Every night, while the body rests, the brain orchestrates a vital cleanup operation. Cerebrospinal fluid, which bathes the brain, flows through its tissues, flushing away the chemical debris of the day. But what exactly happens during the brain’s janitorial shift has puzzled scientists for years.
In a new study, researchers reveal that during non-REM sleep, the brain uses rhythmic contractions of blood vessels, driven by the neurotransmitter norepinephrine, to propel cerebrospinal fluid through its tissues. This mechanism might be the brain’s answer to the lymphatic system, which moves fluid and waste in the rest of the body, but is absent in the brain.
How the Brain Pumps Waste Away
The discovery builds on a 2012 finding by neuroscientist Maiken Nedergaard at the University of Rochester Medical Center, and her colleagues. They identified a drainage system called the glymphatic system, where cerebrospinal fluid flows alongside blood vessels to clear metabolic waste. Since then, studies have suggested this process is critical for brain health, with diminished flow linked to Alzheimer’s and other neurodegenerative diseases.
However, pinpointing what drives the glymphatic system has been challenging. To investigate, Nedergaard’s team had to think outside the box. They surgically implanted electrodes and fiber optics into mice, allowing them to observe natural sleep without anesthesia, which can distort brain activity.
Their observations revealed that norepinephrine levels in the brain fluctuate about every 50 seconds during non-REM sleep. These oscillations cause blood vessels to contract and relax, creating a pulsing effect that propels cerebrospinal fluid deeper into the brain.
“When the vessels clench after a pulse of norepinephrine, cerebrospinal fluid moves in to fill the gap,” Nedergaard explained in an interview with Science. “And when the blood vessels relax, they push the cerebrospinal fluid along.”
To confirm this, the team used a fluorescent tracer to visualize the fluid’s flow. When they artificially sped up norepinephrine pulses, they found the fluid penetrated deeper into brain tissue, reinforcing the idea that these blood vessel contractions act as a pump.
“Thus, the micro-architectural organization of non-REM sleep, driven by norepinephrine fluctuations and vascular dynamics, is a key determinant for glymphatic clearance,” the authors wrote in their study.
The Role of Sleep Aids
The study raises questions about common sleep aids like zolpidem, known by its brand name Ambien. The researchers found that zolpidem diminished norepinephrine oscillations in mice, reducing cerebrospinal fluid flow.
This suggests the drug could interfere with the brain’s waste-clearing process, though the implications for humans remain unclear. In light of these recent findings, it’s now a priority to look into how this kind of medication affects the brain’s cleansing function.
Importantly, the study suggests humans share similar oscillatory patterns, hinting that this mechanism may be universal.
However, this isn’t, by far, the last word on the matter. A previous 2024 study led by Professors Nick Franks and Bill Wisden of Imperial College London, found evidence that the brain’s waste-clearing system may operate more efficiently during wakefulness. They found that the clearance of fluid in the brain significantly decreases during sleep and anesthesia.
Ever More Complex
“It sounded like a Nobel prize-winning idea,” said Franks, reflecting on the initial allure of the theory. “If you are sleep-deprived, countless things go wrong — you don’t remember things clearly, hand-eye coordination is poor. The idea that your brain is doing this basic housekeeping during sleep just seems to make sense.”
“We were, of course, very surprised to observe the opposite in our results,” said Franks. Their findings suggest that wakefulness might actually be a more effective time for clearing toxins from the brain.
This second study stops short of dismissing sleep’s importance. Instead, it shifts attention to other potential explanations for its restorative effects. The researchers speculate that the connection between disrupted sleep and dementia may stem from factors unrelated to waste clearance, such as the role of sleep in memory consolidation and cellular repair.
These differing results underscore the complexity of the brain’s waste-clearing mechanisms and point to the need for further research.
Both perspectives agree on one thing: sleep is vital for health, even if its functions remain elusive. As Wisden put it, “Having good sleep does help to reduce dementia risk for reasons other than clearing toxins.”
The study appeared in the journal Cell.
