Neural Bases of ADHD in Fetal Drug or Alcohol Exposure

产前可卡因(PNCE)和酒精暴露(PNAE)会导致持续性的行为缺陷，在许多方面类似于注意力缺陷多动障碍(ADHD)。虽然这种相似性表明在所有三组中都有相似或重叠的神经回路参与，但特定缺陷及其对刺激的不同反应的细微差异表明，特定回路内的干扰和/或非重叠回路中的干扰的性质不同。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，对苯丙胺(Amph)或哌醋甲酯(Mph)等兴奋剂无效。在人类研究中，数据不那么清楚，至少部分反映了识别纯pnce或pNAE受试者的困难，部分反映了最近才出现测量电路功能的工具的事实。这个项目将汇集三组研究人员，他们在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，主要目标是表征pNCE和PNAE中ADHD行为的神经相关性。 结合使用详细的神经认知测试、事件相关电位和功能、结构和弥散张量(DTI)磁共振成像。我们将研究一组特征良好的18岁非裔美国青少年，他们的PNCE和PNAE是在怀孕期间前瞻性地确定的。这一队列的独特之处在于，招募是分层的，以最大限度地减少酒精和可卡因的混淆。这项研究的具体目的如下：1)使用功能磁共振成像来证实pnce、pNAE和特发性ADHD患者的额纹状体回路功能受损，以及附加的回路功能障碍导致pNAE中的行为缺陷；2)检验pnce相关的ADHD的回路缺陷是突触后的假说，因此对mph没有反应；3)使用结构磁共振和 DTI检查结构异常对与ADHD相关缺陷有关的神经回路功能损害的贡献；4)确定PNAE患者计算障碍的神经相关性，并检验PNAE的特征是服务于数字处理的顶层网络激活的特定缺陷。

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.