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

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.

Exploring functional connectivity in clinical and data-driven groups of preterm and term adults

“…Our post-hoc analyses aimed to explore whether specific enriching factors, or lack of certain social or clinical risk factors, protected the VPT adults belonging to the Resilient subgroup from developing an At-risk behavioural profile. In contrast to previous studies in VPT children, we found that perinatal clinical risk was not higher in VPT adults who belonged to an At-risk (vs Resilient) subgroup (Hadaya et al, 2023; Poehlmann et al, 2015). Social risk, on the other hand, may be specifically related to the difficulties observed in the VPT At-risk subgroup, which contained more VPT adults from more socially disadvantaged backgrounds compared to the Resilient subgroup, while this relationship was not observed in FT adults.…”

“…Our post-hoc analyses aimed to explore whether specific enriching factors, or lack of certain social or clinical risk factors, protected the VPT adults belonging to the Resilient subgroup from developing an At-risk behavioural profile. In contrast to previous studies in VPT children, we found that perinatal clinical risk was not higher in VPT adults who belonged to an At-risk (vs Resilient) subgroup (Hadaya et al, 2023;Poehlmann et al, 2015).…”

“…Nonetheless, it is worth noting, that socio-economic status in our sample only partially explained behavioural outcomes, as our main behavioural and rsFC results remained significant after adjusting for this covariate. It is therefore plausible that additional unmeasured environmental or hereditary factors (e.g., parental mental health or cognitively stimulating home environment) (Hadaya et al, 2023; Lean et al, 2020; Vanes et al, 2021) may have contributed to the behavioural outcomes observed in the distinct subgroups.…”

“…Future studies with more representative samples of VPT adults could help elucidate these potentially inconsistent findings. Another possible limitation is that we did not include known risk factors (such as socio-economic status, parenting or clinical measures) in the clustering model, which may have increased the difficulty in identifying nuanced subgroups exhibiting ‘equifinal’ trajectories (i.e., those with similar behavioural outcomes but distinct underlying risk factors) (Cicchetti and Rogosch, 1996; Hadaya et al, 2023). However, to our knowledge, this is the first study to parse behavioural heterogeneity in VPT adults; therefore, we decided to follow an approach similar to those implemented in the vast majority of studies in VPT children, where individual-level behavioural variables were included as inputs to the clustering model and risk factors were explored post-hoc (Bogičević et al, 2021; Burnett et al, 2019; Johnson et al, 2018; Lean et al, 2020; Poehlmann et al, 2015; Ross et al, 2016; van Houdt et al, 2020).…”

“…A small number of studies in VPT children followed similar methodological approaches and investigated the underlying brain changes differentiating within-group behavioural heterogeneity. Results of these studies showed that early brain insult (Bogičević et al, 2021; Ross et al, 2016) and structural and functional brain alterations (Hadaya et al, 2023; Lean et al, 2020) characterised the distinct subgroups. However, it remains to be explored whether the heterogeneity in behavioural outcomes seen within and between VPT and FT born individuals persists into adulthood, and if it does, whether resting state functional connectivity (rsFC) changes may be associated with distinct data-driven behavioural phenotypes, irrespective of gestational age at birth.…”