Richard E. Harris - US grants

DESCRIPTION (adapted from the application): Pain is one of the major complaints of those seeking professional healthcare. Although recent advances have been made in pharmacological and invasive approaches to relief pain, many patients suffering pain chose alternative healing modalities, such as acupuncture. This application focuses on determining the neurobiological mechanisms of acupuncture analgesia (the relief of pain) in people who suffer from fibromyalgia (FM), a chronic pain condition. All proposed work will occur at the University of Michigan. The first year of funding of this proposed K award would coincide with the final year of funding of the R01 grant, allowing an opportunity to use both the research subjects and information from the existing grant to obtain preliminary data for the remainder of the K award. During the first two years of the K award, the applicant will: 1) establish the ideal conditions for acupuncture induced analgesia, and 2) begin to elucidate the mechanisms of acupuncture induced analgesia by using both psychophysical and fMRI experiments. In the final three years of the K award, the applicant will focus on the techniques that show the most promise for elucidating neural mechanisms underlying the analgesia. Comparisons will be drawn between analgesia of patient?s clinical spontaneous pain as well as evoked pain. In addition to clinical research experience, the applicant will attend didactic lectures, seminars, and conferences designed to increase his knowledge of clinical research. Although the applicant already has training in acupuncture and a strong basic research training in neuroscience, this career development program is designed to allow the Candidate to become a successful independent clinical investigator. There is a strong institutional commitment to see the applicant succeed in this task due to a tremendous need for well-trained clinical investigators in alternative and complementary medicine.

brain imaging /visualization /scanning; community; positron emission tomography; reduction

DESCRIPTION (provided by applicant): The proposed Society for Acupuncture Research (SAR) 2010 Conference, entitled "Translational Research in Acupuncture: Bridging Science, Practice and Community", aims at advancing inquiry into the emerging concept of translational research as it applies to the acupuncture field. This conference will focus on addressing paradoxes emerging from the acupuncture research evidence to-date, harnessing the momentum generated by the SAR 2007 conference, which marked the 10 years since the National Institutes of Health (NIH) Consensus Conference in Acupuncture. In addition, the 2010 Conference will be guided by themes originating from a White Paper, written by the SAR Board of Directors, which summarizes the present state of the evidence on acupuncture basic and clinical research and identifies the emerging paradoxes. The overarching aim of the SAR 2010 conference is to highlight bi- directional translational research in acupuncture as a means of resolving these paradoxes in the field. The SAR 2010 conference is scheduled for March 19-21 2010 in Chapel Hill, N.C. and will be co-sponsored by major academic institutions in the surrounding area and nationwide. The program includes four keynote lectures which will directly address the translational research theme and three symposia, each illustrating a different aspect of translational research. Presentations of original research, including clinical trials, basic science, and research methodology, will be solicited from members of the national and international acupuncture research communities. The Conference objectives are: 1. To evaluate and differentiate strategies that can address challenges in three areas of acupuncture research: understanding the effects of acupuncture treatment components, assessing the effectiveness of acupuncture care, and differentiating specific from non-specific factors;2. To educate the acupuncture research community in the meaning and application of translational research;3. To provide an international forum in which AOM researchers, practitioners, and policy makers can assess translational research strategies to broaden the acupuncture evidence base and to stimulate collaborations/drive future research;4. To foster interdisciplinary dialogue and collaboration in order to develop innovative strategies to address current challenges in acupuncture research. PUBLIC HEALTH RELEVANCE: Translational research that bridges basic science findings to the way that acupuncture is practiced in the community will improve the validity of acupuncture and increase its availability to those in need. As an example, the burden of chronic pain patients on the US health care system is significant and growing. The adoption of a cost-effective intervention such as acupuncture could both improve pain patient outcomes and reduce the burden on society. This conference and its follow-up will advance those aims exponentially.

DESCRIPTION (provided by applicant): There are over 2 million breast cancer survivors today. Persistent cancer-related fatigue (PCRF), a state of being tired or weary, is one of the most common and distressing symptoms experienced by breast cancer (BC) survivors. Rates of significant PCRF in BC survivors range from 30% to 82% within the first 5- years of diagnosis. PCRF is associated with decreased quality of life, decreased sleep quality and depression. Also, subjective reports of low levels of fatigue at diagnosis in BC survivors predict longer recurrence-free (risk ratio [RR] 1.32, 95% confidence interval [CI] 1.13-1.54) and overall survival (RR 1.23, 95%CI 1.05-1.44). Consequently, decreasing PCRF could have a positive impact on women's quality of life and on survival. There are few treatment options for PCRF and these treatments require the availability of a trained practitioner, are associated with significant costs, pose a sizeable burden for the patient, or have unacceptable side-effects. Acupressure is a technique derived from acupuncture, a component of Traditional Chinese Medicine. In acupressure, physical pressure is applied to acupuncture points by the hand, elbow, or with various devices to treat disease. Pilot studies have demonstrated that self-administered acupressure can significantly decrease PCRF by as much as 70% in cancer survivors. Acupressure can also have positive effects on sleep quality in cancer patients and other chronically ill populations. We have performed a pilot clinical trial of acupressure in PCRF. In that trial we observed differential effects of two acupressure formulas, relaxation and stimulatory acupressure, both of which reduced PCRF, with relaxation having a significantly greater effect. Self-administered acupressure is a non-toxic and inexpensive treatment that requires minimal instruction. Acupressure also requires little effort and time on the part of the patient to successfully complete. Thus, acupressure appears to be a promising treatment for PCRF and associated symptoms. As such, we propose a single-blind, placebo controlled study to examine the specific effect of two opposing acupressure treatments compared to standard of care. This study would be conducted in 375 BC survivors at least 12 months after completion of cancer treatments, with moderate to severe PCRF, who will be randomized to one of 3 groups: (1) relaxation acupressure [RA];stimulating acupressure [SA];or standard of care for 6-weeks followed by a 4-week washout period. Our primary aim is to examine the effect of 6-weeks of RA compared to SA or standard of care on fatigue as assessed by: (1) weekly self-report using the Brief Fatigue Inventory;(2) objective daytime physical activity on actigraph;or (3) fatigue patterns assessed 4-times daily using a visual analog scale. Secondary endpoints include the examination of the two acupressure regimes or standard of care on sleep quality, and on important kinetic parameters required for implementation of acupressure in a clinical setting;mainly the time to onset for effects of acupressure on fatigue and sleep during the 6-week treatment period and the duration of effect of RA and SA during the 4-week washout period. PUBLIC HEALTH RELEVANCE: There are over 2 million breast cancer survivors today and persistent cancer-related fatigue (PCRF), a state of being tired or weary, is one of the most common and distressing symptoms experienced by breast cancer (BC) survivors. This study will examine a low cost and safe treatment derived from Traditional Chinese Medicine, self- administered acupressure, to treat fatigue in BC survivors. Decreasing fatigue in these women has the ability to improve their quality of life and possibly delay or prevent BC recurrence.

DESCRIPTION (provided by applicant): The proposed Society for Acupuncture Research (SAR) Conference, entitled SAR 2013: Impact of Acupuncture Research on 21st Century Health Care, aims to critically examine recent advances in research that have the potential to strengthen the traditional practice of acupuncture as a contemporary health care option. This conference will focus on disseminating important findings from acupuncture research that span the translational continuum from basic science, clinical trials, to patient care. In planning this conference, we will harness the momentum generated by our successful SAR 2010 conference as well as draw on our almost 20 years of experience in sponsoring major acupuncture research conferences. The overarching aim of the SAR 2013 conference is to highlight the state of the science of acupuncture research in the 21st century and to explore how this evidence base can impact modern health care trends. The Conference, scheduled for April 18-21, 2013 in Ann Arbor, MI, will be co-sponsored by the University of Michigan Department of Anesthesiology and the University of Michigan Program for Integrative Medicine. Additional sponsors are expected from major national and international academic institutions and organizations, based on sponsorship in prior SAR conferences. The 2013 program contains three keynote lectures that will directly address current research in acupuncture including: 1) the role of Traditional Chinese medicine in combat-related stress disorders, 2) neuroimaging markers to evaluate acupuncture efficacy and mechanism, and 3) the discordance between acupuncture research and acupuncture practice. In addition to keynote lectures, a special panel discussion will directly address the conference theme, the impact of acupuncture research on 21st century health care. We will also hold two symposia, one focusing on heterogeneity of acupuncture techniques and its impact on research conclusions, and the other focusing on contextual and patient-practitioner interactions in acupuncture research. Workshops scheduled within the conference will offer guidance in designing clinical trials in the emerging area of comparative effectiveness research and in incorporating a range of physiological biomarkers into clinical research. Presentations of original research, in acupuncture and allied traditional East Asian modalities, including clinical trials, basic science, and research methodology, will be solicited from members of the national and international research communities for oral and poster presentations. The Conference aims are to: 1. Provide an international forum in which researchers can assess acupuncture findings that clarify and strengthen the evidence base, 2. Foster interdisciplinary dialogue and collaboration in order to develop innovative strategies for addressing current challenges in acupuncture research, and 3. Enhance international communication amongst acupuncture stakeholders (researchers, policy makers, practitioners) to assess the potential impact of acupuncture research in contemporary health care administration and decision making. PUBLIC HEALTH RELEVANCE: The environment in which biomedical research is performed and how health care is administered is changing within the United States. Amidst this changing landscape, research within the field of acupuncture that bridges basic science findings to the way that acupuncture is practiced in the community is emerging. This is significant as the adoption of acupuncture as a cost-effective intervention could both improve patient outcomes and reduce burden on society. This conference and its follow-up will advance these aims exponentially.

Several recent meta-analyses of acupuncture for chronic pain have shown that verum acupuncture is not superior to sham/placebo acupuncture. However, these same meta-analyses have also noted significant heterogeneity in acupuncture methods across trials, which complicates combining results. For example, while electro-acupuncture (EA) was superior to sham acupuncture in relieving pain for fibromyalgia (FM), manual acupuncture (MA) was not. In terms of physiologic action, EA and MA are very different procedures. They effect different peripheral targets and induce different psychophysical perceptions, manifest in different brain response. In fact, somatosensory afference may be a key variable in acupuncture analgesia, and the use of some sham needling devices (e.g. Streitberger Needle (SN)) has been criticized since they also produce somatosensation. Moreover, somatosensation may be a particularly important variable for FM, as this chronic pain disorder is known to display altered sensory and nociceptive amplification. Thus, we hypothesize that EA has been more effective for FM because it functions as a desensitization therapy, which when applied repeatedly over multiple treatment sessions, gradually habituates the nervous system to continuing endogenous pain and somatosensory signaling. Our overall goal is to evaluate the impact of acupuncture-induced somatosensory afference on altered neurobiology and analgesia in FM. To test our hypotheses, we will incorporate neuroimaging into a randomized, blinded, longitudinal trial in FM using acupuncture interventions with significantly different amounts of somatosensory afference: (1) EA and (2) mock laser (ML) acupuncture - a relatively new form of sham acupuncture that does not induce any somatosensory afference. Our first Aim will characterize, at baseline, the altered somatosensory-related neurocircuitry underlying chronic pain in FM. Aim 2 will evaluate longitudinal desensitization effects of electro- and mock laser acupuncture on the neurocircuitry underlying chronic pain in FM. Aim 3 will then evaluate the ability of altered neurocircuitry at baseline to predict clinical response to both electro- and mock laser acupuncture. These analyses will provide much needed information about which patients might benefit most from which acupuncture interventions.

? DESCRIPTION (provided by applicant): The neural mechanisms of anesthesia and analgesia are fundamental scientific questions, with profound clinical relevance for surgical patients. Most general anesthetics potentiate GABA transmission and thus depress neuronal function, predictably inducing unconsciousness. However, ketamine and nitrous oxide are unique drugs with both anesthetic and analgesic properties that are noteworthy exceptions: GABA receptors are not the primary molecular target and both drugs increase high-frequency activity of the electroencephalogram. However, despite these differences at the molecular and neurophysiological level, recent data from our laboratory suggest that these drugs may have mechanistic similarities to GABAergic anesthetics at the level of brain networks. Our long-term goal is to discover fundamental neuroscientific principles of anesthesia and analgesia that can be monitored in the perioperative period. The objective for this application is to identify-using functional magnetic resonance imaging (fMRI), electroencephalography (EEG), cortical multielectrode array recordings, and graph-theoretical analysis-the network-level mechanisms of ketamine and nitrous oxide at analgesic and anesthetic doses. Our central hypothesis is that ketamine and nitrous oxide alter network modularity (i.e., the level of integration of cortical modules) and network efficiency. We specifically hypothesize that lower doses of these drugs increase network efficiency and disrupt pain processing-resulting in analgesia-and that higher doses decrease network efficiency and disrupt cortical representation-resulting in anesthesia. The rationale for the proposed studies extends beyond determining how these particular drugs work. An improved understanding of the network effects of these unique agents could lead to a more fundamental understanding of general anesthetic and analgesic mechanisms. We plan to test our central hypothesis by accomplishing the following specific aims: 1. Identify dose-dependent changes in brain networks using combined fMRI/EEG studies in healthy volunteers receiving ketamine or nitrous oxide. We have successfully developed a paradigm of combined fMRI/EEG in humans receiving anesthetic drugs, with preliminary data supporting our central hypothesis. In the proposed studies we will assess brain responses to ketamine or nitrous oxide at subanesthetic and anesthetic doses, with a focus on network measures such as modularity, efficiency, and hub structure. 2. Assess dose-dependent changes in sensorimotor representations using cortical array recordings in nonhuman primates receiving ketamine or nitrous oxide. We have obtained preliminary evidence that primary cortical representations can persist during ketamine anesthesia, while the cross-modal sensory representation normally found during waking is abolished (e.g., elimination of secondary sensory representation in M1). This innovative study design is the first to measure cognitive representation in brain networks after exposure to anesthetic drugs, as opposed to current techniques of measuring surrogates such as functional connectivity.

? DESCRIPTION (provided by applicant): The proposed Society for Acupuncture Research (SAR) Conference will be titled SAR 2015: Reaching across Disciplines to Broaden the Acupuncture Research Network. This international conference will critically examine recent advances in acupuncture research that both have the potential to strengthen the evidence base for its integration with contemporary health care and better define the agenda for cross-disciplinary and translational acupuncture research in the coming years. A key goal of this conference is to actively disseminate important research findings to the acupuncture research community and multiple related fields of biomedical research. Strategically, the timing and location for this conference will coincide with conferences planned by two other organizations, the Society for Integrative Oncology (SIO) and the Fascia Research Society (FRS). The Conference, scheduled for November 12-14, 2015 in Boston, MA, at Harvard Medical School will be co- sponsored by the Osher Center for Integrative Medicine at Brigham and Women's Hospital, Harvard Medical School. The venue for the event will be the Joseph B. Martin Conference Center, a modern, state-of-the-art facility at the center of the Harvard Medical School campus. The 2015 conference program, in lieu of lengthy keynote lectures, will contain nine 1/2-hour plenary lectures from thought leaders spanning different areas of acupuncture research. These plenaries will be grouped into 3 clusters of 3 talks with complementary content, which will be followed by a moderated and structured panel discussion including audience participation. Workshops scheduled within the conference will provide focused training opportunities targeting researchers and clinicians at a variety of career stages. High quality presentations of original research, including clinical trials, basic science, qualitative studies ad research methodology, will be solicited from junior and established members of the national and international CAM and biomedical research communities for oral and poster presentations. SAR 2015 will culminate in an innovative tri-conference day of cross-disciplinary plenary talks and moderated discussions devoted to the interface of acupuncture, connective tissue biology, and oncology - a coordinated effort led by SAR, SIO, and FRS. Our Aims are to 1) Provide an international forum for researchers to assess acupuncture findings that clarify and strengthen the evidence base and shape future research agenda; 2) Foster interdisciplinary dialogue and collaboration between researchers representing multiple East Asian medicine, CAM and biomedical disciplines in order to develop innovative translational strategies to address current challenges in acupuncture research; and 3) Enhance international communication between acupuncture stakeholders (researchers, policy makers, practitioners) and stakeholders of related biomedical research fields (e.g. fascia research, integrative oncology) to build bridges between these communities and expand the impact of acupuncture research in contemporary healthcare administration.

PROJECT SUMMARY / ABSTRACT PAIN MECHANISMS CORE (PMC) The University of Michigan Fibromyalgia (FM) CORT proposes that presence of centralized pain will render individuals less responsive to analgesic therapies aimed at peripheral/nociceptive pain (surgery, biologics, opioids) and that this centralized pain phenotype has stereotypical clinical and neurobiological features similar to FM even when it is co-morbid with other musculoskeletal pain conditions with disparate underlying pain mechanisms. The PMC will use quantitative sensory testing (QST) and neuroimaging methods to characterize the degree of centralization in three cohorts of musculoskeletal pain patients: osteoarthritis of the hip, rheumatoid arthritis, and carpal tunnel syndrome. We will collect these same measures in individuals with FM and heathy controls, which will enable us to demonstrate that these neurobiological measures are increasingly abnormal in the transition from low (healthy controls) to high degrees of fibromyalgia (FM cohort). The Specific Aims of the CORT supported by the PMC are as follows: 1) To demonstrate that individuals with the highest FM Survey Criteria scores will have similar neurobiological findings of pain centralization, including abnormal QST findings and aberrant findings on functional, chemical and structural neuroimaging. We hypothesize that in all three musculoskeletal pain cohorts, the individuals with greater degrees of pain centralization (i.e. highest scores on the FM Survey Criteria) will demonstrate a) more hyperalgesia and decreased pain inhibition on QST and functional magnetic resonance imaging (fMRI), b) characteristic functional connectivity changes on fMRI (e.g., decreased functional connectivity to descending antinociceptive brain networks and increased connectivity to pronociceptive regions), c) increased CNS levels of excitatory neurotransmitters in pronociceptive regions on proton spectroscopy (i.e., glutamate in posterior insula), and d) increases in primary somatosensory/motor cortex volume. 2) To identify the clinical and mechanistic features of two important subsets of centralized pain: top-down activity independent centralization (i.e. previously termed primary FM) vs. bottom-up activity-dependent pain centralization or central sensitization (i.e. previously termed secondary FM) by exploring changes in QST/MRI measures in OA and carpel tunnel patients 6 months following surgery. It is critically important to better understand these mechanistic phenotypes of centralization since one group will benefit more from aggressive analgesic therapy aimed at the periphery.

Abstract The upcoming Society for Acupuncture Research (SAR) Conference, titled SAR 2017: Advancing the Precision Medicine Initiative through Acupuncture Research,? is an international-targeted conference that will critically examine recent advances in acupuncture research that both have the potential to strengthen the evidence base for its integration with contemporary health care and better define the agenda for cross- disciplinary and translational acupuncture research in the coming years. Held in the San Francisco Bay Area, a key goal of this conference is to actively disseminate important research findings to the acupuncture research community and multiple related fields of biomedical research. The theme of the SAR 2017 conference will explore how the recent focus on personalized medicine can benefit from research on acupuncture and traditional East Asian medicine. Conversely, we will also explore how ideas emerging from personalized medicine can help us better explore individual variability and responders / non-responders that have been a hallmark of clinical and mechanistic acupuncture research studies. This focus will be reflected in specific symposia at the 2017 Conference. However, our key goal has always been to provide a forum to actively disseminate important research findings across the research spectrum, and this conference will continue to do just that. In fact, a new initiative will be to solicit not just abstracts, but also symposia topics from the research community, with the most meritorious submission chosen as a plenary symposium. The primary co-sponsor of this conference will be the Department of Anesthesia at Stanford University. The 2017 conference program will include fifteen 30-minute plenary lectures from thought leaders spanning different areas of acupuncture research as well as precision medicine. These plenaries will be grouped into 5 clusters of 3 talks with complementary content, each of which will be followed by a moderated and structured panel discussion including audience participation. In addition, as in past SAR conferences, high quality presentations of original research will be solicited from junior and established researchers for oral and poster presentations. Workshops scheduled prior to the conference will offer guidance for a range of experience levels. An international Scientific Review Committee, composed of SAR Board members and multiple external reviewers, will employ a rigorous peer review process to assure quality and relevance of original research and to advise the Program Committee in the selection of oral abstract presentations. Broad marketing efforts will target researchers, students, healthcare administrators and health policy analysts. The West Coast locale will in fact encourage attendance by researchers from Asia and Australia. Our Aims will be to (1) Provide an international forum for researchers to assess acupuncture findings that clarify and strengthen the evidence base and shape future research agenda; (2) Foster interdisciplinary dialogue and collaboration between researchers representing multiple East Asian medicine, CAM and biomedical disciplines in order to develop innovative translational strategies to address current challenges in acupuncture research; and (3) Enhance international communication between acupuncture stakeholders (researchers, policy makers, practitioners) and both junior and senior researchers to provide mentoring and build bridges between different research communities. Our SAR 2017 meeting will explicitly explore connections between acupuncture and precision medicine, allowing acupuncture research to inform current clinical mandates.

PROJECT SUMMARY / ABSTRACT Pain in the United States is common and costly, with over 1 in 3 individuals being afflicted causing an economic burden approaching $600 billion annually. This problem results from our lack of understanding the underlying mechanisms of most forms of chronic pain which in turn has hampered our ability to develop new effective treatments. Fibromyalgia (FM) is a common chronic pain condition whose pathology is largely unknown. Existing research suggests that the brain may play a significant role in pain expression in these individuals. Although untested, an imbalance in excitatory and inhibitory brain activity may lead to an unstable neural network sensitized to external stimuli and this may lead to pain in FM. Hypersensitive and unstable networks have been observed in various physical and biological systems, and in such networks, small perturbations can give rise to explosive and global propagation of activity over the system. One underlying mechanism of hypersensitive systems, called explosive synchronization (ES), has been introduced and actively studied over the past decade. ES is a phenomenon wherein small increases in stimulation strength applied to a network, can lead to an abrupt state transition through global network synchronization. Here we hypothesize that ES may be an underlying mechanism of the hypersensitivity of the FM brain, and a targeted approach with non-invasive brain stimulation may reduce conditions or ES and subsequent pain in some of these patients. Our pilot electroencephalogram (EEG) data showed that the FM brain displays network configurations primed for ES. Individuals with more clinical pain had increased ES conditions within their brain networks. Furthermore, when these same patients experienced an increase in pain following an experimental pressure pain stimulus applied to the thumb, they exhibited a concomitant increase in ES. Understanding how the development of hypersensitivity within the brain can lead to chronic pain is an unknown in the medical field and is the major theme of this proposal. We posit that finding the underlying mechanism of hypersensitivity in the FM brain could lead to a more fundamental understanding of the central nervous system sensitization seen in this pain state (and potentially others), and targeting this phenomenon might be an effective new treatment strategy. To achieve this goal, we propose three aims based on interdisciplinary approaches of neuroscience, physics, medicine, and mathematics: Aim 1. Demonstrate that individuals with FM, as compared to pain free controls, display brain characteristics of ES as assessed with EEG. Aim 2. Computationally model the underlying mechanism(s) of the hypersensitive FM brain and identify key target regions that might reduce brain hypersensitivity. Aim 3. Test the ability of high definition transcranial direct current stimulation (HD-tDCS) at discrete network regions to reduce conditions of ES within the brain.

Abstract Chronic pain due to knee osteoarthritis (OA) is a large contributor to disability, affecting over >14 million Americans. However, treatment is difficult and outcomes are poor. This is because pain is not monolithic, and differences in underlying pain mechanisms affect treatment response. While knee OA pain can be due to tissue and joint damage (nociceptive pain), it can also be augmented and maintained by central nervous system (CNS) dysfunction ? i.e., centralized or nociplastic pain. Variable CNS contributions explain why some people have severe radiographic knee damage yet report no pain, while others have ?normal? radiographs yet report severe pain. Our group and others have shown that this centralized phenotype occurs in nearly all chronic pain conditions. Further, we have demonstrated the clinical relevance of matching pain mechanisms with therapies, showing that a greater degree of pain centralization lowers responsiveness to interventions (e.g., opioids and surgeries) directed toward reducing nociceptive pain in knee OA. Differences in underlying mechanisms may explain inconsistent clinical trial results with cannabinoids - the active compounds in Cannabis sativa. Clinical trials suggest that cannabinoids can be effective analgesics, but this has been shown primarily with ?[9]-tetrahydrocannabinol (THC) dominant preparations, which have abuse potential. However, a recent study showed that cannabidiol (CBD) reduced pain and increased function in men with knee OA. CBD is non-intoxicating, and exerts analgesic and anti-inflammatory effects. The proposed studies are the first attempt to understand how CBD and THC affect different chronic pain mechanisms by examining the effects of these compounds on knee OA in individuals with varying degrees of pain centralization. Our overarching hypothesis is that CBD will decrease peripheral inflammation, THC will modify CNS pain processing, and combined CBD+THC will do both. To test this hypothesis, we propose three specific aims. Aim 1: In a randomized, double-blinded, 2x2 factorial design study, longitudinally assess peripheral and CNS effects of CBD and THC on inflammation (interleukin 6) and neurobiological correlates of centralized pain (i.e., default mode network to insula connectivity) using a phenotyping battery of patient reported outcomes, experimental sensitivity testing, and neuroimaging that we have successfully applied to other drugs and pain conditions. Aim 2: Examine effects of THC and CBD and their metabolites on additional indices of brain connectivity and neurochemistry as well as inflammatory markers. Aim 3 (exploratory): Assess whether pain centralization predicts differential analgesic responsiveness to CBD and THC. Given that pain centralization occurs on a spectrum in many chronic pain conditions, our approach in knee OA will act as a translational model that can be applied to nearly all other pain conditions and will have broad implications for developing non-opioid analgesics for pain management.

Abstract The upcoming Society for Acupuncture Research (SAR) Conference titled Pandemics, Pain & Public Health: Roles and Relevance of Traditional East Asian Medicine,? will be held on June 16-20, 2021 with potential in- person attendance at the University of Michigan. A key goal of this conference is to actively disseminate important research findings to the acupuncture and Traditional East Asian Medicine (TEAM) research community and multiple related fields of biomedical research. The primary co-sponsors of this conference will be the Department of Anesthesiology at the University of Michigan and the Osher Center for Integrative Medicine at Harvard Medical School. Our program will focus content on three major issues: 1) the impact of the global Coronavirus Disease (COVID-19) pandemic, 2) the chronic pain/opioid and mental health crisis in the U.S., and 3) the role of disparities in integrative health care, including their underlying impact on public policy. Panel discussions with key international figures will explore these topics with emphasis on strengthening the research base to address these issues. SAR members will be able to submit proposals for plenary symposia on relevant topics of their choice. Our meeting will also include lectures from thought leaders spanning different areas of basic and clinical TEAM research, as well as a keynote presentation by the Director of NCCIH. This conference structure will be unlike any past SAR gathering. Due to the ongoing COVID-19 pandemic, our 2021 event will either be a hybrid meeting, with both in-person and virtual content, or it will be an entirely virtual meeting. This is necessary as some attendees may not be able to travel and attend our event safely. A collateral benefit of having some content be virtual is that attendees unable to travel will still be able to participate remotely. To achieve our goals, the conference plan was set after an in-depth analysis of hybrid and virtual options. By the date of our 2021 conference, SAR will also have had additional experience with virtual conference formats from two international online meetings currently planned. We will leverage the experience from these virtual gatherings to plan for this 2021 conference. Our Aims are: 1) To provide an international forum for researchers to disseminate and assess acupuncture and TEAM findings in order to clarify and strengthen the evidence base, and 2) To foster interdisciplinary dialogue and collaboration to develop innovative strategies that address current challenges in acupuncture and TEAM research, shaping the future research agenda. The SAR 2021 conference will present a platform wherein researchers from various backgrounds can share, explore, and develop novel research strategies. SAR conferences continue to serve as a crossroads for diverse research communities. Indeed the content of our event (e.g. pandemics, pain, and disparities/policy) is relevant for the current global health care climate, and cuts across multiple scientific levels from patients, to researchers, educators, and clinicians, to those driving policy.