STRUCTURAL, SPECTROSCOPIC AND FUNCTIONAL IMAGING DURING COMA

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。创伤是儿童发病率和死亡率的主要原因，而颅脑损伤是决定其严重程度的最重要因素。因此，对创伤性脑损伤的恢复和预后的研究是一个高度优先的问题。昏迷是一种知之甚少的疾病，尤其是在创伤性脑损伤(TBI)的情况下。这源于颅脑损伤被归因于通过各种不同的方式对多个脑区进行弥漫性损伤，从昏迷中恢复是一个逐渐连续的意识恢复过程，这一过程往往让家人和工作人员感到困惑。在那些严重受伤的人的早期康复过程中，很难区分那些将保持持续植物人状态的人和那些将继续恢复的人。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昏迷恢复所涉及的基本大脑机制的了解。提供有关康复期间大脑活动的客观证据不仅有助于更好地了解这些康复机制，而且可以提高评估长期结果的能力，提供有针对性的康复，选择适当的医疗方法，并改善对长期资源的适当利用。先进的成像技术的出现使我们能够以非侵入性的方式观察大脑的结构(如MRI)、代谢(MRS)和功能(FMRI)活动，这是以前不可能的。虽然我们的调查范围似乎很全面，但我们为每项评估设计了在一次扫描会议中进行的所有研究。我们有兴趣使用这三种技术来连续探索脑损伤后结构性损伤的演变；通过获得神经代谢的区域评估和包括NAA和乳酸在内的代谢性脑活动的纵向光谱测量，来了解损伤后通过恢复过程的代谢变化；以及一系列的fMRI研究，以评估昏迷期间和昏迷后功能活动对大脑的激活。这些研究将包括听觉和视觉刺激，用来确定整个康复过程中意识识别的水平。我们假设，儿童从昏迷中苏醒是基于大脑中一组分布的神经元回路之间实现了功能重新连接。我们计划通过功能磁共振成像对昏迷患者苏醒前后进行纵向评估，从而监测功能重联过程，对我们大多数患者来说，这个过程在几天到几周内就能完成。在休克创伤病房和康复项目中，从昏迷中苏醒从功能上被定义为患者遵循简单语言命令的能力。因此，我们将重点关注大脑对声音和单词的反应(中性和积极的奖励)，并将它们与对视觉和其他感官刺激的反应进行比较。我们期望对一系列昏迷患者苏醒前后激活的皮质和皮质下区域的网络进行比较，以揭示为意识提供必要底物的关键网络。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，尾端到吻端的垂直层级和水平的跨皮质网络连接对于昏迷的苏醒是必不可少的。例如，我们预计，脑干、丘脑和皮质通路的组合激活，而不仅仅是脑干结构本身的激活，将是出现的关键。然而，我们预计，仅激活较低的水平加上单一的皮质区域是不够的。动物研究表明，在初级皮质感觉表征之外的多个双侧皮质联合区域的一致招募对于意识的出现是必不可少的。我们希望能够了解这些关键的连接及其拓扑结构。这项工作很可能具有相当大的实用、治疗和基础神经科学价值。从实际的角度来看，家属和治疗团队都急于获得关于大脑中正在发生的事情的客观信息。功能磁共振成像提供了一个了解工作大脑的新窗口，应该有助于观察和等待过程。此外，我们希望这项技术将有助于预测和评估康复干预的客观反应。从根本上讲，我们预计导致意识丧失的创伤性损伤的多样性将使我们能够从多个方向处理意识问题。通过比较有多个分散病变的患者昏迷和突然出现的网络特性，我们可能能够提取使意识成为可能的关键网络链接。此外，一些患者从昏迷中苏醒后会留下明显的残余缺陷。通过昏迷恢复过程对皮质和皮质下回路的评估可能会提供有用的见解，了解为什么在某些情况下会完全恢复，以及这可能如何导致集中治疗方案和给药的时间。

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.