November 11, 2026 by Haley Hansen, PT, DPT
Steve Kerschke: We’re having a little bit of banter. It’s been a couple months since we’ve had webinars, but we’re excited about the lineup for 2025. We’ll be offering 10 new webinars and this first one on the glymphatic system. I know, Jeff, you said it’s going to be a little bit in the weeds, which it might, but I’ve heard this presentation before.
Jeff Snell: Deep in the way.
Steve Kerschke: Absolutely. I’ve heard this presentation before, and the fact that we have a relatively new system, which you’re going to talk to us about was really interesting to me. So hopefully all of our listeners like it. Before we turn it over to Jeff, we will do some housekeeping. So Jeff, we can just flip over. Just quick overview of QLI. Those of you who are attorneys, thanks for joining us again. We always love seeing familiar names. We wish we could see your faces. Those of you who are new to our webinars, these are put on by QLI. We’re based in Omaha, Nebraska. We have a post-acute rehab program. We also have an outpatient telerehab program. For us, it’s really a nice continuum for folks coming usually after a hospital stay. And with our telerehab services, we can help folks as they transition back into the community. So it’s been a really nice part of our program.
Jeff Snell: Steve, I take it that picture was not taken this morning, is that correct?
Steve Kerschke: No, definitely not this morning, Jeff. This is in the summer. So we specialize in brain and spinal cord injury. We have a small chronic pain program. Really anything acquired and we have a limb loss program. So just a little quick blurb about us. Some housekeeping. One of the biggest reasons I know that you all show up other than the information is to get your CEUs. We’re happy to provide CEUs for CCMC only. So those of you who are not CCMC, we apologize, but here’s your disclaimer now. But we do just ask that you spend the majority of the time on the presentation. There will be one poll question. We will denote that at the very end. After Jeff’s presentation, there’ll be a slide dedicated to the polls question. It will pop up on your screen. You just have to answer it. And then upon clicking leave webinar, you will get a popup to submit a survey, and that’s how you get your CEUs.
Your CEUs as well as the slides will be delivered to you automatically after that. We do get folks who sometimes either miss it on the way out or usually it’s on your end in terms of your filters for your web browser or whatever your system is. Let us know if you have issues with that. We’ll get you taken care of. All right, with that, Jeff, let’s talk about the glymphatic system.
Jeff Snell: Thank you very much, Steve. This presentation glymphatic system and how it ties in with sleep, to me, I will tell you I have really enjoyed putting this presentation together because this is something that is relatively new. So if you have not heard of this before or this is something that you are not highly familiar with, don’t be surprised because this is something that really is just coming out over presentations and conference information just within the last few years. The role of the glymphatic system is to maintain a healthy environment within the central nervous system and involves both the delivery of and the removal of substances within the central nervous system. Now, as we’ll talk about, the history of this discovery goes way back before 2012, but that’s when the system was first named and when research really started to catch on and started to detail how this system works.
This term glymphatics was coined in 2012 by a Dutch neuroscientist who at the time was at the University of Copenhagen, Megan Nedegaard. And she had found a largely forgotten paper from 1985 which stated that the cerebral spinal fluid was transported rapidly into the brain along a channel network that surrounded the entire vasculature. The reason this had not caused a bigger stir in 1985 is that other scientists had never replicated that study. That published study was not replicated mostly because those who attempted to do so either used different processes or different animal species in attempting to replicate the original findings. But Dr. Nedegaard and her team successfully reproduced those findings by using state-of-the-art optical imaging techniques and fluorescent dyes rather than surgical procedures. They administered dyes into the cerebral spinal fluid in brains of mice, and then they traced the path followed by that tagged fluid.
You can actually see a presentation by Dr. Nedegaard on YouTube in which she presented their lab findings, and that was in 2018, so not very long ago. Now, the involvement of the cerebral spinal fluid in clearing waste products and circulation within the brain of cerebral spinal fluid has been known for well over a hundred years. The anatomy involved has been known even further back, back to 1851. But the discovery and detailing of the exact mechanism of the structures involved is a relatively new phenomenon, and it highlights the fact that new discoveries about the brain are an ongoing result of new and better tools of investigation. Every time they come out with a new tool for looking at in vivo processes within the body, we find out new things. I absolutely love learning something new and even more so when it involves the brain. So I have really been geeking out over the information that’s been coming out over glymphatics.
So since we’re talking about waste disposal in the brain, let’s start with a more familiar concept, and that is waste removal in the body. Within the body, we have a lymphatic system, a lymph system that is our primary waste removal system. In this image, the red blood vessel on the left is an artery supplying cells of our body with fresh blood, carrying oxygen, carrying nutrients. These are released and utilized by ourselves through capillary exchange. At this point, the fluid carrying oxygen and nutrients diffuses or leaks into the interstitial fluid, interstitial meaning the fluids surrounding our cells. In addition to providing a delivery service for oxygen and nutrients, this capillary exchange also includes filtration of waste products from that interstitial fluid, waste products that have been released by the cells. The lymph capillaries are part of this system and the means by which those waste products are collected.
From there, the collected waste are passed through various lymph nodes and lymph vessels, further filtering out unwanted materials such as bacteria and damaged cellular components. Eventually, this lymphatic fluid drains into the right and left subclavian veins where the then cleaned fluid is returned into the circulating blood. So basically the glymphatic system is similar in purpose to the lymphatic system, but it operates along a slightly different mechanism. This is just another example of the many differences between the physiological processes that exist throughout the body and that have a similar but separate system within the central nervous system. Rather than a dedicated organ system of lymph fluid nodes and vessels within the brain, this job is accomplished by cerebral spinal fluid in the spaces immediately adjacent to the arteries and veins. Glial cells, glial cells, those support cells that are critical in so many different functions within the brain are primary informing the membrane that regulates the permeability and flow of cerebral spinal fluid within the glymphatic system.
And so that’s really how it got its name. Dr. Nedegaard coined that term because it is the glial cells forming what is the equivalent of a lymphatic system. So glial and lymphatic becomes glymphatic.
Now, it makes sense that the brain would have a similar system given that our brain tissue is made up of cells that require oxygen, that require nutrients, and also produce waste products and have a need to transport those waste products out. There’s also a need to transport any damaged tissue components out, which will be important when we talk about the relationship between neurological damage and the glymphatic system. A search of the scientific publications database, PubMed, reveals that the first article reporting these discoveries that used the term glymphatic was published in 2013. Now, since that time, a huge volume of research has further investigated this system. I actually did a search on the term glymphatic yesterday afternoon and it returned a total of 2022 articles or scientific reports that have now been published referencing this word. When I first developed this presentation probably about seven or eight months ago, that number was around 1,500.
So it just shows you this is a blossoming area of brain research. Like most physiological scientific discoveries, advances in imaging tissue has been a necessary component. From microscopes to the most advanced current medical body scanning technology, every time you get new tools, there’s a capability of new discoveries. The detailed description and mapping of the glymphatic system has been heavily dependent upon advances in highly detailed in vivo or live subject imaging, first in animals and then more recently in humans.
So let’s talk about the primary components that make up this glymphatic system. First, there’s cerebral spinal fluid, often simply abbreviated as CSF. This is a fluid that is largely produced from the lining of the ventricles within the brain, left and right ventricles being the largest, and then third and fourth ventricles that are along the path that the fluid takes to exit the brain. That fluid surrounds the brain.
It helps provide buoyancy so that the relative weight of the brain is somewhat neutralized within the skull. It also provides some degree of protection in the form of cushioning against minor blows to the skull that protect the relatively vulnerable brain tissue inside. That fluid also surrounds and helps protect our spinal column. The tissues deep inside your brain lining the ventricles produce cerebral spinal fluid as a rate of about half a liter per day, about 500 milliliters. That’s just over a pint in our measurement. There is individual variation in this production and absorption of cerebral spinal fluid, but given that our central nervous system has on average around 125 to 150 milliliters in it at any given point, that means the supply of cerebral spinal fluid is completely replaced or turned over about four times a day. You can see in this image a representation of the pathway that the cerebral spinal fluid takes from those ventricles out around the brain and down the spinal column.
It circulates around the brain within the arachnoid layer of the meninges. That’s the middle layer of the three layers that make up the meningeal covering of the brain. The outermost layer is the dura matter, Latin for tough mother. Then there is the arachnoid layer, referring to the fine spiderweb looking appearance. And lastly, lying directly on the surface of the brain is the pia matter, Latin for tender mother, a very delicate tissue. The porousness of the arachnoid layer is filled by cerebral spinal fluid and provides that cushioning of movement that helps minimize to the degree physiologically possible sudden movement resulting from minor impacts. It helps dampen the inertial movement of the brain inside the head when the skull is struck or bumps up against something. We like to think of it kind of as the brain’s bubble wrap. It protects against minor impacts, but it can’t deal with every level of force.
Cerebral spinal fluid enters the brain by way of the paravascular spaces, space immediately adjacent to the vasculature and enters the brain tissue around the arteries of the brain. It flows between and around the cells within the cortex of our brain and spinal column within that arachnoid layer that completely envelops our central nervous system. From there, cerebral spinal fluid enters the brain and flows between the cells of the brain. Now, this is another instance in which mechanisms within the body and the brain diverge somewhat. The space between the cells of our body, everything outside of our central nervous system is called the interstitial space, interstitial meaning the intervening space. In our body, this interstitial fluid is a substance primarily composed of water and dissolved components, which is eventually essentially a filtered version of blood plasma. Within the central nervous system, there are similar but separate and different processes.
And within the CNS, cerebral spinal fluid is the interstitial fluid. It’s almost identical to blood plasma, but it is a separate and relatively closed circulatory system. It is closed off from the body by way of the blood-brain barrier, something largely made up of astrocytic infeed cells that we’ll be talking about, and that prevents bacteria and large molecules that may be within our circulatory system from entering the brain. It keeps our brain fluid as a relatively clean space. The space around our vasculature through which the cerebral spinal fluid flows into the brain is formally called the Verkaubin space after a German physician who was the first to provide a detailed description of these microscopic spaces back in 1851 and a French anatomist, Charles Philippe Rubian, who confirmed these findings in 1859. So these channels, these pathways have been known a long time. Steve, these are the weeds that we were talking about earlier.
We are deep in the weeds at the moment. You don’t need to remember all these names. Just know that cerebral spinal fluid is contained within a layer of tissue that surrounds our entire central nervous system vasculature. It’s distributed and collected from all the places that blood flows within the brain, and that means everywhere. This image represents the major blood vessels that distribute oxygen and nutrient carrying blood throughout the brain. From there, now those are just the major vessels. From there, it passes to even more fine arteries and capillary networks. So this is what the blood supply within the brain looks like if you took out all the brain tissue, that’s just the blood supply. It is really, really complicated when you add all those little pieces together. The brain utilizes over 20% of the oxygen that we breathe in, even though it makes up only one to 2% of our body’s mass.
And this is the network that makes sure that all those oxygen-hungry brain cells get the energy that they need. Oxygen and nutrients go to the cells, and then waste products of those cells need to be collected and moved out of the brain. All of this vascular network is mirrored by, encased by the glymphatic system.
Now, the space around the vasculature that supply blood to the brain, known as the paravascular space, in this case, the paravascular arterial space. If you see on the left, that figure, the A and the arrow up at the top, that refers to the arachnoid layer, the subarachnoid space is the SAS, and then that fine matter that I talked about other, the pia matter that lies on the surface of the brain is below there. That pia matter below that pia matter is where cerebral spinal fluid flows, including down into the penetrating artery that project into the outer layers of the brain, into the cortex of the brain.
So these arteries that are supplying blood to the brain are surrounded by a secondary process through which this cerebral spinal fluid can flow down into the brain.
The space around the veins are the paravascular venous space. In this representation here, you see fresh blood being brought in through the artery with a reddish color, and then that blood that flows out of the brain by way of the vein, they’re in a bluish color. That interstitial space then in between the artery and the vein is where flows cerebral spinal fluid. Here you see cerebral spinal fluid with a kind of a yellow orangeish color. It exists within the subarachnoid space. It flows down into the cortex via the paravascular space, then it flows out of that channel and into the interstitial space. It transports oxygen to the cells. It takes waste products away from the cells, and that then flows out by way of pathway around the veins of the brain.
Astrocytes, these are a primary component of what makes up the cellular system that we call that glymphatic process. Astrocytes are a type of glial cell within the brain. They’re one of several support cells of the brain. We have astrocytes, oligodendrocytes, microglia, and epidiamal cells within the brain, but particularly astrocytes are very involved in a lot of functions. They serve as a link between the blood supply and the neurons. They regulate blood flow. Astrocytes can actually monitor neurons and increase or decrease the amount of blood flow to that particular neuron. They can also upregulate and downregulate neurons through direct action as well. They can regulate and upregulate and downregulate synaptic activity, actually making the neuron more or less able to fire off a signal. And astrocytes also communicate with and likely control actions of other types of glial cells. So astrocytes are extremely important cell type within the brain.
In the context of the glymphatic system, astrocytic end feet form the outer wall of the paravascular space. The end feet side by side form that wall. In this cross section, you can see how they surround the vasculature. These are the end feet of the astrocytes on either side of a vein, the astrocytes here that surround an artery. So those feet join up against each other and they form the wall that is relatively impenetrable unless they want to let something through. Again, blood-brain barrier is largely made up of astrocytic end feet. So they surround the vasculature. Those end feet have channels through which cerebral spinal fluid can flow. Those channels are called AQP4 or astrocytic aquaporin-4 channels, and they facilitate fluid movement into and out of the interstitial space. Astrocytes are a type of glial cell, again, support, and you can see how there they surround the cell.
So they form a pipe around a pipe. The artery itself, if you think of it as a pipe that supplies fluid, that supplies blood to the brain, the astrocytes form a more rigid pipe there around the outside of that.
Now again, astrocytes are as the heart pumps, astrocytes form this rigid wall outside of the artery, and you know that arteries, they have a degree of elasticity to them. As the heart pumps, a pulsile wave moves forward through the artery and it provides a mechanism by which cerebral spinal fluid within the paravascular space is pumped forward as well. Now you know that you can take a pulse by resting your finger on an artery in your wrist and you can feel that pulsile action. That pulsile wave moves from the heart outwards all the way to the capillaries, and then veins have a relatively passive role in draining that blood forward.
The veins don’t have that active pumping mechanism. It is simply passive pressure differentials that allow the veins to retrieve that blood back to the heart so that it can be sent to the lungs. So blood is pumped by the heart muscle, but there’s no such pump specific for cerebral spinal fluid. Cerebral spinal fluid is an indirect pumping action resulting from the compression of that available paravascular space. As the pulse of blood in the artery causes expansion of the elastic arterial walls, that squeezing action of expanding and forward moving pulse effectively pushes cerebral spinal fluid in the surrounding relatively inflexible chamber around that artery formed by astrocytic infeed. So you can think of an elastic hose inside of a rigid pipe. So as a bolus pump moves through that rigid pipe, it’s going to push fluid that surrounds that inner elastic hose forward, and that is the process by which cerebral spinal fluid is pushed into the brain.
This drives the differential pressures necessary to make the system work. Cerebral spinal fluids being pushed into the brain tissue in a one-way path along the arteries, flows into and around the cells of the brain, and then that flow follows a one-way path out of the brain and into the paravascular space around the veins.
How are we doing so far, Steve? Hanging in there?
Steve Kerschke: Hanging in there, Jeff.
Jeff Snell: Okay. All right. So this cerebral spinal fluid is constantly being pushed in the brain, forced by the higher pressure pulse of arterial blood flow, and it effectively drains out of the low pressure paravenous system. That efflux of fluid, that outflow of fluid, takes with it waste products that it is collected along the way. You can think of this process as similar to how good rain clears the dirt, dust, and leaves off of a street. In this case, in the case of rain, gravity moves the water or the watershed to the drainage pathways, and that water picks up and moves debris along with it. I have a gravel driveway, so I know when it rains really, really heavy, it’ll actually cut ruts into the driveway and move rocks. So moving water can really carry some heavy stuff with it. YouTube flash flood videos if you want to see what water can carry.
It’s pretty amazing. So within the brain, that cleansing fluid moves through and clears waste from the tissue as a result of these differential pressures. As more fluid is being pushed in, it pushes more fluid out through the lower pressure system that surrounds the veins.
Cerebral spinal fluid enters the brain along these periarterial channels, those surrounding the arteries, and then they are pushed out by way of the venous. Fluid surrounding the artery, it’s a permeable channel created by the astrocytes and exchange that interstitial fluid within the brain. So it is pushed in, goes through that interstitial space, and then gets pushed out along with the waste products. Now, although it’s often portrayed, and I showed you and talked about it as being a pipe within a pipe, within the body, that configuration of cerebral spinal fluid is not really equally distributed around the artery or the vein. Imaging of the system in action shows that it’s really more of a compressed outer wall resulting in a somewhat triangular pathway as you see here. So as the pulsele wave moves forward down that artery, it expands and it pushes forward the cerebral spinal fluid in that space around it.
Now, the reason this historically has been a very difficult system to study, and the reason that there’s not really more known about it before a decade or so ago is because the system only maintains its function in a living blood pumping organism. The architecture of this system is extremely delicate and is dependent upon the living cells that make up its components. So postmortem studies aren’t able to visualize or preserve these components. The process to replace the blood in an organism with a fixative solution to prevent decomposition, which is typically called profusion fixation procedure, does not maintain the integrity of the structures involved. The architecture simply doesn’t hold up. Without the pulsile force of blood moving through the arteries, there’s nothing driving the cerebral spinal fluid and the structure itself collapses. So histological preparations don’t maintain that physiological structure that allows one to see the pathways.
It’s only through processes that allow observation of fluid movement in live subjects and in a hemodynamically typical status that we can actually see how this system actually works. So the tools for that type of in vivo investigation at this level of detail haven’t been around for that long. So that’s one factor that accounts for this being a relatively new discovery.
This system of waste clearance is present throughout the entire central nervous system. Recent work in human subjects has begun to demonstrate the functioning of the glymphatic system within the spinal cord as well. Although less is known about this aspect of the system since most of the earlier investigation is focused on the brain. It is worth remembering though that the spinal cord is part of the central nervous system, although its organizational system differs a little bit from that of the brain and is made up, however, of largely the same cellular components. So it makes sense that it would have a similar driving process.
This is a kind of a video here or animated gif that shows you how this process works. Fluid here represented in green gets pushed in by way of the periarterial spaces and then flows across that interstitial space, the little dots being waste products that get picked up by the flow and pushed off by way of drainage in the perivenous spaces. I thought that was just a pretty good little representation of how that flows. And again, the example that I used before of a heavy rain clearing dirt from the streets, similar kind of process there. That fluid then actually gets dumped into lymphatic vessels that exist within the dural meninges. Again, the dura being the tough outer layer mode, the outermost covering of the brain. Once the cerebral spinal fluid flows into those lymphatic vessels, they empty into cervical lymph nodes and exchange occurs there between the glymphatic outflow and the peripheral lymphatic system that surrounds the brain.
Now, I’ve seen this referred in the literature to meningeal lymphatic structures, which then feed into a larger lymphatic network. There’s also substantial outflow or efflux to the dural lymphatic vessels via the olfactory bulb and along cranial and spinal nerves. So again, major pathways of fluid out of the brain that then interact with our lymphatic system, our external outside of the central nervous system that then allow that fluid to be cleaned and dumped back into the subclavian veins and reintercirculation in the body. This also represents a relatively new finding as cerebral spinal fluid reabsorption into the circulatory system was previously thought to be primarily through structures called arachnoid granulations. These are small protrusions into the arachnoid layer of the brain lining the outer membrane of the dura. That’s what I was taught in school, and that’s just another brain fact that I now have had to update.
Arachnoid granulations do help drain off some cerebral spinal fluid as it is produced, and they are part of the glymphatic system of efflux or outflow, but now we have a more detailed accounting of where that fluid is draining to and the process by which it gets there than we ever did before. One important role that that handoff from the central nervous system into the lymphatic system plays is that of immune response. Again, remember I said the brain is a relatively clean area from an infection standpoint, and so this handoff is accomplished by the blood-brain barrier, which is largely made up of astrocytic infant. That prevents molecules From passing from our circulatory system into the brain, and that blood-brain barrier is created by tightly packed in feet of astrocytes. So then the question becomes, how does the body fight off infections in the brain when they do occur?
Our brain doesn’t have white blood cells like we have in our peripheral body systems. Well, how the brain responds is a multi-step process. The lymphatic system that gets the cerebral spinal fluid runoff from the brain is capable of evaluating that fluid for the presence of indicators of infection. If they are found, this triggers an immune system response, which is passed on to T-cells, which are within our general blood circulatory system. Activated T-cells can pass through the blood-brain barrier and then pass that information along to glial cells. Now, one type of glial cell that I briefly mentioned earlier is microglia. As you can imagine, they are very tiny. They have the capacity to undergo morphological changes and become immunoreactive. Morphological refers to the form of structure of things, and the microphages physically change their function as well. Once they have morphologically changed, we call those cells microphages, micro meaning small and phage, meaning a thing that devours.
Their job is similar to that of white blood cells. They react to damage and to remove the components of that damage from the brain. And like white blood cells in the periphery, they envelop and digest their target, break them down, and then pass them out. I always thought of that kind of like the jello creature from the movie The Blob that came from outer space and was devouring an entire town just by flowing over it and enveloping it. That T-cell signaling causes microglia to convert to microphages, which then attack the infecting agent. They know what to attack because of information that they receive from the T-cell messenger. And then the microphages act upon infectious agents, breaking them down and the cerebral spinal fluid and glymphatic network clears the debris and dumps it out into our lymphatic system where further processing can occur.
Now, regarding information relative to the impact of TBI on the glymphatic system, this is a very new area of research, as you can imagine.
I was able to find several publications that are looking at different aspects of TBI and how that impacts the glymphatic system functioning, all of which were published either in 2024 or in pre-publication status in 2024. There are now papers coming out in 2025 as well on this area of research. The majority of these papers involve animal studies or theories of potential human treatment protocols based on these animal findings. Within the brain following an acquired brain injury between inflammation and tissue damage, whether primary or secondary, there is a heightened need post-brain injury to achieve and maintain physical homeostasis that begins by clearing the waste products that are so plentiful after tissue damage. With that consideration, it makes sense that you want the glymphatic system to operate as efficiently and effectively as possible to clean up the damaged areas as quickly as possible. This is true for neurological insults associated with stroke as well, such as occlusive or hemorrhagic CVAs pictured here, or also severe TBI where there may be significant neurological insults or significant subdural hematoma.
You can also have punctate hemorrhages within the brain and diffuse axonal injuries scattered throughout the brain, all of which can impact the system. One consequence of injury to the brain that is problematic after brain injury is swelling or edema of brain tissue. A shift of midline within the brain is typically a measure that is used to quantify the severity of swelling in one hemisphere relative to the other and the impact that such swelling can have can be seen on these scans. Impact on fluid filled bodies as well, such as the compression or collapse of the lateral ventricles or by severe effacement of the outer cortical tissue on the inside of the skull. In such instances, a craniotomy or craniectomy is often necessary to relieve the increased intercranial pressure to maintain blood flow throughout brain tissue. Now, since we know that pulsile blood flow is the driving force that moves cerebral spinal fluid through the interstitial tissue to allow the cleaning process to occur, anything that impacts and creates a reduction of or even an absence of blood flow is going to significantly adversely impact the effectiveness of the glymphatic system.
So when there is swelling or compression, which has the potential to reduce cerebral perfusion, we also get a compromise of the system that drives cerebral spinal fluid flow through brain tissue. You’re also dealing with a compression of the interstitial space in that case, which means increased intercranial pressure, that is also going to impact the ability of that interstitial fluid to flow and it indirectly cerebral spinal fluid flow as well. One mechanism for edema that has been found in animal studies is impaired perivascular efflux. In other words, an impaired ability for the cerebral spinal fluid in the interstitial space to flow out through the paravenous pathway. You can think of this as the pipe for fluid coming in is flowing relatively freely, but the drain is clogged. You get a buildup of water. When this happens in brain tissue, you get swelling, you get edema, so that is associated with that process.
The term that has been given to this phenomenon is glymphatic stagnated brain edema. That is glymphatic stagnated brain edema. This has been shown to differ in mechanism from stroke in which influx appears to be the major driver. In either case, the system doesn’t work effectively if there are reductions in the amount of cerebral spinal fluid that can get into or out of the interstitial space and factors associated with disruption of the ventricular and cerebral spinal fluid distribution often are compromised after traumatic brain injury. Now, I mentioned a minute ago there, if you have part of the skull taken off that hemicraniectomy, another factor there is it can compromise glymphatic system functioning. Removing a part of the skull, something that we encounter frequently with individuals who’ve experienced a severe TBI, has to be done because of the significant edema that can occur and we need to relieve that intercranial pressure.
But a study in 2019 looked at the impact on the glymphatic system of a hemicraniectomy in an animal model. Again, it’s hard to get human subjects to volunteer for this type of study, and they found an immediate impairment of the glymphatic system. So when you take off part of the skull, your glymphatic system now is not going to work exactly the same. And it is hypothesized to be that the cerebral spinal influx is reduced secondary to reduced arterial pulsality. So those pulsal forces which serve to push the influx of cerebral spinal fluid into the system is reduced when the pressure of the skull is no longer there for a homeostatic existence. The craniectomy was also associated with astrocytic and microglial inflammatory response with observable motor and cognitive deficits. Now, over time, there are astrocytic changes that result in a stronger wall containing the arterial supply lines, and that allows for improved cerebral spinal fluid, but not all the way back to the baseline that exists in a normal hemodynamic state within the rigid container of the skull.
It is really interesting to me though that the astrocytes which have an intelligent response to injury and damage and blood flow need to neurons, those astrocytes can actually modify and change to build that stronger wall if you reduce the pressure around them by taking off part of the skull. Recovery of glymphatic flow preceded reduced gliosis and return of normal neurological function and cranioplasty replacing that skull flap accelerates that recovery. Perhaps that’s sometimes what you see as a bump of improved cognitive and motor functioning after a patient undergoes and recovers from a cranioplasty procedure. The re-implantation of the bone flap reflects a restoration of normal intracranial hemodynamic forces with resultant improved waste clearing from the glymphatic system.
Now, factors impacting the glymphatic system that are associated with traumatic brain injury. We all know that TBI is not a unitary construct. Each injury is unique and there are many factors that are involved that produce wide ranging symptoms after injury. But in a very recent article that involved collaboration between five different sites within the US and the UK looking at brain fluid clearance after TBI, factors directly impacting the functioning of the glymphatic system after TBI were noted to be the overall severity of injury, the quantity of blood and debris that needs to be cleared, the time post-injury, and the damage to the aspects of the fluid clearing systems themselves. So damage to the ventricles, damage to the pathways through which cerebral spinal fluid leaves the ventricles, and on a microscopic level, damage to the cellular components.
Steve Kerschke: Laura, can you hear us? You’re muted.
Jeff Snell: I can hear you, but not Jeff.
Steve Kerschke: All right. It looks like Jeff might’ve had an interruption, so we are working on that right now. Sit tight. I think we jinxed ourself. We were talking about internet interruptions prior to this. All right, Jeff’s back.
Jeff Snell: I do not know what happened there.
Steve Kerschke: It’s all good.
Jeff Snell: Always blame it on sun spots. Oh, did we lose everybody?
Steve Kerschke: No, we just lost you, Jeff.
Jeff Snell: Oh, okay. Good, good. Well, let me see if I can get back to where I was in the presentation. In the meantime, feel free to talk amongst yourselves, right?
Steve Kerschke: If I could answer the two questions that I have in queue, I would’ve done that, but this is way over my head, so I’m going to have to keep waiting for you on that too.
Jeff Snell: All right, let me get back to sharing here. Sorry about that delay. I have no earthly idea what happened. It just completely fell off the map. Are we back? Are we there?
Steve Kerschke: Yep, we got you.
Jeff Snell: Okay. Apologize everyone. So what work has been done suggests that gross changes to the paravascular space are likely to negatively impact lymphatic functions and a suppression of lymphatic function could in turn exacerbate pathology. In other words, there’s a chicken and egg problem here when it comes to worsening symptoms after a brain injury. Lymphatic function is worsened by damage to the brain and impaired lymphatic function potentially delays recovery or causes further damage. One example of this is that TBI induces the release of beta-amyloid peptide and C tau. C tau is a biomarker of brain injury. It’s one of the blood markers that shows the severity of an injury. It’s released in vast quantities and correlates with the severity of a TBI. A more severe TBI results in a greater release of C tau. An emerging hypothesis is the large amount of soluble tau builds up in that interstitial space, which initiates a spiral of cellular uptake, and those form fibrillary aggregates, which attract additional tau.
It’s a vicious cycle, basically a spreading of pathology. In studies that have looked at this, they have noted that after severe TBI, human tau accumulates around large veins, and the amount of tau remaining in the tissue correlates with a decrease in glymphatic clearance. Now, I used the analogy earlier of a good heavy rain clearing dirt and leaves from the street. Well, if enough of it gets pushed into the drains at once, it’ll actually clog up the drain system. If there’s a lot of leaves and trash that clog up the drain, then the drainage system ceases to work as designed. This is the analogy for what’s happening here with this heavy release of tau as a result of a brain injury, which then clogs up the efflux or outflow of the paravenous channels so that the fluid cannot get out. Again, that would make sense as well because it would be associated with an increase in fluid within the brain or what we call edema.
Severe brain injury also results in stroke-like bleeds or occlusions as well. One study found that cerebral hemorrhage in a particular severely impacts glymphatic functioning. Although this image depicts several different types of hemorrhagic events in humans, the study I’m referring to was involved in animal studies. Cerebral hemorrhage suppressed lymphatic functioning primarily by blocking the influx pathways that allow cerebral spinal fluid into the brain tissue. So in other words, if there’s a bleed in the area, it makes it difficult for cerebral spinal fluid to flow into that area as well. In that model of subarachnoid hemorrhage, the application of plasmidogen activator that removed fibrin clots actually improved glymphatic functioning. Another is looking at embolic ischemic stroke, which is the most common type of stroke where there’s a blockage of blood flow, and that seems to impair the outflow, the inhibition of glymphatic function. That outflow is impacted because, again, the driver of the glymphatic system, what pushes cerebral spinal fluid in that system is blood flow.
So if there is a blockage of blood flow, that blood is not pushing through that artery, therefore cerebral spinal fluid is not being pushed through as well. All of this information is in an article, The Glymphatic System of Beginner’s Guide, which is a wonderful primer on all of this information, and that references within the references that you’ll have in the handouts as well. Yes?
Steve Kerschke: Can you talk a little bit about what happens with atrophy of the brain? I mean, is it similar to some of the other aspects that you talked about where there’s a mix up in the pressure and that sort of thing, or do you have information on that?
Jeff Snell: Well, atrophy of the brain really is a loss of tissue. It’s referred to technically as encephalomalacia, a softening of brain tissue that represents missing cells, both neuronal as well as glial in an area that has had a severe ischemic impact. So without blood flow, those cells actually die off. Apoptosis is the formal term for that. They die off, they are broken down, and then you have less brain volume because of those missing cells in that area. So you can have a large number of cells or a small number. The more cells are involved, the more atrophy you’re typically going to see. That’s in the case of an injury or stroke. That’s a different process for something like chronic alcohol abuse, where again, at a microcellular level, you are losing cells throughout the entire brain by those metabolic changes within the brain. Good question.
Steve Kerschke: And then how would that impact the glymphatic system?
Jeff Snell: The glymphatic system is going to be impacted by anything that changes the hemodynamic forces. So anything that changes the amount of force surrounding the vasculature itself is going to either raise or lower the glymphatic system’s efficiency.
Steve Kerschke: Got it. Thank you.
Jeff Snell: But again, all this in humans, this is all new stuff. Most of the research in vivo is being done in animal studies at this point. Some human though is now… Some human studies are now coming out. Now that gets us around to sleep, and I’ve probably got to pick up the pace just a bit here. Sleep is an interesting area of study in and of itself. Sleep is essential for all mammals, but it’s also an extremely vulnerable state that increases the chance of being targeted by predators. So the fact that all mammals sleep, despite that huge risk, suggests that sleep is in and of itself of critical biological importance. The amount of power consumption of our brain only decreases by about 25% when we sleep. That suggests that energy conservation is not the primary need that drives sleep. Research over the last decade has shown that the sleep state is a time of dramatically increased activity in the glymphatic system, and that the glymphatic system is suppressed when we are alert and awake.
In animal studies, that difference in activity is dramatic. The glymphatic system suppresses function by about 90% when we are awake versus when we are asleep. So the glymphatic system in animal studies at least, and we would assume that humans would be somewhat similar in that respect, that glymphatic system almost exclusively works while we are asleep.
Sleep plays a critical role in the functioning of the glymphatic system. So this process, like everything within the brain, is energy dependent and it involves increasing the volume of cerebral spinal fluid within the tissue of the brain. This process is best accomplished and is most efficient and effective at its job during periods of decreased neuronal activity, and in particular during sleep, and even in more particular, during deep sleep. Now, numerous investigations have shown an increase in extracellular space, the porosity, greater presence and flow of fluid in that interstitial space that occurs when we are asleep.
So the overall energy that the brain is using is only reduced by about 25%, but neuronal activity while we are asleep is dialed way, way, way down, and more energy is being used in that case by the cleaning crew, by our glymphatic system that’s coming in and cleaning out all of the waste products in our brain while we sleep. Now, this has been shown in animal studies in that you can introduce norepinephrine directly to brain cells, which causes those cells exposed to norepinephrine to go into a sleep state, to go into slow wave functioning. Neurons I’m talking about. Those sleeping parts of the brain have increased interstitial volume. In other words, there’s more fluid between the cells that facilitates greater flow and clearing of waste products. On the other hand, in studies that have looked at disrupting sleep, and this has been known for many years, there’s a decreased effectiveness of the glymphatic waste clearing system that we’re now seeing as well.
In human studies involving cognition and sleep, we know that cognitive functioning is decreased when sleep is disrupted. This lack of ability to efficiently clear waste products is correlated with such disruption. So we don’t know necessarily that they are causative, but they are definitely correlated. They’re happening at the same point in time.
Well, we all know as well that sleep is often profoundly disrupted by TBI, particularly in more severe injuries. Restoration of a normal sleep-wake cycle is an indicative measure of recovery after injury, and it’s one of the many foci of clinical concern. But again, it’s something of a chicken and egg problem that reduced glymphatic clearance of waste products has been proposed as a mechanism by which impaired sleep is not just associated with, but also contributes to poor TBI recovery. I would also like to note that prior studies specific to the glymphatic system indicate that this system, which operates at its highest efficiency and effectiveness when we sleep, also appears to work if it is natural or induced sleep.
In other words, chemically induced sleep. It does its thing either way. Initial efforts to restore a regular sleep pattern in the acute phase of recovery is likely to include medications designed to promote and maintain regular sleep patterns. And from the perspective of the glymphatic system, perfectly fine with that. It’ll go on and do its job.
We generally want to promote healthy regular routines that are supportive of good quality sleep, and some of the recommendations that are typical are offered here. This is certainly not an exhaustive list, and it would take another entire lecture series to do the topic of sleep hygiene justice, but this is just a short list. Mostly it involves behavioral and environmental changes. Now, there’s also a cognitive behavioral therapy aimed at insomnia called CBTI that looks at the cognitive and emotional aspects and learning to engage in physical relaxation and imagery and things that can also help get to sleep at night.
But some of these things here, going to bed and waking up at the same time every day, the older I get, the more that becomes a routine for me. I used to, on a Saturday, be able to sleep until two in the afternoon when I was a teenager. Man, I am up at six o’clock every day with or without anything to do. So the more you get that routine in place, the more that solidifies. Getting exercise and sunshine, some of that non-milk, Don, and some of that non-milk vitamin D, good for you. Resting during the day, but not napping. So keeping your naps really, really short if you are someone who naps. Avoiding exercising or eating a large meal within a few hours of bedtime. Again, things that otherwise keep the body needing to be active. Mostly kind of treating the bed as a place to sleep, not as a place to work, answer emails or scroll the internet.
Go to bed, get in bed when it’s time to sleep, turn out the lights, nice environment to the degree that you can get interruptions and noise and animals that might otherwise keep you awake out of the bed.
And then one last thing that I just wanted to put in, and this could be a full presentation in and of itself at some point in the future. The reduction noted in animal studies comparing old versus young shows a reduction of around 80 to 90%, a dramatic reduction of glymphatic activity, both in influx of the cerebral spinal fluid into the interstitial space and clearance of waste that efflux out of the brain. This appears to be associated with a reactive gliosis kind of defined by hypertrophy of the astrocytic processes, although the exact mechanism is still unclear, but it is aging related changes that basically make our glymphatic system, make our waste clearing system much less effective over time.
Another thing that could impact it is age-related changes associated with stiffening of the arterial wall. Again, if you reduce that arterial pulsality, that pulse wave, if it becomes less elastic as a result of that hardening of the arteries, buildup of atherosclerotic tissue, that can also reduce the amount of glymphatic flow. And then the highest risk factors for neurodegenerative diseases is aging. The reduction of efficiency and function of the glymphatic system in aging might contribute to the accumulation of proteins and thereby render the brain more vulnerable to developing neurodegenerative pathology or progression of cognitive dysfunction. Most progressive neurodegenerative diseases are characterized by accumulation of aggregate proteins. And again, this glymphatic system is what is responsible for clearing that waste. So again, research into this system is relatively new area and there will undoubtedly be more information in that in time to come. And Steve, I am going to punt it over to you now for the polling question.
Steve Kerschke: I can do the poll while I launch the poll. Well, just again, quick reminder, this is the only poll question. Please answer it. We’ll post the results. Hopefully it’s relatively straightforward. But Jeff, if you could look at… We have three questions in there and just expand on those while I do the poll question, that’d be great.
Jeff Snell: Okay. Let me open up… Is that under Q&A or under chat because I –
Steve Kerschke: Q&A.
Jeff Snell: Q&A, great. Yeah, I lost that when I lost the connection earlier as well. So is there a medical procedure test that can determine if the patient has experienced an increase in tau following TBI to contribute to delayed… Well, there is the blood test that I mentioned earlier for tau C that is currently, I don’t know where it is in FDA approval. It may very well already be approved and utilized, but there are a number of studies that have shown that. Now, it’s not going to show you at a level of that paravenous buildup unless it has been radiologically tagged, which is what they did in those studies. But yes, an increased level of tau within the bloodstream is certainly something that is available and can be done now. The degree to which that could stand up to a court case, I honestly don’t know at this point. And the other question, any documented changes with dementia that can note early signs? Well, as a neuropsychologist, I would say yes. Oftentimes when I’m doing a neuropsychological evaluation, as I’ve done previously in other settings for individuals referred secondary to potential for dementia, early signs are associated with early memory difficulties often that are minimized or explained by other things the person comes up with.
That self-awareness of difficulty, for example, is an area that is very, very common with dementia. The other thing is the olfactory function with certain types, particularly Alzheimer’s dementia, is an early kind of Harbinger kind of sign. When an individual starts to lose their sense of smell, there is that change often that accompanies with different tastes as well. Someone often wants a lot more sweets than they do other types of foods as well. And there’s one, the answer to the question. Oh, okay. Steve, you’re typing an answer to that one, so yes. So I’m just going to say here –
Steve Kerschke: I got that one. There’s a question around the viral bacterial infections.
Jeff Snell: Okay.
Steve Kerschke: You might have to scroll up on your screen if you didn’t see it.
Jeff Snell: I’m not able to scroll up.
Steve Kerschke: So the question is, the person has read that bacterial and viral infections can negatively affect the brain. Is there a way to better boost the glymphatic system or assist the resolution of the secondary inflammation from the infection?
Jeff Snell: Well, I think that’s what a lot of the research is currently looking at with regard to any type of acquired brain injury with bacterial or viral being also something that can cause devastating injuries to the brain. Anything that can impact getting rid of the waste products from those types of infections or the infections themselves, anything that can boost that Certainly would be of huge benefit. And so this area of research when it comes to lymphatic function in human beings is so new that really we’re just on the cusp of defining how the system works at this point. But the goal certainly is to increase the effectiveness of interventions along the way. Anything else that I might’ve missed?
Steve Kerschke: It just says, “Are there normal levels of tau that can be measured?” I’m assuming the answer to that is yes, but –
Jeff Snell: Yes, those proteins are also necessary for other functions within the body. So it’s not something that you would want to completely get rid of because then the brain also wouldn’t work. So that would be an instance of curing the disease and killing the patient.
Steve Kerschke: Got it.
Jeff Snell: Yep. And then somebody said, “Wait, wait, I need to stop taking naps.” No, you can take a small nap, just don’t take enough of a nap that it interrupts your sleep at night. You need that deep sleep for your glymphatic system to kick into high gear, and you typically aren’t achieving that with a nap. Good question though.
Steve Kerschke: All right. Well, it is 10:02.
Jeff Snell: Let me just say here, this wraps it up and good on all of you that stuck with us through this, trekked through the weeds. To me, it’s a very interesting new discovery. These are some selected references from this presentation. And if you have any questions regarding any of the information presented today, I do hope that you will get in touch. And like I said earlier, I love learning anything new about the brain. So this deep dive and putting this presentation together has been a wonderful learning experience for me, and I hope you’ve enjoyed hearing about it as well. Here’s my contact information. Feel free to get ahold of me directly if you like.
Steve Kerschke: Thank you, Jeff. The other thing, just to remind everyone, these are recorded, so we will have these up on our YouTube channel. I’m sure you got everything the first time around, but if you happen to miss a small detail, let us know. We’ll make sure you get that.
Jeff Snell: Oh, come on, Steve. It took me three times presenting this to even pick up on some of the big stuff.
Steve Kerschke: Well, I mean, this is the second time I’ve heard this and I definitely could use a couple more reps. So definitely a good topic. We appreciate it, Jeff. As always, thanks for all your prep and taking something that is extremely complex, but using some great analogies and examples to make sure that everyone else gets some good takeaways. So appreciate it. Thanks again for everyone joining. We’ll be back next month. We’re going to be talking about the impact of immersive cold, immersive heat, and red light therapy, and we’re going to hope to apply that to the rehabilitation process. So that’s the upcoming topic. Thanks again and have a great day.
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