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

项目摘要 脑深部电刺激（DBS）是一种新兴的治疗方法，其靶点为白色物质，而不是特定的核团或皮层 为患有难治性神经或精神疾病的个体提供治疗方法。这种治疗方法 被认为是通过对分布在大脑中的神经活动进行功能性调节而产生有益效果的 通过受到刺激的白色物质连接的网络。然而，简而言之， 供应这意味着有助于治疗的潜在功能和解剖机制 对白色物质DBS的影响了解甚少。缺乏这方面的知识阻碍了这种治疗的完善 以及其用于靶向其他白色物质束的潜在用途。在这里，我们将模拟DBS对猕猴的影响， 确定DBS治疗所涉及的机制，该机制针对三个白色物质束- 小钳，钩束和扣带束重叠在邻近胼胝体下前部的额叶皮质中 扣带皮层（ACC）。我们将采用这个模型，因为先前的工作已经表明，刺激这些束是可行的。 与情感的快速积极变化以及对情感状态的缓慢长期影响有关， 在患有难治性情绪障碍的人身上发展了许多周。我们的目标是建立 脑深部刺激引起的两个时间范围内的微观和中尺度神经系统变化。我们 假设它们由两种不同的机制引起。快速的效果是功能性的结果 而缓慢的变化是白色物质结构变化的结果。为了验证我们的假设， 我们将结合使用脑深部电刺激、静息态功能磁共振成像、神经生理学和死后 猕猴的解剖学使用与人类患者相同的扩散成像纤维束成像方法， 微型深部脑刺激电极将瞄准三个白色物质束的汇合处。然后我们将 评估fMRI静息态功能连接和扩散的渐进性系统水平变化 对这三个部位的深部脑刺激引起的解剖连接进行加权成像估计， 白色物质束。同时，我们将评估由此产生的微观神经生理学变化 的刺激。在这里，我们的实验旨在辨别刺激对功能的直接影响。 通过邻近胼胝体下ACC的白色物质直接连接的区域之间的相互作用以及 区域间功能性沟通的长期变化。最后，我们将描述这些变化 在解剖学上与脑深部刺激对白色物质的全脑功能效应相关。 在这里，我们将使用共聚焦和电子显微镜来辨别由以下原因引起的白色物质的改变： 刺激.完成这些实验将开始揭示的功能和解剖机制， 当它指向白色物质时，DBS。总的来说，我们的发现将提供深入了解如何电路级 功能由DBS调节，并有助于新兴DBS治疗的改进。

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.