Modeling Disorders of Consciousness

意识障碍建模

• 批准号: 9533191
• 负责人: John Charles O'Donnell
• 金额: $ 5.77万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9533191
• 关键词: Acceleration; Acute; Address; Animals; Area; Arousal; Autopsy; Awareness; Basic Science; Behavioral; Brain Injuries; Brain Stem; Breathing; Caring; Case Study; Clinical; Clinical Data; Clinical Research; Clinical Trials; Coma; Conscious; Consciousness Disorders; Control Groups; Data; Data Collection; Deep Brain Stimulation; Deglutition; Diagnosis; Diffuse Axonal Injury; Diffusion Magnetic Resonance Imaging; Disease; Disease model; Electric Stimulation; Environment; Epidemiology; Evaluation; Exhibits; Experimental Designs; Eye; Family; Family suidae; Future; GABA Agonists; Glutamates; Head; Human; Injury; Intensive Care Units; Investigation; Lead; Left; Lesion; Long-Term Care; Maps; Measurement; Measures; Medical center; Mentors; Minimally Conscious States; Modeling; Monitor; National Institute of Neurological Disorders and Stroke; Nature; Neurons; Outcome; Output; Pathologic; Pathology; Patients; Pennsylvania; Periodicity; Pharmaceutical Preparations; Pharmacology; Physiologic Thermoregulation; Pontine structure; Pre-Clinical Model; Predictive Value; Procedures; Process; Prosencephalon; Rattus; Recovery; Reflex action; Research; Resources; Rogaine; Rotation; Sample Size; Self Perception; Severities; Sleep Wake Cycle; Stains; Stimulus; Study models; Survivors; System; Techniques; Testing; Thalamic structure; Therapeutic; Time; Traumatic Brain Injury; Treatment Efficacy; Universities; Wakefulness; accurate diagnosis; awake; axon injury; basal forebrain; base; career; career development; clinical care; disability; experience; experimental study; hypocretin; improved; inclusion criteria; injury and repair; negative affect; neural correlate; novel therapeutics; patient population; patient subsets; pre-clinical research; research and development; response; training opportunity; visual tracking; white matter; white matter damage; white matter injury; zolpidem

Following traumatic brain injury (TBI), as well as other types of brain injury, many patients experience a state of coma in which they are unawake and unaware. Coma very rarely lasts more than two weeks, at which point patients either regain consciousness or emerge into a state of wakefulness (sleep/wake cycles, eye opening, basic reflexes) without regaining awareness of themselves or their environment. These patients suffer from Disorders of Consciousness (DoC), and their level of awareness is assessed for diagnosis into the vegetative (no awareness) or minimally conscious state (periodic increases in awareness). These diagnoses are notoriously inaccurate, offering little predictive value in prognoses. Awareness can return within weeks, years, or never. Patients’ families are therefore left with unimaginably difficult decisions and little information on which to base them. Our understanding of the neural correlates and outcomes of DoC is severely lacking, due to the fact that minimal basic science investigation has been pursued. To date DoC have only been examined in clinical studies, which are often encumbered by high variability, low sample sizes, limited data output, and lack of necessary controls. To address these challenges, the proposed project will establish the first preclinical model for studying DoC to provide more accurate diagnoses and prognoses, improved inclusion criteria for clinical trials, and a platform for developing new therapeutics. Coma results from white matter damage due to rotational acceleration of the head during TBI, not from forces associated with impact or linear acceleration. Currently, the only system in the world that accurately models rotational acceleration-induced TBI is the swine injury model utilized by the Center for Brain Injury & Repair at the University of Pennsylvania. This project will apply the rotational TBI model to induce coma, and subjects will then be cared for in a swine intensive care unit and monitored for emergence into wakefulness without awareness utilizing a battery of electroencephalographic, behavioral, and other analyses. It has been hypothesized that while brainstem injury is necessary to produce coma, recovery from DoC and efficacy of treatments may be dependent upon the extent of diffuse axonal injury throughout the forebrain. Therefore, a pharmacological pontine lesion shown to produce coma in rats will be applied in swine to test whether precise white matter injury in pons is sufficient to lead to DoC. Subjects from each injury group that exhibit DoC lasting one month will be used to evaluate existing treatments for improving awareness. Specifically, deep brain stimulation will be tested in thalamus and basal forebrain, and we will administer the GABA agonist zolpidem while measuring changes in awareness. Additional data will be collected postmortem, including diffusion tensor imaging to map intact white matter tracts, and various pathological and immunochemical staining. This study will open the field of DoC to basic science for the first time, providing clinicians and families desperately needed clarity and establishing a platform for developing future therapeutics.

创伤性脑损伤 (TBI) 以及其他类型的脑损伤后，许多患者会经历昏迷状态，处于昏迷状态，不清醒且不知情。昏迷很少持续超过两周，此时患者要么恢复意识，要么进入清醒状态（睡眠/觉醒周期、睁眼、基本反射），而不会恢复对自己或环境的意识。这些患者患有意识障碍（DoC），他们的意识水平被评估以诊断为植物人（没有意识）或最低意识状态（意识周期性增加）。众所周知，这些诊断不准确，对预后几乎没有预测价值。意识可能会在几周、几年内恢复，或者永远不会恢复。因此，患者家属面临着难以想象的困难决定，而且几乎没有什么信息可以作为决策依据。由于我们进行的基础科学研究很少，我们对 DoC 的神经相关性和结果的理解严重缺乏。迄今为止，DoC 仅在临床研究中进行了检验，而临床研究往往受到高变异性、低样本量、有限的数据输出和缺乏必要的控制的阻碍。为了应对这些挑战，拟议的项目将建立第一个用于研究 DoC 的临床前模型，以提供更准确的诊断和预后、改进的临床试验纳入标准以及开发新疗法的平台。 昏迷是由 TBI 期间头部旋转加速度导致的白质损伤引起的，而不是由与冲击或线性加速度相关的力引起的。目前，世界上唯一能够准确模拟旋转加速度引起的 TBI 的系统是宾夕法尼亚大学脑损伤与修复中心使用的猪损伤模型。该项目将应用旋转 TBI 模型来诱导昏迷，然后受试者将在猪重症监护病房中接受护理，并利用一系列脑电图、行为和其他分析来监测受试者是否在无意识的情况下苏醒。据推测，虽然脑干损伤是产生昏迷所必需的，但从 DoC 中恢复和治疗效果可能取决于整个前脑弥漫性轴突损伤的程度。因此，将在大鼠中产生昏迷的药理学脑桥损伤应用于猪，以测试脑桥中的精确白质损伤是否足以导致 DoC。来自每个损伤组的表现出持续一个月的 DoC 的受试者将被用来评估现有的治疗方法，以提高意识。具体来说，将在丘脑和基底前脑中测试深部脑刺激，我们将在测量意识变化的同时施用 GABA 激动剂唑吡坦。尸检后将收集更多数据，包括用于绘制完整白质束的扩散张量成像，以及各种病理和免疫化学染色。这项研究将首次向基础科学开放 DoC 领域，为临床医生和家庭提供迫切需要的清晰度，并为开发未来疗法建立平台。