NCCIH Research Blog

Are you interested in learning more about how the brain removes waste products through the glymphatic and meningeal lymphatic systems? Can manipulation of these systems help prevent or treat devastating disorders such as Alzheimer’s disease (AD)? A new Nature special volume on this topic features two publications from investigators whose research was funded by the National Center for Complementary and Integrative Health (NCCIH), Jonathan Kipnis, Ph.D., of Washington University in St. Louis, and Li-Huei Tsai, Ph.D., at the Massachusetts Institute of Technology. 

The new study from Dr. Kipnis’s team reports that neurons generating high-energy ionic waves during sleep act as master organizers for brain clearance. These waves facilitate moving fluid through the brain parenchyma, shedding light on roles of neuronal dynamics in the glymphatic system.

The glia-operated glymphatic system, which is unique to the central nervous system, was discovered about a decade ago, and apparently it plays a crucial role in brain clearance and homeostasis. Studies in animals and humans show how meningeal cerebrospinal fluid (CSF) flows into the brain parenchyma via the para-arterial space, exchanges fluid contents with interstitial fluid (ISF), and then drains back to the meninges via the para-venous space. The meningeal lymphatic system, discovered around the same time, connects with the glymphatic system and transports the drained CSF/ISF from meninges to the deep cervical lymph nodes for clearance. Functionally, both systems contribute to brain-wide nutrient delivery, waste removal, tissue homeostasis, and immune functions. Both systems have been implicated in several medical conditions, including AD, migraines, stroke, stress, alcohol use, sleep deprivation, and the aging brain. 

The glymphatic and lymphatic systems are regulated by many factors and can be modulated by several nonpharmacologic approaches, such as physical exercise, continuous theta burst stimulation (cTBS), and deep inhalation-mediated thoracic pressure reduction. 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. 

The NCCIH-supported investigation by Dr. Tsai and colleagues used a noninvasive multisensory intervention—Gamma ENtrainment Using Sensory stimuli (GENUS)—to promote glymphatic function and reduce the accumulation of amyloid in mouse models of AD. Previously, Dr. Tsai’s team found that 1 hour of 40 Hz stimulation, driven by optogenetics, increased gamma waves and significantly reduced the pathogenic amyloid load in AD mouse models, compared to control stimulations. The new study from Dr. Tsai’s team shows that multisensory gamma stimulation activated the influx of CSF and the efflux of ISF fluid in mouse cortex. These findings highlight an interconnected relationship between glial, neuronal, and vascular cells in the regulation of CSF dynamics and establish novel mechanisms to recruit the glymphatic system for brain amyloid removal and potential treatment of neurodegenerative disorders like AD.

For more fascinating details about how lymphatic and glymphatic systems may be relevant to and regulated by complementary and integrative health approaches, you can read the Nature papers by the two NCCIH grantees as well as other relevant publications on the topic of glymphatic system in Nature. 

For More Information

• Neurons Generate Synchronized Rhythmic Waves in Brain’s Interstitial Fluid To Help Clear Metabolic Waste
• Multisensory Gamma Stimulation Promotes Glymphatic Clearance of Amyloid in Alzheimer’s Disease Models