How Many Concussions Are Too Many? Measuring the Cumulative Impact on the Brain with Dr. Joseph Maroon | E79

Dr. Joseph Maroon: 00:01 We're going to get to what we're talking about in terms of dosymetry. How much is too much? So they implanted triaxial accelerometers into this mouthpiece, and then used this in rugby players, and they monitored literally hundreds of thousands of hits to the head. And they found that a 70 G 70 G hit was fairly frequently associated with a concussive blow to the brain. And this subsequently has been mandated for world rugby. And so they took it one step further and they said, so that if there were a 70 G hit and this is in your mouth, your mouth lights up. Dr. Joseph Maroon: 00:55 Your mouth lights up. Dr. Ayla Wolf DAOM: 00:57 Welcome to Life After Impact, the Concussion Recovery Podcast. I'm Dr. Ayla Wolf, and I will be hosting today's episode where we help you navigate the often confusing, frustrating, and overwhelming journey of concussion and brain injury recovery. This podcast is your go-to resource for actionable information. Whether you're dealing with a recent concussion, struggling with post-concussion syndrome, or just feeling stuck in your healing process, know that you are not alone. This podcast can be your guide and partner in recovery, helping you build a better life after impact. Dr. Joseph Maroon, welcome to Life After Impact. Dr. Joseph Maroon: 01:37 Thank you so much, Ayla. Great to be with you. Dr. Ayla Wolf DAOM: 01:40 Yes, it is a big honor to have you on the podcast. You have spent your entire career advancing the science of traumatic brain injuries, concussions, subconcussive hits to the head, repetitive head injuries, and our understanding of neuroinflammation. And you are still going strong. You have so many exciting things that you are doing right now with using mouth guards with sensors on them, looking at glutathione in the brain. I'm so excited to hear everything you have going on. Dr. Joseph Maroon: 02:10 Well, it is. And uh I'm having more fun now uh than I did quite a few years ago because of the research that we're doing and the things that you mentioned. Dr. Ayla Wolf DAOM: 02:22 Yeah. Well, let's dive in. You recently were the lead author on a paper on repetitive head impacts with fast boat operators. And I think that the overarching message here is we need to start looking at people's lifetime exposure burden to repetitive head impacts, which is something you're working on. In medicine, we quantify cigarette smoking exposure in pack years because we know that the cumulative exposure matters. And do you think we need something analogous to repetitive head impacts as a way of quantifying a person's Dr. Ayla Wolf DAOM: 03:00 lifetime exposure rather than simply asking how many concussions they've had? Dr. Joseph Maroon: 03:06 You're exactly right, Ayla. That is what's needed. And that's what we are evolving to, I believe, and what our research uh is involved with now. Um we are well, let me go back. Quite a few years ago, I was the team neurosurgeon for the Pittsburgh Steelers, and I told Coach Chuck Knull, the four-time Super Bowl-winning coach of the Steelers, that his starting quarterback couldn't play against the Dallas Cowboys the next week. He said, Why not? I said, because he had a concussion, and the guidelines say he must stay out a minimum of two weeks. And he said, why not three weeks and why not one week? What data do you have to say two weeks? And he challenged us and me, and I said, you know, you're right. We don't have good data. So he said, if you want me to keep somebody out, I want objective data, not specious guidelines. So I went to a neuropsychologist, Dr. Mark Lovell, a brilliant neuropsychologist with whom I was working then at the Allegheny Health Network. And uh we came up with a test called the impact test and immediate post-athletic cognitive testing. And we subsequently went back and said, if you want objective data, we need to baseline the whole team. Everyone's different. So he and Mr. Dan Rooney, the owner of the Steelers, acquiesced. We did that, and fast forward, the impact test now has become the standard of care in the NHL, NH, NFL, uh, virtually all contact sports, and twenty-five million tests have been done. Twenty-five million. The significance of it is that players were not allowed to return to play after a concussive blow to the head until they've returned to their baseline neurocognitive test. The impact test tests, brain speed, the processing of information, memory. And uh these were things that were not measured prior to that test. Now it's mandatory. It's become mandatory in contact sports. Dr. Ayla Wolf DAOM: 05:45 And there's also a built-in balance component, correct? Dr. Joseph Maroon: 05:48 And a built-in exactly. A sway balance component is also part of the examination. Dr. Ayla Wolf DAOM: 05:54 Right. Because you can't fake good balance. You either have it or you don't. Dr. Joseph Maroon: 05:58 Trevor Burrus, Jr. Exactly. And uh and then it's supplemented with the BOMS, the visual ocular motor sensory examination that is complementary. So that that was a huge step forward. And your question comes to the heart of what's next? Okay, you Dr. Joseph Maroon: 06:20 can't go back until you cleared, but how many concussions are too many? How many when should you quit? Is there cumulative damage to the brain with repetitive hits to the head? And it gets back to your initial question when we recently published in Neurosurgery, the journal Neurosurgery, we surveyed 194 special warfare combat crewmen, SWCC, special warfare combat crewmen. These are the men who transport Navy SEALs to hot spots, various parts of the world. And they drive these high-speed boats, 30, 40, 50 miles an hour over waves two to ten foot tall. So when they're on waves, every second, every second, they have what's called wave slamming. So there's axial loading of the spine, flexion and extension of the neck, and virtually all of them had either a history of concussives, concussions, brain and or cervical, thoracic, and lumbar spine disorders from the axial compression of wave slamming like this, thousands of times. And there have been recently two articles in the New York Times, one on the Coast Guard, Coast Guard individuals who do the same thing in terms boats, as well as the SWIC operators. So we surveyed with the help of Anthony Smith and Sam Wakeland, a brilliant medical student. Uh we surveyed 194 of these SWIC operators and asked them pointed questions and concluded that virtually all of them had brain and or spine pathology and complaints. And some of these complaints were, many of them were multifactorial, multi-system, not only headaches, memory, mood, autonomic nervous system disorders. And because of the plethora and the multiplicity of complaints, oftentimes they were considered psychiatric disorders. And when it was underlying the neuropathology of the brain andor spine and pain, that was the pathogenesis. So that that's part one. So part two is how much is too much? You know, how do you how do you measure these? And that leads to another story. Uh, and the story is that of two neurosurgeons and a biomechanical engineer. Dr. Ed Benzel at the Cleveland Clinic, a nurse surgeon, and Dr. Vince Miel, a nurse surgeon at the University of Pittsburgh, collaborated Dr. Joseph Maroon: 10:01 with Ed Benzel, a brilliant biomechanical engineer in Cleveland. And Dr. Miel was a former boxer, believe it or not, as a nurse surgeon. He was a boxer becoming coming into nurse surgery, and and they knew that boxers wear mouthpieces. And he suggested to Ed to Adam Bartz and Ed Benzel why don't we put accelerometers in the mouthpiece so we can measure the location of a hit to the head, the number of hits, and the G forces that occur in terms of linear or rotational acceleration. Genius. It really is. I mean, this is you know, I'm we're we're very pleased with the impact test as a huge step forward in prevention, preventing athletes from going back when their brains are more vulnerable to getting hit again. Dr. Ayla Wolf DAOM: 11:11 Right. And providing a very easy-to-apply baseline test, too, which was what was missing until you developed that. Dr. Joseph Maroon: 11:18 Yes. 15-minute tests, 15 to 20 minute test. So with this, we're going to get to what we're talking about in terms of dosimetry. How much is too much? So they implanted triaxial accelerometers into this mouthpiece. And then investigators in Ireland and the Great Britain used this in rugby players and they monitored literally hundreds of thousands of hits to the head in rugby players. And they found that a 70 G 70 G hit was fairly frequently associated with a concussive blow to the brain. Dr. Joseph Maroon: 12:16 And this subsequently has been mandated for world rugby. Dr. Joseph Maroon: 12:24 And so they took it one step further and they said they implanted an LED into the mouthpiece so that if there were a 70 G hit and this is in your mouth, your mouth lights up. Your mouth lights up. Dr. Joseph Maroon: 12:44 You can't hide it. You can't hide it. You can't pretend. Dr. Joseph Maroon: 12:47 You can't run from it. That's right, literally. So now we have a device. It's a checkpoint. It's like in your automobile, check your engine, check your oil. Your tires are too low. The red light goes off. It doesn't mean that you're going to have a wreck. It doesn't mean you're damaged. But it means you better check and see if this individual had a concussive blow to the head. Dr. Ayla Wolf DAOM: 13:17 Right. And now I know they've spent so many years putting accelerometers in helmets. It almost seems like a mouth guard would, as you mentioned, be able to better determine some of these rotational forces than something in a helmet. Dr. Joseph Maroon: 13:35 The helmet accelerometers compared to this are 50% inaccurate in terms of their measurements because of the rotation of the helmet and the movement. And they've compared individuals wearing this with accelerator accelerometers in the helmet. And if you draw a chart and a line, this is on the line. The hits from the accelerators and the hemeter on in the helmet is a scattergram. They're all over in terms of measuring the actual forces. So this is the most b this is attached to your skull. It's accurate. It's not going to give you a specious reading from rotation of the head or this or that. So it really gives you a very good very good indication of what I said. In real life, what has happened, those patients, those individuals who are removed don't all have concussions. In fact, more are returned to the game than actually are removed from the game, which is always a concern for the player. You're taken out, I'm no. So it's been a huge safeguard. To get to the other point, so now we have impact for cognitive testing. We have this for measuring the forces and the number Dr. Joseph Maroon: 15:20 of hits. But what we want to know is how much energy is transmitted to the human brain when you get hit in the head. Energy is equal mass, half the mass times velocity squared. Half mass times velocity squared. Force is actual is measured by mass times acceleration. But energy, kinetic energy, is what gets transmitted to the brain. So how do you measure that? On your iPad, sitting in the stands, actually sitting in a laboratory, this data is transmitted immediately, real time, to an iPad, a phone, a computer. And when a hit occurs, there's an immediate spike of force, and then a defervescence down. How long that contact is made with the head and the force involved. Now you have a curve, and with computational analysis, you can calculate the energy under that curve. And energy is measured in joules J-O-U-L-E-S. You can't summate G forces. Dr. Joseph Maroon: 17:04 You can joules. Dr. Joseph Maroon: 17:07 So what we now have the possibility of calculating from a kid playing Pop Warner football to high school, college, and the pros, we have the real possibility of calculating the amount of energy this individual has experienced in terms of to the brain. Dr. Ayla Wolf DAOM: 17:34 And your example off air of the radiologist that has on their jacket a sensor that basically is tracking how much exposure they've had to radiation. When that sensor goes off, that's the indicator you've been exposed to too much. Dr. Joseph Maroon: 17:55 Yeah, that's called a dosimetry badge. And the little things that are sensitive to radiation that picks up the ambient radiation in the area, and it's recorded. And it tells you how much radiation you've been exposed to. Cumulatively. Cumulatively. And I believe, I believe that's where we're we're getting close with this. And then there's two other studies that are being conducted by, again, incredibly bright, brilliant bioengineers at Penn State and Carnegie Mellon University. Reuben Kraft at Dr. Joseph Maroon: 18:40 Penn State and Brad Mayhome at Carnegie Mellon are looking at things that are kind of over my head, so to speak, in terms of finite analysis analysis of MRIs. We now can see the white matter tracks, the axomes. We have our gray cortex, which is primarily the 86 billion neurons in our brain, connected with 100 trillion synaptic connections. The outer cortex, cortex means bark. The cortex of our brain is gray from the cell bodies. The axons, which emanate from the neurons, form the white matter tracts through the brain that come together to form networks, hubs, and the wiring diagram of the brain, which is called the connectome. When there's a rotational or axial force to the brain, there can be shearing of the gray matter, which is denser than the white matter. And you can get exonal disruption from shearing and strain of the white matter. Dr. Ayla Wolf DAOM: 20:08 And now that damages the microtubules inside the tracks, which then I liken it to almost like you've got a tunnel where maybe the outside of the tunnel looks like it's intact from an aerial view, but inside the tunnel you've just had something that created damage where maybe now you've got a bunch of debris inside that tunnel. Dr. Joseph Maroon: 20:39 So yeah, that's it. So no, I I again we go from impact to in-mouth sensors to now extracting that data with computational analysis to get a summation of how much is too much. Now, that last part is hopeful speculation that we will be able in the next five years, four years, three years, I don't know. But there's a foundation in Pittsburgh called the Chuck Knoll Foundation, who hired me uh a hundred years ago with the Steelers. And but it's named after Chuck Knoll, Art Rooney, the owner of the Steelers, uh founded this to support basic research, primarily in traumatic brain injury associated with sports. And they get requests for proposals and proposals uh every year from across the country and actually from other countries for research proposals to assess biomarkers for concussions, blood, sweat. Uh saliva that may indicate a pregnancy test for concussions, so to speak. And uh and two of these tests are from Brad Mahona, Carnegie Mellon, and uh Ruben Kraft at Penn State. So they now are they've done MRIs of the brains of college and high school athletes and measured diffusion tensor imaging, which is visualizing the white tracks, the axons in the brain. And then here in Pittsburgh, at a local high school, Aliquippa High School, they've scanned the team, they're all wearing these mouth guards, and they are able to monitor at a distance on their computers everything I told you from every hit to the head in every player on the team. And using, again, computational analysis under the curve, determining the energy level and correlating it with the white track changes in the MRI before and after the season. Dr. Ayla Wolf DAOM: 23:38 Wow. Hugely meaningful data. Dr. Joseph Maroon: 23:41 It is well, believe me. Dr. Ayla Wolf DAOM: 23:44 Yeah, that is so important. Dr. Joseph Maroon: 23:47 Yeah, I mean, it's a whole new world in terms of and all of this, of course, impacts the contact sports world and the professional athletes and the problem of neurodegeneration, like in Alzheimer's, like in Parkinson's disease, that can occur with repetitive hits to the head, and that we are now doing a study for anyone listening on individuals who have had repetitive hits to the head, former NFL players, NHL players, Navy SEALs, SWIC operators, and those who have had repetitive head hits, were actually paying for them to come to Pittsburgh, have an MRS spectroscopy scan of their brain, look at their microbiome because of the gut-brain connection, and scan them, monitor their glutathione just like I showed you, and put them on a precursor to glutathione called gamma glutamilcysteine, which is an over-the-counter product, continualg.com, that that I take daily as whether as well as other compounds that enhance my glutathione level. Dr. Ayla Wolf DAOM: 25:32 And so the idea is that you're giving the body in the brain the precursors it needs to make glutathione, which is essentially they call it the master antioxidant, and in the brain it helps to modulate the reactive oxygen species that can cause further inflammatory processes to occur? Is that how you would explain it? Dr. Joseph Maroon: 25:54 You said it beautifully. Not you, but I'm gonna give the audience a test question. Speaker 2: 26:00 Okay. Dr. Joseph Maroon: 26:01 Okay. Dr. Joseph Maroon: 26:02 So whoever's listening to this, if you peel a banana or cut an apple in half and you leave it out overnight, what color does it turn in the morning? Dr. Joseph Maroon: 26:15 Brown. It turns brown. Why? Oxidation. It oxidizes. If you put lemon juice on the apple, what happens? It doesn't turn brown as quickly. It doesn't turn brown because lemon juice is an antioxidant. Right? Dr. Ayla Wolf DAOM: 26:33 Mm-hmm. Dr. Joseph Maroon: 26:35 Glutathione is the lemon juice for the brain. Dr. Ayla Wolf DAOM: 26:40 I love that analogy. Dr. Joseph Maroon: 26:41 It prevents it from turning brown, which is called Alzheimer's Parkinson's CTE. Dr. Ayla Wolf DAOM: 26:49 And you've been able to measure glutathione levels in the brain and correlate that to different diseases. Dr. Joseph Maroon: 26:56 Yes, for the first time. And that I say that you said you. I have to give credit to Dr. Pravat Mandel. Dr. Pravat Mandel was the former director of the Indian National Brain Research Institute for all of India. And again, another brilliant neuroscientist who is a world specialist in magnetic resonance spectroscopy. And we were able to recruit him to the University of Pittsburgh. And that's where the studies are now going, building on his lifetime work measuring various chemicals in the brain. Not only can you measure glutathione, the main antioxidant, but with special coils, you can measure phosphorus, lithium, and other agents. By measuring phosphorus, you can actually measure the amount of ATP in the brain. You know, that's for me. You know, I'm a I'm I'm a dumb neurosurgeon in the sense that, you know, I kind of a brain mechanic, removing tumors and blood clots and things like that. Structural problems of the brain. But we we're now getting into the functional aspects of the brain, how the brain functions, structure and function. What do I mean by function? Things like schizophrenia, major depression disorders, anxiety. These all have chemical neurofootprints. And we now, with the neuroimaging that's available and becoming available, are able to correlate neurochemicals in the brain with some of the functional disorders of the brain. Not just neurodegenerative. Dr. Ayla Wolf DAOM: 29:08 And it really seems like the research has focused so much more heavily on mitochondrial function, with, of course, the mitochondria being the powerhouses that produce this ATP. So you're finding ways of being able to actually look at the phosphorus levels and extrapolate the level of mitochondrial health and being able to produce amounts of ATP? Dr. Joseph Maroon: 29:34 That's yes, that's our research interests. And again, for your audience, you're talking about free radicals and mitochondria and all that. There's another analogy, I think, that helps people understand. If you're driving a combustion car engine, not a Tesla, but a combustion car engine, you burn gasoline to make energy to move your car forward. But what comes out of the gas pipe? What comes out is carbon monoxide, carbon dioxide, and other toxins. When your mitochondria take sugar and oxygen and make energy, ATP, it generates carbon monoxide called free radicals. If the free radicals aren't squelched by antioxidants, they oxidize the brain. So glutathione is the main antioxidant that squelches the free radicals, which, if unsquelched, destroys mitochondria and causes what you mentioned oxidative stress. And oxidative stress is the underlying pathogenesis of AD, PD, CTE, and others, ALS. And drug companies have spent billions of dollars, billions, to develop antibodies to remove beta-amyloid plaque from the brain. Dr. Ayla Wolf DAOM: 31:07 Which is also a byproduct, not a front-end problem. Dr. Joseph Maroon: 31:13 Our hypothesis, and we just published this a month ago in the Journal of Alzheimer's disease, is that oxidative stress is a precursor. It's the upstream that causes and is associated with the beta amyloid and the neurofibrillary tangles and taupathy. So again, we're approaching the pathogenesis, the free radicals, oxidative stress that results, we believe, in the neurodegenerative disorders. Dr. Ayla Wolf DAOM: 31:53 And why use the gamma glutamylcysteine a precursor to glutathione versus using Dr. Ayla Wolf DAOM: 32:00 actual glutathione? Dr. Joseph Maroon: 32:03 Excellent question. I'm you know, I used to say I'm in the fourth quarter, but I'm now in overtime. Dr. Ayla Wolf DAOM: 32:14 And going strong. Dr. Joseph Maroon: 32:18 But I'm concerned about my own mental health. One in three people my age have Alzheimer's disease. And so I've been very interested in how to preserve brain function. So several years ago, I contacted a Dr. Wallace Bridges, University of New South Wales in Australia. And they had a compound, this precursor to glutathione, that I was interested in trying myself. And so I contacted them and I said, you know, this is great to take this, but how do I objectively measure whether it's doing anything in my brain? So they said, you know, there's this fellow in India who is doing MR spectroscopy to measure glutathione in the brain. So I contacted Pravat Mandel four years ago. And he and I, so I went from Austral Pittsburgh, Australia, Gergon, India, Pittsburgh. And I we got in contact and we started talking and actually uh doing research together. And that's how I got him here. But your question was exactly that. So how do we get, how do we increase glutathione in our brain and know it and document it, not just say, well, I feel better, I'm thinking better, and document. So that's what how the circle got completed, measuring it in the brain. And to your question, with Parkinson's disease, dopamine is a deficient neurotransmitter. Dopamine is a large molecule that doesn't cross the blood-brain barrier well. Glutathione is similar unless it's taken as a precursor and possibly transdermally. There's some thinking that transdermal, liposomal glutathione may also get into the brain. Glutathione is primarily made, constructed intracellularly. So it has to get into the cells. And we believe that gamma-glutamyl cysteine, which is a precursor to glutathione and the chemical development of it, will is a smaller molecule and will cross into the blood-brain barrier. And there's evidence from Australia and Wallace Bridges and others who with his colleagues that uh this does, this is the case. Dr. Ayla Wolf DAOM: 35:30 And how is this different from Nacetylcysteine, which many people do take for their brains because it donates a cysteine to be able to allow the body to produce glutathione, and cysteine is often kind of part of that rate-limiting step of production. How is this different from N acetylcysteine? Dr. Joseph Maroon: 35:49 Trevor Burrus, Jr. Dr. Joseph Maroon: 35:49 That's another very prescient question. So if you think of the molecule of glutathione, you're exactly right. You have cysteine and glutamine coming together through a enzyme, glutamylcysteine ligase, to form gamma glutamylcysteine. Dr. Ayla Wolf DAOM: 36:15 Gotcha. Dr. Joseph Maroon: 36:17 Gamma glutamylcysteine picks up glycine to make glutathione. Dr. Ayla Wolf DAOM: 36:23 And most of us have plenty of glycine floating around. Dr. Joseph Maroon: 36:26 Yes. But as we get older or if we get hit in the head too much, glutamine cysteine ligase, which is the enzyme that brings these two together, becomes deficient. And also N-acetylcysteine, cysteine also is deficient. So if you what's the most common cause of poisoning of the liver? Besides alcohol. Dr. Ayla Wolf DAOM: 36:58 Oh, besides alcohol? Dr. Joseph Maroon: 37:00 Alcohol and Tylenol. Tylenol is the most common cause of liver transplantation. Overdose of Tylenol. Somebody comes in to the ER with an overdose of tylenol, they give them N-acetylcysteine. They give them because the cysteine will enter into that equation to form glutamil or get gamma glutamilcysteine and then glutathione. Dr. Ayla Wolf DAOM: 37:28 But this product just gets people one step further down that biomechanical pathway to make it easier to then get to the glutathione. Dr. Joseph Maroon: 37:38 Precisely. Dr. Ayla Wolf DAOM: 37:39 And are you saying that the gamma-glutamylcysteine also is able to cross the blood-brain barrier better than the glutathione molecule itself? Dr. Joseph Maroon: 37:49 Better than the g yes, that is our that is our hypothesis. And also that glutathione itself, when taken orally, very poor absorption going through the GI tract, the stomach, and all. So very little, we believe, of most oral glutathione products get absorbed. But we these are things that we need to compare various products. We need to do a whole lot of stuff to confirm our hypotheses. But at the present time, we're encouraged by what we're seeing in patients with Parkinson's disease that we are studying. And we're also, as I said, the very large study supported by the Chuck Knoll Foundation of former NFL and HL players. And uh if you know any of these who are complaining of behavioral or memory issues, have them contact me. Dr. Ayla Wolf DAOM: 39:00 I know a lot of MMA fighters. I can probably send your directions. Dr. Joseph Maroon: 39:04 Please, we are interested in MMA fighters. Really? I really am. I mean, if you have names, we would be we'll pay them to come to Pittsburgh, give them an honorarium and put them on uh a year's supply of gamma glutamilcysteine free. Dr. Ayla Wolf DAOM: 39:23 Okay. Well, I know one that has a podcast, so he can also probably help spread the word. Dr. Joseph Maroon: 39:28 Please. I really mean that. I think it's a lot of opportunities here. Dr. Ayla Wolf DAOM: 39:34 Well, and you have spent your entire career studying neuroinflammation. So the fact that you have landed in a place that is researching an actual product that could be available to everybody, probably much more affordable than, you know, drugs that are $1,300 a month. Um, and that can have actionable effects on brain health, I think is tremendous. And that's what the world needs. People are so afraid of how their brain is going to age. And people are afraid of Alzheimer's, they're afraid of Parkinson's, they're afraid of CTE. To be able to do something supportive and have the research to back it up is what the world needs. Dr. Joseph Maroon: 40:21 Well, we're we're um again. Um I I'm very concerned. I see so many of my friends and associates and players that I've worked with through the years developing mild cognitive impairment. You know, where's my car? Where's my keys? Where did I go to the store? These sorts of things. So I'm very interested in complementary approaches to this. And I Dr. Joseph Maroon: 40:56 feel that we're going to hear a lot more about hyperbaric oxygen therapy. Uh I personally went through 60 dives myself and measured everything possible before and after, and actually did a triathlon before and after, and published it in Frontiers in Neurology. Uh I think photobiomodulation, the use of red light therapy, is going to have a significant role to play in modulating neurofunctional aspects of the brain. And I think Sound and Light. There's a company called Cognito Therapeutics, which has a goggles and earphones together that builds on work done at MIT three to four years ago in which they the investigators showed that in patients with Alzheimer's, there's a in the EEG, there's a marked deficiency of gamma waves, gamma frequency waves in the brain. And they've done studies using light and sound energy sources that actually reduce the beta-amyloid plaque in experimental animals that are programmed to have Alzheimer's disease like thing, and also working with investigators at West Virginia University for people to use sound and light energy sources to treat, neuromodulate patients with mild cognitive impairment and maybe Alzheimer's. Dr. Ayla Wolf DAOM: 43:05 So You recently wrote a review paper looking at the science behind a lot of these technologies, the photobiomodulation, the HBOT. Has that been published? Dr. Joseph Maroon: 43:17 No. We've submitted it for publication. But there are a lot of papers on HBOT. Shy Afradi is a again another genius neuroinvestigator from Tel Aviv who treats 300 patients a day in Tel Aviv with HBOT. Well with all sorts of things from non healing wounds of the extremities, which insurance pays for in this country, but they don't pay for non healing wounds of the brain. PTSD, post concussion syndrome. And stroke, traumatic brain injury. And I think HBOT has a place in all of those as a therapeutic modality to increase oxygen, to increase BDNF, brain-derived neurotropic factor, which enhances neuronogenesis, the formation of new brain cells, synaptogenesis, new synapses, and neuroplasticity. So these are all modalities that I really think presently, if you you unfortunately, if you have early Alzheimer's or MCI, you know, you get lacanimab or one of the antibody drugs to remove the beta-amyloid plaque, which has a 20% complication rate in terms of intracranial hemorrhage and cerebral edema. But after that, it's go make out your will and enjoy your last days. And I think we're missing the opportunity to use various energy sources like sound, light, ultrasound, to neuromodulate, upregulate, downregulate the exonal potentials in the brain. Dr. Ayla Wolf DAOM: 45:23 Well, and the HBOT has a huge effect on those reactive oxygen species and the oxidative stress that we've been speaking about. I just recently interviewed Dr. Joe DeTouri, who's on the team doing one of the largest HBOT studies on veterans with TBI, and they've got 420 people they're enrolling in that study, doing DTI before and after, and a whole host of blood biomarkers that they're planning on banking so that if in the future they need to go back and look at those for you know other compounds that become important, they're going to have that data banked. Dr. Joseph Maroon: 46:01 Where's he doing that? Dr. Ayla Wolf DAOM: 46:03 Out of Florida, University of Florida. Dr. Joseph Maroon: 46:05 Oh, the University of Florida. Okay, yes. I know. They got a huge grant, $23 million grant. Dr. Ayla Wolf DAOM: 46:11 Yeah. Dr. Joseph Maroon: 46:12 I think to do that. Yeah. That's it's really f it's great study. I mean, well, we can talk another hour or two about H, but I I think there clearly is a place for it. I've seen personally incredibly dramatic results in the Navy SEALs, couple Navy SEALs with PTSD. They were in Iraq and Romali uh and uh severely traumatized, not only by what they saw, heard, smell, but also the IEDs, breachers blowing up doors and all this stuff. And and uh d dramatic result in terms of ameliorating the fear, the reactions to stimuli. Dr. Ayla Wolf DAOM: 47:04 With HBOT? Dr. Joseph Maroon: 47:05 With HBOT. Dr. Ayla Wolf DAOM: 47:06 Okay. Yeah. And do you feel that ever since the pandemic and the COVID virus and people being exposed to that, that we do have a lot more neuroinflammation or oxidative stress that people are dealing with? Dr. Joseph Maroon: 47:25 Well, clearly COVID caused uh oxidative stress, not only the brain, but also the heart. You know, I've seen several patients that have had myocarditis. Um and and all of this it gets into an energy factor. And um there's a very good book uh I think it's Brain Energy by a psychiatrist uh from Harvard who correlates various psychiatric disorders with oxidative stress. And we know in PTSD, we know in depression, if you do spinal tap and look at the cytokines, there's an elevation in the inflammatory cytokines, in Leukin 6, 12, 8. And so psychiatric disorders also are a neuroinflammatory process. And when you're under tremendous stress from a divorce, from a child, the sick or dying, from a job in which you've been fired, as you know as well as anyone in the world, Ayla, there's a huge fight or flight response, endocrine response, neuroendocrine, and elevation in cortisol. And cortisol is neurotoxic to the brain when in excess. Destroys the hippocampus and uh also is associated with neuroinflammation of the brain. So, you know, whatever we can do to reduce inflammation, and HBOT is anti-inflammatory, it reduces inflammation. Initially, there is some oxidative stress associated with HBOT, but the body uh adjusts to that and then it becomes anti-inflammatory. It enhances mitochondrial biogenesis, it makes new mitochondria, and this has been shown by Shire Fraudy, middle-aged athletes, he biopsied their gluteal muscles, looked at the mitochondria, gave them 60 treatments, 40 treatments of HBOT, re-biopsied the gluteal muscles, and showed mitochondrial biogenesis. You can't get any more dramatic. It enhances mitochondrial biogenesis, it's anti-inflammatory, makes BDNF, and also new stem cells. Dr. Joseph Maroon: 50:10 So uh it's a very important modality. Dr. Ayla Wolf DAOM: 50:17 Absolutely. I've read that book. I was trying to recall the author's name, and uh I looked over my bookshelf, but my bookshelf is too far away. But yeah, good book. Dr. Joseph Maroon: 50:26 It really is. Uh I I'm what we're doing, you know, I initially I talked about me being a mechanic, so to speak, a structural, I I dealt with structural problems of the brain, but it's the functional problems of the brain and what we're doing, and what you're you're you're very astute in what you were mentioning about oxidative stress, and bringing the functional and the structural pathologies together under a common rubric of oxidative stress and and uh mitochondrial dysregulation. Dr. Ayla Wolf DAOM: 51:12 And have you studied creatine? Dr. Joseph Maroon: 52:47 I think creatine is an outstanding product. I take it every day. Uh I think in terms of its function on the brain, again, and enhancing ATP uh production and function. Uh there are clearly good studies showing that it can facilitate memory, enhance memory. Uh and in older patients, again, it's another thing that's frequently deficient. Uh and and I for muscle mass building, you know, weightlifters and and other athletes have known about creatine for many years uh to enhance muscle enhancement. But recently there have been quite a few papers. If you if you chat GPT, Dr. Claude, uh or whatever, creatine and brain health or brain function and memory, you'll you'll get 30 articles. Dr. Ayla Wolf DAOM: 53:53 Right. I I did stumble across a couple of the mass spectrometry studies looking at creatine in long COVID and showing some depletion of creatine after COVID. So there's definitely a lot of resurgence in looking at creatine as far as brain health now. Dr. Joseph Maroon: 54:12 Yes, glutathione is definitely deficient in long COVID. Again, the oxidative stress. It uses up the glutathione intracellularly. Dr. Ayla Wolf DAOM: 54:23 Yeah. Well, I know I've taken up a lot Dr. Ayla Wolf DAOM: 54:25 of your time. Why don't you let people know one more time how they can find your study that you're enrolling people in to measure uh the precursor to glutathione? Dr. Joseph Maroon: 54:36 Uh yes. You you can write to me directly, uh you know, maroonjc at gmail.com, and I'll connect you with Dr. Mandel and his research associate, and uh be happy to send the information to you. Dr. Ayla Wolf DAOM: 54:56 Fantastic. And then the the gamma glutamylcysteine that you take, what was the company that makes it? Dr. Joseph Maroon: 55:05 Continualg.com is the website. Dr. Ayla Wolf DAOM: 55:09 Okay. Dr. Joseph Maroon: 55:10 Yeah. Dr. Ayla Wolf DAOM: 55:11 Excellent. Anything else we haven't touched on yet today that you wanted to talk about? Dr. Joseph Maroon: 55:18 No, I think this has been a uh a very, very good session. I'm um you're very good at eliciting a lot of information from the Stay Curious, right? Stay curious. This was totally unprepared, uh spontaneous. So uh it came it came out well. Dr. Ayla Wolf DAOM: 55:41 As I said, it's such an honor to talk to you, and I love the direction that you're heading with your research. I think it's gonna help a lot of people. So I'm just very impressed by your entire career. Dr. Joseph Maroon: 55:54 Thank you, Ayla. I've been fortunate. An attitude of gratitude. Dr. Ayla Wolf DAOM: 55:59 Wonderful. That's good for longevity too. Medical disclaimer. This video or podcast is for general informational purposes only and does not constitute the practice of medicine or other professional healthcare services, including the giving of medical advice. No doctor-patient relationship is formed. The use of this information and materials included is at the user's own risk. The content of this video or podcast is not intended to be a substitute for medical advice, diagnosis, or treatment, and consumers of this information should seek the advice of a medical professional for any and all health related issues. 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