ENRICH-2: Stress-Reactivity and Self-Regulation in Infants with Prenatal Alcohol Exposure

摘要/摘要 诊断胎儿酒精谱系障碍(FASD)的新临床指南将自我调节列为一项 受产前酒精暴露(PAE)影响的儿童的关键行为缺陷。有一个基本的 对这种缺陷的潜在机制、谱系和严重程度的认识差距在生命早期和 识别它们的最佳分析方法。此外，产前应激和产后应激的影响 环境对PAE诱导的改变知之甚少。在乙醇的这种更新应用中， 神经发育、婴儿和儿童健康(ENRICH)研究，我们寻求持续支持我们已建立的 招聘/保留管道，并提出新的高度创新的应激反应/调节研究 婴幼儿PAE。长期目标是尽早确定PAE后非典型脑发育的指标。 尽可能使早期干预成为可能。这个应用程序的目标是继续关注适度 PAE和PAE对婴儿应激反应/调节的影响及其机制 下丘脑-垂体-肾上腺(HPA)轴和自主神经系统(ANS)功能改变。我们会 评估PAE(感兴趣暴露)、产前应激(调节因子)、生物学措施之间的关系 HPA轴(介质)和婴儿应激反应/调节的生理和行为测量 (结果)。这项提议的理由是相信HPA和ANS的失调会导致 PAE儿童应激反应/调节的改变可能是PAE诱发的一些关键因素的基础 行为缺陷，并增加了继发性残疾的脆弱性。中心假设是PAE将 与婴儿应激反应增强和自我调节能力较差有关(超出了产前的影响 压力)通过胎儿对HPA轴的编程。这一假设是在以下基础上提出的 UNM的临床前数据和Rich-1当前筹资周期的临床数据，将由 追求三个具体目标，以评估PAE对1)胎儿编程的贡献效果 HPA轴，评估为HPA轴的关键胎盘和脐带标志物的表达；2)婴儿 基础应激源恢复期生理反应性(心率变异性[HRV])的动态变化 在新生儿期和6个月大时进行评估；3)婴儿的行为反应和调节 在新生儿期和6个月大时进行评估。综合多系统方法 本研究所采用的方法具有很高的创新性，以前从未使用过。创新由以下因素进一步推动 我们的重点是适度的PAE和评估受损的应激反应/调节轨迹的能力 (新生儿，为期6个月的评估)在一项大型前瞻性队列研究中。这项研究具有重要意义，因为它 涉及神经内分泌、电生理和 应激反应/调节受损的行为指数，这将导致分析技术的改进 为了在高阶行为缺陷显现之前准确识别婴儿期的PAE缺陷。

SUMMARY/ABSTRACT The new clinical guidelines for diagnosing Fetal Alcohol Spectrum Disorders (FASD) list self-regulation as one of the key behavioral deficits in children affected by prenatal alcohol exposure (PAE). There is a fundamental gap in knowledge about the underlying mechanisms, spectrum, and severity of such deficits early in life and the best analytical approaches to identify them. In addition, the effect of prenatal stress and postnatal environment on PAE-induced alterations is poorly understood. In this renewal application of the Ethanol, Neurodevelopment, Infant, and Child Health (ENRICH) study, we seek continuous support for our established recruitment/retention pipeline, and propose new highly innovative studies of stress reactivity/regulation in infants with PAE. The long-term goal is to identify indices of atypical brain development following PAE as early as possible to enable early interventions. The objective of this application is to continue our focus on moderate PAE and to evaluate PAE effects on infant stress reactivity/regulation and the mechanisms underpinning altered hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS) functioning. We will evaluate the relationship between PAE (exposure of interest), prenatal stress (moderator), biological measures of HPA axis (mediators), and physiological and behavioral measures of stress reactivity/regulation in infants (outcomes). The rationale for this proposal is driven by the conviction that HPA and ANS dysregulation leading to altered stress reactivity/regulation in children with PAE might be the basis for some of the key PAE-induced behavioral deficits, and increased vulnerability to secondary disabilities. The central hypothesis is that PAE will be associated with heightened infant stress reactivity and poorer self-regulation (beyond the effect of prenatal stress) through fetal programming of the HPA axis. This hypothesis has been formulated on the basis of preclinical data at UNM and clinical data from the current funding cycle of ENRICH-1 and will be tested by pursuing three specific aims, which evaluate the contributing effects of PAE on 1) Programming of the fetal HPA axis, assessed as expression of key placental and umbilical cord markers of HPA axis; 2) Infant physiological reactivity (heart rate variability [HRV]) dynamic changes during basal-stressor-recovery periods assessed in the newborn period and at 6-months of age; 3) Infant behavioral reactivity and regulation assessed in the newborn period and at 6-months of age. The comprehensive multi-systemic approach employed in this study is highly innovative and has not previously been used. Innovation is further driven by our focus on moderate PAE and ability to assess the trajectory of impaired stress reactivity/regulation (newborn, 6-months evaluations) in a large prospective cohort study. This research is significant because it involves comprehensive repeated-measures assessment of neuroendocrine, electrophysiological, and behavioral indices of impaired stress reactivity/regulation, which will lead to refinement of analytical techniques for accurate identification of PAE deficits in infancy before higher-order behavioral deficits manifest.