NCCIH - National Center for Complementary and Integrative Health Grants

NCCIH - National Center for Complementary and Integrative Health

Project Summary Natural products research involves highly interdisciplinary fields focused on translation of chemically and biologically complex natural products to applications for human health and health outcomes. The evolution of natural products as potentially multifunctional ligands with highly specific affinities for health-relevant targets has provided opportunities to develop therapeutic agents for cancers, infectious diseases, and neurological disorders, as well as for multisystem, multicomponent diseases and conditions. Natural products from the marine environment have provided unique molecular scaffolds that interact with biological targets and signaling pathways to effect changes in phenotype and physiology, resulting in several that have translated to clinical use. In addition, transformational advances in biosynthesis, target profiling, and analytical technologies are poised for incorporation in computational tools using machine learning for discovery of natural products and their biological signatures. The 2026 Marine Natural Products (MNP) Gordon Research Seminar (GRS) and Gordon Research Conference (GRC) are planned for February 28 – March 6, 2026, in Ventura, California. The GRS is a unique forum for graduate students and postdoctoral fellows to present and exchange new data and innovative ideas across the scope of basic and applied MNP research. The GRC will bring together early career and established researchers from academia, industry, and government (including all GRS participants) to address the discovery, characterization and functional development of MNPs. Sessions will focus on technological advances to spur new discovery, discovery of new molecular targets and receptors, computational informatics challenges and opportunities, symbiosis and microbiome interactions to facilitate discovery, biosynthesis and bioengineering for molecule and target discovery, bioactive molecules from marine sources, integrating novel synthetic approaches for enhanced discovery, and marine biogeochemistry to address microbial challenges. Our specific aims for the conference include: (1) providing a forum for emerging and established scientific leaders to present cutting-edge MNP research; (2) stimulating multi-disciplinary collaborations and providing opportunities for interdisciplinary activities; (3) highlighting biological targets, physiological function, and translational applications of MNPs; and (4) providing training for graduate students and early career scientists to promote broad participation. The collegial atmosphere of the MNP GRS and GRC will foster collaborations, provide training opportunities, and promote exchange of ideas amongst leaders in the field and new participants. NIH support will be used to enhance participation by graduate students, postdoctoral fellows, and early career faculty at the GRC, as well as for postdoctoral fellows and graduate students attending the GRS. Ample opportunities for scientific exchange and networking, both in and outside of meeting sessions, will foster new collaborations that bridge scientific disciplines and potentiate paradigm shifts in natural product sciences.

NCCIH - National Center for Complementary and Integrative Health

PROJECT SUMMARY The two-day scientific conference entitled, "The Science of Tai Chi & Qigong as Whole Person Health: Deepening our Physiological Understanding of Mind-Body Integration” will be held at the Harvard Medical School in Boston, MA on April 30-May 1, 2026. The key goals of this conference are to provide a forum for active dissemination of the current evidence base of Tai Chi, Qigong and related mind-body practices (TCQMB), and exploration and thoughtful dialogue on cross-relevant topics integral to the understanding of physiological mechanisms and the impact of mind-body movement in whole person health within the future of healthcare. The primary sponsor of this conference will be the Osher Center for Integrative Health at Brigham and Women’s Hospital and Harvard Medical School. This scientific conference will build upon the success and momentum of the first-of-its-kind, inaugural conference in 2023 that showcased TCQMB in a rigorous academic setting. This upcoming 2026 conference aims to attract a heterogeneous group of international research scholars, practitioners, healthcare administrators and policymakers to engage in a deeper dive into the science. The conference program will include four plenary panel sessions from leaders in the field focused on the following themes in the context of TCQMB: 1) Aging Brain, Aging Body, and Mind-Body Health; 2) Leveraging Technology in Research and Implementation; 3) Cancer and Integrative Oncology; and 4) Research at the Frontier: Fascia, Fluids, Mitochondria, and Biofields. These plenary panels will each include complementary 20-30 minute plenary presentations followed by an extended panel discussion including audience participation. A Call for Sessions will solicit additional concomitant one-hour ‘breakout’ symposia sessions with priority to the following topics: i. remote delivery/virtual platforms/telehealth, use of wearable sensors, and other biotechnology; ii. Impact of TCQMB on neural, physiological, and biomechanical biomarkers of interoception and resilience; iii. TCQMB for specific populations (e.g., stroke, pediatrics, cancer); iv. TCQMB as part of multicomponent interventions; v. Citizen science, big data, and AI. In addition, we will solicit high-quality scientific abstracts with opportunity for both junior and established investigators to present oral and poster presentations. An international Scientific Review Committee, composed of external reviewers, will employ a rigorous peer review process to ensure rigor and relevance of research. Marketing efforts will aim to target a broad audience nationally and internationally with conference content relevant across the broad field of mind-body medicine. Our overarching Conference Aims are 1) To provide an international forum for researchers to disseminate scientific findings relevant to TCQ and related mind- body practices, assess the evidence base in the context of whole person health, and shape the future research agenda, and 2) To foster interdisciplinary dialogue and collaboration to develop innovative strategies that address current challenges in mind-body research, dissemination and implementation.

NCCIH - National Center for Complementary and Integrative Health

Cardiorespiratory conditions such as the acute respiratory distress syndrome (ARDS), congestive heart failure, COVID pneumonia, and sepsis are among the most common causes of mortality and morbidity. They are also notable for high rates of persistent psychological distress symptoms including depression, anxiety, and PTSD that worsen quality of life and outcomes of the underlying conditions. Yet there are few effective strategies able to overcome barriers of limited access to mental health care. To address this gap, we developed Lift, a completely automated and self-directed mindfulness training intervention, from the ground up with patient input. First, Lift reduced depression symptoms and improved quality of life compared to an education program control in a multicenter pilot RCT (R34 AT008819) among those recently hospitalized with serious cardiorespiratory conditions. Next, a 247-person multicenter 2x2x2 factorial optimization trial (U01 AT00974) compared 8 intervention versions differing by program introduction (app vs. therapist), dose (standard vs. high), and approach to in-the-moment symptom management (app vs. therapist). This trial demonstrated that while all versions had a strong effect on depression, anxiety, and PTSD symptoms, the high dose, app-only version was optimized for effect, adherence, and retention. Given these promising findings, a formal test of the optimized Lift mobile mindfulness intervention’s efficacy is needed. Therefore, we propose a 4-site multicenter RCT with 6-month follow up among 450 cardiorespiratory failure survivors with elevated post-discharge symptoms of psychological distress. Our specific aims will: (1) Test Lift vs. an education program control delivered by similar platforms on symptoms of depression, anxiety, PTSD, and quality of life; (2a) Determine patient-level characteristics associated with a greater treatment response among a priori-defined subgroups using a heterogeneity of treatment effects analysis; (2b) Explore novel adherence metrics and outcomes; and (3) Ensure off-the-shelf intervention readiness with an exploratory mixed-methods hybrid type 1 implementation framework analysis that integrates quantitative trial implementation data with semi-structured trial participant interviews. Innovative and unique elements include a fully automated mobile health delivery system that personalizes content in response to changes in symptom trajectories, a focus on enrolling a population representative of the US, and strong community engagement with formalized roles. This project addresses national research priorities and could advance the field with a personalizable yet population-scalable therapy that has the potential to broadly improve mental health access.

NCCIH - National Center for Complementary and Integrative Health

Project Abstract The American Council for Medicinally Active Plants (ACMAP) Annual Conference is multidisciplinary, in-person meeting that brings together researchers, clinicians, educators, and trainees to advance the scientific understanding of medicinal and bioactive plants. The 20226 ACMAP Annual Conference will be held August 17-20, 2026, at the Holiday Inn Harrisburg (Grantville, PA), with an expected attendance of 100-120 participants predominantly from a range of academic institutions. The scientific program spans the full continuum of medicinal plant research – from ethnobotanical knowledge, through metabolite characterization, preclinical models, and processing methods, to clinical trials for human disease. Sessions will address both the medical potential and safety concerns of natural products and herbal remedies. The conference will feather 10 oral sessions (including one highlight top trainee poster abstracts), two poster sessions, two plenary lectures by internationally recognized scientists, and dedicated networking events to foster collaborations. Growing public interest in natural products for managing a range of health conditions underscores the urgent need for rigorous scientific evidence on their efficacy, mechanisms of action, and safety. The ACMAP conference directly aligns with the mission of the National Center for Complementary and Integrative Health (NCCIH) to determine, through high-quality research, the usefulness and safety of complementary health approaches. The program will emphasize NCCIH priority areas including: elucidating biological mechanisms of natural products, improving methodological rigor in natural product research, and supporting translational studies that bridge preclinical and clinical findings. The meeting is designed to be inviting, with a strong emphasis on participation by early-stage investigators and trainees from a variety of backgrounds and educational institutions. Funds are requested to provide travel awards for trainees, enabling them to present their work, participate in professional development activities, and networking with established investigators. Support is also requested to offset travel costs for two plenary speakers whose expertise will enhance the scientific depth of the meeting and attract a broad audience. By facilitating exchange across discipline, fostering new collaborations, and supporting the next generation of scientists, the ACMAP Annual Conference will accelerate the development of the safe, effective, and evidence- based applications of medicinal plants and plant products in human health.

NCCIH - National Center for Complementary and Integrative Health

Summary: Inflammation is a fundamental response that normally subsides when the triggering event is cleared. Non-resolving inflammation, however, results in continued immune activation, and plays a significant role in the pathogenesis of numerous health conditions including inflammatory bowel disease (IBD). The objective of our study is to establish the feasibility of developing sulfonolipid A (SoL A), a unique lipid produced by human gut microbiota, as an agent to modulate inflammation. We will use IBD as a prototype target disease of SoL A in this Phase I STTR project. IBD affects millions of people worldwide; current treatments either are insufficient to control disease progression or have severe side effects during long-term use; therefore, there is an urgent need for the development of more effective and safer preventive and therapeutic strategies. Microbial dysbiosis leads to persistent immune activation. It is well known that microbes biosynthesize and biotransform metabolites in the gut allowing them to interact with their host environments. While some pathogenic microbes produce toxins leading to increased inflammation, some other commensal microbes produce immunomodulatory metabolites that may protect against inflammation. Notably, Alistipes and Odoribacter are negatively associated with IBD, suggesting that they may protect against IBD-related inflammatory pathogenesis. We developed a unique biosynthetic enzyme-guided disease correlation approach to uncover microbial functional metabolites as potential molecular mechanisms in inflammatory diseases, such as IBD. We first directly connected the expression of gut microbial SoL biosynthetic enzymes to IBD in patients, revealing a negative correlation. This correlation was then corroborated by targeted metabolomics, indicating that SoL abundance is significantly decreased in IBD patients. We experimentally validated our analysis in a mouse model of IBD, showing that SoL production is indeed decreased in diseased mice. In support of this connection, we applied bioactive molecular networking to show that SoLs consistently contribute to the immunoregulatory activity of Alistipes and Odoribacter. We further revealed that SoLs A and B, two representative SoLs, primarily target TLR4 signaling to suppress LPS-induced inflammatory response in macrophages. Importantly, we developed a method to induce bacteria to overproduce SoLs and to purify them. Encouraged by these findings and considering that SoL A showed more potent anti-inflammatory activity than SoL B, we propose in this STTR Phase 1 project to test the feasibility of developing SoL A as treatment for IBD via two specific aims. SA1. To determine the toxicity of SoL A in cultured cells and its PK and safety in mice when it is administered orally or intravenously. SA2. To establish the effectiveness of SoL A in two well-established mouse models of IBD: piroxicam-accelerated colitis in C57BL/6 Il10-/- mice and DSS-induced colitis in BALB/c mice. This STTR Phase 1 project will provide proof-of-concept to use SoL A to treat inflammatory diseases such as IBD. The successful completion of these studies will serve as a milestone and the Go/No Go decision point for the further development effort.

NCCIH - National Center for Complementary and Integrative Health

Over 70% of Emergency Department (ED) visits involve acute pain that continues to be a challenge to manage. Musculoskeletal pain (back, neck, and limb) and non musculoskeletal pain (abdominal, flank) are equally prevalent in the ED. Low-risk and effective ways to improve pain relief (e.g. acupuncture) are needed in the ED. Prior randomized controlled trials (RCTs) of acupuncture in the ED compared to usual care were promising, but there are numerous gaps. ACUITY was our NCCIH-funded R01 multi-center, feasibility RCT that included 3 centers. ED acute pain patients and reporting pain >4 on the 0-10 numeric rating scale (NRS) were randomized to either Acupuncture or Usual Care. NCCIH did not allow any statistical significance testing, but pain intensity decreased more after acupuncture (n=76) than usual care (n=75). Recruitment and retention were feasible, fidelity to the responsive acupuncture intervention protocol was high (98.1%), and 75% of ED providers and 88% of those receiving acupuncture were “satisfied or very satisfied.” Thus, our team has the necessary evidence and expertise to conduct a multi-center, Phase 3 RCT of acupuncture versus usual care. Our aims for the proposed planning UG3 are to: Aim 1: Finalize the infrastructure required to implement ACUITY2 in 5 EDs affiliated with BraveNet clinics. Aim 2: Conduct a 3-month pilot study (15 pts per center) to assess refinements to the responsive acupuncture intervention documentation and other updates in REDCap; and Aim 3: Refine and prepare to implement the protocol in a rigorous, multi-cite RCT. The target population will be 660 adults presenting to the ED with acute pain ≥4 on a 0-10-point NRS. The sample size includes expected attrition rate of 10% with power of 90%. To allow for simultaneous examination of two hypothesis we will enroll: (1) 330 patients with musculoskeletal (limb, back, or neck pain) who will be equally randomized to acupuncture or usual care and (2) 330 patients with non-musculoskeletal (abdominal or flank pain) to be randomized in a similar fashion. Our specific aims for the proposed UH3 are to conduct a Phase 3 RCT. Aim 1: Test whether the between group difference in pain intensity (0-10 NRS) from Pre to Post treatment (~60 min) is >1.3 units for those receiving Acupuncture compared to Usual Care in a (Aim 1a) musculoskeletal cohort and (Aim 1b) non- musculoskeletal cohort. Aim 2: Test whether the between group difference in pain intensity from Pre to 1-week is >1.3 NRS units in Acupuncture versus Usual Care in a (Aim 2a) musculoskeletal cohort and (Aim 2b) non- musculoskeletal cohort. Aim 3: (Exploratory): Test if acupuncture reduces narcotic pain medications utilized in the ED, and/or provision of a narcotic prescription at ED discharge compared to Usual Care in a (Aim 3a) musculoskeletal cohort and (Aim 3b) non-musculoskeletal cohort. Successful conduct of ACUITY2 would provide evidence to support inclusion of acupuncture in EDs across the US for non-pharmacological pain relief and ideally reduced opioid use.

NCCIH - National Center for Complementary and Integrative Health

Project Summary and Abstract More than 600k deaths in the US and Canada have been attributed to opioids since 1999, which continue to present a significant public health threat. Surgery is a key triggering event to introduce opioids to patients, which can lead to long-term dependency. Of the 51.4 million surgeries performed yearly in the US, >3 million previously opioid-naïve patients continue to fill opioid prescriptions past 3 months post-operation every year. This outcome highlights there are not sufficiently effective multimodal pain treatments in practice post-surgery to reduce the need for opioids. Topical cryotherapy is a historically proven method of pain management, but for the >40% of surgeries on the human trunk, the standard of care is still bagged ice, which is not conducive to long-term pain mitigation. The proposed work sets out to design and build a long- duration, radically ergonomic topical cryotherapy system that can deliver pain relief while supporting effective Enhanced Recovery After Surgery (ERAS) protocols. This system will be designed specifically for the human trunk, where patients may not be able to use continuous cold water cryotherapy devices. By leveraging advancements in industrial cooling technologies and consumer electronics, a lightweight, minimal-hassle system is envisioned for continuous multi- week usage to reduce the need for pharmaceutical pain interventions. While this project will not conduct cryotherapy on humans or animals, computer aided design simulations will complement physical prototyping in conducting parametric studies designed to achieve therapeutic temperatures at the human skin. The cooling module and human-device interface will be simulated and then prototyped where final designs will be selected based on performance. Prototype units found to achieve therapeutic benchmarks will be reproduced in a quantity of 10 to establish consistency of the findings. The specific aims are to (1) design and build units to demonstrate concept feasibility, (2) characterize system performance in terms of temperatures, duration, and ergonomic factors, and (3) prepare documentation for future manufacturing.

NCCIH - National Center for Complementary and Integrative Health

Summary The proposed Gordon Conference, on August 2-7 2026 at Bates College, will focus on the development, testing and utilization of microbial therapeutics to treat cancer and other diseases. As our understanding of microbial interactions with the human body deepens, new opportunities are emerging to harness these interactions for therapeutic benefit. Advances in genetic engineering now enable precise manipulation of bacteria, unlocking novel ways to modulate the immune system and metabolism with the potential for long-lasting therapeutic effects. A key focus of the conference will be the use of microbes in cancer therapeutics. Microbial therapies provide solutions to challenges that limit current treatments, including refractory metastatic cancers, multidrug resistance, and immune evasion. With rapid advances in genetic manipulation dramatically shortening the path from concept to clinical trials, microbial therapies are poised to become a cornerstone of modern medicine. This proposal to support the Microbes as Therapeutics Gordon Conference has three Specific Aims. The first Aim of the proposed conference is to accelerate the creation and development of advanced microbial therapies to address unmet medical needs. The second Aim of the proposed conference is to unlock the potential of microbial therapies for human use. The third Aim of the proposed conference is to build the Microbial Therapy community to support early researchers and new ideas. These aims will be achieved by showcasing the latest research in microbial therapies. Many of the invited speakers are generating bacterial therapies to address cancer as well as a long list of other medical indications. A forum where the leading researchers in the field can share their advances has the potential to create revolutionary organisms that are able to address human diseases in ways unapproachable by any other modality. Critical topics that will be addressed include (1) the relationship between bacteria and the immune system, (2) tools for synthetic construction of microbes, (3) the unique abilities of different bacterial species, and (4) novel mechanisms for molecular delivery. These aims will also be achieved by inviting prominent early career investigators and those who are new to the microbial therapy field. Despite numerous labs working on microbial therapies, to date, there are no conferences specifically geared towards this field. This has created a barrier for young scientists. Funds provided by the NIH, combined with funds from industrial sponsors, will be used to facilitate the travel and conference costs of these researchers. Funds will also be used to support the attendance of graduate students from these laboratories and students in established labs that are new to microbial therapies. Bringing together the community of researchers interested in microbial therapies has the potential to have a significant impact on how cancer is treated by accelerating the discovery of new mechanisms; establishing novel methods to reduce toxicity ensure safety; streamlining paths to regulatory approval; and providing the tools necessary to develop these therapeutic organisms into potent anticancer treatments.

NCCIH - National Center for Complementary and Integrative Health

ABSTRACT: Using the NCCIH UG3/UH3 mechanism we aim to conduct a fully powered, single blind, multi-site efficacy trial at 5 geographically diverse Level 1 Trauma Centers (Duke Medical Center, Dell Medical School, Vanderbilt University Medical Center, University of Kentucky Medical Center and Massachusetts General Hospital). We build on a successful NCCIH funded multisite feasibility trial (R01AT010462) which optimized our protocol for study implementation (aim 1), met 29 feasibility benchmarks, and explored clinical benefit in improvement in outcomes and putative mechanistic targets (aim 2). In the UG3, in partnership with the Data Coordinating Center (DCC) at John Hopkins’s METRC (Castillo, PI) we aim to finalize the study protocols, operating procedures and data collections systems to be used in the RCT, fulfill regulatory requirements and obtain DSMB (aim 1), and train and certify study clinicians, conduct start-up activities at all sites, and conduct a run-in period at our new site Duke Medical Center and mock participants at the 4 sites that recruited as part of the prior R01 and are familiar with study procedures. In the UH3, in partnership with the DCC we aim to establish the efficacy (aim 1) of our mind body intervention Toolkit for Optimal Recovery after Injury (TOR) versus our Minimally Enhanced Usual Care control (MEUC) on physical function (primary outcome), and secondary outcomes of pain intensity, depression, post-traumatic stress and putative mechanistic targets (pain catastrophizing, pain anxiety, coping and mindfulness). We hypothesize that TOR will be more efficacious in reducing primary and secondary outcomes compared to MEUC. We also aim to establish whether TOR dependent improvements in the primary and secondary outcomes maintain through 3 months follow up (aim 2) and the degree to which TOR-dependent improvements in physical function, pain, depression and posttraumatic stress symptoms are mediated my improvements in putative mechanistic targets and modified by clinical and demographic variables (aim 3). We bring together an interdisciplinary team who worked together to develop the infrastructure for the current project, and strong multi-site feasibility of TOR and study procedures supporting the efficacy RCT. Findings from this first test of efficacy of TOR will inform a future large hybrid effectiveness-implementation trial to support our larger goal of implementing TOR as standard of care in orthopedic trauma centers across the USA.

NCCIH - National Center for Complementary and Integrative Health

PROJECT SUMMARY/ABSTRACT The goal of this application is to (R61) identify microbial genes, pathways, and strains in hospitalized patients that influence lactate metabolism and (R33) develop a mechanistic probiotic strategy that (1) protects probiotics from co-administered antibiotics and (2) augments host lactate metabolism through precision engineering, contributing to organ recovery and whole-person health. The major barrier to probiotic efficacy among hospitalized patients is concurrent antibiotic administration. Hospitalized patients routinely receive broad-spectrum antibiotics with potent activity against commensal bacteria and probiotics, rendering probiotic trials in hospitalized patients doomed to futility. Lactate metabolism represents an optimal target for therapeutic microbiome modulation. Lactate is the most commonly used metabolic biomarker in hospitalized patients, and participates in metabolic dysfunction. Recent studies in exercise have revealed that blood lactate enters the gut, where it is metabolized by commensal bacteria into metabolites that re-enter the systemic circulation, participate in organ homeostasis. Our team has recently made two fundamental discoveries: (1) Commonly-used antibiotics with activity against anaerobic gut commensals worsen patients’ clinical outcomes and decrease patients’ clearance of blood lactate. (2) By integrating lactate oxidase into an established probiotic strain, we have shown that an orally administered probiotic can accelerate lactate clearance in murine models of lactic acidosis. Aim 1 (R61, Phase 1): Identify gut microbial features associated with variability in host lactate metabolism and clinical outcomes. We will leverage a large, existing biobank of rectal swabs from 1,550 hospitalized patients and a natural experiment created by the 2015–16 piperacillin-tazobactam shortage. Aim 1a: Use instrumental variable analysis to quantify the impact of anaerobe-depleting antibiotics on gut microbial composition and lactate clearance. Aim 1b: Identify microbial gene pathways associated with lactate metabolism and clinical outcomes. Aim 2 (R33, Phase 2): Expand, refine, and translate precision probiotic strategies by testing the causal role of microbial features identified in Aim 1. Aim 2a: Test ribaxamase-mediated protection of B. subtilis in the presence of β-lactam antibiotics, evaluating viability, colonization, and metabolic activity in vivo. Aim 2b: Incorporate microbial genes or functions identified in Aim 1 into B. subtilis and test their effect on lactate metabolism in murine models of lactic acidosis. Aim 2c: Evaluate the most effective strategy in a validated swine model of infection-associated lactic acidosis to assess translational relevance.

NCCIH - National Center for Complementary and Integrative Health

ABSTRACT: Obesity is prevalent among adults (>40%) and children (~20%) in the U.S. and is expected to increase dramatically in the next 25 years. Addressing the obesity epidemic is vital for public health because of its wide range of comorbidities including deadly conditions such as stroke, hypertension, diabetes, heart disease, liver disease, sleep apnea, pregnancy complications, and cancer. Most clinical interventions for obesity target individuals who are already obese. However, a growing body of research demonstrates that obesity can be caused by adverse events during development that drive irreversible effects on metabolic programming. This work highlights a critical need for preventative measures to address the obesity epidemic. Vitamin D is an essential nutrient that has recently been implicated in obesity. This has the potential to impact a large population since up to 80% of pregnant women are deficient in vitamin D (VDD) and emerging studies implicate this may disrupt developmental programming of metabolism and increase offspring susceptibility to obesity later in life. This proposal will leverage our novel mouse model of VDD-induced adiposity (a naturally genetically divergent Collaborative Cross (CC) mouse lineage) to model the human condition so we can better understand the developmental mechanisms driving obesity and target them for effective interventions. The mouse serves as a vital model for studying this important question not only because of its conserved vitamin D biology but also because mouse research allows us to avoid ethical limitations that inhibit studying VDD in human pregnancy and provides control over environmental and genetic confounders present in human populations. The proposed study aims to: (1) Determine the importance of vitamin D sufficiency during pre-, peri-, or post-conceptional windows of development in driving the accumulation of adiposity and risk of obesity-related comorbidities later in life; and (2) Define the developmental timing of VDD-induced transcriptional dysregulation and investigate its role in disruption of metabolic programming. Addressing these gaps in our understanding of the role of VDD in developmental mechanisms of obesity will help determine the relative importance of VitD monitoring and timely interventions for VDD during pregnancy to protect offspring metabolic health so that effective guidance can be developed.

NCCIH - National Center for Complementary and Integrative Health

Project Summary. Polyketide natural products have provided critical therapeutics, and they will remain an important component of new drug discovery and manufacturing. This program aims to develop new technologies to enable the high resolution cryo-EM structural elucidation of Type I polyketide synthases (PKSs) isolated directly from natural producer organisms. To date these megasynthase proteins have proven challenging for structural biology studies due to significant technical challenges, including extremely large molecular weights, difficult heterologous expression and highly dynamic structural features. As such, very few structures have been reported, and most are at low resolution and do not represent full synthases. We have recently developed tools for dual site-selective crosslinking of PKSs that enforces dynamic constraint and has led to the collection of high- resolution cryo-EM structures in single-modular Type I PKSs. Here we propose the development of two key tools. The first will convert native holo-PKSs to their cognate apo- forms to enable crosslinking within native PKSs. The second is the development protein isolation methodologies for very large megasynthases (500 kDa to 2 MDa) from within native producer proteomes, such that the resulting isolated forms can be structurally elucidated by cryo-EM. The amphotericin synthase pathway from producer bacterium Streptomyces nodosus will serve as a model system for high-resolution structural analysis. Together these tools will offer a fundamental step-change in access to molecular detail of PKS megasynthase structure.

NCCIH - National Center for Complementary and Integrative Health

ABSTRACT The gut microbiome is a cornerstone of host health, shaping immune responses, metabolism, and resilience to disease. However, attempts to treat dysbiosis via fecal microbiota transplantation (FMT) are frequently limited by colonization resistance, where resident microbes inhibit new strains from being introduced. Current reliance on broad-spectrum antibiotics to mitigate this competition typically results in only transient engraftment and limited therapeutic efficacy. Furthermore, despite refinements in donor selection and administration, no models or pipelines exist to allow clinicians to accurately predict FMT outcomes or systematically introduce microbiota into the highly variable patient microbiomes. There is a critical gap in understanding how to identify which microbial communities and donor microbiomes can integrate robustly into individual recipients. This proposal addresses this gap by leveraging computational and experimental approaches to identify “orthogonal” donor communities that bypass metabolic niche competition. We hypothesize that donor consortia whose metabolic requirements differ when compared to the FMT recipient microbiota are more likely to stably engraft. In Aim 1, we will use metabolic models (MICOM) to extract metabolic features from microbial communities and train statistical classifiers that predict FMT engraftment outcomes between microbiomes in both murine and human cohorts. In Aim 2, we will develop a culturomics-based strategy to experimentally profile unused niches within recipient microbiomes and introduce donor-derived communities specific to those niches. We anticipate that these aims will yield a novel computational framework for donor-recipient matching as well as an experimental pipeline to identify niche-associated microbial communities that are capable of engrafting in target recipients. These precise and predictable microbial engraftment strategies will allow for personalized microbiome therapies and more durable non-pharmacological treatments for conditions linked to dysbiosis.

NCCIH - National Center for Complementary and Integrative Health

PROJECT SUMMARY/ABSTRACT More than 80% of breast cancer survivors and nearly all family caregivers experience unmet supportive care needs during cancer treatment and throughout survivorship. These unmet supportive care needs are key factors that contribute to poor quality of life for cancer survivors and their caregivers. Emotional, informational, and relational needs are among the most reported unmet needs by cancer survivors and their caregivers, and result from gaps in cancer care services. Interventions to support the unmet needs of cancer survivors have provided no evidence of an underlying mechanism for reducing unmet needs for the survivors, and many caregiver interventions have yielded small effects. Given the known interdependence between cancer survivors and family caregivers’ well-being and the promising effects of mindful resilience-based interventions in other populations such as transplant patients, a systems-level resilience-based approach may be key in addressing these unmet needs. Family resilience, or the ability of family to rebound and grow from adversity, is associated with greater quality of life in cancer survivors and their caregivers. While the relationship between family resilience and unmet needs is unknown, there is evidence that more individual or intrapersonal resilience is associated with fewer unmet supportive care needs. Furthermore, as unmet needs change over the course of the illness trajectory and throughout survivorship, identifying a mechanism that adapts over time and leverages the strengths of the family to cope and manage needs is crucial. This observational cross- sectional study aims to determine the relationship between unmet supportive care needs, family resilience, and quality of life in breast cancer dyads (survivors and caregivers) during two phases of cancer care (active treatment and reentry phase). Using latent variable structural equation modeling, specifically the Actor-Partner Interdependence Model, we will examine whether family resilience partially mediates the relationship between unmet supportive care needs and quality of life in cancer dyads. This advanced statistical method allows us to simultaneously evaluate the actor effects (how we affect ourselves) of survivors’ unmet needs and family resilience on their own quality of life as well as the partner effects (how we affect each other) on their caregivers’ quality of life, and vice versa. A total of 260 dyads will be recruited from a large NCI designated Cancer Center serving over 47 communities in the Midwest and through online platforms throughout the US. Results from this study will identity a critical underlying mechanism, informing future research to design, test, and disseminate mindful resilience-based interventions for families experiencing cancer. The training plan consists of mentorship, courses, and workshops that will facilitate the development of expertise in dyadic research within the context of breast oncology as well as future mindful resilience-based intervention development.

NCCIH - National Center for Complementary and Integrative Health

SUMMARY Irritable bowel syndrome (IBS) is a disorder of gut-brain interaction with a childhood prevalence of up to 5.1% in the United States, and up to 22.6% worldwide. Children with IBS experience debilitating psychosocial and gastrointestinal (GI) symptoms resulting in impaired quality of life (QoL). IBS with constipation (IBS-C) is a subtype characterized by abdominal pain, distension or bloating, straining, and infrequent hard stools. While this is a pervasive issue, little is known about the underlying pathophysiology of IBS-C; it is thought to relate to both bowel dysmotility as well as vagal tone dysfunction. Current treatments for IBS-C are limited and often incompletely relieve pain. Integrative health therapies have become new therapeutic avenues in the management of IBS. Myofascial release (MFR) is a form of hands-on physical therapy that targets the myofascial interspaces to increase abdominal wall tissue motility. MFR used during osteopathic manipulations improves abdominal distention, constipation, and QoL in adults with IBS and increases gastric myoelectrical activity in healthy adults as measured by electrogastrography. However, the effect of abdominal-MFR on the activity of other bowel regions is unknown. We have developed and evaluated an abdominal-MFR protocol and shown that using abdominal-MFR in adolescents with IBS is feasible and well accepted without adverse events. Preliminary studies show a significant improvement in GI symptoms and QoL up to one month after the abdominal-MFR intervention. However, the physiologic mechanisms by which MFR improves IBS symptoms have not been investigated, there is a lack of objective methods to assess these physiologic outcomes, and there are no randomized clinical trials assessing MFR's effectiveness in children. MFR therapies could offer a low risk, high- benefit treatment that can be incorporated into current treatment regimens but are understudied in IBS. Our overall objective is to evaluate the physiologic effect of abdominal MFR that results in symptom improvement in children with IBS-C using a randomized comparative trial design. In Aim 1 we will assess the effect of abdominal- MFR versus light-touch-massage on vagal tone (assessed using heart rate variability) and correlate with GI and psychosocial symptoms. We hypothesize that abdominal-MFR improves both GI and psychosocial IBS- associated symptoms by eliciting an improvement in vagal tone. In Aim 2 we will evaluate the effect of abdominal- MFR versus light-touch-massage on myoelectrical activity (gastric, small bowel, and colonic) using a non- invasive abdominal surface wireless motility monitoring system and correlate with symptoms. We hypothesize that abdominal-MFR will induce statistically significant organ specific differences in bowel activity that will correlate with a significant improvement in GI symptoms. Our innovative approach employs established and new non-invasive vagal tone and bowel activity testing strategies. This study will address several knowledge gaps surrounding the mechanisms behind MFR's improvement in IBS-C symptoms with great potential to support non- invasive evidence-based treatments in other IBS subtypes and disorders of gut-brain interaction.

NCCIH - National Center for Complementary and Integrative Health

PROJECT SUMMARY/ABSTRACT The intestinal microbiome produces a vast and diverse chemical repertoire of microbe-derived metabolites which influence many aspects of host energy metabolism. Despite great potential implications for obesity, type-2 diabetes, and other metabolic diseases, the mechanistic basis for these cross-kingdom metabolic interactions remains largely uncharacterized. My preliminary data demonstrates that lactic acid produced by the gut commensal Lactiplantibacillus plantarum (Lp) more than doubles Drosophila starvation survival by priming oxidative phosphorylation via a non-nutritive, GPCR-mediated signaling mechanism. Building on this discovery, this project will integrate high-throughput survival assays, untargeted metabolomics, mathematical modeling, and in silico screening of ligand-receptor interactions to systematically uncover how microbe- derived metabolites act as endocrine effectors of host energy metabolism. During the K99 phase of this project, I will utilize computational ligand-receptor screening to identify candidate GPCRs predicted to bind Lp–derived lactic acid and perform loss-of-function genetic tests to validate their necessity for enhanced oxidative phosphorylation and starvation survival. Next, I will profile the microbe-derived metabolite profile of an array of human-derived and environmental commensals using untargeted metabolomics and correlate metabolite abundance with host survival phenotypes to pinpoint novel metabolic effectors. During the R00 phase of this project, I will expand the in silico prediction of ligand–receptor interactions to candidate metabolic effectors identified during the K99 phase. I will determine their mechanisms of action by using targeted genetic knockouts, phosphoproteomic mapping, and transcriptomic analyses to delineate the downstream signaling cascades through which these metabolites rewire host energy metabolic pathways. Finally, candidate metabolites will be evaluated for their capacity to prevent or reverse obesity- and diabetes-like phenotypes in Drosophila. By elucidating the molecular mechanisms and signaling networks that underlie microbiome-host metabolic crosstalk, this work will establish fundamental knowledge and mechanistic insight for harnessing the vast potential of microbial metabolites to deliver new therapies for metabolic disease. Executing this project will provide the necessary technical and scientific training to facilitate a successful career as an independent researcher at the intersection of energy metabolism and microbiology. The thriving intellectual community at Stanford, combined with ample opportunities for networking, training, and collaboration in the Bay Area through the Chan-Zuckerberg Biohub ensures I am primed for success. This comprehensive training and research plan establishes a framework that will position me at the forefront of uncovering host-microbe metabolic interactions and create a unique research niche for success as an independent researcher.

NCCIH - National Center for Complementary and Integrative Health

PROJECT ABSTRACT Pain is a leading cause of disability and there is an urgent need to develop improved therapeutic approaches for affected individuals. Natural products, or compounds isolated from biological organisms, account for a large fraction of clinically approved drugs. The small molecules produced by bacteria and fungi associated with plants and animals are an especially promising source for new drug leads, since they have exceptional chemical diversity and include a broad range of neuroactive compounds. However, challenges associated with current drug discovery strategies have limited prior efforts to identify novel natural products with pain-relieving or analgesic activity. This project overcomes these obstacles using a strategy that leverages newly developed in vivo assays and advanced imaging methods. A zebrafish-based model for nociceptive pain was established and used to identify plant- and animal- associated microbial metabolites with analgesic activity. Aim 1 of this project will identify the active principle from microbial extracts. Aim 2 will identify the mechanism of action of previously isolated lead compounds using a combination of in vitro assays with mammalian cells, and in vivo recordings of neural activity using zebrafish. This project is led by a multi-disciplinary team with expertise in both natural products drug discovery and systems neuroscience. It will identify and characterize natural products with in vivo analgesic activity, which are critically needed as drug leads and molecular probes for developing improved treatment options for pain.

NCCIH - National Center for Complementary and Integrative Health

Project summary/abstract New medicines that effectively and safely treat chronic pain are desperately needed, as it is estimated that nearly 20% of the global population actively struggles with this debilitating disease. Opioids, the current standard of care for the treatment of moderate to severe pain, have significant side effects that include respiratory depression and addictive properties, and there are barriers to their equitable use around the globe. In the search for alternatives to opioid analgesics, sigma-1 (σ1R) and sigma-2 (σ2R) receptors are intriguing targets for drug development. σ1R and σ2R ligands can produce analgesia directly, can modulate mu opioid receptor-mediated analgesia, and may be particularly useful for neuropathic pain. Arthropod defensive secretions have been a source of potential new analgesics, with metabolites targeting a variety of neuroreceptors. Chemical investigations into millipedes, a diverse class (Diplopoda) of arthropods, reveal that millipedes produce structurally distinct defensive agents, including heterocyclic terpenoid alkaloids, oxidized aromatics, and cyanide-containing metabolites. Heterocyclic terpenoid alkaloids, produced by a single subterclass (Colobognatha), are structurally the most intriguing defensive secretions but the least studied. Recently, our group discovered ischnocybine A and demonstrated that it is a potent antagonist of the σ1R (Ki = 13.6 nM) with 100-fold selectivity over the σ2R (Ki = 1,292 nM). Initial ADME evaluations of ischnocybine A and a synthetic analog confirmed they possess promising central nervous system (CNS) properties, with good microsomal stability (t1/2 >255 min for analog) and permeability. Antagonists of both σRs have been implicated in the treatment of chronic pain, with several agents currently being evaluated in clinical trials for the treatment of neuropathic pain. Our research team includes natural product chemists, synthetic chemists, and pharmacologists with expertise in pain models at Virginia Tech (VT), University of California at Davis (UCD), and Rowan University, aim to leverage the defensive secretions from millipedes for the development of a new class of analgesics that may have less perceived detrimental effects. This research proposal aims to leverage millipede defensive secretions to treat chronic pain using chemical and biochemical techniques. Our work includes: Establishing preliminary structure-activity relationship (SAR) of ischnocybine A by incorporating natural functionality through semi-synthesis; asymmetric total synthesis of four millipede-derived alkaloids; and pharmacological evaluation of synthetic millipede alkaloids and analogs. Completion of the proposed work will elucidate a preliminary SAR of ischnocybine alkaloids, validate a short synthetic plan to access the natural alkaloid, and confirm that these lipophilic alkaloids can enter the CNS and modulate pain behaviors, thereby paving the way for subsequent detailed studies toward developing a new generation of analgesics.

NCCIH - National Center for Complementary and Integrative Health

Project Summary/Abstract Force-based manipulation (FBM) or manual therapy (e.g., spinal mobilization, spinal manipulation, massage) have proven moderately effective for treating musculoskeletal pain (e.g., low back pain) and are currently recommended by most clinical guidelines as a first-line conservative treatment approach. However, for decades, the lack of FBM delivery standardization and the persistence of mechanism-related knowledge gaps have prevented the therapeutic optimization of FBM. Moreover, considerable heterogeneity in force/pressure dynamics exists during manual delivery between different FBM clinicians, which remains a significant barrier to comparing FBM-related clinical trial results. Indeed, very few imperceptible force/pressure-sensing technologies are available that allow FBM clinicians to quantify mechanical dynamics in high spatiotemporal resolution without tactile interference during FBM delivery, largely due to the grand challenges associated with developing such technologies at the material, manufacturing, and system levels. In our preliminary study, we developed a digital manufacturing process for producing large-scale, soft, pressure-sensing e-skins, featuring highly customizable designs, quick turnarounds, and low costs. Through programmable microstructural engineering, the resulting soft e-skins exhibited exceptional sensing performance, including a broad dynamic range (>560 kPa), rapid response (millisecond-level), high sensitivity (single hair weight detection), and low hysteresis (<5%). When integrated on the hand, we demonstrated that a 256-pixel full-hand e-skin readily enabled large-scale spatiotemporal data collection for complex human grasp analysis. In this R21 project, we aim to modify our personalizable e-skins for real-time quantification of complex mechanical dynamics during FBM, while minimizing tactile interference for clinicians and maximize their FBM delivery performance. In Aim 1, we will design, fabricate, and characterize soft, wearable, pressuring-sensing e-skins tailored for FBM, with their performance and accuracy benchmarked against off-the-shelf sensors. In Aim 2, we will calibrate, optimize, and extend the use of e-skins for measuring complex pressure dynamics during FBM directly at the clinician-patient interface. 12 licensed manual therapy clinicians will wear personalized e-skins and deliver three distinct types of FBM techniques to 12 asymptomatic human participants. Both quantitative pressure dynamics (i.e., peak pressure magnitude, time-to-peak, contact area, duration, spatiotemporal sequence) and qualitative clinician feedback will be collected and statistically analyzed. Once demonstrated as efficacious, this work has the potential to transform the FBM field by providing a long-desired toolkit for quantitative research, which cannot be achieved with existing technologies. It will also open opportunities for standardizing FBM delivery, optimizing prescriptive dosage, and correlating specific force/pressure application characteristics with downstream chemical, physiological, and therapeutic outcomes.

NCCIH - National Center for Complementary and Integrative Health

ABSTRACT Musculoskeletal pain, particularly high impact chronic pain (HICP), is a major public health issue affecting millions. Chronic musculoskeletal pain is often associated with high psychological distress, and while psychological interventions can improve outcomes, psychological distress is frequently neglected in current pain care. Orthopedic settings, where patients commonly present with HICP, offer a promising yet underutilized opportunity to introduce access to effective pain-related psychological resources. However, orthopedic clinicians often lack training in psychological assessment, feel uncomfortable discussing mental health, and face time constraints, which limits patient exposure to psychological resources. To address these challenges, we will test the feasibility and acceptability of a novel Psychological Support and Resource Navigator program. This program helps orthopedic clincians identify patients with high pain-related psychological distress and connect them to evidence-supported psychological resources for pain. An automated alert in the electronic health record will notify clinicians of eligible patients. The navigator will then engage patients through phone, video, or in-person visits to deliver three core components: education, skills training, and facilitation. The navigator will first provide pain psychoeducation to help participants understand the relationship between psychological distress and pain. Second, the navigator will offer a brief intervention, such as relaxation training, to help patients with daily pain self-management. Third, the navigator will review a menu of evidence- supported psychological resources for pain, including free online tools like painTRAINER, psychologically informed physical therapy, and counseling. The navigator will help patients choose options that match their needs and guide them through access and scheduling. Follow-up calls at six and twelve weeks will track progress, reinforce use, and troubleshoot barriers. We will evaluate the feasibility and acceptability of the navigator program in a two-arm trial involving 63 patients with high psychological distress in the Duke Department of Orthopaedic Surgery randomized (2:1) to receive either the navigator program or a brochure with information about psychological resources. We will use a mixed methods approach to assess a variety of primary and secondary outcomes. Benchmarks for feasibility include achieving high rates of (1) enrollment among eligible patients, (2) call completion, (3) fidelity to the navigator program, and (4) psychological resource use by the 12-week follow-up. Acceptability will be measured by participant satisfaction with the program. This study represents a novel approach to integrating evidence-supported psychological care into orthopedic settings, aiming to improve pain-related outcomes. Findings from this study will directly inform the execution of a future pragmatic comparative effectiveness trial of the program, contributing to the broader goal of enhancing the clinical integration of evidence-supported interventions for pain and psychological distress.

NCCIH - National Center for Complementary and Integrative Health

Abstract: We propose a proof-of-concept randomized and partially blinded trial to identify brain mechanisms for placebo pill responses when reinforced by cues and instructions. We will concentrate on chronic back pain patients (CBP) who have a large unmet need to properly control their daily pain, which exacts a huge toll on the individual and society and continues to contribute to the ongoing opioid crisis. Although mechanisms of placebo have been extensively studied in experimental settings, there is minimal knowledge of brain processes that control clinical placebo responses. Pain-relieving drug consumption is ubiquitous in chronic pain patients, even in those who pursue non-pharmacological treatments. The routines for drug consumption, however, remain open-ended and dependent on individuals' momentary decisions. Here, we test the concept of enhancing the placebo pill response by creating multiple feedback loops and reinforcement cues between daily back pain ratings and placebo pill consumption. We hypothesize that this enhanced placebo response is mediated through adaptations of the mesolimbic opioid-dependent circuitry. Prior literature and our preliminary results are consistent with this hypothesis. If we can identify brain circuitry for the enhanced placebo pill response and block this response by naloxone (blocking opioid receptors) through the same brain circuitry, then we would identify the causal mechanism for placebo pill responses. We also hypothesize that an enhanced placebo pill response will diminish experimental pain and improve motor abilities. Thus, we will study mechanisms for expectation-based training of the mind to improve subjective perception and objective bodily performance. 40 CBP (50% female, 50% Black) with back pain ≥ 4/10 (NRS score) are recruited and randomized (1:1) to 2 groups: 1) Reinforced placebo pill use (2 colors, up to 4 pills, positive reinforcement text messages), 2) Placebo pill use in the neutral condition (1 color pill, neutral texts). All participants will initially undergo a 1-week neutral single placebo pill consumption while rating back pain 3 times/day. The study will last 5 weeks. All participants will undergo brain scans and verbal interviews and fill out questionnaires at the start and end of the trial. We will assess motor abilities from smartphone mobility scores and collect the 30-second sit-stand test outcomes. Participants who complete the study undergo a 1-day randomized, blinded placebo/naloxone crossover study with 3 brain scans. We aim (1) to identify brain functional changes related to enhanced placebo, (2) to identify the effects of naloxone on brain activity, and explore sex, race, and socioeconomic influences on these outcomes. The study should be regarded as high-risk (a first effort to demonstrate mechanisms of placebo pill response) and high-impact (potentially can become part of routine chronic pain management).

NCCIH - National Center for Complementary and Integrative Health

PROJECT SUMMARY Sauna therapy, also known as heat or hyperthermia therapy, is a non-invasive intervention traditionally used to improve a broad range of health outcomes, including pain relief, cardiovascular function, immune response, and insulin sensitivity. Emerging evidence suggests that its physiological benefits closely resemble those of aerobic exercise; however, the underlying molecular mechanisms remain poorly understood. This knowledge gap limits the clinical translation of sauna therapy, particularly for individuals with restricted mobility or exercise intolerance, such as the elderly and those with chronic conditions. The objective of this project is to elucidate the molecular pathways through which sauna therapy modulates metabolic and immune functions. We hypothesize that thermal activation of the transient receptor potential vanilloid 1 (TRPV1) channel—a heat-sensitive, non-selective calcium channel—reprograms cell-type-specific responses by enhancing intracellular calcium flux, thereby promoting thermogenic energy expenditure and anti-inflammatory macrophage polarization. Our preliminary studies demonstrate that repeated sauna exposure improves insulin sensitivity, prevents BAT whitening, and suppresses proinflammatory cytokine production—effects abolished in TRPV1 knockout mice. In vitro, heat adaptation increases TRPV1-mediated calcium influx in human brown adipocytes and promotes M2 macrophage polarization. These findings support a central role for TRPV1 in mediating heat-induced immunometabolic adaptations. In Aim 1, we will delineate the mechanisms by which heat adaptation enhances energy expenditure via brown thermogenesis. Using immortalized human brown adipocytes (hBA) and 3D brown adipose organoids (hBAO), we will investigate the interplay between TRPV1 activation, calcium cycling, Ca²⁺/ATPase activity, and both UCP1-dependent and -independent thermogenic pathways, along with effects on glucose/lipid metabolism and BAT-derived endocrine factors. In Aim 2, we will define the immunomodulatory role of sauna therapy in macrophage function. Using human peripheral blood mononuclear cells (PBMCs), we will assess TRPV1- mediated calcium signaling in M1/M2 polarization and efferocytosis. In parallel, we will use human white adipose organoids (hWAOs) to examine how heat adaptation reprograms adipose tissue macrophages (ATMs) during beige adipogenesis. These studies will uncover a novel TRPV1-dependent mechanism of heat-induced metabolic and immune remodeling in human adipose and immune cells. The successful completion of this project will provide a mechanistic foundation for sauna therapy as a scalable, accessible strategy to enhance metabolic health and immune resilience in vulnerable populations.

NCCIH - National Center for Complementary and Integrative Health

PROJECT SUMMARY Spinal Pain (SP) is highly prevalent, costly, and a leading cause of disability, but the management of SP in the United States tends to be inefficient, costly, and sometimes hazardous. Thus, there is an acute need to identify safe, high-quality management strategies for patients with SP. Because SP is often persistent, many patients feel compelled to seek ongoing care, but the chronic use of PDT (primarily opioids and NSAIDs) for SP raises safety concerns. Because the prevalence of SP increases with age, the need for high-quality spine care is critical for older adults with NP, who tend to be comorbid, vulnerable to adverse events, and prone to the utilization of high-cost interventions. Prescription drug therapy (PDT) and non-pharmacological therapies (NPT) which have been shown to offer similar effectiveness in systematic reviews, are widely used treatment strategies for SP, but their comparative quality and value for older adults with SP is uncertain. There is, therefore, a pressing need to compare these two general approaches (NPT and PDT) for management of SP in Medicare beneficiaries. The overall objective of this project is to assess the quality and value of NPT as compared to PDT for management of SP in Medicare beneficiaries aged 65 years and older. With active engagement of students, this project will strengthen the research environment at Southern California University of Health Sciences. The central research question is whether Medicare Fee for Service (FFS) beneficiaries aged 65+ with SP receive superior healthcare quality with NPT, PDT or both. The central question will be answered through analysis of Medicare administrative and claims data to: (1) compare the safety of care for recipients of NPT to PDT and combined NPT+PDT as measured by the likelihood of adverse outcomes, (2) compare the efficiency of care for recipients of NPT to PDT and NPT+PDT as measured by rates of escalation of care for spinal pain, and (3) compare the costs of care for recipients of NPT to PDT and NPT+PDT as measured by payer expenditures. Rigorous methods intended to reduce risk of bias and confounding will include weighted propensity scoring. The approach to this research is innovative because relatively little is known about the quality and value of non-pharmacological treatment approaches for SP among older adults overall. This project promises to challenge the status quo by assessing the value of non-pharmacologic alternatives to high-risk prescription drugs. The availability and utilization of NPT is currently often limited under Medicare by procedure, number of treatments, diagnosis, and provider specialty. Evidence of the superior value of different approaches to care of SP is expected to facilitate an innovative shift toward safer, more efficient care. The project also includes a practical plan for introducing large-scale health services research – with student participation - to an educational institution that trains complementary and integrative healthcare clinicians. The research contribution of this project is expected to be significant because it promises to inform and improve the safety, efficiency, and value of care for older adults with SP.

NCCIH - National Center for Complementary and Integrative Health

PROJECT SUMMARY/ABSTRACT The overarching goal of this project is to gain mechanistic insights into the brain-behavior relationship underlying pain avoidance and its modulation using alpha-frequency transcranial alternating current stimulation (tACS) targeting the dorsomedial prefrontal cortex (dmPFC). While adaptive avoidance of pain aids in survival, maladaptive pain avoidance plays a key role in the development and maintenance of chronic pain hampering physical therapy and rehabilitation, especially in conditions like complex regional pain syndrome (CRPS) with a high burden of psychopathology. An emerging perspective characterizes chronic pain as a learning impairment - an inability to differentiate between situations predicting threat vs. safety - resulting in fear and avoidance spreading to potentially safe activities. Although much of the impairment is attributed to the dysfunction and disinhibition involving the prefrontal networks, the underlying neurophysiology and its causal relationship with pain avoidance behavior is yet to be determined. We take a multimodal approach to study how behavior, brain neurophysiology and autonomic nervous system (ANS) responses are modulated by enhancing the alpha oscillatory power in the dmPFC. Given the alpha oscillations in the dmPFC facilitate inhibitory processes required for decision making and learning, we hypothesize that enhancing alpha power via tACS will promote adaptive pain avoidance behavior in CRPS patients. In Aim 1 will use an instrumental pain avoidance task in conjunction with a computational reinforcement learning model to quantify the effects of tACS on threat and safety learning behaviors. The task will be performed while we collect magnetoencephalography (MEG), a state-of-the-art brain imaging device. Aim 2 will examine both pain avoidance task-related and resting-state MEG activity to quantify the effects of tACS on brain neurophysiology in terms of alpha oscillatory power and connectivity. Aim 3 will evaluate the effects of tACS on ANS responses in terms of heart rate variability – a parasympathetic measure from EKG – and fear arousal – a sympathetic measure from galvanic skin conductance responses. The data from this project will clarify the spectral specificity with which pain avoidance behavior is represented in the dmPFC and ability to directly modulate them. This project is the first of its kind to investigate affective- motivational dimensions of chronic pain using tACS and will establish the foundation for future augmented protocols combining tACS with rehabilitation.