Understanding mechanisms of cortical spreading depression in epilepsy and migraine

皮质扩散性抑制(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、过度去极化和一段时间的电沉默组成。大约30%的偏头痛患者经历了与偏头痛先兆相关的CSD。人们还认为，在癫痫发作期间，CSD和癫痫发作之间存在联系，这种联系可能与癫痫患者的猝死有关。伦敦大学学院皇后广场神经学研究所的Kirill Volynski团队最近开发了一套新的方法来记录局部场电位数据，并结合时空荧光钙离子成像对清醒小鼠的神经元活动进行成像。这些数据表明，大约25%的癫痫发作之后是以CSD典型的慢得多的速度传播的钙波，并且该波之后是电静默。拟议的博士项目将是与Volynski实验室的直接合作，并将用生物约束的数学模型来补充他们由英国癫痫研究中心资助的实验研究计划。总体研究的主要目的将是了解可持续发展背后的机制，以及癫痫发作和可持续发展之间的机制联系。特别是，CSD之后的癫痫发作与没有的癫痫发作有什么不同？大脑皮层如何在不经过癫痫发作的情况下直接转变为CSD？与偏头痛相关的电压门控钙通道的突变是否会导致CSD的传播增加，到达脑干并解释猝死？PHD项目将专注于开发一个模型框架，描述神经元组织中的时空电信号，既支持癫痫发作，也支持CSD。这将使用积分-微分型模型实现，并使用加州大学的电动力学和钙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导致神经网络功能障碍的病理过程，在癫痫、缺血和偏头痛及其变种等几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，人们对这一过程只有部分了解。然而，根据最近获得的钙动力学成像数据，结合清醒小鼠的局部场电位记录，我们可以开始了解潜在的机制，并从长远来看，为相关疾病的治疗提供信息。研究的目的和目标-本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，能够支持癫痫发作和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，并将为验证潜在假说的潜在新实验提供预测能力。研究方法的新颖性-模型的开发将以新的实验数据为指导。此外，据我们所知，目前还没有一个能够使用积分-微分方程组(或反应-扩散型模型)来结合癫痫发作和CSD的模型。潜在的影响、应用和好处-整个项目的主要目标是使用实验方法和数学/计算模型相结合的方法来剖析皮层神经元网络易于癫痫发作和/或CSD的机制。这可能会对易患癫痫和偏头痛的患者产生重大影响，并有助于解释癫痫患者的猝死综合征。研究领域；医疗技术，数学科学外部合作伙伴-国家神经病学和神经外科医院

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