The global burden of disease accounted for by epilepsy is equivalent to lung cancer in men and breast cancer in women, ranking it among the most serious neurological disorders. Our current and proposed research directly addresses "benchmarks" for research to prevent and cure epilepsy, developed by a joint committee of NINDS and the American Epilepsy Society. During the current funding period, we have characterized pathological high-frequency oscillations (pHFOs) as a potential reflection of the fundamental neuronal mechanisms underlying epilepsy, and as a putative biomarker of epileptogenesis and epileptogenicity. We now have acquired evidence from several chronic rat models of human mesial temporal lobe epilepsy (MTLE), and from patients with MTLE, suggesting that pHFOs are generated by discrete neuronal clusters embedded in tissue that does not generate pHFOs, and that an increase in size of these neuronal clusters with subsequent coalescence and synchrony could provide a mechanism for transition to ictus. Given the increasing importance of traumatic brain injury (TBI) and post-traumatic epilepsy (PTE) in returning veterans, we are now proposing to carry out similar studies in a fluid percussion model of TBI/PTE. Our preliminary data indicate that seizures in this model originate in hippocampus, have electrophysiological features resembling ictal onset patterns in rodent models of MTLE, and are associated with both interictal and ictal pHFOs. It is unknown, however, whether the hippocampus is the primary site of seizure generation in this model, or whether neocortical seizures also occur, and if so, whether hippocampal seizures reflect propagation from neocortex. Since the original submission of this proposal, we have recorded epileptiform discharges in neocortex anterior and posterior to the fluid percussion injury, as well as associated neocortical pHFOs. Consequently, we first propose to carry out long-term video-EEG monitoring with multiple microelectrodes to characterize the spatial and temporal patterns of epileptogenesis in this TBI model, and interictal juxtaneuronal recording and labeling to define the firing patterns of identified principal neurons and interneurons during pHFOs recorded from neocortical and hippocampal sites after spontaneous seizures occur. We will also carry out experiments similar to those we have performed in post-status rodent models of MTLE to determine whether mechanisms of transition to ictus are the same in the TBI/PTE rat model. We now have the capability to pursue more detailed and prolonged electrophysiological studies in patients with MTLE during depth electrode recording and will characterize the transition to the different seizure types exhibited by patients with this disorder. For many years, our research has utilized parallel experimental paradigms to investigate human MTLE and animal models of this disorder. We hope eventually to create the same parallel human/animal research paradigm for studying TBI. The ultimate goal of this research direction is to identify targets for intervention that will treat, prevent, or cure epilepsy, and to define reliable biomarkers of epilepsy.

Public Health Relevance

This study is designed to use electrical recordings of brain tissue in patients and animals to identify the fundamental mechanisms causing seizures in patients with mesial temporal lobe epilepsy and post-traumatic epilepsy caused by traumatic brain injury. It is anticipated that the results of these experiments will provide insights into new approaches for the diagnosis, treatment, prevention, and cure of epilepsy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS033310-18
Application #
8288076
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Fureman, Brandy E
Project Start
1994-08-01
Project End
2016-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
18
Fiscal Year
2012
Total Cost
$439,337
Indirect Cost
$154,053
Name
University of California Los Angeles
Department
Neurology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Engel Jr, Jerome; Dichter, Marc A (2014) Epilepsy. Foreword. Adv Exp Med Biol 813:v-xiii
Savic, Ivanka; Engel Jr, Jerome (2014) Structural and functional correlates of epileptogenesis - does gender matter? Neurobiol Dis 70:69-73
Bragin, Anatol; Almajano, Joel; Kheiri, Farshad et al. (2014) Functional connectivity in the brain estimated by analysis of gamma events. PLoS One 9:e85900
Dedeurwaerdere, Stefanie; Shultz, Sandy R; Federico, Paolo et al. (2014) Workshop on Neurobiology of Epilepsy appraisal: new systemic imaging technologies to study the brain in experimental models of epilepsy. Epilepsia 55:819-28
Pitkänen, Asla; Engel Jr, Jerome (2014) Past and present definitions of epileptogenesis and its biomarkers. Neurotherapeutics 11:231-41
Haneef, Zulfi; Lenartowicz, Agatha; Yeh, Hsiang J et al. (2014) Functional connectivity of hippocampal networks in temporal lobe epilepsy. Epilepsia 55:137-45
Engel Jr, Jerome; Thompson, Paul M; Stern, John M et al. (2013) Connectomics and epilepsy. Curr Opin Neurol 26:186-94
Staba, Richard J; Ekstrom, Arne D; Suthana, Nanthia A et al. (2012) Gray matter loss correlates with mesial temporal lobe neuronal hyperexcitability inside the human seizure-onset zone. Epilepsia 53:25-34
Galanopoulou, Aristea S; Buckmaster, Paul S; Staley, Kevin J et al. (2012) Identification of new epilepsy treatments: issues in preclinical methodology. Epilepsia 53:571-82
Bragin, Anatol; Benassi, Simone K; Kheiri, Farshad et al. (2011) Further evidence that pathologic high-frequency oscillations are bursts of population spikes derived from recordings of identified cells in dentate gyrus. Epilepsia 52:45-52

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