Human and Animal network studies of high frequency Oscillations

University Of California Los Angeles, Los Angeles CA

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Abstract

Our studies of high frequency oscillations (HFO) have characterized normal Ripples in the human (80-150 Hz), and rat (100-200 Hz), and identified Fast Ripples (FR) in patients with mesial temporal lobe epilepsy (MTLE) (200-500 Hz), and experimental rat and mouse models of this condition (250-500 Hz). FR preferentially occur in areas capable of generating spontaneous seizures, FR can be recorded in rats during the latent period after status epilepticus before the appearance of spontaneous seizures, and FR are seen at the onset of spontaneous hypersynchronous, and low voltage fast ictal onsets. Consequently, FR have been considered a marker for epileptogenicity and epileptogenesis, but also are believed to reflect some of the fundamental neuronal mechanisms of these processes. Normal Ripples never occur in dentate gyrus (DG), are widely distributed, and represent summated IPSPs, reflecting synchronizing functions of inhibitory interneurons necessary for information transfer. In contrast, FR occur in DG, can be discretely localized to small clusters of neurons imbedded in tissue of the same structure that in adjacent areas does not generate FR, and appear to be associated with synchronous burst firing of principal neurons, bursting neurons being a characteristic of epileptogenic tissue. FR occur not only in DG but, like Ripples, also occur in entorhinal cortex, hippocampus proper, subiculum, and amygdala, all areas presumed to be involved in the epileptogenic mechanisms of MTLE. Recently, we have also identified pathological Ripples (pR) in DG, which raises the question of whether some Ripple frequency oscillations in mesial temporal structures outside DG in human and rat hippocampal epilepsy might also be pathological. This subproject will utilize chronic electrophysiological recording to measure spatiotemporal properties of HFO in human MTLE and the pilocarpine (PILO) rat and selective pathway blockade and lesions in the PILO rat to identify pathological local and more distributed networks in mesial temporal structures that might underlie epileptogenicity; identify unit correlates of normal Ripples, FR, and pR in patients and rats (to complement similar in vitro and acute studies in Subprojects #1 and 2), and correlate electrophysiological features of pathological HFO with quantified MRI evidence of atrophy in patients. We anticipate that elucidation of these fundamental neuronal and network underlying mechanisms will provide novel targets for therapy and prevention of epilepsy, and insights into new approaches to diagnosis.