Epilepsy is among the most common serious neurological disorders. Our current research has focused on mechanisms of seizure generation using a unique parallel reiterative animal/human research paradigm in an effort to identify targets for novel antiseizure therapies to treat these pharmacoresistant patients. We have succeeded in defining electrophysiological disturbances in patients with mesial temporal lobe epilepsy (MTLE), and rat models of this disorder, at the local field potential (LFP) and unit levels, and identified pathological high- frequency oscillations (pHFOs) as biomarkers of epileptic brain tissue. Evidence that pHFOs reflect summated action potentials of small clusters of pathologically interconnected synchronously bursting neurons (PIN clusters) that are spatially stable over time, but expand with changes in the local microenvironment, has led to the hypothesis that spontaneous seizures result from coalescence and synchronization of PIN clusters. We are now also identifying similar pathological changes in perilesional neocortex in rats with posttraumatic epilepsy (PTE), following fluid percussion injury (FPI), in order to study mechanisms of epileptogenesis that might suggest preventive, and disease-modifying, interventions for patients with traumatic brain injury (TBI). A major innovation of the animal work proposed here is the fabrication of MRI-compatible carbon fiber microelectrodes capable of recording pHFOs and multiunit activity, permitting simultaneous continuous electrophysiological monitoring and repeated diffusion tensor imaging (DTI) and functional MRI (fMRI) investigations over many months to identify and localize structural and functional disturbances that distinguish rats that later develop PTE from those that do not. We also will be using these microelectrode and neuroimaging data in an effort to identify pathological features of surface EEG that could be used as noninvasive biomarkers of epileptogenesis clinically, as patients with TBI, unlike those with MTLE, are not usually subjected to invasive EEG evaluations. Our overarching hypothesis is that specific neuronal populations are responsible for epileptogenesis and ictogenesis, and that their characterization and localization will lead to clinically useful biomarkers and novel targets for intervention.
Aim 1 is a new research direction: to monitor EEG, HFOs, multiunit activity, DTI, and fMRI after injury in the rat to identify and localize changes that predict the development of spontaneous epileptic seizures.
Aims 2 and 3 are continuations of current research: to monitor EEG, LFPs, and multiunit activity in the PTE rat to identify and localize functional changes that occur at onset of seizures for comparison with data obtained from MTLE rat models; and to monitor EEG, LFPs, and multiunit activity in patients with MTLE to identify and localize functional changes in neuronal elements that occur at the onset of seizures for comparison with data obtained from rats. Long-term objectives will include utilization of these results to establish biomarkers of epileptogenesis and predictors of ictogenesis, and to identify targets for novel interventions to treat, prevent, and cure epilepsy.

Public Health Relevance

Epilepsy is among the most serious neurological disorders. Current treatments fail to control seizures in 40% of patients with epilepsy, and there is no treatment that prevents epilepsy. We propose to continue our multidisciplinary electrophysiological and neuroimaging studies of patients and rat models of mesial temporal lobe epilepsy and posttraumatic epilepsy, in order to identify biomarkers and targets for novel approaches to seizure control, disease prevention, and cure.

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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Engel Jr, Jerome (2018) Epileptogenesis, traumatic brain injury, and biomarkers. Neurobiol Dis :
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Jozwiak, Sergiusz; Becker, Albert; Cepeda, Carlos et al. (2017) WONOEP appraisal: Development of epilepsy biomarkers-What we can learn from our patients? Epilepsia 58:951-961

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