GABA-mediated connectivity in the preterm brain

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DESCRIPTION (provided by applicant): According to the 2007 Institute of Medicine report, preterm (PT) birth represents one the most important pediatric public health problems in the United States today. More than 60,000 infants born in the US each year weigh 1500 grams or less, and the perinatal care costs for these infants are reported to exceed 18 billion dollars each year. Preterm infants are at high risk for handicap; minor impairment is diagnosed in 30 - 40% and major disabilities are found in almost one-fifth of preterm children at school age, resulting in annual new costs of 4 billion dollars in long term educational and service needs. A major focus of perinatal intensive care is the development of strategies to prevent adverse outcome in the prematurely-born, but the fundamental alterations in brain development responsible for neuro- developmental disability in the prematurely-born remain poorly understood. Sophisticated MRI strategies permit investigation of the impact of preterm birth on developing brain, and recent functional imaging studies suggest the engagement of alternative neural systems for language, memory and executive function in the prematurely-born. Gamma aminobutyric acid (GABA) interneurons are central to the development of these networks, and preclinical data suggest that these cells are vulnerable to the injuries of preterm birth. The overarching hypothesis of this proposal is that there are alterations in resting state connectivity in PT subjects compared to term controls at term equivalent age. Employing a highly innovative functional MRI strategy to create a resting state voxel-based contrast, the intrinsic connectivity contrast (ICC), we will identify those neural circuits influenced by preterm birth in very low birth weight neonates (500 - 1500 g) compared to gender- and age-matched term controls at term equivalent age. GABA-edited magnetic resonance spectro- scopy of preterm and term control infants will assess regional differences in resting GABA concentrations corrected for water; using general linear model analyses, the contribution of GABA, gender and gestational age to ICC changes will be analyzed. These data will provide critical information about the impact of preterm birth on the developing brain and offer fundamental insights into prevention of handicap in the prematurely born. PUBLIC HEALTH RELEVANCE: Preterm birth is one of the most important pediatric public health problems in the United States today and results in significant disability. Using a novel functional imaging strategy, the intrinsic connectivity contrast, we will document changes in neural connectivity in preterm subjects compared to term controls at term equivalent age; these changes may be attributable to alterations in regional GABA concentration. These data will both provide critical information about the impact of preterm birth on the developing brain and offer fundamental insights into prevention of handicap in the prematurely born.