The global burden of disease due to epilepsy is comparable to that of lung cancer in men and breast cancer in women. The current proposal directly deals with the following NIH benchmarks: 1) Understand epileptogenic processes associated with acquired forms of the epilepsies, including those associated with traumatic brain injury, stroke, brain tumor, infections, neurodegeneration, or other insults to the brain. 2) Identify biomarkers that will aid in identifying, predicting, and monitoring epileptogenesis and disease progression, including markers early after injury/insult that identifies those people at rik for epilepsy. In our previous research we've discovered pathological high frequency oscillations (pHFOs) in animal models of chronic epilepsy and patients with temporal lobe epilepsy. These data are confirmed in many other laboratories and now pHFOs are used in patients to help localize the seizure onset zone. It has become evident that epilepsy is a network phenomenon and even focal epilepsy is associated with abnormal changes in connectivity between multiple brain areas. Our understanding of functioning of these networks is limited and approaches are not well developed. In this proposal we are investigating properties of networks in normal conditions and during epileptogenesis in 2 animal models of chronic epilepsy: neocortical and hippocampal. Neocortex is the brain area frequently affected by traumatic injury or/and stroke, and hippocampus is a brain area that reveals cell death in multiple types of epilepsy. We are applying a new approach to study functional connectivity between multiple brain areas by estimating functional relationships of local field potentials in the gamma frequency band. We will identify functional connections that are altered after epileptogenic injury in animals that later develop epilepsy and compare them with those in animals that do not develop epilepsy. We will further investigate properties of normal and pathological functional connections using electrophysiological and pharmacological approaches. Taking into account the spatial limitations of electrophysiological approaches, we are planning to carry out parallel electrophysiological and magnetic resonance imaging experiments, which we believe will yield important complementary data for understanding the properties of normal and pathological networks. Completion of this study will further improve our understanding of mechanisms of epileptogenesis and provide new approaches for treatment of epilepsy.

Public Health Relevance

The goal of this study is to identify and characterize pathological networks that develop after brain lesions, during the process of epileptogenesis using electrophysiological and magnetic resonance imaging approaches. This work will allow the identification of mechanisms causing post-traumatic and temporal lobe epilepsy. We anticipate that results obtained in this study will lead to the discovery of new approaches for the prevention of epilepsy.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Acute Neural Injury and Epilepsy Study Section (ANIE)
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Leenders, Miriam
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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Shimamoto, Shoichi; Waldman, Zachary J; Orosz, Iren et al. (2018) Utilization of independent component analysis for accurate pathological ripple detection in intracranial EEG recordings recorded extra- and intra-operatively. Clin Neurophysiol 129:296-307
Li, Lin; Kriukova, Kseniia; Engel Jr, Jerome et al. (2018) Seizure development in the acute intrahippocampal epileptic focus. Sci Rep 8:1423
Engel Jr, Jerome; Bragin, Anatol; Staba, Richard (2018) Nonictal EEG biomarkers for diagnosis and treatment. Epilepsia Open 3:120-126
Waldman, Zachary J; Shimamoto, Shoichi; Song, Inkyung et al. (2018) A method for the topographical identification and quantification of high frequency oscillations in intracranial electroencephalography recordings. Clin Neurophysiol 129:308-318
Weiss, Shennan Aibel; Alvarado-Rojas, Catalina; Bragin, Anatol et al. (2016) Ictal onset patterns of local field potentials, high frequency oscillations, and unit activity in human mesial temporal lobe epilepsy. Epilepsia 57:111-21
Bragin, Anatol; Li, Lin; Almajano, Joyel et al. (2016) Pathologic electrographic changes after experimental traumatic brain injury. Epilepsia 57:735-45
Weiss, Shennan A; Orosz, Iren; Salamon, Noriko et al. (2016) Ripples on spikes show increased phase-amplitude coupling in mesial temporal lobe epilepsy seizure-onset zones. Epilepsia 57:1916-1930
Reid, Aylin Y; Bragin, Anatol; Giza, Christopher C et al. (2016) The progression of electrophysiologic abnormalities during epileptogenesis after experimental traumatic brain injury. Epilepsia 57:1558-1567
Bragin, Anatol; Almajano, Joel; Kheiri, Farshad et al. (2014) Functional connectivity in the brain estimated by analysis of gamma events. PLoS One 9:e85900
Engel Jr, Jerome; Thompson, Paul M; Stern, John M et al. (2013) Connectomics and epilepsy. Curr Opin Neurol 26:186-94

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