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

项目摘要 脑深部刺激(DBS)针对的是白质，而不是特定的核团或皮质，是一种新兴的治疗方法 治疗难治性神经或精神障碍患者的方法。这种治疗方法 被认为是通过对分布在不同大脑中的神经活动进行功能调节而产生有益效果的 通过被刺激的白质连接的网络。然而，简而言之，这方面的证据是 供给。这意味着潜在的功能和解剖学机制有助于治疗 人们对白质DBS的影响知之甚少。缺乏这方面的知识阻碍了这种治疗的改进 以及它作为其他白质束靶点的潜在用途。在这里，我们将模拟DBS对猕猴和 确定DBS治疗的机制，针对三个白质区域的位置- 小钳子、钩束和扣带束重叠在毗邻扣带下前部的额叶皮质 扣带回皮质(ACC)。我们将采用这个模型，因为先前的研究已经表明，刺激这些区域是 与影响的快速积极变化以及对情感状态的较慢的长期影响有关， 患有难治性情绪障碍的人会在数周内发病。我们在这里的目标是建立 脑深部刺激在两个时间范围内引起的微观和中观尺度的神经变化。我们 假设它们是由两种不同的机制引起的。快速的效果是功能性的结果 而缓慢的变化则是白质结构变化的结果。为了检验我们的假设， 我们将结合使用脑深部刺激、静息功能核磁共振、神经生理学和尸检。 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， 迷你脑深部刺激电极将定位于三条白质束的汇合处。到时候我们会的 评估功能磁共振静息状态功能连接和扩散的渐进性系统水平变化 对这三种脑深部刺激引起的解剖联系的加权成像估计 白质束。同时，我们将评估由此产生的微尺度神经生理学变化。 刺激的力量。在这里，我们的实验旨在辨别刺激对功能的直接影响 直接通过邻近大脑皮质白质连接的区域之间的相互作用以及 地区间功能沟通的较长期变化。最后，我们将描述这些变化 在解剖学中，与脑深部刺激对脑白质的全脑功能影响有关。 在这里，我们将使用共焦显微镜和电子显微镜来辨别白质的变化，这些变化是由 刺激。这些实验的完成将开始揭示神经干细胞的功能和解剖机制。 当它被指向白质时，DBS。总体而言，我们的发现将提供对电路级 功能由DBS调节，并有助于改进新兴的DBS治疗。

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.