Cocaine and Maternal Behavior: Effects on Trajectory of Infant Brain Development

 描述(申请人提供)：产前可卡因暴露(PCE)与婴儿期、儿童期和青春期的认知和行为缺陷有关，但研究结果多样且不一致，出生后环境对此类发育结果起着重要作用。儿童和青春期的核磁共振研究报告说，PCE对大脑结构、激活和与行为的联系的影响类似地不一致。尽管孕期暴露发生在大脑发育和组织异常异常的时期，而且出生后的几个月以大脑结构和连接的大规模扩张为标志，但对于PCE对人类早期大脑发育的影响，可能导致认知功能缺陷的报道，人们知之甚少。其长期目标是了解母婴的影响。 可卡因暴露对大脑结构和功能的早期发育的影响，以及了解出生后因素可能如何保护或进一步损害作为新生认知能力基础的结构的生长和连接。这项建议的目的是量化PCE对出生后1-9个月婴儿大脑结构发育轨迹的影响，确定灰质和白质(GM，WM)生长轨迹对PCE早期认知功能影响的程度，并确定缓和这些影响的母体因素。中心假说是PCE损害了胎儿大脑的发育；GM和WM生长和连通性的缺陷介导了PCE同时发展早期认知技能的效果；出生后母亲的行为与PCE相互作用，影响大脑结构和功能的发育。这一假设是基于申请人强有力的初步数据，这些数据显示，与非毒品婴儿和暴露于其他药物(尼古丁、大麻、酒精、鸦片类药物)的婴儿相比，暴露于可卡因的新生儿的皮质前额叶和额叶GM体积和连接性减少，并且额叶前额叶GM体积与孕期可卡因暴露时间呈负相关。这项研究的基本原理是，纵向研究将确定PCE是否只是推迟或永久改变了脑生长的出生后轨迹，确定了导致大脑发育更大风险或弹性的出生后因素，并为早期干预提出了新的机制和目标。该假说将以三个具体目标进行检验：1)确定PCE对婴儿大脑结构发育轨迹的影响；2)确定PCE对早期认知功能的影响在多大程度上可以通过GM和WM发展轨迹进行预测；3)确定母亲行为对大脑发育的调节作用。该方法具有创新性，因为它将母亲对婴儿的行为和生理反应与宫内暴露近距离的新生儿大脑成像相结合，以量化初始神经缺陷和出生后环境对随后的大脑和认知发育模式的直接和交互影响。拟议的研究具有重要意义，因为收集到的知识有可能为早期干预提供信息，以预防或减少这一弱势群体的认知障碍。

 DESCRIPTION (provided by applicant): Prenatal cocaine exposure (PCE) is related to cognitive and behavioral deficits in infancy, childhood and adolescence, however findings are diverse and inconsistent across studies, and the postnatal environment plays a powerful role in such developmental outcomes. MRI studies in childhood and adolescence report similarly inconsistent effects of PCE on brain structure, activation and links to behavior. Although gestational exposure occurs during a time of extraordinary brain growth and organization, and the months following birth are marked by massive expansion of brain structure and connectivity, little is known about the effects of PCE on early human brain development that may contribute to reported deficits in cognitive function. The long term goal is to understand prenatal effects of cocaine exposure on early development of brain structure and function, and to discern how postnatal factors may protect or further harm growth and connectivity of structures underlying nascent cognitive abilities. The objectives of this proposal are to quantify the effects of PCE on the developmental trajectory of infant brain structure in postnatal months 1-9, to determine the extent to which gray and white matter (GM, WM) growth trajectories contribute to the effects of PCE on early cognitive function, and to identify maternal factors that moderate these effects. The central hypothesis is that fetal brain development is impaired by PCE; deficits in GM and WM growth and connectivity mediate the effect of PCE on simultaneously developing early cognitive skills; and postnatal maternal behaviors interact with PCE to influence growth of brain structure and function. This hypothesis is based on the applicant's strong preliminary data showing reduced cortical prefrontal and frontal GM volume and connectivity in cocaine-exposed neonates compared with drug-free infants and infants exposed to other drugs (nicotine, marijuana, alcohol, opiates), and inverse association between prefrontal GM volume and duration of gestational cocaine exposure. The rationale for this research is that longitudinal study will determine whether the postnatal trajectory of brain growth is merely delayed or permanently altered by PCE, ascertain postnatal factors that contribute to greater risk or resilience in developing brain, and suggest new mechanisms and targets for earlier intervention. The hypothesis will be tested with three Specific Aims: 1) Determine effects of PCE on developmental trajectories of infant brain structure; 2) Determine the extent to which the effects of PCE on early cognitive functions are predicted by GM and WM developmental trajectories; 3) Determine the moderating effects of maternal behavior on brain development. The approach is innovative because it will integrate maternal behavioral and physiological responses to infant with neonatal brain imaging proximal to in utero exposure, in order to quantify the direct and interactive effects of initial neural deficit and postnatal environment on subsequent patterns of brain and cognitive development. The proposed research is significant because knowledge gleaned has potential to inform earlier interventions to prevent or reduce cognitive disabilities i this vulnerable population.