There is a critical unmet need to identify new strategies to control seizures in individuals with epilepsy who fail to respond to currently available drugs. Many of these individuals undergo invasive surgical resection of electroencephalographically aberrant tissue. However, seizures are likely to recur in up to half of these subjects within 5 years of surgery. Resistance to therapies that target electrophysiological mechanisms of aberrant neural activity coupled to post-surgical recurrence of seizures in previously non-ictal tissue may indicate a role for epileptogenic drivers that are non-neural and self-amplifying. Multiple studies have demonstrated changes in peripheral inflammatory factors in individuals with epilepsy, and steroids and other immunomodulatory therapies have proven effective in some patients. Likewise, evidence from animal models clearly supports a role for cytokines such as TNF? and IL1? in seizure activity. Therefore, neuroinflammation may be a critical driver of drug-resistant epilepsy. The central hypothesis of this proposal is that aberrant neural activity triggers local release of chemokines and cytokines that promote infiltration of innate inflammatory effector cells, production of additional inflammatory mediators, and further disruption of neural circuitry. Breaking this cycle may stop ictogenesis and/or epileptogenesis. The specific hypothesis of this proposal is that levels of the chemoattractant CCL2 and the effector cytokines TNF?, IL1?, and/or IL6 are elevated in spatial and temporal association with chemically induced epileptiform activity. This hypothesis will be tested using a strategy based on simultaneous collection of intracortical EEG activity and large molecule microdialysis to measure inflammatory mediators in the extracellular fluid of the peri-electrode space in mice and pigs and in humans undergoing resective surgery for drug-resistant epilepsy. Despite circumstantial evidence in humans indicating a role for inflammation in seizure disorders and epilepsy, no study has yet measured the in situ inflammatory characteristics of the epileptic brain or assessed the relationship between epileptiform activity and local release of inflammatory molecules. Though brain microdialysis has been established as a technique in the neurocritical care setting for assessment of small molecules, this study will be the first to employ an innovative strategy that combines intracranial EEG collection and the use of high molecular weight cut-off membranes (100 kDa) for the capture of chemokines and cytokines in the peri- electrode space. These experiments are significant as they will provide novel insights into the role of inflammatory mediators as both cause and effect of neural circuit dysfunction and they may identify individual inflammatory drivers that can be targeted for personalized treatment strategies. Regardless of outcomes, this study will generate new, fundamental knowledge about the interplay between seizure activity and inflammation. Understanding this relationship may provide support for the use of immunomodulatory therapies in the millions of individuals with epilepsy that are currently underserved by current standards of care.
- National Institute of Neurological Disorders and Stroke: $437,250.00