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

针对丘脑下核（STN）、丘脑腹外侧核（VL）和苍白球（GP）的脑刺激疗法已被确立为治疗PD、ET和肌张力障碍等药物难治性症状的有效方法。丘脑中位核（CMN）的DBS也正在成为难治性癫痫（包括严重儿童期癫痫：Lennox-Gastaut综合征（LGS））的靶点。虽然睡眠功能障碍是这些神经系统疾病的常见合并症，也是患者及其家庭生活质量的关键决定因素，但DBS目前并未在治疗优化中考虑睡眠。Picostim DyNeuMo Mk-2将缓慢适应的基于昼夜节律的刺激模式与快速作用的癫痫发作管理途径相结合，为应用时间生物学的新神经技术铺平了道路。DyNeuMo研究工具改进了现有的DBS系统（例如美敦力Activa、St. Jude和Boston Scientific DBS），提供自适应DBS （aDBS）、低功耗、持续刺激和改善的症状抑制。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、刺激癫痫的前核（ANT）和PD和MSA9的PPN DBS之间的相互关系。新兴的生物电子系统可以提供门诊癫痫患者癫痫发作活动的慢性和客观测量，扩大了人们对癫痫发作预测的兴趣，并提供了人类昼夜节律的验证。此外，最近的研究表明，在人类和药物诱导的癫痫大鼠中，癫痫发作时间可能相对于多期和昼夜节律具有相位偏好。新颖的神经技术和整合时间生物学的创新平台设计可能为神经动力学提供洞见；昼夜节律模式和脑节律随时间波动-有助于刺激参数优化的临床框架。该项目的临床假设是，aDBS -实施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。主要目标是描述神经刺激对患者睡眠结构的影响，并使用DyNeuMo开发闭环疗法。次要目标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转化方法：1。完善并充分整合DyNeuMo研究系统的工具包，使用超昼夜节律和多昼夜节律作为前馈控制信号。获取并分析来自植入物的数据，并描述与睡眠相关的生理标记如何对刺激做出反应。在研究性试验中开发和测试昼夜节律反应性刺激方案。

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.