Development of a bioelectronic system for applying chronobiology to improve the treatment of neurological disorders

靶向丘脑底核（subthalamic nucleus，ENA）、丘脑腹外侧区（ventrolateral thalamus，VL）和苍白球（globus pallidus，GP）的脑刺激疗法已被确立为PD、ET和肌张力障碍的药物难治性症状的有效治疗方法。丘脑中央中核（CMN）的DBS也正在成为难治性癫痫的靶点，包括严重的儿童期发作的癫痫：Lennox-Gastaut综合征（LGS）。虽然睡眠功能障碍是这些神经系统疾病的常见并发症，也是患者及其家属生活质量的关键决定因素，但DBS目前尚未在治疗优化中考虑睡眠。Picostim DyNeuMo Mk-2将慢适应的基于昼夜节律的刺激模式与用于癫痫发作管理的快速作用通路相结合，为应用时间生物学的新神经技术铺平了道路。DyNeuMo研究工具改进了当前的DBS系统（例如，美敦力Activa、St. Jude和波士顿科学DBS）提供自适应DBS（aDBS）、低功耗、连续刺激，改善症状抑制。最近的研究强调了刺激对睡眠结构的影响-例如睡眠、昼夜节律和刺激前核（ANT）治疗癫痫和PPN DBS治疗PD和MSA 9之间的相互关系。新兴的生物电子系统，可以提供长期和客观的测量癫痫发作活动的门诊癫痫患者，放大了越来越多的兴趣，癫痫发作预测，并提供验证的昼夜节律在人类。此外，最近的研究表明，癫痫发作的时间可能有一个相位偏好相对于multidien和昼夜节律的发作间期癫痫样活动在人类和癫痫大鼠。新的神经技术和创新的平台设计集成时间生物学可以提供洞察神经动力学，昼夜节律模式，随着时间的推移和脑节律波动-有助于刺激参数优化的临床框架。该项目的临床假设是，aDBS -实现应用时间生物学的昼夜节律响应和患者特异性治疗-比目前可用的DBS系统更有效。主要目的是验证神经刺激对患者睡眠结构的影响，并使用DyNeuMo开发闭环治疗。次要目的是探索使用不同生物标志物的反馈可用于开发DBS以提供更全面的症状控制的程度。在这个项目中，我将利用应用神经科学和仿生算法的翻译方法：1。使用超昼夜节律、昼夜节律和多昼夜节律作为前馈控制信号，完善并完全集成DyNeuMo研究系统的工具包。2.从植入物中获取和分析数据，并研究与睡眠相关的生理标记如何对刺激做出反应。3.在研究性试验中开发和测试昼夜节律响应刺激方案。

Brain stimulation therapies targeting the subthalamic nucleus (STN), ventrolateral thalamus (VL), and globus pallidus (GP) have been established as effective treatments of drug refractory symptoms of PD, ET and dystonia. DBS of the centromedian thalamic nucleus (CMN) is also emerging as a target for refractory epilepsy including severe childhood-onset epilepsy: Lennox-Gastaut syndrome (LGS). Although sleep dysfunction is a common co-morbidity of these neurological disorders and a key determinant of quality of life for patients and their families, DBS does not currently account for sleep in therapy optimization. The Picostim DyNeuMo Mk-2 introduces a combination of slow-adaptive circadian-based stimulation patterns with a fast-acting pathway for seizure management, paving the way for new neurotechnologies for applied chronobiology.The DyNeuMo research tool improves on current DBS systems (e.g. Medtronic Activa, St. Jude, and Boston Scientific DBS) providing adaptive DBS (aDBS), low power consumption, continuous stimulation, and improved symptom suppression. Recent studies have highlighted the impact of stimulation on sleep architecture - such as the interrelationship between sleep, circadian rhythms, and stimulation of the anterior nucleus (ANT) for epilepsy and PPN DBS for PD and MSA9. Emerging bioelectronic systems that can provide chronic and objective measurements of seizure activity in ambulatory epileptic patients, have amplified the growing interest in seizure forecasting and provided validation of circadian rhythms in humans. Moreover, recent studies have demonstrated that seizure timing may have a phase preference relative to multidien and circadian rhythms in interictal epileptiform activity in humans, and pharmacologically induced epileptic rats. Novel neurotechnologies and innovative platform design integrating chronobiology may provide insight into neural dynamics; circadian patterns, and brain rhythms fluctuation over time - contributing to a clinical framework for stimulation parameter optimization.The clinical hypothesis of this project is that aDBS - implementing applied chronobiology for circadian rhythm responsive and patient-specific therapies - is more effective than currently available DBS systems. The primary objective is to characterise the impact of neural stimulation on patients' sleep architecture and develop closed-loop therapies using the DyNeuMo. The secondary objective is to explore the extent of which feedback using varying biomarkers may be used to develop a DBS to afford a more comprehensive control of symptoms. In this project I will leverage a translational approach of applied neuroscience and biomimetic algorithms to:1. Refine and fully integrate the toolkit for the DyNeuMo research system using ultradian, circadian, and multidien rhythms as a feedforward control signal.2. Acquire and analyse data from the implant and characterise how physiological markers linked to sleep respond to stimulation.3. Develop and test circadian rhythm responsive stimulation protocols in investigational trials.