David Seminowicz, PhD - US grants

DESCRIPTION (provided by applicant): Migraine affects over 12% of the general population and causes major personal and social disability. Mindfulness based stress reduction (MBSR), a standardized type of meditation, has great potential as a treatment for migraine. Migraineurs often do not get relief from standard medications, and many seek out alternative treatments. MBSR has been used to treat various medical ailments including chronic pain disorders, and has proven to be effective in a substantial proportion of patients. The relationship between meditation and brain function and structure has been studied in healthy individuals, but to date there have been no studies examining its effects as a treatment for migraine or other chronic pain conditions. In this project, we aim to assess the efficacy of MBSR for migraine and to determine how brain function and structure change after MBSR treatment. We further aim to assess the relationship between clinical outcomes and brain changes, and determine the effects of MBSR dose through repeated exposure to an MBSR course and long-term practice. Finally, we will examine whether baseline brain measures or early brain changes can predict long-term outcomes related to MBSR treatment. The study will include 90 migraine patients in a randomized control trial comparing MBSR to an educational control group. Patients assigned to the MBSR group will later be randomly assigned to either a second, modified MBSR course, or to usual practice. We will compare clinical outcomes at 3 months (1 month after MBSR or educational control course completion), 6 months (1 month after the second MBSR course completion) and 12 months after study entry. We will perform MRI scans on all patients at baseline and 3 months. Additionally, at 12 months we scan 20 MBSR responders (at least 50% reduction in monthly headache frequency), 20 MBSR non-responders (less than a 25% reduction) and 20 of the educational control group patients who had the greatest reduction in headache frequency. We will also scan a group of 30 healthy age- and sex-matched control subjects at one time point in order to identify aberrant brain structure and function in migraine and observe how these abnormalities resolve with treatment.

DESCRIPTION (provided by applicant): Burning mouth syndrome (BMS) is an orofacial chronic pain disorder affecting approximately 2-3% of the population. It is associated with burning pain of the oral mucosa, particularly the tongue, buccal mucosa, hard palate, and lips. The disease is thought to have multifactorial influences, including of small fiber pathology, sex hormone levels, anxiety, and stress. However, the central nervous system (CNS) mechanisms of the disease remain largely unknown. In our ongoing work, we have found a link between ongoing pain levels in BMS and brain dysfunction in a small sample of patients. We propose a study that will take into account multiple potential CNS abnormalities that could explain the symptomatology of BMS. The study will include 40 patients with BMS and 20 healthy controls. The patients will include 20 with BMS type 1, in which patients describe increasing burning pain as the day progresses, and 20 with BMS type 2, which is associated with constant pain throughout the day. Participants will undergo testing for two days, which will include electroencephalograph (EEG), functional MRI, and quantitative sensory testing (QST). In each BMS patient, we will perform QST and EEG in the morning and in the afternoon to capture the effects of ongoing pain levels (which is expected to vary most in BMS type 1 patients). If our study is successful, it would provide the beginnings of a long-term program to examine the effects of treatment and ultimately improve available treatments for BMS.

Summary Chronic pain disorders are amongst the most burdensome of all diseases in terms of their impact on the individual and the costs to society. The development of novel therapeutic approaches for chronic pain have relied on basic studies involving genetic and molecular approaches in rodent models of pain, but existing drugs generally provide very limited relief for only a small number of patients. The result is that a vast number of people with chronic pain go untreated and have only partial relief. There is substantial and growing evidence from within and outside the pain research fields that indicates neural oscillations reflect cognitive, emotional, and sensory processes, which are all components of the pain experience. Furthermore, we can target these oscillatory patterns to alter perception. In particular, alpha band activity has been associated with chronic pain, and our extensive recent work and preliminary findings indicate that alpha can reliably predict future sensitivity to pain experienced minutes to weeks in the future in healthy subjects. In the proposed studies, we use simultaneous EEG-fMRI to continue our ongoing work on alpha oscillations as pain mechanisms and extend it to test the specificity and sensitivity of the signals and the relationship between alpha, brain networks, and pain. The proposed work would lead to improved understanding of the neurobiology of pain, identify novel brain targets for new or improved interventions, and potentially reveal a prognostic biomarker that would be useful for testing new therapeutic approaches and objectively assessing clinical improvement on an individual basis.

PROJECT SUMMARY/ABSTRACT The purpose of this R61/R33 project is to determine and optimize the neural mechanisms supporting mindfulness-based pain relief in rheumatoid arthritis (RA) patients. The scientific premise is that RA patients? use of an elemental mindfulness meditation practice?mindful breathing (MB)?and a positive emotion generative practice?savoring (SAV)?during noxious thermal stimulation will alter activation in the corticostriatal circuits. Further, an intervention that combines MB and SAV?mindful savoring (MB+SAV)--will optimize corticostriatal engagement and improve RA clinical outcomes. The corticostriatal circuits are attractive neural mechanisms of the putative benefits of mindfulness for RA because directly support cognitive appraisals of aversive stimuli and reward valuation, which are behavioral targets of our interventions. Target corticostriatal regions include the lateral orbitofrontal cortex (LOFC), which supports top-down control of attention and emotional appraisals, and the nucleus accumbens (NAc), which supports positive emotion regulation and reward appraisals. The behavioral output of the corticostriatal circuits is especially relevant for patients with RA, due to the flaring, unpredictable nature of RA pain and the importance of positive emotional function for RA pain coping. In the R61 phase, we will randomize RA patients to a brief 4-session (20-25 minutes each) course of MB (n=20), SAV (n=20), or a sham MB control (n=20). At post-intervention, participants will undergo functional MRI (fMRI) using a perfusion-based arterial spin labeling (ASL) technique during noxious thermal stimulation to determine if MB and SAV are associated with corticostriatal activation when compared to rest, as well as a Sham MB control. In the R33 phase we will randomize RA patients to 4 sessions of MB (n=30), SAV (n=30), or MB+SAV (n=30). Pre- and post-intervention ASL scans will be obtained using the same protocol as in the R61. Additionally, the secondary clinical outcomes of pain severity, unpleasantness and interference, disease activity, and fatigue will be obtained at pre-intervention, post-intervention, and weekly for 3 months. We propose that MB will increase cerebral blood flow (CBF) in the lOFC during noxious thermal stimulation, and SAV will decrease CBF in the NAc, relative to the CBF response to noxious stimulation during rest. We further propose that MB+SAV will optimize engagement of both regions to a greater extent than either MB or SAV alone. We expect that optimizing the engagement of the lOFC and NAc will be associated with improved RA clinical outcomes. Our approach will identify reproducible mechanisms and link them to RA chronic pain outcomes. Our interventions will be ready to disseminate because they are brief and require minimal provider contact. Our results will inform the development of new mindfulness intervention protocols that are guided by neural mechanisms, thereby increasing the efficiency and precision with which they are applied to patients with RA.

Summary Chronic pain is a major health burden associated with immense economic and social costs. Predictive biomarkers that can identify individuals at risk of developing severe and persistent pain, which is associated with worse disability and greater reliance on opioids, would promote aggressive, early intervention that could halt the transition to chronic pain. Our team has uncovered evidence of a unique cortical biomarker signature that predicts pain susceptibility (severity and duration). The biomarker signature combines resting state sensorimotor peak alpha frequency (PAF) measured using electroencephalograph (EEG) and corticomotor excitability (CME) measured using transcranial magnetic stimulation (TMS). This PAF/CME biomarker signature could be capable of predicting the severity of pain experienced by an individual minutes to months in the future, as well as the duration of pain (time to recovery). In the R61 phase of the current proposal, we aim to undertake analytical validation of this biomarker in healthy participants using a standardized model of the transition to sustained myofascial temporomandibular pain (masseter intramuscular injection of nerve growth factor, n=150). We will record PAF/CME at multiple time points before and during the development of pain and use online diaries and in-laboratory assessments of pain, sleep, stress, and other psychosocial variables. Specifically, we will test if the biomarker signature predicts an individual's pain sensitivity (high- or low-pain sensitive) with at least 75% accuracy. We will also test whether the biomarker signature predicts pain severity (on a 0-10 scale) and pain duration (number of days until pain resolves). We will use multiple statistical approaches to optimize and test the performance of the predictive biomarker. In the R33 phase we then aim to perform initial clinical validation to determine whether the optimized PAF/CME biomarker signature predicts pain severity and duration in patients with new onset myofascial temporomandibular disorder (TMD; n=30). We expect our work to result in the delivery of a candidate biomarker signature ready for advanced prospective clinical validation studies.