Functional dissection of therapeutic deep brain stimulation circuitry

 描述（由申请人提供）：脑深部电刺激（DBS）是一种成熟的神经外科治疗方法，用于治疗多种神经系统和精神疾病。在DBS中，电极被立体定向地引导到目标脑核，并且高频（~130 Hz）电刺激通过起搏器样皮下刺激装置递送。它最常用于治疗帕金森病（PD），通常是在其他药物治疗不足或运动障碍无法忍受的情况下。当应用于PD的对症治疗时，经常靶向丘脑底核（subthalamic nucleus，简称PD），通常导致几种标志性PD症状（包括静止性震颤和强直）的显著减少。然而，尽管有这些好处，许多帕金森病症状往往是难治性的，或可能恶化，在STN-DBS。椎间盘在解剖学上是异质的且纤维致密，因此在STN-DBS期间，即使电极放置准确，也很有可能募集脱靶回路。更好地了解DBS如何发挥其治疗效果将允许优化该程序，以提高治疗效果并减少不必要的副作用。该项目旨在解决三个关键的，但难以捉摸的问题：1）哪些神经回路代表了目标和脱靶神经元 DBS效应，2）选择性光遗传刺激脑干神经元是否改善帕金森病运动缺陷，3）治疗性STN-DBS所需的神经回路。为此，我们将使用最先进的功能性磁共振成像（fMRI），功能性连接性MRI（fcMRI），电生理学，光遗传学和行为评估，解剖治疗DBS电路在PD的动物模型，其中运动缺陷的改善是强烈的DBS依赖。我们的中心假设是：1）在靶和脱靶DBS表现出行为相关的、不同的脑活动和连接模式，2）对脑细胞体的高频光遗传学刺激模拟STN-DBS治疗并抑制病理性振荡活动，以及3）在治疗性DBS期间使用光遗传学抑制关键电路元件减弱运动缺陷挽救，从而允许有效的治疗DBS电路与DBS副作用分离。我们的团队在啮齿类动物的DBS功能磁共振成像研究方面拥有丰富的经验。我们的合作研究者也是理解和持续开发DBS，光遗传学和脑网络分析方法的领导者。总之，我们处于独特的地位，进行这一急需的研究路线。该项目将为DBS机制提供新的见解，并为各种神经和精神疾病建立新的DBS治疗靶点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.