Coupling between cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) was studied using multiple sequential administrations of 15O-labeled radiotracers (half-life, 123 sec) and positron emission tomography. In the resting state an excellent correlation (mean r, 0.87) between CBF and CMRO2 was found when paired measurements of CBF and CMRO2 from multiple (30-48) brain regions were tested in each of 33 normal subjects. Regional uncoupling of CBF and CMRO2 was found, however, during neuronal activation induced by somatosensory stimulation. Stimulus-induced focal augmentation of cerebral blood flow (29% mean) far exceeded the concomitant local increase in tissue metabolic rate (mean, 5%), when resting-state and stimulated-state measurements were obtained in each of 9 subjects. Stimulus duration had no significant effect on response magnitude or on the degree of CBF-CMRO2 uncoupling observed. Dynamic, physiological regulation of CBF by a mechanism (neuronal or biochemical) dependent on neuronal firing per se, but independent of the cerebral metabolic rate of oxygen, is hypothesized.