Project Summary/Abstract Infant hydrocephalus is a serious global health problem, with an estimated 400,000 new cases annually. Nearly half of these occur in sub-Saharan Africa, with neonatal infection being the most common cause there. Untreated, hydrocephalus causes progressive brain injury and even death. The standard treatment has long been placement of a ventriculoperitoneal shunt (VPS) but these devices require life-long maintenance and nearly all fail multiple times. Because of this, shunt-dependence is more dangerous in LMIC where emergency access to neurosurgical care is difficult or impossible. CURE Children’s Hospital of Uganda (CCHU) developed an alternate treatment combining endoscopic third ventriculostomy with choroid plexus cauterization (ETV/CPC) to give patients a shunt-free life. An NIH-funded, randomized controlled trial of ETV/CPC vs VPS for infants with post- infectious hydrocephalus (PIH) at CCHU found no significant difference at one-year post-treatment in brain growth or developmental outcomes. Treatment failure is a significant problem for both, occurring in a third. Developmental outcomes were associated with the amount of brain growth, but not with traditional metrics of head or ventricle size. Treatment has always focused on controlling ventricle size, but this has little association with outcomes. Brain growth is a better indicator, and we hypothesize in PIH it depends in part on the integrity of the underlying brain matter after infection and in part on the cerebral circulation’s ability to support regrowth. Consequently, we hypothesize cerebral blood flow and metabolism are more representative of disease severity and treatment response. We developed a novel, combined frequency-domain near-infrared and diffuse correlation spectroscopies (FDNIRS/DCS) technology to measure cerebral blood flow (CBF) and oxygen metabolism (CMRO2) non-invasively at the bedside. In pilot studies at BCH and CCHU, we found untreated hydrocephalus progressively impedes cerebral perfusion and depresses metabolism, while successful treatment immediately restores CBF and CMRO2. Moreover, greater CMRO2 immediately after surgery correlated with better brain growth six months later. We now propose validating these results in a larger group with the goal of leading hydrocephalus treatment away from targeting ventricle size and directing it instead towards measurable improvements in the brain’s physiological health. Such a paradigm shift will have substantial clinical impact in developing countries, the United States, and the rest of the world.