PURPOSE: To develop a sensitive method for detecting minute transient signal changes that can arise due to variations in the extravascular apparent self-diffusion coefficient, D, during neuronal activation. MATERIALS AND METHODS: A three-pulse sequence that reads out a moderately diffusion-weighted (DW) primary echo (PRE) and a heavily DW stimulated echo (STE) was employed to investigate whether small transient signal changes in extravascular D occur in response to a visual stimulus. Contributions to signal changes caused by subtle differences in the transient variations of the apparent transverse relaxation constant, T(2), between the PRE and STE were also quantified. RESULTS: On z-maps obtained from the STE, more voxels showed significant stimulus-related signal changes compared to maps of the PRE. The average maximum signal change of the STE was larger than that of the PRE. The observed increase in the relative signal change was independent of the strength of the diffusion weighting. CONCLUSION: The STE is more sensitive to neuronal activity than the PRE. The discrepancy between the two echoes does not arise from transient changes in D, but from subtle differences in stimulus-related variations of T(2) between the two echoes.