Basal ganglia-thalamic signaling in parkinsonism and deep brain stimulation

帕金森病和深部脑刺激中的基底神经节-丘脑信号传导

• 批准号: 8233292
• 负责人: ROBERT STERLING TURNER
• 金额: $ 36.46万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8233292
• 关键词: Affect; Basal Ganglia; Biological Assay; Bradykinesia; Brain; Carrying Capacities; Cell Communication; Cell Nucleus; Clinical; Code; Collaborations; Communication; Computer Simulation; Data; Deep Brain Stimulation; Development; Disease; Dopamine; Dystonia; Electrodes; Frequencies; Functional disorder; Future; Gilles de la Tourette syndrome; Globus Pallidus; Hodgkin Disease; Impairment; Interdisciplinary Study; Intoxication; Knowledge; Limb structure; Link; Measures; Methods; Modeling; Monkeys; Motor; Motor Cortex; Movement; Muscle Tonus; Neurologic; Neurons; Neurotoxins; Operative Surgical Procedures; Output; Parkinson Disease; Parkinsonian Disorders; Pathologic; Pattern; Principal Investigator; Property; Research Personnel; Role; Sensory; Severities; Signal Transduction; Signs and Symptoms; Specificity; Structure of subthalamic nucleus; Symptoms; Testing; Thalamic structure; Theoretical Studies; Theoretical model; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Time; Work; base; experience; improved; innovation; kinematics; motor control; new therapeutic target; nonhuman primate; novel therapeutic intervention; public health relevance; research study; response; restoration; standard measure; tool; transmission process

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.

描述（由申请人提供）：帕金森病（PD）的运动体征与苍白球内（GPi）（基底神经节（BG）的主要输出核）中神经元的尖峰活动异常存在因果关系。同样地，丘脑底核（subthalamic nucleus，简称DBS）的脑深部电刺激（deep brain stimulation，简称DBS）可以通过抑制GPi活性的异常来缓解帕金森病症状。通过阐明异常GPi活性及其在DBS下的改变影响帕金森病体征的具体机制，将大大加强改进DBS和开发PD新治疗靶点的努力。在这个建议中的实验集中在这样的想法，即GPi和BG受体丘脑之间的通信是帕金森氏症的病理生理学及其改善DBS期间的一个中心因素。将检验两个假设：信息假说假定帕金森病GPi中独立信号传导的丧失降低了丘脑中GPi受体神经元的信息携带能力，而另一种假说假定GPi中的某些放电异常（例如，低频振荡或爆发）诱导丘脑中的病理活动，其破坏下游（例如，在运动皮质中）的功能。每一种假设都预测，神经元活动的相关测量将与帕金森病体征的严重程度及其通过DBS的矫正相关。这些预测将通过创新的跨学科研究计划进行测试。在缓慢、进行性诱导帕金森症之前和期间，以及在亚治疗性和治疗性DBS期间，将使用非人灵长类动物的多电极单单位和局部场电位记录研究GPi和GPi受体丘脑中的神经元活动。独立的信号传导将被量化为核内和核之间的尖峰相关性，以及对不同肢体的本体感受刺激的神经元反应的特异性。将使用测定运动起始（运动不能）、运动学（运动迟缓）和肌张力（僵硬）的任务测量帕金森病体征。来自这些实验的数据将与具有大量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动力学和神经元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。经验结果将被纳入霍奇金-赫胥黎型神经元模型和平均场和信息理论分析，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，帕金森病和帕金森病+DBS条件下丘脑放电特性变化的下游效应。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（包括DBS的优化）提出目标。该结果也可能与涉及BG-丘脑功能障碍的整个临床疾病类别以及DBS用于其他神经系统疾病有关。 公共卫生关系：拟议中的实验测试了关于帕金森病症状和体征的中心思想-帕金森基底神经节的异常输出破坏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，即深度脑刺激，一种标准但知之甚少的帕金森病手术疗法，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病症状的原因以及常见手术治疗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。