There is increasing evidence that interictal EEG abnormalities can result in transitory cognitive impairment. In severe cases, where interictal spikes (IS) dominate the EEG recording, cognitive regression can occur. The mechanisms by which IS result in cognitive impairment are not known. In preliminary studies we have shown that following status epilepticus (SE) or recurrent brief flurothyl-induced seizures IS are common. Following SE or recurrent seizures, animals with IS show more impairment than rats without IS. In preliminary work we found that IS result in a substantially reduced likelihood of action potentials (AP) firing in the hippocampal cells that fire in a particular location of the environment, the so-called place cells. Such reduction in AP firing lasts for up to two seconds following the IS. We also have evidence that IS interfere with the replay of place cell firing, normally observed during the awake state and during slow wave sleep consolidation of memory. Our overall hypothesis is that IS, by interfering with firing patterns of critical cells at critical times, result in cognitive impairment.
In Specific Aim One we will address the hypothesis that IS interfere with memory, and particularly working memory, by preventing accurate encoding and retention of information. We will first determine location of IS by performing current source density analyses using multi-contact depth electrodes in the hippocampus of epileptic rats. To rigorously address the hypothesis that IS interfere with encoding and retention of memory we will take advantage of the place preference test and the delayed non-matching to sample test, tasks which allow us to record place cells while the animal is engaged in a test of spatial memory. By comparing spatial performance with place cell firing during periods with and without IS we will directly determine the effect of IS on spatial learning and memory. The observation that IS are highly coupled to arousal and EEG state will allow us to control IS frequency by manipulating non-theta activity.
In Specific Aim Two we will address the hypothesis that IS during sleep impair cognitive function through disruption of consolidation of memory during replay of place cell firing patterns. In this aim, we will study the effect of nocturnal spikes on recapitulation of place cells firing patterns during sleep using animals previously subjected to status epilepticus or recurrent flurothyl seizures and IS during the awake and sleep states. Project Narrative: If our hypotheses are confirmed the findings would have major clinical implication in regards to the treatment of patients with epileptic encephalopathies. In addition to learning much about the cognitive impairment in epilepsy, our studies will provide enormous insight into processes involved in normal encoding and consolidation of memory.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Developmental Brain Disorders Study Section (DBD)
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Babcock, Debra J
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Dartmouth College
Internal Medicine/Medicine
Schools of Medicine
United States
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Burroughs, Scott A; Morse, Richard P; Mott, Steven H et al. (2014) Brain connectivity in West syndrome. Seizure 23:576-9
Hernan, A E; Holmes, G L; Isaev, D et al. (2013) Altered short-term plasticity in the prefrontal cortex after early life seizures. Neurobiol Dis 50:120-6
Holmes, Gregory L; Milh, M D Mathieu; Dulac, Olivier (2012) Maturation of the human brain and epilepsy. Handb Clin Neurol 107:135-43
Lucas, Marcella M; Lenck-Santini, Pierre-Pascal; Holmes, Gregory L et al. (2011) Impaired cognition in rats with cortical dysplasia: additional impact of early-life seizures. Brain 134:1684-93
Kleen, Jonathan K; Scott, Rod C; Holmes, Gregory L et al. (2010) Hippocampal interictal spikes disrupt cognition in rats. Ann Neurol 67:250-7
Holmes, Gregory L (2009) The 2008 Judith Hoyer lecture: epilepsy in children: listening to mothers. Epilepsy Behav 16:193-202
Holmes, Gregory L (2009) The long-term effects of neonatal seizures. Clin Perinatol 36:901-14, vii-viii
Lenck-Santini, Pierre-Pascal; Holmes, Gregory L (2008) Altered phase precession and compression of temporal sequences by place cells in epileptic rats. J Neurosci 28:5053-62
Holmes, Gregory L (2008) What constitutes a relevant animal model of the ketogenic diet? Epilepsia 49 Suppl 8:57-60
Holmes, Gregory L; Dichter, Marc A (2008) Prolonged febrile seizures: underrecognized and perhaps underappreciated? Neurology 71:162-3