Asynchronous distributed multielectrode neuromodulation for epilepsy

项目总结 癫痫发生在世界1%的人口中，与残疾、伤害、 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。在这些人群中，30%的癫痫病例在医学上是难以治愈的，这使得 手术干预是治疗的唯一选择。鉴于开放切除，目前的 手术标准的治疗，可以产生高达60%-80%的癫痫自由率，这些 通常与认知功能障碍和局灶性神经功能障碍有关。尤其是， 优势半球内侧颞叶癫痫(MTLE)患者的目标人群 对于这项提议，他们面临着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，尽管在 减少癫痫发作，仅在约10%的患者中实现癫痫发作自由。我们最近发现 它传送分布在16个多电极阵列上的异步脉冲 微电极在低(？)频率刺激下比宏观刺激更有效 在控制MTLE啮齿动物模型中的癫痫发作。拟议项目的目标是 在现实的大型动物中优化异步分布式多电极刺激(ADMES) 癫痫模型--非人灵长类动物给予青霉素(PCN) 海马体可诱发反复自发癫痫发作。这项研究将利用 一种新的商业神经刺激系统(RC+S，美敦力)的可用性，该系统独特地允许 我们的新方法即将实施。我们还将利用它的新颖的双向特性 使用ADMES的开环和闭环方法来优化我们的治疗。我们会 首先在我们的NHP模型中实施ADMES，并量化对发作频率和发作时间的影响， 并排除对识别记忆的不利影响。同时，我们将描述响应的特征 生理生物标记物，如与ADMES刺激调节的同步性 外部化的系统。这将使我们能够开发开环和闭环控制策略 以优化这些生物标志物作为癫痫控制的替代指标。最有效的刺激 使用RC+S神经刺激器在8个NHP中实施参数并对癫痫有好处 将对频率和对记忆的影响进行评估。如果癫痫发作减少了50%，那么我们将 推进到早期的临床可行性研究。为此，我们将首先识别电生理学 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MTLE患者侵入性监测中对这些生物标志物的影响并转移到早期 6例ADMES的可行性试验。最终的刺激参数将在 RC+S和行为减痫及记忆安全测试将量化12分以上 月份。在完成这一目标后，我们将证明使用ADMES的可行性 和RC+S；阳性结果应为MTLE的更大规模临床试验奠定基础， 可能适用于其他癫痫患者。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， 以及通过真实的动物模型进行理性、循序渐进的翻译方法，以期达到早期的可行性 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.