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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL071568-10
Application #
8441505
Study Section
Special Emphasis Panel (ZRG1-ETTN-E (10))
Program Officer
Desvigne-Nickens, Patrice
Project Start
2002-07-01
Project End
2014-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
10
Fiscal Year
2013
Total Cost
$427,544
Indirect Cost
$166,847
Name
Johns Hopkins University
Department
Biomedical Engineering
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Geocadin, Romergryko G; Murthy, Santosh B (2014) Prognostication following cardiac arrest: do we have our patients' safety in mind?*. Crit Care Med 42:1959-61
Sutter, R; Barnes, B; Leyva, A et al. (2014) Electroencephalographic sleep elements and outcome in acute encephalopathic patients: a 4-year cohort study. Eur J Neurol 21:1268-75
Mulder, Maximilian; Geocadin, Romergryko G (2014) Will the promise of drug-induced therapeutic hypothermia be fulfilled? Crit Care Med 42:221-3
Bazley, Faith A; Maybhate, Anil; Tan, Chuen Seng et al. (2014) Enhancement of bilateral cortical somatosensory evoked potentials to intact forelimb stimulation following thoracic contusion spinal cord injury in rats. IEEE Trans Neural Syst Rehabil Eng 22:953-64
Naval, Neeraj S; Geocadin, Romergryko G (2014) Brain and blood flow: it takes two to tango. Resuscitation 85:450-1
Chen, Cheng; Maybhate, Anil; Israel, David et al. (2013) Assessing thalamocortical functional connectivity with Granger causality. IEEE Trans Neural Syst Rehabil Eng 21:725-33
Kalanuria, Atul A; Geocadin, Romergryko G (2013) Early prognostication in acute brain damage: where is the evidence? Curr Opin Crit Care 19:113-22
Mulder, Maximilian; Geocadin, Romergryko G (2013) Uncertainties of death and dying in the era of therapeutic hypothermia: Impact on patient care and research. Resuscitation 84:271-3
Wu, Dan; Xiong, Wei; Jia, Xiaofeng et al. (2012) Short- and long-latency somatosensory neuronal responses reveal selective brain injury and effect of hypothermia in global hypoxic ischemia. J Neurophysiol 107:1164-71
Geocadin, Romergryko G; Kaplan, Peter W (2012) Neural repair and rehabilitation: the effect of therapeutic hypothermia on prognostication. Nat Rev Neurol 8:5-6

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