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Postdoctoral Research Training Fellowships - $45,000

Cian McCafferty, Ph.D.
Yale University
fMRI and neural activity underlying impaired behavior in absence seizures
Summary:  Absence seizures are a common feature of epilepsy syndromes, and significantly reduce quality of life. Current treatments have limited efficacy, and patients can suffer long-term impairments of attention even if seizures are treated. The first line treatment has remained the same for 50 years, and so a greater understanding of the neural activity underlying the disease is necessary to improve its treatment. These experiments will investigate the factors that determine the behavioral severity of seizures by imaging (fMRI) and electrical recordings, with the aim of identifying brain networks and regions that might serve as potential therapeutic targets.

Saera Song, Ph.D.
The Rockefeller University
Identifying the Brain Somatic Mutations that Cause Epilepsy
Summary:  One third of people with epilepsy suffer from uncontrollable seizures, and despite advances in our knowledge of the basic mechanism of epilepsy, effective treatment options for pediatric patients with intractable epilepsy are extremely limited. While we have learned a tremendous amount about the genetic causes of generalized disorders of brain development, our understanding of focal cortical dysplasia (FCD) is in its infancy. The proposed research advances this approach into the FCDs, taking multiple technical approaches. The underlying hypothesis is that FCD is due to activating mutations in particular genes within a small percentage of brain cells, which leads to epileptic circuits, FCS and subsequent epilepsy. The research will test this hypothesis utilizing single cell and ultra-deep sequencing from what is probably the largest world-wide collection of FCD resected brain tissue, combined with sampled healthy cells from each subject, which we have assembled for this project. It is our goal to understand the underlying genetic causes of intractable focal-onset epilepsy and describe pathogenic mechanisms eventually leading to development of new and more targeted treatments for epilepsy.

Predoctoral Research Training Fellowships - $20,000

Grant Fiddyment
Boston University
Data-driven modeling of seizure termination
Summary:  How seizures stop remains an open question in neuroscience. The answer holds tremendous potential value since a medical device that terminates seizure could significantly improve patient care. As such, the project aims to build mathematical models of seizure termination and, through model manipulation, identify mechanisms that support this phenomenon. Models will be of two complementary types: statistical and biophysical. Statistical models will be estimated directly from human brain voltage activity during seizure and will identify general spatiotemporal patterns that emerge as seizures end. Biophysical models will capture realistic features of neuronal networks and offer a means for testing specific hypotheses regarding human seizure termination. Furthermore, the model types will interact: Statistical modeling results will constrain the biophysical model, and biophysical models will allow rigorous testing of statistical insights. These two model frameworks are typically used in isolation, and their combination marks an important innovation of the project. In summary, this project will leverage unique human data and powerful computational tools to illuminate how seizures end and, hopefully, suggest new ways to manage epilepsy.

Vivek Nagaraj
University of Minnesota
Development of a Closed-loop Deep Brain Stimulation Therapy for Epilepsy
Summary:  Approximately 1 percent of the world population lives with epilepsy. For many patients, antiepilepsy drugs do not fully control seizures. There is a need for novel therapies. Deep Brain Stimulation (DBS) has successfully been used to treat Parkinson’s disease and is being applied to other neuropathologies such as epilepsy, migraines and depression. While current neuromodulation devices provide a benefit to patients, efficacy can be improved through development of "personalized" closed-loop stimulation therapies. In this stimulation paradigm, therapy is administered only when patient-specific physiological biomarkers indicate the likelihood of a seizure is high. This research will develop novel stimulation protocols for seizure suppression in an animal model of seizures; it will also test a new deep brain target for electrode placement for seizure suppression. The outcome of this research will be a novel closed-loop control therapy to suppress seizures, reduce stimulation energy, and minimize side effects by turning off stimulation in non-seizure brain states.

Alexander Parker
University of Florida
Influence of neonatal seizures on neuronal ciliogenesis
Summary:  Seizures are one of the most common neurological disorders, with the highest incidence occurring in children less than one year of age. Early life seizures (ELS) can result in severe, permanent deficits in cognition, learning, and memory. How such deficits arise is not clear but may be due in part to seizure-induced structural changes of neurons in the hippocampus and neocortex. It is unknown whether primary cilia, a type of cellular “antenna” which grows from every cortical neuron, is impacted by ELS. This is important because disruption of developing neuronal cilia results in significantly stunted dendritic arbors and abnormal circuit integration.  Our preliminary data suggest that developing neuronal cilia are disrupted by ELS across multiple cortical regions. The goal of this project is to determine whether seizure activity itself directly impairs neuronal cilia outgrowth, and whether neurons bearing blunted cilia after ELS also display underdeveloped dendritic arbors. We will use live cell culture, time-lapse microscopy and viral labeling techniques to address these questions. The data will shed light on unexplored neurobiological consequences of ELS that may contribute to long-term brain dysfunction.

Research Grants - $50,000

Suchitra Joshi, Ph.D.
University of Virginia
NMDAR regulation of delta subunit-containing GABAA receptor expression
Summary:  The gamma aminobutyric acid type A receptors (GABARs) mediate fast and slow inhibitory neurotransmission in the brain, and their function is enhanced by endogenous steroid hormone derivatives called neurosteroids. However the expression of delta subunit-containing GABARs is reduced in epileptic animals. This is associated with diminished neurosteroid modulation of the slow tonic inhibition mediated by these receptors. The reduced delta subunit expression appears to play a role in the development of epilepsy. This proposal seeks to determine the molecular mechanisms underlying the observed reduction in the expression of delta subunit-containing GABARs in experimental animals and test whether blocking these changes could suppress the development of spontaneous seizures.

Temitayo Oyegbile, M.D., Ph.D.
Georgetown University
Functional Brain Abnormalities in Children with Temporal Lobe Epilepsy
Summary:  Temporal Lobe Epilepsy (TLE) is a prevalent form of epilepsy that can be chronic and poorly controlled with limited treatment options, especially in children. Children with TLE face significant cognitive challenges leading to academic underachievement. In addition to the expected temporal lobe deficits, children with TLE exhibit poor attention and working memory, indicating the frontal lobe may play a role in the neurologic outcome of TLE. This contrasts with the typical conceptualization of TLE. Investigating frontal lobe abnormalities may reveal underlying mechanisms resulting in cognitive deficits in children with TLE and potentially direct future treatment approaches. Using neuropsychological testing and fMRI, functional networks will be examined. TLE and control subjects will undergo fMRI testing at rest to assess baseline differences, and then while performing tasks involving both frontal and temporal lobes. Next, neuropsychological testing of all brain regions will be conducted. This novel study expects to find that children with TLE will have reduced network connections at rest and while performing tasks compared to controls, which will positively correlate with neuropsychological testing.

Research Training Fellowships for Clinicians - $50,000

Chloe Hill, MD
University of Pennsylvania
Models of Care Delivery for Quality Care of Epilepsy Patients
Summary:  One of the major challenges facing epilepsy currently is the delivery of quality care with limited resources. In the 2010 National Health Interview Survey, it was estimated that 1% of adults in the United States have active epilepsy and of that group, only half had seen a neurologist in the prior year. The recent AAN Neurology Workforce Task Force report describes an unsustainable health care system, citing a current deficit of neurologists that is projected to almost double by 2025, driven by an aging population and new challenges from implementation of the Affordable Care Act. It is clear that we will need to make informed choices going forward to increase availability of neurologic services, yet there is little evidence regarding the interplay of quality of care and efficiency of care delivery in the epilepsy outpatient setting. The aim of this project is to investigate care quality and service efficiency to identify patterns of service associated with high quality epilepsy care.  Two service models will be compared: physician-only care and physician-nurse practitioner care.

Fall 2014: New Therapy Grant Award

New Therapy Grant: $150,000

Utkan Demirci, PhD
Stanford University
Palo Alto, CA
Project Title: Disposable Chips to Measure Antiepileptic Drug Serum Concentrations at POC
Summary:  Epilepsy is a neurological disorder, and nearly one in three patients with epilepsy report dose-related side-effects from their seizure medication(s). These effects can be minimized by adjusting the antiepileptic drug (AED) dosage and timing of the dosage. Here, we propose to develop a disposable AED detection system that can be performed anywhere and automated to handle a drop of blood obtained with a finger prick, can give results in approximately 10 minutes.

Fall 2014: Epilepsy Seal of Excellence Award

Epilepsy Seal of Excellence Award: $20,000

Hitten Zaveri, PhD
Yale University
New Haven, CT
Project Title: Brain Implantable Focal Cooling and Sensing Array
Summary:  We seek to develop a brain implantable array of sensors and cooling elements. This array will allow the continuous measurement of brain activity and on demand controlled cooling of the cortex to stop seizures.

NEXT: Research and New Therapy Awardees - Spring 2015