Basal ganglia-thalamic signaling in parkinsonism and deep brain stimulation

描述(申请人提供)：帕金森氏病(PD)的运动体征与苍白球内核(GPI)神经元的放电活动异常有关，苍白内球是基底节(BG)的主要输出核。同样，丘脑底核(STN)的脑深部刺激(DBS)可能通过抑制GPI活性的异常来缓解帕金森症状。通过阐明异常的GPI活性及其在DBS下的变化影响帕金森症状的具体机制，将极大地加强提炼DBS和开发新的帕金森病治疗靶点的努力。该方案中的实验集中于这样一个观点，即GPI和BG受体丘脑之间的通信是帕金森病及其在DBS期间改善的病理生理学的中心因素。将检验两种假说：信息假说假设帕金森病患者GPI中独立信号的丢失降低了丘脑GPI受体神经元的信息承载能力，而另一种假说假设GPI中的某些放电异常(例如低频振荡或爆发)会引起丘脑的病理活动，从而扰乱下游(例如运动皮质)的功能。每个假说都预测，神经元活动的相关测量将与帕金森症状的严重程度和它们通过DBS纠正的程度同步变化。这些预测将通过一项创新的跨学科研究计划得到检验。在非人类灵长类动物中，将使用多电极单位和局部场电位记录来研究GPI和GPI受体丘脑中的神经元活动，在帕金森病缓慢、渐进诱导之前和期间，以及在STN的亚治疗和治疗性DBS期间。独立的信号将被量化为核内和核间的峰相关，以及神经元对不同肢体本体感觉刺激的反应的特异性。帕金森氏症的体征将通过测试运动启动(动作迟缓)、运动运动学(运动迟缓)和肌肉张力(僵直)的任务来测量。这些实验的数据将与拥有丰富计算经验的研究人员(Rubin和DoIron)合作进行分析，包括帕金森病BG动力学和神经网络中信息传播的工作。计算和理论方法将梳理出GPI输出变化改变丘脑功能的具体方式。实验结果将被纳入Hodgkin-Huxley类型的神经元模型以及平均场和信息论分析，以确定GPI活动如何影响丘脑相关性和信息编码，并预测正常、帕金森和帕金森DBS条件下丘脑放电特性变化的下游影响。这些研究的结果将促进我们对帕金森病病理生理学的理解，并测试DBS的潜在治疗机制，为未来的治疗干预提供目标，包括优化DBS。这些结果也可能与涉及BG-丘脑功能障碍的整个类别的临床疾病相关，也可能与DBS在其他神经系统疾病中的使用有关。 与公共健康相关：拟议中的实验测试了导致帕金森氏症体征和症状的中心思想-帕金森病基底节的异常输出扰乱了运动控制电路的正常功能。这些实验还测试了这样一种想法，即脑深部刺激是一种标准的、但鲜为人知的帕金森氏病手术疗法，它通过使相同大脑回路中的功能正常化来发挥作用。因此，这些实验的结果将促进我们对帕金森氏症症状的原因以及普通手术疗法如何提供临床益处的理解。这些实验的结果可能有助于DBS的优化，并提出新的治疗干预措施。

DESCRIPTION (provided by applicant): The motor signs of Parkinson's disease (PD) have been linked causally to abnormalities in the spiking activity of neurons in the globus pallidus internus (GPi), a major output nucleus of the basal ganglia (BG). Likewise, deep brain stimulation (DBS) of the subthalamic nucleus (STN) may provide relief from parkinsonian signs by suppressing abnormalities in GPi activity. Efforts to refine DBS and develop new therapeutic targets for PD will be greatly enhanced by elucidation of the specific mechanisms by which abnormal GPi activity and its alteration under DBS impact parkinsonian signs. The experiments in this proposal focus on the idea that communication between GPi and BG-recipient thalamus is a central factor in the pathophysiology of Parkinsonism and its amelioration during DBS. Two hypotheses will be tested: the information hypothesis posits that a loss of independent signaling in the parkinsonian GPi reduces the information-carrying capacity of GPi-recipient neurons in thalamus, while an alternate hypothesis posits that certain firing abnormalities in GPi (e.g., low frequency oscillations or bursts) induce pathologic activity in thalamus, which disrupts function downstream (e.g. in the motor cortices). Each hypothesis predicts that the associated measures of neuronal activity will covary with the severity of parkinsonian signs and their rectification via DBS. These predictions will be tested through an innovative interdisciplinary research plan. Neuronal activity in GPi and GPi-recipient thalamus will be studied using multi-electrode single-unit and local field potential recordings in non-human primates, before and during the slow, progressive induction of parkinsonism, and during sub-therapeutic and therapeutic DBS in the STN. Independent signaling will be quantified as spike correlations, within and between nuclei, and as the specificity of neuronal responses to proprioceptive stimulation of different limbs. Parkinsonian signs will be measured using tasks that assay movement initiation (akinesia), movement kinematics (bradykinesia), and muscle tone (rigidity). Data from these experiments will be analyzed in collaboration with investigators (Rubin and Doiron) who have substantial computational experience, including work on parkinsonian BG dynamics and the propagation of information in neuronal networks. Computational and theoretical methods will tease apart specific ways that changes in GPi output alter thalamic function. Empirical results will be incorporated into Hodgkin-Huxley type neuronal models and mean field and information theoretic analyses to determine how GPi activity influences thalamic correlations and information coding, and to predict downstream effects of changes in thalamic firing properties across normal, parkinsonian and parkinsonian+DBS conditions. Results from these studies will advance our understanding of parkinsonian pathophysiology and test potential therapeutic mechanisms of DBS, suggesting targets for future therapeutic interventions including optimization of DBS. The results may also be relevant to the whole class of clinical disorders that involve BG-thalamic dysfunction as well as to the use of DBS for other neurologic conditions. PUBLIC HEALTH RELEVANCE: The proposed experiments test central ideas about what causes the signs and symptoms of Parkinson's disease - that abnormal output from the parkinsonian basal ganglia disrupts the normal functions of motor control circuits. The experiments also test the idea that deep brain stimulation, a standard yet poorly understood surgical therapy for Parkinson's disease, works by normalizing function in the same brain circuits. Thus, results from these experiments will advance our understanding of what causes the symptoms of Parkinson's disease and of how a common surgical therapy provides clinical benefit. Results from these experiments may facilitate the optimization of DBS and suggest novel therapeutic interventions.