Significance: Chronic pain affects approximately 100 million Americans, costs our society half a trillion dollars per year, and is challenging to treat effectively. Functional magnetic resonance imaging (fMRI) of the brain - and more recently the spinal cord - have advanced our knowledge of the central nervous system (CNS) correlates of pain processing in humans. Additionally, brain fMRI is demonstrating much promise as a potential pain biomarker. Convention has been to perform brain/brainstem and, only more recently, spinal cord imaging separately. But a link between the human brain and spinal cord remains conspicuously missing. To fully characterize abnormal CNS mechanisms of chronic pain and pain modulation, we need to understand the intricate interplay between these structures. Preliminary Data: We have demonstrated successful simultaneous spinal cord-brainstem-brain fMRI by overcoming the magnetic field shimming obstacles. We have also demonstrated the ability to image the CNS correlates of pain and pain modulation. We propose to use this innovative technology of simultaneous spinal cord-brain fMRI to more fully characterize CNS mechanisms of chronic pain and pain modulation, and also to develop improved corticospinal biomarkers of the chronic pain condition fibromyalgia (FM). Specific Aims: In Aim 1, we will enhance our innovative simultaneous spinal cord-brain imaging sequence to minimize the impact of cardiovascular-induced spinal cord motion. We will contrast the optimized sequence against our currently working sequence while characterizing the CNS mechanisms of thermal pain intensity encoding. In Aim 2, we will characterize central sensitization (using pressure pain, temporal summation (TS) of pain, and resting state functional connectivity) and in Aim 3, descending modulation of pain (using conditioned pain modulation (CPM) and emotion reappraisal (ER)). Our preliminary data demonstrates feasibility and early insights into these mechanisms. Finally, in Aim 4, we will use the complete CNS imaging of pain and its modulation within our established multivariate pattern analysis (MVPA) models to better inform mechanistic knowledge and classification procedures. Overall Impact: Successful completion of our aims will advance scientific knowledge of the complex interplay between the spinal cord and brain in chronic pain and pain modulation. Our results and technology will be used to investigate other fields of human CNS research (e.g. motor disorders, spinal cord injury, degenerative conditions, etc). Additionally, we will have advanced development of objective biomarkers of pain. Future directions of this research will apply these CNS biomarkers for neuroprognosis and neuroprediction to help reduce the public health crisis of pain.