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

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 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

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

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 Major Depressive Disorder (MDD) afflicts more than 280 million people worldwide and is the leading cause of life years lost to disability. Current treatments have important limitations in efficacy and, in the case of medication, substantial side effects. There is thus a compelling need for additional effective, well-tolerated treatments. Body heating practices, such as saunas, sweat lodges, and hot yoga, have rich traditions across cultures as healing practices. Additionally, recent basic and clinical research, as well as the investigative team’s pilot data, suggest that whole-body hyperthermia (WBH) holds promise for depression treatment. The investigative team therefore hypothesizes that WBH, a body-based heat treatment, may decrease depression symptoms. Additionally, pilot data suggest benefit from combining WBH and cognitive behavioral therapy (CBT), an established mind-based treatment for depression. The UCSF investigative team led an NCCIH- funded project testing WBH and CBT in adults with major depressive disorder and have found the combined treatment to be feasible and acceptable. Additionally, preliminary data from this project suggest a clinically meaningful and statistically significant reduction in depression symptoms. Despite promising initial data from such pilot studies, rigorous and well-designed clinical trials are required to evaluate the efficacy of depression treatments that include WBH. Before the investigative team can conduct a definitive efficacy trial, they must assess the feasibility of key study design components. This proposal will test the feasibility of a multi-site 2 x 2 factorial trial design that randomizes adults (N=60) with MDD to two treatment factors: WBH (yes/no) and CBT (yes/no). The three-site investigative team (University of California San Francisco, Cleveland Clinic Foundation, Massachusetts General Hospital) will capitalize on their established collaborative relationships to assess the feasibility of recruitment, enrollment, randomization, and retention (Aim 1), intervention fidelity and acceptability (Aim 2), and consistency of data collection (Aim 3). The study will include a 2-week screening period, a 10-week intervention period, and a 12-week follow-up period. During the intervention period, participants randomized to WBH will receive four biweekly sessions, and participants randomized to CBT will receive eight weekly sessions. If successful, the proposed multi-site feasibility R01 trial will lay key groundwork for a future multi-site 2 x 2 factorial efficacy trial that will test the effects of WBH, CBT, and their combination on depression symptoms. If successful, this program of research may yield novel non-drug treatment options for millions of individuals struggling with depression.

NCCIH - National Center for Complementary and Integrative Health

SUMMARY The gut microbiome plays a key role in modulating host metabolism and immune responses. Industrialized populations, like U.S. residents, have gut communities with reduced microbial richness and missing key functions, particularly the degradation of microbiota-accessible carbohydrates (MACs, a component of dietary fiber) and the subsequent production of fermentation products, the short-chain fatty acids (SCFAs) acetate, propionate, and butyrate. These changes are linked to increased prevalence of a broad range of inflammatory diseases such as diabetes, metabolic syndrome, and autoimmune disorders. Our human dietary intervention study (NCT03275662) shows that reintroducing high dietary MAC levels in humans fails to restore SCFA production in most healthy adults, likely due to the scarcity of MAC-fermenting microbes in industrialized guts. A minority of participants with the highest microbiota richness did show decreased inflammatory markers and increased fecal butyrate during the intervention, termed “high-fiber responders”. We hypothesize that replenishing MAC-fermenting microbes in individuals with depleted microbiomes can increase SCFA production, reduce inflammatory markers, and improve host health. This project aims to target specific diseases with highly deteriorated gut microbiomes by repopulating the gut with bacteria that can ferment dietary MACs and deliver key metabolites to support human health and recovery. Aim 1 will characterize an existing repository of strains for MAC-degradation and perform additional isolations using a novel protocol for whole-food intact, low solubility fibers. SCFA profiles will be determined, along with functional assays to assess production of secondary bile acids and aryllactates. Aim 1 will result in a comprehensive repository of strains that can ferment various MACs into SCFAs and produce other key metabolites. Aim 2 will use an in vitro fermentation model to test microbial cocktails of 5-20 strains with a goal of optimizing production of SCFA and other metabolites. Augmentation of cocktails with strains possessing additional metabolic capabilities, such as hydrogen consumption or MAC- independent SCFA production pathways, will be explored to enhance SCFA output. Aim 2 will result in optimized candidate cocktails for further testing in mouse models. Aim 3 will evaluate the functionality of these cocktails in mouse models humanized with low richness gut microbiomes including those of people with metabolic syndrome. Mice will be fed a custom MAC-rich diets to promote cocktail engraftment. Impact on the microbiome will be assessed via metagenomic sequencing and SCFA and other metabolites measured. Host immune and metabolic responses will be profiled to understand the impact of enhanced SCFA production on inflammatory and metabolic status. This project leverages the expertise of PIs Sonnenburg and Martens including in the mechanisms connecting diet-microbiome interactions with host biology. Successful completion will provide foundational knowledge linking specific dietary MACs to microbiome function and yield trial-ready microbial cocktails aimed at restoring health-promoting functions in depleted microbiomes such as individuals with metabolic diseases.

NCCIH - National Center for Complementary and Integrative Health

Project Summary Improved treatments for chronic neuropathic pain are needed but hindered by an incomplete understanding of the biological mechanisms of pain development. Sleep disruptions are associated with increased chronic neuropathic pain. Thus, understanding processes critical to sleep may be the key to understanding chronic pain. The glymphatic system is a network of perivascular spaces alongside blood vessels, which facilitates cerebrospinal fluid (CSF) movement into, and interstitial fluid through the brain, ultimately draining into the meningeal lymphatic system. CSF movement between the glymphatic system and the cervical lymphatic system follows circadian (~24h) timing. During sleep, CSF influx and brain solute clearance increase, while direct CSF drainage to peripheral lymphatics predominates during the active phase. The glymphatic system presents a novel therapeutic target for neuropathic pain. This proposal introduces the hypothesis that circadian timing governs CSF movement between the glymphatic and lymphatic systems, driving cytokine redistribution across neuroimmune tissues, regulating nociception and the development of chronic pain. Aim 1 will test whether the daily glymphatic/lymphatic CSF switch deteriorates during the development of chronic pain, altering cytokine distribution across neuroimmune tissues and increasing nociception and hyperalgesia. Aim 2 will test whether the molecular clock controls daily glymphatic/lymphatic CSF distribution and cytokine distribution across neuroimmune tissue, influencing nociception across the day. Aim 3 will assess whether reinforcing circadian timing through food restriction attenuates chronic pain. Aligning peripheral rhythms with central timing provides a non-invasive therapy for chronic pain. These experiments will reveal new insights into chronic pain pathology and explore non-pharmacological interventions for a critical unmet need.

NCCIH - National Center for Complementary and Integrative Health

Our autonomic regulation of respiration, digestion, circulation, and immune functions is closely coupled with emotional states. Anxiety elevates blood pressure, stress induces sighing, and anger suppresses digestion, while slow breathing promotes calmness. Despite these well-documented phenomena, the neural mechanisms underlying the tight coupling between emotion and autonomic control remain poorly understood, limiting the development of complementary therapies for emotional disorders, such as anxiety, phobia, and depression, and autonomic disorders, including hypertension, diabetes, gastroparesis, tachycardia, pulmonary diseases, sleep apnea, and many others. The interoceptive system continuously monitors visceral organ status. Many bodily cues are transmitted via the vagus nerve to the nucleus of the solitary tract (NTS) in the brainstem, the primary sensory gateway for interoception. The NTS processes interoceptive information and distributes it, via its ascending pathways, to multiple brain regions, including autonomic motor nuclei, the hypothalamus, and limbic structures, to orchestrate coordinated whole-body autonomic, emotional, and behavioral responses. The goal of this proposal is to pinpoint the neural substrate that mediate bodily signal-evoked emotional and autonomic responses respectively. Using viral-genetic tracing, our preliminary study shows that single NTS neurons extend highly collateral projections to multiple targets. In particular, we identified a group of NTS neurons that jointly innervate brain regions implicated in aversion/anxiety and autonomic control. This previously uncharacterized ascending interoceptive pathway forms the basis of our hypothesis that axonal collaterals from the same neurons jointly regulate autonomic and emotional responses. Using a portfolio of genetic tools that enable us to precisely record and manipulate genetically defined NTS pathways, we will, through three specific aims, determine the anatomical signatures that underlie the tightly associated emotional and autonomic responses. The completion of this proposal will help establish an anatomical-functional blueprint of ascending brainstem interoceptive circuits, laying the foundation for future investigations. By revealing the multisystem interactions of the interoceptive network, this proposal will provide insight into how complementary approaches, such as meditation and breathing-based therapies, holistically improve autonomic emotional well-being.

NCCIH - National Center for Complementary and Integrative Health

Project Summary/Abstract Chronic pain affects a large portion of people with multiple sclerosis (PwMS), impacting their daily activities and overall quality of life. Mindfulness-Based Cognitive Therapy (MBCT) has shown effectiveness in alleviating pain for people with MS; however, there is considerable variation in how individuals respond to treatment. Consistent home practice is hypothesized to be a key factor in producing therapeutic outcomes. However, mastering a new skill in treatment does not necessarily mean that it will translate to real-life situations, and a consistent barrier to treatment success occurs when individuals fail to practice mindfulness in daily life. As a result, there is a significant need to identify barriers and facilitators to mindfulness practice among people with MS undergoing MBCT for chronic pain. Recent advances in mobile technology allow investigators to examine these barriers in close to real time and provide adaptive and timely intervention. This K23 Career Development Award will provide the candidate training in intensive longitudinal and micro-randomized trial design and analysis, acquire proficiency in just-in-time adaptive intervention (JITAI) development, and enhance grantsmanship and scientific dissemination skills with a focus on developing a successful R01 application utilizing pilot data from this project. This new training will be leveraged to advance understanding and engagement in mindfulness practice among individuals with MS participating in MBCT for chronic pain in three integrated steps. Aim 1 will utilize ecological momentary assessment (EMA) to identify barriers and facilitators to mindfulness practice among 80 individuals with MS during 8-weeks of MBCT. Aim 2 will develop a JITAI informed by the EMA data to deliver personalized “nudges” promoting mindfulness practice during MBCT sessions. This phase will also incorporate human-centered design methods and feedback from PwMS to maximize feasibility. Aim 3 will use micro-randomized trial methodology (MRT) to optimize JITAI components and explore preliminary feasibility for 50 people with MS participating in MBCT. All aims will be supported by didactic, experiential, and mentored training in the fundamentals of clinical research through the Department of Rehabilitation Medicine at the University of Washington School of Medicine. Collectively the research and training aims of this project seek to inform and personalize the delivery of mindfulness-based interventions (MBIs) for chronic pain not only in people with MS but also in other populations experiencing pain. This award will equip the candidate with the expertise to independently lead innovative research in MBIs, advance pain management strategies and enhance quality of life for individuals with chronic health conditions.

NCCIH - National Center for Complementary and Integrative Health

Chronic phantom limb pain (cPLP) is a debilitating chronic pain disorder that is experienced by up to 64% of the 356 million people with amputations worldwide. The prevalence of cPLP is rapidly rising due to the increased incidence of severe diabetes mellitus and vascular diseases. The primary symptom of cPLP is pain, which, in the majority of cases, is severe, treatment resistant and consequently signifies the importance of developing fast acting cPLP treatments. Chronic pain severity and corresponding comorbidities are driven by amplified sensory, self-referential, and negative affective interactions that intensify the transition of acute to chronic pain. Thus, pain therapies that reliably target nociceptive specific and affective mechanisms may produce durable improvements in pain symptomology and well-being. The recent “psychedelic renaissance” has generated wide-reaching interest into the potential efficacy of psilocybin as a pain therapeutic. Psilocybin (4-phosphoryloxy-N, N-dimethyltryptamine), a hallucinogenic drug that modifies self-referential processes, has shown promise at reducing cPLP. Mechanistic appreciation of if and how psilocybin modifies pain is needed. The default mode network (DMN), a midline cortical neural network supporting egocentric and affective pain appraisals, has been revealed as a neural target for chronic pain and psilocybin. Yet, the analgesic effects and supporting brain mechanisms through which psilocybin can modulate chronic pain are unknown. The proposed research activities will significantly expand our understanding of the impact of psilocybin on chronic pain and the corresponding neural mechanisms. In a recently completed pilot clinical trial, 25mg of psilocybin (n = 5) was found to be a safe and feasible treatment for cPLP as compared to niacin (100mg; n = 4). Importantly, four weeks after dosing, psilocybin was associated with reductions in weekly cPLP (- 43%). In contrast, the niacin group exhibited no change in cPLP four weeks after dosing as compared to baseline. Weaker resting state functional connectivity (rsFC) between the DMN and thalamus predicted greater psilocybin-based cPLP relief 4 weeks after dosing. The proposed R01 application will expand on our pilot study and aims to identify the neural processes supporting the effects of psilocybin on cPLP. In the proposed mechanistic clinical trial, 60 patients with lower limb amputations and cPLP will be recruited and randomized to receive double blind administration of 25mg psilocybin (n=30) or 50mg niacin (n=30) after completing baseline assessments. “Past week” cPLP will be assessed at baseline and 1 day, 2-, 4- and 12-weeks post-dosing. Functional MRI will be acquired at baseline, and 1 day and 4 weeks post-dose. We hypothesize that psilocybin induced cPLP relief will be associated with weaker DMN–thalamic rsFC four weeks after dosing when compared to baseline. Exploratory analyses will also test if psilocybin elicits greater cPLP relief when compared to niacin. The knowledge gained from the proposed work will provide novel mechanistic understanding of psilocybin-induced cPLP relief.

NCCIH - National Center for Complementary and Integrative Health

Project Summary/Abstract Research: Fear activates the fight or flight stress-response, leading to rapid changes in behavior and physiological accommodations via the sympathetic nervous system. While the stress response facilitates survival from an acute threat, inappropriate activation or delayed termination after threats have passed can be maladaptive. Indeed, inappropriate sympathetic activation is a hallmark of psychiatric diseases such as post- traumatic stress disorder and major depressive disorder. Conversely, non-invasive brain modulation techniques such as transcranial direct current stimulation, which induces diverse physical and mental health benefits, may function in large part through its ability to mitigate the stress response. Together, this suggests that the neural circuits regulating the sympathetic nervous system could be an important therapeutic target. To map the central circuits regulating the adrenal gland, an essential effector of the fight-or-flight sympathetic response and the principal source of circulating epinephrine, I will use monosynaptic rabies. My preliminary data show that the adrenal medulla receives innervation not only from well-established hypothalamic nuclei, but also, surprisingly, from the motor cortex. The proposed project will expand upon this finding: In Aim 1) I will rigorously map the connections between the motor cortex and the adrenal gland and in Aim 2) I will investigate how these cortical neurons modulate epinephrine release and the physiological and behavioral response to stress. These aims will expand our understanding of this newly discovered neural circuit and its role underlying important mind-body interactions. Career development: This five-year research career development program will advance the career of a promising physician-scientist studying the neural circuits underlying mind-body connections as they relate to the physiological effects of stress. This proposal builds upon the candidate’s extensive background in molecular neuroscience and behavioral genetics, by promoting Dr. Greene’s acquisition of several necessary technical skills and extensive training to ensure that the candidate develops superb professional skills. The training goals are reflected in the expertise of the mentors (Dr. Andrés Bendesky and Dr. Rui Costa), tailored seminars and didactics, and the strong neuroscience training environment at Zuckerman Mind Brain and Behavior Institute. By completing the proposed studies and training plan, the candidate will acquire a unique and highly valued skill set that will support a successful transition to becoming an independent investigator.

NCCIH - National Center for Complementary and Integrative Health

This proposal aims to support the International Congress on Integrative Medicine and Health (ICIMH) annual meeting from 2026-2030, sponsored by the Academic Consortium for Integrative Medicine & Health (“Academic Consortium”), which currently represents over 80 academic health centers and health systems in the U.S. and around the World. The overall goal of the Congress is to provide the premier venue for bringing together rigorous scientific research on a broad range of topics including integrative approaches to cancer, mental health, pain, metabolic health, aging, pediatrics, women’s health, oral health, and substance use disorders. It has provided a key venue for grantees of the NCCIH and other NIH centers and institutes to network and present their scientific work and has been a significant catalyst for growth of the science of the integrative medicine field since the inception of the Congress. This grant is specifically aimed at increasing attendance at the conference of students, trainees, new investigators, and others with financial barriers to attendance and supporting the publication of early investigators abstracts. Most of the funding will be directed at reducing the student registration rate and providing travel scholarships. Travel scholarships will be awarded based on submission of an abstract with strong reviewer ratings, financial need, and bringing trainees from different health disciplines to the conference. The 2026 ICIMH is to be held in Salt Lake City, UT from April 20- 23, 2026; in Minneapolis, MN from April 12-15, 2027; and the 2028, 2029 and 2030 ICIMH will be determined closer to the date. ICIMH will showcase original scientific research involving integrative medicine and whole person health, using keynote and plenary presentations, oral and poster abstracts, symposia, and workshops. Basic science, clinical, and health service researchers will present original research and moderate panel presentations selected through a de-identified peer-review process, using a pool of over 60 expert reviewers. Leaders in whole health and integrative medicine are invited to provide keynote addresses and moderate concurrent research presentations. The oversight of conference planning is a collaboration between an Organizing and Scientific Review committee, Academic Consortium Board of Directors, student advisory group, and NCCIH. The 18-member Organizing Committee, representing diverse leaders in research, education, and clinical communities, has key responsibility for planning the meeting content, including selecting the plenary speakers and meeting symposia. This proposal aims to ensure that the Congress continues to provide a rigorous scientific venue for grantees of the NCCIH and other NIH institutes engaged in research related to whole person health to network and present their scientific work and to advance the meeting’s role as an important catalyst for growth of the science of the integrative medicine field.

NCCIH - National Center for Complementary and Integrative Health

PROJECT SUMMARY/ABSTRACT Since its launch in 2021, the Natural Products Magnetic Resonance Database (NP-MRD, https://np-mrd.org) has become the largest open repository of NMR data on natural products (NPs) as well as the largest collection of general information (nomenclature, structure, biology, chemistry) about NPs in the world. The NP-MRD contains substantial amounts of different types of NMR data including raw NMR data (free induction decays or FIDs), predicted NMR data and literature-derived NMR information (chemical shift assignments, coupling constants). The NMR data in the NP-MRD includes 15,000 sets of experimental NMR spectra (for 3200 NPs), 411,000 simulated NMR spectra (for 21,000 NPs) obtained from literature-derived NMR assignments, and 5.1 million predicted NMR spectra (for all 282,000 NPs). Much of the raw NMR data in the NP-MRD is there due to a concerted effort by NP-MRD, together with the Journal of Natural Products (JNP), to encourage raw data deposition of NMR data used to support novel structure elucidation. For the second phase of the NP-MRD (2025- 2030) we will build on the momentum created in the first phase. Specifically, we will optimize current operations and continue ongoing expansion of both the database content and utility. A major emphasis will be on streamlining NP-MRD operations such that most of its operations will require little human intervention. For example, raw data deposition formerly required two NP-MRD staff in two different locations to interact with the deposited data, and with the depositor. Today, raw data deposition goes automatically into a parser, a set of quality checks and straight into the NP-MRD repository with no human intervention unless (rare) problems occur with the data. Other functions being streamlined, include centralized processes to query, enter and assess NP- MRD data, better processes to annotate NP structures, tools to more efficiently gather biological, medicinal, structural, chemical shift and assignment data from the published literature, as well as workflows to correct entries, remove duplicates and improve accuracy. In terms of data content and utility expansion, major efforts will be undertaken to increase user deposition rates, support the deposition, integration and federation of mass spectrometry (MS) data for NPs into the NP-MRD, implement faster, more “intelligent” NMR, multi-spectral (NMR+MS+CCS+RT) and multi-database (GNPS, MoNA, MassBank, HMDB, FooDB) searches, support more accurate chemical shift, J-coupling and other kinds of “observables” prediction, and create new tools to support automated computer-aided NP structure elucidation (CASE) and dereplication. These streamlining, optimization and database expansion efforts are being done to ensure long-term sustainability of the NP-MRD by making operations cheaper, more automated, more useful and more valuable to the NP community. Outreach to other NP journals and to the NP community will be further expanded, with the expectation that these efforts will triple the data deposition rate to the NP-MRD by 2030, increase community buy-in, increase grant or co-funding support, attract paying subscribers and ensure long-term sustainability of the NP-MRD.

NCCIH - National Center for Complementary and Integrative Health

PROJECT SUMMARY: Rates of depression continue to rise and the mental health impact of COVID-19 has only accelerated trends. While mental health apps, specifically mindfulness apps, are not a panacea, they are popular tools that millions are turning to today for easy access, affordable, and low-stigma help. But increased reliance on mindfulness apps has not been supported by rigorous scientific evidence exemplified by few studies employing appropriate control conditions. Thus, this research is designed to focus on using 100% remote but robust methodology to assess the efficacy of mindfulness apps by applying a novel precision medicine framework. Our study first assesses the impact of the Digital Working Alliance by matching people with depression with a mindfulness app that may better support their personalized needs. We will compare those randomized to the to this matching condition to a digital placebo to better evaluate the efficacy of these mindfulness apps. For the first six weeks, participants will be asked to use the mindfulness app or digital placebo daily, and if not engaged, will receive reminders, allowing for the analysis of clinical outcomes during ideal usage patterns. For an additional six weeks, participants will be asked to use the app or digital placebo naturally, allowing for the elucidation of naturalistic usage patterns and evaluation if these usage patterns impact clinical outcomes. Across the entire study, we will capture smartphone-based digital phenotypes of behaviors (eg sleep, step, screen time), environments (eg home time, greenspace exposure), and symptoms (longitudinal ecological momentary assessment) to create personalized and predictive models of response that can be utilized to better understand factors impacting the efficacy of mindfulness apps, and in the future, better tailor apps to each person.