Abstracts for the NCCIH 20th Anniversary Symposium

Why We Need a Pain Revolution: From Science to Practice

By any metric, persistent pain is one of the most burdensome health problems we face. It is associated with increased risks of depression, cancer, cardiovascular disease, and stroke and is a key player in what is now recognized as a devastating opioid problem. In this talk, Dr. Moseley will present the science and sentiment underlying six target concepts that are at the heart of the Pain Revolution, a community pain education and capacity-building program focusing on rural and regional Australia. He will argue that best practice recommendations—education, active and psychological therapies, and self-management skills—make absolutely no sense according to dominant models of pain, but are completely sensible according to contemporary models that emphasize pain’s biopsychosociality and our remarkable “bioplasticity.” Dr. Moseley will bring his usual mix of scientific rigor, metaphor, and humor to the complex, very serious, and altogether exciting subject of pain.

Molecules and Cells for Touch and Pain

We seek to understand the molecules, cells, and neural circuits that generate innocuous and noxious sensations and uncover how perception is altered by context (e.g., during chronic pain). For our studies we use a wide range of techniques, including genetics, electrophysiology, functional imaging, and behavioral measurements in mice. In parallel, we collaborate with researchers at the National Institutes of Health Clinical Center to examine patients with rare inherited disorders and other conditions affecting somatosensation. A major emphasis is combining clinical and basic science to advance our understanding of pain mechanisms. Recently, we identified individuals with major yet specific deficits in touch and proprioception caused by inactivating mutations in the stretch-gated ion channel PIEZO2. In parallel, our group has been examining the importance of Piezo2 in the cellular representation of mechanosensation using in vivo imaging in mice. Together, our findings reveal the PIEZO2 mechanoreceptor as an essential mediator of touch under normal and inflammatory conditions and suggest that this ion channel might be targeted for treating tactile allodynia.

Watching Cellular Mechanotransduction: Piezo1 in Neural Stem Cell Fate

A major unanswered question in biology is how mechanical forces are generated, detected, and transduced by cells to impact biochemical and genetic programs. Our work is aimed at uncovering the mechanical principles at play in cells and tissues using novel molecular, imaging, and bioengineering tools. Here we present insights gleaned from noninvasive approaches to measure and manipulate mechanical cues in native cellular conditions. We find that the mechanically activated ion channel Piezo1 transduces cell-generated traction forces to regulate lineage choice of neural stem cells. Ongoing work aims to apply these approaches to three-dimensional human brain organoids. These studies will provide quantitative and mechanistic insights on the role of mechanical forces during development, and demonstrate how development fails when they are disrupted.

Dissection of Neural Circuits of Chronic Pain and Analgesia

The perception of pain and the responses to painful stimuli can be enhanced or attenuated by many factors including expectation, experience, and the emotional state of an individual. The ability of organisms to turn pain up and down under different conditions has been linked to changes in brain function, with dysfunction of this pain modulatory system proposed to underlie persistent pathological pain states. Surprisingly, little is known about the brain mechanisms leading to persistent pathological pain states. The NCCIH Division of Intramural Research Section on Behavioral Neurocircuitry and Cellular Plasticity integrates cutting-edge multidisciplinary approaches in mouse models of acute and chronic pain to study the mechanisms underlying the brain’s ability to enhance and decrease pain. Our studies have demonstrated that cell-type-specific bidirectional changes in excitability in the central nucleus of the amygdala (CeA) function as a pain rheostat, attenuating or exacerbating pain-related behavioral outputs in mice. During my talk, I will present the results from these studies as well as our ongoing efforts to dissect out the cell-type-specific neural circuits and cellular mechanisms underlying bidirectional control of pain in the brain.

Learning, Anxiety, and Subjective Pain

My lab investigates the psychological factors that shape pain and emotional experience, and how these relationships might be altered in clinical populations. In this talk, I will introduce our work examining the relationship between anxiety and pain. In collaboration with investigators at the National Institute of Mental Health, we performed a series of studies in youth with anxiety and healthy volunteers. Anxious individuals did not differ in pain threshold or tolerance and exhibited similar magnitudes of expectancy-based pain modulation as healthy individuals (Michalska et al., 2018). However, computational models of reinforcement learning revealed dissociations in the effects of instruction and associative learning that varied as a function of anxiety (Atlas et al., under revision). Individuals with high anxiety updated pain more quickly upon instruction but maintained elevated arousal for initial threats. This indicates that pain-related outcome measures may show distinct patterns of responses in patients with anxiety, and that subjective measures may be more influenced by instructions and psychosocial factors than autonomic responses. I will discuss implications for pain research and the search for objective biomarkers of pain, as well as implications for clinical treatment.

Cannabinoids, Inflammation, and Metabolic Health

The legalization of cannabis for medical and recreational use has increased in the past decade, motivated by the growing social acceptance. Among the qualifying conditions for which medical cannabis can be recommended are HIV- and cancer-related cachexia. Although effective to alleviate nausea and vomiting, clinical trials demonstrated little to no impact of cannabinoids on promoting weight gain among these patients. In addition, we and others have reported attenuated weight gain and decreased prevalence of obesity in cannabis users. A recent National Academy of Sciences, Engineering, and Medicine report on the health effects of cannabis and cannabinoids concluded that there is a need for additional studies to assess the metabolic health effects of cannabinoids and their effectiveness in treating wasting and promoting weight gain. In this talk, I will highlight our efforts to study the role of cannabinoids in systemic inflammation and in metabolic diseases such as obesity and type 2 diabetes mellitus.

Redesigning Plant Metabolism With Synthetic Biology

Plants produce a wealth of biologically active compounds, and thus a major impetus for studying plant natural product biosynthesis has been the goal of elucidating and harnessing these metabolic pathways as a means to produce molecules of interest. The field of synthetic biology has opened the door not only to the engineering of new metabolisms into heterologous hosts, but also the designing of novel pathways that are not known to exist in nature. Here, we expand the biological repertoire of plant metabolism by taking a “plug-and-play” approach to rationally engineer synthetic pathways for the production of target nonnatural compounds. As future endeavors in plant metabolic engineering are becoming increasingly complex, more sophisticated methodologies will be required to deliver on such ambitions. We have developed a number of plant synthetic biology tools to enable the coordinated expression of multiple transgenes simultaneously in order to ultimately facilitate the introduction of these synthetic pathways into relevant crop species.

Heated Yoga for the Treatment of Depressive Symptoms: Background and Methods From a Randomized Controlled Trial

Nonheated yoga and whole body hypothermia (WBH) have both demonstrated the ability to treat depressive symptoms in randomized controlled trial(s). Heated yoga has yet to be evaluated for this indication. Adults with significant symptoms of depression were randomized to 8 weeks of heated yoga (Bikram yoga) vs. an 8-week waitlist control condition. Those in the control condition received 8 weeks of heated yoga after the completion of the control condition. The study is ongoing. Methods will be discussed. Enrollment and feasibility data will be presented. Our published open-label trial will also be discussed, and future implications will be explored.

Mindfulness, Are You There? Improving the Reach of Mindfulness-Based Cognitive Therapy With Telephone Delivery

Mindfulness-based cognitive therapy (MBCT) is a promising intervention for improving depression outcomes in patients with comorbid chronic illness. Yet MBCT remains inaccessible to many who might benefit due to lengthy in-person sessions and a limited number and geographic reach of trained facilitators. We adapted the original MBCT protocol to be delivered in an abbreviated format by telephone (MBCT-T). We evaluated its feasibility, acceptability, and preliminary efficacy for reducing depression in patients with hypertension, a condition highly comorbid with depression. Participants (n=14) with mild-to-moderate depressive symptoms and hypertension were recruited to participate in an 8-week MBCT-T intervention. Recruitment rates, attendance, home-based practice completion, and satisfaction were measured as indices of feasibility and acceptability. Depressive and anxiety symptoms were assessed at baseline and post intervention. Participants attended an average of five of eight sessions. Eighty percent of participants completed all of the assigned home-based practice. Participants reported high satisfaction. Reductions in depressive and anxiety symptoms were clinically meaningful, statistically significant, and comparable to effect sizes found for the original MBCT protocol. The results support the feasibility, acceptability, and efficacy of a scalable and accessible version of MBCT for reducing depressive and anxiety symptoms in patients with chronic disease.

Predicting Analgesic Response to Acupuncture in Chronic Low-Back Pain – A Practical Approach

Chronic low-back pain (CLBP) is the number one chronic pain complaint at the physician’s office. Conventional therapies for CLBP such as surgery, blocks, and medications are expensive, don’t always work, and often lead to significant side effects. Recent evidence supports acupuncture in the management of CLBP. One issue with acupuncture, as well as with many other treatments of chronic pain, is the individual nature of clinical response. Multiple studies suggest that not everyone responds to acupuncture, and the percentage of responders ranges between 40 and 60 percent. My K23 study, funded by NCCIH, proposes to identify acupuncture responders in CLBP by: 1) performing deep phenotypic characterization of patients with CLBP, using measures from demographics, disease characteristics, physical exam findings, vital signs, and comprehensive quantitative sensory testing involving thermal, cold, and tactile stimuli, as well as psychological assessments and traditional Chinese medicine diagnoses; 2) using advanced machine-learning techniques to select key baseline variables to build a simple predictive algorithm. Using an earlier similar CLBP study with acupuncture (also funded by NCCIH) to train our algorithm and the K23 study as the validation set, we were able to confirm performance of a simple algorithm built on traditional Chinese medicine and psychosocial measures.

Cost-Effectiveness of Integrative Therapies for Spinal Pain in the United States Using an Individual Participant Data Meta-Analysis Approach

The U.S. spends roughly $88 billion per year on health care for low-back and neck pain, more than any other condition other than diabetes and ischemic heart disease. Despite this, little is known regarding the value of commonly used treatments (including complementary and integrative approaches) for the management of spinal pain. Dr. Leininger will present preliminary results from his research examining the cost-effectiveness of spinal manipulation, supervised rehabilitative exercise, and home exercise for spinal pain. Using individual participant data from 8 randomized clinical trials including 1,739 participants, this project provided a unique opportunity to combine clinical and economic data from multiple trials that used similar methods and collected similar data.

Improving the Evidence Base To Inform Health Policy

Efforts to improve the value of health care and the sustainability of the health care system are increasingly important in the United States. This presentation discusses a set of research aiming to improve the evidence base behind health policy choices.

Evaluating Chiropractic Care in the Veterans Health Administration

U.S. military veterans suffer from high levels of back pain and concomitant use of analgesics, including opioids. In response, the Veterans Health Administration (VHA) has implemented progressive programs for pain management, with a focus on nonpharmacologic approaches. Chiropractic care is one such approach, with demonstrated evidence of effectiveness and safety for back pain and designation as a Tier 1 treatment modality by the Department of Defense (DoD)/Department of Veterans Affairs (VA) Pain Management Task Force comprehensive pain management program. However, few studies have addressed the role of chiropractic in the care of military veterans and fewer still have assessed integration of chiropractic within VHA settings. Over the past 5 years, NCCIH has supported important work to address these gaps. This presentation will include an overview of previous and ongoing research in this area, including a qualitative stakeholder analysis, the development of clinical care pathways, a completed pilot clinical study to assess the feasibility of evaluating chiropractic care in the VHA, and a recently funded pragmatic clinical trial designed to evaluate “dosing” of chiropractic care in veterans with chronic low-back pain, one of the program projects included under the umbrella of the National Institutes of Health (NIH)-DoD-VA Collaboratory.

The NIH-DoD-VA Pain Management Collaboratory

Abstract: Pain management is a high priority for the U.S. Departments of Health and Human Services (which includes the National Institutes of Health (NIH)), Defense (DoD), and Veterans Affairs (VA). These government agencies have developed strategic initiatives designed to promote timely and equitable access to high-quality integrated, patient-centered, evidence-based multimodal and interdisciplinary pain care. Building upon prior commitments to research on pain and pain management, the NIH-DoD-VA Pain Management Collaboratory was launched in 2017 as a tri-government agency partnership that supports the development and implementation of 11 pragmatic clinical trials on nonpharmacologic approaches for management of pain and comorbid medical and mental health conditions in military and veteran health systems. The background and context for this initiative will be presented, emphasizing high rates of pain and comorbidities, and complexities and challenges of pain management among military service members and veterans, as well as the relatively unique opportunities in the DoD and VA as integrated, learning health systems for addressing these challenges. This will be followed by a description of the structure and functioning of the Pain Management Collaboratory Coordinating Center and a brief overview of the 11 trials. Progress of the Collaboratory will be provided, highlighting significant and innovative processes, products, and results that have emerged from seven Coordinating Center Work Groups, namely: Biostatistics/Study Design, Phenotypes/Outcomes, Ethical/Regulatory, Data Sharing, Electronic Health Record, Stakeholder Engagement, and Implementation Science. The presentation will highlight the significance of this initiative in addressing key scientific knowledge and practice gaps in the field of pain management.

Putting the Integrat(e) Into Complementary and Integrative Health: Using Complementary and Integrative Health Components To Improve Existing Interventions in Military Pain Research

Complementary and integrative health (CIH) has created a “new” frontier for the management of chronic health conditions. Active duty military members and veterans consistently demonstrate high levels of interest in CIH and are more likely to use CIH interventions than many traditional or mainstream options. Chronic pain is a growing concern in military service members and veterans, and studies of military pain increasingly highlight the importance of multifaceted models of care to effectively address pain that often presents in the context of trauma-related comorbidities like posttraumatic stress disorder and traumatic brain injury. CIH offers opportunities to both replace antiquated models of rehabilitation that are no longer effective for more complex military pain, and also to augment existing models to enhance their usability and efficacy. This presentation will review two studies for which the presenter integrated mindfulness into an interdisciplinary treatment model and demonstrated improved treatment outcomes in samples of military service members and veterans with persistent pain. The presenter will review the rationale and models for CIH integration, guidance of CIH integration by military and VA stakeholders, and study outcomes.

Developing Approaches To Restore an Impacted Human Microbiome

The human microbiome is both highly conserved in its overall dimensions and individual-specific in its particular features, and performs important physiologic functions for its host. There is increasing evidence that the microbiome has been perturbed, especially in early life, with metabolic, immunologic, and cognitive consequences. We are progressively understanding the nature of the losses and their specific disease sequelae, as well as the intermediary mechanisms. The next challenge will be to identify effective means for restoring the impacted microbiome and/or the compromised functions. We have been using mice as model systems to examine host-microbial relationships relevant to several important metabolic and immunological diseases of humans. These include studies of obesity and nephrolithiasis as well as type 1 diabetes, inflammatory bowel disease, and asthma. An important focus has been the development of restorative practices with defined pre- and probiotics.

Informative In Vitro Studies of Botanical Dietary Supplements: What Have We Learned From 16 Years of NCCIH-Funded Research?

Plants have been employed since antiquity for the treatment and prevention of disease and are still a major form of health care in the United States and around the world. Plant-based (botanical) medicines are inherently complex mixtures, with composition that differs depending on myriad factors including variability in plant genetics, cultivation conditions, and processing methods. The complexity and variability of botanical medicines makes evaluation of their safety and efficacy extremely challenging. Nonetheless, with support from NCCIH, we have made significant strides over the past several decades in developing effective methodologies to conduct informative basic research studies on botanicals. This presentation will highlight some of these methodologies, with attention to pitfalls and strategies for success. Studies conducted using the botanical medicines echinacea (Echinacea purpurea) and kratom (Mitragyna speciosa) will serve as informative examples.

Growing Up With NCCAM/NCCIH: 16 Years of Development as a Scientist

NCCIH, formerly known as the National Center for Complementary and Alternative Medicine (NCCAM), has played an integral role in my development as a scientist beginning with my first day in graduate school. My scientific journey began in 2003 with the support of an NCCAM training program grant (T32) under my Ph.D. advisor, Dr. Bradley Bennett. This program focused on training Ph.D. students in tropical botany, with strong emphases on plant taxonomy, ethnobotany, field research, authentication of botanical materials, natural products chemistry, and molecular biology. My first experience with grant writing was for an individual predoctoral training fellowship (F31) with NCCAM, followed by an individual postdoctoral (F32) training grant to expand my skills in understanding the impact of plant natural products on microbial pathogenesis. The lessons learned in grant writing, interactions with National Institutes of Health staff and workshops, and research opportunities afforded to me by NCCAM at every stage of my transition from student to postdoctoral researcher were indispensable. When it was time to launch my career as an independent researcher, NCCIH was there again to support me with a project (R01) research grant that integrated techniques and tools gleaned from the years of specific training in the science of botanicals. In this talk, I will retrace my path in research on the antimicrobial properties of medicinal plants and tell the story of how NCCAM/NCCIH shaped the mold of who I am today as a scientist.