Functional dissection of therapeutic deep brain stimulation circuitry

治疗性脑深部刺激电路的功能剖析

• 批准号: 9250225
• 负责人: Yen-Yu Ian Shih
• 金额: $ 38.99万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-15 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9250225
• 关键词: Address; Adverse effects; Anatomy; Animal Model; Area; Attenuated; Basal Ganglia; Behavior; Behavior assessment; Behavioral; Brain; Cell Nucleus; Cells; Cerebrum; Coupled; Critical Pathways; Data; Deep Brain Stimulation; Development; Devices; Dissection; Dyskinetic syndrome; Electric Stimulation; Electrodes; Electrophysiology (science); Elements; Exhibits; Fiber; Foundations; Frequencies; Functional Magnetic Resonance Imaging; Generations; Globus Pallidus; Goals; Human; Image; Imaging Techniques; Magnetic Resonance Imaging; Maps; Mediating; Medical; Mental disorders; Microelectrodes; Motor Cortex; Muscle Contraction; Neural Pathways; Neurologic Symptoms; Neurons; Opsin; Pacemakers; Parkinson Disease; Parkinsonian Disorders; Pathologic; Pathway Analysis; Pattern; Positioning Attribute; Procedures; Proton Pump; Rattus; Recruitment Activity; Refractory; Research; Research Personnel; Rest Tremor; Rodent; Rodent Model; Role; STN stimulation; Smooth Muscle; Stimulus; Structure of subthalamic nucleus; Substantia nigra structure; Symptoms; Techniques; Therapeutic; Therapeutic Effect; Time; Treatment Efficacy; Work; effective therapy; experience; experimental study; imaging study; improved; in vivo; innovation; insight; light gated; loss of function; motor deficit; motor symptom; nervous system disorder; neural circuit; novel; optogenetics; psychiatric symptom; public health relevance; reduce symptoms; relating to nervous system; response; subcutaneous; symptom treatment; therapy outcome; tool

 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.

 描述（由适用提供）：深脑刺激（DBS）是一种针对多种神经系统和精神疾病的良好神经外科治疗。在DBS中，通过定位引导电极到目标脑核，高频（〜130 Hz）的电刺激是通过起搏器样皮下刺激装置传递的。它最常用于治疗帕金森氏病（PD），通常在其他医疗疗法变得不足或运动障碍的情况下，它变得可肠胃。当应用PD的症状治疗时，经常针对丘脑核核心（STN），通常会导致几种标志性的PD症状明显减少，包括静止的树和刚性。但是，这些好处是，许多帕金森氏符号经常难以忍受，或者在STN-DBS期间可能更糟。 STN在解剖学上是异质性和纤维密度的，因此即使有准确的电极放置，在STN-DBS期间也很可能会募集脱靶电路。更好地了解DBS如何执行其治疗作用将允许优化此过程，以增强治疗结果并减少不必要的副作用。拟议的项目旨在解决以下三个关键但难以捉摸的问题：1）神经回路代表在目标上和脱离目标 DBS效应，2）STN神经元的选择性光遗传学模拟是否可以改善帕金森氏症运动缺陷，以及3）哪些神经元电路对于热STN-DBS是必需的。在这些目的方面，我们将使用最先进的功能磁共振成像（FMRI），功能连通性MRI（FCMRI），电生理学，光遗传学和行为评估来解剖PD动物模型的治疗性DBS电路，其中运动的放在dbs中依赖于DBS。我们的中心假设是：1）靶向和脱靶DBS暴露的行为相关，不同的大脑活动和连通性模式，2）STN细胞体的高频上遗传刺激模拟STN-DBS治疗，并抑制病理振荡活动，并允许使用更固定的态度固定型固定型固定型，从而抑制较高的电路固定型的动态剂量distentic distention distenutic distenutic distenutient ottenutic distenuutient distenuutient ottenuutient otentenutient ottenuutient otteneutient otteneutic otenenutient DBS电路将与DBS副作用分开。我们的小组在啮齿动物的DBS-FMRI研究方面具有丰富的经验。我们的共同投资者也是理解和持续发展DB，光遗传学和脑网络分析方法的领导者。共同进行了独特的地位，可以进行这一急需的研究线。该项目将为DBS机制提供新的见解，并为建立新的DBS治疗目标和刺激范式奠定基础，以为多种神经和精神疾病。