What the past decade of glymphatic research tells us about sleep and its important implications for brain health

The brain: whether you give it credit or not, the soft gelatinous mass floating in your skull is responsible for life as you know it. At this moment, your brain is simultaneously maintaining your breathing and heart rate, while turning these black squiggles on a screen into coherent words and thoughts.

The brain is a workhorse and a hungry one at that. While accounting for approximately 2% of the average adult’s weight, it accounts for 20% of its energy consumption, more than any other organ.

Go ahead and give your brain a mental compliment and then think about how meta that was.

Fascinated yet? You’re not alone. Neuroscience research is booming. Growing interest and funding for neuroscience research has given rise to a burgeoning field of interdisciplinary neuroscience that ranges from clinical studies in neurodegenerative and behavioral disorders to basic science studies characterizing brain structure and function at the molecular level– and all this is for good reason.

Neuroscience research has grown consistently over time. (Yeung et al., 2017, Frontiers in Neuroscience)

In 2014, just nine common neurological diseases (Alzheimer’s and other dementias, chronic lower back pain, stroke, TBI, migraines, epilepsy, MS, TSCI, and Parkinson’s) were estimated to cost the American people almost 800 billion dollars, a number that has only increased over time. And despite the abundance of sensationalist reporting that might suggest otherwise, there is currently no panacea for a sick brain.

Yet the research does suggest that quality sleep, among other factors, generally improves brain health and we’re only just starting to understand why.

Breaking into the black box of sleep

Sleep is quite mysterious. Even today, we aren’t completely sure about the true evolutionary function of sleep. Yet surely, it must be important as most mammals die after more than a week of complete sleep-deprivation. So what is really going on behind the scenes?

With the exception of a few brief exciting and oftentimes bizarre dreams in REM sleep, our experience of sleep seems rather boring. While Drake and friends may think they are ‘out like a light’ when they fall asleep, the light is, in fact, still very much on. The “sleeping” brain is still firing, sending electrochemical signals and using lots of energy, particularly during REM sleep.

Previously, sleep research relied heavily on measuring electrical activity on the surface of the brain using EEG or measuring blood flow using fMRI. These tools are popular because they are non-invasive, but they lack the detail that would come from looking at a brain sample after death.

The advances in newer methods such as two-photon microscopy allow highly-penetrant, in-vivo imaging in a precise focal plane. In other words, you can look through the skull to observe microscopic brain structures in alive, sleeping subjects in real-time. How neat is that?

These methods have allowed sleep researchers to make some truly breathtaking discoveries, but before you get woke to some to these rousing findings, let’s take time to review some relevant Neurophysiology 101.

Neurons: the classic nervous system cells that propagate electrochemical signals through action potentials and release of neurotransmitters

Glia: the non-neuronal nervous system cells that keep neurons healthy

CSF or cerebrospinal fluid: the fluid that your brain is suspended in

Arteries: blood vessels carrying blood toward an organ

Veins: blood vessels carrying blood away from an organ

Creating divided traffic and discovering a new path

In an elegantly-designed experiment published in 2012, scientists injected a fluorescent tracer into the CSF of mice to follow its flow. Interestingly, the tracer appeared to be following the network of arteries carrying fresh blood to the brain.

However, the tracer wasn’t in the arteries, just around them. What they eventually found was that the CSF was flowing in the space between the outer walls of the arteries and the surrounding glial cells. If you can imagine putting a smaller pipe into a larger pipe, allowing two distinct fluids to flow in parallel along the same network, you’ve begun to understand periarterial flow.

Arteries are shown in white; tracer paths are in color/green arrows. (Mestre et al., 2018, Nature Communications)

In reality, periarterial spaces look less like donuts and more like eyes. (Tithof et al., 2019, Fluids and Barriers of the CNS)

In addition to the pressure gradient that keeps the fluid moving, the pulses of blood in your arteries also help push the CSF along.

This CSF moves into the water surrounding cells, or interstitial fluid, and washes over them, delivering nutrients and clearing away harmful cellular waste products. It then travels through perivenous spaces, which surround veins, to be dumped into lymphatic vessels where the waste is filtered out.

This, in short, is the glymphatic (glial lymphatic) system and it acts as the brain’s sewer system. Surprisingly, it was discovered just seven years ago by Dr. Maiken Nedergaard’s group at the University of Rochester Medical Center.

A journey through periarterial, interstitial, and perivenous spaces. (Plog and Nedergaard, 2018, Annual Review of Pathology)

Why sleep matters

Perhaps the most interesting quirk about the glymphatic system is that it is only active during sleep. The perivascular tunnels are tightened during wakefulness, limiting CSF flow; this change is likely mediated by norepinephrine, a neuromodulator that is abundant only in wakefulness.

Several studies have shown that as you sleep, the glymphatic system is clearing your brain of neurotoxic substances that have accumulated throughout the day, including amyloid-beta, the protein that forms the characteristic plaques in Alzheimer’s. In a vicious cycle, impaired glymphatic function increases the accumulation of amyloid-beta, which in turn limits CSF influx through the glymphatic system.

And indeed glymphatic efficiency is impaired in the brains of current models of Alzheimer’s disease and generalized aging, although the possibility of a causal relationship presents a less-clear, chicken-or-egg-first type of question.

Fortunately, more people are coming around to the idea that sleep is not a luxury. There is strong evidence for how sleep affects learning, obesity, hypertension, insulin sensitivity, and you don’t need a peer-reviewed article to tell you that sleep affects your mood.

For many young people, not getting enough sleep is no longer a humblebrag for an industrious work ethic, but rather a mark of neglect for one’s well-being. Yet, while surveys suggest that Americans are getting slightly more weekday sleep than in previous years, only 10% of respondents said they prioritize sleep over fitness, work, or their hobbies.

Good hygiene comes in many different forms. Regularity in keeping your hair, teeth, sheets, and home clean are (hopefully) already part of your routine.

It just might be time to add your brain to that list.