Prenatal cocaine exposure and functional connectivity in early infancy

描述（由申请人提供）：产前可卡因暴露（PCE）与婴儿、儿童和青少年的认知功能缺陷有关，但对子宫内可卡因暴露对早期大脑发育的影响知之甚少，而早期大脑发育可能导致这些缺陷。长期目标是更好地理解PCE导致的认知障碍的神经机制。本提案的目的是量化PCE对148名2-6周龄婴儿的功能连接网络的影响，这些婴儿已经确定了可卡因相关的前额叶和额叶皮质灰质（GM）损失。核心假设是，PCE的影响将导致与前额叶和额叶皮质中GM损失相关的功能连接模式的减少，并且子宫内暴露程度越高，连接减少的范围就越广。这一假设是在申请人提供的初步数据的基础上制定的：1)描述了早在2周大的典型发育婴儿中功能性网络的存在；2)表明，在子宫内暴露于可卡因的婴儿，其前额叶和额叶灰质体积比无毒品对照组和暴露于其他药物（尼古丁、酒精、大麻、阿片类药物）的婴儿要小。这项研究的基本原理是，在出生后的第一周测量PCE婴儿的功能连通性，将为研究认知缺陷背后的神经回路发育变化奠定基础，提示增强对这些缺陷的恢复力的因素，并揭示早期干预的目标。这一假设将通过追求两个特定目标来验证：1)利用46名暴露于可卡因和其他药物（PCE）的婴儿、58名无药物对照（CTL）的婴儿和44名暴露于PCE组所经历的相同药物（尼古丁、酒精、大麻和/或阿片类药物）但不含可卡因的婴儿的已有数据，量化PCE对多层次功能连接的影响；2)确定额叶和前额叶连接与婴儿发育的认知、行为和生物学标志物的关系。在第一个目标下，一种经过验证的基于种子的分析、独立成分分析（ICA）和图论分析方法将被用于描述由结构缺陷锚定的前额叶和新生儿前额叶功能网络的强度和密度。在第二个目标下，2-6周的区域、网络水平和全脑功能连接将与3个月时测量的婴儿认知、行为和生理发育的测量有关。这种方法是创新的，因为它将首次应用这些发达的分析方法来描述这一高危群体早期婴儿大脑活动的早期异常。这项提议的研究意义重大，因为它是

DESCRIPTION (provided by applicant): Prenatal cocaine exposure (PCE) is related to deficits in cognitive function in infants, children and adolescents, however little is known about the effects of in utero cocaine exposure on early brain development that may contribute to these deficits. The long term goal is to better understand neural mechanisms underlying the cognitive impairments attributable to PCE. The objective of this proposal is to quantify the effects of PCE on functional connectivity networks in a pre-existing dataset from 148 infants, tested at 2-6 weeks of age, in which cocaine-related prefrontal and frontal cortical gray matter (GM) loss has already been determined. The central hypothesis is that effects of PCE will entail reductions in patterns of functional connectivity that are related to GM loss in prefrontal and frontal cortex, and that greater in utero exposure will be related to more widespread reductions in connectivity. This hypothesis has been formulated on the basis of preliminary data produced by the applicants that: 1) describes the presence of functional networks in typically developing infants as early as 2 weeks of age; 2) shows that infants exposed to cocaine in utero display reduced prefrontal and frontal gray matter volumes compared to drug-free controls and to infants exposed to other drugs (nicotine, alcohol, marijuana, opiates). The rationale for the proposed research is that measurement of functional connectivity in infants with PCE in the first weeks of life will lay the foundation for study of developmental changes in neural circuitry that underlie cognitive deficits, suggest factors that bolster resilience against these deficits, and reveal targets for early intervention. This hypothesis will be tested by pursuit of two specific aims: 1) Quantify the effects of PCE on multi-level functional connectivity using pre-existing data from 46 infants exposed to cocaine and other drugs (PCE), 58 drug-free controls (CTL) and 44 exposed to the same drugs experienced by the PCE group (nicotine, alcohol, marijuana and/or opiates) but without cocaine; 2) Determine the relationship of frontal and prefrontal connectivity to cognitive, behavioral and biological markers of infant development. Under the first aim, a proven approach of seed-based analysis, independent components analysis (ICA) and graph theoretic analysis, which is well-established as feasible in the applicants' hands, will be used to describe strength and density of prefrontal and frontal neonatal functional networks anchored by structural deficits. Under the second aim regional, network level and whole brain functional connectivity at 2-6 weeks will be related to measures of infant cognitive, behavioral and physiological development measured at 3 months. The approach is innovative because it will be first to apply these well-developed analyses methods to characterize early abnormalities in brain activity in early infancy in this at-risk group. The proposed research is significant because it is expected to identify a neurophenotype of cocaine's effects on early brain function prior to exposure to the damaging environmental influences that accompany maternal drug abuse, and provide support for more detailed longitudinal study of PCE's effects on developing trajectories of brain structure and function.