Rhythmic carbon dioxide exposure may enhance brain waste clearance mechanisms

Abnormal clumps of proteins like α-synuclein, amyloid beta and tau are associated with neurodegenerative conditions like Parkinson's and Alzheimer's disease, but a waste removal mechanism called the glymphatic pathway can clear these proteins and other metabolic byproducts from the brain.

Now, a team of researchers from The University of New Mexico School of Medicine, the Mind Research Network (MRN) – a division of Lovelace Biomedical Research Institute – and the New Mexico Veterans Affairs Health Care System is exploring whether intentionally raising and lowering blood levels of carbon dioxide (CO₂) through rhythmic CO₂ exposure or controlled breathing might boost the glymphatic system's effectiveness and improve brain health.

A newly published paper in NPJ Parkinson's Disease describes research led by neuropsychologist Sephira Ryman, PhD, assistant professor in the UNM Department of Neurology and associate professor at the MRN. She led studies at the MRN to evaluate how intermittent breathing of CO₂ could be used to dilate and constrict brain arteries and drive the movement of cerebrospinal fluid through brain tissue to clear unwanted proteins.

The glymphatic pathway is most active when people are deeply asleep. In this state, Ryman said, "respiration slows and the brain exhibits an oscillatory pattern of activity called slow waves that drives the glymphatic pathway to clear the brain." However, for Parkinson's patients, who often experience sleep disturbances, this waste removal process may be impaired, leading to a buildup of toxic proteins in the brain and the pathologic changes seen in this disease.

In a prior study, she found patients with Parkinson's disease have a reduced and delayed cerebrovascular response to intermittent CO₂.

"It's across the board – all the Parkinson's patients had this reduced and delayed response," said Ryman, who sees patients at UNM's Nene & Jamie Koch Comprehensive Movement Disorder Center.

"We wrote a review paper trying to better understand this impaired response of the blood vessels of the brain," Ryman said. "We brainstormed how we could boost this response. That is when we realized that we could reproduce, in the awake state, the glymphatic clearing response usually linked to deep sleep using intermittent CO₂."

Her mentor, Henry Lin, MD, a professor in the Department of Internal Medicine, was instrumental in integrating human and animal studies, revealing the critical insight that shaped the direction of the research. 

As proof of concept, the team administered brief doses of room air with higher-than-normal concentrations of CO₂ in ON and OFF cycles to human subjects. They not only succeeded in reproducing the rhythmic response of the blood vessels of the brain, but also observed the appearance of toxic brain proteins in blood samples following the intervention, which suggested that the waste products were flushed from the brain.

Their novel strategy for enhancing the glymphatic system could preserve brain function, improve cognition and reduce the risk of cognitive decline.

Ryman and her colleagues are investigating whether intentionally practicing slow abdominal breathing, as is commonly practiced in yoga, meditation, martial arts and related disciplines, might be a way to enhance the glymphatic system and preserve brain function, improve cognition and reduce the risk of cognitive decline.

"Breath-centered practices such as yoga, tai chi, and qigong have been utilized for centuries to manage stress and promote psychological well-being," they wrote in a paper accepted for publication in the Journal of Cerebral Blood Flow and Metabolism. "Emerging research reveals an additional benefit: these practices also stimulate cerebrospinal fluid oscillations, potentially activating the glymphatic pathway during wakefulness."

When people engage in rhythmic controlled breath-holds, their CO₂ levels go up, stimulating constriction and dilation of arteries that sends pulses that may promote fluid movement through the brain when applied in ON and OFF cycles, they write."In addition to highlighting the potential for controlled breathing practices to facilitate waste clearance, these findings raise the intriguing possibility that rhythmic, controlled CO₂ exposures may serve as a direct and potentially more effective modulator of glymphatic function."