Determinants of brain glutamate functional magnetic resonance spectroscopy response

非侵入性地研究活着的健康人类大脑对于理解参与执行给定任务的网络部分的连接的大脑区域之间的动态相互作用非常重要。人脑的功能性磁共振波谱（fMRS）是研究大脑兴奋（谷氨酸）、抑制（GABA）和氧化应激（谷胱甘肽）所涉及的大脑化学物质的动态变化的有用方法。使用fMRS，个体脑化学物质的水平现已公布，但目前还没有一个单一的理论框架，可以令人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多巴胺能代谢物反应。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中化学反应的能力。我们以前开发了优化的fMRS测量协议，用于观察大脑谷氨酸，大脑的主要兴奋性神经递质。现在，我们提出了一个更完整的阵列的兴奋（谷氨酸，谷氨酰胺），抑制（GABA）和氧化应激（谷胱甘肽）在基本的任务，旨在了解刺激强度，持续时间，时间和性质的影响，以提供必要的数据来构建更广泛的有效模型的大脑区域的相互作用的aminamatergic代谢标志物的详细观察。这是fMRS技术成熟的关键一步，它将加深我们对正常脑功能反应的理解，超越使用血氧依赖性功能性MRI（fMRI）的血流动力学研究所学到的知识，这是一种基于MRI的原始方法，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，fMRS数据采集技术和数据分析工具仍然需要大量的发展和新一代的科学家熟悉这些方法需要进行培训，如果fMRS是达到相同水平的科学复杂的功能性MRI。 我们建议培养高素质的人才，追求我们的研究计划的以下三个目标：1）通过实施代谢物选择性fMRS方法来优化代谢物能代谢物的fMRS数据采集，所述代谢物选择性fMRS方法在单次采集中分离多达3种感兴趣代谢物的MRS信号，扩展我们目前在静息MRS中的代谢物选择性工作。通过响应于不同持续时间的简单光刺激任务的海马能代谢物的时间交错fMRS测量，表征海马能fMRS信号如何在视觉网络的连接脑区域中变化和强度。3)开发多体素fMRS分析方法，通过使用与所用刺激范例无关的独立分量分析分析fMRS时间过程，识别参与所选脑区之间连接的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.