Abstract Chronic pain is common and often inadequately treated in older individuals. Although opioids are often used to treat chronic pain, their use in older adults is associated with increased rates of falls, fractures, and mortality. Advancing our understanding of non-pharmacological chronic pain treatment in Americans ≥60 years of age will substantially alleviate the burdens caused by this condition. Experimental pain paradigms mimic the experience of clinical pain (both neuropathic via thermal paradigms, as well as musculoskeletal via mechanical paradigms) and provide a rigorously controlled approach to advancing the understanding of pain treatments. Two efficacious, non-pharmacological chronic pain treatments are mindfulness meditation (MM) and self- hypnosis (HYP). Prior research using functional magnetic resonance imaging (fMRI) has shown MM and HYP may target changes in both unique and shared central pain mechanisms. However, it is not yet known whether these same neuromodulatory changes underlie treatment-related reductions in chronic pain in older persons. Given that aging affects the prefrontal cortex and both MM and HYP effectively target this region, these interventions may be particularly well suited to enhance descending inhibitory pain control in older adults via prefrontal cortical mechanisms. There is also a critical lack of research examining patient characteristics that moderate treatment outcome. Our preliminary research using electroencephalography (EEG) has identified pre-treatment brain-state variables that may predict who benefits most from MM and HYP. To identify the neuromodulatory mechanisms of MM and HYP for chronic pain in older individuals, the proposed study will include formal statistical tests of both mediation and moderation in a fully-powered clinical trial with N = 375 older adults with chronic pain (enrolled). The design will employ a 3-arm (MM, HYP, attention control) trial, resulting in tightly controlled tests of treatment mechanisms to accomplish the study aims. Treatment will consist of four, 20-minute sessions delivered over four consecutive days. The primary outcome will be change in chronic pain intensity from pre- to post-training. Aim 1 will use perfusion-based arterial spin labelling fMRI to determine the neuromodulatory mediators of treatment-related chronic pain intensity reductions, relative to the control. Aim 2 will identify pre-treatment psychological and EEG-assessed moderators of reduced chronic pain intensity in response to MM and HYP, relative to the control condition. The knowledge gained from adequately powered, formal tests of mediation will provide an empirical basis for developing more efficacious pain interventions that may also have a preventative-medicine role in older adults, thereby reducing the public health burden incurred with chronic pain in this population. Elucidating the moderators of MM and HYP will inform precision medicine and will also optimize the cost-effectiveness...