Parsing brain-behavior heterogeneity in very preterm born children using integrated similarity networks
Laila Hadaya1,2, Konstantina Dimitrakopoulou3, Lucy D Vanes4
1Centre for the Developing Brain, Department of Perinatal Imaging and Health, Faculty of Life Sciences & Medicine, King's College London, London, UK.
Insights
Children born very preterm (VPT) can be stratified into behavioral subgroups. The resilient group showed better outcomes and specific brain structure, while the at-risk group had higher clinical risk and white matter alterations.
Area of Science:
- Neuroscience
- Developmental Psychology
- Pediatrics
Background:
- Very preterm birth (VPT) is linked to neurodevelopmental challenges.
- Identifying vulnerable VPT infants is difficult due to outcome heterogeneity.
Purpose of the Study:
- To classify VPT children into distinct behavioral subgroups.
- To investigate differences in neonatal brain structure and function between these subgroups.
Main Methods:
- An integrative clustering approach combined neonatal and childhood data from 198 VPT children.
- Neuroimaging (MRI) at term-equivalent age and neuropsychological assessments at 4-7 years were used.
- Subgroups were characterized by outcomes and compared for neonatal brain volumes, functional, and structural connectivity.
Main Results:
- A three-cluster solution identified 'resilient', 'intermediate', and 'at-risk' subgroups.
- The resilient group had higher cognitive/socio-emotional scores and a stimulating environment.
- The at-risk group had higher neonatal clinical risk and white matter alterations; the resilient group showed larger insular/orbitofrontal volumes and connectivity.
Conclusions:
- VPT children can be stratified into clinically meaningful subgroups.
- Distinct neuroimaging profiles correlate with behavioral outcomes.
- This stratification may guide personalized interventions to enhance resilience in VPT infants.
Abstract:
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.
