Central Thalamic Deep Brain Stimulation to Regulate Arousal and Cognition

脑深部电刺激（DBS）是一种用于各种运动障碍的既定疗法，目前正在 研究用于治疗范围不断扩大的神经和神经精神疾病。然而，为了充分认识到 DBS作为一种治疗方法的前景，我们需要更好地了解它是如何调节两者中的神经元活动的。 局部DBS目标和整个大脑。该提案的重点是提出一种新的方法， 场成形中央丘脑-DBS（fsCT-DBS），以调节唤醒和认知。唤醒调节是 严重影响结构性脑损伤患者，是许多患者的常见和未经治疗的后遗症。 患有神经退行性疾病和神经精神疾病的患者。在之前的工作中，我们发现了一种新的 CT-DBS的方法，其中阳极和阴极跨多个植入的DBS电极导线分离， 中央丘脑的特定区域，这里称为“场成形CT-DBS”（fsCT-DBS）。这里我们将 前瞻性测试和表征fsCT-DBS期间动物的行为表现。中央 这里要检验的假设是，通过选择性地调节fsCT-DBS的唤醒， 将电刺激传递到中央丘脑内的特定纤维束，即丘脑的内侧， 丘脑背侧被盖束（DTTm）。该纤维束由起源于中央丘脑的轴突组成 投射到前脑前部的核团和脑干唤醒中心，被认为在大脑中起着重要的作用。 通过调节活动水平和全脑交流，在支持认知方面发挥着至关重要的作用。的 该提案的目的是寻求建立DTTm的解剖学上准确的预测生物物理模型， 系统地测试fsCT-DBS的新模式，以提高认知资源的使用和能力， 健康行为的猕猴首先，最先进的生物医学成像技术将与生物医学相结合， 分辨率光学成像，以构建DTTm的预测性生物物理模型。第二，fsCT的影响- 将通过比较持续注意力/警惕任务的表现来衡量DTTm招募的DBS 在两个需要额外认知资源的范式中，一个是组转移分类任务，另一个是工作分类任务。 记忆任务后两项任务需要认知灵活性，这是一种在大多数人中退化的能力。 患有神经精神疾病和结构性脑损伤的患者。第三，自适应fsCT-DBS的使用将 使用新的临床级闭环DBS设备进行探索。识别和预测生物物理 建立了局部fsCT-DBS目标的DTTm模型，利用多极场整形对模型进行了验证 通过行为和大规模生理学的预测，以及闭环DBS的探索，都是非常重要的 这一建议的创新方面，因为它们将提高我们对如何精确定位fsCT-DBS的理解 稳定可靠地调节前前脑活动并支持认知。使用健康的非- 以人类灵长类动物作为模型来验证所提出的方法对于指导和促进设计是必不可少的 用于人体的新型临床级fsCT-DBS系统的质量标准。

Deep brain stimulation (DBS) is an established therapy for various movement disorders and is now being investigated to treat a widening range of neurological and neuropsychiatric conditions. However, to fully realize the promise of DBS as a therapy, we need to better understand how it modulates neuronal activity within both the local DBS target and in the brain as a whole. The focus of this proposal is to advance a novel method of field-shaping central thalamic-DBS (fsCT-DBS) to modulate arousal and cognition. Arousal regulation is profoundly impacted in patients with structural brain injuries and is a common and untreated sequelae of many patients suffering from neurodegenerative and neuropsychiatric illnesses. In prior work we discovered a novel method of CT-DBS, where anodes and cathodes are separated across multiple implanted DBS leads within a specific region of the central thalamus, here termed `field-shaping CT-DBS' (fsCT-DBS). Here we will prospectively test and characterize behavioral performance of animals during fsCT-DBS. The central hypothesis to be tested here is that robust regulation of arousal with fsCT-DBS arises through selective delivery of electric stimulation to a specific fiber tract within the central thalamus, the medial aspect of the dorsal thalamic tegmental tract (DTTm). This fiber tract consists of axons originating from central thalamic nuclear groups and brainstem arousal centers that project to the anterior forebrain and are believed to play a crucial role in supporting cognition through the regulation of activity levels and brain-wide communication. The aims of this proposal seek to establish an anatomically accurate predictive biophysical model of the DTTm and to systematically test new modes of fsCT-DBS to enhance the use and capacity of cognitive resources in healthy behaving macaque monkeys. First, state-of-the-art biomedical imaging will be combined with ultrahigh- resolution optical imaging to construct predictive biophysical models of the DTTm. Second, the effects of fsCT- DBS on DTTm recruitment will be measured by comparing performance on a sustained attention/vigilance task and in two paradigms requiring additional cognitive resources, a set-shifting categorization task and a working memory task. The latter two tasks require cognitive flexibility, a faculty that is degraded in the majority of patients with neuropsychiatric disorders and structural brain injuries. Third, the use of adaptive fsCT-DBS will be explored using a new clinical-grade closed-loop DBS device. The identification and predictive biophysical modeling of the local fsCT-DBS target, the DTTm, the use of multipolar field shaping to validate the model predictions through behavior and large-scale physiology, and exploration of close-loop DBS are all highly innovative aspects of this proposal as they will improve our understanding of how to precisely target fsCT-DBS to robustly and reliability regulate anterior forebrain activity and support cognition. The use of healthy non- human primates as a model to validate the proposed approach is essential to guiding and facilitating design specifications for a new clinical-grade fsCT-DBS system for use in humans.