Research Project
6804046
Revised Abstract: Functional magnetic resonance imaging (fMRI) has become the major tool for examining human brain function in sensory and cognitive neuroscience. Despite this enormous acceptance across many disciplines, fundamental aspects of the fMRI response remain poorly understood in large part because of difficulties in linking studies in animal models under the confounding effects of anesthesia with those done in awake humans. The studies proposed here are aimed at understanding the links between neural activity in the brain, the blood flow, blood volume and blood and tissue oxygenation changes that follow, and the fMRI signal. These experiments will be performed in an awake animal model. Awake animal models have the greatest relevance to human neuroscience, with the major advantage that they still allow minimally invasive multi-modality measurements of electrophysiology, oximetry and flow. Our previous NIH funded high-resolution fMRI data in humans has motivated us to develop a better understanding of the spatio-temporal characteristics of the fMRI signal. The techniques we will use to accomplish this are fMRI (BOLD and AST based), electrophysiology, fluorescence quenching, laser Doppler and near-infrared spectroscopy at high spatial and temporal resolution in a well-characterized animal model. Well-known modular functional organization of the primary visual cortex (V1) offers us a variety of opportunities to explore the source of the fMRI signal. Our fundamental hypothesis is that hemodynamic responses to neural activity are modulated at a sub-millimeter scale in this model brain system. A consequence of this hypothesis is that we would predict that fMRI signals should reflect functional specialization of neurons at the cortical columnar and lamellar level. In order to test our fundamental hypothesis, we propose 6 experiments with the following 3 Specific Aims. Specific Aim 1 will be to optimize fMRI parameters to obtain the highest spatial selectivity and sensitivity of BOLD and arterial spin tagging (AST) in-vivo. Specific Aim 2 will be to determine the spatial extent and temporal dependence of the fundamental underlying physiological quantities that the BOLD and AST signal depends on. Specific Aim 3 will be to use the responses of the quantities measured in Specific Aim 1 and 2 to generate a multi-parametric model that explains the BOLD effect in terms of its underlying physiological parameters. To quantify BOLD and AST resolution of functional domains in the horizontal direction in the cortex, we will examine the physiologic and fMRI responses in ocular dominance columns (ODCs). To quantify the BOLD resolution in the vertical direction (depth) in cortex, we will measure these responses as a function of cortical layer. Electrical activity will be measured using both local field potentials and unit activity using tungsten electrodes. The redox state of the mitochondrial enzyme cytochrome oxidase (Cyt-aa3) in the cells will be measured using a novel near-infrared (NIR) spectrometer of our own design. The partial pressure of oxygen in the tissue (pO2) will be measured using a commercial fluorescence-lifetime fiber optic technique (Oxylite, Oxford Optronix). The concentrations of oxyhemoglobin [HbO] and deoxyhemoglobin [Hbr] will also be measured using NIR spectroscopy (NIRS). Blood flow will be measured using a commercial fiber optic laser Doppler flow system (Oxyflow, Oxford Optronix).
