Analysis of structural brain asymmetries in attention-deficit/hyperactivity disorder in 39 datasets

ENIGMA ADHD working group

Research output: Contribution to journalArticlepeer-review


Objective: Some studies have suggested alterations of structural brain asymmetry in attention-deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small samples. Here, we performed the largest ever analysis of brain left-right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium. Methods: We analyzed asymmetry of subcortical and cerebral cortical structures in up to 1,933 people with ADHD and 1,829 unaffected controls. Asymmetry Indexes (AIs) were calculated per participant for each bilaterally paired measure, and linear mixed effects modeling was applied separately in children, adolescents, adults, and the total sample, to test exhaustively for potential associations of ADHD with structural brain asymmetries. Results: There was no evidence for altered caudate nucleus asymmetry in ADHD, in contrast to prior literature. In children, there was less rightward asymmetry of the total hemispheric surface area compared to controls (t = 2.1, p =.04). Lower rightward asymmetry of medial orbitofrontal cortex surface area in ADHD (t = 2.7, p =.01) was similar to a recent finding for autism spectrum disorder. There were also some differences in cortical thickness asymmetry across age groups. In adults with ADHD, globus pallidus asymmetry was altered compared to those without ADHD. However, all effects were small (Cohen’s d from −0.18 to 0.18) and would not survive study-wide correction for multiple testing. Conclusion: Prior studies of altered structural brain asymmetry in ADHD were likely underpowered to detect the small effects reported here. Altered structural asymmetry is unlikely to provide a useful biomarker for ADHD, but may provide neurobiological insights into the trait.

Original languageEnglish (US)
JournalJournal of Child Psychology and Psychiatry and Allied Disciplines
StateAccepted/In press - 2021
Externally publishedYes

Bibliographical note

Funding Information:
Mr. Earl is co‐inventor of the Oregon Health and Science University Technology #2198 (co‐owned with Washington University in St. Louis), FIRMM: Real time monitoring and prediction of motion in MRI scans, exclusively licensed to Nous, Inc.) and any related research. Any potential conflict of interest has been reviewed and managed by OHSU. Dr. Biederman has received research support from AACAP, Alcobra, the Feinstein Institute for Medical Research, the Forest Research Institute, Genentech, Headspace, Ironshore, Lundbeck AS, Magceutics, Merck, Neurocentria, NIDA, NIH, PamLab, Pfizer, Roche TCRC, Shire, SPRITES, Sunovion, the U.S. Department of Defense, the U.S. Food and Drug Administration, and Vaya Pharma/Enzymotec; he has served as a consultant or on scientific advisory boards for Aevi Genomics, Akili, Alcobra, Arbor Pharmaceuticals, Guidepoint, Ironshore, Jazz Pharma, Medgenics, Piper Jaffray, and Shire; he has received honoraria from Alcobra, the American Professional Society of ADHD and Related Disorders, and the MGH Psychiatry Academy for tuition‐funded CME courses; he has a financial interest in Avekshan, a company that develops treatments for ADHD; he has a U.S. patent application pending (Provisional Number #61/233,686) through MGH corporate licensing, on a method to prevent stimulant abuse; and his program has received royalties from a copyrighted rating scale used for ADHD diagnoses, paid to the Department of Psychiatry at Massachusetts General Hospital by Ingenix, Prophase, Shire, Bracket Global, Sunovion, and Theravance. Dr. Van Erp has served as consultant for Roche Pharmaceuticals and has a contract with Otsuka Pharmaceutical, Ltd. Dr. Gabel has received funding from the Motor Neurone Disease Association. Dr. Asherson has served as a consultant and as a speaker at sponsored events for Eli Lilly, Novartis, and Shire, and he has received educational/research awards from Eli Lilly, GW Pharma, Novartis, QbTech, Shire, and Vifor Pharma. Dr. Brandeis has served as an unpaid scientific consultant for an EU‐funded neurofeedback trial. Dr. Karkashadze has received payment for article authorship and speaking fees from Sanofi and from Pikfarma. Dr. Mattos has served on speakers’ bureau and/or as a consultant for Janssen‐Cilag, Novartis, and Shire and has received travel awards from those companies to participate in scientific meetings; the ADHD outpatient program (Grupo de Estudos do Déficit de Atenção/Institute of Psychiatry) chaired by Dr. Mattos also received research support from Novartis and Shire. Dr. Banaschewski served in an advisory or consultancy role for Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg GmbH, Shire, and Infectopharm. He received conference support or speaker’s fee from Lilly, Medice, and Shire. He received royalties from Hogrefe, Kohlhammer, CIP Medien, Oxford University Press; the present work is unrelated to these relationships. Dr. Paloyelis has received an unrestricted research grant from PARI GmbH. Dr. Coghill has served in an advisory or consultancy role for Eli Lilly, Medice, Novartis, Oxford Outcomes, Shire, and Vifor Pharma; he has received conference support or speaking fees from Eli Lilly, Janssen McNeil, Medice, Novartis, Shire, and Sunovion; and he has been involved in clinical trials conducted by Eli Lilly and Shire. Dr. Kuntsi has received speaking honoraria and advisory panel payments for participation at educational events sponsored by Medice; all funds are received by King’s College London and used for studies of ADHD. Dr. Mehta has received research funding from Lundbeck, Shire, and Takeda and has served on advisory boards for Lundbeck and Autifony. Dr. Harrison has received research funding from Janssen Pharmaceuticals. Dr. Bellgrove has received speaking fees and travel support from Shire. Dr. Rubia has received a grants from Eli Lilly/Takeda pharmaceuticals for another project. Dr. Walitza has received lecture honoraria from Eli Lilly and OpoPharma, support from the Hartmann Müller, Olga Mayenfisch, and Gertrud Thalmann foundations, and royalties from Beltz, Hogrefe, Kohlhammer, Springer, and Thieme. Dr. Haavik has received speaking fees from Biocodex, Eli Lilly, HB Pharma, Janssen‐Cilag, Medice, Novartis, and Shire. Dr. Lesch has served as a speaker for Eli Lilly and has received research support from Medice and travel support from Shire. Dr. Reif has received honoraria for serving as speaking or on advisory boards for Janssen, Medice, Neuraxpharm, Servier and Shire. Dr. Konrad has received speaking fees from Eli Lilly, Medice, and Shire. Dr. Hoekstra served on the advisory board for Shire. Dr. Ramos‐Quiroga has served on the speakers bureaus and/or as a consultant for Almirall, Braingaze, Eli Lilly, Janssen‐Cilag, Lundbeck, Medice, Novartis, Shire, Takeda, Shionogui, Bial, Sincrolab, and Rubió; he has received travel awards for taking part in psychiatric meetings from Eli Lilly, Janssen‐Cilag, Medice, Rubió, and Shire, Takeda, Bial, Shionogui; and the Department of Psychiatry chaired by him has received unrestricted educational and research support from Actelion, Eli Lilly, Ferrer, Janssen‐Cilag, Lundbeck, Oryzon, Psious, Roche, Rubió, and Shire. Dr. Fair is a founder of Nous Imaging, Inc.; any potential conflicts of interest are being reviewed and managed by OHSU. Dr. Thompson has received funding support from Biogen. Dr. Buitelaar has served as a consultant, advisory board member, and/or speaker for Eli Lilly, JanssenCilag, Medice, Roche, Takeda/Shire, Angelini, and Servier. Dr. Faraone has received income, potential income, travel expenses, continuing education support, and/or research support from Akili Interactive Labs, Alcobra, Arbor, Enzymotec, Genomind, Ironshore, Janssen, KemPharm, McNeil, Neurolifesciences, NeuroVance, Novartis, Otsuka, Pfizer, Rhodes, Shire/Takeda, Sunovion, Supernus, Tris, and Medice; he receives royalties from Elsevier, Guilford Press, and Oxford University Press; he is principal investigator of ; and, with his institution, he holds U.S. patent US20130217707 A1 for the use of sodium‐hydrogen exchange inhibitors in the treatment of ADHD. Dr. Franke has received educational speaking fees from Shire and Medice All remaining authors reported no biomedical financial interests or potential conflicts of interests. Open Access funding enabled and organized by Projekt DEAL. Key points .

Publisher Copyright:
© 2021 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.


  • Attention-deficit
  • brain asymmetry
  • brain laterality
  • hyperactivity disorder
  • large-scale data
  • structural MRI


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