Epilepsy is the most common and highest impact neurological disorder and there are no medical cures because the pathophysiological brain mechanisms are poorly understood. The condition arises from excitation-inhibition imbalance in neocortical networks, with considerable heterogeneity correlating with variable response to antiseizure drugs. Approximately 50-70% patients report that seizures are triggered by changes in internal milieu (e.g. sleep, stress) or external environment (e.g. photosensitivity) under genetic influence (Pal laboratory). Photosensitive patients appear to respond better to sodium valproate.
We hypothesize that photosensitivity is due to a failure of normal adaptation mechanisms, which are restored through medication, and that the origin of photosensitivity results from dysregulated inhibition. The Cooke laboratory is gaining a deep understanding of mechanisms underlying visual adaptation using invasive observational and interventional approaches within defined excitatory and inhibitory neural circuits of the mouse visual system. We have developed readouts, such as plasticity of visual-evoked potentials, that can be measured in mice and non-invasively in humans to reveal adaptation effects across different timescales with different mechanisms.
The aim of this project will be to assess whether visual cortical adaptation is dysregulated in photosensitive PWE by (a) analysing clinical EEG using quantitative methods (Year 1: clinical, spectral and connectivity analyses), (b) assessing the response of this adaptation to antiseizure drugs that target inhibitory mechanisms and investigating demographic, clinical and genotypic stratification (Year 2: multivariable statistical analysis) and (c) confirming in mice the thalamocortical plasticity mechanisms affected by antiseizure medication (Year 3-4: in vivo electrophysiology, drug application and opto/chemo-genetics in mice).