Voxel-based morphometry analysis reveals frontal brain differences in participants with ADHD and their unaffected siblings
Open accessAbstract
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.
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A second fronto-striatal circuit involving the nucleus accumbens and orbitofrontal cortex has been proposed to be associated with ADHD.
“a second fronto-striatal circuit involving the nucleus accumbens and orbitofrontal cortex has been proposed to be associated with ADHD (23–25).”
From Abnormal functional connectivity associated with emotional dysregulation in children with attention-deficit/hyperactivity disorder (2025) · cites this paper as [23]
The Discussion (page not provided) says that ADHD subtyping has been proposed based in part on an orbitofrontal–striatal circuit, supporting the proposed association with ADHD. It does not identify the nucleus accumbens as part of that circuit, and the study reports no structural differences in the corresponding subcortical regions. (LLM, conf=0.85)
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“Grey matter volume in the precentral gyrus, medial orbitofrontal cortex and (accessory) cingulate cortex was significantly smaller in ADHD patients [ 46 ].”
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Unimpaired social cognition in adult patients with ADHD: brain volumetric and behavioral results
Mehren, A., Thiel, C. M., Bruns, S., Philipsen, A., & Özyurt, J. (2021) · Social Cognitive and Affective Neuroscience · doi:10.1093/scan/nsab060 · Cited by 11 · see citing works
Sadat-Nejad, Y., Vandewouw, M. M., Cardy, R. E., Lerch, J. P., Taylor, M. J., Iaboni, A., Hammill, C. F., Syed, B., Brian, J. A., Kelley, E. A., et al. (2023) · Frontiers in Child and Adolescent Psychiatry · doi:10.3389/frcha.2023.1171337 · Cited by 8 · see citing works
Kalig-Amir, M., Berger, I., Rigbi, A., & Bar-Shalita, T. (2019) · Pediatric Research · doi:10.1038/s41390-019-0397-5 · Cited by 8 · see citing works
Novi, M., Paraskevopoulou, M. D., van Rooij, D., Schene, A. H., Buitelaar, J. K., & Schellekens, A. (2021) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2021.109032 · Cited by 8 · see citing works
Self-citationAtypical sulcal pattern in boys with attention‐deficit/hyperactivity disorder
Li, X., Wang, W., Wang, P., Hao, C.-R., & Li, Z. (2021) · Human Brain Mapping · doi:10.1002/hbm.25552 · Cited by 7 · see citing works
“Numerous studies using magnetic resonance imaging (MRI) have revealed an increasing number of ADHD-related brain structural and functional abnormalities.”
BackgroundInfluentialSex differences in neural correlates of common psychopathological symptoms in early adolescence
Biondo, F., Nymberg, C., Xu, B., Chu, C., Jia, T., Ing, A., Quinlan, E. B., Tay, N., Banaschewski, T., Bokde, A. L. W., et al. (2021) · Psychological Medicine · doi:10.1017/s0033291720005140 · Cited by 7 · see citing works
“Core abnormalities in the cingulum have been previously reported for individuals with ADHD (Bonath, Tegelbeckers, Wilke, Flechtner, & Krauel, 2018; Bralten et al., 2016; Bush et al., 1999; Dirlikov et al., 2015; Frodl & Skokauskas, 2012; Liddle et al., 2011; McLeod et al., 2014) including a…”
BackgroundDutta, C. N., Christov‐Moore, L., Ombao, H., & Douglas, P. K. (2022) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2022.938501 · Cited by 7 · see citing works
Fairchild, G. F., Sully, K., Passamonti, L., Staginnus, M., Darekar, A., Sonuga-Barke, E. J. S., & Toschi, N. (2021) · Psychological Medicine · doi:10.1017/s0033291721003202 · Cited by 6 · see citing works
Effects of the SNAP25 on Integration Ability of Brain Functions in Children With ADHD
Yang, Y., Peng, G., Zeng, H., Fang, D., Zhang, L., Xu, S., & Yang, B. (2020) · Journal of Attention Disorders · doi:10.1177/1087054720964561 · Cited by 7 · see citing works
Reduced fronto-striatal volume in ADHD in two cohorts across the lifespan
Cupertino, R., Soheili-Nezhad, S., Grevet, E., Bandeira, C., Picon, F., Tavares, M., Naaijen, J., van Rooij, D., Akkermans, S., Vitola, E., et al. (2019) · bioRxiv · doi:10.1101/790204 · Cited by 5 · see citing works
Self-citationBaboli, R., Wu, K., Halperin, J. M., & Li, X. (2025) · Biomedicines · doi:10.3390/biomedicines13030676 · Cited by 3 · see citing works
Gray matter networks associated with cognitive deficit in ADHD across adolescence and adulthood
Liu, J.-Y., Duan, K., Jiang, W., Rootes-Murdy, K., Schoenmacker, G., Buitelaar, J., Hoogman, M., Oosterlaan, J., Hoekstra, P., Heslenfeld, D., et al. (2020) · medRxiv · doi:10.1101/2020.04.22.20059808 · Cited by 4 · see citing works
Self-citationTürk, Y., Devecioğlu, İ., Küskün, A., Oge, C., Beyazyüz, E., & Albayrak, Y. (2023) · Psychiatry research. Neuroimaging · doi:10.1016/j.pscychresns.2023.111726 · Cited by 3 · see citing works
Zhang, H., Yang, B., Peng, G., Zhang, L., & Fang, D. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.785464 · Cited by 4 · see citing works
“In addition, other studies have found that the gray matter volume in the right precentral gyrus among children with ADHD is statistically significantly reduced as compared with neurotypical children (59).”
ResultRamos, A. A., Boaventura, V., Nascimento, A. A., Leite, L. L. R., & Machado, L. (2025) · Clinical Psychology Review · doi:10.1016/j.cpr.2025.102688 · Cited by 1 · see citing works
Shou, Q., Yamashita, M., Hirano, Y., Yao, A., Li, M., Wang, Y., Kato, Y., Yoshida, T., Matsumoto, K., Tsujikawa, T., et al. (2025) · Molecular Psychiatry · doi:10.1038/s41380-025-03142-6 · Cited by 3 · see citing works
“Reductions in the bilateral middle temporal gyrus and orbito-frontal cortex have been consistently reported [8, 12, 26, 27].”
Li, S., Luo, T., Wang, M., Situ, M., Liu, P., & Huang, Y. (2025) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2025.1700693 · Cited by 1 · see citing works
Tarlacı, S., & Çolak, A. (2026) · International Journal of Developmental Neuroscience · doi:10.1002/jdn.70093 · Cited by 1
“This finding supports the involvement of OFC-related reward and motivational mechanisms in attention regulation.”
InfluentialEs, T., Sprooten, E., Soheili-Nezhad, S., Damatac, C., Franke, B., Buitelaar, J., & Mota, N. (2022) · medRxiv · doi:10.1101/2022.06.16.22276110 · Cited by 1
“Alterations found in prefrontal gray matter, occipital gray matter, and inferior fronto-occipital fasciculus white matter were found not only in ADHD patients, but also in their unaffected siblings relative to controls (Bralten et al., 2016).”
BackgroundSelf-citationPersonality Is Reflected in Brain Morphometry
Petrosini, L., Cutuli, D., Picerni, E., & Laricchiuta, D. (2018) · Neuromethods · doi:10.1007/978-1-4939-7647-8_24 · Cited by 1 · see citing works
Salem, T., Harati, H., & Summaka, M. (2026) · Nordic Journal of Psychiatry · doi:10.1080/08039488.2026.2708719
“Additionally, Bratlen et al. (2016) [19] showed, through ‘voxel-based morphometry’ (VBM) analysis, that ADHD is associated with diminished volume of gray matter in the frontal and precentral regions, including the left precentral gyrus, medial and left orbitofrontal cortices, frontal pole,…”
Baboli, R., Martin, E., Qiu, Q., Zhao, L., Liu, T.-M., Wu, K., Gao, Y., & Li, X.-B. (2026) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2026.111966
“…frontal pole, medial frontal, and subcallosal cortices between adults with ADHD and their unaffected siblings, while Pironti et al., observed reduced inferior frontal volumes across both groups, pointing toward overlapping heritable substrates (Bralten et al., 2016, Pironti et al., 2014).”
Asymmetrical frontal–subcortical aberrations in ADHD: evidence for a developmental network model
Lee, T. (2026) · European Child & Adolescent Psychiatry · doi:10.1007/s00787-026-03034-2 · Cited by 1 · see citing works
Risk of traumatic brain injury among patients with ADHD and their unaffected siblings
Wu, P.-C., Tsai, S., Hsu, J.-W., Huang, K., Chen, T., Pan, T., & Chen, M. (2024) · Pediatric Research · doi:10.1038/s41390-024-03233-0 · Cited by 1 · see citing works
KloÌbl, M., Prillinger, K., Diehm, R., Doganay, K., Lanzenberger, R., Poustka, L., Plener, P., & Konicar, L. (2022) · medRxiv · doi:10.1101/2022.05.24.22275449
“In a large sample of children and young adults with ADHD, a reduction in gray matter volume was found in the precentral gyrus and several other regions (Bralten et al., 2016).”
BackgroundSu, S., Chen, Y.-Q., Dai, Y., Lin, L.-P., Qian, L., Zhou, Q., Zou, M.-S., Zhang, H., Liu, M.-N., Xiang, X., et al. (2021) · Research Square · doi:10.21203/rs.3.rs-349668/v1
Brain Magnetic Resonance Imaging in Attention-Deficit/Hyperactivity Disorder (ADHD)
Fayed, N. M., Morales, H., Torres, C., Fayed, A., & Rios, L. F. A. (2021) · Springer eBooks · doi:10.1007/978-3-030-61721-9_44 · Cited by 1 · see citing works
(2020) · Elsevier eBooks · doi:10.1016/b978-0-12-815002-3.00020-6
- Authors
- Bralten, J., Greven, C. U., Franke, B., Mennes, M., Zwiers, M. P., Rommelse, N. N. J., Hartman, C., van der Meer, D., O’Dwyer, L., Oosterlaan, J., Hoekstra, P. J., Heslenfeld, D., Arias-Vasquez, A., & Buitelaar, J. K.
- Affiliations
- University Medical Center Groningen (NL)
- the Department of Psychiatry, University Medical Center Groningen, Groningen, the Netherlands
- From the Departments of Human Genetics, Cognitive Neuroscience and Psychiatry, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands;
- ORCID
- Venue
- Journal of Psychiatry and Neuroscience
- Publisher
- Canadian Science Publishing
- Published
- 2016-07
- Volume
- 41
- Issue
- 4
- Pages
- 272-279
- ISSN
- 1180-4882 (ISSN-L)
- 1488-2434
- PMC
- PMC4915936
- OpenAlex
- W2221287886
- Cited by
- 66
- References
- 0
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 5 · 2023: 9 · 2022: 9 · 2021: 13 · 2020: 6 · 2019: 8 · 2018: 2 · 2017: 3 · 2016: 2 · 2015: 1
- FWCI
- 4.44
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Psychiatry and Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- VU Research Portal (publishedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
- Funders
- Eli Lilly and Company
- European Commission (305697)
- ZonMw (60-60600-97-193, 433-09-242)
- Radboud Universiteit
- Vrije Universiteit Amsterdam (433-09-242, FP7/2007-2013, 278948)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (433‐09‐242, 175.010.2007.010, FP7 2007-2013, 60-60600-97-193)
- Accare
- Universitair Medisch Centrum Groningen
- Radboud Universitair Medisch Centrum
- Servier
- National Institutes of Health (FP7/2007-2013, 1750102007010, Consortium grant U54 EB020403, EB020403)
- National Institute of Mental Health (R01MH081803, R01MH062873)
- National Institute of Biomedical Imaging and Bioengineering (U54EB020403)
- Cilag
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- attention deficit hyperactivity disorder, unaffected siblings, familiality, brain structural changes, gray matter volume, frontal cortex, orbitofrontal cortex, precentral gyrus, cingulate cortex, adolescents and young adults
- MeSH terms
- Adolescent, Adult, Attention Deficit Disorder with Hyperactivity, Brain, Brain Diseases, Brain Mapping, Child, Cognition, Cross-Sectional Studies, Decision Making, Female, Humans, Intelligence, Magnetic Resonance Imaging, Male, Motivation, Organ Size, Psychomotor Performance, Psychotropic Drugs, Siblings, Young Adult, Gray Matter
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