Dr. Gary Steinberg: How to Improve Brain Health & Offset Neurodegeneration

29:50So now the definition is a little different if there's an, if you do an MR scan and it shows a new abnormality, a new stroke, then it's called a stroke rather than a TIA. So there's a little overlap there, but it's a temporary loss of neurologic function due to lack of lack of blood flow or in some cases a 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. I think most people don't realize this, but the tail end of the brain, the brain stem, as we were talking about before, essentially extends down the spinal column, sort of like a long tail, right, down to the base of the pelvis, really.

30:40So 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 a 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 this side, and by two... So for those listening, sorry, it'll be the stomach side of the body. And it's supplied by two arteries posterior spinal on the backside. 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 a neurologic deficit, depending on where it is.

31:37So if it occurred on the stomach side, that whole artery, which supplies the two thirds 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 a partial sensory deficit, it would cause loss of pain and temperature, because that's where those pathways are. If the problem was on the backside of the cord, it would cause a problem potentially with a light touch sensation in the legs. If it was in the cervical region, and problems with what's called proprioception, that's the ability to recognize where your position of your joints is.

32:28So it depends on where it is. Some of the vascular problems I deal with actually do involve the spinal cord. And you can develop other problems there. For instance, you can have a direct connection between a normal artery and a vein in the spinal cord, which doesn't cause a typical stroke by blocking blood flow, but it causes more of that venous 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 can present with problems walking or sensory problems.

33:15If the spinal cord is involved in the cervical region up high, then the arms can be involved as well. I see. I 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 a good question. Yes, there is. There are the people who indulge or over indulge are at risk for developing stroke problems. So it's another contributor, a contributory factor, which can promote problems with the blood vessels, clots, but also hemorrhage. So it can make the blood vessels more fragile. Another factor I see commonly in patients who develop aneurysms.

34:04Those are blisters on the blood vessels in the brain. They're like little balloons, and as they enlarge, they rupture just like a balloon conversed. Some of the patients I see are not just smokers, but indulge in other drugs. So cocaine, methamphetamines, marked the increase the risk of developing these aneurysms or developing hemorrhage, bursting of a 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 cause hypertension. Yes, it's both factors. So when I operate on these patients and looking at the vessels, they are ragged.

34:50They're very thin. They're not normal vessels. They lack structural integrity. So it contributes to the development of poor vessel integrity, and drugs like cocaine, methamphetamine, can jack the blood pressure up, and that could cause a hemorrhage in these problematic vessels. 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. And throw smoking in there too. It's interesting because for a lot of years there was so much discussion about red wine being good for heart health. Now it's debated. The moment I say that, people will send a bunch of studies that say, yes, my stance on the more recent data is that if you had to pick, you drink less or not, drink as opposed to drink.

35:39But I'm curious what you're taking as well. You know, this is interesting. And I'm always quite amazed at the way people change the behavior based on one study that comes out, even if it's a good study. So yes, it used to be considered beneficial if you drank red wine. And then for a while, a study showed anyone was beneficial in moderation. And that used to be two drinks a day for men, one drink a day for women. And in the latest studies, which have been surfacing this year, suggest no alcohol is good. But next year maybe that we're back to, oh, wine is the best thing you can do for your in moderation for your brain and heart health.

36:28It's tricky. My read of the data, and here I mean the data across multiple, not certainly not every study, but multiple studies is that zero to two drinks per week. It seems to be the range that everyone agrees to say, at least for non -alcoholic adults. And then once you get out past two drinks per week is when it 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 out past four or five servings of alcohol per week, it's pretty clear to me it's not a good situation. Well, that was the prevailing theory until this year.

37:04I don't know if you've kept up, but in the past 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 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 happiness also we know promotes longevity. Absolutely. I agree with you. I'm not heavy handed about the alcohol thing. I always just say do as you wish, but know what you're doing. And I 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.

38:01Because 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, I think it's a really interesting area. As you mentioned, probably lowers stress it probably also disrupts patterns of sleep and the got microbiome. So there's you can't escape in biology. There's always some modulatory influence on something else. Exactly. I'd like to take a brief break and acknowledge our sponsor, AG1. By now, most of you have heard me tell my story about how I've been taking AG1 once or twice a day every day since 2012.

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39:40If you'd like to try AG1, you can go to drinkag1 .com slash huberman to claim a special offer. They'll give you five free travel packs with your order plus a year supply of vitamin D3K2. Again, that's drinkag1 .com slash huberman. Speaking of lifestyle factors, anytime we hear about traumatic brain injury or concussion, people immediately seem to think about football. But I've told by colleagues of ours in neurosurgery at Stanford and in neuroengineering 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.

40:19What is your take on somebody, let's say God for big gets re -rended in a car accident, maybe gets whiplash, maybe they're feeling a little off, maybe they have a 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? Obviously, avoid alcohol or certainly don't get another head injury anytime soon. What do we know about TBI and concussion that can help people move through that period in the weeks and months afterwards where it's really scary.

40:58If you've ever had a hard head hit and they go, they might scan you, they might not see a bleed. But it's kind of scary when you feel a little bit off because you've been hitting the head. Yeah, it's a great question and there's a lot of interesting concussion now. I got very involved in this back in the 90s because I was the 49ers neurosurgeon for a decade from 1990 to 2000. How are they doing that point? I remember the dynasty of the 80s, well the 90s are good. Oh, they were in supergo contention. In fact, I took care of Steve Young. He's a local guy. Yeah, Steve's a great guy and Steve a really smart guy.

41:37In fact, he has a lot of a lot of grief from Brigham Young. Steve was quarterback then and they were in superbowl contention and Steve had had some concussions. And I actually sent him back to play when he recovered. So you can examine someone and get a decent idea of how they were recovering from a concussion. Steve unfortunately had a bad concussion at one point and he ended up retiring, which was the smartest thing I think for him in the end. And he's become very involved with studying concussions and trying to figure out better ways to diagnose them, prevent the sequela for football players, including changes in equipment and in tackling and that kind of thing.

42:32But concussion is we've learned a lot since the 1990s. At that time concussion was not known, even repeated concussion, to cause CTE, chronic traumatic and cephalopathy in football players. CTE, which became a hot topic was known only in boxers. So I became very well informed at the time about concussions and there was surprising little known soccer players had a high incidence of concussion at that time. It wasn't known if there were long term sequela. And usually there are not long term sequela as long as you don't get repeated concussions. So now what we generally recommend, if someone has a concussion, we usually get an MR scan in its severe.

43:28MR scans usually don't show anything. They would show a contusion of the genie bruising of the brain, but they don't show the molecular abnormalities that occur with a concussion. So the best way to figure out how severe it isn't when a person has recovered is to do more sophisticated neurologic testing. Eye tracking is a very sensitive way to detect problems with the brain after concussion because you won't track as well. And in fact, many sports, football hockey are incorporating preseason eye tracking testing to get a baseline. Of course, some of the players will game the systems because they still don't want to be taken out.

44:22So they may try to perform not as well as they could. They throw the tests so their baseline is, I mean, I don't think that's very common, but that's a way you can game the system. But as long as it's performed well, that's a very good way of detecting subtle problems with the brain. What you're a vision scientist, so 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 I see these news, news real highlights of it, you know, a player goes down, they stay down.

45:16And then, you know, they're helped up and everyone cheers. And then they might hobble off, take a 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 I both know that the neurons, the nerve cells in the brain, very likely could be injured maybe even on their way to death after a 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.

45:54And so you don't necessarily want to make the decision to take someone out of a game or a job or have them stop driving if they don't actually need to stop. So it's a tricky thing. It is tricky. And I 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 a good idea. I just staying home in the dark with sunglasses on also not a good idea.

46:37Exactly. So you want to make sure the brain still has input, but you don't want to overstress it when you're recovering from a 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 a lot of good evidence for that. In fact, some studies have suggested that taking statins reduces the risk of cognitive decline, including conditions like Alzheimer's. Interesting. I know that statins are a bit of a controversial topic among listeners.

47:13Because some people report, I think I have this right, that statins can give them a kind of a brain fog if they take the wrong one or excessive amounts. Yeah, I'm not challenging what you're saying. No, no, no, no, it's just here in the shower. In the comment section. And I don't take a statin, but my cholesterol is in check. But I'm hearing more and more about some of these benefits of statins. Yeah, yeah. And the information is still emerging for a traumatic brain injury in general. Not a good idea to take an aspirin as opposed to a stroke or a TIA where you would want to take an aspirin. Right, right.

47:50Because if you have injuries, say you have a contusion to the brain and there's some traumatic damage taking a blood thinner might cause that to worsen or cause a hemorrhage. What about caffeine? Is there any evidence that caffeine can increase stroke or scum? I mean, I like coffee and I like your bombante T. So I'd be reluctant to give it up. But I consume it in moderation. Is there any direct relationship there? I don't know any relationship. Unless you're taking so much that your blood pressure is sky high. My blood pressure tends to be pretty low. Mops of benefits evidently took caffeine in terms of health.

48:27Yeah, I agree with you there. The question about something that many people are starting to do now, which is to get exploratory MRI. I actually did one of these. I wasn't gifted one. I just decided to bite the bullet and pay for it. It is a whole body scan that put me in the tube, did it MRI, get everything from tip to toe. And I learned a few things. I learned that I have like a slight, I think it's L3 or L4 disc bulge that explained a little bit of like pseudo sciatica. And I've been able to work around that and keep that strong. I learned that fortunately for me, I only have one white spot on the brain.

49:05I was told that you could have one per decade. I'm nearing 50. So I feel very lucky there, especially given that I've hit my head a few times, skateboarding and doing martial arts and things like that. But so I feel lucky. But I also know people that go in for these scans and get the report that, you know, they have a growth of some sort or they have multiple white spots as they're called on the brain, which is kind of damaged to tissue, the neural tissue. You know, what is your thought on these exploratory slash preventative scans? You think they're useful. Do you feel like they cause a new concern?

49:40I mean, this is a new thing. People going out and getting their brain scanned. Yeah, and people are getting total body scans. So I 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 a large aneurysm in the brain, which would have a higher tendency to bleed. But many times, and I see patients all the time who were referred for a tiny aneurysm blister on a blood vessel in the brain that was found incidentally on a total body scan. And these aneurysms, which can be one or two millimeters, sometimes we don't even consider those as real aneurysms.

50:23They don't need to be treated in most cases. And so it's a, it's a 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 eye atrogenic injuries. That's eye atrogenic is caused by the physicians. So I think you have to be very thoughtful when you interpret the results of these total body or even brain scans. And I would recommend talking with a specialist about it if you're concerned.

51:13But you know, people wonder, I have this, we were discussing it earlier today actually with one of your colleagues. And what if you're found to have a 1 .75 millimeter aneurysm, if it's really even an aneurysm, should you change your lifestyle? And for something like that, I would recommend no, you should forget about it, get a follow -up scan, but you may very well live and die with this little blister that is of no consequence. So as I say, I think you have to be careful about how you interpret and how you act on these findings. Maybe we can talk about lifestyle factors because I think anyone listening to this is going to think, I don't want to stroke, I don't want transient, schematic attack, I don't want hemorrhage, I don't want any of this stuff.

52:03And we already discussed a little bit about how what's good for your heart generally is good for the brain. But you know, I think most people strive to eat well, meaning not excessively, also not under eat, to hopefully eat a lot of unprocessed or minimally processed foods. And to avoid smoking, perhaps avoid alcohol and excess, avoid hard drugs, get exercise. And so you know, I think people generally try and do all these things, get good sleep, etc. But at some level, I think everyone also wants to know, when are they in their safest kind of shape for avoiding a stroke? Is there sort of a blood pressure cut off where we could say, okay, if you keep your blood pressure, resting blood pressure below blank, you're doing pretty well.

52:54And 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 a life that, you know, reduces the probability of getting a stroke or some other, you know, blood related neural attack. Well, I 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 or 130 or under, that was considered normal and would not lead to problems. Now, the guidelines suggest that 120 or lower is better in large, you know, studies.

53:39But as an example, when my blood pressure gets under 120, I feel lightheaded. In fact, I had an event about 15 years ago when I was overdoing it, like I shouldn't have been overdoing exercise or overdoing everything. I was in my, I was fifth Stanford faculty member that was a joke that among Stanford faculty, I was 56 and I operated all day in two operating rooms. I got done early. It was in the spring. And I took a run up to the dish and then I took a red eye to Houston for a meeting. And I emailed on the flight, got an hour to a sleep, went to the meeting. It was fine. It was a stroke meeting with a bunch of scientists, neurologists and scientists, there were about 120 people.

54:33There were two neurosurgeons there plus me. And I drank some coffee at noon. I went for a run because I like running. And at that day in Houston, it was 90 degrees and 85 % humidity. And got back, had a glass of tea, went back to the meeting, had some more coffee. And then as the afternoon session opened up, I started to feel lightheaded. And next thing I know I'm looking up at the chandelier and they're shouting stroke cardiac arrest seizure and they're starting to pump on my chest. So they rushed me to the hospital where I had a simultaneous workup for cardiac arrest and stroke. And after I'll make the story short after a hundred thousand dollar workup, it was determined I had a faint because I was overdoing it.

55:32So since then I now I try to get seven to eight hours sleep a night. But I clearly the better off of hell. So I increased I used to get three to five hours sleep a night. Now I get seven to nine if I can do it. Cut back on on coffee on caffeine. And I don't push myself to exercise like I used to have I'm feeling a little fatigue. I'm on an anti -hypertensive agent, but I actually don't take it every day because for me it's better to have a 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 a low blood pressure.

56:15So I 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. I mean, this is very interesting. I tend to have low blood pressure. It sort of runs in my family to have low blood pressure. I can definitely relate to the hard driving ambition phenotype. I think it's worth people hearing this because it's characteristic of a lot of people in high intensity professions. And I made the joke about Stanford faculty, but it's true. I think that if you're ambitious, you tend to overdo a bit more. That's something I'm certainly working on.

56:54And I've run a very busy life and learning to slow down prioritize sleep prioritize meditation, non -sleep deep rest is something I've benefited from a lot journaling things of that sort that really just got to slow the pace. I think that 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 that I appreciate that you shared that story. So if somebody has naturally low blood pressure and starts to feel a bit, let's just say kind of sleepier, losing the afternoon, would you recommend that they obviously not take a pressure lowering drug, but that they add a bit of salt to their diet that they feel free to, you know, to exercise less.

57:54I'm a little bit confused. I also love to run and do resistance. Well, I would recommend they take their blood pressure. So you want to try to correlate any symptoms you're having with vital signs that 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. I used to not drink much because I don't want to have to pee in the operating room. I can imagine that you're pretty uncomfortable. I 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 I had a kidney stone, which is common among surgeons.

58:30This was a decade ago. And since then, I've hydrate all the time. So I 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 a little bit of work with people in the special operations community. And I think people hear about them and they think, oh, you know, what's the magic potion that they're taking? What are they doing? And they do a number of very interesting things. But one of them is they really emphasize hydration. That just like hydration water, sometimes water with electrolytes if they're working in in hot conditions.

59:05I was a hydration hydration hydration. It's a good hydration. And I used to dehydrate. I felt better dehydrated and fit, you know, but as I've matured, I think it's very, very important. And for, you know, for your blood pressure, for your general health, and for your kidneys. Yeah, you mentioned sleep. Is there a relationship between sleep deprivation and stroke risk? That's a great question. There's interestingly strokes of chroma commonly during sleep. It's not known why one theory is that it's related to circadian rhythms. I don't know if there's a relationship between sleep deprivation and stroke.

59:51I'd like to take a brief break and acknowledge one of our sponsors, element. Elements 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, I and others on this podcast have talked about the critical importance of hydration for proper brain and body functioning. Even a 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.

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1:00:57Basically, I like all the flavors. And element has also just released a 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 can drink like a soda, but you're getting your hydration and your electrolytes with no sugar. If you'd like to try element, you can go to drink element spelled LMNT .com slash Huberman to claim a free element sample pack with the purchase of any element drink mix. Again, that's drink element .com slash Huberman to claim a free sample pack. I'm going to tell a horror story, but not, I want to repeat not to demonize chiropractors.

1:01:34Here's the positive story. I had a back thing that my back hurt and I wasn't sure what I needed to do. And a chiropractor gave me some exercises to do that essentially were like the up dog movement in yoga that my understanding is it helped the disc bulge kind of work its way back into the spinal column. And it worked terrifically well. I took no medication. I required no surgery. And I eventually learned to correct some imbalances that have led me to not have that issue again. There's really remarkable in this chiropractor essentially saved me from surgery. And I'm forever grateful. So there I think there are excellent carpractors out there.

1:02:14But when I was a postdoc living in San Francisco, I had a roommate. I believe she was a neurology resident. And she came back from the clinic at UCSF and she told me the story that a patient had come in who was experiencing some hemiperalysis of the face. That patient I believe it was a young woman had gone for a neck adjustment or head adjustment at a car factor. We had a dissection of her artery. Right. And something had happened. And she had essentially a stroke. And so I share both these stories to make very clear that I have nothing against chiropractors. But I think like any health practitioners, they come in a range of talents.

1:02:51And this was really like for me an alarm. And I decided at that point I would never allow a car factor to adjust my neck. I said, OK, 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 a heavy dissection. It's a dissection of an artery either the vertebral artery in the back or the carotid artery up closer in the front. So no cutting when you say dissection, they're basically making an adjustment. Yeah. Well, what happens is and I agree I'm going to run the same page. I recommend patients of their going to have chiropractic not to have manipulation of their neck because that's what occurs.

1:03:34It's not common, but I see it. We see it. What happens is the artery is damaged. The manipulation of moving the bone in the soft tissues causes a tear in the wall of the artery. And what occurs, interestingly, is that the blood that's usually in the space, the lumen, the middle of the artery gets into the wall and causes a false lumen, a false passage. And that that blood in the wall pushes part of the wall into the main artery obstructing flow. And sometimes causing a clot to form that can be dislodged and go up to the brain. So there's no way to know whether or not this is going to happen. No, that's why I recommend not having neck manipulation by a chiropractor.

1:04:30Even if it's rare, it's so devastating when it occurs that personally, I would avoid that. Yes, I 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, I realize it's a bit of a niche condition. But what about hanging upside down? I had one of these inversion tables. I really enjoyed that thing. But then once I looked at my camera phone while I was hanging upside down, and it looked like I was going to blow a gasket from all the vascular in my forehead.

1:05:05Is it bad to hang upside down? No evidence says bad. Oh, good. Oh, good. Maybe I'll get an inversion table again. As long as you don't stay there, of course. You got some. Okay, great. Would you let your kids play football or rugby? That's a great question. I would not. That's my personal decision. I think there are a lot of benefits to children playing football rugby like any sport. It's a team sport. A lot of good skills are learned. Besides the, you know, just the physicality of it, the coordination, but being a team player and the socialization. But I think talking about tackle football. I think the risk, there are still risks.

1:05:53We'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. I was a chronic traumatic in cephalopathy. I wanted to play football as a kid. And I'm not that big. I mean, I'm a big guy, but. And my parents didn't let me, which is fortunate because I mean, I'm sure I would have been, would have been, you know, put at risk for injuries, not just head injuries other injuries. My son, who's a very good athlete, he played four years of high school baseball and soccer was asked to try out for the quarterback position is senior year.

1:06:40And 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? Yeah, he went to Menlo. Okay, I 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? I've actually heard that can be problematic, which to me, at first when I heard that, I was like, no, there's no way. I mean, the ball is so light, but is there any evidence that repeated, you know, 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.

1:07:21Again, when I studied this in detail, as a 49ers neurosurgeon back in the 90s, there was very little data, although there was some evidence, even then that soccer players had a high incidence, and particularly female soccer players had a high incidence of concussion surprisingly. But now there's much more evidence that head injuries and even heading the ball may lead to some, you know, some, some injury. I feel like if a sport is not your profession, the risk benefit analysis is pretty clear. Like, like, like, like, why box? I understand it's a great sport. There's a lot to learn there. I don't know a 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.

1:08:13Well, I feel the same way. It is different for professional athletes. I mean, this is their job. You know, I remember talking with Steve Young at one point about, you know, continuing to play or, you know, finally deciding to retire. And I was thinking, what if, you know, I was asked to retire as a neurosurgeon at the prime of my career. You know, it's your profession, it's your income, it's, you know, it's how you identify yourself. You know, your self -esteem is dependent on it. Your family may be put pressure on you as a professional athlete. If you're not a professional athlete, I think for me, and this is my, my own opinion individually, I think there's less of a controversy.

1:09:02And what there's so many other sports, which benefit in the same way as, as football or boxing. Why not, why not, you know, participate in those. That's my feeling. But I know it's a controversial subject. Maybe we can circle back a little bit on a fairly common scenario. You're in the attic and you're looking for something you stand up, you hit your head on a beam and you're kind of dizzy for a 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.

1:09:48Does one need to worry about one kind of dizzy inducing head hit from everyday life? You know, I think a lot of people are kind of scared like they do brain damage. Or is the, the evolutionary adaptation, which is the thick skull. Um, sufficient to, you know, keep us safe in most cases. I don't think you need to worry in general, especially if your symptoms are solved within a relatively short period of time. Such as how long a day or two? Yeah, I mean, you know, even if you have a mild concussion and you recover within a day or two, I don't think there's any need to worry or get a scan or. And it's a commonplace occurrence.

1:10:26Yeah, I think your answer will set a lot of minds at ease because people do worry. I 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. It'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 most important organ. Because after all, the tissue doesn't regenerate. Um, at least not much of it. There are a few areas where there, where there are neurons that can replenish. You know, I'm going to take, um, issue with you at that because the, the prior notion of course was that once.

1:11:05Nerve cells in the brain die, they don't regenerate. And for a long time, it was thought you don't produce any, any new nerve cells, any new stem cells in the brain. Um, and we used to think after an injury, uh, or, uh, a disease like a 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. Uh, it turns out that is not true. And we are learning that I think in recent years. Um, when I trained, there was no hope to restore function in patients who had a stroke, traumatic brain injury, spinal cord injury.

1:11:46Uh, and, um, other diseases, uh, ALS, Lugerix disease, um, Parkinson's disease. Now we are learning that, uh, 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. Um, 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 six months at all, we know that there are ways of, um, promoting, uh, regeneration or recovery of function. And we're still working out the details of that. But, um, for instance, we've done studies, and this is still in, um, clinical trial phase with patients who are years out from a stroke, they've been through rehab, uh, 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.

1:12:55And 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, um, if you, another treatment, which was approved by the FDA, the very first for chronic stroke, if you put a stimulator on the vagus nerve in the neck and stimulate coupled with physical therapy. Intensive physical therapy, you can 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 a stroke can start to recover function in their arms in their legs in their speech.

1:13:42And 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, um, you know, this is part of the, the excitement about, um, discovery and doing research and trying to translate into the clinical arena. Yeah. Yeah, oftentimes this boils down to really critical of the moment decisions. I'll tell a story. I won't reveal the hospital or the exact players involved. But some years ago, an ex -girlfriend of mine, who then was just somebody I was friends with, slash dating contacted me and said that her dad had had a stroke. And I was near that hospital.

1:14:27So I went and spoke to the resident and the resident who was overseeing the case essentially said, look, it's hopeless. There's a huge necrotic piece of tissue in there. The probability of any kind of quality of life is essentially zero. My suggestion and I 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, oh my goodness, right? This is not a situation anyone wants to be in. I made a couple of calls, including to someone who's previously been a guest on this podcast, who's highly qualified to know about the sort of thing.

1:15:06They asked a couple of questions about the location of the stroke, which side of the brain it was on and said, I'm keep him alive. There's a 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, I was told some physical steps at some point with assistance with the walkers gone, done a lot of physical rehab.

1:15:44Obviously, really hard situation, but it told me that oftentimes when we think that all is lost, not all is lost, even in people in their 70s. Right. It has to do with plasticity. And we always 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 a stroke and is paralyzed on one side, usually they can make an excellent, if not complete recovery. This is the, as I recall from my undergraduate years, the Kennard principle, if you're going to have a brain injury, have it early in life.

1:16:28Exactly. So, I mean, you notice this too, when I cut myself now, it can take a week for that cut to heal when my granddaughter, who's six years old, cuts herself the next day, it's totally healed. So, yeah, little kids are like salamanders, right? They almost, it's all by the way, that was a biology joke. They're not like salamanders, but salamanders can regenerate entire limbs by the maintenance of a small stem cell population at the tip of the, the limb bud, or what would be the limb bud. And it is remarkable how kids can regenerate without a scar. They can oftentimes, they can't grow an entire hand back, but it's kind of striking how much plasticity.

1:17:07And 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 vagal nerve as an example, can promote plasticity. And in a 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 mizankamo, or another group made the cells from fetal neural tissue.

1:18:02Okay, so just to orient people inside the bone, you have the marrow. Most people know that because they've ordered it at a restaurant, cow marrow that is typically. The cells within the marrow contain, as I recall, a hemopoietic population, so a population of sort of potential blood cells, you know, cells that can become blood cells, or other things. And if taken out, put into a 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 become neural cells, neurons that will incorporate into the circuitry.

1:18:47Actually, that was the initial notion 20 years ago, and we started doing this, was that these cells you put in become these exogenous cells you inject, become neurons and astrocytes, and only go to the endrocytes, 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 secreting very powerful proteins, molecules, growth factors that promote native recovery. So they promote angiogenesis, they promote native neurogenesis, endogenous gliogenesis, synaptogenesis, but the main benefit may be that they modulate the immune system.

1:19:40That's what we're finding. So by modulating somehow the immune system in the brain, they are able to induce plasticine recover function. Interesting. I'm tempted here to weave in the stories that date back to the 90s, but that we see more and more of mostly studies in rodents, but a few in humans showing that there are dormant stem cell populations in certain compartments of the brain, the dentary gyros of the hippocampus, the olfactory bulb, etc. That upon hyperoxygenation 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.

1:20:24Is that literature reason enough to suggest that people who've had a stroke continue to move their body to walk, get exercise, maybe do resistance training, maybe even some skill related training? Yes, there's a 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 have been done on stroke patients who make a 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.

1:21:15So circuits on the other side of the brain may be contributing to the recovery on the side of the stroke brain. So it's much more complex than we thought it was. Years ago I developed an affection for a literature, it wasn't a very prominent literature, but I found it really interesting. The work of a guy named Timothy Schallert and Teresa Jones, I know what's familiar with this. Yeah, we almost recruited to our department. Yeah, the sort of overarching theme of this literature was it was animal work, but I 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 the movement on the opposite side.

1:22:03And that the tendency for somebody like that is to then over rely on the intact limbs, essentially lean on the intact limbs. And the approach that they took to try and recover function was really interesting. They had these animals, and I think eventually there was some human work done. I could be mistaken. Sort of tie up the more active uninjured arm or leg or hand such that they then had had to rely on the non dominant or let's just call it injured, sometimes even flaccid paralysis limb. And in that way they could generate a 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.

1:22:52I 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 preclinically, 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 a time if you force use of the involved limb too soon, it can be detrimental to the recovery.

1:23:38I 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 neuro protection after an injury to essentially try and rescue neurons that would otherwise die? Right. So this is a very interesting subject. Back in the late 1980s, 1990s, a lot of emphasis was placed on trying to protect the brain against acute stroke. Different pharmacologic agents were tried probably a 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.

1:24:33And it takes some time and it's actually an active process so that release of these excitatory amino acids occurs. So normally, as you know, glutamate, aspartate are important or transmitters in the brain and you need them to function. But after a stroke when there's a deprivation of oxygen and glucose and a mismatch between the metabolism and the supply of oxygen and glucose, for some reason there's a 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 that lead to release of free radicals and which are more damaging and those can cause another type of cell death called apoptotic cell death.

1:25:30That's a cell death that occurs and requires protein synthesis. And then with reprefusion, say the artery opens up, then you got a lot of inflammation. So these pharmacological treatments as I say a thousand of them were tried. And they were found to be very effective in preclinical 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 a 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.

1:26:25And that was a process of reducing the brain temperature and body temperature. Just a few degrees from 37 degrees centigrade to 33. And we were one of the first 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 a common tool for experimentation in neuroscience laboratories. You know, you want to shut down a brain area. Transiently you you cool it down. Right. And in fact, deep hypothermia has a profound effect on shutting down the metabolism. So that's why when someone particularly kids fall into a frozen pond with ice cold water, they can survive there for half an hour and make a complete recovery because their body temperature is dropped down to very low like 20 degrees centigrade.

1:27:24But this is less. This is just a few degrees. So the amount there is a slight decrease in the metabolic activity, but that does not account for all the protection. It's due to the fact that hypothermia, a mild hypothermia blocks many of those detrimental pathways. It blocks partly the release of those excited to 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 multi factorial. It's very effective. And in fact, it was finally shown in the early 2000s in Prospector randomized studies that one type of stroke, actually two types, I should say, two types of stroke are benefited.

1:28:18By cooling the brain quickly. One is cardiac arrest from ventricular fibrillation and Prospector studies, which were published in 2002 showed that if you cool patients who have cardiac arrest and then are resuscitated out into the field down to between 32 and 34 degrees centigrade from 37. Much better outcomes neurologically. That's from global ischemia. That's the noble blood getting the brain briefly. And the other area where it's been shown to have better outcomes is in neonatal, what's called hypostecoschemic injury. Those are neonates who have lack of blood flow for some reason, the brain when they're when they're born.

1:29:03And 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 the mid 2000s, I think it was 2003, the American Heart Association determined it was a standard of care, a guideline that you had to cool patients after cardiac arrest. 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 a cooling blanket actually. In people, we got very interested in this. In fact, when I saw in the laboratory that it was so effective and that we could cure it, you know, mouse and rats proke by cooling, I started cooling my patients in the operating room.

1:29:59Because I felt, you know, even if it hasn't been proven in patients that it was so effective, it's the gold standard now actually for neuro protection against stroke in the laboratory. So back in the 1990s, I started cooling all of my patients. We started by cooling them by putting packing them an ice and putting alcohol on them. But the operating room staff appropriately didn't like that because alcohol is flammable. So then we started using cooling blankets and then a number of companies started developing cooling catheters. And I worked with several of these. So you can actually cool very quickly if you put a catheter into a vessel, say in the groin and infuse cold saline, which doesn't get into the into the circulation, but it cools the blood.

1:31:01And the cool blood and circulates. Other ways of cooling are putting on special devices, which cool quickly. And that's what's used now are external devices. People are working on cooling just the head with helmets. So it's still an active field of investigation for stroke and also for cardiac arrest, actually. It has not been proven in well designed prospective trials that it works for garden variety, focal stroke. It works for cardiac arrest with his global lack of blood flow to the brain like when the hard stops. It hasn't been proven yet for the kind of stroke we've been talking about where there's a single blocked artery to the brain.

1:31:48So interesting. I mean, a lot of times on this podcast, we talk about the critical need for body temperature to drop by one to three degrees to get into deep sleep. We had Craig Heller, our colleague from the biology department at Stanford on the podcast. We talked about some of the Palmer cooling and essentially cooling the souls of the feet, the palms of the hands and the upper part of the face as a way to more rapidly reduced core body temperature. I think these are fascinating areas for exploration that obviously have clinical applications, but also you'd imagine for some of the things we're talking about before, like just to provide a bit of neuro protection after a head hit or provide a bit of neuro protection perhaps even as it relates to aging, you know, spending a little bit of time maybe 10 minutes a day, you know, not badly hypothermic, please people, but slightly hypothermic and then bringing the body temperature back up.

1:32:41Yeah, I mean, I wouldn't recommend if you have a head injury or a TIA to stick your head in a snow bank. But even with traumatic brain injury, severe, not just concussion, but severe TBI, traumatic brain injury, studies were done looking at cooling, hypothermia. And this called mild hypothermia because it's just a 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 I think it's a subject that's still being studied. And as I 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 their, it can cause increased infection if you go too low for too long, but I still felt that my patients cool just a few degrees.

1:33:40And we've had some anecdotal cases where patients have had problems. And because we cooled them, we think it made a benefit. For instance, we had one patient who we hadn't even done, I was getting ready to do a bypass to sow a scalp artery to a brain artery, but we hadn't even, I think, made the skin incision and the patient had a cardiac arrest. So we, and it lasted for a 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 a good recovery, but the patient had been cooled down to 33 degrees before we, by the time it had happened.

1:34:30And, and then we finally got the heart started. We ended up putting some restoring flow through catheters and a heart lung machine and remarkably the kind made a complete recovery. So anecdotal, but cases like that suggest maybe cooling, even a few degrees has a protective effect on the brain. We certainly know it's, it's true for cardiac arrest and global ischemia. What are your thoughts on platelet rich plasma PRP these days we hear so much about PRP I think it's FDA approved for certain things right people will get blood drawn though. Spend down platelets and then put in platelet rich plasma.

1:35:14A 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 a surgery people are starting to do more and more because they can go drop a few thousand dollars and I don't 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.

1:35:53I'm not an expert on platelet rich plasma but my reading of the literature cursorally suggests there's not hard evidence that it's beneficial. I think one has to be a little careful for instance I still get emails every few weeks from people saying I've had a stroke or I've had a head injury and should I go to Russia or India or Mexico and get stem cell therapy. This is a big topic and you may have discussed it another podcast. I have not I'll do a solo episode on stem cells and what they are and what they aren't I just will just start interrupt but I'm aware of a 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.

1:36:53I 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 I I tell patients know 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 sell 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 I discourage that and I was going to bring up even in this country.

1:37:35These clinics and that was published a number of years ago that clinic in Florida those patients had macular degeneration and they were losing their site but they could still see to some extent they had their own adipose tissue taken they sorted it for certain stem cells, mesenchymal stem cells and it was re injected into the into the eye should have been safe right their own cells even and they were going to be in the end of the day. And as you say several of them went blind irreversibly irreversibly so I think this is very important to highlight the dangers of stem cell therapy in general there's a lot of hope for it I mean we're engaged we're just finishing a 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 cost tumors and the study is looking very promising it's a phase one.

1:38:34We're making plans to do a phase two study with control patients which you always want to do but despite the hope there is still a lot of hype and I think it's very important 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 our conversation that there's something very different about a knee from the brain right I'm not saying go get stem cells injected into your knee but should you be this sort of person that wants to do that because you feel that's within your rights you know again I don't tell people what to do and you go to a clinic they get stem cells or I don't know they take stem cells from some source and put them into your knee I mean that's a very important thing to do is to get stem cells and then you know you can get a lot of them in the end of the day and you can get them in the end of the day and you can get them in the end of the day and you can get them in the end of the day and you can get them in the end of the day and you can get them in the end of the day and you can get them in the end of the day and you can get them in the end of the day of the day and then you can get them in the end of the day and you get them in the end of the day and you can get them in the end of the day and we have brought training and the concept of자를 transferred to your body and you investigate it and we pay for the existence.

1:39:41So it draws off the Wizard's Retreat of anential Entr Synaler, it is currently based on a consciousness that is cu Dharma but can you expect us to be into this same kind of process that relates to this car pausing and the way that we address the situation in that practice is done in animals that they work by modulating the immune system systemically. Those cells get trapped in the lung and the spleen which people describe as bio reactors and modulate the immune system, which does make some sense. As I say, 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.

1:40:16But even intravenous delivery can be dangerous to the brain. Yeah, this is an area that we will spend a lot more time on during this podcast. Despite what you just said, I think the data I've seen from your laboratory, and as you told me, there's a trial that's finishing up now that features those data or that is where those data arrive from, rather, are really impressive. I mean, some people who were largely a mobile 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 I think that the future of stem cells in stroke therapy is pretty, pretty bright, at least from where I sit.

1:41:02Yeah, we don't want to oversell this. But some of the results in certain patients are remarkable. I mean, the patients and their families has changed their lives. If you see them before and after, it's almost like a 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 a meaningful way if you use certain scales. So, again, we want to be cautious. We're going to do a prospective randomized blinded controlled study. And that's the way it should be done.

1:41:47And if that's positive, it would lead to a phase three larger study, again, blinded controlled. And if that's positive, then it would lead to commercialization FDA approval. It's a long process. I've spent 23 years and more than 46 million dollars in grants and philanthropy getting it to this stage. Wow. Yeah. Wow. That's a lot of time and a lot of money. Amazing. That's the way science and translation to clinical medicine is. I would be remiss if I 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 designs in medicine?

1:42:37I 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 a factor. It's not the only factor. The FDA is appropriately very cautious. I think other countries, the equivalent of the FDA, moves things along the little quicker, especially for therapies where there's no other treatment. So I think those factors are important and would accelerate it. I 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.

1:43:29You know, there's called this Valley of Death where you get initial encouraging data even clinically, but you move the hurdle to get it into FDA approval because of money in some cases. I've seen, as an example, a number of very good stem cell therapies not make it because the companies went bankrupt, the board of directors of the company felt the results were good, but not good enough, and they pulled the funding. Yeah. So this is a whole area which I was not well informed of until I got into this of how you move through the FDA and how you work with industry. I haven't formed a company yet, but I'm going to have to because for the next trial, this trial I was fortunate to get a grant from Sirham California Institute for Regenerative Medicine of $12 million.

1:44:28That'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 a 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 that's the trials get larger even more. So yeah, we need to figure out a better way to allocate money to make these advances. Sounds like a company or some role of industry is going to be necessary.

1:45:14Well, you might be interested in investing, right? Well, this podcast is always available free at the standard human lab podcast. Our premium channel actually generates money. We do ask me any things and things of that sort. We have donors that come in for a dollar match and we do philanthropy to laboratories at Stanford Salt Institute, Columbia University. We have already done that. We're going to do more of this. Well, I was being I was being facetious. No, no, we could explore it. One of the one of the guidelines is that we fund research on humans exclusively. So we can talk about that. The former colleague of ours at Stanford once told me the joke.

1:45:54We'll see if I 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. We'll see what comes down the pike from that. But many of the technologies and discoveries that have been made at Stanford have spun off into, you know, they're these little companies like Chin and Tak 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.

1:46:24Stanford's getting much better. When I came to Stanford in 1974, it was the medical center was more like an NIH of the West. And there was not a lot of clinical excellence except for cardiac surgery, norm, some way, 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 places.

1:47:12So I 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 the Bay Area now. There's just no escaping that. And I think overall, you know, it's not without its sometimes issues. But overall, I think it's a really good thing. Facilitates the most rapid possible flow between basic science discovery and implementation at large. I want to make sure that we cover just a little bit about vagal stimulation. A lot of listeners, this podcast, are familiar with the vagus nerve as this very extensive pathway connecting brain and body in both directions.

1:47:52The common idea out there is that the vagus is associated with calming because it's in the parasympathetic arm of the autonomic nervous system, the so -called rest and digest pathway. But I happen to know, and I'm sure, you know, from experimentation and from clinical work that oftentimes vagal stimulation is a way of bringing, say, depressed patients up to more alertness, that vagal stimulation is not always about calming. It can be about alerting the brain, more making the brain more alert. So what sort of vagal stimulation are you doing? Given that the vagal pathway is so extensive, you know, like which branch of the vagus do you stimulate?

1:48:31There goes around the year. It's in the neck. It goes down through the gut. I mean, we're talking basically about a super high way of, I mean, it kind of reminds me of the Austin freeway system. If you ever driven in Austin, it's like the freeways going every way direction. So whenever I'm there, I'm like the freeway system here is kind of like the vagus. So avenue, do you stimulate in order to get a desired effect? Right. Well, for stroke, and as I alluded to, vagal nerve stimulation coupled with physical therapy, physical activity, very intensive, was the very first FDA approved treatment for chronic stroke patients.

1:49:05That was approved in 2021, three years ago. And it was shown in the study that compared with non stimulation, in other words, putting the stimulator on, but not stimulating and doing the therapy that patients did better. It was a modest improvement, but it felt to be meaningful. And it was shown to be effective at 90 days, only three months. Now recently at the last international stroke meeting last, this past February, it was presented on, I don't know, it's been published yet, that those results hold up for a, for up to a year. So the way it works, presumably, is that you stimulate the entire vagus nerve in the neck.

1:49:57And 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 a nerve, it doesn't go in one direction. And that's probably how it works for depression also, not a 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 improved depression. But it's brain stimulation that somehow, again, resurrects circuits or induces plasticity in circuits. Again, it's, it's something that we're learning about.

1:50:46And I think not just vagal nerve stimulation, but stimulation of the brain is becoming a very important innovative treatment for many brain diseases and injuries. Is the vagal 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's some, it can cause some problems with swallowing, which are usually temporary, right? Because the vagal nerve, the recurrent vagal 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.

1:51:35Incredible. Gary, Dr. Steinberg, I 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 started recording. You were getting calls about patients. I 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 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 a 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 and nicotine, fortunately caffeine is not on the list, but don't overdo it, folks.

1:52:26Neuroprotection, the discussion about TBI, something we've never discussed on this podcast, trans -anuscomic attacks, and just a really vast survey of things that concern a lot of people. And that also now having heard what you've shared also puts them in a position now to empower themselves to take some agency over their brain health, which is something that I think most people really fear that this thing inside our skulls is outside the reach of our 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.

1:53:03So on behalf of myself and all the listeners and viewers, I 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 has been a 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 Endor and join this podcast, please subscribe to our YouTube channel. That's a terrific zero cost way to support us. In addition, please follow the podcast on both Spotify and Apple by clicking the follow tab.

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