A paper is published that reinforces the hypothesis that the brain removes waste products during sleep, but some scientists criticize it
In recent years, the hypothesis that 'the human brain flushes out waste products through
The Mysterious Flow of Fluid in the Brain | Quanta Magazine
https://www.quantamagazine.org/the-mysterious-flow-of-fluid-in-the-brain-20250326/
The brain is an organ surrounded by the skull and an elaborate protective system, and receives nutrients from the blood through the blood-brain barrier . However, the brain is one of the organs with the highest metabolic rate in the body, and by-products (waste products) must be produced during the metabolic process, so it was a mystery as to how the brain removes these waste products.
In recent years, a hypothesis that has been gaining attention is that cerebrospinal fluid, which fills spaces in the brain called the ventricles and subarachnoid space , serves as a route for flushing waste products from within the brain. Cerebrospinal fluid is a colorless, transparent liquid secreted by the choroid plexus that faces the ventricles, and is also present in the subarachnoid space of the spinal cord.
Because cerebrospinal fluid flows from the spinal cord into the brain at the moment of death, it has been suggested that the living brain keeps the fluid moving in some way, but the exact flow of the fluid has long been unknown. 'Everyone agrees that there must be some kind of flow here,' says Christer Beteholtz , a professor of vascular biology at the Karolinska Institute in Sweden. 'Half a liter of cerebrospinal fluid is produced in the ventricles every day, so it has to drain out. People are still arguing about where the cerebrospinal fluid comes from.'
Meanwhile, in 2012, a research team led by Dr. Maken Nedergaard of the University of Rochester published a paper in which they injected a tracking molecule (tracer) into the cerebrospinal fluid of mice and confirmed that the tracer quickly reached another part of the brain. This suggests that the cerebrospinal fluid moves through channels around blood vessels and may be involved in the removal of waste products in the process.
Furthermore, in a 2013 paper, Nedergaard and his colleagues linked the removal of waste products by cerebrospinal fluid to sleep. Based on the experimental results that showed that cerebrospinal fluid movement was most active in the brains of sleeping mice, the paper proposed the hypothesis that 'sleep not only promotes memory consolidation, but also plays an important role in removing waste products from the brain.'
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Nedergaard says, 'I strongly believe that the restorative part of sleep is not memory consolidation. Maybe that's part of it, but it's the cleansing function of sleep that's really important.' Since this hypothesis was proposed, numerous research results have been published on the removal of waste products from the brain through cerebrospinal fluid.
However, some researchers have criticized the hypothesis that cerebrospinal fluid removes waste from the brain, citing a lack of sufficient evidence. Alan Berkman , professor emeritus at the University of California, San Francisco, points out that some aspects of the theory are physically implausible. For example, he says that the channels that are thought to be the pathways for cerebrospinal fluid cannot actually function as they should. Beteholtz also argues that there is no evidence that cerebrospinal fluid moves around blood vessels that leave the brain.
Another problem with examining cerebrospinal fluid is that 'if you try to make a hole in a closed space such as the ventricles, that will affect the movement of cerebrospinal fluid.' This makes it difficult to come up with new hypotheses.
In a new paper published in January 2025, Nedergaard and his colleagues reported the results of an experiment linking the mechanism by which cerebrospinal fluid is pumped between brain cells to sleep. In this experiment, sensors, wires, tubes, etc. were implanted in the brains of mice, and the vibrations and dynamics of a tracer injected at a single point in the brain were observed.
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As a result, it was found that the tracer concentration increased the most when the mice were in the non-REM sleep stage. Based on this experimental result, the researchers hypothesized that the neurotransmitter norepinephrine (noradrenaline) has the effect of constricting blood vessels, putting pressure on the surrounding cerebrospinal fluid, which is then sent to the brain tissue.
In experiments with mice that can switch the production of neurotransmitters during non-REM sleep, it was confirmed that the amount of cerebrospinal fluid in the brain increases when the concentration of noradrenaline increases, suggesting that noradrenaline affects the cerebrospinal fluid in some way. In experiments with mice that can directly manipulate blood vessel walls, it was reported that quickly moving blood vessels increased the flow of cerebrospinal fluid around them.
From a series of experimental results, the research team linked norepinephrine to the physical movement of blood vessels and the movement of cerebrospinal fluid. 'We have long sought to understand why the brain's washing system works primarily during sleep. This paper shows exactly the answer: we have found the motor or driver that washes the brain during sleep,' said Nedergaard.
But some researchers have pointed out problems with Nedergaard's hypothesis. Donald MacDonald , a UC San Francisco scientist who studies blood and lymphatic systems, criticized the 2025 paper for blurring the line between interpretation and data, and for including a diagram showing cerebrospinal fluid dynamics that doesn't seem to have been derived from experimental results.
'The tracer molecules used in the study were very small, so they may have moved by diffusion rather than cerebrospinal flow. Injecting larger molecules into the cerebrospinal fluid may make the connection between the cerebrospinal fluid and norepinephrine clearer,' said Steven Prue , a cerebrospinal fluid specialist at the University of Bern.
Natalie Haugland, lead author of the new paper and a postdoctoral researcher at the University of Oxford at the time of writing, said: 'There are criticisms of the hypothesis and we're not sure if we understand it the right way. Whatever the hypothesis, the more people who actually work to understand how it works, the more the field will move forward and the more knowledge we'll gain.'
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