Hypoxic-ischemic encephalopathy (HIE) is the leading cause of newborn death and disability worldwide and presents clinically as neonatal encephalopathy that is difficult to classify within a short window after birth to inform neuroprotective interventions. Therapeutic hypothermia (TH) has dramatically improved outcomes in moderate to severe HIE when initiated within six hours of life (HOL), yet trials have not included mild HIE. The difficulties to discern the clinical severity shortly after birth and to analyze the dynamic circulation in sick newborns represent important challenges. As new trials are now considered to target unstudied mild HIE, neurophysiological and neuroimaging biomarkers are critically needed 1) to guide real-time patient selection within a short therapeutic window and 2) to provide insight into timing of the metabolic energy failure and effect on structural and functional brain outcomes. Our team pioneered a “wavelet neurovascular bundle” analytical system to measure neurovascular coupling (NVC) under dynamic conditions and in real time, and to measure regional oxygen consumption one step further into the core of brain energy homeostasis. The parent grant initially focused on infants with moderate to severe HIE during the 72 hours of treatment and resulted in twenty six new publications. The overarching goal of this renewal is to harness our novel physiological biomarkers to focus on untreated mild HIE to identify those who need treatment. Our objective is to test dynamic biomarkers that can predict structural and functional outcomes chosen with input from stakeholders, and inform physiological and metabolic disturbances specific to mild HIE. We plan to enroll a new cohort of 100 neonates with mild HIE (35 per year over 3 years) and to follow up for two years infants for developmental outcomes. Our infrastructure ensures the success of this proposal and includes a multidisciplinary team of experts in hemodynamics and electrophysiology signals (Chalak, Zhang), bioengineering (Liu), and neuroimaging (Liu P, Wisnowski). The high-volume, supportive research environment at Parkland Hospital, including a 3T Siemens Skyra located inside the NICU, permits imaging of sick newborns as early as the first day of life. New knowledge will specifically provide: 1) Development and optimization of neuroimaging and neurophysiological assessments of mild HIE; and 2) improved HIE stratification via multi-modal assessments. Impact. The ability to monitor global neurovascular functions in real time could lead to a paradigm shift by providing the field with sensitive physiological biomarkers to detect the evolution of deficits in mild HIE and allow targeted interventions in this unstudied population. Engaging community stakeholders ensures that the NIH mission remains aligned with the priorities of affected families.

Infants asphyxiated at birth represent a serious problem worldwide. There is a need for development of neurophysiological and neuroimaging biomarkers providing accurate measures of neurovascular and metabolic functions– critical components of brain health in babies. This proposal is relevant to public health as the wavelet biomarkers can improve identification of brain injury at birth, guide patient selection for therapeutic interventions in mild HIE, keeping with the NINDS mission to reduce the burden of neurological disease.