2011 — 2015 |
Staba, Richard |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mapping Cortical Anatomical and Electrophysiological Abnormalities in Human Mtle @ University of California Los Angeles
DESCRIPTION (provided by applicant): The NINDS and several epilepsy organizations have established benchmarks that emphasize the need to develop new therapeutic strategies and optimize current approaches to treat and cure epilepsy. Mesial temporal lobe epilepsy (MTLE) with hippocampal sclerosis (HS) is the most common type of pharmacoresistant epilepsy. Patients with this type of epilepsy are often treated surgically, but surgical outcome studies indicate too many patients continue to have postoperative seizures. Surgical resection is based on determining the epileptogenic zone (EZ), i.e. the brain areas necessary and sufficient for generating spontaneous seizures, and surgical failure is believed to result from an incomplete resection of the EZ. The fundamental challenge in defining the EZ is that it can not be measured directly, but is inferred from diagnostic tests, most important of which is localization of sites of ictal onset and early propagation and the presence of an epileptogenic lesion. Our recent work using advanced structural imaging in patients with MTLE found specific spatial patterns and levels of hippocampal atrophy that were associated with different types of ictal onset. These data indicate there could be several types of MTLE with HS and each associated with specific anatomical abnormalities, ictal and interictal electrophysiological disturbances and clinical features. If this hypothesis is correct, then a combination of these measures of epileptogenicity could define the EZ and provide important information on prognosis for a seizure-free surgical outcome. The proposed studies will use structural imaging and functional measures in an attempt to accurately delineate the EZ in patients with MTLE. Specifically, first, we will quantitatively evaluate the spatial patterns and levels of hippocampal and neocortical gray matter atrophy in patients with different types of depth electrode-recorded ictal onsets and clinical features. Second, we will characterize pathological high frequency oscillations (pHFOs) and localize their sites of generation in hippocampal and neocortical networks that include areas of ictal onset and early propagation and remote areas. Studies by us and others suggest pHFOs represent fundamental neuronal disturbances responsible for spontaneous seizure genesis, and because these abnormal events occur during interictal as well as during ictal periods, recording pHFOs will allow us to identify areas of epileptogenicity more rapidly than capturing seizures. And third, we will determine whether a combination of these measures of epileptogenicity accurately defines the EZ by correlating their removal with seizure-free surgical outcomes. We anticipate completion of these specific aims will develop safer, more accurate and less expensive approaches to defining the EZ and increase the likelihood for postoperative seizure freedom. In addition, we expect that the results of the proposed studies will provide valuable insights into the fundamental neuronal basis of the EZ in MTLE. PUBLIC HEALTH RELEVANCE: Individuals with poorly controlled epilepsy, as well as their families and communities, sustain considerable physical, social and economic costs. This study is designed to identify specific anatomical and electrophysiological disturbances that define the brain areas capable of generating spontaneous seizures in order to more clearly understand mechanisms of seizure genesis, improve surgical treatment and develop new therapies to eliminate seizures and the burden of epilepsy.
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0.915 |
2019 — 2021 |
Staba, Richard |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Defining the Epileptogenic Network and Identifying Which Components Generate Seizures @ University of California Los Angeles
Project Summary Epilepsy is a serious neurological disorder characterized by spontaneous seizures and increased risk of mortality, especially for one-third of the individuals with chronic seizures that cannot be controlled in spite of optimal drug therapy. Currently, the most effective treatment for drug-resistant seizures is resective surgery and in cases such as temporal lobe epilepsy (TLE) with hippocampal sclerosis, the most common form of drug- resistant epilepsy, surgery can reduce or eliminate seizures in most patients. However, it does not help all patients, particularly those with seizures suspected to begin in the temporal lobe but without a MRI lesion or MRI contains a lesion in hippocampus and neocortex or scalp EEG indicates bilaterally. In situations like these the extent of the epileptogenic zone (EZ), which is the brain area that is necessary and sufficient for generating seizures and minimum resection necessary for seizure relief, is uncertain. There is tremendous interest in studies of the epileptogenic network (EN), i.e. the larger brain region that supports the generation and spread of seizures and manifestation of epilepsy, and we hypothesize in difficult cases of TLE, knowledge of the EN could help us to localize the EZ. Even with recent progress from studies of the EN, we still do not know the full extent of brain abnormalities that define the EN, what part is necessary for generating seizures, or how much of the EN needs to be removed to eliminate seizures. This project addresses these issues and we have developed a comprehensive approach to study them, including novel structural and diffusion MRI and EEG functional connectivity tests, as well as studies of high frequency oscillations (HFOs), which are a potential biomarker of the EZ. We will apply this approach to presurgical patients with suspected TLE who require invasive EEG tests as part of their standard diagnostic care. To help us define the EN in Aim 1, we will evaluate structural MRI for gray matter abnormalities and morphological covariance between brain areas; in Aim 2, we will assess diffusion MRI for white matter microstructural and fiber tract anomalies; in Aim 3, we will use a new approach called gamma event coupling in combination with unit and HFO recordings to investigate the functional connectivity encompassing the EN and identify which parts of it are generating seizures and spread; and lastly in Aim 4, we will determine which components of the EN and how much of it needs to be removed to eliminate seizures. In this project, defining the EN should provide important information on the structural and functional mechanisms generating seizures, and ultimately this will help us to localize the EZ, improve diagnosis, advance surgical and non-surgical therapies, develop new therapies, and increase the likelihood for seizure freedom.
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0.915 |