The obesity epidemic is a major public health problem, contributing to various comorbid medical conditions, including diabetes, cardiovascular disease, and brain disturbances. The proposed project is designed to delineate mechanisms underlying the effects of severe obesity on brain health and cognition in the context of bariatric surgery induced weight loss. Besides causing dramatic weight loss in many patients, bariatric surgery alters systemic metabolic and vascular function, including altering insulin and glucose metabolism. We have shown cognitive and neurophysiological benefits of bariatric surgery including enhanced cerebral metabolic and hemodynamic function tied to reductions in A1C and BMI. Improvements in insulin-glucose regulation are significant factors in brain health. Findings from the parent R01 (WISE-01) support our earlier findings of improved cognitive function at 3 months and 18 months post-surgery. We further see changes in fMRI functional connectivity in brain networks known to be critical in cognitive functions and cerebral metabolic milieu such that reduced BMI and A1C are associated with lower brain inflammatory markers (MRS). We also showed that markers of brain function and metabolic states prior to bariatric surgery predict BMI and A1C reductions. Furthermore, white matter integrity prior to surgery is predictive of cognitive improvement post- surgery. Our past findings provide compelling evidence linking systemic, cerebral metabolic, and brain function with successful weight loss and diabetes improvements, but several important clinically and scientifically significant questions remain. The extent to which improvements in cognition and brain function persist over longer periods is unknown, motivating the proposed investigation’s Aim 1, an additional assessment of these factors in WISE-01 participants at >36 months after bariatric surgery. There are multiple mechanisms by which obesity, weight loss, and, specifically bariatric surgery may affect brain and systemic health. Amongst these, vagus nerve contributions are compelling as the vagus is a major conduit by which information is conveyed from the gut to and from the brain. The vagus is commonly cut during bariatric surgery and further, stimulation methods (e.g., transcutaneous vagus nerve stimulation [tVNS]) have promise in affecting physiology relevant to weight loss impacts on brain and systemic health. Thus, in Aims 2 and 3, we will prospectively assess the impact of both of these vagus manipulations on brain/cognitive and systemic health post bariatric surgery (pre- surgery, 3- and 18- months post-surgery). In Aim 2, the effects of cutting and sparing the anterior vagus during Roux-en-Y gastric bypass (RYGB) will be assessed. In Aim 3, the effects of tVNS starting three months post- RYGB will be assessed. These three aims will substantially increase our knowledge of longitudinal effects of bariatric surgery on brain and systemic health as well as the role of the ...