Preterm birth as a determinant of neurodevelopment and cognition in children: mechanisms and causal evidence

在全球范围内，每年有1500万婴儿早产（妊娠期不到37周）。在过去的20年里，出生过早或过小的婴儿的存活率有了显著提高，但幸存者的脑损伤却没有。因此，早产是儿童期发育和学习问题的主要原因。由于现代重症监护的幸存者已经开始进入成年期，很明显，早产的遗产会影响生命历程。脑瘫、自闭症、注意力缺陷多动障碍、低智商、记忆问题、语言和社交困难、抑郁症和精神分裂症在早产儿中更为常见。重要的是，没有有效的治疗方法来促进早产后的大脑健康。围产期医学面临的最大挑战之一是找到减少脑损伤和改善终身结局的新方法。在这个项目中，我们的目标是发现哪些父母/婴儿因素影响早产儿的大脑发育，以及这些因素是如何在生物学上“嵌入”大脑的。为了做到这一点，我们将研究英国范围内的大量人口，以确定早产的哪些方面会影响学龄期的神经发育和能力，以及一个人的社会经济环境是否会改变这些影响。这将有助于我们确定一系列风险/弹性因素对现实世界神经发育结果和学校表现的相对重要性。我们将使用复杂的大脑扫描（MRI）来定义通常影响早产儿的大脑生长变化，并将使用这些来研究早产如何导致大脑发育改变。我们将研究围产期应激环境（下丘脑-垂体-肾上腺轴活动）和/或低水平慢性全身性炎症标志物（DNA甲基化特征）是否将危险因素与MRI上的脑部变化联系起来。为了了解早产如何影响认知，我们将使用功能性MRI研究5岁早产儿和足月出生儿童的大脑。在这项技术中，儿童在MRI扫描仪中观看电影场景，并显示大脑系统对社交思维，注意力和记忆等认知任务的反应。我们希望这项分析能够确定早产儿的大脑网络是否改变了特定的认知能力，以及认知能力是否受到特定或更普遍的认知过程的改变的支持。例如，早产儿在学龄时往往有社交困难，但不知道这是由于推理他人的困难，还是因为语言或注意力方面的更普遍的困难，使社交互动具有挑战性。功能性磁共振成像将帮助我们梳理这些不同的解释，这是设计有针对性的认知训练干预措施的必要的第一步。总之，这项工作计划将解释为什么有些早产儿会发生脑损伤，而另一些则有弹性。它可以为促进健康的大脑生长和长期结果的新疗法铺平道路，因为压力反应和免疫系统是可以改变的，并且对认知缺陷的机械理解对于制定合理的认知训练策略至关重要。

Globally, 15 million infants are born preterm (less than 37 weeks of gestation) each year. Survival rates for infants born too soon or too small have improved dramatically over the past two decades, but brain injury among survivors has not. Consequently, preterm birth is a leading cause of developmental and learning problems in childhood. As survivors of modern intensive care have begun to reach adulthood, it is clear that the legacy of preterm birth can affect the life course. Cerebral palsy, autism, attention deficit hyperactivity disorder, low IQ, memory problems, language and social difficulties, depression, and schizophrenia are all more common in people who were born early. Importantly, there are no effective treatments for promoting brain health after preterm birth. One of the biggest challenges facing perinatal medicine is to find new ways to reduce brain injury and improve life-long outcomes. In this project, we aim to discover which parental/infant factors influence the brain development of preterm infants, and how those factors become biologically 'embedded' in the brain.To do this, we will study a large UK-wide population to determine which aspects of being born preterm impact neurodevelopment and ability at school age, and whether a person's socioeconomic circumstances modify these impacts. This will help us define the relative importance of a range of risk/resilience factors to real-world neurodevelopmental outcomes and school performance. We will use sophisticated brain scans (MRI) to define changes in brain growth that commonly affect premature babies and will use these to investigate how premature birth causes altered brain development. We will investigate whether the perinatal stress environment (hypothalamic-pituitary-adrenal axis activity) and/or markers of low-level chronic systemic inflammation (DNA methylation signatures) link risk factors with brain changes on MRI. To understand how prematurity affects cognition, we will study the brains of 5-year-olds who were born preterm and a comparator group of children born at term using functional MRI. In this technique, children view movie scenes whilst in the MRI scanner, and brain systems that activate in response to cognitive tasks such as social thinking, attention and memory, are revealed. We expect this analysis to determine whether brain networks that underpin specific cognitive abilities are altered in preterm children and whether cognitive capacities are underpinned by alterations in specific or more general cognitive processes. For example, children born preterm often have social difficulties at school age but it is unknown whether this is due to difficulties in reasoning about other people, or because of more general difficulties with language or attention that make social interactions challenging. Functional MRI will help us to tease apart these alternative accounts, which is a necessary first step for designing targeted cognitive training interventions.In summary, this programme of work will explain why some premature children develop brain injury while others are resilient. It could pave the way to new therapies that promote healthy brain growth and long-term outcomes because the stress response and immune systems are modifiable, and mechanistic understanding of cognitive deficits is essential for developing rational cognitive training strategies.