That Glymphatic Flow

Today, we look at how the brain’s detox mechanism, the glymphatic system, works, and more importantly, what we can do to make it work even better.

And, one function of the glymphatic system is the clearance of toxic waste byproducts.

Sleep is a great mystery. A trait shared across animal species, sleep must be of vital importance to survive natural selection pressures to eliminate such a vulnerable state. Indeed, cringeworthy experiments have shown that keeping animals awake long enough can be fatal within eleven to thirty-two days. It turns out “[s]leep is of the brain, by the brain, and for the brain.” One function of sleep that has been elucidated in recent years is the clearance of toxic waste byproducts through a newly discovered drainage system in the brain.

With the invention of the encephalogram (EEG) to measure brain wave activity, the scientific world was quickly disabused of the notion that sleep was a time of rest for the brain. During certain stages of sleep, there was brain-wide activity going on, but what was the brain actively doing? More than 2,000 years ago, Aristotle proposed that sleep helps the body clean the blood. Today, we know sleep may help the body clean the brain.

Until 2012, we thought that the brain was singular among organs for recycling nearly all of its own waste. It had to, since it was separated from the rest of the body by the blood-brain barrier. But the barrier that keeps toxins out of the brain presumably keeps toxins in. Then, in 2012, a brain-wide fluid transport network was discovered, termed the glymphatic system.

By microscopically tracking dye injected into the brains of mice, scientists discovered fluid-filled tunnels surrounding blood vessels in the brain. The pressure wave of arterial pulses with every heartbeat milks the fluid along before eventually draining into the cerebrospinal fluid surrounding the brain. What does this have to do with sleep? The whole system is only really active when sleeping; during wakefulness, these tunnels are clamped down, reducing glymphatic flow by 90 percent. The thought is the fluid shifts might interfere with targeted neurotransmitter chemical communication in the awake state. So, the biological need for sleep may reflect the need for the brain to enter into a state to filter out potentially neurotoxic waste products, like beta amyloid, which is implicated in Alzheimer’s disease.

Perhaps this could help explain why those who routinely get fewer than seven hours of sleep a night are at increased risk of developing cognitive disorders, such as dementia. Randomizing individuals to have their sleep disrupted by a series of beeps administered through headphones in a sleep lab increases amyloid levels, whereas improving sleep, by treating sleep apnea patients with CPAP, for example, improves slow wave activity—deep sleep—and appears to lower amyloid levels. PET scans show even a single all-nighter can cause a significant increase in accumulation of beta amyloid in critical brain areas.

The problem is that glymphatic brain filtration appears to decline with aging. Old mice only have 10 to 20 percent the glymphatic function of young mice. This could be due to a number of factors. As we age, we experience less of the deep, slow-wave sleep, the type of sleep during which brain waste clearance appears to be most active. Further contributing to the stagnancy, our arteries tend to stiffen as we age, reducing the pulsations that drive the glymphatic pump. That also offers one potential explanation as to why hypertension is tied to dementia. The thickening of artery walls with high blood pressure also has a stiffening effect. How can we counter this age-related glymphatic decline and keep our brains cleaner? We’ll explore just that question next.

What can we do to prevent the decline in glymphatic brain filtration as we age?  Let’s find out.

Other than getting enough sleep, what can we do to improve the glymphatic clearance of waste from our brains? The provision of a running wheel, so mice could voluntarily exercise, has been shown to improve glymphatic clearance in aging mice, which was accompanied by a reduced build-up of amyloid deposits and improved cognition. Sleeping position may also make a difference.

Studies on rats show that their natural sleeping position, curled up on their sides, allows for better glymphatic transport than sleeping on their backs or stomachs. People also tend to spend most of their time sleeping on their side, particularly their right side versus left, compared to their backs or stomachs. This may maximize blood outflow from the brain. When we sleep on our right side, our right internal jugular vein—the main blood vessel in our neck draining blood from the head—is wide open, and our left jugular is partially collapsed, and vice versa. Since most people have a dominant right jugular vein, sleeping on their right side might maximize brain drainage. Does it matter? Well, people with neurodegenerative disease, mostly mild cognitive impairment and Alzheimer’s disease, tend to sleep more on their backs than those with normal cognition. About 72 percent spent at least two hours a night on their backs compared to 37 percent of those with healthier brains, raising “the intriguing possibility that head position during sleep could influence the clearance of neurotoxic proteins from the brain.”

In crib death, sudden infant death syndrome, sleeping position can be a lifesaver, leading to slogans like “back to sleep,” or more morbidly, “face up to wake up.” It’s premature for an adult jingle. (Maybe “on your flank to not draw a blank?”) The characteristic position of poor sleepers is on their back though. So, maybe it’s the poor sleeping rather than the position per se that leads to cognitive decline. Or, the causality could be reversed, with dementia deteriorating good sleep habits. Even if sleeping position did matter, it may take a night in a sleep lab to track your movements. It turns out self-reported sleep positions are often false. Should brain benefits to side sleeping ever be established, you can train yourself with so-called “positional therapies,” such as the “tennis ball technique,” which involves wearing a shirt to bed backwards, with a ball stuffed in the chest pocket.

The uncertainties don’t end with sleeping position. The glymphatic mechanism itself was rapidly embraced in scientific circles and the popular press; however, it’s been controversial. It wasn’t until 2019 that the first evidence was published that the glymphatic system discovered in rodents even existed in human brains. Even the relationship between sleep and Alzheimer’s disease is perhaps best summed up in a recent neurology review entitled “It’s complicated …” Yes, those getting less than seven hours of sleep may have higher rates of dementia, but those getting more than eight are at higher risk too. If anything, population studies show that longer sleep durations (more than eight or nine hours) are more strongly linked to Alzheimer’s disease and dementia in general than sleeping less than five or six hours.

The association between dementia and long sleep duration could be reverse causation, where prodromal changes in the brain years before Alzheimer’s is diagnosed cause prolonged sleep. Long sleep duration may also just be a confounding factor, a marker of some underlying health problem that is the real culprit. For example, oversleeping may be a sign of depression, which itself is an established risk factor for dementia. But there is a plausible biological mechanism for how extended sleep duration could increase dementia risk directly. Longer sleep duration, typically defined as sleeping more than eight hours a night, is associated with signs of systemic inflammation––elevated levels of C-reactive protein and Interleukin 6. And, both of those inflammatory markers, in turn, are associated with an increase in dementia risk. So, much more needs to be teased out about the role of the glymphatic system before we make conscious efforts to tweak it.