Developmentally Stable Whole-Brain Volume Reductions and Developmentally Sensitive Caudate and Putamen Volume Alterations in Those With Attention-Deficit/Hyperactivity Disorder and Their Unaffected Siblings
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IMPORTANCE: Attention-deficit/hyperactivity disorder (ADHD) is a heritable neurodevelopmental disorder. It has been linked to reductions in total brain volume and subcortical abnormalities. However, owing to heterogeneity within and between studies and limited sample sizes, findings on the neuroanatomical substrates of ADHD have shown considerable variability. Moreover, it remains unclear whether neuroanatomical alterations linked to ADHD are also present in the unaffected siblings of those with ADHD. OBJECTIVE: To examine whether ADHD is linked to alterations in whole-brain and subcortical volumes and to study familial underpinnings of brain volumetric alterations in ADHD. DESIGN, SETTING, AND PARTICIPANTS: In this cross-sectional study, we included participants from the large and carefully phenotyped Dutch NeuroIMAGE sample (collected from September 2009-December 2012) consisting of 307 participants with ADHD, 169 of their unaffected siblings, and 196 typically developing control individuals (mean age, 17.21 years; age range, 8-30 years). MAIN OUTCOMES AND MEASURES: Whole-brain volumes (total brain and gray and white matter volumes) and volumes of subcortical regions (nucleus accumbens, amygdala, caudate nucleus, globus pallidus, hippocampus, putamen, thalamus, and brainstem) were derived from structural magnetic resonance imaging scans using automated tissue segmentation. RESULTS: Regression analyses revealed that relative to control individuals, participants with ADHD had a 2.5% smaller total brain (β = -31.92; 95% CI, -52.69 to -11.16; P = .0027) and a 3% smaller total gray matter volume (β = -22.51; 95% CI, -35.07 to -9.96; P = .0005), while total white matter volume was unaltered (β = -10.10; 95% CI, -20.73 to 0.53; P = .06). Unaffected siblings had total brain and total gray matter volumes intermediate to participants with ADHD and control individuals. Significant age-by-diagnosis interactions showed that older age was linked to smaller caudate (P < .001) and putamen (P = .01) volumes (both corrected for total brain volume) in control individuals, whereas age was unrelated to these volumes in participants with ADHD and their unaffected siblings. Attention-deficit/hyperactivity disorder was not significantly related to the other subcortical volumes. CONCLUSIONS AND RELEVANCE: Global differences in gray matter volume may be due to alterations in the general mechanisms underlying normal brain development in ADHD. The age-by-diagnosis interaction in the caudate and putamen supports the relevance of different brain developmental trajectories in participants with ADHD vs control individuals and supports the role of subcortical basal ganglia alterations in the pathophysiology of ADHD. Alterations in total gray matter and caudate and putamen volumes in unaffected siblings suggest that these volumes are linked to familial risk for ADHD.
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Some brain volumetric alterations observed in childhood normalize with age, whereas other measures remain fixed.
“Some brain volumetric alterations observed in childhood normalize with age 82,85 , whereas other m easures remain fixed.”
From Attention-deficit/hyperactivity disorder (2015) · cites this paper as [82]
The Discussion (page unavailable) reports that childhood caudate and putamen differences diminished during adolescence, while the Results (page unavailable) say total brain and gray-matter differences were stable across age. But the paper describes normalization as a suggestion from previous studies, and its own results show larger caudate and putamen volumes in the older ADHD group, so it does not establish that those alterations simply normalize with age. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe smaller total brain size in ADHD can be attributed to a reduction of grey matter.
“For example, ADHD is associated with a 3-5% smaller total brain size than unaffected controls 80,81 that can be attributed to a reduction of grey matter 82 .”
From Attention-deficit/hyperactivity disorder (2015) · cites this paper as [82]
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- Authors
- Greven, C. U., Bralten, J., Mennes, M., O’Dwyer, L., van Hulzen, K. J. E., Rommelse, N., Schweren, L. J. S., Hoekstra, P. J., Hartman, C. A., Heslenfeld, D., Oosterlaan, J., Faraone, S. V., Franke, B., Zwiers, M. P., Arias-Vasquez, A., & Buitelaar, J. K.
- Affiliations
- Radboud University Nijmegen (NL)
- Radboud University Medical Center (NL)
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands
- University Medical Center Groningen (NL)
- Vrije Universiteit Amsterdam (NL)
- SUNY Upstate Medical University (US)
- Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands4Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands5Department
- Corresponding author
- Greven, Corina U.
- ORCID
- Venue
- JAMA Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2015-05-01
- Volume
- 72
- Issue
- 5
- Pages
- 490
- ISSN
- 2168-622X (ISSN-L)
- OpenAlex
- W2057394955
- Cited by
- 198
- References
- 59
- Citations by year
- 2026: 12 · 2025: 9 · 2024: 18 · 2023: 20 · 2022: 14 · 2021: 25 · 2020: 23 · 2019: 18 · 2018: 11 · 2017: 20 · 2016: 20 · 2015: 8
- FWCI
- 15.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Psychiatry (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, other-oa)
- Funders
- National Institutes of Health
- National Institute of Mental Health (R01 MH 62873, R01MH062873)
- 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 › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Keywords
- attention deficit hyperactivity disorder, brain volume, caudate nucleus, putamen, gray matter volume, white matter volume, subcortical structures, unaffected siblings, family transmission, neurodevelopmental disorders, brain maturation, nucleus accumbens, hippocampus, thalamus, brainstem, amygdala, globus pallidus
- MeSH terms
- Adolescent, Adult, Age Factors, Amygdala, Attention Deficit Disorder with Hyperactivity, Brain, Brain Stem, Caudate Nucleus, Child, Child Development, Cross-Sectional Studies, Female, Globus Pallidus, Hippocampus, Humans, Magnetic Resonance Imaging, Male, Nucleus Accumbens, Organ Size, Putamen, Risk Factors, Thalamus, Siblings, Adolescent Development, Young Adult, White Matter, Gray Matter
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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