Understanding mechanisms of cortical spreading depression in epilepsy and migraine

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Cortical spreading depression (CSD, also known as spreading depolarisation), a neurophysiological phenomenon in the brain consisting of a wave of neuronal hyperactivity followed by excessive depolarisation and a period of electrical silence. About 30% of patients with migraine experience the CSD associated with migraine aura. It is also believed that there exists a link between the CSD and episodes of seizures during epilepsy and that this link is potentially relevant to sudden unexpected death in patients with epilepsy.Prof. Kirill Volynski's group in the UCL Queen Square Institute of Neurology has recently developed a set of novel methods to record local-field potential data combined with spatio-temporal fluorescence Ca2+ imaging of neuronal activity in awake mice. These data indicate that approximately 25% of seizures were followed by a Ca2+ wave that spreads at a much slower velocity typical of CSD, and this wave is followed by electrical silence. The proposed PhD project will be a direct collaboration with Volynski lab and will complement their experimental research programme funded by the Epilepsy Research UK with biologically constrained mathematical modelling. The main aim of the overall research will be to understand the mechanisms behind the initiation of CSD as well as the mechanistic links between seizures and CSD. In particular, how do seizures that are followed by CSD differ from seizures that are not? How can the cortex transition to CSD directly without passing through a seizure? Can mutations in voltage-gated Ca2+ channels associated with migraine lead to the increased propagation of CSD reaching the brain stem and explaining sudden death?The PhD project will focus on the development of a modelling framework describing the spatio-temporal electrical signals in neuronal tissue that can support both epileptic seizures and CSD. This will be achieved using integro-differential type models and constrained using the experimental data on electrical and Ca2+ dynamics from UCL.The context of the research - Cortical spreading depression is a pathological processes that causes malfunction of neuronal networks and plays a crucial role in several conditions such as seizures, ischemia and migraines and its variants. The process is only partially understood because of its complexity and difficulty obtaining direct experimental data. However with the recently available imaging data of Ca2+ dynamics combined with local-field potential recordings in awake mice we can begin to understand the underlying mechanisms and inform the treatments for the linked conditions in the long term.The aims and objectives of the research - The aim of the project is to develop a novel biologically constrained model of electrical activity in neuronal tissue capable to support epileptic seizures and CSD. This model will help to discriminate between various possible mechanisms linking seizures and CSD as well as it will provide a predictive power for potential novel experiments for validating potential hypotheses.The novelty of the research methodology - Development of the model will be guided by novel experimental data. Moreover, to our best knowledge, there does not exist a model capable of combining epileptic seizures and CSD using the class of integro-differential equations (or reaction-diffusion type models).The potential impact, applications, and benefits - The main goal of this overall project is to dissect the mechanisms that predispose cortical neuronal networks to seizures and/or to CSD, using a combination of experimental methods and mathematical/computational modelling. This might provide a significant impact on patients susceptible to epilepsy and migraine and can help of explaining sudden death syndrome in epilepsy patients.Research area; Healthcare technologies, Mathematical SciencesExternal partner - National Hospital for Neurology and Neurosurgery