Posttraumatic Stress Disorder (PTSD) is highly co-morbid with chronic pain conditions. Pain contributes to more severe PTSD (and vice versa) as evidenced by greater disability, more frequent use of harmful opioid analgesics and increased pain severity. Biomechanisms underlying the entanglement of pain and trauma in Veterans are incompletely understood. This is a renewal application (CSR&D Merit Review CX000816) to continue deciphering the neural networks underlying pain and PTSD co-morbidity in Veterans. The long-term goal is to determine biological markers of heterogeneity within pain-trauma co-morbidity in order to improve symptom prevention and treatments. Understanding unique and overlapping impact of pain and/or trauma symptoms on the underlying neurocircuitry has the potential to optimize existing and pave way to developing new, biologically targeted interventions. The objective of this renewal is to build upon our prior findings and identify the role of expectation in pain-trauma comorbidity in diagnostically heterogeneous Veterans with combat trauma and chronic pain. Our current hypotheses are based on our published and strong preliminary data. We propose to test the “two-component” expectation or anticipation model whereby neural systems underlying anticipation of pain onset (broken in traumatic stress) and pain offset (broken in chronic pain) interact to create biomechanistic vulnerability for pain-trauma comorbidity. We will examine the integrity (i.e., connectivity) and capability (i.e., function) of neural networks underlying pain and pain relief anticipation in diagnostically heterogeneous cohort of Veterans. We will employ advanced neuroimaging (rest and task-based functional MRI) and advanced statistical approaches to uncover multivariable anticipatory biophenotypes within Veterans with comorbid pain and trauma. Aim1: To determine the degree to which traumatic stress affects the capability and integrity of pain anticipation Hypothesis 1a: Traumatic stress will be associated with abnormal pain anticipation response within insula and amygdala during task-based fMRI; Hypothesis 1b: Traumatic stress will disrupt fronto-amygdala-insular connectivity at rest. Aim2: To determine the degree to which chronic pain affects the capability and integrity of relief anticipation. Hypothesis 2a: Chronic pain will be associated with abnormal pain relief anticipation within insula and cingulate during task-based fMRI; Hypothesis 2b: Chronic pain will disrupt fronto-striatal-insula connectivity at rest. Exploratory Aim3: Build robust biophenotypes based on subgrouping anticipatory mechanisms. We will utilize clustering approaches including, but not limited to, graph-based models. The best model will be determined through analysis of training, test, and validation samples. Hypothesis 3: We will be able to separate pain anticipation vs. relief anticipation biophenotypes in diagnostically heterogeneous Veterans with combat trauma and chronic pain. This ...