Using brain lesions and deep brain stimulation to identify an epilepsy circuit

利用脑损伤和深部脑刺激来识别癫痫回路

• 批准号: 10501784
• 负责人: MICHAEL D FOX
• 金额: $ 68.01万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10501784
• 关键词: Affect; Age; Amnesia; Anterior; Atlases; Basal Ganglia; Brain; Brain Diseases; Brain Neoplasms; Brain hemorrhage; Cerebellum; Clinical; Data; Data Set; Deep Brain Stimulation; Disease; Distant; Electrodes; Enrollment; Epilepsy; Foxes; Freedom; Frequencies; Future; Human; Intractable Epilepsy; Ischemic Stroke; Lead; Lesion; Location; Magnetic Resonance Imaging; Maps; Mental Depression; Metastatic malignant neoplasm to brain; Parkinsonian Disorders; Partial Epilepsies; Patients; Penetrating Head Injuries; Pharmaceutical Preparations; Registries; Risk; Seizures; Site; Stroke; Techniques; Testing; Thalamic structure; Time; Trauma; Tuberous Sclerosis; United States National Institutes of Health; Variant; Work; connectome; high risk; implantation; improved; new therapeutic target; novel therapeutics; physically handicapped; post stroke; primary outcome; prospective; response; risk minimization; sex; stroke outcome; stroke patient; stroke trials; therapeutic target; tumor

PROJECT SUMMARY: Using brain lesions and deep brain stimulation to identify an epilepsy circuit Focal epilepsy is common in patients with brain lesions such as stroke, trauma, and tumors. Why some patients with brain lesions develop epilepsy while others do not is unknown. Deep brain stimulation (DBS) offers new therapeutic promise for patients with focal epilepsy, but seizure freedom is rare. Why some patients improve after DBS while others do not is also unknown. Current dogma focuses on the lesion location or DBS site alone. We hypothesize that connectivity of lesion locations and DBS sites to remote nodes distant from the lesion or DBS sites itself can explain variance in lesional epilepsy and DBS response. New techniques developed by the Fox lab (PI) can identify remote nodes connected to lesions causing and DBS sites treating brain diseases. These techniques combine the location of the lesion or stimulation site with a normative atlas of human brain connectivity termed the connectome. As such, they do not require connectivity data from the patients themselves and can be applied to almost any clinical lesion or DBS dataset. This approach has successfully mapped circuits involved in parkinsonism, amnesia, depression, and over 20 other brain diseases. Moreover, identifying circuit nodes connected to both lesions causing and DBS sites treating the disease can identify new or improved therapeutic targets. Our preliminary data in ischemic stroke suggests there is a common brain circuit involved in epilepsy. Lesion locations that cause epilepsy (n = 76) are more connected to the cerebellum and basal ganglia (‘Ce-BG’) compared to control lesions (n = 625). Connectivity of anterior thalamic DBS sites to these same circuit nodes is correlated with seizure reduction after DBS (n=30). While epilepsy is often considered a cortical disease, these subcortical Ce-BG nodes have previously been implicated in the modulation of seizures and cortical excitability. Although promising, further work is needed to determine if these results generalize across lesion types (Aim 1, n = 2,700), prospectively predict epilepsy risk (Aim 2, n = 6,000), and correlate with DBS response (Aim 3, n = 198). For each aim, we will focus on our Ce-BG nodes as an a priori hypothesis, but also perform data-driven (unbiased whole-brain) analyses to minimize risk of false positives or negatives. We will perform all analyses using a functional connectome (primary outcome) and structural connectome. Completion of these aims will determine whether connectivity of lesion locations and DBS sites to a common set of subcortical nodes can explain variance in lesional epilepsy and DBS response. Identifying this circuit could identify patients at high risk for epilepsy, guide DBS programming, and serve as a target for future brain stimulation trials. Collectively, these results could facilitate a shift in focus from the seizure-onset zone itself, which differs in every patient, to a brain circuit that may represent a new therapeutic target for focal epilepsy.

项目摘要：利用脑损伤和深部脑刺激来识别癫痫回路 局灶性癫痫常见于患有中风、外伤和肿瘤等脑部病变的患者。为什么有些患者 脑部病变会导致癫痫，而其他人则不会，这一点尚不清楚。深部脑刺激（DBS）提供了新的 局灶性癫痫患者有治疗希望，但无癫痫发作的情况很少见。为什么有些患者病情好转 DBS之后而其他人没有也不得而知。目前的教条只关注病变位置或 DBS 部位。 我们假设病变位置和 DBS 站点与远离病变的远程节点的连接或 DBS 部位本身可以解释病变性癫痫和 DBS 反应的差异。 Fox 实验室 (PI) 开发的新技术可以识别与病变相关的远程节点 以及治疗脑部疾病的 DBS 网站。这些技术结合了病变或刺激部位的位置 具有称为连接组的人类大脑连接的规范图谱。因此，他们不需要 来自患者本身的连接数据，可以应用于几乎任何临床病变或 DBS 数据集。 这种方法已成功绘制出与帕金森症、健忘症、抑郁症和 20 多种疾病有关的回路。 其他脑部疾病。此外，识别连接到病变部位和 DBS 部位的电路节点 治疗疾病可以确定新的或改进的治疗靶点。 我们对缺血性中风的初步数据表明，癫痫有一个共同的脑回路。 引起癫痫的病变位置 (n = 76) 与小脑和基底神经节 (‘Ce-BG’) 的联系更多 与对照病变相比 (n = 625)。丘脑前部 DBS 站点与这些相同回路节点的连接 与 DBS 后癫痫发作减少相关 (n=30)。虽然癫痫通常被认为是一种皮质疾病，但这些 皮质下 Ce-BG 节点先前被认为与癫痫发作和皮质兴奋性的调节有关。 尽管前景广阔，但仍需要进一步的工作来确定这些结果是否适用于各种病变类型（目标 1， n = 2,700），前瞻性预测癫痫风险（目标 2，n = 6,000），并与 DBS 反应相关（目标 3，n = 198）。对于每个目标，我们将重点关注我们的 Ce-BG 节点作为先验假设，但也执行数据驱动 （无偏见的全脑）分析，以尽量减少误报或漏报的风险。我们将进行所有分析 使用功能连接组（主要结果）和结构连接组。完成这些目标将 确定病变位置和 DBS 站点与一组共同的皮层下节点的连接是否可以 解释病变性癫痫和 DBS 反应的差异。识别该回路可以识别高危患者 治疗癫痫，指导 DBS 编程，并作为未来大脑刺激试验的目标。总的来说，这些 结果可能有助于将焦点从癫痫发作区本身（每个患者的情况不同）转移到大脑 电路可能代表局灶性癫痫的新治疗靶点。