Robert C. Coghill - US grants

DESCRIPTION (provided by applicant): Pain-related disorders cause an incalculable toll in human suffering and present a significant economic problem. The development of new treatments for these disorders is being hindered by a lack of information about the basic brain mechanisms that support sensory aspects of pain experience. Functional imaging studies using functional magnetic resonance imaging (fMRI) provide powerful tools for addressing such issues in human subjects. Using such techniques, a highly distributed network of brain regions that may contribute to sensory discriminative pain processes has been identified. However, the involvement of specific components in supporting conscious awareness of discrete dimensions of pain, such as intensity and location, remains poorly understood. These perceived sensory aspects of pain can be dramatically modulated by cognitive interpretation and expectations about the nature of the stimulus. Yet, the brain mechanisms underlying this modulation remain unknown. A series of combined psychophysical and functional imaging studies will systematically test the hypotheses that 1) activation of the frontal cortex is necessary for subjective awareness of pain, 2) distinct parieto-frontal mechanisms are engaged in processes supporting conscious awareness of the location and intensity of painful stimuli, and 3) that activation within these areas can be modulated by internally-maintained contextual information. These studies will significantly enhance our knowledge of basic brain mechanisms underlying the pain experience, while simultaneously providing new directions for behavioral strategies of pain management. PUBLIC HEALTH RELEVANCE Pain afflicts more Americans than heart disease and stroke, diabetes, and cancer combined. Pain exacts an incalculable toll in human suffering and is a tremendous economic problem. The proposed research will focus on understanding the basic mechanisms that support the most clinically important features of pain - intensity and location - in order to provide a solid knowledge base for the development of improved treatments for pain.

DESCRIPTION (provided by applicant): Pain-related disorders cause an incalculable toll in human suffering and present a significant economic problem. The development of new treatments for these disorders is hindered by a lack of information about the basic neural mechanisms that process pain-related information. To date, investigations of the dynamic activation of mechanisms that facilitate pain have provided substantial insights into the neurophysiology and neuropharmacology of chronic pain. However, understanding of the dynamic response properties of inhibitory mechanisms has remained limited, despite the fact that disruption of inhibition may also contribute substantially to chronic pain. A recently identified analgesic phenomenon, offset analgesia, provides a powerful tool for the study of dynamic activation of inhibitory mechanisms. A series of psychophysical studies in humans subjects will systematically delineate the neurophysiological and neuropharmacological mechanisms that initiate and maintain offset analgesia during acute pain states, and determine the contribution of disrupted offset analgesia to pathophysiological pain states. Together, these studies will significantly enhance our knowledge of basic neural mechanisms underlying pain and will provide a foundation for the development of novel treatments for pain.

1H-Imidazol-2-amine, N-(2,6-dichlorophenyl)-4,5-dihydro-; Absence of pain sensation; Absence of sensibility to pain; Analgesic Agents; Analgesic Drugs; Analgesic Preparation; Analgesics; Anodynes; Antinociceptive Agents; Antinociceptive Drugs; Brain; CRISP; Clinical Research; Clinical Study; Clonidine; Computer Retrieval of Information on Scientific Projects Database; Condition; Dose; Drugs; Encephalon; Encephalons; Esthesia; Feels no pain; Forearm; Funding; Grant; Gray; Gray unit of radiation dose; Heating; Human; Human Figure; Human body; Human, General; Institution; Investigators; Klofenil; Learning; Man (Taxonomy); Man, Modern; Measures; Medication; Medulla Spinalis; NIH; National Institutes of Health; National Institutes of Health (U.S.); Nerve; Nervous; Nervous System, Brain; No sensitivity to pain; Oral; PBO; Pain; Pain-Free; Painful; Participant; Pharmaceutic Preparations; Pharmaceutical Preparations; Placebos; Prescription; Procedures; Process; Range; Research; Research Personnel; Research Resources; Researchers; Resources; Sensation; Series; Sham Treatment; Site; Source; Spinal Cord; Training; United States National Institutes of Health; Visit; Week; Work; analgesia; chronic pain; chronic painful condition; drug/agent; experience; experiment; experimental research; experimental study; new approaches; novel approaches; novel strategies; novel strategy; prescription document; prescription procedure; research study; response; sham therapy

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Offset analgesia is a disproportionately large decrease in pain evoked by small decreases in noxious stimulus intensity. This analgesic phenomenon may represent a centrally mediated temporal contrast enhancement mechanism. Opioid mechanisms are known to naturally occur in the body (Anderson et al., 2002, Goldstein, 1976, Basbaum and Fields, 1978). These act to diminish pain in certain bodily situations. In order to test the hypothesis that offset analgesia is partially supported by these opioid mechanisms, changes in offset analgesia will be assessed in volunteers during intravenous administration of the opioid antagonist naloxone and of the opioid agonist remifentanil. The overall objectives of this study are to systematically delineate the neurophysiological and neuropharmacological mechanisms that subserve offset analgesia.

DESCRIPTION (provided by applicant): Pain is a multidimensional experience that involves sensory, cognitive and affective mechanisms. The constellation of interactions between these factors makes the treatment of clinical pain challenging and often a financial burden. Mindfulness meditation has been found to significantly improve pain symptoms in experimental and clinical settings, but lack of mechanistic data has limited clinical deployment of this cost- effective and narcotic-free treatment. Recent findings from our laboratory determined that meditation, after only four days (20 minutes/day) of training, reduced pain intensity by 40% and pain unpleasantness ratings by 57%. Employing an emerging MRI technique (arterial spin labeling), we found that meditation-related pain relief was associated reduced pain-related brain activity in the primary somatosensory cortex and increased activity in brain regions such as the anterior insula, anterior cingulate cortex, and orbitofrontal cortex. These latter regions are involved in cognitive control, emotion regulation, and executive processing. These findings demonstrate that meditation engages multiple brain mechanisms during pain relief. However, the contribution of other cognitive factors such as expectations, facilitator attention, anxiety reduction, and conditioning /extinction processes remains poorly understood. Such factors are critically involved in the placebo effect. Accordingly, the proposed study seeks to determine if meditation-related pain relief engages brain mechanisms that are distinct from those of placebo analgesia. Functional imaging methodologies will be employed to assess brain activation during mediation-induced pain relief and during conditioned placebo analgesia. The proposed investigation will provide significant insights into the neural substrates involved in the modulatin of pain by cognitive factors.

DESCRIPTION (provided by applicant): Both acute and chronic pain are associated with an incalculable toll in human suffering and present a significant economic problem. One of the major challenges in treating pain arises from the tremendous inter- individual variation in subjective reports of pain. Individuals with similar injuries will frequently report vastly differet experiences of pain. Such individual differences often result in inadequate treatment due to concerns about the validity or veracity of subjective reports of pain. Despite the profound clinica significance of individual differences in pain, remarkably little is known about the basic brain mechanisms that support such differences. Portions of this inter-individual variation in subjective reports of pain may be due to physical factors such as brain connectivity. Other components arise from psychological disposition and may involve factors such as cognitive control, impulsivity, depression, and anxiety. Finally, demographic variables such as sex and ethnicity may also substantially contribute to individual differences in pain sensitivity. Surprisingly littl is known about the brain mechanisms by which these factors influence the construction of the pain experience at the level of a single individual. Thus, the fundamental aim of the proposed research is to delineate the brain mechanisms that give rise to individual differences in pain sensitivity. We will acquire both functional and structural MRI data from a large number (392) of volunteers. Recruitment will be designed to obtain a true community sample in order to facilitate generalizability of findings. As such, this research will involve individuals of differing socio-economic levels, obese individuals, individuals with active depression and anxiety, as well as those in excellent physical and mental health. Participants will also undergo extensive sensory testing and psychological evaluation in order to fully characterize their pain phenotype. Multiple regression statistical analyses will be used to identify brain regions related to inter-individual differences in sensitivity in both structural and functional neuroimaging data. Techniques such as psychophysiological interaction analyses will be used to test hypotheses about the influence of functional connectivity on pain sensitivity. The identification of brain mechanisms that support individual differences in pain sensitivity will contribute substantially to our basic understandingof brain mechanisms of pain and will critically evaluate our existing notions that every individual processes nociceptive information in the same way. The results from the proposed studies will provide a solid rationale for the development of individualized pain treatment strategies.

Project Summary: The Federal Pain Research Strategy highlights the need for investigation of biological mechanisms that underlie the treatment effects of non-pharmacological interventions in pediatric chronic pain patients. Understanding biological mechanisms can advance the use of effective treatments such as cognitive behavioral therapy (CBT) by providing patients and families with a stronger rationale for treatment, thereby decreasing stigma and increasing confidence in and commitment to the care plan. In addition, mechanstic insights foster patients' ability to effectively participate in shared decision-making and self-management, may provide for more individualized and precise care, and will increase uptake by health care providers, patients, and payors. Neuroimaging and quantitative sensory testing (QST) are techniques that can provide insight into the biological basis for pain treatment effects. This project will study migraine, which affects > 6 million youth in the U.S. Cochrane reviews show that psychological therapies for pediatric headache result in better outcomes than control conditions (56% improved vs. 22% in 714 participants), and our CBT+Amitriptyline Study found that 66% of youth with chronic migraine had a ? 50% reduction in headache days compared to 36% in an education control+Amitriptyline (AMI) group. Despite this evidence base, the neural mechanisms supporting the efficacy of CBT for pain remain poorly understood. The lack of mechanistic understanding is a barrier to treatment utilization, particularly given the time, effort, and expense for pediatric migraine patients to receive CBT vs. conventional pharmacological therapy (which in a national trial reduced headache days similar to placebo pill: AMI 52% of participants improved; Placebo 61%). Pilot data from our group demonstrate that: CBT induces changes in brain connectivity/activation, and QST at baseline predicts reduced migraines at 8 weeks. These findings show proof of concept specific to pediatric migraine patients and refined the design of this project, which will recruit 240 youth ages 10 to 17 with migraine to undergo functional MRI and QST before and after 8 weeks of either CBT, placebo, or AMI to address these aims: Aim 1: Does CBT engage brain mechanisms which are distinct from those engaged by pill-based therapy (placebo & AMI)? Aim 2: Are poorer baseline pain modulatory mechanisms measured by QST predictive of greater headache day reduction from CBT vs. pill-based therapy? Exploratory Aims: a. Assess whether brain changes at 8 weeks in those who receive CBT play a mediational role when outcomes are assessed at a 3 month follow-up; b. Test if the findings from Aims 1 and 2 are supported when other pain contextual variables (anxiety, depression, sleep) are included in the statistical models; c. Compare neuroimaging between placebo and AMI; d. All analyses will include age, sex, pubertal status, and brain structural connectivity in the statistical models to assess developmental variables. Pediatric medical and behavioral clinicians can use mechanistic insights from translational investigations such as this project to enhance the care they provide to youth with migraine.

Migraine affects over 6 million children and adolescents in the U.S. and leads to significant pain and disability. Cognitive behavioral therapy (CBT) effectively reduces the number of headache days in pediatric patients. CBT includes distinct components, including mind and body approaches (deep breathing, progressive muscle relaxation, imagery, biofeedback) and cognitive reappraisal training (CR). While the new strategic plan of the National Center for Complementary and Integrated Health highlights ?Neurobiological Effects and Mechanisms? as a top scientific priority for non-pharmacological pain research, the brain mechanisms by which components of CBT work remain poorly delineated. To dissect the neural mechanisms engaged by CBT, we will conduct a mechanistic clinical trial to compare a sample of 80 youth (ages 10 to 17) with migraine who receive relaxation training (BART) to 80 who receive CR training. Functional MRI and quantitative sensory testing (QST) data will be obtained before and after intervention (an 8 week period) to address these aims: Aim 1A. Do BART and CR training differentially alter resting brain activation in a fashion related to headache reduction? Our pilot data indicate migraine patients have pro-nociceptive patterns of functional connectivity with the amygdala while CBT produces anti-nociceptive patterns of amygdalar functional connectivity. We hypothesize that BART will preferentially activate the ventromedial prefrontal cortex (vmPFC) while CR training will preferentially activate the dorsolateral prefrontal cortex (dlPFC) and other regions of cognitive control. To test this, arterial spin labeling (ASL) MRI will be used to compare pre vs. post training differences in steady state brain activation in BART and CR groups. Resting state BOLD fMRI will be used to determine if BART and CR training produce differential alterations of the functional connectivity of the vmPFC and dlPFC with the amygdala. Aim 1B. Does active performance of BART and CR differentially recruit activation of the vmPFC and dlPFC? Preliminary data from CBT were obtained during rest and may reflect tonically active consequences of therapy/headache reduction rather than the phasic mechanisms involved during active engagement of BART/CR strategies. To further determine if BART and CR involve distinct brain mechanisms, both ASL and BOLD MRI will be used to compare brain activation and amygdalar functional connectivity during active performance of each treatment vs. rest. Aim 2. Does the efficiency of pain modulation predict headache reduction following BART vs. CR? QST assessment of the efficiency of conditioned pain modulation (CPM) provides an index of the involvement of endogenous pain modulatory mechanisms in both pain conditions and pain treatments. Our preliminary work has shown that low efficiency of CPM is predictive of headache reduction following CBT. However, it remains unknown if BART vs. CR is more effective in the presence of disrupted endogenous pain modulation. Thus, pre-treatment CPM will be used to test the hypothesis that low efficiency of CPM will be differentially predictive of headache reductions following BART vs. CR.

ABSTRACT Juvenile-onset fibromyalgia (JFM) is a debilitating, chronic pain condition affecting adolescents, primarily females, during a critical period for brain development, and that persists into adulthood for the majority of patients. Due to the lack of definite physical or laboratory findings, JFM has been questioned as a clinical entity, and sometimes regarded as merely an expression of anxiety or depression. This leads to poor understanding, stigmatization, and appropriate disease management, underscoring the need for identifying objective pathophysiology. We have previously used machine learning applied to fMRI data to yield multivariate patterns of distributed brain activity that, together, can identify test subjects as adult FM patients vs. healthy adults with high cross-validated accuracy (93%). However, extrapolating adult FM brain abnormalities to JFM is problematic, given the many factors impacting the developing adolescent brain and the clinical differences between adult and juvenile forms of the disease. The goal of this proposal is to identify brain pathophysiology characteristic of JFM during tailored symptom provocation tasks. There is currently a complete lack of research into the brain correlates of pain in children with widespread pain/JFM. This study will lay the foundation for a line of research in understanding the neurophysiologic underpinnings of JFM, discovering whether brain pathophysiology in JFM differs from adult FM, and assessing treatment effects on specific markers of brain pathophysiology. This study is an R01 ancillary study to the NIH/NIAMS-funded trial (R01 AR070474; Kashikar-Zuck), ?Multi-site randomized clinical trial of Fibromyalgia Integrative Training for Juvenile Fibromyalgia (FIT Teens)?. The exceptionally well characterized cohort of JFM patients from the parent trial presents a unique opportunity to study JFM neural correlates. Our time-sensitive study will transform the scientific output of the parent project by identifying neurophysiological correlates of pain, psychological and physical symptoms in this large, representative, extensively-characterized sample of JFM patients before and after treatment. We hypothesize that machine learning applied to fMRI data during tailored symptom-provocation tasks will identify patterns of neural activity predictive of JFM status (vs. healthy), which will correlate with JFM symptom dimensions (pain, non-painful sensory hypersensitivity, fatigue, and depressive symptoms). This ancillary study will utilize the comprehensive psychological and physical functioning profiles already being captured in the parent R01 trial to identify clinically meaningful neurologic measures in JFM and explore the potential for these measures to change with treatment. This line of research has the potential for a profound impact on understanding and identifying JFM pathophysiology and providing neuro-physiologically informed treatment recommendations.