Functional dissection of therapeutic deep brain stimulation circuitry

 描述(由申请人提供)：深部脑刺激(DBS)是一种成熟的神经外科治疗方法，适用于多种神经和精神疾病。在DBS中，电极被立体定向引导到目标大脑核团，高频(~130赫兹)电刺激通过类似起搏器的皮下刺激装置提供。它最常用于帕金森氏病(PD)的治疗，通常是在其他药物治疗效果不佳或运动障碍变得无法忍受的情况下。当应用于帕金森病的对症治疗时，丘脑底核(STN)经常成为靶点，通常导致几种标志性帕金森病症状的显著减轻，包括静止性震颤和僵硬。然而，尽管有这些好处，许多帕金森症状在STN-DBS期间往往难以治愈或可能恶化。STN在解剖学上是异质性的，而且纤维致密，因此在STN-DBS过程中，即使电极放置准确，也有很高的可能性招募非靶点电路。更好地了解DBS是如何发挥其治疗效果的，将有助于优化这一程序，以提高治疗结果并减少不必要的副作用。拟议的项目旨在解决三个关键而又难以捉摸的问题：1)哪些神经回路代表目标上和目标外的STN DBS效应，2)选择性光遗传刺激STN神经元是否能改善帕金森病患者的运动缺陷，以及3)治疗STN-DBS需要哪些神经回路。为此，我们将使用最先进的功能磁共振成像(FMRI)、功能连接磁共振(FcMRI)、电生理学、光遗传学和行为评估来解剖帕金森病动物模型的治疗DBS电路，在该动物模型中，运动缺陷的改善强烈依赖于DBS。我们的中心假设是：1)靶上和靶外DBS表现出与行为相关的、不同的大脑活动和连接模式，2)对STN细胞体的高频光遗传刺激模仿STN-DBS治疗并抑制病理振荡活动，3)在治疗性DBS期间利用光遗传学抑制关键电路元件以减少运动障碍的挽救，从而使有效的治疗性DBS电路与DBS副作用分离。我们团队在啮齿动物的DBS-fMRI研究方面拥有丰富的经验。我们的合作研究人员也是了解和持续开发DBS、光遗传学和脑网络分析方法的领导者。我们共同处于开展这一急需的研究领域的独特地位。该项目将提供对DBS机制的新见解，并为为各种神经和精神疾病建立新的DBS治疗目标和刺激范例奠定基础。

 DESCRIPTION (provided by applicant): Deep brain stimulation (DBS) is a well-established neurosurgical therapy for multiple neurological and psychiatric disorders. In DBS, an electrode is stereotactically guided to a target cerebral nucleus and high frequency (~130 Hz) electrical stimulation is delivered through a pacemaker-like subcutaneous stimulating device. It is most commonly employed in the treatment of Parkinson's disease (PD), generally in cases where other medical therapies have become inadequate or dyskinesias have become intolerable. When applied for the symptomatic treatment of PD, the subthalamic nucleus (STN) is frequently targeted, often resulting in a marked reduction in several hallmark PD symptoms, including resting tremor and rigidity. However, despite these benefits, many parkinsonian symptoms are frequently refractory to, or may worsen during STN-DBS. The STN is both anatomically heterogeneous and fiber-dense, and thus there is a high likelihood of recruitment of off-target circuits during STN-DBS, even with accurate electrode placements. A better understanding of how DBS exerts its therapeutic effects will allow optimization of this procedure to enhance therapeutic outcomes and reduce unwanted side-effects. The proposed project aims to address three critical, yet elusive questions of: 1) which neural circuits represent on- and off-target STN DBS effects, 2) whether selective optogenetic stimulation of STN neurons ameliorate parkinsonian motor deficits, and 3) which neural circuits are necessary for therapeutic STN-DBS. To these ends, we will use state-of-the-art functional magnetic resonance imaging (fMRI), functional connectivity MRI (fcMRI), electrophysiology, optogenetics, and behavioral assessment to dissect therapeutic DBS circuitry in an animal model of PD, in which the amelioration of motor deficits are strongly DBS-dependent. Our central hypotheses are that: 1) on- and off-target DBS exhibit behavior- correlated, distinct brain activity and connectivity patterns, 2) high frequency optogenetic stimulation of the STN cell bodies mimics STN-DBS therapy and suppresses pathological oscillatory activity, and 3) suppressing pivotal circuit elements using optogenetics during therapeutic DBS attenuates motor deficit rescue, and thus allowing effective therapeutic DBS circuits to be separated from DBS side effects. Our group has extensive experience in DBS-fMRI studies in rodents. Our co-investigators are also leaders in understanding and continuing development of DBS, optogenetics, and brain network analysis approaches. Together, we are in the unique position to undertake this much-needed line of research. This project will provide novel insights into DBS mechanisms, and lay a foundation to establish new DBS treatment targets and stimulus paradigms for a wide variety of neurological and psychiatric disorders.