Functional Dissection of Neural Circuitry in Temporally Patterned Deep Brain Stimulation

时间模式深部脑刺激中神经回路的功能解剖

• 批准号: 10046820
• 负责人: Chunxiu Yu
• 金额: $ 46.37万
• 依托单位: MICHIGAN TECHNOLOGICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10046820
• 关键词: Adverse effects; Anatomy; Behavioral; Behavioral Assay; Biological Markers; Biomedical Research; Bradykinesia; Cells; Clinical; Clinical Research; Clinical effectiveness; Cognitive; Coupling; Deep Brain Stimulation; Development; Dissection; Electrophysiology (science); Environment; Forelimb; Foundations; Frequencies; Globus Pallidus; Goals; Lateral; Light; Mental disorders; Michigan; Modeling; Motor; Neurons; Neurosciences Research; Opsin; Parkinson Disease; Parkinsonian Disorders; Pathologic; Pattern; Performance; Phase; Physiologic pulse; Rattus; Reporting; Research; Research Infrastructure; Rodent Model; Role; Step Tests; Structure of subthalamic nucleus; Testing; Thalamic Nuclei; Thalamic structure; Therapeutic; Therapeutic Effect; Training; Universities; base; design; effective therapy; improved; innovation; insight; interest; motor deficit; motor symptom; nervous system disorder; neural circuit; neuromechanism; neuropsychiatric disorder; novel; optimal treatments; optogenetics; reduce symptoms; relating to nervous system; side effect; treatment strategy; undergraduate student

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.

深部脑刺激 (DBS) 是治疗各种神经和精神疾病的既定方法 包括帕金森病 (PD) 和丘脑底核 (STN) 和苍白球内核 (GPi)。 临床研究报告 DBS 在 PD 中的解剖目标和临床效果没有显着差异。 尽管人们对 GPi-DBS 产生了额外的兴趣，但由于这两个目标之间存在有效的治疗 增加了对 STN-DBS 认知和行为副作用的担忧 DBS 的治疗效果。 高度依赖于选择适当的刺激幅度和刺激参数。 脉冲持续时间、高频率 DBS 可缓解 PD 运动症状。 DBS 的效果也强烈依赖于刺激脉冲之间的时间（时间模式）。 以较低平均频率优化刺激的时间模式可以缓解运动缺陷并减少 尽管有希望的临床益处，但缺乏对时间效应的了解。 DBS 对神经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 我们研究的目标是揭示之间的关系。 STN 和 GPI 中 DBS 的特定时间模式以及 (i) STN 和 GPI 相关回路中的神经活动以及 (ii) PD 中的运动功能我们将结合计算设计、光遗传学操作、电生理学。 我们的具体目标是：（1）设计和验证时间模式。 光遗传学STN-DBS和GPi-DBS治疗帕金森运动症状（2）确定关系； STN-丘脑或 GPi-丘脑神经回路中的神经活动与暂时性运动功能之间的关系 图案化光遗传学 STN-DBS 和 GPi-DBS 这项研究的结果将为阐明 DBS 时间模式在 PD 治疗中的功能作用 更好地了解时间模式的作用。 模式化DBS发挥其治疗效果将为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 PD 和其他疾病中的疗效和效率 神经和精神疾病。