GABA-mediated connectivity in the preterm brain

描述(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。美国每年有超过6万名婴儿出生，体重不超过1500克，据报道，这些婴儿的围产期护理费用每年超过180亿美元。早产儿残疾的风险很高；30%-40%的早产儿被诊断为轻度残疾，近五分之一的学龄儿童出现严重残疾，导致长期教育和服务需求每年新增加40亿美元的成本。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，但导致早产儿神经发育障碍的大脑发育的根本变化仍然知之甚少。复杂的MRI策略可以研究早产对大脑发育的影响，最近的功能成像研究表明，早产儿的语言、记忆和执行功能可能涉及到不同的神经系统。伽马氨基丁酸(GABA)中间神经元是这些网络发展的中心，临床前数据表明这些细胞容易受到早产的伤害。这一建议的主要假设是，与相同年龄段的足月对照组相比，PT受试者的静息状态连通性发生了变化。使用高度创新的功能磁共振策略来创建基于静息状态体素的对比，即内在连接性对比(ICC)，我们将识别极低出生体重(500-1500 g)新生儿中受早产影响的神经回路，并与足月相同年龄的性别和年龄匹配的足月对照组进行比较。经GABA编辑的早产儿和足月对照组婴儿的磁共振波谱将评估经水分校正的静息GABA浓度的地区差异；使用一般线性模型分析，将分析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的影响的关键信息，并为预防早产儿的残疾提供基本的见解。 公共卫生相关性：早产是当今美国最重要的儿科公共卫生问题之一，并导致严重残疾。使用一种新的功能成像策略，内在连接性对比，我们将记录早产儿受试者神经连接性的变化，与足月相同年龄的足月儿对照组相比；这些变化可能归因于局部GABA浓度的变化。这些数据将提供有关早产对大脑发育的影响的关键信息，并为预防早产儿的残疾提供基本的见解。

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.