1 Nearly 2.5 million troops have served in Iraq and Afghanistan . As of November 2013, over 287,000 members of this cohort were diagnosed with posttraumatic stress disorder (PTSD), costing the VA $68 million in outpatient PTSD treatment and $1.94 billion in overall care2.While there are several validated treatment options for PTSD, little objective guidance exists for selecting the best treatment option for a given patient. Based on current knowledge, physiological response patterns to trauma-related imagery are a promising potential measure to fill this gap. Research has consistently shown that PTSD is associated with heightened physiological reactivity to idiographic trauma-related cues3. Although most individuals with PTSD demonstrate heightened reactivity, a substantial minority do not. Upwards of 40% of individuals with PTSD exhibit non-elevated physiological reactivity to cues when tested in the laboratory3-6, despite their reporting the same levels of subjective arousal as physiological responders. Also, those with dissociative subtype of PTSD have been shown to exhibit attenuated reactivity to trauma-related cue5-6. Given their lack of reactivity to trauma-related stimuli, Veterans who are physiologically non-reactive may be less likely to respond favorably to prolonged exposure (PE) therapy7, the leading evidence-based treatment for PTSD. In such cases, the use of other evidence-based treatments may be indicated8 (e.g., CPT). However, this premise has not yet been tested. Our long-term goal is to personalize treatment, improve clinical outcome, and ultimately improve the lives of Veterans with PTSD. As a first step towards this long term goal, the primary objective of the current proposal is to determine whether physiological non-reactors benefit from PE therapy to the same extent as Veteran reactors. Change in PTSD symptom severity (CAPS-5 total score) will serve as the primary outcome measure. PTSD remission (CAPS-5 diagnostic criteria no longer met) will serve as a secondary outcome measure. Based on findings from our work, as well as evidence from the current literature, we hypothesize that non-reactive, compared to reactive, pretreatment physiological response patterns will predict treatment outcome. Primary Aim: To determine the relationship between pre-treatment physiological reactivity to trauma-related cues and PE treatment outcome. H1: Compared to Veteran reactors, non- reactors will demonstrate a smaller change in PTSD symptom severity scores following PE therapy, after adjusting for comorbidities. H2: Compared to Veteran reactors, non-reactors will have a lower rate of PTSD remission following PE therapy, after adjusting for comorbidities. Exploratory Aim: To determine the relationship between dissociative symptoms, pre- treatment physiological patterns and PE treatment outcome. Q1: Do physiologic reactors and non- reactors differ in the level of reported current dissociative symptoms? Q2: Are dissociative symptoms related to treatment outcome? Methods This 2-year prospective SPiRE uses a cohort repeated measures design for the two primary outcomes based on CAPS assessment. The study will require two pre-treatment visits and one post-treatment visit. The first visit will consist of consent, screening, diagnostic assessment wit CAPS (pretest) and SCID, and development of scripts for SDI. The second visit will consist of psychophysiological testing and administration of surveys. The post-treatment assessment will consist of a diagnostic assessment with CAPS (posttest). Treatment will consist of Prolonged Exposure (PE) Therapy, where 9 sessions is typically completed in 10-12 weeks.