PROJECT SUMMARY This proposal aims to use innovative advances in sodium MRI (NaMRI) and proton (1H) diffusion MRI to identify imaging biomarkers of disease in patients with Mild Traumatic Brain Injury (MTBI). NaMRI provides unique in vivo ionic information about the brain, though has historically been plagued by low signal-to-noise ratio (SNR), limiting its utility in studying clinical populations. However, recent technological advances proposed here allow translation to clinical groups such as patients with MTBI. MTBI is a major public health problem yet the underlying pathophysiology remains a mystery and ionic imbalance including sodium dysregulation has been implicated in the disease in cell and animal experiments as well as preliminary studies in human subjects. Quantifying brain sodium in MTBI and finding NaMRI biomarkers for disease is particularly exciting as this could shed light on the mechanism of injury in MTBI and open the door to the development of new treatment pathways which are badly needed. Furthermore, there are promising results from cellular and animal models of MTBI using selective sodium channel blockade that mitigate damage relating to injury, suggesting sodium plays a central but as yet unexplored role in the pathophysiology of MTBI. Our team’s combined strengths in innovative and cutting-edge NaMRI methods, diffusion microstructure imaging, and MTBI will allow us to meet the goals of this project. We propose to leverage technical advances that make NaMRI clinically feasible at 3.0T, including work from our group in multinuclear coil design, image acquisition, image reconstruction and data analysis. The work specifically seeks to quantify NaMRI signal to 1) characterize changes after injury, 2) explore the link between known white matter compromise and altered brain sodium in conjunction with advanced diffusion MRI and 3) determine if sodium mediates the relationship between microstructural changes and clinical symptoms. Identifying surrogate imaging biomarkers to better quantify injury and recovery will allow development of objective return-to-activities recommendations, address the need to develop methods to predict risk for prolonged symptoms, and point to new pathways for therapy.