Neuromodulation of BOLD fMRI Signal during Cognitive Tasks

描述（由申请人提供）：血氧水平依赖性（BOLD）功能性MRI（fMRI）已成为在感觉运动和认知任务期间无创测量大脑活动的主力方法，也是神经系统疾病不可或缺的诊断工具。BOLD信号是局部脑血流量（rCBF）、血容量（rCBV）和局部脑氧代谢率（rCMRO 2）的函数，并且对这些因素与神经元活动的耦合的理解远未完成。在BOLD的这三个因素中，rCBF可能对非局部因素最敏感，如血管活性代谢物（例如CO2）、激素和非局部释放的控制大脑状态（例如警惕、警觉、注意力等）的神经调质。神经调节剂（例如乙酰胆碱、去甲肾上腺素、血清素、多巴胺等）表现出血管活性性质，并且已知脑血管系统受表达这些神经调节剂的神经元末梢的神经支配。其中，胆碱能神经调节系统是特别感兴趣的，因为它在涉及选择性注意、工作记忆和学习机制的认知任务中起重要作用。由于胆碱能神经调节系统也参与脑灌注的全局控制，因此在任务期间对该神经调节系统的脑激活进行成像是有问题的。我们建议解决乙酰胆碱（Ach）的作用，在塑造的局部神经元激活和BOLD反应之间的关系，在认知任务通过测试以下工作假设：区域CBF不仅是由当地的神经元活动，但也控制分配的注意力和工作记忆资源的因素，胆碱能系统介导的。这种对rCBF的系统性调节可能改变神经元活动（以rCMRO 2为指标）与rCBF之间的关系。我们假设，乙酰胆碱释放是必不可少的调解之间的耦合神经元的反应和CBF在注意和工作记忆任务（可能通过激活基底前脑）。我们建议通过测量CBF和BOLD反应使用动脉自旋标记（ASL）方法来测试这些假设。我们将测试注意力资源的分配是否会影响BOLD和CBF信号，以同样的方式刺激单独的视觉stumuli。为了研究胆碱能机制在认知任务中CBF和BOLD之间的耦合中的作用，我们将使用药理学操作来影响胆碱能调节的功效。我们预计，胆碱能调制的药理学操作将影响CBF/BOLD的关系，在相同的方向分配的注意力资源。拟议的实验将奠定基础，系统调查的影响，BOLD信号和潜在的本地神经元活动之间的耦合的神经调节剂，并将开发工具，通过功能磁共振成像来解决认知过程的神经调节机制。

DESCRIPTION (provided by applicant): Blood oxygenation level dependent (BOLD) functional MRI (fMRI) has become a workhorse method for noninvasively measuring brain activity during sensorimotor and cognitive tasks and an indispensable diagnostic tool for neurological disorders. BOLD signal is a function of regional cerebral blood flow (rCBF), blood volume (rCBV), and the regional cerebral metabolic rate of oxygen (rCMRO2), and the understanding of the coupling of these factors to the neuronal activity is far from complete. Among those three factors contributing to BOLD, rCBF is probably most susceptible to nonlocal factors, such vasoactive metabolites (such as CO2), hormones, and non-localy released neuromodulators that control brain states such as vigilance, alertness, attention, etc. Indeed, neuromodulators controlling brain states (e.g. acetylcholine, norepinephrine, serotonin, dopamine, etc) exhibit vasoactive properties and cerebral vasculature is known to be innervated by neuronal terminals expressing these neuromodulators. Among these, cholinergic neuromodulatory system is of special interest, since it plays essential role during cognitive tasks engaging selective attention, working memory and learning mechanisms. Imaging of brain activation during tasks engaging this neuromodulatory system is problematic, since cholinergic neuromodulatory system is also involved in global control of cerebral perfusion. We propose to address the role of acetylcholine (Ach), in shaping the relationship between local neuronal activation and BOLD responses during cognitive tasks by testing the following working hypothesis: Regional CBF is regulated not only by local neuronal activity but also by factors controlling allocation of attention and working memory resources, mediated by cholinergic systems. This systemic regulation of rCBF may change the relationship between neuronal activity (as indexed by rCMRO2) and rCBF. We hypothesize that acetylcholine release is essential for mediation of coupling between neuronal responses and CBF during attention and working memory tasks (probably via activation of basal forebrain). We propose to test these hypotheses by measuring CBF and BOLD responses using arterial spin labeling (ASL) method. We will test whether allocation of attentional resources affects BOLD and CBF signal in the same manner as stimulation by visual stumuli alone. In order to investigate the role of cholinergic mechanisms in coupling between CBF and BOLD during cognitive tasks, we will use pharmacological manipulations to affect efficacy of cholinergic modulation. We expect that pharmacological manipulations of the cholinergic modulation will affect CBF/BOLD relationship in the same direction as allocation of attention resources. Proposed experiments will set the ground for systematic inquiry into effects of neuromodulators on coupling between BOLD signal and underlying local neuronal activity, and will develop tools for addressing neuromodulatory mechanisms of cognitive processes by means of fMRI.