Brain clearance is reduced during sleep and anesthesia, 2024, Andawei Miao et al

Abstract
It has been suggested that the function of sleep is to actively clear metabolites and toxins from the brain. Enhanced clearance is also said to occur during anesthesia.

Here, we measure clearance and movement of fluorescent molecules in the brains of male mice and show that movement is, in fact, independent of sleep and wake or anesthesia. Moreover, we show that brain clearance is markedly reduced, not increased, during sleep and anesthesia.

LINK

 

Our experiments show that brain clearance is reduced during sleep and anesthesia, the opposite conclusion of ref. 3. Those authors observed that fluorescent dyes injected into the cerebrospinal fluid (CSF) via the cisterna magna penetrated further into the cortex during sleep and anesthesia. They interpreted this as showing that molecular movement into the cortex must be faster during these states. However, the concentration of dye in any brain region will always be the difference between its rate of arrival and its rate of departure and so increased dye penetration in sleep and anesthesia can be equally well explained by a reduced rate of clearance rather than an increased rate of entry. Indeed, almost all the experiments that have been interpreted as showing that sleep or anesthesia change brain clearance have involved introducing markers into the CSF, which then move into the brain parenchyma14,26,27,28,29,30. Under these circumstances, entry, exit and redistribution of the marker are all occurring simultaneously, greatly confounding any quantification of clearance.

 

Could that specific marker be cleared differently than the usual waste molecules? Maybe it's binding to cells more or less during sleep or cognitive activity. It's even possible that the molecule can be altered in-situ, so its rate of departure can be different from arrival. If I eat apples, the rate of departure of apples is not the rate of arrival of apples. Depending on the molecule, it could even get masked (non-fluorescent) partway through its travels, or transfer the fluorescing part to a different molecule.

 

CSF isn't going to be a route for metabolite clearance anyway - that would be via reabsorption into blood vessels.

The whole thing seems a lot of confusion - as the authors of this current paper point out.

 

If blood flow out of the brain was reduced could that cause issues?

 

Blood flow out of the brain is always the same as blood flow into the brain. If it is reduced, metabolite clearance is likely to be at the same rate but driven by a slightly higher local build-up concentration.That higher concentration could cause issues.

 

That makes sense. Maybe it's possible for there to be temporary differences in blood flow in and out but after a while the blood would force its way out of the brain or something would break. When blood pools in the hands and feet presumably there is a temporary difference in blood flow to and from these areas. If this sort of thing did happen would the additional pressure in the brain also potentially cause issues in addition to the higher concentrations?

 

Sleep is actually quite interesting e.g. I think genes associated with sleep turned up in a Long COVID genetics study - check out the PrecisionLife presentation at the UniteToFight2024 Conference.
Being able to measure brain clearance would be useful - may provide an insight into ME/CFS.

 

Blood cannot really build up in the brain because it is in a closed bone box filled with non-compressible fluid. Pressure rises very quickly if blood is not flowing out. There are rare situations where outflow is slow, such as sagittal sinus thrombosis, but there is no indication of anything like that ever happening in ME/CFS.

I think is vanishingly unlikely to be an issue.