Central thalamic deep brain stimulation to regulate arousal and cognition

中枢丘脑深部脑刺激调节觉醒和认知

基本信息

批准号：
10372092
负责人：
JONATHAN L BAKER
金额：
$ 61万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10372092
关键词：
3-Dimensional Anatomic Models Anatomy Animal Model Animals Anodes Anterior Arousal Attention Axon BRAIN initiative Behavior Behavioral Biological Markers Brain Brain Diseases Brain Injuries Brain Stem Brain imaging Cathodes Chronic Clinical Clinical Research Cognition Cognitive Communication Data Deep Brain Stimulation Device Designs Devices Dorsal Electric Stimulation Electrophysiology (science)Faculty Family Fatigue Feasibility Studies Fiber Functional disorder Future Geometry Goals Human Impaired cognition Implant Impulsivity Individual Injury Investigational Therapies Knowledge Lead Link Macaca Measures Medial Methods Microelectrodes Mission Modeling Monkeys Motivation Movement Disorders Myelin National Institute of Neurological Disorders and Stroke Nerve Degeneration Neurocognitive Neurologic Neurology Neurons Neurosciences Nuclear Optical Coherence Tomography Outcome Pathway interactions Patients Performance Pharmaceutical Preparations Physiological Physiology Play Positioning Attribute Primates Prosencephalon Public Health Regulation Research Resolution Resources Role Safety Shapes Short-Term Memory Signal Transduction Site Societies Stains System Testing Thalamic structure Traumatic Brain Injury Treatment Efficacy Work base biomedical imaging biophysical model cognitive capacity cognitive performance cognitive task design disability effective therapy electric field experimental study flexibility improved in vivo innovation neuropsychiatric disorder neuropsychiatry neuroregulation nonhuman primate novel optical imaging pre-clinical preclinical study predictive modeling prospective test recruit sustained attention tractography vigilance

项目摘要

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.

深部脑刺激 (DBS) 是治疗各种运动障碍的一种既定疗法，目前正在被广泛应用。研究用于治疗广泛的神经系统和神经精神疾病。然而，要充分认识到 DBS 作为一种疗法的前景，我们需要更好地了解它如何调节两者的神经元活动局部 DBS 目标和整个大脑。该提案的重点是提出一种新颖的方法场塑造中央丘脑 DBS (fsCT-DBS) 来调节唤醒和认知。唤醒调节是对结构性脑损伤患者影响深远，是许多人常见且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本小说 CT-DBS 方法，其中阳极和阴极在多个植入的 DBS 引线之间分开丘脑中央的特定区域，这里称为“场整形 CT-DBS”（fsCT-DBS）。在这里我们将在 fsCT-DBS 过程中前瞻性测试和表征动物的行为表现。中央这里要检验的假设是，fsCT-DBS 对唤醒的强有力调节是通过选择性的产生的。将电刺激传递到丘脑中央（丘脑的内侧部分）内的特定纤维束丘脑背侧被盖束（DTTm）。该纤维束由源自丘脑中央的轴突组成核群和脑干唤醒中心投射到前脑，被认为发挥着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。这该提案的目的是建立一个解剖学上准确的 DTTm 预测生物物理模型，系统地测试 fsCT-DBS 新模式，以增强认知资源的使用和能力行为健康的猕猴。首先，最先进的生物医学成像将与超高分辨率光学成像构建 DTTm 的预测生物物理模型。二、fsCT的影响 DBS 的 DTTm 招募将通过比较持续注意力/警惕任务的表现来衡量在两个需要额外认知资源的范式中，一个集合转换分类任务和一个工作记忆任务。后两项任务需要认知灵活性，而这种能力在大多数情况下都被削弱了。患有神经精神疾病和结构性脑损伤的患者。第三，使用自适应 fsCT-DBS 将使用新的临床级闭环 DBS 设备进行探索。生物物理学的识别和预测局部 fsCT-DBS 目标、DTTm 建模，使用多极场整形来验证模型通过行为和大规模生理学进行预测，以及对闭环 DBS 的探索都具有很高的应用价值。该提案的创新方面，因为它们将提高我们对如何精确定位 fsCT-DBS 的理解稳健可靠地调节前部前脑活动并支持认知。使用健康的非人类灵长类动物作为验证所提出方法的模型对于指导和促进设计至关重要用于人类的新型临床级 fsCT-DBS 系统的规范。