Pain is a multidimensional experience that involves sensory, cognitive and affective factors. The constellation of interactions between these factors renders the treatment of chronic pain challenging and often a financial burden. In fact, chronic pain affects over 100 million Americans and costs the United States approximately $635 billion dollars a year. The widespread use of opioids to treat chronic pain has led to the so-called “opioid epidemic” due to the exponential growth in opioid misuse and addiction. These staggering statistics highlight the importance of developing, testing and validating fast-acting, non-pharmacological approaches to treat pain. Mindfulness meditation is a technique that has been found to significantly reduce pain in experimental and clinical settings. However, lack of mechanistic data and the assumption that extensive meditation training is required to experience analgesia has limited the clinical deployment of this cost-effective and narcotic-free treatment. Recent findings from our laboratory determined that mindfulness meditation, after only four sessions (20 minutes/session) of training, dramatically reduces pain intensity and unpleasantness ratings. Across two functional neuroimaging studies, employing perfusion-based MRI (arterial spin labeling), we found that mindfulness meditation reduces pain through multiple brain mechanisms related to increased cognitive control, emotion regulation and attenuation of ascending nociceptive input. However, these results cannot be generalized to chronic pain because they were associated with healthy, pain-free participants and thermally induced pain. Importantly, the brain mechanisms supporting the modulation of chronic pain by mindfulness meditation remain unknown. Thus, the central aim of the proposed R01 study is to determine the specific mechanisms supporting the modulation of acutely exacerbated chronic low-back pain, the most prevalent and financially burdensome chronic pain condition, by acutely trained mindfulness meditation. We will determine if the neural mechanisms found to attenuate experimentally induced pain by mindfulness meditation (i.e., OFC, sgACC, thalamus) are also associated with modulating chronic low back pain. The neurofunctional connections supporting mindfulness-based pain relief are also unknown. Thus, we will also examine if mindfulness-based pain relief is associated with thalamic-default mode network decoupling to provide mechanistic insight to better develop interventions to target pain.