Modeling Disorders of Consciousness

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，在这种状态下，他们没有清醒和意识。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），而不恢复对自己或周围环境的意识。这些患者患有意识障碍（DoC），他们的意识水平被评估为植物人（无意识）或最低意识状态（意识周期性增加）。这些诊断是出了名的不准确，在预后方面几乎没有预测价值。意识可以在几周，几年内恢复，或者永远不会。因此，患者家属面临着难以想象的困难决定，而且几乎没有信息可以作为决定的依据。由于基础科学研究很少，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查，这些研究通常受到高变异性、低样本量、有限数据输出和缺乏必要控制的阻碍。为了应对这些挑战，拟议的项目将建立第一个临床前模型来研究DoC，以提供更准确的诊断和预后，改善临床试验的纳入标准，并为开发新疗法提供平台。昏迷是由脑外伤时头部旋转加速造成的白质损伤引起的，而不是由与撞击或线性加速相关的力引起的。目前，世界上唯一能够准确模拟旋转加速引起的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进行护理，并利用脑电图、行为和其他分析来监测是否在没有意识的情况下出现清醒状态。据推测，虽然脑干损伤是造成昏迷的必要条件，但DoC的恢复和治疗效果可能取决于整个前脑弥漫性轴索损伤的程度。因此，一种在大鼠中引起昏迷的药理学脑桥损伤将应用于猪，以测试脑桥白质的精确损伤是否足以导致DoC。每个损伤组中表现出持续一个月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，脑深部刺激将在丘脑和基底前脑进行测试，我们将在测量意识变化的同时使用GABA激动剂唑吡坦。其他数据将在死后收集，包括弥散张量成像以绘制完整的白质束，以及各种病理和免疫化学染色。该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，并为开发未来的治疗方法建立平台。

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.