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）会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。现有的研究结果揭示了与PCE相关的多种语言功能缺陷/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（说的单词较少）；4)对听觉刺激的异常反应。观察到的具体发现模式表明，从低水平的感知缺陷（如语音处理）到更高水平的元认知缺陷（如语义、句法、理解），存在多层次的语言处理缺陷。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幼儿，这些语言功能障碍的特征在多大程度上随着系统需求的变化而变化，例如，从语音发展（早期儿童）到对复杂语义和句法关系的理解（童年晚期和青春期），是未知的。考虑到PCE的致畸作用，很可能会影响多个系统，但观察到的损伤也可能因与发展和/或学术压力相关的系统需求变化而有所不同。我们假设观察到的感知缺陷是颞叶听觉感知系统异常发展的结果，而观察到的高级语言缺陷是由于前额叶功能受到更广泛的影响。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元认知障碍的增加。该研究将与一项正在进行的PCE纵向研究合作，以检查PCE青少年行为样本中语言处理缺陷的潜在神经生物学。具体来说，本研究的目标是：1)使用事件相关电位（ERP）来评估PCE青少年和未暴露于可卡因（NCE）的对照组儿童的神经认知语言特征；2)研究早期行为表现（通过语言和认知技能的标准化测试来衡量）与这些神经认知语言概况之间的关系；c)将这些大脑行为模式与与感知或元认知技能（COMT和BDNF）相关的候选基因多态性联系起来，以便建立与PCE儿童语言表现差相关的内表型。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损伤相关的潜在神经生物学之间关系的理解，而关键语言技能对学业和社会成功至关重要。

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.