This is a new application for a Midcareer Investigator Award in Patient-Oriented Research (K24). The applicant, Dr. Sean Mackey, is a physician-scientist, Associate Professor and Division Chief of Pain Medicine at Stanford University. Over the past 5 years, Dr. Mackey has developed expertise in several advanced neuroimaging and psychophysical techniques and applied these to the study of pain. This has led to his developing an independent patient-oriented research (POR) career. This independence is demonstrated by his receiving three independent research awards that use MR techniques to investigate the central neural correlates of pain in patients with chronic pain; he is PI on all three of these awards (one each by NIDA, NINDS and NIDDK). Dr. Mackey has a 10 year history of mentoring junior clinician scientists, postdoctoral fellows, medical students, and graduate students - all performing POR. In addition, Dr. Mackey has active collaborations with many NIH-funded investigators in the area of pain research and its intersection with substance abuse. The current application requests funding (50% salary) for 5 years. This funding will guarantee that the candidate will have at least 75% protected time to conduct his ongoing research and to continue to mentor clinician scientists performing POR. As Dr. Mackey is the Division Chief of Pain Medicine, this award will free time now devoted to administrative and clinical responsibilities to focus more on his research and mentoring activities over the next 5 years. In addition to working on the three ongoing NIH-funded projects, the candidate will obtain additional training in advanced multimodal MR collection and analysis methods (machine learning algorithms, diffusion tensor imaging, genomic imaging) and functional near-infrared spectroscopy imaging. This will allow the candidate to develop new approaches to characterize the central neuroplastic changes that occur in chronic pain and its link with addiction. Given the outstanding resources and collaborations at Stanford, these novel projects are expected to be either renewed or to lead to new directions in pain and substance abuse research, and significantly contribute to our scientific understanding of these disabling conditions.