Grants Awarded in 2008

42 record(s) found.

New Therapy Grants Program

Christopher M. DeGiorgio , M.D. — UCLA Geffen School of Medicine
"Randomized Double-Blind Crossover Trial of External Trigeminal Nerve Stimulation [Ophthalmic Branch] for Intractable Epilepsy"
This study investigates a promising new therapy for epilepsy called Trigeminal Nerve Stimulation (TNS). TNS involves external electrical stimulation of an important nerve located above the eyes and over the forehead. Preliminary data is very promising. The purpose of this study is to determine if TNS is safe and effective using a rigorous clinical trial in 30 days with epilepsy.

Matthew J. During , M.D. — Ohio State University
"Pilot Safety Study Evaluating Hippocampal NPY Gene Transfer in Subjects with Intractable Mesial Temporal Lobe Epilepsy"
The goal of this study is to test the effect of infusing the Neuropeptide Y (NPY) gene vector in a specific area of the brain of a person who has epilepsy to restore it to normal function. The NPY, which already exists in the human body, when introduced in the brain, replaces the neurotransmitters that are depleted. This extremely exciting novel treatment called gene therapy has been proven successful in laboratory animals and may reduce seizure activity and therefore improves a person's quality of life.

Jeffrey L. Noebels , M.D., Ph.D. — Baylor College of Medicine
"Selective T-type Calcium Channel Antagonists as Novel AEDS"
This antiepileptic drug discovery project will screen a new class of highly potent and selective T-type calcium ion channel blockers for efficacy in single gene mouse mutant models of human spike-wave absence and temporal lobe epilepsy.

Partnership for Pediatric Epilepsy Research

Lori L. Isom , PhD — University of Michigan
"Role of sodium channel SCN1B subunits in pediatric epilepsy"
Na+ channels regulate electrical activity in brain. Mutations in the gene encoding one channel subunit, ß1, cause pediatric epilepsy. Juvenile mice lacking ß1 have fatal seizures. We propose that this epilepsy occurs through decreased Na+ current in inhibitory neurons of the hippocampus. Our research will help us to understand the role of ß1 in normal brain development as well understand how mutations in ß1 lead to human epilepsy.

Tianfu Li — Legacy Research
"High neuronal adenosine kinase expression as risk factor for febrile seizure-induced epileptogenesis"
Prolonged febrile seizures during childhood are considered to be a major cause for the subsequent development of epilepsy. This project is based on findings that the brains? own adenosine-based seizure control system is not yet fully developed during childhood. In particular, high levels of the adenosine removing enzyme adenosine kinase (ADK) appear to favor prolonged febrile seizures and subsequent epileptogenesis. This grant aims to identify high expression of ADK as a risk factor for febrile seizures and subsequent epileptogenesis, and to define ADK as a target for therapeutic intervention aimed at the prevention of epileptogenesis.

Janelle Wagner , PhD — Medical University of South Carolina
"Depression Screening in Youth with Epilepsy"
Children with epilepsy are more likely to have depressive symptoms and thoughts of suicide. However, depressive symptoms are often overlooked and these children do not receive mental health treatment. Thus, the proposed study addresses these problems by 1) revising an adult depression screening tool; 2) validating this depression screening tool; and 3) helping with access to mental health care providers for youth ages 12-17 with epilepsy. In this study, youth and parents will complete written surveys and telephone interviews. Youth will be referred for mental health treatment as needed, and this process will be tracked.

Anne Williamson , Ph.D. — Yale University
"Neuronal-Glial metabolism in epileptogenic cortical malformations in patients."
Certain brain malformations can cause medically intractable seizures in children. The goal of this work is to use resected tissue from epileptic patients to obtain a metabolic signature for different types of malformations using a combination of neurochemical and imaging techniques. These studies will allow us to better understand how different classes of cells interact biochemically in different types of epileptogenic tissue. This work will help explain why certain types of malformations produce seizures as well as to identify new targets for therapy.

Postdoctoral Research Fellowship

Stephen Douglas Cranstoun — University of Pennsylvania
"KCNQ Channels in the Proximal Axon: An Integrated Electrophysiological-Computational Study"
Epilepsy affects nearly two million Americans making it the second most common neurologic disorder, however, the origin of epileptic seizures remains elusive. Several forms of epilepsy now have been linked to single gene mutations, some of which are inheritable. One such mutation involves a member of the potassium channel family whose subunits, the KCNQ proteins, have recently been localized to the axon initial segment (AIS). This is an important finding since it has become clear that this is also the site of action potential initiation in neurons and hence, the origin of the principle form of inter-neuronal communication. The location of potassium channels at this site gives them the opportunity to have a powerful influence on this communication, which may be important for the complex computation performed by the mammalian brain. Mutations of these channels, as found in some forms of epilepsy, may have a profound affect on the behavior of neurons and the circuits they form. Studying this potassium channel and its effect on neuron behavior, may lead to a better understanding of some forms of epilepsy and the development of new drugs which target these channels.

Zhengliang Gao — UT Southwestern Medical Center
"Chromatin regulation of seizure-induced neurogenesis"
Current studies have linked aberrant neurogenesis with epilepsy while a causal relationship is yet to be established. The researcher seeks to explore a potentially causal relationship between the two and examine in details the chromatin remodelling and transcriptional mechinery in neurogenesis and how they may impact on epileptogenesis.

Joseph Charalambos Glykys , MD PhD — Massachusetts General Hospital
"GABAergic transmission changes during development and epileptiform activity in vitro determined by Clomeleon"
otransmitter in the brain. However, the end effect of GABA receptor activation depends on the chloride concentration inside the neurons. Early in development, the action of GABA is excitatory while in mature neurons it is inhibitory as intracellular chloride concentrations are high and low respectively. This study will determine and compare the different effects of GABA in developing cortical and subcortical brain regions known to participate in epilepsy as well as study the changes in intracellular chloride concentration during and after brief seizures.

Suchitra Joshi — University of Virginia
"GABAA receptor delta subunit surface expression and tonic GABAergic inhibition during epileptogenesi"
Recurrent unprovoked seizures characterize Temporal Lobe Epilepsy (TLE) and affect approximately 2 million Americans. The unpredictable nature of the seizures has a great impact on day to day as well as social life of the people affected. GABAA receptors are the major inhibitory receptors in the brain and balance neuronal activity. Movement of these receptors to and from the cell surface regulates their function and is thought to be affected in TLE. Status epilepticus (SE) a prolonged epileptic state causes brain trauma that often results in TLE. This proposal aims to understand trafficking of GABAA receptors during a latent epileptogenic phase, the period between SE and first unprovoked seizure. The results of this study could help in developing new therapies.

Sangwook Jung , Ph.D. — University of Washington at Seattle
"Calcineurin Modulation of HCN channel Downregulation in Epilepsy"
HCN channels play an important role in setting the resting potential and regulating neuronal excitability. Seizure-dependent decreases in HCN channel gating might contribute to maintenance of the epileptic state. This research will study the mechanism by which spontaneous seizures decrease HCN channel gating using an animal model of epilepsy and electrophysiological recordings.

Carolyn J. Lacey , Dr. — Stanford University
"The role of Stargazin and AMPA receptors in the generation of absence seizures"
Childhood absence epilepsy causes brief lapses of consciousness and staring spells that can occur hundreds of times per day. These epileptic absence seizures occur in some people due to changes in one or a few genes that affect molecules in the brain. The main aim of this research is to understand how removal of one such gene, called Stargazin, changes the properties of a particular type of brain cell that orchestrates activity throughout the brain during absence seizures. This work will help us understand how seizures begin and end in order to help identify new treatments and/or cures.

Gumei Liu — Duke University Medical Center
"The Role of Actin Dynamics in Epileptogenesis"
Synaptic plasticity is an attractive mechanism underlying epilepsy. Changes in F-actin, a major player in synaptic plasticity, have been observed during epileptogenesis. The role of actin dynamics in epileptogenesis and pathways involved will be investigated in this study.

Edward Oliver John Mann — UCLA School of Medicine
"GABAergic control of cortical excitability in a mouse model of autosomal dominant nocturnal frontal lobe epilepsy"
Neurons in the brain communicate through both excitatory and inhibitory signals. It is generally thought that seizures occur when the balance between these signals tips so far towards excitation, that neurons fall into a vicious circle of hyperactivity. However, a recently developed mouse model, which carries one of the genetic mutations responsible for autosomal dominant nocturnal frontal lobe epilepsy, shows spontaneous seizures that are associated with increases in cortical inhibition. The aim of this proposal is to explore how such increases in inhibition could result in seizure activity.

Pavel Ivanovich Ortinski , PhD — The Children's Hospital of Philadelphia
"Reduced glutamine synthetase expression by reactive astrocytes regulates inhibitory efficacy in temporal lobe epilepsy"
Epileptic seizures are thought to result from an excess of excitatory or insufficient inhibitory activity in the brain. This research project investigates whether one of the reasons for such imbalance lies in the diminished numbers of neurotransmitter molecules used by inhibitory neurons to communicate with each other. Availability of neurotransmitters is regulated by complex, multi-step mechanisms. Knowing exactly which of these mechanisms leads to a decrease of neurotransmitter levels and how inhibitory and excitatory neurons are affected by this decrease will help develop therapies that effectively control seizures and may be prevent them from happening entirely.

Pascale P. Quilichini , PhD — Rutgers University
"Dynamics in the medial entorhinal-hippoccampal network after status epilepticus"
Temporal lobe epilepsy is one of the most common epileptic syndrome and is very difficult to treat with the available drugs. Some brain structures, like the hippocampus and the cortex, are particularly concerned by seizures. It appears that these structures, in normal conditions, communicate by the way of rhythms and are involved in memory. Patients suffering from temporal lobe epilepsy present very often memory deficits. It seems that, in epileptic conditions, the communication between the hippocampus and the cortex fails somehow. The goal of this research plan is to understand what is changed in this communication that could explain the memory deficits. This will be achieved by using an animal model (rat) that mimics temporal lobe epilepsy. The communication between the cortex and the hippocampus consists in rhythmic electrical activity produced and exchanged by these two structures. This will be recorded, analyzed and compared between normal rats and rats after a seizure. State-of-the-art techniques (high density silicone-probe recordings and neuronal rhythms analysis) will be for the first time used for the purpose of epilepsy research. The results of this project will enable to determine important mechanisms that are dysfunctional after a seizure and that prevent a normal memory functioning. These mechanisms could become novel targets in order to develop possible prevention approches and futures new therapeutical solutions.

Sachin Talathi — University of Florida
"Statistical performance analysis of early seizure detection algorithms for their applicability in the development of closed loop seizure intervention systems."
Rat model for chronic limbic epilepsy is employed to study the feasibility of early seizure detection algorithms for use in a closed-loop seizure intervention system. Each detection measure will be evaluated using a prospective out-of-sample approach. Success of this study might result in application of early seizure detection schemes to be used as a basis for responsive intervention, in a closed loop seizure intervention program.

Hiroaki Tani , Dr. — Stanford University
"The role of glutamine glutamate cycle in sustaining hyperexcitability in the rat cortex"
Epilepsy results from excessive excitation in the brain. It has been demonstrated that disrupting the glutamate-glutamine shuttle, a recycling mechanism for the excitatory neurotransmitter glutamate, blocks epileptiform activity. The goal of this project is to further characterize the shuttle's role in hyperexcitability in order to identify new treatments for epilepsy.

Predoctoral Research Training Fellowship

Daniel Tice Barkmeier — Wayne State University
"Translating human gene expression profiles of interictal spiking into a rat model"
In addition to seizures, patients with epilepsy have another type of abnormal brain activity called 'interictal spikes.' Interictal spikes occur between seizures, and are much smaller discharges than seizures which do not spread across the brain, but they occur much more frequently than seizures. Previous studies on human epileptic brain tissues have identified a set of genes that are activated in the epileptic parts of the brain when compared to non-epileptic parts of the same patient's brain. However, the amount of gene activation did not correlate with seizure activity, but did correlate with the amount of interictal spiking in that area of brain. To determine whether interictal spiking alone is sufficient to induce the gene expression changes seen in epileptic brain areas, this project will create an animal model of interictal spiking. Gene expression changes in this animal model will be examined to see if they mirror the gene expression changes previously seen in humans. The hypothesis is that interictal spiking can induce the activity-dependent gene expression changes seen in epileptic areas, which affect neuronal connectivity and synapse plasticity.

Joel Philip Baumgart — University of Virginia
"Structural Analysis of Low Voltage-activated Calcium Channels Associated with Absence Seizures"
A region of the brain known as the thalamus acts as a relay station for nearly all of the information coming to the brain. The cells of the brain in general and those of the thalamus in particular are able to communicate information in the form of electrical currents via the flow of charged molecules known as ions. These currents are carried through specialized proteins in the cell membrane known as channels that allow various ions to travel from outside to inside the cell or vice-versa. The import of calcium into the cell is critically important to the function of brain cells, especially in the timing of cell activity. The calcium channel serves as a pore in the cell membrane through which calcium flows. A number of mutations, which modify the genetic code, have been found in calcium channels genes among those suffering from childhood absence epilepsy (CAE), which affects children between ages 3 and 10. These particular seizures produce brief episodes of blank staring associated with a characteristic ?spike and wave? pattern of firing activity among brain cells. Those afflicted with CAE tend to have very frequent seizures. Given the important role calcium channels serve in absence epilepsy, experiments are needed to develop an understanding of the portions of these channels that determine this type of cell firing. To address this, mutant channels that are missing parts of the normal channel will be created and tested for a number of properties, namely, how much current flows through the mutant channel, how long the channel remains open or closed, and how many channels reside in the surface of the cell. The properties of the mutant channels will be measured against those of the normal channel. The studies proposed here can provide a significant advance in explaining why various mutations in certain regions of calcium channels modify the electric currents in brain cells and how such changes produce seizures. A clearer sense for the structure of ion channels provides a better chance to design effective pharmacological treatments when channel activity is out of balance, as seen in numerous forms of epilepsy. The ultimate goal in understanding the structural properties of calcium channels is to improve treatments for seizures in general, and for absence epilepsy in particular.

Marcel Paz Goldshen-Ohm — University of Wisconsin-Madison
"Inter-subunit communication in the GABAA receptor."
The GABAA receptor is the major inhibitory neurotransmitter receptor in the central nervous system, and plays an important role in shaping the activity of neuronal networks required for normal cognitive function. Several mutations in this receptor are associated with epilepsy in humans, one of which may disrupt communication between the receptor?s constituent subunits. The overall goal of this research is to elucidate the physical mechanisms underlying inter-subunit communication and to understand how its disruption can lead to pathologies such as epilepsy.

Robert F. Hunt — University of Kentucky
"Posttraumatic epileptiform activity following controlled cortical impact in mice."
Every 23s, an American sustains a traumatic brain injury (TBI), and TBI is one of the most common causes for developing epilepsy. Many patients suffer from seizures and develop posttraumatic epilepsy after TBI, and head injury patients often do not respond well to anti-epileptic drug treatments. The mechanisms by which brain injury leads to the onset of epilepsy are not well understood. One reason for this is that animal models for posttraumatic epilepsy have not been well developed. The goal of this research proposal is to identify cellular and functional changes which occur in a controlled cortical impact mouse model of head injury that are also associated with changes seen in temporal lobe epilepsy. Understanding the mechanisms by which brain injury causes seizures may help to promote more effective therapeutic strategies for treating posttraumatic epilepsy.

Michelle Kron — University of Michigan
"Role of Adult Neurogenesis in Hippocampal Remodeling and Hyperexcitability During Pilocarpine-Induced Epileptogenesis"
One percent of the population, more than 3 million Americans, has epilepsy. Mesial temporal lobe epilepsy, or mTLE, is the most common type of intractable epilepsy in young adults. This proposal seeks to study changes in the brain that lead to experimental mTLE, specifically those at the cellular level that may involve neural stem cells.

Amber L. Martell — The University of Chicago
"Electrical Membrane Properties and Seizure Threshold: the Effect of NMDA on Intrinsic Bursting and Network Oscillations."
The goal of this project is to understand the NMDA receptor interaction in seizure genesis by studying how intrinsic oscillation is generated in deep pyramidal neurons and how these neurons interact in a network to drive synchronized network bursts similar to epileptic discharges.

Julie Beth Milder — University of Colorado at Denver and Health Sciences Center
"Oxidative stress-mediated adaptation: a protective mechanism underlying the ketogenic diet."
Epilepsy is a common neurological disorder. Unfortunately, as many as 30% of patients do not respond to current antiepileptic medications. For this reason, the ketogenic diet was developed, and it has been successful in treating seizures in children for many years. However, how the diet works remains a mystery. This project seeks to understand some of its underlying mechanisms with the hope of developing new therapies.

Carol L. Peebles — J. David Gladstone Institute
"Elucidating Arc's role in Epileptogenesis and Synaptic Plasticity"
Seizure activity leads to rapid changes in the cells that make up our brain. Many of these changes fuel future seizure activity by making the cells more sensitive to excitation. However, cells also counteract these changes to prevent the harmful affects of hyperexcitation. This proposal studies how Arc, a protein produced in response to seizure, affects the brain excitability.

Dalin Thomas Pulsipher , M.S. — Rosalind Franklin University of Medicine and Science
"Thalamo-Frontal Circuitry and Executive Functioning in Childhood Idiopathic Generalized Epilepsy: A Longitudinal Study"
This study will examine the developmental course of cognition and brain structure in children with new-onset idiopathic generalized epilepsy. This study combines different methods of brain measurement and assessment of problem-solving skills in the investigation of the underlying features of brain development that may be associated with learning and social difficulties.

Kerry-Ann Angella Stewart — University of Utah
"A novel murine model of viral encephalitis-induced seizures"
CNS infections are associated with an increased risk for seizures and epilepsy. This proposal aims to use a novel animal model to further elucidate the mechanisms underlying infection-induced seizures. It is anticipated that these studies will prove useful in the search for therapies to prevent epilepsy following CNS infection.

Daisuke Takeshita — University of Missouri-St. Louis
"Imaging and modeling the effect of inhibition in focal neocortical seizures"
While some neurons promote activity in other neurons, others inhibit it. This study investigates the relation between inhibition and synchrony in acute neocortical seizures using both computational and experimental approaches. Although the outcome of the proposed research may not be directly applicable for clinical aspects of epilepsy, it may contribute to elucidating the basic mechanism of how epileptic seizures occur.

Research and Training Fellowship for Clinicians

Daniel Friedman — Columbia University
"The role of entorhinal cortex in seizures and epileptogenesis in an in vivo model of temporal lobe epilepsy."
Despite over a century of study, the link between changes in brain structure and seizures in temporal lobe epilepsy is not clear. Many studies have focused on the hippocampus as the structure responsible for generating seizures but more recent evidence points to another area of the temporal lobe, the entorhinal cortex, as a possible origin for seizures in this disorder. This study proposes to look at the role of entorhinal cortex in triggering seizures and the processes that result in epilepsy after brain injury in an animal model of epilepsy. The study?s results will improve our understanding of the brain circuits responsible for temporal lobe epilepsy and may provide targets for future therapies to prevent epilepsy and control seizures.

Sara Krause Inati — Columbia University Medical Center
"Epilepsy Monitoring with Subpial Micro-Electrode Array: Improved Identification of the Epileptogenic Zone"
This research utilizes a very small grid of electrodes called a microelectrode array to record electrical activity in the brains of patients undergoing evaluation for epilepsy surgery. Small groups of neurons involved in the generation of seizures will be identified. Careful analysis of the location of these groups of neurons, and of the patterns of their activity, should lead to more accurate identification of the seizure producing area, with the ultimate goal of improving the efficacy of epilepsy surgery.

Gabriel Ustin Martz — University of Virginia
"Intracerebral Infusion to Treat Limbic Epilepsy"
Epilepsy is a very common disease that affects up to 1% of people. The standard drug treatments don?t work for many of these patients. This may be because the drug causes side effects, or because it isn?t reaching the part of the brain causing the seizures. Putting small amounts of drug right into a key part of the brain may be able to stop the seizure without causing the side effects that occur when the drug goes to the entire brain after taking a pill. The type of device that would be needed is already being used commonly to treat other disorders. Also, doctors are already able to safely place devices into the part of the brain that we will be studying in these experiments. This project aims to show that this treatment will work on animals with seizures so that eventually we can use it in people.

Susan J. Shaw , MD — John Hopkins University School of Medicine
"Investigational physiologic/anatomic studies in patients undergoing clinical investigations for neurological disorders"
When patients with epilepsy have surgery to control their seizures, it is important to know which areas of the brain are needed for speech so that the surgery will not damage them. This is usually done is by stimulating different brain areas to see if it causes interference with speech. However, interference is sometimes found in areas of the brain even though they are safe to remove. This research project uses three new ways of mapping the brain to improve our ability to identify brain areas that are necessary for speech and to improve the safety of surgery for patients with epilepsy.

William Charles Stacey , M.D., Ph.D. — Hospital of the University of Pennsylvania
"Improving the Efficacy of Antiepileptic Devices: From Cellular Models to Bedside"
The goal of this project is to create a computer simulation of a section of epileptic brain. This simulation will then be used to test how an electrical stimulus can be used to stop seizures from occurring. The results of these simulations will later be used to guide development of future, improved antiseizure devices for use in humans.

Research Grants Program

Darrin H. Brager — University of Texas at Austin
"Status epilepticus induced changes in neuron excitability"
This proposal examines how ion channels, the basic unit of nerve cell excitability, are altered in a model of epilepsy. Understanding how changes in these critical elements contribute to hyperexcitability will aid in the development of new therapies for epilepsy.

Baljit S. Khakh — David Geffen School of Medicine
"The role P2X and P2Y receptors and ATP signalling in a mouse model of temporal lobe epilepsy"
Epilepsy is a common disease affecting about 2.3 million Americans. The brain mechanisms that give rise to epilepsy are not fully understood, and there is a need for better treatments for this disease. In this proposal the role of a new family of protiens in epilepsy will be explored. The protiens are called P2X and P2Y receptors. They are normally found in the brain, and contribute to increased excitability. If P2X and P2Y receptors contribute to excitability linked to epilepsy then this will inform about how epilepsy occurs and also may lead to new and better drugs to treat this disease.

Gabriel Kreiman — Children's Hospital Boston, Harvard Medical School
"Effects of electrical stimulation on visual recognition, learning and memory in temporal lobe epilepsy patients"
Certain forms of epilepsy are resistant to pharmacological treatment. Under these conditions, patients may require surgical treatment to remove the brain areas that are responsible for generating seizures. Two key aspects of this intervention involve thoroughly removing the seizure foci and minimizing any adverse cognitive effects. Most studies have focused on ensuring that language areas remain unimpaired after surgery but little is known about other important cognitive functions. Here we will study vision and memory function using physiological recordings, electrical stimulation and behavioral assessment. Correlating neural responses and behavior in recognition and memory will lead to maximizing cognitive function after resections.

Christoph Lossin , PhD — University of California, Davis-School of Medicine
"Rescue of epilepsy-associated premature stop codons with aminoglycosides"
Many children suffer from epilepsy with seizures that are hard to prevent and where the medication carries significant side effects. In some of these epilepsies the problem is genetic, in other words, caused by a DNA defect that creates problems in the children's brains. Recent resarch shows that common antibtiotics - drugs that kill bacteria - can force the body to "ignore" such DNA defects. Is it then possible that antibiotics can safely and easily prevent the development of epilepsy? This study seeks to establish whether such kind of epilepsy treatment would, in principal, work or not.

Gianmaria Maccaferri , MD, PhD — Northwestern University
"Chemokine-mediated epileptiform activity in GABAergic networks of the hippocampus"
Self-sustaining loops may be involved in epilepsy. For example, the occurrence of a seizure makes it likely that additional seizures will occur in the future. However, the underlying biology is not well understood. Seizures may often ?scar? the brain regions involved. A possibility is that the scar (composed mostly by so-called glial cells) produces molecules that can alter neuronal functions and lead to more seizures and hence more scarring, thus generating a self-sustained loop. The aim of this proposal is to test this hypothesis for a specific molecule and a specific neuronal population.

Marco Martina — Northwestern University
"Neurophysiology of febrile seizures"
Febrile seizures are common during early life, involving about 5% of infants and young children. Surprisingly, the electrophysiologic consequences of hyperthermia are largely unknown and no studies are available describing the electric behavior of neurons at febrile temperature. The proposed experiments will fill this gap by studying the effect of hyperthermia on the electrical excitability of hippocampal neurons.

Jokubas Ziburkus — University of Houston
"The role of neuromodulators in inhibitory and excitatory synchrony and epileptiform activity pattern formation."
Epileptic seizures have different electrical, emotional, and physical expression even in the same individual. This variability can be due to the state of arousal of that individual. Levels of arousal (sleepy or alert) are dictated by slow acting substances called neuromodulators. We propose to explain the mechanisms by which neuromodulators change electrical signatures of epileptic seizures.