Optimizing detection of glutamate functional magnetic resonance spectroscopy signals in the human brain

质子磁共振波谱(1H-MRS)已成为无创研究活体人脑谷氨酸的有价值的工具。到目前为止，用~1H-MRS测定静息状态下的谷氨酸被认为是兴奋性神经传递的直接反映。不幸的是，这种解释并不是基于证据的。观察表明，谷氨酸在不同的大脑区域、不同的觉醒/功能状态和疾病状态下是不同的，我们的团队在认知任务(我们称之为谷氨酸FMR的方法)的执行过程中显示出动态变化。这一重要进展加强了谷氨酸水平作为神经活动替代品的解释。谷氨酸FMR仍然是一个不成熟的工具，需要很大的发展才能进入主流神经科学。 目标-我们的长期目标是确定静息和大脑激活期间谷氨酸1H-MRS信号的生物学基础。我们的短期目标将是识别、定位和量化在功能激活过程中对信号起作用的谷氨酸池。 假设-来自感兴趣的1H-MRS体积(1.0-8.0ml)的谷氨酸信号来自数百万个细胞(神经元、神经胶质细胞等)内的分子。在不同的组织类型(灰质、白质)中。我们假设，响应神经元激活的谷氨酸1H-MRS信号来自与静止信号不同的生理池，并且它们的相对信号贡献可以被量化。 方法-1)在单一受试者水平上演示谷氨酸1H-MRS信号如何随着神经激活而线性变化。我们将通过增加刺激编码负荷的水平来调整我们的谷氨酸FMR认知范式，以包括不同水平的难度。2)通过使用独立分量分析来分析FMR的时间进程，确定来自活跃/非活跃谷氨酸池的相对信号贡献。3)开发了一种在任务执行期间评估全脑谷氨酸的方法，而不是使用化学交换饱和转移(CEST)，这是一种成像方法，信噪比比1H-MRS高700倍，因此可以重复获得全脑图。我们将使用定制的脉冲序列和加拿大唯一的7.0特斯拉人体扫描仪。 新颖性/重要性--这项研究将提供坚实的基础，从生理上解释在静息和神经激活期间用1H-MRS获得的大脑谷氨酸水平的变异性来源。这开启了非侵入性功能性脑活动测量的新时代，比传统的BOLD fMRI方法更直接地与神经元放电率相关。这项工作将在健康个体中建立活跃和不活跃谷氨酸池的相对大小的正常值。我们将培训医用生物物理学学生设计和实现谷氨酸FMR和CEST脉冲序列，并开发支持这一新兴研究领域的数据分析工具。

INTRO - Proton Magnetic Resonance Spectroscopy (1H-MRS) has been a valuable tool allowing the non-invasive study of in vivo human brain glutamate. Up to now, measurements of glutamate with 1H-MRS at rest have been interpreted as a direct reflection of excitatory neurotransmission. Unfortunately, this interpretation has not been evidence-based. Observations show that glutamate varies among brain regions, different arousal/functional state and in disease states and our group showed dynamic changes during performance of a cognitive task (a method we call glutamate fMRS). This important advance strengthens the interpretation of glutamate levels as proxy to neural activity. Glutamate fMRS is still an immature tool and requires much development to enter main stream neuroscience. OBJECTIVES - Our long term goal is to determine the biological underpinnings of glutamate 1H-MRS signals at rest and during brain activation. Our short term goal will be to identify, localize and quantify the pools of glutamate contributing to the signal during functional activation. HYPOTHESIS - The glutamate signal from 1H-MRS volumes of interest (1.0-8.0ml) originates from molecules within several millions of cells (neuron, glia, etc.) in different tissue types (grey, white matter). We hypothesize that glutamate 1H-MRS signals responding to neuronal activation originate from a separate physiological pool than resting signals and that their relative signal contributions can be quantified. APPROACH - 1) Demonstrate how glutamate 1H-MRS signals vary linearly with neural activation at the single-subject level. We will adapt our glutamate fMRS cognitive paradigm to include a variable level of difficulty by increasing levels of stimulus encoding load. 2) Determine relative signal contributions from active/inactive glutamate pools by analyzing fMRS time courses using independent component analysis. 3) Develop a method to assess whole-brain glutamate during performance of a task rather using chemical exchange saturation transfer (CEST), an imaging method signal-to-noise ratio 700 times greater than 1H-MRS so that whole-brain maps can be obtained repeatedly. We will use custom pulse sequences and the only 7.0 Tesla human scanner in Canada. NOVELTY/SIGNIFICANCE - The research will provide a solid basis on which to physiologically interpret sources of variability in brain glutamate levels obtained with 1H-MRS at rest and during neural activation. This opens a new era of non-invasive functional brain activity measurement more directly related to neuronal firing rate than the traditional BOLD fMRI method. The work will establish the normal variance in healthy individuals for relative sizes of the active vs inactive glutamate pools. We will train medical biophysics students to design and implement glutamate fMRS and CEST pulse sequences and to develop data analysis tools supporting this nascent field of study.