Establishing the anatomical and functional mechanisms of white matter deep brain stimulation

建立白质深部脑刺激的解剖和功能机制

• 批准号: 10803745
• 负责人: Helen S Mayberg
• 金额: $ 80.97万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-12 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10803745
• 关键词: Acute; Affect; Affective; Anatomy; Anisotropy; Anterior; Anxiety Disorders; Area; Attention; Autopsy; Brain; Brain Diseases; Cell Nucleus; Chronic; Clinical; Communication; Confocal Microscopy; Data; Deep Brain Stimulation; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Dorsal; Electrodes; Electron Microscopy; Experimental Designs; Fascicle; Forcep; Functional Magnetic Resonance Imaging; Goals; Human; Image; Implant; Individual; Knowledge; Location; Macaca; Measures; Mental disorders; Microscopy; Minor; Modeling; Modification; Monkeys; Mood Disorders; Motor; Movement; Neurodegenerative Disorders; Neurologic; Oligodendroglia; Parkinson Disease; Pathway interactions; Patients; Persons; Population; Process; Proliferating; Protocols documentation; Reporting; Resistance; Resolution; Rest; Rodent Model; Site; Structure; Structure of subthalamic nucleus; System; Testing; Thalamic structure; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Time; Work; cingulate cortex; experimental study; frontal lobe; gray matter; insight; interdisciplinary approach; interest; multimodality; myelination; nervous system disorder; neural; neural circuit; neurophysiology; novel; reduce symptoms; targeted treatment; theories; therapy development; tractography; translational approach; white matter

Project Summary Deep brain stimulation (DBS) targeting white matter instead of specific nuclei or cortex is an emerging therapeutic approach for individuals with treatment resistant neurological or psychiatric disorders. This treatment approach is thought to have its beneficial effects through functional modulation of neural activity across distributed brain networks that connect through the white matter that is being stimulated. Evidence for this is, however, in short supply. This means that the underlying functional and anatomical mechanisms that contribute to the therapeutic effects of white matter DBS are poorly understood. Lack of this knowledge hinders refinement of this treatment and its potential use to target other white matter tracts. Here we will model the effects of DBS in macaques and determine the mechanisms engaged by DBS therapy that targets the location where three white matter tracts – forceps minor, uncinate fascicle and cingulum bundle – overlap in frontal cortex adjacent to subcallosal anterior cingulate cortex (ACC). We will employ this model as prior work has shown that stimulation of these tracts is associated with both fast positive changes in affect as well as slower longer-term effects on affective state that develop over many weeks in people with treatment resistant mood disorders. Our aim here is to establish the micro- and meso-scale neurological changes across both time frames caused by deep brain stimulation. We hypothesize that they are caused by two distinct mechanisms. The fast effects are the result of functional changes whereas the slow changes are the result of structural changes to white matter. To test our hypothesis, we will use a combination of deep brain stimulation, resting-state fMRI, neurophysiology, and postmortem anatomy in macaque monkeys. Using the same diffusion imaging tractography approach used in human patients, mini-deep brain stimulation electrodes will be targeted to the confluence of three white matter tracts. We will then assess the progressive systems level changes in fMRI resting-state functional connectivity and diffusion weighted imaging estimates of anatomical connections that are caused by deep brain stimulation of these three white matter tracts. In parallel, we will assess the microscale neurophysiological changes that occur as a result of stimulation. Here our experiments are designed to discern the immediate effects of stimulation on functional interaction between areas that directly connect through the white matter adjacent to subcallosal ACC as well as the longer-term changes in functional communication between areas. Finally, we will characterize the changes in anatomy that are associated with the brain-wide functional effects of deep brain stimulation to white matter. Here we will use both confocal and electron microscopy to discern alterations to white matter that are caused by stimulation. Completing these experiments will begin to reveal the functional and anatomical mechanisms of DBS when it is directed to white matter. Overall, what we discover will provide insights into how circuit-level functions are modulated by DBS as well as aid the refinement of emerging DBS treatments.

项目摘要 靶向白质代替特定核或皮质的深脑刺激（DBS）是一种新兴疗法 具有抗治疗性神经系统或精神疾病的人的方法。这种治疗方法 人们认为通过对分布式大脑的神经活动的功能调节具有有益的效果 通过正在刺激的白色物质连接的网络。但是，简而言之 供应。这意味着有助于治疗的基本功能和解剖机制 白质DB的影响知之甚少。缺乏这种知识阻碍了这种治疗 它的潜在用途来针对其他白质区。在这里，我们将在猕猴中对DB的效果进行建模 确定DBS疗法参与的机制，该机制针对三个白质区域的位置 - 镊子小调，不加束和扣带束 - 在额叶毗邻的额叶皮质中重叠 扣带皮质（ACC）。我们将采用此模型，因为先前的工作表明，对这些区域的刺激是 与情感的快速积极变化以及对情感状态的长期影响相关 在患有抗治疗情绪障碍的患者中，已经发展了数周。我们在这里的目标是建立 由深脑刺激引起的两个时间段的微观和中尺度的神经系统变化。我们 假设它们是由两种不同的机制引起的。快速影响是功能的结果 变化而慢的变化是白质结构变化的结果。为了检验我们的假设， 我们将结合大脑刺激，静止状态fMRI，神经生理学和验尸的结合 猕猴的解剖学。使用在人类患者中使用的相同扩散成像拖拉学方法， 小型深脑刺激电极将针对三个白色物质的汇合。然后我们会 评估fMRI静止状态功能连接性和扩散的渐进式系统水平变化 由这三个刺激深度刺激引起的解剖连接的加权成像估计值 白质区。同时，我们将评估结果的微观神经生理变化 刺激。在这里，我们的实验旨在辨别刺激对功能的直接影响 直接通过与亚易体callosal ACC相邻的白质连接的区域之间的相互作用以及 区域之间功能通信的长期变化。最后，我们将描述更改 在解剖学中，与大脑刺激对白质的脑部功能作用有关。 在这里，我们将同时使用共聚焦和电子显微镜来辨别对白质的改变 刺激。完成这些实验将开始揭示 DBS指向白质时。总体而言，我们发现的内容将提供有关电路级别的见解 功能由DBS调节，并有助于新兴DBS处理的完善。