DBS of the pedunculopontine nucleus in Parkinsonian primate

描述（由申请人提供）：本提案涉及挑战领域15：转化科学和特定挑战主题：神经系统疾病新治疗方法的“概念验证”证明：15-NS-103。帕金森病（Parkinson's disease，PD）是一种慢性进行性神经退行性疾病，其特征是位于黑质、峡部（pars dielectric neurons，SNc）的多巴胺能神经元变性。在丘脑底核（subthalamic nucleus，DBS）和苍白球内侧部（globus pallidus pars internus，GPi）中的慢性脑深部刺激（DBS）已被证明是治疗这种疾病的有效疗法，其在震颤、运动迟缓和僵硬方面产生实质性改善，但在改善步态和姿势稳定性方面不太有效。尽管最近有一些关于脚桥核（PPN）作为治疗PD患者步态和平衡问题的刺激靶点的探索，但迄今为止的数据非常有限，且极具争议。争议部分源于与先前在非人灵长类动物（NHP）以及患有PD的人类中进行的PPN刺激研究相关的局限性。很少有研究系统地评价PPN刺激对PD运动症状的影响，并通过术后成像或人体尸检研究或灵长类动物研究的组织学确认确认PPN内的电极导线位置。此外，迄今为止进行的灵长类动物研究尚未定量评估PPN刺激对步态的影响，而人类研究的数据则相互矛盾。这些限制使得难以确定观察到的效果或其缺乏是否确实是由于PPN中的刺激。尽管PPN被认为是改善特发性PD步态和平衡的潜在有效靶点，但这些局限性导致一些人质疑其疗效，而其他人则急于在建立生理指南以识别PPN并允许准确放置电极导线之前将电极导线植入患者体内。为了解决这些局限性，我们建议：1）在帕金森病灵长类动物模型中，在MPTP给药之前和之后，表征PPN中神经元活动的电生理学特征;以及2）当动物在跑步机上轻快地走动时，在PD的MPTP NHP模型中植入PPN DBS并随后使用客观的定量测量来评估PPN DBS对步态的影响。评估后将对电极导线位置进行组织学确认。本研究还将评估PPN DBS对PD的其他运动体征（包括运动迟缓/运动不能和僵硬）的影响。我们假设，PPN神经元将表现出降低的平均放电率和增加的爆发在PD状态继发于从苍白球（GPi）的内部段的PPN的抑制输出增加。我们还假设PPN DBS将与运动行为的频率依赖性改善相关，具有低频刺激模式（即，5 - 50 Hz）改善步态，运动不能和僵硬，而更高的频率会加剧它们。 公共卫生相关性：本提案涉及挑战领域15：转化科学和特定挑战主题：神经系统疾病新治疗方法的“概念验证”演示：15-NS-103。本研究的目的是确定是否可以使用某些脑区的电刺激来改善与帕金森病（PD）相关的步态和平衡不稳定性。PD动物模型将用于研究脑干脚桥核（PPN）的脑深部电刺激（DBS）对步态功能障碍的影响。许多初步研究认为PPN是改善PD步态和平衡的潜在有效靶点。然而，这些研究有一些局限性，导致一些人质疑其疗效，而其他人则急于在建立足够的指南以准确定位该靶点之前刺激患者的PPN。为了解决这些局限性，本研究将描述PD发生后PPN中神经元活动的变化，帮助确定可用于识别PPN以进行电极导线放置的生理指南，并定量描述PPN DBS对PD运动症状的影响。本研究将确定PPN DBS是否可以有效治疗这些运动体征，并为未来PPN DBS治疗PD症状的临床试验的开发提供基于合理性的方法。作为步态功能障碍的治疗，PPN DBS的效用可能超出PD人群，扩展到其他运动障碍，包括进行性核上性麻痹和多系统萎缩。

DESCRIPTION (provided by applicant): This proposal addresses Challenge Area 15: Translational Science, and Specific Challenge Topic: Demonstration of "proof-of-concept" for a new therapeutic approach in a neurological disease: 15-NS-103. Parkinson's disease (PD) is a chronic, progressive neurodegenerative disorder characterized by degeneration of dopaminergic neurons located within the substantia nigra, pars compacta (SNc). Chronic deep brain stimulation (DBS) in the subthalamic nucleus (STN) and the globus pallidus pars internus (GPi) has proven to be an effective therapy for the treatment of this disorder producing substantial improvements in tremor, bradykinesia, and rigidity, but has been less effective on improving gait and postural stability. Although there has been some recent exploration of the pedunculopontine nucleus (PPN) as a target for stimulation for the treatment of gait and balance problems in PD patients, the data are thus far extremely limited and highly controversial. The controversy stems in part from limitations associated with previous studies of PPN stimulation in non-human primates (NHP) as well as humans with PD. Few studies have systematically evaluated the effect of PPN stimulation on PD motor symptoms with confirmation of lead location within the PPN, either via postoperative imaging or postmortem studies in humans or histological confirmation in primate studies. Moreover, the primate studies performed to date have not quantitatively evaluated the effect of PPN stimulation on gait, while the data from human studies have been contradictory. These limitations make it difficult to determine whether the observed effect, or lack thereof, are indeed due to stimulation in the PPN. Although the PPN is considered a potentially effective target for the improvement of gait and balance in idiopathic PD, these limitations have led some to question its efficacy, while others rush to implant leads in patients before establishing physiological guidelines to identify the PPN and allow for accurate lead placement. To address these limitations we propose to: 1) characterize the electrophysiological features of neuronal activity in the PPN before and after MPTP administration in the parkinsonian primate model; and 2) implant and subsequently assess, using objective, quantitative measures, the effect of PPN DBS on gait in the MPTP NHP model of PD as the animal ambulates briskly on a treadmill. Histological confirmation of lead location will be performed following the assessments. The effect of PPN DBS on other motor signs of PD including bradykinesia/akinesia and rigidity will also be assessed in this study. We hypothesize that PPN neurons will exhibit a decreased mean discharge rate and increased bursting in the PD state secondary to increased inhibitory output from the internal segment of the globus pallidus (GPi) to the PPN. We also hypothesize that PPN DBS will be associated with a frequency dependent improvement in motor behavior, with low frequency stimulation patterns (i.e., 5 - 50 Hz) improving gait, akinesia and rigidity, while higher frequencies will exacerbate them. PUBLIC HEALTH RELEVANCE: This proposal addresses Challenge Area 15: Translational Science, and Specific Challenge Topic: Demonstration of "proof-of-concept" for a new therapeutic approach in a neurological disease: 15-NS-103. The goal of this study is to determine whether electrical stimulation of certain brain regions can be used to improve the gait and balance instabilities associated with Parkinson's disease (PD). An animal model of PD will be used to study the effect of deep brain stimulation (DBS) of the brainstem pedunculopontine nucleus (PPN) on gait dysfunction. The PPN is considered a potentially effective target for the improvement of gait and balance in PD by a number of preliminary studies. However, these studies have several limitations, leading some to question its efficacy, while others rush to stimulate PPN in patients before sufficient guidelines are established for accurate localization of this target. To addresses these limitations, this study will characterize the changes in neuronal activity that take place in the PPN following development of PD, help determine physiological guidelines that can be used to identify the PPN for lead placement, and quantitatively characterize the effect of PPN DBS on PD motor symptoms. This study will determine whether or not PPN DBS can be effective in treating these motor signs and provide a rationale-based approach to the development of future clinical trials of PPN DBS for the treatment of PD symptoms. As a treatment of gait dysfunction, the utility of PPN DBS may extend beyond the PD population to other movement disorders, including progressive supranuclear palsy and multiple systems atrophy.