R01AT011439

The Glymphatic System at the Crossroad of Integrative Health Approaches in Chronic Pain

Abstract:
The glymphatic system is a network of perivascular spaces that function as a waste clearance system, analogous to the peripheral lymphatic system. Reduced glymphatic function has been a hallmark observation in aging as well as models of Alzheimer's disease, diabetes, hypertension, traumatic brain injury, excess alcohol intake, and chronic unpredictable stress. Preliminary data shows that acute and chronic pain, and one night of light all suppressed glymphatic function.

This application will use the murine sparse nerve injury (SNI) model to understand how the brain responds to chronic neuropathic pain. Sleep complaints are prevalent in chronic pain patients, and chronic sleep restriction increases pain sensitivity in mice. Norepinephrine (NE), which disrupts sleep and is released in stressful conditions, suppresses glymphatic function. We hypothesize that increased NE levels in SNI reduce glymphatic function, triggering cytokine accumulation, neuronal excitability, sleep disruption, and pain sensitization in a feedforward loop (Aim 1).

Traditional analgesics have been shown to relieve pain in models of chronic pain. Our preliminary data show that the same agents restore glymphatic function in SNI mice with no effect on glymphatic functions in control mice. We hypothesize that reducing the severity of pain via analgesia improves glymphatic function by reducing NE levels, which in turn reduces cytokine accumulation and excitability and improves sleep quality (Aim 2.1).

Yet, efficacy of modern pharmacology is variable in the patient population, suggesting that while modulation of neural pathways is partially effective, pathology remains. We hypothesize that neuropathic pain induces a CNS maladaptive response involving reduced glymphatic flow, inflammation, and waste accumulation. Because both natural and mind-body interventions target multiple facets of glymphatic disruption (sleep, inflammation, cardiovascular disease), we hypothesize that natural supplements (melatonin and eicosapentaenoic acid (an -3 fatty acid)) and mind-body interventions (voluntary exercise, improved sleep, and acupuncture) will improve glymphatic disruption in chronic pain (Aims 2.2 and 2.3).

The timing of treatment is critical because the circadian system is integrated into every process in the body including the glymphatic system, the immune system, and chronic pain. We propose that targeting therapeutics to reinforce the rhythm in glymphatic function and clearance will optimize the effect of treatment, which can be quantified as an additional decrease in cytokine accumulation and hyperalgesia in SNI (Aim 3). We will time sleep improvements via increased temperature, voluntary exercise, melatonin, and acupuncture to the endogenous rhythm of cerebrospinal fluid (CSF) distribution - high glymphatic clearance during rest and low during wakefulness. Aim 3 is unique in that it tests whether efficacy of mind-body therapies, in improving glymphatic function and reducing pain sensitivity, can change based on when during the day they are administered.

Overall, this application aims to define whether glymphatic activity may serve as a target for complementary therapeutic approaches and also as a biomarker establishing the efficacy of treatment.

University Of Rochester

TO EVALUATE COMPLEMENTARY AND INTEGRATIVE HEALTH APPROACHES. THE FOLLOWING OBJECTIVES SUPPORT THIS GOAL: (1) COORDINATE AND FACILITATE THE INVESTIGATION OF COMPLEMENTARY AND INTEGRATIVE HEALTH APPROACHES THROUGH PEER-REVIEWED GRANT SOLICITATIONS, (2) INTERFACE WITH THE NCCIH NATIONAL ADVISORY COUNCIL, (3) CONDUCT TECHNOLOGY ASSESSMENT CONFERENCES FOR THE PURPOSE OF ESTABLISHING AREAS OF CLINICAL AND PRE-CLINICAL RESEARCH THAT NEED TO BE FURTHER DEVELOPED WITHIN COMPLEMENTARY HEALTH APPROACHES, AND (4) MAINTAIN A COMPREHENSIVE BIBLIOGRAPHIC DATA BASE IN CONJUNCTION WITH THE NATIONAL LIBRARY OF MEDICINE. THE NATIONAL CENTER FOR COMPLEMENTARY AND INTEGRATIVE HEALTH (NCCIH) REGULARLY EXAMINES AND REDEFINES ITS RESEARCH PRIORITIES. IN SETTING RESEARCH PRIORITIES, NCCIH CONSIDERS ITS EXISTING RESEARCH PORTFOLIO, ITS 5-YEAR STRATEGIC PLAN, THE RECOMMENDATIONS OF THE NATIONAL ADVISORY COUNCIL FOR COMPLEMENTARY AND INTEGRATIVE HEALTH, CURRENT SCIENTIFIC ADVANCES, THE PLANS OF OTHER NIH INSTITUTES AND CENTERS, AND INPUT FROM EXPERT PANELS AND STAKEHOLDERS. RESEARCH CONSTITUTING A RIGOROUS EVIDENCE BASE FOR COMPLEMENTARY HEALTH APPROACHES WILL BE DEVELOPED THROUGH A RANGE OF RESEARCH STRATEGIES INCLUDING BASIC AND TRANSLATIONAL RESEARCH, AND CLINICAL INVESTIGATION. PRIORITY SETTING ALSO TAKES INTO ACCOUNT: 1)SCIENTIFIC PROMISE, 2)AMENABILITY TO RIGOROUS SCIENTIFIC INQUIRY,3) POTENTIAL TO CHANGE HEALTH PRACTICES, AND 4) RELATIONSHIP TO USE AND PRACTICE. RESEARCH APPROACHES BASIC, TRANSLATIONAL, EFFICACY/EFFECTIVENESS, AND IMPLEMENTATION RESEARCH FOR COMPLEMENTARY AND INTEGRATIVE HEALTH APPROACHES NEED TO BE STUDIED ACROSS THE RESEARCH CONTINUUM. NCCIH CONTINUES TO EMPHASIZE BASIC RESEARCH THAT DEFINES BIOLOGICAL EFFECTS AND MECHANISMS OF ACTION, THIS RESEARCH IS AIMED AT UNDERSTANDING THE NATURE OF COMPLEMENTARY HEALTH APPROACHES SUCH AS THEIR BIOLOGY, PHYSIOLOGY, AND PHYSICAL, CHEMICAL AND BEHAVIORAL PROPERTIES. NCCIH ALSO SUPPORTS THE DEVELOPMENT OF TOOLS, MODELS, AND METHODOLOGIES FOR STUDYING THESE APPROACHES. NCCIH CONTINUES TO ENCOURAGE EFFICACY STUDIES TO DETERMINE SPECIFIC CLINICAL EFFECTS OF COMPLEMENTARY HEALTH APPROACHES UNDER CAREFULLY CONTROLLED CONDITIONS THAT MINIMIZE NONSPECIFIC AND CONTEXTUAL EFFECTS. THERE IS ALSO THE NEED TO STRENGTHEN TRANSLATIONAL AND PRELIMINARY CLINICAL RESEARCH REQUIRED TO DESIGN AND IMPLEMENT DEFINITIVE CLINICAL RESEARCH AND ""REAL WORLD"" OUTCOMES AND EFFECTIVENESS RESEARCH THAT CAPITALIZES ON THE REALITY THAT MANY COMPLEMENTARY HEALTH APPROACHES ARE IN WIDESPREAD PUBLIC USE. NCCIH'S SUPPORT OF TRANSLATIONAL RESEARCH ADDRESSES THE NEED FOR VALID, RELIABLE AND RELEVANT RESEARCH TOOLS, OUTCOME MEASURES, AND INNOVATIVE METHODOLOGY TO ENHANCE THE RIGOR OF COMPLEMENTARY HEALTH APPROACHES WITHIN CLINICAL STUDIES AND TO ENSURE THAT THEY ARE MAXIMALLY INFORMATIVE. NCCIH EMPHASIZES STUDIES THAT INFORM THE DESIGN OF FUTURE TRIALS SUCH AS THOSE THAT WILL: DEVELOP AND VALIDATE OUTCOME MEASURES, STANDARDIZE TREATMENT PROTOCOLS OR ALGORITHMS, VALIDATE TREATMENT ALGORITHMS AND/OR, DEVELOP MEASURES OF QUALITY CONTROL OR TREATMENT FIDELITY, ASSESS EFFECTS OF VARIOUS DOSES OR INTERVENTION DURATIONS, DEVELOP PRELIMINARY CLINICAL EVIDENCE REGARDING EFFICACY AND SAFETY TO SUPPORT ESTIMATES OF SAMPLE SIZE, OR ESTABLISH FEASIBILITY OF INTERVENTIONS OR STUDY DESIGNS IN SPECIFIC POPULATIONS FOR FUTURE STUDIES. NCCIH'S CLINICAL RESEARCH PORTFOLIO UTILIZES CLINICAL TRIAL, CASE-CONTROL, OBSERVATIONAL, COHORT, QUALITATIVE, AND OTHER EXPERIMENTAL METHODOLOGIES TO DETERMINE SAFETY AND ESTIMATE THE EFFICACY OF COMPLEMENTARY HEALTH APPROACHES. THE CLINICAL RESEARCH PORTFOLIO INCLUDES EFFECTIVENESS STUDIES OF THE CONTRIBUTION TO IMPROVED HEALTH AND WELLNESS MADE BY COMPLEMENTARY HEALTH APPROACHES AS THEY ARE PRACTICED IN ""REAL-WORLD"" SETTINGS. IN GENERAL, PHASE III CLINICAL TRIALS WILL BE SUPPORTED UNDER THE COOPERATIVE AGREEMENT MECHANISM AFTER CAREFUL CONSIDERATION BY NCCIH STAFF. INVESTIGATORS INTERESTED IN PROPOSING PHASE III STUDIES ARE STRONGLY ENCOURAGED TO CONTACT A RELEVANT NCCIH PROGRAM OFFICER (HTTPS://NCCIH.NIH.GOV/TOOLS/EMAILPROGRAMOFFICERS). AREAS OF SPECIAL INTEREST FUNDAMENTAL SCIENTIFIC INQUIRY IS ESSENTIAL TO THE PROGRESS OF BIOMEDICINE BY ENHANCING THE UNDERSTANDING OF HOW LIVING SYSTEMS WORK. THIS UNDERSTANDING SERVES AS A FOUNDATION FOR TRANSLATIONAL AND CLINICAL STUDIES THAT CAN LEAD TO IMPROVED APPROACHES TO THE MANAGEMENT, TREATMENT, AND PREVENTION OF DISEASES AND SYMPTOMS. ONE KEY GOAL IS TO ADVANCE OUR UNDERSTANDING OF BASIC BIOLOGICAL MECHANISMS OF ACTION OF NATURAL PRODUCTS, INCLUDING PREBIOTICS AND PROBIOTICS. NCCIH WILL CONTINUE TO SPONSOR RESEARCH ON COMPOUNDS ISOLATED FROM NATURAL PRODUCTS AS WELL AS COMPLEX MIXTURES FROM WHICH THEY ORIGINATE. ADDITIONALLY, NCCIH WILL CONTINUE TO SUPPORT RESEARCH TO ELUCIDATE THE EFFECTS OF PREBIOTICS AND PROBIOTICS ON THE MICROBIOTA NATURALLY PRESENT IN THE HUMAN BODY. ANOTHER KEY GOAL IS TO ADVANCE OUR UNDERSTANDING OF THE MECHANISMS OF ACTION BY WHICH MIND AND BODY APPROACHES (INCLUDING, BUT NOT LIMITED TO: MEDITATION, SPINAL MANIPULATION, MASSAGE, YOGA, TAI CHI, HYPNOSIS AND ACUPUNCTURE) AFFECT HEALTH, RESILIENCY, AND WELL-BEING. A THIRD KEY GOAL IS TO DEVELOP NEW AND IMPROVED RESEARCH METHODS AND TOOLS FOR CONDUCTING RIGOROUS STUDIES OF COMPLEMENTARY HEALTH APPROACHES AND THEIR INTEGRATION INTO HEALTH CARE. THESE NEW METHODS COULD CATALYZE ADVANCES IN NATURAL PRODUCT METHODOLOGY AND SUPPORT DEVELOPMENT OF NOVEL TECHNOLOGY AND INSTRUMENTS TO CARRY OUT RIGOROUS RESEARCH ON SYMPTOM MANAGEMENT AND FUNCTIONAL CHANGES PRIMARILY FOR MIND AND BODY APPROACHES. TO IMPROVE CARE FOR HARD -TO-MANAGE SYMPTOMS SUCH AS PAIN, ANXIETY, AND DEPRESSION, BOTH MIND AND BODY PRACTICES AND NATURAL PRODUCTS WILL BE RIGOROUSLY STUDIED USING WELL-ESTABLISHED METHODOLOGY. NCCIH WILL ALSO SUPPORT STUDIES IN ""REAL WORLD"" CLINICAL SETTINGS TO TEST THE SAFETY AND EFFICACY OF COMPLEMENTARY HEALTH APPROACHES, INCLUDING THEIR INTEGRATION INTO HEALTH CARE. INDIVIDUAL BEHAVIOR PLAYS A KEY ROLE IN HEALTH PROMOTION AND DISEASE PREVENTION. IT IS WELL ESTABLISHED THAT ADOPTING AND MAINTAINING HEALTHY BEHAVIORS (E.G., DIET AND EXERCISE) AND MODIFYING UNHEALTHY BEHAVIORS REDUCES RISKS OF MAJOR CHRONIC DISEASES. NCCIH WILL INVESTIGATE MECHANISMS OF ACTION OF COMPLEMENTARY AND INTEGRATIVE HEALTH APPROACHES IN HEALTH RESILIENCE AND PRACTICES THAT IMPROVE HEALTH AND PREVENT DISEASE. THESE APPROACHES WILL BE STUDIED ACROSS THE LIFESPAN AND IN DIVERSE POPULATIONS. NCCIH WILL ALSO EXPLORE RESEARCH OPPORTUNITIES TO STUDY AND ACCESS THE SAFETY AND EFFICACY OF COMPLEMENTARY HEALTH APPROACHES IN NONCLINICAL SETTINGS SUCH AS COMMUNITY- AND EMPLOYER-BASED WELLNESS PROGRAMS. TOP SCIENTIFIC PRIORITIES THE TOP SCIENTIFIC PRIORITIES INCLUDE THE NONPHARMACOLOGIC MANAGEMENT OF PAIN, NEUROBIOLOGICAL EFFECTS AND MECHANISMS, INNOVATIVE APPROACHES FOR ESTABLISHING BIOLOGICAL SIGNATURES OF NATURAL PRODUCTS, DISEASE PREVENTION AND HEALTH PROMOTION ACROSS THE LIFESPAN, AND CLINICAL TRIALS UTILIZING INNOVATIVE STUDY DESIGNS TO ACCESS COMPLEMENTARY HEALTH APPROACHES AND THEIR INTEGRATION INTO HEALTH CARE. PAIN IS THE CONDITION FOR WHICH ADULTS IN THE UNITED STATES MOST OFTEN USE COMPLEMENTARY AND INTEGRATIVE HEALTH APPROACHES. GROWING EVIDENCE INDICATES THAT SOME COMPLEMENTARY HEALTH APPROACHES MAY HELP IN ITS TREATMENT AND MANAGEMENT. DISCOVERING THE MECHANISMS BY WHICH A COMPLEMENTARY APPROACH EXERTS ITS EFFECTS COULD HELP IN THE DESIGN OF BETTER TREATMENTS AND PREDICT WHICH PEOPLE ARE MOST LIKELY TO RESPOND. WHETHER AND HOW COMPLEMENTARY HEALTH APPROACHES DIRECTLY MODULATE OR MODIFY THE STRUCTURE AND/OR THE FUNCTION OF THE ENTIRE OR PART OF THE NERVOUS SYSTEM REMAINS UNDERSTUDIED. ADVANCES IN GENOMICS, NEUROSCIENCE, STEM CELLS, SYSTEMS BIOLOGY, AND NEUROIMAGING OFFER EXCELLENT CONCEPTUAL RESOURCES AND OPPORTUNITIES FOR INNOVATIVE AND IMPACTFUL MECHANISTIC STUDIES OF COMPLEMENTARY HEALTH APPROACHES. THE PURPOSE OF INNOVATIVE APPROACHES FOR ESTABLISHING BIOLOGICAL SIGNATURES OF NATURAL PRODUCTS IS TO ADVANCE THE CHARACTERIZATION OF THE BIOLOGIC ACTIVITY OF COMPLEX NATURAL PRODUCTS BROADLY WITH AN EMPHASIS ON DETERMINING METABOLIC PROFILES. THERE HAS BEEN A GROWING INTEREST IN THE USE OF COMPLEMENTARY HEALTH APPROACHES FOR THE PREVENTION OF MENTAL, EMOTIONAL, AND BEHAVIORAL DISORDERS AND FOR THE PROMOTION OF PSYCHOLOGICAL AND PHYSICAL HEALTH, WELL-BEING, AND RESILIENCE. HOWEVER, THE EVIDENCE FOR THE USE OF COMPLEMENTARY MODALITIES IN THE CONTEXT OF PREVENTION AND HEALTH PROMOTION IS MODEST. RIGOROUSLY DESIGNED, DEVELOPMENTALLY APPROPRIATE STUDIES ARE NEEDED TO DETERMINE THE EFFICACY AND EFFECTIVENESS OF COMPLEMENTARY HEALTH APPROACHES FOR HEALTH PROMOTION AND DISEASE PREVENTION ACROSS THE LIFESPAN. EARLY STAGE AND NEW INVESTIGATORS NCCIH IS STRONGLY COMMITTED TO ASSISTING NEW AND EARLY STAGE INVESTIGATORS IN ESTABLISHING A RESEARCH CAREER. EARLY STAGE INVESTIGATORS ARE THOSE WITHIN 10 YEARS OF COMPLETING THEIR TERMINAL RESEARCH DEGREE, OR THEIR MEDICAL RESIDENCY, OR ITS EQUIVALENT. NEW INVESTIGATORS ARE THOSE WHO HAVE YET TO COMPETE SUCCESSFULLY FOR A SUBSTANTIAL (E.G., R01) NIH RESEARCH GRANT. EACH ADVISORY COUNCIL ROUND, BASED ON AVAILABLE FUNDS, NCCIH: 1) WILL CONSIDER EARLY STAGE OR NEW INVESTIGATOR STATUS AS ONE OF THE CRITERIA FOR DESIGNATING GRANT APPLICATIONS AS BEING OF HIGH PROGRAM PRIORITY AND 2) MAY MAKE ADDITIONAL R01 GRANT AWARDS TO NEW AND EARLY STAGE INVESTIGATORS WITH PERCENTILES OR SCORES OUT OF PAYLINE ORDER. NCCIH CONTINUES TO ACCEPT APPLICATIONS IN AREAS NOT LISTED AS A SPECIFIC PRIORITY AREA VIA THE INVESTIGATOR INITIATED FUNDING OPPORTUNITIES. ALL INVESTIGATORS ARE URGED TO DISCUSS POTENTIAL APPLICATIONS WITH THE RELEVANT NCCIH PROGRAM OFFICER (HTTPS://NCCIH.NIH.GOV/TOOLS/EMAILPROGRAMOFFICERS)

93.213 - Research and Training in Complementary and Integrative Health

National Center for Complementary and Integrative Health (NCCIH) [HHS - NIH]

Rochester, New York 14642 United States

Single Zip Code

Exploring the Mechanisms Underlying Modulation of Glymphatic-Lymphatic Systems by Complementary and Integrative Health Approaches (R01 Clinical Trial Optional) (RFA-AT-21-001)

Amendment Since initial award the total obligations have increased 458% from $549,780 to $3,067,927.