There is an ongoing wide ranging search for new therapies for intractable epilepsy. Although drugs with a variety of mechanisms remain a significant focus of therapy development, the current evolution in technology has opened up new possibilities. Stimulation of several regions of the nervous system has attracted significant interest and this approach now includes recognition programs to detect seizures at any early stage and deliver a programmed stimulus to break the seizure. This development has been made possible in part by the progressive miniaturization of electronics. A potential advantage of this approach is that therapy is delivered to a single area of the brain, a technique that may avoid the side effects that can come from the systemic administration of a drug that goes to all parts of the brain. Delivery of a drug to a single point has often been considered and has been shown to have effect in some animal models of seizures, and such therapy targeted to a specific region is one of the NINDS benchmarks for treating epilepsy. However, a practical and reliable method for preclinical screening and a means for chronic delivery have not been available. Recently we have been examining the potential role of the medial dorsal region of the thalamus in limbic seizures and have evidence that suggests that this area may represent a key point in the initial seizure circuit. In this project we will be testing the overall hypothesis that drug infusion into the medial dorsal thalamic nucleus will control spontaneous limbic seizures without significant behavioral side effects. To test this hypothesis we will use a rat model of limbic epilepsy with spontaneous seizures and infuse drugs into the medial dorsal region of the thalamus and determine the effects of this intervention on spontaneous seizures. In the course of this project we will define optimal targets and drugs. Because the issue of cognitive impairment as a consequence of any epilepsy treatment is a concern, we will also determine whether successful treatment with regard to seizure suppression also affects complex behaviors. At the end of this project we will have determined whether the approach of intracerebral drug infusion into a specific region has potential for clinical development by suppressing seizures with no clear cognitive cost. Moving the results of this study to the clinic will be facilitated by the presence of technology for long term continuous drug infusions into the CNS. Finally, if successful we will also have created a technique with which we might identify other, less toxic compounds that may be more effective than the ones tested in this study with less behavior cost.

Public Health Relevance

Epilepsy remains a significant public health problem, as about one third of people with the disorder continue to have seizures in spite of trials with multiple medications. This project proposes to determine whether an entirely new approach to epilepsy therapy, direct infusion of the drug into a well defined region of the brain will improve seizure control while having fewer side effects than current systemically administered drugs. Because local drug infusion is a well established therapy for other conditions with the necessary technology in existence, we will be able to move this approach to clinical trials if successful.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS064438-02
Application #
7821361
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Fureman, Brandy E
Project Start
2009-05-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2012-04-30
Support Year
2
Fiscal Year
2010
Total Cost
$187,481
Indirect Cost
Name
University of Virginia
Department
Neurology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Kendirli, M Tansel; Rose, Dominique T; Bertram, Edward H (2014) A model of posttraumatic epilepsy after penetrating brain injuries: effect of lesion size and metal fragments. Epilepsia 55:1969-77
Sloan, David M; Zhang, DeXing; Bertram 3rd, Edward H (2011) Increased GABAergic inhibition in the midline thalamus affects signaling and seizure spread in the hippocampus-prefrontal cortex pathway. Epilepsia 52:523-30
Sloan, David M; Zhang, Dexing; Bertram 3rd, Edward H (2011) Excitatory amplification through divergent-convergent circuits: the role of the midline thalamus in limbic seizures. Neurobiol Dis 43:435-45
Thom, Maria; Mathern, Gary W; Cross, J Helen et al. (2010) Mesial temporal lobe epilepsy: How do we improve surgical outcome? Ann Neurol 68:424-34