Effects of prenatal cocaine on early brain functional connectivity and behavior

摘要 产前可卡因暴露(PCE)一直与注意力受损以及行为和生理受损有关 婴幼儿的自我调节，表明对基本技能的持续负面影响 最佳学习和社交能力。妊娠期接触可卡因的时间是 非凡的大脑生长和组织，紧随其后的是大规模的扩张和 在生命的第一年，完善大脑结构、功能连接和网络组织。然而， 关于PCE对人类早期大脑发育的影响，人们知之甚少，这可能有助于已报道的 认知和神经行为缺陷。这项提案的目标是量化PCE对 婴儿出生后0-12个月脑功能连通性的发育轨迹 与神经行为和认知结果的关系，并检查具体的产妇护理 这些特征(敏感度、刺激性)会缓和这些影响。我们的中心假设是胎儿的大脑 发展和组织由PCE改变；在发展功能连接方面的缺陷调节 PCE对同时发育的神经行为和早期认知的负面影响 行为和环境与PCE相互作用，影响发展中的联系和 为新兴能力提供辅助的网络。这一假设是基于联合PIs强劲的初步数据 描述功能网络从诞生到2年(GAO)的规范发展，功能网络的中断 新生儿因产前可卡因和其他药物而产生的连通性(Grewen，Gao)，以及联合调查员 艾登对PCE的行为影响及其通过母性行为的调节的纵向研究 婴儿、学步儿童和儿童。我们建议研究婴儿休息状态、功能连通性和行为 3组婴儿在2周、6个月和12个月时的发育：伴有或不伴有PCE的120例 接触其他药物(尼古丁、酒精、大麻和/或鸦片)，100接触相同的其他药物 但不含可卡因(OD)，100%无毒品(CTL)。我们将测量母性敏感度(初级)、母性 刺激性(次级)和累积环境风险指数，以确定出生后的适度 PCE对发展互联互通的影响。理由是纵向研究将揭示产前药物的影响， 确定大脑功能连接的出生后轨迹是仅仅延迟还是永久 被最初的PCE侮辱改变，并确定导致功能更大风险或弹性的出生后因素。 国家网络发展。这种创新的方法将量化初始神经的直接和相互作用的影响 缺陷和出生后环境对大脑和认知发展模式的影响，并将适用于 假设驱动和数据驱动的分析方法，包括机器学习，以表征机制 潜在的PCE对大脑发育轨迹的影响。收集到的知识有可能更早地提供信息， 更有效的干预措施，以预防或减少这一高危人群的学习和行为障碍。

ABSTRACT Prenatal cocaine exposure (PCE) is consistently related to impaired attention and behavioral and physiological self-regulation in infants and young children, suggesting persistent negative impact on skills essential for optimal learning and social competence. Gestational exposure to cocaine occurs during a time of extraordinary brain growth and organization, which is immediately followed by massive expansion and refinement of brain structure, functional connections and network organization in the first year of life. However, little is known about the effects of PCE on early human brain development that may contribute to reported deficits in cognition and neurobehavior. The objectives of this proposal are to quantify the effects of PCE on the developmental trajectory of infant brain functional connectivity in postnatal months 0-12, to determine associations with neurobehavioral and cognitive outcomes, and to examine how specific maternal caregiving characteristics (Sensitivity, Harshness) moderate these effects. Our central hypothesis is that fetal brain development and organization are altered by PCE; deficits in developing functional connections mediate the negative effects of PCE on simultaneously developing neurobehavior and early cognition; postnatal maternal behaviors and environment interact with PCE to influence growth trajectories of developing connections and networks that subserve emerging abilities. This hypothesis is based on the Co-PIs'strong preliminary data describing normative development of functional networks from birth to 2 years (Gao), disruptions in functional connectivity due to prenatal cocaine and other drugs in neonates (Grewen, Gao), and on Co-investigator Eiden's longitudinal studies of the behavioral effects of PCE and its moderation by maternal behaviors in infants, toddlers and children. We propose to study infant resting state functional connectivity and behavioral development at 2 weeks, 6 months and 12 months in 3 groups of infants: 120 with PCE with or without exposure to other drugs (nicotine, alcohol, marijuana, and/or opiates), 100 exposed to the same other drugs but without cocaine (OD), 100 drug-free (CTL). We will measure Maternal Sensitivity (primary), Maternal Harshness (secondary) and an index of cumulative environmental risk to determine postnatal moderation of PCE effects on developing connectivity. The rationale is that longitudinal study will reveal prenatal drug effects, determine whether the postnatal trajectory of brain functional connections is merely delayed or permanently altered by initial PCE insult, and ascertain postnatal factors contributing to greater risk or resilience in func- tional network development. This innovative approach will quantify direct and interactive effects of initial neural deficit and postnatal environmental influences on patterns of brain and cognitive development, and will apply hypothesis-driven and data-driven analytic methods, including machine learning, to characterize mechanisms underlying PCE effects on trajectory of brain development. Knowledge gleaned has potential to inform earlier, more effective interventions to prevent or reduce learning and behavioral impairments in this at-risk population.