Comprehensive volumetric phenotyping of the neonatal brain in Down syndrome
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Abstract
Down syndrome (DS) is the most common genetic cause of intellectual disability with a wide range of neurodevelopmental outcomes. To date, there have been very few in vivo neuroimaging studies of the neonatal brain in DS. In this study we used a cross-sectional sample of 493 preterm- to term-born control neonates from the developing Human Connectome Project to perform normative modeling of regional brain tissue volumes from 32 to 46 weeks postmenstrual age, accounting for sex and age variables. Deviation from the normative mean was quantified in 25 neonates with DS with postnatally confirmed karyotypes from the Early Brain Imaging in DS study. Here, we provide the first comprehensive volumetric phenotyping of the neonatal brain in DS, which is characterized by significantly reduced whole brain, cerebral white matter, and cerebellar volumes; reduced relative frontal and occipital lobar volumes, in contrast with enlarged relative temporal and parietal lobar volumes; enlarged relative deep gray matter volume (particularly the lentiform nuclei); and enlargement of the lateral ventricles, amongst other features. In future, the ability to assess phenotypic severity at the neonatal stage may help guide early interventions and, ultimately, help improve neurodevelopmental outcomes in children with DS.
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Cognitive and brain structure deficits in Down syndrome emerge as early as 6 months of age and progress to have substantial impacts on daily life, academic and occupational outcomes.
“These cognitive and brain structure deficits emerge as early as 6 months of age and progress to have substantial impacts on daily life, as well as academic and occupational outcomes5–7.”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [6]
The Introduction describes cognitive weaknesses in Down syndrome, and the Discussion reports brain-volume differences in neonates. The paper does not establish that cognitive deficits emerge at six months or that these deficits progress to affect daily life, academic outcomes, and occupational outcomes; its Conclusion says the link between neonatal brain development and later outcomes remains unclear. No page numbers were available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredGross anatomical differences in brain structure are apparent in fetal and neonatal brains of individuals with Down syndrome, including reductions in overall brain volume, white matter volume, gyral complexity, sulcal depth and growth of the cortical plate.
“Gross anatomical differences in brain structure are apparent in the fetal and neonatal brains of individuals with DS, including reductions in overall brain volume, white matter volume, gyral complexity, sulcal depth and growth of the cortical plate6,8–15.”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [6]
The Results section reports smaller whole-brain and cerebral white-matter volumes in neonates with Down syndrome. The Discussion also reports reduced fetal whole-brain volume and lower sulcal depth and gyrification index from earlier studies. Our copy does not establish reduced growth of the cortical plate, so that element of the attributed claim is unsupported. Page numbers are unavailable in the indexed passages. (LLM, conf=0.86)
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Accogli, A., Addour-Boudrahem, N., & Srour, M. (2021) · The Cerebellum · doi:10.1007/s12311-020-01224-5 · Cited by 46 · see citing works
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Dimitrova, R., Arulkumaran, S., Carney, O., Chew, A. T. M., Falconer, S., Ciarrusta, J., Wolfers, T., Batallé, D., Cordero‐Grande, L., Price, A. N., et al. (2021) · Cerebral Cortex · doi:10.1093/cercor/bhab039 · Cited by 43 · see citing works
Self-citationIndividualized brain development and cognitive outcome in infants with congenital heart disease
Bonthrone, A. F., Dimitrova, R., Chew, A. T. M., Kelly, C. J., Cordero‐Grande, L., Carney, O., Egloff, A. M., Hughes, E., Vecchiato, K., Simpson, J. M., et al. (2021) · Brain Communications · doi:10.1093/braincomms/fcab046 · Cited by 42 · see citing works
Self-citationCarney, O., Hughes, E., Tusor, N., Dimitrova, R., Arulkumaran, S., Baruteau, K. P., Egloff, A. M., Cordero‐Grande, L., Chew, A. T. M., Falconer, S., et al. (2021) · EClinicalMedicine · doi:10.1016/j.eclinm.2021.100984 · Cited by 40 · see citing works
Self-citationNon‐neuronal cell responses differ between normal and Down syndrome developing brains
Kanaumi, T., Milenković, I., Adle‐Biassette, H., Aronica, E., & Kovács, G. G. (2013) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2013.09.011 · Cited by 39 · see citing works
Absent cavum septum pellucidum: a review with emphasis on associated commissural abnormalities
Sundarakumar, D. K., Farley, S. A., Smith, C. M., Maravilla, K. R., Dighe, M., & Nixon, J. N. (2015) · Pediatric Radiology · doi:10.1007/s00247-015-3318-8 · Cited by 38 · see citing works
Effect of congenital heart defects on language development in toddlers with D own syndrome
Visootsak, J., Hess, B. A., Bakeman, R. A., & Adamson, L. B. (2012) · Journal of Intellectual Disability Research · doi:10.1111/j.1365-2788.2012.01619.x · Cited by 35 · see citing works
Brain ventriculomegaly in Down syndrome mice is caused by Pcp4 dose-dependent cilia dysfunction.
Raveau, M., Nakahari, T., Asada, S., Ishihara, K., Amano, K., Shimohata, A., Sago, H., & Yamakawa, K. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx007 · Cited by 33 · see citing works
Fetal and neonatal neuroimaging
Counsell, S. J., Arichi, T., Arulkumaran, S., & Rutherford, M. (2019) · Handbook of clinical neurology · doi:10.1016/b978-0-444-64029-1.00004-7 · Cited by 33 · see citing works
Self-citationRegional Alterations in Cortical Sulcal Depth in Living Fetuses with Down Syndrome
Yun, H. J., Perez, J. D. R., Sosa, P., Valdés, J. A., Madan, N., Kitano, R., Akiyama, S., Skotko, B. G., Feldman, H. A., Bianchi, D. W., et al. (2021) · Cerebral Cortex · doi:10.1093/cercor/bhaa255 · Cited by 33 · see citing works
Varagur, K., Sanka, S. A., & Strahle, J. M. (2021) · Neurosurgery Clinics of North America · doi:10.1016/j.nec.2021.09.006 · Cited by 31 · see citing works
Influence of CHDs on psycho-social and neurodevelopmental outcomes in children with Down syndrome
Visootsak, J., Huddleston, L. B., Buterbaugh, A., Perkins, A. T., Sherman, S. L., & Hunter, J. E. (2015) · Cardiology in the Young · doi:10.1017/s1047951115000062 · Cited by 31 · see citing works
Live births, natural losses, and elective terminations with Down syndrome in Massachusetts
de Graaf, G., Buckley, F., & Skotko, B. G. (2016) · Genetics in Medicine · doi:10.1038/gim.2016.15 · Cited by 31 · see citing works
McCann, B., Levman, J., Baumer, N., Lam, M. Y., Shiohama, T., Cogger, L., MacDonald, A., Ijner, P., & Takahashi, E. (2021) · NeuroImage: Clinical · doi:10.1016/j.nicl.2021.102815 · Cited by 30 · see citing works
Lee, N., Nayak, A., Irfanoglu, M. O., Sadeghi, N., Stoodley, C. J., Adeyemi, E. I., CLASEN, L. S., & Pierpaoli, C. M. (2020) · Scientific Reports · doi:10.1038/s41598-020-61799-1 · Cited by 29 · see citing works
Assessment of radial glia in the frontal lobe of fetuses with Down syndrome
Baburamani, A. A., Vontell, R. T., Uus, A., Pietsch, M., Patkee, P. A., Wyatt-Ashmead, J., Chin-Smith, E. C., Supramaniam, V. G., Donald Tournier, J., Deprez, M., et al. (2020) · Acta Neuropathologica Communications · doi:10.1186/s40478-020-01015-3 · Cited by 29 · see citing works
Self-citationLevman, J. E. D., MacDonald, A., Baumer, N., MacDonald, P., Stewart, N., Lim, A., Cogger, L., Shiohama, T., & Takahashi, E. (2019) · NeuroImage Clinical · doi:10.1016/j.nicl.2019.101874 · Cited by 28 · see citing works
Aberrant Oligodendrogenesis in Down Syndrome: Shift in Gliogenesis?
Reiche, L., Küry, P., & Göttle, P. (2019) · Cells · doi:10.3390/cells8121591 · Cited by 28 · see citing works
Klein, J. A., Li, Z., Rampam, S., Cardini, J., Ayoub, A., Shaw, P., Rachubinski, A. L., Espinosa, J. M., Zeldich, E., & Haydar, T. F. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.794675 · Cited by 27 · see citing works
Third Ventricle Enlargement Among Newborn Infants With Trisomy 21
Schimmel, M. S., Hammerman, C., Bromiker, R., & Berger, I. (2006) · PEDIATRICS · doi:10.1542/peds.2005-1788 · Cited by 24 · see citing works
A small pons as a characteristic finding in Down syndrome: A quantitative MRI study
Fujii, Y., Aida, N., Niwa, T., Enokizono, M., Nozawa, K., & Inoue, T. (2016) · Brain and Development · doi:10.1016/j.braindev.2016.10.016 · Cited by 21 · see citing works
Behavioural Features of Cerebral Visual Impairment Are Common in Children With Down Syndrome
Wilton, G. J., Woodhouse, R., Viñuela-Navarro, V., England, R., & Woodhouse, J. M. (2021) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2021.673342 · Cited by 18 · see citing works
C21orf91 Regulates Oligodendroglial Precursor Cell Fate—A Switch in the Glial Lineage?
Reiche, L., Göttle, P., Lane, L., Duek, P. D., Park, M., Azim, K., Schütte, J., Manousi, A., Schira‐Heinen, J., & Küry, P. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.653075 · Cited by 14 · see citing works
Ventriculomegaly in very‐low‐birthweight infants with Down syndrome
Movsas, T. Z., Spitzer, A. R., & Gewolb, I. H. (2016) · Developmental Medicine & Child Neurology · doi:10.1111/dmcn.13191 · Cited by 13 · see citing works
Normal Pressure Hydrocephalus in Down Syndrome: The Report of Two Cases
Marano, M., Pompucci, A., Motolese, F., Rossi, M., Coletta, E., Lazzaro, V. D., Fasano, A. A., & Petrella, G. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-200409 · Cited by 6 · see citing works
Down syndrome and fetal ventriculomegaly
Farrell, S. A. (1994) · Prenatal Diagnosis · doi:10.1002/pd.1970140725 · Cited by 5 · see citing works
Flagged first, then by citations
2 of the 118 references couldn’t be matched to a known paper.
Research works printed but not linked: 2
- Aylward EH, Habbak R, Warren AC, Margaret B, Barta PE, Jerram M, Pearlson GD. Cerebellar volume. Arch Neurol. 1997a: 54: 209– 212. 9041863
- Chapman RS, Hesketh LJ. Behavioral phenotype of individuals with down syndrome. Ment Retard Dev Disabil Res Rev. 2000: 6: 84– 95. 10899801
Cited by
Sorted by citations
Consequences of trisomy 21 for brain development in Down syndrome
Russo, M. L., Sousa, A. M. M., & Bhattacharyya, A. (2024) · Nature Reviews Neuroscience · doi:10.1038/s41583-024-00866-2 · Cited by 28 · see citing works
“Fetuses and infants with Down syndrome (DS) exhibit gross anatomical deficits in brain structure, including lower whole-brain volume, thinner cortex, and reduced gyral and sulcal complexity 6,9,10,12–15 .”
Advances in fetal and neonatal neuroimaging and everyday exposures
Lautarescu, A., Bonthrone, A., Bos, B., Barratt, B., & Counsell, S. (2024) · Pediatric Research · doi:10.1038/s41390-024-03294-1 · Cited by 16 · see citing works
Self-citationPeng, T., Lin, Y., Xu, X., Li, J., Liu, M., Zhang, C., Liao, X., Ji, X., Xiong, Z., Gu, Z., et al. (2025) · BMC Medical Imaging · doi:10.1186/s12880-025-01673-6 · Cited by 8 · see citing works
Investigating brain alterations in the Dp1Tyb mouse model of Down syndrome
Navacerrada, M. E. S., Kim, E., Siow, B. M., Ma, D., Gonzalez, L. R., Simmons, C., Hayward, D., Gibbins, D., Singh, N., Strydom, A., et al. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106336 · Cited by 7 · see citing works
Lee, S. E., Baxter, L. L., Duran, M. I., Morris, S. D., Mosley, I. A., Fuentes, K. A., Pennings, J., Guedj, F., & Bianchi, D. W. (2024) · Human Molecular Genetics · doi:10.1093/hmg/ddae160 · Cited by 3 · see citing works
Maccioni, L., Giacomel, A., Pinamonti, M., Francisci, M. D., Pup, F. D., Giubergia, A., Vallini, G., Visani, V., Barzon, L., Dipasquale, O., et al. (2025) · NeuroImage · doi:10.1016/j.neuroimage.2025.121637 · Cited by 6 · see citing works
da Costa, M. D. A., de Rezende, V. L., Bolan, S. J., Ebs, M. F. P., da Silva, G., Pellegrini, L. V., dos Santos, L. S., dos Santos, J. C. C., & Gonçalves, C. L. (2026) · Neurodegenerative Disease Management · doi:10.1080/17582024.2026.2623966 · Cited by 5 · see citing works
Automated craniofacial biometry with 3D T2w fetal MRI
Matthew, J., Uus, A. U., Egloff, A. M., Luis, A., Arulkumaran, S., Fukami-Gartner, A., Kyriakopoulou, V., Cromb, D., Wright, R., Colford, K., et al. (2024) · PLOS Digital Health · doi:10.1371/journal.pdig.0000663 · Cited by 7 · see citing works
Self-citationFew sex differences in regional gray matter volume growth trajectories across early childhood
Long, M., Ostertag, C., Reynolds, J. E., Zheng, J., Landman, B. A., Huo, Y., Forkert, N. D., & Lebel, C. A. (2024) · Imaging Neuroscience · doi:10.1162/imag_a_00154 · Cited by 5 · see citing works
White matter microstructure in school-age children with down syndrome
Garic, D., Al‐Ali, K., Nasir, A., Azrak, O., Grzadzinski, R., McKinstry, R. C., Wolff, J. J., Lee, C.-M., Pandey, J., Schultz, R. T., et al. (2025) · Developmental Cognitive Neuroscience · doi:10.1016/j.dcn.2025.101540 · Cited by 4 · see citing works
Canonica, T., Kidd, E. J., Gibbins, D., Lana‐Elola, E., Fisher, E., Tybulewicz, V. L. J., & Good, M. A. (2024) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2024.1428146 · Cited by 3 · see citing works
Cellularity Defects Are Not Ubiquitous in the Brains of Fetuses With Down Syndrome
Emili, M., Stagni, F., Bonasoni, M., Guidi, S., & Bartesaghi, R. (2024) · Developmental Neurobiology · doi:10.1002/dneu.22953 · Cited by 3 · see citing works
Early White Matter Microstructure Alterations in Infants with Down Syndrome
Azrak, O., Garic, D., Nasir, A., Swanson, M. R., Grzadzinski, R., Al‐Ali, K., Shen, M. D., Girault, J. B., John, T. S., Pandey, J., et al. (2025) · NeuroImage · doi:10.1016/j.neuroimage.2025.121489 · Cited by 5 · see citing works
Early White Matter Microstructure Alterations in Infants with Down SyndromePreprint
Azrak, O., Garic, D., Nasir, A., Swanson, M. R., Grzadzinski, R., Al‐Ali, K., Shen, M. D., Girault, J. B., John, T. S., Pandey, J., et al. (2025) · medRxiv · doi:10.1101/2025.02.26.25322913 · Cited by 1 · see citing works
Investigating Brain Alterations in the Dp1Tyb Mouse Model of Down SyndromePreprint
Navacerrada, M. E. S., Kim, E., Siow, B. M., Ma, D., Gonzalez, L. R., Simmons, C., Hayward, D., Gibbins, D., Singh, N., Strydom, A., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.07.26.550698
Arthun, J., Aldaz, S., Hayes, P., Roberts, J. S., & Olson, L. E. (2023) · PubMed Central · doi:10.17912/micropub.biology.000981
Bartesaghi, R., Chen, X., Johnstone, A. D., Das, U., & Mobley, W. C. (2025) · Springer eBooks · doi:10.1007/978-3-031-89307-0_19
Brain volume trajectories in Down syndrome and autosomal dominant Alzheimer's disease
Kennedy, J. T., Wisch, J. K., Boerwinkle, A. H., Millar, P. R., McKay, N. S., Brickman, A. M., Chhatwal, J. P., Méndez, P. C., Christian, B. T., Cohen, A., et al. (2026) · Alzheimer s & Dementia · doi:10.1002/alz.71103
Early dynamics of the genome in Down syndrome
Haydar, T. F., & Li, Z. (2026) · Science · doi:10.1126/science.aeh0065
Domenico, F. D., Marzia Perluigi, A., Tramutola, A., Bacalini, M. G., Victorino, D. B., Barroeta, I., Bartesaghi, R., Carfì, A., Carmona‐Iragui, M., Cohen, A. D., et al. (2026) · NeuroMolecular Medicine · doi:10.1007/s12017-026-08921-0
Self-citationBonasoni, M. P., Pati, M., Musarò, A., Vanacore, F., Blasi, I., Botticelli, G., Aguzzoli, L., Lin, J., & Haldipur, P. (2026) · Fetal and Pediatric Pathology · doi:10.1080/15513815.2026.2690379
Imaging the fetal brain with ultrasound: bridging research innovation and clinical practice
Wyburd, M. K., Wilson, S., & Namburete, A. I. L. (2026) · Archives of Disease in Childhood Education & Practice · doi:10.1136/archdischild-2025-330057
Fetal brain MRI analysis: Towards clinical translation and impact
Luis, A., Uus, A. U., Story, L., & Rutherford, M. (2026) · Developmental Medicine & Child Neurology · doi:10.1111/dmcn.70460
Self-citationHaberl, C., Palmrich, P., Karner, E., Kienast, P., Glatter, S., Heinzl, F., Moser, P., Prayer, D., Kasprian, G. J., & Binder, J. (2026) · Prenatal Diagnosis · doi:10.1002/pd.70245
- Authors
- Fukami-Gartner, A., Baburamani, A. A., Dimitrova, R., Patkee, P. A., Ojinaga-Alfageme, O., Bonthrone, A. F., Cromb, D., Uus, A. U., Counsell, S. J., Hajnal, J. V., O’Muircheartaigh, J., & Rutherford, M. A.
- Affiliations
- St Thomas' Hospital (GB)
- Corresponding author
- Rutherford, Mary A
- ORCID
- Venue
- Cerebral Cortex
- Publisher
- Oxford University Press (OUP)
- Published
- 2023-05-26
- Volume
- 33
- Issue
- 14
- Pages
- 8921-8941
- ISSN
- 1047-3211 (ISSN-L)
- 1460-2199
- PMC
- PMC10350827
- OpenAlex
- W4378783783
- Cited by
- 24
- References
- 118
- Citations by year
- 2026: 8 · 2025: 6 · 2024: 7 · 2023: 3
- FWCI
- 6.14
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cerebral Cortex (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion, cc-by)
- Funders
- Medical Research Council (MR/K006355/1, MR/LO11530/1, 319456)
- Rosetrees Trust (A1563)
- Sparks and Great Ormond Street Hospital Children’s Charity (V5318)
- Wellcome/EPSRC Centre for Medical Engineering (WT203148/Z/16/Z)
- National Institute for Health Research
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Fetal and Pediatric Neurological Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Keywords
- Down syndrome, neonatal brain, brain tissue volume, white matter volume, cerebellar volume, deep gray matter, lateral ventricle, intellectual disability, neurodevelopmental outcomes, phenotypic severity
- MeSH terms
- Brain, Child, Cross-Sectional Studies, Down Syndrome, Humans, Infant, Newborn, Magnetic Resonance Imaging, White 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.
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