Voxel-based morphometry analysis reveals frontal brain differences in participants with ADHD and their unaffected siblings

Voxel-based morphometry analysis reveals frontal brain differences in participants with ADHD and their unaffected siblings

PDF | Appendix

J Psychiatry Neurosci 2016;41(4):272-279

Janita Bralten, PhD*; Corina U. Greven, PhD*; Barbara Franke, PhD; Maarten Mennes, PhD; Marcel P. Zwiers, PhD; Nanda N.J. Rommelse, PhD; Catharina Hartman, PhD; Dennis van der Meer, MS; Laurence O’Dwyer, PhD; Jaap Oosterlaan, MD, PhD; Pieter J. Hoekstra, PhD; Dirk Heslenfeld, PhD; Alejandro Arias-Vasquez, PhD; Jan K. Buitelaar, MD, PhD


Background: Data on structural brain alterations in patients with attention-deficit/hyperactivity disorder (ADHD) have been inconsistent. Both ADHD and brain volumes have a strong genetic loading, but whether brain alterations in patients with ADHD are familial has been underexplored. We aimed to detect structural brain alterations in adolescents and young adults with ADHD compared with healthy controls. We examined whether these alterations were also found in their unaffected siblings, using a uniquely large sample.

Methods: We performed voxel-based morphometry analyses on MRI scans of patients with ADHD, their unaffected siblings and typically developing controls. We identified brain areas that differed between participants with ADHD and controls and investigated whether these areas were different in unaffected siblings. Influences of medication use, age, sex and IQ were considered.

Results: Our sample included 307 patients with ADHD, 169 unaffected siblings and 196 typically developing controls (mean age 17.2 [range 8–30] yr). Compared with controls, participants with ADHD had significantly smaller grey matter volume in 5 clusters located in the precentral gyrus, medial and orbitofrontal cortex, and (para)cingulate cortices. Unaffected siblings showed intermediate volumes significantly different from controls in 4 of these clusters (all except the precentral gyrus). Medication use, age, sex and IQ did not have an undue influence on the results.

Limitations: Our sample was heterogeneous, most participants with ADHD were taking medication, and the comparison was cross-sectional.

Conclusion: Brain areas involved in decision making, motivation, cognitive control and motor functioning were smaller in participants with ADHD than in controls. Investigation of unaffected siblings indicated familiality of 4 of the structural brain differences, supporting their potential in molecular genetic analyses in ADHD research.

*These authors contributed equally to this work.

Submitted Dec. 16, 2014; Revised May 28, 2015; Accepted Sept. 2, 2015; Early-released Dec. 15, 2015

Acknowledgements: The authors thank all the parents, teachers and children who participated in the study. Funding support for the IMAGE project was provided by the National Institutes of Health grants R01MH62873 and R01MH081803. The NeuroIMAGE project was supported by NWO Large Investment Grant 1750102007010, ZonMW Grant 60-60600-97-193 and NWO Brain and Cognition grant 433-09-242 to J. Buitelaar, funding from the European Community‘s Seventh Framework Programme (FP7/2007–2013) under grant agreement n° 305697, the EU FP7 grant TACTICS (grantnr 278948), and grants from Radboud university medical center, University Medical Center Groningen and Accare, and VU University Amsterdam. The research described here also received funding from the National Institutes of Health (NIH) Consortium grant U54 EB020403, supported by a cross-NIH alliance that funds Big Data to Knowledge Centers of Excellence.

Affiliations: From the Departments of Human Genetics (Bralten, Franke, Arias-Vasquez), Cognitive Neuroscience (Bralten, Greven, Mennes, Zwiers, O’Dwyer, Buitelaar) and Psychiatry (Franke), Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands; the Karakter Child and Adolescent Psychiatry University Center, Nijmegen, the Netherlands (Greven, Rommelse, Buitelaar); the Institute of Psychiatry, Social Genetic and Developmental Psychiatry Centre, King’s College London, London, UK (Greven); the Department of Psychiatry (Rommelse) and Genetics (Arias-Vasquez), Radboud University Medical Center, Nijmegen, the Netherlands; the Department of Psychiatry, University Medical Center Groningen, Groningen, the Netherlands (Hartman, van der Meer, Hoekstra); and the Departments of Clinical Neuropsychology (Oosterlaan) and Neuropsychiatry (Heslenfeld), VU University, Amsterdam, the Netherlands.

Competing interests: J. Oosterlaan has received an unrestricted grant from Shire outside the submitted work. P. Hoekstra has received honoraria from Eli Lilly and Shire and an unrestricted research grant from Shire outside the submitted work. He also declares serving on the advisory board of Shire. J. Buitelaar declares consulting for, serving on the advisory board of and receiving speaker fees from Janssen Cilag BV, Eli Lilly, Bristol-Myer Squibb, Shering Plough, UCB, Shire, Novartis and Servier. No other competing interests declared.

Contributors: J. Bralten, C. Greven, B. Franke, M. Mennes, M. Zwiers, C. Hartman, J. Oosterlaan, D. Heslenfeld, A. Arias-Vasquez and J. Buitelaar designed the study. N. Rommelse was one of the people who acquired the data, which J. Bralten, C. Greven, B. Franke, M. Mennes, M. Zwiers, D. van der Meer, L. O’Dwyer, P. Hoekstra and J. Buitelaar analyzed. J. Bralten, C. Greven, M. Mennes, N. Rommelse and A. Arias-Vasquez wrote the article, which all authors reviewed and approved for publication.

DOI: 10.1503/jpn.140377

Correspondence to: J. Buitelaar, Department of Cognitive Neuroscience (126), Radboud University Medical center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands; Jan.Buitelaar@radboudumc.nl