Impaired Brain Development in a Premature Ex-utero Environment

摘要 尽管早产儿的存活率有了显著提高，严重脑损伤的风险也降低了， 长期持续的高流行率仍然是一个主要的公共卫生问题， 家庭和社会成本。越来越多的证据表明，大脑结构发育受损是可以检测到的 在足月校正年龄之前的早产儿中，即使没有明显的破坏性脑损伤。综合这些 观察表明，在人工子宫外环境中的脑发育不良扰乱了神经心理学， 早产儿存活者的发育。反过来，这表明目前的有效性之间存在差距， 子宫外早产儿脑发育的支持/保护策略，以及正常子宫内早产儿脑发育提供的支持/保护策略 环境缩小这一差距的关键是确定复杂转变之间的破坏性相互作用 大脑成熟/脆弱性的景观，以及早产儿子宫外暴露，其中循环和 氧合（C/O）暴露被认为是神经心理损伤的主要原因。接近 这一挑战的必要步骤是：确定最早的偏差，子宫外脑成熟比较 正常的宫内脑成熟;以确定脑的发病之间的时间关系， 成熟障碍和之前的C/O暴露;以及，确认早期早产成熟变化 预测在足月校正年龄时的大脑结构发育，以及以后的功能结果。迄今为止， （i）缺乏正常宫内脑发育的参考数据，（ii）缺乏连续的 子宫外早产儿大脑发育的测量，以及（iii）缺乏捕获 连续碳氧暴露使用我们的正常子宫内大脑发育和多模式的大型储存库 定量MRI，我们的初步研究表明，在大脑发育发生显着的解剖差异， 在子宫内与子宫外，在足月相当年龄之前即可检测到。我们开发了一套测量系统 以及分析患病早产儿的连续生理信号。在本提案中，我们将联合收割机系列4- 每周一次MRI，同时测量妊娠<36周出生的婴儿的暴露量，以确定 早期脑成熟障碍与早产儿特定的C/O暴露及其相关性之间的关系 患有长期神经心理障碍这些发现可能会为未来的大脑导向支持提供信息， 早产儿，确定神经保护的具体目标，并导致改善神经心理 结果。

ABSTRACT Despite significant advances in survival and the decreased risk of major brain injury in premature infants, the persistent high prevalence of long-term remains a major public health problem, with enormous personal, familial, and societal costs. There is growing evidence that impaired structural brain development is detectable in premature infants before term corrected age, even without overt destructive brain injury. Together these observations suggest that brain dysmaturation in an artificial ex-utero environment disturbs neuropsychological development in prematurity survivors. In turn, this points to ongoing gaps between the effectiveness of current support/protection strategies for ex-utero preterm brain development, and that provided by the normal in-utero environment. Critical to closing this gap is identifying the disruptive interactions between the complex shifting landscape of brain maturation/vulnerability, and preterm ex-utero exposures, among which circulatory and oxygenation (C/O) exposures are considered a leading cause of neuropsychologic impairment. To approach this challenge the necessary steps are: to identify the earliest deviations of ex-utero brain maturation compared to normal in-utero brain maturation; to identify the temporal relationship between the onset of brain dysmaturation and preceding C/O exposures; and, to confirm that the early preterm maturational changes predict structural brain development at term-corrected age, and later functional outcome. To date, progress has been impeded by (i) the lack of reference data for normal in-utero brain development, (ii) the lack of serial measurements of ex-utero preterm brain development, and (iii) the lack concurrent biomarkers that capture continuous C/O exposures. Using our large repository of normal in-utero brain development and multimodal quantitative MRI, our preliminary studies show significant anatomic differences in brain development occurring in utero vs. ex utero, detectable well before term-equivalent age. We have developed systems for measuring and analyzing continuous physiological signals in sick preterm infants. In this proposal we combine serial 4- weekly MRI with concurrent exposure measurements in infants born <36 weeks gestation, to establish the relationship between disturbed early brain maturation, specific preterm C/O exposures, and their association with long-term neuropsychological impairment. These findings may inform future brain-oriented support of premature infants, identify specific targets for neuroprotection, and lead to improved neuropsychological outcomes.