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

质子磁共振波谱（1H-MRS）已成为一种有价值的工具，可以进行体内人脑谷氨酸的非侵入性研究。到目前为止，在静止状态下用1H-MRS测量谷氨酸被解释为兴奋性神经传递的直接反映。不幸的是，这种解释没有证据。观察表明，谷氨酸在不同的大脑区域、不同的唤醒/功能状态和疾病状态中都是不同的，我们的小组在执行认知任务期间表现出动态变化（我们称之为谷氨酸fMRS的方法）。这一重要进展加强了谷氨酸水平作为神经活动代理的解释。谷氨酸fMRS仍然是一个不成熟的工具，需要进一步发展才能进入主流神经科学。我们的长期目标是确定休息和大脑激活时谷氨酸1H-MRS信号的生物学基础。我们的短期目标将是识别、定位和量化谷氨酸在功能激活过程中对信号的贡献。***假设h - mrs感兴趣体积（1.0-8.0ml）的谷氨酸信号来自不同组织类型（灰质、白质）中数百万细胞（神经元、胶质细胞等）内的分子。我们假设，与静息信号相比，响应神经元激活的谷氨酸1H-MRS信号来自一个单独的生理池，并且它们的相对信号贡献可以量化。方法1)在单受试者水平上证明谷氨酸1H-MRS信号是如何随神经激活线性变化的。我们将调整我们的谷氨酸fMRS认知范式，通过增加刺激编码负荷水平来包括可变难度水平。2)利用独立分量分析法分析fMRS时间过程，确定活跃/非活跃谷氨酸池的相对信号贡献。3)开发一种在执行任务时评估全脑谷氨酸的方法，而不是使用化学交换饱和转移（CEST），这是一种比1H-MRS高700倍的成像方法，可以重复获得全脑图。我们将使用自定义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-该研究将为从生理学上解释静止和神经激活时1H-MRS获得的脑谷氨酸水平变化来源提供坚实的基础。这开启了一个非侵入性脑功能活动测量的新时代，与传统的BOLD fMRI方法相比，它与神经元放电率更直接相关。这项工作将建立健康个体中活跃与不活跃谷氨酸池相对大小的正常方差。我们将培训医学生物物理学专业的学生设计和实现谷氨酸fMRS和CEST脉冲序列，并开发数据分析工具支持这一新兴研究领域

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.**