Single Ventricle Reconstruction Trial III: Brain Connectome and Neurodevelopmental Outcomes – Ancillary Study
With dramatic improvement in survival of patients with hypoplastic left heart syndrome and related forms of single right ventricle undergoing staged palliation to the Fontan operation, a high prevalence of neurodevelopment abnormalities has been exposed. The NHBLI-funded Pediatric Heart Network (PHN) Single Ventricle Reconstruction (SVR) III study, “Long-term Outcomes of Children with HLHS and the Impact of Norwood Shunt Type,” is a prospective follow-up study of an existing cohort of children with HLHS and other single RV anomalies who were enrolled in early infancy in a randomized clinical trial of the modified Blalock-Taussig shunt (MBTS) versus right ventricular to pulmonary artery shunt (RVPAS). The parent SVR III study seeks to determine if the shunt assignment at the time of the Norwood operation is associated with cardiac function, transplant-free survival, exercise function, and neurodevelopmental outcomes. We here propose a neuroimaging ancillary study to the parent SVR III study that leverages the neurodevelopmental follow-up of the SVR cohort at age 11 years. We are combining state-of-the-art brain imaging techniques (Resting-BOLD and Diffusion Tensor Imaging) in 140 SVR III patients and 100 referent subjects with innovative brain connectome or “graph” analyses to determine if brain connectivity graph measurements will provide novel neuroimaging biomarkers for neurodevelopmental disabilities and improve our understanding of their inciting mechanisms in the SVR survivors. Our specific aims are: Specific Aim 1: To characterize the global brain network topology of the SVR III cohort; Specific Aim 2: To determine which neurocognitive and behavioral outcomes predict global brain network topology in the SVR III cohort; Specific Aim 3: To determine which patient factors (e.g., birth weight, gestational age, and maternal education) and medical factors (e.g., intraoperative conduct during Norwood procedure, hemodynamic complications, types and number of interventions, and measures of global morbidity) predict global brain network topology in the SVR III cohort; and Specific Aim 4: To precisely characterize the specific relationships between global brain network topology, specific patient/medical factors,and adverse neurocognitive/behavioral outcomes in the SVR III cohort. We will use linear regression and mediation statistical methods to analyze associations of MRI graph measures with SVRIII neurodevelopmental measures and surgical/non-surgical clinical independent risk factors. Upon successful completion, these studies will elucidate the nature and basis of neurodevelopmental disability in single ventricle patients following Fontan palliation. This research will also contribute a novel and robust set of clinical/research tools in the form of neuroimaging biomarkers that can be used to help classify and predict outcomes in complex CHD.