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. ? ?
