Neonatal encephalopathy (NE) due to hypoxia-ischemia is a major public health concern as it occurs in 6/1000 live term births and has devastating consequences. Many affected neonates suffer lifelong motor disabilities and epilepsy, but increasingly the high prevalence of cognitive and behavioral disabilities is becoming appreciated. In hypoxia-ischemia there is a decrease in blood and oxygen delivery, followed by reperfusion with transient energy recovery. What follows is a window of opportunity where excitotoxicity and associated increased cerebral metabolism eventually lead to secondary energy failure and irreversible cell death. In this window, therapeutic hypothermia (TH) is currently the only treatment available with proven efficacy. TH acts primarily by decreasing cerebral metabolism, thus preserving energy stores. Although the current gold standard for brain injury detection is magnetic resonance imaging (MRI), MRI is impractical as a screening tool and cannot provide bedside monitoring to optimize individual responses to therapies. Commercially available continuous wave (CW) near infrared spectroscopy (NIRS) systems provide bedside measures of cerebral oxygen saturation (SO2) but SO2 alone cannot assess oxygen metabolism, as oxygen delivery is not taken into account. What is needed is a bedside tool that can monitor cerebral metabolism to detect elevations in metabolism that suggest evolving hypoxic-ischemic injury, and decreases in metabolism that suggest response to therapy. Cerebral oxygen consumption (CMRO2) is a direct measure of cerebral metabolism and therefore we propose to measure an index of CMRO2 at the bedside using the innovative combination of Frequency Domain Near-Infrared Spectroscopy (FDNIRS) and Diffuse Correlation Spectroscopy (DCS). Our initial studies show that CMRO2 is elevated in neonates with MRI evidence of perinatal brain injury, and confirm that neonates on TH have significantly lower CMRO2 than normal controls. Following these exciting results, and in response to the RFA PAR-10-230 Innovative Therapies and Tools for Screenable Disorders in Newborns we now propose a feasibility study to determine if FDNIRS-DCS can screen for involvement, assess response to treatment, and predict outcomes in one of the largest neonatal populations requiring early screening and immediate intervention: neonatal encephalopathy. To assess early outcomes we propose an innovative combination of advanced neurobehavioral testing, regional FDNIRS-DCS measures and quantitative MRI analysis using MRIs obtained without sedation. If our hypotheses prove true, we will be poised to determine if bedside indices of CMRO2 provided by FDNIRS-DCS can optimize TH for individual neonates, thereby improving neurodevelopmental outcomes. Success at this stage will also allow exploration of the potential for FDNIRS-DCS to determine the additional benefits of emerging new treatments for NE and to screen for other treatable neonatal disorders.

Public Health Relevance

Neonatal encephalopathy continues to cause significant morbidity and the lack of a bedside tool to assess newborn brain health limits progress in neonatal care that could improve neurodevelopmental outcomes. The overall goal of this proposal is to determine if FDNIRS-DCS can screen for acute neonatal encephalopathy, assess response to treatment and predict outcomes in a population of at-risk neonates.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD076258-05
Application #
9540901
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Krotoski, Danuta
Project Start
2014-06-01
Project End
2019-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Boston Children's Hospital
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
Karmacharya, S; Gagoski, B; Ning, L et al. (2018) Advanced diffusion imaging for assessing normal white matter development in neonates and characterizing aberrant development in congenital heart disease. Neuroimage Clin 19:360-373
Jaimes, Camilo; Cheng, Henry H; Soul, Janet et al. (2018) Probabilistic tractography-based thalamic parcellation in healthy newborns and newborns with congenital heart disease. J Magn Reson Imaging 47:1626-1637
Ferradal, Silvina L; Yuki, Koichi; Vyas, Rutvi et al. (2017) Non-invasive Assessment of Cerebral Blood Flow and Oxygen Metabolism in Neonates during Hypothermic Cardiopulmonary Bypass: Feasibility and Clinical Implications. Sci Rep 7:44117
Shellhaas, Renée A; Chang, Taeun; Wusthoff, Courtney J et al. (2017) Treatment Duration After Acute Symptomatic Seizures in Neonates: A Multicenter Cohort Study. J Pediatr 181:298-301.e1
Lin, Pei-Yi; Hagan, Katherine; Fenoglio, Angela et al. (2016) Reduced cerebral blood flow and oxygen metabolism in extremely preterm neonates with low-grade germinal matrix- intraventricular hemorrhage. Sci Rep 6:25903
Dehaes, Mathieu; Cheng, Henry H; Buckley, Erin M et al. (2015) Perioperative cerebral hemodynamics and oxygen metabolism in neonates with single-ventricle physiology. Biomed Opt Express 6:4749-67