The overall aims of this project are to provide a comprehensive and quantitative description of water diffusion in human brain which can be used to explain the variations in water diffusion that occur in normal and pathological conditions and that produce contrast in diffusion weighted MR images. There is now compelling evidence that water diffusion variations are of general interest and importance in a variety of normal and disease conditions. We aim specifically to understand the basis for the changes that occur in diffusion weighted imaging studies of stroke, seizure and neuronal activation. We aim to perform a series of exhaustive measurements of water diffusion properties in normal human brains. These studies will make use of the efficiency for collecting complete sets of data of advanced echo planar imaging techniques in humans to obtain measurements of the apparent diffusion coefficient (ADC) of tissue water, the degree to which diffusion is restricted, and assessments of the degree of diffusion anisotropy. These measurements will be used to infer the sizes of water compartments, the rates of exchange between them, and their intrinsic diffusion coefficients in brain tissues. Improved navigator echo methods will be implemented as well to permit high resolution diffusion images without echo planar acquisition. Measurements will also be made of the detailed nature of the transverse decay of tissue magnetization to permit the decomposition into component decay rates. Images of individual components of these so-called relaxation spectra will be produced and these should reveal correlative information on the spatial extent and exchange of different water environments. These measurements will be complemented with detailed studies of ADC in rat brain models of seizure and electroshock in which correlative electrophysiological measurements will be acquired. The threshold for observing diffusion changes following very brief stimulations will be established. We will also perform high resolution q space imaging of ex vivo preparations of excised rat optic nerve, subjected to different osmotic manipulations, to evaluate the effects of water volume shifts and other changes; and we will continue our extensive computer and theoretical modeling of water diffusion in restricted and compartmented systems to provide quantitative interpretations of these and other clinical observations. We will thereby obtain the information necessary to interpret water diffusion behavior in the brain, to guide the optimal use of MR imaging techniques in patient management and for developing models of tissue water diffusion to more fully explain the MRI changes seen in patients with stroke and other conditions.