PROJECT SUMMARY Brain function is critically dependent on the proper relationship of cerebral blood flow (CBF) and neuronal metabolic demands, a phenomenon referred to as neurovascular coupling. Pathological reductions in CBF are commonly observed in presence of loss of brain function, but paradoxically there is often sufficient oxygen supply to support function. Answering this paradox not only would help understand the loss of brain function, but would also provide important new insights into how to interpret fMRI, which essentially measures neurovascular coupling, at the network down to the microscopic level of brain function. I propose to answer these longstanding questions, via a new approach. Rather than following the decades old path of focusing almost exclusively on oxygen delivery and its coupling to neuronal activity, I will develop and validate imaging methods and mathematical models for studying how neurovascular coupling maintains homeostasis of all of the substrates and products of functional brain metabolism. The importance of maintaining tight regulation of the levels of the metabolic products CO:i and protons, have long been recognized via EEG/MEG studies of respiratory hyper and hypocarbia; yet CO2 and protons homeostasis are mosUy disregarded, likely because non-invasive methodologies that allow their assessments are lacking. My goal is to fulfill this unmet need, and establish a transformative neuroimaging approach that quantifies non-invasively oxygen availability, pH and carbon dioxide accumulation in brain tissue. Achieving this goal requires comprehensive studies and theoretical understanding ranging from microscopic capillary transport to the regulation of systemic physiology, at the center of this project. Here my efforts will pivot to a new direction of unprecedented studies that will combine positron emission tomography (PET), optical imaging, MRI, implanted biosensors, and theoretical modeling. My colleagues and I have already conceptualized the highly innovative framework that grounds the studies of this proposal. In particular, by connecting for the first time the properties of neurovascular coupling to the needs of waste removal originating from the metabolic processes linked to neurotransmission, we paved the way towards accurate calculations of oxygen availability, pH and carbon dioxide accumulation from routine MRI measurements. Such a methodology has a tremendous potential to transform the scope and breadth of basic and clinical investigations of the brain (and beyond}, however rigorous validations are sorely needed in order to realize its potential. By capitalizing on recent advances in imaging platforms available at the CMRR and in partner institutions which I have been collaborating with for years, the time is mature to conduct the proposed high-risk, high-impact studies that can only be executed within the flexible scheme of a Pioneer award. Focusing on pathological mechanisms linking loss of brain function to abnormal accumulations of metabolic waste products, and on non-MRI techniques for validation studies, requires a major research shift for me, but is essential for building the foundation of a much broader agenda that will benefit the basic and translational neuroscience community and ultimately patient care.

PROJECT NARRATIVE By capitalizing on recent new insights into brain neurovascular coupling, the goal of this project is to establish and validate a transformative neuroimaging approach that quantifies non-invasively physiological metrics fundamental to brain function, such as oxygen availability, pH and carbon dioxide accumulation in tissue. The project represents a novel direction of research for Dr. Mangia, who will conduct pioneering studies using the proposed novel neuroimaging approach to explore an innovative conceptual framework linking loss of brain function to abnormal accumulations of metabolic waste products.