Epilepsy affects 65 million people worldwide, one-third of who have seizures that cannot be controlled by medications. Localizing where seizures are generated in the brain can dramatically improve outcome from epilepsy surgery and anti-seizure devices in these patients. Unfortunately current clinical imaging techniques are unable to identify the seizure-generating region in approximately one-third of patients with localization related epilepsy. This proposal applies a novel 7T MRI technique, GluCEST, which images the excitatory neurotransmitter glutamate at high resolution, to localize epileptic networks. Glutamate is widely believed to be central to seizure-generation, and preliminary data indicates that this technique can identify seizure generating regions in patients not-localized by other techniques. GluCEST will be obtained in large cohort patients with lesion and nonlesional epilepsy and in control subjects. Magnetic resonance spectroscopy will be used to validate GluCEST derived glutamate measures and to investigate excitatory/ inhibitory mismatch thought to be present in epileptogenic regions. We expect to demonstrate that GluCEST can identify the epileptic network in patients with temporal lobe and neocortical epilepsies both with and without lesions present on current clinical imaging. The proposed work will produce novel scientific results with the potential to improve treatment for medication-resistant epilepsy, advance our knowledge of its underlying mechanisms, and to be quickly translated to the bedside. GluCEST has the potential to improve accuracy and outcome from epilepsy surgery, and to become a valuable biomarker for assessing novel treatment strategies. Equally important, the proposed project is designed to provide critical career development training to the candidate, an Assistant Professor of Neurology in the Epilepsy Division at the University of Pennsylvania. The proposal builds upon the candidate's established interest in multimodality imaging in epilepsy and her prior training in translational research. The candidate will be mentored by an experienced interdisciplinary team of senior faculty, led by: (1) primary mentor Dr. John Detre, a world renowned expert in neuroimaging who has been critical to development of the novel technique utilized in this work, (2) Dr. Brian Litt, an established investigator with tremendous experience i clinical epilepsy, developing new technologies to localize epileptic networks, epilepsy surgery and implantable brain devices, and (3) Dr. Ravinder Reddy, an established investigator expert in multinuclear magnetic resonance imaging and spectroscopic techniques. These faculty, together with Dr. Davis's other mentors, will assure that the research and training experience proposed in this submission will enable her to establish an independent research program as a clinician-scientist developing and applying multimodality imaging techniques to investigate epilepsy.

Public Health Relevance

Epilepsy is a common disease, and current standard imaging methods cannot pinpoint the seizure onset location in a large portion of epilepsy patients. The goal of this proposal is to use a new imaging technique that measures the most prevalent excitatory neurotransmitter in the brain to identify the brain regions causing seizures. Improved identification of the seizure network in the brain is critical for patients and clinicians to deterine best treatment for a given patient.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Mentored Patient-Oriented Research Career Development Award (K23)
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Neurological Sciences Training Initial Review Group (NST)
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Stewart, Randall R
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University of Pennsylvania
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