Chronic physiologic and behavior changes induced by novel STN DBS patterns for PD

 描述（由申请人提供）：脑深部电刺激（DBS）彻底改变了帕金森病（PD）的治疗，当使用高频等时电脉冲长期刺激苍白球丘脑皮质回路的关键节点时，观察到许多主要运动体征的治疗益处。近三十年后，这些刺激参数基本上没有变化，尽管我们对伴随帕金森病运动体征发展和进展的潜在神经活动变化的理解有了重大进展。最近的几个理论表明，在多巴胺耗尽的苍白球丘脑皮质的“运动”电路的同步振荡的发展改变基底神经节和运动皮质结构之间的功能相互作用，并与运动体征的出现和进展。根据这些理论，已经提出了新的刺激范例，其不仅可以更有效地减轻这些病理变化，而且还可以诱导比刺激递送更持久的治疗益处。迄今为止，只有有限数量的研究试图解决这些新范式的治疗潜力和机制。目前的建议将评估和表征一个这样的范例，协调复位（CR）DBS开发的塔斯，其中涉及的应用程序的随机脉冲串的刺激在空间上不同的区域的丘脑底核（ESTA），以deserminize病理性神经活动的苍白球丘脑皮层电路。使用已建立的PD临床前模型，我们将确定CR DBS在DBS期间和停止后对个体帕金森病运动体征的影响的幅度和时间过程，并将其与传统DBS期间观察到的变化进行比较。此外，我们将使用慢性记录阵列植入皮层，丘脑和基底神经节，以评估的变化同步振荡神经活动发生在整个苍白球丘脑皮层电路符合改善个人帕金森氏症的运动体征。这项研究将提供深入了解CR和传统DBS的治疗潜力和机制，同时提高我们对苍白球丘脑皮质回路关键节点内和跨节点神经活动与帕金森病运动体征表现之间关系的理解。

 DESCRIPTION (provided by applicant): Deep brain stimulation (DBS) has revolutionized the treatment of Parkinson's disease (PD), with therapeutic benefit observed for many of its cardinal motor signs when key nodal points of the pallidothalamocortical circuit are chronically stimulated using high-frequency, isochronal electrical pulses. Almost three decades later, these stimulation parameters have largely gone unchanged despite significant advances in our understanding of the changes in underlying neural activity that accompany the development and progression of parkinsonian motor signs. Several recent theories suggest that the development of synchronized oscillations within the dopamine- depleted pallidothalamocortical 'motor' circuit alter functional interactions between the basal ganglia and motor cortical structures, and are associated with the emergence and progression of motor signs. In line with these theories, novel stimulation paradigms have been proposed that may not only be more effective at mitigating these pathological changes but also induce therapeutic benefit that outlasts stimulus delivery. To date, only a limited number of studies have attempted to address the therapeutic potential and mechanisms of these novel paradigms. The current proposal will evaluate and characterize one such paradigm, coordinated reset (CR) DBS developed by Tass, which involves the application of randomized bursts of stimulation across spatially distinct regions of the subthalamic nucleus (STN) in order to desynchronize pathological neural activity across the pallidothalamocortical circuit. Using an established preclinical model of PD, we will determine the magnitude and time course of CR DBS' effects on individual parkinsonian motor signs, both during DBS and following its discontinuation, and compare those to changes observed during traditional STN DBS. In addition, we will use chronic recording arrays implanted in the cortex, thalamus and basal ganglia to assess the changes synchronized oscillatory neural activity that occur across the pallidothalamocortical circuit coincident with improvements in individual parkinsonian motor signs. This study will provide insight into the therapeutic potential and mechanisms of CR and traditional DBS while improving our understanding of the relationship between neural activity within and across key nodal points of the pallidothalamocortical circuit and the manifestation of parkinsonian motor signs.