Frontostriatal glutamate in ADHD: Neuropsychological and Behavioral Correlates

描述（由申请人提供）：拟议研究的总体目标，“ADHD中的额纹状体谷氨酸：神经心理学和行为相关性”是使用7.0特斯拉的质子磁共振波谱来研究额纹状体多巴胺能代谢在未接受药物治疗的ADHD儿童中的作用，并确定与这些神经递质以及其他神经化学异常相关的认知和行为功能障碍的具体机制。这项研究将是第一次使用7.0特斯拉的MR波谱对儿童ADHD的神经生物学进行调查。 谷氨酸是一种兴奋性神经递质，也是大脑中最丰富的氨基酸。它是皮质-纹状体-丘脑-皮质回路的主要兴奋性神经递质（先前通过体积MRI，fMRI，静息状态fMRI和DTI研究显示ADHD异常）。谷氨酸也是皮质-纹状体传入基底神经节的主要兴奋性神经递质，在纹状体中发挥重要的神经调节作用，并有助于认知和运动功能的效率。大脑中谷氨酸浓度异常与各种神经和精神疾病有关。在ADHD中，谷氨酸盐还可以调节与该疾病有关的其他神经递质的释放，包括多巴胺和血清素。来自动物模型、药理学干预、遗传学和神经影像学研究的聚合结果已经确定了在ADHD核心症状的发展中谷氨酸神经传递增加。 使用在7.0特斯拉短回波时间下获得的单体素1H MR波谱的横截面设计，沿着神经心理学评估，当前研究提出：1）测量额纹状体和（作为对照区域）5-9岁ADHD未用药儿童顶叶谷氨酸水平（与年龄-性别和社会经济地位[SES]匹配的典型发育儿童相比），强调额叶皮层中的谷氨酸盐（前额叶，前扣带）和纹状体区域，以及光谱中观察到的其他代谢物（NAA、Cr、Cho、mI、Gln）;以及; 2）通过Aim 1搜索ADHD中被识别为异常的区域中的谷氨酸水平与执行功能（EF）、非EF技能和ADHD症状严重程度的行为测量之间的关系。 公共卫生相关性：谷氨酸是一种兴奋性氨基酸，也是大脑中最丰富的神经递质。谷氨酸水平与各种神经和精神疾病有关，并与注意缺陷多动障碍（ADHD）的核心症状的发展有关。以前的神经成像研究检查ADHD中的谷氨酸水平取得了有限的成功，因为在小于2.0特斯拉的场强下，很难测量人脑中谷氨酸的绝对水平。拟议调查的总体目标是使用7.0特斯拉的质子磁共振波谱法调查未接受过药物治疗的ADHD儿童中额纹状体多巴胺能代谢的作用，并确定与这些多巴胺能以及其他神经化学异常相关的认知和行为功能障碍的具体机制。这项研究将是第一次使用7.0特斯拉的MR波谱对儿童ADHD的神经生物学进行调查。

DESCRIPTION (provided by applicant): The overall goal of the proposed investigation, "Frontostriatal Glutamate in ADHD: Neuropsychological and Behavioral Correlates" is to investigate the role of frontostriatal glutamatergic metabolism in medication-naive children with ADHD using proton magnetic resonance spectroscopy at 7.0 Tesla, and to determine the specific mechanisms of cognitive and behavioral dysfunction associated with these glutamatergic as well as other neurochemical anomalies. This study will be the first investigation of the neurobiology of ADHD in children using MR spectroscopy at 7.0 Tesla. Glutamate is an excitatory neurotransmitter and the most abundant amino acid in the brain. It is the primary excitatory neurotransmitter for the cortico-striato-thalamo-cortical loop (previously shown to abnormal in ADHD via volumetric MRI, fMRI, resting state fMRI, and DTI studies). Glutamate is also the primary excitatory neurotransmitter for the cortico-striatal afferents to the basal ganglia-playing a crucial neuromodulatory role in the striatum, and contributing to efficiency of both cognitive and motor function. Abnormal glutamate concentrations in the brain have been linked to a variety of neurological and psychiatric disorders. In ADHD, glutamate also serves to modulate the release of other neurotransmitters implicated in the disorder, including dopamine and serotonin. Converging findings from animal models, pharmacologic interventions, genetic and neuroimaging studies have identified increased glutamate neurotransmission in the development of core symptoms of ADHD. Using a cross sectional design of single voxel 1H MR spectroscopy obtained with short-echo time at 7.0 Tesla, along with neuropsychological assessment, the current study proposes to: 1) measure frontostriatal and (as a control region) parietal glutamate levels in medication-naove children with ADHD, ages 5-9 years (compared to age- sex- and socioeconomic status [SES]-matched typically developing children), emphasizing glutamate in frontal (prefrontal, anterior cingulate), and striatal regions of interest, as well as other metabolites observed in the spectrum (NAA, Cr, Cho, mI, Gln) in all brain regions; and; 2) search for relationships among glutamate levels in regions identified as abnormal in ADHD via Aim 1, and behavioral measures of executive function (EF), non-EF skills, and severity of ADHD symptoms. PUBLIC HEALTH RELEVANCE: Glutamate is an excitatory amino acid and the most abundant neurotransmitter in the brain. Glutamate levels are linked to a variety of neurological and psychiatric disorders, and have been implicated in the development of core symptoms of Attention Deficit Hyperactivity Disorder (ADHD). Prior neuroimaging studies examining glutamate levels in ADHD had limited success, because at field strengths less than 2.0 Tesla, it is difficult to measure the absolute levels of glutamate in the human brain. The overall goal of the proposed investigation is to investigate the role of frontostriatal glutamatergic metabolism in medication-naive children with ADHD using proton magnetic resonance spectroscopy at 7.0 Tesla, and to determine the specific mechanisms of cognitive and behavioral dysfunction associated with these glutamatergic as well as other neurochemical anomalies. This study will be the first investigation of the neurobiology of ADHD in children using MR spectroscopy at 7.0 Tesla.