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

背景：对于癫痫药物治疗无效的患者（药物难治性癫痫），癫痫手术切除癫痫发作的大脑部分（癫痫区）可能是一种选择。癫痫手术最严重的并发症之一是记忆力和语言能力下降，如果在手术过程中切除关键的大脑区域。这会影响手术后的生活质量，即使是在手术后癫痫停止的人。到目前为止，还没有标准化的方法来预测手术后谁的记忆力会下降。这是非常重要的，我们能够有一个知情的讨论与人和他们的家人在癫痫手术前。讨论包括通过手术阻止癫痫发作的机会以及所产生的风险，包括记忆力和语言能力下降。钾基因治疗（EKC），其中一个工程钾基因是通过探针/杆神经外科插入到致痫区被证明是有效的，在减少癫痫发作活动的小鼠。步行者教授（项目合作伙伴）和同事获得了MRC发展途径资助计划的I/IIa期试点临床试验，首次在人体试验钾基因疗法治疗药物难治性癫痫。将从国立神经病学和神经外科医院（NHNN）的手术队列中招募10例患者。EKC对大脑结构和功能（包括认知功能和情绪）的风险尚不清楚。主要目的：在本项目中1）我们的目的是描述与健康对照组相比，药物难治性癫痫患者的记忆网络，使用新的连接方法应用于记忆功能磁共振成像（fMRI）和相关的扩散成像（dMRI）2）我们将研究癫痫手术和EKC对大脑结构和功能的影响，这些程序后4个月和12个月。3结合使用这两种不同的扫描，我们的目标是通过创建机器学习（人工智能）预测模型来创建一个预测癫痫手术患者记忆结果的模型。方法：我们将研究30名健康对照，10名EKC和60名手术切除的患者。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是手术切除还是EKC。所有参与者都将接受全面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），以精确显示他们大脑中记忆功能的位置。通过使用弥散MRI（dMRI），我们将研究对记忆功能很重要的脑束。新的图论技术将被用来研究记忆网络。手术和EKC后4个月和12个月，患者将接受相同的记忆、情绪和重复记忆fMRI和dMRI评估。对照组将在三个等同时间点进行与患者相似的评估。然后，我们将同时研究记忆fMRI和dMRI，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的记忆衰退。重要性：1.探索记忆，情绪和相应的MRI网络的变化将是至关重要的，在描述新的基因治疗和传统的手术切除的安全性和有效性，为未来更广泛的应用。2.利用上述信息，在未来，我们将能够个性化癫痫手术。有一个名为EpiNav的计算机程序可以考虑每个人大脑中哪些区域对记忆最重要。使用EpiNav，可以计划通过避开这些关键大脑区域将杆插入大脑进行EKC的最安全轨迹/路径。它还将表明在手术过程中可以安全地切除多少大脑，以降低记忆力下降的风险。

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.