Third-Trimester Development of Central Autonomic Network Connectivity Is Altered in an Extrauterine Environment.

Introduction: The central autonomic network (CAN), which involves complex interconnected brain regions that modulate the autonomic nervous system, may be key to understanding higher risk for psychosocial and behavioral challenges in preterm neonates.

Methods: We compared resting-state functional connectivity of the CAN in 94 healthy term-born controls and 94 preterm infants at term-equivalent age. In preterm infants, we correlated CAN connectivity with postmenstrual age (PMA). The preterm cohort underwent the Infant-Toddler Social and Emotional Assessment at 18-month follow-up, and these scores were correlated with CAN connectivity.

Results: CAN connectivity at the amygdala (p < 0.001), hippocampus (p < 0.001), insula (p < 0.001), brainstem (p = 0.003), and thalamus (p = 0.032) was significantly higher in term (n = 94) than preterm (n = 94) neonates. In preterm neonates, CAN connectivity positively correlated with PMA at the thalamus (r = 0.438, p < 0.001), insula (r = 0.304, p < 0.001), precuneus (r = 0.288, p < 0.001), hippocampus (r = 0.283, p < 0.001), and amygdala (r = 0.142, p = 0.034). At 18-month follow-up (n = 30, mean age 19.8 ± 3.4 months), CAN connectivity at the insula was negatively correlated with externalizing behaviors (r = -0.529, p = 0.003).

Conclusion: In preterm neonates, the CAN evolves dynamically over the extrauterine third trimester and is measurably different compared to term-born neonates in ways that impact developmental outcomes. This is the first study to describe CAN connectivity using resting-state functional MRI in large cohort of term and preterm neonates and to report an association of CAN connectivity and behavioral outcomes.