Got Glymph? Waste Management During Sleep

Maria M. Hadjimarkou, PhD. Lecturer School of Psychology University of Sussex

Our brains and bodies are rather complex, and no matter how much we learn about their structure and function, we are still on that learning curve. Every new discovery reassures us of this complexity and wonder. Today I will be discussing one of these new discoveries and its relation to sleep and health.

We often hear that our bodies are about 70% water. Amazing, but where can this water be found?  The easiest guess would be in the blood, because blood circulates in our arteries and veins, and is pumped by our hearts. Water can also be found in all the cells that make up our bodies and brain, and in the spaces in between. 

In the brain and spinal cord, there is a watery substance called cerebrospinal fluid or CSF for short.  The CSF is produced in the brain at a steady rate each day.  Perhaps you are familiar with the CSF if you had a lumbar puncture. With this test, the doctors withdraw a small amount of CSF found around the spinal cord. Based on the chemicals in the CSF, doctors can decipher things about the brain. Our brains are also surrounded by CSF, in the space between the brain and skull, so in essence, the brain is always bathed in CSF all around, providing a buffer, a cushion that protects it from abrupt movements such as falls and hits. If CSF was not there, our brains would hit the skull and get damaged both at the point of impact (coup) and also at the point right at the opposite side (contrecoup). The CSF also circulates within four interconnected chambers in the brain known as ventricles, the larger being on each side as opposed to the third and fourth ventricles which are smaller and found in the centreline (see picture). 

Last month, I discussed sleep’s contribution to the immune system and mentioned that during sleep, lymphocytes accumulate in the lymph nodes.  The lymph nodes are part of the lymphatic system, which consists of tubules throughout our bodies, but not the brain, that ‘wash’ out our bodies from different chemicals that are not needed so that they can be metabolised by the liver and excreted. 

It turns out that a similar system exists in the brain, discovered as recently as 2012. This system flushes CSF from the perivascular space, the space around the arteries, through the brain tissue and out towards the perivenous space, the space surrounding the veins, before it drains into the periphery via the cervical lymphatic system around our necks. As the CSF is flushed through the brain tissue, it carries metabolic waste and potentially neurotoxic proteins including a protein called amyloid beta, which has been associated with Alzheimer’s disease, although a causal connection is yet to be established. The moving CSF also helps to transfer useful things, such as nutrients and minerals.

This movement of CSF through brain tissue is made possible by special pores, water channels found on glial cells. Glial cells are different types of cells found in the brain besides neurons. For a long time, glial cells were considered to be passive, without any significant role in the function of the brain but recent discoveries have changed this view.  There are different types of glial cells. The ones that contribute to the flushing of waste are called astrocytes, or ‘star-like’ cells because of their shape.  The astrocytes are strategically positioned around the arteries and veins of the brain and with these aqueous pores, they push the CSF through the brain, carrying with it waste. The flow is partly driven by the pulsating arteries, coupled with the beating of the heart and breathing. Because of the role of glial cells and its similarity to the lymphatic system, this brain-based clearance system was named the glymphatic system.  If you have lived in other parts of the world, you may have noticed that garbage collection takes place at night or early at dawn, before people are out and about trying to get to work, school etc. A similar mindset in scheduling is followed by the brain.  The glymphatic system is mainly active during sleep, especially during slow-wave sleep (SWS) which peaks in those first few hours of the night. During that time the activity of the glymphatic system is 90% greater compared to its activity during the day. When we sleep the space between the cells in the brain increases, which facilitates the movement of the CSF even more. During SWS, when the brain and bodily functions are slowing down is the optimal time for flushing out these metabolites and neurotoxic waste that accumulates during the day.

Sleep deprivation in both animals and humans, even for a single night, leads to increased accumulation of waste, including amyloid beta, suggesting a greater risk for Alzheimer’s and other neurodegenerative diseases in sleep-deprived individuals. It is important to note that many of these diseases (Alzheimer’s, Parkinson’s, etc.) have in common the accumulation of proteins in the brain, but their cause remains elusive.

Even though the greatest risk factor for dementia and other neurodegenerative diseases is age, there is a strong association between sleep disturbances, evident long before the development of other symptoms. Also with ageing, there are increases in sleep disturbances and a shift towards lighter sleep compared to younger individuals. This drop in the quality and depth of sleep may be a significant contributor to the reduction of solute clearance via the glymphatic system.

Besides the shift to lighter sleep, with increasing age, there is redistribution of the pores on astrocytes that form the outgoing current that compromises its efficiency, a decline in CSF production, but also a possible stiffening of the arterial walls that provide the pulse needed to propel the CSF. Similar changes have also been observed following traumatic brain injury. 

The discovery of the glymphatic system has advanced our understanding of the brain and has opened up new possibilities in the way that we can perhaps intervene therapeutically to tackle challenging diseases. More importantly, this discovery has highlighted our ability to prevent disease, simply by allowing time for sleep and by maintaining healthy arteries, to support the glymphatic system.  We are empowered! We may not fully understand all the functions that sleep serves, but we can be certain, that one of these functions is the clearing of brain waste.

Key References:

Iliff JJ, et al. (2012). A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med.,15;4(147):147ra111. Nedergaard M, Goldman SA. (2020) Glymphatic failure as a final common pathway to dementia. Science. 2;370(6512):50-56. Xie L, et al (2013). Sleep drives metabolite clearance from the adult brain. Science. 18;342(6156):373-7.