As in the initial submission of Project 1 of this PPG, the overall goal of this research proposal remains the demonstration and validation of NMR imaging techniques that are optimally sensitive for the detection and characterization of regional brain microscopic perfusion and diffusion. The two approaches to the study of microscopic motions originally proposed, using kinetic modeling of injected contrast agents and measuring intrinsic motions via gradient sensitization, will continue to e studied. In addition to hemodynamics (cerebral blood flow or CBF and cerebral blood volume or CBV), our preliminary data suggests that both approaches have the potential to provide important and complementary physiological information on water mobility within, across and outside the microvascular bed. A new aspect of the current proposal is the use of high speed "single shot" or echo planar imaging (EPI) techniques. Recent data suggests that EPI offers considerable improvements to each approach. These methods will be tested in phantoms and normal animals to clarify their ability to extract quantitative information on regional CBF and CBV, water molecular self diffusion (D), and blood-brain barrier (BBB) permeability, and to refine further the theoretical and experimental basis for these methods. Optimized techniques will then be use to verify the ability of the methods to measure brain perfusion and water mobility states in animal models of altered hemodynamics. Finally, NMR techniques will be applied to clinical studies in patients where perfusion/diffusion imaging offers potential diagnostic and patient management advantages.