Consequences of Cardiac Arrest: Brain Injury

描述（由申请人提供）：心脏骤停（CA）后的生存和神经预后仍然很差。我们之前的工作重点是了解CA后神经电活动的恢复，并导致发现a)定量信号处理方法跟踪CA后脑损伤和恢复，b) CA后觉醒恢复期间丘脑皮质网络的恢复，以及c)治疗可能影响恢复的电节律模式和时间过程。最近的临床报告证明了CA后低温治疗的显著疗效，并更好地了解了丘脑在CA后慢性意识障碍中的作用。我们的建议利用这些机会揭示CA后觉醒的急性神经生理机制，以开发临床适用的诊断方法并优化治疗性低温的提供。该项目的具体目标是：目标1：我们将发现临床相关的和经神经生理学验证的CA后昏迷唤醒的电标记。我们将验证以下假设：a)昏迷以丘脑和皮质电位的异常耦合为特征；b)皮质体感诱发电位（SSEP）的定量分析将跟踪正常丘脑皮质偶联的恢复；c)基于熵的定量脑电图（qEEG）分析将捕捉CA损伤恢复过程中丘脑皮质耦合的顺序变化。目的2：我们将研究诱导低温导致神经生理恢复增强的机制。我们将验证以下假设：a)丘脑和皮层的多单元（MU）记录将证明丘脑皮质耦合与诱导的低温加速正常化；b)低温加速SSEP的正常化，表明皮质下通路的恢复；c) qEEG信号的正常化恢复皮质功能。目标3：大多数低温疗法的进展都是盲目地指向更快的冷却，没有大脑对温度反应的客观指标。我们将检验这一假设，即低温的深度和持续时间可以客观地滴定到无创的qEEG和丘脑皮质偶联的SSEP标记物，以最大限度地恢复大脑。这种多方面的方法——从唤醒系统的丘脑皮质成分的直接多单元记录开始，然后是非侵入性的诱发电位和脑电图监测——将允许全面开发实时神经生理学工具来滴定低温治疗。我们的基础研究的第一阶段已经催生了美国国立卫生研究院赞助的IIB期多中心临床试验。在不久的将来，我们的定量、神经电生理学指导的低体温递送优化应该同样适用于监测患者和指导诱导低体温的临床试验。公共卫生相关性：本提案的重点是转化研究：研究心脏骤停（CA）后的全球缺血性脑损伤问题，并开发CA后昏迷和觉醒的神经电标记物的监测技术。基础研究涉及开发损伤的定量电测量和了解这些信号的皮层和皮层下起源。转化研究涉及到利用电信号测量优化CA后诱导低体温的程序。该项目的创新之处在于全面新颖地应用定量方法，即皮质（EEG）、皮质下（EP）和多单元（MU）记录来跟踪损伤和恢复。我们的工作具有引人注目的转化应用：监测CA后患者的脑损伤，并在神经监测的指导下优化CA后的低温递送。

DESCRIPTION (provided by applicant): Survival and neurological outcome after sudden cardiac arrest (CA) remain very poor. Our prior work focused on understanding the return of neuro-electrical activity after CA and led to the discovery of a) quantitative signal processing methods that track brain injury and recovery after CA, b) recovery of thalamocortical networks during restitution of arousal after CA and c) the patterns of electrical rhythms and time course when therapy may impact recovery. Recent clinical reports demonstrate compelling therapeutic benefits of hypothermia following CA and a better understanding of the role of the thalamus in chronic disorders of consciousness after CA. Our proposal harnesses these opportunities to uncover the acute neurophysiologic mechanisms of arousal post-CA to develop clinically applicable diagnostic methods and optimize therapeutic hypothermia delivery. The specific aims of this project are: Aim 1: We will discover the clinically relevant and neurophysiologically validated electrical markers of arousal from coma after CA. We will test the hypotheses that a) coma is marked by abnormal coupling of thalamic and cortical potentials, b) quantitative analysis of cortical somatosensory evoked potentials (SSEP) will track recovery of normal thalamocortical coupling, and c) entropy-based quantitative EEG (qEEG) analysis will capture sequential changes in thalamocortical coupling during recovery from CA injury. Aim 2: We will study the mechanism by which induced hypothermia results in enhanced neurophysiologic recovery. We will test the hypotheses that a) multi-unit (MU) recording from thalamus and cortex will demonstrate accelerated normalization of thalamocortical coupling with induced hypothermia, b) hypothermia accelerates normalization of SSEP indicating restoration of the subcortical pathway, and c) normalization of qEEG signals recovery of cortical function. Aim 3: Most advances in hypothermia are blindly directed toward faster cooling, without objective indicators of the brain's response to temperature. We will test the hypothesis that the depth and duration of hypothermia can be objectively titrated to non-invasive qEEG and SSEP markers of thalamocortical coupling in order to maximize brain recovery. This multifaceted approach - starting with direct multiunit recordings of thalamocortical components of the arousal system followed by non-invasive evoked potential and EEG monitoring - will allow for the comprehensive development of real-time neurophysiologic tools to titrate hypothermia treatment. The first phase of our basic research has already spawned an NIH-sponsored Phase IIB multi-center clinical trial. Our quantitative, neuroelectrophysiology-guided optimization of hypothermia delivery should be similarly applicable to monitoring patients and guiding induced hypothermia clinical trials in the near future. PUBLIC HEALTH RELEVANCE: The focus of the present proposal is on translational research: to study the problem of global ischemic brain injury following cardiac arrest (CA) and develop monitoring technologies for neuro-electrical markers of coma and arousal after CA. The basic research pertains to developing quantitative electrical measures of injury and understanding the cortical and subcortical origins of these signals. The translational research pertains to optimizing the procedure for induced hypothermia after CA using electrical signal measures. The innovation of this project lies in the comprehensive and novel application of quantitative methods, namely cortical (electroencephalography, EEG), subcortical (evoked potentials, EP), and multi-unit (MU) recordings to track injury and recovery. Our work has compelling translational applications: to monitor brain injury after CA in patients and to optimize hypothermia delivery after CA guided by neurological monitoring.