Functional Dissection of Neural Circuitry in Temporally Patterned Deep Brain Stimulation

脑深部刺激(DBS)是一种治疗各种神经和精神疾病的公认疗法。 包括帕金森氏症(PD)。丘脑底核(STN)和苍白球内侧核(GPI)是最常用的核团 DBS治疗帕金森病的解剖靶点及临床疗效。临床研究报告没有显著差异 这两个目标之间的有效治疗，尽管在GPI-DBS方面引起了更多的兴趣 对STN-DBS认知和行为副作用的日益关注。DBS的治疗作用 高度依赖于刺激参数。通过选择合适的刺激幅度和 脉冲持续时间、高频率的DBS可缓解PD运动症状。最近的研究表明， DBS的效应也强烈依赖于刺激脉冲之间的时间(时间模式)。 以较低的平均频率进行优化的时间刺激模式可以缓解运动缺陷并减少 不良副作用。尽管有很好的临床益处，但对暂时性的影响缺乏了解 DBS在神经和行为动力学上的模式限制了这一有希望的治疗策略的发展 以及星展目标的最佳选择。我们研究的目标是揭示 STN和GPI中DBS的特定时间模式和(I)STN和GPI相关回路中的神经活动 (Ii)帕金森病患者的运动功能。我们将结合计算设计、光遗传操作、电生理学 记录，和行为分析，以解剖和优化时间模式的STN-DBS和GPI-DBS在帕金森病啮齿动物模型中的治疗效果。我们的具体目标是：(1)设计和验证时间模式 光遗传STN-DBS和GPI-DBS治疗帕金森病运动症状的研究；(2)确定两者之间的关系 丘脑STN-丘脑或GPI-丘脑环路神经活动与运动功能的关系 图案化光遗传STN-DBS和GPI-DBS。这项拟议研究的结果将有助于揭示 DBS时间模式在帕金森病治疗中的功能作用。更好地理解如何在时间上 图案化DBS发挥其治疗作用将对最佳靶点选择和治疗做出重大贡献 开发新的治疗策略以提高DBS在帕金森病和其他疾病中的疗效和效率 神经和精神障碍。

Deep brain stimulation (DBS) is an established treatment for various neurological and psychiatric disorders including Parkinson’s disease (PD). Subthalamic nucleus (STN) and globus pallidus interna (GPi) are current anatomical targets and clinically effective for DBS in PD. Clinical studies reported no significant difference in effective treatment between these two targets, although additional interest has been prompted in GPi-DBS due to increased concerns about cognitive and behavioral side effects of STN-DBS. The therapeutic effects of DBS are highly dependent on stimulation parameters. With the selection of appropriate stimulation amplitude and pulse duration, high frequencies of DBS alleviate PD motor symptoms. Recent studies demonstrated that the effects of DBS were also strongly dependent on the timing between stimulation pulses (temporal pattern). Optimized temporal patterns of stimulation at a lower average frequency could relieve motor deficits and reduce adverse side effects. Despite the promising clinical benefits, the lack of understanding of the effects of temporal patterns of DBS on neuronal and behavioral dynamics limits the development of this promising treatment strategy as well as optimal selection of DBS targets. The goal of our research is to reveal the relationships between specific temporal patterns of DBS in STN and GPi and (i) neural activity in STN and GPI associated circuits and (ii) motor function in PD. We will combine computational design, optogenetic manipulation, electrophysiological recording, and behavioral assays to dissect and optimize the therapeutic effects of temporally patterned STN-DBS and GPi-DBS in a rodent model of PD. Our specific aims are to: (1) Design and validate temporal patterns of optogenetic STN-DBS and GPi-DBS to treat parkinsonian motor symptoms; (2) Determine the relationship between neural activity in the STN-thalamic or GPi-thalamic neural circuits and motor function during temporally patterned optogenetic STN-DBS and GPi-DBS. The results from this proposed research will shed light on the functional role of the temporal patterns of DBS in PD treatment. A better understanding of how temporally patterned DBS exerts its therapeutic effects will make a significant contribution to optimal target selection and the development of novel treatment strategies to improve the efficacy and efficiency of DBS in PD and other neurological and psychiatric disorders.