Transcription
Hello and welcome to the Brain and Transcranial Photobiomodulation Virtual Summit. I'm your host, Dr. Joe Dururo, and my guest is Professor Dennis Bragan, my co-author. He's going to be enlightening us on the topic of brain detoxification, if you will.
Welcome, Dennis.
Yeah, thank you. Hi! You've been researching this field; you've been working with government contracts a lot with traumatic brain injury. You worked with a mouse model, and your work really brought to our attention when we started to review the Russian work on photobiomodulation and the brain's glymphatic drainage system or the brain's waste removal system. How did you get connected with studying photobiomodulation or light?
Well, when I started my graduate school, I studied photodynamic therapy. In particular, we started with the effect of photodynamic therapy on the so-called stretch receptor neuron of the crayfish to see how it might affect surrounding brain tissue in case of photodynamic therapy for brain tumors. That was my experience with phototherapy. Then I found posts in Germany and in the United States, and for a long time, I didn’t do anything in the way of photobiomodulation or phototherapy, except microscopy, which is also kind of photo-related.
Then I reconnected with a Russian group at Saratov State University who started studying photobiomodulation and the lymphatic system of the brain. We have been having a fruitful collaboration over several years, and I'm moving back now towards photodynamic or photobiomodulation therapy and the lymphatic system.
Now, the two things: photodynamic therapy is using light energy to destroy cells, so it's important for people to know that, whereas photobiomodulation is to enhance some functions of the cells. We are going to find that the Russian research was very heavy and difficult to go through. My study group and the Prolite Group contacted you because those guys have more accent than you do and the time change, so we kind of made sure that this vital new information was made available to other researchers. That's kind of how we put this together.
Right?
Yes, that's great. So, let's go to the slides and start teaching us photomodulation therapy and the lymphatic system—promising applications for improving brain drainage.
Yes, thank you for reading the title. Sorry. My talk will be based mainly on our recent publication entitled "Photomodulation Therapy and the Lymphatic System: Applications for Brain Drainage," which was published last year in cooperation with you. I'll talk a little bit about the seminar work from the Russian group, which I'm proud to be involved in, on the use of photobiomodulation therapy in boosting the brain drainage system.
Here is the Russian group—I just showed a picture of a member of the group. And here is my outline. I'll do some introduction. I'll talk a little bit about the brain lymphatic and meningeal lymphatic drainage system. Then I'll talk about photobiomodulation therapy, followed by conclusions.
So, photobiomodulation is the application of low levels of red or infrared light to stimulate tissues. This has been demonstrated to be an effective approach for promoting cellular respiration, microcirculation, and for relieving pain and edema in various traumatic acute and chronic diseases. Photobiomodulation has also been shown to improve brain hemodynamics along with an increase in cerebral oxygenation and metabolic capacity.
There is an increasing body of evidence to support that photobiomodulation therapy of the brain can ameliorate oxidative stress and inflammation while promoting neurogenesis and synaptic genesis. To date, no serious adverse effects have been reported for brain photobiomodulation therapy. However, it must be considered that high-power sources might be hazardous due to thermal lesions.
What is the lymphatic system? The lymphatic system is a gravity-dependent waste clearance pathway in the brain, devoted to draining away waste metabolic products and soluble proteins such as amyloid-beta protein. The meningeal lymphatic is a network of lymphatic vessels located parallel to the dural venous sinuses and meningeal arteries of the brain. It is responsible for draining immune cells, blood, small molecules, and excess fluid from the brain into the deep cervical lymph nodes. An impaired brain lymphatic system can increase the incidence of neurovascular, inflammatory, and neurodegenerative diseases.
Photobiomodulation therapy can serve as a non-invasive neuroprotective strategy for maintaining and optimizing effective brain waste clearance. Recent preclinical research in rodent models has proven the efficiency of photobiomodulation for maintaining and optimizing effective brain waste clearance in several models of brain diseases.
So, what is a catic system? The lymphatic system is a paravascular pathway that facilitates cerebrospinal fluid (CSF) flow through brain parenchyma and the clearance of interstitial solutes. It was discovered by the Nedergaard group from Rochester in 2012. They injected some fluorescent dye into the brain and observed a movement of this dye through the brain parenchyma. It can be shown here as a video as it goes through the perivascular space of an artery, then through the interstitial space and feet through the brain parenchyma.
As CSF flows, it ends in the venous space. As you can see in this animation, brain toxins, represented by black dots, move out through the perivascular space. It should be noted that last century, or even two centuries ago now, German physician Heinrich Quinke described brain removal of CSF in 1872. He injected dye into the lumbar region and observed movement through the brain parenchyma; however, he did not see any movement in the brain parenchyma, probably due to the large molecule size of the dye.
Here is a scheme of the lymphatic system, so CSF is produced by the choroid plexus, it moves through the brain parenchyma via the paravascular space of arteries, through the brain parenchyma, and goes out with waste through the perivascular space.
This is a more detailed picture showing the involvement of lymphatic cells; that’s why it's called the glymphatic system—to show that it’s a hybrid of a lymphatic-like system.
Another system I want to talk about is the meningeal lymphatic system. In general, it was believed that there was no lymphatic system in the brain. For example, this is a picture from the anatomy book by Decker, which states that there is no lymphatic system in the brain.
However, in 2015, two groups of investigators simultaneously found meningeal lymphatic vessels in the brain. One is an American group headed by Jonathan Kipnis; they injected fluorescent dye into the cisterna magna and discovered specific dye that highlighted lymphatic vessels, finding some in the meninges and also observed that the dye moved to the cervical nodes, indicating it's connected to the lymphatic system.
The same occurred in a Finnish group headed by K. Alwa, who developed mouse models with lymphatic vessels and also observed meningeal lymphatic vessels in the brain and removal of the dye into the cervical node. It should also be noted that this system was first described by Paul Masani in 1787. In his breakthrough work, he completely described the lymphatic system of the whole human body and also observed some vessels in the brain.
What he did was inject mercury into the cisterna magna, and of about thousand cadavers he examined, he found some vessels depicted here in white in the brain, but since he found this system only in corpses, scientists did not believe his discovery, and it was not taken into account for almost a quarter-century until 2015.
This is now how it looks like, a lymphatic system including meningeal lymphatics in the brain, so it should be updated in all anatomy books.
So, how does the system work or connect to the lymphatic system? It was not really clear how, but the lymphatic system moves CSF through the brain parenchyma, and through the perivascular space, it enters the functional meningeal lymphatic vessels. The end point of these is the cervical lymph nodes, where it accumulates and moves forward to the lymphatic system to clear the brain.
In part, meningeal lymphatics have been shown to be very practical for health because toxins accumulated in the perivascular space of the brain cannot exit due to dysfunctional meningeal lymphatics. This has a lot of detrimental effects: it decreases coverage of the meningeal immunity, reduces drainage of CSF, compromises monitoring of CSF antigens, and leads to atrophy. Eventually, it causes accelerated cognitive decline and accumulation of toxic aggregates like amyloid-beta, tau protein, and other proteins, exacerbating inflammation and worsening outcomes in brain accidents like stroke or traumatic brain injury.
Another important part of the brain drainage system is the cribriform plate. It is a bony plate through which lymphatic vessels drain lymph and CSF to the cervical lymph nodes. You can see in this image how CSF flows through the cribriform plate.
So here’s a summarized scheme of the current understanding of how all these systems work. The choroid plexus produces CSF, the brain parenchyma and lymphatic system clear toxins from the brain, which moves through the subarachnoid space to the meningeal lymphatics, then to the main lymphatic system.
However, the question remains: how do solutes from the perivascular space reach the meningeal lymphatics despite these layers being separated? This year, a new layer was discovered in the meninges, called the lymphatic layer. This lymphatic layer is a crucial place of communication between the blood system and lymphatic system.
Several conditions affect the brain's lymphatic system, such as genetics, lifestyle, and pathology, which might lead to decreased lymphatic output, increased inflammatory conditions, and elevated toxin concentrations in the brain. Here’s another scheme showing that insufficient brain clearance causes the accumulation of waste and toxins, leading to sleep disturbances, stress, and hypertension.
Factors that affect this brain drainage system move through several physiological processes, such as cardiac cycles when blood is pumped by the heart, causing pulsatility in the vessels, and respiratory activity. Neuron activity is also important because more active neurons change the perivascular space dynamics.
Another important thing is that this system mainly works during sleep. Here on this image, you can see the activity of the drainage system is more active in the deep phases of sleep. The precise mechanism of this is still unclear, but it shows that during sleep, the perivascular space increases, allowing fluid movement.
Here are just representative MRI images showing the existence of this system in humans. You can see on this MRI image the lymphatic vessels, and in this video, you can see the pulsation of CSF.
Now, I’ll talk a little bit about photobiomodulation and the brain drainage system. How can they be related? I’ll present several experiments from the Russian group showing the efficiency of photobiomodulation therapy in boosting the lymphatic system in the brain.
First, it has been shown that photobiomodulation causes vasodilation of lymphatic vessels in the mesentery area and, it also depends on pulsatility because different conditions show different diameters.
Here is a diameter of these vessels before photobiomodulation and after. You can see that in both cases, it substantially increased. The reason for that increase in the diameter was unclear and was discovered later on. After that, it was shown that photobiomodulation also increases meningeal lymphatic drainage in the brain.
In these experiments, fluorescent dye was injected into the brain parenchyma, and after photobiomodulation therapy, clearance of the fluorescent dye in the treatment group was much faster than in untreated animals, and this dye moved to the cervical nodes in the neck.
It was also tested in a model of intracranial hemorrhage, which is a very severe brain disorder. The blood was injected into the brain, and after several photobiomodulation sessions, the clearance was evaluated. You can see that photobiomodulation increases the diameter of the meningeal lymphatic vessels and boosts clearance, leading to improved outcomes for these animals.
Another example is the use of Evans Blue dye, which also clears from the brain much faster. Here on the red curve, you can see after photobiomodulation, there's a significant contrast in clearance rates compared to the untreated animals.
To answer the question of how photobiomodulation causes vasodilation, it was suggested that probably nitric oxide is involved in this process. Nitric oxide is a well-known vasodilator that regulates homeostasis of blood vessels and lymphatic flows.
In this experiment, L-NAME was used, which is a well-known inhibitor of nitric oxide synthase. It was shown that in the case of inhibition, reducing nitric oxide, there is no effect of photobiomodulation, as you can see here—the diameter does not change, in contrast to active mice without the inhibitor.
At least now we can say that photobiomodulation boosts meningeal lymphatics via a nitric oxide-dependent mechanism. In another experiment, it was shown that photobiomodulation increases beta-amyloid clearance from the brain of mice in an Alzheimer disease model, especially it works much better during sleep. Here is a fluorescent signal from beta-amyloid in the meningeal cervical lymph nodes after photobiomodulation in awake and sleeping animals, showing that the effect is much more pronounced during sleep, which is logical because it has been shown that the brain drainage system works mainly during sleep.
Here is the staining of the brains of these animals, and you can see that in mice with photostimulation, there are significantly fewer amyloid plaques compared to those without photostimulation and even less than in photostimulation during the awake state.
The last experiment I would talk about is photostimulation of the cribriform plate, which shows that we can not only increase clearance from the brain, but we can also promote some drug delivery into the brain through these systems. In this case, mice with glioblastoma had liposomes sprayed into their nose, and photobiomodulation boosted the transportation of these liposomes into the brain. This could be a very interesting new approach for drug delivery.
You can see how it boosts the delivery of the liposomes into the brain through the meningeal lymphatic vessels when sprayed into the cribriform plate area.
All these experiments show that photobiomodulation therapy can be used for boosting the brain drainage system. It can be used not only for the brain but also for other areas, such as through the nostrils, the eyes, or the ears, to enhance the lymphatic system. One of the approaches might be through the cribriform plate elimination to boost cervical lymph nodes.
This is a system that can be tuned for different parameters through CRI light using different wavelengths to affect different mechanisms of photobiomodulation.
In conclusion, I can say that the brain drainage system plays an important role in maintaining water and iron balance of the CSF, waste clearance, and reabsorption of micromolecular solutes. The second physiological function includes communication with the immune system, modulating immune surveillance and response of the brain. Photobiomodulation of cranial and extracranial lymphatics may be a promising approach for the treatment of brain disorders.
Thank you!
Wow, that was phenomenal. What I’m saying is, it's likely never been explained that well—even with all our meetings and adding the new information. This really brings people up to speed on the importance of this lymphatic system, the meningeal system, and then this subarachnoid layer. That was a question that we asked in our meetings: how does this happen?
It was on January 23rd when they put out that research, so that was very helpful for us and in our group and for what you were doing. I think you explained it so well, especially with a tip of the hat to the excellent explanation of the Russian group that really helped all of us to understand these fundamental principles.
I think you make a good point about the multimodal approach. If you want to address this, like when we do our therapy, we use the neck at night to increase the flow to the brain. Intranasal techniques boost blood flow to the brain, and the head wrap goes around the head, the ears, and the forehead. Then we have a top wrap that runs down the middle. Those are the three main areas: the base of the skull, the nose, the eyes, and the ears, and this drainage vein that goes down here.
We use a body pad on the chest most of the time because that’s where the cervical lymphatics drain right under the rib cage. So now we have four or five different applications of light done at evening time because light is circadian medicine, as we talked about in the paper. We need to pay attention; if we're going to highlight the glymphatic system, we need to do it at night or at least close enough to night.
Then in the morning when we wake up and the brain is starting to wake up and returning to normal with its paravascular spaces, we perform the same procedure to help drainage. That’s kind of the whole scenario: do the right therapy, do it at the right time with the right wavelengths, and you’re going to have much better results.
Right?
Yeah, and it may also be done with monitoring of brain sleep phases and automatically modulating the therapy.
However, the thing is, people will say, “What about executive function, Dr. Joe? Are you really trying to improve executive function or memory?”
I step back and say, “It's a multimodal therapy for the brain; it’s not for a specific function.” You know, if the brain has fewer toxins, if the brain has less neuroinflammation and less amyloid-beta, and better circulation, it should be able to do its job. Would you agree with that?
Or should we take a brain that’s all clogged up and try to make it think better? That’s only going to make it more clogged up.
Right, it might be even a preventive measure. I think that when we break it down, we can understand the brain's detox system. We also have to point out that the immune system is very active during that period.
So people would say, “If you have long COVID, you have neuroinflammation,” and you go to the doctor at noon, and you do the light, or you do it at midnight at your house; that’s going to have two different effects.
That’s the first thing to understand. The final common pathway of these diseases is a gunked-up brain—a brain that can’t drain properly. That’s what we’re really finding. So yes, we can stimulate the brain; yes, we can stimulate thinking with photobiomodulation.
However, our focus should be on helping the brain detox and assisting the brain's immune system because that’s the brain’s innate healing process. It’s not going to think more if it’s not healing better.
Thank you for your great presentation and all that you’ve done for this conference. Thank you.