Mechanisms of Cognitive Impairment Following Early-Life Seizures

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Project Summary Epilepsy is a complex disorder which involves much more than seizures. As emphasized by the National Academy of Science-sponsored Committee on the Public Health Dimensions of the Epilepsies,1 epilepsy may be accompanied by a range of associated co-morbid health conditions that can have significant health and quality of life implications. Of these comorbidities, cognitive impairment is one of the most common and distressing aspects of epilepsy. Because the risk of cognitive impairment is greatest in young children, the educational, vocational, social and economic implications are enormous. Remarkably, there are only a handful of laboratories attempting to understand the pathophysiological basis of cognitive disturbances in early-life seizures (ELS). It is the view of our laboratory that prior to preventing, limiting and reversing cognitive comorbidities, it is essential to understand the neurobiological basis of developmental cognitive dysfunction associated with ELS. One of the major difficulties in decoding the complex issue of cognitive outcomes following ELS in children is the gulf between the behavioral/mental spheres in which these deficits are substantiated and the underlying physiological/developmental domains that are both the cause of these deficits and the most likely domains for therapy and intervention. Based on strong preliminary data showing abnormalities in rate and temporal coding in cognitive impairment following ELS, we propose that aberrant neural circuit dynamics are the neurophysiological underpinnings of cognitive impairment. In this proposal, we wish to rigorously study the consequences of ELS on temporal coding using multi-site single cell and local field potentials. To move from correlative to causal experimentation, we will first determine if cognitive rehabilitation following ELS reverses coding abnormalities. Secondly, we will use optogenetic-induced modulation of neuronal circuits to modify coding abnormalities and correct spatial cognitive deficits. Based on compelling preliminary data, we believe our findings will support the concept of dynamic neural discoordination as a causal factor of cognitive dysfunction following ELS.