Progression and differential control of postural and kinetic tremor with deep brain stimulation

摘要 特发性震颤（ET），尽管是最常见的运动障碍，影响4%的40岁以上的成年人， 在其发病机制、神经生理学、临床分类和 根据患者具体情况优化治疗。对于25-55%的药物难治性患者， 症状已成为功能限制，建议手术治疗，最常见的是深 脑刺激（DBS）。然而，尽管DBS电极导线技术最近取得了进展， 尽管是最佳靶点，但副作用频繁发生，高达73%的患者随着时间的推移而失去益处。作为 因此，有一个明确的需要细化和深化理解优化治疗ET。这 该项目将利用一项正在进行的对诊断为ET的人类患者的前瞻性临床研究， 植入定向DBS电极导线，集成高场磁共振成像，患者- DBS的特定通路激活建模、定量传感器和全面的 肌电图测量，以进一步了解背后的神经和肌肉机制 震颤控制和进展。具体来说，目标1将确定小脑-丘脑-皮质通路 参与定向DBS电极导线的动力学和姿势性震颤控制，通路激活优化 算法和定量传感器。目标2将探讨识别震颤控制的潜在机制 从周围肌肉末端用全身肌电图。最后，目标3将确定如何 对刺激的耐受性、疾病进展或电极导线放置导致震颤中的长期DBS失败 控制虽然DBS可以改善临床震颤评分，但医生仍然难以捕获 在短期内抑制震颤，并在长期内维持治疗益处。了解路径 通过基于模型的患者特定编程方法导致震颤和副作用， DBS治疗对患者症状的改善和更一致的控制。

Abstract Essential Tremor (ET), despite being the most common movement disorder affecting 4% of adults over age 40, remains relatively understudied in terms of its pathogenesis, neurophysiology, clinical classification, and optimization of treatments on a patient-specific basis. For the 25-55% of medication-refractory patients whose symptoms have become functionally limiting, surgical management is recommended, most commonly with deep brain stimulation (DBS). However, despite recent advances in DBS lead technology, controversy exists over the optimal target, side effects occur frequently, and up to 73% of patients experience loss of benefit over time. As a result, there is a clear need for refinement and deepened understanding of optimizing treatments for ET. This project will leverage an ongoing prospective clinical study in human patients diagnosed with ET and implanted with directional DBS leads, integrating high-field magnetic resonance imaging, patient- specific pathway activation modeling of DBS, quantitative sensors, and comprehensive electromyography measurements to further understand the neural and muscular mechanisms behind tremor control and progression. Specifically, Aim 1 will identify the cerebello-thalamo-cortical pathways involved in kinetic and postural tremor control with directional DBS leads, pathway activation optimization algorithms, and quantitative sensors. Aim 2 will approach identifying the underlying mechanisms of tremor control from the peripheral muscular end using whole-body electromyography. Finally, Aim 3 will determine how tolerance to stimulation, disease progression, or lead placement contribute to long-term DBS failure in tremor control. While DBS can result in improvement of clinical tremor scores, physicians still have trouble capturing action tremor in the short-term and maintaining therapeutic benefit in the long-term. Understanding the pathways contributing to tremor and to side effects via a model-based, patient-specific programming approach would allow for improved and more consistent control of patients’ symptoms with DBS therapy.