Robust 1H MRSI of GABA, Glutamate, Glutamine, and Glutathione

项目摘要 了解神经递质活性是阐明正常和病变神经元的基础 谷氨酸（Glu）和γ-氨基丁酸（GABA）是大脑的主要兴奋性物质， 抑制性神经递质这种理解对于自闭症谱系障碍（ASD）尤其重要， 神经发育障碍的特点是持续的缺陷，在社会沟通和限制， 重复和刻板的行为模式。虽然在表现和严重程度上有所不同，但ASD发生在 所有族裔和社会经济群体，持续终生，估计每68名儿童中就有1名受到影响， 美国的不幸的是，这些疾病的病因尚未完全了解，并且这种技术 开发新的非侵入性成像工具，用于研究ASD脑神经化学的发展建议 生物标志物是响应NIH PA 10 - 158“自闭症谱系障碍研究”。创新将成为 在这个项目下进行的评估不仅有助于调查ASD，而且还有助于其他神经精神病和 神经发育障碍，需要先进的成像技术。 尽管ASD具有异质性，但患者可能具有最终共同的生化途径， 对类似的治疗有反应，现在假设ASD是由于 兴奋性和抑制性神经递质。被称为“E/I平衡”理论，来自两种动物的发现 模型和人类表明ASD的特征在于关键大脑区域的过度兴奋性， Glu升高和/或GABA降低。虽然这种神经化学失衡的体内证据正在开始 通过使用J编辑的1H磁共振波谱（MEGA-PRESS是目前的 选择的方法）稳健的体内测量是耗时且有问题的。Glu测量是 谷氨酰胺是一种简单的蛋白质，但与密切相关的谷氨酰胺（Gln）分离是困难的。此外，合编 大分子（GABA）与靶向GABA信号重叠并占检测信号的40 - 60%， 导致研究人员将所得数据称为GABA + β或简称GABA+。MRS检测的细菌 还报告显示出区域差异，正常受试者之间的变异性，以及对年龄和性别的依赖性。 和病理即使对于单体素研究，先前提出的MM抑制技术也没有被广泛使用， 这是耗时的或者对B0磁场变化高度敏感。 该提案旨在通过系统化的设计、实施和测试来克服这些限制 强大的MM抑制J编辑的单体素（目标1和2）和多体素（目标3）序列，以测量 这些靶向神经化学物质，从多个大脑区域产生时间有效的测量。这些新 工具将用于评估诊断为ASD的青少年患者的神经化学失衡（目标4）。

Project Abstract Understanding neurotransmitter activity is fundamental to elucidating normal and diseased neuronal function, with glutamate (Glu) and γ-aminobutyric acid (GABA) being the brain's primary excitatory and inhibitory neurotransmitters. Such understanding is particularly critical in autism spectrum disorder (ASD), a set of neurodevelopment disorders characterized by persistent deficits in social communication and restricted, repetitive, and stereotyped patterns of behavior. Although varying in presentation and severity, ASD occurs in all ethnic and socioeconomic groups, has a lifelong duration, and affects an estimated 1 out of 68 children in the United States. Unfortunately, the etiologies of these disorders are not fully understood, and this technical development proposal to develop novel non-invasive imaging tools for studying ASD brain neurochemical biomarkers is in response to NIH PA 10-158 “Research on Autism Spectrum Disorders”. The innovations to be evaluated under this project will help not only investigating ASD, but also other neuropsychiatric and neurodevelopmental disorders where advanced imaging techniques are needed. Despite the heterogeneity of ASD, patients may share final common biochemical pathways and potentially be responsive to similar treatments, and ASD is now hypothesized to result from an imbalance between excitatory and inhibitory neurotransmitters. Known as the “E/I balance” theory, findings from both animal models and humans suggest ASD is characterized by hyper-excitability in critical brain regions due to increased Glu and/or decreased GABA. While in vivo evidence of such neurochemical imbalances is beginning to emerge through the use of J-edited 1H magnetic resonance spectroscopy (MEGA-PRESS being the current method of choice) robust in vivo measurements are time-consuming and problematic. Glu measurement is straightforward, but separation from closely related glutamine (Gln) is difficult. Furthermore, co-edited macromolecules (MMs) overlap the targeted GABA signal and account for 40-60% of the detected signal, leading investigators to refer to the resulting data as GABA+MMs or simply GABA+. MRS-detected MMs are also reported to exhibit regional variations, variability across normal subjects, and dependence on both age and pathology. Even for single-voxel studies, prior proposed MM-suppression techniques are not widely used, being either time-consuming or highly sensitive to B0 magnetic field variations. This proposal seeks to overcome these limitations via the systematic design, implementation, and testing of robust MM-suppressed J-edited single-voxel (Aims 1 and 2) and multi-voxel (Aim 3) sequences to measure these targeted neurochemicals, yielding time-efficient measurements from multiple brain regions. These new tools will be used to assess neurochemical imbalances in adolescent patients diagnosed with ASD (Aim 4).