This thesis addresses the need for continuous cerebral monitoring immediately after birth. For at-risk populations, such tools potentially enable early detection of injury and possible interventions to mitigate further neurological injury. More specifically, adverse neurological outcomes are common in neonates with severe congenital heart defects following cardiac surgeries that employ cardiopulmonary bypass (CPB). Since adequate oxygen delivery and metabolism are both critical for avoiding neurologic injury, we have developed instrumentation to monitor cerebral impacts of CPB, and we have utilized this instrumentation in animal model (swine) experiments which explore the use of mild hypothermic CPB (MH-CPB) for neuroprotection (by decreasing metabolic demand). Here we employ diffuse optics, specifically combined instrumentation based on diffuse optical spectroscopy (DOS) and diffuse correlation spectroscopy (DCS), as a continuous, non-invasive and portable means of measuring absolute blood oxygenation, oxygen extraction fraction, blood flow, and oxygen metabolism in the brain during and after MH-CPB surgery. We applied these technologies to a pre-clinical neonatal model of swine undergoing CPB. Notably, we concurrently obtained other metabolic biomarkers from invasive cerebral microdialysis sampling, including metrics of metabolic distress (lactate-pyruvate ratio) and injury (glycerol). Thus, the work provides comparison metrics for diffuse optics, and the work teaches us about brain physiological response during mild hypothermic CPB. The measurements were performed before, during, and after MH-CPB in a neonatal swine model (n=28). Changes in cerebral physiology during and after MH-CPB were assessed using linear mixed effects models. Importantly, profound changes in hematocrit during MH-CPB (e.g., +54% variation from baseline) motivated the development and application of a hematocrit-corrected analysis for the optical measurements; we found that the hematocrit corrections led to reduced cerebral blood flow and oxygen metabolism values compared to predictions of the conventional analysis of diffuse optical data. We believe that this approach for hematocrit correction is important, because it could impact optical measurements in a plethora of medical procedures wherein hematocrit is likely to change, e.g., blood transfusions, large loss of blood during surgery, or extracorporeal membrane oxygenation (ECMO). Using this correction, and other standard diffuse optics analyses, we learned about brain physiology during and after MH-CPB. While no significant metabolic distress was detected during CPB, we did find that several parameters (i.e., glycerol, StO2) were significantly elevated 0 to 8 hours following MH-CPB and then started to resolve between 8 and 24 hours after CPB. Coupled with our pathology results, this finding suggests that a resolution in neurologic injury from CPB occurs around 8-12 hours post-CPB. Thus, more care may be needed for the first 8-12 hours. We also found that amount of oxygen extracted from blood significantly increased during CPB, while blood flow and cerebral metabolism slightly decreased with increased duration on bypass. This finding could indicate that prolonged exposure to CPB can cause additional neurologic injury. In addition to the hematocrit/MH-CPB studies, this thesis also addressed two weaknesses of the current generation of diffuse optical probes. The first advance developed/demonstrated a chassis coupling technique which improved reproducibility of any diffuse optical measurements that involved attachment and reattachment of the probe to the tissue surface. The second advance improved the capability of the probe to measure blood flow through hair, which is a major absorber of light that reduces signal-to-noise of brain measurements. This scheme placed fibers directly on the scalp, ‘combing’ the hair out of the way; the work identified a path for additional improvements to improve patient comfort and measurement fidelity in clinical settings.