Neurology Live: Could Hyperbaric Oxygen Therapy Improve Cognitive Function in Dementia?
The director of the Sagol Center for Hyperbaric Medicine and Research at Yitzhak Shamir Medical Center offers insight into the attempt to regenerate injured tissue in the brain as a way to potentially treat Alzheimer disease and dementia.
This is the first of a 2-part interview. For Part 2, click here. and below.
Hyperbaric oxygen therapy, which has been approved by the FDA for many different indications, was only recently studied for cognitive challenges, with data suggesting that it may offer new hope for cognitive decline.
It has previously shown statistically significant improvements in all memory measures and indicate that it can lead to significant neurological improvements in post-stroke patients even at chronic late stages.1,2 Now, new data have implied that it may hold promise for those with diseases like Alzheimer and dementia. A randomized controlled clinical trial of 63 healthy older adults compard placebo to hyperbaric oxygen therapy for 3 months, showing that the oxygen therapy appeared to induce cognitive enhancements via mechanisms involving regional changes in cerebral blood flow, as evaluated by perfusion magnetic resonance imaging (MRI). A significant group-by-time interaction in global cognitive function was observed compared to control (P = .0017), with the most impressive improvements in attention (net effect size = 0.745) and information processing speed (net effect size = 0.788).3
The research was led by Shai Efrati, MD, director, Sagol Center for Hyperbaric Medicine and Research, Yitzhak Shamir Medical Center; and associate professor, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University. To find out more about how the clinical study of this method of treatment got to this point, NeurologyLive inquired with Efrati.
NeurologyLive: Could you walk through what prompted this work? How did we get to this point with hyperbaric oxygen therapy?
Shai Efrati, MD: Actually, it all started something like 15 years ago. I started a small study and the goal was to prove that neurons cannot be regenerated. That’s was the goal, and I got the opposite results. Since then, things are moving in a completely different direction.
We are working on regenerating brain tissue. The main issue is to refer to the brain as a tissue. The injury that we have in the brain is just like any other injuries we have in other parts of the body. They have common dominant pathophysiology, whether you want to heal a peripheral wound that you have in the leg, or whether you want to heal a wound that is in your brain. The main difference between the one that we have in the leg and the one in the brain is that the wound in the leg is something that you can see. It’s tangible. You can smell it, you can see it, you understand what is happening. With the brain, it’s high tech. We are looking at it through CT or MRI. We’re speaking about the brain in a mystic fashion, about cognitive personality. But, surprise, surprise—it’s a tissue.
First, what we did is evaluate the wound in the brain just like any other peripheral one, meaning we know that there are several degrees of injury. The would can be necrotic, which is completely dead tissue. Unfortunately, for that tissue, we cannot help. But there might be an integral tissue that is not fully dead. We call it metabolic dysfunction tissue in the brain. We call it hibernating, we call it stumbling, but what does it mean? It means that we have an injured tissue that is stuck. It does not heal.
At the beginning, we started with classical cases of brain injury. We started with stroke, traumatic brain injuries and encephalitis, and things like that. The knowledge that we gained from this is that if we can trigger stem cells and we can bring enough energy—enough oxygen to the damaged tissue—then the body can initiate the regenerative process that it is doing in other parts of the body, in the brain. The main issue now, then, is how do we bring the basics that is needed for the wound care so the body can do what is intended to do. Stem cells, we all know it’s cells that in differentiate into different tissues. We had starting to play a lot with stem cells in our research lab—we can take stem cells out, replicate them in the lab, and inject them back. While I’m a great physician for rats and mice, unfortunately, in human beings, it is not so strong.
If we cannot take the stem cells out and inject them, let’s stimulate our own body to generate stem cells. Amazing idea. The main trigger for stem cell proliferation, is hypoxia—a lack of oxygen. So, if we want the human being to stimulate the stem cells, we can take a person, hold his breath and stop his heartbeat, and then you will have stem cells. There is only one problem. It’s not healthy.
What does the body actually sense? Does the body sense absolute values, or does the body sense the delta, the fluctuation? It happens to be that just like, in real life, there is no absolute values. So, let’s trick the body. Let’s take the oxygen to very high level and then do a fast decline. This decline is being sensed by the body as hypoxia, even though we have hyperoxia. We call it the hyperoxic-hypoxic paradox.
We have found the protocol where we take people into a hyperbaric chamber, we increase the blood oxygenation—let’s say from 100 to 2000, a huge increase. Then, every 20 minutes, we ask the people to take the mask off. The oxygen is going from very high level and then back to normal, and then again, and again, by a certain protocol. By doing that, we stimulate the proliferation of stem cells, and the stem cells are going up gradually from one session to the other. After something like 20 sessions, we have huge amount of stem cells that are flying all over and are looking for place to settle down. We have these stem cells with high oxygen, and then we have the 2 crucial elements needed to regenerate tissue.
To summarize, the brain is a tissue; we are evaluating the wound to say that we are not dealing with the necrotic tissues, we are dealing with areas of metabolic dysfunction tissue; we go into a repeated session and according to the fluctuation we generate, stem cells are going up; and then the tissue can regenerate or heal.
This has been studied for patients with stroke previously. How did the idea to assess its potential for cognitive decline come about?
There are many things that happened to our biology. One of the things that happens to all of us is just like if you have the house. You have the pipes in the house, and the house is going along the aging process, so what will happen to the pipes? They will get occluded. The same thing happens in our body, occlusion of the blood vessels—we call it atherosclerosis process. There are never enough blood vessels, and at the end, it may culminate in occlusion. Now, if you have occlusion of large blood vessels in the brain, we call it stroke. If it’s small blood vessels, then we are losing, again and again, additional amounts of tissue. That will be the cognitive decline. It’s not that you are losing it all immediately. You’re losing some tissue, and then its, “Oops, remind me what your name was?” Then the information processing speed is declining and we’re losing more and more tissue, and at the end, we call it dementia.
By knowing that, what we have done in this study is take people who are 65 years old and fully healthy. They are the so-called “good for their age” group. We took them and we were able to demonstrate with high-resolution MRI that they are healthy, they didn’t have stroke, they didn’t have brain pathology. We were able to demonstrate with the high-resolution perfusion MRI the occlusion of the small blood vessel, the decline in the brain functionality. Then, using our regenerative protocol with hyperbaric oxygen therapy, we were able to demonstrate that angiogenesis in the brain is happening because stem cells are coming up and new blood vessels are generated. More blood vessels are going into the damaged tissue, the tissue is regenerated, and you see the malfunctioning tissue re-activating. Surprise, surprise, the cognitive function related to that issue is improving. Not because we worked on the cognitive function, but because the tissue was regenerated. It’s huge. It’s huge because first of all, we can measure it. We can treat the tissue for normal aging, and it’s more exciting because today, the major threat to the Western society that is growing from ear to ear is age-related function and decline.
This is the No. 1 threat to the Western society. When people have Alzheimer, it’s too late. If you are looking at the brain, you see atrophy. Atrophy means that we don’t see a tissue. So, the main issue is to start early, when you have metabolic dysfunction, but still have a tissue and then you can improve this tissue. Once you are improving the tissue, the cognitive function is improving, and then you can keep on monitoring to see if and when you will need additional treatment. By doing that, if you can measure it, and if you can treat it, the goal is to generate Alzheimer- or dementia-free society. This is the way we aim to do it, and this is the goal. This is the goal for us. We want to function, and function is first of all cognitive function.
REFERENCES
1. Efrati S, Fishlev G, Bechor Y, et al. Hyperbaric oxygen induces late neuroplasticity in post stroke patients–randomized, prospective trial. PLoS One. 2013;8(1):e53716. doi: 10.1371/journal.pone.0053716.
2. Boussi-Gross R, Golan H, Volkov O, et al. Improvement of memory impairments in poststroke patients by hyperbaric oxygen therapy. Neuropsychology. 2015;29(4):610-21. doi: 10.1037/neu0000149.
3. Amir H, Malka DK, Gil S, et al. enhancement of healthy older adults using hyperbaric oxygen: a randomized controlled trial. Aging. 2020; 12(13):13740—13761. doi: 10.18632/aging.103571.
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Regenerating Tissue to Target Disease Pathophysiology With Hyperbaric Oxygen Therapy
The director of the Sagol Center for Hyperbaric Medicine and Research at Yitzhak Shamir Medical Center explained his research with hyperbaric oxygen therapy and explored the potential it may hold as a regenerative treatment.
This is the second of a 2-part interview. For Part 1, click here.
After conducting studies in a number of other conditions, including stroke, early-stage work is now being done to explore hyperbaric oxygen therapy as a possible treatment for patients with mild cognitive impairment, and even dementia.
New data have implied that it may hold promise for those with diseases like Alzheimer and dementia, as a randomized comparison with placebo for 3 months suggested that the oxygen therapy induced cognitive enhancements as evaluated by perfusion magnetic resonance imaging (MRI).
The research was led by Shai Efrati, MD, director, Sagol Center for Hyperbaric Medicine and Research, Yitzhak Shamir Medical Center; and associate professor, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University. All told, it found that a significant group-by-time interaction in global cognitive function was observed compared to control (P = .0017), with the most impressive improvements in attention (net effect size = 0.745) and information processing speed (net effect size = 0.788).
To find out more about hyperbaric oxygen therapy, the promise of these findings, and its future utility as a treatment, NeurologyLive spoke with Efrati.
NeurologyLive: How did you react to the findings and has this prompted any plans for further work?
Shai Efrati, MD: We are very happy to see first of all the correlation between the tissue and the cognitive function. This is great because at the end of the day, we are dealing with physiology, not deep psychology. Psychology is very important, but here we are dealing with pure biology. We have done animal studies, and others have done animal studies, and the main advantage of those is that you can take the brain out, look at it on the microscope—something that we are still not doing on humans.
It’s exciting, and based on this, there is now an ongoing research program with MCI, which is mild cognitive impairment. So not the fully functional brain, it’s a step afterwards. We want to see if we can reverse that as well. We will have to find the optimal candidates—that needs to be defined based on what we see in the biology, not based on the cognitive function. We need to see how far we can take it, meaning, what these the worst patient that can improve with the treatment and we have. We have a lot to learn with regard to that.
Are there any other conditions for which you’re exploring hyperbaric oxygen therapy?
What we have now in our research program includes, of course, stroke—not every stroke is suitable, we need to see the wound and see if the wound is suitable. We also have an ongoing program for TBI or traumatic brain injury; a special focus on the post-concussion syndrome, which is a huge problem; an ongoing program in fibromyalgia, the chronic pain syndrome. Not every fibromyalgia, just the ones where we can see the metabolic dysfunction in the brain.
Generally speaking, it’s looks like we are dealing with a lot of stuff. But we are not. We are dealing with wounds. We characterize the wounds in the brain, and if they are suitable, we will treat them. Now, if this wound was initiated by mechanical injury or by stroke or by hemorrhage, for us, it doesn’t matter because you’re looking at the wound—you’re looking at the final results. You characterize the tissue and then treat it.
This is also something new as an approach. You’re saying, “Okay, I’m dealing with a tissue, let me see what the wound is.” For example, if you have a wound in the leg, it doesn’t matter if a car ran over your leg and caused the problem or somebody hit you in the leg. In the end, it’s a problem that needs to be cured. It’s the same way doesn’t matter if it was induced by that, that, or that. Let’s characterize the wound at the moment, see the physiology, and based on this, make a decision if this can be good for that kind of damage or not. So, it looks like we are dealing with a lot of stuff, but for us, it’s just one thing.
Do you feel that there a specific population of patients with dementia or Alzheimer that might derive benefit from this?
I will start from the group that we have very good efficacy with, which is the mice that have Alzheimer. In mice that have Alzheimer—you can read our publication—we can demonstrate how we can reverse the Alzheimer with this treatment. We can see the amyloid plaque disappearing, the cognitive impairment improving, the brain, all of it. But we are not mice. That’s a small problem.
In human beings, we haven’t done a study in Alzheimer. I think that with Alzheimer, it’s too late. You don’t have tissue. The main issue is to start early, whether it’s normal aging or mild cognitive impairment, it doesn’t matter because with the vascular dementia at the end, you don’t have tissue. But if you start as early as in normal aging, maybe a bit later on in mild cognitive impairment, you still have tissue that can be recovered. That is the main thing. Don’t wait. Start early, keep the tissue, and once you have it, you can continue keeping it up.
Is there a way to identify these patients early enough, or do you think that that’s still going to be a problem with hyperbaric oxygen therapy?
They say a lot about the amyloid because today, it’s quite clear to all of us that the amyloid is not the one that caused the problem. It’s a result of the problem. Once you have continuous inflammation in certain areas of the brain, then you will have the amyloid stuck in over there.
We can say that with confidence today because we know with all the antibodies against the amyloid, we know that they are removing it, but still there is no significant change in the clinical course of the disease. So that’s what we got. For example, if we are treating mice with Alzheimer with hyperbaric, we are not targeting amyloid. We are not moving amyloid out. But as a result of the improvement in the tissue, the amyloid is also declining. Not because we target them amyloid, we are targeting the core issue.
Can we diagnose that early stage? Yes. First of all, you need a certain suspicion, clinical suspicion. People feel that suspicion. If you feel that your cognition is declining a bit, don’t ignore that. That’s the first signal. If you don’t remember the bulk of the page that you just read a couple of minutes before, don’t say, “That’s okay.” Say, “Okay, I have a problem. Let’s see how I can face it.” That’s the first warning sign.
With regard to the brain, if you are doing the type of brain imaging that we have used along the studies, then you can see the decline in perfusion. In normal MRI, you can see some white patches that are popping up all over. That is also a warning sign. The main problem was that until today, we don’t have any biological intervention that can actually do something with regard to the basic of the biology. By doing what we are doing, and what others are now investigating, is to tackle the basic biology that that caused the disease. Not the symptoms, not the neurotransmitter. Those are not the problem. The amyloid plaques are not the problem, they are the results of the pathophysiology process. You need to target the pathophysiology process, not the results of the pathophysiology.
This is this is an understanding we have today in the community. We need to tackle it right away. For example, if you’re changing your habits by playing sports and eating well—which are things that are not related to the brain—in the long term, you’re doing good to your brain because you are reducing the atherosclerosis plaque. You are targeting the basic pathophysiology. It will not go backwards, but you are reducing the rate of the decline. With the hyperbaric oxygen therapy, you can take it backwards because you can generate angiogenesis and other stuff like this. This is the concept.
How quickly do you think this could be used in a widespread fashion, and how expensive would it be potentially for institutions that don’t have access to it to implement it?
Like anything new, when it starts, it cost a lot. You don’t have in a ton of other places. I remember my father with the first cellular phone. He used to have a bag he had to carry all over—you could buy either a house or to buy a cell phone. That was your choice. But today, anybody, everybody can have it.
We have our center in Israel, which is the biggest in the world, where we are treating more than 250 patients a day. Now we have started to have affiliated centers that are working exactly as we are. We are training the physicians, the medical staff. We have the first center built up in the US in Florida, called the Aviv Clinic. It’s a center exactly like we have in Israel. The staff have been trained, they have all the knowledge, all the data. They are doing the same MRI that we are doing over here with the perfusion cognitive test—everything is matched. There are additional centers that are being built all over, and the center that we have now in Florida will be a training center for the additional centers in the US.
It will go but like anything new at the beginning. Unfortunately, it’s not available for all, but it will get there. It will just take some time.
Transcript edited for clarity.
REFERENCE
Efrati S, Fishlev G, Bechor Y, et al. Hyperbaric oxygen induces late neuroplasticity in post stroke patients–randomized, prospective trial. PLoS One. 2013;8(1):e53716. doi: 10.1371/journal.pone.0053716.
