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：在癫痫病不反应癫痫药（药物难治性癫痫）的患者中，癫痫手术可以去除癫痫发作的大脑部分（癫痫区）。癫痫手术最严重的并发症之一是，如果在手术过程中去除关键的大脑区域，记忆和语言下降。这会影响手术后的生活质量，即使在手术后癫痫发作的患者中也会影响生活质量。迄今为止，尚无标准化的方法来预测手术后谁的记忆力可能下降。在癫痫手术之前，我们能够与人及其家人进行明智的讨论非常重要。讨论包括在手术中停止癫痫发作的机会和发生的风险，包括记忆和语言下降。钾基因治疗（EKC），其中通过探针 /杆将神经外神经外科钾基因插入癫痫发作区域可有效减少小鼠的癫痫发作活性。 Walker教授（项目伙伴）和同事为I/IIA阶段试验临床试验获得了MRC发育途径资金计划，以在治疗药物治疗难治性癫痫的治疗中进行首次人类内钾基因治疗试验。我们的10名来自国家神经和神经外科医院（NHNN）的外科队列的患者将被招募。 EKC对大脑结构和功能的风险包括认知功能和情绪，目的是：在此项目中，我们旨在描述具有药物耐火癫痫患者的记忆网络，与使用新型连接性方法相比，使用用于记忆功能磁共振成像（fMRI）和相关扩散成像（DMRI）（DMRI）的健康连接方法（我们将在epssiss）（DMRI）上，我们将效果（DMRI）效应，我们将研究效果（DMRI）2这些程序后四个月和十二个月的功能。 3使用这两种不同的扫描组合，我们旨在创建一种通过创建机器学习（人工智能）预测模型来预测接受癫痫手术的记忆结果的模型。患者将在医院进行临床评估，作为一个多学科组，我们将决定最适合的治疗方法是手术切除或EKC。所有参与者都将拥有完整的记忆和神经精神病学评估。然后，他们将具有内存功能磁共振成像（fMRI），以精确显示其内存功能在其大脑中的位置。通过使用扩散MRI（DMRI），我们将研究对记忆功能很重要的脑部。新型图理论技术将用于研究记忆网络。手术和EKC四个月和12个月，患者将对记忆，情绪和重复记忆fMRI和DMRI进行相同的评估。对照组将在三个同等时间点上与患者进行类似的评估。然后，我们将一起研究记忆fMRI和DMRI，以查看机器学习模型中的这些方法是否有助于预测手术后的记忆下降。探索记忆，情绪和相应的MRI网络的变化对于描述新型基因疗法和常规手术切除的安全性和功效至关重要。 2。使用上面的信息，将来我们将能够个性化癫痫手术。有一个名为Epinav的计算机程序，它将考虑到哪些大脑区域对于每个人的记忆最重要。使用Epinav，可以计划避免这些关键的大脑区域，将杆插入大脑中的最安全轨迹/途径。这也将表明在手术期间可以安全地去除多少大脑，以降低记忆力下降的风险。