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：使用大脑病变和深脑刺激来识别癫痫电路 局灶性癫痫在患有中风，创伤和肿瘤等脑病变的患者中很常见。为什么有些患者 随着脑病变的发展，癫痫病，而其他人则未知。深脑刺激（DB）提供了新的 局灶性癫痫患者的治疗诺言，但癫痫发作自由很少见。为什么有些患者有所改善 在DBS之后，而其他人则不知道。当前的教条仅关注病变位置或DBS网站。 我们假设病变位置和DBS位点与远离病变或远程节点的连通性或 DBS网站本身可以解释病变癫痫和DBS反应的差异。 FOX LAB（PI）开发的新技术可以识别连接到病变的远程节点 和DBS部位治疗脑部疾病。这些技术结合了病变或刺激部位的位置 人脑连通性的正常地图集称为连接组。因此，他们不需要 来自患者本身的连通性数据，几乎可以应用于任何临床病变或DBS数据集。 这种方法已成功地绘制了参与帕金森氏症，失忆症，抑郁症和20多个电路 其他脑部疾病。此外，识别连接到病变的电路节点和DBS位点 治疗该疾病可以识别新的或改善的治疗靶标。 我们的缺血性中风的初步数据表明，癫痫涉及一个普通的脑回路。 引起癫痫病的病变位置（n = 76）更连接到小脑和基本神经节（'ce-bg'） 与对照病变相比（n = 625）。前丘脑DBS位点与这些相同电路节点的连通性 与DBS后的癫痫发作相关（n = 30）。虽然癫痫通常被认为是皮质疾病，但 先前在癫痫发作和皮质刺激性的调节中暗示了皮质下CE-BG节点。 尽管有希望 n = 2,700），前瞻性预测癫痫风险（AIM 2，n = 6,000），与DBS响应相关（AIM 3，n = 198）。对于每个目标，我们将专注于CE-BG节点作为先验假设，但也执行数据驱动 （无偏见的全脑）分析以最大程度地减少误报或负面因素的风险。我们将执行所有分析 使用功能连接组（主要结果）和结构连接组。这些目标的完成将 确定病变位置和DBS位点与一组常见皮层淋巴结的连通性是否可以 解释病变癫痫和DBS反应的差异。识别该电路可以识别高风险的患者 对于癫痫病，指导DBS编程，并作为未来大脑模拟试验的目标。总的来说，这些 结果可能有助于促进焦点从癫痫发作区域本身（每个患者都不同）向大脑的转变 可能代表局灶性癫痫的新治疗靶标的电路。