Magnetic resonance spectroscopic imaging (MRSI) has been developed and used by many groups to localize the regions of injury and seizure onset in human epilepsy. Intrinsic to its success is the common finding of metabolic dysfunction even in the absence of tissue volume loss, e.g., as has been shown in MRI-negative cases of temporal lobe epilepsy. Although this successful detection is useful for subsequent targeted and surgical management of epilepsy, it has been recognized that the treatment of epilepsy could be substantively changed and improved if early detection were feasible and accurate. From both human and animal model experience, the pathophysiology of acquired epilepsy is initiated by a cerebral insult (e.g., the fairly common event of fever-induced or febrile seizures, head trauma or infection), followed by a latent period that precedes the onset of overt spontaneous recurrent seizures ("SRS"), i.e., epilepsy. If early detection were available, there are several strong potential therapeutics that might decrease the likelihood of developing clinical epilepsy (distinct from therapy that simply decreases the likelihood of seizures), e.g., erythropoietin, anti-inflammatory compounds, anti- oxidants. In this study we examine whether MRSI can detect incipient epilepsy during this latent period. We do this using the rat perforant path stimulation (PPS) model, which replicates many of the defining features of acquired human medial temporal lobe epilepsy. Importantly this model does not show widespread brain injury commonly seen in chemoconvulsant models. Our preliminary brain extract data from this 24hour PPS model show that by 4days after initial insult, substantial changes in myo-inositol, glutamine, GABA and N-acetyl aspartate are seen. In this project, we will test the ability of in vivo MRSI to detect 4 das after the stimulation injury the level of injury and the development of incipient epilepsy using a severe and mild version of the PPS model. This will be done in a blinded fashion. As all animals will also be video and EEG monitored, we will also be able to test the ability of the MRSI to identify those animals who go on to develop overt recurrent seizures.

Public Health Relevance

The goal of this project is to integrate advanced MR imaging methodology with a specific need in the management and understanding of human epilepsy. The natural history of epilepsy development typically starts with a cerebral injury (e.g., trauma o febrile seizures), which is followed by a variable and lengthy delay of several years and then recurrence of spontaneous seizures, or epilepsy. In this project our goal is to identify key metabolic biomarkers that can predict the development of epilepsy in an accurate rodent model of human epilepsy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS083035-01
Application #
8507357
Study Section
Special Emphasis Panel (NOIT)
Program Officer
Fureman, Brandy E
Project Start
2013-09-01
Project End
2015-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
1
Fiscal Year
2013
Total Cost
$229,125
Indirect Cost
$79,125
Name
University of Pittsburgh
Department
Neurology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213