GABA-mediated connectivity in the preterm brain

描述（由申请人提供）：根据2007年医学研究所的报告，早产（PT）是当今美国最重要的儿科公共卫生问题之一。在美国，每年有超过6万名出生的婴儿体重在1500克或以下，据报道，这些婴儿的围产期护理费用每年超过180亿美元。早产儿残疾风险高；30% - 40%的学龄前儿童被诊断为轻微残疾，近五分之一的学龄早产儿被发现有严重残疾，导致每年在长期教育和服务需求方面的新成本为40亿美元。围产期重症监护的一个主要焦点是制定预防早产儿不良后果的策略，但对早产儿神经发育障碍的大脑发育的根本改变仍然知之甚少。先进的核磁共振成像技术允许研究早产对发育中的大脑的影响，最近的功能成像研究表明，在早产儿中，语言、记忆和执行功能的替代神经系统参与其中。伽马氨基丁酸（GABA）中间神经元是这些网络发育的核心，临床前数据表明，这些细胞容易受到早产损伤。这一提议的首要假设是，与同等年龄的对照组相比，PT受试者的静息状态连通性发生了变化。采用高度创新的功能性MRI策略来创建基于静息状态体素的对比，即内在连通性对比（ICC），我们将识别出在极低出生体重新生儿（500 - 1500 g）中受早产影响的神经回路，并将其与同等年龄性别和年龄匹配的足月对照组进行比较。GABA编辑的磁共振波谱检查早产儿和足月对照婴儿将评估静息GABA浓度校正水的区域差异；采用一般线性模型分析，分析GABA、性别和胎龄对ICC变化的贡献。这些数据将提供有关早产对发育中的大脑影响的重要信息，并为预防早产儿残疾提供基本见解。

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.