Impaired Brain Development in a Premature Ex-utero Environment

过早的宫外环境中大脑发育受损

• 批准号: 10360580
• 负责人: ADRE Jacques DU PLESSIS
• 金额: $ 66.5万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-12 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10360580
• 关键词: Acute; Address; Age; Anatomy; Behavioral; Biological Markers; Bradycardia; Brain; Brain Injuries; Caring; Cognitive; Complex; Critical Illness; Data; Databases; Development; Dissociation; Early Intervention; Effectiveness; Ensure; Environment; Environmental Exposure; Event; Evolution; Exposure to; Fetus; Functional disorder; Future; Gestational Age; Goals; Growth; High Prevalence; Hypotension; Image; Impairment; Infant; Intervention; Investigation; Knowledge; Lead; Lesion; Link; Magnetic Resonance; Magnetic Resonance Imaging; Measurement; Measures; Metabolism; Nature; Neuropsychology; Outcome; Physiological; Play; Population; Pregnancy; Premature Birth; Premature Infant; Public Health; Risk; Role; Serial Magnetic Resonance Imaging; Services; Signal Transduction; Special Education; Survivors; System; Techniques; Time; aging brain; clinical trial readiness; cost; data acquisition; data repository; disability; fetal; functional outcomes; impaired brain development; improved; in utero; magnetic resonance imaging biomarker; multimodal data; multimodality; neurodevelopment; neuroprotection; postnatal; premature; repository; social; societal costs; tool; trend

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.

摘要 尽管早产儿的存活率有了显著的进步，主要脑损伤的风险也降低了，但 长期的高患病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，结构性大脑发育受损是可以检测到的。 在足月矫正年龄之前的早产儿，即使没有明显的破坏性脑损伤。把这些放在一起 观察表明，在人工体外环境中大脑发育不成熟会扰乱神经心理。 早产儿幸存者的发育。反过来，这也指出了当前政策有效性之间的持续差距。 对宫外早产儿脑发育和正常宫内早产儿脑发育的支持/保护策略 环境。缩小这一差距的关键是确定复杂的转变之间的破坏性相互作用 大脑成熟/脆弱性和早产宫外暴露的情况，其中循环和 氧合(C/O)暴露被认为是神经心理损害的主要原因。接近 这种挑战的必要步骤是：找出最早偏离体外脑成熟的比较 以正常的宫内脑成熟；确定脑发病的时间关系 不成熟和先前的C/O暴露；以及，确认早产早期成熟变化 预测足月校正年龄时大脑结构的发育，以及后来的功能结果。到目前为止，进展 一直受到以下因素的阻碍：(I)缺乏正常宫内大脑发育的参考数据，(Ii)缺乏连续的 对宫外早产儿脑发育的测量，以及(Iii)缺乏同时存在的生物标志物 持续的C/O暴露。使用我们的正常宫内大脑发育和多模式的大型存储库 我们的初步研究表明，大脑发育过程中存在显著的解剖学差异。 宫内和宫外，早在足月同龄之前就可以检测到。我们已经开发了测量系统 以及分析患病早产儿的连续生理信号。在这个方案中，我们结合了序列4- 每周对出生36周的婴儿同时进行核磁共振测量，以确定 大脑早期成熟障碍与特定早产儿C/O暴露的关系及其相关性 有长期的神经心理损伤。这些发现可能会为未来的大脑导向支持提供信息 早产儿，确定神经保护的特定目标，并导致改善神经心理 结果。