PROJECT SUMMARY / ABSTRACT Postural tachycardia syndrome (POTS) is a common, disabling disorder among adolescents, interfering with their schoolwork, physical and social development. It occurs most often in adolescent females post- menarche. The combination of orthostatic symptoms such as dizziness, nausea, weakness, or brain fog with a 40 bpm rise in heart rate in the first 10 minutes of a tilt table test without a drop in blood pressure defines the disorder. Two striking and nearly universal features of POTS are (1) its onset after a major threat such as an infection or trauma and (2) its association with many co-morbid disorders such as migraine headache, fibromyalgia, functional gastrointestinal disorders like irritable bowel syndrome, and others that commonly fall under the classification of chronic overlapping pain conditions (COPC). Although we and others have repeatedly reported these curious associations, no study or pathophysiologic theory has attempted to include either of these observations in a model for the fundamental etiology of POTS. Here we propose that the brain region responsible for the orchestration of “life or death” response to an acute major threat, the periaqueductal gray region (PAG) in the midbrain, does not properly reset after a threat has passed (explaining the observation that POTS onset follows a threat) and continues in a chronic state of threat readiness. We further hypothesize that this chronic state impacts the two major areas of known control by the PAG: cardiovascular autonomic regulation, resulting in POTS, and pain signaling from end-organs, resulting in COPC’s. Such PAG dysregulation likely occurs through the vagus nerve, known to be abnormal in POTS. We will test this hypothesis in 3 aims comparing 60 adolescent and young adult females with POTS to 60 healthy female subjects, 40 of whom will just had an infection severe enough for a hospital admission. In aim 1, we will study the natural history to understand whether POTS and COPC’s flare simultaneously and are typically associated with a preceding identifiable threat, and whether the healthy controls after infection develop any limited symptoms of POTS or COPC that eventually recede. In aim 2 we will image the PAG both at rest and during a “looming threat task” which probes the PAG’s responsiveness to threat. We expect the PAG to be more threat-responsive in the POTS subjects and in the healthy subjects immediately in the wake of the infection compared to subjects without POTS or recent infection. Aim 3 will consist of assessing cardiovascular vagal function through heart rate variability (HRV). We expect that more severe POTS subjects will show lower HRV in association with greater PAG threat readiness, and that changes in PAG threat readiness will be associated with changes in HRV. This project is the first proposal of a unifying hypothesis explaining all the major features of POTS, and the potential for new treatment approaches.