Functional Dissection of Neural Circuitry in Temporally Patterned Deep Brain Stimulation

脑深部电刺激（DBS）是一种治疗各种神经和精神疾病的既定疗法 包括帕金森病（PD）。丘脑底核（Subthalamic nucleus，简称FDN）和内侧苍白球（Globus pallidus interna，简称GPi）是目前研究的热点。 解剖学靶点和临床上有效的PD DBS。临床研究报告， 这两个目标之间的有效治疗，尽管由于 对STN-DBS认知和行为副作用的担忧增加。DBS的治疗效果 高度依赖于刺激参数。通过选择适当的刺激幅度和 脉冲持续时间、高频率DBS缓解PD运动症状。最近的研究表明， DBS的效果也强烈地依赖于刺激脉冲之间的定时（时间模式）。 在较低的平均频率下优化的刺激时间模式可以缓解运动缺陷， 不良副作用尽管有很好的临床效益，但对颞叶癫痫的影响缺乏了解， DBS对神经元和行为动力学的影响模式限制了这种有前途的治疗策略的发展 以及DBS目标的最佳选择。我们研究的目的是揭示 DBS的特定时间模式在脑电刺激和GPi和（i）神经活动在脑电刺激和GPI相关的电路， (ii)PD的运动功能我们将结合联合收割机计算设计，光遗传学操作，电生理学 记录和行为测定来剖析和优化时间模式化STN-DBS和GPi-DBS在PD啮齿动物模型中的治疗效果。我们的具体目标是：（1）设计和验证时态模式 光遗传STN-DBS和GPi-DBS治疗帕金森病运动症状的关系;（2）确定 STN-丘脑或GPi-丘脑神经回路中的神经活动与运动功能之间的关系， 图案化光遗传STN-DBS和GPi-DBS。这项拟议研究的结果将阐明 DBS的时间模式在PD治疗中的功能作用。更好地理解时间上 模式化DBS发挥其治疗效果将对最佳靶点选择做出重大贡献， 开发新的治疗策略，以提高DBS在PD和其他疾病中的疗效和效率， 神经和精神疾病。

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.