This project describes in detail the human microdialysis method to obtain in vivo neurochemical data in selected patients with complex partial epilepsy. The scope and limitations of the technique are discussed in detail and the proposal outlines development and characterization of the method for human use. Perfusion and sample collection is continuous throughout the duration of depth electrode implantation, 7 to 10 days on average. The primary focus of this project is the investigation of glutaminergic and GABAergic neurotransmission within the epileptogenic hippocampus, specifically testing the hypothesis that increased excitability is in part mediated through altered regulation of extracellular fluid (ECF) levels of these transmitters. In addition to amino acids, ECF monoamines will also be quantitated, with dynamic changes correlated with the electroclinical events of patients. The recently developed method of lactography, on-line fluorometric measurement of dialysate lactate, will be used as a sensitive index of local glucose utilization and may also in part reflect n-methyl-d-aspartate (NMDA) receptor mediated transmission. Some parallel experiments will be conducted in the amygdala-kindled rat to further investigate basic neurochemical mechanisms of altered transmission in the development of increased brain excitability. This project is deeply intermeshed with other projects in the program. Specifically, studies on the pharmacology of antiepileptic drugs (AED) will use microdialysis as a probe to obtain ECF drug levels for pharmacokinetic and pharmacodynamic studies, as well as determine ECF neurotransmitter responses to AED. Microdialysis samples will also be used in conjunction with the SPECT imaging project to obtain free brain levels of the radioligand. In addition, in vitro dialysis and rapid chemical sampling will be performed in those projects utilizing brain slices, extending studies of both human and experimental animal slices to include chemical as well as electrophysiological recording and enabling the direct comparison of in vitro with in vivo data.
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