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, 176 (7), 531-542

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

Martine Hoogman  1 Ryan Muetzel  1 Joao P Guimaraes  1 Elena Shumskaya  1 Maarten Mennes  1 Marcel P Zwiers  1 Neda Jahanshad  1 Gustavo Sudre  1 Thomas Wolfers  1 Eric A Earl  1 Juan Carlos Soliva Vila  1 Yolanda Vives-Gilabert  1 Sabin Khadka  1 Stephanie E Novotny  1 Catharina A Hartman  1 Dirk J Heslenfeld  1 Lizanne J S Schweren  1 Sara Ambrosino  1 Bob Oranje  1 Patrick de Zeeuw  1 Tiffany M Chaim-Avancini  1 Pedro G P Rosa  1 Marcus V Zanetti  1 Charles B Malpas  1 Gregor Kohls  1 Georg G von Polier  1 Jochen Seitz  1 Joseph Biederman  1 Alysa E Doyle  1 Anders M Dale  1 Theo G M van Erp  1 Jeffery N Epstein  1 Terry L Jernigan  1 Ramona Baur-Streubel  1 Georg C Ziegler  1 Kathrin C Zierhut  1 Anouk Schrantee  1 Marie F Høvik  1 Astri J Lundervold  1 Clare Kelly  1 Hazel McCarthy  1 Norbert Skokauskas  1 Ruth L O'Gorman Tuura  1 Anna Calvo  1 Sara Lera-Miguel  1 Rosa Nicolau  1 Kaylita C Chantiluke  1 Anastasia Christakou  1 Alasdair Vance  1 Mara Cercignani  1 Matt C Gabel  1 Philip Asherson  1 Sarah Baumeister  1 Daniel Brandeis  1 Sarah Hohmann  1 Ivanei E Bramati  1 Fernanda Tovar-Moll  1 Andreas J Fallgatter  1 Bernd Kardatzki  1 Lena Schwarz  1 Anatoly Anikin  1 Alexandr Baranov  1 Tinatin Gogberashvili  1 Dmitry Kapilushniy  1 Anastasia Solovieva  1 Hanan El Marroun  1 Tonya White  1 Georgii Karkashadze  1 Leyla Namazova-Baranova  1 Thomas Ethofer  1 Paulo Mattos  1 Tobias Banaschewski  1 David Coghill  1 Kerstin J Plessen  1 Jonna Kuntsi  1 Mitul A Mehta  1 Yannis Paloyelis  1 Neil A Harrison  1 Mark A Bellgrove  1 Tim J Silk  1 Ana I Cubillo  1 Katya Rubia  1 Luisa Lazaro  1 Silvia Brem  1 Susanne Walitza  1 Thomas Frodl  1 Mariam Zentis  1 Francisco X Castellanos  1 Yuliya N Yoncheva  1 Jan Haavik  1 Liesbeth Reneman  1 Annette Conzelmann  1 Klaus-Peter Lesch  1 Paul Pauli  1 Andreas Reif  1 Leanne Tamm  1 Kerstin Konrad  1 Eileen Oberwelland Weiss  1 Geraldo F Busatto  1 Mario R Louza  1 Sarah Durston  1 Pieter J Hoekstra  1 Jaap Oosterlaan  1 Michael C Stevens  1 J Antoni Ramos-Quiroga  1 Oscar Vilarroya  1 Damien A Fair  1 Joel T Nigg  1 Paul M Thompson  1 Jan K Buitelaar  1 Stephen V Faraone  1 Philip Shaw  1 Henning Tiemeier  1 Janita Bralten  1 Barbara Franke  1

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

Martine Hoogman et al. Am J Psychiatry.


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.

Conflict of interest statement

Potential conflict of Interest and financial support

These authors all declare no conflicts of Interest:

Hoogman, Muetzel, Guimaraes, Shumskaya, Mennes, Zwiers, Jahanshad, Sudre, Mostert, Wolfers, Earl, Soliva Vila, Vives-Gilabert, Khadka, Novotny, Hartman, Heslenfeld, Schweren, Ambrosino, Oranje, de Zeeuw, Chaim-Avancini, Rosa, Zanetti, Malpas, Kohls, von Polier, Seitz, Doyle, Epstein, Jernigan, Baur-Streubel, Ziegler, Zierhut, Schrantee, Høvik, Lundervold, Kelly, McCarthy, Skokauskas, O'Gorman Tuura, Calvo, Lera-Miguel, Nicolau, Chantiluke, Christakou, Vance, Cercignani, Gabel, Asherson, Baumeister, Hohmann, Bramati, Tovar-Moll, Fallgatter, Kardatzki, Schwarz, Anikin, Baranov, Gogberashvili, Kapilushniy, Solovieva, El Marroun, White, Namazova-Baranova, Ethofer, Plessen, Mehta, Paloyelis, Harrison, Bellgrove, Silk, Cubillo, Lazaro, Brem, Frodl, Zentis, Castellanos, Yoncheva, Reneman, Conzelmann, Pauli, Reif, Tamm, Oberwelland Weiss, Busatto, Louza, Durston, Oosterlaan, Stevens, Vilarroya, Fair, Nigg, Thompson, Shaw, Tiemeier, Bralten.

Potential conflicts of interest for the following authors are reported:

David Coghill served in an advisory or consultancy role for Lilly, Medice, Novartis, Oxford outcomes, Shire and Viforpharma. He received conference support or speaker’s fee by Janssen McNeil, Lilly, Medice, Novartis, Shire and Sunovian. He is/has been involved in clinical trials conducted by Lilly & Shire. The present work is unrelated to the above grants and relationships.

Jonna Kuntsi has given talks at educational events sponsored by Medice; all funds are received by King’s College London and used for studies of ADHD.

Theo Van Erp consulted for Roche Pharmaceuticals and has a contract with Otsuka Pharmaceutical, Ltd.

Anders Dale is a Founder of CorTechs Labs, Inc. He serves on the Scientific Advisory Boards of CorTechs Labs and Human Longevity, Inc., and receives research funding through a Research Agreement with General Electric Healhcare.

Paulo Mattos was on the speakers’ bureau and/or acted as consultant for Janssen-Cilag, Novartis, and Shire in the previous five years; he also received travel awards to participate in scientific meetings from those companies. The ADHD outpatient program (Grupo de Estudos do Déficit de Atenção/Institute of Psychiatry) chaired by Dr. Mattos has also received research support from Novartis and Shire.The funding sources had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript.

Tobias Banaschewski served in an advisory or consultancy role for Actelion, Hexal Pharma, Lilly, Lundbeck, Medice, Neurim Pharmaceuticals, Novartis and Shire. He received conference support or speaker’s fee by Lilly, Medice, Novartis and Shire. He is/has been involved in clinical trials conducted by Shire & Viforpharma. He received royalities from Hogrefe, Kohlhammer, CIP Medien, Oxford University Press. The present work is unrelated to the above grants and relationships.

Katya Rubia received speaker's fees form Shire, Medice and a grant from Lilly for another project.

Jan Haavik has received speaker fees from Lilly, Novartis and Janssen Cilag.

Stephen V. Faraone, in the past year, received income, potential income, travel expenses continuing education support and/or research support from Tris, Otsuka, Arbor, Ironshore, Shire, Akili Interactive Labs, VAYA, Ironshore, Sunovion, Supernus and Genomind. With his institution, he has US patent US20130217707 A1 for the use of sodium-hydrogen exchange inhibitors in the treatment of ADHD.

Joseph Biederman is currently receiving research support from the following sources: The Department of Defense, Food & Drug Administration, Ironshore, Lundbeck, Magceutics Inc., Merck, PamLab, Pfizer, Shire Pharmaceuticals Inc., SPRITES, Sunovion, Vaya Pharma/Enzymotec, and NIH. In 2015, Dr. Joseph Biederman received honoraria from the MGH Psychiatry Academy for tuition-funded CME courses. He has a US Patent Application pending (Provisional Number #61/233,686) through MGH corporate licensing, on a method to prevent stimulant abuse. In 2014, Dr. Joseph Biederman received honoraria from the MGH Psychiatry Academy for tuition-funded CME courses. He received research support from AACAP, Alcobra, Forest Research Institute, and Shire Pharmaceuticals Inc. Dr. Biederman received departmental royalties from a copyrighted rating scale used for ADHD diagnoses, paid by Ingenix, Prophase, Shire, Bracket Global, Sunovion, and Theravance; these royalties were paid to the Department of Psychiatry at MGH.

Kerstin Konrad received speaking fees from Medice, Lilly and Shire.

Josep-Antoni Ramos-Quiroga Josep-Antoni Ramos-Quiroga was on the speakers’ bureau and/or acted as consultant for Eli-Lilly, Janssen-Cilag, Novartis, Shire, Lundbeck, Almirall, Braingaze, Sincrolab, Medice and Rubió in the last 5 years. He also received travel awards (air tickets + hotel) for taking part in psychiatric meetings from Janssen-Cilag, Medice, Rubió, Shire, and Eli- Lilly. The Department of Psychiatry chaired by him received unrestricted educational and research support from the following companies in the last 5 years: Eli-Lilly, Lundbeck, Janssen- Cilag, Actelion, Shire, Ferrer, Oryzon, Roche, Psious, and Rubió.

Klaus-Peter Lesch served as a speaker for Eli Lilly and received research support from Medice, and travel support from Shire, all outside the submitted work.

Pieter Hoekstra received a research grant from Shire and was part of the advisory board of Shire.

Jan Buitelaar has been in the past 3 years a consultant to / member of advisory board of / and/or speaker for Janssen Cilag BV, Eli Lilly, Medice, Shire, Roche, and Servier. He is not an employee of any of these companies, and not a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, royalties.

Barbara Franke has received educational speaking fees from Shire and Medice.

Susanne Walitza has received lecture honoraria from Eli-Lilly, Opopharma in the last five years and her outside professional activities and interests are declared under the link of the University of Zurich

Daniel Brandeis serves as an unpaid scientific consultant for an EU-funded neurofeedback trial.

Georgii Karkashadze received payment for the authorship of the article and speaker fees from Sanofi and from Pikfarma.

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