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.

项目概要 针对白质而非特定细胞核或皮质的深部脑刺激（DBS）是一种新兴的治疗方法 针对患有难治性神经或精神疾病的个体的方法。 人们认为通过分布式大脑的神经活动的功能调节来产生有益的影响 然而，简而言之，通过受到刺激的白质连接的网络。 这意味着有助于治疗的潜在功能和解剖机制。 对白质 DBS 的影响知之甚少，缺乏这方面的知识阻碍了这种治疗的完善。 及其针对其他白质束的潜在用途在这里，我们将模拟 DBS 对猕猴和 确定 DBS 疗法针对三个白质束位置的机制 – 镊子小、钩束和扣带束 – 与胼胝体下前部相邻的额叶皮层重叠 我们将采用这个模型，因为之前的工作表明这些束的刺激是 与情感的快速积极变化以及对情感状态的较慢的长期影响相关 患有治疗抵抗性情绪障碍的人会在数周内出现这种情况，我们的目标是建立 由深部脑刺激引起的两个时间范围内的微观和中观神经变化。 认为它们是由两种不同的机制引起的，快速效果是功能性的结果。 变化，而缓慢的变化是白质结构变化的结果。 我们将结合使用深部脑刺激、静息态功能磁共振成像、神经生理学和尸检 使用与人类患者相同的扩散成像纤维束成像方法，对猕猴进行解剖。 然后，我们将把迷你深部脑刺激电极瞄准三个白质束的汇合处。 评估功能磁共振成像静息态功能连接和扩散的渐进系统水平变化 对这三者深部脑刺激引起的解剖连接的加权成像估计 与此同时，我们将评估由此发生的微观神经生理变化。 在这里，我们的实验旨在辨别刺激对功能的直接影响。 通过与胼胝体下 ACC 相邻的白质直接连接的区域之间的相互作用 最后，我们将描述区域之间功能沟通的长期变化。 在解剖学上，与白质深部脑刺激对全脑功能的影响有关。 在这里，我们将使用共焦显微镜和电子显微镜来辨别由以下因素引起的白质变化： 完成这些实验将开始揭示刺激的功能和解剖机制。 总体而言，我们的发现将提供有关电路级如何发挥作用的见解。 功能由 DBS 调节，并有助于完善新兴的 DBS 治疗方法。