Magnetic resonance imaging and modelling of brain function and microvascular physiology

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Functional magnetic resonance imaging (fMRI) has revolutionized human neurosciences by providing a non-invasive tool for dynamically mapping brain activity without the use of ionizing radiation or exogenous contrast agents. Most fMRI studies exploit the Blood Oxygenation Level-Dependent (BOLD) effect, whereby the oxygen saturation of blood modulates the MRI signal level, to localize changes in blood oxygenation that are related to changing neuronal activity. More recently, quantitative functional imaging techniques have used the BOLD effect to estimate physiological parameters of basic and clinical neuroscientific relevance, such as blood oxygen saturation and the cerebral metabolic rate of oxygen, while alternative "non-BOLD" imaging techniques have been developed to measure additional physiological parameters, such as cerebral blood flow. Because the brain is so heavily reliant on the microvasculature for a continuous and adaptive supply of nutrients, MRI provides a powerful tool for mapping and measuring brain function in health and disease. We now know that conventional BOLD fMRI is influenced by a wide range of factors, both physiological and acquisition related. These complex influences make BOLD fMRI challenging to relate to both the underlying neuronal activity and the vascular physiology. My long-term vision is that by removing or exploiting the biophysical biases of fMRI signals, we will be able to image neuronal activity and microvascular function and structure with greater specificity and sensitivity. In this proposal, we will develop modelling tools to improve our interpretation of the BOLD signal and we will develop MRI acquisition techniques that are sensitive to specific physiological parameters. The main objectives are: 1) Develop and experimentally validate a realistic biophysical model of blood to simulate the MRI signal from blood - a significant yet often ignored component of the BOLD signal. 2) Improve the accessibility and applicability of a technique known as "calibrated fMRI", which can be used to measure changes in oxygen metabolism. 3) Develop novel image acquisition and reconstruction techniques for performing fMRI with reduced image artifacts and for imaging cerebral blood flow with improved specificity and signal-to-noise ratio. This research program will elevate fMRI from a qualitative brain mapping tool that is currently limited by numerous biases to mapping function at increased neuronal specificity and accurately measuring the microvascular physiology. The tools that we develop will allow us to better understand the tight coupling between neuronal activity and hemodynamics, which nearly all functional imaging techniques rely on. Ultimately, these developments can be integrated into basic and clinical human neurosciences, where open questions on alterations of neuronal activity, metabolism, and vascular function over the healthy lifespan and in a host of neurological and psychiatric disorders can be probed.