Determinants of brain glutamate functional magnetic resonance spectroscopy response

非侵入性地研究活着的健康人脑，对于理解参与执行特定任务的网络中相互连接的大脑区域之间的动态相互作用是重要的。人脑的功能磁共振波谱(FMRS)是研究大脑兴奋(谷氨酸)、抑制(GABA)和氧化应激(谷胱甘肽)等脑部化学物质动态变化的有效手段。使用FMR，现在已经公布了单个大脑化学物质的水平，但目前还没有一个单一的理论框架来满意地解释在各种功能刺激类型或任务中观察到的广泛的谷氨酸能代谢物反应。这种对健康大脑如何执行任务的有限理解最终限制了我们解释不健康大脑的化学反应的能力。我们之前开发了优化的FMRS测量方案，用于观察大脑中主要的兴奋性神经递质--大脑谷氨酸。我们现在提议在基本任务中对更完整的谷氨酸能代谢物标记物(谷氨酸、谷氨酰胺)、抑制(GABA)和氧化应激(谷胱甘肽)进行详细观察，旨在了解刺激强度、持续时间、时间和性质的影响，以提供必要的数据，以构建更广泛有效的大脑区域相互作用模型。这是FMR技术成熟的关键一步，将加深我们对正常谷氨酸能脑反应的理解，而不是使用血氧依赖功能磁共振(FMRI)进行血流动力学研究，fMRI是最初的基于MRI的方法，为过去30年的神经科学革命提供了动力。然而，为了实现这一目标，FMR的数据采集技术和数据分析工具仍然需要很大的发展，如果FMR要达到与功能MRI相同的科学尖端水平，就需要培训熟悉这些方法的新一代科学家。我们建议培养追求我们研究计划以下三个目标的高素质人员：1)通过实施代谢物选择性FMR方法来优化谷氨酸能代谢物的FMR数据采集，该方法在单次采集中分离最多3个感兴趣的代谢物的MRS信号，扩展我们目前在静息MRS中的代谢物选择工作；2)通过对谷氨酸代谢物的时间交错FMR测量来表征视觉网络连接的大脑区域中谷氨酸能FMR信号如何变化，以响应不同持续时间和强度的简单光刺激任务。3)发展多体素FMRS分析方法，通过使用与所使用的刺激范式无关的独立分量分析来分析FMRS的时间进程，从而识别参与所选大脑区域之间连接的FMRS信号部分。

Studying the living healthy human brain non-invasively is important in understanding the dynamic interaction between connected brain regions part of a network involved in performing a given task. Functional Magnetic Resonance Spectroscopy (fMRS) of the human brain has been a useful way to study dynamic changes in brain chemicals involved in brain excitation (glutamate), inhibition (GABA) and oxidative stress (glutathione). Using fMRS, levels of individual brain chemicals have now been published, but there is currently no single theoretical framework that allows a satisfactory explanation of the wide range of glutamatergic metabolite responses observed in various functional stimulation types or tasks. This limited understanding of how the healthy brain performs tasks ultimately limits our ability to interpret chemical responses in unhealthy brains. We previously developed optimized fMRS measurement protocols for the observation of brain glutamate, the brain's main excitatory neurotransmitter. We now propose detailed observations of a more complete array of glutamatergic metabolites markers of excitation (glutamate, glutamine), inhibition (GABA) and oxidative stress (glutathione) in basic tasks aimed at understanding the effect of stimuli intensity, duration, timing and nature to provide the data necessary to construct more broadly valid models of brain region interactions. This is a critical step in the maturing of fMRS techniques that will deepen our understanding of normal glutamatergic brain responses beyond what has already been learned from hemodynamic investigations using blood oxygenation-dependent functional MRI (fMRI), the original MRI-based approach that has powered the neuroscience revolution of the last 3 decades. To reach this objective, however, fMRS data acquisition techniques and data analysis tools still require much development and a new generation of scientist familiar with these approach needs to be trained if fMRS is to achieve the same level of scientific sophistication as functional MRI. We propose to train highly qualified personnel pursuing the following three aims of our research program: 1) Optimize the fMRS data acquisition of glutamatergic metabolites by implementing metabolite-selective fMRS methods that isolate the MRS signals of up to 3 metabolites of interest in a single-shot acquisition, extending our current metabolite-selective work in resting MRS. 2) Characterize how glutamatergic fMRS signals vary in connected brain regions of the visual network via temporally interleaved fMRS measurements of glutamatergic metabolite in response to simple photic stimulation tasks of varying duration and intensity. 3) Develop multi-voxel fMRS analysis methods to identify the portion of the fMRS signal that participates to the connection between the selected brain regions by analyzing fMRS time courses using independent component analysis agnostic of the stimulation paradigm used.