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The subventricular zone (SVZ) is the largest pool of neural stem\/progenitor cells in the postnatal brain. Our aim is to determine the effects of cardiopulmonary bypass (CPB) on neurogenesis and cortical maturation in piglets whose SVZ development is similar to human infants.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Three\u2010week\u2010old piglets (n\u00a0=\u00a029) were randomly assigned to control (no surgery), mild\u2010CPB (34\u00b0C full flow for 60\u2009minutes) and severe\u2010CPB groups (25\u00b0C circulatory\u2010arrest for 60\u2009minutes). The SVZ and frontal lobe were analyzed with immunohistochemistry 3\u2009days and 4\u2009weeks postoperatively. MRI of the frontal lobe was used to assess cortical development.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>SVZ neurogenic activity was reduced up to 4\u2009weeks after both mild and severe CPB\u2010induced insults. CPB also induced decreased migration of young neurons to the frontal lobe, demonstrating that CPB impairs postnatal neurogenesis. MRI 4\u2009weeks after CPB displayed a decrease in gyrification index and cortical volume of the frontal lobe. Cortical fractional anisotropy was increased after severe CPB injury, indicating a prolonged deleterious impact of CPB on cortical maturation. Both CPB\u2010induced insults displayed a significant change in densities of three major inhibitory neurons, suggesting excitatory\u2010inhibitory imbalance in the frontal cortex. In addition, different CPB insults altered different subpopulations of inhibitory neurons.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Our results provide novel insights into cellular mechanisms contributing to CHD\u2010induced neurological impairments. Further refinement of CPB hardware and techniques is necessary to improve long\u2010term frontal cortical dysmaturation observed in children with CHD. 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