The Mysterious Flow of Fluid in the Brain

What’s more, during NREM sleep norepinephrine levels change rhythmically. This neurotransmitter could help tie together their hypotheses — the physical movement of CSF through brain tissues and the “brainwashing” occurring during sleep.

The team engineered mice in which they could switch the production of the neurotransmitter on and off. When norepinephrine levels went up, the volume of CSF in the brain went up, they saw, suggesting that it was somehow altering the fluid’s flow.

Then, to test whether the pumping of blood vessels could move CSF, the team engineered mice with blood vessel walls they could manipulate directly. Instead of pumping the vessels slowly, as happens naturally, they moved the walls quickly — once every 10 seconds rather than once every 50. “When we did this, we increased CSF flow on one side of the brain” in a very small area where they were pumping, Haugland said. “It was very local. … Everywhere else in the brain it was the same.”

For Nedergaard, Haugland and their collaborators, the findings tie together norepinephrine, the physical movement of blood vessels, and the flow of CSF in the brain. Nedergaard also asserts that the results are consistent with her group’s earlier finding that there is more brain drainage during sleep than during wakefulness.

“We have been searching for why the glymphatic [system] primarily works when we sleep for a long time,” Nedergaard said. “The paper is really about: Now we’ve found the motor or the driver of how we wash the brain when we sleep.”

However, to critics of the theory, there are still too many open spaces.

Under Pressure

McDonald, of the UCSF School of Medicine, pointed out that the work is complex and requires many intricate methods. However, he’s concerned that Nedergaard is working backward: seeking an explanation for her hypothesis rather than trying to find out how the system actually works. “In this paper, it’s unclear what is interpretation and what is data,” he said. “Very early on, their interpretation gets substituted for what actually are the data.” He pointed to schematics showing flow dynamics that he doesn’t see supported, for instance.

Proulx questioned whether the tracer dye moved via an active force at all. The molecule is so small that it could be traveling by diffusion, he said. He imagines an experiment, using techniques Nedergaard’s lab has used before, where a large molecule is infused into the CSF. If the rhythmic releases of norepinephrine correlate with the arrival of a larger tracer at a sensor on the brain’s surface, that would be a fascinating finding. “That’s what I would have liked to have seen,” he said. To his eye, it would make a clearer connection between fluid flow and norepinephrine than the lab’s work has shown thus far.

The critiques of Nedergaard’s work come on strong in part because this idea is currently the most prominent hypothesis of CSF flow in the brain. That may change if other researchers can introduce other ideas that can be tested. Another wrinkle is that not everyone means the same thing when they talk about the glymphatic system. “Some people use ‘glymphatics’ to mean ‘waste transport system of the brain.’ Other people use it to mean a really specific mechanistic model,” Lewis said. “It’s clear that the brain has and needs a waste clearance system. … It’s really interesting to explore what that is and how that works.”

Haugland, now a postdoc at the University of Oxford, is aware of the controversy about the glymphatic hypothesis. “There is critique of it. I’m also not sure that we understand it in the right way,” she said. “The more people who are actually working on finding out how it works, no matter what their hypothesis is — all that will help drive the field forward and give us more knowledge.

“The results are what they are. They show something about the biology,” she continued. “We are trying to ask a lot of questions and we’re not, maybe, all the time very good at it because we don’t know how it works — the big picture.”

“Nobody has the truth,” Proulx said, about what the brain is doing up there, in our skulls, to rid itself of its waste. “Some people think they know. But I think we don’t know.”

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