Mesial temporal lobe epilepsy (MTLE), that form of temporal lobe epilepsy (TLE) associated with hippocampal sclerosis (HS), is believed to be the most common medically refractory human epileptic disorder. Current antiepileptic drugs (AEDs) may be less effective in MTLE because basic mechanisms underlying this condition appear to be different from those of other epilepsies. TLE is often treated surgically, however, and much has been learned from experiments on resected human tissue. More intensive in vivo studies in patients are now necessary to relate these findings to functions of the intact brain. Experimental animal models are essential to supplement this work. In our chronic in vivo microelectrode investigations of patients with TLE and parallel studies of our kainic acid (KA) rat model, we have described two novel interictal field potentials which we call fast ripples (FR), and epileptiform gamma oscillations. FR, unlike interictal spikes (IIS) and epileptiform gamma oscillations, are of particular interest because they appear to be unique to the area that generates spontaneous seizures. Both patients and rats exhibit two distinct seizure types, one that begins with hypersynchronous hippocampal discharges, and a second that begins with more diffuse low voltage fast (LVF) activity. We propose to extend this research to confirm, in KA rat and in patients with TLE, that FR are a manifestation of epileptogenic neuronal disturbances in hippocampal epilepsy, and that the occurrence of FR, but not IIS and epileptiform gamma oscillations, reliably identifies brain areas capable of generating spontaneous seizures. Accomplishment of these objectives could have important clinical application in presurgical evaluation, as well as screening of novel compounds for antiepileptic properties, and would help to validate the KA rat as a model of human MTLE. In the course of these experiments we will utilize current source density (CSD) and voltage depth profile analysis, and single unit recording in both rats and patients. A major advance of this proposal is the use of a new 17 contact in-line microelectrode bundle and high resolution 3T MRI to perform laminar analysis in human hippocampus, similar to that routinely performed in the rat. We will use these data to pursue hypotheses that the neuronal substrates generating FR also generate hypersynchronous ictal onsets, and that these reflect, in part, resistance to propagation through dentate gyrus (DG), while neuronal substrates giving rise to epileptiform gamma oscillations are involved in generating LVF ictal onsets, and reflect activity that propagates easily out of DG to hippocampus proper. We will also study the influence of the sleep-wake cycle on the occurrence of these interictal and ictal epileptiform events, and their relationship to structural reorganization of hippocampus common to the KA rat and human HS. Results of these studies at the systems level will provide critical data to complement investigations at the intrinsic cellular and synaptic level to be proposed as part of our NIH program project (NS02808) renewal.
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