Neurobiology of language function in adolescents exposed to cocaine in utero

描述（由申请人提供）：产前可卡因暴露（PCE）可能对神经发育和认知产生广泛影响，语言技能通常会受到影响。现有的研究结果显示，与PCE相关的语言功能存在多种缺陷/延迟，包括：1）语言习得年龄延迟，2）接受性语言较差，3）表达性语言较差（说出的单词较少）和4）对听觉刺激的反应异常。观察到的特定模式的发现表明，从低水平的知觉缺陷（例如，语音处理）到更多的元认知缺陷（例如，语义、语法、理解）。目前尚不清楚的是，这些缺陷是否源于相同或不同的潜在神经生物学异常。此外，由于现有的研究着眼于婴儿和幼儿，这些语言功能障碍的特征随着系统需求的变化而变化的程度，例如，从语音发展（幼儿期）到理解复杂的语义和句法关系（幼儿期和青少年期），都是未知的。考虑到PCE的致畸作用，可能会影响多个系统，但观察到的损伤也可能因与发育和/或学术压力相关的系统需求变化而不同。我们假设观察到的知觉缺陷是颞叶听觉知觉系统异常发展的结果，而观察到的更高级别的语言缺陷是由于前额叶功能的更广泛的影响。此外，我们预测与发育相关的受影响系统的相对权重会发生变化，这将导致年龄较大的儿童和青少年的元认知障碍增加。拟议的研究将与正在进行的PCE纵向研究合作，以研究PCE青少年行为样本中语言处理缺陷的潜在神经生物学。具体而言，本研究的目的是：1）使用事件相关电位（ERP）评估PCE青少年和未暴露于可卡因（NCE）的对照儿童的神经认知语言特征; 2）检查早期行为表现之间的关系（通过语言和认知技能的标准化测试测量）和这些神经认知语言概况;以及c）将这些脑行为模式与已经与感知或元认知技能（COMT和BDNF）相关的候选基因中的多态性联系起来，以便建立与PCE儿童的不良语言表现相关的内表型。本提案中概述的研究将直接影响我们对产前可卡因暴露与关键语言技能受损相关的潜在神经生物学之间关系的理解，这些技能对学术和社会成功至关重要。 公共卫生相关性：产前可卡因暴露（PCE）可以改变正常的神经发育，并影响婴儿的认知和行为功能，从而使其成为一个重要的公共卫生问题。一个重要的研究机构现在已经确定，在许多认知任务中，PCE相对于非暴露儿童的表现较差，语言技能经常受到影响。本提案中概述的研究旨在通过识别这些障碍的神经生物学位点并探索PCE中与语言技能相关的认知发展轨迹来完善我们对PCE相关语言障碍的理解。

DESCRIPTION (provided by applicant): Prenatal cocaine exposure (PCE) can have broad effects on neural development and cognition, with language skills routinely being affected. Extant findings have revealed multiple deficits/delays in language function associated with PCE including: 1) delayed age for language acquisition 2) poorer receptive language 3) poorer expressive language (fewer words spoken) and 4) abnormal response to auditory stimuli. The specific pattern of findings observed indicates language processing deficits at multiple levels from low-level perceptual deficits (e.g., speech processing) to more metacognitive deficits (e.g., semantics, syntax, comprehension). What is unknown is whether these deficits stem from the same or different underlying neurobiological anomalies. Moreover, because extant studies have looked at infants and young children, the extent to which these profiles of language dysfunction change as system demands change, e.g., from phonological development (early childhood) to the understanding of complex semantic and syntactic relationships (late childhood and adolescence), is unknown. It is likely, given the teratogenic effect of PCE, that multiple systems are affected, but also that the observed impairments may differ as a function of changes in system demands associated with development and/or academic pressures. We hypothesize that the perceptual deficits observed are a result of anomalous development of auditory perceptual systems in the temporal lobe and that the higher-level language deficits observed are due to a more diffuse effect on prefrontal lobe function. Additionally, we predict a change in the relative weighting of the affected systems associated with development, which will result in an increase in metacognitve impairment for older children and adolescents. The proposed research will partner with an ongoing longitudinal study of PCE to examine the underlying neurobiology of language processing deficits in a well-characterized behavioral sample of PCE adolescents. Specifically, the goals of the proposed research are 1) to use event related potentials (ERP) to assess the neurocognitive language profiles of PCE adolescents and of control children who were not exposed to cocaine (NCE); 2) to examine the relationship between earlier behavioral performance (measured by standardized tests of language and cognitive skills) and these neurocognitive language profiles; and c) to link these brain-behavior patterns to polymorphisms in candidate genes that have been associated with perceptual or metacognitive skills (COMT and BDNF), in order to establish an endophenotype associated with poor language performance in PCE children. The research outlined in this proposal will have a direct impact our understanding of the relationship between prenatal cocaine exposure and the underlying neurobiology associated with impairments in critical language skills that are important for academic and social success. PUBLIC HEALTH RELEVANCE: Prenatal cocaine exposure (PCE) can alter normal neural development and affect the infant's cognitive and behavioral function throughout its lifespan, thus making it an important public health concern. A significant body of research has now identified poorer performance in PCE relative to non-exposed children across a number of cognitive tasks, with language skills routinely affected. The research outlined in this proposal aims to refine our understanding of the language impairments associated with PCE by identifying the neurobiological locus of these impairments and exploring the cognitive- developmental trajectories associated with language skills in PCE.