This project develops and implements a variety of tissue models for microstructure imaging in the brain. It also develops experiment design optimization techniques that use those models to identify economical imaging protocols that are achievable on live human subjects and patients. A starting point is measuring the diameter of axons in white matter of live human subjects, which other groups have demonstrated in vitro. Later stages will use similar approaches to target specific cellular changes known to occur in particular diseases, such as Alzheimer's disease, epilepsy and multiple sclerosis. The intended output is MRI techniques specifically tuned for the pathologies of those diseases, which should improve diagnosis, prognosis and treatment planning and be valuable for drug trials.