Effects of Prenatal Opiates on Infant Brain and Neurobehavioral Development

摘要 在过去的十年中，怀孕期间阿片类药物的使用急剧增加，可能会对健康构成重大影响 母亲使用非法和/或处方药物所生婴儿数量迅速增加面临的挑战 阿片类药物。产前阿片类药物暴露(OE)与受损的神经行为、注意力和 婴儿期和儿童期的认知，暗示着持续的，可能终生的后果。这个胎儿 暴露发生在大脑发育和组织非同寻常的时期，使其成为 易受环境侮辱的影响。然而，人们对OE对早期人类大脑的影响知之甚少 可能导致报告的赤字的发展。这项建议的目标是量化影响。 OE对婴儿出生后1-12个月脑功能连通性发育的影响 与神经行为和认知结果的关系，并检查性别、其他产前药物 暴露和出生后的环境因素会缓和这些影响。我们的中心假设是胎儿 大脑的发育和组织被OE改变；在发展连接和网络方面存在缺陷 调节OE对同时发展神经行为和早期认知的负面影响；性别， 其他药物和出生后环境与OE相互作用，影响快速发展的生长轨迹 为新兴能力提供辅助的联系和网络。这一假设是基于研究小组的 孕期阿片类药物和其他药物暴露的母婴双胞胎的大量研究经验 (Jones，Grewen)，以及显示功能网络标准化发展的强劲初步数据 出生至2岁(GAO)，因产前阿片类药物和其他药物导致新生儿功能连接中断 (Grewen，Gao)，以及关于功能联系和行为效果之间的关联(Grewen，Gao)。 这项拟议研究的基本原理是，纵向研究将量化 初始神经损伤、婴儿性别和出生后环境对发育功能联系的影响。这个 假设将通过3个具体目标进行检验：1)量化OE对发育的损害程度 在2周和12个月时进行功能连接；2)确定OE的影响程度 关于神经行为、注意、自我调节和认知与功能障碍发展轨迹的关系 联系；3)确定婴儿性别、其他产前药物暴露和累积环境 风险指数缓和了OE对发展连通性的影响。这种方法是创新的，因为它将 使用假设驱动的分析以及新颖的探索性数据驱动和机器学习方法来 量化OE和其他药物暴露对功能回路的直接和交互影响。建议数 研究意义重大，因为自2000年以来，产前OE和NAS的比率增加了5倍，与 阿片类药物流行，而且因为收集到的知识有可能确定可能保护或 进一步损害这一高危群体中潜在的新生认知能力的日益增长的功能网络。

ABSTRACT Opioid use during pregnancy has increased dramatically in the past decade, and may pose significant health challenges for the rapidly growing number of exposed infants born to mothers using illicit and/or prescribed opioids. Prenatal opioid exposure (OE) is inconsistently related to impaired neurobehavior, attention, and cognition in infancy and childhood, suggesting persistent, potentially life-long, consequences. This fetal exposure occurs during a time of extraordinary brain growth and organization, making it a critical period of vulnerability to environmental insult. However, little is known about the effects of OE on early human brain development that may contribute to reported deficits. The objectives of this proposal are to quantify the effects of OE on the development of infant brain functional connectivity in postnatal months 1-12, to determine associations with neurobehavioral and cognitive outcomes, and to examine how gender, other prenatal drug exposures, and postnatal environmental factors moderate these effects. Our central hypothesis is that fetal brain development and organization are altered by OE; deficits in developing connections and networks mediate the negative effects of OE on simultaneously developing neurobehavior and early cognition; gender, other drugs and postnatal environment interact with OE to influence growth trajectories of rapidly developing connections and networks that subserve emerging abilities. This hypothesis is based on the study team’s substantial research experience with mother-infant dyads with prenatal opioid and other drug exposures (Jones, Grewen), and on strong preliminary data showing normative development of functional networks from birth to 2 years (Gao), disruptions in neonatal functional connectivity due to prenatal opioids and other drugs (Grewen, Gao), and on associations between functional connections and behavioral effects (Grewen, Gao). The rationale for the proposed research is that longitudinal study will quantify direct and interactive effects of initial neural insult, infant gender and postnatal environment on developing functional connections. The hypotheses will be tested with 3 Specific Aims: 1) Quantify the extent to which OE impairs developing functional connections at 2 weeks and again at 12 months; 2) Determine the extent to which the effects of OE on neurobehavior, attention, self-regulation and cognition are related to developmental trajectories of functional connections; 3) Determine how infant gender, other prenatal drug exposures, and a Cumulative Environmental Risk Index moderate the effects of OE on developing connectivity. This approach is innovative because it will employ hypothesis-driven analyses as well as novel, exploratory data-driven and machine learning methods to quantify direct and interactive effects of OE and other drug exposures on functional circuitry. The proposed research is significant because rates of prenatal OE and NAS have increased 5-fold since 2000, in parallel with the opioid epidemic, and because knowledge gleaned has potential to identify factors that may protect or further harm growing functional networks underlying nascent cognitive abilities in this at-risk group.