Epilepsy is a neurological disorder that affects millions of people worldwide. A common phenomenon in most patients is the appearance of interictal spikes, which are brief abnormal waveforms in electroencephalographic recordings, produced by groups of epileptic neurons discharging synchronously. Interictal spikes can affect intrinsic neural function in the brain region where they originate;however, they are virtually never considered in the clinical management of epilepsy. The hippocampus is a brain region involved in complex learning and memory functions. It is also a major source of interictal spikes in temporal lobe epilepsy, though their impact on its function has not been systematically investigated. This proposal seeks to evaluate the effects of interictal spikes on hippocampal processes. We have gathered preliminary data suggesting that interictal spikes in the hippocampus increase susceptibility to errors in a short-term memory task. In addition, we have observed multiple consistent subtypes of these spikes, which may be originating in divergent hippocampal circuits. We hypothesize that interictal spikes in temporal lobe epilepsy can originate in multiple hippocampal network pathways, consequently impairing their intrinsic cognitive functions by disrupting neurophysiological rhythms. We will evaluate this hypothesis by completing the following Specific Aims: 1) Investigate the neural circuitry of interictal spike genesis and propagation in the intrahippocampal-pilocarpine model of temporal lobe epilepsy. 2) Investigate the impact of interictal spikes in the hippocampus on short-term memory functions and related electro-physiological oscillations. These experiments will utilize novel methods in an established rat model of temporal lobe epilepsy.
Specific Aim 1 will involve high spatial-density depth electrode recordings in the hippocampus and interconnected areas to evaluate the circuitry of interictal spikes.
Specific Aim 2 will use behavioral tasks that specifically involve hippocampal function, along with simultaneous depth electrode recordings to examine the impact of interictal spikes on cognition and related neurophysiological oscillations. This investigation will provide novel perspectives on the neurophysiological and functional consequences of interictal spikes in cognitive processing. Public Health Relevance: Our results may hold considerable clinical relevance, due to the abundance of interictal spikes in patients with epilepsy. Our ultimate goal is to discern whether interictal spikes have the potential to significantly impact patient quality of life, and consequently if their presence should be factored in to clinical treatment decisions.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZNS1-SRB-M (64))
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Fureman, Brandy E
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Dartmouth College
Schools of Medicine
United States
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Kleen, Jonathan K; Scott, Rod C; Holmes, Gregory L et al. (2013) Hippocampal interictal epileptiform activity disrupts cognition in humans. Neurology 81:18-24
Kleen, Jonathan K; Wu, Edie X; Holmes, Gregory L et al. (2011) Enhanced oscillatory activity in the hippocampal-prefrontal network is related to short-term memory function after early-life seizures. J Neurosci 31:15397-406
Kleen, Jonathan K; Sesque, Alexandre; Wu, Edie X et al. (2011) Early-life seizures produce lasting alterations in the structure and function of the prefrontal cortex. Epilepsy Behav 22:214-9
Kleen, Jonathan K; Scott, Rod C; Holmes, Gregory L et al. (2010) Hippocampal interictal spikes disrupt cognition in rats. Ann Neurol 67:250-7