Real time investigation of cerebral blood flow (CBF), and oxy/deoxy hemoglobin volume (HbO,HbR) dynamics has been difficult until recently due to limited spatial and temporal resolution of techniques like laser Doppler flowmetry and MRI. This is especially true for studies of disease models in small animals, owing to the fine structure of the cerebral vasculature. The combination of laser speckle flowmetry (LSF) and multi-spectral reflectance imaging (MSRI) yields high resolution spatio-temporal maps of hemodynamic changes in response to events such as sensory stimuli or arterial occlusion. Ischemia was induced by distal occlusion of the medial cerebral artery (dMCAO). Rapid changes in CBF, HbO, and HbR during the acute phase were captured with high temporal and spatial resolution through the intact skull. Hemodynamic changes that were correlated with vasoconstrictive events, peri-infarct spreading depressions (PISD), were observed. These experiments demonstrate the utility of LSF and Multi-spectral reflectance imaging (MSRI) in mouse disease models.