STRUCTURAL, SPECTROSCOPIC AND FUNCTIONAL IMAGING DURING COMA

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。创伤是儿童发病率和死亡率的主要原因，而创伤性脑损伤（TBI）是严重程度的最重要决定因素。因此，研究创伤性脑损伤的恢复和结果是当务之急。昏迷是一种知之甚少的情况，特别是在创伤性脑损伤（TBI）的情况下。这源于创伤性脑损伤被认为是由多种不同的脑区弥漫性损伤引起的，昏迷的恢复是一个逐渐连续的意识恢复过程，这个过程经常让家属和工作人员感到困惑。在那些严重受伤的患者的早期恢复过程中，很难区分哪些人将继续处于植物人状态，哪些人将继续恢复。此外，很难评估谁的神经功能恢复得更彻底。这种无法充分评估这些患者的原因是缺乏对从昏迷中恢复的基本大脑机制的了解。关于恢复期间大脑活动的客观证据的可用性不仅可以更好地了解这些恢复机制，而且可以提高评估长期结果的能力，提供重点康复，选择适当的医疗，并提高对长期资源的适当利用。复杂成像技术的出现使我们能够无创地观察大脑的结构（如MRI）、代谢（MRS）和功能（fMRI）活动，这在以前是不可能的。虽然我们的调查范围似乎很全面，但我们设计的研究是在每次评估的一次扫描中完成的。我们有兴趣使用这三种技术来连续探索TBI后结构性脑损伤的演变；通过对脑代谢活动（包括NAA和乳酸）的纵向光谱测量，获得神经代谢的区域评估，了解损伤后的代谢变化；以及一系列功能磁共振成像研究，通过昏迷期间和昏迷后的功能活动来评估大脑的激活。这些研究将包括听觉和视觉刺激，以确定在整个恢复过程中的意识识别水平。我们假设，儿童从昏迷中苏醒是基于大脑中分布的神经回路之间的功能重新连接的实现。我们计划通过功能性磁共振成像（fMRI）对昏迷前后的患者进行纵向评估，从而监测功能重连过程，我们的大多数患者在几天到几周内完成这一过程。在休克创伤单位和康复项目中，从昏迷中苏醒的功能被定义为患者遵循简单口头命令的能力。因此，我们将重点关注大脑对声音和词语（中性的和积极的奖励）的反应，并将它们与视觉和其他感官刺激的反应进行比较。我们期望通过对一系列患者昏迷前后激活的皮层和皮层下区域网络的比较，可以揭示为意识提供基本基础的关键网络。由于我们不知道在人类身上有任何类似的工作，所以很难预测结果会是什么。然而，我们预计垂直的尾侧到吻侧的层次结构和水平的跨皮层网络连接将是从昏迷中出现所必需的。例如，我们预计脑干、丘脑和皮质通路的联合激活，而不仅仅是脑干结构的单独激活，将是出现的必要条件。然而，我们预计仅激活较低水平加上单个皮质区域是不够的。动物研究表明，在初级皮层感觉表征之外的多个双侧皮层关联区域的同步募集对于意识的出现至关重要。我们希望能够理解这些关键的连接和它们的地形结构。这项工作可能具有相当大的实用治疗价值以及基本的神经科学价值。从实际的角度来看，家庭和治疗团队都渴望获得关于大脑中发生的事情的客观信息。功能磁共振成像为观察大脑的工作提供了一个新的窗口，有助于观察和等待的过程。此外，我们希望这项技术将有助于预后和评估对康复干预的客观反应。从基本的角度来看，我们期望导致无意识的创伤性病变的多样性将使我们能够从多个方向处理意识问题。通过比较多发分散病灶患者昏迷与苏醒的网络特性，我们或许能够提取出使意识成为可能的关键网络链接。此外，有些病人在昏迷后会留下明显的残余缺陷。在昏迷恢复过程中对皮层和皮层下回路的评估可能会提供有用的见解，解释为什么有些病例会完全恢复，而另一些却没有，以及这可能如何导致治疗方案的集中和这些治疗的实施时间。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Trauma is the leading cause of morbidity and mortality in children, and traumatic brain injury (TBI) is the most important determinant of the degree of severity. Consequently, research into TBI recovery and outcome is a high priority. Coma is a poorly understood condition, especially in cases of traumatic brain injury (TBI). This stems from TBI being attributed to diffuse damage of multiple brain regions through a variety of different Recovery from coma is a gradual continuum of return of consciousness, a process that is often confusing to families and staff. During the early recovery in those with very severe injuries, it can be difficult to distinguish those who will remain in a persistent vegetative state from those whose recovery will continue. In addition, it is difficult to assess who will have a more complete recovery of neurological function. This inability to adequately assess these patients stems from a lack of understanding the basic brain mechanisms involved in recovery from coma. Availability of objective evidence concerning brain activity during recovery would not only lead to a better understanding of these recovery mechanisms but could lead to improved ability to assess long-term outcome, provide focussed rehabilitation, choose appropriate medical, and improve appropriate utilization of long-term resources. The advent of sophisticated imaging techniques now allows us to observe the structural (e.g., MRI), metabolic (MRS), and functional (fMRI) activity of the brain noninvasively in a manner that previously was not possible. While the scope of our investigations appear comprehensive, we have designed the studies to be performed all in one scanning session for each evaluation. We are interested in using these three techniques to serially explore the evolution of structural brain injuries following TBI; the metabolic changes post-injury through the recovery process by obtaining regional assessments of neural metabolism with longitudinal spectroscopic measures of metabolic brain activity including NAA and lactate; as well as serial fMRI studies to evaluate the activation of the brain by functional activities during and after the recovery from coma. These studies will consist of auditory and visual stimuli, administered to determine levels of conscious recognition throughout the recovery process. We hypothesize that emergence from coma in children is based on the achievement of functional reconnections among a distributed set of neuronal circuits in the brain. We plan to be able to monitor the functional reconnection process through fMRI by assessing patients longitudinally before and after the emergence from coma, a process that for most of our patients is completed within days to weeks. In shock-trauma units and rehabilitation programs, emergence from coma is defined functionally as the ability of a patient to follow a simple verbal command. Therefore we will focus on brain responses to sounds and words (neutral and positively rewarding) and compare them to responses to visual and other sensory stimulation. We expect that comparison of networks of activated cortical and subcortical regions before and after emergence from coma in a series of patients will reveal critical networks that provide an essential substrate for consciousness. Since we are not aware of any similar work in humans, it is hard to predict what the results will be. However we expect that both vertical caudal-to-rostral hierarchies and horizontal transcortical network connections will be essential for emergence from coma. For example, we expect that activation of a combination of brainstem, thalamic and cortical pathways rather than simply brainstem structures alone will be essential for emergence. However, we expect that activation of lower levels plus a single cortical area alone will not be enough. Animal studies suggest that coincident recruitment of multiple, bilateral cortical association areas beyond primary cortical sensory representations is essential for emergence of consciousness. We expect to be able to understand this critical mass of connections and their topographic architecture. This work is likely to have considerable practical therapeutic as well as fundamental neuroscientific value. From a practical standpoint, families and the treatment team are both anxious to have objective information about what is going on in the brain. fMRI provides a new window on the working brain that should help the watching and waiting process. In addition, we hope that the technique will help with prognosis and with evaluating objective responses to rehabilitative interventions. From a fundamental standpoint, we expect that the diversity of traumatic lesions leading to unconsciousness will allow us to approach the consciousness problem from multiple directions. By comparing network properties of coma versus emergence in patients with multiple scattered lesions, we may be able to distill the critical network links that make consciousness possible. In addition, some patients are left with noticeable residual deficits following emergence from coma. Assessment of cortical and subcortical circuits through the coma recovery process may provide useful insights as to why full recovery occurs in some cases and not others, and how this may lead to focussing of treatment options and the timing of administration of those treatments.