Effects of prenatal cocaine on early brain functional connectivity and behavior

摘要 产前可卡因暴露（PCE）始终与注意力受损以及行为和生理 婴儿和幼儿的自我调节能力，这表明对婴儿和幼儿的基本技能产生了持续的负面影响， 最佳学习和社交能力。吉西安诺接触可卡因的时间是 非凡的大脑生长和组织，紧接着是大规模的扩张， 在生命的第一年，大脑结构，功能连接和网络组织的细化。然而，在这方面， 关于PCE对早期人类大脑发育的影响知之甚少，这可能有助于报告 认知和神经行为缺陷。本提案的目的是量化PCE对 出生后0-12个月婴儿脑功能连接的发育轨迹，以确定 与神经行为和认知结果的关联，并研究特定的母亲行为如何影响 特性（灵敏度，粗糙度）缓和这些影响。我们的核心假设是胎儿的大脑 PCE改变了发育和组织;发育功能连接的缺陷介导了 PCE对同时发育的神经行为和早期认知的负面影响;产后母亲 行为和环境与PCE相互作用，影响发展中的联系的增长轨迹， 有助于新兴能力的网络。这一假设基于Co-PI强有力的初步数据 描述了从出生到2岁的功能网络的规范性发展（Gao），功能网络的中断， 新生儿中产前可卡因和其他药物引起的连通性（Grewen，Gao），以及合作研究者 Eiden对PCE的行为效应及其受母亲行为调节的纵向研究， 婴幼儿和儿童。我们建议研究婴儿静息状态的功能连接和行为 3组婴儿在2周、6个月和12个月时的发育：120例PCE伴或不伴 暴露于其他药物（尼古丁，酒精，大麻和/或阿片类药物），100暴露于相同的其他药物 但不含可卡因（OD），100无药物（CTL）。我们将测量母体敏感性（主要）， 粗糙度（次要）和累积环境风险指数，以确定出生后的适度 PCE对发展连通性的影响。基本原理是纵向研究将揭示产前药物的影响， 确定出生后大脑功能连接的轨迹仅仅是延迟还是永久性的 改变初始PCE损伤，并确定产后因素有助于更大的风险或弹性的功能， 国家网络发展。这种创新的方法将量化的直接和相互作用的影响， 缺陷和产后环境对大脑和认知发育模式的影响，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 PCE对大脑发育轨迹的潜在影响。收集的知识有可能提前告知， 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.