丘脑底核电刺激治疗帕金森病，不仅能显著改善其震颤、肌强直及运动迟缓等症状，还能减少服用药物引起的运动波动，延长开期时间，已经成为帕金森病治疗的首选外科疗法。然而对冻结步态等中线症状却改善有限，甚至会使其恶化。此外，脑起搏器长期被美国垄断，使该疗法的自主创新成为无源之水。在此背景下，本文通过临床试验和理论创新，验证了清华大学自主研发的可充电脑起搏器治疗帕金森病，尤其是冻结步态的安全性和优效性，为国家高端医疗器械的自主创新工作提供了一个可以借鉴的模式。首先，本文针对清华大学自主研发的脑起搏器，设计了科学合理的随机双盲对照临床试验方案。随后在国内筛选了3家该领域的临床中心，并且招募完成了53例原发性帕金森患者，通过临床试验，充分验证了试验产品的安全性和有效性。此外，由于神经调控类医疗器械的体外无线充电技术在国内尚属首次临床应用，因此在试验过程中也专门对此进行了研究，并给出了具体可执行的操作建议，为后续的临床应用推广打下了基础。作为脑深部电刺激治疗帕金森病的靶点核团，丘脑底核的电生理特征对于机制探索和疗法的进一步优化都至关重要。本文通过对术中微电极记录到的信号进行处理、分析，得到帕金森患者丘脑底核的放电类型、放电频率以及核团长度等电生理特征。而后与相应的临床症状进行相关分析，发现了放电频率与震颤和姿势步态异常的关联，为新疗法的提出提供参考。其后，与理论相结合，首次提出了丘脑底核变频刺激治疗帕金森病冻结步态的新疗法，并针对性地设计了临床试验方案。通过入选28例经过长期高频刺激，仍不能有效改善冻结步态的受试者，在其药物关期状态下研究了不同刺激模式对起立行走能力、运动功能以及相关调查问卷的影响。6个月的随访结果证明了新疗法的安全性和稳定性，而且相对恒频刺激能够更好的改善冻结步态和运动症状。最后，采用事件相关电位技术，系统研究了丘脑底核不同刺激模式对帕金森病患者注意力，尤其是新异刺激加工能力的影响。结合冻结步态发生的机制，提出了不同刺激频率，尤其是变频刺激对其影响的可能机制，为疗法的进一步优化提供了支撑。
Deep brain stimulation can effectively improve motor functions in Parkinson's disease such as tremor, rigidity and bradykinesia. It can also extend the medication on time and reduce motor fluctuations, and is a standard surgical treatment for Parkinson's disease patients. However, the axial symptoms that appear in advanced stages respond poorly to treatment and can even worsen after stimulation. As a typical symptom, freezing of gait is a high risk factor for disability, which has drawn great attention in this field. This dissertation successfully proves the clinical safety and superiority of a Chinese domestic brain pacemaker in the treatment of Parkinson's disease, especially freezing of gait. Our work provides a model for the research and development of medical devices. A randomized, double-blind and multi-center clinical trial was designed for Tsinghua University's developed brain pacemaker. Within this study, 53 Parkinson’s patients at 3 centers were enrolled to investigate the safety and effectiveness of this new device. Additionally, since rechargeable pacemakers have been introduced for clinical application in China for the first time, additional work was done to evaluate the charging process. Thus, preliminary understanding and standard operation procedures were gained for future research. The subthalamic nucleus is a common target in the treatment of Parkinson's disease with electrical stimulation of the brain. Its electrophysiological characteristics are very important for exploration and optimization of deep brain stimulation therapy. The electrophysiological characteristics of the subthalamic nucleus, such as the discharge type, firing frequency and the length of the nucleus were obtained by analyzing the signal collected during intraoperative microelectrode recording. Thus, the relationship between the electrical signal and corresponding clinical symptoms were analyzed, which showed that firing frequency of neurons within the subthalamic nucleus were highly related to tremor and gait abnormalities in Parkinson’s disease patients.Therefore, we proposed for the first time a new variable frequency stimulation pattern for the treatment of freezing of gait in Parkinson's disease. According to clinical trial protocol, 28 patients with stimulation resistant freezing of gait were enrolled after 6 months of parameter optimization. The effects of different stimulation patterns on gait and motor symptoms off medication were studied. Compared with traditional high frequency stimulation, both gait and motor function were significantly improved after variable frequency stimulation. Furthermore, the safety and stability of this novel technique were proved after six-months follow-up.Finally, event-related potentials were used to study the effects of different stimulus patterns on cognition, specifically attention, in patients with Parkinson's disease. Here, a pathophysiological mechanism of freezing of gait is proposed, supporting the use of different stimulation modes, especially multiple frequency stimulation, which will be studied in our future investigations.
