The objectives are to continue development of magnetic resonance spectroscopy (MRS) as a """"""""tool"""""""" for exploring bioenergetic events in the brain in vivo. The present work proposes to explore two hypotheses: 1. That the severity of an hypoxemic insult in the adult brain can be predicted by MRS determination of phosphocreatine (PCr) concentration. 2. That brain work and brain bioenergetics are related by a Michaelis-Menten hyperbola and that metabolic instability can be predicted from MRS measurements. In pursuing these two hypotheses, the changes obtained with MRS will be related to measures of oxygen availability, brain redox state, cerebral metabolism of oxygen and glucose, cerebral production of lactate, brain intracellular pH, cerebral blood flow, neurophysiologic function (electroencephalography and somatosensory evoked potentials), and histopathology (by both light and electron microscopy). Finally, the findings with MRS will be compared to measurements of brain metabolites by standard biochemical techniques to determine the sensitivity and reproducibility of MRS measurements compared to traditional approaches. The experiments will be done on anesthetized dogs, intubated, mechanically ventilated and prepared for invasive monitoring of vital signs. Two different types of experiments will be done: In the first, the dog will be exposed to a period of """"""""stabilized hypoxemia"""""""" in which the degree of metabolic stress is continuously adjusted according to """"""""real time"""""""" determinations of PCr by MRS. At various times oxygen will be restored and the rate of recovery or the development of metabolic instability will be determined. In the second type of experiment, brain work will be increased by administration of a short acting epileptogenic gas. The ability to finely titrate the dose of this agent should allow graded increases in cerebral metabolic rate that will allow determination of the relationship of brain work to brain energy. These experiments have direct relevance to medicine. Many catastrophic brain events involve changes in brain energy production. MRS is the only technique with the potential of determining these changes in man, since it can measure brain energy non-invasively and non-destructively. Basic studies of MRS in animals are required to understand the meaning of the measurements when they are obtained from humans. In addition, the studies will add to the fundamental knowledge concerning the production and utilization of energy in the brain.
