Delayed maturation of the structural brain connectome in neonates with congenital heart disease

There is emerging evidence for delayed brain development in neonates with congenital heart disease (CHD). We hypothesize that the perioperative development of the structural brain connectome is a proxy to such delays. Therefore, we set out to quantify the alterations and longitudinal pre- to postoperative changes in the connectome in CHD neonates and assess risk factors for disturbed perioperative network development relative to healthy term newborns. In this prospective cohort study, 114 term neonates with CHD underwent cardiac surgery at the University Children's Hospital Zurich. Forty-six healthy term newborns were included as controls. Pre- and postoperative structural connectomes were derived from mean fractional anisotropy values of fibre pathways traced using diffusion tractography. Graph theory parameters calculated across a range of proportional cost thresholds were compared between groups by multi-threshold permutation correction adjusting for confounders. Network based statistic was calculated for edgewise network comparison. White matter injury (WMI) volume was quantified on 3D T1-weighted images. Random coefficient mixed models with interaction terms of (i) CHD subtype and (ii) WMI volume with postmenstrual age at MRI respectively were built to assess modifying effects on network development. Pre- and postoperatively, at the global level, efficiency, indicative of network integration, was higher in controls compared to CHD neonates. In contrast, local efficiency and transitivity, indicative of network segregation, were higher in CHD neonates compared to controls (all p<0.025 for one-sided t-tests). Preoperatively these group differences were also found across multiple widespread nodes (all p<0.025, accounting for multiple comparison), whereas postoperatively nodal differences were not evident. At the edge-level, the majority of weaker connections in CHD neonates compared to controls involved interhemispheric connections (66.7% preoperatively; 54.5% postoperatively). A trend showing a more rapid pre- to postoperative decrease in local efficiency was found in class I CHD neonates compared to controls. In CHD neonates, larger WMI volume was associated with lower strength (p=0.0026) and global efficiency (p=0.0097). The maturation of the structural connectome is delayed in neonates with CHD, with a pattern of lower structural integration and higher segregation compared to healthy controls. Trend-level evidence indicated that normalized postoperative cardiac physiology in class I CHD neonates might improve structural network topology. In contrast, the degree of WMI burden negatively impacts network strength and integration. Further research is needed to elucidate how aberrant structural network development in CHD represents neural correlates of later neurodevelopmental impairments.