Neonatal encephalopathy (NE) resulting from birth asphyxia constitutes a major global public health burden for millions of infants every year, and despite therapeutic hypothermia, half of neonates have poor neurologic outcomes. As new neuroprotective interventions are being studied in clinical trials, there is a critical need to establish physiological surrogate markers of therapeutic efficacy, to guide patient selection and/or to modify the therapeutic intervention. The challenge in the field of neonatal brain injury has been the difficulty to clinically discern the NE severity within the short therapeutic window after birth, or to analyze the dynamic aspects of the cerebral circulation in the NE sick newborns. The PI and her bioengineering team have developed a ?wavelet neurovascular bundle? analytical system that can measure cerebral autoregulation (CA) and neurovascular coupling (NVC) at multiple time scales under dynamic, non-stationary clinical conditions. A real time evaluation of the coupling of cerebral blood flow and neuronal activity ?neurovascular bundle? is therefore proposed in order to determine the severity of injury and identify infants that could potentially benefit from added therapies. The proposed approach not only has the ability to capture the evolving non-stationary aspects of the cerebral circulation, but can also quantify the magnitude and duration of the impaired hemodynamics in NE, and their effect on functional and structural outcomes. The PI has published her methodological technology development, together with preliminary observations linking the wavelet bundle measures to short- and long- term developmental outcomes following hypothermia. The long-term goal is to harness the technological advantages of the wavelet neurovascular bundle to optimize outcomes in asphyxiated newborns, by appropriately selecting patients for therapeutic trials and identifying the factors underlying responses to therapy. Erythropoietin (EPO), with postulated effects on cerebral blood flow, neurogenesis and angiogenesis, is currently being evaluated as a new adjunct therapy for moderate to severe NE (High dose EPO Asphyxia; NS092764 NCT02811263 NINDS1U01). The central hypothesis in this ancillary study at UT Southwestern is that the new wavelet neurovascular bundle measures will stratify the NE severity(Aim 1), identify the effects of EPO on CA/NVC during a new randomized neuroprotection trial of EPO + Hypothermia vs. Hypothermia alone (Aim 2), and predict short-term structural and long-term functional outcomes(Aim 3). To test this hypothesis, 100 newborns will be enrolled at UT Southwestern (30 non-treated mild NE and 70 moderate or severe NE who are randomized to treatment with EPO + Hypothermia or Hypothermia alone) and examined for developmental outcomes at 24months. New knowledge gained from the wavelet bundle will specifically provide:1) improved stratification of brain injury severity among newborns with NE, 2) understanding the effect of EPO on cerebral autoregulation and neuronal coupling, and 3) new bio-mediators that can predict responses to therapies in real time, aiming to improve brain outcomes as per NINDS mission.

Public Health Relevance

Infants asphyxiated at birth represent a serious problem worldwide. There is a great need for development of tools that permit non-invasive continuous neuromonitoring and accurate measures of cerebral flow and function? critical components of brain health in babies. This proposal is relevant to public health because the new wavelet neurovascular bundle is expected to improve identification of brain injury at birth, guide patient selection and optimize the efficacy of therapeutic interventions, thereby keeping with the NINDS mission to seek fundamental knowledge about the brain in order to reduce the burden of neurological disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Koenig, James I
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University of Texas Sw Medical Center Dallas
Schools of Medicine
United States
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Chalak, Lina F; Nguyen, Kim-Anh; Prempunpong, Chatchay et al. (2018) Prospective research in infants with mild encephalopathy identified in the first six hours of life: neurodevelopmental outcomes at 18-22 months. Pediatr Res :
Chalak, Lina F (2018) Best practice guidelines on management of mild neonatal encephalopathy: Is it really mild? Early Hum Dev 120:74
Chalak, Lina; Latremouille, Samantha; Mir, Imran et al. (2018) A review of the conundrum of mild hypoxic-ischemic encephalopathy: Current challenges and moving forward. Early Hum Dev 120:88-94
Shankaran, Seetha; Laptook, Abbot R; Pappas, Athina et al. (2017) Effect of Depth and Duration of Cooling on Death or Disability at Age 18 Months Among Neonates With Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial. JAMA 318:57-67
Tian, Fenghua; Morriss, Michael Craig; Chalak, Lina et al. (2017) Impairment of cerebral autoregulation in pediatric extracorporeal membrane oxygenation associated with neuroimaging abnormalities. Neurophotonics 4:041410
Chalak, Lina F; Tian, Fenghua; Adams-Huet, Beverley et al. (2017) Novel Wavelet Real Time Analysis of Neurovascular Coupling in Neonatal Encephalopathy. Sci Rep 7:45958
Ouyang, Minhui; Liu, Peiying; Jeon, Tina et al. (2017) Heterogeneous increases of regional cerebral blood flow during preterm brain development: Preliminary assessment with pseudo-continuous arterial spin labeled perfusion MRI. Neuroimage 147:233-242
Chalak, Lina F; Zhang, Rong (2017) New Wavelet Neurovascular Bundle for Bedside Evaluation of Cerebral Autoregulation and Neurovascular Coupling in Newborns with Hypoxic-Ischemic Encephalopathy. Dev Neurosci 39:89-96
Laptook, Abbot R; Shankaran, Seetha; Tyson, Jon E et al. (2017) Effect of Therapeutic Hypothermia Initiated After 6 Hours of Age on Death or Disability Among Newborns With Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial. JAMA 318:1550-1560