Frontostriatal glutamate in ADHD: Neuropsychological and Behavioral Correlates

描述(申请人提供)：这项名为“额纹状体谷氨酸在ADHD中的作用：神经心理和行为相关性”的拟议研究的总体目标是在7.0特斯拉的质子磁共振波谱下研究额纹状体谷氨酸能代谢在未服用药物的ADHD儿童中的作用，并确定与这些谷氨酸能和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特斯拉的磁共振波谱对儿童ADHD的神经生物学进行调查。谷氨酸是一种兴奋性神经递质，也是大脑中含量最丰富的氨基酸。它是皮质-纹状体-丘脑-皮质环路的主要兴奋性神经递质(先前通过容量MRI、功能磁共振成像、静息状态功能磁共振成像和DTI研究显示ADHD患者异常)。谷氨酸也是皮质-纹状体传入基底节的主要兴奋性神经递质，在纹状体中起着关键的神经调节作用，并有助于认知和运动功能的效率。大脑中异常的谷氨酸浓度与各种神经和精神疾病有关。在ADHD患者中，谷氨酸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5-羟色胺。结合动物模型、药理学干预、遗传和神经成像研究的结果，已发现谷氨酸神经传递增加在ADHD核心症状的发展中。使用在7.0特斯拉短回声时间获得的单体素1H磁共振波谱的横截面设计，结合神经心理学评估，本研究建议：1)测量服用药物的ADHD儿童的额纹状体和(作为对照区域)顶叶谷氨酸水平(与年龄、性别和社会经济地位[SES]匹配的典型发育中儿童相比)，强调额叶(前额叶、扣带前)和感兴趣的纹状体区域的谷氨酸，以及光谱中观察到的所有脑区的其他代谢物(NAA、Cr、Cho、mI、GLN)；以及；2)通过AIM 1寻找ADHD异常区域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。 与公众健康相关：谷氨酸是一种兴奋性氨基酸，也是大脑中含量最丰富的神经递质。谷氨酸水平与各种神经和精神障碍有关，并与注意力缺陷多动障碍(ADHD)的核心症状的发展有关。之前检测ADHD患者谷氨酸水平的神经成像研究成效有限，因为在场强低于2.0特斯拉的情况下，很难测量人脑中谷氨酸的绝对水平。这项拟议研究的总体目标是在7.0特斯拉的质子磁共振波谱下调查未服用药物的ADHD儿童前额纹状体谷氨酸能代谢的作用，并确定与这些谷氨酸能和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特斯拉的磁共振波谱对儿童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.