Tuesday, February 24, 2015

A Beautiful Mind

by Naiyerah Kolkailah

When we’re sleep deprived, it’s not just outward beauty that gets compromised.

Our brains also take a big hit. We have trouble focusing, processing information easily, and remembering things. Sleep deprivation has actually been shown to negatively affect learning, memory, and cause seizures. It can even be fatal in extreme cases. Rodents and flies that didn’t get enough sleep died within days or weeks. Also, people who have insomnia can eventually get dementia if the condition is untreated, and they can die within months or years.

We know sleeping is vital, but the question of why sleep serves a restorative function for our minds has been a mystery for decades. One of the most recent findings on sleep is related to the process of waste clearance in the brain.

In our bodies, waste clearance takes place through the lymphatic system. The lymphatic system is a network of vessels that runs parallel to the cardiovascular system. While blood vessels deliver oxygen and nutrients to the tissues, the lymphatic system collects excess proteins and metabolic wastes that accumulate in the interstitial fluid (between cells) in tissues--and dumps them into the blood for degradation in the liver.

Take a look at the lymphatic system in the image above. You’ll notice that there are no lymphatic vessels in the brain. Unlike blood vessels that form a network within the entire brain volume, lymphatic vessels aren’t even present! The brain is a very metabolically active organ that produces large amounts of metabolic waste. Neurons are also very fragile and sensitive to toxic waste products. Some waste products can hinder synaptic transmissions or cause irreversible injury to neurons. With so much at stake, metabolic waste needs to be cleared efficiently so neurons can function properly. How does the brain manage without a lymphatic system? The answer lies in a unique waste clearance system reserved especially for the brain.

In the brain, there is a clean fluid known as cerebral spinal fluid (CSF). That fluid surrounds the brain, and receives waste products from inside the brain for eventual disposal. How do the metabolic wastes make their way out to the CSF? Instead of using another set of vessels in a tight space packed full of cells, the CSF itself gushes through the brain and washes out the interstitial waste products on the outside of the arteries.

Check out these images from a time lapse video of a living mouse injected with fluorescent CSF tracers.

The left frame shows blood vessels on the brain surface, and the right frame shows the blood vessels inside the brain.

Within a few moments, you can see CSF (fluorescent green) rushing in and coating all the blood vessels! The CSF starts appearing at the brain surface, and then makes its way into the brain.

All the blood vessels are coated within seconds! 

Now, are you wondering where sleep comes in? Ok, here it comes. The researchers who conducted this study (Xie et al.) showed that the influx of CSF that clears waste from the brain doesn’t just happen at any time. It only happens during sleep!

Here is a graph (left) showing CSF influx over a period of 30 minutes. The influx is significantly higher in mice that are awake (green) than mice that are sleeping (orange). The graph on the right compares the intensity of the tracer between the two states (sleep and awake). The graph shows that CSF intensity is significantly higher when the mice are sleeping than when they're awake.

The images below are from a time-lapse video showing the blood vessels (blue) in the brain of an awake mouse (left frame), and the blood vessels in the mouse when it sleeps (right frame). 

The CSF appears in red and coats the blood vessels, but only after the mouse falls asleep.

The researchers wanted to test if the sleep-wake cycle is what induces the CSF influx, so they conducted a similar experiment on anesthetized mice. They used Ketamine/xylazine (KX) to anesthetize the mice, and they found very similar results as in the natural sleep experiment.

The graph on the left above shows the CSF tracer increasing over time in the anesthetized state but not the awake state. The graph on the right shows that the intensity of the CSF is significantly higher in the anesthetized state than in the awake state.

The results of this second experiment show that it is the sleeping state itself (whether natural or anesthetically induced) that allows CSF influx into the brain. In another part of this study, the researchers found that during sleep, the interstitial space volume expands by over 60%. It is that expansion that allows CSF to effectively flow through the brain and clear out metabolic waste.

One of the most dangerous metabolic waste products that get cleared from the brain during sleep is Amyloid beta (Aβ). Aβ is a protein that accumulates in the brain when we’re awake, and it is linked to neurodegenerative diseases. Clinical studies have shown that Alzheimer’s patients who didn’t sleep well or didn’t get enough sleep had a buildup of Aβ in their brains. These studies show that the brain’s inability to clear out waste can contribute to the development of Alzheimer’s and similar neurodegenerative diseases.

Xie et al. wanted to compare the clearance rate of Aβ from the brain during sleep and during wakefulness, and they found that Aβ is cleared most efficiently during sleep.

The left graph above shows a time-disappearance curve of radiolabeled Aβ (I-Aβ) in three groups of mice: awake (orange), asleep (green) or anesthetized with KX (red). The curves show I-Aβ clearing at a faster rate in the sleeping and anesthetized mice than in the mice that are awake. The bar graph on the right gives the rate constant of Aβ clearance from the clearance curves. Aβ cleared twofold faster in the sleeping mice than in the awake mice, and there was no significant difference between the clearance rate in the sleeping and the anesthetized mice.

Figuratively, we know that sleep helps clear the mind. Now, this study shows how that clearance happens physiologically. Sleep is very precious! It’s essential. Make sure you get quality sleep to keep that beautiful mind of yours. Now, I’ll take my own advice so I don’t end up doing this.


Illif, J. One more reason to get a good night’s sleep (Video). Accessed from web Feb. 24, 2015. <http://www.ted.com/talks/jeff_iliff_one_more_reason_to_get_a_good_night_s_sleep?language=en#t-443069>

McKinley, J., A. McCarthy, and T. Lynch. 2013. Don’t lose sleep over neurodegeneration-it helps clear amyloid beta. Front Neurology 4: 206

Stickgold, R. 2006. Neuroscience: a memory boost while you sleep. Nature 444: 559-60.

Xie, L., H. Kang, Q. Xu, M. Chen, Y. Liao, m. Thiyagarajan, J. O’Donnell, D. Christensen, C. Nicholson, J.J. Iliff, T. Takano, R. Deane, M. Nedergaard. 2013. Sleep Drives Metabolite Clearance from the Adult Brain. Science 342: 373-377.


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