How to Improve Brain Health Offset Neurodegeneration Dr Gary Steinberg

Welcome to the Huberman Lab podcast, where we discuss science and science-based tools for everyday life. I'm Andrew Huberman and I'm professor of neurobiology and opthalmology at Stamford School of Medicine. My guest today is Dr. Gary Steinberg. Dr. Gary Steinberg is medical doctor, PhD, professor of neurosurgery, neurosciences, and neurology at Stanford University School of Medicine. He is world expert in what is called the cerebrovascular architecture of our brain, which is scientific term explaining how blood flow to the brain supplies oxygen and critical nutrients to our neurons, our nerve cells, as well as playing critical role in removing waste products from our brain in order for our brain to function normally. During today's discussion, he explains in very clear terms how blood flow to the brain occurs and how disruptions in blood flow in things like stroke and aneurysm impact brain functioning. We also discuss concussions and TBI or traumatic brain injuries which unfortunately are very common and what can be done to treat concussion and traumatic brain injury. Dr. Steinberg also shares with us recent findings from his laboratory and clinic revealing how stem cells can be used to recover function in the human brain and spinal cord after things like concussion, TBI, stroke and other disruptions to the cerebrovascular architecture. and he shares with us the science supported tools that is protocols that any of us can use to improve the health and functioning of our brains. So if you or somebody that you know has experienced concussion or traumatic brain injury, stroke or aneurysm, today's discussion is sure to include vital information for you. And for those fortunate enough to not have experienced those conditions, today's discussion will also review the latest science and protocols for improving brain health. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is however part of my desire and effort to bring zerocost to consumer information about science and science related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast. Our first sponsor is eight. Eight makes smart mattress covers with cooling, heating, and sleep tracking capacity. Now, I've spoken many times before on this podcast about the fact that sleep is the critical foundation for mental health, physical health, and performance. Now, one of the key things to getting the best possible night's sleep is to control the temperature of your sleeping environment. And that's because in order to fall and stay deeply asleep, your body temperature actually needs to drop by about 1 to 3°. And in order to wake up feeling refreshed and alert, your body temperature actually has to increase by about 1 to three degrees. 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AeroPress achieves this because it uses very short contact time between the hot water and the coffee. And that short contact time also means that you can brew an excellent cup of coffee very quickly. The whole thing takes only about 3 minutes. started using an AeroPress over 10 years ago. And learned about it from guy named Alan Adler, who's former Stamford engineer who's also an inventor. He developed things like the Aerobi Frisbee. In any event, I'm big fan of Adler inventions. And when heard he developed coffee maker, the AeroPress, tried it and found that indeed it makes the best possible tasting cup of coffee. It's also extremely small and portable. So, started using it in the laboratory when travel on the road and also at home. And I'm not alone in my love of the AeroPress coffee maker. With over 55,000 five-star reviews, Aeropress is the best reviewed coffee press in the world. If you'd like to try Aeropress, you can go to Aeropress.com/huberman to get 20% off. AeroPress currently ships in the USA, Canada, and to over 60 other countries around the world. Again, that's aeropress.com/huberman. usually mention this at the end of episodes, but if you're learning from and or enjoying the Hubberman Lab podcast, please click the subscribe button on YouTube. And if you listen to the podcast on Spotify or Apple, make sure you click the follow tab on Spotify and or Apple. And on both Spotify and Apple, you can also leave us up to five-star review. And now for my discussion with Dr. Gary Steinberg. Dr. Gary Steinberg, welcome. Thank you, Andrew. Pleasure to be here. have lot of questions. know people are interested in keeping their brains healthy and sadly things happen to the brain. sometimes as consequence of aging, sometimes as consequence of certain activities. Maybe you could just explain for us right off the bat. What is stroke? What is an aneurysm? What is hemorrhage? Where do these terms overlap? How are they different? Obviously, none of us want these things. and we will talk about ways to prevent them and your ways of treating them as well, of course. But just to start off, maybe we can just lay down the nomenclature. Sure. So stroke is like heart attack of the brain. it involves disruption of blood flow to the brain either in the form of blocked vessel or less likely hemorrhage. About 87% of strokes are due to clot either forming in the brain artery itself or forming closer to the heart in the heart or in the corateed artery and dislodging and blocking blood flow to the brain. About 13% are caused by hemorrhage, bursting of blood vessel and that results in lack of oxygen and glucose being delivered to the brain cells and that ultimately causes death of tissue and disruption of bodily functions, neurologic function. That's what stroke is. How do we know if we have clots residing in our body that could be dislodged? know that some people when they fly will wear compression socks. know that some people have genetic mutations that affect clotting. I'll raise my hand here and I'll do disclosure. did some genetic testing. am hetereroygote for factor 5 lighten which is clotting factor. hetererozygote folks means have one mutant copy. So fortunately don't suffer from excessive bleeding or clotting but there are lifestyle factors that can exacerbate an existing mutation like that. People who are homozygous mutants for factor 5 lighten of course at much greater risk for clotting and bleeding. so just disclosed lot. maybe you could comment on some of the clotting factors and lifestyle factors that impact clotting. How would somebody know if they're like they've got clot that could potentially go to their brain? Sure. Well, you might not know. In many cases, you don't know. and that's the problem. You can have predisposition as you say due to certain genes that are mutated or represented that predispose to to clots. And those clots can occur on the arterial side or the venus side. The arterial side is what generally causes stroke, an eskeemic stroke. on the Venus side, you can sometimes have problems. when you talk about flying not moving your legs, developing clots in your legs, wearing compression boots, that's on the Venus side and that can cause something like deep vein thrombosis which is not good because it can travel to the lung and cause pulmonary embolis that generally on the Venus side does not go to the brain. good. In my case, that feels fortunate. Yeah, exactly. you can develop some venus problems in the brain which can cause venus tri type stroke. That's much less common. And the way that causes stroke is not lack of blood flow being delivered to the brain but by having clot in an important vein. The blood can't get out of the brain. It backs up and causes swelling or edema. but that's much less common. generally we talk about strokes as being arterial in nature. and you know either that either blockage of blood vessel or bursting of of vessel. What are some things that impact clotting and or excessive bleeding? my understanding is these factor 5 liden mutations are one example. The other is let's say somebody takes say blood thinning agent like baby aspirin or told and I'll have to check this. I'm sure people will say in the YouTube comments that if you take lots and lots of say fish oil or things like that you can become more of bleeder. Some are people out there are hemophiliacs. And then my understanding is also that certain forms of oral contraception for women can increase the rates of bleeding. so tell me if I'm wrong about any of those and if any of those things predispose people to more stroke or hemorrhage. Sure. So, different kinds of drugs thin the blood and they can predispose you to having larger hemorrhage than you would if something bursts or if you fall and have some traumatic injury to your brain or anywhere in the body. in general, they don't cause hemorrhage because they're fairly safe. But if there's as say some is some interruption to the to the body like bruise it would be much worse type of bleed. so aspirin is type of antipllet agent that thins the blood. There are many types of antiplatlet agents and they're very very useful for treating people who have predisposition to develop clots because they thin the blood. Anti-coagulants are another type. they're they're called they're known as couadin, warferin, eloquis. There's lots of lots of new agents. and they're often taken orally or can be given introvenously. Hepin is another one. again, they thin the blood so they would put someone at somewhat increased risk for hemorrhage. then as far as oral contraceptives, if you go back to the 1970s when the oral contraceptives were first generation were coming out, it turns out and they were heavily estrogen dominated rather than progesterone. they did and they still to some extent increase the risk of developing clouds. So women back in the 70s who took oral contraceptives and smoked had very very high incidence of developing clots and and es schemic strokes and clots elsewhere in the body. The newer generations are are much safer in terms of de developing clots. But for my patients many of whom have had strokes or at risk for stroke, we recommend that the women do not take oral contraceptives that they use some other form. IUD for instance may have little bit of progesterone which is released locally but it doesn't cause large increase in estrogens or or progesterone systemically. So we still believe that the oral contraceptives increase the risk somewhat not the way it did for first generation. And then there are other modifiable factors besides the genetic ones. So smoking is very high risk factor for developing clots which can lead to strokes, heart attacks, peripheral vascular disease. high lipids is another. So, when people have high bad cholesterol, LDL, it's recommended that if they can't reduce it with diet that they take statin. the statins are very very effective in lowering the bad cholesterol, preventing strokes and heart attack. Interestingly, the statins have also been shown to be highly beneficial for the for the blood vessel integrity even if you don't have high LDL. Interesting. So, they have other beneficial properties. So, again, for my patients, often recommend they take statin even if they don't have high cholesterol. Interesting. And then hypertension is another risk factor for for developing clots and and arterial disease. When you say that smoking dramatically increases the risk of stroke, is that because of nicotine per se? Is it the vasoc constriction and blood pressure elevation that comes from nicotine itself? Or is there something about smoking, maybe even vaping? don't know that the contaminants, the other chemicals in cigarettes or vape chemicals that increases the stroke risk or is it nicotine itself? It's not just nicotine. Nicotine is one of the factors, but it's the other products that are produced by by smoking that that can have an effect. So given that so many fewer at least Americans and think worldwide people are smoking less are we seeing less stroke? Yes, the the incidence of stroke is actually decreasing. it may be in part due to decreased smoking but it also is in part due to other modifiable factors. So hypertension is much better treated now than it used to be. People take better care of themselves in terms of other lifestyle factors. So people exercise more. There's lower incidence in some subgroups of obesity. Those are risk factors also for for for developing strokes and as well as heart attack. What is the relationship between heart health and brain health as it relates to stroke? would imagine that anything that's good for our heart is probably good for our brain. given the enormous amounts of blood and glucose that the the brain requires to function normally. Yeah, it's it's good point. In general, the things that are good for the heart are good for the brain. There there are differences between the heart and the brain but they they both depend very much on blood flow. The brain's unique though because the brain represents only 2% of the body weight yet it draws 15% of the total blood flow and remarkably it consumes 20% of the body's oxygen. So the brain, still think the brain is the most important organ. not the heart, not the kidneys, but I'm biased, of course. Yeah. You've spent some time in in in the landscape of the brain. Yeah. It's it's clear that of all the tissues in the body, if you had to pick one tissue to remove one, you know, cubic millimeter of that tissue that your brain and probably the neural retina would be your your least favorite choice just given the deficits that can result, right? And of of course the brain also is what makes us human, right? Speaking of which, if we take little departure into neurosurgery itself, your your specialty, of all the years of of doing brain surgery, can you recall maybe one of the most incredible moments or days that allowed for some insight into how the brain works by virtue of, let's say, stimulating given brain area or removing given brain area or or something of that sort. asked this because you know so very few of us will ever have the opportunity to do what you do and if were here talking to an astronaut and by the way consider neurosurgeons the astronauts of neuroscience. if were sitting here with an astronaut I'd say you know tell me something interesting about being in space that wouldn't know from looking at pictures or videos of it. What is an example of maybe one of the more profound insight stimulating moments from doing brain surgery? there. mean, every every patient is different. So, I'm always learning and that's why still enjoy it that it's challenge and you have to think quickly. it's not it's not simply mechanical. But for instance, couple weeks ago, had patient who had vascular malf for which was located we thought right in her speech area. So in order to operate safely first we did what's called functional MR scan before surgery and that gives us some idea of where the speech area is. we can map it out on an MR scan. And the way it's mapped out is we have the patient awake talk to us when they do the scan. And because there's coupling between blood flow and and the neur neuronal activity, when the speech area, the language area is stimulated by talking, there's increased blood flow to that area. And we can see that on an MR scan. That's how the MR scan works. So we have some idea that this was very close if not in the speech area. But the most accurate way of determining that is to operate on the patient with her awake. So we took what we did was we sedate the patient. We don't put tube down and induce general anesthesia. We numb up the scalp. We take off piece of bone after cutting the scalp. open the membrane covering the brain called the dura. And then we allow the patient to wake up more from the sedation. And then what did on this particular patient was to use tiny stimulator, little probe, and can stimulate areas of her cortex with her awake and see if the stimulation impairs her ability to speak or understand language. And quite surprisingly there was no activity in the corridor that chose. Sometimes when we see an area that is involved with speech that's eloquent, we have to choose different pathway to get to the underlying vascular problem. And so that's what we did in this case. And she talked to us the entire case. She told us about her daughter who was very involved in debate and all of her successes. While we were operating, while was taking out this vascular malf for under 20 magnification with very special instruments, use laser now which has diameter of the fiber optic cable. the laser tip is 0.5 So that think is the gentlest way. Other times I've been surprised about brain function is operating deep in the brain. There's part of the brain called the brain stem which you know well it's small area that connects the phalamus. Those are the signals coming from the cortex go through the phalamus to get down to the face, arm and leg to move the muscles. And all the sensory information which comes from the arms and legs and face goes through the brain stem up to the thalmus and then to the cortex. In this area although it's very small are contained very closely packed fiber tracks and nuclei. Those are the cell bodies of very important neurons. And when trained back in the 80s, we never operated in that area because we couldn't do it safely. With developments in computer technology and imaging and anesthesia, we can now find safe corridors to get into the brain stem. And sometimes we stimulate for other pathways, not language, but other pathways. And I'm continually amazed. this last week took out two vascular malf for and they're not big. mean they measure between 8 and centimeter but they can wreak havoc in the brain stem because it's such high price real estate. And these had bled but found safe corridor to go through. took it out and I'm amazed that you hardly set the patients back in some cases because in the past we would have clobbered the patients doing that. Amazing. Yeah, it's remarkable to me how much can be done now with imaging. So visualizing the brain and being able to target specific location and you mentioned fiber optic cables. I've also heard of things like the gamma knife and lasers. So how much of neurosurgery nowadays is actually burrowing down through the brain to given location to stimulate or remove tissue versus you know using these laser or fiber optic approaches to sort of triangulate and get to something without having to basically drill down through the brain. Right? Neurosurgery is becoming much less invasive and this is something that really tried to push when was chair of of the department for 25 years at Stanford. so minimally invasive techniques include operating through the vessels right so now my don't do this myself but my colleagues some of whom are neurosurgeons some are interventional radiologists they can go through the groin in the femoral artery or through the radial artery they can thread catheter backwards into the brain from the groin they can go up into the aorta then up into the corateed artery From there they can go up into the brain arteries, the middle cerebral artery and they can treat some of the hemorrhagic problems like aneurysms by deploying thrombogenic coils there or new devices. They can pull clots out if there's an acute stroke from clot in an artery in the brain. It it's really it's really quite impressive. then we've we and others have developed techniques to use focus radiation on the brain and that's called radio surgery. So examples of that are gamma knife cyber knife was invented at Stanford by one of my colleagues actually and this uses beams of radiation. Gamma knife uses cobalt source multiple sources of cobalt. The cyber knife uses X-rays. when started was very involved with using cyclron generated heavy particles like helium and proton and they can be focused. And the advantage of this is you don't have to open the skull. You focus it on very small area and you can eliminate vascular malf formations called arteriovenous malf formations, tumors. You can even use it for some pain conditions like trigeminal neuralgia. It's not risk-free because even though radiation is not is doesn't require opening the skull, it still is form of energy that's damaging that. That's how it works. It causes for the AVMs, it gradually clots off the blood vessels, but it's much easier and much safer than some of the invasive techniques that we use. We operate now through tiny openings. Even when we do open surgery, when trained, we used to shave the whole head. We would open huge area of the of the skull. Now we operate through tiny air, very small areas. When take out vascular malf forations in the brain stem, for instance, sometimes operate through openings in the side of the brain stem that are 2 to 3 millimeters. Wow. another form of non-invasive treatment that neurosurgeons use is called focused ultrasound. Again, it's you don't have to open the skull. It focuses sound waves on areas of the brain. We're using that to treat essential tremor or Parkinson's disease. it's starting to be used for treating tumors. So these are all advances that were not present when when trained. Another way of treating minimally invasive although it still requires hole in the head is to put in an electrode and stimulate the brain. So that was first used for treating Parkinson's disease very effective for medically intractable Parkinson's. It's used to treat chronic pain. Recently it was shown to be beneficial for epilepsy. In fact the two major trials prospective randomized trials that were done were led by physicians neurologists at Stanford and showed the benefit of stimulation of the brain to to treat very difficult epilepsy. So this think is going to be the future is minimal more and more minimally invasive. In fact, we're using some of these techniques to even treat psychiatric disorders like depression, obsessivecompulsive behavior. Incredible. should have asked this earlier, but TAS, transient eskeemic attacks. think most people assume or know that the symptoms of stroke include, you know, sudden weakness, maybe hemi paralysis of the face, confusion, slurring of the words. Of course, these symptoms can be the consequence of other things as well. what are some of the symptoms of transient eskeemic attacks and is there anything that people can take for transient eskeemic attacks and of course would love for you to inform us what transient eskeemic attack is right so transient eskeemic attack or TIA is reversible stroke it results in temporary loss of function such as inability to move partial paralysis or complete paralysis, but then it resolves inability to speak, visual problems, double vision, blurred vision, loss of vision. it can cause slurred speech, or difficulty understanding language, imbalance, problems walking, even cognitive problems. So, it can vary depending on what part of the brain it affects. In the past, it was defined as neurologic deficit due to lack of blood flow that lasted less than 24 hours. But now that we have such sophisticated imaging like MR scan, some of these patients who have TI, what would have been considered TIA before lasting minutes or up to 24 hours on MR scan have been shown to have little stroke. So now the definition is little different. If there's an if you do an MR scan and it shows new abnormality, new stroke, then it's called stroke rather than TIA. so there's little overlap there, but it's temporary loss of of neurologic function due to lack of lack of blood flow or in in some cases hemorrhage. My understanding is that people can also have strokes in their spinal cord because spinal cord tissue is after all central nervous system tissue. think most people don't realize this, but the the tail end of the brain, the the brain stem, as we were talking about before, essentially extends down the the spinal column, it's sort of like long tail, right? down to the base of the pelvis really. so we call it the spinal cord, but it's all brain. It's contiguous with the brain. So how often do you observe spinal strokes and what are some of the symptoms of spinal stroke? Yeah, it's much less common than stroke involving the brain. probably because there's less tissue involved. the spinal cord is supplied by an anterior spinal artery. That's an artery on on on this side and by two So for those listening, sorry, it would be the on the stomach side of the of the body. Yeah. And it's supplied by two arteries posterior spinal on the back side. So if there's an interruption to blood flow in any of those arteries, it can cause death of tissue in the spinal cord and that would result in neurologic deficit depending on where it is. So if it occurred on the stomach side, that whole artery which supplies the the two/irds of the spinal cord on the stomach side and it involved both sides of the spinal cord, it would cause paralysis of both legs and partial sensory deficit would cause loss of pain and temperature because that's where those pathways are. If the problem was on the back side of the cord, it would cause problem potentially with light touch sensation in the legs. if it was below the it was in the below the cervical region and problems with what's called propriception. That's the ability to recognize where your position of your joints is. So it depends on where it is. some of the vascular problems deal with actually do involve the spinal cord and you can develop other problems there. for instance you can have direct connection between abnormal artery and vein in the spinal cord which doesn't cause typical stroke by blocking blood flow but it causes more of that venus problem we discussed where there's so much blood going directly from the artery to the vein bypassing the capillaries that the veins become engorged the blood can't get out of the spinal cord and the spinal cord becomes congested and patients present with problems walking or sensory problems. If the spinal cord is involved in the cervical region up high, then the arms can be involved as well. see. should have asked this earlier, but is there any relationship between alcohol intake and the propensity for stroke or hemorrhage or any of these other things? Yeah, that's good question. Yes, there is. they're they're the people who who indulge or overindulge are at risk for developing stroke problems. So it's another contribut contributory factor which can promote problems with the with the blood vessels clots but also hemorrhage. So it can make the blood vessels more fragile. Another factor see commonly in patients who develop aneurysms, those are blisters on the blood vessels in the brain and they're like little balloons and as they enlarge they rupture just like balloon can burst. some of the patients see are not just smokers but indulge in other drugs. So cocaine, metamemphetamines marketkedly increase the risk of developing these aneurysms or developing hemorrhage, bursting of blood vessel. And is that because those drugs tend to increase blood pressure during their use? it's because they damage the vessels and they also can cause hypertension. Yes, it's both factors. So when operate on on these patients and looking at the vessels they are rag they're ragged they're very thin they're not normal vessels they lack structural integrity so it contributes to the development of of poor vessel integrity and drugs like cocaine and metampetamine can jack the blood pressure up and that could cause hemorrhage in these these problematic vessels. Yes. So, it sounds like the message is clear. avoid cocaine use, avoid methamphetamine use, and avoid excessive alcohol intake if you want to avoid stroke, right? And throw smoking in there, too. It's interesting because for lot of years, there was so much discussion about red wine being good for heart health. Now, it's debated. The moment say that, people will send bunch of studies that say, "Yes, my stance on the more recent data is that if you had to pick, you'd drink less or not drink as opposed to drink." but I'm curious what your take is on this. Well, you know, this is interesting and I'm always quite amazed at at the way people change their behavior based on one study that comes out, even if it's good study. So, yes, it used to be considered beneficial if you drank red wine. And then for while, studies showed any wine was beneficial in moderation. And and that used to be two drinks day for men, one drink day for women. And then the latest studies which have been surfacing this year suggest no alcohol is good. Yeah. But you know, next year maybe that we're back to you know, wine is the best thing you can do for your in moderation for your your brain and heart health. So it yeah, it's tricky. my read of the data and here mean the data across multiple certainly not every study but multiple studies is that zero to two drinks per week is seems to be the range that everyone agrees is safe at least for non-alcoholic adults. and then once you get out past two drinks per week is when gets into the gray zone where some people say it's good, some people say it's neutral, some people say it's bad. But that once you get up past, you know, four or five servings of alcohol per week, it's pretty clear to me it's not good situation. Well, that was the prevailing theory until this year. And don't know if you've kept up, but in the past, you know, few months, there have been several articles published saying no wine, no alcohol is good. But then you have to balance that against the fact that alcohol for many people tends to relieve stress. So you know if you're relieving stress maybe it counteracts any adverse effects. So complicated issue but my theory is moderation is the key to life. and you know and happiness also we know promotes longevity. Yeah. Absolutely. agree with you. I'm not heavy-handed about the alcohol thing. always just say you know do as do as you wish but know what you're doing. and think many people who heard our podcast episode about alcohol, who stopped drinking alcohol or who elected to drink less, did so, I'm told, because they really didn't enjoy it that much to begin with. So, it more or less gave them permission to drink less. not that they needed it, but they took it. anyway, think it's really interesting area. As you mentioned, it probably lowers stress. It probably also disrupts patterns of sleep and the gut microbiome. So there's, you know, you you can't escape in biology, there's always some mod modulatory influence on something else. Exactly. I'd like to take brief break and acknowledge our sponsor, AG1. 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Speaking of lifestyle factors, anytime we hear about traumatic brain injury or concussion, people immediately seem to think about football. but I'm told by colleagues of ours in neurosurgery at Stanford and in neuro engineering that most head injuries are not from football. They're not even from sport. They're from construction work accidents. They're from car accidents. What is your take on, you know, somebody, let's say, god forbid, gets rearended in in car accident, maybe gets whiplash, maybe they're feeling little off, like maybe they have minor concussion, maybe there was some movement of the brain that wasn't good. What's the going consensus on how to deal with that? sleep more, but then they tell you not to sleep excessively. should people take blood thinning agents? mean, obviously avoid alcohol or certainly don't get another head injury anytime soon, but you know, what do we know about TBI and concussion that that can help people move through that period in the in the weeks and months afterwards where it's really scary, you know, if you've ever had hard head hit, you know, and they go, they might scan you, they might not see bleed, but it's it's kind of scary when you feel little bit off because you've been hit in the head. Yeah, it's great question and there's lot of interest in concussion now. got very involved in this back in the 90s because was the 49ers neurosurgeon for decade from 1990 to to 2000. How were they doing in that point? remember the dynasty of the 80s or the 90s. good deal. they they were in Super Bowl contention. In fact, took care of Steve Young. Yeah, he's local guy who Yeah, Steve's great guy. And Steve really smart guy. he in fact he has law law degree from Brigham Young. Steve was quarterback then and they were in Super Bowl contention and Steve had had some concussions and actually sent him back to play when he had recovered. So you can examine someone and get decent idea of how they're recovering from concussion. Steve unfortunately had bad concussion at one point and he ended up retiring which was the smartest thing think for him in the end and he's become very involved with studying concussions and trying to figure out better ways to to diagnose them prevent the squella for football players including changes in equipment and and and in tackling and that kind of thing. but concussion is we've learned lot since the 1990s. At that time concussion was not known even repeated concussion to cause CTE chronic traumatic encphylopathy in football players. CTE which became hot topic was known only in boxers. So became very well informed at the time about concussions and there was surprisingly little known soccer players had high incidence of concussion at that time. It wasn't known if there were long-term squella and usually there are not long-term squella. as long as you don't get repeated concussions. so now what we generally recommend if someone has concussion we usually get an MR scan if it's severe. MR scans usually don't show anything. They would show contusion if there's any bruising of the brain but they don't show the the the molecular abnormalities that occur with concussion. So the best way to figure out how severe it is and when when person has recovered is to do more sophisticated neurologic testing. eye tracking is very sensitive way to to to to detect problems with with the brain after concussion because you won't track as well. And in fact, many sports football, hockey are incorporating pre-season eyetracking testing. see. To get baseline. To get baseline. Interesting. Of course, some of the players will game the system because they still don't want to be taken out. So, they may try to perform not as well as they they could on their track. Yeah. On their See, they throw the test. They throw the test. So their baseline is mean you know don't think that's very common but that's way you can game the system but as long as it's performed well that's very good way of of detecting subtle problems with the brain. Well, you're vision scientist, so you you understand how important all the circuits are in terms of and the visual system is unique because it tests the brain from the retina all the way back to the occipital lobe. So, it's the whole longitudinal access of the brain that's being tested. Yeah. I'm always struck by when see these news news real highlights of you know player goes down, they stay down and then you know they're helped up and everyone cheers and then they might hobble off, take few moments and then you know how are they gauging the decision to put the person back in? And the reason it's perplexing to me how they would determine that is that you and both know that the neurons, the nerve cells in the brain very likely could be injured maybe even on their way to death after head injury. But that the actual dying off of the tissue could take several minutes, hours, maybe even days. So putting someone back in to get hit more seems really risky, but at the same time that's their profession, that's their choice. And so you don't necessarily want to make the decision to take someone out of game or job or have them stop driving if they don't actually need to stop. So it's tricky thing. It is tricky and think we have better methods of even at the if you're talking about sports on the sideline of doing testing. there are neurosurgeons there now who are part of the process. as far as recovering in general it's good to not stress the brain but total absence of sensory you know information sensory deprivation for long periods is not good idea. Right. Just staying home in the dark with sunglasses on also not good idea. Exactly. So you want to make sure the brain still has input but you don't want to overstress it when you're recovering from concussion. Sounds like doing all the things to keep blood pressure relatively low, LDL cholesterol relatively low. So interesting what you said earlier that statins might be vascular protective even in the absence of high cholesterol. Yeah, there's lot of good evidence for that. In fact, some studies have suggested that taking statins reduces the risk of cognitive decline in including conditions like Alzheimer's. Interesting. know that statins are bit of controversial topic among listeners because some people report think have this right that statins can give them kind of brain fog if they take the wrong one or excessive amounts. yeah, it it I'm not challenging what you're saying. just just hear the shouts in the in the in the comment section and I'm just don't take statin but my cholesterol is in check. but I'm hearing more and more about some of these benefits of statins. It's interesting. Yeah. Yeah. And the the the information is still emerging. For traumatic brain injury in general, you not good idea to take an aspirin as opposed to stroke or TIA where you would want to take an aspirin, right? Because if you have injury, say you have contusion to the brain and there's some some traumatic damage, taking blood thinner might cause that to worsen or cause hemorrhage. What about caffeine? Is there any evidence that caffeine can increase stroke or eskeemia? like coffee and like yerba mate tea, so I'd be reluctant to give it up, but consume it in moderation. Is there any direct relationship there? don't know any relationship unless it unless you're taking so much that your blood pressure is skyhigh. My blood pressure tends to be lots of benefits evidently to to caffeine in terms of of health. Yeah, agree with you there. have question about something that many people are starting to do now, which is to get exploratory MRI. actually did one of these. wasn't gifted one. just decided to bite the bullet and pay for it. Is whole body scan. They put me in the tube, did an MRI, get everything from tip to toe. and learned few things. learned that have like slight think it's L3 or L4 disc bulge. that explained little bit of like pseudociatica and I've been able to work around that and keep that strong. learned that fortunately for me only have one white spot on the brain. was told that you could have one per decade. I'm nearing 50 so feel very lucky there especially given that I've hit my head few times skateboarding and doing martial arts and things like that. But so feel lucky. But also know people that go in for these scans and get the report that you know they have growth of some sort or they have multiple white spots as they're called on the brain which is kind of damage to to tissue to neural tissue. You know what is your thought on these exploratory/preventative scans? Do you think they're useful? do you feel like they cause undue concern? mean this is new thing people going out and getting their brain scanned. Yeah. Yeah. And people are getting total body scans. So think there are benefits and risks involved. So the benefit is that you might pick up something that should be treated like an early cancer or large aneurysm in the brain which would have higher tendency to bleed. But many times and see patients all the time who were referred for tiny aneurysm blister on blood vessel in the brain that was found incidentally on total body scan. And these aneurysms which can be one or two millimeters sometimes we don't even consider those as as real aneurysms. they don't need to be treated in most cases. and so it's it's little controversial because people can be worried about them even if they're reassured. Other examples are you find something in the brain or elsewhere in the body, not sure what it is and then in order to determine what it is, patients start having more invasive biopsies and tests which can lead to what we call iatrogenic injuries. That's iatrogenic is caused by the physicians. So, think you have to be very thoughtful when you interpret the results of of these total body or or or even brain scans. And would recommend talking with specialist about it if if if you're concerned. But you know people wonder have this we were discussing it earlier today actually with one of your colleagues and what if you're found to have 1.75 millimeter aneurysm if it's really even an aneurysm should you change your lifestyle and for something like that would recommend no you should forget about it get follow-up scan but you may very well live and die with with this little blister that is of no consequence. So, as say, think you have to be careful about how you interpret and and how you, act on on these, findings. Maybe we can talk about lifestyle factors because think anyone listening to this is going to think, don't want stroke. don't want transient eskeemic attack. don't want hemorrhage. don't want any of this stuff. And we already discussed little bit about how what's good for your heart generally is good for the brain. But, you know, think most people strive to eat well, meaning not excessively. also not undereat. to hopefully eat lot of unprocessed or minimally processed foods and to avoid smoking perhaps avoid alcohol in excess, avoid hard drugs, get exercise and so you know think people generally try and do all these things get good sleep etc. but at some level think everyone also wants to know like when are they in their safest kind of shape for avoiding stroke is is there sort of blood pressure cut off where we could say okay you know if you keep your blood pressure resting blood pressure below blank you're doing pretty well. and if your cholesterol is below blank, you're doing pretty well. And then you just, you know, while keeping moderation in mind, try and live life that you know, reduces the probability of getting stroke or or some other, you know, bloodrelated neural attack. Well, think it has to be individualized to some extent and over time the standards and the guidelines have changed. It used to be if your systolic blood pressure that's the upper number was under 130 130 or under that was considered normal and and it would not lead to problems. Now the guideline suggests that 120 or lower is better in large you know studies but as an example when my blood pressure gets under 120 feel lightaded. In fact, had an event about 15 years ago when was overdoing it like shouldn't have been overdoing exercise or over doing everything. was in my was Stanford faculty member that does something that was joke that among Stanford faculty was 56 and operated all day in two operating rooms. got done early. it was in the spring and took run up to the dish and then took redeye to Houston for meeting and emailed on the flight, got an hour or two asleep, went to the meeting, was fine. it was stroke meeting with bunch of scientists, neurologists and scientists. There were about 120 people. There were two neurosurgeons there plus me. And, drank some coffee. At noon, went for run because like running. And in at that day in Houston, it was 90 degrees and 85% humidity. And got back, had glass of tea, went back to the meeting, had some more coffee, and then as the afternoon session opened up, started to feel lightheaded. And next thing know I'm looking up at the chandelier and they're they're they're shouting stroke, cardiac arrest, seizure, and they're starting to pump on my chest. So they rush me to the hospital where had simultaneous workup for cardiac arrest and stroke. And after I'll make the story short. After $100,000 workup, it was determined had faint because was overdoing it. So since then now try to get 7 to eight hours sleep night, but that's clearly the bedrock of health. So increased used to get three to five hours sleep night. Now get seven to nine if can do it. cut back on on on coffee on caffeine. And don't push myself to exercise like used to. If I'm feeling little fatigued, I'm on an anti-hypertensive agent, but actually don't take it every day because for me, it's better to have pressure 125 to 135. and it's true for some of my patients. If you've got some disease in your arteries, you may not want to have such low blood pressure. So, would individualize it. But in general, you want to take care of your body like I've learned and probably maybe you've learned over time. I'm learning. mean, this is very interesting. I've tend to have low blood pressure. It sort of runs in my family to have low blood pressure. can definitely relate to the hard driving ambition phenotype. think it's it's worth people hearing this because it's characteristic of lot of people in highintensity professions. And made the joke about Stanford faculty, but it's true. think that if you're ambitious, you tend to overdo bit more. That's something I'm certainly working on and I've run very busy life and learning to slow down, prioritize sleep, prioritize meditation, non-sleep deep rest is something I've benefited from lot. Journaling, things of that sort that really just kind of slow the pace. think that you know in the landscape of health optimization we can often put ourselves into modes of excess in the other direction. meaning doing so much to try and avoid issues with health that we end up creating issues with health. But yeah certainly reducing caffeine intake and prioritizing sleep are key. So appreciate that you shared that story. So, if somebody has naturally low blood pressure and starts to feel bit let's just say kind of sleepy or woozy in the afternoon, would you recommend that they obviously not take pressure-lowering drug, but that they add bit of salt to their diet, that they feel free to you know to to exercise less? I'm little bit confused. also love to run and and do resistance training. Well, would recommend they take their blood pressure. So, you want to try to correlate any symptoms you're having with vital signs that you modify, right? So, take your blood pressure if you're feeling faint. If it's low, one thing you can do, easily is to hydrate. That was something else. used to not drink much because don't want to have to pee in the operating room. Yeah, can imagine that'd be pretty uncomfortable. don't want to be the patient that you're operating on when you have to go use the bathroom. Yeah. So now and then I'll reveal that had kidney stone which is common among surgeons. this was decade ago and since then I've hydrate all the time. So hydrate to the point that my urine is crystal clear all the time and that helps with some of the brain clarity. So interesting. I've done little bit of work with people in the special operations community and you know think people hear about them and they think you know what's what's the magic potion that they're taking? What are they doing? And they do number of very interesting things. but one of them is they really emphasize hydration. They just like hydration, water, sometimes water with electrolytes if they're working in in in hot conditions. Hydration, hydration, hydration. Skeptical. and used to dehydrate. felt better, dehydrated and fit, you know, but as I've matured think it's very very important and for you know for for your blood pressure, for your general health and for your kidneys. Yeah, you mentioned sleep. is there relationship between sleep deprivation and stroke risk? that's great question. There's interestingly strokes occur more commonly during sleep. It's not known why. One theory is that it's related to circadian rhythms. don't know if there's relationship between sleep deprivation and and and stroke. I'd like to take brief break and acknowledge one of our sponsors, Element. Element is an electrolyte drink that has everything you need. That means the electrolyte, sodium, magnesium, and potassium in the correct amounts and ratios, and nothing you don't, which means no sugar. Now, and others on this podcast have talked about the critical importance of hydration for proper brain and body functioning. Even slight degree of dehydration can diminish cognitive and physical performance. It's also important that you get adequate electrolytes. The electrolytes, sodium, magnesium, and potassium are critical for the functioning of all the cells in your body, especially your neurons, your nerve cells. Drinking element dissolved in water makes it very easy to ensure that you're getting adequate hydration and adequate electrolytes. To make sure I'm getting proper amounts of hydration and electrolytes, dissolve one packet of Element in about 16 to 32 ounces of water when wake up in the morning. And drink that basically first thing in the morning. I'll also drink Element dissolved in water during any kind of physical exercise I'm doing, especially on hot days when I'm sweating lot, losing water and electrolytes. They have bunch of different great tasting flavors of Element. My favorite is the watermelon, although confess also like the raspberry and the citrus. Basically, like all the flavors. And Element has also just released new line of canned sparkling element. So these aren't the packets you dissolve in water. These are cans of Element that you crack open like any other canned drink like soda. But you're getting your hydration and your electrolytes with no sugar. If you'd like to try Element, you can go to drinkelement spelled lmnt.com/huberman to claim free element sample pack with purchase of any element drink mix. Again, that's drinkelement.com/huberman to claim free sample pack. I'm going to tell horror story, but not want to repeat not to demonize chiropractors. Here's here's the positive story. had back thing that my back hurt and wasn't sure what needed to do. And chiropractor gave me some exercises to do that essentially were like the up dog movement in yoga that my understanding is it helped the the disc bulge kind of work its way back into the spinal column and it worked terrifically well. took no medication. and required no surgery and eventually learned to correct some imbalances that have led me to not have that issue again. It was really remarkable and this chiropractor essentially saved me from surgery and and I'm forever grateful. So there think there are excellent chiropractors out there. but when was posttock living in San Francisco, had roommate. believe she was neurology resident and she came back from the clinic at UCSF and she told me this story that patient had come in who was experiencing some hemi paralysis of the face. That patient, believe it was young woman, had gone for neck adjustment or head adjustment at chiropract with dissection of her artery, right? And something had happened and she had essentially stroke. Yes. And so share both these stories to make very clear that have nothing against chiropractors, but think like any health practitioners, they come in range of talents. and this was really like for me an alarm and decided at that point would never allow chiropractor to adjust my neck. said, "Okay, you can you can make adjustments to my back. You can give me suggestions about exercises to do, but how common are these?" this you said it's hemi dissection. it it's dissection of an artery either the vertebral artery in the back or the corateed artery up closer in the front. So no cutting when you say dissection. They're make basically making an adjustment. Yeah. Well, what happens is and agree with and we're on the same page. recommend patients if they're going to have chiropractor not to have manipulation of their neck because that's what occurs. It's not common but see it. We see it. What happens is the artery is damaged. the manipulation of moving the bone and the soft tissues causes tear in the wall of the artery. And what and what occurs interestingly is that the blood that's usually in the the space the lumen the middle of the artery gets into the wall and causes false lumen, false passage. And that that blood in the wall pushes part of the wall into the the main artery obstructing flow and sometimes causing clot to form that can be dislodged and go up to the brain. Yikes. So, and there's no way to know whether or not this is going to happen. No. That's why recommend not having neck manipulation by chiropractor, even if it's rare. it's it it's so devastating when it occurs that personally would avoid that. yes, tell the chiropractor stay away from anything above the shoulders, please. and then the back work has been beneficial. Again, these exercises, perhaps the most beneficial thing about it. as long as we're there, realize it's bit of niche condition, but what about hanging upside down? had one of these inversion tables. really enjoyed that thing. But then once looked at my camera phone while was hanging upside down and it looked like was going to blow gasket from all the vascule in my forehead. Is it bad to hang upside down? No evidence that it's bad. good. good. Maybe I'll get an inversion table again. as long as you don't stay there, of course you Okay, great. would you let your kids play football or rugby? That's great question. would not. that's my personal decision. think there are lot of benefits to children playing football, rugby, like any sport. it's team sport. lot of good skills are learned besides the you know just the the the physicality of it, the coordination but being team player and the socialization. But think talking about tackle football think the risk there is still risk. We're just learning about it. And even high school players who who many years ago were found to have multiple concussions are showing up when they when they're doing autopsies with some of this chronic traumatic encphylopathy. wanted to play football as kid and I'm not that big. mean, I'm big guy, but and my parents didn't let me, which is fortunate because mean, I'm sure would have been would have been, you know, put at risk for injuries, not just head injuries, other injuries. my son, who's very good athlete, he played four years of high school, baseball and soccer, was asked to try out for the quarterback position his senior year. and we went out to try out but and he decided you know with my encouragement not not not to play. Did he go to Gun High School? he went to Menllo. Okay. went to Gun. Our football team was at that time was bad enough that there was no incentive to play. What about soccer and heading the ball? actually heard that can be problematic which to me at first when heard that was like no there's no way. mean the ball is so light. But is there any evidence that repeated you know heading? There is. It's again it's it's it's not incontrovertible but there is some evidence that multiple headings can can cause some some concussions and some long-term injury. again, when studied this in detail, as 49ers neurosurgeon back in the 90s, there was very little data, although there was some evidence even then that soccer players had high incidence and particularly female soccer players had high incidence of of concussion surprisingly. but now there's much more evidence that head injuries and even hitting the ball may lead to some you know some some some injury. feel like if sport is not your profession, the risk benefit analysis is pretty clear like like why box? understand it's great sport. There's lot to learn there. done little bit of it in the past, but but unless you're going to get paid substantial amounts of money and maybe even then it's probably not worth it. Well, feel the same way. it is different for professional athletes. mean, this is their job. you know, remember talking with with Steve Young at one point about, you know, continuing to play or, you know, finally deciding to retire. And was thinking what if you know was asked to retire as neurosurgeon at the prime of my career. you know it's your profession, it's your income, it's your you know it's how you identify yourself. you know your self-esteem is dependent on it. Your family maybe put pressure on you as professional athlete. if you're not professional athlete, think for me, and this is my my own opinion individually, think there's less of controversy and what there's so many other sports which benefit in the same way as as football or or boxing. why not why not, you know, participate in those? That's my feeling, but know it's controversial subject. Yeah. Maybe we can circle back little bit on fairly common scenario. you're in the attic and you're looking for something, you stand up, boom, you hit your head on beam and you know kind of dizzy for bit. Or recently our podcast team was on tour in Australia and the way that the the shelf over the kitchen sink in our Airbnb was arranged, it was certain that everyone pretty much would hit their head hard on that thing at some point. Does one need to worry about one kind of dizzy inducing head hit from everyday life? You know, think lot of people are kind of scared like do they do brain damage or is the the evolutionary adaptation which is the thick skull sufficient to you know keep us safe? In most cases don't think you need to worry in general especially if your symptoms resolve within relatively short period of time such as how long? day or two. Yeah. mean, you know, even if you have mild concussion and you recover within day or two, don't think there's any need to worry or get scan or and and it's commonplace occurrence. Yeah, think your answer will set lot of minds at ease because people do worry. mean, there's something so mysterious about the stuff that occurs inside the cranial vault. We can't look to something. We can't, you know, take our pulse. there's just, you know, it's so hard to know what's going on in there. Well, as you say, that's why we develop very thick skulls to protect the the most important organ because after all, the tissue doesn't regenerate. at least not much of it. There are few areas where there where there are neurons that can replenish. You know, I'm going to take issue with you at that because the the prior notion of course was that once nerve cells in the brain die, they don't regenerate. And for long time it was thought you don't produce any any new nerve cells, any new stem cells in the brain. and we used to think after an injury or disease like stroke when that tissue was damaged and you were paralyzed or you couldn't talk that there was no way to recover that those circuits were were dead. it turns out that is not true and we are learning that think in recent years. when trained there was no hope to restore function in patients who had stroke, traumatic brain injury, spinal cord injury, and other diseases ALS, Lucaric's disease, Parkinson's disease. Now we are learning that there is hope. We know that stem cells do form in the adult brain. that's not controversial anymore. We know that other circuits can take over for circuits that were dead. and we know now, and this is some of the work that we're doing with chronic stroke patients who we thought could not recover after 6 months at all. We know that there are ways of promoting regeneration or recovery of function. We're still working out the details of that. But for instance, we've done studies and this is still in clinical trial phase with patients who are years out from stroke. They've been through rehab. they've been through physical therapy and 90% or more of recovery after stroke occurs in the first six months. After that time, you know, patients are not going to recover. And now we are finding in some of our early trials with patients that if you for instance put in stem cells into the brain or if you another treatment which was approved by the FDA the very first for chronic stroke if you put stimulator on the vagus nerve in the neck and stimulate coupled with physical therapy intensive physical therapy you can improve improve arm function in those patients. In our patients that we've treated in multiple trials, we're seeing early indications that patients years out from stroke can start to recover function in their arms, in their legs, in their speech. And we don't know all the mechanisms, but the old notion that these circuits are dead is simply not true. They can be resurrected. And so, you know, this is part of the the the excitement about, discovery and, doing research and trying to translate into the clinical arena. Yeah. Often times this boils down to really critical of the- moment decisions. I'll tell story. won't reveal the the hospital or the the exact players involved, but some years ago, an ex-girlfriend of mine, who then was just somebody was, friends with slashdating contacted me and said that her dad had had stroke. And was, near that hospital. So, went and spoke to the resident. And the resident who was overseeing the case essentially said, "Look, it it's hopeless. there's huge necrotic piece of tissue in there. the probability of any kind of quality of life is essentially zero. My suggestion and was there as as the resident made the suggestion would be to remove him from life support essentially. And the other members of the family were like, my goodness, right? This is not situation anyone wants to be in." made couple of calls, including to someone who's previously been guest on this podcast who's highly qualified to know about this sort of thing. They asked couple of questions about the location of the stroke, which side of the brain it was on, and said keep him alive. There's good chance that he'll have some degree of recovery of function. So, that's what they did. And indeed while he lost some motor abilities lost some speech abilities and has some disruption of affect where he'll sort of spontaneously laugh or cry from time to time he has at least by my observation been able to enjoy substantial amounts of life interacting with grandkids enjoying holidays and actually took was told some some physical steps at some point with assistance with walker's gone done lot of physical rehab obviously really hard situation But it told me that often times when we think that all is lost, not all is lost. Even in people in their 70s, right? It it has to do with plasticity. And we all wish we were neonates or infants because the body including the brain is so plastic. That's the ability to regenerate tissue and circuits and recover. So if an infant has stroke and is paralyzed on one side, usually they can make an excellent if not complete recovery. this is the as recall from my undergraduate years the Kennard principle. If you're going to have brain injury, have it early in life. Exactly. So mean you notice this too when cut myself now it can take week for that cut to heal. When my granddaughter who's 6 years old cuts herself the next day it's totally healed. So, little kids are like salamanders, right? They almost It's By the way, that was biology joke. They're not like salamanders that, but salamanders can re regenerate entire limbs by the maintenance of small stem cell population at the at the tip of the the limb bud. or what would be the limb bud? and it is remarkable how kids can regenerate without scar. They can often times they can't grow an entire hand back but it's kind of striking how much plasticity there and that's what we're trying to develop are new ways of promoting plasticity in the adult brain as an example. So we think stem cells injected through various mechanisms stimulation of the brain or the veagal nerve as an example can promote plasticity. In sense we think what's happening is that these methods can turn the adult brain into an infant brain in some ways. Where are the stem cells coming from in these experiments? It depends. there are different sources. So some of the studies I've done previously with other companies they made the stem cells either from bone marrow donors. So they were misenal or another group made the cells from from fetal neural tissue. Okay. So just to orient people inside the bone you have the marrow. Most people know that because they've ordered it at restaurant cow marrow that is typically the cells within the marrow contain as recall hemopoetic population. And so population of of sort of potential blood cells, you know, cells that can become blood cells or other things. And if taken out, put into petri dish and given the appropriate factors, you can drive the fate of those stem cells to be say neurons or cardiac cells. And then you're taking those cells and you're injecting them into the brains of patients in the hopes that they will re become neural cells, neurons that will incorporate into the circuitry. Actually that was the initial notion 20 years ago when we started doing this was that these cells you put in become these exogenous cells you inject become neurons and astroytes and alodendrites all the cells in the brain and that the neurons reconstitute circuits. That is not how they work. The way they work and this is why it may not matter what particular type of stem cell you put in. The way they work primarily is by secretreting very powerful proteins, molecules, growth factors that promote native recovery. So they promote angioenesis, they promote native neurogenesis, endogenous glyogenesis, synaptogenesis. But the main benefit may be that they modulate the immune system. That's what we're finding. So by modulating somehow the immune system in the brain, they are able to induce plasticity and recover function. Interesting. I'm tempted here to weave in the the stories that date back to the 90s but that we see more and more of mostly studies in rodents but few in humans showing that there are dormant stem cell populations in certain compartments of the brain the dentate gyus of the hippocampus the oldactory bulb etc that upon hyper oxygenation or increasing blood flow to the brain largely by virtue of exercise but also sometimes by way of engaging in learning tasks and exercise that you can basically cause the release of stem cells that normally would lie dormant. Is that literature reason enough to suggest that people who've had stroke continue to move their body to walk, get exercise, maybe do resistance training, maybe even some skill related training. Yes, there's lot of evidence that activity, physical therapy, even forced activity is very beneficial and it's not just stimulating endogenous stem cells in the brain, but it's multiple mechanisms. it's recruiting circuits that were not involved before. For instance, studies that have been done on stroke patients who make recovery show that not only is the side of the stroke improving in some cases, but the other side of the brain is showing increased activity. So circuits on the other side of the brain may be contributing to the recovery on the the side of the stroke brain. So it's much more complex than we thought it was. years ago, developed an affection for literature. It wasn't very prominent literature but found it really interesting is the work of guy named Timothy Shallert and Teresa Jones. Yeah, know. You familiar with this? Yeah, we almost recruited Tim to to our department. Yeah. The sort of overarching theme of this literature was it was animal work but think some of it might have been translated to humans which was that for instance if somebody has damage on one side of the brain because of the way the circuits are organized and of course you know this better than anyone Gary but that one might experience deficits in limb movement on the opposite side and that the tendency for somebody like that is to then over rely on the intact limbs essentially lean on the the intact limbs and the approach that they took to try and recover function was really interesting. They had these animals and think eventually there was some human work done. could be mistaken to sort of tie up the the more active uninjured arm or leg or hand such that they then had had to rely on the nondominant or let's just call it injured sometimes even flaccid paralysis limb. And in that way they could generate lot of plasticity that normally would escape the patient especially in the days and weeks following the injury. just forcing movement or forcing the attempt to move of the injured pathway. find this literature to be so striking and maybe one that should deserve more attention. Yeah. It's called constraint therapy and not only has it been shown in animal studies preclinally, but it's been shown in some clinical studies of patients with stroke. In fact, one of the trials we did with transplanting stem cells into the brain included restraining the good limb to force use of the other limb. So, there's some very intriguing data suggesting that that's important. However, some of the animal studies also suggest that you may have to wait time. If you force use of the involved limb too soon, it can be detrimental to the recovery. see. So there may be an important temporal factor there in terms of the timing of when you do that. Is there anything that people can do or take for neurop protection after an injury to essentially try and rescue neurons that would otherwise die? Right. So this is very interesting subject. back in the late 1980s 1990s lot of emphasis was placed on trying to protect the brain against acute stroke. Different pharmacologic agents were tried probably thousand different drugs were tried which blocked the pathway leading to cell death. So interestingly when you deprive the the brain and the neurons of oxygen and glucose they don't die immediately and it takes some time and it's actually an active process. So the release of these excitatory amino acids occurs. So normally as you know glutamate aspartate are important neurotransmitters in the brain and you need them to function. But after stroke, when there's deprivation of oxygen and glucose and mismatch between the metabolism and the supply of oxygen and glucose, for some reason there's release of these excitatory amino acids like glutamate and that causes an influx of calcium into the neurons which is the final common pathway to dying. And then there are other pathways that can then lead to release of free radicals and which are more damaging and those can cause another type of cell death called apoptotic cell death. That's cell death that occurs and requires protein synthesis and then with reprofusion say the artery opens up then you got lot of inflammation. So these pharmacological treatments as say thousand of them were tried and they were found to be very effective in pre-clinical stroke models. So we could cure stroke in the lab. My lab studied this for probably 15 years and you know there was no doubt we could cure stroke if we got the drugs on board even after the stroke within few hours but it never was able to be translated to the clinical arena except for one case. So besides drugs that were tried another method of protecting the brain was tried called mild hypothermia and that was process of reducing the brain temperature and body temperature just few degrees from 37° centigrade to 33. And we were one of the first to to show that that was protective even after the stroke in animals. my understanding is that when you cool neural tissue, you quiet its electrical activity. In fact, this is common tool for experimentation in neuroscience laboratories. You know, you want to shut down brain area transiently. You you cool it down, right? And in fact, deep hypothermia has profound effect on shutting down the metabolism. So that's why when someone particularly kids fall into frozen pond with with ice cold water they can survive there for half an hour and make complete recovery because their body temperature is dropped down to very low like 20° centigrade but this is less this is just few degrees so the amount there is slight decrease in the metabolic activity but that does not account for all the protection it's due to the fact that hypo hypothermia. Mild hypothermia blocks many of those detrimental pathways. It blocks partly the release of those excitatory amino acids, glutamate. It blocks the calcium influx. It blocks the inflammation. and so that's probably why it works so well. It even blocks that other pathway of program cell death. because it hits all these pathways. It's multiffactorial. It's very effective. And in fact, it was finally shown in the early 2000s in prospective randomized studies that one type of stroke actually two types should say two types of stroke are benefited by cooling the brain quickly. One is cardiac arrest from ventricular fibrillation. And prospective studies which were published in 2002 showed that if you cool patients who have cardiac arrest and then are resuscitated out in the field down to between 32 and 34 degrees centigrade from 37 much better outcomes neurologically. That's from global eskemia. That's the no blood getting to the brain briefly. And the other area where it's been shown to have better outcomes is in neonatal what's called hypothesis eskeemic injury. Those are neonates who have lack of blood flow for some reason to the brain when they're when they're born. And if you cool them, it's been shown in studies up to 10 years later that they have better cognitive outcomes. So for cardiac arrest in in in the mid 2000s think it was 2003 the American Heart Association determined it was standard of care guideline that you had to cool patients interesting after cardiac arrest. Yes. How was the cooling done in the experiments that you were involved in? Yeah. So there are many ways to do it but in the animal models you can just cool them with cooling blanket. Actually in people we got very interested in this. In fact when saw in the laboratory that it was so effective and and that we could cure you know mouse and and rat stroke by cooling. started cooling my patients in the operating room because felt you know even if it hasn't been proven in in in patients that you know it was so effective. It's the gold standard now actually for neuro for neurop protection against stroke in the in the laboratory. So back in the 1990s started cooling all of my patients. We started by cooling them by putting packing them in ice and putting alcohol on them. But the the operating room staff appropriately didn't like that cuz cuz alcohol is inflammable. So then we started using cooling blankets and then number of companies started developing cooling catheterss and work with several of these. So you can actually cool very quickly if you put catheter in the into vessel say in the groin and infuse cold saline which doesn't get into the into the circulation but it cools the blood and the cooled blood then circulates. other ways of cooling are to putting on special devices which cool quickly and that's what's used now are are external devices. People are working on cooling just the head with helmets. so it's still an active field of of investigation for stroke and also for cardiac arrest. Actually, it has not been proven in welldesigned prospective trials that it works for garden variety focal stroke. It works for cardiac arrest where there's global lack of blood flow to the brain like when the heart stops. It hasn't been proven yet for the kind of stroke we've been talking about where there's single blocked artery to the brain. So, interesting. mean, lot of times on this podcast, we talk about the critical need for body temperature to drop by 1 to 3 degrees to get into deep sleep. We had Craig Heler, our colleague from the biology department at Stanford on the podcast where he talked about some of the palmer cooling and I'm essentially cooling the soles of the feet, the palms of the hands and the upper part of the face as way to more rapidly reduce core body temperature. think these are fascinating areas for exploration that obviously have clinical applications, but it but also you'd imagine for some of the things we're talking about before like just to provide bit of neurop protection after head hit or provide bit of neurop protection perhaps even as it relates to aging. you know, spending little bit of time, maybe 10 minutes day, you know, not badly hypothermic, please people, but slightly hypothermic, and then bringing the body temperature back up. Yeah. mean, wouldn't recommend if you have head injury or or or TIA to stick your head in in snowbank. But even with traumatic brain injury, severe, not just concussion, but severe TBI, traumatic brain injury, studies were done looking at cooling hypothermia, and it's called mild hypothermia because it's just few degrees. And the studies were very suggestive, but didn't get to the point that it was proven. although certain subgroups who were cooled quickly seem to do better. So think it's subject that's still being studied. and as say, it's easy for us to do in the operating room. You don't want to cool too much because that can then interfere with other metabolic functions and clotting parameters and there it can cause increased infection if you go too low for too long. But still let my patients cool just few degrees. And we've had some anecdotal cases where where patients have had problems and because we cooled them, we think it it it made benefit. For instance, we had one patient who we hadn't even done was getting ready to do bypass to sew scalp artery to brain artery, but we hadn't even think made the the the the skin incision and the patient had cardiac arrest. So we and and it lasted for long time. So we were pumping on the chest couldn't restore function and it was way outside the amount of time that you would have expected good recovery but the patient had been cooled down to 33° before we by the time it had happened and and then we finally got the heart started. We ended up putting some restoring flow through catheterss and and heart lung machine and remarkably the guy made complete recovery. So anecdotal, but cases like that suggest maybe cooling even few degrees has protective effect on the brain. we certainly know it it's true for cardiac arrest and global eskemia. What are your thoughts on plateletri plasma PRP? These days we hear so much about PRP. think it's FDA approved for certain things, right? people will get blood drawn, they'll spin down platelets and then put in plateletri plasma. few years ago, people were making claims out there about PRP containing stem cells. just for the record, my understanding, I'm sure someone will argue with me online. They always do. But my understanding is that PRP contains very few if any stem cells and that it's not legal to assert that PRP is stem cell therapy. But PRP seems to be something that after an injury or in anticipation of surgery, people are starting to do more and more because they can go drop few thousand dollars and don't know, get this infusion of PRP. Does it does it work to help recover brain tissue or preserve brain tissue? Is there any evidence of that whatsoever? I'm not an expert on on plletri you know plasma but my reading of the literature cursorally suggests there's not hard evidence that it's beneficial. think one has to be little careful. For instance, still get emails you know every few weeks from people saying I've had stroke or I've had head injury and should go to Russia or India or Mexico and get stem cell therapy? Yeah, this is big topic. Yeah. And and you may have discussed it on another podcast. have not. I'll do solo episode on stem cells and what they are and what they aren't. just will just sorry to interrupt, but I'm aware of clinic in Florida that was injecting stem cells into the eyes of patients with macular degeneration and some other eye issues and those patients rapidly went blind. was going to bring that up and that's what led the FDA to really clamp down on stem cell clinics in the US. although they haven't clamped in on those type clinics as well as they should. But tell patients no. If you go out of the country, often you don't know what you're getting if there's not an equivalent of an FDA, which is overseeing it. you don't know whether these cell where they come from. Sometimes they're not published literature. you don't know where they're derived. We've seen cases of patients going elsewhere getting injections into the brain or the spinal cord and developing tumors or other problems. So discourage that and was going to bring up even in this country these clinics and that was published number of years ago that clinic in Florida those patients had macular degeneration and they were losing their sight but they could still see to some extent. They had their own atapost tissue taken. They sorted it for certain stem cells, meenal stem cells, and it was reinjected into the into the eye. Should have been safe, right? Their own cells even. And as you say, several of them went blind irreversibly. Irreversibly. So, think this is very important to highlight the the dangers of of stem cell therapy in general. There's lot of hope for it. mean, we're engaged. We're just finishing trial, first in human trial at Stanford using cells we developed in my lab 20 years ago. It took us 20 years to prove that they were safe, effective, didn't cause tumors and the study is looking very promising. It's phase one study and we we're making plans to do phase two study with control patients which you always want to do. but despite the hope there is still lot of hype and think it's very important to to be careful about getting therapies that are not proven. Yeah. And while we wouldn't want anyone to take any kind of unnecessary risk, you know, to me anyway, this goes back to the beginning of of our conversation that there's something very different about knee from the brain, right? I'm not saying go get stem cells injected into your knee, but should you be the sort of person that wants to do that because that you feel that's within your rights. You know, again, don't tell people what to do and you go to clinic, they get stem cells or don't know, they they take stem cells from some source and put them into your knee. mean, that's very different situation than injecting into the brain or spinal cord. You know, what some of the approaches to treat diseases of the brain or injuries to the brain are not injecting directly into the brain. they're injecting intravenously or intraarterial, threading catheter up as we discussed and injecting in the brain. Those cells, it turns out, don't even get into the brain. and the idea is that in some of the better studies that have been done in animals that they work by modulating the immune systemically. Those cells get trapped in the lung and the spleen which people describe as bioreactors and modulate the immune system which does make some sense. As say, we we think one of the main benefits of these stem cells is that they modulate the immune system and that helps with plasticity in the brain. But even intravenous delivery can be can be dangerous to the brain. Yeah, this is an area that we will spend lot more time on during this podcast. despite what you just said, think the the data I've seen from your laboratory and as you you told me there's trial that's finishing up now that features those data or that is where those data arrive from rather are really impressive. mean some people who were largely immobile or aphasic that couldn't speak in some cases are able to speak or move and that's really remarkable. It's really exciting. So think that the future of stem cells and stroke therapy is pretty pretty bright at least from where sit. Yeah, we don't want to oversell this but some of the results in certain patients are remarkable. mean the patients and their families has changed their lives. If you see them before and after, it's almost like miracle. Others are not as impressive, but so far in our trial and we've treated 17 of the 18 intended patients. almost all the patients have recovered to some extent and many of them have improved in meaningful way if you use certain scales. So again, we want to be cautious. We're going to do prospect of randomized blinded controlled study. and that's the way it should be done. And if that's positive, it would lead to phase three larger study, again, blinded controlled. And if that's positive, then it would lead to commercialization, FDA approval. it's long process. I've spent 23 years and more than $46 million in grants and philanthropy getting it to this stage. Wow. Yeah. Wow. That's that's lot of time and lot of money. Amazing. That's the way science and and and translation to clinical medicine is. would be remiss if didn't ask you know what are some of the things that you think could accelerate that process or is that just the slow iterative process that is science and medicine? mean for instance if there was five times as much money would the science progress at you know five times the rate? Probably not. no but money is factor. it's not the only factor. the FDA is appropriately very cautious. think other countries the equivalent of the FDA moves things along little quicker especially for therapies where there's no no other treatment. so think those factors are are important and would accelerate it. think greater collaboration with industry and promoting more academic industry kinds of relationships would help because the government agencies do not provide enough money to do the final stage. You know there's called this valley of death where you get initial encouraging data even clinically but you can't move the hurdle to get it into FDA approval because of of money in some cases. I've seen as an example number of very good stem cell therapies not make it because the companies went bankrupt. board of directors of the company felt the results were good but not good enough and they pulled the funding. Yeah. So, this is whole area which was not well well informed of until got into this of how you you know move through the FDA and how you you know work with industry. haven't formed company yet, but I'm going to have to because for the next trial, this trial was fortunate to get grant from SERM, California Institute for Regenerative Medicine of $12 million. That's taxpayer dollars. Exactly. Great use of taxpayer money putting it to really forward thinking research. But the next trial and our results are good enough that we probably will only need, if we do statistical power analysis, 69 patients. Initially, we thought we'd need 170 patients, but the results keep getting better and better. So, now it seems we would only need about 69 patients. That will cost at least 45 million. and as the trials get larger, even more. So, yeah, we need to figure out better way to allocate money to to make these advances. Well, it sounds like company or some role of industry is going to be necessary. well, you might be interested in investing, right? mean, you Well, that the the this podcast is always available free. The standard human lab podcast. Our premium channel actually generates money. We do ask me anything and things of that sort. We have donors that have come in for dollar match and we do philanthropy to laboratories at Stanford Sulk Institute, Colombia University. We've already done that. We're going to do more of this. Well, was being was being facicious. no. Listen, we could explore it. One of the one of the guidelines is that we fund research on humans exclusively. so we could talk about that. The former colleague of ours at Stanford once told me the the joke we'll see if get in trouble for this joke which is that there are two kinds of Stanford faculty. Stanford faculty with companies and Stanford faculty with successful companies. So we'll see we'll see if we'll see what comes down the pike from that. But you know mean many of the technologies and and discoveries that have been made at Stanford have spun off into you know there these little companies like you know Chinentech and you know other companies like that that are not strictly Stanford relations but of course other universities too but you know universities are where the basic research is done and then somebody has to implement those. Stanford's getting much better. When came to Stanford in 1974, it was the medical center was more like an NIH of the west and there was not lot of clinical excellence except for cardiac surgery, Norm Shamway and radiation oncology. Henry Kaplan who had developed the first radiation method for treating lymphoma. and we were great at making basic discoveries, not very good at translating them. But over you know the last what 50 years Stanford has gotten much better at translating them into you know clinical therapies and even doing some of that work at Stanford not farming it out to other other places. So think that's another area that we need to we need to encourage. Well, the proximity to big tech is sort of built into the fabric of of the Bay Area now. There's just no escaping that. And think overall you know, it's not without its sometimes issues, but overall think it's really good thing. facilitates the most rapid possible flow between basic science discovery and implementation at at large. want to make sure that we cover just little bit about veagal stimulation. lot of listeners to this podcast are familiar with the Vegas nerve as this very extensive pathway connecting brain and body in both directions. the common idea out there is that the vagus is associated with calming because it's in the parasympathetic arm or the autonomic nervous system the so-called rest and digest pathway. But happen to know and I'm sure you know from experimentation and from clinical work that oftenimes veagal stimulation is way of bringing say depressed patients up to more alertness. that veagal stimulation is not always about calming. It's can be about alerting the brain or making the brain more alert. so what sorts of veagal stimulation are you doing? given that the veagal pathway is so extensive, you know, like like which branch of the vagus do you stimulate? There's it goes around the ear, it's in the neck, it goes down through the gut. mean, we're talking basically about super highway of mean it kind of reminds me of the Austin freeway system. If you ever driven in Austin, it's like the freeways going every which direction. That's how whenever I'm there, I'm like the freeway system here is kind of like the Vegas. So, which avenue do you stimulate in order to get desired effect? Right. Well, for stroke and as as alluded to veagal nerve stimulation coupled with physical therapy, physical activity, very intensive, was the very first FDA approved treatment for chronic stroke patients. that was approved in 2021, 3 years ago. And it was shown in the study that compared with non-stimulation, in other words, putting the stimulator on but not not stimulating and doing the therapy that patients did better. It was modest improvement but felt to be meaningful and it was shown to be effective at 90 days, only 3 months. Now, recently at the last international stroke meeting last this past February, it was presented and don't don't know if it's been published yet that those results hold up for for up to year. So the way it works presumably is that you stimulate the entire vagus nerve in the neck and it's not the peripheral effects on the heart or the other autonomic organs where it's working. It's stimulation that goes back to the brain, right? Because when you stimulate nerve, it doesn't go in one direction. And that's probably how it works for depression also, not systemic, but and the vagus has lots of connection with brain functions, right? and so that's it's not completely clear which areas are being stimulated to recover from stroke or or improve depression, but it's brain stimulation that somehow again resurrects circuits or induces plasticity in circuits. again it's it's it's something that we're learning about and think not just veagal nerve stimulation but stimulation of the brain is becoming very important innovative treatment for many brain diseases and injuries. Is the veagal stimulation is it invasive or can you use an external stimulator? It's invasive. You have to do an operation. It's low risk. very few side effects. Occasionally there are some it can cause some problems with swallowing which are usually temporary right because the veagal nerve the recurrent veagal nerve supplies the the larynx the vocal cord but so it's an implanted stimulator but the stimulation can be turned on and off with an external magnet device. incredible Gary. Dr. Steinberg, want to thank you for several things. First of all, for coming here today to share with us right up until the point we hit, hot mics, meaning we we started recording, you were getting calls about patients. know you're still in the operating room. You were our department chair for more than two decades. 25 years. 25 years. Thank you for that. and you know still just so active in this area doing cutting edge research and stem cells and so much more. so as an extremely busy person who has many important duties, you are literally brain surgeon to take the time out of your schedule to come here and share with us all this information about how to keep our brain healthy, the relationship between alcohol, nicotine, fortunately caffeine's not on the list, but don't overdo it, folks. neurop protection, the discussion about TBI, something we've never discussed on this podcast, transient eskeemic attacks, and just really vast survey of things that concern lot of people and that also now having heard what you've shared also it puts them in position now to empower themselves to take some agency over their brain health, which is something that think most people really fear that this thing inside our skulls is outside the reach of our effort. efforts to try and maintain health and clearly you've explained how that is not the case and there are things we can do to both protect ourselves and to overcome challenges should they arise. So on behalf of myself and and all the listeners and viewers, just want to say thank you so much and hopefully as these trials continue to develop you'll come back and update us on the progress. Andrew, it's been real pleasure. Thank you for inviting me. Thank you for joining me for today's discussion with Dr. Gary Steinberg. To learn more about the research in the Steinberg laboratory and clinic, please refer to our show note captions. If you're learning from andor enjoying this podcast, please subscribe to our YouTube channel. That's terrific zerocost way to support us. In addition, please follow the podcast on both Spotify and Apple by clicking the follow tab. And you can leave us up to five-star review. Please also check out the sponsors mentioned at the beginning and throughout today's episode. That's the best way to support this podcast. 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