dramsdahl, Margaretha ; Tamm, Leanne ; van Erp, Theo G.M. ; Dale, Anders ; Schork, Andrew ; Conzelmann, Annette ; Zierhut, Kathrin ; Baur, Ramona ; McCarthy, Hazel ; Yoncheva, Yuliya N. ; Cubillo, Ana ; Chantiluke, Kaylita ; Mehta, Mitul A. ; Paloyelis, Yannis ; Hohmann, Sarah ; Baumeister, Sarah ; Bramati, Ivanei ; Mattos, Paulo ; Tovar-Moll, Fernanda ; Douglas, Pamela ; Banaschewski, Tobias ; Brandeis, Daniel ; Kuntsi, Jonna ; Asherson, Philip ; Rubia, Katya ; Kelly, Clare ; Martino, Adriana Di ; Milham, Michael P. ; Castellanos, Francisco X. ; Frodl, Thomas ; Zentis, Mariam ; Lesch, Klaus Peter ; Reif, Andreas ; Pauli, Paul ; Jernigan, Terry L. ; Haavik, Jan ; Plessen, Kerstin J. ; Lundervold, Astri J. ; Hugdahl, Kenneth ; Seidman, Larry J. ; Biederman, Joseph ; Rommelse, Nanda ; Heslenfeld, Dirk J. ; Hartman, Catharina A. ; Hoekstra, Pieter J. ; Oosterlaan, Jaap ; Polier, Georg von ; Konrad, Kerstin ; Vilarroya, Oscar ; Ramos-Quiroga, Josep Antoni ; Soliva, Joan Carles ; Durston, Sarah ; Buitelaar, Jan K. ; Faraone, Stephen V. ; Shaw, Philip ; Thompson, Paul M. ; Franke, Barbara. / Subcortical brain volume differences in participants with attention deficit hyperactivity disorder in children and adults: a cross-sectional mega-analysis. In: The Lancet Psychiatry. 2017 ; Vol. 4, No. 4. pp. 310-319.
@article{e930ab8e517e4a74a037bffee5693f1f,
title = "Subcortical brain volume differences in participants with attention deficit hyperactivity disorder in children and adults: a cross-sectional mega-analysis",
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.",
author = "Martine Hoogman and Janita Bralten and Hibar, {Derrek P.} and Maarten Mennes and Zwiers, {Marcel P.} and Schweren, {Lizanne S.J.} and {van Hulzen}, {Kimm J.E.} and Medland, {Sarah E.} and Elena Shumskaya and Neda Jahanshad and Zeeuw, {Patrick de} and Eszter Szekely and Gustavo Sudre and Thomas Wolfers and Onnink, {Alberdingk M.H.} and Dammers, {Janneke T.} and Mostert, {Jeanette C.} and Yolanda Vives-Gilabert and Gregor Kohls and Eileen Oberwelland and Jochen Seitz and Martin Schulte-R{\"u}ther and Sara Ambrosino and Doyle, {Alysa E.} and H{\o}vik, {Marie F.} and Margaretha Dramsdahl and Leanne Tamm and {van Erp}, {Theo G.M.} and Anders Dale and Andrew Schork and Annette Conzelmann and Kathrin Zierhut and Ramona Baur and Hazel McCarthy and Yoncheva, {Yuliya N.} and Ana Cubillo and Kaylita Chantiluke and Mehta, {Mitul A.} and Yannis Paloyelis and Sarah Hohmann and Sarah Baumeister and Ivanei Bramati and Paulo Mattos and Fernanda Tovar-Moll and Pamela Douglas and Tobias Banaschewski and Daniel Brandeis and Jonna Kuntsi and Philip Asherson and Katya Rubia and Clare Kelly and Martino, {Adriana Di} and Milham, {Michael P.} and Castellanos, {Francisco X.} and Thomas Frodl and Mariam Zentis and Lesch, {Klaus Peter} and Andreas Reif and Paul Pauli and Jernigan, {Terry L.} and Jan Haavik and Plessen, {Kerstin J.} and Lundervold, {Astri J.} and Kenneth Hugdahl and Seidman, {Larry J.} and Joseph Biederman and Nanda Rommelse and Heslenfeld, {Dirk J.} and Hartman, {Catharina A.} and Hoekstra, {Pieter J.} and Jaap Oosterlaan and Polier, {Georg von} and Kerstin Konrad and Oscar Vilarroya and Ramos-Quiroga, {Josep Antoni} and Soliva, {Joan Carles} and Sarah Durston and Buitelaar, {Jan K.} and Faraone, {Stephen V.} and Philip Shaw and Thompson, {Paul M.} and Barbara Franke",
year = "2017",
doi = "10.1016/S2215-0366(17)30049-4",
language = "English",
volume = "4",
pages = "310--319",
journal = "Lancet psychiatry",
issn = "2215-0374",
publisher = "Elsevier Limited",
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Hoogman, M, Bralten, J, Hibar, DP, Mennes, M, Zwiers, MP, Schweren, LSJ, van Hulzen, KJE, Medland, SE, Shumskaya, E, Jahanshad, N, Zeeuw, PD, Szekely, E, Sudre, G, Wolfers, T, Onnink, AMH, Dammers, JT, Mostert, JC, Vives-Gilabert, Y, Kohls, G, Oberwelland, E, Seitz, J, Schulte-Rüther, M, Ambrosino, S, Doyle, AE, Høvik, MF, Dramsdahl, M, Tamm, L, van Erp, TGM, Dale, A, Schork, A, Conzelmann, A, Zierhut, K, Baur, R, McCarthy, H, Yoncheva, YN, Cubillo, A, Chantiluke, K, Mehta, MA, Paloyelis, Y, Hohmann, S, Baumeister, S, Bramati, I, Mattos, P, Tovar-Moll, F, Douglas, P, Banaschewski, T, Brandeis, D, Kuntsi, J, Asherson, P, Rubia, K, Kelly, C, Martino, AD, Milham, MP, Castellanos, FX, Frodl, T, Zentis, M, Lesch, KP, Reif, A, Pauli, P, Jernigan, TL, Haavik, J, Plessen, KJ, Lundervold, AJ, Hugdahl, K, Seidman, LJ, Biederman, J, Rommelse, N, Heslenfeld, DJ, Hartman, CA, Hoekstra, PJ, Oosterlaan, J, Polier, GV, Konrad, K, Vilarroya, O, Ramos-Quiroga, JA, Soliva, JC, Durston, S, Buitelaar, JK, Faraone, SV, Shaw, P, Thompson, PM & Franke, B 2017, 'Subcortical brain volume differences in participants with attention deficit hyperactivity disorder in children and adults: a cross-sectional mega-analysis' The Lancet Psychiatry, vol. 4, no. 4, pp. 310-319. https://doi.org/10.1016/S2215-0366(17)30049-4

Subcortical brain volume differences in participants with attention deficit hyperactivity disorder in children and adults: a cross-sectional mega-analysis. / Hoogman, Martine; Bralten, Janita; Hibar, Derrek P.; Mennes, Maarten; Zwiers, Marcel P.; Schweren, Lizanne S.J.; van Hulzen, Kimm J.E.; Medland, Sarah E.; Shumskaya, Elena; Jahanshad, Neda; Zeeuw, Patrick de; Szekely, Eszter; Sudre, Gustavo; Wolfers, Thomas; Onnink, Alberdingk M.H.; Dammers, Janneke T.; Mostert, Jeanette C.; Vives-Gilabert, Yolanda; Kohls, Gregor; Oberwelland, Eileen; Seitz, Jochen; Schulte-Rüther, Martin; Ambrosino, Sara; Doyle, Alysa E.; Høvik, Marie F.; Dramsdahl, Margaretha; Tamm, Leanne; van Erp, Theo G.M.; Dale, Anders; Schork, Andrew; Conzelmann, Annette; Zierhut, Kathrin; Baur, Ramona; McCarthy, Hazel; Yoncheva, Yuliya N.; Cubillo, Ana; Chantiluke, Kaylita; Mehta, Mitul A.; Paloyelis, Yannis; Hohmann, Sarah; Baumeister, Sarah; Bramati, Ivanei; Mattos, Paulo; Tovar-Moll, Fernanda; Douglas, Pamela; Banaschewski, Tobias; Brandeis, Daniel; Kuntsi, Jonna; Asherson, Philip; Rubia, Katya; Kelly, Clare; Martino, Adriana Di; Milham, Michael P.; Castellanos, Francisco X.; Frodl, Thomas; Zentis, Mariam; Lesch, Klaus Peter; Reif, Andreas; Pauli, Paul; Jernigan, Terry L.; Haavik, Jan; Plessen, Kerstin J.; Lundervold, Astri J.; Hugdahl, Kenneth; Seidman, Larry J.; Biederman, Joseph; Rommelse, Nanda; Heslenfeld, Dirk J.; Hartman, Catharina A.; Hoekstra, Pieter J.; Oosterlaan, Jaap; Polier, Georg von; Konrad, Kerstin; Vilarroya, Oscar; Ramos-Quiroga, Josep Antoni; Soliva, Joan Carles; Durston, Sarah; Buitelaar, Jan K.; Faraone, Stephen V.; Shaw, Philip; Thompson, Paul M.; Franke, Barbara.

In: The Lancet Psychiatry, Vol. 4, No. 4, 2017, p. 310-319.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - Subcortical brain volume differences in participants with attention deficit hyperactivity disorder in children and adults: a cross-sectional mega-analysis

AU - Hoogman, Martine

AU - Bralten, Janita

AU - Hibar, Derrek P.

AU - Mennes, Maarten

AU - Zwiers, Marcel P.

AU - Schweren, Lizanne S.J.

AU - van Hulzen, Kimm J.E.

AU - Medland, Sarah E.

AU - Shumskaya, Elena

AU - Jahanshad, Neda

AU - Zeeuw, Patrick de

AU - Szekely, Eszter

AU - Sudre, Gustavo

AU - Wolfers, Thomas

AU - Onnink, Alberdingk M.H.

AU - Dammers, Janneke T.

AU - Mostert, Jeanette C.

AU - Vives-Gilabert, Yolanda

AU - Kohls, Gregor

AU - Oberwelland, Eileen

AU - Seitz, Jochen

AU - Schulte-Rüther, Martin

AU - Ambrosino, Sara

AU - Doyle, Alysa E.

AU - Høvik, Marie F.

AU - Dramsdahl, Margaretha

AU - Tamm, Leanne

AU - van Erp, Theo G.M.

AU - Dale, Anders

AU - Schork, Andrew

AU - Conzelmann, Annette

AU - Zierhut, Kathrin

AU - Baur, Ramona

AU - McCarthy, Hazel

AU - Yoncheva, Yuliya N.

AU - Cubillo, Ana

AU - Chantiluke, Kaylita

AU - Mehta, Mitul A.

AU - Paloyelis, Yannis

AU - Hohmann, Sarah

AU - Baumeister, Sarah

AU - Bramati, Ivanei

AU - Mattos, Paulo

AU - Tovar-Moll, Fernanda

AU - Douglas, Pamela

AU - Banaschewski, Tobias

AU - Brandeis, Daniel

AU - Kuntsi, Jonna

AU - Asherson, Philip

AU - Rubia, Katya

AU - Kelly, Clare

AU - Martino, Adriana Di

AU - Milham, Michael P.

AU - Castellanos, Francisco X.

AU - Frodl, Thomas

AU - Zentis, Mariam

AU - Lesch, Klaus Peter

AU - Reif, Andreas

AU - Pauli, Paul

AU - Jernigan, Terry L.

AU - Haavik, Jan

AU - Plessen, Kerstin J.

AU - Lundervold, Astri J.

AU - Hugdahl, Kenneth

AU - Seidman, Larry J.

AU - Biederman, Joseph

AU - Rommelse, Nanda

AU - Heslenfeld, Dirk J.

AU - Hartman, Catharina A.

AU - Hoekstra, Pieter J.

AU - Oosterlaan, Jaap

AU - Polier, Georg von

AU - Konrad, Kerstin

AU - Vilarroya, Oscar

AU - Ramos-Quiroga, Josep Antoni

AU - Soliva, Joan Carles

AU - Durston, Sarah

AU - Buitelaar, Jan K.

AU - Faraone, Stephen V.

AU - Shaw, Philip

AU - Thompson, Paul M.

AU - Franke, Barbara

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=85012931344&partnerID=8YFLogxK

U2 - 10.1016/S2215-0366(17)30049-4

DO - 10.1016/S2215-0366(17)30049-4

M3 - Article

VL - 4

SP - 310

EP - 319

JO - Lancet psychiatry

JF - Lancet psychiatry

SN - 2215-0374

IS - 4

ER -