New sleep study ignites brain cleaning controversy

For something that we spend a third of our lives doing, our knowledge about what sleep is for is surprisingly patchy. One idea, though, is that it's the time when toxins and metabolic waste that has accumulated in the brain during the day are cleared away. It's even been suggested that chronically poor sleep may contribute to, or cause, Alzheimer's disease, which is characterised by a build-up of toxic proteins.

Recent work in Nature Neuroscience, led by researchers at the UK Dementia Research Institute at Imperial College London, now challenges the idea that waste clearance is a key function of sleep, however. If the team is right, there are potentially serious implications for ideas about treatments for Alzheimer's, as well as for our understanding of the fundamental functions of sleep. Still, the methodology used in these new experiments has been questioned by some researchers the field.

The 'glymphatic system hypothesis' holds that a network of channels carry cerebrospinal fluid (CSF) through the brain to flush away toxins, and that this cleaning system is primarily 'turned on' during deep non-REM sleep. This idea, pioneered by Maiken Nedergaard at the University of Rochester, was first proposed in 2013 and has been hugely influential — though also controversial.

Earlier work in this area involved introducing tagged molecules into CSF, and following their pathway through the brain. This work suggested that the movement and clearance of these molecules is far greater during deep sleep.

For their new study, Andawei Miao and colleagues instead injected fluorescent molecules directly into the brain tissue of mice that were awake, anaesthetised, or asleep. They then watched how long it took for this dye to reach another region of the brain, and to be cleared. The team found that the rate of clearance was about 30% lower in sleeping versus awake mice, and 50% lower in mice that had been anaesthetised versus awake mice. Clearance, they write, was "markedly reduced, not increased, during sleep and anaesthesia."

In a comment issued at the time, study co-leader Nick Franks at Imperial College said: "The field has been so focused on the clearance idea as one of the key reasons why we sleep that we were very surprised to observe the opposite in our results."

Exactly how anaesthetics and sleep may inhibit clearance is unclear, the researchers write in their paper. However, other work has found that anaesthesia reduces the flow of CSF from the brain, so perhaps this is part of the explanation. "Whatever the mechanism, however, our results challenge the idea that the core function of sleep is to clear toxins from the brain," the team concludes.

This methodology has been challenged, however. The team injected the tracer molecules directly into brain tissue, rather than CSF, because they felt that this would better mimic waste molecules that need to be cleared from the brain. Nedergaard argues, though, that these injections would not only have damaged brain tissue, which could have interfered with normal processes, but that there are no glymphatic pathways connecting the site of the team's injections and the region where the tracer levels were evaluated. What's more, the team used a relatively small tracer molecule, rather than a larger, more biologically relevant molecule, such as amyloid beta, which has been used in earlier research in this area.

An important next step for all the teams working in this area will be to explore what happens in human brains, not just mouse models. If further work supports the new findings, and the brain's ability to clear itself of toxins is reduced rather than increased during sleep, this doesn't mean that poor sleep does not play a role in Alzheimer's. As noted by researcher Bill Wisden, director of the UK Dementia Research Institute, "it may well be that having good sleep does help to reduce dementia risk for reasons other than clearing toxins.

"The other side to our study is that we have shown that brain clearance is highly efficient during the waking state," Wisden added. "In general, being awake, active and exercising may more efficiently clear the brain of toxins."  

Read the paper in full:

Miao, A., Luo, T., Hsieh, B., Edge, C. J., Gridley, M., Wong, R. T. C., Constandinou, T. G., Wisden, W., & Franks, N. P. (2024). Brain clearance is reduced during sleep and anesthesia. Nat Neuroscience 27, 1046–1050. https://doi.org/10.1038/s41593-024-01638-y