PROJECT SUMMARY Traumatic brain injury (TBI) represents a major public health concern in the United States. TBI can result in long-term neurological complications, including neurodegeneration, behavioral dysfunction, depression and epilepsy that seriously affect patient quality-of-life. Brain glucose utilization has been found decreased in 60% of patients with chronic TBI and is one of the prognostic indicators for the long-term outcome of TBI. Both animal and human studies have identified that the neurovascular uncoupling between cerebral blood flow (CBF) and brain tissue energy demands is a key factor for cerebral metabolic crisis in the TBI brain. The neurovascular uncoupling results in energy mismatch that disrupts normal neuroglial function and arrests repairing process. Despite numerous clinical trials on potential therapies, there is no U.S. Food and Drug Administration approved drug therapy for the treatment of TBI. One of the reason clinical trials failed is due to the inability that can accurately evaluate the region-specific perturbations of brain glucose metabolism and determine if a treatment can restore neurovascular coupling in the TBI brain. Existent glucose measuring techniques, including microdialysis, continuing blood glucose monitoring, spectroscopy, or positron emission tomography (PET) which uses tracer radioisotopes, provide insufficient resolution to determine region-specific glucose utilization in the brain. In this proposal, we determine to assess the utility of a novel MRI-based Chemical Exchange Saturation Transfer (CEST) imaging, to provide the needed high-resolution for measuring region-specific metabolism for TBI. The glucose detecting CEST MRI (glucoCEST) measures brain glucose by detecting the exchangeable proton signals of glucose without using radioisotopes and generates glucose mapping in a resolution >100 times higher than PET scans. Our preliminary and published data have demonstrated that glucoCEST may be feasible to detect the delayed hypometabolism of diffuse TBI in rats. We propose to combine high-resolution glucoCEST and the Dynamic Contrast Enhanced (DCE) perfusion MRI for concomitant CBF measurements to identify the neurovascular coupling state following TBI over time. Our aims are designed to (1) Identify the contrast mechanism of in vivo glucoCEST in the TBI brain to enhance the sensitivity and specificity of glucoCEST with advanced acquisition scheme and analytical models, (2) Characterize perturbations in brain glucose metabolism and perfusion deficits in the TBI brain, and (3) Demonstrate the potential application of the dual-modality CEST-DCE MRI to noninvasively monitor the treatment effects of a clinically-recommended intervention for TBI. Overall, these studies will provide a strong technical and scientific foundation to move the field forward in utilization of advanced MRI for personalized care in the clinical arena and determine the best treatment strategy for the brain injured patients.