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：使用脑损伤和脑深部刺激来识别癫痫回路 局灶性癫痫在中风、创伤和肿瘤等脑部病变的患者中很常见。为什么有些病人 有脑部病变的人会患癫痫，而其他人不会，这是未知的。深部脑刺激(DBS)提供了新的 局灶性癫痫患者有望获得治疗，但癫痫发作自由的情况很少见。为什么有些患者病情好转 在星展之后，而其他人没有，也是未知的。目前的教条只关注病变位置或星形细胞瘤部位。 我们假设病变位置和DBS位置与远离病变的远程结节或 DBS站点本身可以解释癫痫和DBS反应的差异。 狐狸实验室(PI)开发的新技术可以识别连接到病变的远程节点 和治疗脑部疾病的DBS网站。这些技术结合了病变或刺激点的位置 有一份关于人脑连接的标准图谱，称为连接体。因此，它们不需要 连接性数据来自患者本身，可应用于几乎任何临床病变或DBS数据集。 这种方法已经成功地绘制出与帕金森症、健忘症、抑郁症和20岁以上的人有关的电路 其他脑部疾病。此外，识别连接到引起病变和DBS站点的电路节点 治疗这种疾病可以确定新的或改进的治疗靶点。 我们在缺血性中风中的初步数据表明，癫痫与常见的大脑回路有关。 导致癫痫的病变部位(n=76)更多地与小脑和基底节(‘ce-bg’)相连。 与对照组(n=625)比较。丘脑前部DBS部位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结节以前被认为与癫痫发作和皮质兴奋性的调节有关。 虽然很有希望，但还需要进一步的工作来确定这些结果是否适用于不同的病变类型(目标1， N=2700)，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，以最大限度地减少假阳性或假阴性的风险。我们将执行所有分析 使用功能性连接体(主要结果)和结构连接体。完成这些目标将 确定病变位置和DBS位置到一组公共皮质下结节的连通性是否可以 解释癫痫和DBS反应的差异。识别这个回路可以识别高危患者 对于癫痫，指导DBS编程，并作为未来脑刺激试验的目标。总而言之，这些 结果可能有助于将重点从癫痫发作区域本身转移到大脑，每个患者的发作区域不同。 可能代表局灶性癫痫治疗新靶点的回路。