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

Adults born very preterm (i.e. at <33 weeks' gestation) are more susceptible to long-lasting structural and functional brain alterations and cognitive and socio-emotional difficulties, compared with full-term controls. However, behavioural heterogeneity within very preterm and full-term individuals makes it challenging to find biomarkers of specific outcomes. To address these questions, we parsed brain-behaviour heterogeneity in participants subdivided according to their clinical birth status (very preterm versus full term) and/or data-driven behavioural phenotype (regardless of birth status). Participants were followed-up in adulthood (median age 30 years) as part of a wider longitudinal case-control cohort study. The Network Based Statistic approach was used to identify topological components of resting state functional connectivity differentiating between (i) 116 very preterm and 83 full-term adults (43% and 57% female, respectively) and (ii) data-driven behavioural subgroups identified using consensus clustering (n = 156, 46% female). Age, sex, socio-economic status and in-scanner head motion were used as confounders in all analyses. Post hoc two-way group interactions between clinical birth status and behavioural data-driven subgrouping classification labels explored whether functional connectivity differences between very preterm and full-term adults varied according to distinct behavioural outcomes. Very preterm compared with full-term adults had poorer scores in selective measures of cognitive and socio-emotional processing and displayed complex patterns of hyper- and hypo-connectivity in sub-sections of the default mode, visual and ventral attention networks. Stratifying the study participants in terms of their behavioural profiles (irrespective of birth status) identified two data-driven subgroups: an 'At-Risk' subgroup, characterized by increased cognitive, mental health and socio-emotional difficulties, displaying hypo-connectivity anchored in frontal opercular and insular regions, relative to a 'Resilient' subgroup with more favourable outcomes. No significant interaction was noted between clinical birth status and behavioural data-driven subgrouping classification labels in terms of functional connectivity. Functional connectivity differentiating between very preterm and full-term adults was dissimilar to functional connectivity differentiating between the data-driven behavioural subgroups. We speculate that functional connectivity alterations observed in very preterm relative to full-term adults may confer both risk and resilience to developing behavioural sequelae associated with very preterm birth, while the localized functional connectivity alterations seen in the 'At-Risk' subgroup relative to the 'Resilient' subgroup may underlie less favourable behavioural outcomes in adulthood, irrespective of birth status.