Project Summary/Abstract Traumatic brain injury (TBI) continues to be a major cause of death and disability worldwide. The Center for Disease Control estimates that each year in the United States alone, approximately 2.5 million people sustain a TBI, resulting in 283,000 hospitalizations and 52,000 deaths. TBI encompasses a complex set of pathophysiological stages, including damage to blood vessels, blood-brain barrier (BBB) dysfunction, axonal shearing, cellular excitotoxicity, neuroinflammation, the rise of intracranial pressure, the release of oxygen free radicals, acidosis, and hypoxia/ischemia that lead to further brain damage if not prevented or treated. Parasympathetic activation by vagus nerve stimulation (VNS) via delivering electric impulses to the nerve has been shown to reduce proinflammatory responses, increase norepinephrine concentrations, attenuate glutamate-mediated excitotoxicity, and improve BBB function leading to improvement in cognitive and motor functions following TBI. Recent clinical trials on the use of non-invasive VNS (nVNS) to treat migraine headaches and post-traumatic stress disorders have shown to be effective. Furthermore, nVNS has been shown to improve outcomes in preclinical models of ischemic and hemorrhagic strokes. Our preliminary data for the use of nVNS therapy in a rat TBI model indicates a reduction of the brain lesion volume and anxiety, but further investigations are needed to better understand the true impact of the nVNS therapy on improving the outcome of TBI. Here we propose to conduct a 2-year study to determine the effect of five nVNS in a rat model of TBI. Our primary hypothesis is that nVNS treatment will reduce in brain lesion volume leading to improved cognitive and functional outcomes. Further, we hypothesize that this reduction of symptoms reflects a decrease in BBB dysfunction and proinflammatory processes related to TBI as assessed through neuroimaging, histological, and biochemical studies. For the proposed project, we intend to deliver nVNS therapy in acute settings by delivering five 2x2-min (4 minutes) stimulations, 10 minutes apart on day 1 (within 1 or 6 hours from injury onset) using the gammaCore device (electroCore Inc., NJ). The gammaCore is a handheld (the size of a mobile phone) non-invasive device with a good safety record. It is important to note that the gammaCore device is already FDA-approved for migraine headaches. To date, clinical trials have failed to produce effective treatments to combat the devastating effects of TBI. Therefore, safe and effective treatments are desperately needed to improve the quality of life of service members and civilian populations affected by TBI and promote better recovery and community re-integration after their injury. This proposal has important implications for the field of brain injury by providing necessary information for launching larger preclinical and clinical studies on the use of nVNS.