Longitudinal structural and cognitive functional imaging and outcome prediction in focal epilepsy treated with gene therapy and surgical resection.

基因治疗和手术切除治疗局灶性癫痫的纵向结构和认知功能成像及结果预测。

• 批准号: MR/X031039/1
• 负责人: Meneka Kaur Ranjit Singh Sidhu
• 金额: $ 27.56万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX031039%2F1
• 关键词: Longitudinal; structural; cognitive; functional; imaging

Background:In people whose epilepsy does not respond to epilepsy medications (drug refractory epilepsy), epilepsy surgery to remove the part of the brain where seizures arise (the epileptic zone), may be an option. One of the most serious complications of epilepsy surgery is memory and language decline if critical brain areas are removed during surgery. This affects quality of life after surgery even in people whose seizures stop after surgery. To date, there is no standardised way of predicting whose memory may decline after surgery. It is very important that we are able to have an informed discussion with people and their families before epilepsy surgery. Discussions include the chance of stopping seizures with surgery and the risks incurred, including memory and language decline. Potassium gene therapy (EKC) where an engineered potassium gene is inserted neurosurgically into the epileptogenic zone via a probe /rod was shown to be effective in reducing seizure activity in mice. Professor Walker (project partner) and colleagues secured a MRC Developmental Pathway Funding Scheme for a Phase I/IIa pilot clinical trial for the first in-human trial of potassium gene therapy in the treatment of medication refractory epilepsy. 10 patients from our surgical cohort at the National Hospital for Neurology and Neurosurgery (NHNN) will be recruited. The risk of EKC to brain structure and function including cognitive functions and mood is not known.Main aims:In this project1) we aim to describe the memory network in people with drug refractory epilepsy compared to healthy controls using novel connectivity methods applied to memory functional magnetic resonance imaging (fMRI) and related diffusion imaging (dMRI)2) We will then study the effect of both epilepsy surgery and EKC on brain structure and function four and twelve months after these procedures. 3 Using these two different scans in combination, we aim to create a model of predicting memory outcome in people undergoing epilepsy surgery by creating a machine learning (artificial intelligence) model of prediction.Method:We will study 30 healthy controls, 10 EKC and 60 patients who will have surgical resection. Patients will be clinically assessed in hospital and as a multidisciplinary group we will decide if the best suited treatment for them is surgical resection or EKC. All participants will have a full memory and neuropsychiatric assessment. They will then have memory functional magnetic resonance imaging (fMRI) to show precisely where in their brain their memory functions lie. By using diffusion MRI (dMRI) we will study brain tracts that are important for memory functions. Novel graph theory techniques will be used to study the memory network. Four and 12 months after surgery and EKC, patients will have the same assessments of memory, mood and repeat memory fMRI and dMRI. Controls will have a similar assessment at three equivalent timepoints to patients. We will then investigate both memory fMRI and dMRI together to see if these methods in combination in a machine learning model will be useful in predicting memory decline after surgery.Importance:1. Exploring the changes in memory, mood and corresponding MRI networks will be critical in describing the safety and efficacy of both novel gene therapy and conventional surgical resection for future wider application. 2. Using the information above, in the future, we will be able to individualise epilepsy surgery. There is a computer programme called EpiNav that will take into account which brain areas are most important for memory in each person. Using EpiNav, the safest trajectory/ pathway for inserting the rod into the brain for EKC by avoiding these critical brain areas can be planned. It will also suggest how much of the brain can be safely removed during surgery to reduce the risk of memory decline.

背景：对于癫痫药物治疗无效的患者(药物难治性癫痫)，癫痫手术切除出现癫痫发作的大脑部分(癫痫带)可能是一种选择。癫痫手术最严重的并发症之一是，如果在手术中切除关键的大脑区域，记忆和语言能力就会下降。这会影响手术后的生活质量，即使是手术后癫痫发作停止的人也是如此。到目前为止，还没有标准的方法来预测手术后谁的记忆力可能会下降。非常重要的是，我们能够在癫痫手术前与患者及其家人进行知情的讨论。讨论包括通过手术停止癫痫发作的机会以及由此产生的风险，包括记忆力和语言能力下降。钾基因治疗(EKC)，即通过探针/棒将工程钾基因插入神经外科手术中的致痫区域，被证明能有效地减少小鼠的癫痫发作活动。Walker教授(项目合作伙伴)和他的同事获得了一项MRC发展路径资助计划，用于第一阶段/第二阶段临床试验，这是钾基因疗法治疗药物难治性癫痫的首个人体试验。我们将从国家神经病学和神经外科医院(NHNN)的外科队列中招募10名患者。EKC对包括认知功能和情绪在内的脑结构和功能的风险尚不清楚。主要目的：1)在本项目中，我们的目标是使用应用于记忆功能磁共振成像(FMRI)和相关扩散成像(DMRI)的新的连接方法来描述药物难治性癫痫患者和健康对照组的记忆网络。2)然后，我们将研究癫痫手术和EKC在手术后4个月和12个月对大脑结构和功能的影响。3结合使用这两种不同的扫描，我们的目标是通过创建一个机器学习(人工智能)预测模型来建立一个预测癫痫手术患者记忆结局的模型。方法：我们将研究30名健康对照组、10名EKC和60名将接受手术切除的患者。患者将在医院接受临床评估，作为一个多学科小组，我们将决定最适合他们的治疗方法是手术切除还是EKC。所有参与者都将接受完整的记忆和神经精神评估。然后，他们将进行记忆功能磁共振成像(FMRI)，以准确显示他们的记忆功能在大脑中的位置。通过使用弥散磁共振成像(DMRI)，我们将研究对记忆功能很重要的脑区。新的图论技术将被用来研究记忆网络。在手术和EKC后4个月和12个月，患者将进行相同的记忆、情绪和重复记忆fMRI和dMRI评估。控制组将在三个与患者相同的时间点进行类似的评估。然后，我们将一起研究记忆功能磁共振成像和数字磁共振成像，看看这些方法在机器学习模型中的组合是否有助于预测手术后记忆下降。重要提示：1.探索记忆、情绪和相应的MRI网络的变化对于描述新型基因治疗和传统手术切除的安全性和有效性以及未来更广泛的应用至关重要。2.利用上述信息，在未来，我们将能够个体化癫痫手术。有一个名为EpiNav的计算机程序，它将考虑每个人的大脑中哪些区域对记忆最重要。使用EpiNav，可以规划通过避开这些关键大脑区域将杆子插入EKC大脑的最安全轨迹/路径。它还将表明，在手术期间可以安全地切除多少大脑，以降低记忆衰退的风险。