Towards biomarkers of resiliency in the extremely preterm child: a multimodal neuroimaging study of brain and environment

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Prematurity is a public health crisis impacting 10% of all births. There is significant risk for neurocognitive impairment, including language. This can adversely impact quality of life. Current prognostic tools leave a significant proportion of variance in later language scores unexplained, focus on risk factors which are often not modifiable, and fail to identify resiliency, or positive outcome despite risk. There is a critical need for advanced neuroimaging studies of well-performing extremely preterm (EPT, <28 weeks gestation) children at school-age and beyond to identify brain-based markers of resiliency while explicitly accounting for socioenvironmental factors. The proposed experiments will address this need by leveraging an existing cohort of 45 EPT children with no overt brain injury and 45 term comparison children. These EPT children were found to have increased functional and structural connectivity--including an extracallosal interhemispheric pathway--versus term children, which positively correlated with language at 4 to 6 years of age for EPT children exclusively. The central hypothesis is that EPT children performing within normal limits on language tasks do so via adaptive neural networks--which are extracallosal and bypass areas vulnerable to white matter injury of prematurity--and the environment in which EPT children are developing drives this adaptive hyperconnectivity. The objective of the proposed research is to determine if this hyperconnectivity remains a brain-based biomarker of resiliency at 8- 11 years and analyze the influence of the child’s social environment on hyperconnectivity. The first aim is to determine if the extracallosal hyperconnectivity (versus term children) we observed at 4-6 years of age in the EPT group persists to 8-11 years of age. The second aim is to determine the extent to which language scores at 8-11 years relate to hyperconnectivity for EPT children. The third aim is to evaluate the extent to which environmental factors drive brain connectivity. Children will be assessed longitudinally with magnetoencephalography, functional magnetic resonance imaging (MRI), and diffusion MRI to validate unique neuroimaging signatures previously identified. Environment-based factors will be assessed at birth (through linkage with birth records), 4-6 years, and 8-11 years to evaluate the extent to which they influence preterm brain connectivity. The candidate’s long-term goal is to reduce the burden of neurodevelopmental impairment for children born EPT by uncovering adaptive, neuroprotective mechanisms and developing imaging markers that can subsequently be used to improve prediction of outcomes before language can be reliably assessed. Through formal coursework, workshops, and hands-on training during the proposed research with her interdisciplinary committee of expert advisors and mentors, the candidate will gain expertise in epidemiological methods to evaluate socioenvironmental risk across generations and in the science of adversity and resiliency. This is a critical next step to establish scientific independence as an investigator and a leader in the study of socioenvironmental resiliency, language development, and neuroprotective mechanisms in the preterm brain.