Understanding mechanisms of cortical spreading depression in epilepsy and migraine

了解癫痫和偏头痛皮质扩散抑制的机制

• 批准号: 2271294
• 金额: --
• 依托单位: University of Warwick
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2271294
• 关键词: Understanding; mechanisms; cortical; spreading; depression

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

皮层扩散性抑制（CSD，也称为扩散性去极化），是大脑中的一种神经生理现象，由神经元过度活跃波，随后是过度去极化和一段时间的电沉默组成。大约30%的偏头痛患者会经历与偏头痛先兆相关的CSD。也有人认为，癫痫发作期间的CSD和发作之间存在联系，这种联系可能与癫痫患者的突然意外死亡有关。伦敦大学学院皇后广场神经病学研究所的Kirill Volynski教授的小组最近开发了一套新的方法来记录清醒小鼠神经元活动的局部场电位数据结合时空荧光Ca 2+成像。这些数据表明，约25%的癫痫发作后，以慢得多的速度传播的典型的CSD的Ca 2+波，并且该波之后是电沉默。拟议的博士项目将与Volynski实验室直接合作，并将通过生物约束数学建模来补充由英国癫痫研究所资助的实验研究计划。总体研究的主要目的是了解启动CSD背后的机制以及缉获和CSD之间的机械联系。特别是，由惩教署跟进的缉获与未跟进的缉获有何不同？大脑皮层怎么能不经过癫痫发作就直接转变成CSD呢？与偏头痛相关的电压门控钙通道突变是否可导致CSD到达脑干的传播增加并解释猝死？博士项目将专注于开发一个建模框架，描述神经元组织中的时空电信号，可以支持癫痫发作和CSD。这将通过使用积分微分型模型来实现，并使用UCL的电和Ca 2+动力学实验数据进行约束。研究背景-皮质扩散性抑制是一种病理过程，会导致神经元网络功能障碍，并在癫痫发作，缺血和偏头痛及其变体等多种情况下发挥关键作用。由于其复杂性和难以获得直接的实验数据，该过程仅被部分理解。然而，通过最近获得的Ca 2+动态成像数据与清醒小鼠的局部场电位记录相结合，我们可以开始了解其潜在机制，并为相关疾病的长期治疗提供信息。研究的目的和目标-该项目的目的是开发一种新的神经元组织电活动的生物约束模型，能够支持癫痫发作，CSD。该模型将有助于区分癫痫发作和CSD之间的各种可能机制，并为验证潜在假设的潜在新实验提供预测能力。研究方法的新奇-模型的开发将由新的实验数据指导。此外，据我们所知，不存在能够使用积分微分方程类将癫痫发作和CSD结合的模型潜在的影响、应用和益处-该总体项目的主要目标是剖析使皮层神经元网络易于癫痫发作和/或CSD的机制，使用实验方法和数学/计算建模的组合。这可能会对癫痫和偏头痛患者产生重大影响，并有助于解释癫痫患者的猝死综合征。研究领域;医疗技术，数学外部合作伙伴-国立神经病学和神经外科医院