The imaging of brain activity with positron emission tomography (PET) and functional magnetic resonance imaging has assumed a central position in psychiatry. Functional imaging signals arise from changes in the neurophysiological parameters of glucose and oxygen consumption mediated by blood flow. Recent in vivo (13)C nuclear magnetic resonance (NMR) neurochemical studies have established a quantitative coupling between the rates of glucose oxidation and glutamate neurotransmitter flux in rats and humans, thereby linking measured neurophysiological parameters to brain function. These results show that in the awake, resting, and unstimulated states, 70%-80% of brain energy consumption is devoted to the same glutamate/glutamine neurotransmitter signaling as are the small percentages stimulated by tasks. Furthermore, in anesthetized animals, in which unstimulated activity is reduced, the total signal rather than a particular increment is required for a response. On this basis, the total signal, as well as the difference in the signal, measures cortical neurotransmitter flux. The total signal in a region therefore contains valuable information about required brain activity. Although signal change is often more easily measured, certain PET and (13)C NMR methods can quantify total regional signal activity and thereby provide another measure of neurotransmitter activity.