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.

抽象的 尽管早产儿的生存率取得了显着进步，严重脑损伤的风险也降低了，但 长期持续的高患病率仍然是一个重大的公共卫生问题，对个人、 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。一起这些 观察表明，人工子宫外环境中的大脑发育不良会扰乱神经心理 早产幸存者的发育。反过来，这表明当前的有效性之间持续存在差距。 子宫外早产大脑发育以及正常子宫内提供的支持/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伤的主要原因。接近 这一挑战的必要步骤是： 确定与子宫外大脑成熟相比的最早偏差 正常的子宫内大脑成熟；确定大脑发作之间的时间关系 成熟不良和之前的 C/O 暴露；并且，确认早期早产的成熟变化 预测术语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，进展 受到以下因素的阻碍：(i) 缺乏正常子宫内大脑发育的参考数据，(ii) 缺乏序列 宫外早产大脑发育的测量，以及（iii）缺乏同时捕获的生物标志物 连续 C/O 暴露。使用我们的正常子宫内大脑发育和多模式的大型存储库 定量 MRI，我们的初步研究显示大脑发育发生显着的解剖学差异 子宫内与子宫外的差异，在足月相当年龄之前就可以检测到。我们开发了测量系统 并分析患病早产儿的连续生理信号。在这个提案中，我们结合了系列 4- 每周对妊娠 <36 周出生的婴儿进行 MRI 并同时进行暴露测量，以确定 大脑早期成熟障碍、特定早产 C/O 暴露及其关联之间的关系 患有长期神经心理障碍。这些发现可能会为未来以大脑为导向的支持提供信息 早产儿，确定神经保护的具体目标，并改善神经心理学 结果。