Ramirez A, Peyvandi S, Cox S, Gano D, Xu D, Tymofiyeva O, McQuillen PS. Neonatal brain injury influences structural connectivity and childhood functional outcomes. PLoS One. 2022 Jan 5;17(1):e0262310. doi: 10.1371/journal.pone.0262310. PMID: 34986206; PMCID: PMC8730412.
Neonatal brain injury may impact brain development and lead to lifelong functional impairments. Hypoxic-ischemic encephalopathy (HIE) and congenital heart disease (CHD) are two common causes of neonatal brain injury differing in timing and mechanism. Maturation of whole-brain neural networks can be quantified during development using diffusion magnetic resonance imaging (dMRI) in combination with graph theory metrics. DMRI of 35 subjects with CHD and 62 subjects with HIE were compared to understand differences in the effects of HIE and CHD on the development of network topological parameters and functional outcomes. CHD newborns had worse 12-18 month language (P<0.01) and 30 month cognitive (P<0.01), language (P = 0.05), motor outcomes (P = 0.01). Global efficiency, a metric of brain integration, was lower in CHD (P = 0.03) than in HIE, but transitivity, modularity and small-worldness were similar. After controlling for clinical factors known to affect neurodevelopmental outcomes, we observed that global efficiency was highly associated with 30 month motor outcomes (P = 0.02) in both groups. To explore neural correlates of adverse language outcomes in CHD, we used hypothesis-based and data-driven approaches to identify pathways with altered structural connectivity. We found that connectivity strength in the superior longitudinal fasciculus (SLF) tract 2 was inversely associated with expressive language. After false discovery rate correction, a whole connectome edge analysis identified 18 pathways that were hypoconnected in the CHD cohort as compared to HIE. In sum, our study shows that neonatal structural connectivity predicts early motor development after HIE or in subjects with CHD, and regional SLF connectivity is associated with language outcomes. Further research is needed to determine if and how brain networks change over time and whether those changes represent recovery or ongoing dysfunction. This knowledge will directly inform strategies to optimize neurologic functional outcomes after neonatal brain injury.
While using brain connectivity as a predictive tool is the ultimate aim of their work, Dr. McQuillen said it was encouraging to see that, overall, the children had good outcomes given their conditions—a testament to the value of therapeutic hypothermia for HIE, or birth asphyxia.
“One way to put it would be, they did surprisingly well,” he said. For the congenital heart disease cohort, he said, “we could find some more areas that they performed worse in, but by and large they're doing OK. This is not a devastating brain injury that babies with congenital heart disease have. It's just that they have a lot of problems in a lot of different areas.”...
“We found distinct differences in how the brains are wired in children with congenital heart disease as compared with children with birth asphyxia,” Dr. McQuillen said.
Because the CHD group had the worse developmental scores in language, researchers examined pathways that have been associated with language in adults. They found connectivity in two areas—superior longitudinal fasciculus (SLF) tract 2 and SLF tract 3—to be linked with language scores. The greater the connectivity of SLF2, which connects the inferior parietal to the frontal lobe, the lower the expressive language scores were at 30 months. And the greater the connectivity of SLF3, which connects the supramarginal gyrus to the frontal lobe, the lower the overall language scores were at 12 to 18 months.
It might seem counterintuitive that greater connectivity might lead to worse outcomes, but it makes sense given the complex nature of brain connectivity and function, Dr. McQuillen said.
“In order to get normal language function, you have to have the orchestrated involvement of a number of different pathways,” he said. “So, any sort of imbalance can lead to dysfunction.”...
Gabrielle deVeber, MD, a pediatric neurologist and professor of pediatrics at the Hospital for Sick Children in Toronto, noted how well the children fared. “Cardiac kids actually still do quite well even in this study,” she said. “The majority, 50 percent or above, scored normally in cognitive, language, or motor [domains] by 30 months. However, an important point is that outcomes may be even better than this report if the full spectrum of children with congenital heart disease are studied and not just the ones who are sick newborns, in-patients, and are imaged in the newborn period,” meaning they are more likely have more severe versions of CHD.
She said the study also shows that the presence of intact connectivity may not be sufficient to ensure normal network function.