Basal ganglia-thalamic signaling in parkinsonism and deep brain stimulation

描述（由申请人提供）：帕金森病（PD）的运动体征与基底神经节（BG）的主要输出核——内苍白球（GPi）神经元的尖峰活动异常有因果关系。同样，丘脑底核（STN）的深部脑刺激（DBS）可能通过抑制GPi活性异常来缓解帕金森症状。通过阐明DBS下异常GPi活性及其改变影响帕金森症状的具体机制，将大大促进DBS的完善和PD治疗新靶点的开发。本实验的重点是GPi和bg受体丘脑之间的通信是帕金森病病理生理及其在DBS期间改善的核心因素。两种假设将被测试：信息假设假定帕金森GPi中独立信号的丧失降低了丘脑中GPi受体神经元的信息承载能力，而另一种假设假定GPi中的某些放电异常（例如，低频振荡或爆发）诱导丘脑的病理活动，从而破坏下游（例如在运动皮质中）的功能。每个假设都预测神经元活动的相关测量将随帕金森症状的严重程度及其通过DBS的纠正而变化。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，GPi和GPi受体的神经元活动将使用多电极单单元和局部场电位记录，在缓慢的进行性帕金森诱导之前和期间，以及在STN的亚治疗和治疗性DBS期间进行研究。独立信号将被量化为核内和核间的峰值相关性，以及不同肢体本体感觉刺激下神经元反应的特异性。帕金森症状将通过检测运动起始（运动迟缓）、运动运动学（运动迟缓）和肌肉张力（僵硬）的任务来测量。来自这些实验的数据将与具有丰富计算经验的研究人员（Rubin和Doiron）合作分析，包括在帕金森BG动力学和神经网络中信息传播方面的工作。计算和理论方法将梳理出GPi输出改变丘脑功能的具体方式。实验结果将纳入霍奇金-赫胥黎型神经元模型、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，并预测在正常、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。这一结果也可能与包括脑丘脑功能障碍在内的所有临床疾病有关，也可能与在其他神经系统疾病中使用DBS有关。

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.