Development and application of signal analysis methods for preclinical and fundamental research in epilepsy

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Epilepsy is a neurological disorder characterized by epileptic seizures, which are sudden excessive neuronal discharges, sometimes accompanied by loss of consciousness. It is a common neurological disease, affecting approximately 1% of the world population and representing about 0.5% of total medical costs. While progress has been achieved in understanding and treating the epilepsies with anti-epileptic drugs and surgery, about 30% of epileptics continue to experience the devastating impact of seizures despite all efforts at treatment. It is well recognized that the mechanisms of epileptogenesis (the process of developing epilepsy as a disease) and of ictogenesis (the progression of individual seizures) are quite intricate and varied. Particularly relevant for eventual therapies is bridging the scientific gap between exquisitely detailed understanding of the disease at the molecular and cellular levels with clinical imaging data in living patients. Much of this bridge rests on the coupling between local neuronal activity and the vascular response that is observed with non-invasive imaging techniques. One such imaging technique is near-infrared spectroscopy (NIRS). NIRS measures changes in oxygenated and deoxygenated hemoglobin concentrations associated with neural activity. It offers distinct advantages over other imaging techniques, such as long-term monitoring, portability, safety, and low cost, making it the only imaging contender in some applications. Over the past few years, our group has taken a lead role in the research activity applying NIRS to epilepsy. We demonstrated that NIRS is adequate to detect various kinds of seizures and we studied epileptic spikes, quantifying the nonlinearity of their hemodynamic response. Since we found that NIRS was effective at detecting seizures, we propose here to develop this real-time monitoring technology, by itself or in combination with electroencephalography (EEG), for long-term monitoring of patients. This effort could eventually lead to a new clinical tool over a 5 to 10 year horizon. One part of this project is the development and validation of a real-time framework for detecting seizures with NIRS (and EEG). For this effort to succeed, further progress should be made for reducing the confounding aspects due to the very complex response patterns observed in epileptic patients, reflected in false positive rates for seizure detection that are too high at present for a robust clinical application. We hypothesize that an animal model may be the best strategy to better understand these patterns so as to make the diffuse optical imaging observations in human more reliable. In mice, we will perform advanced and invasive microscopic imaging experiments after inducing epileptic seizures with a neurotoxin. They will be extended later to a more realistic model of human epilepsy, a mesio-temporal lobe epilepsy (MTLE) model, noting that in our data, MTLE patients exhibit especially cryptic NIRS responses. Using optogenetic technology, to control neuronal spiking at the millisecond time scales, we will measure the neuronal and the blood responses to seizures when perturbed by optogenetic stimulation, while monitoring key physiological variables such as heart rate, respiration rate and peripheral oxygen saturation. We will then use sophisticated signal processing tools including biophysical models to understand these observed behaviors. This will help bridge the microscopic understandings in animals with the macroscopic observations in humans. The final result will be a clinical tool that could concretely improve care and the lives of patients admitted to the hospital at risk for recurrent seizures, stroke and brain oxygen desaturation.