Tissue preparation has recently been utilized for detection of neuronal activation in multiple non-BOLD based functional MRI studies to eliminate vascular contamination. However, undesired signal change could still occur in such systems due to the concentration change of dissolved O2 upon tissue activation. To estimate the impact of such effects, the O2 concentration distribution and the consequent susceptibility field in tissue-solution systems were simulated with various tissue geometries and experimental parameters. Our results indicate that substantial signal change between the resting and activated states could potentially be induced by the O2 effect in highly oxygenated solutions, and thus caution should be taken in interpreting any signal change observed in such experiments. Magn Reson Med, 2011. © 2010 Wiley-Liss, Inc.