Neuromodulation of BOLD fMRI Signal during Cognitive Tasks

描述(申请人提供)：血氧水平依赖(BOLD)功能磁共振成像(FMRI)已成为在感觉运动和认知任务中非侵入性测量大脑活动的主要方法，也是神经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(RCMRO2)的函数，对这些因素与神经元活动的耦合作用的了解还远未完全。在导致BOLD的三个因素中，rCBF可能最容易受到非局部因素的影响，如血管活性代谢物(如二氧化碳)、激素和控制大脑状态的非局部释放的神经调节剂，如警觉性、警觉性、注意力等。事实上，控制大脑状态的神经调节剂(如乙酰胆碱、去甲肾上腺素、5-羟色胺、多巴胺等)表现出血管活性特性，已知脑血管系统由表达这些神经调节剂的神经末梢支配。其中，胆碱能神经调节系统因其在参与选择性注意、工作记忆和学习机制的认知任务中起着重要作用而备受关注。由于胆碱能神经调节系统也参与了脑血流的全局控制，因此在参与这种神经调节系统的任务期间对大脑的激活进行成像是有问题的。我们建议通过检验以下工作假设来研究乙酰胆碱(Ach)在认知任务中局部神经元激活和大胆反应之间的关系中的作用：局部CBF不仅受局部神经元活动的调节，还受胆碱能系统介导的控制注意力分配和工作记忆资源的因素的调节。这种对rCBF的系统调节可能改变神经元活动(以rCMRO2为指标)与rCBF之间的关系。我们假设，在注意和工作记忆任务中(可能通过激活基底前脑)，乙酰胆碱的释放对于调节神经元反应和CBF之间的耦合是必不可少的。我们建议通过动脉自旋标记(ASL)方法测量CBF和BOLD反应来检验这些假说。我们将测试注意资源的分配是否影响BOLD和CBF信号，其方式与单独使用视觉球茎刺激的方式相同。为了研究在认知任务中胆碱能机制在CBF和BOLD偶联中的作用，我们将使用药物操纵来影响胆碱能调节的效果。我们预计，对胆碱能调节的药理学操作将以与注意资源分配相同的方向影响CBF/BOLD关系。拟议中的实验将为系统研究神经调节剂对BOLD信号和潜在局部神经元活动之间耦合的影响奠定基础，并将开发工具，通过功能磁共振成像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.