Neural Bases of ADHD in Fetal Drug or Alcohol Exposure

产前可卡因（PNCE）和酒精暴露（PNAE）导致持续的行为缺陷，在许多方面类似于注意缺陷多动障碍（ADHD）。虽然这种相似性表明在所有三组中涉及相似或重叠的神经回路，但特定缺陷及其对刺激物的不同反应性的细微差异表明特定回路内的中断和/或非重叠回路中的中断的性质存在差异。对动物的研究表明，PNCE导致多巴胺（DA）神经传递的突触后缺陷，这对兴奋剂如安非他明（AMPH）或哌甲酯（MPH）是难治的。在人类研究中，数据不太清楚，至少部分反映了识别纯PNCE或PNAE受试者的困难，部分反映了测量电路功能的工具最近才出现的事实。该项目将汇集三组研究人员，他们在子宫内酒精和可卡因暴露的发育后果，功能和结构神经成像以及ADHD方面具有专业知识，其总体目标是表征PNCE和PNAE中ADHD行为的神经相关性 个体，使用详细的神经认知测试，ERP和功能，结构和弥散张量（DTI）MRI的组合。我们将研究一组18岁的非裔美国青少年，他们的PNCE和PNAE在妊娠期间被前瞻性地确定。该队列的独特之处在于对招募进行了分层，以尽量减少酒精和可卡因的混淆。该研究有以下具体目的：1）使用fMRI来证实PNCE、PNAE和特发性ADHD个体的额-纹状体回路功能受损，并且额外的回路功能障碍有助于PNAE中的行为缺陷; 2）检验PNCE相关ADHD中的回路缺陷是突触后的，因此对MPH无反应的假设; 3）使用结构MRI， DTI检查结构异常对与ADHD相关缺陷相关的神经回路功能障碍的贡献; 4）识别PNAE患者计算障碍的神经相关因素，并检验PNAE的特征是有助于数字处理的顶叶网络激活的特定缺陷的假设。

Prenatal cocaine (PNCE) and alcohol exposure (PNAE) result in sustained behavioral deficits similar in many respects to attention deficit hyperactivity disorder (ADHD). While this similarity suggests the involvement of similar or overlapping neural circuits in all three groups, subtle differences in the specific deficits and their differential responsiveness to stimulants suggest differences in the nature of the disruptions within a specific circuit and/or disruptions in non-overlapping circuits. Studies in animals suggest that PNCE results in a post-synaptic defect in dopamine (DA) neurotransmission that is refractory to stimulants, such as amphetamine (AMPH) or methylphenidate (MPH). In human studies, the data are less clear, reflecting, at least in part, the difficulty of identifying subjects with pure PNCE or PNAE, and, in part, the fact that tools for measuring circuit function have only recently become available. This project will bring together three groups of researchers with expertise in developmental consequences of alcohol and cocaine exposure in utero, functional and structural neuroimaging, and ADHD, with the overarching goal of characterizing the neural correlates of ADHD behaviors in PNCE and PNAE individuals, using a combination of detailed neurocognitive testing, ERP, and functional, structural, and diffusion tensor (DTI) MRI. We will study a well characterized cohort of 18-year-old, African American adolescents, whose PNCE and PNAE were ascertained prospectively during gestation. This cohort is unique in that recruitment was stratified to minimize the confounding of alcohol and cocaine. The study has the following Specific Aims: 1) To use fMRI to confirm that individuals with PNCE, PNAE, and idiopathic ADHD have a functional impairment in fronto-striatal circuits and that additional circuit dysfunctions contribute to behavioral deficits in PNAE; 2) To test the hypothesis that the circuit defect in PNCE-associated ADHD is postsynaptic and, therefore, unresponsive to MPH; 3) To use structural MRI and DTI to examine the contribution of structural abnormalities to the functional impairment in neural circuitry linked to ADHD-related deficits; 4) To identify the neural correlates of dyscalculia in individuals with PNAE and test the hypothesis that PNAE is characterized by a specific deficit in activation of parietal networks subserving number processing.