Early Indices of Atypical Neurodevelopment with Fetal Alcohol Exposure

描述(由申请人提供)：众所周知，患有胎儿酒精综合征(FAS)特征的面部变形症的儿童有认知和行为缺陷。然而，更多有产前酒精暴露(PAE)史的儿童也有认知加工障碍，即使没有面部变形。这种更广泛的表型，称为胎儿酒精谱系障碍(FASD)，其患病率至少是Fas的10倍，占总人口的1%以上。在缺乏典型的面部变形障碍的情况下，目前还没有可靠的生物行为标记物来识别患有FASD的幼儿，这往往会推迟干预，直到学龄儿童的行为缺陷变得明显。我们研究计划的长期目标是解决临床挑战，即在婴儿中开发早期和可靠的PAE指标，以便干预 可以在开发的早期阶段实施。本研究项目的目标是通过结合使用一组新颖的母婴酒精生物标记物和有效的产妇问卷，建立132名儿童的出生队列，使用一种创新的方法来评估PAE，然后使用最先进的脑磁图和脑电图仪(MEG/EEG)和行为测量来测量6-20个月大时的神经发育，以确定这些儿童功能性脑损伤的早期指标。拟议工作的基本原理是，较早的识别和干预有助于 仅靠行为测量还不能可靠地确定与PAE相关的长期不良神经行为后果的高危儿童。我们先前的工作表明，生物标志物和调查问卷的结合将为确认妊娠中期或晚期的酒精暴露提供最佳的敏感性和特异性。此外，基于我们之前对幼儿所做的工作，我们假设患有PAE的儿童将表现出感觉运动功能延迟或受损，这可以通过脑磁图/EEG在婴儿中进行测量，这些测量将表明PAE对与行为缺陷相对应的大脑发育产生更广泛的影响。为了验证这一假设，我们将使用同步的脑磁图/脑电图确定6个月和20个月大的PAE婴儿感觉运动障碍的神经生理学指标，以及它们与更广泛的行为和认知障碍的对应关系。最后，我们将确定酒精生物标记物的预测能力，以及在6个月龄时收集的一系列神经成像和神经行为测量，以确定20个月龄时的大脑功能和行为缺陷。这项创新的前瞻性研究将建立一个具有良好特征的出生队列，使用多方面的方法来确认PAE，并随后将使用独特的多模式神经成像和行为测试方案来确定婴儿非典型脑发育的早期指标。这项拟议研究的意义在于为克服FASD儿童早期诊断的挑战奠定了临床基础，取得了重大的纵向进展。

DESCRIPTION (provided by applicant): It is well-established that children with the facial dysmorphias characteristic of fetal alcohol syndrome (FAS) have cognitive and behavioral deficits. However, many more children with a history of prenatal ethanol exposure (PAE) also have impaired cognitive processing, even in the absence of facial dysmorphia. The prevalence of this broader phenotype, termed fetal alcohol spectrum disorder (FASD), is at least 10 times greater than FAS and represents greater than 1% of the population. In the absence of the characteristic facial dysmorphia, there are currently no reliable bio-behavioral markers to identif young children with FASD, which often delays intervention until behavioral deficits become apparent in school-aged children. The long-term goal of our research program is to address the clinical challenge of developing early and reliable indices of PAE in infants so that interventions can be implemented at earlier stages of development. The objective of this current research project is to establish a birth cohort of 132 children using an innovative approach for the assessment of PAE, through the combined use of a novel panel of maternal and infant ethanol biomarkers and validated maternal questionnaires, and then to measure neurodevelopment using state-of-the-art magneto- and electro- encephalography (MEG/EEG) and behavioral measures at 6 & 20 months of age to identify early indices of functional brain damage in these children. The rationale for the proposed work is that earlier identification and intervention leads to better outcomes; and behavioral measures alone have yet to reliably identify children at- risk for the long-term adverse neurobehavioral consequences associated with PAE. Our prior work suggests that a combination of biomarkers and questionnaires will provide the best sensitivity and specificity for confirming 2nd or 3rd trimester alcohol exposure. Furthermore, based on our prior work in toddlers, we hypothesize that children with PAE will demonstrate delayed or impaired sensorimotor functioning that can be measured with MEG/EEG in infants and these measures will indicate a broader impact of PAE on brain development corresponding to behavioral deficits. To test this hypothesis, we will identify neurophysiological indices of sensorimotor deficits in 6- & 20-month-old infants with PAE using simultaneous MEG/EEG and their correspondence to broader behavioral and cognitive deficits. Finally, we will determine the predictive ability of ethanol biomarkers and the battery of neuroimaging and neurobehavioral measures collected at 6 months of age to identify functional brain and behavioral deficits at 20 months of age. This innovative, prospective study will establish a well-characterized birth cohort using a multi-faceted approach to confirm PAE and will subsequently use a unique multimodal neuroimaging and behavioral testing regimen to identify early indices of atypical brain development in infants. The significance of the proposed research lies in the prospect of establishing a clinical foundation for a significant vertical advancement in overcoming the challenge of earlier diagnosis in children with FASD.