Together, the present results on oxygenation, flow, and metabolism indicate that the prevalence of nonoxidative glycolysis and associated lactate production during the initial phase of activation is replaced by the upregulation of oxidative glucose consumption (see sketches in Fig. 5). Following rapid circulatory changes the gap between oxygen availability and oxygen consumption gradually closes until a recoupling of perfusion and oxidative metabolism is achieved a few minutes after switching the state of neural activity. While brain glucose and lactate concentrations reflect an initial prevalence of anaerobic glycolysis, the changes in blood oxygenation suggest that the rapid adjustment of blood flow (enhanced oxygen delivery) is followed by a slower upregulation of oxidative metabolism (enhanced oxygen consumption). The physiological uncoupling of perfusion and oxidative metabolism emerges as a transient phenomenon in response to both onset and end of stimulation. Recoupling at enhanced cerebral metabolic rates of oxygen (CMRO2) and glucose occurs a few minutes after switching the state of neural activity. Since glycolysis takes place primarily in astrocytes, the stimulus-related increase and decrease of lactate seen here may reflect a transfer of astrocytic lactate to neurons where it is converted into pyruvate and channelled into oxidative phosphorylation. This model of metabolic responses to functional activation is supported by a recently detected pathway for glutamate-stimulated glycolysis in astrocytes that provides a simple mechanism linking astrocytic glucose utilization to neuronal activity (Pellerin and Magistretti, 1994). In summary, evidence has accumulated that the physiological uncoupling of perfusion and oxidative metabolism associated with the onset of functional activation is a transient phenomenon leading to an only temporal mismatch of oxygen delivery and consumption. Recoupling at enhanced though balanced levels of glucose and oxygen consumption is most remarkably documented by the pronounced "negative" uncoupling at the end of stimulation.