Using Brain Lesions and Deep Brain Stimulation to Identify an Epilepsy Circuit

项目总结：使用脑损伤和脑深部电刺激识别癫痫回路 局灶性癫痫常见于脑损伤患者，如中风、创伤和肿瘤。为什么有些患者 脑损伤发展癫痫，而其他人没有是未知的。脑深部电刺激（DBS）提供了新的 对于局灶性癫痫患者的治疗前景，但癫痫发作自由是罕见的。为什么有些病人会好转 而其他人DBS后不也是未知数。目前的教条集中在病变部位或DBS部位。 我们假设病变部位和DBS部位与远离病变的远端淋巴结的连通性， DBS部位本身可以解释病灶性癫痫和DBS反应的差异。 福克斯实验室（PI）开发的新技术可以识别与病变相关的远程节点， 和治疗脑部疾病的DBS站点。这些技术联合收割机将病变或刺激部位的位置 一个关于人类大脑连接的标准图谱叫做连接体。因此，它们不需要 这些数据可以从患者自身获取，并且可以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了帕金森氏症，健忘症，抑郁症和20多个神经回路。 其他脑部疾病。此外，识别连接到病变引起部位和DBS部位的回路节点 治疗该疾病可以鉴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有一个共同的脑回路。 导致癫痫的病变位置（n = 76）与小脑和基底神经节（“Ce-BG”）的联系更多 与对照病变（n = 625）相比。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， 皮质下的Ce-BG节点先前已经涉及癫痫发作和皮质兴奋性的调节。 虽然有希望，但需要进一步的工作来确定这些结果是否适用于病变类型（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，我们将专注于我们的Ce-BG节点作为先验假设，但也进行数据驱动 （无偏全脑）分析，以尽量减少假阳性或阴性的风险。我们将进行所有分析 使用功能连接体（主要结果）和结构连接体。实现这些目标将 确定病变位置和DBS部位与一组共同的皮质下节点的连通性是否可以 解释病灶性癫痫和DBS反应的差异。识别这种回路可以识别高风险患者 用于癫痫，指导DBS编程，并作为未来脑刺激试验的目标。总的来说，这些 结果可能有助于将焦点从每个患者都不同的癫痫发作区本身转移到大脑 电路，可能代表一个新的治疗靶点局灶性癫痫。

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.