PROJECT SUMMARY/ABSTRACT Hypoxic ischemic encephalopathy (HIE), a major cause of perinatal mortality and long-term morbidity, affects 1- 5/1000 live births. Hypoxic ischemic insults (HII) lead to HIE through a cascade of neuronal injury that continues for hours to days. Therapeutic hypothermia (TH) proved that brain injury from HII can be avoided, revolutionizing treatment of HIE. Despite TH success, additional improvements are urgently needed as up to 63% of infants still die or have long term cognitive deficits. Also, guidelines for treatment are highly subjective, with no consensus on when to treat mild HIE. Our first premise is that adverse outcomes are due to ongoing neuronal injury after HII. As neurons are the primary consumer of oxygen, measures of cerebral oxygen metabolism (CMRO2) would provide a potential means to monitor neuronal health and the evolution of injury. Our second premise is that hemodynamic instability contributes to adverse outcomes through secondary neuronal injury. Secondary injury may be preventable with bedside measures of cerebral blood flow (CBF) to ensure the brain’s metabolic needs are met. In fact, direct CBF measures enable assessment of cerebral autoregulation (CA) and neurovascular coupling (NVC), which reflect hemodynamic stability. Bedside measures of CMRO2 and CBF could enable treatment optimization to prevent secondary injury and inform decisions on who to treat. In R01HD076258, our major achievement was performing >500 Frequency-Domain NIRS and Diffuse Correlation Spectroscopy (FDNIRS- DCS) measurements in >100 neonates with HIE, demonstrating that routine direct bedside measurement of CBF and CMRO2 are possible. Our major finding is that CMRO2 in the days after TH was the only early predictor of outcome, with higher CMRO2 strongly associated (r=0.62, P=0.002) with better 18-month cognitive scores of Bayley Scales of Infant Development 3rd edition (BSID-3). Our renewal goal is to perform early, continuous bedside monitoring of CMRO2 and CBF, demonstrating their potential as vital signs with three aims: Aim 1: Extend current infrastructure to enable continuous, real-time bedside monitoring of neonatal CBF and CMRO2 at 100Hz, integrated with data from other clinical monitors. Aim 2: In neonates with HIE, determine evolution of CMRO2, CA and NVC during TH and their association with post-TH CMRO2; validate that post-TH CMRO2 predicts 2-year outcome. Aim 3: In controls and neonates at risk for HIE but not meeting criteria for TH, determine CMRO2, CA and NVC during the first 24 hours; determine if day 1 CMRO2 predicts 2-year outcome. In the first grant, we demonstrated that bedside measures of CBF and CMRO2 are feasible and discovered that CMRO2 after TH predicts of outcome. In this renewal, we propose to turn CMRO2 and CBF into early, continuous, real-time, bedside vital signs. Our goal is to determine if there is evidence of neuronal injury (decreased CMRO2) mediated by cerebral hemodynamic instability (impa...