Asynchronous distributed multielectrode neuromodulation for epilepsy

项目摘要 癫痫，发生在世界人口的1%，与残疾，受伤， 认知和神经功能障碍、抑郁、生产力丧失、社会经济衰退 甚至死亡在这一人群中，30%的癫痫病例在医学上是难治性的， 手术是唯一的治疗选择。而开放切除术，目前 手术治疗标准，可以产生高达60- 80%的癫痫发作自由率，这些 通常与认知功能障碍和局灶性神经缺陷有关。特别地， 优势半球内侧颞叶癫痫（MTLE）患者，目标人群 对于这项提议，有记忆力显著下降和相关残疾的风险。唯一的 目前，这些患者的选择是电神经调节，尽管电神经调节在 减少癫痫发作，仅在约10%的患者中实现无癫痫发作。我们最近发现 在16个电极的多电极阵列上传递分布的异步脉冲， 微电极，并在低（θ）频率刺激，是更有效的比宏刺激 在啮齿动物MTLE模型中控制癫痫发作。拟议项目的目标是 在真实大型动物中优化异步分布式多电极刺激（ADMES） 癫痫模型-已给予青霉素（PCN）的非人灵长类动物（NHP）， 海马体诱发反复自发性癫痫发作。这项研究将利用 新的商业神经刺激系统（RC+S，Medtronic）的可用性， 我们的新方法我们还将利用这一新颖的双向功能， 单位，以优化我们的治疗与开环和闭环的方法，以ADMES。我们将 首先在我们的NHP模型中实现ADMES并量化对癫痫发作频率和持续时间的影响， 排除对认知记忆的负面影响。与此同时，我们将描述反应的特征， 生理学生物标志物，如在一个人的ADMES刺激的调整同步性 外化系统。这将使我们能够开发开环和闭环控制策略 来优化这些生物标志物作为癫痫控制的代表。最有效的刺激 将使用RC+S神经刺激器在8个NHP中实施参数，并从癫痫发作中获益 将评估频率和对记忆的影响。如果癫痫发作减少≥50%，则我们将 进行早期临床可行性研究。为此，我们将首先确定电生理 生物标志物和表征从我们的NHP研究中获得的刺激参数的影响 在对MTLE患者进行侵入性监测期间， ADMES可行性试验6例。最终刺激参数将在 RC+S和行为癫痫发作减少以及安全性记忆测试将在12个月内进行量化 个月在完成这一目标时，我们将证明使用ADMES的可行性 和RC+S;阳性结果应为更大规模的MTLE临床试验奠定基础， 可能应用于其他癫痫。这项研究利用了一个强大的 临床医生、科学家和工程师之间的学术/行业/国家实验室合作， 以及通过现实的动物模型实现早期可行性的合理的逐步转化方法 在患者中进行测试，将新的神经技术和控制理论应用于 主要的健康问题。

PROJECT SUMMARY Epilepsy, occurring in 1 percent of the world’s population, is associated with disability, injury, cognitive and neurological dysfunction, depression, loss of productivity, socioeconomic decline and even death. Of this population, 30 percent of epilepsy cases are medically intractable, leaving surgical interventions as the only option for treatment. Whereas open resection, the current surgical standard of treatment, can yield seizure freedom rates as high as 60-80 percent, these are often associated with cognitive dysfunction and focal neurological deficits. Particularly, patients with dominant hemisphere mesial temporal lobe epilepsy (MTLE), the target population for this proposal, are at risk for significant decline in memory and associated disability. The only option for these patients at present is electrical neuromodulation which, although effective at reducing seizures, only achieves seizure freedom in ~10% of patients. We have recently found that delivering asynchronous pulses distributed across a multielectrode array of 16 microelectrodes, and stimulated at low (theta) frequency, is more effective than macrostimulation in controlling seizures in a rodent model of MTLE. The objective of the proposed project is to optimize asynchronous distributed multielectrode stimulation (ADMES) in a realistic large animal model of epilepsy - non-human primates (NHP) that have been administered penicillin (PCN) in the hippocampus to induced repeated spontaneous seizures. This research will capitalize on the availability of a new commercial neurostimulation system (RC+S, Medtronic) that uniquely allows our novel approach to be implemented. We will also exploit the novel bi-directional feature of this unit to optimize our therapy with both open-loop and closed-loop approaches to ADMES. We will first implement ADMES in our NHP model and quantify effects on seizure frequency and length, and rule out adverse effects on recognition memory. In parallel, we will characterize the response of physiological biomarkers such as synchrony to adjustment of ADMES stimulation in an externalized system. This will allow us to develop both open-loop and closed-loop control policies to optimize these biomarkers as a proxy for seizure control. The most effective stimulation parameters will be implemented in 8 NHPs using the RC+S neurostimulator and benefit on seizure frequency and effects on memory will be evaluated. If seizure reduction is ≥50% then we will advance to an early clinical feasibility study. For this, we will first identify electrophysiological biomarkers and characterize the effects of stimulation parameters informed from our NHP study on those biomarkers during invasive monitoring of MTLE patients and then move to an early feasibility trial of ADMES in 6 patients. The final stimulation parameters will be implemented in RC+S and behavioral seizure reduction and memory testing for safety will be quantified over 12 months. At the completion of this aim we will have demonstrated the feasibility of using ADMES and the RC+S; positive results should lay the foundation for a larger clinical trial for MTLE, with possible application to the other epilepsies. This research capitalizes on a strong academic/industry/national laboratory collaboration between clinicians, scientists and engineers, and a rational, stepwise translational approach through a realistic animal model to early feasibility testing in patients, to bring new neurotechnology and control theory applications to bear on a major health concern.