Modeling Disorders of Consciousness

在创伤性脑损伤(TBI)以及其他类型的脑损伤之后，许多患者经历了一种昏迷状态，即他们没有意识到自己是清醒的。昏迷很少持续两周以上，在这一点上，患者要么恢复意识，要么进入清醒状态(睡眠/清醒周期、睁眼、基本反射)，而没有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，对预后几乎没有预测价值。意识可以在几周、几年内恢复，或者永远不会恢复。因此，患者家属面临着难以想象的艰难决定，几乎没有信息可供参考。我们对Doc的神经相关性和结果的了解严重不足，因为我们一直在进行最低限度的基础科学调查。到目前为止，Doc只在临床研究中进行了检查，这些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对照的阻碍。为了应对这些挑战，拟议的项目将建立第一个研究Doc的临床前模型，以提供更准确的诊断和预后，改进临床试验的纳入标准，并建立一个开发新疗法的平台。昏迷是由颅脑损伤期间头部旋转加速造成的脑白质损伤造成的，而不是由与撞击或线加速相关的力造成的。目前，世界上唯一能准确模拟旋转加速诱发的脑损伤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。该项目将应用旋转脑损伤模型来诱导昏迷，然后受试者将在猪的重症监护病房接受护理，并利用一组脑电、行为和其他分析监测是否在没有意识的情况下苏醒。虽然脑干损伤是导致昏迷的必要条件，但DOC的恢复情况和治疗效果可能取决于弥漫性轴突损伤在整个前脑的程度。因此，将在猪身上应用药理脑桥损伤导致大鼠昏迷，以测试脑桥精确的白质损伤是否足以导致Doc。来自每个伤害组的受试者将被用来评估现有的提高意识的治疗方法，这些受试者将展示一个月的DOC。具体地说，深部脑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。其他数据将在尸检后收集，包括扩散张量成像以绘制完整的白质束图，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澄清，并为发展未来的治疗学建立一个平台。

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.