GABA和谷氨酸盐与脑活动的关系之多模态影像学研究

Activity in the brain is constituted in the main by the balance between the action of excitatory cells and inhibitory ones. In order to understand the brain we must investigate how the neurotransmitters that instantiate excitation and inhibition - glutamate and GABA, respectively - are related to its function. A burgeoning field of human multi-modal imaging studies combining functional magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (MRS) attempts to do this. Important questions remain however. Firstly, there is a discrepancy between the observed relationship of MRS measures of glutamate to task-induced BOLD responses and what would be expected given the excitatory role of glutamate. Secondly, the role that GABA plays in moment-to-moment activity variability, an important new direction in human brain imaging, remains to be investigated. The goal of the proposed research is to use a combination of different imaging techniques in two separate experiments to answer these questions. The first experiment will use FDG-PET to measure baseline activity in the medial prefrontal cortex (mPFC). This baseline activity level will then be included in the correlation between fMRI activity in the same region in response to a simple task and mPFC glutamate concentrations. Without this baseline correction it is predicted that there will be no glutamate-fMRI correlation; with the correction we expect to see a positive correlation to emerge. The second experiment will use a combination of resting-state and task fMRI with MRS in order to study how GABA relates to moment-to-moment variability in the BOLD signal. It is expected that GABA will be negatively correlated with variability, in line with it's inhibitory role. In addition, we expect variability to increase with task difficulty and for this increase to be related to GABA concentrations. This study has important implications for the interpretation of all multi-modal imaging results and for our fundamental understanding of brain function. In addition, it will be of relevance to disease conditions where there are alterations in glutamatergic and GABAergic function, such as major depressive disorder, schizophrenia, and age-related cognitive decline.

快速发展中的fMRI、MRS结合技术正试图阐明兴奋性（谷氨酸，Glu）和抑制性递质（γ-氨基丁酸，GABA）与脑活动之间的关系，但一些重要问题尚未解决。1）MRS测量到的Glu和任务引发的血氧信号之间的关系与Glu的兴奋性作用不一致；2）作为一个新方向，GABA在时时变化着的脑活动中的作用尚不清楚。本项目将通过多种脑成像技术结合的两组实验研究上述问题。实验一采用FDG-PET测量内侧前额叶活动基线，然后分析它与Glu浓度和任务诱发的血氧信号之间的关系。我们预期，若任务诱发信号受基线调控，Glu与血氧成正相关，反之则没有相关性。实验二将静息、任务fMRI与MRS结合，研究GABA和血氧信号变异之间的关系。据GABA抑制作用预期，两者会表现出负相关，而且上述变异会随任务难度增加而增大，且与GABA浓度相关。本项目将对解释多模态成像结果甚至脑基本功能做出贡献，也有助于理解相关疾病的病理机制。

大脑中的活动主要由兴奋性细胞和抑制性细胞的作用之间的平衡构成。为了理解大脑，我们必须研究神经递质是如何与其功能相联系的（如兴奋性和抑制性的神经递质- 谷氨酸和GABA）。结合功能磁共振成像（fMRI）和磁共振波谱分析（MRS）技术的人类多模态成像研究试图对此进行考查。然而，还存在一些重要的问题有待回答。首先，观察到的与任务诱导的BOLD反应相关的谷氨酸的MRS测量与预期之间存在差别。其次，GABA在即时活动变异性中扮演的角色，是人脑成像方面的一个重要新方向，仍然有待研究。本项目的目标是综合采用多模态脑成像技术、通过三个研究来回答这些问题。在处理这些问题之前，我们还试图回答一个重要的方法学问题——GABA MRS的使用问题。第一个研究考查了使用大分子抑制与未抑制的MRS序列来估计GABA浓度的效果。该研究发现，使用大分子抑制序列可能更为有利，同时还发现测量噪声是该方法使用中的一个重要变量。这项工作已经投稿，目前正在审稿修改进程中。第二个研究，试图将枕叶皮质中的GABA估计与相同区域内神经活动的时间复杂性联系起来，大脑活动通过视觉刺激来调节。结果发现，GABA浓度与时间复杂性之间存在显著的相关性。然后，我们与合作者一起使用MRS和EEG进行了一项补充实验，以查看fMRI探查不到的频率的复杂性。在枕叶电极发现了类似的结果。这项工作正在准备发表中。在我们的第三个研究中，考查了脑区的基本活动特性以及它们与葡萄糖消耗的关系。该实验是研究任务诱导的活动的必要基础。结果发现，脑区活动的局部空间变异性与葡萄糖消耗显著相关。我们正在与合作者合作，将这些新的发现纳入到关于神经功能的计算模型中；这项工作将在完成建模后发表。总之，本项目的工作深化了对MRS方法学的理解，并提供了关于神经递质的神经成像测量与神经活动特征之间的重要联系的证据。

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