More than 400,000 sudden cardiac deaths occur in the USA annually. Among survivors of cardiac arrest (CA), brain injury is the biggest impediment to functional recovery. Induced hypothermia is currently the only form of therapy that improves both survival and neurological outcome for CA survivors. However, for decades, hypothermia delivery has been blindly directed toward faster cooling, and without objective indicators of the brain's response to temperature. So far, there is no monitoring methodology to guide hypothermia therapy and to improve its efficiency. A major hindrance for more beneficial results of this therapy is that optimal level and duration of hypothermia is unknown. The detail mechanisms underlying the protective effect of hypothermia are also largely unknown.
Aim 1 : Our first goal is to develop and evaluate novel, non-invasive, quantitative EEG (qEEG) marker of functional outcome after CA. We test the hypotheses that a) qEEG analysis, based on our novel entropy based algorithms, will capture electrophysiological recovery to pre-CA baseline, and b) sequential recovery in subbands will have highly differentiated entropy level, and correspondingly show greater sensitivity to different phases of recovery after injury and effects of therapeutic hypothermia.
Aim 2 : We will use the qEEG marker to obtain feedback on brain's response to the a) depth (temperature level) and b) duration of hypothermia delivery. We will test the hypothesis that electrophysiological monitoring by qEEG will serve as a biomarker of the brain's recovery and, thus, will provide objective guidance for hypothermia delivery.
Aim 3 : Our last broad goal is to provide an objective analysis of hypothermia's effect on spatio-temporal pattern of glucose utilization (via small animal positron emission tomography (PET) imaging and electrophysiological recovery (EEG)) after CA. We test the hypotheses that hypothermia will increase the glucose re-utilization and change the spatial pattern in subcortical and cortical brain regions, which contribute to corresponding EEG changes signaling recovery with an earlier return of normalization, to improve the functional outcome after CA. The significance of this project is three fold: 1) development and systematic evaluation of simple and objective qEEG monitoring tools of brain injury after CA, 2) the expected benefits of improved functional and electrophysiological outcomes with dynamic hypothermia titration, and 3) expected discovery of the protective mechanism behind therapeutic hypothermia and consequent glucose utilization and cortical electrophysiological function. The innovation in this project lies in 1) comprehensive and novel quantitative algorithm to systemically monitor and predict arousal after CA, 2) for the first time, guiding hypothermia delivery by the qEEG markers of brain's response to temperature, and 3) unique dual monitoring approach (PET and EEG) after CA to uncover hypothermia's protective mechanism. The approach to assess the improvement using glucose metabolic and electrophysiological recovery (EEG) patterns will be highly important to understand the mechanisms and develop a rational approach to hypothermia treatment. Our experimental model and the proposed technical approaches readily lend themselves to clinical translation: for example qEEG markers could easily be incorporated in a clinical bedside monitor. Like ubiquitous external defibrillator revolutionized heart protection, our novel monitoring and titration of hypothermia we hope will enter clinical practice.

Public Health Relevance

This project will develop novel quantitative EEG based neuro-electrical markers of coma and arousal after cardiac arrest, and modulate therapeutic hypothermia by quantitative electrophysiological markers toward improved functional outcome. It will explore the impact of therapeutic hypothermia on spatio-temporal pattern of glucose utilization measured by small animal positron emission tomography (PET) imaging, and electrophysiological recovery after cardiac arrest.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Acute Neural Injury and Epilepsy Study Section (ANIE)
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Desvigne-Nickens, Patrice
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Johns Hopkins University
Biomedical Engineering
Schools of Medicine
United States
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Jia, Xiaofeng (2016) Translational Medicine: Creating the Crucial Bidirectional Bridge between Bench and Bedside. Int J Mol Sci 17:
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Choi, Young-Seok (2015) Information-Theoretical Quantifier of Brain Rhythm Based on Data-Driven Multiscale Representation. Biomed Res Int 2015:830926
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Deng, Ruoxian; Xiong, Wei; Jia, Xiaofeng (2015) Electrophysiological Monitoring of Brain Injury and Recovery after Cardiac Arrest. Int J Mol Sci 16:25999-6018

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