Functional Connectivity at Birth and Longitudinal Neurocognitive Development in Very Preterm Infants

Importance: Understanding how neonatal functional connectivity at birth is associated with later cognitive performance in infants born very preterm (VPT) may help identify early neuroimaging markers of neurodevelopment. Objective: To examine the associations between functional connectivity at birth and cognitive performance at age 2 and 3 years in children born VPT. Design, Setting, and Participants: This prospective cohort study included infants born VPT (gestational age ≤32 weeks) from 5 level III and IV neonatal intensive care units in the greater Cincinnati, Ohio, area between September 16, 2016, and November 19, 2019. Maternal, pregnancy, delivery, and infant clinical data were collected from birth through discharge from the neonatal intensive care unit. Participants underwent magnetic resonance imaging at full-term-equivalent age at Cincinnati Children's Hospital using the same scanner. Image preprocessing and statistical analyses for this study were conducted between January 25, 2025, and July 30, 2026. Main Outcomes and Measures: Cognitive outcomes were assessed at corrected age 2 and 3 years using the Bayley Scales of Infant and Toddler Development, Third Edition and the Differential Ability Scales, Second Edition, respectively. Functional connectivity was measured within and between the default mode network (DMN), somatomotor network (SMN), dorsal attention network (DAN), frontoparietal control network, visual network (VIS), and cingulo-opercular network (CO). Associations between neonatal functional connectivity and longitudinal cognitive outcomes were examined using a bayesian hierarchical linear mixed-effects model. Results: A total of 257 infants born VPT (mean [SD] gestational age, 29.2 [2.5] weeks; 132 male [51.4%]) were included in the final longitudinal analysis. Stronger neonatal connectivity involving the DMN was positively associated with cognitive performance, including intra-DMN (0.23; 95% credible interval [CrI], 0.06-0.39) and DMN connections with the frontoparietal control network (0.24; 95% CrI, 0.07-0.40), SMN (0.20; 95% CrI, 0.02-0.37), VIS (0.32; 95% CrI, 0.13-0.51), and CO (0.39; 95% CrI, 0.21-0.56). Positive associations were also observed for SMN-VIS (0.27; 95% CrI, 0.12-0.43) and SMN-CO (0.26; 95% CrI, 0.09-0.44) connectivity. The SMN-VIS was the only connection showing a difference between assessments, with a less pronounced association at 3 years than at 2 years (interaction, -0.09; 95% CrI, -0.20 to <0.01). Conclusions and Relevance: In this cohort study of infants born VPT, neonatal functional network organization was associated with cognitive performance at corrected age 2 and 3 years. The findings highlight the relevance of distributed connectivity involving the DMN and SMN to later cognitive outcomes and support further investigation of neonatal functional connectivity as an early marker of neurodevelopment.