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Introduction: Mutant mouse models with congenital heart disease (CHD) were observed to have distinct brain dysplasia, prompting an assessment for brain anomalies in CHD patients. CHD infants with brain magnetic resonance imaging (MRI) assessments were recruited and scored using a novel brain dysplasia index. Validation was conducted with parallel brain connectome analysis and neurodevelopment outcome assessments. Methods: The Ohia mutant mouse line and others were analyzed for brain defects using 3D episcopic confocal histopathology. In parallel, we recruited 220 CHD neonates with MRI scans from two large centers. This included pre and postoperative conventional MRI sequences and diffusion tensor imaging (DTI). Brain connectivity measurements with DTI-graph analysis and neurodevelopmental testing at 18 months of age (Battelle Developmental Inventory) were obtained. Results: The CHD mouse mutant analysis revealed high prevalence of brain dysplasia involving the olfactory bulb, cerebellum, hippocampus, corpus callosum and choroid plexus. Based on these findings, a brain dysplasia index (BDI) was developed for clinical assessment of CHD patients, with one point for abnormality in any of these structures right or left and for presence of extra-axial cerebral spinal fluid. Analysis of 220 CHD neonates yielded BDI scores ranging from 1 to 17, with average score of 4.1. An elevated BDI score was seen across a spectrum of cardiac lesions, and was similar pre-op and post-op. DTI graph connectivity measurements (reduced nodal efficiency) correlated with high BDI score (p Conclusion: A brain dysplasia index was developed based on brain anomalies seen in CHD mutant mouse models. Infants with CHD of a broad spectrum with high BDI score showed abnormal brain connectivity and poor neurodevelopmental outcome. These findings suggest the poor neurodevelopmental outcome associated with CHD may involve subtle brain dysplasia with a shared developmental etiology with the structural heart disease.

Objectives: Term congenital heart disease (CHD) neonates demonstrate pre-operative (op) abnormal brain metabolism (reduced N-acetylaspartate (NAA), elevated lactate) on long echo MR spectroscopy (MRS). We sought to delineate associations between serial brain metabolism and patient and perioperative clinical factors in term neonates with CHD using short echo MRS. We measured NAA and lactate as well as other metabolites important for brain connectivity such as neurotransmitters glutamate/glutamine and GABA. Methods: Subjects were prospectively enrolled to undergo pre and post-op 3T short echo single voxel MRS of parietal white matter with absolute quantitation of 15 metabolites using LCModel. Neurodevelopment (ND) was assessed via 18 month Battelle Developmental Inventory. Linear and logistic regression with false discovery rate correction was used for statistical analysis. Results: Eighty subjects were enrolled 2009-2015 and 21 term CHD infants underwent both pre and post-op MRS. Eight infants had at least one MRS and ND. NAA and glutamate were significantly decreased post-op compared to pre-op (p Conclusion: In term CHD neonates, serial brain metabolism by MRS demonstrates alterations beyond NAA, including neurotransmitters GABA and glutamate/glutamine. These abnormalities are associated with multiple clinical pre and post-op factors and also predict prolonged hospital stay and 18 month ND.