Sean C. Mackey, MD, PhD - US grants

Abstract Not Provided.

Abstract Not Provided.

Chronic pain has a tremendous impact on individual patients, their families, and society. Functional magnetic resonance imaging (fMRI) has been used to investigate nociceptive processing and central sensitization in the brain to better understand, and to ultimately develop improved therapies for chronic pain. The spinal cord is important in the processing of nociception, and direct animal and indirect psychophysical and behavioral human studies have demonstrated its role in the generation and maintenance of hyperalgesia and allodynia. Our overall goals are to use human spinal fMRI to elucidate mechanisms of nociceptive processing and spinal cord plasticity in healthy subjects and patients with chronic neuropathic pain. Our Hypotheses are that: (1) increases in noxious thermal stimuli will produce a corresponding increase in fMRI signal activation in the human spinal dorsal horn and increases in spatial and rostrocaudal activity; (2) a thermal-capsaicin induced experimental allodynia/hyperalgesia model and (3) chronic upper extremity neuropathic pain will result in increased spinal dorsal horn activity to non-noxious mechanical stimuli with increased rostrocaudal and spatial activity compared to the unaffected side. Specific AIMS: (1) optimize human spinal fMRI by characterizing the hemodynamic impulse response function;(2) characterize spinal cord activity (fMRI signal and spatial activation properties) in response to noxious thermal stimuli and compare to non-noxious mechanical and thermal stimuli;(3) elucidate the response of the human spinal cord to a heat/capsaicin pain model of allodynia and hyperalgesia in response to normally non-noxious mechanical stimuli;(4) characterize dorsal horn responsiveness to normally non- noxious thermal and tactile stimuli in patients with chronic neuropathic pain. We also plan to compare spinal fMRI activation patterns from noxious thermal stimuli in healthy subjects with normally non-noxious but painfully perceived thermal stimuli in chronic neuropathic pain patients. This will provide further insight into mechanisms of spinal plasticity in chronic neuropathic pain. Significance: These studies will advance our understanding of nociceptive processing in the human spinal cord and the effects of neural plasticity in experimental pain models and chronic neuropathic pain. This will enhance our knowledge of how chronic pain states are generated, maintained, and potentially treated. Furthermore, we will have a more objective means of assessing neural function in patients with peripheral nerve and spinal cord injury.

DESCRIPTION (provided by applicant): Attaining control over specific neural processes can enable people to influence associated perceptions, behaviors, and cognitions, with potential clinical application to a range of brain- based disorders, including substance abuse (SA). Using real-time fMRI (rtfMRI), our team recently demonstrated that such control can be learned in the anterior cingulate cortex (ACC), leading to clinically significant reductions in pain. If this exciting initial finding can be generalized to SA, it would have major implications for clinical intervention. Our proposal attempts to take a major step in this direction, which seems likely to be productive given that during rtfMRI of the ACC, we identified activated brain regions involved in SA related reward driven behavior. To make rtfMRI a more useful clinical tool, we propose to resolve four potentially problematic issues identified in our prior rtfMRI studies. First, optimal regions for feedback control need to be determined. Second, subjects employ different cognitive strategies to modulate brain activity, producing variability in brain regions activated and subsequent efficacy in learned control. Third, the strength of connectivity between brain regions may influence cognitive processes and may be a better target for learned control. Fourth, there are significant individual differences in how well subjects are able to modulate their brain activity. We plan to address these issues in the following aims: (1) Enhance and test a system to perform real-time control of brain activity and strength of connectivity between multiple SA and pain related brain regions;(2) Determine optimal cognitive strategies (distraction and reappraisal), and individual differences in ability to control distributed brain regions;(3) Characterize the learned control of the strength of brain connectivity;and (4) Pilot the optimized rtfMRI parameters in a group of SA patients. Our overall goals are to develop rtfMRI as an efficacious clinical therapy for patients with SA and other brain disorders. PUBLIC HEALTH RELEVANCE: Substance abuse is a highly prevalent and debilitating condition that presents a terrible burden to affected patients, their families, and society as a whole, resulting in enormous economic costs. Completion of the proposed aims will lead to an improved understanding of brain modulatory systems. This will also introduce a potentially novel clinical therapy for substance abuse patients as well as patients with overlapping central nervous system illnesses, including chronic pain conditions, depression, and anxiety.

? DESCRIPTION (provided by applicant): The primary goals of this K24 competing renewal application are to allow Sean Mackey, M.D., Ph.D. to 1) continue to devote near full time effort to his program of pain and prescription opioid research; and 2) provide high-quality and intensive mentorship of early-career investigators in patient-oriented research (P0R). A K24 renewal will continue to provide Dr. Mackey with the critical protected time for POR and mentoring that would otherwise be spent on administrative and clinical responsibilities. Dr. Mackey is the Redlich Professor and Division Chief of Pain Medicine at Stanford University. Since receiving a K24 award Dr. Mackey has accomplished the major goals of his original application and much more. Dr. Mackey's research plan for this K24 renewal application includes work as a P01 PD to investigate mechanisms of chronic low back pain (CLBP) and four therapies; characterizing the effects of opioids on brain structure in patients with CLBP; expanding his work in neuroimaging based biomarkers (Co-I on R01); continuing role in the NIDDK Multi-Disciplinary Approach to the Study of Chronic Pelvic Pain network; further development, implementation and dissemination of the Stanford-NIH based partnership for an open-source, free health registry (PI). Dr. Mackey's mentoring plan includes training his mentees in: 1) designing and implementing pain research studies; 2) preparing scientific papers and presentations; 3) writing successful grant applications; 4) responsible conduct of research; and 5) successful navigation of the academic process to achieve scientific independence. This mentoring plan will be applied to his direct mentees as well as those he oversees as the PD for his NIDA T32 Interdisciplinary Research Training in Pain and Substance Use Disorders. Dr. Mackey will accomplish this through a combination of role modeling, individual and group meetings, collaborative mentoring, and integration with Stanford's Clinical and Translational Science Award (CTSA) mentoring program. Dr. Mackey's career development plan includes further training in machine learning approaches for neuroimaging analysis as well as for his health registry; multimodal MRI collection and analysis methods; analysis of large data sets and longitudinal data. With the outstanding resources and collaborations at Stanford and novel projects, the ongoing projects are expected to be either renewed or lead to new directions in pain and substance use research and significantly contribute to our scientific understanding of these disabling conditions. Further, these projects and Dr. Mackey's mentorship will support the need to train the next generation of investigators conducting important pain and substance abuse POR.

DESCRIPTION (provided by applicant): Until recently, it was unclear if people could attain control over specific neural processes to influence their associated perceptions, cognitions and behaviors. Using real-time fMRI (rtfMRI) neurofeedback, we recently demonstrated that healthy subjects and patients with chronic pain can learn to control activity in the anterior cingulate cortex, leading to significant and clinically meaningful reductions in their pain. We propose to extend this exciting finding to patients with chronic low back pain (CLBP). CLBP is a highly prevalent and difficult to treat condition with a pressing need for novel therapies. Although underlying mechanisms in CLBP are not well understood, basic science has revealed that abnormalities in central pain modulatory and emotion regulatory systems play a crucial role. At the same time, a robust clinical literature suggests the value of mind-body therapies (MBTs) and cognitive/emotion regulatory strategies in the management of chronic pain. What is not clear is how the basic and clinical science findings are linked, such that MBTs alter the functioning of the brain systems involved in pain. This project proposes to use rtfMRI neurofeedback as an innovative technique to manipulate key brain systems related to pain and then translate mechanistic findings to optimize clinical therapies for chronic pain. We will advance this critical area by resolving three issues identified in our previous rtfMRI studies: (1) because patients employ different cognitive strategies to modulate brain activity, their activated brain regions and efficacy in learned control vary, (2) multiple brain regions are activated and deactivated during single region feedback control, suggesting control of multiple, distributed regions may be more effective than control of a single region, and (3) significant individual differences exist in how well patients can modulate their brain activity. Therefore, our overall aims are to: (1) characterize CLBP patients' cognitive strategies for optimally controlling single and multiple distributed brain regions, and (2) identify mediators of pain relief due to rtfMRI. Our overall objective is to advance our scientific knowledge of mind-body therapies, specifically how learned control of specific neural processes leads to reduction in chronic pain.

The Stanford CAM Center for Chronic Low Back Pain brings together a variety of scientific discplines and researchers in a collaborative effort to advance our knowledge of CAM treatments for low back pain. The Administrative Core will function within this Center as a centralized resource to each of the individual Projects and other Cores. By providing an integrated infrastructure for the logistical and management requirements of the Center components, the Core will increase productivity, enhance efficiency, and promote unified efforts toward achieving the Center Goals. To facilitate the research goals of the Center, the Core will aim to: 1. Facilitate communication among Scientific Cores and individual Research Projects to advance the overall Center and individual Project goals; and 2. Provide financial management and day-to-day administrative support to increase efficiency and productivity of individual Projects and Cores.

Emotion dysregulation is thought to be a core mechanism underlying many medical and psychiatric disorders. In particular, emotion dysregulation is believed to play a crucial role in physical and emotional responses to pain. A growing body of basic research is beginning to illuminate the neural correlates and behavioral sequelae of emotion dysregulation and perception of pain. Concurrently, a growing body of clinical research supports the efficacy of selected psychosocial interventions for pain. However, little is known about how these treatments modulate emotional reactivity to pain. The proposed study will directly address this knowledge gap by examining how two, distinct psychosocial treatment modalities-Cognitive- Behavioral Therapy (CBT) and Mindfulness-Based Stress Reduction (MBSR)-impact two specific forms of emotion regulation-cognitive regulation (CR) and attention regulation (AR)-in patients with CLBP. Back pain affects up to 85% of people over their lives; up to 5% of all adults experience severe and debilitating effects of CLBP. CLBP is associated with a huge disease burden: it has a high rate of recurrence and is highly comorbid with psychiatric disorders, including major depression (MOD), substance abuse, and anxiety disorders. Although CLBP is a major cause of functional disability and suffering, how psychosocial treatments reduce that suffering is not well understood. Our overall approach is to use behavioral and neural measures of emotion regulation in the context of an RCT to examine the differential impacts of CBT versus MBSR on pain symptoms and well-being in patients with CLBP (Aim 1), to differential changes in CR and AR related to CBT versus MBSR (Aim 2), and to determine whether CR and AR mediate treatment outcome (Aim 3). The broad, long-term objective of this translational research program is to provide an empirical basis for refining and/or integrating specific components of CBT and MBSR for CLBP and strengthen our understanding of the role specific emotion regulation processes play in CLBP, as well as other medical and psychiatric disorders.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Cognitive behavioral therapy has long been used as a strategy for modulating chronic pain. Functional connectivity is an imaging technique to examine the strength of timecourse covariance of two neural entities. To better understand connectivity in the supraspinal modulation of pain, we looked at functional connectivity of the "pain matrix" as chronic pain patients modulated pain intensity with cognitive behavioral therapy. Five patients with chronic NP in a limb were instructed and trained on the cognitive behavioral strategies of attention, distraction, and positive and negative reappraisal. Each subject completed 4 scans using each strategy to modulate their pain, and a resting state scan. After performing resting state fMRI using a 3T MRI, the connectivity for each subject was calculated as the pair-wise correlation between average ROI time-courses. Subsequently, the average connectivity was determined by averaging across subjects. Finally, connectivity in different scans was compared using the Fisher's Z transformation. To read about other projects ongoing at the Lucas Center, please visit http://rsl.stanford.edu/ (Lucas Annual Report and ISMRM 2011 Abstracts)

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Chronic lower back pain (CLBP) affects millions of people and cost billions of dollars per year in the United States alone. Recent evidence indicates that chronic back pain may cause structural changes in brain gray matter (GM), suggesting that GM changes may be an important metric in evaluating the efficacy of pain treatments. In this double-blind crossover study, we used tensor based morphometry (TBM) to test our hypothesis that treatment with duloxetine (a specific serotonin-norepinephrine reuptake inhibitor) would cause GM changes that are distinct from those caused by treatment with placebo. 14 male subjects with CLBP were recruited. They rated pain as at least 4/10 on average for the two weeks prior to the start of the study and were not on pain medications. Study design was a double blind, placebo control, 12 week crossover study utilizing duloxetine as the active drug. Structural scans were conducted at baseline and at the end of each drug period. To read about other projects ongoing at the Lucas Center, please visit http://rsl.stanford.edu/ (Lucas Annual Report and ISMRM 2011 Abstracts)

Until recently, it was unclear if people could attain control over specific neural processes to influence their associated perceptions, cognitions and behaviors. Using real-time fMRI (rtfMRI) neurofeedback, we recently demonstrated that healthy subjects and patients with chronic pain can learn to control activity in the anterior cingulate cortex, leading to significant and clinically meaningful reductions in their pain. We propose to extend this exciting finding to patients with chronic low back pain (CLBP). CLBP is a highly prevalent and difficult to treat condition with a pressing need for novel therapies. Although underlying mechanisms in CLBP are not well understood, basic science has revealed that abnormalities in central pain modulatory and emotion regulatory systems play a crucial role. At the same time, a robust clinical literature suggests the value of mind-body therapies (MBTs) and cognitive/emotion regulatory strategies in the management of chronic pain. What is not clear is how the basic and clinical science findings are linked, such that MBTs alter the functioning of the brain systems involved in pain. This project proposes to use rtfMRI neurofeedback as an innovative technique to manipulate key brain systems related to pain and then translate mechanistic findings to optimize clinical therapies for chronic pain. We will advance this critical area by resolving three issues identified in our previous rtfMRI studies: (1) because patients employ different cognitive strategies to modulate brain activity, their activated brain regions and efficacy in learned control vary, (2) multiple brain regions are activated and deactivated during singleregion feedback control, suggesting control of multiple, distributed regions may be more effective than control of a single region, and (3) significant individual differences exist in how well patients can modulate their brain activity. Therefore, our overall aims are to: (1) characterize CLBP patients'cognitive strategies for optimally controlling single and multiple distributed brain regions, and (2) identify mediators of pain relief due to rtfMRI. Our overall objective is to advance our scientific knowledge of mind-body therapies, specifically how learned control of specific neural processes leads to reduction in chronic pain.

Acupuncture is increasingly used by the American Public for the treatment of chronic pain. Two recent seminal clinical trials have established its superiority to usual care for the treatment of chronic low back pain (CLBP). However, one key issue remains: minimal clinical difference is found between verum acupuncture (VA) and placebo acupuncture (PA). Meanwhile studies in animals and healthy human models reveal distinct central mechanisms for VA and PA. However, little work has been done to translate the findings from healthy human models to chronic pain conditions such as CLBP. Our aim is to focus on elucidating mechanisms by which acupuncture exerts its therapeutic effects above and beyond the placebo effect. Dysregulation in central pain and emotional processing is increasingly recognized as a key contributor to the pathogenesis of CLBP. Works from others and our group show that acupuncture exerts therapeutic influence in the same central processes as those involved in the pathogenesis on CLBP. These processes include central pain modulation and emotional regulation. In addition, expectations of benefit has also been shown to be an important mediator of response to acupuncture. We hope to delineate the common and differential mechanisms of VA and PA in the CLBP by characterize their effect on the aforementioned biological and psychological factors. In a series to two innovative designs, we plan to a) isolate and elucidate the unique mechanism of VA among those who have NOT responded to PA; b) compare the mechanisms of VA and PA by randomizing those who HAVE responded to either VA or PA. The specific mechanisms that we will study are mechanisms of pain facilitation and inhibition, mechanisms involved in emotion regulation that are known to modulate the pain experience, and the role of expectancy.

The Clinical Research Core will serve as a scientific resource to each of the individual components of the Stanford CAM Center for Chronic Back Pain, advancing the scientific aims fo the Center by enhancing the collaboration and coordination among the Research Projects and Scientific Cores. In order to elucidate the mechanisms of CAM therapies and optimize treatments, the Research Projects rely on an interdisciplinary approach. Furthermore, the Scientific Cores will contribute to each of the Projects as well as the Center as a whole in characterizing the patient population and advancing our mechanistic understanding of the treatments under investigation. These collaborative relationships will be fostered by the Clinical Research Core, which will link the individual components through centralized recruitment, data management and biostatistical, and regulatory resources. To advance the aims of the Center through coordinated scientific efforts, the Clinical Research Core will: 1. Manage participant recruitment, randomization, and monitoring of accrual and retention; and 2. Support interdisciplinary analyses and quality assurance through centralized data management, biostatistical expertise, and internal data monitoring; and 3. Provide oversight of regulatory requirements, participant safety, and human subjects research protections.

The Stanford CAM Center for Chronic Low Back Pain has the goal of characterizing the neural mechanisms of four CAM therapies (mindfulness-based stress reduction, cognitive behavioral therapy, real-time fMRI neurofeedback and acupuncture) and translating these mechanisms into tailored and effective treatments for chronic low back pain (CLBP). The Neuroimaging Core will function synergistically with the Behavioral and Psychophysics Core to provide the critical infrastructure and common methodology needed to characterize neural mechanisms across the Center's Projects. To facilitate the research goals of the Center, the Core will aim to: 1. Provide shared neuroimaging resources for the Center's Projects; 2. Provide a common neuroimaging research protocol that can address neuroimaging research questions within and between the Center's Projects; and 3. Serve as a consulting resource for neuroimaging objectives of specific projects.

The Stanford CAM. Center for Chronic Low Back Pain has the goal of characterizing the neural mechanisms of four CAM therapies (mindfulness-based stress reduction, cognitive behavioral therapy, real-time fMRI neurofeedback and acupuncture) and translating these mechanisms into tailored and effective treatments for chronic low back pain (CLBP). The Behavioral and Psychophysics Core will function synergistically with the Neuroimaging Core to provide the critical infrastructure and common methodology needed to characterize neural mechanisms of pain modulation and emotional regulation across the Center's Projects. To facilitate the research goals of the Center, the Core will aim to: 1. Provide shared behavioral and psychophysics resources for the Center's Projects; 2. Provide a common behavioral and psychophysics research battery that can address research questions across the CAM Projects; and 3. Serve as a resource for capturing and analyzing specific Project measures.

DESCRIPTION (provided by applicant): The magnitude of the problem of pain in the US is astounding. More than 100 million Americans have pain that persists for weeks to years. The financial toll of this epidemic cost over $500 billion per year according to the Institute of Medicine's (IOM) recent report, Relieving Pain in America. Similarly, there is a tremendous personal and society cost associated with substance abuse disorders (SUDs). Contemporary neurobiologic, psychological, and epidemiologic research has shown a clear intersection of pain and SUDs. Two of the IOM committee's recommendations for improving research at a national level are (1) increase support for interdisciplinary research in pain, and (2) increase the trainin of pain researchers. In this proposal, we describe a collaborative, postdoctoral (PhD, MD/PhD and MD), interdisciplinary, training program that will produce scientists with rigorous grounding in pain and SUDs research. The 18 accomplished faculty are all committed to interdisciplinary collaboration, which possess complementary expertise that ranges from cells-to- society. The training program includes both required and elective coursework, mentored research experiences, an individual integrated research project, seminars, and exposure to professional development skills, including grant proposal and manuscript writing. The training program in the Division of Pain Medicine, Department of Anesthesia, Stanford University School of Medicine, is intended to develop postdoctoral trainees' skills, so that they will become independent investigators in the fields of pain, SUD and their intersection. The training program will be led b Dr. Sean Mackey, in collaboration with a steering committee comprised of senior and successful scientists. They will oversee the training, scientific, and administrative aspects of the program, including a rigorous process of internal and external evaluation. In summary, this training program will bring together a talented group of post-doctoral trainees, an accomplished team of interdisciplinary mentors, an effective administrative structure, and a world-class research environment at Stanford University. The combination of talent and environment will launch the next generation of researchers who will advance our scientific knowledge and practice of pain and substance use disorders.

? DESCRIPTION (provided by applicant): Chronic low back pain (CLBP) is the most common chronic pain condition and is the second leading cause of disability in the U.S. Pain catastrophizing (PC)--a pattern of negative cognitive-emotional responses to actual or anticipated pain-is significantly associated with the development and maintenance of CLBP as well as disability. PC undermines CLBP treatments, thus contributing to a cycle of treatment futility and wasted expenditure. While Cognitive Behavioral Therapy (pain-CBT) treats PC, group treatment involves 6-10 sessions and thus poses substantial burdens of time, travel, and cost. Therefore, there is a critical need to develop and disseminate efficient, low-cost treatments that specifically reduce PC. Accordingly, we developed a single-session, 2-hour pain-CBT class that solely treats PC (From Catastrophizing to Recovery; FCR). Our pilot data revealed large effect sizes for FCR in a chronic pain sample and superior outcomes for medical and psychological across PROMIS domains, as compared to a 'treatment as usual' matched clinic cohort. We propose to conduct a 3-arm comparative efficacy RCT in 231 patients with CLBP comparing: (A) FCR, (B) a health education control, and (C) an 8-session pain-CBT class. Our primary endpoint is PC 3 months post- treatment and our secondary endpoint is PC 6 months post-treatment. We hypothesize that FCR will be superior to active control and non-inferior to the 8-session pain-CBT class for improving PC and pain-related outcomes measured by our PROMIS platform. An innovative aspect of the application is our proposal to develop and validate a brief version Daily PCS measure, and apply the measure with high frequency sampling methods to elucidate the mechanics of PC, and to characterize how positive response to active intervention reduces the influence of PC episodes. Additional novel methods our specialized PROMIS platform; actigraphy for objective sleep and activity measurement; and a customized 'FCR Relaxation Resource' app (on Nexus 7 tablets) to objectively quantify skills use in the FCR group. Our rich dataset will allow for detailed phenotyping of responders / non-responders for both active treatments using machine learning and other advanced analytics. We will use daily ratings across a longitudinal timeframe to characterize how PC changes in response to treatment, as well as the mechanistic influence of PC on pain, sleep, activity, and other variables. Our proposal addresses the NCCAM priorities to (1) alleviate chronic pain, (2) study our mind-body intervention in a real-world setting, and (3) advance scientific understanding of the mechanisms of PC.

Project Summary/Abstract: This competing application seeks an additional five years (Years 6-10) of support for a post-doctoral research training program in pain and substance use disorders. The magnitude of these two problems in the US is astounding. More than 100 million Americans have pain that persists for weeks to years and over 20 million meet diagnostic criteria for an alcohol/drug use disorder. According to the National Academy of Medicine?s (NAM) report, Relieving Pain in America and the Surgeon General?s report Facing Addiction, these problems cost society almost $1 trillion annually. Contemporary neurobiologic, psychological, and epidemiologic research as well as the tragic experience of the opioid addiction epidemic show a clear intersection of pain and SUDs. Two of the NAM committee?s recommendations for improving research at a national level are (1) increase support for interdisciplinary research in pain, and (2) increase the training of pain researchers. Similarly, NIDA?s strategic goals and the Surgeon General?s report call for the multidisciplinary training of scientists to address the complexities of SUD research. In this proposal, we describe a collaborative, postdoctoral (PhD, MD/PhD and MD), interdisciplinary training program that will produce scientists with rigorous grounding in pain and SUD research. The accomplished faculty are all committed to interdisciplinary collaboration and mentorship across their substantive areas of expertise, which range from cells-to-society. The training program includes both required and elective coursework, mentored research experiences, an individual integrated research project, seminars, and exposure to professional development skills, including grant proposal and manuscript writing. The training program housed in the Division of Pain Medicine, Department of Anesthesiology, Stanford University School of Medicine, is intended to develop postdoctoral trainees? skills, so that they will become independent investigators in the fields of pain, SUD and their intersection. The training program will be led by Dr. Sean Mackey, in collaboration with a steering committee comprising senior scientist/mentors. They will oversee the training, scientific, and administrative aspects of the program, including a rigorous process of internal and external evaluation. In summary, this training program will bring together a talented group of post-doctoral trainees, an accomplished team of interdisciplinary mentors, an effective administrative structure, and a world- class research environment at Stanford University. The combination of talent and environment will launch the next generation of researchers who will advance our scientific knowledge and practice of pain and substance use disorders.

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.