Over 100 million Americans suffer from chronic pain, which causes more disability than any other medical condition in the United States at a cost of $560–$635 billion per year. Opioid analgesics are frequently used to treat CP. However, long term use of opioids can cause brain changes such as opioid-induced hyperalgesia that, over time, increase pain sensation. Also, opioids fail to treat complex psychological factors that worsen pain-related disability, including beliefs about and emotional responses to pain. Cognitive behavioral therapy can (...) be efficacious for CP. However, CBT generally does not focus on important factors needed for long-term functional improvement, including attainment of personal goals and the psychological flexibility to choose responses to pain. Acceptance and Commitment Therapy has been recognized as an effective, non-pharmacologic treatment for a variety of CP conditions. However, little is known about the neurologic mechanisms underlying ACT. We conducted an ACT intervention in women with chronic musculoskeletal pain. Functional magnetic resonance imaging data were collected pre- and post-ACT, and changes in functional connectivity were measured using Network-Based Statistics. Behavioral outcomes were measured using validated assessments such as the Acceptance and Action Questionnaire, the Chronic Pain Acceptance Questionnaire, the Center for Epidemiologic Studies Depression Scale, and the NIH Toolbox Neuro-QoLTM scales. Results suggest that, following the 4-week ACT intervention, participants exhibited reductions in brain activation within and between key networks including self-reflection, emotion, and cognitive control. These changes in connectivity strength were correlated with changes in behavioral outcomes including decreased depression and pain interference, and increased participation in social roles. This study is one of the first to demonstrate that improved function across the DMN, SN, and FPN may drive the positive outcomes associated with ACT. This study contributes to the emerging evidence supporting the use of neurophysiological indices to characterize treatment effects of alternative and complementary mind-body therapies. (shrink)