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To understand the diffusion attenuated MR signal from normal and ischemic brain tissue in order to extract structural and physiological information using mathematical modeling, taking into account the transverse relaxation rates in gray matter.We fit our diffusion model to the diffusion-weighted MR signal obtained from cortical gray matter in healthy subjects. Our model includes variable volume fractions, intracellular restriction effects, and exchange between compartments in addition to individual diffusion coefficients and transverse relaxation rates for each compartment. A global optimum was found from a wide range of parameter permutations using cluster computing. We also present simulations of cell swelling and changes of exchange rate and intracellular diffusion as possible cellular mechanisms in ischemia.Our model estimates an extracellular volume fraction of 0.19 in accordance with the accepted value from histology. The absolute apparent diffusion coefficient obtained from the model was similar to that of experiments. The model and the experimental results indicate significant differences in diffusion and transverse relaxation between the tissue compartments and slow water exchange. Our model reproduces the signal changes observed in ischemia via physiologically credible mechanisms.Our modeling suggests that transverse relaxation has a profound influence on the diffusion attenuated MR signal. Our simulations indicate cell swelling as the primary cause of the diffusion changes seen in the acute phase of brain ischemia.