Neurophysiology Research Lab

Kevin M. Kelly, M.D., Ph.D

The focus of this laboratory has been the study of epilepsy in aging brain.  In the elderly, stroke is the dominant cause of epilepsy, yet there is little understanding of the pathophysiological mechanisms of aged brain following stroke that cause or predispose to the development of epileptic seizures. In an effort to establish reliable animal models of poststroke epilepsy, we have used two different models of experimental stroke: 1) transient unilateral middle cerebral artery and common carotid artery occlusion (MCA/CCAO), and 2) cortical photothrombosis.  We have discovered that each model can result in poststroke epilepsy, but in significantly different ways.  In the MCA/CCAO model, aged (20 month old) but not young adult (4 month old) rats developed epileptic seizures 1-2 months after stroke characterized by recurrent episodes of bilateral forelimb clonus or continuous running, jumping, rearing, and falling.  In the photothrombosis model, young adult animals developed epileptic seizures, also 1-2 months after stroke, which appeared to originate in the area of brain surrounding the area of stroke.  However, unlike aged animals in the MCA/CCAO model, seizures were manifested by motor arrest of the animal, not convulsions.  These results form the basis of more detailed studies aimed at elucidating the mechanisms by which injured brain generates epileptic seizures.  These studies incorporate techniques of electroencephalography, patch clamp electrophysiology, neuropharmacology, molecular biology, and immunohistochemistry.  By establishing reliable animal models of poststroke epilepsy in the elderly, we hope to identify potential targets for antiepileptogenic strategies in this patient population and thereby shift the focus of therapeutic approaches from control of seizures, to prevention and cure.

A growing area of focus of the laboratory is the application of animal models of epilepsy to the field of seizure prediction.  Over the last 4 years, we have evaluated nonlinear dynamical measures of brain functioning (short term Lyapunov exponent and pattern match regularity statistic) in response to intraventricular injections of midazolam in a model of temporal lobe epilepsy.  Additionally, we have assessed these same dynamical measures peri-ictally in young adult and aged rats with and without cortical infarction to characterize infarction-related differences in the expression of genetic, age-related generalized spike-wave discharges (absence seizures).  The long term goal of these studies is the development of implantable control devices for patients with intractable epilepsy so that seizures can be predicted, therapy initiated, and seizures prevented from occurring with little or no disturbance to the patient. 

Supported by grants from the National Institutes of Health (NINDS R01NS046015, R21 NS052722, and NIA Pilot Study Research Support), the Pennsylvania Department of Health (Health Research Formula Fund RFAs 01-07-26 and 04-07-09), the American Heart Association (GIA 0151398V), and the Epilepsy Foundation’s Targeted Initiative for Seniors.