There are significant differences in cerebral metabolism between the immature and mature nervous system observed under normal and pathological conditions that affect the care and treatment of infants and children. The ability to investigate in vivo cerebral metabolism non-invasively in this age group will provide important information to both, make a more rational choice of therapy and allow one to monitor its effect. The use of in vivo NMR spectroscopy and stable isotopes with magnetic properties can furnish this information, but must be first validated in animal studies before its application to humans. The goal of this project is to establish that in vivo 1H and 13C NMR spectroscopic methods using 1-13C glucose will provide a measure of the fluxes through various pathways of carbohydrate and intermediary metabolism in the immature nervous system of the pig. The turnover of the cerebral lactate and amino acid pools in the neocortex will be measured in vivo in both the resting state and during generalized seizures. This data will be analyzed by modified computer modeling schemes previously delineated by radioisotope studies to generate a measure of the fluxes through the glycolytic and citric acid cycle pathways. These measurements will be validated both by performing high resolution NMR studies on tissue extracts in vitro and by using both glucose and lactate with the carbon label in other positions. This later method which has been well established by previous radioisotope studies will both provide a more accurate measure of the fluxes through other pathways such as the pentose cycle and pyruvate carboxylase and evaluate the use of alternative substrates by the brain. This information will then be used to refine the modeling program and allow a more accurate determination of the glycolytic and citric acid cycle fluxes from the original in vivo data. The changes of these fluxes and the use of lactate as an alternative substrate in the brain both during a generalized seizure and in the post-ictal period will be determined. The results of the experiments in this project will provide new information about the changes in metabolic fluxes occurring in the neocortex during generalized seizures in the immature nervous system. In addition, the data will be used to define the protocols required to perform similar non-invasive studies in humans.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
First Independent Research Support & Transition (FIRST) Awards (R29)
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Human Development and Aging Subcommittee 3 (HUD)
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Yale University
Schools of Medicine
New Haven
United States
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