OBJECTIVES: The effect of cortical spreading depression (CSD) on extracellular K(+) concentrations (K(+)), cerebral blood flow (CBF), mitochondrial NADH redox state and direct current (DC) potential was studied during normoxia and three pathological conditions: hypoxia, after NOS inhibition by L-NAME and partial ischemia. METHODS: A SPECIAL DEVICE (MPA) WAS USED FOR MONITORING CSD WAVE PROPAGATION, CONTAINING: mitochondrial NADH redox state and reflected light, by a fluorometry technique; DC potential by Ag/AgCl electrodes; CBF by laser Doppler flowmetry; and K(+) by a mini-electrode. RESULTS AND DISCUSSION: CSD under the 3 pathological conditions caused an initial increase in NADH and a further decrease in CBF during the first phase of CSD, indicating an imbalance between oxygen supply and demand as a result of the increase in oxygen requirements. The hyperperfusion phase in CBF was significantly reduced during hypoxia and ischemia showing a further decline in oxygen supply during CSD. CSD wave duration increased during the pathological conditions, showing a disturbance in energy production.Extracellular K(+) levels during CSD, increased to identical levels during normoxia and during the three pathological groups, indicating correspondingly increase in oxygen demand. 5. The special design of the MPA enabled identifying differences in the simultaneous responses of the measured parameters, which may indicate changes in the interrelation between oxygen demand, oxygen supply and oxygen balance during CSD propagation, under the conditions tested. 6. In conclusion, brain oxygenation was found to be a critical factor in the responses of the brain to CSD.