This laboratory is using a new animal model of chronic limbic epilepsy to investigate the natural history of untreated epilepsy. This study will provide the basis for examining a variety of factors which may affect long-term outcome. In addition, the functional anatomy of limbic seizures is under investigation to determine which brain regions are critical to the generation of spontaneous seizures. These studies include the evaluation of physiologic and anatomic interactions among these areas to determine how normal function and connectivity may be altered to achieve this pathologic state.
Clinical investigation centers on the evaluation of patients for surgical treatment of intractable epilepsy, concentrating on improving monitoring and imaging techniques that will better localize the epileptogenic region. These studies involve investigators from neurosurgery, neuroradiology, neuropathology, neuropsychology, and biomedical engineering.
Noteworthy Honors, Accomplishments and Positions:
2002-2004: Research Consultant, SEIN (Epilepsy Institute of the Netherlands), Heemstede
2007: Editor, Epilepsia; Information Officer, Executive Committee International League Against Epilepsy.
Dr. Burns's academic research has focused on the development of two novel outcome measures for myasthenia gravis (MG), the “MG Composite” and “MG-QOL15.” These two measures are now in widespread use around the world, both in clinical trials and everyday clinical care. The MG Composite, for example, was recently selected by an MGFA Task Force to be the recommended primary outcome measure for MG clinical trials. Dr. Burns is also in the process of validating a patient-reported outcome measure for chronic, immune-mediated polyneuropathies. He is involved in many other ongoing neuromuscular projects, including studies for amyotrophic lateral sclerosis and inclusion body myositis.
Erin P. Foff, M.D., Ph.D.
Major research interests are centered on providing an understanding of the pathophysiology of myotonic dystrophy, the most common adult muscular dystrophy. Current efforts are focused on characterization of a novel target that we've identified which appears to play a critical role in muscle pathology in the presence of RNA toxicity. The genetic, molecular, and cell culture models that we are utilizing are providing an understanding of a pathway that has implications for future therapeutics development. Future experiments are being designed to foster an understanding of the mechanisms of cognitive and central nervous dysfunction in this multisystemic disease.
Nathan B. Fountain, M.D.
Clinical pharmacology of experimental antiepileptic drugs and
development of novel therapies for refractory epilepsy are examined
through the infrastructure of the Epilepsy Clinical Research Program.
The natural history of epilepsy is studied through a large clinical
relational database. Investigations of nonconvulsive status epilepticus
are intended to define its pathophysiology, classification and natural
Howard P. Goodkin, M.D., Ph.D.
We have previously demonstrated that the reduction in GABA-mediated synaptic inhibition that occurs during status epilepticus is, in part, the result of rapid, activity-dependent, subunit-specific trafficking of GABAA receptors. We are currently employing electrophysiological and immunohistochemical methods to investigate age- and model-dependent changes in GABAA receptor trafficking, changes in the probability of presynaptic GABA release, and the second messenger control of GABAA receptors during status epilepticus.
Major interests are in acute stroke intervention, management of cerebral vasospasm following subarachnoid hemorrhage, and noninvasive assessment of the cerebral circulation. Funded projects in progress include a randomized, controlled trial of a glycine antagonist in acute stroke.
The principal focus in the laboratory is on the cellular mechanisms of neuropharmacologic actions in the striatum. The current emphasis is on interactions of dopamine and acetylcholine in regulating striatal output neurons because of the relevance of these transmitters to the pathophysiology and treatment of neurodegenerative disease. Dr. Harrison and colleagues have used retrogradely transported neurotoxins or "suicide transport" agents to produce selective lesions of striatonigral and striatopallidal neurons to examine localization and regulation of neurotransmitter receptors. With this technique, they have demonstrated selective localization of specific dopamine and muscarinic receptor subtypes to striatonigral neurons using receptor autoradiography and in situ hybridization. In a collaborative project, investigators have examined dopaminergic regulation of acetylcholine release in the striatum using striatal slices and acutely dissociated striatal neurons. With the same technique, they are now studying selective muscarinic receptor actions on striatal output neurons and their interactions with dopaminergic receptor effects. In addition, the laboratory has begun work to characterize effects of a selective immunotoxin lesion of cholinergic interneurons.
Research interests involve the overlap areas of neurology and emergency medicine. Current projects include studies in acute seizures and acute cerebrovascular disease. Computer-aided education of physicians in residency and fellowship training is another focus area.
Clinical research interests focus on improving stroke patient outcomes. Research activities include acute stroke clinical trials, and outcomes research as well as neurological outcomes in other patient populations. Acute therapy trials currently being offered include antiplatelet and glucose lowering treatment trials.
Clinical trials methodology research involves exploration of improved techniques for development and conduct of stroke trials. Specific areas of pursuit include use of adaptive design in acute stroke trials.
The Stroke Hyperglycemia Insulin Network Effort (SHINE) Trial is a
large, randomized, controlled, multicenter phase III efficacy trial of
intensive insulin therapy versus standard care for hyperglycemic acute
ischemic stroke patients. This trial is being funded by the NIH-NINDS.
Details and updates on the progress of the SHINE trial can be found at
www.SHINEtrial.com or clintrials.gov.
There are three major areas of study in the laboratory all related to synaptic plasticity. First, we seek to understand the pathophysiological mechanisms underlying status epilepticus, which is a prolonged life threatening seizure. Our past studies initially established loss of GABA-mediated inhibition in the hippocampus and altered function of GABAA receptors in hippocampal neurons as key mechanisms initiating status epilepticus. Current studies focus on mechanisms underlying the plasticity of GABAA receptors during status epilepticus. They suggest that status epilepticus differentially alters the function of synaptic and extrasynaptic GABAA receptors and the GABA release from presynaptic terminal is diminished. Other studies in the lab focus on the role of excitatory neurotransmission in the pathogenesis of status epilepticus were prompted by the novel finding that N-methyl-D-Aspartate (NMDA) receptor antagonists could treat prolonged status epilepticus, refractory to currently used agents. Initial mechanistic studies suggest that there is increased presynaptic release of glutamate during status epilepticus.
Second area of research is to understand hormonal regulation of seizures. Although seizures appear unpredictable, biological rhythms and external stimuli can modulate seizure frequency, partly through circulating steroid hormones. Neurosteroids like allopregnanolone are synthesized in the brain from circulating steroids like progesterone and have powerful anticonvulsant effects. We observed that physiological concentrations of allopregnanolone potently enhance GABA mediated inhibition in hippocampal neurons of naïve rats, but fail to do so in hippocampal neurons of epileptic rats. Future studies test the hypothesis that decreased allopregnanolone modulation is due to altered expression of synaptic and extrasynaptic receptors. In collaboration with Dr Edward Bertram we study loss of GABAergic interneurons in the hippocampus and thalamus in a model of temporal lobe epilepsy.
Pregnenolone sulfate is one of the most abundant neurosteroids in the brain and plays an important role in age related memory decline. Our studies demonstrate that concentrations of pregnenolone sulfate commonly observed in the hippocampus inhibit GABAergic synaptic transmission by diminishing release of GABA from the presynaptic terminal. These findings for the first time demonstrate an effect of physiological concentration of this neurosteroid on synaptic transmission. Ongoing studies seek to understand the mechanism of action of pregnenolone sulfate.
Third area of interest is to understand normal and abnormal development of GABAergic synapses in vitro and in vivo. The in vitro studies combine electrophysiological characterization of synapse development with immunocytochemistry in low-density cultures of hippocampal neurons. We plan to investigate the role of neuronal activity and seizures on the development of GABAergic synapses. A direct application of these studies is to investigate the development of GABAergic synapses in cortical dysplasias, which can lead to seizures. In collaboration with Dr. Kevin Lee of the Department of Neuroscience, we seek to investigate the development of GABAergic synaptic transmission in a rat model of focal cortical dysplasia.
Jennifer E. Langer, M.D.
Ivan S. Login, M.D.
With the recent advances in diagnosis and management of migraine and other headache disorders, Dr. Login has initiated a dedicated interest in this field. Patients are seen on referral with new or complex headache problems to help establish a diagnosis or to offer advice on therapeutic strategies. Selected patients may be enrolled in clinical research protocols to evaluate new agents or investigate new applications of established agents.
The major aim of research is to investigate the impact of neurodegenerative disease on cognitive processes. Of particular interest are individuals with cognitive deficits resulting from a variety of conditions including old age, Alzheimer's disease, and Parkinson's disease. Emphasis is placed on 1) early and subtle changes in cognition and 2) cognitive change and neurodegenerative disease in rural and minority populations. Current research initiatives involve the UVA Alzheimer’s Disease Research Center Satellite Clinic of the University of Pittsburgh which focuses on rural minorities, and a project examining the impact of vascular risk factors in African-Americans.
Dr. Nathan's research is centered around the Nerancy Neuroscience Intensive Care Unit (NNICU). Here research is done in the pathophysiology of diseases such as subarachnoid hemorrhage, intracerebral hemorrhage, traumatic brain injury, fever, meningitis, encephalitis and other CNS infections. Additionally, Dr. Nathan has a strong interest in medical education and in research to develop new methods of teaching the neurosciences.
Overview: Dr. Phillips' research is center in the Clinical Electromyography Laboratory. It is clinically based in neuromuscular disease, and much of it is done in collaboration with other investigators at the University of Virginia and other institutions.
Amyotrophic Lateral Sclerosis: The research involves multi-center treatment trials of various proposed therapies for ALS. Past trials have included glutamate antagonists such as riluzole and various neurotrophic factors, including insulin-like growth factor, brain-derived neurotrophic factor, and ciliary neurotrophic factor. Current trials include creatine and pramipexole.
Myasthenia Gravis: The research is devoted to multi-center treatment trials of new immunosuppressive drugs for myasthenia gravis. Current trials are testing the effect of mycophenolate mofetil (CellCept) as an immunosuppressive drug in patients with myasthenia. Trials in the planning stages include a study of the effect of low-dose Prednisone on the natural history of ocular myasthenia and a study of the efficacy of thymectomy on the course of generalized myasthenia. Additional research is devoted to the development of clinical research standards in myasthenia gravis.
Epidemiology of Neuromuscular Diseases: Investigations into the epidemiology of myasthenia gravis and other neuromuscular diseases utilize classical population-based studies and meta-analysis of the literature.
Axonal excitability testing: Studies into the behavior of ion channels in peripheral motor nerve using axonal excitability measures are ongoing. The purpose of this research is to expand the role of nerve conduction testing in various diseases of peripheral nerve and muscle.
Benjamin Purow, M.D.
I am a neuro-oncologist physician-scientist whose laboratory is dedicated to finding new ways to treat glioblastoma, the most common and lethal brain tumor. We are particularly interested in identifying and leveraging new targets, both genes and microRNAs. In this vein we were the first to show the Notch pathway to be a potential therapeutic target in glioblastoma, and we have also reported microRNAs with tumor-suppressive functions that regulate critical signaling pathways such as EGFR, Akt, and Notch. Given the genetic complexity of glioblastoma and the need for therapies that attack multiple pathways simultaneously, we are now investigating a number of genes and microRNAs that each regulate or mediate several critical pathways. Our microRNA studies are suggesting promising new targets in glioblastoma, including a kinase and its phospholipid product.
Mark S. Quigg, M.D.
Laboratory research centers on the interaction of circadian regulation and the temporal clustering of partial seizures with the goal of defining the anatomic and neuroendocrinological modulation of temporal lobe epilepsy. This research involves both an animal model of chronic limbic epilepsy and human subjects with medically-refractory partial seizures.
Clinical investigations center on the diagnosis and treatment of medically-refractory epilepsy, including epilepsy surgery. These studies involve development of electrographic and neuroimaging techniques that can better identify the epileptogenic zone. Participation in anticonvulsant drug trials is also ongoing.
Dr. Rust's clinical and research interests encompass the areas of epilepsy, headache, neonatal neurology, degenerative disorders, and clinical pharmacology.
Dr. Schiff's research focuses principally on developing and conducting clinical trials to improve outcomes for surgically incurable brain and spinal cord tumors. Particular areas of interest include glioblastoma, lower-grade gliomas, primary CNS lymphoma, brain metastases, meningioma, and spinal cord compression. The recent FDA approvals of bevacizumab (Avastin) and Novo-TTF for recurrent glioblastoma were based on clinical trials conducted in part at University of Virginia under his supervision.
Nina Solenski, M.D.
The aim of the research in this laboratory is to elucidate the role of oxygen free radicals during reversible focal ischemia by characterizing their temporal and spatial characteristics during and after ischemic conditions and by understanding their relationship to known excitatory amino acids and nitric oxide related mechanisms. Research focuses on elucidating specific targets of free radical species, including the role of neuronal mitochondria in acute ischemic damage. Specifically, these experiments couple the well-established technique, brain tissue microdialysis, to a reliable focal ischemia model in the rat. This experimental design allows for the in situ recovery of stable free radical adducts and the administration of pharmacological substances.
Dr. Wooten's principal research interests focus on the treatment of Parkinson's disease and other movement disorders. In addition, Dr. Wooten and colleagues in the Movement Disorders Program are utilizing an extensive clinical database to address prospectively several issues that are relevant to the pathogenesis of Parkinson's disease. The Movement Disorders Program also participates in numerous multicenter clinical trials of potential new drugs to treat Parkinson's disease.
Dr. Worrall's research focuses on genetic and inflammatory issues in cerebrovascular disease approaching from several angles. He is currently funded by the NIH-NINDS and NHGRI to investigate genetic risk and pharmacogenomic factors in ischemic stroke. Dr. Worrall also conducts prospective stroke genetics clinical trials at the University of Virginia as a part of multicentered studies investigating intracerebral hemorrhage, venous sinus thrombosis, cervical artery dissection, and intracranial aneurysms. He is a founding member of the International Stroke Genetics Consortium currently developing an effort to conduct a large-scale genome-wide scan in ischemic stroke and pursue next generation genomics. He is a non-resident faculty member of the Center for Public Health Genomics. He also works with other members of the UVA stroke group in ongoing clinical trials.