From Our Neurons to Yours

Surgery as a window into brain resilience | Martin Angst

• Wu Tsai Neurosciences Institute at Stanford University, Nicholas Weiler, Martin Angst • Season 7 • Episode 8

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We've all heard stories about someone who went in for surgery and came out...different. A grandmother who struggled with names after hip replacement, or an uncle who seemed foggy for months following cardiac bypass. But why does this happen to some people while others bounce right back?

This week, we explore this question with Dr. Martin Angst, a professor of anesthesiology at Stanford who's studying the biological factors that determine cognitive outcomes after surgery. With support from the Knight Initiative for Brain Resilience, Martin and his team are following hundreds of cardiac surgery patients, tracking everything from blood biomarkers to cognitive performance both before and after their procedures.

Their findings are revealing fascinating insights about what makes some brains more resilient than others when faced with the significant stress of major surgery - insights that could help physicians better advise patients and potentially lead to interventions that enhance resilience.

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Episode Credits

This episode was produced by Michael Osborne at 14th Street Studios, with sound design by Morgan Honaker. Our logo is by Aimee Garza. The show is hosted by Nicholas Weiler at Stanford's Wu Tsai Neurosciences Institute and supported in part by the Knight Iniative for Brain Resilience.

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Nicholas Weiler:

Welcome to From Our Neurons to Yours, from the Wu Tsai Neurosciences Institute at Stanford University. Bringing you, as always, to the frontiers of neuroscience. 

We probably all know stories of an older friend or a relative who went into the hospital for a routine surgery or something more major, like a hip surgery or cardiac bypass. When they came out, they just weren't quite the same. Something had changed in their thinking, their memory, but the story is all too common. The question is, is this just anecdotal or is there something more important going on here? It turns out this is something that surgeons and neurologists have been aware of for a long time.

But there's not actually a lot of great data that links major surgeries to people's vulnerability to cognitive decline and that slide into dementia that sometimes happens all too suddenly. Today's guest, Martin Angst, is an anesthesiologist at Stanford who is trying to turn this question on its head. In his work with the Knight Initiative for Brain Resilience, he's asking not just what predicts whether someone is at risk of cognitive decline after surgery, but why is it that some people bounce back even after a major invasive surgery like a cardiac bypass? This is something that really ought to affect the brain, but some people seem much less affected. Why is that?

Martin's interest as an anesthesiologist in how we heal after surgery has led to a major research study that he's conducting with the Knight Initiative. Following hundreds of patients, both before and after major cardiac surgery, looking at all kinds of factors, from blood biomarkers to cognitive performance, to try to understand what are the factors that predict resilience or vulnerability to cognitive decline after surgery. In our conversation today, we'll explore what Martin and his team have discovered so far and what it might mean not just for how we help advise people going in for surgery, but also for our understanding of brain resilience more broadly. Let's get into the conversation.

Nicholas Weiler:

Martin, welcome to From Our Neurons to Yours. It's so great to have you on the show.

Martin Angst:

Thank you. Thanks for having me.

Nicholas Weiler:

Martin, the first thing I wanted to ask you about, we've been putting together this article for the Knight Initiative for Brain Resilience about the work you've been doing. There was a moment in it that stuck out to me. I know that you're a clinician scientist, you're an anesthesiologist, and you also have a research lab. My understanding is that your research started out focusing on the mechanisms by which opioid drugs work in the brain, but that about 10 years ago you had a change in the focus of your work. You switched up what you were interested in studying. I wonder if you could think back to what was going on at that time and tell us a little bit about how you came to the area of research that you're focused on now.

Martin Angst:

Yeah, so there was definitely a reflection point in my scholarly endeavors at Stanford. As you pointed out, I started out in clinical pharmacology, and I had a significant interest in understanding opioid pharmacology and the benefits, but also the potential adverse effects of opioids. Many listeners will be familiar with, obviously, the opioid epidemic crisis, addiction. We studied some of the biology, and in the early 2000s there were these studies that we looked at candidate genes and we were interested in understanding some of the genetics and the genetic background. If you could explain why some respond favorably and some respond non-favorably to opioid pharmacology or opioid exposure.

That came to a halt because as technology advanced, whole genome sequencing became a big thing and you need thousands of participants to study the genetics in a meaningful way. It became clear that what we could do in the lab setting at Stanford became quite limited, given these new technologies. At the same time, it did strike me that as an anesthesiologist, I witnessed patients undergoing surgery every day, and very close to what I do as a clinician was the fact that these patients all sustain significant bodily injury. Obviously, the intention is a good one. You want to basically replace a failing hip or knee, but the way to do this by surgery goes along with a bodily injury.

Nicholas Weiler:

The surgery itself is the major injury?

Martin Angst:

Yeah, surgery itself. It did strike me that there was a significant opportunity to actually study the biology of healing from injury. That the operating room in some ways is almost like a laboratory where you could study human biology. It was very close to who I am as a clinician and what I witnessed. The limitations in my first life as a researcher at Stanford and the opportunity I had, that just did strike me as this is really what I should do, and so that's how it all started.

Nicholas Weiler:

I love that idea of using surgery as an opportunity to study healing. We talk sometimes about natural experiments. This is maybe not a natural experiment exactly, but a necessary experiment. Someone needs cardiac surgery, someone needs a hip replacement, they need it, they really need it. But in the course of that, there's this whole injury and healing process that goes on. I love that perspective as an anesthesiologist. We've had Boris Heifets on the show from your department, and the perspective of the anesthesiologist as a part of the clinical team who's really responsible for the patient's wellbeing and recovery in a certain way, aside from the clinical procedure that's actually going on, is quite interesting to me.

Martin Angst:

Yeah, in many ways you could think of us as travel companions. We think about patients ahead of surgery or ahead of injury. Can we optimize how they come to surgery? Can we basically make them fit for surgery? Are there things we can do so they will basically recover faster? We are companions ahead, and then obviously, we are there with the patient during surgery. Then, we think about how do they recover, how do they heal? There's this continuity of care that may not necessarily be obvious if somebody thinks about an anesthesiologist. In many ways, we think about patients on a system basis. It's not an organ that you think about like a heart or a liver.

All of these organs, the patient and the patient and all the humanity around the patient, all of these things act together. As anesthesiologists, we ideally think of all these things, how do you come in, how do we get you through? How do you recover? How do we basically transition you back to a normal life or hopefully a better life?

Nicholas Weiler:

Yeah. As part of this new focus of your work, you took up a collaboration with Igor Feinstein and Michael Greicius, who's a friend of the show, he's been on the show before, and other colleagues at Stanford to try to understand this somewhat anecdotal observation at the time, that often after surgery, particularly for people who are older, in their 60s, 70s, 80s, there are often these stories that after surgery people experience some level of cognitive decline, problems with memory, with thinking, recognizing people, and so on. How well was that known or documented at the time that you and your collaborators started this study?

Martin Angst:

As you pointed out, there are a lot of anecdotes or patient reports. The story typically goes at surgery, a hip replacement, my dad, my mom had a hip replacement, and suddenly they couldn't recall names, phone numbers, and to your question, how much do we know about this? We do know that surgery, and particularly major surgery, including cardiac surgery, is associated with what we'll call post-op cognitive decline, or let's say impaired brain health. You mentioned memory function, which is the most obvious one, so that's documented. It's a low percentage of patients that will suffer permanently from cognitive decline.

What's also not well understood is, why is there so much diversity? Some patients seem to do just fine. They have the same surgery, the same insult, the same age. They may even look quite similarly clinically, but then others basically suffer from these consequences. In today's world, given many of the technological advances that we have, we can now get into the question, what are the biological determinants next to clinical determinants or epidemiological determinants that actually drive cognitive health or cognitive decline in the context of suffering from a major bodily injury? Cardiac surgery is one example.

Nicholas Weiler:

Well, I love that you're highlighting two sides of the coin there, which is, we see that many people have this experience of either temporary or in rare cases, permanent cognitive decline. Why does that happen? What's going on? That's, I feel like, typical response of clinicians and scientists, like, here's a problem, what's causing it. But then, flipping it all over and saying, "Well, but it doesn't happen to everyone. There are a lot of people who are perfectly fine. Why are they fine?" We're doing this major intervention. We're cutting open the body, we're messing with their organs, we're rerouting their bloodstream, in the case of cardiac bypass, how is it that they're fine?

Martin Angst:

Yes.

Nicholas Weiler:

Tell us a little bit about the genesis of this 2021 study that you published. What were you trying to figure out specifically in that study, and how you set that up?

Martin Angst:

Yes, this study was initiated based on actually a particular interest of Igor, who is helping conducting the current study. Igor and I have a mentor-mentee relationship. We have known each other for a long time. He was particularly interested as a cardiac anesthesiologist in cardiac anesthesia and consequences thereof. One of his major interests was related to understanding how the brain responds. He was particularly interested in imaging technology at the time. We designed the study using imaging modalities to look at brains ahead and after surgery. It turned out that this was a huge challenge.

It became impossible because COVID hit and we were basically sitting on multiple patient samples as we collected serial blood from these patients enrolled in this imaging efforts. That's when we met with Mike. Mike said, "You have these wonderful samples and you have this major surgery as, you can think of it as a stress or an intervention. Let's look at these samples and let's look at some of the biological markers that we know are associated with brain stress or brain insult." We said, "We have these samples. This study came to a halt. Let's look at these samples." We looked at some proteins that are associated with neuronal stress and neuronal death.

They got the results back and we were all a little shocked by how dramatically these proteins became elevated during and after surgery. There was a protein that relates to neuronal stress. You would think if the protein is elevated, neurons in the brain have been stressed, and we observed six to tenfold increases. Again, importantly, not everybody, but some patients. Then, there is another protein that became elevated after surgery, and that protein is related to neuronal death, so an indication that actually neurons die. Again, six, seven, eightfold elevation in some patients, but not in others. That was how this all started.

We said, "Wow, these patients undergo this intervention and we have now markers in blood that tell us something about our neuron's stressed, and subsequently many neurons actually die."

Nicholas Weiler:

These were in patients both undergoing cardiac bypass and then other patients were having a hip replacement, if I remember right. Is that right?

Martin Angst:

Yeah, we had these two populations and interestingly enough, hip surgery, hip replacement surgery was associated with similar changes, but they were less pronounced than what we observed in patients undergoing cardiac surgery. That likely relates just to the type of injury. Cardiac surgery is probably one of the most invasive procedures, and for good reasons, but the fact that we saw quite dramatic differences between these two populations indicated that the type of surgery and the type of injury and the magnitude of injury actually matters in how relevant this becomes.

Nicholas Weiler:

I appreciate you talking about this at a high level and not dipping us in the pool of jargon. But in this case, these are also proteins that are associated with things like Alzheimer's disease. We see the same protein, I think it was phosphorylated tau and neurofilament light. This is word salad for some people, I'm sure, but these are proteins that experts in Alzheimer's disease would immediately go, "Oh, that's not good. We don't want to see that in the brain."

Martin Angst:

Yes, you see that in plasma, and you talked about the p-taus, the p-taus measured in plasma or in block are highly predictive of Alzheimer's disease years down the line. These markers become elevated years ahead of anybody becoming clinically symptomatic, so p-taus, NfL, neurofilament light, those are markers well known in the field of cognitive and cognitive decline, including Alzheimer's disease. That obviously was another connector where we all go like, that is concerning.

Nicholas Weiler:

Yeah, very concerning. Well, the thing that it speaks to to me, and I think you mentioned this earlier when we were talking about the anecdotal reports about everyone knows someone who went in for surgery and came out and it took them a while to get back to their baseline. It makes me think of these studies that have been coming out recently about how aging is really non-linear, right? We don't age the same amount all the time. We'll often see with relatives and sometimes looking in the mirror, aging can happen very fast at times. This opportunity to look at, what is one of these stresses, what is one of these things that can really dramatically change someone's cognitive state, is a really interesting opportunity.

Martin Angst:

Definitely how we look at it. I also want to put, as concerning as it is, a positive spin on it. We now have the tools to study resilience. If somebody is really vulnerable, we may want to think about how invasive do we want to be going forward. I can think of ways we could actually consult patients and down the line give them data-driven and biology-driven advice of, you are in a high-risk group or you are not. The other thing, and you mentioned that initially is, what are we going to do about it? Could we actually make patients more resilient and give them hope that you'll fare well? That's probably something we should talk about.

Nicholas Weiler:

Absolutely. Yeah. Martin, I want to talk more about this idea of, where do you go from here? Now that you've seen this elevation of these concerning molecules in the blood plasma of people undergoing surgery and in the weeks following. But before we do that, I feel like we need just a bit more of a picture of, what does this surgery actually involve? What is actually going on when someone is going through a cardiac bypass surgery? You've mentioned that it's a significant challenge to the body and to the brain. What do you think might be triggering some of these signs of neuronal death and stress?

Martin Angst:

Yeah, the patients we study in cardiac surgery are patients who go on bypass, which means the heart stopped. Of course, the heart stopped, you need to oxygenate the blood. In order to oxygenate the blood, you have that blood diverted out of the body. You oxygenate the blood, and then you give it back, so you can think of it as a hose coming out of the body and then blood gets oxygenated, and then blood is fed back to the body while the heart is arrested. Just to get to the heart, you open the chest. You have significant incision, significant tissue that's dissected, but then also blood diverted to an oxygenation source outside the body.

All of these things cause inflammation and inflammation has been recognized as a driver of adverse outcomes. We think that patients who inflame a lot are at higher risk. Now, obviously, you need some inflammation because inflammation is the way you initiate healing. You respond to insult and you initiate healing, but maybe there is too much inflammation. The term used clinically here will be you're a hyper-inflamer, or you inflame particularly above what an average person would inflame in a given circumstance. In many ways, cardiac surgery triggers a significant inflammatory response. This inflammatory response varies based on who you are biologically.

Then, we think the magnitude of how much you inflame is responsible for driving some of the outcomes. We know that from the trauma literature, that patients who suffer trauma and who inflame dramatically, as measured by blood tests, are patients who are more likely to stay longer in the ICU and are patients who are at higher risk of significant morbidity and actually mortality as well.

Nicholas Weiler:

Hearing your description of what is actually going on during cardiac surgery, I really get a better sense of what you're saying about how amazing it is that some people recuperate so well from a procedure like this. It's maybe not so surprising that there are some cognitive effects of something major like that that's going to trigger inflammation and involve a lot of healing. After this study, if I understand right, this is when you and your collaborators partnered with the Knight Initiative for Brain Resilience or got support from the Knight Initiative to look at a longer timeline. What is actually going on before surgery? What's going on after surgery?

Following these patients for a longer time. Can you tell me a little bit about the group of patients that you have brought together to go on this research journey with you?

Martin Angst:

Yeah, all these patients obviously have heart surgery using bypass. The methodology that I described to oxygenate the blood while the heart is in arrest to do the surgery. The patient population is typically 60 to maybe 85 years old, so it's an elderly population. We recruit patients from all over California. Patients are coming in with comorbidities. Obviously, they come in because they have a heart issue, sometimes they have other health issues. It's an elderly population undergoing major surgery, and some of these patients have significant other comorbidities.

Nicholas Weiler:

They're volunteering to have you take their blood and spinal taps as well?

Martin Angst:

We do if there is a catheter placed close to the spinal cord. That on its own is required in minority of patients, but we do serial blood samples. We study on these patients longitudinally, so before surgery and then multiple times after surgery. Then, we follow three months after surgery and then one year. All of the patients have agreed to be part of the study for at least five years. Now moving forward, we would love to study these patients lifelong and see how they evolve. We look at cognitive outcomes. We have a battery of tests that we can apply remotely. We sent them iPads, and then we communicate them through iPads.

We test them in 14 or 15 different domains of what we call cognitive function, which includes memory functions, long-term memory, short-term memory. The idea being that we really follow them as long as we can, and that's a significant shortcoming of many of the studies that have been done in the field, many of these studies. At three months or one year, we are really interested to understand what does that actually all mean long-term? Then, also related to things like, okay, so we have these test results. What does it actually mean for how you function in your life?

Nicholas Weiler:

Yeah, I was going to ask, so what is it big picture that you're hoping to learn from this long-term study?

Martin Angst:

The big picture is we would love to learn from resilient people as to why they're resilient. We would love to use that knowledge to help patients who are not as resilient or vulnerable. All of that has to be somehow relevant to the patients. Can you actually do the things you do in your life? Daily activities, be socially active, hang out with your friends, be back to a level that makes your life enjoyable. That's our mandate. Research is exciting, but at the end, I'm also a clinician, and at the end I'm also a human being. I'm really interested in, can we make our patients as well as they can be?

Nicholas Weiler:

I know you're only a couple years into this effort, or maybe only a year into this effort. Is there anything you can share with us so far about what you're starting to see with this patient population before and after surgery?

Martin Angst:

Yes, I'm happy to share our results. There are preliminary, we have now studied about 80 patients. We hope to study up to 500 patients long term. But the first thing that we learned is what we observed in our really small study initially happens to be true. These p-taus peak dramatically during surgery, six, eightfold in some patients, followed by peaks of neurofilament light, and neurofilament light, an indicator of neuronal death, actually continues raising until patients are discharged. It's not like day one or day two. That's the peak. Actually, if we follow patients to day seven, these levels go up. We have been able to relate the magnitude of this elevation to some of the cognitive outcomes that we study at least for three months.

We have strong indication that if you have high levels of neurofilament light after surgery, you're more likely to have memory issues three months out of surgery.

Nicholas Weiler:

Just to make sure I'm tracking, so you're seeing this p-tau indicator of neuronal stress during surgery, and then in the week following surgery, until discharge, you're seeing this increase in neurofilament light, which is interpreted to mean cells are actually dying off, cells that got overstressed.

Martin Angst:

Yes.

Nicholas Weiler:

You're saying that connects to the level of cognitive decline up to three months later?

Martin Angst:

Yes, so the other thing I want to point out is the response, if you think about the biology, is drastically different in the patients we have studied. Again, there are patients who have really, really high levels and there are patients who don't, and who are these patients? It's not all explained by the type of surgery. It's not all explained by the particular chronological age. There is a predisposition to be resilient or predisposition to be vulnerable. Now, the question is, can we actually capture that? At some point we have, okay, John is showing up for cardiac surgery and can say, "John, based on what we can measure, you're very likely going to be resilient to the intervention, or you may be vulnerable."

What does that mean for this patient's journey? If you think about informed consent, this could be your next level. A patient could actually make an informed decision and say, "I understand the risk, but I'm willing to take the risk because there are benefits to this particular procedure." Or, you could say, maybe we choose an alternative pathway, a pathway that's less invasive, less disturbing to the system. There's the hope that we can make meaningful prediction that would eventually allow us to be competent consultants to our patients. Can we do something about making you from being vulnerable to making you being resilient?

What we learned in surgery, we may actually be able to translate into other settings. What we learn here may be highly relevant to cognitive health in a population that doesn't necessarily undergo surgery. Hopefully, what we learn here in terms of biology has broader implications. I think that resonates well with the Knight Initiative, which is not focused on surgery but general brain health.

Nicholas Weiler:

Right, it's maybe not completely surprising to listeners that with an intervention, with an insult, as we say, as extreme as cardiac bypass, it's going to have cognitive effects. There's going to be healing required. But it's such an extreme thing that to see resilience even to such an extreme intervention makes it a really interesting model to say, "Okay, if you can be resilient to this, what's the secret of being resilient to something as extreme as cardiac bypass?" As you say, that's something that hopefully we can take and apply to other areas as we age, as we look at other ways that we can make our brains resilient to the insults of time.

Martin Angst:

Yeah, I like that spin. I think that's really it. That's the inspiration here.

Nicholas Weiler:

There was one other thing I wanted to ask you about. Do I remember correctly that you are also seeing that some of the people in the trial, since you're taking these blood samples and spinal fluid samples and things, that some people who are vulnerable perhaps already had early signs of some of the molecules in the brain that we associate with Alzheimer's disease? Maybe there's also the opportunity of making sure that now that we have these amazing biomarkers that we can actually look at blood and spinal fluid and detect some of these neurodegenerative disorders before they start expressing themselves in the clinic.

Maybe that helps us make decisions about who really should undergo these surgeries or whether they need some kind of preparation or some other way of increasing their resilience before they go in there.

Martin Angst:

Yes. No, you're correct. We do have markers ahead of surgery that indicate that some of our patients have conditions that we typically call pathological amyloidosis of the brain, which has been linked to Alzheimer. In many ways, there is a real chance that we can study patients who have a predisposition for cognitive decline, including Alzheimer's disease. If you think about the long-term perspective, we would love to study these patients lifelong. We may actually be able to learn how surgery influenced or may have accelerated or aggravated the condition. I think there is a direct link to chronic cognitive diseases including Alzheimer's disease. Yes, to your particular question, we have markers in blood that indicate that some of these patients have a predisposition to develop Alzheimer's disease.

Nicholas Weiler:

We were talking a moment ago about things we might do to increase resilience in patients and things that might have broader implications beyond just surgery. Earlier this year, you and your team published some findings that spoke to one angle on that. Tony Wyss-Coray, who's I think a collaborator of yours, who's been on the show several times and is the director of the Knight Initiative, he famously showed that there are molecules in the blood plasma of young animals that can have a rejuvenating effect on older animals. Of course, this caught some public attention. It was parodied on Silicon Valley with older people taking the blood of the young to stay young. But it's really an exciting idea in fact that somewhere in our blood there is this molecular fountain of youth.

That's an overblown term, but there's something in the blood that actually can affect the aging process. I know that Tony's lab is interested in distilling what exactly is that, what are those molecules. But in your study, you applied this to your interest in the resilience to surgery. Can you tell us what you did there?

Martin Angst:

Yeah, happy to talk about that. Tony calls all the proteins in plasma and blood the communicum, and the idea is proteins do communicate with cells, proteins have signaling functions, and we have many thousands that circulate in the bloodstream. The idea, could some of these proteins in a higher content and in a certain composition have rejuvenating effect, is the idea that comes out of his work. One of the issues was, how do we translate that into humans? In many of these animal studies, you can do a lot of invasive things and you can not do that in humans. For example, you can take a brain biopsy, you can take the brain out and slice it, it then die. It's not going to happen in a human being.

Is there a way to actually do a study that proves the principle, you give young plasma to an elderly population and you use a stress model to test, does that actually do anything? If I say do anything, this is really do anything at the level of the biological level. You would measure inflammatory mediators, you would measure immune cells and immune cell function before and after the fact.

Nicholas Weiler:

This is where your surgical model came in?

Martin Angst:

I'm sure the surgical model came in, and again, the surgical model, it's an injury model. If you think about injury, injury is, from an evolutionary point humans had to survive injury, otherwise they would not have evolved. It's a very fundamental challenge that actually activates systems that are very old evolutionary and the program that's very old evolutionary. Then, you respond, the idea is, you heal or you don't. If you look and search in this context of fundamental injury tests, very fundamental mechanisms and differences in how these mechanisms are engaged, so this was the idea. We have a surgical injury model, and one of the advantages is you can actually do things ahead of surgery.

Then, you can study things ahead of surgery. You can study things as they evolve during surgery and then after surgery. The fundamental idea is pretty simple. You have patients undergoing, in this particular context, knee and hip replacement surgeries. You would randomize them to either get young plasma or a placebo, normal saline. You would measure inflammatory molecules, proteins, actually a large area of proteins as well as immune cell, immune cell functions before surgery, after surgery. The idea being, does the immune response and inflammatory response to surgery differ in patients who received young plasma, and we're talking 35 years old on average, or normal saline?

It was a really compelling idea because, is what we see in mice somehow true in humans? We did the study. We randomized patients to young plasma and randomized them to normal saline. We were all positively surprised that if you actually give young plasma to patients, you change their immune response and their inflammatory response to the surgical insult. The way you change it makes sense. You actually modulate pro-inflammatory pathways. If anything, you dampen the pro-inflammatory response. Interestingly enough, patients who are particularly inclined to be pro-inflamers showed the most profound effects.

Nicholas Weiler:

Oh, interesting.

Martin Angst:

Going back to this idea, not everybody is the same. If you give young plasma to a vulnerable population, they likely profit. If you give it to a resilient population, they probably don't.

Nicholas Weiler:

Right. Maybe the resilient population already has a youthful immune system.

Martin Angst:

Exactly. Yeah. That was the conclusion of the study, and we were positively surprised that, yes, it's nice, right? What you observe in mice translates to humans.

Nicholas Weiler:

Very nice. It doesn't always happen.

Martin Angst:

Yeah.

Nicholas Weiler:

Well, we're almost out of time for today. This has been such a fascinating conversation. I wonder if you could leave us with, where do you see this going? What would you like to see us be able to do in understanding the nature of resilient healing?

Martin Angst:

Yeah, so a couple of things that I already mentioned. One is, can we actually predict who does how? If so, could we be better consultants to our patients in what a surgical insult actually may mean? We talk about brain health in this particular context, and obviously, the brain matters greatly, but we can think of human health, cardiac health, liver health, kidney health. There is really broad spectrum. If you think about resilience, there are many ways to define it and to think about it. But given the Knight Initiative, the focus clearly resides with the brain here. Could we make predictions? If we can make predictions, could we actually consult our patients and make pathway decisions?

Okay, maybe not major surgery, maybe minor surgery, maybe conservative approach as opposed to an invasive approach. I very much see this as a dialogue with patients because we want to just give them information that they need to make a decision. Somebody who is vulnerable may still decide to have an invasive procedure, but these patients will be better informed. The other pocket obviously, see, what are you going to do about it? Can we actually change trajectories? Young human plasma, it's a little futuristic right down the line. Could we think of a plasma fraction that could be given? Potentially. But there are other things that are maybe more immediate and more practical.

If we are able to demonstrate in larger samples using large-scale proteomics where we measure thousands of proteins, and we can actually start thinking about biological pathways that get activated differently in patients who are resilient or patients who are vulnerable, one possible outcome is that we learn that hyper-inflammation is a really big problem. Hyper-inflamers are the one that basically have more inflamed brains and the ones that suffer more severe consequences. Then, the logical choice would be, can we actually dampen that pro-inflammatory response? If you want to do this, how would you do that? I just give you one snippet that's non-traditional.

We can always talk about drugs and medication and pharmacology, but could you, for example, say we just decrease stress level ahead of surgery? Because stress is associated, acute stress and chronic stress particularly, with the pro-inflammatory profile. I'm not going to propose this. Maybe I'll leave with a little bit of humor here, the pre-surgical vacation, could that be a thing?

Nicholas Weiler:

That sounds like a great idea. Take the vacation, come into surgery feeling as relaxed as you can. I imagine there are other things too. Diet influences inflammation, exercise influences inflammation.

Martin Angst:

Exercise, absolutely. Dietary interventions, obviously, still a young field, but the microbiome, what's the influence there? Obviously, there are many ways, pharmacological, non-pharmacological, interventional dietary, behavioral interventions that we can think of, and that has become a big topic. The term that's used in the literature is pre-habilitation. You actually get ready before the fact and not after the fact. That's a topic of significant interest. Again, anesthesia as a field is heavily involved in thinking about these things.

Nicholas Weiler:

Wonderful. Well, Martin, thank you so much for coming on the show and telling us all about this research in progress. I look forward to hearing more about it as the project goes forward.

Martin Angst:

Well, thank you. I'm happy to come back and give an update.

Nicholas Weiler:

I hope you will.

Martin Angst:

Thanks so much.

Nicholas Weiler:

Thanks again to our guest, Dr. Martin Angst. He's a professor in the Department of Anesthesiology at Stanford Medicine. To learn more about his research and his project with the Knight Initiative for Brain Resilience, check out the links in our show notes. We actually have a feature article that's just come out highlighting this project. We'll also include links to some of the studies we discussed on the show. We would love to hear from you. Please send us a note at neuronspodcast@stanford.edu with any thoughts you have on the show, your suggestions for future topics in the frontiers of neuroscience, or questions for past or future guests.

From Our Neurons to Yours is produced by Michael Osborne at 14th Street Studios, with sound design by Morgan Honaker. Our logo is by Aimee Garza. The show is hosted by me, Nicholas Weiler at Stanford's Wu Tsai Neurosciences Institute, and supported in part by the Knight Initiative for Brain Resilience. Until next time.