Concept: Mechanisms Underlying Modulation of the Glymphatic and Lymphatic Systems by Complementary and Integrative Health Approaches

Project Concept Review

Council Date: June 7, 2019

Program Officer: Yisong Wang, Ph.D.

Background

The meninges reside under the skull, where they protect the central nervous system and contain immune cells critical for the brain. The subarachnoid (SA) space in the meninges holds cerebrospinal fluid (CSF). The glymphatic (glial-lymphatic) system is an important clearance pathway for CSF, which flows into the brain via the para-arterial space, exchanges fluid contents with interstitial fluid (ISF), and then drains back to the SA space via the paravenous space. The meningeal lymphatic system connects with the glymphatic system to transport the drained CSF/ISF from the SA space to the peripheral deep cervical lymph nodes for clearance. Together, the two systems play a critical role in removing solutes and waste products, such as β-amyloid (Aβ), tau, lactate, and proinflammatory cytokines, from the brain. Functionally, the glymphatic system also contributes to brainwide nutrient delivery, whereas the meningeal lymphatic system shares similar functions as the peripheral lymphatic system in carrying out tissue homeostasis and immune trafficking/surveillance functions.

The glymphatic system has been implicated in several medical conditions. For instance, glymphatic clearance is suppressed in Alzheimer’s disease (AD), cortical spreading depression–associated migraine aura, traumatic brain injury (TBI), subarachnoid hemorrhage/ischemic stroke, multiple microinfarcts, diabetes-associated cognitive impairment, chronic stress, high-dose alcohol use, sleep deprivation, and the aging brain. Similarly, experimental disruption of the meningeal lymphatic system exacerbates Aβ deposition and cognitive impairment in mice. Molecules such as vascular endothelial growth factor C (VEGF-C) have been shown to enhance cognitive function of aging mice by promoting meningeal lymphatic flow. Therefore, understanding how the glymphatic/lymphatic systems are regulated may help in the development of therapeutic strategies to prevent or delay a variety of diseases and disorders, including brain dysfunction.

The glymphatic and lymphatic systems have been shown to be highly regulated by many factors and several complementary approaches. For example, the glymphatic system is regulated by the sleep-awake state and is predominantly active in rodents during sleep. In addition, glymphatic flow can be partly driven by cerebral arterial pulsation, whereas lymph flow is primarily propelled by the surrounding smooth muscle cell contraction of the collecting lymphatic vessels. Multiple nonpharmacologic approaches, such as physical exercise, continuous theta burst stimulation (cTBS), and deep inhalation–mediated thoracic pressure reduction, have also been shown to regulate brain lymphatic flows. Furthermore, osteopathic lymphatic pump manipulations and lymphatic drainage massage can regulate peripheral lymphatic flows. Dietary supplements such as omega-3 polyunsaturated fatty acids have been shown to promote amyloid-β clearance through facilitation of aquaporin-4 (AQP4)-dependent glymphatic function in mice. However, significant knowledge gaps remain in evaluating whether many other complementary approaches, including acupuncture, yoga, and meditation, may also modulate the lymphatic system in the central nervous system and/or peripheral tissues.

As many complementary and integrative health approaches are widely used by the public for conditions related to the lymphatic and glymphatic systems, there is a strong need to stimulate rigorous research that will systematically examine the effects of these approaches on the glymphatic or lymphatic systems as well as the underlying mechanisms by which the approaches exert their effects on these systems. A thorough understanding of the mechanistic interactions between these approaches and the lymphatic and glymphatic systems will help us optimize therapeutic strategies and potentials for disease treatment, disease prevention, and promotion of health and well-being.

Purpose of Proposed Program

The goal of this initiative is to encourage research on the mechanisms underlying the modulation of the glymphatic and lymphatic systems by complementary and integrative health approaches. Modulation of these systems could result in prevention or delay of diseases and disorders as well as promotion of health and well-being. Complementary and integrative approaches may include mind/brain-focused practices (i.e., meditation, hypnosis), body-based approaches (i.e., acupuncture, massage, spinal manipulation, cTBS, or repetitive transcranial magnetic stimulation [rTMS]), meditative exercise (i.e., yoga, tai chi, qi gong), or natural products (i.e., botanicals, dietary supplements, probiotics), in isolation or in combination with conventional medical treatments. Diseases and disorders of high programmatic interest include pain, Alzheimer’s disease, anxiety, depression, and other symptoms. Studies focusing on health promotion and well-being, rather than specific diseases and disorders, are also encouraged. Preclinical studies using relevant animal models and human mechanistic studies are appropriate for this initiative.

Objectives

Given the paucity of research on how complementary and integrative health approaches modulate glymphatic/lymphatic functions and how manipulation of these functions may influence a variety of diseases and health conditions, researchers are encouraged to address such unmet needs through this initiative. Topics of interest relevant to this initiative include, but are not limited to, the following:

• Physiological, biomechanical, biological, neuroimmunological, and/or neural mechanisms by which complementary and integrative health approaches may regulate glymphatic and lymphatic activity and function.
• Glymphatic and lymphatic mechanisms by which complementary and integrative health approaches affect a variety of physiological or pathological processes relevant to diseases or health conditions, such as:
  • Central pain modulatory processes, for example, changes of astrocytosis/gliosis status and central proinflammatory cytokine, chemokine, and neuromodulator trafficking and clearance in chronic pain
  • Toxic/unwanted material clearance, immune cell/modulator trafficking, and immune surveillance, for example in aging brain or neuroinflammatory and neurodegenerative diseases and dementia
  • Preventing age-related failure of cerebral arterial pulsation or cerebral amyloid angiopathy, and facilitating recovery from stroke, tau pathologies, and sleep disruption post TBI.
• Development and optimization of complementary and integrative health approaches in animal models and human subjects to identify active intervention components that facilitate modulation of glymphatic and lymphatic functions.