Neurochemical Correlates of Brain Abnormalities in Prenatal Alcohol Exposure

产前酒精暴露中大脑异常的神经化学相关性

• 批准号: 9160564
• 负责人: JENNIFER G. LEVITT
• 金额: $ 54.86万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9160564
• 关键词: Advisory Committees; Affect; Aftercare; Age; Alcohol abuse; Alcohols; Anisotropy; Anterior; Attention; Attention deficit hyperactivity disorder; Back; Behavioral; Bilateral; Biological Markers; Brain; Brain Chemistry; Brain Injuries; Brain imaging; Child; Childhood; Choline; Clinical; Cognitive; Corpus striatum structure; Data; Development; Diagnosis; Diffusion Magnetic Resonance Imaging; Disease; Dopamine; Etiology; Exhibits; Exposure to; Family history of; Fetal Alcohol Exposure; Fetal Alcohol Syndrome; Fetal alcohol effects; Fiber; Glutamates; Goals; High Prevalence; Investigation; Link; Literature; MRI Scans; Magnetic Resonance Spectroscopy; Measures; Methods; Modeling; Monitor; National Institute on Alcohol Abuse and Alcoholism; Neurocognitive; Neurons; Nucleus Accumbens; Output; Pathway interactions; Patients; Performance; Pharmaceutical Preparations; Physiology; Protons; Public Health; Recommendation; Research; Sampling; Sensitivity and Specificity; Siblings; Strategic Planning; Structure; Symptoms; Techniques; Testing; United States; United States National Institutes of Health; Ventral Tegmental Area; Work; abstracting; alcohol effect; behavior test; brain abnormalities; cingulate cortex; clinically relevant; design; executive function; gamma-Aminobutyric Acid; improved; in vivo; indexing; magnetic resonance spectroscopic imaging; nerve supply; neurobehavioral; neurochemistry; neurodevelopment; neuroimaging; potential biomarker; pre-clinical; preclinical study; prospective; putamen; research study; response; treatment response; treatment strategy; white matter

Abstract Prenatal alcohol exposure (PAE) affects up to 5% of children in the United States, and is the topic of several NIH directives calling for research initiatives. Most children with PAE are diagnosed with ADHD, although current research demonstrates significant differences in symptom profiles and treatment response between ADHD due to PAE and idiopathic ADHD. This suggests corresponding clinically important differences in brain physiology between PAE ADHD and ADHD not associated with PAE (non-PAE ADHD). The research literature and our preliminary data demonstrate that aspects of executive function differentiate PAE ADHD from non- PAE ADHD. Further, in healthy and brain-injured subjects, metrics of executive function and attention have been correlated with fractional anisotropy (FA) in the anterior corona radiata (ACR) - a white-matter tract in which we found lower FA in children with PAE ADHD than in children with familial non-PAE ADHD. In the same group of children, using proton magnetic resonance spectroscopy (MRS), we also found lower levels of choline-compounds (Cho) in ACR in the children with PAE ADHD than in the children with familial non-PAE ADHD. Thus we propose that low FA and low Cho in ACR may provide objective neuroimaging markers to distinguish PAE ADHD from non-PAE ADHD. Fibers composing the ACR include those connecting the striatum and the anterior middle cingulate cortex (aMCC), a cingulate subregion heavily implicated in ADHD by functional neuroimaging. In our recent RC1, we found lower glutamate (Glu) in aMCC in children with familial ADHD (i.e., one or more siblings with ADHD, no PAE, and no family history of alcohol abuse) than in healthy controls. In PAE in contrast, pre-clinical literature suggests elevation of Glu in the cortex, along with reduction in gamma-aminobutyric acid (GABA). We propose that Glu/GABA ratios in aMCC may be an additional biomarker distinguishing PAE ADHD from familial non-PAE ADHD. In this investigation, we propose to use leading-edge MRS techniques (MRSI and MEGA-PRESS) in tandem with state-of-the-art diffusion tensor imaging (DTI) to test these brain imaging endpoints (FA and Cho in ACR, Glu/GABA in aMCC) that putatively differentiate PAE ADHD from familial non-PAE ADHD. We will furthermore explore relations between these endpoints and clinically relevant neurocognitive measures of attention and other executive functions. If successful, this proposal may inform the design of and the monitoring of in vivo effects of prospective treatments for PAE, which to date has been poorly tractable. This proposal responds to recommendations of the National Task Force on Fetal Alcohol Syndrome and Fetal Alcohol Effects to improve understanding of the mechanisms of alcohol's action on the brain through neuroimaging and to identify potential biomarkers of prenatal alcohol exposure and to the NIAAA Strategic Plan for Research which has identified “developing increasing understanding of the effects of alcohol on neurodevelopment,” as a key public health goal.

抽象的 在美国，产前酒精暴露 (PAE) 影响着多达 5% 的儿童，并且是多个话题的话题 尽管 NIH 指令呼吁开展研究活动，但大多数患有 PAE 的儿童都被诊断为 ADHD。 目前的研究表明，不同人群的症状特征和治疗反应存在显着差异 PAE 和特发性 ADHD 引起的 ADHD 表明大脑中存在相应的临床重要差异。 PAE ADHD 和与 PAE 无关的 ADHD（非 PAE ADHD）之间的生理学研究文献。 我们的初步数据表明，执行功能的各个方面将 PAE ADHD 与非 ADHD 区分开来。 此外，在健康和脑损伤受试者中，执行功能和注意力的指标也有变化。 与前放射冠 (ACR) 中的分数各向异性 (FA) 相关 - 前放射冠中的白质束 我们发现 PAE ADHD 儿童的 FA 低于家族性非 PAE ADHD 儿童。 一组儿童，使用质子磁共振波谱（MRS），我们还发现较低水平 PAE ADHD 儿童 ACR 中的胆碱化合物 (Cho) 高于家族性非 PAE 儿童 因此，我们提出 ACR 中的低 FA 和低 Cho 可能提供客观的神经影像标记。 为了区分 PAE ADHD 和非 PAE ADHD，组成 ACR 的光纤包括连接 ACR 的光纤。 纹状体和前中扣带皮层 (aMCC)，扣带皮层与 ADHD 密切相关 在我们最近的 RC1 中，我们发现患有 AMCC 的儿童中谷氨酸 (Glu) 含量较低。 家族性多动症（即一名或多名兄弟姐妹患有多动症，无 PAE，且无酗酒家族史） 相比之下，在 PAE 中，临床前文献表明皮质中的 Glu 升高，同时 我们认为 aMCC 中的 Glu/GABA 比例可能是一种减少。 在这项研究中，我们使用了区分 PAE ADHD 和家族性非 PAE ADHD 的其他生物标志物。 建议结合使用最先进的 MRS 技术（MRSI 和 MEGA-PRESS） 扩散张量成像 (DTI) 用于测试这些脑成像终点（ACR 中的 FA 和 Cho，aMCC 中的 Glu/GABA） 可能将 PAE ADHD 与家族性非 PAE ADHD 区分开来，我们将进一步探讨两者之间的关系。 这些终点与临床相关的注意力和其他执行神经认知测量之间的关系 如果成功，该提案可以为体内效应的设计和监测提供参考。 PAE 的前瞻性治疗方法，迄今为止一直难以处理。 国家胎儿酒精综合症和胎儿酒精影响工作组的建议 通过神经影像学提高对酒精对大脑作用机制的理解 确定产前酒精暴露的潜在生物标志物以及 NIAAA 战略计划 研究表明“人们越来越了解酒精对身体的影响” 神经发育”作为一项关键的公共卫生目标。