Oxygen balance was evaluated in the cerebral cortex, using the surface fluorometry technique of the intramitochondrial NADH redox state, exposed to various physiological and pathological situations. Using flexible fiber optic light guide, connected to the brain surface via a cemented holder, the measurements were done continuously from the awake rat and gerbil. In few experiments the NADH redox state was correlated with the electrical and ionic activity (measured by surface K + and DC electrodes). Three different animal models were used in the study: the adult rat, the very young rat (20 g) and the adult gerbil. Those 3 models were used in studying the effect of hypoxia, partial ischemia, and anesthesia on the metabolic and ionic activities measured from the awake brain. Spreading cortical depression (elicited by topical KCl solution) was used as a standard stimulation of the ionic and metabolic activities of the cerebral cortex. Two typical metabolic responses to spreading depression (SD) were recorded, namely ‘oxidation cycle’ and ‘reduction cycle’ depending upon the ability of the tissue to compensate for the extra amount of oxygen needed for the higher mitochondrial activity. It was found that the adult rat brain showed oxidation cycles in most conditions (besides partial ischemia), while the young rat and the gerbil brains were much more sensitive to the various perturbations of the brain and exhibited reduction cycle (as a response to SD) under all pathological situations tested. We conclude from our detailed studies that the type of response to SD, as measured by NADH surface fluorometry, represents the oxygen balance which exists in the tissue under various conditions.