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Parsing brain-behavior heterogeneity in very preterm born children using integrated similarity networks

Research output: Contribution to journalArticlepeer-review

Original languageEnglish
Article number108
JournalTranslational psychiatry
Issue number1
Early online date3 Apr 2023
Accepted/In press14 Mar 2023
E-pub ahead of print3 Apr 2023
PublishedDec 2023

Bibliographical note

Funding Information: We would like to thank participant families and children that took part in this study as well as research radiographers, administrative staff and clinical personnel that made this work possible. This work was supported by the Medical Research Council (MRC), UK [grant numbers: MR/K006355/1 and MR/S026460/1], Action Medical Research and Dangoor Education [grant number: GN2606] and King’s College London member of the MRC Doctoral Training Partnership in Biomedical Sciences [MR/N013700/1] and a MRC/Sackler Foundation grant [MR/P502108/1]. This study uses data acquired during independent research funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research Programme [grant number: RP-PG-0707-10154] and the research is supported by the NIHR Biomedical Research Center, Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, the NIHR Clinical Research Facility, Guy’s and St Thomas’. The authors acknowledge use of the research computing facility at King’s College London, Rosalind ( ), which is delivered in partnership with the National Institute for Health Research (NIHR) Biomedical Research Centers at South London & Maudsley and Guy’s & St. Thomas’ NHS Foundation Trusts, and part-funded by capital equipment grants from the Maudsley Charity [award 980] and Guy’s & St. Thomas’ Charity [TR130505]. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, King’s College London, or the Department of Health and Social Care. Publisher Copyright: © 2023, The Author(s).


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King's Authors


Very preterm birth (VPT; ≤32 weeks' gestation) is associated with altered brain development and cognitive and behavioral difficulties across the lifespan. However, heterogeneity in outcomes among individuals born VPT makes it challenging to identify those most vulnerable to neurodevelopmental sequelae. Here, we aimed to stratify VPT children into distinct behavioral subgroups and explore between-subgroup differences in neonatal brain structure and function. 198 VPT children (98 females) previously enrolled in the Evaluation of Preterm Imaging Study (EudraCT 2009-011602-42) underwent Magnetic Resonance Imaging at term-equivalent age and neuropsychological assessments at 4-7 years. Using an integrative clustering approach, we combined neonatal socio-demographic, clinical factors and childhood socio-emotional and executive function outcomes, to identify distinct subgroups of children based on their similarity profiles in a multidimensional space. We characterized resultant subgroups using domain-specific outcomes (temperament, psychopathology, IQ and cognitively stimulating home environment) and explored between-subgroup differences in neonatal brain volumes (voxel-wise Tensor-Based-Morphometry), functional connectivity (voxel-wise degree centrality) and structural connectivity (Tract-Based-Spatial-Statistics). Results showed two- and three-cluster data-driven solutions. The two-cluster solution comprised a 'resilient' subgroup (lower psychopathology and higher IQ, executive function and socio-emotional scores) and an 'at-risk' subgroup (poorer behavioral and cognitive outcomes). No neuroimaging differences between the resilient and at-risk subgroups were found. The three-cluster solution showed an additional third 'intermediate' subgroup, displaying behavioral and cognitive outcomes intermediate between the resilient and at-risk subgroups. The resilient subgroup had the most cognitively stimulating home environment and the at-risk subgroup showed the highest neonatal clinical risk, while the intermediate subgroup showed the lowest clinical, but the highest socio-demographic risk. Compared to the intermediate subgroup, the resilient subgroup displayed larger neonatal insular and orbitofrontal volumes and stronger orbitofrontal functional connectivity, while the at-risk group showed widespread white matter microstructural alterations. These findings suggest that risk stratification following VPT birth is feasible and could be used translationally to guide personalized interventions aimed at promoting children's resilience.

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