PROJECT SUMMARY/ABSTRACT Every year in the United States about 30% of the 60,000 infants born extremely premature (<30 weeks gestational age and <1000 g birth-weight [ELGA]) develop intraventricular hemorrhage (IVH). IVH is associated with high risk for cerebral palsy and significant intellectual disability, causing lifelong implications for affected children and their families and considerable economic burden. IVH is caused by the rupture of the fragile capillaries in the germinal matrix which cannot withstand fluctuations in cerebral blood flow (CBF). In >90% of cases, these injuries occur during the first three postnatal days during a period of cardiorespiratory instability that has a direct effect on CBF, which results in periods of cerebral hypo- and hyper-perfusion. Current management strategies, such as changes in ventilation or inotrope support, are blind to the impact on CBF. Improved bedside technologies to continuously monitor CBF are urgently needed to allow the clinician to make informed decisions, to optimize current strategies and foster the development of new interventions to reduce the incidence of IVH in ELGA infants and to improve developmental outcomes. Building on 149 Medical founding team’s ten years of success measuring infants with non-invasive bedside optical methods, we propose to design and build a novel fast multi-distance diffuse correlation spectroscopy (DCS) system, optimized for continuous monitoring of CBFi in ELGA infants. DCS directly quantifies an index of cerebral blood flow (CBFi) by measuring the temporal fluctuations of light generated by the dynamic scattering of moving red blood cells. To be of use in the ELGA infant, this bedside monitor needs to be safe, continuous, precise, reliable, quantitative and gently wearable. These pre-requisites will be met by designing an optical sensor which can be gently applied to the ELGA infant. The novel DCS system will be initially tested by the 149 Medical’s team in phantoms to verify performance and demonstrate precision and accuracy of flow estimates. The system will then be tested in more mature, stable premature infants at the Brigham and Women's Hospital (BWH) NICU to evaluate feasibility of long measurements, compatibility with the NICU environment, skin integrity after long monitoring periods, and in-vivo algorithm validation. Finally, the device will be used in 50 ELGA infants during the first 72 hours of life to test our hypothesis that DCS-measured CBFi fluctuations and pressure-passive events correlate with incidence and severity of IVH. Our goal is to provide a much-needed cerebral blood flow monitor to guide individualized treatment with the goal of reducing the risk of IVH and improving long term neurodevelopmental outcomes among ELGA infants. This study in 50 ELGA infants will set the stage for a larger trial alongside commercialization.