Examining Prenatal Inflammation and Neurodevelopment in a Longitudinal Fetal-to-Age 9 Imaging Study

项目摘要 早期炎症和儿童神经行为发育改变之间的联系是无可争议的， 对这种关联背后的神经学现象的理解几乎完全缺乏。研究 动物表明，甚至在出生之前，炎症就作用于发育中的神经连接，从而改变了这一过程。 发展质量和然而，这些关键的关联仍然需要在人类大脑中进行测试。在这里，我们将 检查产前炎症，胎儿神经编程的影响，并在一个统一的儿童神经发育 框架.我们将利用现有的纵向队列研究来评估产前炎症是否会影响胎儿的健康。 周期对发育中的胎儿神经连接体产生影响，随后增加了 儿童疾病。我们将对胎儿静息状态功能连接（RSFC）MRI的进展与 创新的牙齿生物标志物测定，以解决产前神经免疫相互作用，并使用先进的 建模技术将严格调查生命早期的保护和恢复因素， 儿童适应不良的后果。为达致这些目标，我们会从 儿童参加了纵向神经发育协议，其中包括胎儿脑RSFC MRI。一个新 数据收集浪潮，部分与NIH的青少年大脑认知发展（ABCD）相协调 研究方案，将在9岁时进行，并将包括在产前使用的同一扫描仪上进行MRI。在这些 参与者，胎儿全身性炎症，胎儿脑功能连接和儿童 将检查神经行为发育。我们的技术涉及高时间分辨率采样， 5种炎症标志物，C反应蛋白，白细胞介素（IL）1，6，10，TNF-α，在怀孕后15周， 通过产后12周，使敏感期和相互作用的影响隔离。的主要目标 这个项目是（i）确定胎儿大脑连接体异常与产前高血压有关， 炎症，（ii）表征产前高血压长期脑和行为后果 炎症，和（iii）分离出生后环境中的保护因子，预测有利的长期- 长期成果。因此，我们将能够有意义地评估是否以及如何产前炎症事件 影响发育中的胎儿大脑的功能性神经回路，以及长期的神经行为后果 这些协会。这项工作将大大促进我们不仅了解 长期影响产前炎症，也是孩子神经系统疾病的起源。

PROJECT SUMMARY The association between early inflammation and altered child neurobehavioral development is indisputable, but understanding of neurological phenomena underlying this association is almost entirely lacking. Studies in animals suggest that, even before birth, inflammation acts on developing neural connections to alter the course of development. However, these critical associations remain to be tested in the human brain. Here, we will examine prenatal inflammation, fetal neural programming effects, and child neurodevelopment in a unified framework. We will leverage an existing longitudinal cohort to evaluate whether inflammation in the prenatal period exerts influence over the developing fetal neural connectome, and subsequently increases risk for childhood disorders. We will pair advances in fetal resting-state functional connectivity (RSFC) MRI with innovations in tooth-biomarker assays to address prenatal neural-immune interactions, and using advanced modeling techniques will rigorously investigate protective and resilience factors in early life that mitigate maladaptive childhood outcomes. To achieve these objectives, we will attain deciduous tooth samples from children enrolled in a longitudinal neurodevelopmental protocol that included fetal brain RSFC MRI. A new wave of data collection, partially harmonized with the NIH’s Adolescent Brain Cognitive Development (ABCD) study protocol, will be conducted at age 9 and will include MRI on the same scanner used prenatally. In these participants, associations between fetal systemic inflammation, fetal brain functional connectivity, and child neurobehavioral development will be examined. Our technique involves high temporal resolution sampling of five inflammatory markers, C reactive protein, Interleukin (IL) 1, 6, 10, TNF-a, across post conception week 15 through postnatal week 12, enabling isolation of sensitive periods and interactive effects. The primary aims of this project are to (i) identify fetal brain connectome abnormalities associated with heightened prenatal inflammation, (ii) characterize long-term brain and behavioral consequences of heightened prenatal inflammation, and (iii) isolate protective factors in the postnatal environment that predict advantageous long- term outcomes. We will thus be able to meaningfully evaluate whether and how prenatal inflammatory events affect functional neurocircuitry of the developing fetal brain, and the long-term neurobehavioral consequences of those associations. Such work would constitute a substantial advance in our understanding of not only the long-term effects of prenatal inflammation, but also the origins of child neurological disorders.