Early Indices of Atypical Neurodevelopment with Fetal Alcohol Exposure

描述（由申请人提供）：众所周知，具有胎儿酒精综合征（FAS）特征的面部畸形的儿童具有认知和行为缺陷。然而，更多有产前乙醇暴露史（PAE）的儿童也有认知加工受损，即使没有面部畸形。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，占人口的1%以上。在没有特征性面部畸形的情况下，目前没有可靠的生物行为标记物来识别FASD幼儿，这通常会延迟干预，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，即开发婴儿PAE的早期和可靠指标，以便干预措施 可以在开发的早期阶段实施。目前这项研究项目的目的是建立一个132名儿童的出生队列，使用一种创新的方法评估PAE，通过联合使用一组新的孕产妇和婴儿乙醇生物标志物和经验证的孕产妇问卷，然后用最先进的磁脑电描记术（MEG/EEG）和行为测量来测量6岁和6岁时的神经发育。20个月大，以确定这些儿童功能性脑损伤的早期指标。拟议工作的理由是，早期识别和干预导致 更好的结果;而行为测量本身还不能可靠地识别出与PAE相关的长期不良神经行为后果的风险儿童。我们之前的工作表明，生物标志物和问卷调查的组合将为确认第二或第三孕期酒精暴露提供最佳的灵敏度和特异性。此外，基于我们之前在幼儿中的工作，我们假设患有PAE的儿童将表现出延迟或受损的感觉运动功能，可以在婴儿中用MEG/EEG测量，这些测量将表明PAE对大脑发育的更广泛影响，对应于行为缺陷。为了验证这一假设，我们将确定在6个月和20个月大的婴儿与PAE的感觉运动缺陷的神经生理学指标，同时使用MEG/EEG和他们的对应关系，以更广泛的行为和认知缺陷。最后，我们将确定乙醇生物标志物的预测能力和在6个月大时收集的神经成像和神经行为测量的电池，以确定20个月大时的功能性大脑和行为缺陷。这项创新的前瞻性研究将使用多方面的方法建立一个特征良好的出生队列来确认PAE，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大脑发育的早期指标。拟议研究的意义在于为克服FASD儿童早期诊断的挑战建立一个显著的纵向进步的临床基础的前景。

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.